PAGENO="0001"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4971
COMPANY
CIBA
Dome
duPont
Eaton Laboratories
Endo Laboratories
Flint Laboratories
Glenwood
Hoechst
Ives Laboratories
NO. ISSUES
11
7
6
10
6
3
4
7
3
2
2
10
9
8
7
12
Total...
Total...
Total...
Total...
Total...
Total...
PRODUCT
1. Doriden
2. Ismelin
3. Regitine
4. Ritalin
5. Ser-Ap-Es
1. Pminet
1. Syimnetrel
1. Furadantin
1. Percodan
2. Valpin
1. Choloxin
1. Butazolidin
2. Hygroton
3. Pertofrane
4. Preludin
5. Tofranil
1. Patoba
1. Lasix
1. Isordil
NO. PAGES
18
21
6
23
19
87
3
7
7
3
2
5
6
20
21
16
14
23
94
12
36
2
Total...
12 Total...
9 Total...
2 Total...
98
81-280 O-69--pt. 11--44
PAGENO="0002"
4972 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY NO. ISSUES NO. PAGES
Key Pharmacal
1. Nitroglyn 9 Total... 9
Lakeside Laboratories
1. Cantil 6 Total... 6
Lederle Laboratories
1. Aristocort 6 12
2. Artane 6 12
3. Declomycin 6 12
4. Diamox 4 4
5. Hydromox 7 14
6. Pathibatnate 10 20
Total... 74
Lilly, Eli, & Co.
1. Aventyl 10 28
2. Dymelor 12 39
3. Darvon 12 24
Total... 91
McNeil
1. Butiserpine 11 11
2. Butisol 11 22
Total... 33
Massengill Company
1. Oberdrin-LA 9 Total... 9
Mead-Johnson
1. K-Lyte 4 8
2. Mucomyst 5 20
3. Peri-Colace 11 11
4. Quibron 3 6
5. Vasodilan 12 48
Total... 93
99
PAGENO="0003"
4986 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
AMERICAN FAMILY PHYSICIAN
1966
COMPANY DRUG NO. ISSUES NO. PAGES
Abbott
1. Compocillin 5 10
2. Erythrocin-Sulfas 7 18
3. Surbex-T 1 1
Total... 29
Armour
1. Chymar 1 2
2. Chyinoral 2 4
3. Pentritol 1 6
Total... 12
Cole
1. Indo-Niacin 3 Total... 6
Endo
1. Hycoinine 2 4
2. Valpin 12 12
Total... 16
Fesler
1. Trichotine 5 Total... 5
9~z~
1. Butazolidine-Alka 6 6
2. Persantin 7 10
3. Pertofrane 2 14
4. Preludin 4 8
Total... 38
Hankskraft
1. Zymenol 5 Total... 5
Lederle
1. Peretinic 6 Total... 6
Massengill
1. Obedrin-LA 6 Total... 6
113
PAGENO="0004"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4987
DRUG NO. ISSUES NO. PAGES
COMPANY
McNeil
Mead-Johnson
Neisler
Ortho
Parke-Davis
Pfizer
Roche
1.
Butigel-Zyme
4
4
2.
Butiserzapide
11
20
3.
Butiserpine
5
5
4.
Parafen-Forte
12
12
5.
Tylenol
9
19
Total...
60
1.
Trind
8
8
2.
Vasodilan
4
32
.
Total...
40
1.
Rynatan/Rynatuss
3
6
2.
Dainite-KL
5
Total...
5
11
1.
Delfen
3
3
2.
Ortho-Novuni
10
Total...
22
25
1.
Benadryl
7
7
2.
Benylin
7
7
3.
Cosanyl
3
3
4.
Carbrital
12
12
5.
Initia
5
5
6.
Myadec
7
7
7.
There-Camber
11
Total...
11
52
1.
Bonine
2
4
2.
Daric:xi
3
3
3.
Diabinese
3
Total...
11
18
1.
Libriuiu
8
8
2.
Yalium
5
5
Total...
13
114
81-280 O-69-pt. 11-45
PAGENO="0005"
CONTENTS V
Article: "To Label or Not to Label," from the Journal of the American Page
Medical Association, vol. 194, P. 1311, December 1965 4644
Report: Excerpts From "Proceedings of the AMA House of Delegates,"
November 1966 4647
Brochure: "Advertising in the Annals of Internal Medicine__Exhibiting
at the Annual Sessions" 4730
Chart: Annals of Internal Medicine advertising income, 1964-1968 4733
Letter to Benjamin Gordon, staff economist, :Select Committee on Small
Business, U.S. Senate, from Dr. Edward C. Rosenow, Jr., executive
director, American College of Physicians, dated April 7, 1969, re adver-
tising in Annals of Internal Medicine 4734
Memorandum to Dr. Robert S. Long, president, ASIM, from W. R.
Ramsey, dated March 11, 1969, re American Society of Internal Medi-
cine finances, 1963-1969 4741
Correspondence between Benjamin Gordon, staff economist, Select Com-
mittee on Small Business, U.S. Senate, and Mac F. Cahal, J. D., execu-
tive director and general counsel, American Academy of General Prac-
tice, with accompanying material 4778
Article: "Vive La Difference!" from American Academy of General Prac-
tice, January 1965 4780
Article: "Phenacetin and the Nephrologists," from American Academy
of General Practice, June 1965 4779
Article: "Drug Removal," from American Academy of General Practice,
September 1967
Article: "Another Look at Immunizations," from American Academy of
General Practice, April 1969 4779
Charts: American Family Physician income and expense analysis, January
1961-November 30, 1968 4781
APPENDIXES
I. Article: "The Image of the Drug Industry, as Seen by Town and
Gown"-results of a questionnaire with regard to the phar-
maceutical industry and products are presented-by Drs. W. J.
Hagood, Jr., and J. A. Owen, Jr., from the Virginia Medical
Monthly, vol. 94, February 1967, pp. 110-114 4789
II. Article: "Teaching the Evaluation of Drug Advertising to Medical
Students," by D. R. H. Gourley, Ph. D., from the Virginia Medi-
cal Monthly, vol. 93, August 1966, pp. 459-461 4793
III. Letter, dated April 22, 1969, to Dr. :W. J. Hagood, Little Retreat
Clinic, Clover, Va., from Senator: Gaylord Nelson, chairman,
Monopoly Subcommittee, with accompanying NAS-NRC studies 4795
IV. Article: "Fatal Circulatory Collapse in Premature Infants Receiving
Chloramphenicol," by L. E. Burns, M.D., J. E. Hodgman, M.D.,
and A. B. Cass, M.D., from the New England Journal of Medicine,
vol. 261, No. 26, December 24, 1959 4799
V. Article: "Safe and Effective Chioramphenicol Dosages for Pre-
mature Infants," by J. E. Hodgman, M.D., and L. E. Burns,
M.D. from American Journal of Diseases of Children, vol. 101,
February 1961 4804
VI. Article: "i3acterial Meningitis," by P. F. Wehrle, A. W. Mathies,
J. M. Leedom, and D. Ivler, from Annals New York Academy of
Sciences, 1967, pp. 488-498 4812
VII. Article: "Management of Bacterial Meningitis," by P. F. Wehrle,
M.D., A. W. Mathies, Jr., M.D., Ph. D., and J. M. Leedom, M.D.,
from Clinical Neurosurgery, Chapter IV, vol. 14, pp. 72-85 - -- 4820
VIII. Article: "Antibiotic Antagonism in Bacterial Meningitis," by
A. W. Mathies, Jr., J. M. Leedom, D. Tyler, P. F. Wehrle, and
B. Portnoy, from Antimicrobial Agents and Chemotherapy, 1967,
pp. 218-224 4829
IX. Article: "Ampicillin in the Treatment of Acute Suppurative Menin-
gitis," by F. F. Barrett, M.D., W. A. Eardley, M.D., M. D. Yow,
M.D. and H. A. Leverett, from the Journal of Pediatrics, Septem-
ber 1966, vol. 69, No. 3 4834
PAGENO="0006"
VI CONTENTS
X. Article: 11fl* Influenzae Meningitis: A Controlled Study of Treatment
With Ampicillin," by L. D. Thrupp, J. M. Leedom, D. Tyler, P. F.
Wehrle, J. F. Brown, A. W. Mathies, and B. Portnoy, from Post Page
Graduate Medical Journal, December 1964, Pp. 119-125 4844
XI. Article: "Experience With Ampidillin in Bacterial Meningitis,"
by A. W. Mathies, Jr., J. M. Leedom, L. D. Thrupp, D. Ivier,
B. Portnoy, and P. F. Wehrle, from Antimicrobial Agents and
Chemotherapy, 1965, pp. 610-617 4850
XII. Excerpts of affidavits submitted to the Food and Drug Administra-
tion from various physicians re prescribing of drug Thalidomide
based on information given by detail men 4857
XIII. A study of pharmaceutical advertising in selected medical journals,
prepared by the Education and Public Welfare Division, Legisla-
tive Reference Service, Library of Congress 4863
HEARING DATES*
February 19, 1969:
Morning session 4297
February 20, 1969:
Morning session 4321
February 26, 1969:
Morning session 4351
February 27, 1969:
Morning session 4371
March 13, 1969:
Morning session 4477
March 18, 1969:
Morning session 4583
Afternoon session 4675
March 25, 1969:
Morning session 4709
March 26, 1969:
Morning session 4753
sThe testimony for May 15, 16, 17, June 7 and 8, 1967, appears in pt. 1 of these hearings; the testimony
for June 27, 28, 29, July 24, and Aug. 8, 10, 1967, appears in pt. 2 of these hearings; the testimony for Sept.
13, 14, 29, and Oct. 13, 1967, appears in pt. 3 of these hearings; the testimony for Oct. 31, Nov. 9, 15, 16, and
28, 1967, appears in pt. 4 of these hearings; the testimony for Dec. 14, 19, 1967, Jan. 18, 19, and 25, 1968, ap-
pears in pt. 5 of these hearings; the testimony for Nov. 29, 1967, Feb. 6, 8, 27, 28, and 29, 1968, appears in
pt. 6 of these hearings; the testimony for Apr. 23, 24, and May 1, 1968, appears in pt. 7 of these hearings;
the testimony for May 2, 3, and Sept. 17, 1968, appears in pt. 8 of these hearings; the testimony for Sept. 18,
19, and 25, 1968, appears in pt. 9 of these hearings; the testimony for Dec. 11, 17, 18, 19, 1968, and Jan. 23, 1969
appears in pt. 10 of these hearings.
PAGENO="0007"
COMPETITIVE PROBLEMS 1N THE DRUG INDUSTRY
WEDNESDAY, FEBRUARY 19, 1969
U.S. SENATE,
MONOPOLY SUBCOMMITTEE OF THE
SELECT COMMITTEE SMALL BUSINESS,
Wa8hington,D.C.
The subcommittee met, pursuant to notice, at 10 a.m., in the caucus
room, Old Senate Office Building, Senator Gaylord Nelson (chairman
of the Subcommittee) presiding.
Present: Senators Nelson, McIntyre, and Dole.
Also present: Senator Byrd of Virginia.
Chester H. Smith, staff director and general counsel; Benjamin
Gordon, staff economist; Jay Cutler, acting minority counsel; and
Elaine C. Dye, clerical assistant.
Senator NELSON. The committee is pleased to welcome this morning
the Senator from Virginia, Senator Harry Byrd, who will at this time
introduce one of his distinguished constituents as the first witness
this morning.
Senator Byrd.
STATEMENT OP HON. HARRY P. BYRD, JR., A U.S. SENATOR PROM
THE STATE OP VIRGINIA
Senator BYRD. Thank you, Mr. Chairman, Senator McIntyre. I
appreciate the committee giving me the opportunity to present this
morning to the committee, a splendid, outstanding citizen of Virginia,
Dr. William J. Hagood, Jr., from Clover in Halifax County.
For the benefit of my New Hampshire friends I might say that
Halifax County is near the border of North Carolina. It is one of
the larger counties of our State, and Dr. Hagood, along with his cousin,
Dr. Warren Hagood, his uncle, Dr. James D. Hagood, practice medi-
cine and operate a medical clinic in Halifax County.
These are Virginians, all three, who have the confidence of the people
of their area. Dr. William J. Hagood, Jr., who will speak this morning,
is well known throughout the State. He is public spirited. He takes
a keen interest in the problems of the people of our State.
I might say that his partner, and his uncle, Dr. James D. Hagood,
is the senior member of the Virginia Senate. He is the president pro
tempore of the Virginia Senate. He is chairman of the senate finance
committee. He has been elected to the Virginia Senate more times
than Carl Hayden was elected to the U.S. Senate, and he is equally as
beloved in our State, and in the Virginia Senate, as was Senator
Hayden in the U.S. Senate.
4297
PAGENO="0008"
4298 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
So it is a privilege and a pleasure to present to this distinguished
committee a very fine Virginian, and one in whom the people of Vir-
ginia have great confidence, Dr. William J. Hagood, Jr.
Senator NELSON. Thank you, Senator Byrd.
Dr. Hagood comes from a part of your State where my wife has so
many relatives, it is almost a mathematical certainty that one of them
was a patient of the Hagood Clinic.
Senator BYRD. I might say, Mr. Chairman, that we in Virginia are
very proud of the fact that Mrs. Nelson is a native of Wise County
in our State.
Senator NELSON. Thank you, Senator Byrd.
First let me mention that Senator Tom McIntyre is a new member
of the Senate Small Business Committee, and a new member of the
Monopoly Subcommittee, and, as chairman, I am pleased to have him
join us this morning in these hearings.
This morning the Senate Small Business Committee's Monopoly
Subcommittee resumes its hearings on problems in the drug industry.
Our first witness was to be Dr. Philip R. Lee, Assistant Secretary
for Health and Scientific Affairs with the Department of Health,
Education, and Welfare. I should have said the "former" Assistant
Secretary because Dr. Lee's resignation became effective just this past
Monday. Dr. Lee has resigned from his post with HEW to accept the
position of chancellor at the University of California Medical Center
in San Francisco and he was asked to report to the university
immediately.
We are, of course, disappointed that he is unable to be with us in
person. However, Dr. Lee has submitted his statement for the record
and it will be printed in the record in full. This statement has been
distributed to the press.
(The statement of Dr. Lee follows:)
STATEMENT BY PHILIP R. LEE, M.D., ASSISTANT SECRETARY FOR HEALTH AND
SCIENTIFIC AFFAIRS, U.S. DEPARTMENT OF HEALTH, EDuCATION, AND WELFARE
Mr. Chairman, last September 25th, I had the honor of appearing before the
Subcommittee to report on some of the interim findings and recommendations
of the Task Force on Prescription Drugs. At that time, we had not reached our
findings on the principal charge to the Task Force-to determine whether it
is both necessary and feasible to include prescription drugs as a benefit in the
Medicare program.
We have now completed our studies and the answer to both questions is an
unequivocal yes.
To reach this conclusion, the Task Force needed and obtained detailed infor-
mation about the manufacture, distribution, promotion, prescribing, and use of
prescription drugs in this country and abroad. We have made this information
widely available in a series of five interim reports and four background papers,
entitled "The Drug Users," "The Drug Makers and The Drug Distributors,"
"The Drug Prescribers," and "Current American and Foreign Programs." A
fifth background paper, "Approaches to Drug Insurance Design," and a final
summary report are in press and will be released very shortly. Mr. Chairman,
I am pleased to submit these reports for the Subcommittee's records.
These reports say a great deal about the use of prescription drugs in our
society. Most central to our mission, however, was their use by the elderly.
We found that our 20 million citizens age 65 and older spend nearly three times
as much each year for prescription drugs as the average for all Americans. We
found that a significant number of these drugs are used over long periods of time
in the treatment of serious chronic conditions. At the same time, we found that
for many of the elderly, their incomes, assets, protection through health insur-
PAGENO="0009"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4299
ance, and the relief they obtain through income tax deductions are simply
inadequate.
These and other findings point directly to :the need for a Medicare drug insur-
ance program, and we have spelled out in great detail the alternatives for the
development of such a program. The recommendations of the Task Force related
to the Medicare program are now under study in the Departmnt, and I expect
that the Secretary will reach a decision on this within the next few weeks. He
has not yet had the opportunity to review many of the other recommendations
of the Task Force.
In reaching our conclusions, Mr. Chairman, the members of the Task Force
were not unaware of the sensitive social and economic issues that are involved
in the marketing of prescription drugs. We were aware of the significant price
differences between brand name drugs arid their generic name counterparts,
and of questions that have been raised about their relative efficacy. We also
had to consider the profusion of available drugs, including large numbers of
combination products and so-called "me-too" drugs, and whether Federal funds
should be used to support the market for these and other non-essential drugs.
In other words, we had to decide whether the scope of benefits in a Medicare
drug program could be restricted without~ reducing the quality of health care
and without depriving physicians of access to valuable therapeutic agents.
Although these and other aspects of the Task Force investigations were all
related to the question of including prescription drugs as a Medicare benefit,
many of them have much wider significanëe. One of them that is of particular
concern to me, has to do with the explosive growth of drug research, develop-
ment, promotion, and marketing, and the profound effect this has had upon the
use of drugs, and indeed, upon the entire practice of medicine.
In our lifetime, the pharmaceutical industry has become an increasingly
complex research and development enterprise. Beginning with research at the
turn of the century related to epinephrine and other sympathomimetic drugs,
we can trace a continuing series of developments, including vitamins, insulin,
the sulfonamides, analgesics, antibiotics, steroids, antimalarials, tranquilizers,
antihistamines, and the growing battery~ of modern chemotherapeutic agents
and biologicals. Drug development, produétion, and sales in the last thirty years
have raised the drug industry in the United States from a $300 million to a $5
billion-a-year operation.
The striking growth in the availability of increasingly potent and dramatically
effective drugs has done much to increase the effectiveness of the physician in
lengthening life and alleviating suffering. At the same time, it has made the
pharmaceutical industry, the makers and sellers of drugs, among the most in-
fluential members of what has been called "the health team." Its influence has
been brought about not only as a result of epochal advances in biology, phar-
macology, chemistry, and medicine, but also because of profoundly significant
changes in the scope and methodology of drug promotion.
Much has been said in these hearings and elsewhere about the use of advertis-
ing and promotion to create a market for new drugs and maintain markets for
older ones. The Task Force has expressed similar concerns. Substantially less
interest has been aroused, however, by the efforts of industry to mold the
attitudes of medical students, medical faculty members, professional organiza-
tions, and those who are responsible for large-scale purchase of or reimbursement
for prescription drugs, including both public and private agencies.
This problem was highlighted by the recent decisions on the part of students
at two medical schools, Western Reserve and Harvard, to return drug industry
gifts. These actions clearly reflected the concern of these students about the
involvement of the drug industry in programs of medical education and informa-
tion, because the drug industry is engaed here not only in educating but in
selling.
It is through his early medical training that the physician-to-be forms attitudes
about the use of drugs, their relative merits, and the function of drug manufac-
turers as sources of reliable information. In many medical schools it is not
unusual for representatives of drug firms to take part actively in physician
training as lecturers, consultants, and simply as sources of information. The
medical student, under these circumstances, naturally associates drugs with
their suppliers as well as with their chemical and clinical properties. And here,
Mr. Chairman, is the point at which the strategy of names begins to take on
great importance. For it is during his training that the student begins to associ-
ate useful medicinal drugs with their trade names as well as, and often in place
of, their geueric names.
PAGENO="0010"
4300 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
It is also important to note the extent to which those who are responsible for
the teaching of pharmacology and pharmacy are supported by the pharmaceuti-
cal industry. All indications are that the major drug houses provide financial sup-
port to departments of pharmacology, schools of pharmacy, and individual sci-
entists engaged in teaching and research that is very considerable indeed.
Through grants, contracts, fellowships, guest lectureships, and unrestricted sup-
port, many in academic medicine have developed very close ties to the drug mak-
ers for necessary support which amounts to millions of dollars each year. That
this academic-industrial relationship has been productive, there is no doubt. But
there can also be no doubt that the medical profession, our medical students, and
the public have the right to an honest and open accounting of this relationship.
In the case of the American Medical Association, for example, it would appear
that more than half of its total revenue is derived from the pharmaceutical
advertising carried in various AMA publications.
The effect of the very substantial involvement of the pharmaceutical indus-
try in the practice of medicine, Mr. Chairman, finds its ultimate expression in
the drugs prescribed by physicians.
Last year, over a billion prescriptions were filled in the United States at a
retail cost of over three billion dollars. Each of these prescriptions represented
a tacit assurance by the physician that the patient was receiving the most appro-
priate drug that could be prescribed-the most appropriate in terms both of
performance and cost. Yet I wonder bow many physicians were really prepared
to give that assurance.
The problem is not a simple one for the physician or his patient. There are
now more than 7,000 prescription drugs available in this country. This therapeu-
tic arsenal includes some 1,200 generally available drugs and 6,000 combina-
tions, most of them marketed in a number of different dosage forms.
In the past twenty years there have been 715 new single chemical entities mar-
keted. Duplicate single products have numbered 1,407; compounded products
3,840; and new dosage forms 1,820. Thus a total of 7,782 new products and new
dosage forms have been marketed in the last two decades alone.
How does the physician respond to this profusion of new products? Of the 1.1
billion prescriptions written last year, 67 percent were written for 200 drugs
and 85 percent for 500 drugs. Among the 200 most frequently prescribed drugs
are 119 single chemical entities and 81 combination products. The development
and use of fixed drug combinations, as we have noted in our reports, has become
increasingly popular within the past twenty years, but the widespread reliance
on their use has generated sharp criticism. The Council on Drugs of the American
Medical Association has long held the prescribing of such fixed drug mixtures
to be irrational, and you will recall that near the outset of your own hearings, a
noted authority on infectious diseases said:
"A careful review of fixed branded combinations on the market, including com-
binations of penicillin and sulfonamides, penicillin and streptomycin, tetracycline
and antifungal agents, and tetracycline and novobiocin, does not substantiate the
claims that the combination is superior to one of the agents used separately. The
combinations are expensive, deny the physician flexibility in dosage, are pri-
marily promotional devices, and have the inherent problem that the patient
undergoes the risk of serious adverse reactions to two or more drugs rather than
a single defined agent. The physician cannot determine which component is
causing trouble if a bad reaction is encountered. I personally believe that we
would do much better without these preparations."'
The National Academy of Sciences National Research Council has completed a
careful evaluation of the 2,824 drugs marketed between 1938 and 1902, the
year in which the Food, Drug and Cosmetic Act was amended to require that
drugs marketed be both safe and effective. The NAS-NRC has taken a similar
position with respect to a number of the fixed drug combinations. The actions by
the Academy and the Food and Drug Administration are sure to rouse the ire of
industry, but more importantly they should make many of the physicians who
have been prescribing drugs now described as ineffective question their own obser-
vations with respect to these drugs.
One of the consequences of the introduction of safe and effective drugs is bet-
ter health and well-being for many people. Another consequence is drug-induced
IKunin, Calvin M.: Statement in U.S. Senate, Subcommittee on Monopoly Select Com-
mittee on Small Business, "Compefitivc Problems in the Drug Industry" U.~. Government
Printing Office, Washington, D.C., 1907.
PAGENO="0011"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4301
disease, or what Moser2 has called diseases of medical progress. His recent book
includes 27 chapters describing a host of problems from discoloration of the teeth,
to drug dependance and death. A search of the medical literature during a recent
four-year period revealed 178 citations on the untoward effects of iron; in less
than three years, 03 articles on the effect of tetracyclines on teeth; and in a four
and one-half year period, 112 articles on the adverse effects of LSD.
Attention is now being directed to many of these problems. In one recent
study, of 830 patients with chronic illness admitted to the medical wards of a
hospital for treatment and rehabilitation, approximately 35 percent reported at
least one adverse reaction to drugs administered during their hospital stay. This
incidence of adverse drug reactions is considerably higher than the 5-20 percent
reported in earlier studies of hospitalized patients.3 It should also be noted that
80 percent of the reactions observed were moderate or serious.
Studies of adverse `drug reactions on an' outpatient or ambulatory basis are,
of course, far more difficult. In recent years several computer based systems
have been developed that will permit study of this problem as well as the pre-
scribing habits of physicians. At the University of Southern California a study
of prescribing patterns has identified four types' of inappropriate prescribing:
(1) Inappropriate drug quantities by single prescription; (2) inappropriate
amounts of individual drugs in patients' possession that result from multiple
prescriptions; (3) inappropriate concurrent prescriptions; and (4) inappro-
priate drugs for specific disease entity.4 One example of the kind of problem
uncovered in this study was the patient who received over 100 prescriptions
for trannquilizers and hypnotics over a~ nine-month period. She received the
prescriptions from her regular clinic and from a hospital emergency room.
Neither facility `has access to the other's medical records. At the end of the nine
months, the patient had over 1,100 fifty-milligram capsules of chlorpromazine,
2,000 ten-milligram tablets of trifluoperazine, and' 650 two hundred-milligram
capsules of amobarbital theoretically in her possession. The potentials for abuse
in such a situation are obvious.
Another kind of problem more subtle and more difficult to assess has recently
been discussed in an excellent editorial in' the New England Journal of Medicine.3
This is the duress imposed by the attitudes of the medical profession and society.
The physician knows he will be more severely criticized if he fails to treat a
curable condition than if he overtreats a dozen that require little or no treat-
ment. As the editorial stated.
"Actions speak stronger than words, but strong words scold inaction. Treat-
ment, moreover, is gratifying to both doctor and patient in proportion to its
specificity, incisiveness and magnitude. Under conditions when choice is possible,
operation is preferred to pills, pills to diet, diet to nothing at all. The patients'
desires, the doctors' peace of mind, the opinion of the medical profession, and
the societal attitudes press for vigorous treatment. Is it therefore any surprise
that the physician who has to choose between over- and under-treatment almost
invariably `opts for the former?"
The editorial concluded: "Basic to ~good treatment are the physician's in-
tegrity and education. The shape of the therapeutic structure erected on these
two foundations is determined by the interaction between individual and cir-
cumstances. It is a complex process which pharmaceutical advertising in-
fluences but usually does not dominate, and constraints placed on this factor
alone will improve therapeutics but little. A better appreciation of the principles
of medical therapy is required by society at large, and the necessary educa-
tional process must involve everyone-those who give, those who receive, those
who intermediate, and the many who ,choose to write about what's wrong with
medicine. When one man treats another, the exchange involves not only a whole
patient, but also a total physician."
Mr. Chairman, I have tried to describe and diagnose, if you will, a malady
that affects physician, patient, and the public generally. If the diagnosis is
accurate a prescription is in order.
One of the basic ingredients of this prescription must be education. In pharma-
cology, the major problem is that the; subject is taught early in the medical cur-
2 Moser, H. H.: Diseases of Medical Progress, Springfield, Illinois, Charles C. Thomas.
3Bo~da, `~: T., Sloan, D., and sack, H.: "Assessment of Adverse Reactions Within a Drug
Surveillance Program," JAMA 205 :644-647, August 26, 1968.
Maronde, Robert, M.D., Professor of Medicine and Pharmacology School of Medicine,
University of Southern California: Personal Communication.
5Editorial: "Treatment by the Whole: Individual," New England Journal of Medicine
280 :271-272, January 30, 1069.
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4302 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
riculum as a basic science when it really is a clinical science as well. As a re-
sult, the clinical uses of drugs do not receive the attention they deserve.
The situation was very well stated by the President of the American Medical
Association in a recent address:
"Certainly there needs to be a recognition by all elements concerned with
medical education that pharmacological principles should not and cannot be
limited to a single or conservative series of courses given fairly early in the
curriculum of the modern medical student, which almost universally now in-
eludes 4 years of medical school and 4 more years of internship and residency.
"The goal of pharmacologic teaching is not a theoretical one. It is not limited
to action at the molecular level. It must in part be practical and it should in-
clude information concerning safe and effective use of drugs. A key principle is
that all drugs are potentially toxic. The student as well as the practicing phy-
sician must remain continually aware of the possibility that any drug may do
harm as well as good. Such continual awareness comes only from repeated ex-
posure to pharmacologic education."
And he stated: "It is my belief, which I share with many other people who are
concerned with this problem, that ideally students should be educated in pharma-
cology in such a way that as physicians they will have the basic tools for con-
tinued learning about new drugs and new developments in therapeutics that
will appear during their years of active practice. Furthermore, they should be
educated so that during the years of practice they will be oriented to the con-
tinuing education of pharmacologic experts in medical schools and not to the
advertising of pharmaceutical manufacturers."
In its background paper, "The Drug Prescribers," the Task Force reported on
steps taken at a number of medical schools to bridge the gap between pharma-
cology as a basic and clinical science.
At Harvard University, for example, students are offered an elective seminar
on advanced pharmacology in the fourth year which employs a case history ap-
proach to drug therapy in which emphasis is placed on problems of drug inter-
action and adverse drug reactions. I understand that twice as many students
apply for admission to this course as can be accepted.
At Columbia University and the University of Florida, clinical pharmacology
is now being taught in the third and fourth years in addition to the basic sci-
ence course.
A number of other schools have begun or are plannng to offer similar courses.
The Task Force has recommended that a course in clinical pharmacology be in-
cluded as part of the regular medical curriculum in all schools and that Federal
support be provided where the need is apparent.
Perhaps even more important than the urgent need to improve the educational
opportunities in our schools of the health professions is the need to improve
educational programs and sources of drug information for interns, residents,
and practicing physicians, for unless the physician is prepared to go on learning
for as long as he practices medicine, there is little hope that he will be able to
deal effectively with the obstacles to rational prescribing.
Information on prescription drugs reaches the physician from many sources:
medical journals; journals of prescribing such as The Medical Letter and
Ph arm acology for Physicians; drug compendia; formularies; textbooks; in-
dustry advertising; drug samples; detail men; and postgraduate education.
Surprisingly few of these sources, however, provide the objective, current,
and comparative data that the physician needs in order to make sound thera-
peutic judgments. You may recall, Mr. Chairman, that when I last appeared
before the Subcommittee, I spoke of the need to support the efforts of State and
local medical societies, in cooperation with medical schools and other health
institutions, to provide regularly scheduled postgraduate seminars of current
developments in drug therapy. I also discussed the Task Force recommendations
about establishments of a comprehensive drug compendium and support for a
journal of prescribing.
These are recommendations which I felt should be of tremendous interest to
the medical profession, and so on November 7, 1968 I sent a letter to all of the
Nation's 306,000 physicians describing our recommendations to provide better
drug information and asking for their comments. I am pleased to submit a copy
of my letter for the record.
Wilbur, Dwight L.: "Pharmacology and the Practicing Physician," Proceedings of the
Western Pharmacology Society 10:5-11 (1968).
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4303
During the first several weeks, through December 4, we received 3,307 replies.
Of these 2,554 contained comments and 753 were simply requests for copies of the
Task Force reports. Since that time we have received several hundred more
replies which we have not fully tabulated, but the nature `and direction of the
response did not appear to differ from the early replies.
Of those with comments, 1,709 or 66.9 percent were favorable to the recom-
mendations overall, 529 or 20 percent were clearly negative, and 316 or 12.4
percent could not be judged either favorable or unfavorable.
On the specific issues discussed in the letter, the responding physicians indi-
cated as follows:
1,621 physicians commented on our proposal for a comprehensive drug
compendium. Of these, 1,246 or 77 percent were in favor and 375 or 23 per-
cent were opposed.
1,419 replied to the recommendation for a journal of prescribing. 858 of
them or 60 percent were favorable and 561 or 40 percent were opposed.
1,138 commented on the expansion of~ undergraduate training in clinical
pharmacology. 751 or 66 percent were in favor and 387 or 34 percent were
opposed.
1,070 physicians discussed our proposed support for continuing education
courses in drug therapy. 789 or 74 percent were in favor and 281 or 26
percent were opposed.
What do these replies mean? First, they indicate the serious thought that
many physicians have given to the problems involved in obtaining objective and
reliable prescribing information. Beyond that, any judgments must be tempered
with caution. This was not a survey in any,: statistical sense and it i's therefore
impossible to say that it does or does not represent the thinking of the entire
medical community. But these replies clearly do show that a significantly large
number of physicians are finding it difficult to live with the traditional ways of
obtaining drug information.
Much more can be done, Mr. Chairman. For example, medical centers could
establish drug information centers, staffed on around-the-clock basis very much
like the existing poison control centers, to provide rapid access and complete
information on the use of drugs as well as on the handling of adverse reac-
tions. The National Library of Medicine is now developing through the Lister
Hill Biomedical Communications Center, a plan for a communications network
that would put such information at the physician's fingertips. The potential
of this program, not only as a source of up-to-date drug information, but
as a mechanism for continuing education, must not be overlooked.
In order to assess the impact of various kinds of information, programs of
drug utilization review should be undertaken. These should help to identify
thoughtless or harmful prescribing and to promote more rational therapeutic
decisions. The Department of Health, Education, and Welfare, which already
has a substantial stake in this problem, has not supported nearly enough re-
search in the past, and to help remedy the situation I have established an
Interdepartmental Committee on Drug Utilization Review. This committee will
review and coordinate the Department's research efforts in this area.
Education is important but it is not enough. Another basic essential is forceful
but reasonable Federal drug regulation. Some in the medical profession, includ-
ing those in academic medicine, have tended to disparage the Food and Drug
Administration, and in the past, some of this may have been justified. Even
today, despite the dramatic gains of the past few years, more remains to
be done. Experience, some of it tragic, has made it very clear that the Food
and Drug Administration needs to be strengthened in the public interest and
for the benefit of the medical profession and the pharmaceutical industry.
Critics of the FDA, friend and foe alike, agree that it needs a broadened
scientific capability, that its scientific base is considerably less than that of
the pharmaceutical industry it is charged to regulate. To meet this need, the
Task Force has recommended establishment of a drug research center within
the FDA which would provide additional opportunities within the agency for
the kinds of drug research which underlie its regulatory mission. The Task
Force has suggested in its Fifth Interim Report a number of examples of
research that could be undertaken by such:a center.
Education of the physician and the regulation of industry are but two ele-
ments; the third is a far better understanding on the part of society of the
principles and problems of medical therapy. I believe that one of the most
effective means of achieving better public understanding has been Congressional
hearings such as these. They have generated wide public in'terest and they
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4304 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
have provided a means of determining the extent to which those of us In
public service are discharging our responsibilities with wisdom, integrity, and
energy. I believe that Congress needs to be provided with greater staff resources
and funds for special studies in order to fulfill its obligation to society. Legis-
lation and appropriations are but two key Congressional functions. Oversight
of the Executive Branch is of equal importance.
Another essential for better public understanding is better public information.
These hearings and the reports of the Task Force on Prescription Drugs have
aroused considerable concern about the use and cost of prescription drugs,
thanks to the efforts of but a few dedicated journalists. But these are matters
which vitally affect all Americans and they deserve much broader public
discussion.
It is important for those outside of the medical profession to look Inside,
at us. But it is equally important that we in the profession critically appraise
our own activities and our own responsibilities. We should demand, for example,
to know how much support our medical societies obtain from sources outside
of the profession, particularly how much comes from the drug industry.
We should be interested in knowing where the support for publication of
drug studies comes from. Certainly every study done under a Federal grant
is identified as such. Should we want to know less about funding of such
studies by private sources?
In conclusion, Mr. Chairman, I would like to state my conviction that the
problems facing the medical profession in the use of prescription drugs must
be solved by doctors themselves. We can benefit greatly from the attention
that has been drawn to the problems of drugs in our society. But I doubt
that any solution that comes from outside of the profession, or that lacks
the understanding and support of physicians can produce the changes that
are urgently needed in medical education, prescribing practices, and the protec-
tion of the American people.
But there is growing evidence thaf physicians-and medical students-are
deeply concerned, and I expect that this concern will be evidenced in support
of measures both public and private to help assure that the medical profession-
not the makers and sellers of drugs-will retain its critical responsibilities in
this area.
Thank you, Mr. Chairman.
Senator NELSON. I would like, at this time, to pay tribute to Dr.
Lee. During his tenure of office with HEW he proved to be a very
able and dedicated public servant. He will be sorely missed. We have
had many occasions to call upon his services and he never failed
to respond promptly and to cooperate fully. He has been present at
a good many of our hearings, and his good counsel has added im-
measurably to the study we are conducting. Our thanks and best
wishes go with him as he undertakes his new duties.
Today's witness will be Dr. W. J. Hagood of the Little Retreat
Clinic in nearby Virginia. Dr. Hagood is in private practice and is
one of several physicians who requested an opportunity to appear
before the subcommittee. The Pharmaceutical Manufacturers Asso-
ciation also asked us to extend an invitation to Dr. Hagood and we
are happy to do so.
We have a biographical sketch of Dr. Hagood which will be printed
in the record prior to Dr. Hagood's statement.
(The biographical sketch of Dr. Hagood follows:)
BIoGR~uIcAL DATA
Name: William Joseph Hagood, Jr.
Born: Victoria, Virginia, January 6, 1918
Education:
Harlan High School, Harlan, Kentucky
Eastern State Teachers College, Richmond, Kentucky (Bachelor of Science)
MedIcal College of Virginia, Richmond, Virginia (MD) 1943
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4305
Fraternity: Phi Chi (Medical)
Internship: Medical College of Virginia
Private Practice:
Associated with Dr. James D. Hagood and Dr. Warren C. Hagood in General
Practice at the Little Retreat Clinic, Clover, Virginia
Medical Activities:
Member, Medical Society of Virginia, 1946-
Member, American Medical Association,: 1946-
Member, American Academy of General Practice, 1949-
President, Halifax County Medical Society, 1949
Member, State Board of Medical Examiners, 1949-1954
Chief of Staff, Halifax Community Hospital, 1956
President, Virginia Academy of General Practice, 1961-1962
Special Consultant in General Practice to Medical College of Va., 1962-
Member, Medical Education Advisory Committee of State Council of Higher
Education, 1962
Alternate Delegate, American Academy of General Practice, 1962-1964
Delegate, American Academy of General Practice, 1963-1965
Member, Radiation Advisory Board, Virginia, 1965
Member, Advisory Committee on Regional Medical Programs, Va., 1966-
Vice-Speaker, Congress of Delegates, American Academy of General Practice,
1965-1967
Speaker, Congress of Delegates, American Academy of General Practice,
1967-
Civic Activities:
Member, Lions Club
President, Lions Club
Zone Chairman, Lions International
County Chairman, United Fund, Halifax County, Virginia
Member, Parent's Advisory Committee, Bridgewater College, Bridgewater,
Virginia, 1966-1968
Member, Executive Board of the Piedmont Area Council, Boy Scouts of
America, 1967-
Military Activities:
Army of United States, Dec. 1943-March 1946
Battalion Surgeon, 84th Infantry
*Campaigns: Rhinelandç Ardennes, Central Europe
Decorations and Citations: Purple Heart, European African Middle Eastern
Service Medal, Meritorious Service Unit Plaque, Bronze Star Medal, Com-
bat Medical Badge, Rank, Captain.
Hobbies: Raising roses, Writing, Public Speaking
Religious Activities:
Denomination, Southern Baptist
Member, Clover Baptist Church
Deacon, Clover Baptist Church
Sunday School Teacher, 1950-
Vice Moderator Dan River Baptist Association 1952
Moderator Dan River Baptist AssOciation, 1953-1954, 1956-1959
Member, Virginia Baptist General Board, 1957-1962
Member, Executive Committee, Virginia Baptist General Board 1957-1963
Chairman, Committee on New Baptist Building, Virginia Baptist Board,
1958-1962
Vice-President, Baptist General Association of Virginia, 1962-1963
President, Baptist General Association of Virginia, 1964-1965
Member, Committee on Boards, Southern Baptist Convention, 1963, 1968
Member, Faculty Christian Focus Week:
Bluefield College, Virginia, 1961
Campbell College, Buies Creek, N. C., 1962
Chowan College, Murfreesboro, N. C., 1964-1966
Averette College, Danville, Va., 1967-1968
Married: Aileen Brilihart, Troutville, Virginia
Children:
Dianne 23, R.N., married Jon A. Lucy and living in Gloucester Point, Va.
Nancy 21, Senior, Bridgewater College, Bridgewater, Virginia
Jean 15, 9th Grade
Mark 12, 7th Grade
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4306 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. Doctor, you may proceed to present your state-
ment in any fashion you see fit, either reading it or if at any time you
wish to extemporize on any aspect of your statement, you are cer-
tainly free to do so. Your statement will be printed in full in the
record as well as whatever extemporaneous remarks you make.
I trust you have no objection that if a question occurs to us from
time to time during the course of your statement, we ask it.
Dr. HAGOOD. No, sir.
Senator NEI50N. Thank you, Dr. Hagood. We appreciate your tak-
ing time from your busy practice to make your contribution toward
these hearings we have been conducting for almost 2 years now.
STATEMENT 01' DR. WILLIAM 3. HAGOOD, FR., PRIVATE PHYSICIAN,
LITTLE RETREAT CLINIC, CLOVER, VA.
Dr. HAGOOD. Thank you, Senator Nelson and Senator McIntyre. I
appreciate very much the opportunity of you letting me appear before
your subcommittee, and also I wish to thank you again for letting me
change the date because of a conflict in schedule.
I would like the record to state that I am appearing as a private
citizen. This statement I make this morning is my own. I do not repre-
sent any organization. I do not own any stock in any drug company.
In fact I am not beholden to any drug company in any manner at all.
I am William J. Hagood, Jr., M.D., of Clover, Va. I am a general
practitioner, and while there are some people who would like to be-
lieve that the GP has no business in the airy goings-on of political
Washington, I think to the contrary we have something very impor-
tant to contribute. I am grateful to you for letting me come, and I
earnestly hope my being here will be helpful.
I said I live in Clover. You can get there from here by going south
100 miles to Richmond, the site of the Medical College of Virginia.
That is where I got my academic medical education the same years
a certain nurse trained there who later married the distinguished
chairman of this committee. From Richmond you turn south and west
on Route 360 for another 100 miles; there you'll find Clover, a tobacco
farming community, near Danville, in south-central Virginia. In
Clover my uncle, Dr. J. D. Hagood, started the Little Retreat Clinic
that has served that farming community for over four decades. I've
been in practice there 23 years and now operate the clinic with my
cousin, Dr. Warren C. Hagood, who has been there 15 years.
We are, as I guess the foregoing suggests, small operators, if you
compare us with some of the larger institutions that have presented
their testimony here previously. We are professionals who continually
strive to give the public in our area the best in medical care using as
aids to accomplish this these two things-continuing education and the
best of physical facilities.
Our clinic is completely equipped for the type of service Warren
and I wish to offer the public, and that is comprehensive and continu-
ing medical care. We have modern X-ray equipment that we use care-
fully and regularly. We have a. laboratory sufficient and adequate for
our needs. My associate and I da.ily sta.ke our reputations on the
results handed us by our laboratory technician. She does blood counts,
throat and urine cultures, cholesterol and uric acid levels, et cetera.
Warren and I have over 150 diabetics in our practice and this techni-
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4307
cian tells us what any given one's blood sugar level is 20 minutes after
she takes the specimen. We have four identical and completely equipped
examining rooms, with the best diagnostic aids available, down to the
point of having pushbutton adjustable examining tables. A room has
been set aside and especially equipped to test vision, hearing, and to do
electrocardiograms. Another room is equipped with a hospital bed,
oxygen, ultrasonic and diathermy equipment. Warren and I have some
convictions that are evidenced by printed signs and lack of printed
signs, that is, we have conspicuously posted "No Smoking" and
there is a conspicuous absence of "Colored only" and "White only"
signs. In all modesty, I doubt that many patients in large cities have
more modern or comfortable or more effective medical care facilities
than ours. You, Mr. Chairman, or anyone is welcome to inspect our
clinic at any hour where Warren and I give daily a 24-hour service
to our patients.
`We have no medical specialists staffing our clinic. But we have, and
we use, every necessary specialty in medicine available to us. In sur-
rounding cities we can call upon urologists, orthopedists, psychiatrists,
dermatologists when needed. We have surgeons, internists, obstetri-
cians, gynecologists and a pediatrician at our community hospital just
17 miles away. And we use them. We have built up over the years, a
good relationship with these people. Of course, our primary reason for
doing this is about 15 percent of our patient's problems require services
we are not trained to supply. A second, important reason for our regu-
lar contact with them is that they teach us. They show us how we can
better diagnose conditions we might otherwise miss or misidentify.
They educate us to handle what we can handle and equally important,
they help us to recognize situations we cannot adequately meet. A third
reason is we teach them about our medical way of life. These three
reasons mold both groups of physicians into a useful team whereby
Warren and I can deliver comprehensive and continuing medical care.
Essentially, then, what we have in Clover is a group practice with-
out walls. We look isolated. We are not. As a matter of fact, we are
very much in touch. Back in the days when artificial kidneys were
experimental curiosities the life of one of our patients was threatened
by a mounting potassium level in his bloodstream. Smith `Kline &
French made a service item, an exChange resin, that would attack and
reverse this lethal trend in our patient. Four hours and twenty minutes
after a phone call to Smith Kline & French in Philadelphia this drug
was delivered to the front door of the Halifax Community Hospital,
South Boston, Va. The patient recovered thauks to the drug. The cost
to the patient, nothing.
This was a service item Smith Kline & French made available to the
medical profession gratis. They didn't even ask for a report on the
results of their drug.
Unfortunately some of the witnesses who have testified before your
committee have left the impression drug companies have doctors as
prisoners. In my experience, it is the companies who are captives of
the doctors. The drug companies do what doctors want them to do;
and that is, doctors want good drugs, successful firms have produced
them, and those pharmaceutical houses have been justly recognized for
their performance by the repeated prescribing of their reliable drugs.
To be sure, there have been drugs manufactured and marketed by
reputable drug houses that were not what they had been represented
81-280-69--pt. il-2
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4308 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
as being. Laws have been passed by the most reliable governmental
deliberative body in the world, the Congress of the United States, and
some of those laws were not what they had been represented as being.
Fortunately, drug houses and Congress, each in its own time, have
removed no good drugs and no good laws from the people. And I need
not remind you of the time record or the batting average. My point is,
both institutions are good but not perfect, and both need constant
attention in order to get the desired results.
Let me tell you what enters into my consideration in choosing a drug
for my patient.
To do so, I must again illustrate how unrealistic it is to pretend it is
drug companies alone that make up my mind for me.
Senator NELSON. May I interrupt for a second, Doctor.
Dr. HAGOOD. Yes.
Senator NELSON. I don't think we have had any testimony that I
can recall before the committee that asserted that drug companies
alone make up the minds of all doctors in prescribing the drugs. But
the testimony has been that it is a variable situation in which some
doctors rely much too heavily upon the advertising and the promotion
of the companies. It has not been that we have had witnesses saying
all doctors rely upon the drug companies to make up their minds.
Dr. HAGOOD. It was my feeling that this was alluded to, as I read
through some of the proceedings of this. For instance. On page 570 of
the Nelson hearings there is a statement there by Dr. Cluff; on
May 15, 1967, there was a statement by Dr. Holloman; Dr. Carstenson
on May 17, 1967, made the statement that led me to make this state-
ment. Dr. Modell in June 1967 and Dr. Magee on page 492 of the Nelson
hearings, and these were the statements from which I drew this.1
Senator NELSON. Did any of those witnesses in their statements,
state that drug companies are the only influence on doctors, for all
doctors on all drugs that they prescribed.
Dr. HAGOOD. To my knowledge they did not say that drug com-
panies alone do this.
Senator NELSON. That was the reason I was raising this. You see,
so many of the medical publications, throwaways supported exclu-
sively by' drug advertising, other publications supported heavily by
drug advertising, would take excerpts from statements and then draw
a broad conclusion from them which caused doctors to believe that
witnesses before the committee, distinguished witnesses, were saying
that all doctors are simply victims of the propaganda of the drug com-
panies and all doctors rely solely upon drug company promotion `and
advertising for `their prescribing practices. I am not aware of any
testimony to that effect.
Please go ahead.
Dr. HAGOOD. I am, I suspect, no more an avid reader than most
G-P's; that is to say I read, regularly and rather fully, two or three na-
tional medical journals. In addition, I am active in my local and State
medical societies. I am a member of the AMA. I belong to the Ameri-
can Academy of General Practice. A look at any one of the dozens of
programs of AAGP in promoting postgraduate education shows the
1 See hearings, "Competitive Problems in the Drug Industry"; testimony of: Dr. Clufl~,
pt. 2, pp. 559H580; Dr. Holloman, pt. 1, pp. 4-54; Dr. Carstenson, pt. 1, pp. 228-2~7~ Dr.
Modell, pt. 1, pp. 283-305; Dr. Magee, pt. 2, pp. 486-499.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4309
extent of information offered me from that source. Indeed, member-
ship in that association requires each meniJber to complete every 3
years 150 hours of approved postgraduate. education. The fact that
over 31,000 general practitioners are part of AAGP shows we GP's are
indeed interested in, and are obtaining, the professionally organized
and administered postgraduate education some of your witnesses have
in effect suggested does not go on.
I am not operating in a vacuum, you see. In addition to all the
more formal types of communication I've just touched upon I have
the valuable, indeed, invaluable guidance of my fellow physicians.
Everyone in the profession is informed speedily when a new pharma-
ceutical becomes available, thanks in a large measure to efforts of drug
companies who produce them. We all agree, certainly, not all new
drugs are destined to become essentials of medicine. Personally, I
would rarely want to have the distinction of being the first physician
to use any new drug the day it reached the pharmacy; nor do I want
to be the last. In deciding whether, and when, to try a new drug, I
find it most helpful to have the advice of my professional friends.
There are, of course, publications aimed at providing early guidance
on the new drugs. The Medical Letter is a well-known source. I am
proud today I am a charter subsCriber to that letter, and I still retain
volume I, No. 1, in my office, near my desk and close at hand. I think
of the letter as a source of useful opinion, and that is saying a great
deal. But, at the same time, Mr. Chairman, it is no Bible, and its au-
thors do not, I am sure, want anyone to think it is one. Many doctors
consider the Medical Letter to be entirely too negative, if not nihilistic,
and I think it does have a certain pontifical, academic ring about it.
I am afraid doctors who spend their entire day seeing patients tend
to be a little annoyed at what appears to be ivory tower pronounce-
ments from on high.
Senator NELSON. Could you tell me in what way-I am not a reader
of the Medical Letter, of course-in what way it is negative or
nihilistic.
Dr. HAGOOD. Their conclusions are rather tersely drawn, and they
are very forthright in saying that this is good, this is not good, and
in doing this there is this feeling out in the practicing profession,
there we use drugs and we know, to begin with, there is a large ele-
ment of the placebo effect, for one instance. We also know that there
are differences in patient reactions to drugs. In fact, in my own prac-
tice I know that there are families, if you please, in which I can use
certain drugs and that there, are other families that I cannot use these
drugs, and this is one of the reasons for this. Someone in one of those
families has had a reaction to a drug, and this becomes known in the
family. So when the same condition comes up in another member of
this family, and maybe this is a first drug of choice and I would like
to prescribe this, and if I mention this drug, why they immediately
say, "No, sir, Doctor, I am just not going to take this because this made
my aunt so sick we thought she was going to die," or she had a rash
or something of that sort.: As a result, why, we use another drug or
fortunately we have other' drugs that we can use.
Nevertheless, as you read the Medical Letter you find that this
thing is somewhat cut and,dried.
PAGENO="0020"
4310 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY
As I said, I read this letter, I take this into my consideration, but
again I have to make my own decisions based upon the situation as
it arises daily in my office.
Senator NELSON. Thank you.
Dr. HAG0OD. May I proceed?
Senator NELSON. Yes, sir.
Dr. IJAGOOD. I suspect they are not entirely unique in this regard;
1 imagine practical politicians feel the same way toward those proud
theoreticians of political science who make profound analyses of poli-
tics but who have never actually taken the risk of running for office.
What I am saying, gentlemen, is there is a whole ranges of sources
of information, impressions, and advice operating side by side with
commercial sources. To pretend the doctor has only drug companies'
opinions to look at is to ignore reality. The fact is we have a great
many coiumunication channels, all of them of value, and none of
them unleavened by others. So long as drug therapy is heavily sub-
ject to professional judgment rather than solely to hard science, this
multichannel approach will be the best one overall. The last thing we
need now and in the future is a monolithic concept of therapy, which
says this drug, in this patient, in this dosage, is the alpha and the
omega of therapy. That approach, I am positive, has no basis in either
medicine or science.
Senator Nr1~soN. May I interrupt for a moment?
Dr. HAGOOD. Yes, sir.
Senator NELSON. I don't think anybody before this committee has
suggested one monolithic approach. Do you know of any?
Dr. HAGOOD. No; I do not and I certainly hope its does not arise.
Senator NELSON. Thank you.
Dr. HAGOOD. This leads me-may I proceed?
Senator NELSON. Yes, sir.
Dr. HAGOOD. This leads me to comment on the concept of a single
drug compendium, that has been discussed before this Subcommittee.
\Ve have, of course, the Physicians' Desk Reference, and I must say
that book, as good as it is, is becoming a bit large for my desk. It is not
perfect, but I find it outrageous it is condenmed because it is "just
advertising" as some have said. Of course, the material in it is paid
for by drug companies. But what of that? Currently, meaning 1969,
isn't every syllable in it written in conformance with labeling require-
ments of the Food and Drug Administration? Where can you show me
evidence entries violate FDA-approved descriptions of drugs? Surely,
if any do, FDA has ample power to correct the matter. But on what
basis is the PDR to be brushed aside?
Gentlemen, I am not here to glorify that book, or any other. But I
will tell you this; the current edition of PDIR has an estimated circula-
tion of 450,000. That is 318,500 more than the combined estimated
circulation of this country's three official compendia of standards; U.S.
Pharmacopeia, National Formulary, and Homeopathic Pharmacopeia
of the United States. That book, the PDIR, is one doctors use more
than any other. Take that one away, and you will have removed a
working reference. Is it inadequate? Fix it. Is it incomplete? Expand
it. But look at it. It now contains entries on nearly 2,600 drugs. It is
now 1,415 pages long, 2 inches thick, and weighs 3 pounds, Di/2 ounces.
Yes, I weighed the 23d edition on my baby scales when it was delivered
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COMPETITIVE PROBLEMS IN: THE DRUG INDUSTRY 4311
to my office January 19. Fortunately, the PDR won't triple its weight
this year, as does a newborn its first year of life, but the book will add
three-quarters of a round during the year as the four quarterly sup-
plements are glued in. The prospect of one immense book that fully
describes all drugs in PDR plus several thousands of others is not
attractive to me in the least. Such a book may be an interest to some-
body; but not to me. I am a practicing physician, not a librarian. I
need to know a great deal about less than a hundred drugs, not 2,000,
as there are now in PD1R, and certainly not the 6,000 of 7,000 that
would be found in an encyclopedia of the sort being described.
Unless you make your compendium more valuable and practical
than the PDR, your compendium will be replaced by a private tome
that does this. So you are asking for competition now. Maybe your
compendium will force the PDR to, become even better. I say this be-
cause in the day-to-day active medical practice the doctor wants cor-
rect, practical information that ~S concisely stated. And please-no
fine print because one can't underline passages that need emphasis
without blotting out print. You may force the physician to keep a copy
of your compendium in his office, but you will never force him to use it
unless it fits his needs better than other available sources. The sine qua
non your new book must offer, practicability in practice. My final note
on the compendium is-I don't know what you will have published, but
you must leave the ultimate choice of the drug, the dose of the drug,
and the source of the drug to the; physician who is charged morally,
ethically, professionally, and legally to treat the patient. If he assumes
the full responsibility of treating; any patient he must be free to pre-
scribe the drug he wants.
Senator NELSON. May I interrupt a moment there, Doctor?
Dr. HAGOOD. Yes, sir.
Senator NELSON. So far as I know, no witness before this coimnittee
has suggested that the ultimate choice of the drug not be left to the
physician. What puzzles me is that we have had several witnesses who
put in this sentence which to me leaves the implication that somebody
before this committee, or the committee itself, is suggesting that the
responsibility for prescribing a drug be taken away from the physi-
cian. There has been no such testimony before this committee, and it
has not been the position of anybOdy on this committee.
Dr. HAGOOD. I said this for emphasis, Senator Nelson, because I
certainly hope this would never be given any serious consideration
before this committee. This is a thing that must remain with the
physician.
Senator NELSON. We have not, as I said, heard any testimony to this
effect. The Pharmaceutical Manufacturers Association in some of its
propaganda has left that im~ilication, because I received a number of
letters from practicing physicians who raised the same point. I just
wanted to assure you that nobody before this committee has made that
suggestion, and nobody on the committee has made that suggestion.
Dr. HAGOOD. Thank you.
May I proceed?
Senator NELSON. Yes, sir.
Dr. HAGOOD. Mr. Chairman, I have related in brief some of the more
formal influences upon my prescribing practices. Now if I may, I
should like to relate some other, secondary but real factors no physi-
cian concerned about medicine and people over the long range can corn-
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4312 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
pletely ignore. These influences are somewhat analogous to a precinct,
county, or township that repeatedly delivers the vote.
About 13 years ago a 3-year-old child was brought to me, the daugh-
ter of a man I know who farms near Clover, and who has a good old-
fashioned farming family-a large one. This little girl had a sore
ankle. We puzzled over it for a few minutes; it is not unusual to find
the young child in a large family is more used to listening than talk-
ing, and this one was one of those who wouldn't say much about her
problems. The thought struck me she might have an early case of osteo-
myelitis. I X-rayed the leg, did other tests and soon determined she did
indeed have an infected bone. I put her on a drug called Signemycin.1
Now it is important in acute osteomyelitis to begin treatment
promptly with an effective drug, prescribed in adequate dose and con-
tinued past the point of clinical healing. The infection is found in the
bone and if unchecked, it spreads quickly, killing bone tissue as it pro-
ceeds, causing immense pain, leaving wrecked bones and destroyed
joints in its wake.
I had some Signemycin in the office, and I gave what I had to the
child. I wrote her a prescription for some more. Knowing her family's
situation, I felt sure between cost of raising six other children and
problems they were having with their farm, they would be hard put
to bear the cost of this necessary cost of therapy.
Wben the detail man from J. B. Roerig and Co. came around, I ex-
plained the problem to him. I made it clear, eventually, this farmer
would pay for the drug, but right now it would be difficult. I asked
him if he could do something for this child. As it turned out. Roerig
supplied gratis the entire amount estimated to retail at $350.00. That
was a lot of money 13 years ago.
Fortunately. the little girl responded beautifully. I have a whole
series of X-rays that show the gradual regression of the infection.
I would like to show you the child now; she is now 16 and she has
an interest in miniskirts, but for this experience, she might not other-
wise have.
Gentlemen, I will not ignore memories like that, and I hope you
don't think I should.
When I began practice 25 years ago, chronic osteornyelitis was fairly
common. The resultant death of bone, t.he painful involvement and
destruction of joints, the formation of large quantities of pus, and the
unpleasant outlook all made for an exceptionally ugly situation. The
antibiotic era has made chronic osteomyelitis an uncommon disease;
it has the prompt and effective cure of acute osteomyelitis almost
routine.
I can't forget things like that. Call it hearts and flowers if you wish.
It is human to thank, and I thank the drug companies that discover
these drugs. I am even more appreciative to find when the situation
warrants, the best of them are more than willing to provide their prod-
ucts at a loss. This is responsible behavior, and it goes unheralded, ex-
cept, of course. by the patient who benefits from it.
Another hind of example I mention is Aureomycin, made by Lederle
Laboratories, the first tetracycline. I remember two things in particular
about Aureomycin. The first., it caused a lot of my patients to vomit;
and, it cost wholesale $1.50 per capsule when it was first introduced.
1 See App. III, pp. 4795-4799. infra, with reference to Signemycin.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4313
Whether there was a causal relationship between these two points I
leave to your judgment. I used to tell my patients every time they
failed to keep one down they were throwing $1.50 in the basin, that
helped them keep it down.
Anyway, it wasn't long before the drug firms manipulated the tetra-
cycline molecule and other tetracyclines came along. They corrected the
two objections; very few people vomit the newer ones, and, through
competition, the price is down to less than a tenth of what it was.
Senator NELSON. May I interrupt a moment?
Dr. HAGOOD. Yes, sir.
Senator NELSON. You see, this committee has been conducting hear-
ings about what we consider to be some problems that need public
discussion involving the drug industry and the medical journals and
profession. The committee has not, of course, at any time taken the
position that the drug industry has not made a great contribution to
medicine. I think everybody on the committee, I think every witness
we have had for 2 years, is willing to concede that the drug industry
has made a great contribution to medicine, and that it is a very
imporLant industry.
But any time hearings are conducted involving an industry, the
position of the industry usually is "we have done great things you
aren't giving us credit for and you shouldn't expose to public view
critical aspects." This happened to me when I introduced the tire and
automotive safety legislation. The auto companies and others attacked
me as criticizing a great industry. It is a great industry and we were
criticizing it because the tire companies and auto companies were put-
ting purposely, knowingly, rather unsafe tires on the highway, and
still are. So the fact that we raise these questions about some practices
that we consider improper does not mean we are making a general
indictment of the drug industry.;
We have raised questions on pricing practices which the industry
can't answer. You mention on page 10 of your statement:
I am even more appreciative to find when the situation warrants, the best of
them are more than willing to provide their products at a loss.
Then you mention tetracycline on page 11.
I assume you are aware that Pfizer, Lederle, Bristol, Squibb, and
Upjohn were found guilty in a criminal case of conspiring to fix
prices, and that they just made an offer of settlement, a free offer of
their own, of settlement of $120 million to the people they cheated
for ten years. Itwas a criminal conspiracy; it was cheating. They were
gouging the public and, of course, they could afford to give any doctor
who asked for it for a patient, such as yours, free tetracycline because
they were cheating the people so badly that it didn't cost them any-
thing. This is the kind of thing that we have been exposing. I don't
think you, or even the drug companies themselves, could defend price-
fixing and price-gouging of the public, could you?
Dr. HAGOOD. Senator Nelson, may I go back for just a moment
there? I read this piece in the paper you are referring to now, I guess
it is 2 weeks or something ago. It was not my impression from the re-
lease that I read that these people had been found guilty of this. They
had offered to set aside $120 million of dollars to pay off any claims
that may be forthcoming by the 6th of March in this situation but it
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4314 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
was not my understanding that they had been proven guilty of this,
and that they had purposely and willfully cheated.
Senator NELSON. That was the finding, December 1967, guilty of
criminal conspiracy to fix prices. Guilty on three counts. It was a jury
trial. This isn't the only one, hut they were found guilty.
This is the point I would like to make with you, Doctor. This corn-
mittee is conducting hearings on practices which we think, as they
evolve, are inexcusable and the public is entitled to know them. That
doesn't mean that a company doesn't also do some good research, but
the posture taken by the Pharmaceutical Manufacturers Association
in the propaganda they spread so effectively because they have vast
amounts of money to do it, is that this committee is making a general
indictment of doctors, a general indictment of the medical profession,
a general indictment of the medical journals. That is not the case at
all. We are raising those questions in those areas where there is an
important public issue, and whereas a company is entitled to credit
for research and healthful discoveries, they are entitled and should
receive criticism when they gouge the public, and that is what these
hearings are all about.
Thank you.
Dr. HAGOOD. Now that I have used the words Signemycin and tetra-
cycline I wifi express myself on the subject of generic versus brand
name.
I will continue to prescribe brand name drugs until I can be assured
a generic drug is as effective, no more toxic, as convenient to give and
is cheaper than the brand name drug. And these assurances must be
present batch after batch after batch. Furthermore, I prefer these
assurances be arrived at by a nongovernmental source or a source com-
posed of representatives from the medical profession, the pharmaceu-
tical industry and the Federal Government.
As far as price is concerned I am not knowledgeable enough to make
a firm statement other than to say I don't believe you are going to set
a price that will produce more than ephemeral satisfaction to the pub-
lic. Doctors, hospitals, and drugstores have always been targets of
dissent and they always will be because they represent sickness, bad
health, unhappiness-something no one wants. True-many patients
are grateful and probably the majority are at times. Nevertheless,
nobody cares to be associated with any part of the medical profession
any longer than absolutely necessary. Yet, when they are involved with
the medical profession they expect good results.
And results leads to the much discussed subject of equivalency. To
me, equivalency boils down to who is involved. If the drug is made by
what I consider a reputable drug house I will accept it. If it is made
by a drug firm unfamiliar to me but vouched for by my local pharma-
cist I have known for 15 years I wifi give it serious consideration, then
decide whether I will accept it.
The third point on generic versus brand name drugs concerns the
flame of the drug. I would prefer to reduce confusion of drug names
so a specific drug is known by the same name with the drug manufac-
turer's name following it. This suggestion opens up discussion for
many other problems, such as, patent rights, royalties, profits, et cetera.
And again, I am not knowledgeable in these areas-but would it be
reasonable to allow the initial manufacturer to name the drug with
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4315
the approval of the organization that inspects his facilities and ascer-
tains his quality control is what it should be?'
Senator NELSON. Let me say, Doctor, that is a proposal that other
distinguished witnesses made as a suggestion to the committee. We
have introduced legislation to that effect, and I think every dis-
tinguished person from the medical or pharmacy field who has
appeared before the committee endorses this concept as suggested by
you. I suspect that the drug companies will oppose it, but because
brand name domination of the marketplace is their method of extend-
ing the patent long beyond the time a patent expired, but I think
good prescribing practices according to professional witnesses before
the committee would support the concept you suggest here.
Dr. HA000D. Thereafter, other firms manufacturing this drug
would use this approved name followed by the~ secondary manu-
facturer's name. This would serve as an incentive to research. I realize
this may well give the primary manufacturer a sales advantage which
could be offset by changing the 17-year patent rights period.
Regardless of what is done this section of our incomparable free
enterprise system, the drug industry, must be protected, preserved and
promoted; else a disservice will have been done not only to Americans
but the entire population of this globe.
Finally, let me say a word about promotional efforts of drug firms,
which are, I am told, very costly, and which, no doubt, involve a
degree of waste. I have every confidence in the earnestness of those
who would reduce the cost of drugs by reducing this effort, but here
again, as with the PDR, we have an established tool, the detail man,
who in my opinion is not as effective as he could be.
In 1964 I had the privilege of addressing the public relations sec-
tion of the Pharmaceutical Manufacturers Association. At that time
I said the caliber of a physician's practice of medicine will be no
larger than his continuing education effort. Time is limited. There-
fore, every learning tool and every avenue through which learning can
be projected must be large caliber to be effective. Please, don't send
out any small bore detail men.
I still believe the detail man has a minor but important place in
the well balanced continuing education program of the practicing
physician. Those detail men I spend time with bring information
about drugs-sometimes new drugs of major import, sometimes ones
I will elect to forget, and he brings it in person. So I can challenge
him and his company. So I can ask for and receive additional infor-
mation, quickly. I don't know whether elimination of detail men
would bring a significant reduction in drug cost, but I do know it
I Dr. Hagood subsequently submitted the following:
"On transcript page 5567, Senator Nelson interrupted, then stated my, point `had been
made in several previous `testimonies. He was referring to my statement: I'd prefer to
reduce confusion of drug names so a specific drug is known by the same name with the drug
manufacturer's name following it. And that's true. However, I don't believe I made my
innovation, to this often repeated point, clear to the Senator. The innovation is this: allow
the initial manufacturer to name the drug with the approval of the organization that
inspects his facilities and ascertains `his quality control is what it should be. An example
of this innovation, follows.
"Ciba discovers a drug `that will cure hemophilia. Ciba consults with the organization
that inspects Ciba's manufacturing process of the drug and they agree to name the drug
Hemophiliam. Thereafter, the drug is officially called Hemophiliam wi'th Ciba's name
following-thun-He'mophiliam Ciba. Under the current patent laws Ciba would be the
sole producer of this drug for 17 years. At the expiration of the 17 years other companies
could produce the drug. However, the drug would be called Hemophiliam and~ the secondary
manufacturer's name would follow the drug name. Now the drug could be prescribed
Hemophiliam Ciba, Hemophiliam Lilly, Hemophiliam Abbott, etc."
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4316 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
would be a costly step in terms of the loss of communication. Inci-
dentally, I doubt that elimination of the detail man would reduce
cost of drugs to patients as much as the cost of merchandise to all
Americans would be reduced if there could be a 50-percent reduction
in shoplifting.
Senator NELSON. May I interrupt again, Doctor?
Dr. HAGOOD. Yes, sir.
Senator NELSON. We have here a bit of conflicting testimony on
detail men, although I would guess from memory that most witnesses
have taken the position you have, critical of detail men and some
have testified that they made a valuable contribution.
I notice in the Virginia Medical Monthly, volume 94 of February
1967 on page 113, in an article' written by you, you stated that:
If the ideal detail man exists he is clearly outnumbered by his imperfect
brethren who reportedly interrupt the office routine, parrot stereotyped
encomiums, hawk their wares in a truculent manner and talk without listen-
ing. This confrontation destroys one thing the physicians want, an opportunity
to learn valuable information.
Dr. HAGOOD. What you have said exists in that paper but this is
not the entire story there. I am searching here for the-there were
other statements in there. In fact 80 percent of the group of people
that I interviewed by questionnaire felt very kindly toward the
detail man. They wanted to see him continued. Many of them said
that his service could be improved, but to say this was a typical state-
ment that has been made by the group is not entirely accurate.
Senator NELSON. I was not trying to suggest that. I was quoting
your statement, not the statement of the people you polled. This was
a quotation, as I understand it, from your article. It is on page 113
in an article written by you and John 0. Owen, Jr., of Charlottesville.
In the right-hand column, the bottom one third, this is on page 113.
This is a statement which I assume you and Dr. Owen agreed upon
in evaluating the detail man.
Dr. HAGOOD. This, I must accept the responsibility for, because
my name is attached to this. I would say this simply in the way of
explanation, that the writing of this was largely done by Dr. Owen
because at that time I was engaged in some other activities, and I
simply said to him, "Jolm, if you write this you will have to do it
yourself because I am busy at this time." He did send me copies of
this for my comments and any corrections, and I must say that
this statement here does not now reflect my feeling toward this. Had
I, if I had my druthers, I would have done it differently, but neverthe-
less I wrote it, my name is signed to this. I will have to accept
responsibility, but I `feel differently.
Mr. GORDON. Dr. Hagood-
Dr. HAGOOD. Yes, Mr. Gordon.
Mr. GORDON (continuing). I notice you quoted a figure of 85 per-
cent of the rural physicians giving the detail man a strong vote of
confidence.
Now, in the same paper that the Chairman was discussing we are
coming now to the younger doctors, 37.5 percent of the residents, had
unfavorable opinions of detail men, and only 3 percent were fav-
orable, and about 60 percent neutral.
1See app. I beginning at p. 4789, infra.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4317
in your survey of residents, interns and students only 9 percent
of respondents were favorably disposed to the advertisements of the
drug industry and 52 percent expressed gross dissatisfaction with
advertisements.
Dr. HA000D. Mr. Gordon, let me explain, this paper is written from
questionnaires, two questionnaires. One, the general practitioner,
myself, sent out to a group of 200 rural general practitioners. A
separate questionnaire, made by Dr. Owen, was circulated among the
house staff and the medical students of the University of Virginia,
and this is his portion of this paper there.
Mr. GORDON. But it is rather interesting to see how the rural
practitioner differs from those at the university, the "Town and
Gown" as you have named the article, the great disparity, the great
difference in attitude toward the detail man. Would you say it is
rather interesting?
Dr. HAGOOD. This is certainly interesting. I would think that the
comment in the first paragraph of the coiument should be brought
out here, which says "it would be imprudent to attempt multiple
interpretations of the responses to two different questionnaires dis-
tributed to two different and heterogeneous groups with such a
variable percentage of replies."
Senator NELSON. Fine, Doctor. Go ahead. You were at the top of
page 14.
Dr. HA000D. Yes. We must be realistic in viewing this form of
communication. Obviously his basic function is to sell. Obviously he
is not there to extol the competition's product any more than one would
expect Republicans or Democrats to praise the opposition. The doctor
isn't so foolish as to assume such things, and because of that the
detail man is identified in the physician's mind as a biased, albeit
honest, source. To be successful, the detail man must appreciate the
fact he is seen with a bit of doubt, and he must therefore, if anything,
be overly conscious of the need for honesty. A show of ignorance, of
deception or fraud, and he may permanently damage his company
in the doctor's view; and he certainly will be making his last visit to
my office.
Going back to the 1964 talk I made to PMA people, I told them
80 percent of doctors practicing in rural areas in Virginia answering
my questionnaire said they favored continuing use of detail men by
drug companies. That questionnaire was mailed to 200 doctors in
rural settings in Virginia. I received returns from 80 doctors in 55
counties, who had practiced medicine from three to 61 years in corn-
munities, varying in size from open rural country to a town of
4,200.
in general, I believe drug company promotions, and their repre-
sentatives, are both helpful and reliable. Imperfect, of course. But
their function is not withOut real value, and I know of no workable
or less costly alternates. Lacking better substitutes, I suggest we
concentrate on improving them, rather than deploring them.
Mr. Chairman, again I thank you for allowing me, a general prac-
titioner from rural Virginia, to tell you my views on some of the
knotty problems facing this committee. I earnestly suggest you hear
more from practicing physicians from all over America. By practicing
physicians I mean those who make their living daily by fee for
service. That is where the action is. The National Center for Health
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4318 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Studies said during the 1-year period from July 1966 to June 1967,
an estimated 71.8 percent of all physician visits took place in the
physician's office. This figure is growing because this represented an
increase of 10 percent over the 1957-58 study year.
A further breakdown of NCHS figures shows general practitioners
accounted for 64 percent of office visits and 85 percent of house calls.
Patient visits to all physicians totaled 831.1 million.
That many millions of visits to doctors doesn't impress one until
it is related to a concern of this committee. Mr. Chairman, every one
of those visits to a physician represents at least one prescription writ-
ten or reffiled. And that means if all these prescriptions were written
at once and distributed to the population of these United States each
man, woman, and child would each have four prescriptions in their
hand.
Senator NELSON. Are you saying there that every patient receives
a prescription for a drug?
Dr. 1HIAGOOD. I am saying this represents a prescription or a refill
prescription. This is my assumption.
Senator NELSON. That everybody who visits a doctor gets a pre-
scription for a drug or a reffil.
Dr. BIAGOOD. No, I was trying to relate this figure to something that
was of concern to this committee, so that I simply used this to empha-
size the number of patient visits to doctors throughout this country.
Senator NELSON. But you weren't saying that every patient who
comes to your office gets prescribed a drug?
Dr. BIAGOOD. No, I was not saying that.
Senator NELSON. I want to thank you very much, Doctor, a.gain for
taking the time from your busy practice to come here.
Just so that you won't have any misunderstanding about how this
committee is proceeding, we have made it clear from the first day that,
on every issue raised of any consequence before the committee, that the
committee would invite the viewpoint, every viewpoint, as to that issue
raised. That is what we have been following. A number of times the
PMA has made attacks on the committee saying the witnesses are
handpicked, the committee is unfair, the viewpoints aren't being heard,
and that is a gross misrepresentation.
It shocks me to see how often the PMA representing this great
distinguished industry would intentionally propagandize in this
fashion.
Our position has been that first preference goes to the drug com-
panies on any issue raised which concerns them. We have invited every
drug manufacturer in America, publicly several times, to appear be-
fore this committee on any aspect of these hearings they wished. Very
few of them have volimteered. We have invited them all repeatedly.
We have invited every company who is criticized before this com-
mittee, immediately, as soon as we could arrange it, to have an oppor-
tunity to appear to discuss the criticism that is made of them. I don't
see how we could be more fair than that.
We have made it clear that we will hear the viewpoints of all med-
ical organizations in this country, and including the Academy of Gen-
eral Practitioners because I happen to think it is a. very important as-
pect of the practice of medicine in this country.
You may be assured there is not a single viewpoint group of any
significance at all that won't be amply heard. If they think that the
PAGENO="0029"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4319
time assigned to them isn't adequate we will welcome them back again.
We are inviting them all. We have been attacked because some of them
haven't been invited before others. But if we are going to hear wit-
nesses over a period of 2, 3, 4 years, as I am sure you appreciate, you
can't hear them all at once. You have to hear them in some order or
another.
But I want you to leave here knowing that the general practitioners
are going to be amply heard, including the American Academy of
General Practitioners, all other majOr medical organizations, and any
distinguished individuals who have something to contribute to it, as
well as the PMA, which we have already heard, and have told they can
come back again. I want to assure you that the hearings here are not
stacked in any way.
There are now nine volumes printed, and any organization that has
been involved, any medical organization, any medical journal, any
industry, any company or any individual can read those hearings and
if they wish to respond to something on it they can send in their state-
ment on it or they can ask for hearing time and in due time they will
be heard, so these will be balanced hearings, and that is one of the rea-
sons you are here today.
Dr. HAGOOD. Thank you, sir.
Senator NELSON. Thank you very much, Doctor.
Counsel had one question on the advertising of the drug companies.
Mr. Goi~uoN. In your statement, on page 14, you stated:
"A show of ignorance, of deception or fraud, and he may per-
manently damage his company in the doctor's view; and he certainly
will be making his last visit to my office." You are referring to detail
men here.
In an article' by Dr. Gourley of the University of Virginia entitled
"Teaching the Evaluation of Drug Advertising to Medical Students,"
which appeared in the Virginia Medical Monthly in August of 1966,
we find that students were particularly impressed with the number of
quoted references which were not available even in a good medical
library-
Senator NELSON. Was this in the advertising?
Mr. GORDON. The advertising, yes. But when they really got around
to looking into it, they found that they couldn't even find 95 percent
of the references.
Now, how is the practicing physician going to know whether he is
really being had or whether they are proper references when he sees
this advertising or even when a detail man gives you a whole line of
references.
Dr. HA000D. Mr. Gordon, the only way I can answer this is from a
personal standpoint. Advertising in itself means very little to me, and
as far as checking on the references that are quoted in the advertising
material, I don't recall ever once looking into this because I use other
sources from which I have fOrmed my opinion, and, of course, I have
stated those in my statement here.
Senator NELSON. Again, thank you very much, Doctor, we appre-
ciate your taking time to come here.
Senator McIntyre.
Senator MCINTYRE. Thank you.
~ See app. II beginning at p. 4793, Infra.
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4320 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
I just want to say, Doctor, I read your statement last night and Ii
found it to be most readable and I consider it an excellent statement.
overall. I am not sure that you are representative of the average doc-
tor, but I certainly was impressed with it as a probative argument.
I think tha.t your decision to enter in the medical profession was
probably a loss that the legal profession had to sustain.
Thank you very much.
Dr. HAGOOD. Thank you, Senator, you are most kind.
I would like to make a statement if I might, please, sir.
Senator NELSON. Yes.
Dr. HAGOOD. First of all, I want to thank you for the opportunity
of coming before this group. To me this represents, and this gives
very positive evidence of, the great country that we have here. That an
individual from a little hamlet in our country can come before a corn-
mitte~e of the Senate of the United States of America and state his
views. I thank you very much for this.
Senator NELsoN. Thank you, too, Doctor. I think, it being my experi-
ence in committees of Congress, that almost all chairmen, given tha
time, are willing to hear all the viewpoints and try to get all the view-
points although sometimes some people around the country have an
impression we don't. But again thank you very much.
Dr. HAGOOD. Thank you.
(Whereupon, at 11:10 a.m., the committee was adjourned, to recon~
vene at 10 a.rn., Thursday, February 20,1968.)
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
THURSDAY, FEBRUARY 20, 1969
11.5. SENATE,
MONOPOLY Strl300MMIrrEE OF THE
SELECT `COMMIrEEE ON SMALL BUSINESS,
Washington, D.C.
The subcommittee met, pursuant to notice, at 10:10 a.m., in the Cau-
cus Room, Old Senate Office Building, Senator Gaylord Nelson (chair-
man of the subcommittee) presiding.
Present: Senator Nelson.
Also present: Chester H. Smith, staff director and general counsel;
Benjamin Gordon, staff economist Jay Cutler, acting minority coun-
sel; and Elaine C. Dye, clerical assistant.
Senator NELSON. Our witness this morning is Dr. Robert Moser,
chief, Department of Medicine, Walter Reed General Hospital.
Doctor, the committee is very pleased to have you come and present
your testimony this morning.
You have submitted your biographical background, which will be
printed in the record.
(The biographical sketch of Dr. Moser follows:)
CURRICULUM VITAE, ROBERT H. MOSER, COLONEL, MO, USA
Born: Trenton, N. J., 16 June 1923. Married to former Stella Neeson~ - 2 sons:
Steven, age 19'; Jonathan, age 16
College:
Loyola College of Baltimore, 1940-1942
Villanova College, 1942-1943 (B.S.)
Medical School: Georgetown University, 1944-1948 (M.D.)
Internship: District of Columbia General Hospital, 1948-1949
Residency:
Internal Medicine;
Fellow in Pulmonary Disease, D.C. General Hosptal, (Dr. Sol Katz)
1949-1950
Assistant Resident, Georgetown University Hospital, 1952-1953
Resident in Cardiology, Brooke General Hospital (with Colonel Weldon
Walker), 1956-1957
Associate Professor of Medicine, Baylor University College of Medicine,
1958-1959
Fellow in Hematology, Salt Lake City Hospital (with Dr. Maxwell M. Win-
trobe), 1959-19~30
Military:
U.S. Navy, December 1943-July 1948
U.S. Army, July 1948 until present
Chief, Department of Medicine, U.S. Army Hospital, Salzburg, Austria,
1953-1955
Chief, Department of Medicine, U.S. Army Hospital, Wurzburg, Germany,
1955-1956
Physician to the American Delegation "Foreign Ministers Meeting," Geneva,
1956
4321
PAGENO="0032"
4322 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Assistant Chief, Department of Medicine, and Director of Education, Brooke
General Hospital, 1957-1959
Assistant Chief, Department of Medicine, and Director of Education, U.S.
Army Tripler General Hospital, 1960-1964
Medical Flight Control Team-"Project Mercury"-participating in all
suborbital and orbital missions, May 1959 until termination of program
Command and General Staff College-1964 (Fall Associate Course)
Chief, Department of Medicine, William Beaumont General Hospital, Jan-
uary 1965-June 1967
Chief, Department of Medicine, Brooke General Hospital, June 1967-July
1968
Chief, Department of Medicine, Walter Reed General Hospital, July 1968-
Certiflcation-s: Certified in Internal i~Iedicine, 1955.
Organization~s.~
(1) American Medical Association
(2) Fellow, American College of Physicians, 1961-
(3) American Therapeutic Society, 1964-
(4) Assn. Mil. Phys. 1966-
(5) Bexar County Medical Society 1968
Journal Activities:
Book reviewer for Military Medicine, 1960-
Author of monthly column, "Diseases of Medical Progress" for "Clinical
Pharmacology & Therapeutics" Journal 1962-
Author of monthly column "Of Tomes and Tangents" for "Medical Opinion
& Review" Journal-July 1966-
Contributing Editor-"Medical Opinion & Review" 1966-
Editorial Board-"Mffltary Medicine", Jan. 1967-
Book Review Editor (Editorial Board)-"Archives of Internal Medicine."
`Jan 1967-
Author of bi-monthly column "The Training Scene" for "The House Physi-
cian Reporter", Sep 1967-
Consulting Editor of the Medical Annals of the District of Columbia Oct 68-
Committees:
(1) Consultant In Internal Medicine to Queen's Hospital, Honolulu, 1960-
1964
(2) Member, Advisory Panel of the Registry of Adverse Reactions, Council
on Drugs, AMA, 1960-1967
(3) Consultant to AMA Council on Drugs publication "New Drugs," 1966-
1967
(4) Consultant in Internal Medicine to "Medical Tribune," 1966
(5) Consultant in Internal Medicine to Manned Spacecraft Center, Project
Gemini, NASA and Member of Medical Evaluation Team, Project Gem-
ini-1964 until completion of project
(6) Consultant in Internal Medicine to Manned Spacecraft Center, Apollo
Project-1967-
(7) Appointed to AMA Council on Drugs, March 1968
(8) Appointed to Editorial Board, Medical Opinion & Review, April 1968
(9) Appointed Editor of American Lecture Series in Medical Writing and
Communication, Chas. C. Thomas Pub. Co., 1969
Teaching Aj~Uiatian~s:
Associate Professor, Baylor University College of Medicine, 1957-1959
Clinical Professor-Georgetown Univ Sch of Med 1968-
PuBLIcATIoNs
1. Diseases of Medical Progress, 0. S. Thomas & Co., Springfield, 1960.
2. Diseases of Medical Progress, 2nd Ed., Edited by Col. R. H. Moser and 12
co-authors. C. S. Thomas & Co., Springfield, 1964.
3. "Steroid-Induced Adrenal Insufficiency Aggravated by Severe Medical ill-
ness," Amer. J. Med. Sci., 239, Mar 1960.
4. "Back Door" Digitalis Intoxication: Review and Report of a Case, U.S.
Armed Forces Med. J. 11:391-402, Apr 1960.
5. "Renal Biopsy" 11:307-317, U.S. Armed Forces Med. J., Mar 1960.
6. "Malignant Carcinoid: Report of a Case Confined by Percutaneous Hepatic
Biopsy," Texas State J. Med., (Jul) 1960.
7. "An Atlas of Sternheimer-Malbin Staining Technique in Examination of
Urinary Sediments" What's New 218 (Summer) 1960 and 226 (Oct-Nov).
PAGENO="0033"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4323
8. "Diseases of Medical Progress-Report", Olin. Pharm. & Ther. 2:446-522,
(Jan) 1961.
9. "The Man in the Loop" Hawaii Med. J. 23 :109-113, (Nov-Dee) 1963
(Editorial)
10. "On Speaking to Patients," Ann. Tnt. Med. 51, (Sept) 1964.
11. "Congenital Inclusion Body Hemolytie Anemia Associated with Epilepsy
and Disordered Pyridoxine Metabolism," Blood 24, (Aug) 1964.
12. * "Of Plagues and Pennants," Mu. Rev.! 45:71-84 (May) 1965.
13. "Are Drug Hazards Overstressed," Issues 1 :1-14, (Dee) 1964.
14. "Man in Space," Southwestern Med. 1:45-48 (Feb) 1966.
15. "Hypertension and Hypercalcemia," Ann. Tnt. Med. 64:378-381, 1966.
(co-author)
16. "Malaria," Southwestern Med. 47 :213-219 (Aug) 1966.
17. "The Modern Aspect of Leprosy," Texas Medicine J. (Aug) 1966.
18. "Non-Spherocytic Hemolytic Ane'mia in Pyruvic Kinase Deficient Erythro-
cytes" (co-author) pending publication.
19. "Percutaneous Renal Biopsy in Chimpanzees" Am. J. Vet. Res. VoL 28,
No. 126, 1631-1634, Sep 1967 (co-author)
20. "Evidence for a Reservoir of Red Blood Cells in Man" by M. C. Nusynowitz,
R. L. North, R. H. Moser (submitted to J. Olin. Invest.)
21. "To the Physician-Soldier"-commencement address to Medical Field Serv-
ice School, August 1967.
22. Diseases of Medical Progress, 3rd Ed. Edited by Col R. H. Moser and
12 co-authors. 0. S. Thomas & Co., Springfield (pending publication)
2~J. Urinary Sediment Handbook, Clay-Adams, Inc., September 1968.
24. "latrogenic Disorders" Medical College of Virginia Quarterly 3(2) :91-100,
1967.
25. "ATP Metabolism in Pyruvate Kinase Deficient Erythrocytes" by Jeremiah
J. Twomey, Floyd B. O'Neal, Clarence P. Alfrey and Robert H. Moser Blood,
Vol XXX, No. 5, November 1967.
26. "Iatrogen Disorders" Animals and Clinical Pharmacologic Techniques in
Drug Evaluation edited by Peter E. Siegler, M.D. and Hohn H. Moyer, III, M.D.
Year Book Medical Publishers, Inc., Chicago, 1967.
27. Moser, R. H.: "Tatrogenic Disorders," in Proger, S.: The Medicated So-
ciety, New York, The Macmillan Company,: 1968.
28. "Hereditary Chronic Nephritis Complicated by Nephrotic Syndrome."
Arch Int lIed, 122:156 (August) 1968 (Co-author)
29. Moser, R. H.: "The New Ethics" in Kutscher, A. H.: But Not to Lose,
New York, Frederick Fell, Inc., 1968 (In press)
~0. "Prospective Epidemiology Studies," Drug Information Bulletin, p. 92,
July/September 1968
31. Editorial, "A Proposal from the Periphery," Military Medicine, 133:849
(Oct) 1968
32. "More . . . On Speaking to Patients" Medical Arts and Sciences, Vol 21,
2d Qtr, 1967
Senator NELSON. I have read your statement and I think it is an
excellent presentation. It makes a very fine contribution to the comrn
mittee's deliberations. :
You may present your testimony in any way you see fit. If you find
it best to read it, you may. If you wish to extemporize on any particu-
lar point, just feel free to do so. I assume that you have no objection
to us interrupting with questions, as they might occur to us.
STATEMENT OP Bit. ROBERT H. MOSER, OHIE~', DEPARTMENT OP
MEDICINE, WALTER REED GENERAL HOSPITAL, WASHINGTON,
D.C.
Dr. MOSER. Thank you, Senator Nelson.
Senator NELSON. Please speak into the microphone so they can hear
in the back of the room.
*Awarded "Military writing achievement" by Military Review.
81-280-69-pt. 11-S
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4324 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Dr. MOSER. At the outset, I would like to state that I am not a
clinical pharmacologist. My subsequent remarks, sir, represent my per-
sonal opinion as a practicing internist interested in the drugs I pre-
scribe. I am not speaking for the U.S. Army Medical Department,
nor for the AMA Council on Drugs, of which I am a member.
My interest in drugs has centered primarily around the problem of
adverse effects of drugs, drug interactions, and related areas.
Most of the comments I am about to make are quoted or paraphrased
from sections of books, chapters of books, and papers I have written
on this subject in the course of recent years.
The physician and his patient are the beneficiaries of the most dra-
matic expansion of medical capability in the long history of our art.
But the rapid proliferation of medical knowledge has not been entirely
bemgn.
Our reverses have been minor when contrasted to our advances,
but negative effects cannot be ignored or derogated.
Pertinent to this evolution of medical capability has been the im-
provement in quantity and quality of drugs. In the early days new
drugs came in a trickle. There was time for the physician to become
familiar with their virtues and idiosyncracies.
Soon the trickle became a stream and there was less time for study
and reflection. The stream has now become a torrent; it is impossible
for the physician to keep pace. One might say his little black bag
runneth over.
It has been stated that drug-induced adverse effects are the price
we must pay for more effective and better medicaments, and there can
be no quarrel with this statement; it is the high price we are haggling
about. The thalidomide disaster indicated how expensive it can be.
By last count there were 2,625 amelic and phocomelic children born
in West Germany-these were children with extremity deformities-
between 1958 and 1962. About 1,000 of these deformed children will
be obliged to remain under regular prosthetic care and supervision
for the rest of their lives; about 100 with the most serious deformities
will remain under medical supervision the rest of their lives. For-
tunately between 80 and 90 percent of the deformed children were in
school by the end of 1967, and 60 to 70 percent were attending regular
schools.
From the financial aspect, the Health Ministry of West Germany
has spent $2.8 million in research, treatment, rehabilitation, and de-
veloping facilities for the deformed children.
This sobering catastrophe had the effect of catalyzing international
concern about adverse effects of drugs, a sentiment of rather amor-
phous configuration before thalidomide.
It is true that each year a mere handful of important new drugs
ultimately emerge from the profusion of products offered to the phy-
sician. But it takes time and experience to sort out nuggets from
gravel.
Senator NELSON. May I interrupt you, Doctor, for just a moment?
Dr. MOSER. Yes, sir.
Senator NELSON. In 1968, according to the statistics our committee
has, there were 101 new drugs introduced, of which only 14 were new
chemical entities, and of these five new single drugs and two bio-
logicals had any significance. Do you have any comment to make
PAGENO="0035"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4325
about the great profusion of new drugs,: such as 101, of which only 14
were new entities?
What is the value of the other 90 or so drugs coming into the mar-
ketplace?
Dr. MosER. That's rather difficult to answer, sir. The problem is
that when a new drug emerges it is extremely difficult to figure out
what its ultimate place is going to be, and it does take time to sort
them out. It takes considerable clinical study before one can be sure
that this drug is indeed going to be a valuable contribution. It is a
bit more than the average physician can do without the help of some
fine investigators. I hadn't thought about 14 specific drugs, but I
would assume that is a fairly good average of what we would get each
year. The effective new agents do represent a handful.
Senator NELsoN. What about those 87 new drugs which are simply
the same chemical entities that are already in the marketplace now
introduced as new drugs in some other combination? What is the
pattern historically of the value of these new combinations?
Dr. Mosi~ii. Well, again, I think it is hard to generalize. I would
suspect that many such drugs come out as a result of competitive drug
manufacture. I don't know if combinations ever represent any signifi-
cant contribution. Chlorothiazide when it first came out was super-
ceded by hydrochlorothiazide. This was offered as a better drug,
but ultimately it turned out to be quite similar.
I can't cite specific instances, but I:think there are many cases where
these combination drugs add very much to our ability to take care
of patients.
Senator NELSON. Thank you.
Dr. MOSER. To continue, once the physician does manage to figure
out which of the new drugs are indeed valuable agents-and this is
not easy-the pressure may come from patients and often from one's
own peers, this pressure to try a new, unfamiliar compound-that
has been effectively merchandised-is an additional force to be con-
sidered in the therapeutic capability of the individual physician.
Yet I have observed an expanding spirit of skepticism and dis-
content with empiricism in therapeutics. I find more and more that
modern practitioners demand drugs that have proper credentials.
And this has precipitated a virtual renaissance in drug investigation.
The demands of the clinician to know more about drugs are being
met by increasing capaibility in the laboratory. New insight and ap-
preciation of the complexities of drug effects have come from several
diverse avenues of investigation. Percutaneous biopsy, which is a tech-
nique using a needle where one can get a piece of tissue from the lung,
liver, and so forth, and examine it on a microscope, electron microscopy,
and immunofluorescent techniques have-~which are techniques that
can be used to identify specific substances within tissues that have
been taken with biopsy, have resulted in dramatic revelations; the
mysteries of intracellular morphology and physiology in the living
organism has begun to yield.
Often, we are able to observe the specific site of drug action within
the cell and subcellular structures. In other areas techniques continue
to be perfected for assay of blood any tissue levels of drugs, intern'ie-
diate products, enzymes, and hormones and thus we have come to
learn more of the wonders and hazards of contemporary therapeutic
agents.
PAGENO="0036"
4326 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
The prdblems of adverse drug effects are many. Reduced to simplest
elements, when drug A is introduced into the body, ultimately it or
its intermediate products will be carried in blood and body fluids to
bathe virtually all cells of the organism.
The effects of drug A become perceptible only when the function
of certain organs is modified, by whatever mechanism, and this may
be either beneficially or detrimentally, to the point of producing
clinically perceptible changes, and it is by these phenomena that we
learn to characterize the nature of drug A.
Yet as we focus attention upon the anticipated response of a specific
organ (or organs), we are inclined to forget that drug A is also in
contact with other tissues of the organism. Effects in these areas are
not in immediate evidence, but subtle often nefarious influences may
be at work, which become manifested clinically, at a much later date.
Such long-range effects may never be correlated with the antecedent
administration of our drug A and if one were to add drugs B, C, D,
E, F, and so forth, one begins to appreciate the endless combinations
and permutations.
The identification of a significant adverse reaction follows a long but
familiar pattern. First, scattered unsubstantiated reports-and these
may come by hearsay, anecdote, word of mouth, in the cloakroom at
the hospital-are encountered, hinting that a certain drug has caused
a certain undesirable effect.
Then begins the tedious process of painstaking retrospective analy-
sis. Many suspected cases must be scrutinized, and perhaps, ultimately
the suspected culprit-the provocative drug will be revealed.
To depart from the text, there are several mechanisms wherthy this
is done. The most familiar, of course, is the FDA gathering of their
forms 1639 where any physician, who encounters an adverse re-
action may complete the form and send it to the FDA where it will be
plugged into their computer system. The AMA Council on Drugs also
collects similar types of reports from private physicians throughout
the country, which again will be introduced to their computer. And if
physicians in the North, South, East, or West~ all unrelated and un-
known to each other, seem to report the same kind of reaction occur-
ring with a specific drug, then the wheels are set into motion for the
beginning of an investigation.
Senator NELSON. May I interrupt you a moment?
Dr. MOSER. Yes.
Senator NELSON. How effective is the reporting system, that is, what
percentage of the doctors around the country who discover a side ef-
fect from using a drug, report it to the FDA or AMA Council on
Drugs?
Dr. MOSER. Senator, if you will bear with me, I will get to that
toward the end.
At this point one must follow with a meticulously controlled pro-
spective study which will involve provocative testing in animals and
often in men, before we can prove that indeed it was the suspected drug
that causes this difficulty. It is a tedious, frequently unrewarding proc-
ess. But it is the only valid technique currently available to medicine.
This is a shadow world of pathophysiology, where relation of cause
to effect is at best difficult to assess. I need only cite the stifi raging
PAGENO="0037"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4327
controversy over analgesics and renal disease to demonstrate this dif-
ficulty, and there are other problems.
Perhaps the most careful, definitive study of adverse drug reactions
is being conducted by Dr. Nelson Irey of the recently established Reg-
istry of Tissue Reactions to Drugs. In reviewing the firsl 509 cases
discussed in the new registry, Dr. Irey cited four principal areas of
difficulty in his investigations.
Senator NELSON. Who established the Registry of Tissue Reactions
to Drugs?
Dr. Mosi~n. This was a joint effort, as I understand it, sir. The reg-
istry is sponsored by AMA, Food and Drug Administration, PMA,
and NIH. But the organization operates independently, and Dr. Irey
is an outstanding scientist. They were in the old Army Institute of
Pathology, and at the present time they are in interim headquarters,
and I am told that they will occupy a wing at the new Armed Forces
Institute of `Pathology on the campus at Walter Reed when that build-
ing is completed. That is where the new headquarters for the Armed
Forces Medical Museum will be. Dr. Iiey told me several months ago
that that is where they ultimately will keep their registry.
So it is a very independent organization. I think it is a fine study.
Dr. Irey cited in one of his publications four principal areas where
he is having difficulty identifying these types of reactions. One, there
is incomplete time relationship between the drugs and the disease.
Second, in most instances there is a multiplicity of drugs admin-
istered (this makes it difficult to pin down which drug or drugs is
involved). Often there is a lack of objective means of demonstrating
a correct relationship between the drug and the reaction.
And, finally, there is a limited number of reaction patterns of the
body to the entire range of physical, chemical, and biologic causes of
disease.
In other words, the body has a restricted nunTher of ways in which
it can respond to harmful stimuli regardless of their source whether
it is bacteria or a drug or a climatic condition, et cetera.
The liver, for example, can only respond in a limited number of
ways. Very frequently it is extremely difficult to say whether a drug
or a virus has been the cause of a specific liver dysfunction, such as
hepatitis.
Thus, following the appropriately rigid criteria demanded by the
registry, it was observed that in only 8 percent could a specific drug
be definitely called the causative factor. In 40 percent it was con-
sidered to be "probable"; in 32 percent "impossible"; and in 15 percent,
"coincidental." In 4 percent there was no apparent relationship. The
contribution of drug interactions to this complex milieu will be
discussed later.
The widely quoted adverse reaction studies of Cluff and associates
at the Johns Hopkins Hospital has pointed up dramatically, the "ice-
berg" nature of this problem. This was an intensive prospective assault
on the question, conducted by highly motivated house officers; 714
such patients with adverse drug reactions were discovered during a
3-month period at the Hopkins.
Cluff has stated that 13.6 percent of patients acquired an adverse
drug reaction during the period of hospitalization, and the other re-
sults that he found were also rather astonishing.
PAGENO="0038"
4328 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. Are you saying 13 percent of all patients admitted?
Dr. MOSER. That is right; 13 percent of the patients who were in
the hospital came in with an adverse reaction or acquired one while
in the hospital.
Now, 4 percent of these patients were admitted to the general
medical services with an adverse reaction. This was the cause of the
mission, 4 percent. This was the admitting diagnosis. Of this particular
group 30.4 percent acquired another drug reaction during the course
of hospitalization. The Oluff team observed a 4.2-percent incidence of
reactions among patients who were receiving six to 10 drugs while in
the hospital, 24.2 percent with 11 to 15 drugs, 40 percent m patients
who were receiving between 16 and 20 drugs, and astonishingly, 45
percent of patients suffered adverse reactions who were receiving 21
or more drugs in the hospital.
Now, this may seem like a lot of drugs but anytime this fact has
been studied, it is found that many patients are receiving between 8
and 12 drugs while they are in the hospital, and this is a fair repre-
sentation of the drugs being given to individual patients in fine uni-
versity hospitals.
Now, in the Cluff study, antimicrobial agents (antibiotics), and car-
diac drugs were implicated most often, accounting for 21.2 percent of
all reactions each, or 42.4 percent of the total. Hypnotics, another
word for sleeping medication, and sedatives, produced 13.0 percent re-
actions; insulin, 8.9 percent; and antihypertensive drugs, 8.2 percent.
The clinical manifestations of adverse drug reactions were: gastro-
intestinal, 35.6 percent; neuromuscular reactions (muscle aches and
pains) 15.8 percent; metabolic disturbances, 13 percent; cardiovas-
cular disturbance, 11.6 percent; skin rashes, 10.3 percent; hematologic,
4.9 percent; renal, 3.4 percent, and multiple systems (this would be
heart, liver, kidneys, combinations of systems) were involved in about
2.7 percent. And, finally, pulmonary (that is, lung) and other mis-
cellaneous types of reactions accounted for 1.4 percent each.
About 7 percent of aU~ adverse reactions observed during this 3-
month period of study were life threatening or fatal, and five deaths
in this series were attributed to adverse drug reactions.
Over two-thirds of the in-hospital adverse reactions were detected
within 4 days after the causative drug had been started. Allergic re-
actions usually developed between the fifth and 10th day, and some
came on in an accelerated fashion. Nausea, vomiting, or diarrhea
were the most common manifestations, and these occurred most fre-
quently in women. Adverse reactions were more common in patients
over 50; whites suffered more than blacks; women more than men. The
average duration of hospitalization for patients with adverse drug re-
actions was 20.8 days. This is in contrast with 14.3 days for patients
on the medical wards.
This is a significant increase.
In another well-known study of adverse drug reactions performed
by five cooperating medical school hospitals in the Philadelphia area,
namely, Halmernann, Jefferson, Temple, Penn, and Women's 772
adverse drug reactions were reported during a 24-month period of
study.
In this study dermatologic and allergic reactions were the most corn-
mon and accounted for 65 percent of all case reports. Penicillin was
PAGENO="0039"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4329
suspected in 101 reactions; phenobarbital and digitalis preparations
in 21, and aspirin in 20.
In this study the overall incidence of adverse reactions was .49 per-
cent of all hospitalized patients for the first year of the study, and .41
percent for the second year.
And, incidentally, it was during this Greater Philadelphia study
that the first demonstration of a positive Cöombs test in patients taking
cephalothin sodium was detected.
The differences in incidence of adverse reactions between the Cluff
study, the Schimmel report (in which 10 percent of hospitalized pa-
tients suffered adverse drug reactions) the Greater Philadelphia pro-
gram, and others, may be related to techniques of data gathering and
definition of what constitutes an "adverse drug reaction."
For example, the Philadelphia group and Koch-Weser at the Mas-
sachusetts General Hospital required that for admission to their proto-
col, a reaction must be "severe enough to be commented upon in the
progress notes." And those familiar with the terse and often sparse
progress notes written by the busy house officer might consider this
to be a chancy qualification. Of course, this was not a determinant in
the Cluff and Schiminel studies where the incidence figures of adverse
reactions was much higher.
Finally, Cluff and Schimmel utilized a prospective method while
other groups used a retrospective method. In other words, they set
out to seek reactions on the wards while the others waited for them to
occur and be reported.
The problems of adverse reactions to placebos or spontaneously
occurring symptoms due to nondrug causes cannot be entirely dis-
counted, especially when one is evaluating minor reactions to drugs.
However, I feel it is equally safe to assume that for every ~patient
who becomes sufficiently ill with an adverse drug effect to trek to
emergency room or physician's office, there are perhaps 10 who will
not.
This is my own estimate.
Senator NELSON. In other words, are you saying that about One-
tenth, one out of 10 cases of drug reactions are reported?
Dr. MOSER. No, not quite that. One out of 10 drug reactions are
severe enough to bring them to clinical attention, to come to a doctor's
office or to come to a clinic. And I think it is fair to say that with non-
drug-induced illnesses it may be the same.But I think the point is that
adverse drug reaotions represent illnesses just like other diseases, and
the same ground rules apply. Probably one out of 10 come to clinical
attention, and that is a fair guess.
The reasons are plentiful: The reaction may be mild, one may fear
loss of time from the job, et cetera (the same reasons that one doesn't
go to see a doctor for a non-drug-related disease). At the present time
there are man~y studies underway throughout the country to gather
more meaningful data on this subject. And I will comment upon these
later.
Let's approach the problem from still another aspect. What is
known of the role played by drugs in predisposing the organism to
attack by micro-organisms or degenerative disease? One example is
the effect of long-term corticosteroids in predisposing the leukemia
or lymphoma patient to systemic fungus infections.
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4330 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
We have heard a great deal in medical literature about the so-called
"opportunistic organisms." I consider this a semantically poor euph-
emism, but that's not the point. It is important to our thesis to mention
the fungus Gandida aibican.s. This is one of a group of saprophytes.
A. saprophyte is an organism that is normally found in the gut and
usually does no harm; it is of limited pathogenicity under normal
circumstances.
Candida may emerge as a systemic infection and seed into man
organs during or following broad spectrum antibiotic therapy wit
or without concomitant cort;icosteroids or immunosuppressive drugs.
This phenomenon has been related to suppression of susceptible in-
testinal bacteria with disruption of the normal ecologic balance. Every-
one's intestinal tract exists in a state of balaiice between various groups
of micro-organisms. We acquire these as soon as we begin to live;
(literally), and they exist in symbiosis with the host throughout life.
However, when one gives antibiotics occasionally this balance will be
disrupted, and organisms that are not killed by this particular anti-
microbial agent may gain ascendency. They will proliferate and often
they will escape the intestinal confines, and if one is also receiving
corticosteroids or immunosuppressive drugs, this occurs at a time when
the normal defense mechanisms (to resist infection) are all but para-
lyzed, and one can get a systemic infection with fungus.
Another example is the devastating influence of prolonged-
Senator Nri~soN. Is there any drug that is effective against the
fungus?
Dr. MOSER. Yes. There is amphotericin B which is a fairly effective
systemic fungicide agent.
Another example is the devastating influence of prolonged corti-
costeroid therapy upon the elderly patient who is somewhat immobi-
lized by cardiovascular disease or arthritis. In these individuals accel-
erated demineralization is encouraged through the antianabolic effect
of corticosteroids. In other words, the corticosteroids will actually
accelerate the normal tendency of the bones to lose calcium and some of
their protein matrix. And again this is a classic demonstration of exac-
erbration, or making more severe, a degenerative process induced by
a drug. In this situation we start; with one disease, and our treatment
for it produces another disease.
Let's modify the question again. What is known of the effects of
drugs upon a previously diseased organ, with limited capability to
metabolize or detoxify or otherwise cope with a drug given to treat
another illness? Now, I have mentioned the phenacetin controversy.
The discussion here revolves around the status of analgesic compounds
in the provocation of a variety of interstitial kidney infection and
destruction of papillary tips of the kidney in a normal organ. This
is a longstanding controversy in which some of the analgesic drugs
are thought to be able to cause specific disease of the kidney. But this
discussion is about what they do in a normal kidney. And I ask what
effect does phenacetin or aspirin or caffeine have upon a sick kidney,
already poorly disposed to resist assault from either microorganisms
or nephrotoxic drug?
Mr. GORDON. May I interrupt here for a moment?
Dr. MosER. Yes.
Mr. GomoN. This is the APO tablets?
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4331
Dr. MOSi~R. Yes.
Mr. GORDON. These are also sold overthe counter without a prescrip-
tion? Isn't that right?
Dr. MOSER. Most of them have had phenacetin removed, according
to my information. I think there may be a few companies that still pro-
duce it, but I think most of the APC's have the phenacetin removed.
Now, I want to say that this is a far from settled business. I don't
mean to sit here and tell you that I know the answer to this problem,
because many fine people have devoted a lot of time to trying to work
this out. I don't want to take a stand on this because I really don't
know. Let us say that there is perhaps an increased mcidence of inter-
stitial nephritis and papillitis in patients who have taken a variety
of analgesic compounds. What the specific agent (or agents) is I don't
really know.
I would like to go on to discuss now the phenomenon of delayed
excretion of drugs or their active intermediate products (which we
call metabolites), by an organ which is already diseased. In this situa-
tion the unanticipated high blood levels introduce a whole new spec-
trum of toxic effects. And what happens to the diseased kidney of
itself, if the drug which it has been reticent to excrete, happens to be
specifically toxic to the kidney and then.becomes superconcentrated in
the countercurrents of the kidney medulla.
All this means is that in the lower part of individual kidney units
(in the lower part of the nephron) where there is exhaberant water
absorption, any product that is coming through the kidney will be
concentrated in this particular portion. And I pose the thought that
in the event that the drug which with we are dealing happens to be
nephrotoxic, the kidney may suddenly be receiving a very concentrated
dose of this particular drug. It is an interesting area.
Or, consider the patient with a subclinical liver disease-a mild cir-
rhosis, if you will. What happens when he is given halothane or chlor-
promazine or phenylbutazone, drugs known, occasionally, to be unkind
to the normal liver? What happens when it is given to a previously
diseased liver?
One could cite many examples wherein an organ with marginal
function may be further insulted by a drug administered, most inno-
cently, to treat another ailing system? The thought remains a continu-
ing source of uneasiness in all drug therapy.
The mechanisms of adverse drug reactions have been a subject of
many taxonomies, and I have selected one feasible classification as
modified from a paper by Long, and he lists seven classifications:
Hypersensitivity or allergy; idiosyncrasy; immunological injury;
enzyme induction (which means acceleration of the metabolism of a
drug), enzyme potentiation (or inhibition of drug metabolism), car-
cinogenesis (which means cancer), teratogenesis and mutagenesis,
which mean the induction of congenital conformities.
I don't feel it is pertinent to this presentation to delve in depth into
the mechanisms of drug interactions or specific physiologic mecha-
nisms that cause adverse reactions. However, a few general remarks
may facilitate understanding of some of the problems that beset the
practitioner in his effort to employ drugs effectively.
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4332 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
PHARMACOGENETICS
Perhaps the most fascinating new dimension in drug reactions was
the identification of a relationship between enzyme systems and drug
effects.
In 1959, Vogel introduced the term "pharmacogenetics" into clinical
medicine. This was defined as "the study of genetically determined
variations that are revealed solely by the effects of drugs."
The genetic aberration results in the absence or insufficiency of cer-
tain specific enzyme systems. This mechanism, the revelation of smol-
dering enzyme insufficiencies, has already been cited as one major ex-
planation of the extraordinary human variability in response to con-
ventional doses of conventional drugs.
Here we are discussing the effects of a single drug (A) upon a
patient with congenital or inborn disorder of a specific enzyme or
enzyme system. And I leave you to ponder the possibilities of what
might happen if the drug (A) inhibits or stimulates enzymes respon-
sible for the metabolism of Drug B or C. We will discuss this later in
more detail, but I would like to cite a few notable examples of the
phenomenon of pharmacogenetics.
The historical and classical prototype is the hemolytic anemia-this
is a variety of anemia where the red cells burst-suffered by some
members of certain ethnic groups, specifically Mediterranean basis
dwellers, rare Scandinavians, and Negroes, individuals who have a
quantitative or a qualitative deficiency of a critical enzyme that resides
in red blood cells. Brisk rupture of these blood cells may follow ex-
posure to many common therapeutic agents, and among these are cer-
tain antimalarials, certain sulfonamides, aspirin and perhaps a dozen
other so-called "oxidant" type drugs. Even our old nemesis, the medi-
cal student's friend, the notorious Fava bean, continues to kill a few
Sardinian children each year by triggering a catastrophic hemolytic
anemia on the same basis.
And I might add whimsically that the excitement generated by
the discovery that drugs could be employed to delineate specific
enzyme insufficiency syndromes has done a great deal to increase the
status of drug research as a respectable means of earning a livelihood.
It is very respectable to do basic research in enzymes. Now that the
drugs have been discovered to unmask such enzyme disorders, a lot of
people are becoming interested in drug research.
The cause of this red cell destruction is a genetically transmitted
defect that results in various degrees of deficiency, quantitative or
qualitative, of this enzyme.
These patients are clinically normal. They have no apparent, either
by appearance or by physiologic testing, abnormality of their red
cells, until one of the provocative drugs is given, and then they will
develop a brisk anemia.
Deficiency of this important red cell enzyme is somewhat of a prob-
lem in the chloroquine-primaquine antimalarial prophylaxis program
in Southeast Asia. Soldiers known to suffer the clinical manifestations
of this disorder are restricted from duty in endemic malarious areas,
because we don't want to give them the chloroquine or primaquine
tablets. .
And there are dozens of other fascinating pharmacogenetic dis-
orders, and new ones continue to emerge. If one reflects for a moment
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4333
upon the multitude of known enzyme systems as well as those suspected.
or latent or subclinical, but not as yet identified, one could predict that
many* drug effects that are now classified as idiosyncratic or even
allergic will gradually be herded in the fold of pharmacogenetic dis-
orders or perhaps enzyme insufficiencies that are acquired as the result
of disease.
DRUG INTERACTIONS
One of the more complex, fascinating, and disturbing areas of phar-
macology which has direct pertinence in any discussion of adverse
drug effects is "drug interactions." Efforts to establish a feasible
classification continue as new mechanisms, are discovered. Dr. Hart-
shorn defines drug interaction `as-and this is the best definition I could
find-"The phenomenon which occurs when the effects of one drug are
modified by the prior or concurrent administration of another-or the
same-drug (s). Drug interactions may arise either from `alteration of
the absorption, distribution, biotransformation, or excretion of one
drug by another or from combination of their actions or effects."
He makes a distinction between interaction and drug incompatibil-
ity. He reserves the latter form for reactions which occur either in the
bottle as one mixes two drugs or in the syringe before they are given
to a patient.
Dr. Irey has also been involved `in interaction and he lists another
classification of interaction in categories.
1. Interaction with other drugs or themselves. This is an induction
process.
2. Then `there may be interaction with endogenous physiologic
chemical agents. And the example here is monoaminoxidase inhibitors
and epinephrine.
3. Interaction of the drug with components of the diet, as in the
`administration of MAOI drugs with tyramine as one would get in
cheddar cheese.
4. Interactions with chemicals used in diagnostic tests or the results
of such tests. And an example of this would be the oral contraceptives
which may modify the glucose tolerance tests.
Two of the more fascinating aspects of drug interactions have to do
with enzyme induction `and enzyme inhibition, and I would like to
discuss these briefly, in turn, just to illustrate the magnitude of the
problem.
ENZYME INDUCTION .
Many drugs, when taken over a period of time, can cause `a marked
acceleration of their own metabolism or can accelerate the metabolism
of other drugs being administered concomitantly or subsequently. This
effect is mediated through stimulation of drug metabolizing enzymes
in the liver. This process is calle.d "enzyme induction," and it has be-
come an extremely important . aspect of drug toxicity. Induction can
lead to an escalating requirement for maintenance doses of a given
drug, each of which can be acutely toxic. .
Fortunately, most drugs do not involve enzyme induction, but it
must be conceded that not all drugs have been subjected to this rather
difficult and time-consuming type of testing. Nor is it known if all
individuals are susceptible to' enzyme induction by a specific drug.
And this brings us to another aspect of this effect. Not oniy may a
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4334 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
drug accelerate its own metabolism, but it may affect others. The ad-
ministration of drug A may stimulate hepatic enzymes which ac-
celerate the metabolic breakdown of drug B. If this phenomenon is
not appreciated and anticipated, it may result in lower than expected
blood levels of drug B.
I would like to show a. slide a.t this moment to illustrate this point,
if I may.
The point is this. Here we have a patient who comes to see a doctor.
The diagnosis is made, and the patient is started on a conventional
dose of this drug. He is given one gram a day. Over a period of time
over the next few days the patient gets the desired therapeutic effect,
and the patient is going quite well.
However, by the fourth day the patient is seen by another doctor
or by the same doctor and is then given drug B for some other
complaint.
Now, drug B happens to be a drug capable of causing mduction of
drug A. In other words, it accelerates its metabolism, and the blood
level of drug A rapidly falls off. So you see we have now a lack of
effect. The patient comes back to the original doctor and says, "Doc-
tor, I am certainly not getting the same response that I got from that
drug (A) you gave me." But she neglects to tell him that she is also
taking drug B,; so he increases the dose of the first drug (A). After
a few days she gets back up to the same therapeutic level, and then
for one reason or another drug B is stopped, and this was the drug
which was inducing and accelerating the metabolism of drug A. It is
gone and suddenly we have a patient who becomes toxic from drug A~
And if the physician does not know about this mechanism, he will
become very confused and may think that the drug is no longer
effective. And this is why enzyme induction is dreadfully important
to us.
The cardinal principle involved is that individual doses of drugs
may be required that are quite toxic in an effort to maintain blood
levels that were achieved with much lower does earlier in the course
of drug therapy. And the corollary is equally as important. One may
consider that a drug is ineffective, when the actual fact is that the
blood levels are too low, despite the administration of proper doses.
ENZYME INHIBITION
Now, the next phenomenon, one that is more familiar to physicians,
that is antithetical to the concept of enzyme induction and accelerated
drug metabolism. This is inhibition of the metabolic breakdown of
one drug by another with a potentiation of its effect.
And we have another slide to illustrate this.
Now, here we have exactly the reverse situation. The patient comes
in and is given drug A (drug A becomes more notorious as we pro-
ceed) and gets a therapeutic effect as anticipated.
At this particular time drug B is given by someone else. Drug
B in this situation, rather than accelerate the metabolism of drug A,
as occurred previously, now inhibits the metabolism. Therefore, drug
A remains in the blood stream longer than was anticipated, begins to
accumulate, and suddenly the patient develops toxic effects from
drug A.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4335
The physician at this point scratches his head and says, "1iVell, this
patient may be unusually sensitive to this drug." So he drops the dose
to half. And within a few days the blood level is back down, and the
patient has lost the toxicity desired. A few days later drug B is
stopped and inhibition of the first drug ceases. Now the physician is
giving this patient an inadequate dose and the loss of therapeutic
effect becomes evident. The importance is realization of the fact that
two drugs can modify the effect of one upon the other.
It is a fairly common occurrence, can cause great consternation in
any physician, if he does not appreciate this phenomenon. And we
are just beginning to appreciate the complexities of drug interactions.
There are several other mechanisms involved, and I will not go into
them in any great detail. Occasionally disease of the excretory organ,
such as the kidney, can be made worse by a drug. This may cause
inhibition of the excretion of another drug, and then drug B (the
second drug), will persist in the blood for longer than anticipated
periods of time.
Another mechanism is the physical displacement of drugs from
blood protein (carriers). Most drugs are bound by circulating pro-
teins, and therefore are relatively ineffective. They only become effec-
tive when released from their protein binding sites, and this is again
calculated into the dosage requirements. But if you give a second drug
that bumps the first drug off of its protein binding site, you will then
have more of the free drug A circulating, and in this situation you can
get toxicity.
DRUG EXCRETION
A few words about drug excretion seem appropriate. A prototype
drug involved in this problem of excretion is phenylbutazone, which
is an antiarthritic drug. When given in conjunction with a aceto-
hexamide, a popular antidiabetes drug, the phenylbutazone will
inhibit the excretion of the acetohexamide and one can get a higher
than anticipated level of the latter. This can cause very low blood
sugar levels and occasionally in an elderly patient can cause some
hypoglycemic shock.
A drug that is known to inhibit the excretion of penicillin, through
blocking kidney reabsorption, is probenecid. This is a drug normally
used to accelerate uric acid excretion.
Now, this is a beneficial effect. In this situation we frequently
employ penicillin with probenecid, specifically to maintain higher
blood levels of penicillin than normal. This is frequently used in
patients who have bacterial endocarditis with resistant micro
organisms.
RESIDUAL DRUG EFFECTS
Residual drug effects remain another enigmatic area. For example,
reserpine, an antihypertensive drug, continues to exert its influence in
certain patients for several weeks after it has been discontinued. And
it may cause unpredictable responses to general anesthesia. If the
anesthesiologist is not very careful, he may get into some difficulty
in the process of inducing anesthesia. It is a fine drug, but one must
know that it may cause these responses.
In another area, elevated levels c~f iodine bound to protein were
found to persist for 7 years in the sera of women who had received
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4336 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
iophenoxic acid, an agent used to take X-ray pictures of gall bladders
And babies born several years after their mothers had ingested this
dye had extremely high levels of protein bound iodine, although they
did not have any clinical manifestation of hyperthyroidism.
These agents may lie dormant in fat depots for many years, ap-
parently innocuous but in curious contradiction to the usual tendency
of the organism to rid itself of foreign substances.
One might ask what other drugs are stored for prolonged periods.
Do they exert adverse effects? One might summarize the complex prob-
lem of drug interactions with this final diagram. This is a Venn
diagram that I think summarizes the total picture.
It is a little hard to see, but the point can be made.
Here we have drug A at the top, drug B at the bottom. We have an
enzyme system as it is involved in the metabolism of drug A and
drug B, and finally we have the organ that is going to respond, the
organ we are trying to treat with this combination. It is not just a
simple matter of two circles, drug A and drug B acting upon the
end organ. They are involved quite intimately with each other, with
the enzyme system and with the end organ. And one could add on
a whole sequence of circles that would intersect at various levels if
you wanted to add enzymes B aand C which may be involved in the
interaction. And all organs of the body are going to be involved. The
physician is dealing with this, the middle of this complex situation,
and therefore when drugs are being given it is not just a simple matter.
It can be a rather complex business.
WHAT DOES ALL THIS MEAN?
Now that we have seen something of the broad introductory area
of drug-induced diseases and drug interactions, a logical question
might be, what will be the ultimate effect of these new therapeutic
endeavors? And the answer must lie somewhere in the interface be-
tween philosophy and physiology.
The evolution of man is a continuing source of wonderment to stu-
dents of physiology. Through the centuries of evolutionary meta-
morphosis, each challenge thrown at man by his environment was met
by gradual genetic modulation that enabled him to survive. The
species have arrived at the current state of advanced physiologic
capability, admirably adapted to its environment.
We can dig diamonds at 9,000 feet in 123 degree heat and 100 per-
cent humidity; we can spend a lifetime niinmg tin at 14,900 feet
elevation; we can hike across the pole, and we can float weightless for
14 days in space.
But in the past few decades we have devised methods unprecedented
in the entire previous experience of the species to challenge the adapt-
ability of the organism. We have designed molecules unique to human
physiology and insinuated them into blood and tissue by techniques
that are also unique physiologic experiences.
Intravenous, intramuscular and subcutaneous injections, positive
pressure inhalation, rectal administration, and agents facilitate
passage of molecules through intact skin-all are unfamiliar modes
of gaining access to the body.
Add radiation-by X-ray, beta ray, gamma ray and neutron, plus
oxygen under greatly increased barometric pressure, and some other
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4337
modalities that I have doubtlessly forgotten-and one `begins to ap-
preciate the magnitude and genius of man's conspiracy to bypass the
conventional avenues for introducing new environmental factors to
the physiology of man.
In the past we only had to cope with naive nature and misubtie
environment. And they were confined to the gastro-intestinal tract,
lungs, and occasionally the abraided skin, as avenues of access for
alien materials to get at the core of man.
The implications of these ingenious tactics of assault, these strange
manmade chemicals and emanations upon the beleagured human
mechanism are fascinating to contemplate. One could speculate that
this incredibly resilient physiologic engine of ours is sufficiently ad-
vanced in design `to be able to cope with `all environmental
transgressors.
We have evolved defenses at all `levels from the simplest reflex to
the most complex immune reactions to meet the daily challenges of
environment. And we have done very well in the matter of self-
preservation.
Yet it is quite evident that some of these unprecedented therapeutic
intrusions overtax the ability of the body to accommodate-and it
will react with displeasure, if not violent rejection. And, of course, this
is the heart of our thesis-drug-induced diseases.
CONCLUSIONS
Adverse Reaction Reporting
At this juncture I feel obliged to reiterate that these observations
I am about to make are my own and do not necessarily reflect the
opinion of the Army Medical Department or the AMA Council on
Drugs.
Drug-induced disorders will be with us forevermore. They cannot
be swept under the rug either by clinician or drug producer. My own
naivite in the world of commercial enterprise is revealed by my admis-
sion t'hat I think a fine new `drug will become known to the profession
on the basis of its merit. I am embarrassed when this noble commodity
is demeaned by merchandising techniques, however subtle or artful,
better suited to less vital products of commerce.
I do not feel that drugs shOuld be propagandized to the medical
profession. The pressure of commercial competition is not conducive
to objectivity in the presentation of drug detailmen or in published
advertisements. I feel that these factors add to the confusion in
the already difficult problems of evaluating the efficacy and/or adverse
effects of new drugs.
The requirement for an impartial agency that can provide current,
reliable and objective data about the characteristics of new drugs,
and alert the physician to their beneficial effects and toxic hazards
is abundantly evident.
Senator NELSON. We have had testimony similar to your statement
about the advertising and promotion of drugs. On the other hand,
we have had claims by some doctors and the industry th'at promotion
by detailmen is the most effective way of informing the American
medical profession that the drug does exist.
Are you satisfied-I take it you are, from your statement-that if
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4338 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
there was not this wide drug promotion by advertising in medical
journals and by promotion by detailmen that the medical profession
would discover the drug and its merits and its appropriate uses just
as well.
Dr. Mosi~ii. Yes I do. And I will speak to that as we progress.
I will briefly summarize some of the efforts that have been made
in this area. Both AMA and the FDA became immersed in the busi-
ness of trying to obtain data on adverse drug reactions. The AMA
had a potential information source of over 7,000 hospitals and 250,000
physicians. How many reports were received? The total as of Decem-
ber 1968 was 8,733.
Senator NELSON. From what date to what date?
Dr. MOSER. I think the study actually began in the early 1960s
with the registry on blood dyscrasias and is still going on.
At times the quality and the accuracy of these reports was appalling.
However, the original registry on blood dyscrasias fed information
back to the profession in the form of semiannual tabulations. And
these provided much helpful information. For example, knowledge
of chlora.mphenicol and dipyrone toxicity was documented and f a-
cilitated through this mechanism.
Senator NELSON. We had rather extensive testimony here by a
number of distinguished experts on the misuse or the use of chloram-
phenicol for nonindicated cases. Testimony, unrefuted thus far at
least by any witnesses, including the drug industry was that anywhere
from 90 to 99 percent of the patients who received chloramphenicol
received it for nonindicated cases.
Now, if the toxicity of chloramphenicol was documented, why was
there a failure to convey this information adequately to the medical
profession?
Dr. MOSER. I can't answer that, Senator. I think the informabion
has been abundantly available from many sources.
I am familiar with Dr. Best's report that received fairly wide
dissemination in the Journal of the AMA and there has been informa-
tion in the the Medical Letter. Virtually every publication that has
come out in recent years has carried admonitions about careful selec-
tion of indications in the use of chloramphenicol.
It is difficult for me to understand how this information is not
very broadly used. And I would be inclined to think-at least let's
say I hope, that this misuse of chlormaphenicol is limited to a very
few physicians. The actual indications are quite restricted and if the
drug is used without proper indication, it is very bad. It is dreadful.
I can't answer your questions as to why it continues to be used
without proper indication.
Senator NELSON. Well, if the testimony and the information we
have is correct, approximately 4 million people are prescribed chlo-
ramphenicol annually. We have had estimates here from-I am not
attributing this estimate to any one of these people-Dr. Dameshek
from Mount Sinai, Dr. Best, Dr. Lepper, and two or three others,
that anywhere from perhaps 10,000 or 15,000 to 20,000 out of the 4
million received this drug for an indicated case. This seems to me
to involve a tremendous amount of misprescribing; if it is 4 million,
the other 3,900,000 shouldn't have received it at all.
Have you followed, have you noticed, the advertising in the medi-
cal journals of chlormaphenicol?
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4339
Dr. MOSER. No, sir. I must confess that for the last several years
I have not been reading the journal advertisements.
Senator NELSON. If a doctor opens up Goodman & Gilman, or any
such source of information, and reads any `article on the use of
chloramphenicol, he will probably find that the specific limited indi-
cations of its use are listed very carefully, The package inserts that
go with the medicine, which probably most doctors don't see because
it goes to the pharmacist, lists the indicated uses and precautions
and dramatic side effects in certain instances.
What I am curious to find out, if all this information is available,
why has it been so widely misprescribed, if the testimony of these
doctors is correct?
Dr. MOSER. Of course I cannot answer that, but one partial explana-
tion resides in the fact that the average physician, in `the course of a
lifetime, may never see a case aplastic anemia. The incidence has been
quoted at from 1 in 20,000 to 1 in 100,000 administrations of chloram-
phenicol. The rationale, as far as I can figure it, is that a physician
may say, this is so rare it just isn't going `to happen to me.
And chloramphenicol is a good drug. It is quite an effective drug.
In fact, it is one of the most effective oral antibiotics tha't we have.
Unfortunately, it has this potentially `devastating complication.
I suspect that a physician will be tempted to prescribe this drug
when it is not absolutely indicated because he just hasn't seen a case
(aplastic anemia) himself. And there is a great tendency in medicine
to rely on one's experience. This is dangerous; that is why we have the
medical literature.
Senator NELSON. I think there is a problem with that statistic from
the California study, which was about I in 20,000, I believe, nobody
knows what percentage of cases are reported. Obviously, if a doctor
uses it for acne, sore throat, headaches, upper respiratory problems,
gum infections, hangnails, all of which are specific cases for which
it has been used, and aplastic `anemia results, which it has in all of
these cases, he is not going to report it when he is liable in a lawsuit
for the damage done. And there have been some very dramatic law-
suits in the past and many on the way now. We have `testimony from
doctors here that nobody is going to report that themselves.
So when you say 1 in 20,000 it may be 10 or 15 or 100 times that
figure. The figure is high, but even so, even though the testimony is
that it is an `excellent drug, it is for such a limited number of indica-
tions that if you just read it once, you wouldn't use it as a broad spec-
trum `antibiotic for which it obviously is being used.
Dr. MOSER. I do not feel that chloramphenicol should ever be used
outside the hospital. It is a drug that should be used on inpatients for
the treatment of very specific infections.
Senator NELSON. Thank you.
Dr. MOSER. Now, getting back to the discussion of the compilation
of adverse reaction data, the AMA Registry continued to gather and
tabulate its information until 1964, when it was decided that the data
should be transferred to computer storage. And unfortunately this
conversion never came to fruition. Also `an'ticipated plans for free com-
munication between the AMA and the FDA programs also never
achieved a working reality. Through both programs it has been eet~-
mated that roughly 1 percent to 2 percent of adverse re,n,etioiiq th~ t,
81-280-69-pt. ii-4
PAGENO="0050"
4340 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY
were occurring in the United States were being reported. The FDA
continues to receive reports from about 85 hospitals, mostly military
and Federal, throughout the country.
The AMA Registry continues to receive reports from interested
physicians who detect adverse reactions. At the present time, the coun-
cil on drugs of the American Medical Association is in the process of
devising an elastic prototype program that will enable hospitals of
every size and mission to establish ongoing studies on adverse drug
reactions and drug utilization practices.
As a working member of this committee, I can assure you that prog-
ress is being made. If such machinery can be established-and we
have every reason to believe that it will be-and the data gatherin
made painless for the physician, yet pertinent to the statisticians, an
we begin to help physicians learn more about drugs, this will cer-
tainly be worth the effort.
At this point I would like to say a word about the hospital
pharmacist.
In this schema-and that's the one that we are devising for the
AMA council to begin to do drug utilization studies-the hospital
pharmacist will play an essential role. Under optimal circumstances,
he should be integrated into the therapeutic team as an active mem-
ber. While I feel it is inappropriate to have pharmacists participate in
patient care decisions-an area which should remain the exclusive prov-
ince of the physicians-pharmacists should serve as therapeutic ad-
visers. The treatment of a patient includes too many variables beyond
drug therapy. Social and psychologic perturbations, in addition to
physiologic disruptions, add up to escalate the problems of "treat-
ment" to a plane beyond consideration of drug therapy per se.
Nevertheless, the pharmacist has a vital role. In our hospital, phar-
macists are active members of the therapeutic agents board and the
drug utilization and adverse drug reactions committee. Teams of
pharmacists visit all wards of the hospital twice each week and contact
individual ward officers to inquire about adverse drug reactions that
have occurred. The pharmacists then complete the FD 1639 form from
information derived from the patient's chart and from direct com-
munication with the responsible ward officer.
The FDA forms are reviewed by our drug utilization and adverse
drug reactions committee, whch consists of one physician and three
pharmacists; the pertinent data is presented at the next meeting of the
therapeutic agents board, and then copies of FD 1639 are forwarded
to the FDA and to the Army Surgeon General's Office.
In the future it is anticipated that our hospital, the Drug Utiliza-
tion and Adverse Reactions Committee, will conduct drug utilization
studies and ultimately drug efficacy studies.
In addition, the pharmacists-and this is the case at Walter Reed-
maintain a ready file of FDA adverse reactions reports as a rapid
information source for physicians. They also maintain current files
of books and journals-available to physicians for immediate infor-
mation on drugs, including efficacy, interactions, and toxicity.
Thus the pharmacist, with his special interest in pharmacology,
has become an essential, permanent member of the therapeutic team.
A logical question at this juncture might be, "What is the source of
drug information utilized by most prescribing physicians ?"
PAGENO="0051"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4341
And I would like to preface my remarks by saying that I look upon
all these statistics with some concern. The validity of a response by a
given physician to this type of question from my personal observation
is not necessarily candid.
In one famous national survey sponsored by the Pharmaceutical
Manufacturers Association, the principal sources of drug information
utilized by physicians was investigated: 61 percent said that they
received the information from the Physicians' Desk Reference, a
publication distributed free by the pharmaceutical industry; 37 percent
of physicians said they received their information through personal
experience and knowledge; 27 percent through journals and medical
periodicals, and 19 percent from detail men. Other sources consisted
of colleagues, consultants, medical society meetings, medical literature
textbooks.
Compendia and drug reference books were the source utilized by
10 percent.
Senator NELSON. Didn't any doctor attribute his information to
a drug ad?
Dr. MOSER. I assume that that was, sir, included in the 27 percent
who said their information came from journals and medical period-
icals. This was my assumption. It may not be valid.
Response to the question of the relative frequency with which
sources of drug information were used: The Physicians Desk Refer-
ence was used by 82 percent; the Medical Letter by 2 percent, the
Merck Manual by 2 percent. And there were 19 percent of the physi-
cians in this group who had never heard of the Medical Letter.
One could quote many other studies done by private organizations
which usually reveal that the principal source of drug information
is derived from publications or visits that have their source material
derived from the commercial drug industry.
On the 5th of February of this year, I had the privilege of partici-
pating in a meeting that was concerned with the problem of continuing
education of physicians with regard to drugs. This meeting was held
under the auspices of the Drug Research Board of the National
Academy of Sciences in conjunction with the Food and Drug Admin-
istration and the regional health medical program of HEW. They
had gathered about a hundred distinguished scientists from many
disciplines representing clinical medicine, pharmacology, sociology,
and psychology.
They were a conscientious, perceptive, dedicated group of men and
women. From 9 o'clock in the morning until 10:30 that night we ham-
mered away at the problem. It was quite reminiscent of other similar
sessions I have attended in the chambers of the American Medical
Association, Council on Drugs in Chicago and several other meetings
throughout the country in recent months of equally concerned groups.
And the theme was always the same.
We have a problem: There is urgent need to improve our methods
of transmitting drug information to prescribing physicians at all
echelons of medicine. And invariably at this point the discussion
falters and usually founders on the matter of methods.
Some have suggested a drug compendium, a sort of grand formulary
that would contain authoritative, current information about all drugs
that a contemporary physician might seek. This, they say, would be a
PAGENO="0052"
4342 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
significant first step. I feel a drug compendium would just be another
big book that would gather dust on the shelf, standing next to several
other unread tomes containing authoritative current information on
drugs.
Others have championed the concept of a cadre of therapeutic con-
sultants, a group of well-trained, practical-minded, clinical pharma-
cologists based at university teaching centers who would size up the
needs of their local area and assist physicians or local hospitals in
establishing practical programs on clinical pharmacology and
therapeutics.
Still others have suggested periodic medical examination with
successful passage being a requisite for relicensure.
I have personally favored the program I mentioned earlier, of
activating or revitalizing therapeutics boards in hospitals of all sizes
by initiating a program of continuing drug utilization surveillance.
This would be a hospital committee that would undertake periodic
review of therapeutic practices by individual members of the staff
as a means to improve therapeutic practices.
Senator NELSON. What would you do about the doctor who is not
hospital affiliated?
I think we had testimony that. over one-third of the doctors in New
York City have no hospital affiliation. And then you have t.housands
and thousands of others in rural areas or in cities who have no hospital
affiliation. What is their source of information?
Dr. MOSER. Well, the cadre concept that has considerable appeal
would bring such men into this program. The clinical pharmacologist
who is based at the imiversity hospital would work not only with the
local hospitals but actually get out in the community and visit these
physicians. Or, he will train others who will go out and do that sort
of thing.
Physicians who are not hospital affiliated are a very difficult group
to reach. I suspect that a personal type of approach would be the only
way that they could be reached.
Another possibility would be that therapeutics agents boards in
regional hospitals-and I am speaking of small hospitals of 75- to 100-
beds. Such local hospitals could periodically invite these unaffiliated
men in for sessions where they could give them information on con-
temporary advances in therapeutics.
I think these are all difficult things to do, and this unaffiliated group
is indeed the hardest to reach.
I feel that all too often these individuals have been unduly singled
out for criticism; I think that many of them are superb clinicians
who do a very fine job. Many of my own acquaintances are men who
are almost obsessive, compulsive readers. They keep themselves cur-
rent because they know they are isolated, and these represent a sig-
nificant proportion of American practitioners. I think what we are
talking about is a minority, and I don't know how we can reach them.
You can lead a horse to water but it is very hard to make him read.
Senator NELSON. What single objective source is there in the litera-
ture for a doctor to refer to?
Dr. MOSER. I will get to that.
Each of the plans that I have mentioned have their merits and its
failings, as we have been discussing. The basic need is to motivate the
PAGENO="0053"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4343
busy physician to learn more about the drugs he is using. And this is
the heart of the problem. As I said, I feel that most physicians practice
rational medicine. As a group they are intelligent, empathetic indi-
viduals, dedicated to the welfare of their patients. And I think we
are speaking of a noisy but certainly an important minority.
In this same breath, I feel obliged to emphasize that effective drug
therapy represents only one facet of the problem of postgraduate
medical education in the United States. Admittedly, a proper knowl-
edge of drugs is terribly important, but what about information about
new diagnostic techniques, new physiologic principles, even new dis-
eases and syndromes. The proliferation of medical information is not
confined to therapeutics alone. If one were to solve this far broader
problem of total continuing medical education, the enlightened use
of therapeutic agents would fall into place.
Now, several months ago, in my column "Tomes and Tangents,"
which I write each month for the journal, Medical Opinion and Re-
view, I outlined such a plan for continuing postgraduate medical edu-
cation which I consider practical and feasible.
Mr. Cumi~. I was just wondering, would the availability of the
price information be helpful to the physician on drugs?
Dr. MosER. I don't quite understand-in what context?
Mr. CUTLER. In the context of prescribing medicines in the hospital,
if he knew the cost of the individual drugs, price of one drug as op-
posed to another.
Dr. MOSER. Are we talking about physicians in the hospital or out-
side of the hospitals?
Mr. CUTLER. In either instance.
Dr. MOSER. I think it would be a factor, but I don't think it would
be the sole factor. I think the most important thing that makes a
doctor select a drug is will that drug work for him.
Now, if you show me two drugs; one is cheaper than the one I use
now, better, and you can prove to me that the cheaper drug is just as
good as the other, I will certainly switch. But if you come and say that
these drugs are the same, but you cannot document this to me, I will
not go for the cheaper drug. And I think this is common sense.
Senator NELSON. Your hospital has a formulary, doesn't it?
Dr. MosER. Yes.
Senator NELSON. And you have a formulary committee and your
hospital buys drugs on bids, I take it.
Dr. MOSER. Yes.
Senator NELSON. So that answers the question raised by minority
counsel in the seuse of cost to the patient, because all, I think all of the
leading hospitals that use a formulary, have their own pharmacist and
pharmacologist and their own clinical experience to draw upon and
decide whether or not they are therapeutically equivalent and then
accept the bids. And they may very well select the lowest bid or will
select it, I assume, if they decide it is equivalent to all the rest of
them.
I think the question raised by minority counsel refers to the fact
that a practicing physician who isn't practicing with the use of a
formulary in a hospital doesn't have that advantage. He does not
know what the price is probably, or doesn't have the backup of a
formularly committee that has evaluated the use of the drug.
PAGENO="0054"
4344 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
I think that is the point that he is making.
Dr. MOSER. Well, I am certainly not qualified to speak from the
aspect of a physician in private practice because this is not my area,
but it would seem quite logical that a physician who is working in a
community would know what the prices are on the drugs that he uses
arid have some feel for competitive pricing. But again, I am speaking
with lack of personal experience.
Senator NELSON. That really doesn't help the physician in private
practice in many instances because brand name identification is such
that the only drug being prescribed is the brand name version. To use
the example of prednisone, the market is dominated by Meticorten
and is usually the one that the doctor prescribes. The Medical Letter
listed 22 versions of this drug which were tested and then using the
advice of their clinicians around the country concluded that they were
all equivalent.
The price range was from Meticorten at $17.90 a hundred tablets to
the pharmacist to Paracort at $17.88 a hundred to Merck's $2.20 to
$1.80 to others at 59 cents. But you very seldom find the lower priced
drugs in the drugstore because no one writes that on the prescription.
They write Meticorten.
That is the problem here. So the patient is paying up to $33 to $40
for 100 tablets when he ought to be getting it for maybe $2.
That is the kind of problem I think minority counsel was raising.
Dr. MOSER. Sir, if that physician was getting the Medical Letter, he
would know that, you see.
Senator NELSON. That's one of the problems, of course. The Medical
Letter, from all the expert testimony we have, is a superb source of
information, but I think the circulation is about 35,000 out of over
300,000 physicians.
Dr. MOSER. That is true, and I am about to comment on this matter.
This column that I spoke of, details this program of continuing
postgraduate medical education, which I would really like to stress.
This may not be the proper platform for this particular discussion.
Senator NELSON. Yes, it is. We have had testimony along that line
previously and it is the right forum.
Dr. MOSER. I think all of us interested in medical education feel
very strongly about this. The subject of therapeutics simply cannot
be divorced from the big picture. It is perhaps the most essential aspect,
but it must be included in the broad concept of continuing postgradu-
ate medical education, which represents the most significant problem
facing medicine today.
Senator NELSON. The lack of it?
Dr. MOSER. Sir?
Senator NELSON. The lack of adequate postgraduate education.
Dr. MOSER. I think that continuing postgraduate medical education
should be a prime concern of all American physicians and all educators.
Let's get back to the subject of what sources does the average physi-
cian have to find out about new drugs.
As I said before, it is my conviction that every physician who treats
patients should subscribe to the Medical Letter.
For $14.50 a year-less for House officers-one can obtain current,
unbiased, candid information on new drug efficacy and toxicity.
This publication arrives about twice a month. It can be read and
digested in about 15 minutes. It comes in looseleaf form and can be
PAGENO="0055"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4345
filed with ease and the data retrieved with facility. Index issues arrive
about four times a year. In addition, I would suggest that every pre-
scribing physician own "Drugs of Choice" by Walter Modell, which
comes out every other year, or "Current Therapy," by Howard Conn,
which comes out every year, and one good current pharmacology text.
Sometimes in 1969, the comprehensive "American Medical Associa-
tion Drug Evaluation" book will be available. This should serve as a
most valuable adjunct to the physican who desirees to learn about
drugs and should quell all dialog about the compendium. Of course,
I would be delighted if everyone purchased a copy of my third edition
of "Diseases of Medical Progress." But with this cluster of books
within pivot-and-reach distance of his prescription pad, any physician
will possess all the basic tools he needs to keep abreast of new drug
developments and revised concepts of old drugs.
Gentlemen, drug information is abundantly available. The problem
resides in kindling the initiative-in firing up the enthusiasm to get
physicians to reach for that information.
Our remarkable therapeutic arsenal is a tribute to the commercial
drug industry and the devoted chemists and pharmacologists of our
medical schools. But neither AMA, FDA, nor the industry can solve
the problem completely.
For the past 15 years, in lectures and articles my plea has been
directed to the physician on the firing line, the doctor who prescribes
the drug. It is farthest from my intention ever to suggest therapeutic
timidity or homeopathy. Our predecessors in medicine had limited
diagnostic and therapeutic resources.
The complement of nostrums in their little black bag was austere,
but those drugs were regarded as old familiar friends. Some were
worthless, others were dangerous; some were impure and unstand-
ardized to the point of unpredictability.
The few effective drugs were trusted allies whose strengths and
weaknesses were well known. The practitioner of the past attempted
to compensate for lack of material resources with meticulous attention
to his patients, personal charm, kindness and above all, a pervading
equanimity.
His lonely hours of private hell, when he was tormented by his
inability to come to grips with most of the severe illnesses that he
encountered, constitute a long, bleak chapter in medical history.
The modern physician is afforded rare glimpses of this agony when
faced wih terminal malignancy or severe degerenative disease or
irreversible neurologic illness. Modern pharmacology has brought this
unhappy era to an end, and today we enjoy the privilege of fine, power-
ful, well standardized therapeutic weapons.
Now we must work to create an atmosphere of rational caution and
critical evaluation, where each physician will pause before putting pen
to prescription pad and ask himself, "Do I know enough about this
drug to prescribe it? Does the possible benefit I hope to derive from
this drug outweigh its potential hazard ?" I do not preach nihilism but
rather therapeutic rationalism.
Thank you.
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4346 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
(The attachments to Dr. Moser's statement follow:)
TABLE NO. 1.-SOURCES WHICH SERVED AS THE FIRST NOTICE TO DOCTORS OF THE AVAILA~LITY OF NEW
DRUGS CONFERENCE ON CONTINUING EDUCATION FOR PHYSICIANS IN THE USE OF DRUGS
Source
Percent of doct
ors naming as fi
rst source-
Caplow and
Raymond
Ferber and
Wales
Coleman,
et al.
Detail men
Medical journals:
Articles
Advertisements
Direct-mail advertisements
Colleagues
Medical meetings
Others
Number of doctors answerIng
31
19
6
16
14
`
7
~
38
25
19
6
~`
8
52
9
22
10
~
3
100
100
99
182
328
87
Sources: Caplnw, T., and Raymond,J.J. Marketing 19:18-23 (July) 1954 Ferber, R., and Wales, H. G.: `The Effectiveness
of Pharmaceutical Promotion, Urbana, II." 1958, P. 22. Coleman, J. S., Katz, E., and Menzel, H. "Medical Innovation" A
diffusion study, Indianapolis, the Bobbs-Merrill Co., Inc., 1966, p. 59.
TABLE NO. 2.-SOURCES WHICH LED TO FIRST USE OF A DRUG
Source
Percent of
doctors namin
g source
Coleman and
others
Ferber and
Wales
Gaffin
Detail men
Medical journals:
Articles
Advertisements
Direct mail advertisements
Colleagues
Medical meetings
Others
Total
Number of doctors answering
5
2 42
2
14
28
8
1
21
28
18
13
4
16
1 41
15
26
~
2
9
100
100
100
87
328
1, 011
1 Some doctors named more than 1 source. Percentages have been adjusted to 100 percent
2 This includes professional journals (21 percent) and periodicals published by drug companies (21 percent).
Sources: Coleman, J. S., Katz, E., and Menzel, H.: "Medical Innovation: A diffusion Study," Indianapolis, The Bobbs,
Merrill Co., Inc., 1966, p. 59. Ferber, R. and Wales, H. G.: "The Effectiveness of Pharmaceutical Promotion," Urbana, III-
1958, p. 24. "Attitudes of U.S. Physicians Toward the American Pharmaceutical Industry," Chicago, Ben Gaffin & Asso-
ciates, Inc., 1959, p. C-13.
TABLE No. 3.-What is the most important source of drug information?
Percent
Detail men 68
Medical meetings -
Journal advertisements 32
Direct mail advertisements 32
Collea~ies 24
Journal articles 20
Senator NELSON. I would like to ask just one general question about
drug combinations which have come into wide use.
We had testimony-and I will just quote a statement or two-from
Dr. Calvin Kunin, of the University of Virginia Medical School,
before this subcommittee in part 2, page 731 of these hearings:
A careful review of ftxecl-branded combinations on the market, including com-
binations of penicillin and sulfonamides, penicillin and streptomycin, tetra-
cycline, and antifungal agents and tetracycline and novobiocin, does not
PAGENO="0057"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4347
substantiate claims that the combination is superior to one of the agents used
separately. These combinations are expensive, deny the physician flexibility in
dosage, are primarily promotional devices, and have the inherent problem that
the patient undergoes the risk of serious adverse reaction to two or more drugs
rather than to a single defined agent. The physician cannot determine which
component is causing trouble if a bad reaction is encountered. I personally
believe that we would do much better without these preparations.
Then, as you know, the National Academy of Sciences under the
Kefauver Act of 1962 has under review all of the drugs manufactured
prior to then, and they have been making recommendations on vari-
ous combination drugs that have been in the marketplace for a long
time suggesting their-recommending their removal.
On Panalba, which is a combination of tetracycline, phosphate com-
plex, and novobiocin sodium, evaluation "ineffective as a fixed com-
bination," and then some "comments from the panel report. It does
not seem rational to expose a patient to the hazards of two drugs
when the beneficial effects are no greater than those resulting from
the use of one. Again, it has not been shown each active ingredient
makes a contribution to the effect of the combination claimed."
I am not reading the whole statement. The last sentences are:
A large number of papers purporting to demonstrate clinical efficacy of this
combination were reviewed. No control studies were located and most consisted
of reports of a few patients treated, with variable results. It is the considered
judgment of the panel that this combination has no place in rational therapeutics
and should not be marketed.
This particular drug is among the top 200 most prescribed drugs.
I think the National Academy of Sciences as of now has recommended
removal of six of these combinations and is continuing its studies.
Do you have any comment from your experience or studies to
make on the question of the developing, expanding production of
combination drugs?
Dr. Mosrin. Well, Senator, I guess the only thing that ever started
the use of combination drugs was the simplicity of delivery where
the patient takes one pill instead of two. But I am familiar with
Dr. Kunin's statement, and I think this is reflected throughout the
profession. You immediately hamstring yourself when you put two
drugs in a fixed dosage together, and it is just not widely done in
hospitals where I have been. I don't recall having used a drug
combination in the last 5 years.
Senator NELSON. Does your formulary carry any fixed
combinations?
Dr. MOSER. It carries one, to my knowledge. This is a combination
of triameterene and hydrochiorothiazide.
Senator NELSON. You don't prescribe them yourself?
Dr. Mosnrt. No, I don't; because I like to adjust my doses, and I
am not permitted by the fixed combination. And I think most phy-
sicians feel the same way. One prefers the elasticity that comes with
being able to adjust dosages. Also, they are more expensive.
Senator NELSON. You mentioned a few moments ago what you
considered an adequate source of information for physicians in pre-
scribing drugs including the Medical Letter and some text and other
sources. If the National Academy of Sciences is correct, and if your
judgment about the use of them in your own practice is correct, on
what basis do you suppose these drugs are so widely prescribed?
PAGENO="0058"
4348 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
In other words, what source of information is the physician using,
because they are widely prescribed and widely sold, and Panalba is
one of the top 200-if all of these sources of information are so
readily available to the physician, how do you account for the fact
that these fixed combinations are so widely used?
Dr. MOSER. Well, I think it is because of the fact they are propa-
gandized to the profession. I think that the detail men are well trained
in the techniques of sales. They are very pleasant individuals who
have time and give a very straight forward pitch. Their presentations
are not cluttered by having to give you comparisons with other drugs.
And I think there are other very effective means of promoting drugs.
Drug advertisements are skillfully done and present a very straight-
forward approach. In the very same journal you occasionally find a
very colorful, well done advertisement, and tucked away somewhere
in bowels of the text will be an article that says exactly the reverse.
But the advertisement is brief and simple, and it takes too long to read
the drab article. It is very easy to flip the pages and come up with
this attractive, arresting advertisement. It is just a matter of good
salesmanship.
I think our problem is to encourage physicians to take the same
amount of time that they do in listening to the detail men or reading
these advertisements to read the Medical Letter or Modell or any of
the other sources of drug information that are abundantly available.
I think this is the problem, and it doesn't make sense to me that a
physician would not utilize these sources of information.
I suspect we just have not told them about it. 1 think we have to
educate physicians that there are good information sources available.
As I say, you can read the Medical Letter in 15 minutes. And this
is a very worthwhile investment in time; One will learn about drugs.
The time will `be spent expeditiously.
Mr. GORDON. Doctor, throughout your paper you use only the official
or generic names. Why didn't you use brand names? Why did you
use only generic names?
Dr. MOSER. 1 guess it is because I am stubborn. I find it a challenge
to try to get people to use generic names. I find that the trade names
are used simply because they are more euphemistic. With the TJSAN
committee now working very hard to create the generic names that
have less than 25 syllables, we will begin to see a greater use of generic
words.
I think it is more personal than anything else. I encourage all of
my staff to use generic names unless a trade name represents the sole
available drug form and is only known by that name. But it is just
a personal idiosyncrasy, 1 guess. I just like the intellectual drill.
Senator NELSON. Dr. Modell and all others who have testified on
this point before the committee have advocated the use of generic
names in prescribing. It has been suggested before this committee on
several occasions that all prescriptions that go to the patient should
include the generic name. And, of course, if the doctor desires, he
can indicate the brand name, too, unless there was some reason the
patient, the doctor felt, shouldn't know what drug he was receiving.
The reason advocated for that was, in addition to good prescribing
practice, the fact that there is such a multiplicity of brand names that
nobody can keep up with them.
PAGENO="0059"
COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4349
I asked a doctor who appeared before the committee whether he
recognized a few brand names of thalidomide, none of which he rec-
ognized, none of which he would be expected to recognize. In the case
of thalidomide, long after its harmful effects were known all over the
world, it was still in the marketplace in South America and Spain and
other places under brand names even though the profession knew it
should not have been used. If it had said thalidomide, it wouldn't
have been used. And many suspect that it is still on the shelves and
in medicine caibinets around the world yet, simply because there is no
identification.
Would you advocate the concept that the generic name be required
on the label, with the doctor's choice as to whether he wants the brand
name on, too ~
Dr. MOSER. Yes, sir. I believe that. I think that prescriptions should
be so written, unless the physician has a specific desire for the trade
name product, based on his own experience or knowled~e. And there
are a few instances where physicians that I know, certainly feel quite
strongly that they want a definite trade name; this product they feel
is superior to another. I frequently challenge them to provie it, be-
cause often it proves to be more visceral than scientific. But for the
most part we do order in generics. Our hospital pharmacist will notify
us if someone does order by trade name and the pharmacist does not
carry it. He will call the physician and notify him about substituting
another drug.
My personal reaction is that we should use generic names, and if
you desire to specify a company, it should be put in parentheses next
to the generic name on the prescription pad.
I think this would solve the problem of trying to remember hundreds
of trade names.
Senator NELSON. Well, Doctor, I want to thank you very much for
your very valuable and thoughtful contribution to these hearings. We
appreciate your taking time from your activities at Walter Reed
Hospital to come here and testify today.
Dr. MOSER. Thank you, sir.
Senator NELSON. Thank you very much.
(Whereupon, at 11:45 a.m. the hearing was adjourned.)
PAGENO="0060"
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
WEDNESDAY, FEBRUARY 26, 1969
U.S. SENATE,
MONOPOLY SUBCOMMITTEE OP THE
SELECT COMMITrEE ON SMALL BUSINESS,
Washington, D.C.
The subcommittee met, pursuant to notice, at 10:20 a.m., in the Cau-
cus Room, Old Senate Office Biñlding, Senator Gaylord Nelson (chair-
man of the subcommittee) presiding.
Present: Senator Nelson.
Also present: `Chester H. Smith, staff director and general counsel;
Benjamin Gordon, staff economist'; `Jay Cutler, acting minority coun-
sel; and Elaine C. Dye, clerical assistant.
Senator NELSON. Today we resume our hearings on the drug chlor-
iunphenicol-widely advertised under the Parke, Davis brand name
of Chloromycetin.
The drug is known to cause serious blood dyscrasias, including
~plastic anemia. Though it is a valuable drug when properly used, all
expert witnesses agree that it is indicated for use in an extremely lim-
ited number of cases-whe,n the disease is serious, when no other drug
is effective, and when the organism involved is susceptible to
chloramphenicol.
In 1967, over 4 million people were administered this drug, though
expert testimony before this committee is that 90 to 99 percent of these
patients received it for nonindicated cases. That means that over 31/2
million persons were being needlessly exposed to the threat of serious
side effects.
As a result, many thousands have tragically and unnecessarily con-
tracted blood diseases including aplastic anemia.
The widespread publicity given to this situation by these hearings
resulted in a dramatic drop in the use of this drug in capsule form dur-
ing the first 9 months of 1968~~~~from 31.9 to 9.5 million grams-a
decrease of 70 percent over the comparable period in 1967. Injectables
decreased from 7.3 to 2.9 million grams, a decrease of 60 percent.
However, it is alarming tO note that use of capsules has again in-
creased during the last 3 months of 1968-from 3.6 to 4.9 million grams,
an increase of 36.7 percent, as compared with the last 3 months of 1967.
It is interesting to note that the use of the injectable form, usually con-
fined to hospitals, went down during this 3-month period from 1.6 mil-
lion to 500,000 grams, a decrease of 68 percent.
The purpose of these hearings is to continue to focus attention on
this serious problem.
No other example that has' come before this committee more dramat-
ically demonstrates the ineffectiveness of the medical leadership of
the Nation on drug education when measured directly against the pow-
4351
PAGENO="0062"
4352 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
er and persuasiveness of drug company promotion and advertising.
Every medical journal, every reputable drug reference, and every
authority on this drug has repeatedly cautioned against misuse of
chioramphenicol. Yet, against the combined authorative voice of the
whole medical profession, drug company promotion has carried the
day hardly drawing a deep breath.
If this does not alarm the AMA, I fear that nothing ever will.
Our witness this morning is Dr. Paul F. Wehrle, chief physician,
children's division, pediatrics and communicable diseases service
at the University of Southern California School of Medicine. It that
correct ~
Dr. WEmun. In the Los Angeles County General Hospital.
Senator NELsoN. Doctor, the committee appreciates very much
your taking the time from your busy schedule to appear before the
conmiittee~ today to testify.
Your biographical sketch has been presented to the committee and
will be printed in full in the record, prior to your statement.
(The biographical sketch follows:)
CuxuIculuM VrrAE-PADI FRANCIS WEHRLE
Birthdate: December 18, 1921.
Birthplace: Ithaca, New York.
High School: Tucson Senior High School, Tucson, Arizona, 1937-1940,
Coilge:
University of Arizona, 1940-1943 and summer session, 1946, B.S. (Zoology)
1947.
Tulane University of Louisiana, School of Medicine, M.D. 1947.
University of Illinois Graduate School, Chicago, Course in Virus Techniques-
1949, no degree.
Johns Hopkins University, Baltimore, Immunochemistry-1954, no degree.
Internship: Scott and White Hospitals, Temple, Texas, 1947-1948.
Residency: University of Illinois', Research and Educational Hospitals (Pedi-
atrics) 1948-1950.
Positions Held:
1950-1951:
(1) Assistant Medical Superintendent, Chicago Municipal Contagious
Disease Hospital Jan. 1950-June 1951.
(2) Clinical Instructor in Pediatrics University of Illinois, College of
Medicine July 1950-une 1951.
1951-1953:
(3) S.A. Surg (R) Public Health Service Epidemiology Intelligence
Service, Communicable Disease Center, Atlanta, Georgia, July
1951-July 1953. (Promoted to Surg. (R) Inactive, 1958).
(4) Research Associate, Dept. of Epidemiology and Microbiology, Uni-
versity of Pittsburgh Graduate School of Public Health, Sept.
W51-July 1953.
(5) Lecturer in Public Health Administration, Duquesne University,
Pittsburgh, Pa., 1951-1953.
(6) Staff Assistant for Allocation of Gamma Globulin, National Re-
search Council, National Academy of Sciences, Washington, D.C.
1953.
1953-1955:
(7) Research Associate, Poliomyelitis Laboratory Department of Epi-
demiology, Johns Hopkins University, Baltimore, Maryland, July
1953-June 1955.
(8) Attending Pediatrician, Baltimore City Hospitals July 1953-June
1955.
(9) Staff Assistant, Hepatitis Program, Committee on Sterilization of
Blood and Blood Products, National Research Council National
Academy of Sciences, April 1955-56.
PAGENO="0063"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4353
1955-1959:
(10) Assistant Professor of Pediatrics, State University of New York,
Upstate Medical Center, Syraëuse, N.Y. July 1955-May, 1959.
(11) Assistant Medical Director City Hospital, Syracuse, N.Y., July
1955-April 1961 and Associate Attending Physician, Syracuse
Memorial Hospital.
(12) Poison Control Officer, City of Syracuse, Department of Health,
January 1957-April 1961.
(13) Acting Chairman, Department of Microbiology, State University
of New York, Upstate Medical Center, Syracuse, N.Y., October
1959-April 1961.
1961-1968
(14) Hastings Professor of Pediatrics, University of Southern Cali-
fornia School of Medicine, Los Angeles, April 1, 1961 to present.
(15) Head Physician, Communicable Disease Service, Los Angeles
County General Hospital.
(16) Chief Physician, Children's Division (Pediatrics and Communi-
cable `Disease) July 1, 1964to present.
(17) Lecturer, Epidemiology-Infections Disease and Tropical Medi-
cine, University of California at Los Angeles Schools of Medicine
and Public Health, 1966 to present.
Military Service:
U.S. Navy 1942-45 (much of this time in various training programs, no over-
seas service).
U.S. Public Health Service 1951-1953. Present rank is Surg. (R) Inactive.
Specialty Board Certificate:
American Board of Pediatrics 1953.
Personal Data:
Married 1944, 4 sons.
Professional Societies:
American Academy of Pediatrics
American Association for the Advancement of Sciences
American Association of Immunologists
American Association of University, Professors
American Epidemiological Society
American Federation for Clinical Research
American Pediatric Society
American Public Health Association (Fellow)
American Society for Microbiology
California Medical Association
Infectious Diseases Society of American
International Epideini'ological Association
Los Angeles Medical Society
Los Angeles Academy of Medicine
Los Angeles Pediatric Society, (President 66-67, Vice President 65-66)
Sigma Xi
Society for Pediatric Research
Western Society for Pediatric Research
Western Association of Physicians
Southwestern Pediatric Society
Organizations and Activities:
(a) TJ.2.U. and Hospital:
Member of Faculty Senate, U.S.C. (1962-1967)
Member of Faculty Executive Committee, U.S.C. School of Medicine
1961-present)
Member, U.S.C. Computer Advisory Committee (1963-65)
Member, Admissions Committee, U.S.C. School of Medicine 1962-68
Member, General Hospital' Attending Staff Board of Directors (1962-
present)
Secretary, Research Committee, Los Angeles County General Hospital
Attending Staff (1963-present)
Member, Internship Advsiory Committee, Los Angeles County General
Hospital (1964-present)
Consultant, Staff of Hun'tington Memorial Hospital, Pasadena (1968-
present)
Consultant, Staff of Children's Hospital of Los Angeles (1968-present)
Member, Milk Commission, Los Angeles County (1968-72)
PAGENO="0064"
4354 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
(b) Local Medical Organizations:
Chairman, Public Health Committee Los Angeles Pediatric Society and
Southern California Chapter of the Academy of Pediatrics (1963-66)
1Jice President, Los Angeles Pediatric Society, (1965-66).
President, Los Angeles Pediatric Society, (1966-67).
Member, Executive Committee, Southern California Chapter of Acad-
emy of Pediatrics (1962-63)
Member, Infectious Disease Committee, Los Angeles Tuberculosis and
Health Association (1962-64)
Chairman, Los Angeles Virus Club (1963-64)
Scientific Advisor, Los Angeles County Medical Association Sabin Polio
Vaccine Program (1962-63)
(c) State Organizationss
Consultant to the California State Health Dept.
1. Ad Hoc Advisory Committee on Phophylaxis of Poliomyelities (1962-
1964)
2. Epidemiology, in Water Reclamation (1962-1967)
3. Air Pollution Medical Studies Unit (1962-1967)
Member, State Hospital Advisory Board, State of California (1965-69)
(d) Other Universities:
The Johns Hopkins University: Consultant to Health Resources Evalua-
tion Program, Peru (Division of International Development) 1962-63.
(e) 1Vationa~:
1. Consultant, Human Resources and Development, Agency for Inter-
national Development, U.S. State Dept. (1963-ii~67)
2. Member, Environmental Hazards Committee, Academy of Pediatrics
(1962-1967) Chairman (1968 to present)
3. Member, Air Pollution Training Committee, Division of Air Pollution,
United States Public Health Service, Washington, D.C. (1962-1966)
4. Member, Advisory Committee on Immunization Practices to the Sur-
geon General, U.S. Public Health Service (1964-1968)
5. Member, Program Area Committee on Child Health, American Public
Health Association (1963-1967), Chairman, (1967 to present).
6. Member, Committee on Infections Within Hospitals, American Hos-
pital Association (1964-present).
7. Consultant, to the Commanding General, Sixth U.S. Army (1965-
present).
8. Member, Subcommittee on Epidemiologic Use of Hospital Data, sub-
committee of the U.S. National Committee on Vital and Health Statistics
1965-present).
9. American Red Cross, Vaccine Immune Globulin Consultant Com-
mittee (1964-present)
10. Member, Committee on Diagnostic Standards in Respiratory Dis-
ease, American Thoracic Society, Medical Section of the National Tuber-
culosis Association (1965-present)
11. Consultant in Pediatrics & Infectious Diseases, Long Beach Naval
Hospital (1968-present)
12. Member, Drug Efficacy Study Panel National Research Council,
National Academy of Science (1966-1968)
13. Member, Epidemiology and Disease Control Study Section, Division
of Research Grants, U.S. Public Health Service, National Institutes of
Health, Bethesda, Md. (1967-present)
PUBLICATIoNs
1. lVehrle, P. F. and Lapper, M. H.: Aureomycin Treatment of Pertussis, J.
Fed. 39 :435-441, October 1951
2. Lepper, M. H., Wehrle, P. F. and Blatt, N.: Treatment of H. Influenza
Meningitis, Am. J. Dis. Child. 83:763-768, June 1952.
3. Hammon, W. MeD., Coriell, L. L., Wehrle, P. F. and Klimt, C. R. and Stokes,
J. Jrs.: Evaluation of Red Cross Gamma Globulin as a Prophylactic Agent for
Poliomyelitis. III. Preliminary Report of Results Based on Clinical Diagnosis,
J.A.M.A. 150 :757-760, October 25, 1952.
4. Lapper, Mark H., Dowling, Harry W., Wehrle, P. F., Blatt, N. H., Spies,
H. W. and Brown, M.: Meningococcic Meningitis, Treatment with Large Doses
of Penicillin Compared to Treatment with Gantrisin, J. of Lab. & Clin. Med.,
40 :891-900, December 1952.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4355
5. Lepper, M. H., Blatt, N. H., Wehrle, P. F. and Spies, El. W.: Treatment of
Bacterial Meningitis of Unusual Etiology and Purulent Meningitis of Unknown
Origin, A.M.A. Am. J. Dis. Child., 85:295-302, March 1953.
6. Hammon, W. McC., Coriell, L. L., Wehrle, P. F. and Stokes, J. Jr.: Evalua-
tion of Red Cross Gamma Globulin as a Prophylactic Agent for Poliomyelitis, IV.
Final Report of Results based on Clinical DiagnosIs, J.A.M.A. 151 :1272-1285,
April 11, 1953.
7. Perlstein, M. A~, Andelman, M. B., Rosner, P. C. and Wehrle, P. F.: In-
cidence of Hypertension in Poliomyelitis, Pediatrics 11 :628-633, June 11953.
8. Maclachlan, W. W. G., Crum, H. E., Kleinschmidt, R. F., Wehrle, P. F.:
Psittacosis, Am. J. Med. Sci. 226:157-163, August1953
9. Hammon, W. MeD., Coriell, L. L., Ludwig, E. H., McAllister, R. H., Greene,
A. E., Sather, G. E., and Wehrle, P. F.: Evaluation of Red Cross Gamma Globulin
as a Prophylactic Agent in PoliOmyelitis, 5. Re-Analysis of Results Based on
Laboratory Confirmed Cases, J.A.M.A. 156:21-27, September 4, 1954.
10. Wehrle, P. F.: The Epidemiology of Poliomyelitis. Study of an outbreak in
Payson, Utah, 1951. California Med. 82 :314-318, 1955.
11. Wehrle, P. F.: The Risk of Poliomyelitis Infection Among Exposed Hos-
pital Personnel. Pediatrics 17:237-246, February, 1956.
12. Hammon, W. MeD., Coriell, L. L., Ludwig, E. H., McAllister, R. H., Sather,
G. E., Greene, A. E. and Wehrle, P. F.: Effect of Passive Immunity on Infection
with the Poliomyelitis Viruses, Poliomyelitis. Papers and discussions presented
at the Third International Poliomyelitis Conference, pp. 159~-166, I. B. Lippincott
Co., Philadelphia, 1955.
13. Wehrle, P. F.: The Diagnosis and Management of Oral Infections, Pediatric
Clinics of North America, 3:871-884, 1956.
14. Wehrle, P. F., Feldman, H. A. and Kuroda, K.: Effect of Penicillins V and
G on Carriers of Various Streptococcal Groups in a Children's Home, Pediatrics,
19 :208-216, 1957.
15. Wehrle, P. F., Feldman, H. A., Mou, T. W. and Shields, F.: Penicillin V
Therapy of Scarlet Fever and Acute Streptococcal Pharyngitis. Clinical and
Serological Response, Antibiotics Annual, 1956-57, Medical Encyclopedia, Inc.,
New York.
16. Wehrle, P. F., Hammon, W. MeD., Coriell, L. L. and McAllister, R. M.:
Spread of Poliovirus Infection During an Epidemic of Unusual Severity. Am. J.
Hyg. 65:386-403, 1957.
17. Duffy, P. E., Portnoy, B., Mauro, J. and Wehrle, P. F.: Acute Infantile
Hemiplegia Secondary to Spontaneous Carotid Artery Thrombosis, Neurology,
7:664-666, September, 1957.
18. Wehrle, P. F., Reichert, R., Carbonaro, 0. and Portnoy, B.: Influence of
Prior Active Immunization on the Presence of Poliovirus in the Pharynx and
Stools of Family Contacts of Polio Cases, Pediatrics, 21 :353-361, 1958.
19. Wehrle, P. F., Aronovitz, G., Parkman, P. and Zechnich, R.: Poliovirus
Neutralizing Antibody Levels in Pediatricians and Pre-Clinical Faculty Mem-
bers, A.M.A. Am. J. Dis. Child., 95:341-348,1958.
20. Portnoy, B., Draper, T. and Wehrle, P. F.: Intramuscular Tetracycline
Phosphate Complez: Serum Concentration and Local Tolerance in Infants and
Young Children, Antibiotics Annual, 11957-58, p. 386-390, Medical Encyclopedia,
Inc., New York.
21. Wehrle, P. F.: Mumps, Current Therapy, W. B. Saunders Co., 1959.
22. Wehrle, P. F.: Recent Development in the Epidemiology of Poliomyelitis,
Bull. of the Chicago Med. Soc., 61 :60~-66, July 26, 1958.
23. Wehrle, P. F. and Hammon W. McD.: Absence of Active Immunization
Against Infectious Hepatitis. Follow: up study after administration of gamma
globulin, J.A.M.A., 167:2062-2065, August 23, 1958.
24. Berger, S. H., and Wehrle, P. F.: Kanamycin Serum Levels in Infants and
Children. Bull. N.Y. Acad. Sd., 76:136-139, 1958.
25. Goldstein, G. and Wehrle, P. F.: The Influence of Socioeconomic Factors
on the Distribution of Hepatitis in Syracuse, N.Y., Am. J. Pub. Health, 49 :473-
480, 1959.
26. Berger, S. H., Bergstrom, W. H. and Wehrle, P. F.: Renal Clearance of
Kanamycin in Children, A~ntibiotics Annual 1958-59, pp. 684-686, Medical Ency-
clopedia, Inc., N.Y.
27. Wehrle, P. F., Judge, M. E., Parizeau, M. P., Carbonaro, 0., Miller, M. and
Zinberg, S.: Disability Associated with ECHO Virus Infection. N.Y.S.J. of Med.,
59:3941-3945, 1959.
81-280 O-69--pt. 11-5
PAGENO="0066"
4356 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
28. Wehrle, P. F.: Clinical Problems Associated with Enterovirus Infection.
Bull. Chicago Med. Soc. Vol. 62, No. 39, March 26, 1960.
29. Willie, C. V., Harris, Virginia G. and Wehrle, P. F.: The Epidemiology of
accidental poisoning in an urban population. I. Selection of the population sample
and interviewing techniques. American J. Pub. Health, 50:1705-09, 1960.
30. Wehrle, P. F., Day, P. A., Whalen, J. P., Fitzgerald, J. W. and Harris,
Virginia G.: The epidemiology of accidental poisoning in an urban population II.
Prevalence and distribution of poisoning. American J. Pub. Health, 50 :1925-33,
1960.
31. Wehrle, P. F., DeFreest, L., Penhollow, J. and Harris, Virginia: The
Epidemiology of accidental poisoning in an urban population. III. The repeater
problem in accidental poisoning. Pediatrics, 27:614-620, 1961.
32. Wehrle, P. F., Hagan, F. and Carbonaro, 0.: Transmission of Polioviruses.
I. Spread of naturally-occurring poliovirus Type I in a partially immunized
school population. Pediatrics, 27:748-54, 1961.
33. Wehrle, P. F., Hagan, F. and Carbonaro, 0.: Transmission of Polioviruses
II. Spread of attenuated poliovirus Type III in a partially immunized school pop-
ulation. Pediatrics, 27:755-61, 1961.
34. Wehrle, P. F., Carbonaro, 0., Day, P. A., Whalen, J. P., Reichart, R., and
Portnoy, B.: Transmission of polioviruses. III. Prevalence of polioviruses in
pharyngeal secretions of infected household contacts of patients with clinical
disease. Pediatrics, 27:762-64, 1961.
35. Day, Paul A., Osborn, Winifred, Mesibov, W., Rodidoux, H. and Wehrle,
P. F.: Dimethoxyphenyl penicillin: A study of its use as a prophylactic agent
in the newborn nursery and in the treatment of infectious diseases in pediatric
patients. Monograph prepared under the auspices of the State University of New
York, edited by Paul A. Bimn, M.D., 1961.
36. Day, P. A., Osborn, Winifred, Weinberger, H. L., Mesibov, W. R., Obidoux,
H., and Wehrle, P. F.: The Clinical Efficacy and Prophylactic Use of 2,6 Di-
methoxyphenyl Penicillin in Children and Newborn Infants. American J. Dis.
Child., 102:785-792, 1961.
37. Wehrle, P. F.: Acute Respiratory Disease. Bull. of Wadsworth General
Hospital, 5:3-10, 1961.
38. Wehrle, P. F.: Hospital Acquired Staphylococcal Infections. Medical Bull.
Children's Hospital of Los Angeles, 1961.
39. Wehrle, P. F., and Portnoy, B.: Viral Infection of the Respiratory Tract,
Current Therapy, pp. 104-1i06, ed. H. F. Conn, W. B. Saunders Co., Phula., 1962.
40. Wehrle, P. F.: Recent Developments in Poliomyelitis Prevention. The Bul-
letin L.A. County Medical Society, 10, October 4, 1962.
41. Wehrle, P. F.: Control of Accidental 1~oisoning. Pediatrics Digest, 5 :19-24,
1963.
42. Nation, N. S., Pierce, N. F., Adler, S. J., Chinnock, R. F. and Wehrle, P. F.:
Human Hyperimmune Globulin in the Treatment of Tetanus. Calif. Med.
98 :305-6, June 1963.
43. Wehrle, P. F.: Poliomyelitis Prevention. Analysis of L.A.C.1I1.A. Program.
Bull. Los Angeles County Med., Vol 93, No. 11, pp. 16-18, June 6, 1963.
44. Oelsner, T., Massey, F. Portnoy, B., and Wehrle, P. F.: Acute Respiratory
Disease and Air Pollution in Los Angeles. Arch. Env. Health, 8:182, 1964.
45. Wehrie, P. F.: Management of Acute Viral Central Nervous System
Disease. Rounds of the Teaching Staff (Wadsworth V.A. Hospital, Los Angeles),
7:431-434, No. 1, 1963.
46. Wehrle, P. F.: Treatment of Influenza. Pediatric Therapy edited by
S. Gellis and B. M. Kagan, W. B. Saunders, Philadelphia, 1964, pp. 568-569.
47. Portnoy, B., and Wehrle, P. F.: Respiratory Disease of Viral Etiology.
Current Concepts of Chest Diseases, Vol. III, No. 2, September 1963.
48. Wehrle, P. F.: Viral Central Nervous System Disease, GP, 28:116-123,
1963.
49. Wehrle, P. F., Leedom, J.M., Portnoy, B., Pierce, N. F., and Cowper, H. H.:
Safety of Sabin Oral Poliovaccine Strains, Los Angeles County 1962-63, J.A.M.A.
186:821-826, November 1963.
50. Pierce, N. F., Portnoy, B., Leeds, N., Morrison, R. L., and Wehrle, P. F.:
Encephalitis Associated with Herpes Simplex Infection Presenting as a Temporal
Lobe Mass. Neurology, 14 :708-713, August, 1964.
51. Ivler, D., Thrupp, L. D., Leedom, J. M., Wehrle, P. F., and Portnoy, B.:
Ampicillin in the Treatment of Acute Bacterial Meningitis Antimicrobial Agents
and Chemotherapy Conference, 1963, Antibiotics Annual, 1963, pp. 335-345.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4357
52. Portnoy, B., Leedom, J. 1VI., Hanes, B., and Wehrle, P. F.: Factors Affecting
ECHO 9 Virus Recovery from Cerebrospinal Fluid. Amer. J. Med. Sd. 248:521-
527, No. 5, November 1964.
53. Wehrle, P. F.: Meningitis, Acute, Bacterial. Current Therapy, W. B. Saun-
ders Co., Philadelphia, pp. 24-25, 1965.
54. Wehrle, P. F.: Food Service Management on Communicable Disease Serv-
ices. American J. Dietetics, 46 :465-467, No. 6, June 1965.
55. Wehrle, P. F.: Mumps. Current Diagnosis, W. B. Saunders Co., 1966, pp.
21-22.
56. Wehrle, P. F.: Current Immunization Methods and Precautions. Calif.
Med., 101 :153-159, 1964.
57. Wehrle, P. F.: Lampton, A. K., and Portnoy, B.: Prevalence and Type of
Muscle Weakness Associated with ECHO 4 Infection (in preparation).
58. Thrupp, L. D., Leedom, J. M., Tyler, D., Wehrle, P. F., Brown, J. F.,
Mathies, A. W., and Portnoy, B.: H. influenza Meningitis: A Controlled Study
of Treatment with Ampicillin. Post-Grad. Med. J. (supp), 40 :119-125, December
1964.
59. Hammer, D. I., Portnoy, B., Massey, F. M., Wayne, W., Oelsner, T., and
Wehrle, P. F.: The Relationship of Symptoms to a Single Air Pollutant During
A Selected Twenty-Eight Day Period. Arch. Env. Health, 10 :475, March 1965.
60. Wehrle, P. F.: Immunization Agents and Their Utilization in Our Modern
Society. Proc. of First Annual Immunization Conference, U.S. Public Health
ServiceS Published by Communicable Disease Center 1964, pp. 16-23.
61. Portnoy, B., Leedom, J. M., Hanes, B., Kunzman, E. E., Pierce, N. F., and
Wehrle, P. F.: Aseptic Meningitis Associated with ECHO virus Type 9 Infec-
tion: With Special Reference to Variability by Sex and Incidence of Paralytic
Sequelae. California Med., 102 :261-267, April 1965.
62. Ivier, D., Leedom, J. M., Thrupp, L. D., Wehrle, P. F., Portnoy, B., and
Mathies, A. W.: Naturally Occurring Sulfadiazine Resistant Meingococci. Anti-
microbial Agents and Chemotherapy, pp. 444-450, 1964.
63. Wehrle, P. F.: Immunization Against Viral Diseases. Calif. Med. 103 :79-
86, August 1965.
64. Wehrle, P. F.: Influenza. Current Ped. Therapy, Ed. by Gellis and Kagan,
W. B. Saunders Co., Philadelphia, 1965, pp. 750-751.
65. Wehrle, P. F: Salmonellosis. Current Ped. Therapy, Ed. by Gellis and
Kagan, W. B. Saunders Co., Philadelphia 1965, pp. 715.
66. Wehrle, P. F. Landry-Guillain-Barre-Strohl Syndrome. Present Concepts
of Etiology and Management. Bull. Los Angeles Neurological Society, (in press).
67. Wehrle, P. F.: Communicible Disease Control in Schools. Ped. Clinics of
North America, 12 :985-993, No. 4, November 1965.
68. Leedom, J. M., Ivler, D., Mathies, A. W., Phrupp, L. D., Portnoy, B., and
Wehrle, P. F.; Importance of Sulfadiazine Resistance in Meningococcal Disease
in Civilians. N. Eng. J. of Med., 273:1395-1401, No. 26, Dec. 1965.
69. Tyler, D., Leedom, J. M., Mathies, A. W., Fremont, J. C., Thrupp, L. D.,
Nortnoy, B., and Wehrle, P. F.: Correlates of Sulfadiazine Resistant in Men-
ingococci Isolated from Civilians. Antimicrobial Agents and Chemotherapy-
1965 pp. 358-365, 1966.
70. Mathies, A. W., .Leedom, J. M., Thrupp, L. D., Tyler, D., Portnoy, B., and
Wehrle, P. F.: Experience with Anpicillin in Bacterial Meningitis. Antimicro-
bial Agents and Chemotherapy-1965, pp. 610-617, 1966.
71. Thrupp, L. D., Leedom, J. M., Ivler, D., Wehrle, P. F., Portnoy, B., and
Mathies, A. W.: Ampicillin Levels in the Cerebrospinal Fluid During Treatment
of Bacterial Meningitis. Antimicrobial Agents and Chemotherapy-1965, pp. 206-
213, 1966.
72. Wehrle, P. F. and Mathies, A. VT.: Psittacosis, Cat-Scratch Disease and
Inclusion Conjunctivitis, Tice Practice of Medicine, Publ. VT. F. Prior Co., 1966,
pp. 509-516.
73. Wehrle, P. F.: 1) Available Vaccines Against Measles, Procedings St.
Louis Immunization Conference, United States Public Health Service, Com-
municable Disease Center, April 21, 1966. 2) The Future of Immunization.
74. Wehrle, P. F.: Current Recommendations for Poliomyelitis Immunization,
Los Angeles County Medical Association Bulletin, pp. 14-15, August 18, 1966.
75. Wayne, W. S., Wehrle, P. F., and Carroll, R. E.: Oxidant Air Pollution
and Ath1et~c Performance. J.A.M.A., 199 :151 154, No. 12, March 20, 1967.
76. Wehrle, P. F.: Therapy for Acute Central Nervous System Infections,
Proceedings of Research Conference, National Institute of Child Health and
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4358 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Human Development and the University of Texas, Cherry Hill, Pennsylvania,
June 11, 1966, pp. 295-302.
77. The Prevention of Mental Retardation Through Control of Infectious
Disease, Edited by H. F. Eichenwald, PES, Pub. #1692, 1968. U.S. Government
Printing Office #0-271-454.
78. Wehrle, P. F.: Immunization Against Poliomyelitis, Joint Meeting of
Council on Environmental Health, American Medical Association and Com-
municable Disease Center, Atlanta, Georgia, October 17, 1966, Archives of
Environmental Health, Vol. 15, October 1967, pp. 485-490.
79. Wehrle, P. F., Mathies, A. W., and Leedom, J. M.: Management of Bac-
terial Meningitis, Proceedings of the International Congress of Neurosurgeons,
October 18-21, 1966, San Juan, Puerto Rico, Published by Wilkins and Wilkins,
Clinical Neurosurgery, Vol. 14, pp. 72-85.
80. Wehrle, P. F., Mathies, A. W., Leedom, J. M., Ivler, D.: Bacterial Men-
ingitis, Presented at Conference on Comparative Assessment of the Broad Spec-
trum Penicillins, The New York Academy of Sciences, New York City, Decem-
ber 12 & 13, 1966. N.Y. Acad. Sd., 145:488-498, 1967.
81. WehrTe, P. F.: The Role of Education in the Control of Hospital Infec-
tions, Presented at the American Hospital Association Conference on Environ-
mental Control in Hospitals, Chicago, Illinois, December 16, 1966. Infection
Control Bull., Published by Medical Plastics, Inc., Minneapolis, Minn., American
Hospital Products, February, 1967. pp. 929-938.
83. Wehrl, P. F., Leedom, J. M., and Mathies, A. W.: Treatment of Men-
ingococcal Menginitis Modern Treatment, Harper and Row, Publishers, Vol. 4,
No. 5, September, 1967.
83. Wehrle, P. F.: Editorial, Youth Also Pays, Arch. Environmental Health,
Vol. 14, pp. 377, March 1967.
84. Wehrle, P. F.: Vaccines on the Horizon. Presented at the 4th Annual
National Immunization Conference, March 28-30. 1967, San Antonio, Texas.
Published by the National Communicable Disease Center, Atlanta, Georgia.
85. Leedom, J. M., Ivler, D., Mathies, A. W., Thrupp, L. D., Fremont, J.,
Wehrle, P. F., and Portnoy, B.: The Problem of Sulfadiazine Resistant Menin-
gococci. Antimicrobial Agents and Chemotherapy, 1966, pp. 281-292. Published
1967 by the American Society for Microbiology.
86. Wehrle, P. F.: Hemophilus Influenzae Infections, Current Pediatric
Therapy, 1967-68, Edited by Gellis, S. and Kagen, B. M., W. B. Saunders Com-
pany, Philadelphia, 1967, pp. 765-767.
87. Wehrle, P. F., Ivler, D., Leedom, J. M., Mathies, A. W. and Portnoy, B.:
Variables Important in Survival From Pneumococcal Meningitis. Presented at
the International Symposium on Antibiotics, June 27th, 1967, Vienna, Austria.
Published by the International Congress of Chemotherapy. B 1/5 pp. 27-34.
88. Wingert, W. A., Wehrle, P. F.: Respiratory Infections: Epidemiology,
Recognition; Prevention and Treatment. Sinusitis; Pneumonia. Ambulatory
Pediatrics, Edited by Green, M. and Haggerty, R. pp. 884-890, 909-918. W. B.
Saunders, 1968.
89. Mathies, A. W., Jr., and Wehrle, P. F.: Management of Bacterial Men-
ingitis in Children, Pediatric Clinics of North America, W. B. Saunders Co.,
February, 1968. pp. 185-195.
90. Mathies, Allen W., Leedom, John M., Ivler, Daniel, Wehrle, Paul F., and
Portnoy, Bernard: Antibiotic Antagonism in Bacterial Meningitis. Antimicrob.
Agents and Chemotherapy, 1967.
91. Wehrle, P. F.: Approaches to New Schedules of Immunization. Presented
at the Fifth Annual Immunization Conference, National Communicable Disease
Center, held in San Diego, California. March 14, 1968. In press NCDC.
92. Wehrle, P. F.: T~e Immune Response With Reference to the Use of
Multiple Immunizations. Presented at the 97th Annual Session of the California
Medical Association, San Francisco, California, March 27, 1968. In press, Cali-
fornia Medicine.
93. Egeberg, Roger 0., Frasier, .S. P.. and Wehrle, P. F.: Student Health
Organization: A Faculty Appraisal, Medical Opinion & Review, Vol. 4, No. 11,
November, 1968.
94. Wehrle, P. F.: Meningitis, Communicable and Infectious Diseases, Edited
by Franklin H. Top, Sr., 6th Edition, Chapter 37, pp. 374-390, C. V. Mosby Co.,
Saint Louis, 1968.
95. Wayne, Walborg, Wehrle, P. F.: Oxidant Air Pollution and School Absen-
teesim. Archives of Environmental Health, DREW, P118, in press.
PAGENO="0069"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4359
96. Leedom, J. M., Wehrle, P. F., Mathies, A. W., Ivier, D., and Warren, W. S.:
Comments about the Role of Gentamicin in the Treatment of Meningitis in
Neonates, Adapted from discussion presented at Gentamicin Conference, Chicago,
Illinois, October 31, 1968, at the University of Illinois College of Medicine. (In
press).
PUBLIOATIONS RESULTING Fno~r COMMITTEE WORK FOR VARIOUS ORGANIZATIONS
(Member of Committee, Collaborator or Editor)
1. The Student Health Project 1966; University of Southern California, 1967
2. Standards of Child Health Care: American Academy of Pediatrics, 1967
3. Guide for Services for Children with Eye Problems; American Public Health
Association, 1968
4. Guide for Children with Communicative Disorders; American Public Health
Association, 1968
5. Guide for Children with Cerebral Palsy; American Public Health Associa-
tion, 1968
6. Tuberculosis Programs for Children; American Public Health Association
(In Press)
7. Working Conference on Smallpox (Report); Office of International Re-
search, N.I.H. Bethesda, 1968
8. Control of Infections Within Hospitals; American Hospital Association
(In Press)
9. Use of Hospital Data for Epidemiologic and Medical Care Research; Report
of Subcommittee on Epidemiologic Use of Hospital Data of National Center for
Health Statistics (Submitted for final review)
10. Conference on the Pediatric Significance of Peacetime Radioactive Fallout;
American Academy of Pediatrics, Lee E. Parr, Editor, Pediat. 41: Part 2, 165-378,
1968
11. Diagnostic Standards for Respiratory Disease; American Thoracic Society-
National Tuberculosis and Respiratory Disease Association. (In Press)
Senator NELSON. You may present your statement in any way you
see fit, and if at any time you wish to extemporize on any aspect of your
statement and elaborate on it, we will be pleased to have you do so. I
assume you have no objection to questions during the course of your
testimony.
Dr. WEHRLE. No, sir; I do not.
Senator NELSON. Thank you very much, Doctor.
Dr. WEHRLE. Would you like to have me simply read the statement
as-
Senator NELSON. That is probably the best way to approach it, and
then any aspect of it that you would like to elaborate on, just feel free
to do so, so that we get the best possible explanation in the record.
STATEMENT OP DR. PAUL F. WEHRLE, CHIEF PHYSICIAN, CHIL-
DREN'S DIVISION, PEDIATRICS AND COMMUNICABLE DISEASE
SERVICE, LOS ANGELES COUNTY-UNIVERSITY OP SOUTHERN
CALIFORNIA MEDICAL CENTER
Dr. WEHRLE. Several important antibiotics have been developed
since the licensure of chioramphenicol in 1949. Controlled studies have
shown that the newer drugs have equalled or surpassed chioram-
phenicol in efficacy against most of the infections for which this drug
had been used previously. At the present time, the only clear indica-
tions for the use of chloramphenicol appear to be in typhoid fever and
in severe salmonellosis.
Senator NELSON. May I interrupt there just a moment? Do you know
how many cases of typhoid fever occurred-
PAGENO="0070"
4360 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Dr. WEHRLE. Approximately 400 cases each year recently. There
were 398 cases dunng the last year for which figures are available.
Senator NELSON. Is there any estimate on the number of cases of
severe salmonellosis?
Dr. WEHRLE. Severe salmonellosis is very difficult to estimate. If
one takes another totally different disease, measles, in years past where
we had good data on cases reported to health departments and cases
actually occurring by sample surveys, the reporting of measles is about
ten percent. So that if you assume that salmonellosis is recorded in the
same proportion as measles in contrast to the actual extent in the pop-
ulation, this would mean then that with 18,000 approximately reported
in 1967, that this might be 181,000 or maybe 200,000.
Senator NELSON. Of severe cases?
Dr. WEHRLE. Well, here again, one has all gradations, and the 18,000
probably iepresents the most severe portion of what must be a much
larger number.
In salmonellosis chloramphenicol may be particularly advantageous
in d~bilitated patients with bacteremia, localized soft tissue or bone
infections. It should be noted that even in these conditions other drugs
are often effective.
Occasionally, serious diseases due to other organisms which are
found to be susceptible in vitro to chlora.mphenicol but resistant to less
toxic drugs may be treated with chloramphenicol. It should be empha-
sized that this latter situation is an unusual occurrence.
Until recently in pediatrics, chloramphenicol was considered the
drug of choice for Hemophilus influenza infections, particularly
in meningitis due to this organism. During the last few years, reports
from our institution and others clearly indicate that Ampicillin, one
of the newer penicillins, is at least as effective and is substantially
safer. Consequently, we have not used chloramphenicol in the treat-
ment of this condition in our hospital since the completion of our con-
trolled evaluation in 1966.
Senator NELSON. Which hospital are you referring to?
Dr. WBma~. This is formerly the Los Angeles County General
Hospital. It is now known as the Los Angeles County-University
of Southern California Medical Center.
Senator NELSON. How large a hospital is that?
Dr. WEHRLE. It is a hospital of over 2,000 beds. It cares for approxi-
mately close to 200,000 inpatients per year, and the total inpatient and
outpatient load is nearly a million patient visits per year.
Senator NELSON. Counting both outpatients and-
Dr. WEm~. Counting both outpatients and inpatients. It is in my
understanding the largest acute hospital in the world.
Senator NELSON. Do you have any statistics on how many times
during the past year or for any recent year chloramphenicol has been
prescribed for children within your hospital?
Dr. WEHRLD. The use in children has been reduced substantially
during the last 5 years, and at the present time, the use in children is
negligible. This drug is used in our hospital most frequently on the
obstetrical service and on the surgical services.
Senator NELSON. Are there any rules or practices followed within
your hospital in the use of the drug; that is, if a prescription is written
for the drug, does it have to be countersigned by anybody?
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4361
Dr. WEHELE. If the prescription is written for this drug, the attend-
ing physician in charge of that service ~ expected to approve its use.
In the Children's Division, we use it for cases of typhoid, which is seen
most frequently among people who visit in Mexico and from Mexicans
who develop the disease in Los Angeles County. For severe sal-
monellosis, we also use it. We rarely use it for other conditions on our
service.
Senator NELSON. I am sorry I didn't follow you. You said if it is
prescribed by whom, the attending physician must approve?
Dr. WEHRLE. The system that we have in our hospital is very
similar to the system in other large teaching hospitals. The attending
physician, whether he be a member of the full-time faculty or whether
he be a well-qualified physician in practice in the community and our
clinical faculty is in charge of his particular service in the hospital.
Prescription orders written by the intern or the resident must be done
with the approval of the attending physician on that service.
Senator NELSON. Is any record kept in your hispital of the use of
chioramphenicol and the indications for which it was used?
Dr. WEHRLE. The Therapeutics Committee did this for a period of
time. The usage of chloramphenicol has fallen substantially, and after
monitoring it on a very careful individual basis for several years,
this practice was delegated to the chief of each service about, I guess,
3 or 4 years ago.
Senator NELSON. Do you have any records which the hospital has
kept over the past half dozen years on the use of chloramphenicol?
Dr. WEHRLE. Yes; I have figures that were supplied to me by Mr.
Stanley Seibert, our chief pharmacist, on the usage of chioramphen-
icol. If you would like a copy of these-
Senator NELSON. Yes; I would like to see that.
Dr. WEHRLE. These records, I : believe, are of particular interest,
and if I may, I would like to call your attention to two things. First
I would like to call your attention to two things. First I would call
your attention to the fact that 250 milligram capsules are recorded in
the first column on the left so that one must devide by four in order to
determine the number of grams. Usage for the preparations in the
intermediate three columns is negligible. In the column on the far
right chlora~mphenicol for parenteral use is recorded in grams.
Senator NELSON. The far right column is grams?
Dr. WEHRLE. The far right column is grams. The far left is 250
milligrams individual capsules.
The two features these figures show very clearly are, No. 1, the
peak usage of this drug was achieved in the 1958 through 1960 period
when staphylococcal disease was a major problem and before the time
when the semisynthetic penicillins were available to any extent or
were well known.
Senator NELSON. Is that Ampicillin?
Dr. WEHRLE. This was Methicillin that came out first.
Senator NELSON. It is Ampicillin that is used now?
Dr. WEHRLE. Ampicillin came out later. I believe that Ampicillin
was made available in 1963, I believe. Am I correct? Does anyone
know?
I believe it was around 1963, possibly 1964.
The peak usage then was back sometime ago at a time when we didn't
have many of the kinds of drugs that we have at the present time.
PAGENO="0072"
4362 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
The other thing that I would point out is the sharp decline in the last
several years, a progressive decline from 157,000 capsules in 1963 down
to last year with some 32,000 capsules, which represents about 8,000
grams.
I would call your attention to the fact that the 8,000 grams in cap-
sules is roughly equivalent to the 8,000 grams used in the parenteral
form. These two are approximately equal at this time.
I would further point out that our hospital is one that is set up and
designed expressly for the care of the desperately ill individual, and
it is our responsibility to care for all patients in Los Angeles County
that are deemed hazardous in terms of infectious problems for other
hospitals in that area. We have the Communicable Disease Service.
Senator NELSON. What percentage of chloramphenicol is admin-
istered in your hospital by capsules vis-a-vis injectables, do you know?
Dr. WEHRLE. Parenteral use is equivalent to the capsule use in
terms of numbers of grams of drugs dispensed. This would indicate to
me that relatively little of this is used for the treatment of outpatients.
Senator NELSON. Very little of what?
Dr. WEHRLE. Very little of the drug is going into patients who are
ambulatory and treated in our outpatient program.
The reason for this is that this drug is well absorbed. It is well tol-
erated by the gastrointestinal route and consequently after the initial
serious, desperate illness is over, the physician is likely to change to
the oral use of the drug while the patient is still in the hospital simply
to save the discomfort of injection and the additional nursing time
necessary for injection.
Senator NELSON. This chart will be printed in the record at this
point.
(The chart follows:)
CHLORAMPHENICOL PURCHASES OF LOS ANGELES COUNTY-UNIVERSITY OF SOUTHERN CALIFORNIA MEDICAL
CENTER-UTILIZATION OF CHLORAMPHENICOL PRODUCTS
Year
Chloramphenicol
250 mg capsules
Chloramphenicol
solution
0.5 g./2 cc.
Chloramphenicol
palmitate
125 mg.14 cc.
Chloramphenicol
1.0 g. I.M.
Chloramphenicol
sodium succinate
1 gm.f1O cc.
1952
1953
1954
1955
1956
1957
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
25,104
35,792
27,600
64,800
118,700
182,400
271,800
330,300
395,200
79,000
104,200
157,900
147,600
131,700
119,600
93, 600
32,400
348
8,320
15,548
5,490
10,250
18,580
32,340
16,520
(1)
(`)
(1)
(`)
(`)
(`)
20
(`)
(`)
598
1,800
2,278
4,026
4,896
6,048
7,272
8,352
8,768
1,800
2,007
1,598
2,016
1,008
1,440
480
48
(1)
(1)
106
4,800
1,500
16,600
24,882
26,000
23, 200
3,000
4,250
7,000
4,000
4,000
5,000
4, 500
1,000
(1)
(1)
(`)
(1)
(`)
(`)
(`)
200,220
355, 000
127,000
25,802
36,494
42,924
46,000
35,000
23, 188
8,000
1 Data not available.
Senator NELSON. Please go ahead, Doctor.
Dr. WEHELE. The continued widespread usage of chioramphenicol,
often for what are apparently minor illnesses, or illness for which
another drug is of at least equal or greater effectiveness, is difficult to
understand in view of the mounting evidence of serious toxicity. While
the specific toxicity of this drug to newborn infants can be controlled
PAGENO="0073"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4363
by reducing the dosage-this is the gray baby syndrome-no method
of predicting or preventing bone marrow depression has yet been
found. The California Medical Association study, published more than
2 years ago, indicated a fatal outcome attributed to this drug in one of
each approximately 20,000 patients treated with chloramphenicol. The
continued pattern of frequent usage, despite the availability of other
drugs of equal or greater effectiveness, appears to be due to at least
five factors.
Senator NELSON. May I interrupt for a moment. I have been cu-
rious about the statistics in the California study in that we have had
witnesses, doctors, testify that in a case where the doctor discovers that
it was administered for a nonindicated case he obviously isn't going to
report it because he's subject to a lawsuit. I don't know how they
extrapolated or how they got this figure, one in 20,000, from the study.
How accurate an estimate do you think this record represents?
Dr. WEHRLE. I think this is certainly subject to error in each direc-
tion. I think this is the best estimate that anyone has come up with to
date, but it should be regarded as an estimate and one that may be
inaccurate and presents only part of the picture in each direction. I
simply don't know whether this is iii the center or whether this is to
one extreme, the high extreme or the low extreme. I simply don't know.
Senator NELSON. Are there any other blood dyscrasias that result
as a result of administration of chloramphenicol?
Dr. WEHRLE. I think it should be recognized that this is based on
fatal episodes, and this is a death certificate type of reporting. I would
not-let me back up one moment. There are other kinds of problems
that do occur. For example, in patients treated in the controlled evalu-
ation when we were comparing chlorarnphenicol and Ampicillin in the
treatment of meningitis, about 10 percent of the patients who received
chlora.mphenicol had some evidence of marrow depression in terms of
development of anemia or some lowering of the white count.
One of these patients developed a severe granulocytopenia; in other
words, a very marked depression of the bacteria-fighting cells of the
blood. He developed a staphiocci pneumonia, presumably as a conse-
quence, which was an extremely serious infection. This was fortunately
controlled by the use of the Methicillin.
Now, I have no idea in these one of 20,000 patients whether there
are additional patients who may have died of asepsis secondary to
marrow depression with the use of this particular drug. On the
other hand, there is no way of knowing how many of these patients
may have had a suppression of the marrow for presently unknown
and unrelated reasons.
Senator NELSON. Is it possible that they may have had some bone
marrow depression which they lived with a good many years without
dying, of course, and not being reported in the statistics?
Dr. WEHRLE. I think this quite possible; yes.
Senator NELSON. Did I understand you to say that the one in 20,000
figure was based on death certificate-
Dr. WEHRLE. This was a survey of deaths or fatalities, and I am
not certain whether this was from the vital statistics approach or
a survey approach.
Senator NELSON. Well, obviously then, if these statistics were based
on deaths as a consequence of aplastic anemia, they certainly don't
PAGENO="0074"
4364 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
include any statistics of those physicians who didn't report that it
was caused by chioramphenicol.
Dr. WEIIRLE. This is certainly correct, and I think some of the
problems in death certificate reporting are well known to the members
of your committee. The death certificate reporting is as good as we
have for many kinds of problems, but still such reporting is still
not entirely accurate by any means.
Senator NELSON. You may proceed, Doctor.
Dr. WEHRLE. The five factors which may be at least in part respon-
sible for the continued usage are:
1. The initial availability at a time when widespread staphylococcal
disease was occurring and the preferred drugs, the newer penicil-
linase resistant penicillins, were not yet available.
2. Its preferred role by most pediatricians for the treatment of
Hemophilus meningitis and other serious illnesses for many years.
Just parenthetically, it is apparent that a drug that can effectively
treat a condition that is 100-percent fatal if untreated is a most im-
pressive drug and develops an aura quickly that may spread to many
other conditions.
3. The excellent diffusion, both in vitro and in vivo. This charac-
teristic gives impressive zones of inhibition in the usual hospital
bacteriology laboratory, whereas another antibiotic with smaller zones
of activity may be equally effective clinically.
Mr. Go1u~oN. Doctor, may I go back to No. 2. Do you think the
pediatricians throughout the country are generally aware that Ampi-
cillin is better for Hemophilus meningitis?
Dr. WEHRLE. I think there has been a considerable change in most
hospitals around the country in the use of this drug for this condition.
Dr. Martha Yow in Houston has published on a number of occa-
sions. There have been several Canadian hospitals that have reported
their experiences with this drug, in Toronto particularly. One of the
Boston hospitals has reported experience with this particular drug.
My associates and I have made several reports, and I think have the
largest experience with this particular drug. But I think as in any-
thing else the physician's admonition of don't be the first to take up
the new, nor the last to discard the old holds here. A change has
taken place over the last 2 or 3 years and I think the acceptance of
Ampicillin has made a profound difference in the consumption of
chioramphenicol by pediatricians around the country.
Mr. GORDON. Would you know whether the manufacturers of Am-
picillin are pushing that particular drug for this particular use with
as great vigor as Parke, Davis pushed their drug?
Dr. WEHRLE. It is my impression that people who make Ampicilirn
are most anxious to sell it wherever they can.
Mr. GORDON. Your hospital did a study of relative efficacy between
Ampicillin and chloramphenicol. Was it for this disease only or
for what?
Dr. WEHELE. This was the main and I think the most important
one of the antibiotic controls of the control studies that we have done
in recent years. We have done others, but this one I think is the one
that bears directly on this problem.
Mr. GORDON. Can we get a copy of that?
PAGENO="0075"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4365
Dr. WEHRLE. Yes, sir. I will have to mail you one. I seem to have
forgotten my copies. The references are attached to the last page
of my bibliography. We have also included the Houston studies,
reference No. 6, by Barrett, Eardley, Yow, and Leverett; and the
studies from our institution are items Nos. 3, 4, 5, 7, and 8.'
The first two references pertain to Drs. Burns, Hodgman, and
Cass, and Drs. Hodgman and Burns concerning the problem with
the gray baby syndrome in young infants who receive this drug in
what we now consider excessive dosage. Those are also from the Los
Angeles group.
In addition to the laboratory studies that I just mentioned where
the extreme diffusibility of this drug is clearly evident, item 4 points
out-
Senator NELSON. May I interrupt for 1 second. I have a question.
Dr. WEHRLE. Yes.
Senator NELSON. You say, "whereas another antibiotic with smaller
zones of activity may be equally effective clinically," are you referring
to the situation whereas chloramphenicol may be very effective, an
invitro study may indicate that another antibiotic with a smaller zone
of activity, as you put it, may be just as effective? Is that what you are
referring to?
Dr. WEHRLE. Yes, sir. This is exactly what I mean. In other words,
chloramphenicol is a drug that does diffuse very beautifully through
tissues, into the eye, for example, into ~joints, areas such as this. It also
diffuses very well through culture media used to test for antibiotic sus-
ceptibility. Consequently, two drugs that may have the same activity
in tube dilutions where you have the drug already diluted may be
different, on an agar plate where diffusion plays a part in determining
the disk or zone size.
So consequently, chloramphenicol, a drug that diffuses very beauti-
fully, gives very impressive rings where the bacteria don't grow
around the disk containing this particular antibiotic, whereas one that
diffuses very poorly, like polymyxin, for example, may have the same
tube activity, yet the zone is very difficult to see. It is a very small zone.
Now, this can mislead the hospital bacteriologist on occasion unless
experienced in this problem, and can certainly mislead the physician
if the physician stops and looks at the plates from the laboratory on
his way to the patient's bedside.
Senator Nm~soN. Haven't clinical studies indicated over the past
few years those instances where, say, Ampicillin would be as effective
as chloramphenicol though less toxic?
Dr. WEHRLE. I personally feel so; yes sir.
4. A continuing aggressive advertising and detailing program, sug-
gesting that the physician can "trust" this drug. This has continued
to perpetuate the habit, established in earlier years, of prescribing this
drug for both major as well as minor problems.
5. The availability of both oral and parenteral dosage forms which
are comparatively free from minor gastrointestinal and local reaction.
I think it is annarent that a physician is interested in the welfare
of his patient. This drug is so well tolerated by the intravenous route
as well as by the oral route that in fact, I think, has often influenced
the physician's judgment in prescribing it.
~ See apps. IV-XI, pp. 4799-4857, infra.
PAGENO="0076"
4366 COMPETITIVE P OBLEMS IN THE DRUG INDUSTRY
The problem of continuing substantial usage of a potentially haz-
ardous drug despite decreasing indications poses a problem with no
easy solution. There are several possible avenues of approach and per-
haps one or a combination of several may help place the future usage
of this drug in a position more consistent with its indications. These
are:
1. Limiting of availability to the hospital pharmacy. This drug
could still be made available from such pharmacies to the occasional
ambulatory patient for whom it might be indicated. The obvious dis-
advantages to this restriction are a likelihood of increased drug cost
to the patient and considerable inconvenience to at least some of the
patients, since in the rural areas particularly there are more neighbor-
hood pharmacies than there are hospitals. The obvious inference to the
physician with such a limitation would be that he should think of
alternates if it were to be considered hazardous enough to require dis-
pensing only by the hospital pharmacy. Regardless of these obvious
disadvantages, this approach would seem preferable to the use of regis-
try numbers on prescriptions as is the case with narcotics.
2. Restrictions on advertising and detailing of this product. Despite
changes in recent years, the notice of hazards is often in smaller type
and in a less conspicuous location than is the statement regarding real
or presumed benefits.
Advertising should be restricted to illnesses for which the drug is
preferred by a responsible group. Misleading illustrations, such as the
bronchoscope, should be avoided. Such illustrations imply that chlor-
amphenicol is useful for a variety of respiratory illnesses.
Senator NELSON. May I interrupt a moment there?
Dr. WEH.RLE. Yes.
Senator NELSON. I have seen a number of those ads in which the
bronchoscope is pictured. Are there any respiratory illnesses for which
chloramphenicol is indicated?
Dr. WEHRLE. In my opinion, none whatsoever. I think we have less
toxic drugs for these infections at the present time.
Senator NELSON. Is it indicated for any of the virus infections?
Dr. WEm~E. Absolutely not.
Senator NELSON. It would seem to me, at least, that the FDA ought
to prohibit the use of the picture of the bronchoscope which obviously
indicates to the physician the area in which the drug is effective.
Dr. WEHRLE. This, in my opinion, would be a great step forward.
Physicians should indicate gross violations in claims by pharma-
ceutical house representatives, whose position is obviously dependent
on sales of this particular drug. Such representatives have been well
known to suggest antibiotic X for influenza. And by "antibiotic X,"
I do not mean chloramphenicol specifically but I mean any antibiotic
that the particular representative is interested in selling.
I would also point out that there are extremely ethical detail people
who present the facts very clearly and very fairly. There are people
who tend to deviate, and I personally feel strongly that it is the respon-
sibility of the physician to indicate such violations very clearly to
the pharmaceutical house and as well perhaps to the FDA.
3. Improving data regarding hazards, and publicizing this informa-
tion to the medical profession. Methods of improving both hospital
and death certificate information should be considered. Individual
physician reporting for infectious diseases has failed and it not likely
PAGENO="0077"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4367
to be more effective for reporting drug reactions. Oniy the more severe
drug reactions would be discovered from hospital and death reporting,
but these instance are, of course, our greatest concern. The greater
attention currently devoted to hospital organization and toward de-
partmental program and function by the Joint Commission on Ac-
creditation of Hospitals provides substantial assurance that hospital
sources of information may be improved.
4. Surveillance of local or regional usage patterns of particular
drugs. Given the authority and personnel to do so, the Food and Drug
Administration might be able to detect factors which- influence exces-
sive usage of a drug in a region or in a local area. This approach
appears to deserve study, as it may give a better insight as to why well-
motivated and skillful physicians continue to persist in particular
patterns of behavior after the factors establishing those patterns have
ceased to operate. Comparative usage figures of an antibiotic such as
chloramphenicol for several areas during a widespread influenza out-
break might be particularly revealing and may also be helpful in
designing appropriate methods of approach.
Senator NELSON. Is it indicated for influenza~?
Dr. WEHRLE. Absolutely not, butT think that this point might give
a hint as to where the problem really is. One of the things that I would
love to know, for example, is where the drug is going in Los Angeles,
just as a matter of curiosity to see what types of physicians are using
it and for what purposes.
I think that one of the responsibilities that medicine has is in terms
of the education and the assistance of the members of the profession.
And I would feel very strongly that such information would be most
helpful to guide efforts on the part of either the Food and Drug Ad-
ministration or the post graduate programs in medical education in
many of the schools and hospitals. The staff in many of the hospitals
is providing guidance, and indications as to drug usage. I would not
restrict this to chloramphenicol. I think that these would be data that
would be very helpful to those charged with the responsibility of post
graduate education of physicians.
Senator NELSON. How would you find those statistics?
Dr. WEHRLE. These could be collected in several ways. The easiest
way would be to simply look at the distribution of a drug in a com-
munity, and you know pretty well the physicians in the neighborhood
and what pattern of practice they have. And if the usage is eight
times or 10 times or 20 times as high in East Los Angeles as it is in
San Gabriel or if you see other widespread differences in pattern, then
1 think it would be possible to be more selective in terms of who is
prescribing and for what general kind of conditions.
This would give a lead for the first time as to where the drug is
going within a community.
Senator NELSON. Well, mechanically, how would you collect it; how
- much is sold to the pharmacist in the area and how it was dispensed,
that sort of thing?
Dr. WEHRLE. I would think that data on sales from pharmacies
should be kept by the pharmacist. He's got to keep track of his stock
and how much is going in and how much is going out. And I see no
reason why such figures could not be made available.
Senator NELSON. But then you'd only be guessing, unless you did
some survey about how it was used, wouldn't you?
PAGENO="0078"
4368 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
`Dr. WEHRLE. That is correct. But I think this gives at least a picture
as to whether this is a uniform problem or a prc~b1em restricted to par-
ticular areas. It may be that most of the Nation's chloramphenicol is
going into particular portions of ten of the major cities or maybe it
is predominantly a rural problem for the practitioner who does not,
because of one of several reasons, get into the medical center to see
what is happening.
This technique is at least a step toward finding out where the prob-
lem really is. I simply don't know drug usage patterns even in Los
Angeles.
In conclusion, the widespread usage of chloramphenicol, a drug
with limited and decreasing usefulness, has continued during a period
of substantial publicity and resulting greater awareness of its hazards.
This poses a problem in designing the proper method of reducing
usage without the establishment of unduly burdensome restrictions.
Several methods of approach to this problem are suggested which may
also have application for other particularly hazardous drugs in the
future.
Senator NELSON. Your primary suggestion was, as I recall it, the
same as Dr. Dameshek's, and perhaps some others, before the commit-
tee that it only be dispensed in a hospital or through a hospital phar-
macy, is that correct?
Dr. WEHRLE. This is the easiest one I think to accomplish. There
will be obvious objections to this, and I have indicated some of my
concerns. But I think this would be the most workable of several dif-
ferent approaches.
As far as the usefulness of this and hampering its use by such a
route, I would point out that about equal quantities of the drug have
been used for some time in the oral and injectable forms in our hos-
pital which would again indicate that the great bulk of this is going
into hospitalized patients for inpatient use.
Senator NELSON. We've had some of the doctors, including one at
the FDA, who expressed the view that most of the injectables are
used in hospitals. We hope to have some statistics on that tomorrow.
But at least that is what I was advised by a couple of different doc-
tors. And if that is the case, that would explain the statistics of the
past year-that is, the dramatic drop in the use in both capsule form
and injecta~ble, and then in the first 6 months of 1968 versus the first
month of 1967. And then for some reason, and this may be the reason,
capsule use in the last 3 months of 1968 increased from 3.6 million
to 4.9 million grams, that is, 1968 over 1967, a 36-percent increase of
1968 over the last 3 months of 1967, whereas in injectable form it went
down during this 3-month period from 1,600,000 grams to 500,000
grams, If, in your hospital, it was 50-50, that was typical of hospital
administration, then something else has to account for the increase of
the capsule use elsewhere.
Dr. WEHRLE. That is correct. And I wondered and speculated a bit
about this. Now, if there is no artifact in these figures, in other words,
if the producers of chioramphenicol are not getting large numbers of
grams approved for next year's use, something like that, then I would
think that it is most interesting that this is happening during the
respiratory disease season and during the influenza outbreak, first
the Hong Kong variety and currently the B which is beginning arise
in some areas. So I think that this would indicate the need to at least
PAGENO="0079"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4369
explore item 4 in the suggestions to find out where this drug is really
going.
I would also like to urge you to think very carefully about the state-
ment that most injectabies are used in hospitals. There are some con-
spicuous drugs which don't follow this pattern. I cite particularly
benzathine penicillin. Benzathine penicillin is one with a very long
action. Intermediate doses provide low levels of ~penicillin for a period
of 2 weeks approximately and larger doses for a period of about a
month. This is a most popular drug for outpatient use in the treat-
ment of streptococcal pharyngitis and in the prevention of rheumatic
fever for the short and the longer periods respectively.
Senator Nri~soN. I was using the injectable cases applying solely to
chloramphenicol.
Dr. WEHRLE. I would certainly agree.
Senator NELSON. I suppose there is some confusion about it. We
liave had testimony here from people like Dr. Lepper, Dr. Best, Dr.
Dameshek and others, all of whom have stated it is widely overused,
and I think Dr. Dameshek said it only ought to be administered in hos-
pitals. If, in fact, it is used for the purposes, the limited purposes in-
dicated, that is, in general that the disease must be very serious, no
other antibiotic is effective, and chloramphenicol is effective against
a particular organism, if that is the case, then you have, you probably
have a patient who is or ought to be in the hospital. And hospital
administration conforms much more consistently to the indicated use
than outside the hospital. I believe the testimony was that Johns
Hopkins, for quite some time, has simply had a rule that anytime it
is prescribed, it has to be countersigned by the head of the service
or someone else.
This is a difficult state to get to, but in any event, my statement,
based on conversations with some of the doctors, referred only to
chloramphenicol as to injectables.
Dr. WEHRLE. Yes.
Senator NELSON. We had testimony from the doctors I just men-
tioned and some others, all of whom estimated that chloramphenicol
was much more widely used than it should have been and their esti-
mates were that 90 to 99 percent of the chloramphenicol administered
was in their judgment administered for a nonindicated case. Do you
have any judgment or view on the administration of chloramphenicol
in this respect?
Dr. WEHELE. Yes, sir. I think 1 would like, though, to qualify this
very carefully by indicating that it is difficult for a physician in one
particular field to be completely comfortable about all of the indica-
tions and concerns that people in other fields have.
Now, the best estimate that I can come up with concerns an extrap-
olation of the pattern of usage in our particular institution. We might
approach this from the standpoint of current usage and consider this
drug to be used predominantly in inpatients. If we begin by indicating
that the average of 1967-1968 usage was some 27,000 grams, about
half parenteral and half oral, in the 798,000 patient visits to our
hospital during the single year,: this would work out to approximately
35 milligrams per patient visit. Obviously, relatively few patients are
receiving this drug.
Now, if you further restrict this to only inpatients; these would aver-
age 188,000 patients for each of these 2 years. If all chloramphenicol
PAGENO="0080"
4370 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
used were in inpatients, this would average approximately 140 milli-
grams per inpatient, that is per patient who was actually admitted to
the hospital and remained for some time. Applying these data to the
nearly 30 million hospital inpatients in the United States last year,
as reported in the August 1968 issue of the Journal of Hospitals,
published by the American Hospital Association, one would come to
a total of approximately 2 million grams, about 1 million parenteral,
about 1 million oral, for these 30 million patients admitted to hospitals
all over the United States, including ours, providing our yardstick
applied to the other hospitals. This figure takes account of the decreas-
ing utilization in our hospital during recent years.
Now, if you further recall that this figure is based on a hospital
that cares for more seriously ill, more long-neglected, more difficult to
treat and referred patients than the average hospital in the United
States, the figure of about 1 million oral and 1 million parenteral
grams usage would be in my opinion a high level or a conservative
level as far as total usage goes.
Senator NELSON. Do I understa.nd you to be saying that if the same
yardstick that is applied for the use of chloramphenicol in your hospi-
tal were applied to all hospitals in the United States, that would mean
&0 million patients in all hospitals; is that correct?
Dr. WEHRLE. That is correct.
Senator NELSON. 30 million patients in all hospitals, during a single
year would receive, would be administered 2 million grams, is that
correct?
Dr. WEHIWE. This is correct, about half of which would be oral,
about half of which would be parenteral.
Senator NELSON. In 1967, total number of grams used in the country
was 42,800,000. In 1968, it dropped to 17,500,000. In 1967 and even
in 1968, far and away most of the drug was being prescribed outside
the hospital.
Dr. WEHRLE. Yes, sir. I would certainly agree. It looks as though
the usage in the profession as a whole around the country is running
approximately tenfold, at least tenfold higher than we are currently.
Senator NELSON. You mean in the whole profession?
Dr. WEHRLE. Pardon?
Senator NELSON. Who is using it tenfold higher, that is the average
use in medicine in general is tenfold higher
Dr. WEHRLE. Yes.
Senator NELSON (continuing). And in your hospital?
Dr. WEHRLE. Yes, sir; this is correct. This is what it would appear
here. Obviously there are at least 10 times as many grams being mar-
keted in respect to the numbers of patients admitted to other hospitals
than to ours.
Senator NELSON. And this is despite the qualitative figure in terms
of your patient, that is, that you have a high percentage of seriously
ill patients, is that correct?
Dr. WEHRLE. This is correct, yes.
Senator NELSON. Well, thank you very much, Doctor, for your most
valuable testimony. We appreciate your taking time to come here and
appear before the committee. It has been most helpful to us.
We will recess until tomorrow morning at 10 o'clock.
(Whereupon. at 11:15 a.m., the subcommittee adjourned, to recon-
vene at 10 a.m., Thursday, February 27, 1969.)
PAGENO="0081"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
THURSDAY, FEBRUARY 27, 1969
U.S. SENATE,
MONOPOLY SuBooMMIrri~E OF THE.
SELECT COMMITI'EE ON SMALL BUSINESS,
Wa~shington, D.C.
The subcommittee met, pursuant to recess, at 10:10 a.m., in the
Caucus Room, Old Senate Office Building, Senator Gaylord Nelson
(chairman of the subcommittee) presiding.
Present: Senator Nelson.
Also present: Chester H. Smith, staff director and general counsel;
Benjamin Gordon, staff economist; Jay Cutler, acting minority coun-
sel, and Elaine C. Dye, clerical assistant.
Senator NELSON. Our witness this morning is Dr. Herbert Ley,
Commissioner of Food and Drugs.
Dr. Ley, the committee appreciates your taking time to come here
this morning and present your testimony. You may proceed to present
it in any fashion you desire. And if at any time you wish to elaborate
on anything in your prepared text, feel free to do so. We may have
some questions from time to time.
Go ahead, Dr. Ley.
STATEMENT OF DR. HERBERT L. LEY, JR., COMMISSIONER OF FOOD
AND DRUGS, CONSUMER PROTECTION AND ENVIRONMENTAL
HEALTH SERVICE, PUBLIC HEALTH SERVICE; ACCOMPANIED BY
DR. B. HARVEY MINCHEW, ACTING DIRECTOR, BUREAU OF
MEDICINE, FDA; AND WILLIAM W. GOODRICH, GENERAL COUN-
SEL, OEFICE OF GENERAL COUNSEL, HEW
Dr. LEY. Mr. Chairman, I appreciate the opportunity of appear-
ing before your committee today to discuss the current status of the
antibiotic, chioramphenicol.
Approximately 1 year ago, we came before you to discuss FDA's
actions and intentions in regulating the interstate distribution of this
drug. Today, I would like to report on the steps we have taken and
the results of these actions.
Shortly after the hearing in February of 1968, we notified the
Parke, Davis Co. which markets the antibiotic under the trade name
Chioromycetin, that substantial revision in the labeling would be
necessary. The new labeling was completed and approved in April
1968.
Senator NELsoN. In preparing the new label, who does the original
preparation?
Dr. LEY. The original preparation in this particular case was done
81-280 O-69-pt. 11-6
4371
PAGENO="0082"
4372 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
by the Bureau of Medicine's staff and then subsequently discussed with
the firm. The firm had themselves prepared another draft so that
actually the preparation was bilateral in this case.
Senator NELSON. What is the normal practice?
Dr. LET. The normal practice, Senator, is for the firm to initiate
the labelmg change.
Senator NELSON. Arid if my recollection is correct, the firm prepares
the labeling and at some stage the FDA reviews it, but ordinarily the
FDA does not approve it prior to its being used?
Dr. LET. That is correct, Senator.
Senator NELSON. In this particular case your department-
Dr. L~r. May I make one minor correction?
Senator NELSON. Yes, sir.
Dr. LET. The labeling must be approved by FDA before it is used to
accompany packages of the drug.
Senator NELSON. What about the indications and precautions and
description of uses that are put in advertising?
Dr. LET. The advertising claims and promotional claims need not
be precleared by the FDA. However, they are based on labeling which
is, and must be cleared by the agency before the labeling may be used
as a basis for the advertisement or promotion.
Senator NELSON. Referring to that aspect of the advertising which
lists the warnings and the precautions, does that have prior approval?
Dr. LET. The body of information from which the warnings and
precautions in an advertisement comes must have approval. Recent ads
and the only current ad for this product features the entire package
insert language for warnings and precautions.
Senator NELSON. On chloramphenicol, you mean?
Dr. LET. Yes, sir.
Senator NELSON. Is this a special case?
Dr. LET. This as it has evolved is a special case. With other drugs
the manufacturer may prepare a brief summary which summarizes
information in the package insert. That was not done in the case of
this drug in any of the advertisements that were created after the
committee hearing last year.
Senator NELSON. What about other ads where they are, of course,
required to insert a warning and the precautions. Is that the language
of the manufacturer, or is it language specifically approved by the
FDA for all drugs?
Dr. LET. In the case where specific warning statements are featured
in the package insert and reproduced in the advertisements, that lan-
guage must be approved by the agency.
Senator NELSON. But if they write an advertisement, do they have to
include the warnings and precautions as are included in the package
insert?
Dr. LET. They must include these.
Senator NELSON. You may proceed.
Dr. LET. The revised labeling included a carefully worded indica-
tions section expressed in restrictive terms. It included an estimate of
the incidence of fatal anlastic anemia, based on a report made Jan-
uary 1, 19G7, by the California Medical Association and State depart-
ment of public health. It also states the desirability of hospitalizing
patients being treated with chioramphenicol to facilitate observation
during therapy.
PAGENO="0083"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4373
Senator NELSON. The figure used on the incidents of aplastic anemia
from the California study-I'm not exactly clear from my memory
how that study achieved the statistics. It was the opinion, I believe, of
Dr. Wehrle, who testified yesterday, that these statistics were gathered
prom death certificates. Is that correct?
Dr. LEY. If I may, Senator, I would like to outline the details of
the California study leading to the determination of two separate
risk incidents of aplastic anemia following chloramphenicol adminis~
tration, and I'm referring specifically to the summary at the beginning
of the California report.
The California group chose from death certificates filed in Califor-
nia for an 18-month period all those who were related to hematologic
disorder. They then separated from these patients who had aplastic
anemia and subsequently those that had fatal aplastic anemia. From
this culling-
Senator NELSON. These were all death certificates?
Dr. LET. These were all death certificates. That was the basic source
of information. From this culling they uncovered 10 patients who had
received chioramphenicol who died from aplastic anemia. This gives
a numerator figure. For the denominator the total number of patients
in California who had received chloramphenicol over the same period,
they then made a survey of physicians and pharmacies to determine the
usage. And they estimated that 220,000 patients had received chloram-
phenicol over the corresponding period.
There is one other computation which is critical here in arriving at
the risk figure which the California group published in the determina-
tion of the average dosage per patient of chloramphenicol, I read di-
rectly from the report.
"If the risk is calculated on the average dose of 4.5 grams during
1965, the risk is one in 40,500."
Senator NELSON. Would you please start that sentence over again.
Dr. LEY. "If the risk is calculated on the basis of an average dose
of 4.5 grams per patient"-that was my insert-"during 1965, the
risk"-and I insert "of aplastic anemia developing"-"is one in
40,500." The next sentence, "If the risk is calculated on the basis of an
average dose of 7.5 grams-I insert "per patient"-"it"-the risk-"is
one in 24,200."
These were the two figures of risk identified by the California group
which bracketed in their opinion the probability of the chloramphen-
icol-receiving patient developing aplastic anemia.
Senator NELSON. Well, doesn't this extrapolation made from these
statistics have a built-in conservative factor; that is, you find 10 cases
reported to have died from aplastic anemia. How often are you going
to have cases in which the drug was prescribed for a nonindicated case
and the physician simply isn't going to report that this was the case?
Dr. LEY. There is a possible bias here in the initial failure to report
a death due to aplastic anemia. It could introduce a bias as you sug-
gest. Death certificates are now required in all of our States and must
indicate a specific diagnosis, primary diagnosis as the cause of death.
The group chose those death certificates in which physicians had en-
tered the diagnosis, aplastic anemia, as the cause of death. Now, it is
possible that they may have been some death certificates that did not
include this information. That is a possibility in the study.
PAGENO="0084"
4374 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. Well, the statistics in the California report would
be 10 more cases out of two hundred and some thousand and you've
doubled the incidents.
Dr. LEY. That is correct, sir.
Senator NELSON. Please go ahead.
Dr. LEY. Cautionary information is included regarding use of the
antibiotic in pregnancy and lactation. Leukemia is listed as an addi-
tional adverse reaction.
On May 7, 1968, following approval of the new labeling, we sent a
"Dear Doctor" letter to every physician in the country calling atten-
tion to the proper indications for use and the strengthened warning
about the hazards of this drug. The letter was also sent to all hospital
administrators. The revised labeling was included with the letters,
along with a facsimile of our Drug Experience Report form. Physi-
cians were requested to report any adverse reactions associated with
the use of chloramphenicol. I'd like to submit for the record a copy of
this letter and the enclosures.
Senator NELSON. Thank you. Those will be included in the record.
(The information follows:)
PAGENO="0085"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4375
DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
FOOD AND DRUG ADMINISTRATION
WASHINGTON. D.C. 20204
May 7, 1968
Dear Doctor:
Serious and often fatal blood dyscrasias are known to occur following the
administration of chloramphenicol. Prominent warning to this effect has been
part of the approved labeling for this drug since 1952, and this information
has been disseminated in the medical and lay press, including editorials in
the Journal of the American Medical Association.
Because the amount of chloramphenicol distributed exceeds that to be expected
if the drug were prescribed only for its valid indications, the Food and Drug
Administration believes that chloramphenicol is often prescribed for conditions
for which it is not indicated, including trivial conditions such as acne, the
common cold, and simple infections. Fatal reactions have been associated with
use in these conditions.
To enlist your aid in ending the over-prescribing of this drug, the Food and
Drug Administration asks that you carefully study the following "box warning'
the substance of o~hich has been and will continue to be part of the recently
revised labeling of this drug:
WARNING
Serious and fatal blood dyscrasias floes of the throaf; or as a prophy-
(aplastic anemia. hypoplastic one- lactic agent to prevent bacterial
mia, thrombocytopenia. and granu- infections.
locytopenia) are known to occur
after the administration of chioram-
phenicol. In addition, there have Precautions: It Is essential that ade-
been reports of aplastic anemia quate blood studies be made during
attributed to chloramphenicol which treatment with the drug. While
later terminated in leukemia. Blood blood studies may detect early
dyscrasias have occurred after both peripheral blood changes, such as
short term and prolonged therapy leukopenia. reticulocytopenia, or
with this drug. Chloramphenicol granulocyfopenia. before they be.
must not be used when less poten. come irreversible, such studies can.
tially dangerous agents will be not be relied on to detect bone
effective, as described in the "mdi. marrow depression prior to develop.
cations" section. It must not be ment of aplastic anemia. To faciii.
used in the treatment of trivial tate appropriate studies and obser.
infections or where it is not mdi- vation during therapy, it is desirable
cated, as in colds, influenza, infec- that patients be hospitalized.
PAGENO="0086"
4376 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
To clarify further the status of this drug in the therapy of infectious disease,
the indications for use have been stated in the recently revised labeling as
follows:
The revised labeling suggests that patients being treated with chlorarnphenicol
be hospitalized where indicated to facilitate observation during therapy. It
also includes cautionary information regarding use in preg'nancy and lactation,
and the listing of leukemia as an additional adverse reaction. An estimate of
the incidence of fatal aplastic anemia is included based on a report to the
California State Assembly and Senate by the California Medical Association and
State Department of Public Health, January 1, 1967.
1. ACUTE INFECTIONS CAUSED BY
SUSCEPTIBLE STRAINS OF SAL-
MONELLA TYPHI
Chioramphenicol is a drug of choice.°
It is not recommended for the routine
treatment of the typhoid "carrier
state",
INDICATIONS: IN ACCORD WITH
TIlE CONCEPTS IN THE "WARNING
BOX" AND THIS INDICATIONS SEC-
TION, CHLORAMPHENICOL MUST
BE USED ONLY IN THOSE SERIOUS
INFECTIONS FOR WHICH LESS
POTENTIALLY DANGEROUS DRUGS
ARE INEFFECTIVE OR CONTRA-
INDICATED. HOWEVER CHLORAM-
PHENICOL MAY BE CHOSEN TO
INITIATE ANTIBIOTIC THERAPY
ON THE CLINICAL IMPRESSION
THAT ONE OF THE CONDITIONS
BELOW IS BELIEVED TO BE PRES-
ENT; IN VITRO SENSITIVITY TESTS
SHOULD BE PERFORMED CONCUR-
RENTLY SO THAT THE DRUG MAY
BE DISCONTINUED AS SOON AS
POSSIBLE IF LESS POTENTIALLY
DANGEROUS AGENTS ARE IN-
DICATED BY SUCH TESTS. THE
DECISION TO CONTINUE USE
OF CHLORAMPHENICOL RATHER
THAN ANOTHER ANTIBIOTIC
WHEN BOTH ARE SUGGESTED BY
IN VITRO STUDIES TO BE EFFEC-
TIVE AGAINST A SPECIFIC PATHO-
GEN SHOULD BE BASED UPON
SEVERITY OF THE INFECTION,
SUSCEPTIBILITY OF THE PATHO-
GEN TO THE VARIOUS ANTIMICRO-
BIAL DRUGS, EFFICACY OF THE
VARIOUS DRUGS IN THE INFEC-
TION, AND THE IMPORTANT ADDI-
TIONAL CONCEPTS CONTAINED IN
THE "WARNING BOX" ABOVE:
2. SERIOUS INFECTIONS CAUSED
BY SUSCEPTIBLE STRAINS IN
ACCORDANCE WITH THE CON-
CEPTS EXPRESSED ABOVE:
a. Salmonella species
b. H. influenzae, specifically men-
ingeal infections
c. Rickettsia
d. Lymphogranuloma-psittacosis
e. Various gram-negative bacteria
causing bacteremia, meningitis,
or other serious gram-negative
infections
f. Other susceptible organisms
which have been demonstrated
to be resistant to all other ap-
propriate anti-microbial agents.
3. CYSTIC FIBROSIS REGIMENS
In the treatment of typhoid fever some
authorities recommend that chlorampheni
eol be administered at therapeutic levels
for 810 days after the patient has becnme
afebrile to lessen the possibility of relapse.
PAGENO="0087"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4377
The revision of the labeling of chloramphenicol was approved by a special com-
mittee of experts in hematology, infectious diseases and other medical fields
convened by the Food and Drug Administration on February 26, 1968. A copy of
the revised labeling is enclosed for your attention.
To assist us in further evaluation of this problem, the Food and Drug Adminis-
tration requests that you report to us any adverse reactions associated with
the use of chloramphenicol. A facsimile of our Drug Experience Report (FD 1639)
is reproduced on the reverse side for your information. If you wish a supply,
please write to the Food and Drug Administration, Bureau of Medicine, Washington,
D.C. 2O2O~.
Sincere~y yours,
"Commissioner of Food and Drugs
Enclosure:
Revised Labeling
PAGENO="0088"
050 WELFARE DRUG EXPERIENCE REPORT 1 BUDGET BUREAU NO 57-00004
1~ TIENT INITIALS ANO IDENTIFICATION NUOIRER J.IUC1CISIQNNOIFHOFDAHSP00101 1 i~
~ ~.... ~ ~::t:~:..::.~i .. i. ......:.~
lbs LICAUC Li NEGRO Li ORIENTAL ~ AMENCUN Li oro~o OD~E CF000CTIONNARC
lioopllst, otP)(N000 If ,spoofio~f Ph}S1CISM 10 0. ADDRESS OF SOURCE (Gil's Stops), City, Slots, ~td Zip CCdP.)
AOVER SE REACTION(1I) AND ASO FORRI OLE ASSOCIATION WITIITIIC DRUG(S) INVOLOED 2 OUTCOME OF REACTION TO
L1ALIIIIIWITIOSCIIUELAE
Li RECOVERED
Li STILL UNDER TREATMENT
Li DIED (Gil's dRo ,tod E0055)
ORDER OF SUSI'IC ION (RIROIIIRF100PPI List NDA C? IND NO.)
MANUFACTURERS DOSAGE
(
TOTAL
ROUTE
(
ill, dEl
DURATION
0
ECTIQ IIM8 YANT ItOO)P 818 OATA
RT STUDIES (CZ1OIEIIILSbC?CIIC?y,At topsy, X-Rsy, SIC.) CLINICAL LAS: POSE ATTAChE 0 Li NOT DONE
RIOPSY/AUTOPST: ~ DONE Li ATTACOED Li NOT DONE
IOUS OR ENVIRONMENTAL FACTORS (loElCds hoosshold ptCdUCfs, Iodottolsl ~od SgI'ICISIICISI EhPOICSIS)
LIVES Liso
(b) IF PREGNANT I~. MAT THE SOURCE OF TRIS REPORT 0 ERELEASED TO ROE ARMED FORCES
000ITT "~ WEEDS OF GESTATION INSTITA E 0 P OLO Li V ES Li NO
FOR FDA USE ONLY FOR MFS USE ONLY
TWO ORMORE DRUGS Li DRUGN000SED ACCORDING TOLARELING LiORUG WUTDATED
Li OCE000SAGE Li DRAG MISLUOELEO Li CONTAMINATION OF DOUG Li OTCER DRUG MISUSE ISPSCIIF)
FORM FD-1639 (R.o 8/67)
Uss Od21IICOOI SRSSI If osEssss,y.
PAGENO="0089"
ci
0
0
w
t~j
t!j
ci
ci
CI)
PAGENO="0090"
4380 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
8. Precaution should be used in therapy
during lactation because of the pos-
sibility of toxic effects on the nursing
infant.
9. The use of this antibiotic, `as with
other antibiotics, may result in an
overgrowth of nonsusceptible orga-
nisms, including fungi. If infections
caused by nonsusceptible organisms
appear during therapy, appropriate
measures should be taken.
ADVERSE REACTIONS:
1. Blood Dyscrasias
The most serious adverse effect of
chloramphenicol is bone marrow de-
pression. Serious and fatal blood
dyscrasias (aplastic anemia, hypoplas-
tic anemia, thrombocytopenia, and
granulocytopenia) are known to
occur after the administration of
chloramphenicol.
An irreversible type of marrow de-
pression leading to aplastie anemia
with a high rote of mortality is char-
acterized by the appearance weeks
or months after therapy of bone
marrosv aplasia or hypoplasia. Pe-
ripherally, pancytopenia is most often
observed, but in a small number of
cases only one or two of the three
major cell types (erythmcytes, leuko-
cytes, platelets) may be depressed.
A reversible type of bone marrow
depression, which is dose related,
may occur. This type of marrow
depression is characterized by vacu-
olization of the erythroid cells, re-
duction of reticulocytes and leuko-
penia, and responds promptly to the
withdrawal of chloramphenicol.
An exact determination of the risk
of serious and fatal blood dvscrasias
is not possible because of lack of
accurate information regarding 1) the
size of the population at risk, 2) the
total number of dmg-associated
dyscrasias, and 3) the total number
of non-drag associated dyscrasias.
In a report to the Califomia State
Assembly by the Califomia Medical
Association and the State Department
of Public Health in January 1967,
the risk of fatal aplastic anemia was
estimated at 1:24,200 to 1:40,100
based on two dosage levels.
There are reports of aplastic anemia
terminating in leukemia ,attributed to
ehloramphenicol.
Paroxysmal noctumal hemoglobinuria
has also been reported.
2. GastroIntestinal Reactions
Nausea, vomiting, glossitis and stoma-
titis, diarrhea and enterocolitis may
occur in low incidence.
1. Neurofoxic Reactions
Headache, mild depression, mental
confusion, and delirium have been
described in patients receiving chlor-
amphenicol. Optic and* peripheral
neuritis have been reported, usually
following long-term therapy. If this
occurs, the drag should be pramptly
4. Hypersensitivity Reactions
Fever, macular and vesicular rashes,
acigioedema, urticaria ,and anaphyla'xis
may occur. Hersheimer reactions have
occurred during, therapy for typhoid
5. "Gray Syndrome"
Toxic reactions including fatalities
have occurred in the premature and
newborn; the signs and symptoms
associated with these heactions have
been referred to as the "gray syn-
drome". One case of "gray syndrome"
has been reported in an infant bum
to a mother having received chlor-
ampheniccsl during labor. One case
has been reported in a 3 - month
infant. The following summarizes the
clinical and laboratory studies that
have been made on these patients;
(1) In most cases therapy with
chloramphenicol had been insti-
tuted within the first 48 hours
of life.
(2) Symptoms first appeared after
1 to 4 days of continued treat-
ment with high doses of chlor-
amphenicol.
(1) The symptoms appeared in the
following order;
(a) abdominal distension with
or without emesis;
(b) progressive pallid cyanosis;
Ic) vasomotor collapse, fre-
quently accompanied by
irregular respiration;
(d) death within a few hours
of onset of these symptoms.
(4) The progression of symptoms
from onset to exitus was acceler-
ated with higher dose schedules.
(5) Preliminary blood serum level
studies revealed unusually high
concentrations of chlorampheni-
cal (over 90 meg/mI. after re-
peated doses).
(6) Termination of therapy upon
early evidence of the associated
symptomatology frequently re-
versed the process with com-
plete recovery,
DOSAGE AND ADMINISTRATION
DOSAGE RECOMMENDATIONS FOR
ORAL CHLORAMPHENICOL
PREPARATIONS
The majority of micro-organisms sus-
ceptible to chloramphenicol will respond
to a concentration between 5 and 20
meg/mI. The desired concentration of
active drag in blood should fall within
this range over most of the treatment
period. Dosage of 50 mg/kg/day di-
vided into 4 doses at intervals of 6
hours will usually achieve and sustain
levels of this magnitude.
Except in certain cirrumstances (e.g.,
premature and newborn infants and
individuals with impairment of hepatic
or renal function) lower doses may not
achieve these concentrations. Chlor-
amphenicol, like other potent drags,
should be prescribed at recommended
doses known to have therapeutic ac-
tivity. Close observation of the patient
should be maintained and in the event
of any adverse reactions, dosage should
be reduced or the drag discontinued,
if other factors in the clinical situation
permit.
Adults-Adults should receive 50 rag.!
kg/day (approximately one 250 mg.
capsule per each 10 lbs. body weight)
in divided doses at 6-hour intervals.
In exceptional cases patients with in-
fections due to moderately resistant orga-
nisms may require increased dosage up
to 100 mg/kg/day to achieve blood
levels inhibiting the pathogen, but these
high doses should be decreased as soon
as possible. Adults with impairment of
hepatic or renal function or bath may
have reduced ability to metabolize and
excrete the drag. In instances of impaired
metabolic processes, dosages should be
adjusted accordingly. (See discussion
under "Nesvborn Infants.") Precise con-
trol of concentration of the drag in the
blood should be carefully followed in
patients with impaired metabolic
processes by the available microtech-
niques (information available on re-
quest).
Children-Dosage of 50 mg/kg/day
divided into 4 doses at 6-hour intervals
yields blood levels in the range effective
against most susceptible organisms.
Severe infections (e.g., bacteremia or
meningitis), especially when adequate
cerebrospinal fluid concentrations are
desired, may require dosage up to 100
mg/kg/day; however, it is recom-
mended that dosage be reduced to 50
mg/kg/day as soon as possible. Children
with impaired liver or kidney function
may retain excessive amounts of the
drag.
Newborn Infanfs-(See section titled
"Gray Syndrome" under "Adverse Re-
actions.") A total of 25 mg/kg/day
in 4 equal doses at 6-hour intervals
usually produces and maintains concen-
trations in blood and tissues adequate
to control most infections for which the
drag is indicated. Increased dosage in
these individuals, demanded by severe
infections, should be given only to main-
tain the blood concentration within a
therapeutically effective range. After the
first two weeks of life, full-term infants
ordinarily may receive up to a total of
50 mg/kg/day equally divided into 4
doses at 6-hour intervals. These dosage
recommendations are extremely import-
ant because blood concestration in all
premature infants and full.term infants
under two weeks of age differs from
that of other infants. This difference is
due to variations in the maturity of the
metabolic functions of the liver and the
kidneys.
When these functions ace immature, (ox
seriously impaired in adults), high con-
centrations of the drag are found which
tend to increase with succeeding doses.
Infants and Children with Immature
Metabolic Processes-In young infant:
and other children in whom immature
metabolic functions are suspected,
dose of 25 mg/kg/day will usually pro.
duce therapeutic concentrations of thi
drag in the blood. In this group par.
ticularly, the concentration of the drag
in the blood should be carefully followec
by microtechniques. (Information avails
ble on request.)
April 1968 Fond and Drug Administration / U.S. Department of Health, Education, and Welfare / Washington, D.C. 20204
PAGENO="0091"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4381
Dr. LEY. As a result of this letter, we received approximately 275
letters or notes from physicians. Most important, we received 22 ad-
verse reaction reports, as follows-and if I may, let me read them-
five cases of aplasti.c anemia, fatal; three cases of pancytopenia, fata;
three cases of pancytopenia, persistent (not fatal); four leukopenia,
transient, recovered; one nosebleed and paresthesias, recovered; two
cases anemia, recovered; three cases aplastic anemia, still under treat-
ment; and one case of erythema multiforme, recovered.
At the time the "Dear Doctor" letter was mailed, we also contacted
various professional publications-Medical Tribune, Medical World
News, AMA News, and the journals of every State medical society-
asking their cooperation in publicizing the proper use of the drug and
the hazards associated with its use. The labeling revisions and the
warning letter also were widely publicized in the general news media.
Senator NELSON. Doctor, did the FDA do a specific check of all the
State society journals and the AMA and various other medical jour-
nals to see what they did say and do about this.
Dr. LEY. We did not do a specific check of all State society journals.
I have here, if the Senator wishes, a listing of all journals to whom we
supplied this information which can be made available for the record,
if you choose.
Senator NELSON. This is a list of the journals thwt you requested?
Dr. LEY. Yes, sir.
Senator NELSON. Do you have any list of the journals that responded
to the request positively?
Dr. LEY. We have not, sir, as of this date doublechecked all of these
journals to determine whether or not they did make specific references
to the letter and material which we provided them. In some of the more
widely distributed medical publications, the letter and the enclosures
received considera~ble publicity, and I am speaking of "AMA News,"
"Medical World News," "Medical Tribune," and so forth.
Senator NELSON. They did that?
Dr. LEY. They did indeed feature it, and we have copies of the ar-
ticles that appeared in those publications which we would be pleased
to submit for the record.
Senator NELSON. Including JAMA?
Dr. LEY. I will have to check with the staff to determine whether
"JAMA" is included in that list or not.
We were unable to find any reference within "JAMA" itself. How-
ever, "AMA News," which is published by the AMA as a weekly news
magazine, did feature the item significantly.
Advertisements for chloramphenicol-particularly the "reminder"
ads which include no warning information-were also of concern in
connection with the excessive use of this drug.
On April 25, 1968, Dr. James, L. Goddard, then Commissioner of
Food and Drugs, sent Parke, Davis & Co. a letter requesting them to
discontinue such reminder advertisements and reminder labeling for
chloramphenicol. With your permission, I would like to submit a copy
of this letter for the record.
Senator NELSON. You are talking solely about reminder ads of the
kind such as "when it counts, Chloromycetin?"
Dr. LEY. Yes, sir.
Senator NELSON. You requested the discontinuance of this kind of ad
and the company complied with the request?
PAGENO="0092"
4382 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Dr. LEY. That is my belief; yes, sir.
Senator NELSON. None of these reminder ads are being run on Chlor
omycetin any longer?
Dr. LEY. The only ad copy of which we are aware today is this ad
copy here which carries that same front page that you illustrated there-
but is accompanied by the full prescribing information including the
warning in the label.
Senator NELSON. Well, doesn't the company, in many instances~
achieve the same results it was seeking to achieve with the reminder
ads for all those who don't bother to read the fine print?
Dr. LEY. The first page of this spread carries an additional state'
ment, "See following page for prescribing information." If a physician
is to use the drug, unless he has had experience with the dosage in the
past, he would usually refer either to the information in the advertise
ment or to the Physicians~ Desk Reference, which carries exactly the
same information. So that he would be reading the warning and all of
the other information. I cannot however, guarantee that he does this
Senator NELSON. But if the FDA felt it was important enough to
stop the company from using the reminder ad as it stands alone-such
as the example here-it seems pretty obvious to me that the purpose
sought in the ad is to get the benefit of the reminder ad since many
people might not carefully read the fine print. Isn't there a problem
though in that the indications for the use of chioramphenicol have been
changing rapidly in the past half dozen years? And I think, if I re-
member correctly the National Academy of Science Report-it does
not specifically list chloramphenicol as the drug of choice in any case.
Dr. LEY. It does not carry the words, "The drug of choice" in any
case in the present labeling-a drug of choice, yes, with typhoid.
Senator Niii~soN. Pardon?
Dr. LEY. There is the wording, "a drug of choice" for typhoid fever
Senator NELSON. So here you have a situation in which the testi-
mony of all the experts appearing before the committee-unrefuted
by the company or any other witnesses-is that chloramphenicol con-
tinues to be widely prescribed for nonindicated uses. Some of these
nonindicated uses were, I would guess, indicated uses prior to, say,
Ampicillin and some of the newer drugs. So that when a practicing
physician who has been using the drug 5 or 6 years, prior to the re-
vised judgment of what its indications are-sees the 1abelin~ in the
ad, he just doesn't bother to read it-since he may have read it many
times years ago. So isn't thiE, then, really, in effect, a~ reminder ad
with the same effect on that physician-why read this fine print again
for the 10th time?
Dr. LEY. I acknowledge that the physician may not read the fine
print. However, that same physician was exposed to a letter from Dr.
Goddard the text of which specifically highlighted the significant
and important changes in the labeling. Again, I cannot guarantee that
the physician read the letter. But the combination of the letter and
the considerable publicity given after your hearings of last year in
"Medical World News," "AMA News," and "Medical Tribune," I
think must have had an effect of reeducating the physician concern-
ing the indications of use for this drug.
Senator NELSON. Well, there is no question but that the statistics
demonstrate a dramatic drop in the use of the drug, comparing the
PAGENO="0093"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4383
first 6 months of 1967 vis-a-vis the first 6 months of 1968. And, of
course, you have and are presenting the statistics of what happened
the last 3 months of 1968 versus the last 3 months of 1967 when there
was a dramatic increase in the use of the capsule form as contrasted
with the injectable which went down.
The point, it seems to me, still is that it is* widely misprescribed for
nonindicated uses, and every conceivable effort has been made to as-
sure that it will not be used for nonindicated uses. In the wording of
the package insert, FDA, including Dr. Goddard and yourself, takes
the position of the use of the drug should be limited to hospitals. The
committee has had a number of distinguished experts who took that
position. Yet FDA `has not been prepared to confine it to hospital use.
If it were administered only in hospitals, there is no question but that
there would be much more significant control, and a more significant
factor in educating `the doctor about the precautions of this drug.
But since the FDA isn't prepared to do that, and since it continues
to be prescribed widely for nonindicated cases, it seems to me that
FDA ought to be doing every thing else within its power to stop it.
And it seems to me this use of the reminder ad with the fine print
attached still promotes the drug for nonindicated cases. You really
ought to consider whether `this type of ad-even with the fine print-
can be justified.
(The information previously referred to follows:)
DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE,
FOOD AND DRUG ADMINISTRATION,
Washington, D.C., April 25, 1968.
Dr. AUSTIN SMITH,
Parke Davis ~ Co.,
Detroit, Mioh.
Di~&R DR. S~1ITH: Under the existing regulations pertaining to advertisements
for prescription drugs, producer sponsored advertisements have been permitted
an exemption from the requirement of providing a statement of information
in brief summary relating to side effects, contraindications `and effectiveness if
an advertisement contains no information as to indications or dosage recoin-
mendations. In the case of Chioromycetin, we are aware of your use of so-called
reminder advertisements for that product which contain no "Brief Summary."
Taking into account the recent disclosures regarding the broad use of chloram-
phenicol and the urgent need to bring warning information regarding the drug
to the attention of physicians by every means feasible, I am asking that your
firm immediately discontinue using so-called reminder advertisements and re-
minder labeling in the promotion of chioramphenicol, whether or not any such
promotion is entitled to exemption under the reminder advertising or reminder
labeling provisions of the existing regulations.
While we believe that we could require prior approval of chloramphenicol
advertisements under the terms of section 1.105 (j) of the regulations, I would
prefer not to consider proceeding under that concept at this time.
Will you please let me have your comments as soon as possible concerning your
willingness to meet the above request.
Sincerely yours,
JAMES L. GODDARD, M.D.,
Commissioner of Food and Drngs.
PAGENO="0094"
4384 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Chioromycetin
(chioramphenicol)
PARKE-DAVIS
when it counts
PAGENO="0095"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4385
[From Thejournal ofthe American Medical Association,Jan. 22, 1968, pp. 162-163]
may be i nd Ic ated ~ are
short-term and prolonged administration of the drug. Among
in certain severe the reactions reported are blood dyscrasias as mentioned in
the warning. When, during the course of therapy, blood
counts show unusual deviations which may be attributable to
respiratory infections i:~e;~~0::
tinued. Also reported are certain gastrointestinal reactionx
resulting in glossitis and stomatitis, which are indications to
Because of its wide antibacterial spectrum and its ability to diffuse stop the drag On rare occasions, superimposed infection by
into infective foci, CHLOROMYCETtN may be of value in the treat- Candida albicans may produce widespread oral lesions of the
ment of selected severe respiratory tract infections due to suscep- thrush type. Diarrhea and irritation of perianat tissues have
tible microorganisms. However, as with any antibacterial agent, the been reported Pseadomembranous enlerocolilis has been
administration of CHLOROMYCETIN must be adjunctive to the over- reported in a few patients Hypersensitivity reactions
all therapeutic approach to this family of diseases. Appropriately manifested by angioneurotic edema and vesicular and
treated, good results can be expected in bacterial pneumonia and maculopapular types of dermatitis have been reported in
empyema, in bacteria! complications of bronchiectasis and chloramphenicol-sensitive patients. Urticaria and vesicular
bronchitis; all of which are severe disorders often chronic and lesions have been observed They are usually mild in character
difficult to eradicate, and ordinarily subside promptly upon cessation of treatment.
The decision to choose CHLOROMYCETtN from among a group of Febrile reactions have been reported.
antibiotics suggested by in vitro studies to be potentially effective
against a specific respiratory tract pathogen(s) should be guided by A reaction of the Jarisch-Herxheimer type has been reported
severity of infection, relative susceptibility of the pathogen(s) to the following therapy in syphilis, brucellosis, and typhoid fever.
various antibacterial drugs, relative efficacy of the various drugs in Typhoid fever patients have exhibited a shock-type reaction
this family of infections, and the important additional concepts con- characterized by circulatory collapse attributed to sudden
d' th "`b" release of endotoxin. Neurotoxic react:ons, including optic
and peripheral neuritides, headache, mild depression, "dazed
Patients with respiratory tract infections usually become afebnile in feelings," internal ophthalmoplegia, mental confusion, and
18 to 72 hours on recommended doses; roentgenographic clearing delirium have been reported. Symptoms of peripheral neuritis
may be slower, or decreased visual acuity call for prompt withdrawal of the
Neoptastic, fungal, and mycobacterial disease as a cause of persist- antibiotic and the possible use of large doses of oral or
ing respiratory disease should be ruled out by appropriate means. parenteral vitamin B complex. When prolonged high dosage
is necessary, toxic side effects may occur which call for
dosage reduction or discontinuance of chloramphenicol
therapy. Adults and children with impaired liver or kidney
__________________________________________________________ function, or both, may retain excessive amounts of the drug.
____________________ 5 chd I th the d rn wth mf t 1
have resulted from high concentrations of the drug in the
premature and newborn age groups. One case of "gray
syndrome" has been reported in an infant born to a mother
Chioromycetin havmg received cNorarnphenmoi dunng taboc The foPowing
Del I d f m I I d g d t o d dos ge ppe bhl mph ~i h db t dw th th f 4P8Y~w th
he package inserts of CHLOROMYCETIN products for systemic use. of life (2) Symptoms first appeared after 3 to 4 days of
~onsult the appropriate package insert, continued treatment with high doses of chloramphenicol.
(3) The symptoms appeared in the following order: (a) abdom-
Warning: Serious and even fatal blood dyscrasias (aplastic inxl distention with or without emesis; )b) progressive pallid
anemia, hypoplastic anemia, thrombocytopenia, granulocy- cyanosis; (c) vasomotor collapse, frequently accompanied
topenia) are known to occur after the administration of by irregular respiration; and (d) dealh within stew hours of
chloramphenicol, Blood dyscrasias have occurred after both onset of these symptoms. (4) The progression of symptoms
short-term and prolonged therapy with this drug. Bearing in from onset to exilus was accelerated with higher dose
mind the possibility that such reactions may occur, chlor- schedules~)5) Preliminary blood serum level studies revealed
amphenicol should be used only for serious infections caused unusually high concentrations of chloramphenicol after
by organisms which are susceptible to its antibacterial effects. repealed doses. (6) Terminxtion of therapy upon early
Chloramphenicol should not be used when other less poten- evidence of the associated symptomatology frequently
bully dangerous agents will be effective. ft must not be used reversed the process with complete recovery
in the trealment of trivial infections such as colds, influenza, : p t' - " r `n bo `f r r xli ns
or infections of the throat; ores a prophylactic agent to ore- ` p
vent bacterial infections. The use of this antibiotic, as with other antibiotics, may result
Precautions: It is essential that adequate blood studies be in an overgrowth of nonsusceptible organisms, including
m d d g f atm t w th th d g Wh I blood t d e m y f g C I dbb iv I ~ bi I e t I I If ew
or during therapy, the drug should be discontinued and appro-
studies cannot be relied on to detect bone marrow depression ~
prior to development of aplastic anemia. Monitoring of liver and kidney function should be accom-
plished during therapy in patients with existing liver or
~HLOROMYCETIN, an antibiotic having Iherapeutic activity against kidney disease.
i wide variety of organisms, must, in accordance with the cont,dpIs Supplied: CHLOROMYCETIN is available in a variety of forms
the "warning box" above, be used only in certain severe infections, including Kapseals° of 250 mg.
~ontraindicatIons: Chloramphenicol is contraindicated in individuals
with a history of previous sensitivity reaction to it,
must not be used in the treatment of trivial infections such as colds,
nfluenza, or infections of the throat; or as a prophylactic agent to
irevent bacterial infections.
PAGENO="0096"
4386 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
when it counts
CHLOROMYCETIN® Kapseals®
(CHLORAMPHENICOL CAPSULES)
DESCRIPTION
Chloramphenicol is an antibiotic that is clinically useful for, and
should be res~d fur seeions infections caused by organisms sus-
ceptible so its antimiceobial effects when less potentially hazardous
therapeutic agents ace ineffective ue consraindicoted. Sensitivity
testing is essential to determine its indicated use, but maybe per-
formed concoreensly with therapy initiated on clinical impression that
one of the indicated conditions mists (see "Indications" section).
ACTIONS AND pHARMACOLOGY
Isivitso chloramphenicol meets mainly a hacteriossatic effecton a wide
range of gram-negative and gram-positive bacteria and is active irs
vitro against rickettsias, she lymphogranuloma'psittacosis group and
Vibsio cliolesae. Is is particularly active against Salmonella typhi and
Hemopliilss irsfluesoae. The mode of action is through interference
orinbibition of protein synthesis in insacscells and in cell-freesystemo.
Chloramphenicol administered orally is absorbed rapidly from the
intestinal tract. In controlled stoodiro in adult volunteers using she
recommended dosage of 30 mg/kg/day, a dosage of 1 gm. every 6
hours foe 8 do ses tvas gisen. Using she microbiological assay method,
the average peak scram level was 11.2 meg/mI. one hour after she
first dose. A cumulative effect gave a peak rise so 18.4 meg/mI. after
she fifth dose of 1 gm. Mean scram levels ranged from 8-14 mcg./ml.
over the 48-hour period. Total urinary rocre sion of chloramphenicol
in these studies ranged fmm a low of 68% to a high of 99% over a
three-day period. From 8 to 12% of the antibiotic excreted is in the
form of free chloramphenicol; the remainder consists of microbio-
logically iosacsise mesabolites, principally the conjugate with gb-
curonic acid. Since she gburaronide is excrete d rapidly, most
chloramphenicol detected in she blood is in the mierobiobogically
active free form. Despite the small proportion of unchanged drag
excreted in the urine, the concentration of free chboramphenicol is
relatively high, amounting to several hundred meg/mI. in patients
receiving divided doses of SO mg/kg/day. Small amounts of active
drug are found in bile and frces. Chboramphenicol diffuses rapidly,
bus its distribution is not uniform. Highest concentrations are
found in liver and kidney, and lowest coocentrasions are found in
brain and cerebeospinal fluid. Chboramphenicol corers cerebeospinal
fluid even in the absence of m eningeal inflammasioo, appearing in
concentrations about half of those found in the blood. ,Measurable
level sate also detected in pleural and in ascisic fluids, saliva, milk
and in the aqueous and vitreous humors. Transport across the placen-
ral barrier occurs svith somewhat loiter concentration in rued blood
of newborn infants than in maternal blood.
INDICATIONS
IN ACCORD WITH THE CONCEPTS IN THE "WARNING
BOX" AND THIS INDICATIONS SEcTION, CHLORAMPHEN-
ICOL MUST BE USED ONLY IN THOSE SERIOUS INFEC-
TIONS FOR WHICH LESS POTENTIALLY DANGEROUS
DRUGS ARE INEFFECTIVE OR CONTRAINDICATED.
HOWEVER, CHLORAMPHENICOL MAY BE CHOSEN TO
INITIATE ANTIBIOTIC THERAPY ON THE CLINICAL
IMPRESSION THAT ONE OF THE CONDITIONS BELOW IS
BELIEVED TO BE PRESENT; IN VITRO SENSITIVITY
TESTS SHOULD BE PERFORMED CONCURRENTLY SO
THAT THE DRUG MAY BE DISCONTINUED AS SOON AS
POSSIBLE IF LESS POTENTIALLY DANGEROUS AGENTS
ARE INDICATED BY SUCH TESTS. THE DECISION TO
CONTINUE USE OF CHLORAMPHENICOL RATHER THAN
ANOTHER ANTIBIOTIC WHEN BOTH ARE SUGGESTED BY
IN I'ITRO STUDIES TO BE EFFECTIVE AGAINST A
SPECIFIC PATHOGEN SHOULD BE BASED UPON SE-
VERITY OF THE INFECTION, SUSCEPTIBILITY OF THE
PATHOGEN TO THE VARIOUS ANTIMICROBIAL DRUGS,
EFFICACY OF THE VARIOUS DRUGS IN THE INFECTION,
AND.THE IMPORTANT ADDITIONAL CONCEPTS CON-
TAINED IN THE "WARNING BOX" ABOVE:
1. Acute infections caused byssosceptible strains of
Salsetisetellit typhi
Chloramphenicol is a drug of choice.' It is not recommended for
the routine treatment of the typhoid "carrier state."
`In she s,rasmrxi of ,yphoid feces some au,hoeisies eeecmmrod hoe chloe
omphenicol he odmiois,rsed or shesopeusic rant foe 0.10 do ys ohee she
posirus has become ufebsile so rtiss she pussibiiiiy of ,eiupsr.
2. Serious infections caused by susceptible strains in accordance
with the concepts expressed aboves
a. Salmonella species
b. H. ixfluerinae, specifically meningeal infections
c. Ricketesia
d. Lymphogranuloma.psittacosis group
e. Various gram-negative bacteria causing bacteermia, meningitis
or other serious gram-negative infections
Other susceptible organisms which have been demonstrated tube
resissa us so all other appropriate anti-microbial agents.
3. Cystic fibrosis regimens
CONTRAINDICATIONS
Chboramphrnicol is consraindicated in individuals wish a history of
previous hypersensitivity and/or toxic reaction suit. Is muss not be
used in she treatment of trivial infections or xvhrrr it~~iiidièated,
~1~'colcis, influenza, infections of the throat; orasaprophybactic
ijOi8so prevent bacterial infections.
PRECAUTIONS
I. Baseline blood ssodirs should be folloxved by periodic blood
studies approximately every two days during therapy. The drag
should be discontinued upon appearance of mesicubocytopenia,
leukopenia, sheombocysopenia, anemiu, or any other blood srady
findings attributable so chloramphenicob. Hoo~evrr, is should be noted
shot such sradirs d onus rxc lode she possible later oppearance of she
irreversible type of bone morrow depression.
2. Repeated courses of she drag should be avoided if as all possible.
Treatment should not be continued longer than required so produce
cure wish little or no risk of relapse of she disease.
3. Concurrent therapy xvish other drugs shot may cause bone
marrox depression should be avoided.
4. Excessive blood levels may result from administration of she
recommended dose so patients svish impaired liver or kidney func-
tion, including shot due so immature metabolic processes in she infant.
The dosage should be adjusted accordingly or, preferably, she blood
concentration should be determined as appropriate intervals.
5. Tb err are no studies so establish she safety of this drag in
pregnancy.
6. Since ebboramphenicol readily crosses she placental barrier,
caution in use of she drug is particularly important during preg-
nancy as term or during labor because of potential tonic effects on
she feras (gray syndrome).
7. Precaution should be used in therapy of premature and full-term
infants so avoid "gray syndrome" toxicity. (See "Adverse Reactions.")
Scram drag levels should b ecarefully followed during therapy of
she neo'born infant.
8. Precaution should be used in therapy during lactation because of
she possibility of toxic effects on she nursing infant.
9. The use of this antibiotic, as xsish usher antibiotics, may result in
anoveegrooth of nonsuscepsible organisms, including fungi. If
infections caused by nonsuscepsible organisms appear during therapy,
appropriate measures should be token.
WARNING
Serious and fatal blood dysceasias (aplastic anemia, hypu-
plastic anemia, theombocytopeOia, and granulocylopenia)
are known so occur after the admioistratiun of chtoram-
phenicol. In addition, there hate been reports of aplastic
anemia attributed to chloramphmnicol which later termi-
nated in Irukemia- Blood dyscrasias hose occurred after bush
short term and prolonged therapy with this drug. Chboram-
phenicol must nut hr used when less potentially dangrrous
agents will be effective, as described in the "Indications" see-
~Thihdqbtd~
made during trratmmnt with the drug. While blood studies
may detect early peripheral blood changes, such as leuko-
pmnia, reticulocytopenia, or geanulocytopenia, before they
become irreversible, such studies cannot be relied on to detect
bone marross deprestion peioe to deselopment of aplassic
anensia. To facilitate appropriate studies and observation
during therapy, it is desirable that patients he hospitalired-
PAGENO="0097"
ADVERSE REACTIONS
1. Blood Dyscrasias
The most serious advesseeffect of chloramphenicol is bone marrosv
depression. Serious and fatal blood dyscrasias (aplastic anemia,
hypoplastic anemia, thrombocytopenia, and granulocytopenia) are
known to occur after the administration of chloramphenicol. An
irreversible type of m arrow dopeession leading to aplastic anemia svith
a high rate of mortality is characterized by the appearance sveeks or
months after therapy of bone maccow aplasia or hypoplasia. Periph-
erally, pancytopenia is most often observed, but in a small number
of eases only one or two of the three major cell types (eeythrocytcs,
leukocytes, platelets) maybe depressed.
A reversible type of bone marrow depression, which is dust related,
may occur. This type of marrow depression is charactenard by var-
uolization of the eryshcoid cells, reduction of reticulocytes and leuko-
peniu, and responds promptly to the withdrawal of chloramphenicol.
Anexactdeterminationofthreiskofseeiousand fatalblooddyscrasias
is not possible because of lack of accurate information regarding 1) the
size of the population at risk, 2) the total number of drug-associated
dysceasias, and 3) the total number of non-dflug associated dyscrasias.
In a report to the California State Assembly by the California
Medical Association and the State Department of Public Health in
January 1967, the risk of fatal aplastic anemia was estimated at
1:24,200 to 1:40,500 based on twa dosage levels.
There have been reports of aplastic anemia attributed to chloram-
phroicol sshich later terminated in leukemia.
Parosysmal nocturnal hemoglobinuria has also been reported.
2. Gastrointestinal Reactions
Nausea, vomiting, glossitis nod stomatitis, diarrhea and entero-
colitis may occur in low incidence.
3. Neurotoxic Reactions
Headache, mild depression, mental confusion and delirium have
been dcsceibed in pati rots receiving chlocamphenicol. Optic and
peripheral neuritis have been reported, usually follawinglong-teem
therapy. If this nccnrs, the drug should be promptly withdrawn.
4. Hypersensitisity Reactions
Fever, maculac and vesicul areas hes, anginedema, oetieaeia and
anaphylanis may occur. Heexheimer reactions have occurred daring
therapy for typhoid fever.
5. "Gray Syndrome"
Tonic reactions including fatalities have occurred in the premature
and nesvborn; the signsand symptoms associated with these reactions
have been referred to as the "gray syndrome". One case of "gray
syndrome" has been reported in an infant born to a mother having
received chloramphenicol daring labor. One case has been reported in
a 3 month infant. The follosving summarizes the clinical and labo-
ratory studies that have been made on these patients:
(I) Inmost cases therapy with chloramphenicol had been instituted
svithin the first 48 hours of life.
(2) Symptoms first appeared aftee 3 to 4 days of continued treatment
svith high doses of chloramphenicol.
(3) The symptoms appeared in the follosving order:
(a) abdominal distension svith or without emesis;
(b) progressive pallid cyanosis;
(c) vasomotor collapse, frequently accompanied by irregular
(d) death within a few hours of onset of these symptoms.
(4) The progression of symptoms from onset to coitus was accelerated
with higher dose schedules.
(5) Preliminary blood serum level studies revea led unusually high
concentrationsofchloeamphenicol(over9O meg/mI. of see ccpeated
doses).
(6) Termination of therapy upon early evidence of the associated
symptomutology frequently reversed the process with complrtr
recovery.
DOSAGE AND ADMINISTRATION
DOSAGE RECOMMENDATIONS FOR ORAL
CHLORAMPHENtCOL PREPARATIONS
The majority of microorganisms susceptible to chloramphenicol svill
respond so a concentration betsveen 5 and 20 meg/mI. The desired
concentration of active drug in blood should fall svithin this range
over most of the treatment period. Dosage of SO mg/kg/day
divided into 4 doses at intervals of 6 hours svill usually achieve and
sustain levels of this magnitude.
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4387
Encept in certain circomstances (e.g., premature and newborn in-
fants and individuals scith impairment of hepatic or renal function)
losser doses may not achieve these concentrations. Chloramphenicol,
likeothee potent drugs, should be prescribed at recommended doses
known to has'e therapeutic activity. Close observation of the patient
should be maintained and in the event of any adverse reactions,
dosage should be reduced or the drug discontinued, if other factors
in the clinical situation permit.
Adults
Adults should receive 50 mg/kg/day (approximately one 250 mg.
capsule per each 10 lbs. body weight) in divided doses at 6-hour
intervals. I nesceptional cases patients with infections due to moder-
ately resistant organisms may require increased dosage up to
100 mg/kg/day to achieve blood levels inhibiting the pathogen, but
these high doses should be decreased as soon as possible. Adults with
impairment of hepatic or renal function oe both may have reduced
ability to metabolize and excrete the drug. In instances of impaired
metabolic processes, dosages should be adjusted accordingly. (See
discussion under Ness'born Infants.) Precise control of concentration
of the drug in the blood should be carefully followed in patients with
impaired metabolic processes by the available miceotechniques
(information available on request).
Children
Dosage of 50 mg/kg/day divided into 4 doses at 6-hour intervals
yields blood levels in th ecange effective against most susceptible
organisms. Severe infections (e.g., bactreemia or meningitis), especially
when adequate cerebrospinal fluid concentrations ace desired, may
require dosage up to 100 mg/kg/day; however, it is eecommended
that dosage be reduced to 50 mg/kg/day as soon as possible. Chil-
deco svith impaired liver or kidney function may retain excessive
amounts of the drug.
Newborn Infants
fSee section tilled "Gray Syndrome" under "Adverse Ifleoelions.")
A total of 25 mg/kg/day in 4 equal doses at6-liose inseevals usually
produces and maintains concentrations in blood and tissues adequate
to control most infections foe which the drug is indicated. Increased
dosage in these individuals, demanded by severe infections, should be
given only to maintain the blood concentration svithi nathera prod-
cally effective range. After the first two weeks of life, fall-teem infants
oedinaeily may receive up to a total of 50 mg/kg/day equally
disided into 4 doses at 6-hour intervals. These dosage recommenda
tions are esteemely important because blood concentration in all
premature infants and full-term infants under two weeks of age differs
from that of other infants. This difference is due to variations in the
maturity of the metabolic functions of the liver and the kidneys.
When thesefunutiunsure immatuer(orseriouxlyimpuiredioadults),
high concentrations of the drag are found which tend to ioveruse with
succeeding doses.
Infants and Children with Immature Metabolic Processes
In young infants and other children in whom immature metabolic
functions ace suspected, a dose of 25 mg/kg/day will usually pro-
dare therapeutic concentrations of the drug in the blood. In this
group particularly, the concentration of the drug in the blood should
be carefully follosved by microtechniques. (Information available
on request.)
PACKAGE INFORMATION
Kapseals No. 379, Chloromycetin (chloramphenicol capsules), each
contain 250 mg. chloramphenicol, supplied in packages of 16 and
100, and Roll-Pak° of 100.
Capsules No. 477, Chloromycenin (chloramphenicol capsules), each
contain 50 mg. chloramphenicol, supplied in packages of 25 and 100.
Capsules No. 480, Chloromycetin (chloramphenicol capsules), each
contain 100 mg. chloramphenicol,supplied in packages of 25 and 100.
Oral Suspension Chlocomycetin Ichlocamphenicol) Palmitate, each
4cc. represents 125 mg. chlocamphenicol, (each cc. contains chloe-
amphenicol palmitate equivalent to 31.25 mg. chloramphenicol with
0.5% sodium beozoate as preservative), in bottles of 60cc.
Chloramphenicol Palmitate is hydrolyzed to chloramphenicol
before absorption. Resulting blood concentration is similar to that
produced by the oral administration of chloramphenicol.
CHLOROMYCETIN, brand of chloramphenicol, Reg. U.S. Pat. Off.
Parke, Davis & Company, Detroit, Michigan 48232
PARKE-DAVIS
81-280 0-69-pt. 11-7
PAGENO="0098"
4388 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. Please go ahead.
Dr. LEY. In a letter dated May 1, 1968, the firm notified us that it
had discontinued all "reminder advertisements" in March of 1968,
with the exception of those ads that were too far along in the publica-
tion process to be cancelled.
Dr. L. M. Lueck, of Parke, Davis, also said in this letter that the
distribution from Detroit of all "reminder" pieces-such as rulers,
pencils, and calendars-had been discontinued. He said this practice
also was being discontinued in the field as rapidly as possible. Since
that time, ads for the drug have carried essentially the full disclosure
information from the package insert of the dangers and side effects
associated with the use of chloramphenicol and the "box warning"
that is part of the labeling.
On June 27, 1968, we issued a revision of the prescription drug ad-
vertising regulations applicable to "reminder" advertising which took
into account our experience with chloramphenicol. Under these regula-
tions, if the Commissioner finds there is evidence of a significant in-
cidence of fatalities or serious side effects associated with the use of
a particular drug, he can, by notifying the firm forbid the use of
"reminder" advertisements that omit warning information.
On March 12, 1968, we met with representatives of Parke, Davis
`and the Pharmaceutical Manufacturing Association to determine
whether the advertisement which appeared in the Reader's Digest is-
sue of February 1968 "was caused to be disseminated" by the drug
firm. This a.d, in our view, recommended the drug for uses that were
not warranted and seriously understated the hazards, side effects,
and contraindications.
As a result of the meeting, we learned that the idea for this ad
originated with the advertising agency handling the public relations
program for PMA. The copy was reviewed and approved by PMA.
Parke, Davis was subsequently asked to review the copy and to give
permission for the use of the names of Dr. Payne and Dr. Burkholder.
Funds for the advertising program which included this ad were con-
tributed `by approximately 100 members of PMA. Dr. Goddard ac-
cepted the explanation that PMA, not Parke, Davis was responsible
for the ad.
Senator NELSON. May I interrupt for a moment.
We discu~sed this at great length with Dr. Goddard in the spring
of 1968 and I raised the point that it didn't seem rational to permit
Parke, Davis as a contributing membei of the PMA to sort of duck its
responsibility since it was the advertising firm and PMA that paid for
the ad with Parke, Davis, in fact, reviewing the ad. There is a further
question-as a member of the PMA any member company must have
imputed to it responsibility for whatever the corporation is that they
really own and control. If that is not the case, then any company can
escape responsibility for an ad, which really violates FDA rules and
regulations, by simply saying, well, it was the advertising firm and
the PMA; although they all run the PMA, in this way they escape
responsibility. I thought it was a very inappropriate ruling on the part
of FDA.
My question is, What is the policy as to future situations such as
this? Will the `company `be held accountable or will they be excused?
PAGENO="0099"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4389
Dr. LEY. I would like to ask our General Counsel, Mr. Goodrich to
respond to this question, if I may, Senator.
Mr. GOODRICH. When we were here last spring we did have this
conversation about imputing the responsibility to the company Dr.
Goddard and I concluded that before making any recommendations
we should get PMA and Dr. Smith, the president of Parke, Davis, in
to find out what the relationship was. The facts that we developed are
as stated in this statement. It is possible legally to argue that mere
membership, contribution to this PR fund is the causing tof the dis-
semination of the ad, but this would be a very difficult point to make
in a criminal case, and Dr. Goddard accepted the explanation on this
ad.
In the future, of course, we are going to try to avoid this sort of
thing. We expressed both to Parke, Davis and to PMA our displeasure
with this ad, and you had done the same thing. I do not think it will
occur again, and it has not in the future advertisements of this type
which appeared after this ad in the Reader's Digest.
Senator NELSON. Well, I suppose as lawyers we may have a differ-
ence of opinion as to what may or may not be difficult to prove.
Mr. GOODRICH. Right.
Senator NELSON. I would think it would be almost automatic if
the facts are as stated here, where the company itself, and 99 or so
other associates own the PMA; it is their creature; next, all the ads
are paid for by contributions to the PMA, it has no independent status
of its own at all, then the ad is reviewed by Parke, Davis, and it makes
broader claims than the FDA would approve. I don't think there
would be any question in the world but what the firm would be as-
signed a responsibility for that ad in any kind of a lawsuit. You may,
of course, differ on that. My concern would be, at least, that they be
notified that in any future case you: will try it.
Mr. GOODRICH. Right.
Senator NELSON. You will try a lawsuit and then find out what the
law is.
Mr. GOODRICH. That was done.
Senator NELSON. You did try it?
Mr. GOODRICH. That we have told them that this kind of practice
in the future would be considered for possible prosecution.
Senator NELSON. I see. All right. Please continue.
Dr. LEY. Let me turn now to another problem associated with
chioramphenicol. In May 1968, after reviewing all the blood-level
data in our files on chlorampheniool for parenteral use, we concluded
that chioramphenicol sodium succinate injection produced lower blood
levels than the oral preparations. We suspended certification of chior-
amphenicol succinate pending resolution of the question about the
therapeutic effectiveness of these lower blood levels. Certification was
resumed in September 1968, as will be explained shortly when I discuss
revision of the labeling of parenteral forms of chloramphenicol.
Senator NELSON. May I interrupt for a moment?
Dr. LEY. Certainly.
Senator NELSON. As I recall it, the issue was raised a year ago in
December; is that correct?
Dr. LEY. September 1967.
PAGENO="0100"
4390 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELsoN. Yes. The question raised was that the other chlor-
amphenicols in the marketplace did not achieve the same blood level
at the same time as Parke, Davis' chloramphenicol, is that correct?
Dr. Lny. That is correct, sir.
Senator NELSON. Is there a.ny clinical evidence at all that demon-
strates that one blood level has a better therapeutic aspect than the
others?
Dr. LEY. There is no evidence of this sort currently in our files. I
would like, if I may, to trace the history of that particular incident
because it might be valuable in further discussion here this morning.
Senator NLr~soN. Fine.
Dr. LEY. In October of 1966, the date the chloramphenicol patent
protection expired, several other firms petitioned us to approve cer-
tification for competing brands of chloramphenicol. In retrospect, the
decision that was made at that time was in error. The staff of scientists
at FDA considered that with a drug which could be synthesized, such
as chloramphenicol can, which can be analyzed carefully and accu-
rately, that permitting marketing on the basis of purely chemical
standards of purity, identity, et cetera, would provide a product which
was comparable in every respect to the original product in the market-
place. This assumption was subsequently found to be false.
At this point, when we recognized the blood levels from the later
competing manufacturers of the product were at variance, in that they
appeared more slowly than the blood levels from the Parke, Davis
product, we faced the question of whether we could clearly define a
blood level as being effective for this condition or that condition.
The decision which we finally made in December of 1967, Mr. Chair-
man, was a decision that each one of the competing firms could have
one or the other of two choices. Either they could demonstrate by test-
ing in human substance that the blood level which their product pro-
duced was equivalent to the same blood level of the Parke, Davis prod-
uct which was supported by adequate clinical data in the past, or as
their second choice, they could collect and submit to us clinical data
demonstrating the efficacy of their product even though it had a lower
blood level. None of the manufacturers elected to ta.ke the second
course; all chose the first course of action. So that at this point in
time, the three manufacturers of chloramphenicol who are currently
marketing their product all have blood levels which are essentially
identical when tested in human substance.
Senator NELSON. So there is no positive clinical evidence that one
blood-level achievement in x period of time is more effective than
another.
Dr. LEY. The information of this sort is extremely rare, and there
are several studies in progress at the moment that might eventually
prove that a lower dosage of chioramphenicol would be effective in
treating, let's say, typhoid fever than the dosage which was first given
in the literature, but these data are not yet in. This is the extent to my
knowledge-and I'll have to ask Dr. Minchew to be absolutely cer-
tain-of the type of data that are available linking blood levels with
clinical efficacy for this product. Is this correct?
Dr. MINOHEW. Yes.
Senator NELSON. Because the claims made by the PMA at that time,
you know, were that this just proves the case that generics or that
PAGENO="0101"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4391
the brand names are better, and so forth, when, in fact, it didn't prove
anything except they achieved different blood levels. You could have,
I suppose, a situation where the companies that came in last were,
in fact, companies who discovered the drug and then along came
another company that achieved a higher blood level 17 years later.
Without some clinical tests, it doesn't prove anything one way or
another; is that correct?
Dr. LEY. That is the position we have taken. I believe it is a sound
one.
Senator NELSON. Mr. Gordon.
Mr. GORDON. Mr. Chairman, I have just one question.
Concerning the succinate form of chloramphenicol, am I correct
that the intramuscular and the subcutaneous forms are effective only
through the intravenous route?
Dr. LEY. We came a little later to this point in discussing the
Academy recommendations. Let me say that current labeling for the
succinate labeling that is currently being distributed with new suc-
cinate entering the market, limits in its indication the use of succmate
through the intervenous route. The instramuscular and subcutaneous
routes are not recognized on the basis of clinical `data submitted to us
as appropriate routes for administration of succinate form at this
point in time.
Mr. GORDON. Are there any drugs on the market now of chloram-
phenicol which is labeled intramuscular and subcutaneous?
Dr. LEY. Material which was distributed into the market prior to
the revision of the labeling still contains in the package for that prod-
uct labeling which was prepared under the old set of guidelines before
we received the Academy comments. The other means of getting in-
formation on succinate; namely, the Physicians' Desk Reference, and
current package inserts which may be requesed from the firm by
physicians, are all revised to include the intravenous route only.
Mr. GoRDoN. If you have a mislabeled drug on the market, you gen-
erally recall it, don't you?
Dr. LEY. This is a question that depends upon the particular cir-
cumstances. If there is an immediate and clear-cut hazard in the
taking of such a drug by a patient, let's say contamination, super-
potency or subpotency, the drug itself would be recalled. In this case,
we do not question the drug itself.
It is the insert that accompanies the drug which has been modified
in the subsequent period since this drug was put into warehouses,
pharmacies, and so forth.
Mr. GORDON. What happened with the products of the smaller com-
panies that were on the market when there was mislabeling?
Dr. LEY. That was not simply a question of mislabeling. That was a
question in which our laboratory tests demonstrated that the product
of the smaller companies, without exception, as nearly as we could
determine, had a drug on the market, irrespective of the labeling,
which was not capable of performing in a comparable fashion to the
original reference product, the Parke, Davis product. That was a
defective drug.
Mr. GORDON. Are you speaking of the injeotables?
Dr. LEY. No, I am speaking of the oral in that case.
Mr. GORDON. We are now talking about the succinate form, the
injectables.
PAGENO="0102"
4392 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
Dr. LEY. All right.
Mr. GORDON. How were the smaller companies treated?
Dr. LET. There is only one other firm besides Parke, Davis which
is marketing succinate at this point in time. That firm's application for
approval of the product was submitted-do you remember the exact
date that came in?
Dr. MINOHEW. It was in, I think, late 1967.
Dr. LET. Approximately late 1967-and approved following the
receipt of the Academy recommendations on the succina.te product.
All labeling for that product is the new labeling revised along the
lines of the Academy recommendations.
Senator NErsoN. Please proceed, Doctor.
Dr. LET. As a part of the overall review of drug efficacy being con-
ducted for FDA by experts selected by the NAS-NRC, the Panel on
Anti-Infective Drugs has been studying the various dosage forms of
chioramphenicol. On August 9, 1968, we received reports from the
Academy giving the results of this study. I submit copies for the
record.1 These reports showed that the Panel on Anti-Infective Drugs:
(1) Endorsed the warnings that FDA required in the ltheling
of chioramphenicol.
(2) Emphasized the toxicity of the antibiotic.
(3) iRecommended the use of less hazardous agents where they
could be expected to accomplish the desired therapeutic effect.
FDA reviewed the Academy reports and agreed with them.
We also reviewed, in the light of these reports, the labeling we had
developed in May for the various chioramphenicol preparations and
concluded that:
(1) The labeling of chloramphenicol capsules was consistent
with the Academy's recommendations.
(2) The labeling of chloramphenicol palmitate oral suspension
was consistent with the recommendations.
(3) The labeling for parenteral forms of chloramphenicol re-
quired further revision. The panel had noted the higher and pref-
erable blood levels obtained by intravenous use, compared with
intramuscular administration. It also recommended a change to
the oral chloramphenicol as soon as possible since these gave bet-
ter blood levels. The new labeling reflecting these recommenda-
tions, was approved on September 3, 1968. I submit a copy of
the revised labeling for the record.'
The Academy reports also discussed the effectiveness, or probable or
possible effectiveness, of chioramphenicol in treating a variety of spe-
cific conditions for which it had been promoted-such as various sur-
gical infections, respiratory tract infections, and urinary tract infec-
tions-but none of these are listed specifically in the drug's current
labeling, which is oriented to causative organisms rather than sites of
infection.
Senator NELsoN. Do I understand, then, that this kind of ad, which
shows a bronchoscope, is now prohibited?
Dr. LEY. That ad is no longer running. We would not look with
favor upon such an ad.
Senator NELSON. Was there any valid medical reason for using the
`See information, pp. 4407-4470.
PAGENO="0103"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4393
bronchoscope associated with chloramphenicol at any time in the his-
tory of this drug?
Dr. LEY. This is difficult to say. In the 1950's perhaps this might
have been a very reasonable correlation, bronchoscopy, severe pulmo-
nary infection, lung abcess, and chioramphenicol. We have very care-
fully looked at this and the similar cystoscope ad, and although the
text is absolutely word-for-word as stated in the package insert, we
feel at this point in time that that type of visual display with that copy
is inappropriate.
Senator NELSON. The drug has never been indicated, has it, for any
upper respiratory diseases?
Dr. LEY. No, sir. It is not so indicated now. However, in the very
early days in antibiotic therapy, chloramphenicol, tetracycline, and so
forth, were widely used for many infections. That was in the late
1940's and early 1950's. Times have changed.
Senator NELSON. It is well known in the scientific community that
if the ad were ever justified, it was many, many years ago, is that
correct?
Dr. LEY. We believe that statement is correct.
Senator NELSON. And this ad was run on February 5,1968?
Dr. LEY. I'm aware of that. It has since terminated.
Senator NELSON. So this ad was run many years after any conceivable
claim could have been made for this kind of indication?
Dr. LEY. I would agree.
Senator NELSON. Fine.
Dr. LEY. The same orientation, I might add, will be used for other
antibiotics as labeling is revised to carry out efficacy recommendations
of the National Academy. The rational choice of an antibiotic should
be predicated on the judgment of the prescribing physician as to the
causative organism. It also should take into consideration the possible
adverse effects of an antibiotic as well as its established efficacy. The
current package insert for chloramphenicol, as I indicated a moment
ago, illustrates this approach. The indications section is basically ori-
ented to causative organisms and the labeling also highlights the seri-
ous adverse effects of the drug.
I know that the committee is specifically interested in the overall
use of this antibiotic. After the hearing before this committee last Feb-
ruary, the issuance of the FDA "Dear Doctor" letter, and the discon-
tinuance of "reminder" advertising for the drug, the quantities of
chloramphenicol certified dropped materially. In calendar year 1968,
we certified for all dosage forms for systemic use slightly less than
half as much as in 1967.
This is still, in our opinion, more than is needed for all of the ap-
proved uses of the drug and we are exploring further measures that
may be in order.
Senator NELSON. Yesterday, Doctor Wehrle-I hope my memory is
correct-in making some judgment about the use of chloramphenicol
and using the statistics from his hospital and extrapolations from
there, concluded that of the 30 million hospitalized patients annually,
if the same standards for use were applied as were established for his
hospital, about 2 million grams a year would be used on hospitalized
patients. I am sure you are aware this was formerly Los Angeles Gen-
PAGENO="0104"
4394 COMPETITIVE PROBLEMS~ IN THE DRUG INDUSTRY
eral, now `associated with the university. I think it is the largest hospi-
tal in the United States.
He made the further point that they had a much higher incidence of
very serious illness in that hospital than the ordinary hospital had.
So they would use more of the drug on the average per patient than
most hospitals would.
Anyway, his conclusion was, extrapolating from their usage and
the controls they have established over usage, that about 42 million
grams, or slightly over, were used in 1967.
Dr. LEY. That is correct.
Senator NELSON. Then it dropped to 17, is that correct?
Dr. LEY. Our figures on certification for systemic forms of therapy-
that would be parenteral and oral capsules-are approximately, within
a few hundred thousand, 20 million grams certified for last year.
Senator NELSON. Versus 42 million grams for 1967?
Dr. LEY. Yes, sir.
Senator NELSON. Do you have any statistics that might be in any
way comparable to Dr. Wehrle's showing how many grams of chlor-
amphenicol would be indicated if it were confined to its proper use?
Dr. LEY. This is a very difficult question to answer, Senator Nelson.
We have put considerable thought on this particular question within
the past several weeks. We have certain focal points that we can be
reasonably certain of. For example, the fact that there were in 1967,
396 cases of typhoid fever in this country which would be suitable
candidates for therapy. There were reported-and this is just a small
fraction of the total-18,120 salmonellosis severe enough to warrant
the attention of physicians.
Senator NELSON. May I interrupt for just one second?
Dr. LEY. Yes, sir.
Senator NELSON. Dr. Wehrle's extrapolation from that was, assum-
ing that 10 percent of those were reported, you get a figure then of
180,000 cases that might indicate its use. Is that, in your judgment, a
reasonable estimate?
Dr. LEY. This would be a rough estimate of the nature of salmo-
nellosis in this country that conceivably could need therapy.
We included in the labeling a strong insistence of the Cystic Fibrosis
Association, a specific use of the drug in cystic fibrosis regimens. There
are according to the foundation 7,000 such children and young adults
who may require continuous ant.ibiotic prophylaxis to prevent serious
infection and death in this rather tragic disease.
Senator NELSON. That doesn't mean that chloramphenicol is indi-
cated for all 7,000, does it?
Dr. LEY. Not necessarily, Senator, although the drug is preferred in
many of these infants and children because of the problems of giving
multiple drugs and because the risk of death due to infection is very
high in this group. But if we take these figures, we have a total of
396, 180,000, and 7,000, which would be roughly 190,000, 200,000
patients.
Senator NELSON. And as I recall it, estimates were that in 1967
about 4 million people were administered chloramphenicol, is that
about correct?
Dr. LEY. This is based upon the assumption of an average dose per
patient and the total certification. The total certification does not nec-
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4395
essarily represent sales for the same time period, although the two are
closely related over a longer time span.
Senator NELSON. I would assume that is the case, since in June of
1968, you certified zero, which we assume meant that it was still used
in the United States, but that some had been left on the shelf.
Dr. LEY. That is correct. The California data indicated that on the
average in the patients who have received chloramphenicol there are
a very small amount of the drug was given, approximately four to
four and a half grams. However, in treatment of typhoid fever and
salmonellosis, a very typical total dosage for an adult would be a total
of 50 grams of the drug, approximately 4 grams per day over an ex-
tended period of 10 to 12 to 14 days.
Senator NELSON. Was that a small number of people percentage-
wise?
Dr. LEY. That is a small number of people. In terms of salmonella
infections, amounts in the order of 30 grams over a period of a week
would be typical. The estimates of how many people received the drug
are based, to my best knowledge-and Mr. Gordon, I think is well
aware of this-on dosage levels of the order of 4 grams per patient.
* Senator NELSON. Pardon me?
Dr. LEY. The estimate of the number of patients receiving the drug
is made on the basis of an average : dose of about 4 grams per patient.
Senator NELSON. It was my understanding 9.5.
Dr. LEY. 9.5?
Senator NELSON. I may be wrong about that. My memory was 9.5.
There is a significant difference.
Mr. GORDON. The California study showed that the average dose
was 9.55 grams.
Senator NELSON. I suppose none of these statistics are very firm.
Dr. LEY. They're not.
Senator NELSQN. I notice some dosages are as low as 4 grams and
you have cited instances of 30 and 50. In any event, a very large num-
ber of people are receiving it?
Dr. LEY. However, I would point out, Senator, that if you take a
dosage for the material certified last year, for example, and if you
accept for the systemic form of therapy an average dose of 10 grams,
the number of patients who would be treated by that amount would
be somewhat less than the 4 million figure. I would be between 1 and 2
million on the basis of last year's certification.
Senator NELSON. And the year before that?
Dr. LEY. The year before that would be close to 4 million.
Senator NELSON. Doesn't that dramatic drop indicate that it was
being more widely used in 1967 for nonindicated cases than in 1968?
Dr. LEY. I cannot draw any other conclusions, Senator.
We know from discussions between our staffs, Mr. Chairman, that
you are interested in a month-by-month listing of the quantities of
the drug certified. I submit such a listing for the record.
Senator NELSON. It will be printed in the record.
(The information follows:)
PAGENO="0106"
4396 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
TOTAL CHLORAMPHENICOL CAPSULES CERTIFIED FROM 1966 TO PRESENT ON A MONTH-BY-MONTH BASIS
Month
[In grams]
1966 1967 1968 1969
January
February
March
April
May
June
July
August
September
October
November
December
3, 323, 275 4, 566, 323. 0 1, 045, 900. 0 248, 575
2,817,750 4,954,775. 0 2,855, 325. 0
2,064,525 5,109,650.5 256,900.0
2,329,800 3,938,725.0 513,475.0
2,437,920 2,120,100.0 259,950.0
2,050,675 2,371,955.0 0
1,024,975 2,599,725. 0 `1,702,250.0
1,797,800 4,206,550.0 2,618,927.5
2,049,925 2,026,219.0 291,150.0
2, 704, 875 2 1, 836, 925. 0 3 1, 992, 466. 0
3,371,675 1,779,900.0 1,927,561.0
(5, 805, 702 0 1, 023, 307. 0
Month
1966
1967
1968 1969
January
February
March
April
May
June
July
August
September
October
November
December
502,503
430,307
36,475
1,981,253
1,321,105
934,244
215, 752
842,420
715,779
728,666
1,534,408
1,325,461
796,4565
651,646.0
562,053.0
894,380.0
620,122.0
748,484.0
48, 809. 0
646,709.0
753,732.0
533,007.0
583,898.0
481,300.0
385,635 0
602,619
525,680
191,116
341,655
(1)
(1)
125,707
2275,328
92,883
319,686
98,990
Annualtotal
10,568,373
7,320,596.5
2,959,299
1 Certification of chloramphenicol injection temporarily discontinued while FDA evaluated blood-level studies for drug.
2 Includes initial certification of injectable of chloramphenicol from firms other than Parke, Davis.
TOTAL CHLORAMPHENICOL ORAL SUSPENSION CERTIFIED FROM 1966 TO PRESENT, ON A MONTH-BY-MONTH
BASIS
[In grams]
January
February
March
April
May
June
July
August
September
October
November
December
265, 913 560, 754. 0
688,969 181,980.0
87,195 361,434.4
362, 633 628, 000. 0
270,233 0
769, 466 682, 066. 3
88,875 274,841.0
378 583 0
0 80,145.0
891,126 0
451,450 0
454,680 0
Annualtotal 31,778,897 35,510,847.5 14,487,211.5
`Includes certification of generic chloramphesicol for Rachelle Laboratories.
2 Certification of generic chlsramphenicol discontinued because of low blood levels.
3 Includes certification of generic chloramphenicol for McKessen Laboratories.
~This includes initial certification of a total of 3,441,852 grams of chloramphenicol from firms other than Parke, Davis.
TOTAL CHLORAMPHENICOL INJECTIONS CERTIFIED FROM 1966 TO PRESENT, ON A MONTH-BY-MONTH BASIS
[In grams]
Mosth 1966 1967 1968 1969
674,721.0 0
271,162.5
131, 310.0
272,216.0
266,640.0
Annual total 4, 709, 123 2, 769, 220. 7 1, 616, 049. 5
PAGENO="0107"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4397
TOTAL CHLORAMPHENICOL OPTHALMIC AND OTIC VIALS CERTIFIED FROM 1966 TO PRESENT, ON A MONTH-BY-
MONTH BASIS
[In gramsj
Month
1966
1967
1968 1969
January
February
March
April
May
June
July
August
September
.
1,833
1,931
2, 591
1, 806
4, 971
1,102
1, 448
6, 542
2, 513
1,796.2
2,028.5
2, 039. 8
6, 530. 0
2, 292. 0
1,215.5
1, 540. 0
4, 105. 7
809. 0
1,023.7 3,431
1,735.5
2, 540. 3
4, 906. 9
2,760. 9
678.3
1, 842. 9
1,327. 0
704. 7
October
1,099
1,936.0
666.0
November
1,152
2,104.0
1,507.0
December
3, 092
1, 313. 0
4, 110. 0
Annual total
30, 080
27, 709. 7
23, 803. 2
TOTAL CHLORAMPHENICOL OINTMENT CERTIFIED FROM 1966 TO PRESENT, A MONTH-BY-MONTH BASIS
[In gramsj
Month
1966
1967
1968 1969
January
February
March
April
May
June
July
August
September
October
November
December
1,378
9,244
5,265
3,440
7, 093
6, 977
6, 385
6, 760
3,511
2,625
10, 800
2,603
3,328.9
1,639.0
8,463.6
3,409.2
4,687. 6
9,440. 3
15, 583. 5
17, 008. 8
22,605.5
11, 540. 0
12,856. 0
18,259.0
18,409.8 11,334
897.0
9,239.9
6,823.6
5, 904. 9
6,912. 4
13,714. 0
14,657. 0
11,097.5
5,894. 0
875. 0
5,711.0
Annual total
66, 081
128, 821. 4
100, 136. 1
Dr. LEY. In January 1969, we decided to again convene our ad hoc
committee on chioramphenicol. It had been approximately a year
since this advisory group had last met. We wanted the committee's
evaluation of the steps taken in regard to chloramphenicol during this
time, as well as its consideration of additional measures for the future.
The meeting took place on February 20, 1969.
After reviewing the certification figures for 1968, the committee con-
cluded that the publicity concerning chloramphenicol had had signif-
icant impact upon its use. The committee took note of the increase
in the number of capsules certified in the last quarter of 1968, but
noted also the sharp drop that occurred in January of 1969.
Senator NELSON. May I ask a question at this points, Dr. Ley?
Dr. LEY. Certainly.
Senator NELSON. There was, as you know, a dramatic increase in the
use of capsules, chloramphenicol capsules, in the last 3 months of
1968 over the last 3 months of 1967. Our statistics from your agency are
that it increased from 3.6 million grams in the last 3 months of 1967
to 4.9 million grams in the last 3 months of 1968, which is a 36.7
percent increase. Are thse figures correct?
Dr. LEY. I believe the figures `are correct, Senator, but there is an
additional factor which must be considered in making such a compar-
ison. This is noted in footnotes with the material which we have
PAGENO="0108"
4398 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
submitted for the record, and I believe the same data was also provided
at an earlier request from a member of your staff.
In 1967, beginning on the month of October, certification of generic
chloramphenicol was discontinued because of the low blood level that
I previously mentioned, and during the month of December no chlor-
amphenicol at all was certified for any manufacturer until we resolved
this question of equivalency among the oral products.
Senator NELSON. I had forgotten that. I do recall now. How does the
last 3 months of 1968 compare with the last 3 months of 1966.
Dr. LEY. They were considerably lower in 1968 than in 1966. I
would have to do a quick addition here. It is approximately 3 million
grams for 1968 and for the last 3 months of 1966-then this is not a
good comparison because in the month of DecenTher of 1966 the generic
manufacturers appeared on the scene-but the total for the months
of October and November of 1966 is 6 million grams for those 2 months
alone without the generic.
Mr. GORDON. May I interrupt here?
Dr.LEY. Certainly.
Mr. GORDON. What percentage of the total did the small manu-
facturers contribute? As I understand it, it is a very, very small
percentage
Dr. LEY. It was a small proportion for the entire period. There were
certain months immediately after the small manufacturers began to
apply for certification in which they represented a significant part of
certification for a single month. I think the significant point here is
that if we go so far as to exclude the month of December altogether, the
total for October and November of 1966 is 6 million grams. For Octo-
ber, November, and December of 1968, it is 3 million grams. I think
that the comparison of 1966 and 1968 again demonstrates-four, I'm
sorry.
Senator NELSON. 4.9.
Dr. LEY. Four. I'm sorry.
Senator NELSON. 4.9, isn't it?
Dr. LEY. Right.
Mr. GORDON. And you think that the small companies made up that
36.7 percent-
Dr. LEY. We have more detailed information on the graphic-
Senator NELSON. Are you saying that nobody manufactured in
December of last year?
Dr. LEY. There were no certifications of chloramphenicol in the
month of December 1967.
Senator NELSON. For any company?
Dr. LEY. Oral capsules.
Senator NELSON. Oral?
Dr. LEY. Oral capsules.
Senator NELSON. How much in injectables?
Dr. LEY. Half a. million grains, roughly. Four hundred eighty-one
thousand grams of injectables in that month.
Senator NELSON. This had nothing to do with FDA. It was just
a question of Parke, Davis not submitting any batches for testing in
December for capsules.
Dr. LEY. I'm afraid, Senator, it did have something to do with the
FDA. Tjntil we reached our eventual decision on the 20th of December,
we chose not to certify any that month.
PAGENO="0109"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4399
Senator NELSON. I see. That was action of the FDA then?
Dr. LET. That is right.
Senator NELSON. So then I would guess that you have to conclude
from this that you just about have to measure year versus year rather
than particular months, although at certain times of the year, there is a
rise in the number of certifications which I assume is associated with
the incidence of the cases for which it may be indicated; is that correct?
Dr. LET. Yes.
Senator NELSON. Please go ahead.
Dr. LEY. The committee saw no need for any further labeling
changes in the warning section or in the indications for use of the
drug. A number of other suggestions which had been made in the past
for controlling the use of this antibiotic were also considered by the
committee. This includes such steps as restricting the use of the drug
to hospitals, requiring a procedure of countersigning prescriptions, or
licensing the drug as a narcotic. The committee was unanimously
opposed to such restrictions. Neither did the committee consider it
advisable to add warning information on the labeling provided the
patient. The commitee did, however, recommend the exploration of
further means of emphasizing to the medical community the proper
uses for this drug and its possible adverse effects.
On the basis of the committee's recommendations and our own con-
sideration of this matter, we have started, or will promptly initiate
the following actions:
1. We have asked the American Medical Association for assis-
tance in communicating at the county medical society level infor-
mation as to the misuse of chloramphenicol, the limited areas of
its proper usefulness, and the grave hazards associated with the
drug.
2. The AMA News has agreed to give further publicity to the
chloramphenicol problem in an early issue.
3. Both the American Hospital Association and the Joint Com-
mission on Accreditation of Hospitals will be asked to support
and encourage the broader use of pharmacy and therapeutic com-
mittees in hospitals, a point that Dr. Wehrle made in his testi-
mony to you yesterday.
4. The AMA Council on Drugs has proposed that these com-
mittees exercise more effective control over drug use and improve
the reporting of adverse reactions. We intend to fully support the
council in this recommendation.
5. We have received the Parke, Davis promotional material,
noting the discontinuance not only of the "reminder" ads, but also
of a group of ads headlined to promote the drug for respiratory
and urinary infections, which we discussed here earlier.
6. We have checked the detailing piece used by Parke, Davis in
the promotion of the drug and it is in conformity with the
package insert.
In summary, Mr. Chairman, I believe we have made considerable
progress in dealing with an exceedingly difficult problem. I intend
to make every possible effort in the months ahead to assure that this
progress continues.
I thank you for your time and attention, and if there are any ques-
tions,I will be happy to answer them.
PAGENO="0110"
4400 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. The only statistics we have as of now showing
the reduction in the use of the drug are statistics of 1967 versus 1968.
If I interpret what you have said correctly, it still is the judgment of
the FDA, or of you, that it is still more widely prescribed than it
should be; is that correct ?
Dr. LEY. This is my belief Senator.
Senator NELSON. Now supposing next year-as the president of
Parke, Davis predicted last ,June, that once the hearings were for-
gotten, the use would rise again-suppose that occurs, what steps does
the FDA intend to take?
Dr. LEY. At that point in time, I would be forced to reconsider this
whole matter. I wish in the coming year to place very strong pressures
on additional means of communicating the facts relating to the
adverse reactions to chloramphenicol to the people who prescribe the
drug. And I hope to be able to elicit the help of such groups as the
AMA in this effort.
Assuming that this does take place, fine. If it is not possible to
obtain assistance from this group, I think we in FDA are going to
have to consider our own means of getting significant information of
this sort before the medical profession-possibly including still another
letter.
But I would say that we should give the steps I've outlined here a
trial to see what they are capable of doing, because I do not believe
these steps have ever been taken before.
Senator NELSON. I suppose one of the problems here is, or has been
from the beginning, to actually bring this matter of the indicated
uses directly and forcefully to the attention of the prescribing physi-
cian in such a way that he ends up being persuaded.
We had some testimony here on one occasion from a very fine doctor
who knew what chloramphenicol was used for but did not realize at
the moment that the National Academy of Sciences had revised the
indicated uses. In other words, there were substitutes, and so forth,
and he wasn't quite aware of that. I think this is part of the problem
that one might use this over a period of years. We have had some
testimony on its use among the pediatricians to the effect that, because
of the historical factor, they know about the drug and they use it.
Then the indicated uses change for v~arious reasons and that fact
isn't brought home to them. How are you going to bring it home to the
physicians of the country that the National Academy of Sciences now
says it is not "the" drug of choice for any condition? How do you get
that home to them?
Dr. LEY. I think it can be covered in two separate ways; each will
have its impact, and yet ~`ith both. I cannot assure you that every
physician will receive the message. We have plans scheduling an inter-
view between the AMA News and myself in the near future. I wish to
feature in that interview not only the types of adverse reactions which
have been reported to us over the past several years, but also the
appropriate indications for use. And I think we can even support
the estimates that have been given by several previous people who
have appeared before you, that as nearly as we can tell the drug is
appropriately called for perhaps in roughly 10 percent of the patients
who receive it.
Senator NELSON. In your judgment that statistic still stands?
PAGENO="0111"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4401
Dr. LJEY. That statistic is as good an estimate as we can make, and
I believe your prior witnesses here could get no better statistic. We
have not been able to find anythinp~ closer ourselves.
Senator NELSON. If I understand you correctly, about 90 percent
of the people receiving chioramphenicol are getting it for nonindicated
cases. Is that what you are saying?
Dr. LEY. Nonindicated cases under present labeling, that is correct.
Senator NELSON. And that is in 1968 as well as 1967?
Dr. LEY. It is too early, Senator, to really make this judgment. The
course of aplastic anemia is a protracted one. We would normally not
receive the report until the patient's death which may be a year after
the initiation in the fatal cases.
Senator NELSON. Let me understand this. The question of whether
or not somebody died from aplastic anemia may not have anything
to do with others who received it for an indicated case? You might
receive it for a sore throat or infected gums or acne, without getting
aplastic anemia, and it is still prescribed for a nonindicated case?
Dr. LEY. That is correct. Yet, we have to enter the data system at
some point and the only point available to us to enter it is the terms
of the adverse reactions reported to us. In other words, we see the
adverse reaction reports. In looking over the adverse reaction reports,
it is our best judgment at this point in time that about 10 percent of
the patients reported as having reactions of a whole spectrum of
types receive the drug on appropriate indications. The indications are
also outlined telegraphically in the reports.
Now, if we are to see any change with time in the incidence of
aplastic anemia as a result of your committee hearings last year and
the increased interest this year, it will take us at least a year because
of the delay in reporting such tests to have any evidence statistically
of a change in incidence of aplastic anemia. That was the point I was
trying to make earlier.
Senator NELSON. Of course, the only study tha.t has been called to
the attention of the committee is the California study which heaven
knows is skimpy enough when you are dealing with a factor of 10
deaths and trying to extrapolate from them. The other factor, of
course, is that literally tens of thousands of people may receive chlor-
amphenicol for a nonindicated case, and get no reaction at all, and that
statistic is nowhere to be found. I don't suppose it would be possible.
Dr. LEY. Dr. Best in his review several years ago of serious side
reactions, I believe, arrived at the same figure of appropriate usage of
10 percent, 10 percent of the patients who were reported to him as
having reactions had been given the product on the basis of what
would be an acceptable indication.
Senator NELSON. I was thinking it was 1 percent, but I believe it
was Dr. Weston, the pathologist, who thought that 99 percent received
it for nonindicated cases. And :as I recall his testimony from a year
ago, he had never seen a case in which death resulted from aplastic
anemia in which the drug had been given for an indicated case, not one.
Well, now, what concerns me is getting the information out. It is
perfectly understandable that doctors become acquainted with the drug
at some period in history-there are thousands of drugs-and they
may not have reason or have gotten around to keeping up on the
changes for its use.
PAGENO="0112"
4402 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY
Now, the National Acade1ny of Sciences has made their report. As
I understand it, FDA agrees with that report.
Dr. LET. We have not only agreed, but we have taken definite action
with reference to this product.
Senator NELSON. The literature will certainly carry references about
this. There will be some news here and there in the medical journals.
But the fact is one reason for advertising is to promote the drug. Gen-
eral Motors made a public announcement calling back 4,900,000 cars
on the ground that it is a public hazard. This is a matter of public
health. Shouldn't Parke, Davis be required now to say it is a different
bail game; there are other drugs, this is not the indicated drug, the
drug of choice in any disease, and run ads in the medical journals say-
ing that? This is what General Motors did. And we all agree, all the
experts agree, and you do, that it appears that 90 percent of the people
are getting this drug for nonindicated cases. It is no greater tragedy
to die from an automobile accident than from this drug unnecessarily.
General Motors has made the front page announcement. That is what
the law requires. Why shouldn't Parke, Davis be required now to
advertise what the fact is?
For whatever purpose the ads were valid in the past, they aren't
now, and it is not the drug of choice for any disease and it ought to be
called to the attention of t.he medical profession by ads in all the
journals. Why shouldn't that be done? WTe aren't willing to restrict
their practice, saying they can only use it in the hospitals, but a lot
of doctors should be told about this. Well, you aren't doing that. Just
make them tell the truth. What is wrong with that?
Dr. LEY. We have essentially through our own letters last year said,
look, to the physician recipient, the indications of this product have
changed. It is a different ball game. Parke, Davis has not said this.
And I'd have to turn to the General Counsel to see if there is any way
that FDA could be instrumental in arriving at such a statement from
Parke, Davis. I have doubts whether we could.
Mr. GooDmon. Well, I think we have required them to do that in
this very ad. If you will read the box warning, it does tell them that
the ball game has changed, that the indications have changed, that
the warnings are stronger, and we have, by telling them to discontinue
the reminder ads, required that this message go with all promotional
material.
Now, we do not have the specific authority of the Automobile Safety
Act to require notification of defects, but this went to every physician
in the United States a.nd keeps going in every ad used, in the detailing
piece and in the Physicians' Desk Reference. So I believe we've done
more than just say, just modified the labeling in terms of indications.
The indications were written in a very special way in a box form, and
the side effects and hazards were emphasized both in wording and in
outlay and display.
Senator NELSON. Well, we are talking, of course, about two different
things: One is the package insert, that aspect of the fine print in the
ad that you require, and the other is to counteract the history of a
whole page stating, "when it counts."
Mr. GooDRICH. That was the purpose of the letter to every physician
in the United States, and rather than have Parke, Davis send it out
we sent it out. We made sure it went not only to every physician but
PAGENO="0113"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4403
to every hospital administrator, and we have followed that up by fol-
lowing the promotion to make sure that those defects which we have
outlined in the statement did not appear, such as that cystoscope and
the headline series on respiratory infections, serious urinary tract
infections, that now the message on chioramphenicol be oriented to its
use only on the basis of an identified causative organism, not to be used
where another less potentially hazardous product is available, and
not to be used except in these specific indicated cases.
This is the kind of message I think you are talking about that should
be sent to the physician, and since we send it ourselves, first-class mail,
with a notice on the front of the envelope, we think we communicated
that to the physicians. They need to be told again, and as Dr. Ley's
statement says, we are planning to try to communicate with them
through the AMA at their local county medical society meetings to
see if we can't emphasize this, tdo.
Senator NELSON. But the test is the result?
Mr. GOODRICH. Right.
Senator NELSON. The testimony still is that 90 percent of the people
receive it for a nonindicated case. It really wouldn't have done any
good for General Motors to have announced that a whole lot of these
cars have this defect, including a carburator that might induce lethal
gases from the exhaust into the car, had a story on that, and that is all.
It would have about the same effect as what the FDA is saying to the
doctors. Some people would notice it and do something about it and
most would not. And most apparently haven't done aything about
this.
Mr. GOODRICH. Well, there's been a substantial reduction in the use
of the drug. I think we have started by agreeing with that.
Senator NELSON. Correct.
Mr. GOODRICH. And our point was that while some progress, some
very good progress had been made,much remains to be done, and we've
suggested a program of going at it.
Senator NELSON. What I am getting at is, whether or not it is
adequate.
Now, it is a fact that it is no longer the drug of choice in any case.
At one time it was the drug of choice in certain circumstances. And
millions and millions of dollars were spent to demonstrate that it was
the drug of choice. Apparently as a consequence of this kind of promo-
tion, it was much more widely used than its indications warranted.
This is a matter of public health. It is a matter of life and death to
anybody who gets it for a nonindicated case and dies.
Why shouldn't Parke, Davis be told that they should now run an
ad in all journals saying "here is what the National Academy of
Sciences now says-it is not the drug of choice for any disease, and
here is specifically how to use it?" They got to the doctors in promoting
it. Why shouldn't they get to the doctors in depromoting it, is my
question?
Mr. GOODRICH. That was the point of the statements in the indica-
tions sections: "Chioromycetin must be used only in those serious infec-
tions for which less potentially dangerous drugs are ineffective or
contraindicated."
Senator NELSON. Even the package insert doesn't tell the case. Why
shouldn't the package insert say right at the top, this is no longer the
82-280 O-69--pt. ii--8
PAGENO="0114"
4404 CO~PETITIVE PROBLEMS IN THE DRuG INDuSTRY
dru.g of choice for any disease in this country? It doesn't say that. I
know what happens. I have had doctors say, "who reads these package
inserts !" In the first place, they don't see them. They all go to the
pharmacists. They see them if they get a free drug. So they really
aren't seeing the ad anyway but they do see that ad in the medical
journals.
So, what you are really saying is we've gotten reasonably tough
about the package insert which never goes to the doctor who prescribes
it. I don't think this is fair to the consuming American public.
Mr. GOODRICH. We have put into the record a copy. of the package
insert which is a detailing piece that goes with the free samples. We've
also put into the record the ads. Now, if that is not satisfactory, then
it is not satisfactory, but that is what's been done.
Senator NELSON. Well, I don't think it is satisfactory because I
think we have to go by the test of results. All the distinguished wit-
nesses, including Dr. Goddard and Dr. Ley, and all the other experts
who have testified have said in public that about 90 percent of the peo-
ple are getting this drug for nonindicated cases. And Dr. Goddard
sat in that witness chair and said "I am at wits end," to quote him pre-
cisely, "on how to stop the use of this drug." Well, I'm not at my wits
end. I'll give you some suggestions.
I think they ought to have to run an ad saying this is what it is now
indicated for. I would think in the package insert, which most physi-
cians don't really see, it should say right at the top in a box, quote:
Not the drug of choice in any case. Here is what it is to be used for: Never
to be used except in a case where the disease is serious; never to be used except
when no other antibiotic will do the job, and never to be used unless the organism
involved is susceptible to chioramphenicol.
Not a whole lot of print, just concise and to the point. And then in
the ad that goes in the paper, I would think you ought to print at the
top, exactly what I've said. You know, if we had accomplished our
purpose with what we had done a year ago, what Dr. Goddard did, I
think there would be no argument, but we haven't. We've come a long
way. There is no question about that. We have reduced the usage from
42 million grams to 20, but we are talking about people who are going
to unnecessarily die. And I think that we ought to tell every doctor in
America, in ads and package inserts, that here is the present status of
the recommended use of the drug.
Are you., for example, going to send out the "Dear Doctor" letter
saying here is what the National Academy of Sciences says-not
the drug of choice?
Dr. LEY. This is a perfectly satisfactory option for us to consider,
and I will weigh this very carefully. We have, Senator, also embarked
on another effort which is broader in scope than this but very similar.
Early this month, we cosponsored a. conference with the NIH on
the continuing education of physicians in which Dr. Dowling chose
chloramphenicol as a. beautiful example of the difficulty in updating
the physicians' knowledge on drugs. His remarks were very similar
to your own a few moments ago. He pointed out that there are a variety
of influences operating on the physician. None of these are perfect.
Public interest, newspaper publicity, to some extent the labeling, all
are important in molding his reaction. However, the response which
he indicated here is attractive in terms of the decrease in certification
PAGENO="0115"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4405
over the past year, is one which must be continually pressed for by
new means and more effective means of communication between us
and the community at large.
Senator NELSON. Well, now, I hope you will consider a "Dear
Doctor" letter. I know that there will be those who get it for headaches
and acne and flu and die from it, but these people are entitled to the
most vigorous protection possible.
Then it seems to me the advertising should contain what the
National Academy of Sciences now says and with which the FDA
agrees-this ought to be boxed in a very prominent place. I know
enough from political advertising about how to cover up the warts
and exaggerate the good qualities, but it would seem to me the FDA
ought to require a very prominent place in the whole medical journal
advertising. This is new. It is not the drug of choice.
Now, why shouldn't that be considered? You can approve the
advertising. All you are doing is saying tell the doctors what the
National Academy of Sciences says.
Dr. LEY. This is a possibility to consider that has wider ramifica-
tions than merely this product. There are at present, and will soon be
many more, examples of drugs whose indications are being drastically
revised by the Academy's action and review. I think that the problem
of communication of such changes of appropriate indication for the
older class of drugs marketed between 1938 and 1962 is a very impor-
tant problem for us to consider. How may we get this information,
not just for chloramphenicol, but for the entire spectrum of drugs
marketed between 1938 and 1962 effectively before the physician
population of this country?
It is a difficult problem, one that we have been looking at and
exploring possible avenues of approach. We do not have an answer
as of this time.
Senator NELSON. I am sure it is a difficult problem. I'm sure you
know how much more difficult a problem it is than this committee does.
But I am concerned that we vigorously pursue it. And it does seem
to me that the medical profession is entitled now to be told what the
National Academy says. I am not critical-nobody conceivably could
be critical of a practicing physician who doesn't know what the
National Academy of Sciences now says. How is he going to know
that? And the continuing education problem is certainly a tough one.
I think the friends I have in the medical profession are very conscien-
tious people. Some have a complicated, difficult problem to keep up
on all these matters. But it seems to me in a case like this the situation
is clear, though the FDA has done a lot, there is more it ought to do
in terms of the advertising and the packaging insert and notifying
the doctors, otherwise I think we'll have the tragedy of a rising use
of the drug again. We will have more at the end of next year and we
will still be talking about it at the end of next year.
I wonder if perhaps you would take a look, when it is printed, at
Dr. Wehrle's testimony, in which he made a suggestion about trying
to find out just where geographically chioramphenicol is being used,
for what purpose, and what doctors are prescribing it. He thought
that you could perhaps set up some sample areas and do a survey of
how much is being used in this area and what are the reasons for its
use.
PAGENO="0116"
4406 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
I don't know whether you would consider that a useful enterprise
or not, but it might very well be. I don't know whether you have the
facilities to do that, but perhaps they may be available in NIH or
HEW. I believe it would be valuable because nobody seems to be able
to tell us, you know, what the variations are, nor why.
Dr. Wehrle raised the question yesterday, for example, whether or
not chloramphenicol was prescribed widely or not at all or in fair
amount during the flu epidemic? Does anybody know that?
Dr. Li~nr. No. This is a q~uestion we asked our consultants and they
had no firm answer at this time.
Senator NELSON. I wish you would take a look at it. It may well
be that you could get some helpful information.
It isn't indicated for influenza, is it?
Dr. LEY. No, sir, it would not be indicated for influenza under any
condition.
Mr. GORDON. Coming back to the Reader's Digest of February
1968, you stated the ad recommended the drug for uses that were not
warranted and seriously understated the hazards, side effects, and
contraindications. Could anything have been done along these lines
to make the Reader's Digest perhaps rmn a remedial ad?
Dr. LEY. This is a question I would like to turn over to our
General Counsel.
Mr. GOODRICH. We have no direct authority to require any type of
remedial ad. We have required some by persuasion, if you might call
it that, where we had a choice of taking action against the company
or its drug, but we would not have authority over Reader's Digest
at all.
Mr. GoiwoN. How about moral or ethical authority? Couldn't you,
for example, approach the Reader's Digest and say, look, this is a
false and misleading ad. How about correcting it for the sake of the
public welfare?
Mr. GOODRICH. Sure, that could be done.
Mr. GomoN. That wasn't done, though, was it?
Mr. GOODRICH. That was not.
Mr. GORDON. Thank you.
Senator NELSON. I want to thank you, Dr. Ley, for your very valu-
able testimony. I wouldn't want you to feel that because we might
have had some differences that I do not think the FDA in the past-
since Dr. Goddard's administration and yours-hasn't been doing a
superior job.
Dr. LEY. Thank you, very much.
Senator NELSON. Thank you, Doctor.
(The supplemental information submitted by Dr. Ley follows:)
PAGENO="0117"
6. QuantItative Formula
Estobliohod (Non.Ptop~iototyi Nonto of Aotioo lng!odionts (in otdot shoot tobol)
Chlorarnphenicol
Attoottt (pot tobi.t, pn~ ni.,
0.5 Gm./2 cc. vial
7. Dosogo Foon (tobtots, ott.) ampoule
0. Root. of Adnt. (O~ol, oft. Whot, too d.tg opplicotion
diffocont ,o~ttos of odnivictcotion, sopototo fotns shoold bo osod.) parenteral
9. Th.top.otin Cloitttc-Attoch 10 lob.), ond 10 pockogo insotto (if nod) to ociginol Foon A bk,.) ond copy to dcphcoto Ponn A (ohits).
10. List of )itOtOtttc. tofoconoos tnost pocfln.nt to on ooolctotlon of ho offsotinonoss of Oh. dtccg On. oh. pcctpos.s fon nthlch it is off.t*d in th. lob.),
tho pockog. ins.tt, ot boochoto. Apptooinotoly S to 10 boy f.tonooo no. toqoostod, if onoiloblo. (Attoch 10 copiss to otigitot Foon A (bios)
ond I copy to dopiioote Fotn A (ohito).)
1. Tho oppikont is inoitod, if ho so docitos, to sobnit oty onpo blishod nototiol hot is pootinont to ho onolootion of ho dnog by ho Aoodottty-
Rncoonch CoUncil. This soppinnontoty ,,totonioi ohocid be pocbogod ocith Fonno A (ohits). A sing). oopy of this motstioi ist.qccesf.d.
12. iv this spots, plooso list ond dosctibo bti.tly ch. soppi.tt.ntony nototioi hot is sc bttt)tted ocith Fot,tt A (ohito).
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4407
NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL
Division of Medical Sciences
DRUG EFFICACY STUDY
Form A
(To be submifed in dup)icate by opp)icanf)
6D307~ ~ 2. Dote Otiginolly Appnon,d December 3. 1953 3. Co OTt 0
Chloromycetin Solution
Parke, Davis & Company
,Toseoh Camoau at the River: Detroit. Michiman
1. NDA N,,nb.n~___.
4. BnondNovo_____
5. Appliconts Non.
PAGENO="0118"
4408 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
Panel on Anti-Infective Drugs (1111
INDICATIONS
I. Staphylococcal infections, by implication of the discussion on the
first page of the insert, may be an indication: "in a survey of
experimental and clinical experiences of susceptibility of staph-
ylococci to chloramphenicol, it was found that the incidence of
chloramphenicolresistant staphylococci appears unrelated to fre-
quency or to intensity of use of this antibiotic. Development of
resistance to chloramphenicol can be regarded as minimal for staph-
ylococci and many other species of bacteria."
EVALUATION: Possibly effective.
COMMENTS: Although chloramphenicol was useful for the treatment of
some staphylococcal diseases during the mid-1950's, it now seems to
be rarely indicated. Its major trial was in the staphylococcal
pneumonias accompanying the influenza epidemic of 1957. Its effective
ness was somewhat less than expected, even for sensitive strains. The
statement concerning resistance is not true in the opinion of the Pane
(see below). In the description of invitFp work just before the sen-
tence quoted above, there is no reference to the transfer of episomal
particles carrying chloramphenicol resistance. The advent of better
agents for staphylococcal disease relegates this drug to a very rarely
needed alternate choice.
DOCUMENTATION:
1. Bloomer, W.E., S. Giamruona, G.E. Lindskog, and R.E. Cooke.
Staphylococcal pneumonia and empyema in infancy. J. Thorac.
Surg. 30:265-274, 1955.
2. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953.
3. Hausrnann, W., and A.J. Karlish. Staphylococcal pneumonia in
adults. Brit. Med. J. 2:845-847, 1956.
4. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
5. Lepper, M.H., P. Tillman, and R. Devetsky. Patterns of transmis-
sion of staphylococci. Ann. N.Y. Acad. Sci. 128:404-427, 1965.
6. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and M. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal
pneumonia complicating influenza. A.M.A. Arch. Intern. Med.
103:532-542, 1959.
7. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955.
II. Rickettsial diseases: epidemic and murine typhus, Brill's disease,
scrub-typhus, Rocky Mountain spotted fever, and rickettsial pox.
PAGENO="0119"
COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY 4409
EVALUATION: Effective, but
COMMENTS: That chloramphenicol is effective in the diseases listed
is well established, except in rickettsial pox, a condition so in-
frequently seen that few data are available. However, if the warning
is to be taken seriously--"chloramphenicol should not be used when
other less potentially dangerous agents will be effective'---the
tetracyclines, which have been shown to be as effective as chloram-
phenicol, should be considered the choice and chloramphenicol used
only if toxicity to these or failure to respond has occurred. The
duration of therapy recommended appears adequate.
DOCUMENTATION:
1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and
chloramphenicol: use in typhus, typhoid and brucellosis. J.
Clin. Invest. 28:1052-1053, 1949. (abstr.)
2. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol
in the treatment of the acute manifestations of brucellosis.
Amer. J. Med. Sci. 219:627-638, 1950.
3. Ley, H.L., Jr., T.E. Woodward, and J.E. Smadel. Chloramphenicol
(chloromycetin) in the treatment of murine typhus. J.A.M.A.
143:217-219, 1950.
4. Murray, E.S., G. Baehr, G. Shwartzman, T.A. Manderbaum, N.
Rosenthal, J.C. Doane, L.B. Weiss, S. Cohen, and J.C. Snyder.
Brill's Disease; clinical and laboratory diagnosis. J.A.M.A.
142:1059-1066, 1950.
5. Pincoffs, M.C., E.G. Guy, L.M. Lister, T.E. Woodward, and J.E.
Smadel. The treatment of Rocky Mountain spotted fever with
chloromycetin. Ann. Intern. Ned. 29:656-663, 1948.
6. Smadel, J.E., T.E. Woodward, H.L. Ley, Jr., and R. Leuthwaite.
Chloramphenicol (chloromycetin) in the treatment of tsutsugamushi
disease (scrub typhus). J. Clin. Invest. 28:1196-1215, 1949.
III. Typhoid fever.
EVALUATION: Effective, but . .
COMMENTS: Chloramphenicol has often been listed as the drug of
choice in typhoid fever. It is not clear that ampicillin has changed
this claim, but if they were of equal activity, the claim of "drug of
choice" would have to be revised because of the toxicity warning.
There is no mention of the carrier problem and relapses of positive
stool cultures
DOCUMENTATION:
1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and
chioramphenicol: use in typhus, typhoid and brucellosis. J. Clin.
Invest. 28:1052-1053, 1949. (abstr.)
2. Smadel, J.E., H.L. Ley, Jr., and F.H. Diercks. Treatment of
typhoid fever. I. Combined therapy with cortisone and chioram-
phenicol. Ann. Intern. Med. 34:1-9, 1951.
PAGENO="0120"
4410 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
IV. Other salmonelloses.
EVALUATION: Possibly effective.
COMMENTS: Because of variability of clinical course with each species
and the large variety of species, there is little reason to presume
that a generalization is possible. In a condition of short symptorna-
tic duration like gastroenteritis, the use of the drug is most diffi-
cult to evaluate. The variable courses of the systemic forms do not
allow the assurance of effectiveness that has been derived for typhoid
fever, which is more uniform. These differences between typhoid and
the other salmonelloses illustrate the difficulty of generalization
from one species to the next. It is likely that localized salmonella
infections, such as osteomyelitis, empyersa or other diseases should
have a therapeutic trial with chlorarnphenicol. The treatment of
carriers with positive stool cultures should not be recommended and
the insert should so state. Although the stools may be negative while
the drug is continued, there is no evidence that the carrier state is
terminated more frequently than would occur otherwise with a similar
passage of time. Obviously, the inability to define drug effectiveness
in salmonelloses also applied to other drugs, such as ampicillin; hence,
a reliable comparison between drugs is not possible.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 56-58.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
V. Urinary tract infections.
EVALUATION: Effective, but . .
COMMENTS: As specified in the insert, outcome of treatment of urinary
tract infections is influenced by anatomic factors, but these have
little importance in the choice of drug except that, in situations in
~hich cure is unlikely, the use of toxic agents is probably not justi-
fied. The susceptibilities of the organisms involved are of prime
importance (chloramphenicol does not work any better against chloram-
phenicol-susceptible organisms than other agents work against organisms
susceptible to them). Hence, when organisms are susceptible to less
toxic agents, chloramphenicol should not be used even if it is effective
i~ vitro unless the others have failed. It is unusual for chloramphen-
icol to succeed when other agents with satisfactory in vitro activity
have failed. Of the three species singled out, Escherichia ~ is
often treatable with other chemotherapy, but chloramphenicol may be a
secondary choice. Streptococcus fecalis infections are probably
better treated with other agents, such as penicillin and streptomycin
or erythromycin. Various Proteus species are different in their
susceptibility to different drugs; hence, the generalization "Proteus
species" should be avoided. Proteus morgani, vulgaris, and rettgeri
PAGENO="0121"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4411
are often susceptible only to chloramphenicol.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 105-
108. Antibiotics Monographs No. 8. New York: Medical Encyclo-
pedia, Inc., 1958.
VI. Surgical infections: postoperative wound infections.
EVALUATION: Possibly effective.
COMMENTS: Postoperative wound infections have a variety of etiologic
agents, but ococcus aureus is the single most common. Chlor-
amphenicol is effective against many of these agents, but is not the
most effective against the Staphylococcus. For this reason, plus the
toxicity warning, it is not the first choice in most infections unless
an organism is isolated against which chloramphenicol is most active
in vitro, or other preferred drugs cannot be given or have been inef-
fective.
DOCUMENTATION: Most favorable report is reference 1 (Altemeier).
1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chlorornycetin)
and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951.
2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph-
ylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30:
265-274, 1955.
3. Carmichael, C.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953.
4. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults.
Brit. Med. J. 2:845-847, 1956.
5. Kanof, A., B. Epstein, B. Kramer, and I. Nauss. Staphyloccal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
6. Lepper, M.H., P. Tillman, and R. Devetsky. Patterns of trans-
mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965.
7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and M. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia
complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959.
8. Waliman, 1.5., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955.
VII. Surgical infections: cellulitis.
EVALUATION: Possibly effective.
COMMENTS: Cellulitis (other than postoperative) is most often caused
by streptococci or staphylococci for which chloramphenicol is not the
most effective drug. For this reason, plus the toxicity warning, it
is not the first choice unless an organism against which chloramphenicol
is the mos.t active has been isolated, or the preferred drug cannot be
given or has failed.
PAGENO="0122"
4412 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
DOCUMENTATION: Same as for Indication VI.
VIII. Surgical infections: infected sinus tract.
EVALUATION: Possibly effective.
COMMENTS: Chloraniphenicol may be useful in some instances in which
the organisms have been shown to be sensitive only to it. Many sinus
tract infections are caused by tuberculosis and actinomycosis. Chior-
amphenicol is not indicated in tuberculosis, and other agents are
preferred in actinomycosis. Some sinus tracts associated with fistulas
from viscera, including intestines, may be predominantly infected with
fecal flora. In these, chloramphenicol may be the single most effective
agent. When other agents appear equally effective in laboratory testing
they should be tried first. There is rarely great urgency in treating
sinus tract infections with antibiotics.
The specific organisms for which chloramphenicol has been proved
effective therapy (in this condition) should be listed.
DOCUMENTATION:
1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromyceti
and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951.
2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph-
yloccal pneumonia and empyema in infancy. J. Thorac. Surg. 30:
265-274, 1955.
3. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953.
4. Hausmann, W., and A.J Karlish. Staphyloccal pneumonia in adults.
Brit. Med. J. 2:845-847, 1956.
5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. * Staphylococcal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
6. Lepper, M.H., P. Tillman, and R. Devetsky. Patterns of trans-
mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965.
7. Martin, C.M., C.N. Kunin, L.S. Gottlieb, and M. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal
pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:
532-542, 1959.
8. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Ned. J. 2:1423-1427, 1955.
9. Woodward, T.E., and C.L. Wissernan, Jr. Chloromycetin, pp. 122-
124. Antibiotics Monographs No. 8. New York: Medical Encyclopedia
Inc., 1958.
IX. Surgical infections: peritonitis or intra-abdominal abscesses from
ruptured intestines, diverticula, or appendix.
EVALUATION: Possibly effective.
PAGENO="0123"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4413
COMMENTS: These infections are often caused by mixed flora from the
intestinal content . In the acute stage of peritonitis, a drug often
must be selected empirically for surgical preparation or immediately
postoperatively. Judged by statistical probability chloramphenicol
is a good choice in such a situation. It should be given parenterally,
however, because oral therapy in these infections is probably inap-
propriate. In other less acute complications listed in the insert,
chloramphenicol should be shown to be the most effective agent against
the organisms isolated before it is used, or other less toxic agents
should have failed or be contraindicated.
The specific causative organisms for which chloramphenicol has been
proved effective therapy (in these conditions) should be listed.
DOCUMENTATION: Same as for Indication VIII.
X. Respiratory tract infections.
EVALUATION: Possibly effective.
COMMENTS: This heading is ambiguous. The package insert should list
specific organisms (and the site of respiratory infection) for which
chloramphenicol has been proved effective therapy.
In general, the etiology of these conditions is varied and chloram-
phenicol is the best agent for only a few. In streptococcal, pneumo-
coccal, and staphylococcal diseases of the respiratory tract, other
drugs are preferable. Chloramphenicol should be used only in Kiebsiella
infections and perhaps other necrotizing pneumonias caused by E. coli
or related organisms when they are shown in vitro to be resistant to
ampicillin, cephalothin, and kanamycin. Hempphilus influepz~ infec-
tions of the respiratory tract respond well to ampicillin; hence,
chloramphenicol is best used only when ampicillin is not tolerated
or fails.
DOCUMENTATION: -
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 63-72.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
XI. Meningeal infections.
EVALUATION: Probably effective.
COMMENTS: The three most common causes of meningitis are the meningo-
cocci, pneumococci, and Hemophilus influenzae. All are susceptible
to chloramphenicol, as are many staphylococci and the gram-negative
aerobic rods that often infect newborns. Moreover, it is true that
the drug does get into the spinal fluid well. As a drug of choice
PAGENO="0124"
4414 COMPETITIVE PROBLEMS IN THE. DRUG INDUSTRY
for empiric use, however, it is probably not first, because it is
likely to be less effective in pneumococcal disease than is penicillin.
Although many believe it is first choice in Hemophilus infections,
tetracycline is probably as good and ampicillin is, too. It is likely
that this claim (drug of choice in H. influenzae meningitis) is no
longer justified. In menigitis of the newborn kanamycin is preferred
as the drug of choice for empiric treatment. In older patients, when
a diagnosis has been made and the organisms shown to be more susceptiblE
to chloramphenicol than to other agents, it may be the drug of choice.
As indicated, in the insert, initial treatment should be parenterally
administered.
The package insert should list the specific organisms for which
chloramphenicol has been proved effective therapy in meningitis.
DOCUMENTATION:
1. Parker, R.T., N.J. Snyder, R.S.J. Liu, J.W. Looper, Jr., and T.E.
Woodward. Therapeutic range of chloramphenicol in purulent men-
ingitis. Antibiot. Ned. Clin. Ther. 1:192-200, 1955.
XII. Brucellosis.
EVALUATION: Effective, but .
COMMENTS: Chloramphenicol, like other drugs, is capable of control-
ling symptoms of acute brucellosis, but the relapse rate is high. It
does not appear to be superior to the less toxic tetracyclines.
DOCUMENTATION:
1. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol
in the treatment of the acute manifestations of.brucellosis. Amer.
J. Med. Sci. 219:627-638, 1950.
2. Spink, W.W. The Nature of Brucellosis. Minneapolis: The
University of Minnesota Press, 1956. 464 pp.
3. Woodward, T.E., J.E. Smadel, W.A. Holbrook, and W.T. Raby. The
beneficial effect of chloromycetin in brucellosis. J. Clin.
Invest. 28:968-976, 1949.
XIII. Bartonellosis.
EVALUATION: Probably effective.
COMMENTS: Chloramphenicol is reported to be an effective antibiotic
in these infections. Of the references suggested by the manufacturer
(see Documentation below): two are reports of studies involving a
total of 25 patients whose bartonellosis was treated with chioramphen-
icol with good success, and two are textbook discussions of bartonel-
losis and its treatment. Of the latter discussions, one feels that
the effectiveness of chloramphenicol is best documented, the other
feels that other agents are probably as good.
PAGENO="0125"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4415
DOCUMENTATION:
1. Bartonellosis, pp. 603-606. In G.W. Hunter, III, W.W. Frye, and
.J.C. Swartzwelder, Eds. A Manual of Tropical Medicine. (3rd ed.)
Philadelphia: W.B. Saunders Co., 1960.
2. Payne, E.H., and 0. Urteaga. Carrion's disease treated with
chloromycetin. Antiobiot. & Chemother. 1:92-99, 1951.
3. Pinkerton, H. Bartonellosis (Carrion's disease, Oroya fever,
Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott,
Eds. Cecil-Loeb Textbook of Medicine. (11th ed.) Philadelphia:
W.B. Saunders Co., 1963.
4. Urteaga, B.O., and E.H. Payne. Treatment of the acute febrile
phase of Carrion's disease with chloramphenicol. Amer. J. Trop.
Med. 4:507-511, 1955.
XIV. Relapsing fever.
EVALUATION: Possibly effective.
COMMENTS: Treponema (Borrelia) recurrentis infections in experimental
animals are susceptible to chloramphenicol. On a weight basis, how-
ever, penicillin G is more active. In human infections, no direct
comparison has been made, and, although chloramphenicol has been used
successfully, penicillin should be tried first if it is tolerated.
DOCUMENTATION:
1. Hirschboeck, N.M. Use of chloramphenicol in relapsing fever.
Amer. J. Trop. Med. 3:712-713, 1954.
XV. Granuloma inguinale.
EVALUATION: Effective, but . . .
COMMENTS: It has been reported that chloramphenicol caused the
disappearance of Donavan bodies more rapidly than either tetracycline
or streptomycin. Relapses after chloramphenicol have seemed to be
less than 107. Although chloramphenicol may be slightly better than
tetracycline, the latter may be, preferred for toxicologic reasons.
DOCUMENTATION:
1. Greenblatt, R.B., W.E. Barfield, R.B. Dienst, R.M. West, and
N. Zises. Five-year study of antibiotics in treatment of
granuloma inguinale. Amer. 3. Syph. 36:186-191, 1952.
2. Robinson, R.C.V., and T.L. Wells. Intramuscular chloramphenicol
in the treatment of gonorrhea and granuloma inguinale. Amer. 3.
Syph. 36:264-268, 1952.
XVI. Plague.
EVALUATION: Effective, but
PAGENO="0126"
4416 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMMENTS: All forms of plague have been shown to respond to chlor-
amphenicol when it is given in large doses early in the disease.
There is no clear evidence that it is superior to tetracycline or
s treptonycin.
DOCUMENTATION:
1. McCrumb, F.R., Jr., S. Mercier, J. Robic, M. Bouillat, J.E.
Smadel, T.E. Woodward, and K. Goodner. Chloramphenicol and
terramycin in the treatment of pneumonic plague. Amer. J.
Med. 14:284-293, 1953.
XVII. Ornithosis.
EVALUATION: Possibly effective.
COMMENTS: In embryonated eggs and experimental animal infections,
chloramphenicol is less effective than the tetracyclines. Results
of therapy of human infections have been variable and relapses have
been frequent. The role of the drug in this disease is not well
established.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 70-71.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
GENERAL COMMENTS
The "Warning" section appears justified in view of the seriousness
of aplastic anemia.
Tissue distribution appears to be favorable. The distribution into
the cerebrospinal fluid is good, as pointed out in the insert, and
is reasonably good into brain tissue, which is important when cerebrit
accompanies meningitis. The distribution into bile is not as high as
that of the tetracyclines and some of the penicillins. The very small
amount in the feces is of interest as is the fact that the fecal con-
tent is higher when the palmitate has been given.
The penetration into the eye is a plus factor for this drug. Trans-
placental transfer was shown by chemical methods which may not measure
the active drug.
Emphasis should be put on the recommended dose, because a smaller dose
is often given, particularly postoperatively. The fate of the drug
when the metabolic mechanisms are disturbed should remain as stated.
As to blood dyscrasias, it should be mentioned that frequent blood
counts do not necessarily assure that aplastic anemia can be prevented
In fact, it may occur after the drug has been stopped.
PAGENO="0127"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4417
The roles of organisms other than candida and staphylococci in
resistance and superinfection have been demonstrated, particularly
Pseudomonas and some other gram-negative aerobic rods that are re-
sistant. This should be pointed out in the section discussing resis-
tance.
Intravenous administration of chloramphenicol produces a rapid peak
in blood levels and is preferred over oral or intramuscular admini-
stration in critically ill patients. Because the oral form is so
highly absorbed, as soon as the patient can take it, there is little
reason to continue the I.V. use. This buffered solution is recom-
mended for intravenous use only.
It may be less ambiguous if there were a specific package insert that
eliminated the references to the succinate and the intramuscular form.
The lag in the use of the succinate is probably of little clinical im-
portance, but if the insert were designed specifically for this form
of the drug there could be little difficulty in making clear that
there is a little lag in hydrolysis with a somewhat lower level of
antibacterial activity at 15 mm. Only the paragraph on page 3 (con-
cerning ampoule No. 258) is needed in this insert.
ApprOV~ by
CM1i~
The Drug Efficacy Study of the National Academy of Sciences -
National Research Council has requested that the following
qualifying addendum be conveyed with their reports to the
ultimate recipients of these reports
"Drugs of identical chemical composition (so-called
generic drugs) formulated and marketed by numerous
individual firms under generic or trademarked names
have been evaluated for efficacy as a group without
consideration of `therapeutic equivalence.' In the
event that no evidence for pharmacological availability
or therapeutic efficacy in man can be presented for
any of the indications claimed for the use of any
of the drugs in the attached listing, their classifications
of effectiveness may need to be modified if regulations
of the Food and Drug Administration require such proof."
PAGENO="0128"
4418 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL
Division of Medical Sciences
DRUG EFFICACY STUDY
Form A
(To be submitted in duplicate by appticanf(
1. NSA N,,t,be, 6D3l5~j~Oj~)2 Dote Otigically A~~,0,~d...~Februarv 20, 1959 ~. t, OTt ~
4. t,c,d Na,,. Chloromycetin Sodium Succinate Steri-Vial, 1 Gm.
5. Applicants Nan,e Parke, Davis & Company
aed Add,e,, Joseph Campau at the River; Detroit, Michigan
6. Quantitative Formula
Estabtish.d tNee.Fnepcietanyt Nam, at Aetine legnedi.ets tin atden shace, on tebet( Anaccet (pen tablet, pet tnt.,
Chloramphenicol Sodium Succinate 1 Gm. base/vial
7. Dosage Fete (tabtets, etc.t steri-vial
8. teute of Ad,,. (Otet. etc. Whene a eeoc d~ccg applicetian ecee
diffenent eactes at adeinisteatian, sepenate tot,,, shccctd be ccsed.( parenteral
9. Thenapeutie Ctaiens-Attach tO tcbet, and 10 package inseCs (it cued) a atiginet Fan,, A (btuet and 1 eapy a duplicate Fete A (cehite).
15. L,st at tcteeetcae tet,eeeees nest pentitneet a an eenlccatiae at the effsetiee,ess at the decg ten the pcnpas.s fan sehleh It is affen.d Inc the abet,
the paek.a. iesent, en b,aehune. Apptaeintately 5 to 10 key netenences ate tequested, it ecaileble. (Attach 10 eapies a etiginat Fete A )btue(
end 1 copy to duptieate Pane A lohitet .1
11. The applccant is incited, if he sO desites, to subecit any cnpcc bushed etatctiat that is pe~tieent a the snalccatia, at the dtug by ths Acadsey-
teseanch Cauneil. This suppleeentc,y eete,ict shanld be packaged acith Fate A lahitel. A siegts copy at this mateniat is e.qusstsd.
12. tn thcs space, please list and desc,ibe bniefly the suppleeente,y aate,ial that is scbeitted aith Fate A lahitel.
PAGENO="0129"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4419
Panel on Anti-Infective Drugs (III)
INDICATIONS
I. Staphylococcal infections, by implication of the discussion on the
first page of the insert, may be an indication: "in a survey of
experimental and clinical experiences of susceptibility of staph-.
ylococci to chloramphenicol, it was found that the incidence of
chioramphenicol-resistant staphylococci appears unrelated to fre-
quency or to intensity of use of this antibiotic. Development of
resistance to chloramphenicol can be regarded as minimal for staph-
ylococci and many other species of bacteria."
EVALUATION: Possibly effective.
CONMENTS: Although chloranphenicol was useful for the treatment of
some staphylococcal diseases during the mid-l950's, it now seems to
be rarely indicated. Its major trial was in the staphylococcal
pneumonias accompanying the influenza epidemic of 1957. Its effective-
ness was some~hat less than expected, even for sensitive strains. The
statement concerning resistance is not true in the opinion of the Panel
(see below). In the description of in vitro work just before the sen-
tence quoted above, there is no reference to the transfer of episonial
particles carrying chloramphenicol resistance. The advent of better
agents for staphylococcal disease relegates this drug to a very rarely
needed alternate choice.
DOCUMENTATION:
1. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke.
Staphylococcal pneumonia and empyema in infancy. J. Thorac.
Surg. 30:265-274, 1955.
2. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Med. .1. 4:287-294, 1953.
3. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in
adults. Brit. Med. J. 2:845-847, 1956.
4. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
5. Lepper, M.H., P. Tiliman, and R. Devetsky. Patterns of transmis-
sion of staphylococci. Ann. N.Y. Acad. Sci. 128:404-427, 1965.
6. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal
pneumonia complicating influenza. A.M.A. Arch. Intern. Med.
103:532-542, 1959.
7. Waliman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Med. J. 2:1423-1427,. 1955.
II. Rickettsial diseases: epidemic and murine typhus, Brill's disease,
scrub-typhus, Rocky Mountain spotted fever, and rickettsial pox.
81-280 O~-69-pt. 11-9
PAGENO="0130"
4420 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
EVALUATION: Effective, but .
COl4NENTS: That chloramphenicol is effective in the diseases listed
is well established, except in rickettsial pox, a condition so in-
frequently seen that few data are available. However, if the warning
is to be taken seriously--"chloramphenicOl should not be used when
other less potentially dangerous agents will be effective'-- - the
tetracyclines, which have been shown to be as effective as chloram-
phenicol, should be considered the choice-and chloramphenicol used
only if toxicity to these or failure to respond has occurred. The
duration of therapy recommended appears adequate.
DOCUMENTATION:
1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and
chloramphenicol: use in typhus, typhoid and brucellosis. J.
Clin. Invest. 28:1052-1053, 1949. (abstr.)
2. Knight, V., F. RuizSancheZ, and W. McDermott. Chloramphenicol
in the treatment of the acute manifestations of brucellosis.
Amer. .J. Med. Sci. 219:627-638, 1950.
3. Ley, H.L., Jr., T.E. Woodward, and J.E. Smadel. ChloramphenicOl
(chloromycetin) in the treatment of murine typhus. J.A.M.A.
143:217-219, 1950.
4. Murray, E.S., G. Baehr, G. Shwartzman, T.A. Manderbaum, N.
Rosenthal, J.C. Doane, L.B. Weiss, S. Cohen, and .J.C. Snyder.
Brill's Disease; clinical and laboratory diagnosis. J.A.M.A.
142:1059-1066, 1950.
5. Pincoffs, M.C., E.G. Guy, L.M. Lister, T.E. Woodward, and J.E.
Smadel. The treatment of Rocky Mountain spotted fever with
chloromycetin. Ann. Intern. Med. 29:656-663, 1948.
6. Smadel, J.E., T.E. Woodward, H.L. Ley, Jr., and R. Leuthwaite.
Chloramphenicol (chloromycetin) in the treatment of tsutsuganushi
disease (scrub typhus). J. Clin. Invest. 28:1196-1215, 1949.
III. Typhoid fever.
EVALUATION: Effective, but .
COMMENTS: Chloramphenicol has often been listed as the drug of
choice in typhoid fever. It is not clear that ampicillin has changed
this claim, but if they were of equal activity, the claim of "drug of
choice" would have to be revised because of the toxicity warning.
There is no mention of the carrier problem and relapses of positive
stool cultures.
DOCUMENTATION:
1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and
chloramphenicol: use in typhus, typhoid and brucellosis. J. Clin.
Invest. 28:1052-1053, 1949. (abstr.)
2. Smadel, J.E., H.L. Ley, Jr., and F.H. Diercks. Treatment of
typhoid fever. I. Combined therapy with cortisone and chioram-
phenicol. Ann. Intern. Med. 34:1-9, 1951.
PAGENO="0131"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4421
IV. Other salmonelloses.
EVALUATION: Possibly effective.
CO?IMENTS: Because of variability of clinical course with each species
and the large variety of species, there .is little reason to presume
that a generalization is possible. In a condition of short symptoma-
tic duration like gastroenteritis, the use of the drug is most diffi-
cult to evaluate. The variable courses of the systemic forms do not
allow the assurance of effectiveness that has been derived for typhoid
fever, which is more uniform. These differences between typhoid and
the other salmonelloses illustrate the difficulty of generalization
from one species to the next. It is likely that localized salmonella
infections, such as osteomyelitis, empyema or other diseases should
have a therapeutic trial with chloramphenicol. The treatment of
carriers with positive stool cultures should not be recommended and
the insert should so state. Althoughthe stools may be negative while
the drug is continued, there is no evidence that the carrier state is
terminated more frequently than would: occur otherwise with a similar
passage of time. Obviously, the inability to define drug effectiveness
in salmonelloses also applied to other drugs, such as ampicillin; hence,
a reliable comparison between drugs is not possible.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wissernan, Jr. Chloromycetin, pp. 56-58.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
V. Urinary tract infections.
EVALUATION: Effective, but . .
COMMENTS: As specified in the insert, outcome of treatment of urinary
tract infections is influenced by anatomic factors, but these have
little importance in the choice of drug except that, in situations in
which cure is unlikely, the use of toxic agents is probably not justi~
fied. The susceptibilities of the organisms involved are of prime
importance (chloranphenicol does not work any better against chloram-
phenicol-susceptible organisms than other agents work against organisms
susceptible to them). Hence, when organisms are susceptible to less
toxic agents, chioramphenicol should not be used even if it is effective
in vitro unless the others have failed. It is unusual for chloramphen-
icol to succeed when other agents with satisfactory in vitro activity
have failed. Of the three species singled out, Escherichia ~]*j is.
often treatable with other chemotherapy, but chloramphenicol may be a
secondary choice. Streptococcus fecalis infections are probably
better treated with other agents, :such as penicillin and streptomycin
or erythromycin. Various Proteus species are different in their
susceptibility to different drugs; hence, the generalization "Proteus
~p~cies" should be avoided. Proteus mor~app, v~4garis, and rettgeri
PAGENO="0132"
4422 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
are often susceptible only to chloramphenicol.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wissenan, Jr. Chloronycetin, pp. 105-
108. Antibiotics Monographs No. 8. New York: Medical Encyclo-
pedia, Inc., 1958.
VI. Surgical infections: postoperative wound infections.
EVALUATION: Possibly effective.
COMMENTS: Postoperative wound infections have a variety of etiologic
agents, but ! ylococcu~ ~ is the single most common. Chlor-
amphenicol is effective against many of these agents, but is not the
most effective against the Staphylococcus. For this reason, plus the
toxicity warning, it is not the first choice in most infections unless
an organism is isolated against which chloranphenicol is most active
in vitro, or other preferred drugs cannot be given or have been inef-
fective.
DOCUMENTATION: Most favorable report is reference 1 (Altemeier).
1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromycetii
and aureonycin in surgical infections. J.A.M.A. 145:449-457, 1951.
2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph-
ylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30:
265-274, 1955.
3. Carmichael, C.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953.
4. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults.
Brit. Med. J. 2:845-847, 1956.
5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphyloccal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
6. Lepper, M.H., P. Tillman, and R. Devetsky. Patterns of trans-
mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965.
7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia
complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959
8. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. staphylococcal
pneumonia in infancy. Brit. Ned. J. 2:1423-1427, 1955.
VII. Surgical infections: cellulitis.
EVALUATION: Possibly effective.
COMMENTS: Cellulitis (other than postoperative) is most often caused
by streptococci or staphylococci for which chloramphenicol is not the
most effective drug. For this reason, plus the toxicity warning, it
is not the first choice unless an organism against which chloramphenicOl
is the most active has been isolated, or the preferred drug cannot be
given or has failed.
PAGENO="0133"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4423
DOCUMENTATION: Same as for Indication VI.
VIII. Surgical infections: infected sinus tract.
EVALUATION: Possibly effective.
COMMENTS: Chioramphenicol may be useful in some instances in which
the organisms have been shown to be sensitive only to it. Many sinus
tract infections are caused by tuberculosis and actinomycosis. Chlor-
amphenicol is not indicated in tuberculosis, and other agents are
preferred in actinoniycosis. Some sinus tracts associated with fistulas
from viscera, including intestines, may be predominantly .infected with
fecal flora. In these, chloramphenicol may be the single most effective
agent. when other agents appear equally effective in laboratory testing,
they should be tried first. There is rarely great urgency in treating
sinus tract infections with antibiotics.
The specific organisms for which chloramphenicol has been proved
effective therapy (in this condition) should be listed.
DOCUMENTATION:
1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromycetin)
and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951.
2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph-
yloccal pneumonia and empyema in infancy. J. Thorac. Surg. 30:
265-274, 1955.
3. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953.
4. Hausmann, W., and A.J Karlish. Staphyloccal pneumonia in adults.
Brit. Ned. J. 2:845-847, 1956.
5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
6. Lepper, N.H., P. Tillrnan, and R. Devetsky. Patterns of trans-
mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965.
7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal
pneumonia complicating influenza. A.M.A. Arch. Intern. Ned. 103:
532-542, 1959.
8. Waliman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Ned. J. 2:1423-1427, 1955.
9. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 122-
124. Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
IX. Surgical infections: peritonitis or intra-abdoniinal abscesses from
ruptured intestines, diverticula, or appendix.
EVALUATION: Possibly effective.
PAGENO="0134"
4424 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
COMMENTS: These infections are often caused by mixed flora from the
intestinal content . In the acute stage of peritonitis, a drug often
must be selected empirically for surgical preparation or immediately
postoperatively. Judged by statistical probability chlorampheniCOl
is a good choice in such a situation. It should be given parenterally,
however, because oral therapy in these infections is probably inap-
propriate. In other less acute complications listed in the insert,
chloramphenicol should be shown to be the most effective agent against
the organisms isolated before it is used, or other less toxic agents
should have failed or be contraindicated.
The specific causative organisms for which chloramphenicOl has been
proved effective therapy (in these conditions) should be listed.
DOCUMENTATION: Same as for Indication VIII.
X. Respiratory tract infections.
EVALUATION: Possibly effective.
COMMENTS: This heading is ambiguous. The package insert should list
specific organisms (and the site of respiratory infection) for which
chloramphenicol has been proved effective therapy.
In general, the etiology of these conditions is varied and chloram-
phenicol is the best agent for only a few. In streptococcal, pneumo-
coccal, and staphylococcal diseases of the respiratory tract, other
drugs are preferable. Chloramphenicol should be used only in Kiebsiella
infections and perhaps other necrotizing pneurnonias caused by E.coli
or related organisms when they are shown invitr~q to be resistant to
ampicillin, éephalothin, and kanamycin. ~ infec-
tions of the respiratory tract respond well to ampicillin; hence,
chioramphenicOl is best used only when ampicillin is not tolerated
or fails.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wissernan, Jr. Chloromycetifl, pp. 63-72.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
XI. Meningeal infections.
EVALUATION: Probably effective.
COMMENTS: The three most common causes of meningitis are the meningo-
cocci, pneumococci, and ~~pphilus influenzae. All are susceptible
to chioramphenicol, as are many staphylococci and the gram-negative
aerobic rods that often infect newborns. Moreover, it is true that
the drug does get into the spinal fluid well. As a drug of choice
PAGENO="0135"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4425
for empiric use, however, it is probably not first, because it is
likely to be less effective in pneumococcal disease than is penicillin.
Although many believe it is first choice in Hemophilus infections,
tetracycline is probably as good and ampicillin is, too. It is likely
that this claim (drug of choice in H. influenzae meningitis) is no
longer.justifjed. In menigitis of the newborn kanamycin is preferred
as the drug of choice for empiric treatment. In older patients, when
a diagnosis has been made and the organisms shown to be more susceptible
to chloramphenicol than to other agents, it may be the drug of choice.
As indicated, in the insert, initial treatment should be parenterally
administered.
The package insert should list the specific organisms for which
chloramphenicol has been proved effective therapy in meningitis.
DOCUNENTP~TION:
1. Parker, R.T., N.J. Snyder, R.S.J. Liu, J.W. Looper, Jr., and T.E.
Woodward. Therapeutic range of chloramphenicol in purulent men-
ingitis. Antibiot. Ned. Clin. Ther. 1:192-200, 1955.
XII. Brucellosis.
EVALUATION: Effective, but . .
COMMENTS: Chioramphenicol, like other drugs, is capable of control-
ling symptoms of acute brucellosis, but the relapse rate is high. It
does not appear to be superior to the less toxic tetracyclines,
DOCUMENTATION:
1. Knight, V., F. Rui~-Sanchez, andW. McDermott. Chloramphenicol
in the treatment of the acute manifestations of brucellosis. Amer.
J. Med. Sci. 219:627-638, 1950.
2. Spink, W.W. The Nature of Brucellosis. Minneapolis: The
University of Minnesota Press, 1956. 464 pp.
3. Woodward, T.E., J.E. Smadel, W.A. Holbrook, and W.T. Baby. The
beneficial effect of chloromycetin in brucellosis. J. Clin.
Invest. 28:968-976, 1949.
:111. Bartonellosis.
EVALUATION: Probably effective.
COMMENTS: Chloramphenicol is reported to be an effective antibiotic
in these infections. Of the references suggested by the manufacturer
(see Documentation below): two are reports of studies involving a
total of 25 patients whose bartonellosis was treated with chloramphen-
icol with good success, and two are textbook discussions of bartonel-
losis and its treatment. Of the latter discussions, one feels that
the effectiveness of chloramphenicol is best documented, the other
feels that other agents are probably as good.
PAGENO="0136"
4426 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
DOCUMENTATION:
1. Bartonellosis, pp. 603-606. In G.W. Hunter, III, W.W. Frye, and
J.C. Swartzwelder, Eds. A Manual of Tropical Medicine. (3rd ed.)
Philadelphia: W.B. Saunders Co., 1960.
2. Payne, E.H., and 0. Urteaga. Carrion's disease treated with
chloromycetin. Antiobiot. & Chemothbr. 1:92-99, 1951.
3. Pinkerton, H. Bartonellosis (Carrion's disease, Oroya fever,
Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott,
Eds. Cecil-Loeb Textbook of Medicine. (11th ed.) Philadelphia:
W.B. Saunders Co., 1963.
4. Urteaga, B.O., and E.H. Payne. Treatment of the acute febrile
phase of Carrion's disease with chloramphenicol. Amer. J. Trop.
Ned. 4:507-511, 1955.
XIV. Relapsing fever.
EVALUATION: Possibly effective.
COMMENTS: Treponema (Borrelia) recurrentis infections in experimental
animals are susceptible to chloramphenicol. On a weight basis, how-
ever, penicillin G is more active. In human infections, no direct
comparison has been made, and, although chloramphenicol has been used
successfully, penicillin should be tried first if it is tolerated.
DOCUMENTATION:
1. Hirschboeck, N.M. Use of chloramphenicol in relapsing fever.
Amer. .1. Trop. Med. 3:712-713, 1954.
XV. Granuloma iriguinale.
EVALUATION: Effective, but . .
COMMENTS: It has been reported that chloramphenicol caused the
disappearance of Donavan bodies more rapidly than either tetracycline
or streptomycin. Relapses after chloramphenicol have seemed to be
less than 1O7~. Although chioramphenicol may be slightly better than
tetracycline, the latter may be preferred for toxicologic reasons.
DOCUMENTATION:
1. Greenblatt, R.B., W.E. Barfield, R.B. Dienst, R.M. West, and
N. Zises. Five-year study of antibiotics in treatment of
granuloma inguinale. Amer. J. Syph. 36:186-191, 1952.
2. Robinson, R.C.V., and T.L. Wells. Intramuscular chloramphenicol
in the treatment of gonorrhea and granuloma inguinale. Amer. 3.
Syph. 36:264-268, 1952.
XVI. Plague.
EVALUATION: Effective, but . .
PAGENO="0137"
COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 4427
COMMENTS: All forms of plague have been shown to respond to chlor-
amphenicol when it is given in large doses early in the disease.
There is no clear evidence that it is superior to tetracycline or
streptomycin.
DOCUMENTATION:
1. McCrumb, F.R., Jr., S. Mercier, J. Robic, N. Bouillat, J.E.
Smadel, T.E. Woodward, and K. Goodner. Chloramphenicol and
terramycin in the treatment of pneumonic plague. Amer. J.
Med. 14:284-293, 1953.
XVII. Ornithosjs.
EVALUATION: Possibly effective.
COMMENTS: In embryonated eggs and experimental animal infections,
chloramphenicol is less effective than the tetracyclines. Results
of therapy of human infections have been variable and relapses have
been frequent. The role of the drug in this disease is not well
established.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 70-71.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
ENERAL COMMENTS
The `Warning" section appears justified in view of the seriousness of
aplastic anemia.
Tissue distribution appears to be favorable. The distribution into
the cerebrospinal fluid is good, as pointed out in the insert, and is
reasonably good into brain tissue, which is important when cerebritis
accompanies meningitis. The distribution into bile is not as high as
that of the tetracyclines and some of the penicillins. The very small
amoUnt in the feces is of interest as is the fact that the fecal con-
tent is higherwhen the palmitate: has been given.
The penetration into the eye is a plus factor for this drug. Trans-
placental transfer was shown by chemical methods which may not measure
the active drug.
Emphasis should be put on the recommended dose, because a smaller dose
is often given, particularly postoperatively. The fate of the drug
when the metabolic mechanisms are disturbed should remain as stated.
As to blood dyscrasias, it should be mentioned that frequent blood
counts do not necessarily assure that aplastic anemia can be prevented.
In fact, it may occur after the drug has been stopped.
PAGENO="0138"
4428 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
The roles of organisms other than candida and staphylococci in
resistance and superinfection have been demonstrated, particularly
Pseudomonas and some other gram-negative aerobic rods that are re-
sistant. This should be pointed out in the section discussing resis-
tance.
Intravenous administration of chloramphenicol produces a rapid peak
in blood levels and is preferred over oral or intramuscular admini-
stration in critically ill patients. However, because the oral form
is so highly absorbed, as soon as the patient can take it, there is
little reason to continue the I.V. use.
It would be less ambiguous if there were a specific package insert
that eliminated the references to the buffered I.V. and the intra-
muscular form. The delay in achieving peak blood levels in the use
of the succinate form is probably of little clinical importance, but
if the insert were designed specifically for this form of the drug
there could be little difficulty in making it clear that there is a little
lag in hydrolysis with a somewhat lower level of antibacterial activity
at 15 mm.
Approveci by k~!
Chairman
The Drug Efficacy Study of the National Academy of Sciences -
National Research Council has requested that the following
qualifying addendum be conveyed with their reports to the
ultimate recipients of these reports:
"Drugs of identical chemical composition (so-called
generic drugs) formulated and marketed by numerous
individual firms under generic or trademarked n~s
have been evaluated for efficacy as a group without
consideration of `therapeutic equjvalence*~ In the
event that no evidence for pharmacological availability
or therapeutic efficacy in man can be presented for
any of the indications claimed for the use of any
of the drugs in the attached listing, their classifications
of effectiveness may need to be modified if regulations
of the Food and Drug Administration require such proof."
PAGENO="0139"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4429
NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCL
Division of Medical Sciences
DRUG EFFICACY STUDY
Form A
(To be submitted in duplicate by applicant)
* NDA ~ 2. Data Oiginally Appoooed O~~OhPV 5, 1951 3. Cc ~ OTt D
* Bnond Nonoe- Chioromycetin Palmitate oral Sunpensli~in
* Apphcont's Na,na~Parke, navis ~ Ccampany _~ -
andAddntss_..IQ~~P~L~t the River; Detroit. Michigan
6. QuantitatIve Formula
eblished )Noo.Pcoptietacy Noon. of Adios togradlants (in ocden shoucn an label) Atttoant (pen tablet, pen ni.,
hioramphenicol Palmitate 125 mg./4 cc.
Dosage Poem (tablets, etc.) suspension
foote of Adco,. (0,cl, etc. Whtnt a ncou dnag opplicatio,c cacaos oral
d~ff,nant nodes of od,ninistnofion, sepanate fonone shoald be csed.(
Thetapecctic C(abcc-Attach 0 labels aod 10 package insects (it aced) to onigina( Fontn A (blat( and 1 copy to daplicot. Pen,, A (ohits).
List at titenetccee cetseectats meet pettiocent to en eoali',tlan of the .ffaatinenass of the doug foe the pccpos.s fcc mhlah It (s affec.d In the tab.),
the package insect, oc boachcne. Appnoai,noteiy 5 to 10 bay teftnancts one naqoestad, if anailabie. (Attach 10 copies to aniginol Fanno A (bias)
end 1 copy to daplicatt Font, A )unhite).t
Theappl~cantisincited,,fhesodas,nes,tasab,,,t onyccnpabiished cnatnnia) that is pontictt,ctto the ocaloalian of the dncg by the Aaad.nty-
Restoncf, Cococil. Th,s sappitnttotony tnatan.al sliocld be packaged onith Fono A )mh(te(. A single copy of this tnaten(a( Is raqcc.stad.
In this space, please list and desaniba bciafy the scppletttsttacy mafani~) that is scbntitted acith Fanm A (oohite).
PAGENO="0140"
4430 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Panel on Anti-Infective ~ (nfl
INDICATIONS
I. Staphylococcal infections, by implication of the discussion on the
first page of the insert, may be an indication: "in a survey of
experimental and clinical experiences of susceptibility of staph-
ylococci to chloramphenicol, it was found that the incidence of
chloramphenicol-resistaflt staphylococci appears unrelated to ire-
quency or to intensity of use of this antibiotic. Development of
resistance to chloramphenicol can be regarded as minimal for staph-
ylococci and many other species of bacteria."
EVALUATION: Possibly effective.
CONItENTS: Although chloramphenicol was useful for the treatment of
some staphylococcal diseases during the mid-l950's, it now seems to
be rarely indicated. Its major trial was in the staphylococcal
pneumonias accompanying the influenza epidemic of 1957. Its effect~
ness was somewhat less than expected, even for sensitive strains. `1
statenent concerning resistance is not true in the opinion of the P~
(see below). In the description of in vitro work just before the SE
tence quoted above, there is no reference to the transfer of episom
particles carrying chloramphenicol resistance. The advent of bette:
agents for staphylococcal disease relegates this drug to a very rar
needed alternate choice.
DOCUMENTATION:
1. Bloomer, W.E., S. Gia~ona, G.E. Lindskog, and R.E. Cooke.
Staphylococcal pneumonia and enpyema in infancy. J. Thorac.
Surg. 30:265-274, 1955.
2. Carmichael, D.B., J~. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Ned. J. 4:287-294, 19~
3. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in
adults. Brit. Med. 1. 2:845-847, 1956.
4. Kanof, A., B. Epstein, B. Kramer, and I. Nauss. Staphylococcal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
5. Lepper, N.H., P. Tillmau, and R. Devetsky. Patterns of transmi~
sion of staphylococci. Ann. N.Y. Acad. Sci. 128:404-427, 1965
6. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal
pneumonia complicating influenza. A.M.A. Arch. Intern. Med.
103:532-542, 1959.
7. Wallrnan, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955.
II. Rickettsial diseases: epidemic and murine typhus, Brill's disease,
scrub-typhus, Rocky Mountain spotted fever, and rickcttsial pox.
PAGENO="0141"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4431
EVALUATION: Effective, but .
COMMENTS: That chloramphenicol is effective in the diseases listed
is well established, except in rickettsial pox, a condition so in-
frequently seen that few data are available. However, if the warning
is to be taken seriously--"chloramphenicol should not be used when
other less potentially dangerous agents will be effective:'--- the
tetracyclines, which have been shown to be as effective as chloram-
phenicol, should be considered the choice and chloramphenicol used
only if toxicity to these or failure to respond has occurred. The
duration of therapy recommended appears adequate.
DOCUMENTATION:
1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and
chioramphenicol: use in typhus, typhoid and brucellosis. J.
Clin. Invest. 28:1052-1053, 1949. (abstr.)
2. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol
in the treatment of the acute manifestations of brucellosis.
Amer. J. Med. Sci. 219:627-638, 1950.
3. Ley, H.L., Jr., T.E. Woodward, and J.E. Srnadel. Chioramphenicol
(chioromycetin) in the treatment of murine typhus. J.A.M.A.
143:217-219, 1950.
4. Murray, E.S., C. Baehr, G. Shwartzman, T.A. Manderbaum, N.
Rosenthal, J.C. Doane, L.B. Weiss, S. Cohen, and J.C. Snyder.
Brill's Disease; clinical and laboratory diagnosis. J.A.M.A.
142:1059-1066, 1950.
5. Pincoffs, M.C., E.G. Guy, L.M. Lister, T.E. Woodward, and J.E.
Smadel. The treatment of Rocky Mountain spotted fever with
chloromycetin. Ann. Intern. Ned. 29:656-663, 1948.
6. Smadel, J.E., T.E. Woodward, H.L. Ley, Jr., and R. Lcuthwaite.
Chloramphenicol (chloromycetin) in the treatment of tsutsugamushi
disease (scrub typhus). 3. Clin. Inyest. 28:1196-1215, 1949.
III. Typhoid fever.
EVALUATION: Effective, but . .
COMMENTS: Chloramphenicol has often been listed as the drug of
choice in typhoid fever. It is; not clear that ampicillin has changed
this claim, but if they were of equal activity, the claim of "drug of
choice" would have to be revised because of the toxicity warning.
There is no mention of the carrier problem and relapses of positive
stool cultures.
DOCUMENTATION:
1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureonycin and
chloramphenicol: use in typhus, typhoid and brucellosis. 3. Clin.
Invest. 28:1052.1053, 1949. (abstr.)
2. Smadel, J.E., H.L. Ley, Jr., and F.H. Diercks. Treatment of
typhoid fever. .1. Combined therapy with cortisone and chloram-
phenicol. Ann. Intern. Med. 34:1-9, 1951.
PAGENO="0142"
4432 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
IV. Other salmonelloses~
EVALUATION: Possibly effective.
CO~1MENTS: Because of variability of clinical course with each species
and the large variety of~species, there is little reason to presume
that a generalization is possible. In a condition of short symptoma-
tic duration like gastroenteritis, the use of the drug is most diffi-
cult to evaluate. The variable courses of the systemic forms do not
allow the assurance of effectiveness that has been derived for typhoid
fever, which is more uniform. These differences between typhoid and
the other salmonelloses illustrate the difficulty of generalization
from one species to the next. It is likely that localized salmonella
infections, such as osteomyelitis, enpyema or other, diseases should
have a therapeutic trial with chloramphenicol. The treatment of
carriers with positive stool cultures should not be recommended and
the insert should so state. Although the stools may be negative while
the drug is continued, there is no evidence that the carrier state is
terminated more frequently than would occur otherwise with a similar
passage of time. Obviously, the inability to define drug effectiveness
in salmonelloses also applied to other drugs, such as ampicillin; hencE
a reliable comparison between drugs is not possible.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chioromycetin, pp. 56-58.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
V. Urinary tract infections.
EVALUATION: Effective, but .
COMMENTS: As specified in the insert, outcome of treatment of urinary
tract infections is influenced by anatomic factors, but these have
little importance in the choice of drug except that, in situations in
which cure is unlikely, the use of toxic agents is probably not justi-
fied. The susceptibilities of the organisms involved are of prime
importance (chioramphenicol does not work any better against chloram-
phenicol-susceptible organisms than other agents work against organisms
susceptible to them). Hence, when organisms are susceptible to less
toxic agents, chloramphenicol should not be used even if it is effecti'~
in vitro unless the others have failed. It is unusual for chloramphen-
icol to succeed when other agents with satisfactory in vitro activity
have failed. Of the three species singled out, Eseherichia coil, is
often treatable with other chemotherapy, but chioramphenicol may be a
secondary choice. St~ptococcus fecalis infections are probably
better treated with other agents, such as penicillin and streptomycin
or erythrornycin. Various Proteus species are different in their
susceptibility to different drugs; hence, the generalization "Proteus
species" should be avoided. Proteus rnor~gani, vul~aris, and rettgeri
PAGENO="0143"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4433
are often susceptible only to chloramphénicol.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 105-
108. Antibiotics Monographs No. 8. New York: Medical Encyclo-
pedia, Inc., 1958.
1. Surgical infections: postoperative wound infections.
EVALUATION: Possibly effective.
CONMENTS: Postoperative wound infections have a variety of etiologic
agents, but ~~phyj~occus aureus is the single most common. Chior-
amphenicol is effective against many of these agents, but is not the
most effective against the Staphylococcus. For this reason, plus the
toxicity warning, it is not the first choice in most infections unless
an organism is isolated against which chioraruphenicol is most active
in vitro, or other preferred drugs cannot be given or have been inef-
fective.
DOCUMENTATION: Most favorable report is reference 1 (Altemeier).
1. Altemeier, W.A., and W.R. Culbertson. Chioramphenicol (chloromycetin)
and aureoniycin in surgical infections. J.A.M.A. 145:449-457, 1951..
2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph-
ylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30:
265-274, 1955.
3. Carmichael, C.B., Jr. Fatal bacterial endocarditis dua to
staphylococcus aureus. U.S. Armed Forces Ned. J. 4:287-294, 1953.
4. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults.
Brit. Med. J.. 2:845-847, 1956.
5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphyloccal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
6. Lepper, M.H., P. Tillman, and R. Devetsky. Patterns of trans-
mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965.
7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and M. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococ.cal pneumonia
complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959.
8. Waliman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955.
1. Surgical infections; cellulitis.
EVALUATION: Possibly effective.
COMMENTS: Cellulitis (other than postoperative) is most often caused
by streptococci or staphylococci for which chloraruphenicol is not the
most effective drug. For this reason, pius the toxicity warning, it
is not the first choice unless an organism against which chiorampitenico].
is the most active has been isolated, or the preferred drug cannot be
given or has failed.
PAGENO="0144"
4434 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
DOCUMENTATION: Same as for Indication VI.
VIII. Surgical infections: infected sinus tract.
EVALUATION: Possibly effective.
COMMENTS: Chioramphenicol may be useful in some instances in which
the organisms have been shown to be sensitive only to it. Many sinus
tract infections are caused by tuberculosis and actinornycosis. Chior-
amphenicol is not indicated in tuberculosis, and other agents are
preferred in actinomycosis. Some sinus tracts associated with fistula
from viscera, including intestines, may be predominantly infected with
fecal flora. In these, chloramphenicol may be the single most effecti.
agent. When other agents appear equally effective in laboratory testi
they should be tried first. There is rarely great urgency in treating
sinus tract infections with antibiotics.
The specific organisms for which chioramphenicol has been proved
effective therapy (in this condition) should be listed.
DOCUMENTATION:
1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromyce
and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951.
2. Bloomer, W.E., S. Giaminona, G.E. Lindskog, and R.E. Cooke. Staph-
ylocca). pneumonia and empyema in infancy. J. Thorac. Surg. 30:
265-274, 1955.
*.i. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Ned. .3. 4:287-294, 1953.
4. Hausmann, W., and A.J Karlish. Staphyloccal pneumonia in adults.
Brit. Med. .3. 2:845-847, 1956.
5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
6. Lopper, N.H., P. Tillman, and R. Devetsky. Patterns of trans-
mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965
7. Martin, C.M., C.N. Kunin, L.S. Gottlieb, and M. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal
pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:
532-542, 1959.
8. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Med. .3. 2:1423-1427, 1955.
9. Woodward, T.E., and C.L. Wissenian, Jr. Chloromycetin, pp. 122-
124. Antibiotics Monographs No. 8. New York: Medical Encycloped
Inc., 1958.
IX. Surgical infections: peritonitis or intra-abdominal abscesses from
ruptured intestines, diverticula, or appendix.
EVALUATION: Possibly effective.
PAGENO="0145"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4435
COMMENTS: These infections are often caused by mixed flora from the
intestinal content . In the acute stage of peritonitis, a drug often
must be selected empirically for surgical preparation or immediately
postoperatively. Judged by statistical probability cliloramplienicol
is a good choice in such a situation. It should be given parenterally,
however, because oral th~rapy in these infections is probably map-
propriate. In other less acute complications listed in the insert,
chioramphenicol should be shown to be the most effective agent against
the organisms isolated before it is used, or other less toxic agents
should have failed or be contraindicated.
The specific causative organisms for which chloramphenicol has been
proved effective therapy (in these conditions) should be listed.
DOCuMENTATION: Sane as for Indication VIII.
X. Respiratory tract infections.
EVALUATION: Possibly effective.
COMMENTS: This heading is ambiguous. The package insert should list
specific organisms (and the site of respiratory infection) for which
chioramphenicol has been proved effective therapy.
In general, the etiology of these conditions is varied and chloram-
phenicol is the best agent for only a few. In streptococcal, pneurim-
*coccal, and staphylococcal diseases of the respiratory tract, other
drugs are preferable. Chloramphenicol should be used only in Klebsiella
infections and perhaps other necrotizing pneumonias caused by E.coli
or related organisms when they are shown in vitro to be resistant to
ampicillin, cephalothin, and kanamycin. Hemophilus influenzae infec-
tions of the respiratory tract respond well to anipicillin; hence,
chloranphenicol is best used only when ampicillin is not tolerated
or fails.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 63-72.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
XI. Meningeal infections.
EVALUATION: Probably effective.
CO~-~NTS: The three mast common causes of meningitis are the meni.ugo-
cocci, pncumococci, and Hemophilus influenzae. All, are sueceptible
to chioraniphenicol, as are many staphylococci and the gram-negative
aerobic rods that often infect newborns. Moreover, it is true that
the drug does get into the spinal fluid well. As a drug of choice
81-280 0-69-pt. ll-lO
PAGENO="0146"
4436 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
for empiric use, however, it is probably not first, because it is
likely to be less effective in pneumococcal disease than is penicillin.
Although many believe it is first choice in Ilemophilus infections,
tetracycline is probably as good and ampicillin is, too. It is likely
that this claim (drug of choice in H. influenzae meningitis) is no
longer justified. In menigitis of the newborn kanatnycin is preferred
as the drug of choice for empiric treatment. In older patients, when
a diagnosis has been made and the organisms shown to be more susceptihi
to chloramphenicol than to other agents, it may be the drug of choice.
As indicated, in the insert, initial treatment should be parenterally
administered.
The package insert should list the specific organisms for which
chloraraphenicol has been proved effective therapy in meningitis.
DOCUMENTATION:
1. Parker, R.T., M.J. Snyder, R.S.J. Liu, J.W. Looper, Jr., and T.E.
Woodward. Therapeutic range of chloramphenicol in purulent men-
ingitis. Antibiot. Ned. Clin. Ther. 1:192-200, 1955.
XII. Brucellosis.
EVALUATION: Effective, but .
COMMENTS: Chloramphenicol, like other drugs, is capable of control-
ling symptoms of acute brucellosis, but the relapse rate is high. It
does not appear to be superior to the less toxic tetracyclines.
DOCUMENTATION:
1. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol
in the treatment of the acute manifestations of brucellosis. Amer
J. Med. Sci. 219:627-638, 1950.
2. Spink, W.W. The Nature of Brucellosis. Minneapolis: The
University of Minnesota Press, 1956. 464 pp.
3. Woodward, T.E., J.E. Smadel, W.A. Holbrook, and W.T. Raby. The
beneficial effect of chloromycetin in brucellosis. J. Clin.
Invest. 28:968-976, 1949.
XIII. Bartonellosis.
EVALUATION: Probably effective.
COMMENTS: Chloramphenicol is reported to be an effective antibiotic
in these infections. Of the references suggested by the manufacturer
(see Documentation below): two are reports of studies involving a
total of 25 patients whose bartonellosis was treated with chlor;implien-
icol with good success, and two are textbook discussion~; of barioinl-
losis and its treatment. Of the latter discussions, onu fcels thai
the effectivenoss of chlorampltenicol is best docunsnt~d, the other
feels that other agents are probably as good.
PAGENO="0147"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4437
DOCUMENTATION:
1. Bartonellosis, pp. 603-606. In G.W. Hunter, III, W.W. Frye, and
J.C. Swartzwelder, Eds. A Manual of Tropical Medicine. (3rd ed.)
Philadelphia: W.B. Saunders Co., 1960.
2. Payne, E.H., and 0. Urteaga. Carrion's disease treated with
chioronycetin. Anti~biot. & Chemother. 1:92-99, 1951.
3. Pinkerton, H. Bartonellosis (Carrion's disease, Oroya fever,
Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott,
Eds. Cecil-Loeb Ttxtbook of Medicine. (11th ed.) Philadelphia:
W.B. Saunders Co~, 1963.
4. Urteaga, B.0., and E.H. Payne.~ Treatment of the acute febrile
phase of Carrion's disease with chloranphenicol. Amer. J. Trop.
Med. 4:507-511, 1955.
XIV. Relapsing fever.
EVALUATION: Possibly effective.
COMMENTS: Treponema (Borrelia) recurrentis infections in experimental
animals are susceptible to chloramphcnicol. On a weight basis, how-
ever, penicillin G is more active. In hurna~i infections, no direct
comparison has been made, and, although chioramphenicol has been used
successfully, penicillin should be tried first if it is tolerated.
DOCUMENTATION:
1. Hirschboeck, M.M. Use of chloranphenicol in relapsing fever.
* Amer. J. Trop. Med. 3:712-713, 1954.
XV. Granuloma inguinale.
EVALUATION: Effective, but . .
COMMENTS: It has been reportedthat chloranphenicol caused the
disappearance of Donavan bodies more rapidly than either tetracycline
or streptomycin. Relapses after chloramphenicol have seemed to be
less than l07~. Although chlorarnphenicol nay be slightly better than
tetracycline, the latter may be preferred for toxicologic reasons.
DOCUMENTATION:
1. Greeublatt, R.B., W.E. Barfield, R.B. Dienst, R.M. West, and
M. Zises. Five-year study of antibiotics in treatment of
granulorua inguinale. Amer. J. Syph. 36:186-191, 1952.
2. Robinson, R.C.V., and T.L. Wells. Intramuscular cliloramphenicol
in the treatment of gonorrhea and granuloma inguinale. Amer. J.
Syph. 36:264~268, 1952.
XVI. Plague.
EVALUATION: Effective, but
PAGENO="0148"
4438 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMMENTS: All forms of plague have been shown to respond to chlor-
amphenicol when it is given in large doses early in the disease.
There is no clear evidence that it is superior to tetracycline or
s treptomycin.
DOCUMENTATION:
1. McCrumb, F.R., Jr., S. Mercier, J. Robic, M. Bouillat, J.E.
Smadel, T.E. Woodward, and K. Goodner. Chloramphenicol and
terramycin in the treatment of pneumonic plague. Amer. J.
Med. 14:284-293, 1953.
XVII. Ornithosis.
EVALUATION: Possibly effective.
COMMENTS: In embryonated eggs and experimental animal infections,
chloramphenicol is less effective than the tetracyclines. Results
of therapy of human infections have been variable and relapses have
been frequent. The role of the drug in this disease is not well
established.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 70-71.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
GENERAL COMMENTS
The "Warning" section appears justified in view of the seriousness
of aplastic anemia.
Absorption after oral administration is good, in that 75-9O7~ of a
dose can be accounted for by metabolic products found in the urine.
Tissue distribution appears to be favorable. The distribution into
the cerebrospinal fluid is good, as pointed out in the insert, and
is reasonably good into brain tissue, which is important when cerebrit:
accompanies meningitis. The distribution into bile is not as high as
that of the tetracyclines and some of the penicillins. The very small
amount in the feces is of interest as is the fact that the fecal con-
tent is higher when the palmitate has been given.
The penetration into the eye is a plus factor for this drug. Trans-
placental transfer was shown by chemical methods which may not measure
the active drug.
Empahsis should be put on the recormuended dose, because a smaller dose
is often given, particularly postoperatively. The fate of the drug
when the metabolic mechanisms are disturbed should remain as stated.
As to blood dyscrasias, it should be mentioned that frequent blood coui
do not necessarily assure that aplastic anemia can be prevented. In
PAGENO="0149"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4439
fact, it may occur after the drug has been stopped.
The roles of organisms other than candidá and staphylococci in
resistance and superinfection have been demonstrated, particularly
Pseudomonas and some other gram-negative aerobic rods that are re-
sistant. This. should be pointed out in the section discussing resis-
tance.
Appro',~ ~r (,)
C1~a1rLafl j\-kU~
The Drug Efficacy Study of the National Academy of Sciences -
National Research Council has requested that the following
qualifying addendum be conveyed with their reports to the
ultimate recipients of these reports:
`tDrugs of identical chemical composition (so-called
generic drugs) formulated ~nd marketed by numerous
individual firms under generic or trademarked names
have been evaluated for efficacy as a group without
consideration of `therapeutic equivalence.' In the
event that no evidence for pharmacological availability
or therapeutic efficacy in man can be presented for
any of the indications claimed for the ~ of any
of the drugs in the attached listing, their classifications
of effectiveness may need to be modified if regulations
of the Food and Drug Administration require such proof."
PAGENO="0150"
4440 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
- NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL
Division of Medical Sciences
DRUG EFFICACY STUDY
Form A
ITs be submitted in duplicate by applicant)
1. NDA Nunb,,. ~.6D3l5,m (`1ol'i~.) 2. Dut, O~iginniiy App,n,,d .~eptember 20, 1963 3. 8~ oic 0
4. Otund Nun. Chioromycetin Sodium Succinate - Infant, 250 mg.
5. Appiknnts Nnne Parke, Davis & Company
Add,,ss .Toseph Campau at the River; Detroit, Michigan
6. Quantitative Formula
Estabtish.d tNsn-P,,p~i.tmyi Nan, at Attin~ Ingmdistts Ii, ~ shun, un tnb,tl Aenunt IF" tabi,t, p,n tel..
chioramphenicol Sodium Succinate 250 mg. base/vial
7. Dss,g. Fnnm ltabi.ts. ,tu.l ster~-via1
8. Rnut, *8 Adm. lOnnI, .tt. Wh.e. a n.e des,g nppiknLnnnnn.es
diff,e,nt nnutes nt ndnieistnntine. s,pntnt. fntees shnuld b. us,d.l parenteral
9. Thetnp.utis Clnims-Attnth 10 lnb,ls ned 15 penbng. iesnets lit us,dl tn neigient Fnem A lbiu,l ned t unpy tu dupi~uut. teem A lehitsi.
10. List *8 titsentun, nnt.e.eet, mast p.ntittset te nn nun iuntinn at the .C.atin.esssnt tfa dnug fat th, puepns.s tnt nhlnh is nffstsd in th. t,b.t,
th, puabng. les,nt. en bnenhue.. Appen*etnt.iy 3 a 10 b,y nst~e,euns nec n.qu.stsd. if nnniiabi,. tAttnuh tO unpi,s a neigieni Face A Ibtuet
ned 1 nnpy ta dupiiunts Fete A Inhitsi.)
11. The nppiiunet is ieait.d, it h, sa d,sin.s, a submit ney cuepu blish,d mntneint that is psntie.nt ta th. *nnluntiae at the deug by th. Aundsety-
R,s,nnuh Cnueail. This suppi,eaetney entetini shnuid bs pnuknged niih Facet A tnhitsl. A siegi. unpy of this ,ent,ni,t tst.qu.st.d.
12. te this spnu,. pl.ns. list ned dssunib, beisfy the suppiseecetany ent,nint that is sub'ttittsd atith Facet A chits).
PAGENO="0151"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4441
Panel on Anti-Infective Dr~gs (]~~I~
INDICATIONS
I. Staphylococcal infections, by implication of the discussion on the
firs.t page of the insert, may be an indication: "in a survey of
experimental and clinical experiences of susceptibility of staph-
ylococci to chloramphenicol, it was found that the incidence of
chloramphenicol-resistant staphylococci appears unrelated to fre-
quency or to intensity of use of this antibiotic. Development of
resistance to chloramphenicol can be regarded as minimal for staph-
ylococci and many other species of bacteria."
EVALUATION: Possibly effective.
CONMENTS: Although chloramphenicol was useful for the treatment of
some staphylococcal diseases during the inid-l950's, it now seems to
be rarely indicated. Its major trial was in the staphylococcal
pneiirnonias accompanying the influenza epidemic of 1957. Its effective-
ness was somewhat less than expected, even for sensitive strains. The
statement concerning resistance is not true in the opinion of the Panel
(see below). In the description of ~_y~itro work just before the sen-
tence quoted above, there is no reference to the transfer of episomal
particles carrying chioramphenicol resistance. The advent of better
agents for staphylococcal disease relegates this drug to a very rarely
needed alternate choice.
DOCUMENTATION:
1. Bloomer, W.E., S. Ciamoona, G.E. Lindskog, and R.E. Cooke.
Staphylococcal pneumonia and empyema in infancy. J. Thorac.
Surg. 30:265-274, 1955.
2. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953.
3. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in
adults. Brit. Med. J. 2:845-847, 1956.
4. Kanof, A., E. Epstein, B. Kramer, and L Mauss. Staphylococcal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
5. Lepper, M.H., P. Tiliman, and R. Devetsky. Patterns of transmis-
sion of staphylococci. Ann. N.Y. Acad. Sci. 128:404-427, 1965.
6. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and M. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal
pneumonia complicating influenza. A.M.A. Arch. Intern. Med.
103:532-542, 1959.
7. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955.
II. Rickettsial diseases: epidemic and murine typhus, Brill's disease,
scrub-typhus, Rocky Mountain spotted fever, and rickettsial pox.
PAGENO="0152"
4442 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
EVALUATION: Effective, but .
C0~1ENTS: That chioramphenicol is effective in the diseases listed
is well established, except in rickettsial pox, a condition so in-
frequently seen that few data are available. However, if the warning
is to be taken seriously-- "chloramphenicol should not be used when
other less potentially dangerous agents will be effective'---the
tetracyclines, which have been shown to be as effective as chlorain-
phenicol, should be considered the choice and chloramphenicol used
only if toxicity to these or failure to respond has occurred. The
duration of therapy recommended appears adequate.
DOCUMENTATION:
1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and
chloramphenicol: use in typhus, typhoid and brucellosis. J.
Clin. Invest. 28:1052-1053, 1949. (abstr.)
2. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol
in the treatment of the acute ~nifestations of brucellosis.
Amer. J. Med. Sci. 219:627-638, 1950.
3. Ley, H.L., Jr., T.E. Woodward, and JE. Smadel. Chioramphenicol
(chloromycetin) in the treatment of murine typhus. J.A.M.A.
143:217-219, 1950.
4. Murray, E.S. G. l3aehr, G. Shwartzman, T.A. Manderbaum, N.
Rosenthal, J.C. Doane, L.B. Weiss, S. Cohen, and J.C. Snyder.
Brill's Disease; clinical and laboratory diagnosis. J.A.M.A.
142:1059-1066, 1950.
5. Pincoffs, M.C., E.G. Guy, L.M. Lister, T.E. Woodward, and J.E.
Srsadel. The treatment of Rocky Mountain spotted fever with
chloromycetin. Ann. Intern. Med. 29:656-663, 1948.
6. Smadel, J.E., T.E. Woodward, H.L~ Ley, Jr., and R. Leuthwaite.
Chloramplienicol (chi~'romvoet:n) in the treatment of tsutsugamushi
disease (scrub typhus). J. Clin. Invest. 28:1196-1215, 1949.
III. Typhoid fever.
EVALUATION~ Effective, but .
COMMENT'~ Chtoramphenicol has often been listed as the drug of
choice in typhoid fever. It is not clear that ampicillin has changed
this claim, but if they were of equal activity, the claim of "drug of
choioe" would have to be revised because of the toxicity warning.
There is no mention of the carrier problem and relapses of positive
stool cultures.
DOCUMENTATION:
1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycim and
chloramphenicol: use in typhus, typhoid and brucellosis. J. Clim.
Invest. 28:1052-1053, 1949. (abstr.)
2. Smadel, J.E., H.L. Ley, Jr.; and F.H. Diercks. Treatment of
typhoid fever. I. Combined therapy with cortisone and chlorate-
phenicol. Ann. InLern. Med. 34:1-9, 1951.
PAGENO="0153"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4443
IV. Other salmonelloses.
EVALUATION: Possibly effective.
COM~1ENTS: Because of variability of clinical course with each species
and the large variety of species, there is little reason to presume
that a generalization is possible. In a condition of short symptoma-
tic duration like gastroenteritis, the use of the drug is most diffi-
cult to evaluate. The variable courses of the systemic forms do not
allow the assurance of effectiveness that has been derived for typhoid
fever, which is more uniform. These differences between typhoid and
the other salmonelloses illustrate the difficulty of generalization
from one species to the next. It is likely that localized salmonella
infections, such as osteomyelitis, empyema or other diseases should
have a therapeutic trial with chloramphenicol. The treatment of
carriers with positive stool cultures should not be recommended and
the insert should so state. Although the stools may be negative while
the drug is continued, there is no evidence that the carrier state is
terminated more frequently than would occur otherwise with a similar
passage of time. Obviously, the inability to define drug effectiveness
in salmonelloses also applied to other drugs, such as ampicillin; hence,
a reliable comparison between drugs is not possible.
DOCUMENTATION:
I. Woothrdrd, T.E., and C.L. Wieseman, Jr. Chloromycetin, pp. 56-58.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
V. Urinary tract infections.
EVALUATION: Effective, but .
CONMENTS: As specified in the insert, outcome of treatment of urinary
tract infections is thfiuenced by anatomic factors, but these have
little importance in the choice of drug except that, in situations in
which cure is unlikely, the use of toxic agents is probably not justi-
fied. The susceptibilities of the organisms involved are of prime
importance (chioramphenicol does not work any better against chloram-
phenicol-susceptible organisms than other agents work against organisms
susceptible to then). Hence, when organisms are susceptible to less
toxic agents, chloramphenicol should not be used even if it is effective
in vitro unless the others hzvc failed. It is unusual for chloramphen-
icol to succeed when other agents with satisfactory in~vi.t.~o activity
have failed. Of the three species singled out, Escherichia c:~j, is
often treatable with other chemotherapy, but chloramphenicol may be a
secondary choice. Streptococcus fecalis infections are probably
better treated with other agents, such as penicillin and streptomycin
or erythromycin. Various Proteus species are different in their
* susceptibility to different drugs; hence, the generalization "Proteus
species" should be avoided. Proteus morgani, vulgaris, and rettgeri
PAGENO="0154"
4444 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
are often susceptible only to chloramphenicol.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 105-
108. Antibiotics Monographs No. 8. New York: Medical Encyclo-
pedia, Inc., 1958.
VI. Surgical infections: postoperative wound infections.
EVALUATION: Possibly effective.
COMMENTS: Postoperative wound infections have a variety of etiologic
agents, but St~p lococcus aureus is the single most consnon. Chlor-
amphenicol is effective against many of these agents, but is not the
most effective against the Staphylococcus. For this reason, plus the
toxicity warning, it is not the first choice in most infections unless
an organism is isolated against which chioramphenicol is most active
in vitro, or other preferred drugs cannot be given or have been inef-
fective.
DOCUMENTATION: Most favorable report is reference 1 (Altemeier).
1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromycetin)
and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951.
2. Bloomer, W.E., S. Giamniona, G.E. Lindskog, and R.E. Cooke. Staph-
ylococcal pneumonia and empyeraa in infancy. J. Thorac. Surg. 30:
265-274, 1955.
3. Carmichael, C.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U~S. Armed Forces Med. J. 4:287-294, 1953.
4. Hausmann~ W., and A.J. Karlish. Staphylocioccal pneumonta in adults.
Brit. Med. 3. 2:845-841, 1956.
5. Kanof,A., B. Epatein~ B. Kramer, and I. Mauss. Staphyloccal
pneumonia and cmpyema. Pediatrics 11:385-392, 1953.
6. Lepper, N.H., P. Tillman, and R. Devetsky. Patterns of trans-
mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965.
7. Martin, C.M., CJ1. Kimin, L.S. Gottlieb, and N. Finland. Asian
influenza A in Boston, 1957-58. IT. Severe staphylococcal pneumonia
complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959.
8. Wa?lman, 1.8., BC. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Ned. 3. 2:1423-1427, 1955.
VII. Surgical infections: cellulitis.
EVALUATION: Possibly cffective.
COMMENTS: Cellulitis (other than postoperative) is most often caused
by streptococci or staphylococci for which chloramphenicol is not the
most effective drug. For this reason, plus the toxicity warming, it
is not the first choice unless an organism against which chloramphenicol
is the most active has been isolated, or the preferred drug cannot be
given or has failud.
PAGENO="0155"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4445
DOCUMENTATION: Same as for Indication VI.
VIII. Surgical infections: infected sinus tract.
EVALUATION: Possibly effective.
COMMENTS: Chloramphenicol may be useful in some instances in which
the organisms have been shown to he sensitive only to it. Many sinus
tract infections are caused by tuberculosis and actinomycosis. Chlor-
amphenicol is not indicated in tuberculosis, and other agents are
preferred in actinomycosis. Some sinus tracts associated with fistulas
from viscera, including intestines, may be predominantly infected with
feca]. flora. In these, chloramphe.nicol may be the single most effective
agent. When other agents appear equally effective in laboratory testing,
they should be tried first. There is rarely great urgency in treating
sinus tract infections with antibiotics.
The specific organisms for which chloramphenicol has been proved
effective therapy (in this condition) should he listed.
DOCUMENTATION:
1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromycetin)
and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951.
2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph-
yloccal pneumonia and empyema in infancy. J. Thorac. Surg. 30:
265-274, 1955.
3. Carmichael, D.B., Jr. Fatal bacterial endocardit.is due to
staphylococcus aureus. U.s. Armed Forces Med. J 4:287-294, 1953.
4. Hausmann, W,, and A.J K~r]li~h. Staphyloccal pneumonia in adults.
Brit. Med. .1. 2:845~847, 1956.
5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal
pneumonia and empyema. Pediatrics ll~385-392, 1953.
6. Lepper, M.II., P. Tillman, and R. Devetsky. Patterns of trans-
mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965.
7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and M. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal
prieumo~ia complicating influenza. A.M.A. Arch. Intern. Med. 103:
532-542, 1959.
8. Waliman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955.
9. Woodward, T.E.~, and C.L. Wisseman, Jr. Chloromycetin, pp. 122-
124. Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
IX. Surgical infections: peritonitis or intra-abdominal abscesses from
ruptured intestines, diverticula, or appendix.
EVALUATION: Possibly effective.
PAGENO="0156"
4446 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMMENTS: These infections are often caused by mixed flora from the
intestinal content . In the acute stage of peritonitis, a drug often
must be selected empirically for surgical preparation or immediately
postoperatively. Judged by statistical probability chloramphenicol
is a good choice in such a situation. It should be given parenterally,
however, because oral therapy in these infections is probably inap-
propriate. In other less acute complications listed in the insert,
chloramphenicol should be shown to be the most effective agent against
the organisms isolated before it is used, or other less toxic agents
should have failed or be contraindicated.
The specific causative organisms for which chloramphenicol has been
proved effective therapy (in these conditions) should be listed.
DOCUMENTATION: Same as for Indication VIII.
X. Respiratory tract infections.
EVALUATION: Possibly effective.
COMMENTS: This heading is ambiguous. The package insert should list
specific organisms (and the site of respiratory infection) for which
chloramphenicol has been proved effective therapy.
In general, the etiology of these conditions is varied and chloram-
phenicol is the best agent for only a few. In streptococcal, pneumo-
coccal, and staphylococcal diseases of the respiratory tract, other
drugs are preferable. Chloramphenicol should be used only in Kiebsiella
infections and perhaps other necrotizing pneumonias caused by E. coli
or related organisms when they are shown in vitro to be resistant to
ampicillin, cephalothin, and kanamycin. ~~ilus influenzae infec-
tions of the respiratory tract respond well to ampicillin; hence,
chloramphenicol is best used only when ampicillin is not tolerated
or fails.
DOCUMENTATION:
1. Woodward, T.E., and C.L~ Wisseman, Jr. Chloromycetin, pp. 63-72.
Antibiotics Monographs No. 8~ New York: Medical Encyclopedia,
Inc., 1958.
XI. Meningeal infections.
EVALUATION: Probably effective.
COMMENTS: The three most common causes of meningitis are the meningo-
cocci, pneumococci, and Hemophilus influenzae. All are susceptible
to chioramphenicol, as are many staphylococci and the gram-negative
aerobic rods that often infect newborns. Moreover, it is true that
the drug does get into the spinal fluid well. As a drug of choice
PAGENO="0157"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4447
for empiric use, however, it is probably not first, because it is
likely to be less effective in pneumococcal disease than is penicillin.
Although many believe it is first choice in Hemophilus infections,
tetracycline is probably as good and ampicillin is, too. It is likely
that this claim (drug of choice in IL influenzae meningitis) is no
longer justified. In menigitis of the newborn kanamycin is preferred
as the drug of choice for empiric treatment. In older patients, when
a diagnosis has been made and the organisms shown to be more susceptible
to chloramphenicol than to other agents, it may be the drug of choice.
As indicated, in the insert, initial treatment should be parenterally
administered.
The package insert should list the specific organisms for which
chloramphenicol has been proved effective therapy in meningitis.
DOCUMENTATION:
1. Parker, R.T., M.J. Snyder, R.S.J. Liu, J.W. Looper, Jr., and T.E.
Woodward. Therapeutic range of chloramphenicol in purulent men-
ingitis. Antibiot. Med. Clin. Ther. 1:192-200, 1955.
XII. Brucsllosis.
EVALUATION: Effective, but . .
COMMENTS: Ch~ orar~phenicol, like other drugs, is capable of control-
Hog symptoms of--acute bruceilosis, but the relapse rate is high. It
does not appoa~ to be superior to the less toxic tetracyclines.
DOCITh~NT~TION:
1. Knight, V., F. ~.`iiz-Sanchez, and W. McDermott~ Chloramphenicol
in the treatment of the acute manifestations of brucellosis. Amer.
J. Med. Sci, 219:627-638, 1950.
2. Spink, W.W, The Nature of Brucellosis. Minneapolis: The
University of Minnesota Press, 1956. 464 pp.
3. Woodward, T.E., J.E. Smadel, LA. Holbrook, and W.T. Raby. The
beneficial effect of chloromycetth in brucellosis. J. Clin.
Invest, 28:968-976, 1949.
XIII. Bartonellosis.
EVALUATION: Probably effective.
CONMENTS: Chioramphenicol is reported to be an effective antibiotic
in these infections. Of the references suggested by the manufacturer
(see Documentation below): two are reports of studies involving a
total of 25 patients whose bartonellpsis was treated with chloramphen-
icol with good success, and two are textbook discussions of bartonel-
losis and its treatment. Of the latter discussions, one feels that
the effectiveness of chloramphenicol is best documented, the other
feels that other agents are probably as good.
PAGENO="0158"
4448 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
DOCUMENTATION:
1. Bartonellosjs, pp. 603-606. In G.W. Hunter, III, W.W. Frye, and
J.C. Swartzwelder, Eds. A Manual of Tropical Medicine. (3rd ed.)
Philadelphia: W.B. Saunders Co., 1960.
2. Payne, E.H., and 0. Urteaga. Carrion's disease treated with
chloromycetin. Antiobiot. & Chemother. 1:92-99, 1951.
3. Pinkerton, H. Bartonellosis (Carrion's disease, Oroya fever,
Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott,
Eds. Cecil-Loeb Textbook of Medicine. (11th ed.) Philadelphia:
W.B. Saunders Co., 1963.
4. Urteaga, B.O., and E.H. Payne. Treatment of the acute febrile
phase of Carrion's disease with chlorampheniàol. Amer. .1. Trop.
Med. 4:507-511, 1955.
XIV. Relapsing fever.
EVALUATION: Possibly effective.
CONMENTS: Tr~ponenia (Borrelia) recurrentis infections in experimental
animals are susceptible to chloramphenicol. On a weight basis, how-
ever, penicillin C is more active. In human infections, no direct
comparison has been made, and, although chloramphenicol has been used
successfully, penicillin should be tried first if it is tolerated.
DOCUMENTATION:
1. Hirschboeck, M.M. Use of chloramphenicol in relapsing fever.
Amer. J. Trop. Med. 3:712-713, 1954.
XV. Granuloma inguinale.
EVALUATION: Effective, but .
COMMENTS: It has been reported that chloramphenicol caused the
disappearance of Donavan bodies more rapidly than either tetracycline
or streptomycin. Relapses after chloramphenicol have seemed to be
less than 10%. Although chloramphenicol may be slightly better than
tetracycline, the latter may be preferred for toxicologic reasons.
DOCUMENTATION:
1. Greenblatt, R.B., W.E. Barfield, R.B. Dienst, R.M. West, and
M. Zises. Five-year study of antibiotics in treatment of
granuloma inguinale. Amer. J. Syph. 36:186-191, 1952.
2. Robinson, R.C.V., and T.L. Wells. Intramuscular chloramphenicol
in the treatment of gonorrhea and granuloma inguinale. Amer. 3.
Syph. 36:264-268, 1952.
XVI. Plague.
EVALUATION: Effective, but . . .
PAGENO="0159"
* COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4449
COMMENTS: All forms of plague have been shown to respond to chlor-
amphenicol when it is given in large doses early in the disease.
There is no clear evidence that it is superior to tetracycline or
s treptomycin.
DOCUMENTATION:
1. McCrumb, F.R., Jr., S. Mercier, J. Robic, M. Bouillat, J.E.
Smadel, T.E. Woodward, and K. Goodner. Chloramphenicol and
terramycin in the treatment of pneumonic plague. Amer. J.
Med. 14:284-293, 1953.
XVII. Ornithosis.
EVALUATION: Possibly effective.
COMMENTS: In embryonated eggs and experimental animal infections,
chloramphenicol is less effective than the tetracyclines. Results
of therapy of human infections have been variable and relapses have
been frequent. The role of the drug in this disease is not well
established.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 70-71.
Antibiotics ~kv~.ographs No. 8. New York~ Medical Encyclopidia,
Inc., 1958.
GENERAL CO~NTS
The warning section appears justified in view of the seriousness
of aplastic anemit.
Tissue distribution appears to be favorab1e~ The distribution into
the cercbrospinal fluid is good as pointed out ~.n the insert, and is
reasonably good into brain tissue, which is important when cerebritis
accompanies meningitis. The distribution into bile is not as high as
that of the tetracyclines and some of the penicillins. The very small
amount in the feces is of interest as is the fact that the fecal con-
tent is higher when the palmitate has been given~
The penetration into the eye is a plus factor for this drug. Trans-
placental transfer was shown by chemical methods which may not
measure the active drug.
Emphasis should be put on the recomoended dose, because a smaller
dose is often given, particularly postoperaçively~ The fate of the
drug when the metabolic mechanisms are disturbed should remain as
stated. As to blood dyscrasias, it should be mentioned that frequent
blood counts do not necessarily assure that aplastic anemia can be
prevented. In fact, it may occur after the drug has been stopped.
PAGENO="0160"
4450 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
The roles of organisms other than candida and staphylococci in
resistance and superinfection have been demonstrated, particularly
Pseudomonas and some other gram-negative aerobic rods that are
resistant to chloramphenicol. This should be pointed out in the
insert in the section discussing resistance.
Intravenous administration of chloramphenicol produces a rapid peak
in blood levels and is preferred over oral or intramuscular admini-
stration in critically ill patients. Because the oral form is so
highly absorbed, as soon as the patient can take it, there is little
reason to continue the I.V. use. This succinate solution is recom-
mended for intravenous use only.
The unique feature of the succinate is the delay in achieving peak
concentrations of active drug because of the hydrolysis required. The
material (about Steri-Vial 148) on page 2 of the insert points out the
unique features of the design for the infant and instructions for each
route. The instructions and dose recoranendations are good. In this
case, the insert pertains to the one preparation and is also good from
that point of view.
Approved by _______________
Chair~n
The Drug Efficacy Study of the National Academy of Sciences -
National Research Council has requested that the following
qualifying addendum be conveyed with their reports to the
ultimate recipients of these reports:
"Drugs of identical chemical composition (so-called
generic drugs) formulated and marketed by numerous
individual firms under generic or trademarked n~s
have been evaluated for efficacy as a group without
consideration of `therapeutic equivalence.' In the
event that no evidence for pharmacological availability
or therapeutic efficacy in man can be presented for
any of the indications claimed for the use of any
of the drugs in the attached listing, their classifications
of effectiveness may need to be modified if regulations
of the Food and Drug Administration require such proof."
PAGENO="0161"
COMPETITIVE PROBLEMS IN THE DRUG INDuSTRY 4451
NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCiL
Division of Medical Sciences
DRUG EFFICACY STUDY
- FormA
(To be submitted in duplicate by applicant)
1. NDA Number 6n3O2~ (LLSS) 2. Onto Originally Approtmd December 8, 1950 3. Ba OTC 0
4. Brand ~ Chioromycetin, 50 mg. & 100 mg. Capsules, 250 mg Kapseals
5. Applicants Nanre Parke, Davis & Company
and Addr.ss .Toseph C~npau at the River; fletrnil-, M~u'h~gun
6. QuantItative Formula
itabtishad tNan.Pnapd.t,ty) Nanc. af Actin. tngr.dlsnte (in order sharon on lab,l) Amount par tabl.t, p.r ni.,
1. Chloromycetin, 50 mg. Capsule
Chloramphenicol 50 mg./capsule
2. Chioromycetin, 100 mg. Capsule
Chloramphenicol ` 100 mg./capsule
3. Chloromycetin, 250 mg. Kapseal
Chloramphenicol 250 mg./kapseal
Desage Farm (tablsts, dc.) capsules crnuyu~~
t. Rout, at Ade. (Oral. dc. Wham a naro drug application cooers
different routes at adrmini,tratign, separate tormnc chould be used.)___~_~~ oral
I. Thsrap.otic claims-Attach 10 labels and 10 package incamls lit used) to original Form A lblunl ond I copy to duplicats Farm A (ohite).
I. List at Ilteretune rater mast partin.nt to on ecaluetlan of thn *ff.ctiosn.ss at th. drug fan the parpae.s for rohlch it Is affared In the lab.)
tha peckags Ins.mt, or brochure. Approarmatnly 5 to 10 k.y noterencns oma raqu.it.d. it ocailabla. (Attach 10 copies to original Farm A tblu.)
and 1 copy to duplicat. Form A )mhit.).)
* Thu applicont is innit.d, ,t ha so dssrrss, to submit any unpublished rtotcrial that is pertinent to lbs ecaluclion at th. drug by the Aced.my-
Research Council. Thrs supplementary mot.riul should be pachagnd mith Form A )cnhitsl. A slngl. capy at this material Is r.qu.st.d.
* In this space, please (ret and descmibn bniefy the supplementary material that is submitted mith Farm A (mhit.).
81-280 11329
81-280 O-69-pt. 11-11
PAGENO="0162"
4452 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Panel on Anti-Infective Dr~gs (II~
INDICATIONS
I. Staphylococcal infections, by implication of the discussion on the
first page of the insert, may be an indication: "in a survey of
experimental and clinical experiences of susceptibilit.y of staph-
ylococci to chloramphenicol, it was found that the incidence of
chioramphenicol-resistant staphylococci appears unrelated to fre-
quency or to intensity of use of this antibiotic. Development of
resistance to chloramphenicol can be regarded as minimal for staph
ylococci and many other species of bacteria."
EVALUATION: Possibly effective.
COM~1ENTS: Although chloramphenicol was useful for the treatment 0:
some staphylococcal diseases during the mid-l950's, it now seems t(
be rarely indicated. Its major trial was in the staphylococcal
pmeumonias accompanying the influenza epidemic of 1957. Its effeci
ness was somewhat less than expected, even for sensitive strains.
statement concerning resistance is not true in the opinion of the I
(see below). In the description of in vitro work just before the
tence quoted above, there is no reference to the transfer of episor
particles carrying chloramphenicol resistance. The advent of bett
agents for staphylococcal disease relegates this drug to a very ra~
needed alternate choice.
DOCUMENTATION:
1. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke.
Staphylococcal pneumonia and empyema in infancy. J. Thorac.
Surg. 30:265-274, 1955.
2. Carmichael, D.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Ned. J. 4:287-294, l~
3. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in
adults. Brit. Med. J. 2:845-847, 1956.
4. Kanof, A., B. Epstein, B. Kramer, and I. Nauss. Staphylococca
pneumonia and empyema. Pediatrics 11:385-392, 1953.
5. Lepper, N.H., P. Tillman, and R. Devetsky. Patterns of transm:
sion of staphylococci. Ann. N.Y. Acad. Sd. 128:404-427, l96~
6. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asiai
influenza A in Boston, 1957-58. II. Severe staphylococcal
pneumonia complicating influenza. A.M.A. Arch. Intern. Med.
103:532-542, 1959.
7. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococca.
pneumonia in infancy. Brit. Ned. J. 2:1423-1427, 1955.
II. Rickettsial diseases: epidemic and murine typhus, Brill's disease
scrub-typhus, Rocky Mountain spotted fever, and rickettsial pox.
PAGENO="0163"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
EVALUATION: Effective, but .
4453
COMMENTS: That chloramphenicol is effective in the diseases listed
is well established, except in rickettsial pox, a condition so in-
frequently seen that few data are available. However, if the warning
is to be taken seriously--"chloramphenicol should not be used when
other less potentially dangerous agents will be effective'---the
tetracyclines, which have been shown to be as effective as chloram-
phenicol, should be considered the choice and chloramphenicol used
only if toxicity to these or failure to respond has occurred. The
duration of therapy recommended appears adequate.
DOCUMENTATION:
1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureonycin and
chloramphenicol: use in typhus, typhoid and brucellosis. J.
Clin. Invest. 28:1052-1053, 1949. (abstr.)
2. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol
in the treatment of the acute manifestations of brucellosjs.
Amer. J. Med. Sci. 219:627-638, 1950.
3. Ley, H.L., Jr., T.E. Woodward, and J.E. Smadel. Chloramphenicol
(chloromycetin) in the treatment of murine typhus. J.A.M.A.
143:217-219, 1950.
4. Murray, E.S., C. Baehr, G. Shwartzman, T.A. Manderbaum, N.
Rosenthal, J.C. Doane, L.B. Weiss, S. Cohen, andJ.C. Snyder.
Brill's Disease; clinical and laboratory diagnosis. J.A.M.A.
142:1059-1066, 1950.
5. Pincoffs, M.C., E.G. Guy, L.M. Lister, T.E. Woodward, and J.E.
Smadel. The treatment of Rocky Mountain spotted fever with
chloromycetin. Ann. Intern. Med. 29:656-663, 1948.
6. Sraadel, J.E., T.E. Woodward, H.L. Ley, Jr., and R. Leuthwaite.
Chloramphenicol (chloromycetin) in the treatment of tsutsugamushi
disease (scrub typhus). J. Clin. Invest. 28:1196-1215, 1949.
III. Typhoid fever.
EVALUATION: Effective, but . .
COMMENTS: Chioramphenicol has often been listed as the drug of
choice in typhoid fever. It is not clear that ampicillin has changed
this claim, but if they were of equal activity, the claim of "drug of
choice" would have to be revised because of the toxicity warning.
There is no mention of the carrier problem and relapses of positive
stool cultures.
DOCUMENTATION:
1. Knight, V., W. McDermott, and F. Ruiz-Sanchez. Aureomycin and
chioramphenicol: use in typhus, typhoid and brucellosis. J. Clin.
Invest. 28:1052-1053, 1949. (abstr.)
2. Smadel, J.E., H.L. Ley, Jr., and F.H. Diercks. Treatment of
typhoid fever. I. Combined therapy with cortisone and chioran-
phenicol. Ann. Intern. Med. 34:1-9, 1951.
PAGENO="0164"
4454 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
IV. Other salmonelloses.
EVALUATION: Possibly effective.
COMMENTS: Because of variability of clinical course with each specie
and the large variety of species, there is little reason to presume
that a generalization is possible. In a condition of short symptoma-
tic duration like gastroenteritis, the use of the drug is most diffi-
cult to evaluate. The variable courses of the systemic forms do not
allow the assurance of effectiveness that has been derived for typhoi
fever, which is more uniform. These differences between typhoid and
the other salmonelloses illustrate the difficulty of generalization
from one species to the next. It is likely that localized salmonella
infections, such as osteomyelitis, empyema or other diseases should
have a therapeutic trial with chloramphenicol. The treatment of
carriers with positive stool cultures should not be recommended and
the insert should so state. Although the stools may be negative whul
the drug is continued, there is no evidence that the carrier state is
terminated more frequently than would occur otherwise with a similar
passage of time. Obviously, the inability to define drug effectivene
in salmonelloses also applied to other drugs, such as ampicillin; hee
a reliable comparison between drugs is not possible.
DOCUMENTATION:
h Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 56-58.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
V. Urinary tract infection~.
EVALUATION: Effective, but . .
COMMENTS: As specified in the insert, outcome of treatment of urinar
tract infections is influenced by anatomic factors, but these have
little importance in the choice of drug except that, in situations ir
which cure is unlikely, the use of toxic agents is probably not justi
fied. The susceptibilities of the organisms involved are of prime
importance (chloramphenicol does not work any better against chloram-
phenicol-susceptible organisms than other agents work against organic
susceptible to them). Hence, when organisms are susceptible to less
toxic agents, chloramphenicol should not be used even if it is effect
~n vitro unless the others have failed. It is unusual for chloramphe
icol to succeed when other agents with satisfactory in vitro activity
have failed. Of the three species singled out, Escherichia ccli is
often treatable with other chemotherapy, but chloramphenicol may be a
secondary choice. Streptococcus fecalis infections are probably
better treated with other agents, such as penicillin and streptomycir
or erythromycin. Various Proteus species are different in their
susceptibility to different drugs; hence, the generalization `Proteus
species" should be avoided. Proteus morgani, vulgaris, and rett~eri
PAGENO="0165"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4455
are often susceptible only to chloramphenicol.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chioromycetin, pp. 105-
108. Antibiotics Monographs No. 8. New York: Medical Encyclo-
pedia, Inc., 1958.
1. Surgical infections: postoperative wound infections.
EVALUATION: Possibly effective.
COMMENTS: Postoperative wound infections have a variety of etiologic
agents, but Staphylococcus aureus is the single most common. Chlor-
amphenicol is effective against many of these agents, but is not the
most effective against the Staphylococcus. For this reason, plus the
toxicity warning, it is not the first choice in most infections unless
an organism is isolated against which chioramphenicol is most active
in vitro, or other preferred drugs cannot be given or have been inef-
fective.
DOCUMENTATION: Most favorable report is reference 1 (Altemeier).
1. Altemeier, W.A., and W.R. Culbertson. Chioramphenicol (chioromycetin)
and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951.
2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph-
ylococcal pneumonia and empyema in infancy. J. Thorac. Surg. 30:
265-274, 1955.
3. Carmichael, C.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953.
4. Hausmann, W., and A.J. Karlish. Staphylococcal pneumonia in adults,~
Brit. Med. J. 2:845-847, 1956.
5. Kanof, A~, B. Epstein, B. Kramer, and I. Nauss. Staphyloccal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
6. Lepper, N.H., P. Tillman, and R. Devetsky. Patterns of trans-
mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 1965.
7. Martin, C.N., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal pneumonia
complicating influenza. A.M.A. Arch. Intern. Med. 103:532-542, 1959.
8. Wallman, I.S., R.C.' Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955.
Surgical infections; cellulitis.
EVALUATION: Possibly effective.
COMMENTS: Cellulitis (other than postoperative) is most often caused
by streptococci or staphylococci for which chloramphenicol is not the
most effective drug. For this reason, plus the toxicity warning, it
is not the first choice unless an organisni against which chloramphenicol
is the most active has been isolated, or the preferred drug cannot be
given or has failed.
PAGENO="0166"
4456 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
DOCUMENTATION: Same as for Indication VI.
VIII. Surgical infections: infected sinus tract.
EVALUATION: Possibly effective.
CONNENTS: Chloramphenicol may be useful in some instances in which
the organisms have been shown to be sensitive only to it. Many sinus
tract infections are caused by tuberculosis and actinomycosis. Chlor
amphenicol is not indicated in tuberculosis, and other agents are
preferred in actinomycosis. Some sinus tracts associated with fistul
from viscera, including intestines, may be predominantly infected wit
fecal flora. In these, chloramphenicol may be the single mbst effect
agent. Wrien other agents appear equally effective in laboratory test
they should be tried first. There is rarely great urgency in treatin,
sinus tract infections with antibiotics.
The specific organisms for which chloramphenicol has been proved
effective therapy (in this condition) should be listed.
DOCUMENTATION:
1. Altemeier, W.A., and W.R. Culbertson. Chloramphenicol (chloromyc
and aureomycin in surgical infections. J.A.M.A. 145:449-457, 1951
2. Bloomer, W.E., S. Giammona, G.E. Lindskog, and R.E. Cooke. Staph
yloccal pneumonia and empyema in infancy. J. Thorac. Surg. 30:
265-274, 1955.
3. Carmichael,-D.B., Jr. Fatal bacterial endocarditis due to
staphylococcus aureus. U.S. Armed Forces Med. J. 4:287-294, 1953
4. Hausmann, W., and A.J Karlish. Staphyloccal pneumonia in adults.
Brit. Med. J. 2:845-847, 1956.
5. Kanof, A., B. Epstein, B. Kramer, and I. Mauss. Staphylococcal
pneumonia and empyema. Pediatrics 11:385-392, 1953.
6. Lepper, N.H., P. Tillman, and R. Devetsky. Patterns of trans-
mission of staphylococci. Ann. N.Y. Acad. Sci. 128: 404-427, 196
7. Martin, C.M., C.M. Kunin, L.S. Gottlieb, and N. Finland. Asian
influenza A in Boston, 1957-58. II. Severe staphylococcal
pneumonia complicating influenza. A.M.A. Arch. Intern. Med. 103:
532-542, 1959.
8. Wallman, I.S., R.C. Godfrey, and J.R.H. Watson. Staphylococcal
pneumonia in infancy. Brit. Med. J. 2:1423-1427, 1955.
9. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 122-
124. Antibiotics Monographs No. 8. New York: Medical Encyclope
Inc., 1958.
IX. Surgical infections: peritonitis or intra-abdominal abscesses from
ruptured intestines, diverticula, or appendix.
EVALUATION: Possibly effective.
PAGENO="0167"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4457
COMMENTS: These infections are often caused by mixed flora from the
intestinal content . In the acute stage of peritonitis, a drug often
must be selected empirically for surgical preparation or immediately
postoperatively. Judged by statistical probability chloramphenicol
is a good choice in such a situation. It should be given parenterally,
however, because oral therapy in these infections is probably inap-
propriate. In other 1e~s acute complications listed in the insert,
chloramphenicol should be shown to be the most effective agent against
the organisms isolated before it is used, or other less toxic agents
should have failed or be contraindicated.
The specific causative organisms for which chloramphenicol has been
proved effective therapy (in these conditions) should be listed.
DOCUMENTATION: Same as for Indication VIII.
X. Respiratory tract infections.
EVALUATION: Possibly effective.
COMMENTS: This heading is ambiguous. The package insert should list
specific organisms (and the site of respiratory infection) for which
chloramphenicol has been proved effective therapy.
In general, the etiology of these conditions is varied and chloram-
phenicol is the best agent for only a few. In streptococcal, pneumo-
coccal, and staphylococcal diseases of the respiratory tract, other
drugs are preferable. Chioramphenicol should be used only in Klebsiella
infections and perhaps other necrotizing pneumonias caused by E. coli
or related organisms when they are shown in vitro to be resistant to
ampicillin, cephalothin, and kanamycin. Hemophilus influenzae infec-
tions of the respiratory tract respond well to ampicillin; hence,
chloraraphenicol is best used only when ampicillin is not tolerated
or fails.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 63-72.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
CI. Meningeal infections.
EVALUATION: Probably effective.
COMMENTS: The three most common causes of meningitis are the meningo-
cocci, pneumococci, and Hemqphilus: irtfluenzae. All are susceptible
to chioramphenicol, as are many staphylococci and the gram-negative
aerobic rods that often infect newborns. Moreover, it is true that
the drug does get into the spinal fluid well. As a drug of choice
PAGENO="0168"
4458 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
for empiric use, however, it is probably not first, because it is
likely to be less effective in pneumococcal disease than is penicillin.
Although many believe it is first choice in Hemophilu~ infections,
tetracycline is probably as good and ampicillin is, too. It is likely
that this claim (drug of choice in H. influenzae meningitis) is no
longer justified. In menigitis of the newborn kanamycin is preferred
as the drug of choice for empiric treatment. In older patients, when
a diagnosis has been made and the organisms shown to be more susceptibi
to chloramphenicol than to other agents, it may be the drug of choice.
As indicated, in the insert, initial treatment should be parenterally
administered.
The package insert should list the specific organisms for which
chloramphenicol has been proved effective therapy in meningitis.
DOCUMENTATION:
1. Parker, R.T., M.J. Snyder, R.S.J. Liu, J.W. Looper, Jr., and T.E.
Woodward. Therapeutic range of chloramphenicol in purulent men-
ingitis. Antibiot. Med. Clin. Ther. 1:192-200, 1955.
XII. Brucellosis.
EVALUATION: Effective, but .
COMMENTS: Chloramphenicol, like other drugs, is capable of control-
ling symptoms of acute brucellosis, but the relapse rate is high. It
does not appear to be superior to the less toxic tetracyclines.
DOCUMENTATION:
1. Knight, V., F. Ruiz-Sanchez, and W. McDermott. Chloramphenicol
in the treatment of the acute manifestations of.brucellosis. Amer.
J. Med. Sci. 219:627-638, 1950.
2. Spink, W.W. The Nature of Brucellosis. Minneapolis: The
University of Minnesota Press, 1956. 464 pp.
3. Woodward, T.E., J.E. Smadel, W.A. Holbrook, and W.T. Raby. The
beneficial effect of chloromycetin in brucellosis. J. Clin.
Invest. 28:968-976, 1949.
XIII. Bartonellosis.
EVALUATION: Probably effective.
COMMENTS: Chloramphenicol is reported to be an effective antibiotic
in these infections. Of the references suggested by the manufacturer
(see Documentation below): two are reports of studies involving a
total of 25 patients whose bartonellosis was treated with chloramphen-
icol with good success, and two are textbook discussions of bartonel-
losis and its treatment. Of the latter discussions, one feels that
the effectiveness of chloramphenicol is best documented, the other
feels that other agents are probably as good.
PAGENO="0169"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4459
DOCUMENTATION:
1. Bartonellosis, pp. 603-606. In G.W. Hunter, III, W.W. Frye, and
J.C. Swartzwelder, Eds. A Manual of Tropical Medicine. (3rd ed.)
Philadelphia: W.B. saunders Co., 1960.
2. Payne, E.H., and 0. Urteaga. Carrion's disease treated with
chloromycetin. Antiobiot. & Chemother. 1:92-99, 1951.
3. Pinkerton, H. Bartonellosis (Carrion's disease, Oroya fever,
Verruga peruviana), pp. 327-329. In P.B. Beeson and W. McDermott,
Eds. Cecil-Loeb Textbook of Medicine. (11th ed.) Philadelphia:
W.B. Saunders Co., 1963.
4. Urteaga, B.0., and E.H. Payne. Treatment of the acute febrile
phase of Carrion's disease with chloramphenicoi. Amer. J. Trop.
Med. 4:507-511, 1955.
XIV. Relapsing fever.
EVALUATION: Possibly effective.
COMMENTS: ~ponema (Borrelia) ~çurrentis infections in experimental
animals are susceptible to chloramphenicol. On a weight basis, how-
ever, penicillin G is more active. In human infections, no direct
comparison has been made, and, although chloramphenicol has been used
successfully, penicillin should be tried first if it is tolerated.
DOCUMENTATION:
1. Hirschboeck, M.M. Use of chloramphenicol in relapsing fever.
Amer. J. Trop. Med. 3:712-713, 1954.
XV. Granulorua inguinale.
EVALUATION: Effective, but . .
COMMENTS: It has been reported that chloramphenicol caused the
disappearance of Donavan bodies, more rapidly than either tetracycline
or streptomycin. Relapses after chloramphenicol have seemed to be
less than 107,. Although chioramphenicol may be slightly better than
tetracycline, the latter may be preferred for toxicologic reasons.
DOCUMENTATION:
1. Greenblatt, R.B., W.E. Barfield, R.B. Dienst, R.M. West, and
M. Zises. Five-year studyof antibiotics in treatment of
granuloma inguinale. Amer. J. Syph. 36:186-191, 1952.
2. Robinson, R.C.V., and T.L. Wells. Intramuscular chloramphenicol
in the treatment of gonorrhea and granulorna inguinale. Amer. J.
Syph. 36:264-268, 1952.
XVI. Plague.
EVALUATION: Effective, but
PAGENO="0170"
4460 COMPETITIVE PROBLEMS IN THE DRuG INDIJSTRY
COMMENTS: All forms of plague have been shown to respond to chior-
amphenicol when it is given in large doses early in the disease.
There is no clear evidence that it is superior to tetracycline or
streptomycin.
DOCUMENTATION:
1. McCrumb, F.R., Jr., S. Mercier, J. Robic, M. Bouillat, J.E.
Smadel, T.E. Woodward, and K. Goodner. Chloramphenicol and
terramycin in the treatment of pneumonic plague. Amer. J.
Med. 14:284-293, 1953.
XVII. Ornithosis.
EVALUATION: Possibly effective.
COMMENTS: In embryonated eggs and experimental animal infections,
chloramphenicol is less effective than the tetracyclines. Results
of therapy of human infections have been variable and relapses have
been frequent. The role of the drug in this disease is not well
established.
DOCUMENTATION:
1. Woodward, T.E., and C.L. Wisseman, Jr. Chloromycetin, pp. 70-71.
Antibiotics Monographs No. 8. New York: Medical Encyclopedia,
Inc., 1958.
GENERAL COMMENTS
The Warning" section appears justified in view of the seriousness
of aplastic anemia.
Absorption after oral administration is good, in that 75-90% of a
dose can be accounted for by metabolic products found in the urine.
Tissue distribution appears to be favorable. The distribution into
the cerebrospinal fluid is good, as pointed out in the insert, and
is reasonably good into brain tissue, which is important when cere-
britis accompanies meningitis. The distribution into bile is not as
high as that of the tetracyclines and some of the penicillins. The
very small amount in the feces is of interest as is the fact that the
fecal content is higher when the palmitate has been given.
The penetration into the eye is a plus factor for this drug. Trans-
placental transfer was shown by chemical methods which may not measure
the active drug.
Emphasis should be put on the recommended dose, because a smaller dose
is often given, particularly postoperatively. The fate of the drug
when the metabolic mechanisms are disturbed should remain as stated.
As to blood dyscrasias, it should be mentioned that frequent blood
counts do not necessarily assure that aplastic anemia can be prevented.
PAGENO="0171"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4461
In fact, it may occur after the drug has been stopped.
The roles of organisms other than candida and staphylococci in
resistance and superinfection have been demonstrated, particularly
Pseudomonas and some other gram-negative aerobic rods that are re-
sistant. This should be pointed out in the section discussing resis-
tance.
Intravenous administration of chloramphenicol produces a rapid peak
in blood levels and is preferred over oral or intramuscular admini-
stration in critically ill patients. However, because the oral form
is so highly absorbed, as soon as the patient can take it, there is
little reason to continue the I.V. use.
This package insert is identical in every way with that for Chloro-
mycetin Palmitate Oral Suspension, Log 2263. This preparation is
the straight drug without palmitate.
The dose recommendations are accurate.
~p~ro~ea by
Chairman
The Drug Efficacy Study of the National Academy of Sciences -
National Research Council has requested that the following
qualifying addendum be conveyed with their reports to the
ultimate recipients of these reports:
"Drugs of identical chemical composition (so-called
generic drugs) formulated and marketed by numerous
individual firms under generic or trademarked nemes
have been evaluated for efficacy as a group without
consideration of `therapeutic equivalence.' In the
event that no evidence for pharmacological availability
or therapeutic efficacy in man can be presented for
any of the indications claimed for the use of any
of the drugs in the attached listing, their classifications
of effectiveness may need to be modified if regulations
of the Food and Drug Administration require such proof."
PAGENO="0172"
4462 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
SPC~M EN
FOR INTRAVENOUS ADMINISTRATION
CHLOROMYCETIN®
(CHLORAMPHENICOL)
SODIUM SUCCINATE
[~ARKE.DAVIS I
WARNING
$erlous and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia,
Ihrombocytopenia, and granulocytopenia) are known to occur after the
administration of chloramphenicol. In addition, there have been reports of
~lastic anemia attributed to chloramphenicol which later terminated in
Iukemia. Blood dyscrasias have occurred after both short term and pro-
longed therapy with this drug. Chloramphenicol must not be used when
Isss potentially dangerous agents will be effective, as described in the
14tndications" section. It must not be used in the treatment of trivial infec
:~fl5 or where it is not indicated, as in colds, influenza, infections of the
~oat; or as a prophylactic agent to prevent bacterial infections.
Precautions: It is essential that adequate blood studies be made during
beatment with the drug. While blood studies may detect early peripheral
mood changes, such as leukopenia, reticulocytopenia, or ~ranulocytopenia,
bfore they become irreversible, such studies cannot be relied on to detect
bene marrow depression prior to development of aplastic anemia. To
~Cilitate appropriate studies and observation during therapy, it is desirable
that patients be hospitalized.
IMPORTANT CONSIDERATIONS IN PRESCRIBING
NS4ECTABLE CHLORAMPHEN1COL SODIUM SUCCINATE.
1. Chloramphenicol sodium succinate must be hydrolyzed to its microbiolog-
ically active form and there is a lag in achieving adequate blood levels com-
pared with the base given intravenously.
12. The oral form of chloramphenicol is readily absorbed and adequate blood
levels are achieved and maintained on the recommended dosage.
3. Patients started on intravenous chloramphenicol sodium succinate should be
changed to the oral form as soon as practicable.
4. Chloramphenicol sodium succinate is recommended for intravenous use only.
Use of this product by the intramuscular route in emergency situations has
been described, but this route is not recommended, because lower blood
levels are attained and there is a lack of evidence that it is effective when
~lven by this route.
DESCRIPTION
O~Joramphenicol is an antibiotic that is clinically useful for, and should be
reserved for, serious infections caused by organisms susceptible to its anti-
mIcrobial effects when less potentially hazardous therapeutic agents are
Ineffective or contraindicated. Sensitivity testing is essential to determine its
inditated use, but may be performed concurrently with therapy initiated on
clinical impression that one of the indicated conditions exists (see "Indications"
section).
HH
PAGENO="0173"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4463
CHLOROMYCETIN
(CHLORAMPHENICOL)
SODIUM SUCCINATE
ACTIONS AND PHARMACOLOGY
In vitro chloramphenicol exerts mainly a bacteriostatic effect on a wide range
of gram-negative and gram-positive bacteria and is active in vitro against
rickettsias, the lymphogranuloma-psittacosis group and Vibrio cholerae. It is
particularly active against Salmonella typhi and Hemophilus inf/uenzae. The
mode of action is through interference or inhibition of protein synthesis in
intact cells and in cell-free systems.
Chloramphenicol administered orally is absorbed rapidly from the intestinal
tract. In controlled studies in adult volunteers using the recommended dosage
of 50 mg/kg/day, a dosage of 1 gm. every 6 hours for 8 doses was given. Using
the microbiological assay method, the average peak serum level was 11.2 mcg./mI.
one hour afterthe first dose. A cumulative effect gave a peak rise to 18.4 mcg./ml.
after the fifth dose of 1 gm. Mean serum levels ranged from 8-14 mcg./ml. over
the 48-hour period. Total urinary excretion of chloramphenicol in these studies
ranged from a low of 68% to a high of 99% over a three-day period. From 8 to 12%
of the antibiotic excreted is in the form of free chloramphenicol; the remainder
consists of microbiologically inactive metabolites, principally the conjugate with
glucuronic acid. Since the glucuronide is excreted rapidly, most chloramphenicol
detected in the blood is in the microbiologically active free form. Despite the
small proportion of unchanged drug excreted in the urine, the concentration
of free chloramphenicol is relatively high, amounting to several hundred mcg./mI.
in patients receiving divided doses of 50 mg./kg./day. Small amoUnts of active
drug are found in bile and feces. Chloramphenicol diffuses rapidly, but its
distribution is not uniform. Highest concentrations are found in liver and kidney,
and lowest concentrations are found in brain and cerebrospinal fluid. Chlor-
amphenicol enters cerebrospinal fluid even in the absence of meningeal
inflammation, appearing in concentrations about half of those found in the
blood. Measurable levels are also detected in pleural and in ascitic fluids, saliva,
milk and in the aqueous and vitreous hUmors. Transport across the placental
barrier occurs with somewhat lower concentration in cord blood of newborn
infants than in maternal blood.
INDICATIONS
IN ACCORD WITH THE CONCEPTS IN THE `WARNING BOX" AND THIS
INDICATIONS SECTION, CHLORAMPHENICOL MUST BE USED ONLY IN
THOSE SERIOUS INFECTIONS FOR WHICH LESS POTENTIALLY DANGEROUS
DRUGS ARE INEFFECTIVE OR CONTRAINDICATED. HOWEVER, CHLORAM-
PHENICOL MAY BE CHOSEN TO INITIATE ANTIBIOTIC THERAPY ON THE
CLINICAL IMPRESSION THAT ONE OF THE CONDITIONS BELOW IS BELIEVED
TO BE PRESENT; IN VITRO SENSITIVITY TESTS SHOULD BE PERFORMED
CONCURRENTLY SO THAT THE DRUG MAY BE DISCONTINUED AS SOON
AS POSSIBLE IF LESS POTENTIALLY DANGEROUS AGENTS ARE INDICATED
BY SUCH TESTS. THE DECISION TO CONTINUE USE OF CHLORAMPHENICOL
RATHER THAN ANOTHER ANTIBIOTIC WHEN BOTH ARE SUGGESTED BY
IN VITRO STUDIES TO BE EFFECTIVE AGAINST A SPECIFIC PATHOGEN
SHOULD BE BASED UPON SEVERITY OF THE INFECTION, SUSCEPTIBILITY
OF THE PATHOGEN TO THE VARIOUS ANTIMICROBIAL DRUGS, EFFICACY
OF THE VARIOUS DRUGS IN THE INFECTION, AND THE IMPORTANT ADDI-
TIONAL CONCEPTS CONTAINED IN THE "WARNING BOX" ABOVE:
PAGENO="0174"
4464 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
CHLOROMYCETIN
(CHLORAMPHENI~OL)
SODIUM SUCCINATE
1. Acute infections caused by Salmonella typhi
Chloramphenicol is a drug of choice. It is not recommended for the routine
treatment of the typhoid carrier state".
2. Serious infections caused by susceptible strains in accordance
with the concepts expressed above:
a. Salmonella species
b. H. influenzae, specifically meningeal infections
c. Rickettsia
d. Lymphogranuloma-psittacosis group
e. Various gram-negative bacteria causing bacteremia meningitis or other
serious gram.negative infections
f. Other susceptible organisms which have been demonstrated to be resistant
to all other appropriate anti-microbial agents.
3. Cystic fibrosis regimens
CONTRAIN DICATIONS
Chloramphenicol is contraindicated in individuals with a history of previous
hypersensitivity and/or toxic reaction to it. It must not be used in the treatment
of trivial infections or where it is not indicated, as in colds, influenza, infections
of the throat; or as a prophylactic agent to prevent bacterial infection.
PRECAUTIONS
1. Baseline blood studies should be followed by periodic blood studies approxi-
mately every two days during therapy. The drug should be discontinued upon
appearance of reticulocytopenia, Ieukopenia, thrombocytopenia, anemia, or
any other blood study findings attributable to chloramphenicol. However, it
should be noted that such studies do not exclude the possible later appearance
of the irreversible type of bone marrow depression.
2. Repeated courses of the drug should be avoided if at all possible.Treatment
should not be continued longer than required to produce a cure with little or
no risk of relapse of the disease.
3. Concurrent therapy with other drugs that may cause bone marrow de-
pression should be avoided.
4. Excessive blood levels may result from administration of the recommended
dose to patients with impaired liver or kidney function, including that due to
immature metabolic processes in'the infant. The dosage should be adjusted
accordingly or, preferably, the blood concentration should be determined at
appropriate intervals.
5. There are no studies to establish the safety of this drug in pregnancy.
6. Since chloramphenicol readily crosses the placental barrier, caution in use
of the drug is particularly important during pregnancy at term or during labor
because of potential toxic effects on the fetus (gray syndrome).
7. Precaution should be used in therapy of premature and full-term infants to
avoid "gray syndrome" toxicity. (See "Adverse Reactions.") Serum drug levels
should be carefully followed during therapy of the newborn infant.
8. Precaution should be used in therapy during lactation because of the
possibility of toxic effects on the nursing infant.
*ln the treatment of typhoid fever some authorities recommend that chloramphenicol be administered
at therapeutic levels for 8-10 days after the patient has become afebrile to lessen the possibility
of relapse. - -
PAGENO="0175"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4465
CHLOROMYCETIN
(CHLORAMPIIENICOL)
SODIUM SUCCINATE
9. The use of this antibiotic, as with other antibiotics, may result in an over-
growth of nonsusceptible organisms, including fungi. If infections caused by
nonsusceptible organisms appear during therapy, appropriate measures should
be taken.
ADVERSE REACTIONS
1. Blood Dyscrasias
The most serious adverse effect of chloramphenicol is bone marrow depres-
sion. Serious and fatal blood dyscrasias (apiastic anemia, hypoplastic anemia,
thrombocytopenia, and granulocytopenia) are known to occur after the admin-
istration of chloramphenicôl. An irreversible type of marrow depression leading
to aplastic anemia with a high rate of mortality is characterized by the appear-
ance weeks or months after therapy of bone marrow aplasia or hypoplasia.
Peripherally, pancytopenia is most often observed, but in a small number of
cases only one or two of the three major cell types (erythrocytes, leukocytes,
platelets) may be depressed.
A reversible type of bone marrow depression, which is dose related, may
occur. This type of marrow depression is characterized by vacuolization of the
erythroid cells, reduction of reticulocytes and leukopenia, and responds promptly
to the withdrawal of chloramphenicol.
An exact determination of the risk of serious and fatal blood dyscrasias is
not possible because of lack of accurate information regarding 1) the size of
the population at risk, 2) the total number of drug-associated dyscrasias, and 3)
the total number of non-drug associated dyscrasias.
In a report to the California State Assembly by the California Medical Associa-
tion and the State Department of Public Health in January 1967, the risk of
fatal aplastic anemia was estimated at 1:24,200 to 1 :40,500 based on two
dosage levels.
There have been reports of aplastic anemia attributed to chloramphenicol
which later terminated in leukemia.
Paroxysmal nocturnal hemoglobinuria has also been reported.
2. Gastrointestinal Reactions
Nausea, vomiting, glossitis and stomatitis, diarrhea and enterocolitis may
occur in low incidence.
3. Neurotoxic Reactions
Headache, mild depression, mental confusion and delirium have been de-
scribed in patients receiving chloramphenicol. Optic and peripheral neuritis
have been reported, usually following long-term therapy. If this occurs, the drug
should be promptly withdrawn.
4. Hypersensitivity Reactions
Fever, macular and vesicular rashes, angloedema, urticaria and anaphylaxis
may occur. Herxheimer reactions have oôcurred during therapy for typhoid fever.
5. "Gray Syndrome"
Toxic reactions including fatalities have occurred in the premature and new-
born; the signs and symptoms associated with these reactions have been
referred to as the "gray syndrome". One case of "gray syndrome" has been
reported in an infant born to a mother having received chloramphenicol during
labor. One case has been reported in a 3 month infant. The following sum-
marizes the clinical and laboratory studies that have been made on these
patients:
PAGENO="0176"
4466 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
CHLOROMYCETI N
(CHLORAMPHENICOL)
SODIUM SUCCINATE
(1) In most cases therapy with chloramphenicol had been instituted within
the first 48 hours of life.
(2) Symptoms first appeared after 3 to 4 days of continued treatment with
high doses of chloramphenicol.
(3) The symptoms appeared in the following order:
(a) abdominal distension with or without emesis;
(b) progressive pallid cyanosis;
(c) vasomotor collapse, frequently accompanied by irregular respiration;
(d) death within a few hours of onset of these symptoms.
(4) The progression of symptoms from onset to exitus was accelerated with
higher dose schedules.
(5) Preliminary blood serum level studies revealed unusually high concentra-
tions of chloramphenicol (over 90 mcg./ml. after repeated doses).
(6) Termination of therapy upon early evidence of the associated sympto-
matology frequently reversed the process with complete recovery.
ADMINISTRATION
Chloramphenicol, like other potent drugs, should be prescribed at recommended
doses known to have therapeutic activity. Administration of 50 mg./kg./day
in divided doses will produce blood levels of the magnitude to which the
majority of susceptible microorganisms will respond.
AS SOON AS FEASIBLE AN ORAL DOSAGE FORM OF CHLORAMPHENICOL
SHOULD BE SUBSTITUTED FOR THE INTRAVENOUS FORM BECAUSE AD-
EQUATE BLOOD LEVELS ARE ACHIEVED WITH CHLORAMPHENICOL BY
MOUTH.
The following method of administration is recommended:
Intravenously as a 10% solution to be injected over at least a one-minute in-
terval. This is prepared by the addition of 11 cc. of an aqueous diluent such as
water for injection or 5% dextrose injection.
The "Infant Size" package (Steri-Vial No. 148) contains 250 mg. This should
be reconstituted with 2.75 cc. of diluent.
DOSAGE
Adults
Adults should receive 50 mg./kg./day in divided doses at 6-hour intervals. In
exceptional cases patients with infections due to moderately resistant organisms
may require increased dosage up to 100 mg./kg./day to achieve blood levels
inhibiting the pathogen, but these high doses should be decreased as soon as
possible. Adults with impairment of hepatic or renal function or both may have
reduced ability to metabolize and excrete the drug. In instances of impaired
metabolic processes, dosages should be adjusted accordingly. (See discussion
under Newborn Infants.) Precise control of concentration of the drug in the blood
should be carefully followed in patients with impaired metabolic processes by
the available microtechniques (information available on request).
Children
Dosage of 50 mg/kg/day divided into 4 doses at 6-hour intervals yields blood
levels in the range effective against most susceptible organisms. Severe infec-
tions (e.g., bacteremia or meningitis), especially when adequate cerebrospinal
fluid concentrations are desired, may require dosage up to 100 mg./kg./day;
however, it is recommended that dosage be reduced to 50 mg./kg./day as soon
as possible. Children with impaired liver or kidney function may retain exces-
sive amounts of the drug.
PAGENO="0177"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4467
CHLOROMYCETIN
(CHLORAMPHENI~OL)
SODIUM SUCCINATE
Newborn infants
(See section titled "Gray Syndrome" under "Adverse Reactions.")
A total of 25 mg./kg./ day in 4 equal doses at 6-hour intervals usually produces
and maintains concentrations in blood and tissues adequate to control most
infections for which the drug is indicated. Increased dosage in these individuals,
demanded by severe infections, should be given only to maintain the blood
concentration within a therapeutically effective range. After the first two weeks
of life, full-term infants ordinarily may receive up to a total of 50 mg/kg/day
equally divided into 4 doses at 6-hour intervals. These dosage recommendations
are extremely important because blood concentration in all premature infar~s
and full-term infants under two weeks of age differs from that of other infants.
This difference is due to variations in the maturity of the metabolic functions of
the liver and the kidneys.
When these functions are immature (or seriously impaired in adults), high
concentrations of the drug are found which tend to increase with succeeding
doses.
Infants and Children with Immature Metabolic Processes
In young infants and other children in whom immature metabolic functio:~
are suspected, a dose of 25 mg/kg/day will usually produce therapeutic con-
centrations of the drug in the blood. In this group particularly, the concentraV~n
of the drug in the blood should be carefully followed by microtechniqu
(Information available on request.)
PACKAGE INFORMATION
Steri-Vial No. 57, Chloromycetin (chloramphenicol) Sodium Succinate provides
the equivalent of 1 Gram chloramphenicol in a rubber-diaphragm-capped vial.
Available individually and in packer units of 10.
CHLOROMYCETIN, brand of chloramphenicol, Reg. U.S. Pat. Off.
CA4f~
PARKE, DAVIS ~1b~ & COMPANY
121 865000
A DETROIT, MICHIGAN, U.S.A. -
Aug. 1968k
81-280 0-69-pt. 1l-12
PAGENO="0178"
4468 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
FOR INTRAVENOUS ADMINISTRATION
CHLORAMPHENICOL SODIUM
SUCCINATE, STERILE, UIISIIPI
WARNING
Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia,
thrombocytopenia, and granulocytopenia) are known to occur after the
administration of chloramphenicol. In addition, there have been reports of
aplastic anemia attributed to chloramphenicol which later terminated in
leukemia. Blood dyscrasias have occurred after both short term and pro-
longed therapy with this drug. Chloramphenicol inust not be used when
less potentially dangerous agents will be effective, as described in the
`Indications" section. It must not be used in the treatment of trivial infec
tions or where it is not indicated, as in colds, influenza, infections of the
throat; or as a prophylactic agent to prevent bacterial infections.
Precautions: It is essential that adequate blood studies be made during
treatment with the drug. While blood studies may detect early peripheral
blood changes, such as leukopenia, reticulocytopenia, or granulocytopenia,
before they become irreversible, such studies cannot be relied on to detect
bone marrow depression prior to development of aplastic anemia. To
facilitate appropriate studies and observation during therapy, it is desirable
that patients be hospitalized.
IMPORTANT CONSIDERATIONS IN PRESCRIBING
INJECTABLE CHLORAMPHENICOL SODiUM SUCCINATE
1. Chloramphenicol sodium succinate must be hydrolyzed to its microbiolog-
ically active form and there is a lag in achieving adequate blood levels com-
pared with the base given intravenously.
2. The oral form of chloramphenicol is readily absorbed and adequate blood
levels are achieved and maintained on the recommended dosage.
3. Patients started on intravenous chloramphenicol sodium succinate should be
changed to the oral form as soon as practicable.
4. Chloramphenicol sodium succinate is recommended for intravenous use only.
Use of this product by the intramuscular route in emergency situations has
been described, but this route is not recommended, because lower blood
levels are attained and there is a lack of evidence that it is effective when given
by this route.
DESCRIPTION
Chloramphenicol is an antibiotic that is clinically useful for, and should be
reserved for, serious infections caused by organisms susceptible to its anti-
microbial effects when less potentially hazardous therapeutic agents are
ineffective or contraindicated. Sensitivity testing is essential to determine its
indicated use, but may be performed concurrently with therapy initiated on
clinical impression that one of the indicated conditions exists (see `Indications"
section).
- DSA-HH
PAGENO="0179"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
4469
ACTIONS AND PHARMACOLOGY
In vitro chloramphenicol exerts mainly a bacteriostatic effect on a wide range
of gram-negative and gram.positive bacteria and is active in vitro against
rickettsias, the lymphogranuloma-psittacosis group and Vibrio cholerae. It is
particularly active against Salmonella typhi and Hemophilus influenzae. The
mode of action is through interference or inhibition of protein synthesis in
intact cells and in cell-free systems.
Chloramphenicol administered orally is absorbed rapidly from the intestinal
tract. In controlled studies in adult volunteers using the recommended dosage
of 50 mg/kg/day, a dosage of 1 gm. every 6 hours for 8 doses was given. Using
the microbiological assay method the average peak serum level was 11.2 mcg./ml.
one hour after the first dose. A cumulative effect gave a peak rise to 18.4 mcg./mI.
after the fifth dose of 1 gm. Mean serum levels ranged from 8-14 mcg./mI. over
the 48-hour period. Total urinary excretion of chloramphenicol in these studies
ranged from a low of 68% to a high of 99°/~ over a three-day period. From 8 to 12%
of the antibiotic excreted is in the form of free chloramphenicol; the remainder
consists of microbiologically inactive rnetabolites, principally the conjugate with
glucuronic acid. Since the glucuronide is excreted rapidly, most chloramphenicol
detected in the blood is in the microbiologically active free form. Despite the
small proportion of unchanged drug excreted in the urine, the concentration
of free chloramphenicol is relatively high, amounting to several hundred mcg./ml.
in patients receiving divided doses of 50 mg/kg/day. Small amounts of active
drug are found in bile and feces. Chloramphenicol diffuses rapidly, but its
distribution is not uniform. Highest concentrations are found in liver and kidney,
and lowest concentrations are found in brain and cerebrospinal fluid. Chlor-
amphenicol enters cerebrospinal fluid even:in the absence of meningeal in-
flammation, appearing in concentrations about half of those found in the blood.
Measurable levels are also detected in pleural and in ascitic fluids, saliva, milk
and in the aqueous and vitreous humors. Transport across the placental barrier
occurs with somewhat lower concentration in cord blood of newborn infants
than in maternal blood.
INDICATIONS
IN ACCORD WITH THE CONCEPTS IN THE `WARNING BOX" AND THIS
INDICATIONS SECTION, CHLORAMPHENICOL MUST BE USED ONLY IN
THOSE SERIOUS INFECTIONS FOR WHICH LESS POTENTIALLY DANGEROUS
DRUGS ARE INEFFECTIVE OR CONTRAINDICATED. HOWEVER, CHLORAM-
PHENICOL MAY BE CHOSEN TO INITIATE ANTIBIOTIC THERAPY ON THE
CLINICAL IMPRESSION THAT ONE OF THE CONDITIONS BELOW IS BELIEVED
TO BE PRESENT; IN VITRO SENSITIVITY TESTS SHOULD BE PERFORMED
CONCURRENTLY SO THAT THE DRUG MAY BE DISCONTINUED AS SOON
AS POSSIBLE IF LESS POTENTIALLY DANGEROUS AGENTS ARE INDICATED
BY SUCH TESTS. THE DECISION TO CONTINUE USE OF CHLORAMPHENICOL
RATHER THAN ANOTHER ANTIBIOTIC WHEN BOTH ARE SUGGESTED BY
IN VITRO STUDIES TO BE EFFECTIVE AGAINST A SPECIFIC PATHOGEN
SHOULD BE BASED UPON SEVERITY OF THE INFECTION, SUSCEPTIBILITY
OF THE PATHOGEN TO THE VARIOUS ANTIMICROBIAL DRUGS, EFFICACY
OF THE VARIOUS DRUGS IN THE INFECTION, AND THE IMPORTANT ADDI-
TIONAL CONCEPTS CONTAINED IN THE "WARNING BOX" ABOVE:
DSA-HH
PAGENO="0180"
4470 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
1. Acute infections caused by Salmonella lyphi
Chloramphenicol is a drug of choice.* It is not recommended for the routine
treatment of the typhoid "carrier state".
2. Serious infections caused by susceptible strains in accordance
with the concepts expressed above:
a. Salmonella species
b. H. Influenzae, specifically meningeal infections
c. Rickettsia
d. Lymphogranuloma-psittacosis group
e. Various gram-negative bacteria causing bacteremia, meningitis or other
serious gram.negative infections
f. Other susceptible organisms Which have been demonstrated to be resistant
to all other appropriate anti-microbial agents.
3. Cystic fibrosis regimens
CONTRAINDICATIONS
Chloramphenicol is contraindicated in individuals with a history of previous
hypersensitivity and/or toxic reaction to it. It must not be used in the treatment
of trivial infections or where it is not indicated, as in colds, influenza, infections
of the throat; or as a prophylactic agent to prevent bacterial infection.
PRECAUTIONS
1. Baseline blood studies should be followed by periodic blood studies approxi-
mately every two days during therapy. The drug should be discontinued upon
appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or
any other blood study findings attributable to chloramphenicol. However, it
should be noted that such studies do not exclude the possible later appearance
of the irreversible type of bone marrow depression.
2. Repeated courses of the drug should be avoided if at all possible. Treatment
should not be continued longer than required to produce a cure with little or
no risk of relapse of the disease.
3. Concurrent therapy with other drugs that may cause bone marrow de.
pression should be avoided.
4. Excessive blood levels may result from administration of the recommended
dose to patients with impaired liver or kidney function, including that due to
immature metabolic processes- in the infant. The dosage should be adjusted
accordingly or, preferably, the blood concentration should be determined at
appropriate intervals.
5. There are no studies to establish the safety of this drug in pregnancy.
6. Since chloramphenicol readily crosses the placental barrier, caution in use
of the drug is particularly important during pregnancy at term or during labor
because of potential toxic effects on the fetus (gray syndrome).
7. Precaution should be used in therapy of premature and full.term infants to
avoid "gray syndrome" toxicity. (See "Adverse Reactions.") Serum drug levels
should be carefully followed during therapy of the newborn infant.
8. Precaution should be used in therapy during lactation because of the
possibility of toxic effects on the nursing infant.
Cm the treatment of typhoid fever some authorities recommend that chioramphenicol be administered
at therapeutic levels for 8.10 days after the patient has become afebrile to lessen the possibility
of relapse. -
DSA-HH
PAGENO="0181"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4471
9. The use of this antibiotic, as with other antibiotics, may result in an over-
growth of nonsusceptible organisms, including fungi. If infections caused by
nonsusceptible organisms appear during therapy, appropriate measures should
be taken.
ADVERSE REACTIONS
1. Blood Dyscrasias
The most serious adverse effect of chloramphenicol is bone marrow depres-
sion. Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia,
thrombocytopenia, and granulocytopenia) are known to occur after the admin-
istration of chloramphenicol. An irreversible ty~e of marrow depression leading
to aplastic anemia with a high rate of mortality is characterized by the appear-
ance weeks or months after therapy of bone marrow aplasia or hypoplasia.
Peripherally, pancytopenia is most often observed, but in a small number of
cases only one or two of the three major cell types (erythrocytes, leukocytes,
platelets) may be depressed.
A reversible type of bone marrow depression, which is dose related, may
occur. This type of marrow depression is characterized by vacuolization of the
erythroid cells, reduction of reticulocytes and leukopenia, and responds promptly
to the withdrawal of chloramphenicol.
An exact determination of the risk of serious and fatal blood dyscrasias is
not possible because of lack of accurate information regarding 1) the size of
the population at risk, 2) the total number of drug-associated dyscrasias, and 3)
the total number of non-drug associated dyscrasias.
In a report to the California State Assembly by the California Medical Associa-
tion and the State Department of Public Health in January 1967, the risk of
fatal aplastic anemia was estimated at 1 :24,200 to 1 :40,500 based on two
dosage levels.
There have been reports of aplastic anemia attributed to chloramphenico~l
which later terminated in leukemia.
Paroxysmal nocturnal hemoglobinuria has also been reported.
2. Gastrointestinal Reactions
Nausea, vomiting, glossitis and stomatitis, diarrhea and enterocolitis may
occur in low incidence.
3 Neurotoxic Reactions
Headache, mild depression, mental confusion and delirium have been de-
scribed in patients receiving chloramphenicol. Optic and peripheral neuritis
have been reported, usually following long-term therapy. If this occurs, the drug
should be promptly withdrawn.
4. Hypersensitivity Reactions
Fever, macular and vesicular rashes, angioedema, urticaria and anaphylaxis
may occur. Herxheimer reactions have occurred during therapy for typhoid fever.
5. "Gray Syndrome"
Toxic reactions including fatalities have occurred in the premature and new-
born; the signs and symptoms associated with these reactions have been
referred to as the "gray syndrome". One case of "gray syndrome" has been
reported in an infant born to a mother having received chloramphenicol during
labor. One case has been reported in a 3 month infant. The following sum-
marizes the clinical and laboratory studies that have been made on these
patients: -
DSA-HH
PAGENO="0182"
4472 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
(1) In most cases therapy with chloramphenicot had been instituted within
the first 48 hours of life.
(2) Symptoms first appeared after 3 to 4 days of continued treatment with
high doses of chloramphenicol.
(3) The symptoms appeared in the following order:
(a) abdominal distension with or without emesis;
(b) progressive pallid cyanosis;
(c) vasomotor collapse, frequently accompanied by irregular respiration;
(d) death within a few hours of onset of these symptoms.
(4) The progression of symptoms from onset to exitus was accelerated with
higher dose schedules.
(5) Preliminary blood serum level studies revealed unusually high concentra-
tions of chloramphenico) (over 90 mcg./ml. after repeated doses).
(6) Termination of therapy upon early evidence of the associated sympto.
matology frequently reversed the process with complete recovery.
ADMINISTRATION
Chloramphenicol, like other potent drugs, should be prescribed at recommended
doses known to have therapeutic activity. Administration of 50 mg/kg/day
in divided doses will produce blood levels of the magnitude to which the
majority of susceptible microorganisms will respond.
ASSOON AS FEASIBLE AN ORAL DOSAGE FORM OF CHLORAMPHENICOL
SHOULD BE SUBSTITUTED FOR THE INTRAVENOUS FORM BECAUSE AD.
EQUATE BLOOD LEVELS ARE ACHIEVED WITH CHLORAMPHENICOL BY
MOUTH.
The following method of administration is recommended:
lntravenously as a 10% solution to be injected over at least a one-minute in-
terval. This is prepared by the addition of 11 cc. of an aqueous diluent such as
water for injection or 5% dextrose injection.
The Infant Size" package (Steri.Vial No. 148) contains 250 mg. This should
be reconstituted with 2.75 cc. of diluent.
DOSAGE
Adults
Adults should receive 50 mg/kg/day in divided doses at 6-hour intervals. In
exceptional cases patients with infections due to moderately resistant organisms
may require increased dosage up to 100 mg./kg./day to achieve blood levels
inhibiting the pathogen, but these high doses should be decreased as soon as
possible. Adults with impairment of hepatic or renal function or both may have
reduced ability to metabolize and excrete the drug. In instances of impaired
metabolic processes, dosages should be adjusted accordingly. (See discussion
under Newborn Infants.) Precise control of concentration of the drug in the blood
should be carefully followed in patients with impaired metabolic processes by
the available microtechniques (information available on request).
Children
Dosage of 50 mg./kg./day divided into 4 doses at 6-hour intervals yields blood
levels in the range effective against most susceptible organisms. Severe infec-
tions (e.g., bacteremia or meningitis), especially when adequate cerebrospinal
fluid concentrations are desired, may require dosage up to 100 mg./kg./day;
however, it is recommended that dosage be reduced to 50 mg./kg./day as soon
as possible. Children with impaired liver or kidney function may retain exces-
sive amounts of the drug.
DSA-HH
PAGENO="0183"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4473
Newborn Infants
(See section titled "Gray Syndrome" under "Adverse Reactions.")
A total of 25 mg/kg/day in 4 equal doses at 6-hour intervals usually produces
and maintains concentrations in blood and tissues adequate to control most
infections for which the drug is indicated. Increased dosage in these individuals,
demanded by severe infections, should be given only to maintain the blood
concentration within a therapeutically effective range. After the first two weeks
of life, full-term infants ordinarily may receive up to a total of 50 mg/kg/day
equally divided into 4 doses at 6-hour intervals. These dosage recommendations
are extremely important because blood concentration in all premature infants
and full-term infants under two weeks of age differs from that of other infants.
This difference is due to variations in the maturity of the metabolic functions of
the liver and the kidneys.
When these functions are immature (or seriously impaired in adults), high
concentrations of the drug are found which tend to increase with succeeding
doses.
Infants and Children with Immature Metabolic Processes
In young infants and other children in whom immature metabolic functions
are suspected, a dose of 25 mg./kg./day will usually produce therapeutic con-
centrations of the drug in the blood. In this group particularly, the concentration
of the drug in the blood should be carefully followed by microtechniques.
(Information available on request.)
cA4f~,
PARKE, DAVIS & COMPANY
121 852250
A DETROIT, MICHIGAN, U.S.A. DSA-HH
Aug. 1968
PAGENO="0184"
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PAGENO="0185"
Not suitable for laboratory diagnostic use.
To prepare a 10% solution, add 11 cc. of
sterile aqueous diluent such as Water for
Injection or 5% Dextrose Injection.
USUAL ADULT DAILY DOSE--SO mg. per Kg.
See package insert.
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CAUTION-Federal law prohibits dispens-
ing without prescription.
WARNING-Blood dyscrasias may be as-
sociated with the use of chioramphenicol.
It is essential that adequate blood studies
be made. See enclosed warnings and pre.
cautions.
Parke, Davis & Company
Detroit, Michigan 48232 U.S.A.
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PAGENO="0186"
4476 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Not suitable for laborato,y diagnostic use.
To prepare a 10% solution, add 11 cc. of
sterile aqueous diluent such as Water for
Injection or 5% Dextrose Injection.
USUAL ADULT DAILY DOSE-
50 mg. per Kg. See package insert.
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CHLORAMPNENICOL SODIUM
~ SUCCINATE, STERILE, U.S.P.
FOR INTRAVENOUS ADMINISTRATION
Equivalent to I Gram of chloramphenicol, U.S.P.
PARKE, DAVIS & COMPANY
DETROIT, MICHIGAN 48232 U.S.A.
Caution: Federal law prohibits dispensing
without prescription
Ci.) Warning: Blood dyscrasias may be associated
with the use of chloramphenicol. It is essen-
tial that adequate blood studies be made. See
L enclosed warnings and precautions.
-
(Whereupon, at 11:45 a.m., the subcommittee adjourned.)
PAGENO="0187"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
THURSDAY, MARCH 13, 1969
U.S. SENATE,
MoNopoLy SUBCOMMITTEE OF THE
SELECT CoMMIrrui~ ON SMALL BUSINESS,
Washington,D.C.
The subcommittee met, pursuant to recess, at 10:10 a.m., in the
Caucus Room, Old Senate Office Building, Senator Gaylord Nelson
(chairman of the subcommittee), presiding.
Present: Senators Nelson and Hatfield.
Also present: Chester H. Smith, staff director and general counsel;
Benjamin Gordon, staff economist; and Elaine C. Dye, clerical
assistant.
Senator NELSON. I regret that our: hearing yesterday had to be can-
celled. Dr. Dale Console, who was to be our witness, was unable to
come because of ill health. His work within the drug industry as for-
mer medical director for E. B. Squibb and Company and his experi-
ence in private practice make him especially well qualified to comment
on the various matters which have been dealt with in the course of our
continuing study of the drug industry.
Dr. Console's biographical sketch and prepared statement, which
was submitted to us, will be made a part of our hearing record. The
questions I had planned to ask will be sent to Dr. Console, and his
answers will be placed in the record immediately following his state-
ment.
(Dr. Console's biographical sketch, prepared statement, and supple-
mental information follow:)
BIOGRAPHY, A. DAr,n CONSOLE, M.D.
Born: 1915.
Training:
B. S. Cornell University 1937.
M.D. Cornell Medical college 1941 (Polk Prize for General Efficiency).
Intern, Asst. Res., Resident Surgeon, New York Hospital 1941-1946.
Resident Neurosurgeon, New York Hospital 1946-48 (John and Mary Markle
Foundation Grant).
Research Fellow in Psychiatry, Pennsylvania Hospital 1957-1958.
Research Fellow in Psychiatry, Payne Whitney Clinic 1958-1959.
(Psychiatric Division of Cornell-New York Hospital)
Experience:
Consultant to Surgeon General (Neurosurgery), Fort Dix.
Asst. Clinical Professor of Surgery, (Neurosurgery), Cornell Medical College.
Attending Surgeon (Chief of Neurosurgery), St. John's Hospital.
Research Consultant, New Jersey Neuropsychiatric Hospital.
Director of Research and Training, N.J. State Hospital at Marlboro.
Psychiatric Consultant, Douglass College.
Assoc. Medical Director and Medical Director, E. R. Squibb & Sons.
Research Assoc. in Psychiatry, Cornell Medical College.
4477
PAGENO="0188"
4478 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Certification:
Diplomate of the American Board of Surgery.
Diplomate of the American Board of Psychiatry and Neurology
(Psychiatry).
Memberships:
American Psychiatric Association.
Society of University Surgeons.
American Group Psychotherapy Association.
New Jersey State and Mercer County Medical Societies.
Alpha Omega Alpha.
Publications:
15 Pa~ers dealing primarily with Hypertension and the Sympathetic Nerv-
ous System.
STATEMENT BY A. DAIu CONSOLE, M.D.
INTRODUCTION
Before presenting my prepared statement I should like to make some intro-
ductory comments. I have prepared my statement with the understanding that
representatives of the drug industry, the PMA and the AMA either have had or
will have their days in court. The drug industry and its friends have demon-
strated in the past that they are more than able to speak for themselves. I do
not exect them to support my views of the problems. I feel no need to support
theirs.
I also wish to make it clear that I am not an academician. For almost ten years
I have devoted 90% of my time to the private practice of psychiatry, and my
contact with the so-called "white towers of medicine" has been minimal. During
those ten years I have held only one academic position and that is a part-time
one, Research Association in Psychiatry at Cornell Medical College.
I speak for myself and myself only. The primary justification for my appear-
ance here derives from a degree of expertise I gained during the six and one-half
years I spent as Associate Medical Director and Medical Director of E. R. Squibb
& Sons.
LICENSING AND INSPECTION
I have always found it curious that a process that started in late 1959 as an
investigation of "administered prices in the drug industry" ended in 1962 with
the passage of legislation that had no effect on drug prices. Actually no one w-ho
was knowledgeable expected that the Kefauver-Harris Amendments of the Drug
Act would affect prices and it seems clear that the late Senator Kefauver accepted
the bill in its final form only because it was the best compromise he could get at
the time. Even so he made a last-ditch effort to introduce a patent amendment
and was defeated.
The record is clear and it demonstrates that the attack on drug prices had
two prongs. One of these was contained in the patent provisions. The other w-as
directed against the allegation that generic equivalents are inferior and unreli-
able drugs. In drafting S. 1552, Kefauver and his staff sought to increase price
competition by encouraging generic prescribing. Realizing that they could not
accomplish this unless assurance was given that any drug on the market had to
meet standards of purity, safety, and efficacy determined by the FDA, they drafted
Section 508. Let me quote some of the pertinent language: "Paragraph (b) pro-
vides that no license shall be granted unless the applicant demonstrates that the
establishment . . . meets such standards . . to insure . . . the purity, safety,
and efficacy of the drug. . . . When the Secretary (of HEW) determines that
the establishment no longer meets the standards, he shall revoke or suspend the
license."
The intent of the language is crystal clear, and it w-as emphasized in Kefauver's
opening statement in the first session of the hearings on S. 1552. Referring to the
licensing and inspection provisions, he said, "These provisions put real teeth into
the Food and Drug Act. By realizing that any firm w-hich produces inferior drugs
can have its license to do business suspended or revoked, the physician should
gain assurance that any drug sold in the country, w-hether produced in this coun-
try or abroad, whether made by large companies or small companies, and whether
marketed under a brand name or generic name, is of adequate and acceptable
qualitij" (emphasis mine).
PAGENO="0189"
COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY 4479
Perhaps Kefauver and his staff were naive in thinking that these provisions
would effectively neutralize the mountain of propaganda produced by self-pro-
fessed reliable drug companies and by the PMA. They may have been naive in
believing that the average physician's prescribing habits could be changed that
easily. In any case, the theory never has been tested. During `the process of leg-
islative hocus-pocus, Section 508 disappeared and a toothless version appeared
in its place. It calls for registration of name and place of business. The inspection
provisions are so vague that they defy interpretation.
It has taken some five years for other to recognize the need to put more teeth
into the Food and Drug Act. I have studied the Interim Report and recommenda-
tions of the Task Force on Prescription Drugs, published in August 1968, with
great care. No one in my opinion has made so exhaustive a study of the many
problems posed by the ethical drug industry and expressed the findings in such
balanced and temperate language. Among its recommendations it urges consid-
eration of a registration and licensing system and strict quality control. Recog-
nizing that this might raise the prices of some drugs, it feels that the increased
quality would offset any increase in prices. While I am not an economist, I share
the view that was held by Kefauver and his staff, namely that, overall, increased
price competition would tend to low-er prices and at the same time ensure the
quality and efficacy of all drugs.
The need to strengthen the existing law has also received support from an
unexpected quarter. It has been the practice of Medical Tribune to commission
a Professor of Governments, Joseph D. COoper, Ph.D. to write extensive series
of articles on the FDA, Generic Equivalency, and other subjects of interest to
physicians. The tenor of Professor Cooper's comments and the editorial policy of
Medical Tribune are quite obvious: It would require a rather remarkable distor-
tion to characterize either as hostile to the drug industry. For this reason alone,
it is of interest that a series of articles on the FDA that appeared in mid-1967,
Professor Cooper called for a system that he labeled "licensed self-regulation."
In describing the system, he went on to say, "the power of this method of control
lies in the fear of the company that part or all of its license might be revoked."
One can almost hear the ghost of the late Senator Kefauver.
I strongly urge that Congress give early consideration to licensing and inspec-
tion provisions similar to those proposed in the original S.1552. If the 1962 legis-
lation had contained these provisions we probably would not find ourselves in the
generic equivalency mess that now exists. In any case, the search for adequate
guidelines would have started five years earlier than it did.
MONETARY REWARDS AND OBJECTIvITy
In his letter inviting me to appear before `this Committee, Senator Nelson men-
tioned "growing concern that the medical profession has forfeited too much
responsibility for the continuing education of physicians to the pharamaceutical
industry and that the increasingly close financial relationship between the indus-
try and the profession may be contrary to the best interests of the medical pro-
fession and the public."
I, too, share this concern; I have shared it for almost 18 years. It is now-
almost nine years since I appeared before the "Kefauver Committee" and said:
"Unfortunately drugs are not always prescribed wisely, and while the physician
and patient among others must share the responsibility for this with the pharma-
ceutical industry, it is the industry that carefully nurtures and encourages the
practice. .. . The pharmaceutical industry is unique in that it can make ex-
ploitation appear a noble purpose. It is the organized, carefully planned, and
skillful execution of this exploitation that constitutes one of the costs of drugs
which must be measured not only in terms of dollars but in terms of the inroads
the industry has made into the entire structure of medicine and medical care.
With the enormous resources at its command, it has usurped the place of the
medical educator and has successfully substituted propaganda for education."
At another point in the same statement, I said, "The abdication of leaders and
educators in medicine is disturbing. Postgraduate medical education is their
province, not the pharmaceutical industry's."
I am also disturbed, however, over the tendency to focus on financial rela-
tionships. While I feel that this is important and requires attention and correc-
tion, I am also convinced that we would be making a grave error if we decided
that the total problem could be corrected simply by cutting financial ties. The
well-known articles by Dr. Charles May: and Dr. William Bean cover the problems
of "payola" and other financial entanglements. I believe I can accomplish more
PAGENO="0190"
4480 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
if, instead of repeating what they have already said so well, I try to draw your
attention to an area of equal importance; perhaps even of greater importance.
The relationship that exists between the medical profession and the drug
industry is an unhealthy one and in many ways a corrupt one. It is important to
remember, however, that it is not only money that has the power to corrupt.
Having spent more than six years in the business of influencing doctors and
investigators, and some five years as a member of Fellowships and Grants Com-
mittee, I can assure you that while large grants and other monetary rew-ards
play an important role, that role is minor relative to other inducements and
techniques that can be used to destroy objectivity. An incident that will always
remain fresh in my memory will perhaps illustrate the point I wish to make.
Sometime in 1956, when I was still a Medical Director, the lagging sales of one
of our products led management to decide that the product needed a boost. The
boost took the form of obtaining an endorsement from a physician who was a
prominent authority in the field. We knew that the particular physician was
being subsidized by another drug company and so management decided that
it would be simple for me as Medical Director to `buy" him. I objected since
I felt that the doctor was incorruptible and because I felt the product did not
deserve endorsement. My business colleagues overruled me and I was left with
a blank check to win his favor. I was free to offer him a large grant to support
any research of his choice "without strings" or to retain him as a consultant
with generous annual compensation. I was quite certain that the doctor would
throw me out of his office if I approached him w-ith any of the techniques sug-
gested by my colleagues. They all had the obvious odor of a bribe. I decided,
therefore, to use a strategem that was more likely to be effective and that I
thought (at the time) would be easier on my own conscience.
I took the doctor to lunch, and after the usual two Martinis, I told hiiii
exactly what had been going on and of my disagreement with my colleagues.
In this manner we established a physician-to-physician relationship in which we
were both deploring the questionable tactics used by the drug industry. Conversa-
tion gradually shifted to the product and, to make a long story short, we got our
endorsement almost as a personal favor. My travel expenses and the price of
the lunch made up the entire cost to the company.
I recall this out of a hundred similar incidents only because the doctor w-as,
and still is, a highly respected authority. My attitude toward him still is one
of profound respect and admiration, since I must confess that the device that
gulled him would have fooled me had I been in his place.
We are still human in spite of being physicians. As humans, we are vulnerable
to all forms of flattery, cajolery, and blandishments, subtle or otherwise. The
drug industry has learned to manipulate this vulnerability with techniques
whose sophistication approaches perfection. It was this knowledge that led me
to write a letter that appears in the record of the "Humphrey Hearing" (p. 2289).
Referring to the methods that can be used to destroy objectivity I said, "Any
employee of a drug firm who is worth his salt has an expert's appreciation of
their power, a gourmet's taste for their subtleties, and the deft delicate touch
that leads the doctor to hang himself." These techniques are used not only by
physicians employed by a drug company but also by more experienced
detailmen.
I know of no effective way to deal with this type of hanky-panky that goes
on every day between the medical profession and the drug industry. It seems
impossible to convince my medical brethren that drug company executives and
detailmen are either shrewd businessmen or shrewd salesmen, never philan-
thropists. They make investments, not gifts.
As further evidence of this manipulation of the physician's vulnerability,
let me quote from the literature that was uncovered during the thalidomide
scandal. A document written by the William S. Merrefl Company w-as sent to
"special representatives" before Kevadon (thalidomide) w-as approved for mar-
*keting. It set up minimum goals and objectives, including contacting teaching
hospitals and the chiefs and senior members of hospital departments "for the
purpose of selling them on Kevadon and providing them with a clinical supply."
In the instructions the representatives were told: "Appeal to the doctor's ego-
we think he is important enough to be selected as one of the first doctors to use
Kevadon in that part of the country" ("Humphrey Hearings," p. 1918). I can
assure you that even this simple device will open many doctor's doors.
Let me hasten to add that during my time as Medical Director I w-orked
with many physicians who were incorruptible. Many of them received large
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4481
grants but they produced studies that were models of objectivity. These were
truly cooperative efforts in which both the drug industry representatives and
the investigators were seeking the truth. There is no doubt in my mind that
similar cooperative efforts exist today.
On the other hand, during my time as Medical Director, I can remember only
six to eight drugs that were truly exciting and interesting. I also remember a
hundred humdrum concoctions and combinations that would bore any doctor to
death. These, however, must also be studied and in trying to find "investigators"
who are willing to do the job, one must scrape the bottom of the barrel. As a
result, the drug industry doctor must rub shoulders not only with the giants
in medicine but also with its dregs. In my 1960 statement I called the latter
"stables" using the vernacular of the industry.
Drug testing is a costly, burdensome, and often a boring chore. Those who do
the work well should receive adequate compensation. Both because there
are doctors who are incorruptible and because someone must pay for drug
testing, I think it is wrong to damn monetary rewards in a `blanket fashion. I
do believe, however, that clinical testing and the choice of investigators should
be taken out of the hands of the drug industry. So long as we have a system
that allows drug companies to buy the claims that will sell a drug, we have a
potentially corrupt system.
I am convinced that the public interest ~vill be best served when we devise
a system that preserves anonymity between the drug company that has a pro-
prietary interest in a drug and the investigator whose research results may
or may not supply the claims that will sell the drug.
During the writing of this statement I learned that many physicians who
preceded me recommended a "Drug Institute" or a similar central agency. I
do not believe the recommendation can be repeated too often. A central agency,
supported both by federal funds and by fees paid by drug companies, should
serve as an impartial intermediary between drug companies and clinical investi-
gators. By preserving anonymity and by selecting investigators on the basis of
their qualifications, we could raise drug testing to a level it has never known.
Since I believe in the theory of the unconscious (as well as the existence of
incorruptible physicians), I am convinced that any thing that falls short of
this system cannot insure objectivity.
The larger problem of destroying objectivity by appealing to the doctor's
ego is as old as man. I do not intend to offer a solution. I think it iS important
that we remain aware of its existence and of the fact that physicians are just
as human as everyone else. Unfortunately, what I said on this matter in my
statement of 1960 is as true today as it was then. "There are far too many
physicians who must still be taught the difference between a free golf ball,
the magnetic personality of a detailman, and a scientific fact as criteria for
the evaluation of a drug."
THE PHYSICIAN'S PRIVILEGES AND PREROGATIVES
The ease with which objectivity can be destroyed is only one of many signs
that the relationship between the drug industry and a considerable segment of
the medical profession is contaminated. Both the AMA and individual physicians
have demonstrated that they are quite willing to pull the drug industry's
chestnuts out of the fire when they can, at the same time, serve their own
interests. Both the AMA and the PMA have long paid lip service to the principle
of upgrading the scientific Stature of the FDA. Yet each time this principle has
been tested, either the AMA or the PMA or both have demonstrated that they
are not prepared to practice what they preach. They have proposed instead glib
anti-scientific solutions.
The AMA probably represents the majority of the nation's more than 200,000
physicians. Whether it speaks for them is not clear. In any case, the cozy "you
scratch my back and I'll scratch yours" relationship that exists between the
AMA and the drug industry raises some serious questions.
One of the first major confrontations between government and medicine
(regarding drugs) came in the "Kefauver Hearings." At that time, to use the
words of Dr. William Bean, ". . . the AMA in its fear . . . euchred itself into
[an] astonishing posture . . ." It suggested a solution that made "every physi-
cian his own Pasteur." Even after the bill became law, anti-science still reigned,
and the AMA House of Delegates resolved that "the AMA attempt to have
removed from the Kefauver-Harris Amendments those provisions which author-
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4482 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
ize the U.S. Food and Drug Administration to determine the effectiveness of
drugs." Anti-science is still with us.
Another major confrontation came in 1963 when the FDA, following the
recommendations of a panel nominated by the prestigious National Academy
of Sciences proposed banning the sale of antibiotics in combination with cold
preparations intended for symptomatic relief. The response of the drug industry,
the PMA, the APA, and individual physicians constitutes one of the most
shocking episodes in the history of American medicine. Although it is docu-
mented in the record of the "Humphrey Hearings" (pp. 1502-1530) and has been
described by Morton Mintz in By Prescription Only, it has received little
attention in the medical community.
I had intended simply to mention this episode and give the references. During
the preparation of this statement, however, it became clear that we were heading
into another major confrontation between the FDA and the drug industry,
which is almost exactly the same as the confrontation that took place in 1963.
In the hope that it might help to prevent a repetition of the 1963 episode, it
seems worthwhile to give some account of the genesis, the life and the death of
the proposed ban.
Sometime in 19f32 became concerned about the inclusion of antibiotics in
mixed cold preparations intended for symptomatic relief and in throat lozenges
and troches. Concern about these products had been expressed in the medical
literature since 1953. The FDA finally decided that these uses of antibiotics
were irrational and should be studied. It requested nominations for a panel of
experts from the NAS and selected from the nominations a panel chaired
by Dr. Harry Dowling, an internationally recognized expert on infectious
diseases and antibiotics.
The report and recommendations of the panel led Dr. Ralph Smith of the FDA
to write to his superior recommending (as the law requires) publication in the
Federal Register of a proposal to remove antibiotic containing cold preparations
from t.he market. In his letter, Dr. Smith said, "the proposal is likely to be
met by substantial industry opposition." This will probably stand as one of the
greatest understatements of all time.
I doubt that more than a handful of practicing physicians read the Federal
Register and so the information reached physicians through other channels.
These were accounts in the media controlled by the AMA, in throw-away journals
that subsist on drug advertising, and in letters mailed to physicians by a large
drug company.
I have a clipping from the J.A.M.A. of November 23, 1963 which is typical of
accounts that help to mold the opinions of the medical profession. It is too long to
read it in its entirety, but I request that it be made part of the record. In it both
the PMA and the AMA take turns labeling the proposed ban "unauthorized inter-
ference with the practice of medicine . . . goveimment fiat . . . governmental
dictation . . . regulatory fiat . . . (and) coercion."
To expect the average physician to consider any issue dispassionately when
presented in such inflammatory language is equivalent to expecting a bull to
become reasonable by waving a red flag at him.
The response of physicians w-as hardly surprising. One account (The Pinl~ Sheet
September 16, 1963) stated that "over 100 letters of protest" were received by the
FDA. Another account (John Troan, Tvashington Daily News, November 12,
1963) stated "about 1,000 physicians have filed protests with the FDA." This
larger figure may reflect the difference that appeared in the month that separated
the tw-o reports. It appears that only one physician, Dr. Joseph K. Ackerman,
wrote to the FDA approving its proposed action. His letter appears in the record
of the "Humphrey Hearings", (p. 1523) and I quote part of it: "The opinion of
a minority of experts is of much greater value than the opinion of a majority
of practitioners who have had an irregular and inadequate exposure to com-
petent and objective pharmaceutical literature. Whether their opinion has the
political leverage is another thing again."
There w-as one other letter that supported the FDA position but it was sent
to Medical World News rather than the FDA. I wrote the letter in response to a
news article entitled "Curb on Cold Remedies Faces Fight" which appeared in
the September 13, 1963 issue of that journal. The letter appears in the record
of the "Humphrey Hearings", (p. 1523) and I quote it in part from that source.
"If the drug industry is successful in urging medical leaders to lodge a formal
protest against the proposed ban on antibiotic mixtures . . . the caduceous
should be at half mast . . . If `thousands of physicians' have found these mix-
tures useful, it should be easy to collect conclusive data demonstrating that
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4483
utility. The drug indus:try can answer the FDA's objections better by collecting
and submitting those data than by blowing up an emotional storm over `inter-
ference' with the physician's prerogatives . . . the real need is for data not
protest."
At the same time I sent a personal letter to one of the members of Dr. Dowl-
ing's panel in which I exhorted him to stand fast and to urge the panel not to be
swayed by irrational protest regardless of its volume. I pointed out that if the
panel and the FDA capitulated they would set a precedent for an incredible
policy, namely drug evaluation by mass protest and by testimonial.
Subsequent events demonstrated that the majority of practicing physicians
with "irregular and inadequate exposure" had the "political leverage" and pre-
vailed. The FDA retreated and extended the period for filing comments for two
months. Subsequently, it appears, both the FDA and the panel did capitulate
and this bold, but rational, step toward sound medical practice came to naught.
Capitulation in the face of voluminous and vehement protest is understandable,
but nonetheless regrettable. It is incredible that testimonials and irrational pro-
test can be so effective.
If scientific data ever were presented I have no knowledge of such data. Even
the AMA (in `the article quoted above) gave a pathetically weak and specious
argument to justify the continued use of these irrational combinations of drugs.
In defense of these products the AMA said: "It seems that many phsyicians in
practice prefer to prescribe such a mixture of drugs because they believe that
each drug in the mixture will have a specific desirable purpose." The AMA still
dlings to the fiction that every physician is his own Pastuer. It would probably
Prefer to forget that there was a time when it refused to accept advertising for
drug combinations.
The AMA also gave its usual glib solution as the answer to the problem of
irrational antibiotic-cold preparations. According to the AMA the answer lies
not in FDA action but in "education of physicians" and "labeling." If the ex-
perience with chlorainphenicol is an example of what can be accomplished by
physician education and labeling, it is high time we began to search for other
solutions.
The weight that should be given to the average practitioner's concept of the
problem is reflected in one of the letters to the FDA quoted by John Troan. The
latter came from a small local medical society and said: "We deeply resent this
proposed usurpation of our prerogative to treat and diagnose our individual
patients and our prerogative to err if that be the case." I have added the em-
phasis because as a psychiatrist I have always found the Freudian slip that
reverses the order of the terms diagnose and treat of special interest. I am still
awed by the arrogance the latter expresses.
According to the PMA and the AMA these views should be given the same
or greater weight than that given to scientific evidence derived from controlled
studies. Testimonials are still testimonials regardless of their numbers. The irra-
tional does not become rational by virtue of volume.
If the entire antibiotic combination episode is an illustration of how `the drug
industry, the medical profession, and their chosen representatives the PMA, and
the AMA seek to enhance the scientific stature of `the FDA and how they seek to
promote sound medical practice, it leaves much to be desired.
Curiously, all the sound and fury was over nothing since the proposed ban
did not interfere with the physician's prerogative to prescribe as he chooses. It
did proscribe the marketing of certain irrational mixtures, but the physician was
still free to prescribe a cold preparation and to write a prescription for any anti-
biotic of his choice in those cases where it was indicated.
If the FDA cannot proscribe the marketing of irrational mixtures of drugs
because that proscription infringes on the privileges of physicians, Congress and
the people should re-examine those privileges. This is clearly an abuse of priv-
ilege and should not be tolerated. According to a Supreme Court decision the
people give privilege to professions and the people may take it away.
The stage for the pending confrontation between the FDA and the drug in-
dustry was set in 19G2 when Congress approved the efficacy provisions of the
Kefauver-Harris Amendments of the Drug Act. At that time Congress had a clear
choice between exempting drugs approved for safety only during the period be-
tween 1938-1962, under a grandfather clause, or making the efficacy provisions
retroactive. In choosing the latter course Congress gave the FDA a clear mandate
to re-evaluate all such drugs for efficacy and unleashed forces of explosive
potential.
81-280 0-69-pt. ii-i:~
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4484 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Probably because the leaders of the FDA recognized this explosive potential
they elected not to exercise the authority given them by Congress until 196G. At
that time the FDA, under the inspired leadership of former Commissioner God-
dard, accepted the assistance of the FAS-NRC and select panels began the long
review. The findings and recommendations of these panels have begun to filter
down and the FDA either has published or plans to publish its intention to ban
the marketing of certain irrational combinations. The most recent decisions deal
with irrational antibiotic mixtures. While these steps are rational they fail to
make allowance for the irrationality of the drug industry, the AMA, and a seg-
ment of the medical profession. The drug industry and its friends operate under a
different set of rules which can be stated quite simply. Whenever a drug, through
rational or irrational usage, has acquired a place in the Art of Medicine it is no
longer subject to any scientific scrutiny. Morton Mintz caustically labelled this
the "Hussey-Stetler Test of Time." Any attempt to subject a drug that is already
on the market to sicentific scrutiny is met with howls of protest over interference
with the privileges of physicians. If we accept this abuse of privilege we set scien-
tific concepts of drug therapy back to the Middle Ages.
The spectacle of the drug industry acting as the champion of the privileges
and prerogatives of the physician would be amusing if it did not have such
serious consequences. The drug industry is interested in encouraging irrational
prescribing and thereby increasing sales volume, not the rights of the physician.
In my statement of 1960 I said: "The incidence of disease cannot be manipulated
and so increased sales volume must depend, at least in part, on the use of drugs
unrelated to their utility or need or, in other words, improperly prescribed."
Today I would go a step ftrther than I did in 1960. Probably the major part of
the sales volume of many drugs (and especially combinations) is dependent on
their being prescribed improperly or irrationally.
We can only hope that the FDA and the panels will not be swayed as they were
in 1963. We have bad more than enough of drug evaluation by mass protest. We
have had more than enough of political leverage. We have had more than enough
of irrational prescribing, and of anti-science. If there is such a thing as a science
of medicine then let us behave as if we believe it. The pharmacologic action of
drugs is a Science not an Art. Those who believe it is an Art should limit their
prescribing to innocuous placebos whose activity does indeed depend on art.
Unfortunately there are rumors that the FDA may be returning to the
doldrums it was in for more than 30 years prior to Dr. Goddard's leadership.
Dr. Goddard was a realist and recognized that the industry had to be dealt with
as an adversary. To deal with the drug industry in any manner than as an
adversary is noj only unrealistc; it is nonsense.
IRRATIONAL PRESCRIBING
rI'he Task Force on Prescription Drugs simply accepts the existence of irration-
al prescribing. For obvious reasons it makes no attempt to answer the all-impor-
tant question about the incidence of irrational prescribing. It does state: "We find
that few practicing physicians seem inclined to voice any question of their com-
petency in this field. We have noted, however, that the ability of an individual to
make sound judgments under these quite confusing conditions is now a matter of
serious concern to leading clinicians, scientists and medical educators."
There are two quite different ways to practice medicine. One calls for precise,
pinpoint diagnosis and the aiming of a handloaded rifle bullet at the center of the
target. Unfortunately, this method is not always available; an overwhelming po-
tentially fatal infection is an obvious exception, but this is the primary method
taught in medical schools. The other method, which is not taught in medical
school, seeks only some general categorization of the patient's illness, such as
anemia, infection, or gastro-intestinal disorder and either letting loose a shotgun
blast in the hope that one of the pellets will find the mark, or firing one or more
rifle bullets in random fashion hoping, again, that one will reach the bull's eye.
These are examples of irrational prescribing and unsound medical practice.
This latter method of practice requires far less skill, much less time, and uses
much more medication than sound medical practice. Because it is easier, it has
more and more appeal as the physician becomes more hurried, more harried.
and more confused. Because it uses more drugs, the drug industry encourages
the practice in the "education" it gives in its advertising and promotion efforts.
It is easier than you will believe to fall into the habit of thinking fever equals
infection equals a prescription for chloramphenicol. Viewed in this light, the mis-
use of chloramphenicol becomes more understandable since chloramphenicol is
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4485
one of the biggest shotguns of them all. As I said in my statement of 1960: "Too
many physicians, pressed for time, would like to believe that medicine can be
practiced with a clinical thermometer and a bottle of pills."
There is nothing new or unique in this description of irrational prescribing. As
far back as 1953 Dr. Maxwell Finland, an eminent authority on antibiotics, dealt
with the problem in a scientific paper. Under the heading "Omnibiotics" Dr. Fin-
land said: "The physician in practice, and many of his patients as well, are con-
stantly on the lookout for some simple substance or formula which they can
apply with universal success. The busy practitioner is particularly desirous of
having some major weapon on which he can always rely to be successful in all
types of infections, and would thus relieve him of the responsibility and trouble
involved in the complicated or even simple diagnostic procedures" ("Humphrey
Hearings" p. 1507).
In addition to precision in diagnosis (and treatment), medical schools also
teach the painful and anxiety provoking process of watchful waiting when the
diagnosis is not clear and a laissez faire attitude when the complaint is not
serious. Watchful waiting does provoke anxiety and requires much more con-
tinuous attention to the patient's changing condition. Laissez faire leads many
patients to object because they feel their complaint has not been taken seriously.
In either case, only too often, the physician feels compelled to write a prescrip-
tion, even though the prescription does more good for his anxiety or his conveni-
ence than it does for the patient's illness. It also exposes the patient to the addi-
tional hazard of drug induced illness which may or may not obscure the underly-
ing cause of the original illness, and may or may not make the cure worse than
the disease.
Because it feels that rational prescribing and sound medical practice cannot be
legislated, the Task Force leans heavily on education, at both the medical school
and the post-doctoral levels, for a partial solution of the problem. While I can-
not gainsay the value of education I am dubious about the effectiveness of physi-
cian education in this particular area. I am forced to ask the question I asked
in 1960. Since it is a long one, I will paraphrase it. Is it reasonable, I asked, to
expect legitimate education to compete with modern methods of advertising and
promoting drugs? My answer was then, and still is, an unqualified no. Education
is not enough and I believe the experience with chloramphenicol, among other
drugs, proves it. I agree that rational prescribing and sound medical practice
cannot be legislated. We can, however, enforce legislation that exists and con-
sider new legislation, if necessary, to choke off at least part of irrational pre-
scribing and thereby contribute to sound medical practice.
The irrational use of drugs has at least two facets. On one hand we must deal
with single drug entities which have specific but limited use and, while they may
be irrationally prescribed, are still the drugs of choice in some disorders. Chloram-
phenicol and penicillin are examples' of drugs that have specific uses but are often
improperly prescribed for disorders for which they are not indicated. On the
other hand, we have irrational combinations of drugs which serve only to encour-
age irrational prescribing. If the use of these drugs were limited to those occa-
sional cases where they might by stretching reason, be indicated *they would
wither on the vine and their sale would become unprofitable. Invariably the pur-
pose of these drugs can be served equally or better by prescribing the ingredients
separately in those rare cases where more than one drug is indicated. Antibiotic
containing cold preparations and the combination of amphotericin B with tet-
racycline are examples of combinations in this category. We cannot ban products
in the first category. We will have to accept the mususe and abuse of these
drugs until education or publicity or both reduce such improper use. We should,
however, ban the marketing of irrational combinations even if it requires new
legislation. We probably w-ill have to interfere with the privilege of the medical
profession arrogates to itself but rational prescribing and sound medical practice
must take precedence over the AMA's the PMA's or the individual physician's
concept of privilege.
Naturally it woul be preferable if the medical profession policed itself. If
the AMA could cure itself of its phobia over government control it could serve
a useful pui~pose in contributing to sound medical practice. So long as it adopts
astonishing postures it invites regulatory control. Experience has demonstrated
that the AMA is phobic and that neither the drug industry nor a considerable
segment of the medical profession is prepared to police itself. Actually the AMA
and the medical profession should serve as the first line of reserves behind the
FDA in the battle to curb `the excesses of the drug industry. Instead of sup-
porting the FDA, the AiMA and a segment of the medical profession have joined
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4486 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
forces with the drug industry and as allies they wage war against a common
enemy, the FDA. The combined efforts of the drug industry and its allies make
the anti-regulatory forces so powerful that it is doubtful that the FDA alone can
deal with them. Reform and tighter regulation of drugs (and especially com-
binations) is clearly required. Firm action and support of the FDA by Congress,
the people, and the leaders and educators in medicine is in order.
In conclusion, let me quote Senator McCumber, who, arguing for the Food
and Drug Act passed in 1900, said: "You cannot, for years, surround a people
with crime and deceit and imposition on every side without it, in time, affecting
the moral character of the people. Constant association with crime and deceit
calls our senses to offenses of that nature." I do not believe that his language
is anachronistic. We have come dangerous close to repeating the conditions he
described.
PRINCETON, N.J., March 26, 1P69.
Hon. GAYLORD NrisoN,
U.S. Senate, Washingtoa, D.C.
DEAR SENATOR NEr~soN: Let me take this opportunity to express my regret that
I was unable to be present at the hearing.
Under separate cover I am sending you the answers to the questions raised by
you and by Mr. Gordon regarding my prepared statement. Whereas my statement
was, indeed, prepared and went through several drafts and revisions before it
took on a form I was partially satisfied with, I have not used this method in
answering the questions.
I have simply sat with a typewriter and allowed myself to reminisce allowing
the flow of one thought to lead on to the next. This gives the answers a random
and sometimes even a repetitive quality. Nevertheless, it is essentially what I
would have said had I been present at the hearing. I have added exhibits and
source material which brings this part of my statement up to date.
If there are questions that remain unanswered, or if the answers raise further
questions or need clarification, please do not hesitate to let me know.
Sincerely,
A. DARE CONSOLE, M.D.
DR. CONSOLE'S ANSWERS TO QUESTIONS SUBMITTED BY SENATOR NEr~soN
Qnerfion. (a) How can legitimate education compete with the millions wpon
miflions of dollars spent on advertising and prcnnotion, gifts and financial grants
to physicians, financing of journal-s and meetings and gifts to students? Wouldn't
you say that this is a rather uneven struggle? (b) What has been the role of the
~nedical organizations in, helping the doctors get scientific, un7iia~scd informa-
tion?
Answer. The struggle is indeed, an uneven one. As I pointed out in previous
testimony, industry alone commands the resources necessary to make propaganda
effective. How can legitimate education compete with the carefully contrived
distortions driven home by the triphammer effect of weekly mailings, the regular
visits of the detailman, the two page spreads, and the ads that appear six times
in the same journal; not to mention the added inducement of the free cocktail
party and the golf outing complete with three golf balls stamped with the
name of the doctor and the company in contrasting colors? Drug advertising
and promotion efforts encourage the doctor to believe that there is an easy way
to practice medicine. They offer larger and larger shotguns which make pinpoint
diagnosis, or for that matter any diagnosis at all a pedantic exercise and a
troublesome inconvenience that only the less informed academician bothers with.
The sound practice of medicine is a rigorous discipline. There are no short-cuts.
There are no easy ways to achieve the necessary goals. There are no omnibiotics
or shotguns Fthat eliminate the need to think, and to worry. The disparity between
legitimate education and drug advertising and promotion is not only in the
quantity of the blandishments the drug industry offers, but also in the quality of
the piece of candy dangled in front of the physician's nose.
With respect to the role played by medical organizations, it is difficult to
generalize. There are thousands of such organizations ranging from county
medical societies to the select clubs consisting almost exclusively of blue bloods.
I have maintained my membership in the Society of University Surgeons pri-
marily because it tends to fall in the latter category. Although I have been a
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4487
member for almost 20 years I have never known it to offer a program intended
for drug promotion. This is in contrast to the New York Academy of Science
from which I, among others resigned because it began to sponsor obviously
biased "symposia" which were nothing more than grandiose promotion programs
intended to push a particular product.
So long as the average practioner is the captive of the drug industry, and I am
convinced he is, and medical organizations are made up of physicians who are
captive, it follows `that the organizations are in turn captive. The real question
is not whether they are captive but rather the degree to which they are cap-
tive. Those who publish a journal and derive income from drug advertising
are probably even more captive that the average practitioner. Those who derive
such income cannot deny that a conflict of interest exists. The AMA's contention
that it is not a party in a tacit conspiracy wit'h t'he drug industry is not convinc-
ing. Its denial fails to explain the astonishing, unscientific, pro-drug industry
positions it has taken. It has given `shelter to the `drug industry under the cloak
of immunity given to physicians, and the drug industry has been more than will-
ing to accept the shelter since it gives the industry an ethical image while it uses
the same profit-oriented tactics of any big busines. It pays well for the shelter
by buying advertising pages. As I suggested in my prepared statement, the AMA
is serving its own interests and the support it gives the drug industry is sec-
ondary. In my opinion this is simply a definition of conflict of interest. I would
not expect the AMA to put the drug industry's interests before its own. I wish to
make it clear that I `have used the term propaganda to describe the drug indus-
try's "education", in terms of one of Webster's definitions of propaganda; "any
systematic, widespread, deliberate indoctrination, or plan for such indoctrina-
tion; now often used in a derogatory sense connoting deception or distortion".
As we speak of propaganda as opposed `to education I am reminded of recent
reports in which the AMA, trying to keep its significant income derived from
drug advertising tax free, has quoted Dr. Goddard to the effect that drug adver-
tising is educational. I do not know the source of this quota'tion or whether the
quotation is being used in or out of context. If it is accurate and in context, I
can only say that I disagree with Dr. Goddard. The concept that the merchant
who hawks his wares serves an educational: purpose is a travesty.
Finally let me point out that I devoted a major portion of my 1960 statement
to exploding the myth that drug advertising is educational. I enclose a mimeo-
graphed copy of that statement which you may wish to make a part of the record
of these hearings.
Question. On page 3 of your statement you refer to your ecvperience in getting
the endorsement for a particular product. Was the product worthy of an endorse-
ment?iWhat form did the endorsement take?
Answer. I have `deliberately kept t'his part of my statment vague since I would
not want, under any circumstances, to reveal the name of the physician involved.
I have said in my statement that I did not `believe the product deserved en-
dorsement at the time of the incident. Since that time nothing has happened to
change my opinion. I can add, that it was a combination product which as a
fixed `combination was rarely, if ever indicated. The doctor involved was a vocal
opponent of all such products and frequently men'tioned our product by name.
The "endorsement" was actually an agreement on his part to discontinue this
practice. I essentially promised that we would limit our claims, but over the
year,s the promise was not kept. The doctor did not know that the mere fact th'at
we could market it with any claims at all `had already led to widespread misuse.
Question. When you were a drug company medical director, did you ever
`instruct detail men in how to sell drugs? What kind of techniques of selling did
you present to the detail mun? How effective were these techniques on the phy-
sicians? Was the aim to make physicians prescribe more intelligently?
Answer. `During my time in the drug industry I had a close ongoing relation-
ship with detailmen. It was from one of them that I learned the simple maxim
I drew atten'tion to in my 1960 statement; "If you can't convince them, confuse
them". During my time I attended detailing "clinics" and "workshops" and I
played an important role in introducing new products to the entire detail staff (I
believe it was about 500 men at that time).
The primary purpose of detailing (as is true of all advertising and promotion
efforts) is to sell the company's products. Any and all other goals are second'ary.
The company that has exclusive rights to a new drug that is truly useful is for-
tunate, indeed. This is a rare occurrence and those companies (e.g. Smith,
Kline and French) who have been in such a position even for `a few years `have
PAGENO="0198"
4488 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
made a fortune. Even so SKF made a strong bid for the Miltown ma~rket in its
detailing, advertising and promotion.
Most often the new product is a duplicative "me too" that resulted from patent
evading molecular manipulation, a combination that has, at best, an extremely
limited market, or an uninspired drug that must compete with a host of com-
petitive drugs already on the market. Not infrequently a drug that represents
a real breakthrough is useful only in a very small nunTher of patients (simply
because the disorder is a rare one) and there is always the temptation to increase
its sales volume by extending the indications to include patients who do not need
the drug. In teaching and instructing detailmen one must attempt to instruct
and inspire them over a product that is, more often than not, uninspiring in order
to increase sales volume to its maximum point.
A detailman is a salesman and, as is true of any salesman, his enthusiasni
about the product he is selling plays an important role in how many sales he
makes. The members of my staff and I were only a part of the manpower used
to whip up enthusiasm over a humdrum concoction. In addition, innumerable
prizes ranging from cutting boards to sets of monogrammed glasses are given
to those detailmen who reach or exceed a pre-set quota of sales. Since I was the
confidant of many of the detailmen I learned that many of them had convinced,
or confused, a doctor to prescribe one of our products by telling the doctor that
*they were only one step away from winning a prize.
It is my considered opinion, regardless of what may be said by even a majority
of average practitioners, that detailmen are nothing more or less than extremely
expensive parasites. The Task Force estimates that there are 20,000 detailmen
employed by the drug industry. I estimate that the cost of maintaining a detail-
man is somewhere near $20,000 per year. This is a minimum rather than a
maximum estimate, and so we are speaking of an expenditure on the order of one
half billion dollars. This amount is, of course, deducted as part of the cost of
doing business when income tax is calculated. In brief, the public pays a large
part of the expense for the support of the detail man and pays it twice.
I went into psychiatry on the crest of the wave of psychopharmacology and so
I am psychopharmacologically oriented. I use drugs when they are indicated and
I use many of them. In almost 10 years of practice I have never seen a detailman
and only about a half dozen have called my office trying to make an appointment.
My refusal to see detailmen is based both on my experience in training them and
on their confiding to me the methods they use to make a sale. I am not aware that
my ability to practice psychiatry or my knowledge of the many drugs used in
psychiatry have suffered by the absence of the detailman. I would rather take
the advice of an uninvolved, impartial expert than be guided by the claims made
by the merchant hawking his wares. I can express my overall opinion about
detailmen best by paraphrasing Oliver Wendell Holmes; if all detailmen were
dumped into the sea it would result in the betterment of mankind and detri-
ment to the fishes. The primary purpose of the detailman is to make a sale even
if it involves irrational prescribing and irrational combinations that contain a
prophylactic ingredient furnish an ideal path to confusion. There are drugs
whose merit is such that there is no need to mislead or confuse the physician.
If the physician does any reading at all, he has no need for the detailman. If
we could legislate the detailman out of existence this could well prove to be the
most important piece of drug legislation enacted. The detailman is not the expert
both the industry and the apologists claim he is. His detail is often "canned" or
is at best a paraphrasing of what he has been told to say. A standard answer to
a question he has not been drilled on is to be modest and claim he would not
want to tell the doctor how to practice medicine (not much). Or the detailman
tells the doctor that he will forward his question to the home office. In this case
an expert does the confusing rather than the inexpert detailman.
Question. Dr. Paul Low inger of Wayne State University recommended to the
coin mitt ee that investigators working on a drug know who the other investigators
are and the results of their work. This could save a lot of time by pointing out
faifures and pi.tfaiir. What do you think of this idea?
Answer. In any kind of large scale research, proper coordination of the research
is almost as important as the research itself. My suggestion that a central agency
act as an impartial intermediary between the drug company and the investigators
was predicated on the assumption that the central agency would serve as a coordi-
nator. So long as rights regarding publication are respected, failure to follow Dr.
Lowinger's suggestion would be foolish.
Question. The AMA testified before the Kefauver Committee (Pt. I, p. 87 Drug
Industry Antitrust Act):
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4489
inevitably a useless drug will not be, used because of the training and
experience of physicians because of their experience with this useless drug, if it is
permitted to be marketed.
"* * We feel that a profession fully knowledgeable in a free market economy
will soon bring about the withdrawal from the market of a useless drug."
What do yon think abont this?
Answer. I believe this is much more a semantic exercise than a statement that
requires refutation. In the first place, if we use the AMA's definition of utility,
there is no such thing as a "useless drug". Milk sugar or any other ine.rt ingredient
when put into the form of a tablet, a capsule, a solution for injection, or any other
dosage takes on the properties of any placebo. Administered as a drug it can
produce temporary relief in a host of disorders and even cure in disorders. that
are self limited. It can also produce side effects that lead the patient to refuse
to take the "medication". If we use a pharmacological definition, milk sugar is a
useless drug. If, on the other hand, we use changes that may be observed in
some patients by physicians who do not know that it is an inert substance, and
especially if they have been preconditioned to expect beneficial effects, milk sugar
becomes a useful drug. This is the yardstick used by the AMA.
A combination of meprobamate and benactazine (Deprol) has been marketed
as a useful agent in the treatment of depression for at least ten years. Most
experts agree that it has no demonstrable value in the condition for which utility
is claimed. Yet it has withstood the "Hussey-Stetler Test of Time" which the
AMA, by its own admission, feels is the ultimate test of the utility of any drug.
Vitamin B 12, especially in the forni of 1,000 microgram injections, has an
extremely limited use. If its use were restricted to those patients who really
need it I would guess that the amount now used in one year would be enough to
treat patients with true Vitamin B 12 deficiency for almost one hundred years.
The absurd limits to which average practitioners go is illustrated by my own
experience with Vitamin B 12 during the time I was Medical Director. Because
claims for its utility in many neurological disorders ranging from peripheral
neuritis to trigeminal neuralgia and herpes zoster, as well as claims for utility
in loss of appetite, underweight, poor growth, etc, were based purely on testi-
monial evidence I refused to approve such claims in our literature on the drug.
I answered the detailmen's immediate complaint by pointing out that our brand
of Vitamin B 12 was therapeutically equipotent with any brand `on the market.
If the doctor believed that it was indicated in any condition other than true
Vitamin B 12 deficiency, our brand would meet the need as well as any other
brand. For many months after I made this decision I received letters of complaint
not only from detailmen but also from practitioners (who were probably told by
detailmen that I would like to hear from them). `Our sales volume fell off, and
there is adequate reason to conclude that many practitioners actually believe that
the pharmacological effects of a drug are dependent upon the labeling that accom-
panies a drug. This is true not only of labeling that makes claims but also of
labeling that does not make claims. Many physicians obviously believe that a
drug that is identical with competitive drugs becomes inferior by virtue of the
fact that it makes fewer claims than the competitive products. This is one of the
more obvious illustrations of the irrationality of practitioners and the irration-
ality of their prescribing habits.
The rapid rate of obsolescence of drugs is dependent not on the wisdom im-
puted to the average practitioner by the AMA, but rather on his lack of wisdom.
"Since so much depends on novelty, drugs change like women's hem-lines and
rapid obsolescence is simply a sign of motion, not progress as the apologists would
have us believe . . . with a little luck, proper timing, and a good promotion pro-
gram any bag of asafoetida with a unique chemical side chain can be made to look
like a wonder drug. The illusion may not last, but it frequently lasts long enough.
By the time the doctor learns what the company knew at the beginning it has
two new products to take the place of: the old one." Not infrequently the doctor
never learns and the obsolete drugs remain on the market. Oral Mephenesin is
a good example.
The "Hussey-Stetler Test of Time" deserves the contempt that Morton Mintz
heaped on it. The uncontrolled observations of average practitioners constitute
testimonials and as such have zero validity in the scientific evaluation of a drug.
Whether we multiply zero by 1,000, 10,000, or 300,000 the answer is still zero.
The contention that the fate of a drug in the `market place is an accurate index
of its value as a drug simply is not true.
Actually my first exposure to the principle of the test of time and the market
PAGENO="0200"
4490 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
place came at least five years before the AMA gave its incredible testimony in
the "Kefauver hearings."
The position taken by the AMA was criticized by several medical experts in-
cluding Dr. Bean, Dr. Butler, and Dr. Goodman, among others. Perhaps the
clearest (and the most humorous) description of the AMA's position is that given
by a layman, Miss Barbara Yuncker, a reporter for the New York Post. I enclose
a photostat of her article entitled "AMA Delirium" and have marked it Exhibit
#5. I request that the entire article be made part of the record or that the portion
bracketed in pencil be quoted as part of my statement.
I believe it was in 1953 that Squibb arranged an exclusive licensing agreement
with a German firm that gave us rights to market some of their products. They
were asked to send me supporting data that would permit me to decide which
products I could approve. The supporting data they sent were sales volume figures
for various countries where the drugs were marketed and the advertising and
promotional material found most successful. When I asked for scientific data
consisting of laboratory studies and controlled clinical trials they behaved as if I
were mad. I still find myself chuckling when I am reminded that the Germans
did not use the terms advertising and promotion. All such material was labeled
"propaganda" and one needs only to give the word a Germanic inflection to under-
stand how it was used. The word is `obviously borrowed `from English and the
Germans either did not know or did not care about the connotation the word
has in English. They actually believed that the test of time and the marketplace
plus the suggestive effect of their "propaganda" was an adequate basis for my
evaluation of the drugs. Broken down to simple language this is exactly what
*the AMA suggests. In this particular area I, in contrast to the average practi-
*tioner, was an expert. `While it is shocking, it is probably true that the chances
that an average patient will get the right drug, in the right `amount, at the right
time is in the order of fifty percent. `Ineffective drugs, drugs that are not indi-
cated, drugs `that are effective in disorders different from the patient's illness,
unnecessary ingredients in combinations, and placebo doses are only some of the
pit-falls. The unluckiest patient of all is the one who needs no `drug since, if he
has a complaint it is almost impossible to get out of the average practitioner's
office without a prescription.
Question. Isn't it true that there have been dangerous drugs put on the mar-
ket? And many of them have been taken off the market? Do you know of any
case in the last ten years of the AMA urging that a drug be taken off the market
because of lack of safety or efficacy?
Answer. The list of drugs that are dangerous and have had to be taken off the
market is long. Some of them unfortunately are still on the market and should be
removed. Off hand I think of MER/29, Orabilex, and Marsalid in the first cate-
gory. Parmate (tranylcypromine) is, in my opinion, in the second category. We
may have reached the point where chioramphenicol is also in that category.
If in the last ten years the AMA has initiated action to take a drug off the
market because of lack of safety or efficacy that action has not come to my atten-
tion. It has played an important role in fighting quackery (e.g. Krebiozen), but
it seems to be determined to deny that quackery exists in the ethical drug
industry.
Question. (a) What Ia the role of testimonials in the advertising and promo-
tion of drugs with respect to efficacy and safety?
(b) How about reprints of articles in journals which subsist only on the pur-
chase of reprints by the industry?
(c) Do you know of cases when independent doctors signed their names to
articles and letters written by the drug company?
(d) How did you get testimonials (when you were a medical director)?
(e) Did you pay for them?
(f) Were they included under research or advertising?
(g) Have you had any ecper'ience of distinguished physicians and scientists
turning down a drug and then by sendin~g the drug to the "right type" of doctor,
"proof" of the drug's usefulness was finally secured?
(h) Is it a common practice for drug firms to purchase reports in favor of
drugs?
Answer. Before answering this question I wish to make it clear that I bear no
malice tow-ard Squibb. Actually, I regret the need to implicate Squibb at all, but
if my testimqny is to carry any weight I must choose between mentioning them
or remaining silent. Since I interviewed innumerable physicians w-ho had served
other companie~ as possible candidates for my staff, and had other dealings with
PAGENO="0201"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4491
other drug firms I came to the belief that Squibb was, if anything, more ethical
than most.
In the enclosed mimeographed copy of my 1960 statement I have bracketed
an excerpt beginning on page 7 and concluding on page 8. I request that this
excerpt be quoted in my statement as a partial answer to your questions regard-
ing testimonials.
There were proof mills that would deliver data at so much per head and in
entreme cases we used them. There were drugs that were declared useless after
clinical trial by experts that subsequently became marketable using the testi-
monials of less experienced physicians to prepare a New Drug Application. I have
adequate reason to believe that other firms were less fastidious than we were and
purchased favorable reports. I always felt that a bribe was degrading not only
to the one who accepted the bribe but also to the one who offered it. The testi-
mony regarding Henry Welch in the "Kefauver Hearings" is an extreme example
of the lengths to which `some companies went. My 1960 statement made an oblique
reference to the Welch affairs since it was made before the investigation exposed
his activities. In retrospect the language is quite clear.
As I recall, there were at least two journals that subsisted on purchases of
reprints used for advertising and promotion. They may still exist.
Drug studies are almost invariably included under research expense and I
pointed out the absurdity of the practice in my 1960 statement.
Question. Dr. Frederick Wolff estimated before this committee that out of $10
spent on drugs, $6 are spent unnecessarily. Dr. George Baehr of New York said
that the $6 figure was too low-that more than, 60% of the drugs prescribed are
not needed. Would you be willing to make an estimate?
Answer. I know of no way to make an accurate estimate of the percentage of
drugs that patients pay for unnecessarily. In so far as prescription drugs are
concerned I would keep my estimate consistent with the answer I have already
given, namely about 50%. I should not be surprised if an actual study yielded
a higher percentage of unnecessary drug expense. Naturally if we include over-
the-counter drugs the unnecessary medication expense would be much higher.
I should like to amplify the comment that the antibiotic-cold preparation
episode I described is being repeated by Upjohn and Squibb regarding Panalba
and Mysteclin-F. I gave a reasonably detailed account of the 1963 episode be-
cause I feared that the present confrontation would follow- the same pattern and
that the final outcome might be the same. Recently Morton Mintz reported that
Upjohn sent out 22,000 letters and that Squibb had put its detail staff to work on
the problem.
Just as I was intrigued by the report that Lederle sent out 7,500 letters in 1963,
I find 22,000 equally intriguing. Why 22,000 out of more than 300,000 physicians?
Obviously a process of selection was used in 1963 and a process of selection is
being used now.
We would have to be naive, indeed, if we concluded that these figures represent
a random sampling of physicians and, it would constitute an incredible indict-
ment of the medical profession as a whole if it were a random and representa-
tive sample. If I were a drug company executive faced with this problem and
had to decide how to get the most mileage out of the letters I would use a sim-
l)le logical process.
I have already said that a detailman is an expensive piece of property. Since
his time is limted, it cannot be squandered and so drug companies try to develop
a set of rules that will make it possible to use the detailmen's time most prof-
itably. One of the indices used is a rating scale of the physician's prescribing
habits. Squibb used a scale of four categories, and I doubt that other companies
use a substantially different method. At one end of the scale is the non-prescriber
or occasional prescriber. I would probably fall into this category since I write
between 100 and 150 prescriptions per year. The infrequent attempts of de-
tailmen to try to see me tends to confirm my position on the scale. At the other
end of the scale is the "heavy prescriber". For our purposes we can accept the
definition given in the AMA's Fond du Lac study that appeared in the record
of the "Kefauver Hearings". A heavy prescriber is a physician who writes
over 10,0 prescriptions per week! This is the prime target of the detailman and in
this group w-e probably have the least discriminating physicians in the country.
I find it difficult to believe that anyone can write that number of prescriptions
and still ta1~e time `to discriminate. In this group we also have the physicians
most likely to raise a howl of protest over the prospect of taking away one of
their toys. This is the group to whom I w-ould send the letter and I feel reasonably
certain that this was the group selected. The letters of protest come, not
PAGENO="0202"
4492 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
from a representative group, but from `the least discriminataing physicians and
from the physicans least qualified to give an intelligent scientific appraisal of
the problem.
Again, if I were a drug company executive, and I had an adequate detail staff,
I would choose Squibb's method over that of Upjohn. The detailman is best ac-
quainted with the prescribing habits and the different ways the physicians in his
territory think. He is best able to determine which is the most fertile ground in
which the seed of discontent and protest can be planted. As I said in 1963, "the
real need is for data not protest". I hope Commissioner Ley will pay some
attention to this.
One of the differences between the 1963 episode and the present confrontation
is the lack of publicity given to the present confrontation in the throw-away
news media. This is probably only a lull before the storm. I enclose with my
statement Exhibit #6 which is quite typical of letters of protest and is the first
pertinent article that has come to my attention. -I clipped it from the "Letters to
Tribune" section of the March 24, 1969 issue of Medical Tribune. As usual the
letter to the FDA does not contain a scrap of scientific data and is a tirade full
of illogical irrelevancies. In his letter Dr. Johnson says, "The FDA was created
as an agency to prevent the movement in channels of interstate commerce of
adulterated and/or misbran4ed food, drugs, and cosmetics" (my emphasis).
Apparently Dr. Johnson is not aware of the efficacy provisions of the 1902 leg-
islation. The FDA's proposal to take Panalba and Mysteclin-F off the market,
as I interpret the law, falls within the statutory authority given to the FDA.
The interference with Dr. Johnson's concept of the practice of medicine is an
unfortunate side effect of regulatory action.
This is only one of some 3,000 letters the FDA is reported to have received.
I expect we will see more of them. Actually I believe that the FDA could do
a valuable public service by publishing a large random sample of the letters it
has received. I feel that if the protesters are given enough rope they will hang
themselves.
Question. Isn't it strange that although the AMA's Council on Drugs has
always been against the use of combinations, the AMA still accepts advertising
for them!? How do you account for this?
Answer. The answer to the question of the discrepancies that exist between
the AMA's Council on Drugs, the AMA's advertising staff, and the AMA's edi-
torial policy can be `found in the record of the Kefauver Hearings. Following the
Ben Gaffin Survey, which is reported in the record, the AMA apparently came
to the realization that there is gold in drug advertising and that i.t was giving up
a significant source of income. The AMA Seal of Acceptance was dropped and as
I recall the Council on Drugs no longer had any voice in advertising policy.
The record of the Kefauver Hearings covers some 13,000 pages and while I
have a reasonable knowledge of all of it, I cannot keep all of it always at my
finger-dips. If my memory serves me, one of the members of the Council on Drugs
who disagreed with the official position of the AMA in the Kefauver Hearings
stated that the Council was not consulted even though the main issue was drugs.
You probably are acquainted with the disparity Dr. Charles May exposed
regarding the editorial and advertising policies of the AMA. Although the AMA
carried a scientific article indicating that Norlutin produced masculization in
female fetuses with sufficient frequency to consider its use unsafe, the advertising
pages blithely continued to carry advertisements for Norlutin which made no
mention of this danger. The schizophrenic policies of the AMA are strange and
are not amenable to the laws of logic and reasonS Miss Yuncker's term "delirium"
understates the diagnosis and prognosis. Delirium implies an acute transient dis-
order. The AMA's disease is chronic and probably incurable.
Question. What is the role of the Medical Director in allocating research funds?
Does he determine what field is to be looked into? What criteria are used? sales
needs or medical needs? Cam you tell vs something about the quantity and quality
of the research undertaken?
Answer. During the time I served as a member of the Fellowship and Grants
Committee, the committee was composed of 4 members; the Vice-President for
Research and Development, the Director of Laboratories, the Medical Director,
and the Vice-President in charge of Promotion (sic). As I recall the budget avail-
able for clinical research done by my staff was between $2~0,000 and $3~0,0O0.
While I had virtually complete command of the funds allocated for clinical
studies of drugs, I had little or no authority in the selection of the drugs to be
~tudied. If I recommended a clinical study it was almost invariably approved
unanimously.
I believe that the total Squibb Research and Development budget was in the
order of $0000,000 throughout my tenure. Most decisions regarding the overall
PAGENO="0203"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4493
Research budget were made by the Executive Management Committee of which
I was a member. I had one of six to eight votes. Many research programs were
instituted not because they promised a worthwhile drug, but because they prom-
ised profit. Molecular manipulation came into its own during my time in the
industry. In my opinion about 20 to 25% of the total Research and Development
budget was spent on worthwhile projects.
The actual dollar figures given by drug companies for "Research and Develop-
ment" are probably accurate, but the term Research and Development covers a
multitude of sins.
Question. What kind of doctors did you get to perform your clinical investiga-
tions? Did you have any experiences with so-called "proof" mills? (Can you
name any?)
Answer. As I indicated in my prepared statement the drug industry doctor must
rub shoulders not only with the giants of medicine, but also with its dregs. I
doubt that by experience was different from that of others who serve or served
the same function. Since the uninspired concoctions outnumber the worthwhile
drugs by at least 10 to 1 most of the contact is with a rather shabby lot. I would
prefer to name no names. I did work with proof mills, but again I would prefer
not to name them.
When one views the scene groin inside the drug industry he witnesses strange
occurrences. I remember clearly an occasion when we were making preliminary
studies of a drug that was being produced in very small quantities by a laboratory
operation. We sent a highly placed authority enough of the drug to treat two
patients and were somewhat puzzled by the fact that he sent us favorable data on
three patients. When, shortly thereafter, he :sent US laboratory data containing
an item dated one day after the posit mark on the letter, we black-listed him. To
put the incident in its proper context I must confess that black-listing him con-
sisted of taking his name out of the file of reliable investigators who could serve
as adequate guides to important decisions. His card was transferred to another
file that indicated that he could be used as a proof-mill when and if we should
have need for one. It was one of the most obvious illustrations of what the FDA
has called "graphite data" (i.e. data derived from a pencil rather than from
laboratory studies) that came to my attention. We did not report it to the FDA
and the secret was kept "within the family". To the best of my knowledge, it
still is.
Question. Precisely what functionu does a drug firm's medical director perform
in determini'ng what should or should not be said in advertising? (If the medical
director doesn't have this responsibility, then who does?)
Answer. About four years ago I prepared an essay entitled The Good Life of a
Drug Company Doctor. It was intended for publication in a lay magazine and
*in it I tried to give a distillate of my experience, in non-technical language,
giving an account of both the advantages and disadvantages of such a career.
In it I pointed out the doctor's function in the "review" and "approval" of ad-
vertising copy as one of the disadvantages.
"Drug companies boast that all advertising copy is reviewed or approved by
the medical staff. Most require approval since review is pointless if the doctor
has no voice in determining what is and what is not acceptable. This pos~es
problems for the doctor. In the first place all advertising copy makes a mountain
of paper, some of which is difficult to digest. Over-all the task is dull and boring.
In addition, the doctor who does not apprOve the majority of copy that reaches
his desk is not likely to keep his job. Yet over and again he is faced with ad-
vertising that is obviously misleading and which he cannot approve in good
conscience. The dilemma is best resolved by a bizarre process of reasoning.
"Drug advertisements are never simple expositary statements; they are works
of art. The artist who puts a house in his landscape does not have to draw in
every brick of the wall or every shingle on the roof. A line here and there, proper
shading and texture, and the mere suggestion of totality usually suffice. The eye
and the mind of the viewer fill in the gaps in a manner that is predictable and
therefore can be manipulated. A drug advertisement is a total composition sub-
ject to the same rules. It allows considerable latitude in creating ambiguities.
This, too, constitutes an obvious objection to a compendium since it would not
permit this latitude.
"The doctor who reviews advertising copy must learn to ask himself not
whether the advertisement is misleading, but rather whether it can pass. An
over-simplified illustration of what can and What cannot pass is furnished by a
well known optical illusion. Two lines, exactly equal in length, can bemade to
PAGENO="0204"
4494 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
appear unequal by placing arrow-heads that converge at the ends of one line
and diverge at the ends of the other line. The misleading nature of this device
and the predictable response are not important. If one line is labeled `effect
of Drug A' and the other `effect of Drug B' it can pass provided' that the adver-
tisement does not specifically state that the lines are unequal. Under these
conditions the advertisement can be defended against any attempt to prove it
false or misleading. Obviously that which cannot be proved false must be true
and the truth cannot be misleading. The doctor who wishes to keep his job in the
drug industry will find it mandatory to use this kind of reasoning.
"In desperate situations what can pass can be stretched to almost infinite
limits. The determining factors are the mental and verbal facility of the doctor
or lawyer who must defend it. One can always escape under a smoke-screen
of words and if worse comes to worse, he can admit to an `honest error' and
challenge anyone to prove that there was any intent to mislead. Typical examples
of these techniques are documented in the record of the Kefauver Hearings."
As Dr. Goddard said in his article in Esquire: "High-priced lawyers will spend
hours in conference with FDA officials, haggling over the wording of promo-
tional material, engaging in semantic arguments as to whether a certain section
of government regulations does or does not give FDA the right to limit the
company's `freedom' in a certain area". About three and one half years after I
deplored the type of advertising that leads to the chain reaction: fever equals
infection equals a prescription for an antibiotic, I clipped the advertisement I
have marked Exhibit #1 from the J.A.M.A. I believe it speaks for itself.
To demonstrate the kind of advertising that apparently meets the new FDA
requirements I have clipped tw-o advertisements from the March 19G9 issues of
Medical Tribune. These are marked Exhibits #2 and #3. The difference between
Exhibit #1 and #2 is only in the degree of sophistication used and that the
FDA requirement for full disclosure and "balance" have been met. Nevertheless
the basic technique of creating a short circuit between a sign, and symptom, a
complaint, a catch-all syndrome, or a catch-all diagnosis and the name of a
drug that can be written on a prescription pad is followed to the letter. Ex-
hibit #2 is in extremely poor taste not only because the woman depicted in the
photograph can be suffering from anything from simple exhaustion, to anemia,
through chronic schizophrenia, and on to any chronic debilitating disease, but also
because it is only slightly, if at all, removed from the crass television commer-
cials that say she has "tired blood" and needs Geritol, or those that say she has
the "blahs" and needs AlkaSeltzer. She needs careful diagnostic work-up and
not a prescription for Valium t.i.d. or q.i.d. The advertisement is a total compo-
sition deliberately intended to convey the impression that the "always weary"
(a diagnositic category unknown to me) can be treated by writing a prescrip-
tion for Valium.
Exhibit #3 is even worse and probably represents the best in advertising and
the very worst in drug advertising. Advertising becomes more effective as it
makes a stronger appeal to the irrational unconscious needs of the reader. To
imply that the extremely variable and complex psychodynamics that may lead to
symptom formation or psychopathology in this critical period of many men's
lives can conveniently be dropped into a wastebasket labeled "Torschlusspanik"
and treated with Librium approaches criminal neglect. I know of no scientific
evidence that supports this oversimplified diagnosis and recommendation for
therapy.
At the time when Dr. Fritz Freyhan (in the March issue of the American
Journal of Psychiatry) is deploring the deficiencies in the training that even
psychiatric residents get in psychopharmacology, and states that drug therapy
cannot be divorced from an understanding of the basic principles of psychiatry,
we have drug companies educating physicians about "Torschlusspanik." Signif-
icantly these advertisements appear in the Medical Tribune and not in the
Psychiatric News or the American Journal of Psychiatry of the same period.
It seems that they are directed at the more unwary average practitioner. It
gives him another name he can write on a prescription pad thereby increasing
his concept of his own omnipotence and fostering the delusion that every hu-
man problem can be solved with a prescription pad.
A question that is frequently asked, and it is invaribly asked in a tone that
conveys amazement and total disbelief is; "Do doctors actually prescribe on
the basis of advertising?" This device was used frequently in the Kefauver
Hearings and most witnesses avoided the question since an affirmative answer
left one open to the accusation that he was questioning the intelligence and
integrity of his colleagues.
PAGENO="0205"
COMPETITIVE PROBLEMS IN THII DRUG INDUSTRY 4495
I note that Dr. Annis, the AMA's official representative, conceded that the
chioramphenicol-bronchoscope advertisement was a "Madison Avenue Trick."
According to the New York Times Dr. Annis said you were calling doctors dolts
by suggesting that they would prescribe a drug on the basis of what they had
read in an advertisement. It is important to note that dolts is Dr. Annis' term
and not yours. The same peculiar reversal was true throughout the Kefauver
Hearings. The mere suggestion that doctors are: indeed influenced by advertising
became an accusation (that they were incompetent bunglers, dolts, or both.
I am not prepared to characterize the majority of my colleagues as dolts
because I do not believe it is true, nor could I support such an accusation. I
am willing, however, to state categorically that my colleagues are human and as
human (the majority of them are influenced by advertising when they write
a prescription. Most medical experts and advertising experts who have examined
the question agree that advertising takes the form that is most effective. Ulti-
mately advertising-and it does not matter whether it is drug advertising or
advertising for any other product-4akes a form that is determined both by
the rule of the survival of the fittest and a variation of Gresham's law. I have
never found evidence that drug companies waste money on profitless gestures.
To imply that the multi-millions spent on drug advertising is spent only because
an occasional doctor will be influenced into writing a prescription is not only
unrealistic; it is totally illogical.
The common practice of distributing desk accessories (calendars, letter open-
ers, appointment books, etc.) boldly imprinted with the name of one or more
drugs is not motivated by the company's wish to waste money on useless gim-
micks and gadgets. The mere fact that one of these accessories is on his desk
influences the prescription the doctor writes even if the stimulus is sub-liminal.
The notion that doctors study drug advertisements is absurd, and so I question
the effectiveness of the "full disclosure" regulation. One "reads" advertisements
by turning pages and Exhibits #1, #2, and #3 are examples of my total work
of art description. If exhibits #2 and #3 are examples of "balance" then I have
no notion of the definition of the word balance. The total effect of the imbalance
in these ads is to negate completely any effect that full disclosure might have.
Accepting the Task Force's penchant for understatement I still find it difficult
to understand why, on one hand, the Task Force feels that rational prescrib-
ing canno)t be achieved by rules and regulations, but seems to feel that good
drug advertising can be achieved by these methods. It says, "The frequency of
biased, inaccurate drug advertising has apparently been reduced since the en-
forcement of new advertising regulations by the FDA began in 1967."
I find the concept of unbiased advertising untenable since it is a contradic-
tion. The concept of degrees of bias in drug advertising holds, for me, the same
connotation as the standard joke about being "slightly pregnant." If Exhibits
#2 and #3 are examples of the improvement in drug advertising, may heaven
help us! The notion that "training and experience" imbue the physician with
God-like qualities that make him immune to the effects of advertising is non-
sense. Such a concept betrays a remarkable ignorance of the fact that (con-
trary to the average patient's belief) the: physician is neither omniscient nor
omnipotent. It also betrays an incredible ignorance of the psychology of adver-
ti~sing. Just as advertising affects the personal purchases a doctor makes, it
also influence the purchase orders he writes for his patients.
It was the AMA that said :that drug advertisements are "reminders."
Reminders of what?
Question. We have seen, with respect to chioramphenicol, important differences
in the advertising and promotion of identical products by the same company
in the domestic and foreign markets. In other words, the efficacy and safety of
the drug seems to vary with the person's nationality.
(a) Do yon know of any other products to which this applies?
(b) What do you think about it?
(c) When you were in the industry, Who reviewed overseas advertising?
(d) What criteria were used for domestic and overseas advertising?
Answer. About four years ago I attended a professional meeting in Mexico.
Because I was still entertaining the notion that I would write a book about the
drug industry I decided to gather some ammunition. Marsalid had been taken
off the U.S. m'arket some two years before because its danger outweighted its
utility. Accompanied by an interpreter I went to a drug store and after some
difficulty in giving Marsalid the proper Spanish inflection I was offered a
bottle of the drug over the counter (a common practice in Mexico). Until about
PAGENO="0206"
4496 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
1955 Squibb had only one Medical Director and his authority extended to the
overseas market as well as the domestic market. This resulted in a constant
source of friction between the Medical Division and the advertising and pro-
motion department of the Overseas Division. The Overseas Division held not
only the notion that the safety and efficacy of a drug varied with the patient's
nationality, but also that the advertising and promotion of drugs depended
on the nationality of the physician. Physicians in any of the countries south of
the border were considered less sophisticated than U.S. physicians and a "simpler"
approach had to be used. This simpler approach resulted in some rather remark-
able distortions. There were many products that were sold south of the
border that had become obsolete in the domestic market but I recall only one,
an Elixir of Glycerophosphates that had magical tonic qualities south of the
Rio Grande and was useless in the States. More frequently, the difference
was in the claims made for the same drug.
The real eruption occurred in about 1955 when, as I understood it, Parke-
Davis had offered Squibb a license to market chloramphenicol in some of `Squibb's
South American markets. (Parke-Davis apparently felt that Squibb had a
firmer position in these markets and that they could realize more profit from
royalties on Squibb's sales than on their own sales.) I was presented with the
prospect of marketing chloramphenicol under the Squibb label making all the
excessive claims for the drug and excluding a warning statement since it was
not required in the countries in which sale is proposed. I refusdd to approve
the tentative copy and made it clear that I would tender my resignation before
I would approve the copy. Apparently my colleagues thought I was sufficiently
valuable and instead of making a confrontation out of the issue they decided
to use an end play. The Overseas Division appointed its own Medical Director who
was in no way responsible to me. Curiously Squibb never did market chloram-
phenicol, at least not to my knowledge. I do not know the reasons why.
As I think back I recall one absurd proposal intended for the South American
markets. It was proposed that we add to our injectible penicillin a substance
that would produce the taste of garlic when it was absorbed. This, it was said,
would impress the patient and would lead him to believe that he had, indeed,
been given effective medication. The Medical Division did not approve it. Let me
add that to anyone who believes in placebo medication and the mumbo-jumbo
of the art of medicine the proposal has merit. It has no place in modern con-
cepts of a science of therapeutics.
To get the full flavor of the kind of jockeying that went on you must understand
that during my tenure as Medical Director I used a philosophy of giving in on
the smaller issues and reserving veto power on large issues backed up by a
letter of resignation I carried in my pocket for almost two years. I still have
it in my files and it shows obvious signs of wear.
Question. Why did you leave Squibb?
Answer. Since it is almost 12 years since I resigned I have had sufficient time
to reconsider the decision. I cannot count the number of times the question has
been asked nor the number of answers I have given. I believe that the best
answer can be found in my unfinished essay on The Good Life of a Drug Company
Doctor. Toward the end I said: "These are only some of the things a drug com-
pany doctor must learn if he is to be happy in the industry. After all, it is a
business, and there are many more things he must learn to rationalize. He
must learn the many ways to receive the FDA and, failing in this, how to seduce,
manipulate, or threaten the physician assigned to the New Drug Application into
approving it even if it is incomplete. He must learn that anything that helps
to sell a drug is valid even if it is supported by the crudest testimonial, while
anything that decreases sales must be suppressed, distorted and rejected because
it is not absolutely conclusive proof. He must learn to word a warning statement
so it will appear to be an inducement to use the drug rather than a warning
of the dangers inherent in its use. He must learn, when a drug has been found
too dangerous for use in this country, he can approve its use in other countries
where the laws are less stringent and people have less protection. He must learn,
when a drug has been found useless on one side of the Rio Grande, it can be sold
as a panacea on the other side and that he is expected to approve the claims made
for it. He will find himself squeezed between businessmen w-ho will sell anything
and justify it on the basis that doctors ask for it and doctors w-ho demand prod-
ucts they have been taught to want through the advertising and promotion schemes
contrived by businessmen. If he can absorb all this, and more, and still main-
tain any sensibilities he will learn the true meaning of loneliness and alienation."
During my tenure as Medical Director I learned the meaning of loneliness and
PAGENO="0207"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4497
alienation. I reached a point where I could no longer live with myself. I had com-
promised to the point where my back was against a wall and I had to choose
between resigning myself to total capitulation or resigning as Medical Director.
I chose the latter course.
Actually I have never understood, completely, the reasons that Squibb did not
fire me long before I resigned. While I had a magical touch with detailmen and
came to be known as "Mr. Raudixin" because I engineered most of the investi-
gation as well as the advertising, promotion and detailing of rauwolfla serpentina
(which for many years was Squibb's biggest money maker) I was nonetheless a
thorn in the side of most of my business colleagues. Part of my durability can be
attributed to the fact that Squibb went through three different sets of manage-
inent during the time I was with them. Nevertheless, at some time, the honeymoon
would have ended and I certainly would have been fired. My successor has long
since left Squibb and is in another drug company. For a time, I considered other
drug companies but I rapidly learned that no one else would have me and that,
even if they did, I would be jumping from the frying pan into the fire. One com-
pany made it clear that the president made all final decisions including medical
decisions. I could not envision myself as a yes man approving medical decisions
made by a layman.
Question. What do you recommend be done about irrational prescribing?
Answer. This question stimulates a rush of many diverse thoughts. First, since
I am neither a lawyer nor a legislator I cannot claim any competency in the draft-
ing of legislation. Since I served as one of the many consultants used by Kefauver
and his staff during the drafting of S. 15~2 I am influenced by the philosophy they
adopted.
Next, it has been many years since I became disenchanited (and from the tenor
of Dr. Goddard's Esquire article I assume that, one of the reasons he left his posi-
tion as Commissioner of the FDA, is that he, too, became disenchanted) with the
notion that the drug industry can be restrained by legislation. To quote Dr. God-
dard, "Operating on an undisclosed, multimillion dollar budget in dues paid by
the companies * the PMA is able to present a united front to protect the
Establishment's business interests against forays `by the public, Congress, or any
of the federal regulatory agencies `~ *. The Drug Establishment functions with
all the smoothness of an intricate Swiss watëh."
Although I have studied drug industry practices for 18 years and have become
inured to the point where nothing surprises me, I am still awed `by the amazing
versatility the drug industry demonstrates. It seems impossible to write legisla-
tion that does not contain loopholes through which the drug industry lawyers can
slip. Although the 1962 legislation has resulted in some improvement in some
areas, the brave new world it promised has not materalized. If the `slightest chink
is left in the armor, the drug industry will widen it until a barge can be passed
through it. The drug industry's manner of dealing with the full disclosure and
balance requirements in drug advertising is an excellent example.
It took 32 years to add to the primitive concepts of drug regulation, enacted
in 1906, the concept of safety. At the time the opponents of the legislation claimed
that a juridical definition of safety was impossible. The Elixir of Sulfanilimide
tragedy salvaged the safety requirement. It:took another 24 years to introduce the
concept of efficacy and again the opponents claimed that a juridical definition of
efficacy was an impossibility. Had it not been for the thalidomide scandal the
PMA and AMA lobbies might have won the point. A bill that had been butchered
to death was partially resurrected and won unanimous approval. I do not believe
that it `should be necessary to wait another quarter of a century, or for another
tragedy to add to the concepts of safety and efficacy, the concept of rationality.
We have reached a point where drugs, and especially combinations, must `be
proved not only safe and effective but, also, rational. The opponents will claim
that this too, is juridically impossible.
My disenchantment with the effectiveness of legislation alone has not led me to
the conclusions that attempts `to enact legislation with teeth is futile. On the con-
trary I believe that there is greater need for carefully considered and extremely
carefully worded restrictive legislation. Since this is not my province I can only
offer guide lines based on scientific concepts and my limited knowledge of `the
draftng of legislation. I have had enough experience (or perhaps insufficient
experience) to comment that if we are not prepared to engage in a Gargantuan
struggle. the proposal of effective legislation is a hollow gesture. We can and
should try.
PAGENO="0208"
4498 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
In the patent provisksis of the original 5. 1552, Kefauver proposed that a pat-
ent application for "any molecular modification of any patented or unpatented
drug or for any combination of two or more drugs" would not be granted a
patent unless "the Commissioner (of patents) 0 * * determined that the change
from the prior art made by the modification or combination would not have been
obvious to a person having ordinary skill in the `art, and (B) the Secretary (of
HEW) has determined that the therapeutic effect of `such a modification is sig-
nificantly greater than that of the drug so modified or that the therapeutic effect
of such drugs taken in combination is significantly greater than the therapeutic
effect of such drugs when. taken separately". [My emphasis.]
The legislation I have hi mind would simply substitute for patent application
a new drug application and in place of granting a patent; granting a license to
market. Like the efficacy provisions of the 1962 legislation I would make the
legislation retroactive. In determining the definition of significantly greater
therapeutic effect I would again `be guided by the definition of efficacy that ap-
pears in the Kefauver-Harris Amendments of the Drug Act, "substantial evidence
means evidence consisting of adequate and well-controlled investigations, incluci-
ing clinical investigations, by experts qualified by scientific training and experi-
ence to evaluate the effectiveness of the drug involved, on the basis of which it
could be fairly and responsibly concluded by such experts that the drug `will have
the effect it purports or is represented to have under the conditions of use pre-
scribed, recommended, or suggested in the labeling or proposed labeling thereof".
In brief, the legislation I have in mind has already been written. Making it
applicable to drug combinations requires changing a few words. I am not un-
realistic enough to believe that such legislation could get past the PMA and AMA
lobbies without a `Gargantuan struggle. Nonetheless it is required if we are going
to `put teeth into the drug act.
A valid objection that would be `raised is that prescriptions for two or more
drugs would cost more. This is a moot point and we must weigh it against the
fact that a combination such as `Achrocidin is prescribed for at least 10 patients
who do not need it, for one who may need it and all patients pay for the anti-
biiotic they may or may not need. The antibiotic constitutes the major part of the
cost of the combination. The argument that rational prescribing would cost more
than irrational prescribing is, in my opinion, inane and `I do not believe that it
could survive in any fair debate over the issue
Raising the question of the cost of drugs, I am reminded that I intended to
clarify the question of whether licensing. inspection, and strict quality control
would raise or lower the cost of drugs. The Task Force Report states: "Any
company, large or small, brand name or generic name `producer, can institute
and maintain an effective quality control program, and most companies have
`apparently done so. The cost of such a program ha's been estimated to be about
2.4% of sales for a large company, but may be somewhat more for a smaller
firm".
The term "somewhat more" is vague but I believe we can satisfy it if we mul-
tiply 2.4% by more than four times and `assume that strict quality control for
a generic drug would raise its price by 10%. The Committee is aware that the
spread between brand name and generic drugs can be in the order of ten times or
more, but these are extreme examples. Let us take an average example with
which I am well acquainted. Generic Sodium `Pentobarbital sells for `approxi-
mutely $4 per thousands. In the catalogues seI~t to me (a copy of which is en-
closed) by wholesale `houses the price has varied from $3.85 to $4.40. This is an
umbrella price at which I can buy the drug in quantities of 1,000. The pharmacist
probably pays less; he certainly does not pay mere. In the same catalogue the
price of Nembutal (Abbott's brand name for the same drug) remains fixed at
$17.00 per thousand. If we assume that the generic `bran'd is not qual'i'ty con-
trolled an'd that the institution of quality control would raise the price by 10%
we ~tlll have a figure of $4.40, or at most, $5.00 per thousand. Even an idiot can
conclude that in a competitive market the $17.00 brand would `have to lower its
price to meet the competition or be forced `off the market. It is conceivable that
it could be reserved for the carriage trade sin'ce there are those people who auto-
matically conclude that anything that cost.s more must be better. The physician
who writes prescriptions for patients cannot and should not indulge in `this
luxury.
While the relative wholesale price of brand name drugs as compared with
generic drugs is just as available to other physicians as it is to me, any attempt
to translate these prices into the price the patient pays for his prescription
PAGENO="0209"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4499
requires the application of an infinitely variable constan$t. I almost invariajdy
wr~te generically (I must confess thsit about 50% of the time I am able to con-
vince myself that writing Trifiuoperazine instead of Stellazine is a pedantic
exercise that accomplishes nothing since only the patented version of the drug
is available). Since I write relatively few prescriptions, I can take time in the 5~
minutes I see each patient to have him bring in the filled prescription and
determine whether it has been filled by a brand name or a generic drug when I
have prescribed generically and a generic brand is available, and inquire who
filled it, and how much it cost. The pharmacists cost for 30 capsules of Sodium
Pentobarbital is in the order of 12 cents whereas his cost for 30 capsules of
Nembutal is about 52 cents. The most frequent practice is to fill a generic pre-
scription for Sodium Pentobarbital with the brand name and to charge accord-
in~gly.. Some pharmacists who fill it with the generic brand charge $1.15 indicating
that they can meet the cost of overhead and make a profit by charging slightly
over $1.00 to fill the prescription. When the prescription is filled with the brand
name the price varies from $1.85 to $2.25 and he charges between $1.3t~ and $1.7~
to fill the same prescription for the same drug with the brand name version of
the drug.
To take another more extreme example, we can use imipramine (Tofranil).
This is a commonly prescribed antidepressant. which is patented and no generic
equivalent exists. I frequently write a prescription for 100 fifty milligram tablets.
The umbrella price for me is $105/thousand. The pharmacist probably pays $100/
1.~00O ($liO/100) or less. Yeit the patient's cost for a prescription for 100 tablets
ranges from $15 to $20. These are figures given to me by my patients. Curiously
the drug comes prepackaged in quantities of 100 tablets (which is part of the
eeason I prescribe that quantity). The pharmacist needs only to affix a pre-
scription label to the bottle; yet he charges from $5 to $10 for this service.
I was pleased when I read the testimony of Dr. William S. Apple, Executive
Director of the American Pharmaceutical Association, and found he among
others, questioned the equity of the present mark-up system and recommended a
fixed fee system. Until such a system becomes the standard practice of pharma-
cists, the physician is completely in the dark and the actual price the patient
will pay for `his prescription is unknown. I Strongly urge that a fixed fee system
replace the variable and unpredictable system Of a mark-up which is subject to
the whims of the individual pharmacists and is based on the concept of what the
traffic will bear. A fixed fee system would bring order and sense into the price
that patients pay for a prescription. It seems that the practices of pharmacists
are fully as subject to investigation as the practices of the drug industry and the
medical profession. All of the causes of the high price of prescription drugs
cannot be laid at the doorstep of the drug industry.
Question.. Do yon have any other suggestions besides legislation to solve the
problem of irrational prescribing?
Answer. Like Dr. Goddard I, too, am at my wits end in trying to come Up
with a reasonable solution to the problem of irrational prescribing. As I have
indicated., I believe new legislation regarding irrational combinations can serve
as the first step.
Beyond that I would tend to combine suggestions made by others at different
times. Dr. Goddard spoke of Therapeutic Committees but was extremely fastidi-
ous over the matter of interfering with the practice of medicine. I can understand
his reluctance since he was in a very sensitive position. The antagonism of the
average practitioner toward the FDA hardly needed fanning `by Dr.' Goddard.
I do not know if some hospitals call their Formulary Committees Therapeutic
Committees. Dr. Goddard's suggestion, as I understand it would model Thera-
peutic Committees along the lines of Tissue Committees which, I believe, are
essential if .a hospital is to get accreditation.
There was a time (and to a much lesser extent there still is) when some
surgeons made a practice of removing organs from the body, not because the
organ w-as diseased and required removal but, rather, because the surgeon needed
a fee. I do not remember the exact chronology but there was a time when un-
necessary operations became a cause celebre which received much publicity.
Whether the formation of Tissue Committees preceded or followed this I ani
not sure. In any case, the function of a Tissue Committee is to examine the
pathological reports on organs removed in surgery. The surgeon who makes
more .than his share of honest errors soon comes to the attention of the Tissue
Committee and he may be censured or even lose his hospital privileges if he
continues to indulge in the practice.
81-280 0-69--pt. 11-14
PAGENO="0210"
4500 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Again, as I understand Dr. Goddard's suggestions, Therapeutic Committees
would review the doctor's prescribing habits just as Tissue Committees review
his surgical habits. The task will be much more difficult than reviewing patho-
logical reports on organs but just as the uterus and the appendix are prime
targets for Tissue Committees certain prescribing habits would similarly become
prime targets of Therapeutic Committees.
There is another suggestion made first (I believe) by Dr. Barbara Moulton
who was formerly with the FDA. Dr. Moulton suggested a special category for
drugs that were hazardous and tended to be over-prescribed. She suggested that
a prescription for such a drug would not be permitted without the approval of a
consultant. I believe the idea has merit and should be given further consideration.
The FDA should be given authority to form a category of "Dangerous Drugs".
Supplies and prescriptions for these drugs would be handled in the manner that
now holds for narcotics. These would be target areas for Therapeutic Commit-
tees but could also be spot checked by FDA inspectors. Since it is impossible to
anticipate every contingency I would not insist on a consultation and allow
emergency prescription when approval by a consultant or by a Therapeutic
Committee would, because of time involved, not be in the best~interests of the
patient. The doctor should know, however, that when he prescribes such a drug
in an emergency and without approval, he may, if he cannot justify its emergency
use, expose himself to censure, loss of hospital privileges, or in cases of repeated
offenses, suspension of his license.
Offhand I think of only two drugs I would place in that category, chlorampheni-
col and .tranylcypromine (Parnate). There probably are others and there cer-
tainly will be others in the future. I am dubious about the possibility that the
medical profession would adopt this method of self regulation voluntarily and
it is possible that irrational prescribing will have to become a cause celebre and
that publicity might force its adoption. If Congress gave the FDA authority to
form a category of "Dangerous Drugs" the remaining steps would almost cer-
tainly have to follow.
In summary, irrational prescribing can be reduced by legislation requiring
that a drug combination be rational as well as safe and effective; by steps that
would lead to the formation of Therapeutic Committees, by the creation of a
class of "Dangerous Drugs", and by publicity, publicity, and more publicity.
Question. What are your feelings regarding a Compendium?
Answer. I know that the Committee and the FDA are enthusiastic about a
compendium. I wish I could share the enthusiasm. The tenor of my prepared
statement makes it clear that I would favor anything that leads to more scientific
practice of therapeutics and takes the black magic out of medical practice. A
compendium would be a step in the right direction. The task of preparing it
would be monumental, and it would have to be encyclopedic in scope.
My doubts are raised not by its scientific value but by the reception it would
get from the average practitioner who needs it most. Like the Medical Letter it
would be used by those who are already skeptical and have less need for it.
I enclose a clipping from Medical World News dated January 31, 199 and
which I have marked as Exhibit #7. When the President of the American
Academy of General Practice was asked about the compendium hi~ reply
(according to MWN) was he "* * * would not want a new drug compendium to
be put out by the government because it w-ould be `garbaged up' by all the
material the FDA requires". It is difficult to determine how one should respond
to this statement of principle. We can hope that it expresses the views of an
individual rather than the official views of the Academy over which he presides.
The hope is probably a vain one since a negative response to a compendium is
essentially the party line handed dow-n by the PMA and the AMA, and is
the response one should expect if he has any knowledge of the thinking of the
average practitioner.
Probably the greatest fault of the average practitioner is his inability to
understand and to admit the limits of his ow-n competence. The secure physician
who is confident about the knowledge he does have is much more ready to admit
that he does not know- everything, and that there are areas where he needs help.
Such physicians would probably welcome a compendium that would help them
to find their way through the drug jungle.
As the average practitioner becomes more hurried, more harried, and more
confused, the gap between w-hat he does know and what he does not know widens
and his inability to admit the existence of such a gap increases. An admission
that he does need a drug compendium becomes a tacit admission that up to this
time he has been groping in the dark.
PAGENO="0211"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4501
In addition, it is. important to be aware of the exalted position the physician
has in the lives of his patients. While many patients have become disenchanted
with the AMA, organized medicine, etc., most still cling to the impression that
their personal physicians are both omnipotent and omniscient. This is under-
standable since it insures that the doctor will be better able to help the patient
in the time of his need.
Unfortunately many physicians enter into the fantasy entertained by their
patients and fulfill their own infantile wishes to be omnipotent and omniscient.
The average physician is not about to step off the throne that makes him God.
A compendium will still be a legitimate educational tool and it will have to
compete with Madison Avenue tricks. It would be more likely to be successful
if we could fill it with free gifts, gimmicks, and gadgets, and in the long run,
we may have to learn Madison Avenue triëks which will give us some chance
of beating the drug industriy at its own game.
STATEMENT OF DR. DALE CONSOLE AT THE KEFAUVER HEARrNGS, 1960
I wish to introduce this statement by making my position clear. I am here
by invitation and assume that invitation was extended to rue because it was felt
that my experience as a former Medical Director in the pharmaceutical indus-
try would enable me to assist this committee in its work. I am not here as a
witness against the firm with which I was associated. Since I destroyed the
records in my private file when I resigned from. the industry, I can offer nothing
which can be construed as proof. I can offer a distillate of my experience and the
opinions I have formed as a result of that experience. These are opinions and
are intended to serve only as guides.
There is a simple maxim, I learned from detailmen, which is known to most
if not all in the pharmaceutical industry. "If you can't convince them, confuse
them." This is a valuable tool in the industry and I have seen it in operation
as a guide to detailing as well as to other forms of advertising and promotion of
drugs. It operates in what Dr. Lasagna has so aptly called the "numbers racket"
with its never-ending barrage of new products, confusing names, conflicting
dosage schedules and indications, claims and counter claims. I have seen it in
operation here in statements made by industry spokesmen.
Part of that confusion arises from. the unqualified use of the term "drugs". Not
all drugs are the same arid unless we understand this we cannot understand each
other. For our purposes I would classify drugs roughly in four categories:
1. Effective drugs prescribed only for patients who need them.
2. Effective drugs prescribed for patients who do not need them.
3. Drugs from which all patients derive either no benefit or no more benefit
than would be derived from an inexpensive substitute.
4. Drugs which have a greater potential for harm than for good.
These are all products of the pharmaceutical industry and it should be
clear that the cost of drugs cannot be measured by price alone. When a patient
pays for a drug which he does not need or for one from which he derives no
benefit the cost is excessive regardless of price. To assume that all drugs fall
into the first category and to concentrate on lowering the price of a broad
spectrum antibiotic pill from sixty cents to fifty or even to forty cents is to
miss the point. If we include everything from research cost to the salary of
the detailnian the total cost of creating, producing and selling drugs in the last
three categories exceeds that of effective drugs properly prescribed.
Unfortunately drugs are not always prescribed wisely, and while the physician
and patient, among others, must share the responsibility for this with the
pharmaceutical industry it is the industry which carefully nurtures and en-
courages the practice. The incidence of disease cannot be manipulated and so
increased sales volume must depend at least in part on the use of drugs unre-
lated to their utility or need, or in other words, improperly prescribed. Human
frailty can be manipulated and exploited and this is fertile ground for anyone
who wishes to increase profit. The enormous sales of so-called tranquilizers
are only a small part of the crop reaped from this ground. The pharmaceutical
industry is unique in that it can make exploitation appear a noble purpose.
It is the organized, carefully planned, and skillful execution of this exploitation
which constitutes one of the costs of drugs which must be measured not only
in dollars but in terms of the inroads the industry has made into the entire
structure of medicine and medical care. With the' enormous resources at its
PAGENO="0212"
4502 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
command it has usurped the place of the medical educator and has effectively
substituted propaganda for education. It is generally accepted that after the
average practitioner leaves medical school the drug industry represents the most
potent influence determining many aspects of how he practices.
In its desire to create a favorable image the industry confirms this when
it justifies the enormous expense of advertising and promotion by claiming
that it serves the purpose of postgraduate medical education. Now some of
the effects of propaganda and education are identical, but to conclude that
drug advertising and promotion in education is one of the many fallacies intro-
duced into these discussions.
Perhaps the committee will get a better understanding of this euphemism if
we examine some aspects of it. Since I wish to describe practices which apply
to many products and most if not all companies, I shall make my examples
general and slightly hypothetical. Since I cannot name them all it would be
unfair to brand the one named in the example. I can assure you, however, that
the disguise is so thin and the practices so w-idespread that there will be no
difficulty in finding adequate promotional material to document them.
First an extremely simple example. While in medical school the physician
is taught; when the patient has a fever, determine its cause, and then treat
it accordingly. The drug brochure teaches: when the patient has a fever think
of-and here the name of a company's antibiotic follows. (See Exhibit 1 re a
thermometer and erythromicin.) There are many variations on this theme and
often the symptom and name of the drug appear in bold colored type to elimi-
nate the effect of any intervening words. One need only change the symptom
[or sign] and the drug to multiply the examples. To help drive this valuable
lesson home in one promotional program a free clinical thermometer was sent
to physicians. The invitation is delightfully tempting. Too many physicians,
pressed for time, would like to believe that medicine can be practiced with a
thermometer and a bottle of pills. The authority of the w-ritten word driven
home by repetition is often enough to tip the balance. The exercise of judg-
ment takes far more time and uses less drug. If this is education then we
should also include lessons on how to smoke an opium pipe.
This approach is used only by the more naive since it does antagonize some
physicians. It hardly does justice to the ingenuity of the more experienced drug
house.
A better approach is one which is used frequently in the promotion of so-
called tranquilizers, but with minor variations spreads to many other drugs.
Either in the course of legitimate investigation or in the search for a new
promotion device it is found that a drug which is claimed to be effective in
relieving anxiety, produces, in rats, specific objectively mensurable changes in
a particular area of the brain. Now this is an interesting truly scientific finding
but in the present state of our knowledge its significance is unknown. To the
promotion people this lack of significance is unimportant since it is both in-
triguing and impressive. It is presented in an advertisement or a brochure com-
plete with accurate anatomical illustrations of the brain beautifully executed
in vivid colors. This is coupled with the claim that the drug relieves anxiety.
The usual response of the average practitioner who is not, and is not expected
to be, an expert in neuro-physiology is to associate the two and to assume that
they support each other. To the expert, however, any attempt to relate the
claim and the ftnding is absurd since there is no known relationship between
human anxiety and this finding. It is no more absurd to relate the claim to this
finding than to the finding that the drug, when given to cats, makes their tails
curl up and form a square knot. The latter is obvious, the former is not. Be-
cause it is not, the impressive but irrelevant fact is carefully presented in vivid
form. The clarifying facts are equally carefully omitted. The desired effect is
achieved by encouraging false associations and the frequency with which this
approach is used is adequate evidence of its success. This, too, is called education.
Another example makes good use of the confusion technique. When the novelty
of more potent vitamin pills began to wear thin, someone conceived of adding
minerals and trace elements. Among these is zinc and since I am not an expert
on zinc it may not be significant that I know of no evidence of zinc deficiency
in man. If, however, one searches the literature long enough he will find that
when chickens are deprived of zinc they cannot form a hard shell on the eggs
they lay. When this curious fact is added to others similarly curious and mixed
with some which are significant one ends up with an impressive array of "cvi-
dence" for the rationale of the product being advertised and apparent reasons
PAGENO="0213"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4503
why the doctor should prescribe this mixture of vital ingredients. Now let us
look at only one of the facts which are carefully omitted. No mention is made
of the fact that the zinc deficiency can only be produced by extremely careful
and expensive purification of the diet. Every trace of zinc must be eliminated
and if the chickens get only an occasional meal by random pecking in the barn-
yard they obtain enough zinc to destroy the effect. In short, the deficiency is a
laboratory artifact and has no counterpart outside the laboratory. Or stated
differently, if one is to draw logical conclusions the zinc makes the vitamin
pills invaluable for laboratory chickens provided, of course, that one is willing
to go to the expense of purifying their diet.
Here the physician is bludgeoned with a barrage of irrelevant facts he has
iieither the time, the inclination, nor frequently the expert knowledge to examine
critically. Multiply this by a dozen detailmen each selling a dozen products and
backed by a dozen wizards in the home office who hold a dozen conferences
trying to determine the best way to make nothing appear like a pot of gold.
This, too, is called post graduate medical education.
But let me turn to the practice which forms the backbone of all advertising
and promotion of drugs. This is the use of the testimonial as scientific evidence
of the efficacy of drugs.
It was a practice in the Middle Ages for some people to wear suspended from
the neck a cloth bag filled with asafoetida. The foul smell was believed to ward
off plague. Apparently someone had observed that some people who used this
medicinal fetish did not contract plague. Either it was not observed or not con-
sidered important that some who did not use it also did not contract plague.
Since it is considered unscientific the practice has long since been abandoned.
But it flourished a long time simply because it gave some people a greater sense
of security and made them feel better, at least until they contracted plague.
While the practice has been abandoned the principle which determined it re-
niains with us essentially unchanged. Since the beginning of time men have
stumbled over the meaning of the simple fact that when something is done for
or to a person, especially if that something has magical or emotional significance,
that person frequently feels better. At the *present time it is better recognized
but still poorly understood. It has been given the unfortunate title placebo effect.
Similarly since the dawn of time men have stumbled over the error of attribut-
ing to various agents the ability to ward off or to cure disease without taking
into account what happens to those who do not get he benefit of the agent. This
practice was not abandoned in the Middle Ages and one need only examine any
current medical journal to find examples of it masquerading as science.
Since the committee has had adequate exposure to the controlled study, the
double blind, and the placebo, I shall not take the time to expand on this. Let
me emphasize that no drug study is fool proof, but that the scientific validity
of any study can be immeasurably increased by proper experimental design. (A
drug trial which makes no allowance for placebo effect, and which fails to
make accurate comparison with an untreated group is suspect, and the vast
majority of reports on such studies are simply testimonials, not scientific evi-
dence. A testimonial written by a doctor, even when it is given the additional
cloak of respectability afforded by publication in a scientific journal, is still a
testimonial. It has no more scientific validity than the opinion expressed by the
woman who caught the largest tuna on record, that a certain brand of cigarettes
are kind to the throat even when it appears in color on the back cover of a maga-
zine. Yet the claims for the efficacy of an amazing number of modern drug
products are based exclusively on this type of evidence.
Testimonials are used not only to give apparent substance to the advertising
and promotion of relatively worthless products, but also to extend the indica-
tions of effective drugs beyond the range of their real utility. They appear either
as complete reprints or as priceless quotations in advertisements or brochures.
They convince too many physicians that they should prescribe these drugs.
Now the true nature of these testimonials is well known to the industry and its
own contempt for them is shown by its vernacular for sources from which they
are easily obtained. These are called "stables". Still it is an important function,
usually of the medical division, to send representatives with generous expense
accounts to all `parts of the country searching out these sources. The burlesque is
compounded `by calling the drug trials "scientific studies" and `by supporting them
with grants which are charged to research cost.]
PAGENO="0214"
4504 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
(These are some of the techniques used in this travesty of medical education.
While not all drug advertising and promotion is of this type, too much of it is.
Some is educational but there is ample evidence to indicate that the industry is
only too ready to depart from its self-professed role of the Knight in Shining
Armor totally `dedicated to Science and the Healing Arts. These practices and
others more vicious such as the subtle persuasion to use indiscriminately drugs
(such a chloramphenicol) which are dangerously *toxic and indicated only in
selected desperately sick patients suggest that dedication is primarily to profit,
even at the expense of good medical care.]
While the industry's practices and policies in advertising and promotion `are
necessarily exposed for examination, this is not true in most other areas. Here
the camouflage of euphemisms and self-proclaimed virtue is not so easy to pene-
trate. Research is a good example.
`While the industry spokesmen w-ould have us believe that all research is on
wonder drugs or better medicinal products this is no more true than the eu-
phemism of post-graduate medical education. They stress that there are many
failures for each successful drug. This is true since it is the very essence of re-
search. The problem arises out of the fact that they market so many of their
failures. Between these failures which are presented as new drugs and the use-
less modifications of old drugs (the addition of zinc to vitamins is a good exam-
ple) most of the research results in a treadmill which moves at a rapid pace but
goes nowhere. Since so much depends on novelty, drugs change like women's hem-
lines and rapid obsolescence is simply a sign of motion, not progress as the apolo-
gists would have us believe.
There is an interesting relationship between research and `advertising and pro-
motion. In many companies there is considerable `antagonism since the advertising
people feel, with justification, that they are expected to do what research cannot.
The perennial cry is "if research would give us a good drug we could turn out a
really good promotion program". Actually they `do remarkably well with what
they get. Lacking facts which are convincing *they invent fictions which are
confusing.
I am only slightly amused by the breast beating, statistics juggling, and com-
parisons with the research costs of other industries. Even the statistics are
suspect since I wonder how many cigarette companies charge the cost of paid
testimonials to research rather than advertising. I doubt that there are many
other industries in which research is so free of risks. Most must depend on
selling only their successes. If an automobile does not have a motor no amount
of advertising can make it appear to have one. On the other hand, with a little
luck, proper timing, and a good promotion program a bag of asafoetida with
a imique chemical side-chain can be made to' look like a wonder drug. The illusion
may not last, but it frequently lasts long enough. By the time the doctor learns
what the company knew at the beginning it has two new products to take the
place of the old one. This, too, is well recognized' and in some companies calls for
casuistry of a high order. In others it is simply called a "business decision".
While I doubt that it actually does, with this advantage, the pharmaceutical
industry can well afford to spend more on "research".
For those who are interested in comparisons I would suggest examination,
not of prices, but of the advertising and promotion of identical products by the
same company in its domestic and foreign markets. This will proba~bly reveal
the rather remarkable fact that the efficacy of some drugs varies according to
the position of the Rio Grande.
Now I am more aware than most of the worthwhile contributions of the
industry, especially since it was my privilege to play a small part in some of
them. I have no wish to minimize them, nor to deny the apologists their right
to exaggerate them. To imply, however, that these contributions make up *the
total, or even the major effort in research, or in other endeavors, is gross
distortion.
At this point let me remind you of an old French proverb which states "There
are more buyers than sellers". The victim of exploitation is a victim only
because in being exploited he serves some purpose of his own. A brief examina-
tion of the other side of the coin gives a better understanding of the nature and
scope of the problem.
The physician is human and his medical degree does not change this. Since
he likes to believe that he helps his patients the wish fulfilling phantasy of the
PAGENO="0215"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4505
pill affects him as well as his patient. One need only observe the reactions of
many physicians or being exposed to valid evidence de~unking a pill they have
been using with the delusion of confidence. These vary from mild denial and
disbelief to irate protest and one is reminded of the varied reactions of children
on being told that there is rio Santa Claus or of adults on learning that TV quizzes
are frauds.
Keeping up with the voluminous medical literature is an enormous task, and
the busy practitioner is forced to neglect it to an increasing degree as his
practice increases. Many feel guilty about this. They can read the condensed and
pre-digested pap of drug advertising and promotion in the same time it takes to
throw it in the waste basket or get a five minute education in the latest advances
in medicine from the detailman. It is not surprising that they enter into a folie a
deuce and foster the delusion of advertising and ~promotion as postgraduate
medical education.
The patients contribute their share. Too many are unable to accept that the
physician in spite of his limitations is still best able to determine the proper
treatment. The best doctor is not necessarily the one who gives a shot for every
complaint, and the more conservative physician who does not prescribe the latest
drug reported in Coronet may be far more competent than the one who does. But
fear of disease did not end with the plagues and patients still seek their bag
of asafoetida. It is this anxiety which leads some to avoid black cats, and most
to seek newer, stronger and more impressive magic from the doctor. Too many
physicians respond to this pressure not by dealing with it directly but by trying
to produce ~i. tangible symbol of the magic. To the pharmaceutical industry this
is an open invitation to exploit both the patient and the doctor, and so it claims
to have the magic all wrapped up in pretty packages and with a price tag which
makes the magic all the more impressive.
The simple fact that anxiety is virtually impossible to evaluate objectively
and that it responds to almost any bag of asafoetida accounts for the market in
the so-called tranquilizers. In modern times the anxiety is stirred up not by an
epidemic of plague but by advertising and promotion, and the meteoric rise of
one of these drugs was not deterred by the early appearance of two lengthy testi-
monials, back to back, in the Journal of the American Medical Association.
This leads one to wonder what motivates editors to accept these articles which
do not merit publication. Since they do not accept every paper which they receive
they cannot hide behind their usual protest against censorship. Perhaps they
are unaware of the damage which can be done by the cloak of respectability they
lend and how well they serve the interests of the pharmaceutical industry to
whom these atrocities are like manna from Heaven. I do not know if paid
advertising influences this.
I have a better notion why public platforms ostensibly dedicated to the dis-
semination of scientific information are turned over to drug companies to launch
programs of obviously biased drug promotion under the guise of scientific sym-
posia. Even the platform of a government agency has been perverted to intro-
duce, on the flimsiest evidence, a new drug which later came under the fire of
the Federal Trade Commission. In this case the abuse was so flagrant that it
aroused effective protest from a small group of indignant merical educators.
This latter phenomenon is so rare that one must wonder about the responsi-
bility of the leaders and educators in medicine. Most face the problem~ with
denial, complacency, or a sense of futility. Perhaps *this is understandable in
the light of the fact that the industry alone commands the resources necessary
to make propaganda effective. How can legitimate education compete with the
philosophy of the opium pipe and the carefully contrived distortions driven home
by the trip-hammer effect of weekly mailings, the regular visits of the detailman,
the two-page spreads, and the ads which ~ippear six times in the same journal,
not to mention the added inducement of the free cocktail party and the golf
outing complete with three golf balls stamped with the name of the doctor and
the company in contrasting colors.
While I feel that restrictive legislation is necessary to curb the excesses this is
a partial answer at best. In all areas relating to the healing arts vulnerability and
the facility and temptation to exploit it are so great that self-imposed restraint
has always been considered a necessary prerequisite. If the industry could prac-
tice this instead of proclaiming virtue we would have the ideal solution. I am un-
aware of any tendency in this direction and the internal problems in the industry
PAGENO="0216"
4506 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
are such that I see little hope for it. Rules of conduct are laid down but they are
intended only `as public relations gestures and their force is apparent rather than
real. The older, well established, conservative houses once did resist many of the
abuses. However, the entry of newer, solely profit-oriented competitors has
encouraged an ever-increasing substitution of the more profitable practice for the
ethical, and all firms have found themselves under increasing pressure to adopt
the practices in order to survive. One can no longer think of pharmaceutical
houses as black or white. All are shades of gray and while some are almost black
none to my knowledge is white. In this setting it is difficult to conceive of en-
forcement of rules of conduct from within since one hesitates to throw stones
when his own house is made of glass. Participation in intra-industry meetings
will convince anyone of this. It is my conviction that unless sweeping reforms are
instituted a truly ethical house cannot survive in the present competitive
wrangle. The pressure for those reforms will almost certainly have to come from
without.
An intelligent program of education should l~elp but it is well to remember
that it generally takes several years of intensive analytic treatment to signifi-
cantly alter one's belief in and need for magic. The abdication of leaders and
educators in medicine is disturbing. Post graduate medical education is their
province, not the pharmaceutical industry's. Unfortunately, I can contribute far
more to a definition of the problem than to its solution, and I am not unapprecia-
tive of the potential of the adversary they face. There have, however, been en-
couraging moves by courageous medical educators to ascertain and disseminate
unbiased information on drugs. Unfortunately, the principal audience for this
information consists of those who are already skeptical. There are far too many
physicians who must still be taught the difference between a free golf ball, the
magnetic personality of a detailman, and a scientific fact as criteria for the
evaluation of a drug. It is of interest that the industry generally shrugs off
these moves since experience has taught that they do not affect its best
customers.
Finally, I suggest with hesitation the consideration of a central agency em-
powered to approve or to disapprove the sale of drugs on the basis of objective
evidence of efficacy and to ban misleading and ambiguous advertising and pro-
motion. I recognize that it will be virtualiy impossible to set up proper criteria
but there are some areas where it is better to be guided by the dictates of good
common sense rather than tortured legal constructions. It is a curious fact that as
things stand now proof of the efficacy of a drug, to which some scientific rules
can be applied, is governed essentially by the rule that anything goes if it
cannot be shown that it probably will kill too many people who take it. On the
other hand, a drug claim which is obviously misleading must be proved so by a
process requiring the mental gymnastics of an insane philosopher. Surely a
panel of experts, who can distinguish between privilege and license, charged with
the responsibility for protecting medical care can make these decisions better
than someone who has something to sell, `and who simply makes ~"business
decisions".
I cannot believe that a distraught mother whose infant lies desperately ill
faces the same problem and emotions that she does in selecting a cereal from
the Super Market shelves. While the physician is interposed between the patient
and the drug industry there is a chain of responsibility and each member must
accept his share. Drugs are a part of medical care and medical care has unique
requirements. If the industry cannot exercise the necessary restraint it should
not be free to exp~loit the privileges. It is this the industry fears most since so
much of its sales volume is dependent on exploiting the privilege and since it
recognizes the danger of being hoist by its own petard. I know of nothing more
likely to generate the pressure necessary to persuade the industry to clean its
own house.
PAGENO="0217"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4507
EXHIBIT 1
[From the journal of the American Medical Association, Sept. 21, 1963]
0
sign symbol
of of
infection? therapy!
Ilosone is better absorbed-It provides high, long-lasting levels of antibacterial activity-two
to four times those of other erythromycin preparations-even on a full stomach. Ilosone is bac-
tericidal-It provides bactericidal action against streptococci, pneumococci, and some strains
of staphylococci. Ilosone activity is concentrated-It exerts its greatest activity against the
gram-positive organisms-the offending pathogens in most common bacterial infections of the
respiratory tract and soft tissues. Usual adult dosage: 250 mg. every six hours,
In summary: Ilosone is an antibiotic indicated in infections caused Gastrointestinal disturbances not enunciated with hepatic effects
by micro-organisms sensitive to erythromycin, especially strepto- are observed in a small proportion of individuals as a result of a
cocci, staphylococci, and pneumococci. Even though llosone is local stimulating action of the medication on the alimentary tract.
the most active oral form of erythromycin, the incidence of side- cutaneous manifestations of hypersensitivity may be observed
effects is very low. Infrequent cases of drug idiosyncrasy, mani- occasionally; maculopapular skin eruption or urticaria has been
tested by a form of intrahepatic cholestatic jaundice, have been noted in less than 0.5 percent of putients. In eotremely rare in-
reported. There have been no fatal or definite residual effects. stances, anaphylaxis has occurred with erythromycin therapy.
Ilosone® works to speed recovery
Erythromycin Estolate . I ~ I
Additional information available upon request. Eli Lilly and company, Indianapolis 6, Indiana, _____________
PAGENO="0218"
4508 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
EXHIBIT 2
[From the Medical Tribune, Mar. 6, 1969]
\TaliUnr(diazepam)
helps relieve psychic tension with
associated depressive symptoms
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dtptttdttttttt1,, p,tyttttty, 1tt6ttt ti tbild-
bttttitgtgt,ittighpttttttitlbtfittgtitptttibltthtttttd.
Pt,ttttt6tt,ts: if cttttbitttd ttith tthtt ptythttttpitt
ttttitttttltttttt,tttidttttttt,ftllyphitgytftgttttt
tt,pitytd. Uttti pt titttt ittditttttd ittpttittttttt,ttttiy
dtpttttttd, tt ttith itt,ttt dtptttttittt, tttith tttiddtti
dtttti,t. Obt,tttt tttttti pttt ttitttt it, itttptittd ,tt,ti
htpttit f,,,,ttit,,. Li,,,it dtttgttttttttilttt tlf,t6tt
itt ,ld,,lyttdd,biIi,tttttdttptttdtdtttttttittttttttttttdttittt.
Sidtt Effttttst D,tttitttttt, ttt,tftttit,t, dipltpitt, hyptttttt-
tit,t, tbtttgtt itt libidt, ttttttttt, fttigtt~, dtpttttittt, d0-
t,th,it, jttttdkt, ,ki,, tttth, tnttit, tttttttipttittt, h,td
i,ttttttitttttttt, thtttgttt it, tttiittttit,t, tht,,ttd tptttth,
t,tttttt, ttttigt, t,,itttty t,t,t,tittt, bltt,,td ,`itittt. Ptttt-
dtttitti t,tttit,tt t,tdt tt tt,ttt hypttttttitttd ttt, ttttti-
ttty, htllttit,ttitt,t, i,,t,tttttd tt,tttdt tptttitity, i,ttt,ttt,it,
ttgt, tltttp ditttt,btt,tttt, ttit,tttittit,t, htttt btttt tttptttttd;
thttld thttt, tttttt, ditttt,,6t,tttt d,ttg. ittitt,d tttptt-tt tf
,tttttttptttit, jtttttditt; ptti t,~tt,t~
tdit blttd ttuttt ttd 1it~ ~~Roche
ftt,,ttit,t tttttt tdtittbl, d,tt- L_J.~J.t~ttt,t,ttt
itgitt,g-t,tt,tthttttpy.
Psychic support for
the "always weary"
When psychic tension is the
reason for chronic fatigue, Va1ium~
(diazepam) can help provide the
right kind of support. In proper
maintenance dosage, Valium calms
the tense, tired patient while seldom
dulling the senses or interfering with
functioning. The patient thus may be
better able to cope with stress, and
retum to a more relaxed mental state
with energy enough to enjoy the day.
And whenever psychic tension.
is the reason for insomnia, Valium
n~ay be helpful. An h.s. dose added.
to t.i.d. regimen can provide just the
right amount of relaxation needed
for natural sleep.
PAGENO="0219"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4509
EXHIBIT 3
[From the Medical Tribune, Mar. 10, 1969]
a victim of
~o~j~1u$pani11 **,
PAGENO="0220"
4510 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
Librium
(chiordiazepoxide HCI)
5-mg, 10-mg, 25-mg capsules
Torschlusspanik. For one patient, it may begin on the day somebody else gets the
promotion he thought was "his." Suddenly, he realizes that he's gone as far as he's.going to
in the firm-and that he's reached an age where ob-switching is both difficult and risky. With
mounting panic, he takes stock of himself, How little, he reflects in dismay, he has actually
accomplished in his life so farl And now-time seems to be running out.,.
The intense anxiety typical of such a "middle-aged crisis" may not always be overtly
expressed. In many individuals, anxiety may manifest itself as a functional complaint or through
such anxiety-linked symptoms as insomnia and unexplained fatigue. Anxiety can also con-
tribute to some of the organic diseases commonly seen in middle-aged men-diseases such as
duodenal ulcer and hypertension.
But no matter what form the patient's anxiety may take, it can usually be relieved with
adjunctive Librium (chlordiazepoxide HCI). Librium has a prompt calming and antianxiety
effect that helps reduce emotional pressures and relieve psychogenic symptoms. Feeling
calmer and more in command of himself, the patient is often able to consider his problems
more objectively and to cope with thedi more capably.
For the anxious middle-aged patient, Librium:
quickly relieves anxiety-Librium, by its prompt and reliable antianxiety action,
usually helps relieve immediate emotional distress and encourages cooperation in required
diagnostic and therapeutic procedures.
helps improve response in psychophysiologic disorders-Librium, by reducing
excessive anxiety and related symptoms, often proves a useful adiunct to primary therapy
whenever anxiety contributes to or exacerbates gastrointestinal, cardiovascular, musculo-
skeletal, gynecologic or dermatologic disorders.
seldom impairs mental acuity on proper maintenance dosage-Librium, on
proper maintenance dosage, generally relieves excessive anxiety without impairment of mental
acuity; therefore, it is usually suitable for ambulatory patients.
helps break the anxiety-insomnia cycle-Librium, in an additional h.s. dose, can
help relieve the patient's anxiety-induced insomnia.
has wide margin of safety- Librium, after more than eight years' use, continues to
demonstrate an impressive record of safety. In general use, the most common side effects re-
ported have been drowsiness, ataxia and cpnfusion, particularly in the elderly and debilitated,
(See prescribing information,)
Before prescribing, please coosolt complete product in-
formation, a summary of which follows:
Indications, lodicated when anoiety, tension and appre-
hension are significant components of the clinical profile.
Contraindications: Patients with known hypersens:l:vity
to the drug.
Warnings: caution patients about possible combined
effects with alcohol and other CNS depressonts. An with
all ctts-acting drugs, caution patients against hazardous
occupations requirirg complete mental alertness leg.,
operating machinery, drivingl. Though physical and psy-
chological dependence hove rarely been reported on
recommended doses, use caution in administering tu
addiction-prone individuals or those who might increase
dosage; withdrawal symptoms lincludiog convulsionsl,
following discontinuation of the drug and similar to those
seen with barbiturates, have been reported. Use of any
drug in pregnancy, lactation, or in women of childbearing
age requires that its potential benefits be weighed
against its possible hazards.
Precautions: In the elderly and debilitated, and in chil-
dren over sin, limil to smallest effective dosage initially
10 mg or less per dayl to preclude ataxia or overseda-
ion, increasing gradually as needed and tolerated. Not
recommended in children under six Though generally
not recommended, if combination therapy with other
psychutropics seems indicated, carefully consider in-
dividual pharmacologic effects, particularly in use of
potentiatieg drugs such as MAO inhibitors and pheno-
thiazines. Observe usual precautions in presence of im-
paired renal or hepatic function. Paradoxical reactions
e.g., excitement, stimulation and acute ragel have been
reported in psychiatric patients and hyperactive aggres-
sive children. Employ usual precautions in treatment of
anxiety states with evidence of impending depression;
suicidal tendencies may be present and protective
measures necessary. Variable effects on blood coagula-
tion hove been reported very rarely in patients receiuieg
the drug and oral anticoagulants; causal relationship
has not been established clinically.
Adverse Reactions: Drowsiness, ataxia and confusion
may occur, especially in the elderly and debilitated.
These are reversible in must instances by proper dosage
odlustment, but ore also occasionally observed at the
lower dosage ranges. In a few instances syncope has
been reported. Also encountered are isolated instances
of skin eruptions, edema, minor menstrual irregularities,
nausea and constipation, extrapyromidal symptoms, in-
creased and decreased libido-all infrequent and gen-
erally controlled with dosage reduction; changes in EEG
patterns low-voltage fast activityl may appear during
and after treatment; blood dyscrosias lincluding agranu-
locylosisl, aundice and hepatic dysfunction have been
reported occasionally, making periodic blood counts and
liver function tests advisable during protracted therapy.
~ARoche
LABORATORIES
Nutley. NemJet'enOSttO
PAGENO="0221"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4511
PAGENO="0222"
4512 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
EXHIBIT 4
[From the New York Times, Feb. 2, 19691
STUDENTS SEND BACK DRUG MAKER'S GIFTS
One-third of the first-year medical students at Columbia University's College
of Physicians and Surgeons said yesterday that their "dissatisfaction with the
exploitative pricing and promotional practices of the American drug industry"
had compelled them to return gift stethoscopes to Eli Lilly & Co.
This follows a similar move announced Friday by 45 second-year students
at Harvard Medical School. The Harvard students, returned to the Lilly com-
pany a black bag and kit of diagnostic instruments-including a stethoscope.
Robert S. Pynoos, spokesman for the protesting Columbia students, said his
group had written a letter to Lilly in which they had expressed disapproval
with "the motivation behind these gifts."
The letter said in part: "Promotional programs of this sort are obviously
intended to initiate the establishment of close ties between physician and phar-
maceutical house, for mutual benefit."
"Such a relationship" the letter continued, "relegates the needs of the patient
to a role of secondary importance."
Henry F. DeBoest. vice president of corporate affairs for Lilly, said yester-
day that the medical instruments "have been offered with the prior approval
of the medical schools." The gifts were "a mark of appreciation for their [the
students] willingness to undertake the long, difficult road of an education as a
physician."
EXHIBIT 5
[From the New York Post, July 10, 1961]
AMA DELIRIUM
Speaking of the real and the unreal, we wish that we could get rid of the feeling
that the American Medical Association is out of this world.
We know better. But the miasma floating from the Senate Caucus Room as
the mighty medics battle the Kefauver drug bill did little to clear our heads.
Dr. Hugh H. Hussey, there to speak his piece as chairman of the AMA's Board
of Trustees, is dean of a medical college and by all accounts a literate, gracious
gentleman. Yet there he sat, through three long sessions, pursuing an argument
which went roughly like this:
It is better that a worthless drug be marketed than run the risk of a worth-
while drug being lost so therefore the Food and Drug Administration shouldn't
be given power to rule on drug usefulness because the AMA is doing it better in
a program that will be working by 1963 and is the only wholly objective agency
able to handle the chore since more than half its income comes from the drug
industry, the job being one that cannot and should not be done because no company
tries to market a worthless drug and FDA already has power to stop them and
is making adequate and effective judgments now inasmuch as FDA is incompetent
to evaluate at all because drug evaluation is a highly complex and technical
matter requiring skilled teams of test designers, pharmacologists, clinicians and
statisticians and therefore has to be left to the individual family doctor treating
you and me.
Is everythting clear?
EXHIBIT 6
[From the Medical Tribune, Mar. 24, 1969]
CHALLENGE TO FDA
Editor, Medical Tribune:
Below is a copy of a letter sent to Herbert L. Ley, Jr., M.D., Commissioner of
Food and Drugs, Washington, D.C.:
"1. The editorial from the MEDICAL TRIBUNE, January 30, 1969, is self-explana-
tory. Mycolog is produced by Squibb.
PAGENO="0223"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4513
[The editorial dealt with the inability of a dermatologist to obtain the separate
ingredients of Mycolog for patch testing because this would require the formal-
ities of a new-drug investigation.]
"2. Mysteclin F i's produced by Squibb `and the FDA has requested Mysteclin F
no longer be made available as a drug to be prescribed by physicians.
"3. I need a license to practice medicine. The practice of medicine is many
things to many people.
"4. Congress never authorized the FDA to assume control of the medical pro-
fession nor to direct physicians how to practice medicine.
"5. As a practicing physician, there are many patients in whom I believe Mys-
teclin F is the drug of choice. I assume the responsibility for each decision I make.
I do not believe the reason given for removing Mysteclin F from the market is a
legitimate one. . . `indiscriminate use of antifungal agents is to be avoided.'
"6. The FDA was created as an agency to prevent the movement in channels of
interstate commerce of adulterated and/or misbranded foods, drugs, and cos-
metics. Your agency has no authority in the areas concerned with the practice of
medicine. It only has supervisory control over t'he pharmaceutical industries, not
the medical profession.
"7. There is a big difference between pharmacology, pharmacological efficacy,
and the practice of medicine and the medical uses of drugs. Drugs are used in the
practice of medicine. Each patient is genetically different from every other pa-
tient. Physicians are taught to think and act using the tools of medicine. Pharma-
cology is but one subject of many taught to physicians. There has been no Con-
gressional authority granted to the FDA to make comments about the medical
profession and its actions. Your continued usurpation of granted powers must be
recognized and stopped. Your continued intimidation of physicians and drug
houses must be challenged and stopped. It must' be recognized that your primary
concern is not the patient but your own self-preservation according to the best
legal minds under the tutelage of Mr. Goodrich. Anonymity of responsibility is
your biggest and most powerful weapon since the Supreme Court refuses to pass
judgment on any specialized agency such as yours. Knowledge of this isolaton
and freedom from legal recourse has made yOur department wicked and un-
scrupulous. But who can do anything about it?
"8. Not only am I and my patients to be your victims but you and your family
too. By what authority do you presume to have "the right to tell physicians how
to use drugs medically and when-except by usurping powers not granted you ?"
JAMES H. JOHNSON, M.D.,
Chicago, Ill.
EXHIBIT 7
[From Medical World News, J'a4n. 31, 1969]
SOME PRACTICING PHYSICIANS REPLY
Senator Nelson's subcommittee hasn't invited,' and therefore hasn't heard,
testimony from the practicing doctors whose drug-prescribing competence has
been so severely questioned by pharmacologists and other academicians. To get
the other side, MWN has solicited reactions from the president of the American
Academy of General Practice, the chairman of the AMA Council on Drugs, and
an Oregon internist who says he has repeatedly, but vainly, tried to testify.
The AAGP president, Dr. Maynard I. Shapiro of Chicago, expects to appear be-
fore the subcommittee on a yet unspecified date. "I can't agree with the conten-
tion that doctors are unable to prescribe drugs accurately on the basis of the
information available to them," he says. "I'm confident I have knowledge of the
drugs I prescribe. If some question is not answered by the material at hand-
the package inserts, ads, and such-I make it my business to find out." He says
his additional sources are journal club discussions, curbstone consultations with
colleagues, and the companies. "If there `is something specific I want to know,
I go to the professional services department of a drug company."
Dr. Shapiro feels the doctor may already get too much information. "FDA
requires every adverse reaction to be listed-like, for example, one skin lesion
in 10,000 cases. This looks a little foolish to some of us in practice. Already
the circulars are getting so long and detailed and the type is so tiny I'm afraid
a lot of men are not reading them."
PAGENO="0224"
4514 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Dr. Shapiro would not want a new drug compendium to be put out by
the government because it would be "garbaged up" by all the material the
FDA requires. He expects the AMA's forthcoming compendium to `be more
useful. "It will not be a PDR. It will be a scientifically composed book with
therapeutic and symptom information the government does not provide." Dr.
Shapiro says it would be handy if the AMA volume would include cost in-
formation. "But I have solved that problem. I keep a copy of the pharmacists'
Red Book, which gives all costs, in my office desk drawer."
The chairman of the AMA council, Dr. John Adriani of New Orleans, also
believes that the information currently supplied doctors is sufficient for them
to prescribe drugs safely. "But the doctor needs more information than what
he gets from the package inserts, ads, and detail men," says Dr. Adriani. "The
information put out by drug companies is all right for safety. But the `why'
and `how' you've just got to go out and get yourself."
Considerably more angry about the hearings is Dr. Clinton S. McGill Jr. of
Portland, Oreg. "It seems very clear that Senator Nelson does not want anyone
to tell the story from the private practitioner's point of view, or even to
allow us to defend ourselves against the scurrilous attacks that are. now a
part of the public record," Dr. McGill told a recent meeting of the Pharmaceutical
Manufacturers Association. Dr. McGill accused the subcommittee of believing
that "we doctors are simple boobs, so snowed under by drug advertising that
we can't select the right therapeutic agents for our patients.
"Anyone who has even casual acquaintance with medical literature knows
that long before any important new product is ever marketed, there will be a
number of articles on it in our professional journals. Next, it will be described
in some detail in the JAMA section on new drugs. All of this, mind you, before
the product is distributed."
Dr. McGill defended the content of drug advertising and described detail men
as "trained professionals who provide us with valuable information." He does
not look with favor on government drug publications. "I am sure the physicians
of this country have a great ideal more confidence in our own council on drugs
than we would ever have, in a publication of the Department of Health, Educa-
tion, and Welfare-at least as long as the present atmosphere exists."
Senator NELSON. Beginning today, and continuing throughout the
month of March, the committee hearings will be devoted exclusively
to major medical associations and a medical consultant who was for-
merly a professor of pharmacology.
Our witnesses today are Dr. Blaise Alfano and Dr. John C. Krantz,
Jr., of the Huntingdon Research Center, Inc. of Baltimore~ Md.
He is professor emeritus of `the Department of Pharmacology of
the University of Maryland.
Our first witness this morning is Dr. Bli~ise Alfano, executive secre-
tary of the American Society of Abdominal Surgeons.
You have submitted a biographical sketch which will be printed in
the record prior to your statement, Doctor.
(The biographical sketch of Dr. Alfano follows:)
BIoLoGICAL SKETCH OF Br~&IsE F. ALFANO, M.D.
Date of Birth: September 14, 1923-Boston, Massachusetts.
Boston Latin School: 1942
Harvard University, A.B., 1946:
Accelerated course- (1942-1944 and summer of 1946) Degree awarded in
1952.
Secretary-Treasurer, Harvard Student Council.
Secretary to Philip Brooks House.
Elected to 1946 Class Committee 1946 to date.
1946 Class Treasurer 1946 to 1956.
U.S. Navy active duty 1943-1946: Ensign, USNR, Aleutian Islands
Tufts Medical School: M.D. 1950.
Internship: Cambridge City Hospital-July 1, 1950 to June 30, 1951.
Surgical Residency: Cambridge City Hospital, July 1, 1951 to June 30, 1954.
Chief Surgical Resident: July 1, 1953 to June 30, 1954.
Instructor in Surgery: Tufts Medical School
PAGENO="0225"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4515
Instructor Anatomy: Harvard Medical School, 1952.
Advanced Surgery given at Massachusetts General Hospital by Harvard Medical
School-1954.
Hospitals:
Senior Surgical Privileges at:
Cambridge City Hospital, 1954 to 1964
Melrose-Wakefield Hospital-1954 to date
New England Sanitarium and Hospital 1954 to date
Winchester Hospital-1954 to date
Surgical teaching staff at Cambridge City Hospital-1954 to 1964
Societies and Associations:
American Medical Association.
Massachusetts Medical Society.
Middlesex East District Medical Society.
Secretary, American Board of Abdominal Surgery.
Executive Secretary, American Society of Abdominal Surgeons.
Fellow, International College of Applied Nutrition.
Founder-Diplomate, International Board of Applied Nutrition.
American College of Gastroenterology.
American Association for the Advancement of Science.
Association of Medical and Allied Publications.
Institute for Advancement of Medical Communication.
American Medical Writers' Association.
Medical Society Executives' Association.
Phi Beta Pi (Honorary) Medical Fraternity.
Board of Governors, International College of Applied Nutrition.
Associate Editor, Journal of Applied Nutrition.
Director of Publications, Journal of Abdominal Surgery.
Executive Secretary, Clinical Congress of Abdominal Surgeons.
Fellow, American Geriatrics Society.
Leaders in American Science.
Who's Who in the East.
Secretary, Section on General Surgery, A.M.A. 1962-1965.
Advisory Board-Middlesix County National Bank 1966.
Official Observer, Apollo 8 Launch, December 21, 1968.
Elected Chairman Advisory Board-Middlesex County National Bank-
January 1969.
Senator NELSON. Dr. Alfano, we are pleased to have you here today.
You may proceed to present your statement in any way you desire.
If you wish to depart from the text at `any~ time to elaborate on any
aspect of your statement, feel free to do so. Your full statement will
be printed in the record, as well as any other extemporaneous com-
ments you wish to make. I assume if we have some questions from time
to time, you will not mind being interrupted.
STATEMENT OP DR. BLAISE P. ALPANO, EXECUTIVE SECRETARY
OP THE AMERICAN SOCIETY OP ABDOMINAL SURGEONS, MEL-
ROSE, MASS.
Dr. ALFANO. Fine.
I wish to thank Senator Nelson and the members of the Monopoly
Subcommittee for this opportunity to speak before the committee.
American medicine is known and acclaimed throughout the world
as providing the highest level of medical care. This is so despite the
statements of the detractors who quote the statistics of infant mor-
tality. This is an area that needs improvement, to be sure, but the raw
statistics do not necessarily indicate a weak spot in medical care; close
evaluation most likely will reveal that other factors play a significant
role.
Senator NELSON. Let me interrupt, Doctor, On the point of infant
81-280-69-pt. 11-15
PAGENO="0226"
4516 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
care. You note in those statistics and some reports indicate that the
incidence is very high in those areas where the poorest people live.
Is it not likely that the problem here is that there are poor people who
cannot pay to get medical care?
Dr. ALFANO. That is one of the problems, a socioeconomic problem.
There is also an education factor involved. There are some people m
the country who are fearful of hospitals. That still exists. Their care
is rendered outside of hospitals.
Senator NELSON. More so than people from other countries, who
have a lower incidence of infant mortality? Why in this country?
Dr. ALFANO. I believe you will find in those countries with a lower
incidence of infant mortality, they have a higher mcidence of hospital
deliveries and their prenatal care is, say, regulated. Most of these coun-
tries, I believe Sweden and Norway, have a low incidence.
Senator NELSON. `It does say something about supplying medical
care in this country, then? It is a significant factor?
Dr. ALFANO. It is not just medical care. I believe there are other
factors besides medical care. If the doctors saw all these individuals,
prenatally and through the delivery, we would find our incidence of
infant mortality would be down. It would be the same or better than
other countries. The fact is that the physicians do not have an oppor-
tunity to care for these people. Therefore, you have a higher rate of
infant mortality.
Senator NELSON. Nonetheless, it does say something about the kind
of care and delivery provided in this country-the richest country in
the world. It indicates~ does it not, that this problem deserves the at-
tention of the public?
Dr. ALFANO. Yes. It certainly needs correction and attention, I
would say, yes.
I am not saying that we cannot improve our system of medical care.
I believe we ca.n. Changes and improvements are occurring constantly
as they have over the years.
I do submit that legislation that disrupts the physician-patient rela-
tionship, which is the basis of medical care, can cause deterioration of
the system it purports to help. I refer to the proposal that ~vhen a
physician prescribes a brand name drug the pharmacist may substitute
a generic drug as he see fit, and the only determining factor is the price
of the drug.
Senator NELSON. May I interrupt for a moment, Doctor?
Dr. ALFANO. Yes.
Senator NELSON. Whose proposal it that? I am not aware of such
a proposal.
Dr. ALFANO. There was a proposal-I believe Senator Long had
a. proposal. We have a iroposa.l now in Massachusetts that states a
pharmacist can substitute a generic drug for a trade name drug.
Senator NELSON. Committee counsel advises me that Senator Long's
proposal only refers to the question of reimbursement; that is, that
reimbursement under the medical programs would be solely at the
price of the generic drug. It does not require that the doctor prescribe
it, but the Government will not pay more than the price of the equiva-
lent generic.
Dr. ALFANO. I am sorry, I do not have that bill with me here. But
as I recall, they do have a factor where there could be discussion-
PAGENO="0227"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4517
not only, as you say, the price factor. But at any rate, we do have in
Massachusetts a bill now pending that generic drugs be substituted for
brand name drugs. This stems, as I believe, anyway, from legislation
that has been submitted or talked about here in Washington.
Senator NELSON. I will have to take another look at that proposal
of Senator Long's. I am not aware that there is any proposal pending
that-
Dr. ALFANO. There was. I do not believe it is pending now. It was;
in the previous Congress, I believe. I have not seen it for this Congress~
Senator NELSON. As I say, I do not remember specifically what that
bill proposed. I do not believe there is any bill that just gives a blanket
authorization to a pharmacist to substitute a generic for any brand
name. I might be wrong, but I do not recall that there is such a
proposal.
There have been proposals that would require, as I said, reimburse-
ment only at the generic cost. That, ultimately, I suspect, will become
the law in public-funded programs, because of these dramatic cases
of price variances of equivalent drugs. You may be familiar with the
Medical Letter case on prednisone. The price varied from 59 cents for
100 tablets to $17.90 for 100 tablets of the brand name Meticorten. This
is just to the druggist. The Medical Letter flatly asserted that in their
chemical tests and in their consultations with clinics, they were all of
therapeutic equivalence, and they listed 22 of them. I suspect the public
is not going to use public funds very long to pay $17.90 a 100 plus the
markup, when the drug is available at 59 cents. Would you think they
would?
Dr. ALFANO. No; I agree with you. But I do not believe that because
you have a case or several cases, that should change the system. As I
understand it-excuse me, Senator-the medical profession has a way
of correcting this. You are speaking of Schering's product, I believe.
Senator NELSON. Yes, sir.
* Dr. ALFANO. They had 100 percent of the market. Now they have,
what is it, 5 percent, or less than 5 percent of the market.
Senator NELSON. They get a large percentage of the retail market,
but they do not get very much of the general hospital market, the
city of New York, institutional markets, Defense Supply or Vet-
erans' Administration, because they get outbid all the time. The inter-
esting thing about it, and this is true of all brand names, is that no one
who testifies on this question ever explains the reasons behind this.
After our hearings, Schering reduced the price on its Meticorten-
prednisone-from $17.90 for 100 to $10.50. Parke, Davis reduced their
price of Paracort-prednisone_later from $17.88 a 100 to $3.25 a 100.
It is perfectly clear to anybody that Schering is gouging the public,
but they can do it because doctors write the name, "Meticorten." If they
write Meticorten, that is all the pharmacists can prescribe.
At that time, they were selling to pharmacists for $179 a thousand.
That was the equivalent of their $17.90 a 100. However, to New York
City, they offered it at $12 a 1,000. They wanted the New York City
bid and knew they would be in competition. That is $1.20 a 100 versus
the $17.90 they were charging the pharmacist on the same day, across
the street from city hall. New York City awarded the contract to
Lannett, who bid $4.58 a 1,000, which is 45 cents a 100.
PAGENO="0228"
4518 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Now, is there any reason in the world why any public program or
any program ought to be paying $17.90 a 100 when it is available at
45 cents?
~\Te have the same company, Schering, selling for $17.90 to pharma-
cists and bidding for the U.S. Defense Supply Agency at 82 cents a
100. Do you have any defense for that?
Dr. ALFANO. No; I certainly cannot defend that type of action,
Senator. What I was stating was, I think the physicians learn of this
over a period of time. That is why Schering's portion of the market
has dropped down considerably.
Senator NELSON. It has been dropping as a consequence of some
publicity here in Washington, I think.
But it is not only Schering. Let me give you Ciba's reserpine. Ciba
sells that to the pharmacists for $39.50 a 1,000. However, they bid to
the Defense Supply Agency not $39.50, but $3.95 a 100. The winner
if you can imagine this incredible figure, the bid 89 cents. Now, ~9 cents
for a 1,000 versus $39.50. The only reason they can charge $39.50 in
the retail marketplace is that they have used your publication and
other medical publications to sell the brand name. So the doctor writes
the brand name. The poor patient is getting gouged day in and day
out.
Defense Supply is buying both brand names and generics. Defense
Supply is making a good choice of a drug. I do not think there is any
question about that. Why should the public pay that price?
This is what comes about, I think, from the continuous promotion
of brand names, which you advocate in your statement, and which
other doctors testifying before the committee have also. They have
taken the drug company line on brand name and physicians become
convinced that you have to use a brand name, then they become con-
vinced that it has to be a certain brand name, like Meticorten. Thus,
the public is constantly gouged.
Quite frankly, I think the drug industry has brainwashed the medi-
cal profession.
Dr. ALFANO. I am sorry you do not have confidence in the members
of the medical profession, but it is not the fact of brainwashing the
physicians. Physicians have faith and confidence in a particular phar-
maceutical firm. They have had experience over a period of time with
thousands of doses of medication. They are not willing to take a chance
with an unknown preparation. A manufacturer not known to
you-how can you feel secure in prescribing this for your patient?
Senator NELSON. This is the problem that troubles this committee.
Every witness before the committee speaks with great admiration of
the quality and integrity and scientific distinction of the Medical
Letter, even the Pharmaceutical Manufacturers Association. Each wit-
ness, when asked, answered, we have a high regard for it.
Now, the Medical Letter here lists 22 brands of prednisone, Meti-
corten at $17.90, American Pharmaceutical at $1.80, Bryant Pharma-
cal, $1.65, Darby, 61 cents, Wolins Pharmaceutical, 59 cents. In their
statement to the physicians over the country, they say the great price
spread among the tablets purchased from different pharmaceutical
companies suggest the desirability of prescribing by generic name and
specifying at least for patients of little means that the perscription be
filled with low priced prednisone tablets. Why would not the medical
PAGENO="0229"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4519
profession rely upon the Medical Letter more than the claims of the
advertisers in promotional shares? Which one would you put your
confidence in-this Medical Letter or the particular name of the brand
name company?
Dr. ALPANO. I do not think it is a simple answer either way. Per-
sonally, I would not use either one myself. You have to make your own
judgments.
I know one or two of those names. I know one of them is a distribu-
tor, not a manufacturer. Therefore, they have gotten their particular
drug that they are selling, I believe you said at 61 cents. They get it
from somewhere else, somewhere along the line. But where is it from?
I am afraid to give it to my patient until I know about it.
I will say, yes; I can try a particular known drug, run an experi-
ment with my patients, carefully watch them, see them more fre-
quently. It requires more recordkeepin'g. Then I can determine for
myself as far as the efficacy or the therapeutic equivalent of that drug
that I experiment with or am trying versus the one I have been using
regularly. If I find it works out, I am satisfied with the results, cost-
wise, it is better, naturally, I would use the one that costs less and yet
produces the same effect. I think that is logical to do.
But not just because it has a price of 61 cents or $1 versus $17. I am
not going to use it for price consideration primarily.
Senator NELSON. On what basis would an individual doctor, for
example, decide to continue to prescribe Meticorten at $17.90 per 100
when Merck sells at $2.20? That is a distinguished brand name
company.
Dr. ALFANO. I do not have the figures with me, but I will be glad to
send them. But I believe Schering, which `had 100 percent of the mar-
ket, is down to 5 percent or less, which is an indication that the medi-
cal profession recognizes this factor of cost and has chosen other drugs
than Schering's product.
Senator NELSON. I think we had testimony on Meticorten a year
ago as to its share of the market. I do not have it before me. You
might be correct that that is the share of the world market. They have
a much higher share than that of the retail market.
When they have to bid in competition, they get beaten quite regu-
larly, unless they lower the bids. It is the brand name retail market-
place, where brand name predominates, which is the important ques-
tion. I will check and see what share they have now. But, of course,
they have had a lot of publicity in the past year on their price and they
did redu'ce that price to $10.50.
Dr. ALFANO. I believe the medical profession then is cognizant of
this price differential and does not blindly follow, say, Meticorten,
which has been advertised or so-called brainwashed. They do not use it
indiscriminately or continually. They change products or companies
who can provide a quality product at a lower price. I believe all physi-
cians throughout the country would do that.
Senator NELSON. Well, they certainly dominated the retail market-
place for a long, long time when other equivalents were available.
That is the point.
On this whole field of pricing structure, which is what we are dis-
cussing, let me give you another example. The defense continually
made before this committe about the prices they charge-the witnesses
PAGENO="0230"
4520 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
testify that they do a lot of research and use new drugs and so they
are entitled to certain rewards and, of course, they get that in a 17-year
patent. They are not entitled to anything after 17 years except fair
and honest competition. But they do not get fair and honest competi-
tion in the marketplace even after the 17 years. The doctors are in the
habit, after 17 years, of writing the brand name and they continue
to do so.
I have had doctors say to me, when I explained the price differential,
well, I have been writing Meticorten for x number of years and I
suppose I will write it the rest of my life. That is the attitude of
physicians, even though their patients could get it at one-thirtieth the
price.
Now, I would like to ask you a question on this point. How would
you explain that Schering, who sells for $179 a 1,000 to the pharmacist
here, sells it in Berne, Switzerland, for $43? In other words, $17.90 a
100 here versus $4.37 in Berne, Switzerland, after assuming the cost
of packaging and shipping it overseas?
Dr. Ai~r~o. Senator, first, I would like to say I am certainly not
trying to defend the drug company, trying to justify some extremes
in cost of drugs. I cannot explain various extremes in costs of drugs.
1 am not in the drug industry. I do not know these factors.
Senator NELSON. Well, I do not want to be unfair to you. I ask
because the pattern of your testimony, like the pattern of a number of
other very distinguished physicians who defended the pharmaceutical
manufacturers-take their line on brand name, on the cost of the
services they get, on every single point the pharmaceutical manufac-
turers make. Therefore, I think it is fair to raise the issue of the wide
price differences with those who defend the arguments of the manufac-
turers. That is what a good part of this hearing is about, the fact that
the doctors say we cannot rely on anything but brand names.
Strangely, the best hospitals in America, the Defense Supply Agency,
and the Veterans' Administration, all buy large amounts of generics.
They have their own pharmacologists, they take competitive bids.
They find no difierences in those drugs versus the brand name drugs.
Dr. ALFANO. I know, Senator, but if I had the facilities, if I had
the setup that the Defense Department has for investigating drug
firms and testing out the drugs, I could purchase a large number of
drugs and use them because I have tested them. As I understand, they
reject what is it, 40 to 50 percent of the drugs submitted to them. But
they, I think, are the only Facility capable of testing as they do.
There was another point I wanted to state. The patients in this
country are not that naive. I have had patients come back and com-
plain of the cost of a particular drug. They make known to the doctor
the cost. The doctor, in turn, will make it his business to find out what
the costs of these particular drugs is when patients come in. It is not
that this is unknown to the doctor. He does not know the cost-I
believe that is the history of Meticorten. He had no choice, he had to
use the higher priced drug, but as qualified drugs, so to speak, came
on the market, the doctors used them. That is why Schering's share
of the market has dropped. Otherwise, it would be as high as it was
in the beginning. If, as you say, the doctors are brainwashed, are
creatures of habit where they are not thinking concerning the cost of
drugs.
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COMPETITIVE PROBLEMS IN', THE DRUG INDUSTRY 4521
Senator NELSON. With respect to the use of the phrase "brain-
washed"-I only use it on the question of price and brand name. I am
not using it any other way. In other words, all I am saying is the
promotion is so effective that doctors become convinced that they
should prescribe this particular brand, name, and that holds the price
of that brand up. As an example you can take almost any drug you
want in which there has `been a patent, it has been on the market a
long time, `the patent runs out. That brand name still holds a very
strong place in the marketplace at a very high price compared to
other available drugs.
For example, we can take dextroamphetamine. Smith Kline and
French put out Dexedrine. They charge the pharmacist $22.60 for a
1,000 five-milligram tablets. They offer it to the Defense Supply
Agency for $1. So. while they are convinced that because of their
promotion, their brand name Dexedrine is going to `be, written by
the doctor and there will be no substitute, they charge $22.60. When
they want the Defense Supply Agency `business, they bid $1. That
is incredible to me.
In New York City, they did not bid, but the winning bid was 57
cents. So, New York is buying dextroamphetarnine at 57 cents for a
1,000. The poor customer in the retail market place i's paying $22.60
plus the druggist's markup, for Dexedrine, for the very simple rea-
son that Smith Kline and French, through a vast program of pro-
motion, has convinced the doctor to write Dexadrine. He writes it
and his poor patient is paying $30 and $35 when New York City is
buying it for 57 cents. That is what I am talking about when I say
the companies have done a magnificent job of selling the brand name.
Every witness who comes in to testify on the side of the company
gives that line of argmnent. They never answer why it is that they are
able, the same company, to charge $22.50 and then turn around and
offer to sell it to the Government for $1 when they have competition.
Dr. Ai~r~o. Certainly as I said before, I cannot speak for the drug
company on their costs. But I can say that the drug-not that the
drug company sells the drug. The drug sells itself. The doctors have
used it and found it works and they know how it works. Therefore,
they will continue to use it until they have another product that will
come along that will do the job and cost less, but not use a drug be-
cause it costs 10 cents versus a drug that cost $1. A doctor first must
consider the condition he is treating and his patient. Secondarily,
the cost factor comes into treatment, not primarily.
Senator NELSON. Well, of course, to all~ the hospitals that have a
formulary and to the Defense Supply and to all the rest, cost is a
very important factor to them. Every major hospital in this country
has its own therapeutics committee, sets up its own formulary. In
that formulary, you will find brand name drugs and you find gen-
eric drugs, lots of them. The formulary, as you know much better than
I, is designed by the best clinicians, representing all aspects of the
profession in the `hospital, along wth the pharmacist and so forth-a
group evaluation of what drugs should be in the formulary. They do
not pay anywhere nearly as much. In fact, you find the brand name
companies bidding to the hospitals, just as they do to Defense Supply
Agency, at a price way below what they are charging the pharma-
cists, because the brand name does not do them any good with the
PAGENO="0232"
4522 CO~ETITIVE PROBLEMS fl~ TI~ DRUG INDUSTRY
Defense Supply Agency. The important question is, does the drug
meet USP standards?
Dr. ALFANO. I believe it is more than just TJSP standards on that.
They have their own testing for drugs.
Senator NELSON. They test on TJSP standards, I take it.
Dr. ALFANO. I will not speak on that I understand there is a clinical
evaluation of these products. They inspect the drug companies, the
factories where they manufacture.
Senator NELSON. I am not aware tha.t they do any clinical evalu-
ation when they take bids on drugs. They analyze them on their own
to see if they meet USP standards.
Dr. ALFANO. It is my understanding that 44 percent of these drugs
are rejected. That must mean they are rejected on substandard manu-
facturing reasons.
Senator NELSON. I would suspect they reject as many brand names
as they do generic. The only test we have is the test of the FDA of
4,600 drugs, 2,600 of them generic, the other 2,000 brand name, for
potency. Of the brand name drugs, 8.8 percent did not meet the IJSP
potency test; 7.7 percent of the generics did not. So, in a miscel-
laneous test of 250 manufacturers of 4,600 drugs on potency, the
generic drag was better quality, met the standards slightly better
than the brand name.
What would be your observation about that? If that is the only test
you went on, would you not be saying, you could not trust the brand
name, I will gamble with the generics, because they meet the potency
tests better?
Dr. ALFANO. If that is the only test you go by. Was not that test
rejected as not valid? The one you quoted?
Senator NELSON. Dr. Goddard testified on that. Out of the 4,600,
there was a mistake on something like half a dozen.
Dr. ALFANO. I will have to send that in. I do not have it here. But
as I understand, that is dramatically different from the original fig-
ures you quoted.
(Material not received.)
Senator NELSON. Here is the testimony from Dr. Goddard. It has
been in the record for a long time, unrefiited by anybody. You would
imagine it would be refuted the next day by the pharmaceutical manu-
facturers, if it were possible.
In six samples involving five firms, after the review of the original
data, they did concede that they had made an error. So they conceded
six errors out of 4,600. It still would not change the percentage. The
generic drug names met the standards of potency better than the
brand name.
Dr. ALFAN0. I believe there is something later than that. I could
not give it to you now.
Senator NELSON. No; there has been nothing later. The quote is-
Dr. Goddard-"Now the other original findings I still say are correct.
We stand behind these as long as it is understood that this is not a
representative sample of the marketplace." That is, they were mis-
cellaneous collection from 250 manufacturers.
All I say is-
Dr. ALFANO. What does he mean, not representative?
Senator NELSON. Well, they did not try to take a representative
sample. They were just drugs that were from 250 different manu-
PAGENO="0233"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4523
facturers, with 2,600 of them generic drugs and 2,000 brand names.
But it is the biggest and best test that we have, and it indicates that
the generic drugs met the standard potency better.
Now, do you have any evidence-we have had none by any repre-
sentative before the committee-of tests showing that brand names
are better? The only test we have is that the generics win.
Dr. ALFANO. The only test, really, is in the field. You are working
with patients, you are. prescribing drugs, you know it works. I do
not think we can come up with anything better than that. After all,
that is what we are working on, treating patients. If we come out with
good results, fine.
If you can show me that I can use another drug that costs less and
is equivalent to the drug that I am using, which costs more, naturally,
I will use the drug that costs less and does the job.
But certainly, I am not going to go ahead and run experiments on
my patients every day, say giving unknown drugs until I can evaluate
them. It would he impossible for an individua.l physician to carry
out this type of experimentation with many, many patients. He can
do it over a period of time.
Senator NELSON. Of course, it is not possible for an individual
physician, as a practical matter, to make comparisons of the efficacy
of a half dozen different drugs of the same compound, anyway. You
get a testimonial. But you do not get scientific evidence. The doctor
may very well conclude correctly, after experience, that this is a good
drug and it works. He sees it work. That is his experience. That does
not prove that another one does not work. It does not prove anything.
It just proves that the one he is using, as far as he is concerned,
does work.
Dr. ALFANO. Well, in the final analysis, that is what counts, is it
not, the confidence the doctor has in his particular treatment? That
is very important, regardless of the benefits of other types of drugs
and medications that are around. He is using a particular drug, and
it is important that he have faith and confidence in that particular
drug.
How can I treat a patient when I do not have confidence myself
in what I am giving this patient? I would be a nervous wreck. I
would be out of practice of medicine inside of a week.
Senator NELSON. Well, I submit that the classic example is the
Medical Letter again.
Dr. ALFANO. Well, I do not believe everyOne has that sort of faith
in the Medical Letter.
Senator NELSON. Pardon?
Dr. ALFANO. I do not believe everyone has that blind faith in the
Medical Letter. I do not subscribe to it, I do not have it, but my chief
of medicine feels it is fine, but there are certain limitations to it.
Senator NELSON. There are limitations to everything. The Medi-
cal Letter had the drug prednisone tested chemically, and 22 all met
USP standards. Then they consulted with their clinicians around
the country, distinguished professional men.
Dr. ALFANO. They do not say who they are, though. do they?
Senator NELSON. Well, they list the editorial board, of course. Now,
their advisory board is Dr. Gardner, professor of pediatrics, State
University of New York, Upstate Medical `Center; Lewis S. Good-
man, professor, head of the Department of Pharmacology at the Uni-
PAGENO="0234"
4524 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY
versity of Utah, College of Medicine; Dr. Lasagnia, associate professor
of medicine, director of the Division of Clinical Pharmacology, Johns
Hopkins Medical School; Dr. Lavietes, associate clinical professor
of medicine, Yale University Medical School; Dr. Mark Lepper,
professor of preventive medicine, University of Illinois Medical
School; Dr. George E. Moore, clinical professor of~ surgery, State
University of New York at Buffalo, director of Roswell Park Memori-
al Institute; Maxwell Wintrobe, professor and head of Department
of Medicine, University of Utah, College of Medicine; Dr. Robert
Wise, professor and head of Department of Medicine, Jefferson Medi-
cal College. They use other consultants. They consult with people
who are in the field using this particular drug; then with the benefit
of their chemical analysis and their consulting with clinicians, they
come to a conclusion about the drug.
Now, nobody has refuted this, including the company. The company
testified. They have not refuted this. No one has refuted it.
What I am saying to you is-certainly, you want to be sure that
your drug is employed. But this committee~ as one part of the hearings,
is concerned about the pricing structure of the drug industry and the
fact that in the retail marketing place by their brand name identi-
fication, they are able to charge an excessively high price which they
cannot get from a general hospital or Defense Supply or Veterans'
Administration. It is just a. clear cut case of gouging the public. In-
credible gouging.
They could not answer why they charged one-fourth as much in
Berne, Switzerland, for their drug, after shipping it over, as they
charged here. They said that the standard of living is lower over there.
Then I pointed out that the standard of living is much lower in
Mexico City and they charge three times as much in Mexico City.
He said he would ask the comptroller of the company to look into
that and write me. That was over a year ago. We have not heard yet.
But~ in my view, this is a case of gouging the public by the drug
companies, with the support of a lot of the medical profession who
say, "Stick to the brand name."
Now, it would seem to me that if I were practicing medicine, I would
go get the best formulary from the nearest hospital, in other words,
rely upon the judgment of the distinguished doctors at that hospital,
and prescribe from their formulary. That would answer a lot of these
questions.
Dr. ALFANO. I do not believe you would wa.nt that, Senator. You
want your physicians then to be herded into one group. Physicians
are individuals. They. will decide what they feel is proper for their
particular patients. I do not believe-you use the word "gouging". I am
not going to try to justify variations in pricing, but I believe there
are reasons why trade name drugs cost more than generic drugs. Trade
name or ethical pharmaceutical firms provide services that we do not
get from generic companies. In fact, most physicians do not know
the generic companies. I believe I have in here in~ this statement some
of the services rendered by the pharmaceutical firms.
For example, the medical department of the drug company. You
certainly would not want the American public and the medical pro-
fession to go without the services of the medical department of a drug
firm. We do not ha.ve medical departments in generic firms. Certainly,
PAGENO="0235"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4525
that will cost money and if the generic firms had a medical depart-
ment, their drugs would have to be up by that certain amount. Then
if they had professional relations departments and other services that
benefit the patient and the profession, the generic drugs, certainly,
there would not be that wide difference in costs.
Senator NELSON. Well, that exact position has been put to this com-
mittee a number of times and I have responded with this question,
`which has not been answered yet: What is the purpose of the patent?
If they discover a new drug, the Congress has said you can have 17
years to charge any price you please. And when you consider that
Schering was charging $17.90 for a 100 tablets and Wolins was selling
at a price of 59 cents a 100, you can imagine what kind of profit they
made.
So they had 17 years. They know how much it costs for drug re-
search, they know what their overhead is. They wanted to make a
profit. It is the highest profit in America. So they had 17 years. `What
justification at the expiration of the patent is there for charging a
high price? They are able to do it, I submit, Doctor, because that
brand name becomes so well know they can stick with the high price
and gouge the public. Otherwise, `Wolins would be selling more of
their product in the retail market, and so would American Pharmacal
and Merck. So what answer is there? They have the patent. What
else do they need?
Dr. ALFANO. I cannot discuss patents and other types of things. I
know nothing about that type of thing. I am just stating that ethical
pharmaceutical firms do offer services which are of benefit to the pa-
tient and to the profession which we do not get from generic firms.
These costs, these services, do amount to a certain amount of money
and this amount of money has to be applied to the drug as the patient
purchases it.
As to justifying extreme costs, I cannot do that and I do not intend
to try to justify an extreme cost. I am only stating that we do have
benefits from ethical pharmaceutical firms.
Senator NJ~I~soN. On the question of whether anyone would rely
upon or use a good hospital formulary, did I understand your answer
to be that the doctor is an individualist and would not want to do that?
Are you saying that you do not think the formulary system in our
major hospitals is a good system, that the collective judgment of all
the distinguished specialists and clinicians in that hospital is not better
than the single judgment of a single practitioner?
Dr. ALFANO. All hospitals do not have a formulary system. I am
on three hospitals. None of them have formulary systems. They are all
accredited community hospitals.
I have not worked under a formulary system. There are problems
with formulary systems where the physician is handicapped. Most
physicians will not join the staff of a hospital where it is required that
he use only the formulary system. He will jOin if~ he may use beside
the formulary system drugs of his choice that possibly are not listed
on the formulary system list.
But what I understood you to say is the doctor is out in practice
outside the hospital. He comes to the hospital and he has to be gov-
erned by these drugs that, are listed by the hospital pharmacy or
formulary system. That, I believe, would be objectionable.
PAGENO="0236"
4526 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator ~ELSOX. I would not say he would have to be governed,
by any means. All I am saying; for example, is "I am a doctor, I am
trying to help my patient, trying to get the best drug. If I am a sole
practitioner, I like to get the best sources of information possible. I
would be happy to check with the hospital and say, what are you using
for prednisone? I have been prescribing a brand sold to the druggist
for $17.90, a.nd costing my patients, with the markup, $30 or $35.
What do you use?"
They say, well, we are using Merck's at $2.20, Wolins at 59 cents.
What is your experience? Very good. We cannot find any difference.
That is the sort of thing I would consider; that the collective judg-
ment and practice and experience of that hospital might be very useful
to me and I would be glad to get that information.
But in any event, 88 percent of the a.ccredited hospitals in America
use a formula.ry. None of them that I know of-that is, of those who
testified-have a formulary in which it was compulsory under all
circumstances that the doctor use the drug in the formulary. If he has
a specific reason for desiring a particular brand name, he has that
leeway.
Dr. ALFANO. I do not believe they have any choice. The medical pro-
fession would not stand for a closed type of system. They would not
go for it. The patients are their prime concern, not the hospital pharm-
ac.y or whatever it is in
Senator NELSON. What happens is that as a matter of practice, most
all the drugs prescribed in the hospital come right out of the formu-
lary. The exception is rare, percentagewise.
When the hospital in Atlanta went to a formulary 2 or 3 years ago,
the doctors testifying here said they saved, I believe it was, a quarter
of a million dollars and that they found the generics they used to be
very good.
Dr. ALFAN0. I think there are two different systems of formularies,
though. There are some hospitals that you are required to use these
particular drugs in. If you write a tra.de name, they will give the drug
in stock for that drug. Then, there is a system whereby a formulary
does exist and it is permissive as far as you may or may not use it,
depending on how you feel concerning your patient at that time.
Senator NELSON. I imagine there are. hundreds of them, so there is
a great variety in their use. I only wanted to make the point that-of
the doctors who testified here, those practicing in a hospital with a
formulary-these doctors said that within their hospital any physician
desiring a specific brand name, though it might not be in the hospital
formulary, would be free to prescribe that particular brand. No one
would quarrel with that.
Dr. ALFANO. You may rightly ask how does the cost of the drug
interfere with the physician-patient relationship-does a more costly
drug improve this relationship? Of course not. But anything that
shakes the confidence of the physician or patient interferes with this
necessary relationship. A physician who writes a prescription for a
particular medication knowing full well that the pharmacist will sub-
stitute a generic drug in filling the patient's prescription does not
have the confidence that the drug received by the patient will do the
job. The doctor prescribed a known drug but the patient will take an
unknown product. Will the generic drug have more of an effect than
PAGENO="0237"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4527
desired, the same effect as the prescribed drug or will it provide less
than the desired effect. Since the doctor is not sure that the medication
received by the patient is doing the job properly he will have to see the
patient more frequently. Thus the savings in the cost achieved by the
use of the generic drug will be more than offset by the extra visit or
visits
Under our present system the physician prescribes a drug which is
known to him and manufactured by a known reputable firm. More
important however, the physician has personal knowledge and experi-
ence with the particular product. He can advise the patient, anticipate
results and accurately judge when he should see the patient again.
The doctor has a working knowledge of the particular product. Under
the present system of generic drugs the doctor can never gain a work-
ing knowledge of the product.
Under the generic system each time a patient has a prescription
filled for the same drug he could receive a drug produced by a different
manufacturer. Each of the products can react differently since each
manufacturer has his own method of producing the finished product.
This problem is compounded by the fact that it is not possible to iden-
tify the manufacturer. Under these circumstances no physician can
gain a working knowledge of a generic drug.
The most significant point of all, I believe, is the fact that a chem-
ically equivalent drug does not mean it is therapeutically equivalent.
Senator NELSON. What evidence do we have of that specifically?
Dr. ALFANO. Well, studies of Max Sadove, an anesthesiologist in
Chicago. lie has done a study of the generic versus the trade-name
drugs. Then there is a study of Pfizer on oxytetracycline. There is a
difference which, I believe the FDA has confirmed.
Senator NELSON. We have not been able to get any convincing evi-
dence from the manufacturers or anybody else that drugs that met
USP standards are not therapeutically equivalent.
Dr. ALFANO. You have no evidence?
Senator NELSON. The best
Dr. ALFANO. Well, I will send you the material concerning these
studies that there is a difference.
(Material not received.)
Senator NELSON. We have those studies. They have been refuted.
Dr. ALFANO. When were they refuted? I do not recall seeing this.
Mr. GORDON. In one of our earlier volumes, specifically volumes 1
and 2.
Dr. ALFANO. Was it not the chloramphenicol, too, that there was a
difference?
Senator NELSON. That is the only drug we are aware of and there
is no proof yet. Dr. Lee testified on that recently. There is no proof
that the different blood level achievement of Chloromycetin versus the
other chloramphenicols, indicates that one ~as any more efficacious,
that there was any difference in therapeutic effect. There may be, but
what happened was that in the tests, the brand name, Chloromycetin,
achieved a higher blood level more quickly. The FDA took the other
two, I believe, off the market because they did not achieve the same
blood level. They wanted uniformity in bloOd level achievement. Dr.
Lee says there is no evidence that either or any one of these was a more
efficacious or a better drug than the other. They may find this to be so
PAGENO="0238"
4528 COi~~tPETITIVE PROBLEMS IN THE DRUG INDUSTRY
some day. All they had was a differeilt blood level achievement in a
different period of time.
Dr. ALFANO. There is a study on oxytetracycline, I think. I can
send you a copy of that.
(Material not received.)
Senator NELSON. But the evidence was that there was no
therapeutic significance to the difference.
The following is a line of questioning of Dr. Lee, former Assistant
Secretary of HEW, on this question of equivalency.
Mr. GORDON. I have one nitpicking question. You say there are only two
or three which demonstrate an initial lack of equivalency and one of them has
no practical clinical importance. Are there two or three? Which is it?
Dr. SILVERMAN. There are two. One of them, as you probably surmised, is
chioramphenicol.
The second one is tetracycline. In the article in this publication, the scientists
that wrote this article pointed out quite clearly that although differences were
detected, this was not of any clinical importance.
Dr. ALFANO. That is tetracycline?
Senator NELsoN. Yes.
Dr. ALFANO. There is one on oxytetracycline, a new one.
Senator NELSON. In any event, the USP, the formulary, and the
FDA, can cite only one of two cases.
Dr. Kiwc'rz. May I speak to this, because it is very apropos of this?
Senator NELSON. Yes.
Dr. KRANTZ. The Department of Defense a few years ago, after
having bought these brand name items at low price as generics, brought
me 19 of them that did not show complete therapeutlc efficacy. These
are these drugs: Reserpine, thiopental sodium, tolbutamide, tedral,
tobocurarine chloride, Warfarin, Heparin sodium injection, oxytocin
injection, diphenylhydantoin sodium, digitoxin or digoxin, phenolsul-
fonphthalein, pentaerythrityl tetranitrate, succinyicholine chloride
(Anectine), bromsulphalein solution, sustained release tablets, meth-
enainine mandelate (enteric coating), Dexamyl.
Senator NJ~r~sON. We will check the record further. Counsel advises
me that the task force on these drugs went into this and found out
that-
Dr. KRANTZ. They came to me for the purpose of finding pharma-
cological data which would show the generic equivalency of these
drugs.
Senator NELSON. Were these drugs you cited here-I have not read
`that report-were these drugs that did, in fact, meet USP standards?
Dr. Kiw~rrz. Oh, yes; they put them through the USP test. This
is very simple for them to do.
Senator NELSON. Did they meet the USP standards or fail them?
Dr. Kn~z. Met the USP standards but the diphenylhydantoin
`did not control epilepsy. The meprobamate did not produce sedation.
`The thyroid did not change the metabolic rate.'
Senator NELSON. You are certain that these are cases where the
drug met the USP standards, not failed the standard tests when
`tested?
Dr. IclLu~rz. The pharmacopeia standards are only standards of
identity, purity, and also the rate of tablet disintegration.
Senator NELSON. Potency?
~ See pp. 4555-4557 of Dr. ICrantz' testimony.
PAGENO="0239"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4529
Dr. KRANTZ. Identity and purity.
Senator NELSON. The coramittee is well aware of that, Doctor.
What I am saying is did each one of the drugs named under test
meet the U.S. pharmacopeia standard or did they fail to meet the
standard?
Dr. KRANTZ. I was so informed by the colonel who brought them
to me, that they had met the pharmaco~eia standards.
Senator NELSON. I would question it for this reason. We have dis-
cussed this question with the Directors of the National Formulary and
U.S. Pharmacopeia and they flatly state that they cannot find any
cases, excepting one or two, in which `a drug met USP standards or
U.S. Formulary standards and was proven not to be therapeutically
eqivalent. Now, I will take these and recheck them, but this has been the
testimony by the Director of the FDA, by the U.S. Formulary, the
U.S. Pharmacopeia, and by a number of distinguished pharmacolo-
gists. If they met the standard, there have been only one or two cases
where that was proved not to be therapeutically equivalent. If there is
further evidence of exceptions, of course, the committee would like to
have it.
Dr KANTZ. Well, this came from the Army source of supply in
Philadelphia. The colonel came to see me in my laboratory about a
year ago and asked me if we could develop pharmacologic tests which
could prove their pharmacologic activity in addition to the fact that
they had already proved their chemical identity.
Senator NELSON. Dr. Lee testified for the Department of Health,
Education, and Welfare on December 23 respecting the Task Force
Report. Twill read what I said to him and what he said:
Just on one point of your conclusion-
that is the conclusion of the Task Force Report-
that when drugs are chemically equivalent and meet all the chemical standards,
they are therapeutically equivalent except in rare instances, as you are aware.
We have had distinguished pharmacologists and elinicians appear before this
Committee and give the same testimony I assume that when you refer to the
fact that you have relied upon the literature, and clinicians, and past experi-
ence and so forth, that that also involves the rather vast experience of the
Defense Supply Agency, the Veterans Administration, and general hospitals
and others who buy on competitive bidding. And on one occasion they get one
brand of prednisone and one brand of another drug.
Dr. LEIS. Tetracycline.
Senator NELSON. And their experience over the years has been that if they
meet the same standard and have the same chemical composition, that they are
therapeutically equivalent; is that correct?
Dr. LEE. That is correct. Because this is a highly charged and controversial
area, the task force made a very extensive study. The task force study has been
going on for well over a year. We consulted with the leading experts in the
field; our staff reviewed the literature; we had the special studies carried out;
we reviewed the experience of the Defense Supply Agency and other agencies
who have had just the kind of experience that you have described. Our con-
clusions really are based on a detailed examination of the information that is
available today.
Senator NELSON. Thank you.
I have to go vote, but the committee counsel tells me that he cannot
find anything in your material, Dr. Krantz, that says these drugs,
in fact, met USP standards. Could you show him where that is?
I will be back as soon as possible.
(A recess was taken.)
PAGENO="0240"
4530 CO~ETITflTE PROBLEMS IN THE DRUG INDUSTRY
Senator NErsoN. We will resume the hearing.
It was called to my attention during the recess that on our dis-
cussion about hospital formularies, that all hospitals must have
formulary committees to be eligible to collect for medicare patients.
Dr. ALFANO. Committees, yes, but not formularies. You are talking
about committees. A committee and a list are two different things.
Senator NELsON. What is the purpose of having a formulary com-
mittee if they do not select a group of drugs to fit the formulary?
What is the point?
Dr. ALFANO. Supposedly, they check all the drugs that do come
into the hospital pharmacy, regardless of whether it is a generic or
trade name. The formulary committee makes sure that the hospital
does not have a drug within the walls of the hospital, the type of drug
that may be harmful or cause problems that may be detrimental to
the hospital.
Senator NELSON. You are saying that under the medicare law, in
your judgment, hospitals are not required to have a drug formulary in
order to get medicare payments for medicare patients? Is that what
you are saying the law is? I do not know what the law is.
Dr. ALFANO. I do not believe it is a law that you must have a
formulary committee-a formulary. I believe they do require the
Joint Commission on Hospital Accreditation to have a formulary
committee, but not necessarily a formulary.
Senator NELSON. I am still puzzled about what the formulary
committee would do if they did not devise a formulary for the hospital.
Dr. ALFANO. A formulary is a list of drugs. If it is so restricted,
you can only use this list of drugs within the hospital. The formulary
committee reviews all drugs that come into the hospital and are used
within the hospital. They will prevent a drug coming into the
hospital that may be harmful and cause a. danger as far as the patients
within the hospital or causa problems for the hospital corporation
a.nd the staff.
If I, as a doctor, want to come in with a drug that is not approved,
not accepted, if we have no formulary committee, I could bring any
drug I wanted to into the hospital. There is no protection, therefore,
for the hospital and the hospital staff and the hospitalized patient.
The forinulary committee will prevent that from occurring.
Senator NELSON. Please continue.
Dr. ALFANO. Thus when a physician has a patient on a generic drug
produced by an unknown manufacturer he is conducting an experi-
ment because he does not know how the patient will respond. The
patient must be seen more frequently in order that the physician ~
evaluate the therapeutic effect.
With a brand name product the physician over a period of time
has obtained a working knowledge of the specific drug and does not
have to see the patient as frequently as is required with an unknown
product.
From the patient's standpoint the substitution of a generic drug can
have a profound effect upon the patient's confidence. For example, the
physician orders a particular drug while the patient is hospitalized
and upon discharge writes a prescription for continuation of the
medication at home. The druggist substitutes a generic drug which
may be a round red pill rather than the oblong yellow medication the
PAGENO="0241"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4531
patient received in the hospital. What is the result? After discussion
with the pharmacist the patient is not convinced that he received the
proper medication. The next natural thing to do is to contact the
physician in order to determine if the medication dispensed is in fact
the one prescribed. Unfortunately the phy,sician cannot identify the
generic drug by its shape, size, and color and must contact the pharma-
cist to determine if an error was made or if the patient actually has
the medication which was prescribed. If you were that partmcular
patient I'm sure that your confidence would be thoroughly shattered.
Senator NELSON. May I interrupt, Doctor? I would like to make
the point that exactly the same thing happens all the time. As I said,
88 percent of accredited hospitals of America have a formulary. Every
witness we have had from every major hospital has a formulary and
uses generic drugs in the formulary. So to use your argument, the
patient is in the hospital; the hospital gives him a generic brand drug.
It is a little round red one. He gets out of the hospital, goes to the
doctor and the doctor prescribes the little round yellow one and you
shatter his confidence. Nonsense.
Dr. ALFANO. I can only testify from my experience. In my experi-
ence, if I prescribe a trade name drug, that is what the patient gets
in the hospital. If I discharge the patient and the law requires that
they substitute a generic drug, then they get a different one.
Senator NELSON. All I am saying is it works both ways. All the
major hospitals in America are using a formulary. In those hospitals,
the doctors are using the drugs in their formulary with rare excep-
tions. So the patient leaves the hospital, goes to another doctor, gets
a little red pill instead of a little yellow one and his confidence is
shattered. I must say even if it is shattered, it is shattered both ways.
Dr. ALFANO. I do not believe the formulary system is the way you
understand it, really. The physicians on the staff, the formulary coin-
mittee will make up a formulary and the drugs of choice are listed
on that formulary. It is not made up primarily as a cost limit for the
hospital.
Senator NELSON. Oh, it is a very important part of the cost. We
have witnesses testifying to that. As I pointed out, one hospital saved
a quarter of a million dollars a year.
Dr. ALFANO. If you are stating the formulary is made up for cost
reasons, I condemn that type of system. I think the patient is the
primary consideration.
Senator NELSON. I did not say that at all. All I am saying is the
formulary is made up by a group of doctors representing the disci-
plines practiced in the hospital. I am just repeating what the expert
testimony is, that using the knowledge and experience of a group
of physicians who make up a formulary. It is expected that the doc-
tors will use it and they do use it. They do have a caveat that if the
doctor insists, has some reason to use a particular brand or another, he
is completely free to do so. But this is an exception to the rule, not the
rule.
So all I am saying is that in these hospitals, lots of patients are
getting a generic drug. When they leave the hospital instead of getting
a little round red one, they get a little round yellow one, a brand name.
I simply submit that if it shatters their confidence one way, it shatters
their confidence the other way. But I would be amazed if a great deal
81-280-69-pt. 11-16
PAGENO="0242"
4532 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY
of shattering were going on. If there were, perhaps the hospital should
be required to continue to use on that patient the same generic drugs,
the same brand drugs, so that the patient's confidence would not be
shattered when the doctor changes from a generic to a brand or from
a brand to a generic.
All I am saying is your argument is full of holes. It works both
ways.
Dr. ALFANO. I do not believe so, because you are talking about a
formulary system. The staff has a formulary committee. The staff then
submits the drugs they wish to use. You have a staff that have on the
formulary the drugs they wish to use, the drugs they use on their
patients, inside the hospital and outside the hospital. There is no
other change, no other outside force that comes between them. The
formulary system belongs to the staff and is controlled by the staff.
Senator NELsoN. Correct.
Dr. ALFANO. They have the drugs they wish on that. So it is not
the same as you say, that they can have one drug in the hospital and
another drug outside. The doctors on the staff submit the types of
drugs they want on the formulary, because the formulary is derived
primarily for the benefit of the patients and the staff, secondarily, for
the cost. And I am sure-I do not have the figures, but if the hospital
bought a large amount of a drug, a trade name drug or a generic drug,
their prices or cost would be less than if they bought smaller amounts
for, say, individual medications rather than a wholesale purchase. So
there is a savings on both generic and trade name drugs.
Senator NELSON. There is no question about that. All I'm saying is
one of the purposes of the formulary is economic. That is one of the
purposes. The fundamental, primary idea in the selection of any drug
is to be sure that you have a quality drug that does what the drug is
supposed to do. That is fundamental. There would not be anyone who
would argue about that.
Then another factor is the economics and it is an important factor,
the difference between $17 a hundred and 59 cents is quite a bit. Any
hospital that used a substantial number of drugs but did not develop
a formulary to take competitive bids is a poorly managed hospital.
When they design the formulary, they design it to be used. The testi-
mony of the witnesses here is that it is used and it is the exception when
a doctor insists that he wants to give Meitcorten or Paracort instead of
Merck's prednisone or Wolin's. If he has a reason, he may. But that is
the exception.
So patients are going into hospitals and often going back to their
own or another physician, who is not associated with that particular
hospital. And this physician decides that he will prescribe Meticorten
instead of Paracort and the little red tablet becomes a little yellow one
and you have shattered the patient's confidence. That is all I am saying.
It works both ways.
So to use your argument, you just turn it around and use this one.
It happens all the time. I wonder about how much shattering, but I
suppose it happens.
Dr. ALFANO. I know it happens.
I recently spoke by telephone to a colleague at the Naval Air Station,
Alameda., Calif., and asked if he had any problems with generic drugs
versus brand name drugs. At the naval air station it is customary to
use both brand name and generic drugs. He related one experience
PAGENO="0243"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4533
that illustrates the problem. A patient was hospitalized in order to
achieve a therapeutic blood level by a particular drug. Upon dis-
charge, the patient was given a prescription for the drug and instructed
on how to take the medication. The patient presented the prescription
at the pharmacy and received the generic drug of the brand name prod-
uct he received while in the hospital. A week later the patient returned
to see the doctor. The patient stated he had not taken the prescription
medication because it was different from the medication :he received
as a patient in the hospital. The patient had to be readmitted to the
hospital and treatment was started all Over again. It is quite obvious
that there can be fatal consequences with interference to the physician-
patient relationship.
Senator NELSON. Let me ask a question. That is one example. Now
suppose a patient had been `admitted to the hospital and had been get-
ting a generic drug. He comes out of the hospital and the doctor pre-
scribes a brand name drug. He goes to the pharmacy and sees the brand
name drug as a little yellow one instead of a little red one. He refuses
to take it. He has to go back to `the hospital. What are you proving?
In one case, it was a brand name he got in the hospital and rejected the
generic. In the other case, he got out and refused to take the brand
name. What are you proving? That the brand name is better than the
generic?
Dr. ALFANO. I don't believe the practiàe is as you stated. The phy-
sician doesn't change medication on the patient that way. A physician
will use medication and carry it on to the point where if that medica-
tion is not working any more, he will change the prescription and order
a new medication.
Senator NELSON. Are you saying in this case at the hospital, the
doctor prescribed the brand name and the pharmacist illegally substi-
tuted the generic name?
Dr. ALFANO. No, this is a system here. They have both brand name
and generic drugs. While in the hospital, evidently, the brand name
was used and at the pharmacy, the generic drug was dispensed. It
could be the other way around.
Senator NELSON. Of course. But what does it prove?
Dr. ALFANO. It proves that you must have consistency as far as the
medication. A patient gets confused. I have seen it happen.
Have you ever gotten medication, you get one type of medication,
it is for a certain condition, and you go to a pharmacy and you have a
different type of medication and it is foreign to you, that you do not
question it? Do you feel, well, it is a different color and must be the
same? It is irrational to say it is the same.
Senator NELSON. I assume you could have some instances on six
or seven drugs and they switch. But you are using the case where the
patient goes to the hospital and is taken care `of in that hospital by the
specialists, goes on back to a local physician in another city. The doc-
tor there knows he is supposed to get prednisone, so he' writes a brand
name that he likes. It is not generic. So the patient's confidence is
shattered again.
Dr. ALFANO. No, no, it isn't. It is understood. This is the patient-
physician relationship that exists. There is no disturbance there. I write
a prescription for a patient, tell the patient, you take it. They fill that
prescription. You are talking about `another doctor's prescription?
PAGENO="0244"
4534 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. Yes, so his confidence is shattered.
Dr. ALFANO. ~o, it is not.
Senator ~ELSOX. There are tens of thousands of patients who go
into hospitals and get a drug and go back to a doctor in their rural
coimnirnities. The doctor has been notified that the patient is supposed
to get this particular drug. He will be notified, most likely, in generic
terms, that he should be getting, for example, prednisone. So the doctor
will say, well, I will select Paracort. In the hospital, he got Meticorten.
So he is upset. Or in the hospital, he got Wolins' generic. So he is upset.
All I am asking is, what are you proving?
Dr. ALFANO. You are trying to change this around, Senator, because
the patient is treated by Dr. A in the hospital a.nd has a certain medi-
cation. He goes home, Dr. B states, I will write a prescription for you
to cover what you have been taking. Here is my prescription for the
same medication made by a. different company. There is no confusion
by the patient. They accept the fact. They have a new prescription.
it is the same medication, made by a different manufacturer. There
is no confusion.
Senator NELSON. So he writes a prescription and all of a sudden, the
patient loses his confidence because it is a different pill. But if the
doctor explains to him, you have been getting a little round yellow one.
Dr. ALFANO. The patient knows that.
Senator NELSON. I know, but now I am going to prescribe one for
you and it is going to be a little round red one. Don't let that upset you.
Dr. ALFANO. if he knows it, he had better tell the patient that,
because the patient will be. confused if he has a different type of nmdi-
cation. This has happened in practice. This is not a theoretical type
of problem.
Senator NELSON. I am sure it happens, and I am sure the example
I have given where the patient gets a generic in the hospital and he
gets a brand name back in the town where he comes from and he
refuses to take it and they have to put him back in the hospital, as far
as I am concerned, that proves you should have continued to give him
the drug under its generic name.
Dr. ALFAN0. You have turned around what I was trying to say.
Senator NELSON. Just applying the same logic to both situations.
Please proceed.
Dr. ALFANO. This same sort of thing would happen when a patient
refiled a prescription and, in the meantime, thie pharmacist purchased
the generic drug from a different company. Also, this would happen
when the patient changed drugstores.
In all cases, the extra physician visits required to reassure the patient
and to reestablish the contact between the physician, patient, and the
medication in use would do away with all the savings achieved by
requiring the use of generic drugs.
Confidence on the part of the patient in his physician is absolutely
necessary for the physician-patient relationship, and vital to the
patient's response to a course of treatment. A patient who loses confi-
dence in his physician or is not secure in the medication received does
not respond to the treatment, which results in a delay in returning to
full productivity.
A physician cannot adequately treat his patient if he does not have
full confidence in the medication taken by the patient. The individual
PAGENO="0245"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4535
physician has developed confidence and faith in a particular drug and
in the manufacturer over a period of time. Experience with a drug
which consistently produces the desired effect results in confidence.
No amount of advertising in journals, by mail, at conventions, or per-
suasion by the detailman can short circuit the process of developing
confidence in a particular drug.
The pharmaceutical firms know that, confidence on the part of the
physician is essential for the existence of the company. As a result,
these firms are constantly striving to prpduce quality medications and
to improve their methods of production. A bad result with a drug
or misleading information cutting corners, or a bad batch of `a particu-
lar medication can be disastrous for a pharamaceutical firm. Each pro-
prietary company is identified with every one of its brand-named drugs
and puts its reputation on the line with each and every package that
leaves the plant.
A generic drug is anonymous. By inspection there is no way of
telling what the drug is, let alone the manufacturer. The generic drug
firm if it so desires can cut corners and if a bad result occurs, the
attention is not focused on the manufacturer. There is no need for
the generic firms to gain the confidence of the medical profession be-
cause there is no way of identifying the drugs produced with the
generic firm. Once there is product identification, the company is a
brand-named firm and must have the confidence of the medical
profession.
Senator NELSON. Let me ask a question here.
Again, what we seek to get in the evidence here-and we ask about
this constantly-is what are the examples of adequacy or inadequacy
of the generic drug versus brand name? We have been asking that for
2 years and really have not been getting any adequate answers. We
get the assertion that you can't trust generics, you h'ave to have confi-
dence, you have to stick to the brand name company. But, we just do
not get any real evidence that this is, in fact, so.
Dr. ALFANO. As I stated, I will send that report on oxytetracycline
that has come out.
(Material not received.)
Senator NELSON. Conirnittee counsel tells me that that would not
quite fit the circumstance, because that drug is only produced by one
company, Pfizer.
Dr. ALFAN0. I do not have the report. I cannot go discussing it.
Senator NELSON. Is this Terramycin? If it is Terramycin, it is under
patent to be produced by one company.
Dr. ALFANO. As I have said, I do not have it, and I could not come
up with the answers.
But you could just, on chioramphenicol, `have one product and show
that-as far as I know, there has been evidence to show that the generic
product was not therapeutically equivalent to the trade name product.
Senator NELSON. The FDA testified that that is not the case. I
asked Dr. Ley who was here just last week. I asked him if FDA had
any evidence that there was any difference in the therapeutic equiva-
lency of the chloramphenicol they took off the market? He said there
is no such evidence. They achieved a different blood level at a different
period of time. That is all.
Dr. ALFANO. What was that period of time?
PAGENO="0246"
4536 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELsoN. It is in part 6 of our hearings. All I am saying is
that there is no evidence that Dr. Ley knows about, and I guess he
would know it, because they have asked us about every single brand
of drugs-but they wanted to achieve the same blood level over the
same period. So they set that standard.
Dr. ALPANO. Was there any blood level?
Senator NELSON. Oh, yes.
Dr. ALFANO. I saw that thing in a generic product just in dissolving
it. Over a half hour, it never dissolved.
Senator NELSON. We have that both ways. We have as many brand
names that do those things as generics. As I said, according to the only
test we have had on potency that is big, the brand name companies
did not meet the standards of the generics.
Dr. ALFANO. I am saying here, Senator, once a generic name is
identified, a generic drug is identified with a manufacturer, then it
is essentially a brand name. It is identified. There is knowledge of this.
I am not saying that the generic drugs are not worthy of being used
or that type of thing.
Senator NELSON. As I am sure you know, a number of purely ge-
neric manufacturers manufacture compounds for the brand name
companies. One of the distinguished companies is Strong, Cobb &
Amer. Many brand name companies buy from Strong, Cobb &
Amer.
Dr. ALFANO. Oh, yes, but while they have no name of manufac-
turer as to source, there is a question mark as far as the medical pro-
fession is concerned, and there should be.
Senator NELSON. All I am saying is that you hear the fiat assertion
all the time that brand names are better and yet the only test to date
says that generics are better.
Dr. ALFANO. I am only Saying that generics with a known manufac-
turer is a brand name. They do not have identification as you do with
an ethical pharmaceutical firm. There are ways of identifying them
with name. initials, and so forth.
Senator NELSON. I assume the pharmacist knows whether it is
Lannett, American Pharmical or Merck or anything else. He knows.
There it is. It is a little label on his jar, manufactured by this com-
pany. The tablets, except for one company, are not identified. The
identity code is only used, so far as I know, by one company.
All I say is we continue to hear these assertions from the people who
come before us, but when I ask for examples, I do not get them.
For example, let us take a recent case. This involves Parke, Davis.
Have you heard of the TinnerhoZn-t case involving Parke, Davis & Co.,
a 1968 case which involved a brand-named vaccine, sold under the
name of Quadrigen by Parke, Davis & Co. In 1968, the Court said:
Evidence in action against manufacturer of vaccine for damages resulting
from infant's having been injected with vaccine by physician established that
vaccine was defective and that defect was proximate cause of infant's injuries.
Since that time he has been retarded in his mental development, being clas-
sified in the imbecile-idiot range.
evidence established that there existed sufficient number of both unreal-
istic and conflicting reports from field to have required manufacturer to take
serious second look at its product before placing it on the market.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4537
Then, in another case, the Court said:
Of the severe reactions reported, the first apparent instance in which death
resulted was in March of 1959. It does not appear that Parke, Davis made any
effort to determine the cause of the high incidence of reactions, and only a
cursory attempt was made to investigate the cause of a death attributed to
the use of Quadrigen.
This is just one brand name. We do nOt have such cases on a generic
company. Were you aware of these cases
Dr. ALFANO. No, Senator, I was not aware of that.
Senator NELSON. This raises an interesting example, Doctor. I will
wager that hardly anybody in the medical profession is aware of these
cases. But if this had been a generic company, you would have seen the
Pharmaceutical Manufacturers AssociatiOn grind out a load of propa-
ganda attacking generics, reciting the deaths which resulted, saying
it was a generic company, you cannot trust them, and all of the medical
journals in the country would have run their stories. Because every
time you make an attack like that, they get publicity. The case of
chioramphenicol is an example.
So you have an interesting case here of a distinguished brand
name manufacturer. Nobody knows about these cases. Because you
can bet your hat that the Pharmaceutical Manufacturers Association
did not spend money to notify the medical journals, and the medical
journals have a tendency, from my reading of them in general-some
of them much worse than others-to more or less ignore such things
when it involves a brand name company that advertises in the journal.'
I think these are interesting cases and I shall put them into the record
at the end of today's proceedings.'
Dr. ALFANO. I believe the example of Parke, Davis, when it was
known that chioramphenicol or Chloromycetin caused aplastic anemia,
I believe the record shows that the medical profession reacted to the
bad result or this complication of the drug. Their sales dropped off. It
was reported that way. You will probaibly find that the medical pro-
fession does not depend on outside agencies to get this type of informa-
tion. The American Medical Association~ 1 `am sure, will list this
result.
Senator NELSON. On this I think you will find there is an interesting
relationship. Part of the committee consideration here is to ascertain
the relationship between the medical profession and the manufactur-
ers. What I am saying is that they would have ground out the story
in big press releases and announcements and all the medical journals
would carry it, attacking and saying, here is another example why
you can't trust a drug under its generic name. The doctor reads that
and says, oh, oh, you have to stick with the brand name. This is a
fantastic propaganda machine.
`Dr. ALFANO. I do not believe a doctor chooses on that basis, really.
At least, I hope not. Otherwise, we are in trouble in this country.
Senator NELSON. You mentioned the case" of chloramphenicol. I
believe that was the most tragic case of misprescribing of drugs prob-
ably in modern history. But the organized medical profession `did not
make a point of informing its members-those who were misprescib-
ing. This committee conducted extensive hearings, and because of
the vast publicity and the lawsuits started around this country, the
1 See information beginning at p. 4558, infra.
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4538 CO~ETITIVE PROBLEMS ~ THE DRUG INDUSTRY
use of chioramphenicol dropped after our hearings. In the year 1968,
it dropped from 40 million grams prescribed down to about 20.
But the testimony before this committee by distinguished doctors
and pharmacologists and authorities in the field is that about 90 to 99
percent of the patients receiving chloramphenicol are receiving it for
nonindicateci cases, an incredible number.
Dr. ALFANO. Ninety to 99 percent, is that?
Senator NELSON. One of the witnesses testified that in his judgment,
less than 1 percent of the people getting cliloramphenicol are getting
it for indicated cases and that of every death he had ever seen from
chloramphenicol, not one had received it for an indicated case.
Dr. Dameshek, the distinguished hematologist who has written for
the AMA on this question, testified that perhaps about 10 percent
received it for indicated cases.
Our files are filled with letters, two more last week-I get some
every week-of cases of doctors prescribing chloramphenicol for non-
indicated cases-acne, infected gums, flu, sore throat-the last one,
a woman died from getting it for flu-hangnails, all kinds of things.
How did it get that way? It got that way by some fantastic promo-
tion in the medical journals in this country. That is what misled phy-
sicians. They did not correct it.
Dr. ALFANO. I have never seen it advertised for hangnail or flu or
acne or that type of thing.
Senator NELSON. No; it is just advertised-Chloromycetin, when
it counts. Very cleverly over the years, it has been promoted-at least
it ends up this way-for use as a broad-spectrum antibiotic for all
kinds of things. I do not think the doctors promoted it. I think it is
the company's promotion that was effective through their detail men,
through their advertising, through their promotion.
Or maybe somebody else has an explanation. The medical profession
did not reform itself. The reduction in use has come about from the
broad publicity this committee is getting.
Last week, Dr. Ley testified that still about 90 percent of the patients
are getting it for nonindicated cases.
Dr. ALFANO. I am glad the committee has had a beneficial effect, but
I believe we should not condemn the pharmaceutical industry or
the PMA. I think it is a function of the medical societies, the medical
organizations, to improve their continuing education programs. I
believe you, through the committee, have probably functions in that
regard. I do not believe you can condemn advertising per se as the
cause of a problem `that exists probably based on something else.
I am involved in continuing surgical education and there is a prob-
lem as far as stimulating the individuals to participate in courses and
methods of instruction.
Senator NELSON. Well, what responsibility does the profession
have? The fact is known. The medical journals, I suppost all of
them-I do not know whether 1 have seen an ad in your journal on
Chloromycetin, but I assume you have had them. I have seen them
in all kinds of medical journals, including the AMA journal.
Dr. ALFANO. It is a good drug.
Senator NELSON. Yes, but the indication is~
Dr. ALFANO. It has uses.
`Senator NELSON. But the indications are very, very fiinited.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4539
Dr. ALPANO. I know, `but when you do use it as a lifesaving drug,
you have nothing else to use. This is it.
Senator NELSON. As you probably know, the National Academy
of Sciences has said it is not the drug of choice for any case. But inchca-
tions have been that it is only to be used if the disease is serious, if no
other drug will do the job, and only if the disease will respond, the
organism causing the disease will respond to this drug. But that is
not the way it has been used.
The AMA itself is aware that 90 percent of the people are getting
it for nonindicated cases and they still accept big drug ads promoting
the drug. You would think the AMA would require them to put a big
box in the ad saying, "This is being widely misprescribed," that they
would run headline stories saying, "Doctors are misprescribing this
drug and killing people with it"-would you not? Or else refuse to
take the ads on the ground that the promotion has resulted in the mis-
use of the drug. What's the answer there?
Dr. ALFANO. I don't believe they have substantiated these claims
by individuals and when they have, the medical profession will do
something. I don't believe they have gotten it down to that, that only
10 percent of the cases are prescribed right. This has not been proved.
Senator NELSON. That is true.
Dr. ALFANO. I am not aware that the medical profession is-but it
should be working toward that end-coming up with the facts as far
as they can to determine which way they should act concerning cer-
tain drugs.
Senator NELSON. Five of our witnesses, doctors2 stated `that it was
their guess, their best guess, that it was about this way, based upon
what they have seen, each of them having a wide experience with the
drug.
Dr. AL1~ANO. No, Dr. Dameshek; he is a hematologist. He would
have the end result of a complication, not a wide use of that particular
drug in his patients. I do not believe he would use it at all.
Senator NELSON. When he sees a patient and 90 percent of them got
the drug for nonindicated cases-
Dr. ALFANO. That is retrospect, also. There is another problem in
there. Looking back, you can get 10 doctors, a hundred doctors, you
will not find they all agree 100 percent as to the course of treatment,
type of drugs. Medicine has considerable variation in treatment and
methods of treatment. You can have experts all disagreeing.
Senator NELSON. That is correct. But when you get one of them testi-
fying that in every death he had seen from aplastic anemia, not a
single patient had received it for an indicated case-if you see all
five of them testify along the same line, so they conclude as they look
at people with aplastic anemia that if nine out of 10 of them are
`getting it for a nonindicated case, that might give you a pretty good
guess that where nine out of 10 people did get it for a nonindicated
case, they just didn't get aplastic anemia.
Dr. ALFANO. No, I would not say you can project it that way on
just a small sampling of indications. At least, 1 would not accept it
that way.
Senator NELSON. Please go ahead.
Dr. ALFANO. Awareness of the name of a manufacturer by the
physician and indeed by the patient is in the best interests of the pub-
lic. The manufacturer must produce a drug of the highest quality
PAGENO="0250"
4540 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY
possible because he knows that an inferior batch of one drug will
adversely affect his entire line of products. He must protect his repu-
tation as does any other manufacturer. In fact, the drug manufacturer
is more vulnerable than other manufacturers because the word travels
fast throughout the medical profession when something goes wrong.
This is certainly in the best interest of the public.
I would like to point out that the pharmaceutical firms provide
services for the patients and medical profession which are essential
for proper medical care. Generic drug firms do not provide these
services.
A vital and indispensable service offered by the ethical pharmaceu-
tical firms is a medical department available 24 hours a day every day
of the year. If a physician finds he has an untoward reaction caused
by a particular medication he can call upon the medical department
for assistance and advice. When a drug does not seem to have the de-
sired effect the medical department is available to help solve the prob-
lem. It must be remembered that the medical department has
accumulated the reports of physicians from all section of the country
representing the sum total of millions of doses for each medication.
How can we overlook the importance of this one particular service for
the sick of our country. We must not gloss over this service by stating
we know and appreciate the contributions made by the pharmaceutical
firms but comparisons show that the generic drugs are cheaper for
the most part and therefore the patient has been gouged by the brand
name drug firm. This price differential would not be as great if the
generic drug firms offered the services of a medical department.
I don't believe that this committee or the American public would
tolerate the loss of the services of the medical departments of the
ethical pharmaceutical firms. Indeed, this committee should insist
that the generic drug firms provide the services of a medical depart-
ment similar to the services provided over the years by the medical
departments of the proprietary drug firms.
The medical department is only one of many services provided
by the pharamaceutical firms and these services cost money which
is reflected in the cost of drugs.
Another example is the professional relations department which
will respond to a wide variety of requests made by the individual
physician.
Pharmaceutical firms are always ready to supply a rare drug or
a drug in short supply for a single patient. A simple telephone call
by a physician starts in motion the mechanism to bring to a patient
the required lifesaving drug. The cost in man-hours expended for
the benefit of one patient plus the other costs involved are not re-
covered by the drug firms. It is a service.
Senator NELsoN. Doctor, let me interrupt for one moment. It is
all included in the cost of production like any other overhead cost.
They put it in the price of the drug. It is a cost of operation, just
as an advertisement is a cost of operation. They recover it from the
drugs all right, otherwise it would not be the highest profit industry
in this country.
Dr. ALFANO. I know, but it is a service to the patient. The generic
firms do not offer this to the doctor or the patient.
Senator NELSON. I just want to say it is included in the cost of
the drug.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4541
Dr. ALPANO. Oh, sure, this accounts for part of the cost of the
drug, right.
Senator NELSON. Of course.
Dr. ALFANO. A detail man is more than a salesman. In my area most
of these men are registered pharmacists. The detail man provides the
physician with information on new products plus a review of estab-
lished drugs.
True, he endeavors to have the physician use his firm's products.
It's logical because without sales the firm would go out of existence.
However, the detail man's first job is to inform the physician about
the drug, how it works, the side effects, and contraindications.
He must provide the research reports and reprints of clinical trials
of the drug, answer questions and supply or obtain whatever addi-
tional data the doctor may desire.
A drug detail man is more than salesman, he is a professional
who is well informed about drugs. A liaison between his firm and
the individual physician, he is the man turned to by the hospital,
the pharmacist, and the physician to obtain whatever is required
either in drug information or services.
Research at the rate of more than a million dollars a day is carried
on by the pharmaceutical firms. Naturally, each company strives to
come up with a product which will return the money spent for re-
search. But this does not happen with predicted regularity. But all
this is not lost because both the positive and negative results con-
tribute to mankind.
Pharmaceutical firms support continuing medical education. They
support postgraduate programs by grants to pay for emminent speak-
ers. The firms do not require that their products be mentioned or
discussed in the post graduate programs. In fact, they made a point
of stating that all they desire is a credit line indicating the company
is sponsoring the program in part.
They support continuing medical education because they know it
is vital for the medical profession and the public. Certainly they
are aware that a better informed profession will result in benefits
to the entire pharmaceutical industry.
The pharmaceutical firms provide almost unlimited quantities of new
drugs to clinical investigators in order to determine the effectiveness
and safety of the new product. Financial support is given to carry
out the clinical trials of a new drug which entails the keeping of
extensive records, almost constant laboratory examinations and close
observation of the patient.
After a drug has successfully passed the clinical trials, the drug
firms support scientific exhibits which present the results of the clini-
cal trials. It is in the interest of the pharmaceutical firm to support
a scientific exhibit which is centered around one of its products. How-
ever, a scientific exhibit is an excellent method of making known to
the profession the existence of a new drug. Scientific exhibits use
the generic name of drugs in the display material and mention the
trade name and the manufacturer as a footnote. Most important, the
physician who participated in the clinical trials is available at the
booth to answer questions and to add whatever additional explanation
may be needed. The scientific exhibit's purpose is to make known
the existence of a new drug and the results of the drug with patients
during clinical trials.
PAGENO="0252"
4542 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Without scientific exhibits, published reports and reprints the
benefits of a new drug could possibly take years before it reached
the members of the medical profession, and also their patients.
If the generic firms provided these services there would be little
difference in prices between the generic drugs and the proprietary
drugs.
Senator NELsoN. May I interrupt a moment? I raise the question
again of how you can assert that with confidence? If so, how can
you explain that Schering can sell its drugs for $1.20 a hundred to
New York City and sell it for $4.25 a hundred in Berne, Switzerland,
but stayed in the marketplace until after these hearings at $17.90 a
hundred? Why were they not selling it here at less than the price at
which they were selling it in Berne, Switzerland. You say they have
to have these prices in order to do all these services. Why do they
not have to have that price when they sell to New York City, De-
fense Supply, or Berne, Switzerland?
Dr. ALFANO. As I said before, I cannot explain these extremes. I
am talking about the average, the usual that is going on in medicine,
not specifically isolated types of examples or a handful or whatever
number of examples are available.This does not occur throughout
the entire industry.
Senator NELSON. Every single brand name drug that was patented
has the same time-17 years. Every company sells it cheaper to New
York City by far, than they do in the marketplace.
Dr. ALFANO. What I am saying is, there is a difference. The cost
is increased by these services. I am not trying to justify an extreme
cost by these particular types of services. These services are provided
by the ethical pharmaceutical firms and not provided by the generic
firms.
Senator NELSON. But this is continually asserted by the manufac-
turers as the reason for their prices. All I point out is they get a patent.
That is the only protection they are entitled to. Nobody else in Amer-
ica who gets anything patented is able to stay in the retail marketplace
once the patent runs out at an exorbitantly high price. For example,
you have invented a new lawnmower, you are selling it at a high price
because the patent ha.s been in effect and it is a good lawnmower. Then
the patent runs out. You can't get by in the marketplace selling it in
competition with other lawnmowers, because the consumer can make
a judgment that another one is just as good at a cheaper price. But the
consumer camiot make the same judgment on drugs. The drug com-
panies know he cannot. The purchaser for New York City or the
Defense Supply Agency, or the Veterans' Administration, that buyer
can make the judgment and he does. And the drug company dramati-
cally drops its price.
So on the same day they are charging 30 times as much to the phar-
macist, they are offering it for one-thirtieth as much because they
know they have to compete with other brand names and the generics.
In the retail marketplace, however, the buyer is not qualified to make
any distinction at all. The doctor writes a brand name. }-Ie prescribes
and the buyer, the patient., pays.
These great discrepancies apply to all the drugs that I have looked
at. Everybody comes in with the assertion that they have to have this
price because they do all these services, but nobody ever explains how
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4543
they can make a profit of $1.20 and make a profit in Berne, Switzer-
land, of one-fourth as much.
I just say, to you, Doctor, and I do not want to be unfair to you
because a number of other witnesses have said the same thing-I just
say that in my judgment, your statement is not supported by the facts
and what you are repeating is what the pharmaceutical manufacturers
have been saying year after year. Most of the medical profession also
has been saying this. Most of the medical profession has never heard
what the industry charges in New York City or in Switzerland and
London and Rome. We have checked all these cities. The physicians
do not know what is being done over there. If they did, I think they
would say to the companies, how do you explain that you are selling it
cheaper, one-fourth as much, in another country and my patient has
to pay four times as much?
I have never heard a doctor say that. I, know why. He has not heard
about it. But he has heard from the company at the rate of $4,000 or
$5,000 advertising each year to each physician. So the company has
convinced the physician.
What you are saying to me-and I am not critical of you for it-is
what nine out of 10 doctors say to me when they talk to me across the
country. I had a meeting in Wisconsin with four doctors. One of them
started to say to me, here's the reason why the firms have to charge
more.
I said, you just hold that for a minute, and I called another doctor
aside and said, here is what he is going tO tell me, and I lined up all
the arguments by the pharmaceutical industry. And we went back to
the group and the doctor told me every one of these items. Because
that is what he has heard from PMA. The evidence supports that
every single one of the doctors and the pharmaceutical manufacturers
said the same thing.
Dr. ALFANO. I am telling you what I say did not come from the
PMA. About 2 years ago, I wrote to the pharmaceutical firms asking
for the services provided by these companies. If you wish, I could send
a couple of suitcases of material down to you. This is what I got from
being in the practice and being exposed to the services provided. I
do not believe I have anything in here that comes from the pharma-
ceutical manufacturers, at least that I received and put into this
statement.
Senator NELSON. I believe that a number of my good friends make
the same argument. I am not saying there is anything illegal about
that. I am just saying that the manufacturers have made what to the
doctors have been a compelling, convincing case and the doctors be-
lieve it. All I say is I do not think the doctors know the whole story,
because when I have asked the doctors about these prices, they have
never heard it before. They can't explain it. But the record can't stand
without having these examples saying, why can they sell in Berne,
Switzerland at $4.50 and sell here at $fT.90. I call that gouging.
Dr. ALFANO. Have the companies not been in to explain the differ-
ences in costs?
Senator NELSON. Yes; when I asked Mr. Conzen-I had the whole
list of foreign prices-he said, they charge less in Berne, Switzerland,
because the standard of living is lower over there. But they charge
more in Mexico City by three times than in Berne, Switzerland. When
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4544 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY
I asked him about that, he said he did not know the answer and he
would have to ask the comptroller of the company. I said you ask him
and write me. That is a year ago and I have not heard.
Dr. ALFANO. I do not believe the medical profession can answer
these questions of cost and the differences, really. However, I have more
faith in myself and my colleagues, that they will not knowingly write
prescriptions for a high-priced drug when they know full well that
there is an available drug that will do the job and cost a lot less.
Senator NELSON. I am confident of that. I think the medical profes-
sion is a profession of integrity, but they do not know these facts.
That is the problem. So when the spokesmen of the medical profession
say the drug companies do all these very fine things and the generic
companies do not, therefore that shows the price differential---
Dr. ALFANO. It accounts for a proportion of that price. The price
can't be equal when one is providing certain services and another is
not. There have to be differences. What the difference is, I could not
give you. That I do not know.
Senator NELSON. But to make this unqualified defense all the time
of the industry, not being able to explain-as a matter of fact, not
knowing-that the company they are defending is selling at one-
twentieth the price to New York City and the Veterans' Aciministra-
tion, and one-quarter the price in Berne, Switzerland-I am just say-
ing this argument does not hold water because they are charging a
fraction of that price in other parts of the world and in the Defense
Supply Agency.
I see I have a rolicall vote. I will try to be back in a couple of
minutes.
(Short recess.)
Senator NELSON. Please forgive me, Doctor. Will you proceed?
Dr. ALFANO. A compendium which lists all prescription drugs un-
der their generic names together with all the necessary prescribing in-
formation and a supplement of the brand names, the suppliers and the
prices at which the drugs are available at first seems to be a laudable
endeavor. As I understand it, the compendium would list 7,000 drugs
with 21,000 dosage forms. This type of listing would not be practical
since it could not be easily used by the prescribing physician. For ex-
ample, the PDR contains about 600 drugs and is more than 2 inches
thick; the compendium would contain almost eight times the number
of drugs listed in PDR and would be at least 16 inches high. Even
if special paper were used the book would be 15 inches high because
it would contain 10,000 to 12,000 pages. The compendium would not be
used and the PDR would continue to be used by the busy physician.
Why is it necessary to list all of the 7,000 prescription drugs when
in reality physicians are in the habit of using a small number of drugs.
~\Then it becomes necessary to prescribe an infrequently used drug, the
physician can obtain the required information from the appropriate
reference material.
Mr. GoRDoN. May I ask you a question at this point, Doctor?
Dr. ALFANO. Yes.
Mr. GoRDoN. You are a surgeon?
Dr. ALFANO. Yes.
Mr. GORDON. Can you give us an idea of the number of drugs, on
the average, the abdominal surgeon prescribes in a year?
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4545
Dr. ALFANO. The number of drugs?
Mr. GoiwoN. Number of different drugs.
Dr. ALFANO. No; I could not. I have actually been out of practice
the last 6 or 7 years, so I could not give it to you right from actual
experience now.
Mr. GoimoN. Could you give us an idea?
Dr. ALFANO. A surgeon uses less drugs than, say, an internist or a
general practitioner.
Mr. GORDON. Would you say about 25 or
Dr. ALFANO. Well, about 25 would be a reasonable number that
are constantly being used-pain medications, infection, control of
infection, that type of thing.
Mr. GORDON. I see. Around 25.
Dr. ALFANO. I could be way off on that. I am guessing. really.
Mr. GORDON. What would be his principal source of information
about toxic and dangerous properties of a new drug?
Dr. ALFANO. On a new drug that he is using now?
Mr. GORDON. Yes.
Dr. ALFANO. We have had a survey in the past on why does a physi-
cian, why does one of our members use a particular drug? What causes
him to use that particular drug? Twenty-three percent stated an ar-
ticle in the journal was the No. 1 reason they used-
Senator N1n~soN. You are talking about surgeons?
Dr. ALFANO. Members of the American Society of Abdominal Sur-
geons, right.
Senator NELSON. You are talking about your journal, or all articles
in-
Dr. ALFANO. No, no; any medical journal.
Senator NELSON. Twenty-three percent, did you say?
Dr. ALFANO. Twenty-three percent; yes, sir.
Mr. GORDON. How about the rest?
Dr. ALFANO. I have that, I am pretty sure. Do you want to know
what influences a physician to use a particular drug?
Mr. GORDON. No; the surgeons.
Dr. ALPANO. The surgeons; yes. This was a survey sent to members
of the American Society of Abdominal Surgeons.
Senator NELSON. How many do you have?
Dr. ALFANO. 9,000.
Senator NELSON. How many responded? 9,000 responded?
Dr. ALFANO. No. The questionnaire was sent to 1,500 surgeons and a
total of 20.53 percent of the surgeons responded and completed the
questionnaire.
Senator NELSON. When was the survey coflducted?
Dr. ALFANO. 1964.
Senator NELSON. And what other sources did they use?
Dr. ALFANO. Presentation at a medical meeting-at a meeting. It
does not say medical meeting-presentation at a meeting, 19.8 percent.
The detail man, 19.6 percent. Exhibits at a meeting, 11.6 percent.
Recommendations from a colleague, 11.5 percent. Journal advertise-
ment, 7 percent.
Senator NELSON. Advertisement in a-
Dr. ALFANO. In a journal.
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4546 COMPETITIVE PROBLEMS ~ TI~ DRUG INDUSTRY
Senator NELSON. Medical journals in general, you are talking
about?
Dr. ALFANO. Yes; because a surgeon would get, say, the Journal of
the American Medical Association.
Mr. GORDON. What percentage is that?
Dr. ALFANO. Seven percent. Advertising sent by mail, 4.6 percent.
Miscellaneous, 2.5 percent. That first figure, journal article, exactly is
23.4 percent.
Senator NELSON. This was a survey as to where they got their infor-
mation or began to use a new drug, is that what you are talking about?
Dr. ALFANO. Yes; the factors that influenced them to use a particu-
lar preparation, what caused them to use this particular preparation,
brand new, the first time they used it.
Mr. GORDON. What percentage did you get for detail men?
Dr. ALFANO. 19.6.
Mr. GORDON. And the percentage of those learning from colleagues?
Dr. ALFANO. 11.5 percent.
Mr. GORDON. It could be, of course, that the colleague could well
have secured his information from, say, the detail men or advertising
or a journal. We just do not know. That does not mean too much,
really.
Dr. ALFANO. No, no, but this is-that is right, the colleague has to
get the information originally from some particular spot. I would say
it probably follows the same, though it would be a journal article or a
presentation at a meeting or a detail man.
Senator NELSON. Please continue.
Dr. ALFANO. I suppose if a smaller listing of prescription drugs was
undertaken it would be a duplication of the PDR and would serve no
additional purpose but would create the problem of what drugs to list
and who would make the selection.
It appears that the American Medical Association's drug evaluations
currently being developed would serve the purpose of the medical pro-
fession because it would include the 500 most commonly prescribed
drugs. It also would give a comparison of drugs within the same class.
Information on the pharmacology of the drugs would be included
in the AMA publication much of which is lacking in the package
inserts. The proposed compendium would lack the pharmacology nec-
essary to knowing all about a drug since the compendium, as I under-
stand it, would be made up of the package inserts.
Senator NELSON. We have had some testimony on the concept of a
compendium. We have introduced legislation, but as to what the nature
or makeup of a practical compendium would be, we have not really
gone into it in any depth, nor have we received the advice of all the
appropriate sources, the medical profession and organizations and
the manufacturers and so forth. So I would guess when we have hear-
ings on a compendium, if such a bill were recommended by the com-
mittee, it would be one that was developed as a consequence of testi-
mony from a broad number of authoritative sources. As to whether
it would be package inserts or something else, I do not know and I
would not want to form a firm opinion until I listened to the appropri-
ate experts in the field.
Dr. ALFANO. If it is the intent of the compendium to bring bef ore
PAGENO="0257"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4547
the physician a list of the generic drugs and a price comparison then
this could be done by a supplement to the AMA drug evaluations.
However, if the intent of the compendium is to change the prescrib-
ing habits of the medical profession then I don't believe that this can
be accomplished by the compendium.
The chairman of the Monopoly Subcommittee stated in invitation to
speak before the committee that some witnesses have expressed concern
about the dependence of medical organizations upon funds derived
from the drug industry. I can speak for the American Society of
Abominal Surgeons and state that the society does not depend upon
funds from the drug industry. The society can function without any
outside help.
In 1961 drug advertising accounted for 7 percent of the cost of pub-
lishing the Journal of Abdominal Surgery. In 1962 it was 8 percent;
1963, 17 percent; 1964, 21 percent; 1965, 28 percent; 1966, 49 percent;
1967, 61 percent; 1968, 41 percent.
Senator NELSON. May I ask a question at this point?
Dr. ALFANO. Yes.
Senator NELSON. When was the journal founded?
Dr. ALFANO. The first issue was February of 1959.
Senator NELSON. We have the percentage figures here supplied by
the Legislative Reference Division of the Library of Congress.1 Do
you have the dollar figures?
Dr. ALFANO. Yes.
Senator NELSON. That is, the dollar figures of advertising?
Dr. ALFANO. I have the net advertising income.
Senator NELSON. What does that mean?
Dr. ALFANO. That means the advertising income-for example, in
1961, it was $5,533 of advertising income. Subtracted was the commis-
sions that went to the advertising agency plus our own space repre-
sentative who gets a commission.
Senator NELSON. So the figures you are going to give us now are the
net, not the gross?
Dr. ALFANO. Not the gross, billing, yes. For example, 1961, it was
$5,533 as a gross. The net was $2,846.
Senator NELSON. Could you give them to us for e.ach year?
Dr. ALFANO. Yes. 1961, $2,646; 1962, $3,520; 1963, $8,657; 1964,
$10,592; 1965, $15,214; 1966, $41,941; 1967, $55,734; 1968, $42,138.
Senator NELSON. What was the figure for 1967?
Dr. ALFANO. $55,734.
Senator NELSON. Now, were these all net figures?
Dr. ALFANO. Those are the net figures, yes.
Senator NELSON. I see.
Mr. GORDON. What percentage of your total income would that be?
Dr. ALFANO. That is what I have over here-no, that was the per-
centage of the cost of publishing the journal. I do not have the percent-
age of the total income that I can give you. I gave you-these figures
are the percentage of the total cost of publishing the journal. For
example, 1968, the cost of publishing the journal was $103,850; that
$41,000 represents 41 percent.
1 See Appendix XIII, "A Study of Pharmaceutical Advertising in Selected Medical
Journals," pp. 4863-4998, infra.
81-280-69-pt. ii-17
PAGENO="0258"
4548 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. Of the cost of publication?
Dr. ALFANO. Right.
Senator NELSON. I see.
Then what's the other income from, subscriptions?
Dr. ALFANO. Yes.
Senator NELSON. Do these two factors constitute the total income,
subscriptions and advertising?
Dr. ALFANO. Yes, subscriptions, advertising, and there is a small
amount from reprints of articles that are published in the journal. An
author may wish to have a hundred or a thousand reprints, whatever
he desires. There is a cost for that.
The income from drug advertising allows a publication to publish
more articles per issue and special features which benefits the profes-
sion and the public. For example, I would like to have more advertis-
ing income in order to develop a monthly feature on surgical anatomy
and surgical technique. This is a very expensive endeavor since it
requires the talents of medical artists and surgical anatomists. I hope
that all will agree that this is a worthwhile endeavor.
Mr. GORDON. Doctor, may I interrupt? When you say you would like
to have more drug advertising to publish more articles, what you are
really saying is you would like to have the public, the drug-consuming
public, pay for this. Surgeons do very well financially. Why should
they not pa.y through higher membership rates or higher subscription
rates?
Dr. ALFANO. Well, I have not tried that system. You mean assess the
individuals who receive the journal higher amount?
Mr. Gor~oN. When you say you want more advertising, you are
really saying that you want the consuming public to pay for it.
Dr. ALFANO. Well, the public, I am hoping, are the ones who benefit
from the results of the journal, or from the journal itself. They are
the ultimate ones to benefit from it.
Mr. GORDoN. But it is pretty indirect.
Senator NELSON. Please continue.
Dr. ALFANO. A medical publication does not come in contact with
the drug companies who advertise in the publication or the drug com-
panies who are potential advertisers. A medical journal has a space
representative who contacts the advertising agencies representing the
drug companies. Thus, there are two independent companies between
the medical journal and the drug company.
The men and women engaged in medical publications have earned
the respect and trust of their readers and that is really what counts
regardless of what some out.siders may say in an attempt to undermine
the integrity of medical publications and the sponsoring medical
societies.
Senator NELSON. In any event, does not the fact that a medical
journal-any medica.l journal-that depends in substantial part on
advertising by a drug firm, does it not really end up having, even un-
consciously, a subtle effect upon the position the journal might take
on the kind of promotion that is in the ad, or criticism of the industry
itself? The publication is relying-it does not make any difference
whether it is a medical publication or newspapers or what have you,
when they receive substantial moneys from an important advertiser, is
it not just potentially inherent in the case that they are going to be
PAGENO="0259"
COMPETITIVE PROBLEMS IN, THE DRUG INDUSTRY 4549
quite reluctant to be very critical of the one who is supplying the
money that is important to the publication?
Dr. ALFANO. I do not believe so. Not in medicine, sir. You can
probably find it in other types of advertising, but in medicine, if there
is a just criticism of the drug company or the entire industry, that
criticism will be made regardless of the number of advertisers in the
journal. Because this industry that is limited to 350,000 doctors;
therefore, the profession is not a captive of the individual drug coin-
panies or the industry. If there is a valid justified criticism, I believe
every medical journal and every society would make it known and
would not hesitate because they have `advertising or money coming in
because of ads in their particular journal.
I would never be afraid to put anything in the journal criticizing
the drug industry. If I have something that is valid, I will put it in.
Senator NELSON. Well, is it not just human nature, the nature of
human beings, whether it is medical publication or any other, that if
an important source of money is coming from a particular place, it
creates a potential bias. It could be conscious or unconscious.
I read some of these publications. I am not referring to yours-I
have not read it, so I do not direct this at you at all. But I read quite
a few of the publications that rely heavily upon drug company ad-
vertising. Sometimes I cannot quite identify the hearing they are
talking about because of the bias they put into the .stories. Actually
they are these hearings. If you just look at them regularly, you will
find a lot of bias in favor of the company. I suppose that is just
natural.
If that publication is critical and tough on an advertiser, who they
think is doing something wrong, that advertiser is likely not to spend
any money with them. I do not see how that is avoidable.
So it just seems to me that medical journals and medical publica-
tions are compromised by the substantial amount of money that they
rely upon from an industry which needs independent critical evalua-
tion from the medical profession all the time. I do not see how you
avoid that.
Dr. ALFANO. WTell, I believe the checks and balances-the American
indivicltial is critical. They are critical individuals. If you have an
association with a publication that tries to 15ut something over on its
membership, that publication, that society will hear about it, because
they have hundreds of thousands of members who are reading. They
will not stand for something which they feel is iiot correct or proper.
I do not think they can put something over on the members is what I
am saying, because of money from advertising.
Senator NELSON. There is no doubt in my mmd that as professions
go, I am biased toward the medical profession. I was raised in a family
with lots of doctors. I think there is not any profession that has a
higher percentage of conscientious people in~ it. I think it probably
has more conscientious people than any other profession because of
the nature of the person who is inclined to select that profession in
order to take care of the health of someone else. But that does not
mean they are all perfect. We all know that. I happen to be a lawyer,
but I think there is more dedication, a higher percentage of the people
who are really dedicated, in the medical profession, doing good for
other people, than there is in my profession, though we have a sub-
stantial number of highly dedicated people, too.
PAGENO="0260"
4550 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
So I would not raise any question about that. I think if a publication
conscientiously misrepresented or defended a bad cause in the medical
field, practically all individual doctors would be very critical of it.
So I am not raising that question.
I simply say that if you are a publication and you rely heavily
upon an advertiser-in this case, it is drugs-you lust may omit criti-
cizing them. You do not have to mislead by commission, you can mis-
lead. by omission. I think it is true of almost every magazine or paper
that relies heavily upon some industry for advertising.
I do not see tough criticisms in various publications of the major
advertiser in that publication, when it is a daily newspaper. They are
pretty careful. If something breaks and they have to cover the news,
maybe they do.
But here is a case where the profession has the primary obligation
to the public and its patients. And it is important that the profession
at all times be vigorously, conscientiously evaluating all aspects of
medicine, including the promotion of drugs and the use of drugs and
advertising, policies and claims for drugs. The fact is that there are
just endless examples of the drug companies making claims for their
drugs that are not acceptable to the FDA.
Dr. ALFANO. They do not a.ppear in journals, to my knowledge,
that type of ad. They cannot. The journal must have the approved
information.
Senator NELSON. Counsel advises me that last year-within about
the last year and a half-as a consequence of paid drug ads in publica-
tions, medical publications, the FDA required 29 "Dear Doctor"
letters-ui other words, 29 times in the last year and a half, because
of misleading advertising, the FDA has required the company to
write a letter to every single doctor in America correcting the mis-
leading claim. That is quite a bit. But it appeared in the journals.
Dr. ALFANO. These were ads that appeared in journals?
Senator NELSON. In medical journals.
Dr. ALFANO. Excuse me, the Medical Tribune is not a medical
journal.
Senator NELSON. I do not want to mislead you. Some of them
were in these other publications which rely exclusively upon drug
advertising.
I recogi~1ze a dist.inction between a. publication that receives 100 per-
cent of its money from drug advertising and one that receives 50
percent. But if they receive a large percentage, I think that they can-
not really be independent and objective in the fashion they ought to
be in order to protect the interests of medicine itself. Do you really?
Dr. ALFANO. I believe the scientific medical journals, journals that
are published by societies, they are published by these same individ-
uals who you state are the most dedicated group in the country. I do
not believe they would be influenced one way or the other by the
amount of money that comes in by an ad. If they have something
valid to sa.y in criticism of a particular company or of the industry,
t.hey would put it in.
Now, there are more than just scientific medical journals that carry
the same ads. I am only speaking as far as the medical journals that
are published by medical societies.
Senator NELSON. Counsel advises me that 19 of the 29 "Dear Doc-
tor" letters were based upon ads in medical journals.
PAGENO="0261"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4551
Dr. ALFANO. I know, I have seen these "Dear Doctor" letters. I
have received them and some of the criticism, they are not that im-
portant as regards the patient and the result of the medication. There
is a dispute between the FDA and the drug companies that I do not
know that much about. But it does not seem that it makes that much
difference. But these letters come out and, as you say, there were 19.
But I am sure they do not affect the policy that the journal, if it is
something vital, will certainly make it known in the next edition that
they did publish an article that was misleading and they would make
it known.
Mr. GoRDON. Doctor, are you aware that certain criminal cases have
been brought against drug companies for advertising in medical
journals?
Dr. ALFANO. I do not believe so. Which ones are you referring to?
Mr. Goi~oN. Well, the criminal cases are Pree MT, Esidrix K, Esi-
drix, and the civil case is Enduron.
Dr. ALFANO. I do not know about those cases.
Senator NELSON. I have another rollcall and I do not want to hold
you over. We are late as it is. I think this is an important question,
however. As I say, I do not think it is so much a question of reputable
journals misleading intentionally. I do not think they do that. But
the argument remains that you might omit to do something that you
ought to do-I mean broadly, any journal; because that is the nature
of human beings. I find it very hard to be critical of a good personal
friend of mine because I like him. I overlook defects or something
wrong with somebody I like, and so do you. And you end up in a posi-
tion-that is, the medical journals end up-in a position, it seems to
me, where just in the nature of the case, they compromise themselves
and condone some of these things that they ought not to.
Dr. ALFANO. There is no close relation between a journal and a
drug company as such. As I stated, there are other individuals or com-
panies that come between the journal and the drug company.
Senator NELSON. But the financial relationship, when it reaches
a substantial amount-is a close financial relationship. And if you
are depending upon that and you would like to have more advertis-
ing, or any of the rest of them would, I do not see how any publica-
tion can avoid being compromised by it. It is the nature of the animal,
I think.
Dr. ALFANO. I disagree. I do not believe that this type of thing
exists where they would knowingly withhold information which essen-
tially is unethical for a medical publication or a man who is editor of
a publication to withhold information. He must make known-what-
ever he knows must be made known to his colleagues.
Senator NELSON. I would not suggest that they willingly withhold,
but maybe they fail to criticize. I think Chloroinycetin is a dramatic
case in point.
Now, many of the medical journals carried articles by distinguished
authorities on the drug explaining and emphasizing that it is over-
prescribed, was being widely misprescribed, at the same time they were
receiving it, carrying lots of clever advertising promoting the drug.
This is a terrible case, it is a terrible indictment of those in the pro-
fession who misused the drug and the promoters of the drug. I would
have a thought that every medical journal in America ought to have
PAGENO="0262"
4552 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
front page, cover stories, and if necessary, a national meeting about
it. I never saw that. It took the dramatic publicity from these hearings
to do it. The medical profession should have done that.
Of course, they will say, we ran an article a few years ago. We ran
one another time. But the fact is the wide misprescribing continued
and the leaders of the medical profession knew it and they did not
stop it.
Dr. ALFANO. These are the opinions of certain individuals. You
mentioned Dr. Dameshek, that 10 percent only needed or it was neces-
sary to use Chloromycetin. I say when this is substantiated and it is
an absolute fact, you will find it in all the medical journals that x
drug should not be used because it has more dangers than it has bene-
fits. Until that happens, I do not believe that you should expect a
journal or a society to arbitrarily take action against a particular
drug, particularly the one you mentioned, which is known to be an ex-
cellent drug, with its indications.
Senator NELSON. There is not a medical organization or a leading
distinguished authority in America who has doubted the drama of
this situation-that it is being widely misprescribed. I have a file
you could cry reading. I get letters every month. I have a file that
high: "My daughter came home from college with a sore throat and
got Chloromycetin and died." One from a husband last week with a
30-year old wife who had Chloromycetin for the flu and died. "My son
had a hangnail and died"-"an infected gum, and died." Every single
case nonindicated. Every single case.
I did not see the profession or the journals screaming to the high
heavens about it. I think it is an indictment.
Dr. ALFANO. Did the profession get that information? I have not
seen a letter come to our organization or the journal concerning these
specific cases of misuse. However, you must remember, there are 831
million patient visits a year. Certainly there are going to be exceptions
to good medical care out of that 831 million patient visits. But I do
not believe because you have some examples that you have to condemn
the whole professioi~ or the system.
Senator NELSON. But when you have distinguished authorities say-
ing in their judgment, 90 percent is for nonindicateci cases, one of
them saying 99 percei~t in his judgment, nobody is refuting it. Maybe
it is only 85 percent, maybe it is 95, but it is terribly high. And these
pubhicatioi~s all take ads.
Dr. ALFANO. It may be 89 percent in his case, it may be 1 percent
to someone in practice out in the suburbs. I do not know what those
figures are.
Senator NELSON. There are certainly a number of doctors who never
misprescribe at all. We know that. But this figure is awfully big and
it dropped by half when the hearings started.
I have imposed on you enough and I appreciate very much your tak-
ing the time to come. I do not want to have you come back again. I
thank you for your willingness to testify today.
I will be back in about 10 minutes.
(Short recess.)
Senator NELSON. Dr. Krantz, I am sorry we have had some inter-
ruptions. The Senate would be a lot better place if I were running it,
but I am not.
PAGENO="0263"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4553
Our next witness is Dr. John C. Krantz, Jr., of Huntingdon Re-
search Center, Inc., in Baltimore. Dr. Krantz is a professor emeritus
of the Department of Pharmacology at the University of Maryland.
Go ahead, Doctor. We are very pleased to have you here today and
we apologize for being delayed so long in getting to your testimony.
STATEMENT OP JOHN C. KRANTZ, JR., PH. B., HUI'TTINGDON
E~SEARCH CENTER, INC., BALTIMORE, MD.
Dr. KRANTZ. Senator, Mr. Counsel, every animal is capable of a cry
characteristic of its species; man alone speaks. All along the tortuous
road of ascent, articulate speech has been the sharp line of distinction
between man and other primates. Speech gave him a history, speech
enabled him to transmit knowledge, and speech has marched with a
fidelity that is unwavering in the vanguard of advancing civilization.
But when speech or any form of communication is unclear it may
serve as the source of misunderstanding and mischief. In medicine,
with the prescribing of drugs, it can be the difference between the
"quick and the dead." St.. Paul, in his letter to the Church in Corinth,
gave us the word, "Except ye utter by the tongue words easy to be un-
derstood, how shall it be known what is spoken? For ye shall speak
into the air."
This thesis is a plea for simplicity in the nomenclature of drugs.
I have been advocating this principle for four decades. Its first target
was the preposterous use of the Latin titles in the official compendia
and on prescriptions. I have witnessed the complete demise of this
anachronism.
For three decades I taught pharmacolOgy to medical students in
the School of Medicine in the University of Maryland. It was extraor-
dinarily difficult to have the student become familiar with two
names and sometimes three or four for the same drug. It was more
difficult to explain to an intelligent person why this cumbersome and
confusing practice existed. This confusion did not prevail only with
the student but also with trained physicians.
My proposal is simple and would bury the so-called created generic
name in the same cemetery with the Latin titles. I propose that a new
drug be assigned a name by its manufacturer, approved by the FDA
and/or USAN, with a suitable suffix, representing the manufacturer.
For example:
Benadryl-Parke, Davis-not diphenhydramine hydrochloride.
Dramarnine-Searle-not, dimenhydramate.
Isordil-Ives-not isosorbide dinitrate.
Capla-Wallace-not mebutamate.
Such a name then becomes the only name that the drug has other
than the true chemical name that may appear in small print on the
label.
At the termination of the patent, other manufacturers could syn-
thesize and market the product, using the assigned name without the
originator's suffix. Thus, the names Benadryl, Dramamine, Isordil
and Capla would be the equivalent of the generic name used today.
This has happened in the case of aspirin. Manufacturers are free to
market aspirin but, Aspirin-Bayer has withstood the ravages of time
and competition. This leaves us still with the age old problem of
PAGENO="0264"
4554 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
"generic equivalency." The advocates of the purchase of generic named
drugs, on the basis of economy, are only correct in a comparatively few
cases.
1. The report of the study of this problem by the AMA asserts,
"Except in a few cases, there is no economy achieved in the purchase
of generic named drugs."
Senator NELSON. May I interrupt there a second?
Dr. KRANTZ. Yes.
Senator NELSON. About a year ago, two drug chains, Peoples and
C-ray's-I am going by memory here-I think representing about 300
drugstores, both announced that they were going to stock a line of
generic drugs, that the manufacturer would be Strong, Cobb & Amer.
Dr. KRANTZ. The Cleveland company? I think it is the Cleveland
company; a very fine company.
Senator NELSON. They have a good reputation, I understand. This is
on price. The stores have announced that the average price of their
generic drugs would be one-half the price of the brand names, on the
average. So that is in direct contradiction to the AMA report.
Is this a study that the AMA did about a year ago in December?
Dr. KRANTZ. And published in their newsletters.
Senator NELSON. I am going to have to take another look at it, but
I think there were some fatal defects in it. They did some buying at
drugstores and then announced a price. They made purchases at the
retail level and ended up by saying that they did not gain anything
in price. This is very simple to explain.
Under all the laws of this country, if a doctor prescribes a~ generic
name, the pharmacist can supply anything he wants, any brand. If
ho prescribes a- brand name in some 40-odd States, there can be no sub-
stitution. Maybe it applies in all States now, I do not know. But I think
it is 42.
Now, all that happens is that if you go to a drugstore, as the AMA,
I understand did, and you ask for prednisone and the store is only
carrying meticorten, you pay the same price as if you went into the
store and asked for meticorten.
So I was impressed by that study of theirs, really, because I
think that was a fatal defect in it.
I shall look at the record and be sure I am not mistaken in what I
state here. If I am, I shall correct it.
Dr. KRANTZ. Senator, if you follow this suggestion, you will elimi-
nate all those worries. You will not have that problem any longer.
Senator NELSON. WTell, I think the suggestion made-we have had
some testimony along this line of simplification, and I think the sug-
gestion you make here is a very simple one and might very well be
exactly what ought to be done.
Dr. KRANTZ. May I continue?
Senator NELSON. Yes.
Dr. KRANTZ (reading). 2. The purchase of generic-named drugs on
price from manufacturers of unknown reputation involves the risk of
an inferior or even an ineffective product. This is tantamount to throw-
ing dice for the destiny of the patient.
Senator NELSON. Might I say there, Doctor, we mentioned Strong,
Cobb & Amer. I am not qualified to make any independent judgment
of my own about the quality of any product put out by any company.
PAGENO="0265"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4555
Strong, Cobb & Arner, I understand, sells to many companies and,
from everything I have heard, has a fine reputation.
Dr. KRANTZ. That is right.
Senator NELSON. As to your item No. 2, what risk would there be to
a pharmacist who announced, as Peoples & Gray's did, that we are
going to stock `a brand of generics `by Strong, Cobb & Amer because
we know that they are a distinguished company with good quality.
Dr. KRANTZ. None whatsoever.
Senator NELSON. Thank you.
Dr. KRANTZ. You say I qualify this `by stating that unknown repu-
tation.
3. There is no substitute for integrity and pharmaceutical expertise
of the manufacturer. To be sure, the originator of the product would be
the most likely source of a dependable, uniformly formulated and
active product.
Notice I say, most likely. To assert that skilled pharmaceutical
scientists employed by reliable manufacturers cannot formulate ef-
ficacious `and uniformly dependable dosage forms of medicaments is
equivalent to saying that pharmacy and biopharm'aceutics do not exist.
As a member of the Committee on Revision of the U.S. Pharm'a-
copeia, I have also advocated the use of trade names in the mono-
graphs. But there are those who stated if, for example, the title Capla-
Wallace were used in an official compendium, the trade m'ark rights
would be abrogated. I have recently read, the law pertaining to these
matters and am of the opinion that this was an unfounded judgment.
The advantages of this suggestion are as follows:
1. One name for each drug enhances safety and ease in prescribing.
If we stop right after "safety," this justification is enough for doing
this.
2. The manufacturer is always identified with the product.
3. The manufacturer stands to gain `by such `a process of simplifica-
tirni by having `his name or insignia attached to the only name of the
drug.
Senator NELSON. Well, I would certainly agree that from the evi-
dence we have had over the past 2 years from other distinguished wit-
nesses, that the question of simplifying the names in identification
of the drugs is an important question.
I would certainly agree with you, based upon other witnesses, like
you who have testified on this question, that it ought to be done. I do
not know the best way to accomplish it, I am not certain in my own
mind, but I think the present system is, as you say, very cumbersome
and confusing.
Well, I thank you very much.
Mr. GounoN. Do you have that list of drugs you talked about
before?
Dr. KRANTZ. It is the only list I have.
Senator NELSON. D'octor, what is the significance of-I have not
had a chance to study it-the document you have submitted with the
list of drugs?
Dr. KRANTZ. Well, the statement was made `this morning that these
generic-equivalent drugs are always, or generally, the therapeutic
equivalent of the trade mark item. I simply stated that a colonel from
the Army-I suppose it would be their purchasing agent-
Mr. GoRDoN. Do you know his name?
PAGENO="0266"
4556 CO~ETITIVE PROBLEMS fl~ THE DRUG INDUSTRY
Dr. KRANTZ. No. I do not know his name, but. I have it in my records
at home. It has been about a. year ago since he appeared. He came and
told me one day that they had purchased a number of these items by
price and they had not worked well in the patients. They have not
given the required therapeutic results that they expected.
So I delineated a series of tests that we could do on animals that
would enable him, in turn, to be sure within a reasonable doubt that
the item that he was purchasing would be tantamount to the trade
mark item. At the present time, we are considering the same situation
for the Maryland Hospital Association, which includes some 56 hos-
pitals and spends roughlv $13 million a year on drugs.
It is their contention that if they could buy with certainty a drug
that was generically labeled instead of trade mark labeled, they may
save some money.
So if we apply these tests, I think we can assure them that they are,
within reason, the therapeutic equivalent.
Senator NELSON. I see no indication here of the test that was made
on each of these drugs, if it was made, to determine whether it might
be up to DSP standards. \T\Tho made that test?
Dr. KRAXTZ. Some of these products are not in the Pharmacopeia,
you see. Tedral, for example, one of them, is not an official product.
Senator NELSON. Of those that are, where was the test made to see
whether it met the DSP standards? Who made it?
Dr. KRANTZ. I presume it was made by the laboratory of the Army
procurement group, but I do not know.
Senator NELSON. So you are not certain whether or not any of
these drugs met DSP standards?
Dr. KRANTZ. No; I did not have any of the drugs.
Senator NELSON. I think that this is a crucial question.
The testimony before the committee has been that if the drug
meets DSP standards, it is their judgment that it is therapeutically
equivalent and there has not been any significant evidence except as
Perhaps to one drug, and that is a maybe, that if they met DSP
standards, they were therapeutically equivalent. We do not know,
then, whether the drugs you mentioned, met DSP standards?
Dr. KRANTZ. I agree.
Senator NELSON. WTe recognize, and I know you do, as an expert,
that brand name companies and generic companies manufacture drugs
and, for reasons of quality control, a certain percentage of them do
not meet DSP standards. As I have said earlier in the hearing, the
one big test made showed that generic companies had a better per-
centage in meeting a potency test than did the brand name companies,
by 1 percentage point.
So these are not submitted, then, as part of that?
Dr. KRANTZ. Oh, no, no.
Senator NELSON. I see.
Mr. GORDON. I might also mention that tolbutamide is not sold by
the generic name. It comes only under the brand name of Orinase.
It is manufactured by only one company, Dpjohn.
Dr. KRANTZ. I thought the patent had expired.
Mr. GORDON. Not yet. It will expire soon, but has not yet. As of
now, only Dpjohn manufactures that.
Dr. Kn~&x'rz. Dp to this time, and this was about a year ago, the
patent had not expired on Miltown and EquaniL which was the same
PAGENO="0267"
COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4557
drug, meprobamate. I asked the colonel about this, because I was
interested in the inclusion of meprobamate in the pharmacopeia,
because I was director of Scope
Mr. GolmoN. I said that, with respect to tolbutamide, there is no
other company making this but Upjohn.
Dr. KRANTZ. You cannot be sure.
Mr. GORDON. Is Tedral a brand name?
Dr. KRANTZ. This is an asthmatic, remedy that contains amino-
phyilin ephredrine and some other agents-I do not remember.
Mr. GORDON. Is this a. brand name or a trade name?
Dr. KRANTZ. A trade name.
Mr. GORDON. So you have trade names on your list?
Dr. KRANTZ. There is no other name. It is a mixture.
Mr. GORDON. I still cannot understand what the significance of this
list is.
Dr. KRANTZ. Let me explain it to you very carefully and very
slowly: Our laboratory engages in scientific research, developmental
procedures, and so forth. This colonel from the Procurement Office of
the Army in Philadelphia called and asked if he could have an
appointment.
1-le came down and spent a whole afternoon with me and told me his
problem was this: By Government mandate, he is forced to buy drugs
on price. Now, we have bought these drugs that he has mentioned
there and they have not, in the hands of our doctors, met the stand-
ards, or met the clinical equivalency would be better-clinical equiva-
lency-of the trademark product.
Senator NELSON. May I interrupt there? Did your lab conduct the
clinical tests, how many patients were involved, and where were they
conducted?
Dr. KRANTZ. I do not know this. This was in the Army. They were
giving them to soldiers and people in veterans hospitals, I presume.
Senator NELSON. So we do not know what kind of tests they con-
ducted and whether it was a scientific, clinical test or not. We do not
know whether the drugs met USP standards or not?
Dr. KRANTZ. That is correct. It is simply an opinion.
Senator NELSON. We do not know how many were generics and
how many were trade names, either?
Dr. KRANTZ. Well, I got the impression from him-this conversa-
tion has been over a year ago, so it is not all clear in my mind-that
there were several companies that were making these items prior ~o
expiration of the patents. Now, I can readily see how most any com-
pany could make something comparable to Tedral by simply mixing
the ingredients. They know the formula, it is available, so they could
call it most anything they wanted-psuedo-Tedral or anything of the
sort.
Senator NELSON. Of course, if it is under patent, they could not
market it.
Dr. KRANTZ. I doubt if it is patentable, a mixture of this kind.
Senator NELSON. All right. Thank you very much, Doctor. We
appreciate your taking the time to come here. I apologize for having
delayed so long in getting you on.
The committee will stand in recess until Tuesday, March 18, at
10a.m.
PAGENO="0268"
4558 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
(The supplemental information submitted by Senator Nelson
follows:)'
[From Federal Supplement, vol. 257-cases argued and determined in the U.S. District
Courts-U.S. Customs Court-pp. 991-998]
SHANE STROMSODT, a minor, by Robert M. Stromsocit, his guardian ad litem,
Plaintiff,
V.
PARKE-DAVIS AND COMPANY, a corporation, Defendant.
Civ. No. 3992
United States District Court, D. North Dakota, Northeastern Division-
September 28, 1966,
Product liability case involving defendant's ethical drug which allegedly
caused injuries to infant plaintiff. The District Court, Ronald N. Davies, J.,
held that evidence established that defect in defendant's drug caused damage
to brain and central nervous system of infant, that such defect constituted
breach of implied warranty of merchantability, that defendant was chargeable
with negligence in failing adequately to test product and adequately to warn
of dangers inherent in its use and that infant was entitled to award of $500,000,00.
Judgement for plaintiff.
1. Druggists ~1O
Evidence established that competent, producing cause of damage to brain and
central nervous system of infant was defect in defendant's ethical drug, a quad-
ruple antigen with a prophylaxis against diphtheria, pertussis, tetanus and
poliomyelitis, and that chronologically and etiologically, infant's condition was
traceable directly to the drug administered to him.
2. Sales ~284(1)
Defect in drug resulting in damage to brain and central nervous system of
infant to whom drug was administered constituted breach of implied warranty
of merchantability.
3. Sales ~255
Asserted lack of privity is not defense in North Dakota in an action by ulti-
mate consumer against manufacturer of drug for breach of implied warranties,
where, through advertising or other media of education and information, defend-
ant manufacturer has persuaded medical profession to prescribe defendant's
drug.
4. Druggists ~9
Finding that defendant drug manufacturer breached implied warranty of
merchantability and that infant plaintiff's injuries were caused thereby did not
preclude finding that manufacturer was also chargeable with negligence in fail-
ing adequately to test product and adequately to warn of dangers inherent in
its use.
5. Druggists ~1O
Evidence established that adequate test performed prior to marketing of
defendant's ethical drug would have disclosed product's potency instability as
well as cause of greater incidence of reaction and that defendant was negligent
in failing to adequately test product, in suit for damage to brain and central
nervous system of infant resulting from defect in defendant's drug which was
administered to infant.
6. Druggists ~9
Even though drug manufacturer met all of government regulations and
requirements in production and marketing of drug, manufacturer still owed
duty to warn of dangers which were inherent in use of drug and of which it
knew or should have known in exercise of reasonable care.
~. Druggists ~9
For drug manufacturer to be liable for injuries caused by use of its drug on
basis of its failure to warn of dangers which are inherent in use of drug and
1 See p. 4537, supra.
PAGENO="0269"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4559
of which it knows or should know in exercise of reasonable care, danger must
be reasonably foreseeable and injury must be proximately caused by failure to
warn.
8. Druggists ~1Q
Evidence established that defendant drug manufacturer knew or should have
known that its ethical drug, a quadruple antigen with a prophylaxis against
diphtheria, pertussis, tetanus and poliomyelitis might cause encepbalopathies in
some users and that it was negligent in failing to give adequate warning of that
danger, in action for damage to brain and central nervous system of infant
resulting from use of drug.
9. Druggists ~
Even if case of encephalopathy was the first occurring after administration of
defendant's ethical drug, that did not preclude finding that such as foreseeable
by defendant and that defendant was negligent in failure to give adequate
warning.
10. Dainages~132(3)
Where plaintiff as a baby suffered convulsions following administration of
defendant's defective drug and at time of trial, when plaintiff was seven years old,
he walked unsteadily, lacked coordination, spOke but a few words, had none of
basic childhood skills normally possessed by children of this age, plaintiff suffered
permanent and irreversible injuries to his brain and central nervous system and
plaintiff would in all probability be institutionalized shortly for inability of his
parents to give him necessary care, plaintiff was entitled to award of $500,000.
Melvin M. Belli, of Belli, Ashe, Gerry & Ellison, San Francisco, Cal., Mart R.
Vogel of Wattman, Vogel, Vogel, Bright & Peterson, Fargo, N.D., Carlton G. Nel-
son, and Jerome J. Mack, of Nelson & Mack, Grand Forks, N.D., for plaintiff.
Harold D. Shaft, of Shaft, Benson, Shaft & McConn, Grand Forks, ND., for
defendant.
MEMORANDUM AND ORDER
RONALD N. DAVIES, District Judge.
This is a product liability case tried to the Court without jury, involving the
ethical drug Quadrigen made by the Defendant, Parke-Davis and Company, con-
taining four antigens: diptheria toxoid, tetanus toxoid, pertussis (whooping
cough) vaccine and poliomyelitis vaccine. It was also described as a quadruple
antigen with a prophylaxis against diphtheria, pertussis, tetanus and poliomye-
litis. Jurisdictional requirements of 28 U.S.C.A. § 1332, have been met.
The Plaintiff was originally shown as "Robert M. Stromsodt, guardian ad
litem of Shane Stromsodt, a minor." By ex parte order entered by this Court April
1, 1906, leave was granted Plaintiff to amend the caption of the amei~ded coin-
plaint to iaclude "and Robert M. Stromsodt, individually." The Defendant
moved the Court to set aside this order, urging that it was given no opportunity to
object to it and contending that the North Dakota Statute of Limitations had
run as against any claim of Robert M. Stromsodt, individually. A ruling was
reserved on this motion.
To make certain that the issues are solidly joined in this cause, and that its
ultimate resolution may not be attacked by reason of any real or fancied future
claim to which the Defendant may think itself exposed, the Defendant's motion
upon which ruling was reserved, must be and it is hereby granted. The Defend-
ant's motion to dismiss the cause of action as to Robert M. Stromsodt, individ-
ually, must be and it is hereby granted. for the reason that the complaint fails to
state a cause of action as to Robert M. Stromsodt, individually. This case is order-
ed captioned as it appears herein, that is, "Shane Stromsodt, a minor, by Robert
M. Stromsodt, his guardian ad litem. Plaintiff, versus Parke, Davis and Company,
a corporation, Defendant," and as so styled it will be adjudicated.
In 1953 Parke, Davis commenced studies for the purpose of determining the
feasibility of combining poliomyelitis vaccine with the company's trivalent anti-
gen sold under the trade name "Triogen," containing diphtheria toxoid, tetanus
toxoid and pertussis vaccine. Parke, Davis' product, Quadrigen, which has here-
tofore been described, was finally developed and licensed March 25, 1959, and
its manufacture authorized by the Department of Health, Education and Wel-
fare (HEW). Commercial marketing of the drug under the trade name "Quadri-
PAGENO="0270"
4560 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
gen" commenced in July of 1959 with Quadrigen having an expiration dating
period of twelve months after manufacture, and six months after issue.
On April 13, 1961, the Division of Biologics Standards (DBS) of the National
Institutes of Health (NIH) issued a memorandum to manufacturers of mul-
tiple antigen products containing pertussis and poliomyelitis vaccines that the
products could contain no less than 14 units of pertussis potency (previously 12)
and be labeled with an expiration date of six months after manufacture, and four
months after issue. This change was necessitated when studies indicated a sig-
nificant loss of pertussis potency in quadruple antigen vaccines after marketing.
No comparable loss of pertussis potency had been found in triple antigen products
not containing poliomyelitis vaccine.
DBS then determined that some lots of inactivated poliomyelitis vaccine con-
tained a live vacuolating agent (SV 40), from the monkey kidney cells on which
poliomyelitis virus w-as grown. Resultantly, a memorandum was issued May
20th, 1961, requiring the subsequent lots of vaccines containing components grown
on monkey kidney cells be free of live SV 40.
On August 23, 1961, DBS issued a regulation or letter placing a new toxicity
test requirement on all products containing pertussis vaccines; and on September
21, 1961, provided a new reference vaccine for the pertussis potency test which
effected an additional increase in the potency requirement. The new toxicity test
required additional treatment of the pertussis component. This treatment ad-
versely affected the pertussis potency to the extent that the potency requirement
could not consistently be met. Various articles appearing in medical literature
indicated that the poliomyelitis component and the preservative being used might
be the cause of the instability in multiple vaccines. Production and marketing of
"Quadrigen" was finally halted in November, 1962.
Shane Stromsodt was born in Grand Forks, North Dakota, May 24th, 1959. His
mother's pregnancy and his birth were entirely normal and uneventful, accord-
tag to her physician, Dr. John H. Graham. On August 26th, 1959, Shane was tak-
en for examination to Dr. Graham's office; and on that date Quadrigen was ad-
ministered to him intermuscularly. The infant seemed to suffier no ill effects, and
his mother recalled no reaction which caused her any alarm. On October 1, 1959,
some five weeks later, Shane was again taken to Dr. Graham's office, examined
and once more Quadrigen was injected into the child's body, between four and
five o'clock that afternoon. Mrs. Stromsodt bundled up the child and took him
to the family car in which her husband, Robert, was waiting. She reached the car
some five or ten minutes after Shane had received the Quadrigen, removed the
blankets from about the child, and noticed a fine red rash on his face.
The Stromsodts drove to their home where Shane was undressed, and the rash
was noticed on his face and the upper part of his body. Mrs. Stromsodt gave Shane
his bottle immediately after the family had had their meal. Shane promptly
vomited the bottle's contents, something he had never done before. Mrs. Stromsodt
laid the child on the bed and testified the baby bad a "seizure." She described his
eyes as rolling back in his head, his heels and head dug in~to the bed, his back
arched and his fingers grasping. Mrs. Stromsodt believes the convulsion may have
lasted five minutes. Having no idea of what was happening, she watched Shane,
and when the seizure was over, telephoned Dr. Graham. She described to the Doc-
tor what had happened to Shane and added that she thought the baby had the
measles. The Doctor, however, thought it was a reaction from' the shot given
Shane and instructed Mrs. Stromsodt to watch him and to telephone next morn-
ing if the child was no better. Shane seemed normal the next morning, and Mrs.
Stromsodt did not call the Doctor nor see him again until November 4, 1959, when
the baby was taken to Dr. Graham's office for a third shot. Shane slept most of
the next two days following the initial seizure, but he had two more convulsive
attacks after the first one, both of which were prior to November 4, 1959.
When Shane was taken to Dr. Graham's office, November 4, 1959, Mrs. Strom-
sodt recited his condition to the Doctor. She told him the baby had suffered from
two "spells" since the last Quadrigen shot, that he had been sleeping more and
"it seemed like he wasn't doing anything any more." In short, the child was not
progressing normally. The Doctor concluded that Shane should not be given
Quadrigen because of the severe reaction suffered by the infant following the
October 1 injection of that drug, and thus, on his third trip Shane was given
Triogen which contained diphtheria toxoid, pertussis vaccine and tetanus toxoid
(DPT). Poliomyelitis vaccine was not given on this date.
Shane continued to have difficulties which stemmed from the October 1st in-
troduction of Quadrigen into his body and repeatedly had seizures until January,
1960. Mrs. Stromsodt testified the baby was making no progress. On January
PAGENO="0271"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4561
13, 1960, the Stromsodts sought the advice of a specialist in pediatrics and took
Shane to Dr. Samuel L. Pettit in Grand Forks. The Doctor prescribed phenobar-
bital for the child and testified that he finally prescribed a conventional dosage
of one-quarter grain phenobarbital three times a day for Shane, which amounts
he continues to receive.
When trial of this case began Shane was nearly seven years old. The record
show he walks unsteadily, lacks coordination, speaks but a few words has none
of the basic childhood skills normally possessed by children of his age and can
neither read nor write. Uncontroverted medical testimony disclosed that he has
damage to the brain and central nervous system. Shane is definitely, permanently
and `irreversibly injured, and in all probability his parents shortly will be unable
to give him the necessary care and the boy will have to be institutionalized.
[1] A careful weighing of all the credible medical testimony in this case leads
this Court to the inescapable conclusion that the competent producing cause of
Shane `Stromsodt's condition was Quadrigen, and that chronologically and etiolog-
i'cally Shane's condition is traced directly to the Quadrigen administered to him
October 1st, 1959.
Of the several theories under which the Plaintiff seeks to recover in this ac-
tion, only two are sustainable and require discussion here. They are breach of
an implied warranty and negligence.
EREACH OF IMPLIED WARRANTY
"The liability in negligence of a manufacturer or other supplier for damage
caused by his product is `based on the supplier's failure to exercise reasonable
care. Hence, negligence is a tort concept `based on fault.
"Although the courts are occasionally confused a'bout the matter, warranty,
on the other hand, is not a concept `based on fault or on the failure to exercise
reasonable care. But this does `not mean `that warranty is necessarily contractual
or nontortuous in nature. Liability in warranty arises where damage is caused
by the failure of a product to measure up to express or implied representations
on the part of the manufacturer or other supplier. Accordingly, an injured person
is not required to prove negligence in a warranty-products liability ease.
"This has `been concisely summarized as follows:
"`There seems `to be some confusion in understanding `the nature of im-
plied warranty liability. In the first place, `concepts of negligence and fault,
as defined by negligence standards, have no place in warranty recovery cases.
Proof of negligence is unnecessary `to liability for `breach of implied warranty
and lack of it is immaterial to defense there'of. Since the warranty is implied
[emphasis by court] either in fact `or in `law, no express representations or
agreements by the manufacturer are needed. Implied warranty recovery `is
based upon two factors: (a) The product or article in question has been
transferred from the manufacturer's possession while in a "defective" state,
more specifically, the product fails to be "reasonably fit for the partic-
ular purpose intended" or of "merchantable quality," as these two terms,
separate but often overlapping, are defined by the law; and (b) as a result
of being "defective," the product causes personal injury or property dam-
age.'" 2 Frumer & Friedman, Products Liability, Chapter 3, Sec. 16.01[1].
[2] None of `the experts called by either party `Could or would state `which par-
ticular ingredient in Quadrigen caused `the damage to Shane Stromsodt Plain-
tiff's witness, Dr. Ronald Okun, testified that there was evidence to show that
pertussis en'dotoxin made the other components of Quadrigen more liable to cause
an anaphylactic sort of reaction in a patient. Other evidence indicated `that the
product was rendered defective by the instability of potency in the pertussis vac-
cine. The evidence justifies the conclusion that the Plaintiff's injuries and dam-
ages were caused `by a defect in `the Quadrigen, and `that `such defect constitutes
a breach of the implied warranty of merchantability.
[3] The asserted lack of privity is not a `defense in North Dakota `to a claim
based upon breach of an implied warranty. See Lang v. General Motors Corpora-
tion, 136 N.W.2d 805 (N.D.1965) Thi sapparently would be particularly true in
actions by the ultimate consumer against a manufacturer for breach of implied
warranties where "through advertising or other media o'f education and informa-
tion defendant has convinced and persua'ded the medical profession to prescribe
its drrig, since it is in the very competitive field of supplying drugs and medicines
for the alleviation of human suffering as well as for its own pecuniary advan-
tages." Bennett v. Richardson-Merrell, Inc., D.C., 231 F.Supp.150
PAGENO="0272"
4562 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
NEGLIGENCE
[4] The finding that Parke, Davis breached the implied warranty of mer-
chantability and that Plaintiff's injuries were caused thereby does not preclude
a finding that the Defendant is also chargeable with negligence in failing ade-
quately to test the product and adequately to warn of the dangers inherent in its
use.
The insert,1 under "Reactions", reads:
"When given in accordance with suggested methods, local and systemic
reactions following the administration of Quadrigen are usually mild. The
incidence is usually no greater than is normally experienced with trivalent
vaccine. Local reactions and fever of short duration may occur, however,
and parents should be cautioned not to apply local treatment, such as wet
dressings or heat. Any child who shows a febrile reaction should be kept
quiet, should be offered water repeatedly and may be given one or more doses
of aspirin as indicated. Occasionally, a residual induration or circumscribed
nodule may persist for a week or more.
"In instances of more marked reaction, the immunization may be coin-
pleted with monovalent antigens or other combinations of antigens.
"Local reactions have been known to be more severe when the child is in
the incubative stage of pertussis. Encephalitic symptoms occasionally occur
with acute pertussis though rarely with the use of the prophylactic vaccine.
Such severe symptoms of the central nervous system include convulsions
and lethargy. They may be followed by mental or lhysical manifestations,
sometimes permanent, or even by death; but fortunately such reactions are
extremely rare.
"The poliomyelitis vaccine components of Quadrigen contains small
amounts of penicillin and streptomycin used in culturing the virus. During
the adsorption process most of the antibiotic content is removed. In fact,
residual antibiotics in the adsorbed product are usually not demonstrable by
ordinary laboratory technics. However, consideration should be given to
the possibility of allergic reactions in individuals sensitive to these anti-
biotics and they should be tested for sensitivity where this possibility exits.
"The value and importance of maintaining continuing antibody levels in
the infanct in relation to the possibility of provocation of paralytic poliomye-
litis by injection are self-evident. In modern clinical practice the admin-
istration of medication by hypodermic injection is generally accepted. and
the hazard of thereby provokng poliomyelitis is increasing. If, however,
basic immunity against poliomyelitis as evidenced by circulating antibody
has been achieved, provocation is quite unlikely. Also, it should be noted
that Quadrigen is considered less likely to provoke paralysis than is the
trivalent product not containing poliomnyelitis vaccine. With products not
containing poliomyelitis antigen the patient is at some risk following each
injection. With Quadrigen. on the other hand, after the first injection,
basic immunity is developing and risk is greatly decreased for subsequent
inoculations. Furthermore. if current recommendations are followed, the
course of immunization will be started during the first 6 months of life under
the protection of passive maternal antibody. How-ever, the hazard of provo-
cation in the face of an epidemic. particularly with the first dose of Quadri-
gen, cannot be ignored and the physician should exercise discretion. as with
any injectable."
Clinical trials of Quadrigen prior to marketing were conducted by Dr. Clar-
ence D. Barrett of Detroit beginning in 1956 and terminating in 1959. These
tests used Quadrigen considered "fresh" in that the product was less than six
months of age from the date of "pooling" of the poliomnyelitis component with
the DPT fraction. The trials were designed to determine antibody response and
the earliest age in infancy at which immunization against poliomyelitis, diph-
theria, tetanus and pertussis would be started, using a multiple antigen against
`Exhibit 46 is a tiny bottle of Quadrigen contained in a small cardboard box which
included also Parke-Davis' insert showing what the product was designed to do. It is
observed that the bottle itself contained no warning whatever, the cardboard box in which
it was enclosed contained no warning whatever. The insert itself, a single sheet of paper
containing in the main very small print, showed the nature of the product, when to
immunize, dosage and administration, recall or booster doses, reactions and storage in-
structions, and was printed on a sheet measuring approximately four by seven inches,
in which were compressed approximately 1,444 words, excluding the reference list on
the bottom of the reverse side.
PAGENO="0273"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4563
all four diseases. No clinical reactions of any serious consequence were reported
or observed.
Quadrigen was then made available to selected members of the medical pro-
fession who were requested to comment on their use of the product. These
"field trials" indicated a marked increase in reactions among patients given
Quadrigen over those being given DPT and poliomyelitis vaccine. Of the severe
reactions reported the first apparent instance in which death resulted was in
March of 1959. It does not appear that Parke-Davis made any effort to deter-
mine the cause of the high incidence of reactions, and only a cursory attempt
was made to investigate the cause of a death attributed to the use of Quadrigen.
[5] It appears to this Court that adequate tests performed prior to marketing
would have disclosed the product's potency instability as well as the cause
of greater incidence of reaction, especially in view of the number and serious-
ness of the reactions being reported. This w-as not a situation w-here an epi-
demic existed or where need justified the risk of premature marketing since
products were already available to the medical profession that satisfactorily
accomplished that Quadrigen was designed to do.
[6] Although all of the Government regulations and requirements had beeii
satisfactorily met in the production and marketing of Quadrigen, the standards
promulgated were minimal. The Defendant still owes a duty to warn of dan-
gers of which it knew or should have known in the exercise of reasonable care.
Love v. Wolf, 226 Cal.App.2d 378, 38 Cal.Rptr. 183. See also Ebers v. General
Chemical Co., 310 Mich. 261, 17 NW. 2d 176; Brown v. Globe Laboratories, 165
Neb. 138, 84 N.W.2d 151; Gonzalez v. Virginia-Carolina Chemical Company, 239
F.Supp. 567 (DC, SC, 1965).
[7, 8] The danger must be reasonably foreseeable and the injury must be
proximately caused by the failure to warn. The Defendant knew or should have
known that Qnadrigen might cause encephalopathies in some users and to warn
of the danger.
[9] Though this may have been the first case in which encephalopathy 2 oc-
curred after the administration of Quadrigen, it does not preclude the finding
of foreseeability and negligence. See Roberts v., United States, 316 F.2d 489 (3
Cir., 1963).
The warning "Local reactions have been known to be more severe w-hen the
child is in the incubative stage of pertussis" on the insert accompanying the
product, not only would not have warned members of the medical profession, but
might have misled them to believe that only in cases where the child was in the
incubative stage of pertussis would encephalitic symptoms occasionally occur.
There is no competent evidence in the entire record, medical or other, to
show that Shane's condition arose out of or from any susceptibility or predis-
position, nor that the child had any congenital disease or disorder or defect
of any kind, nor that he had any allergy or idiosyncrasy, nor that heredity was a
factor that might account for his present condition.
This Court being of the opinion that the Defendant is liable both for breach
of an implied warranty and for negligence, it becomes unnecessary to forecast
whether the Supreme Court of North Dakota would apply Sec. 402 A of the
Restatement of Torts in a situation such as is here presented.
As pointed out in 2 Frumer-Freidman, Chapter 3, Sec. 16A [4]
"Strict liability in tort in the products liability area is in its infancy. There-
fore, the precise scope of the rule and the defenses thereto have not as yet
been clearly defined. It is believed, however, that strict liability in tort is for
the most part no different than strict liability in warranty, that similar
results can be achieved under either theory. Comment in to § 402A of the
Restatement of Torts seems to agree. It states:
"`There is nothing in this sec:tion which would prevent any court from
treating the rule stated as a matter of "warranty" to the user or
consumer.'
"But in the next sentence it is pointed out that,
"`if this is done, it should be recognized and understood that the
"warranty" is a very different kind of warranty from those usually
found in the sale of goods, and that it is not subject to the various con-
tract rules which have grown up to surround such sales.'
"If a court does not require, inter alia, privity of contract, a sale, or notice
of a breach of warranty, does it matter that the defendant is being held
strictly liable in warranty rather than in tort? The answer seems obvious.
2 degenerative disease of the brain.
81-280-69-pt. 11-18
PAGENO="0274"
4564 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
If a court imposes strict warranty liability irrespective of contract and
sales rules, then strict liability in warranty and tort are synonymous."
The Plaintiff has sustained the burden of proving, by a fair preponderance of
the credible evidence adduced upon trial, that Parke-Davis has breached an
implied warranty, and in addition, has been guility of tortious negligence. The
verdict which this Court reaches, and the damages awarded, are supported by
either one or both of these theories.
[10] It is my conclusion that the sum of $500,000.00 constitutes a fair, just and
adequate award to Shane Stromsodt, considering the totality of circumstances in
this lawsuit.
Counsel for the Plaintiff are directed to prepare and submit through the Clerk
of this Court findings of fact, conclusions of law, order for judgment and judg-
ment with the least practicable delay.
[From Federal Supplement, voL 285-cases argued and determined in the U.S. District
Courts-U.S. Customs Court-pp. 432-454]
Enic R. TINNERHOLM, an infant under the age of fourteen years, by his Guardian
ad Litem, Carl F. Tinnerholm, and Carl F. Tinnerholm, Individually, Plaintiffs,
`V.
PARKE, DAVIS & Co., Defandant.
No. 62 Civ. 4006.
United States District Court, S. D. New York-May 15, 1968
Action against manufacturer of vaccine for damages resulting from doctor's
administration of vaccine to infant. The District Court, Tenney, J., held that
evidence established that manufacturer breached its implied warranty and war-
ranty of merchantability and manufacturer was guilty of negligence. That Court
further held that plaintiffs were entitled to damages in the sum of $651,783.52 to
reimburse father for loss of services and medical expenses incurred and for
infant's loss of w-ages, future medical expense, and pain and suffering.
Judgment accordingly.
1. Druggists ~1O
Evidence established that release of endotoxin into fluid contained in vaccine
injected into infant w-as cause of unusually high fever which, in turn, caused
severe and permanent brain damage.
2. Druggists ~10
In action against manufacturer of vaccine for damages resulting from infant
being injected with vaccine, plaintiffs need not disprove every possible ground
of causation suggested by manufacturer nor must findings of court meet stand-
ards of laboratorian.
3. sales ~42T
Liability for "breach of warranty" arises where persons or property are dam-
aged because of product's failure to live up to an express or implied represerita-
tion by manufacturer or other supplier.
See publication Words and Phrases for other judicial constructions
and definitions.
4. Sales ~=`427
"Breach of warranty" is distinguished from negligence liability in that it is
not based upon fault or upon failure of such manufacturer or supplier to exercise
reasonable care.
5. Sales ~=26O
An "express warranty" will arise where manufacturer, supplier or other seller
positively represents a fact concerning goods he sells.
See publication Words and Phrases for other judicial constructions
and definitions.
PAGENO="0275"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4565
6. Sales c~434
Allegation that vaccine was fit for use as immunizing agent against various
ailments and was of good merchantable quality constituted an allegation of
"implied warranty".
See publication Words and Phrases for other judicial constructions
and definitions.
7. Sales ~279
Warranty of "merchantability" is that thing sold is reasonably fit for general
purpose for which it is manufactured and sold.
See publication Words and Phrases for other judicial constructions
and definitions.
8. Sales ~~273(1)
Implied warranty of fitness for particular purpose is distinguished from
merchantability warranty in that in merchantability warranty there is reliance
on particular seller's skill and judgment.
9. Sales ~=~55
In action by New York residents against manufacturer of vaccine for damages
resulting when infant was injected with vaccine, court was bound by New York
law of warranty.
10. Sales ~255
Under New York law, doctrine of privity did not apply to action against manu-
facturer of vaccine for damages resulting from infant's being injected with
vaccine by physician.
11. Sales ~=~246
Even if sale is necessary in order to impose warranty liability, such require-
ment was fulfilled in action against manufacturer of vaccine for damages result-
ing from vaccine having been administered to infant by doctor.
12. Druggists ~=~1O
Evidence in action against manufacturer of vaccine for damages resulting from
infant's having been injected with vaccine by physician established that vaccine
was defective and that defect was proximate cause of infant's injuries.
13. Sales ci~=z441(1)
In action against manufacturer of vaccine for damages resulting from vaccine
administered to infant, evidence established that manufacturer breached an im-
plied warranty in manner that increased chances of party injected with vaccine
of contracting an encephalopathy.
14. Sales ~=~441 (3)
In action against manufacturer of vaccine for damages resulting from doctor's
administering vaccine to infant, evidence established that manufacturer breached
its warranty of merchantability.
15. Druggists ~9
Finding of implied warranty liability did not preclude court from finding manu-
facturer of vaccine liable in negligence for damages resulting from doctor's
administering vaccine to infant.
16. Federal Civil Procedure ~=2571
While finding of implied warranty liability would not preclude finding liability
based on negligence, plaintiffs are limited to one recovery.
17. Druggists ~=1O
In action against manufacturer of vaccine for damages resulting from doctor's
administering vaccine to infant, evidence established that manufacturer was
negligent in failing to adequately test its product, for releasing product for com-
mercial distribution in face of certain danger signs emanating from test results,
and in failing to adequately warn medical profession of risks inherent in its use.
PAGENO="0276"
4566 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY
18. Druggists ~9
Where drug manufacturer develops new drug subsequently found to produce
harmful side effects which manufacturer failed to discover in course of testing
product, manufacturer is liable in negligence if drug in fact was inadequately
tested or manufacturer failed to exercise due care in development of product
prior to its release on market for commercial distribution.
19. Druggists ~9
Where it was well known that variations in temperature could have marked
effects on safety and effectiveness of vaccine, and it was also know that many
lots could not be shipped under refrigerated or storage conditions, it was incum-
bent upon manufacturer of vaccine to subject their pre-release lots to those fore-
seeable variations in temperature to which their product would be exposed prior
to point of inoculation so as to insure that this exposure would not produce
deleterious effects.
20. Druggists ~9
Although it would be negligence for manufacturer to disregard regulations
established by National Institutes of Health in manufacture of its drug products,
manufacturer could not exempt itself from liability in negligence for failure to
exercise due care in area not covered by specific regulation.
21. Druggists ~9
Manufacturer of vaccine was negligent in using, as basis for its representation
that vaccine yielded no greater local or febrile reactions than n-as experienced
with former vaccine, a clinical study which lacked controls for diagnostic and
reporting procedures and used vaccines which contained ingredient that had
been in cold storage for two years.
22. Druggists ~1O
In action against manufacturer of vaccine for damages resulting from doctor's
administering vaccine to infant, evidence established that there existed sufficient
number of both unrealistic and conflicting reports from field to have required
manufacturer to take serious second look at its product before placing it on
market.
23. Druggists ~9
Where products were already available to medical profession which satisfac-
torily accomplished that which new vaccine was designed to do, there was no
epidemic or need justifying risk of premature marketing.
24. Druggists ~1O
In action against manufacturer of vaccine for damages resulting from doctor's
administering vaccine to infant, evidence established that manufacturer n-as
negligent in not adequately warning medical profession of dangers inherent in
vaccine's use.
25. Druggists ~9
Drug manufacturer is under duty to warn medical profession of dangers in-
herent in its biological drugs which, in exercise of reasonable care, it knew or
should have known to exist.
26. Druggists ~9
Watering down substance of warning so as to give false assurance to medical
profession that drug or biological can be safely administered, thereby minimizing
danger which exists in use of product, amounts to inadequate warning.
27. Druggists ~9
Doctors have right to and in fact do rely on brochures sent to them by drug
manufacturers regarding safety and use of their products.
28. Druggists ~9
Drug manufacturer who, after reporting results of its test to Food and Drug
Administration, and on strength of those reports markets its products, discovers
new harmful side effects produced by drug, yet fails to send out warnings of
this new development to foreseeable users, is negligent.
PAGENO="0277"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4567
29. Druggists ~9
Any significant increase found to exist in reaction rate of particular drug must
be disclosed by manufacturer.
30. Druggists ~=9
Where manufacturer of vaccine had noted that study revealed that seven per
cent of children inoculated with vaccine suffered fevers of 104 degrees and above,
manufacturer was under duty to timely amend brochure included with its prod-
uct in order to inform medical profession of information which would reasonably
be expected to affect doctor's decision to use vaccine.
31. Druggists ~9
Manufacturer of vaccine marketed in 1959 was under duty to warn medical
profession of possibility of allergic reaction.
32. Damages ~=~1
Under New York law damages are compensatory, not punitive.
33. Parent and Child ci~=~7(1)
Father is entitled to recover for loss of injured child's services and for medical
attendance and expenses.
34. Damages ~60
"Collateral source" doctrine has been severely limited in its application.
35. Damages ~60
Where liability for care of mentally defective infant may be asserted by state
against infant and his father, doctrine of "collateral source" does not apply.
Mental Hygiene Law N.Y. ~ 24 and subds. 5(b), 9(b).
36. Mental Health ~32
Where state has provided care for mentally defective infant, damages awarded
father for past period of institutionalization are subject to lien of state and
defendant may move to have lien determined. Mental Hygiene Law, N.Y. § 24
and subds. 5(b), 9(b).
37. Damages ~43
In absence of proof that nursing services performed by infant's mother were
other than would normally have been rendered by mother to her child, damages
for such services would not be awarded.
38. Damages ~133
Father was entitled to damages in amount of $2,500 for loss of services of
infant who became mentally retarded as result of receiving vaccine at age of
three months.
39. Damages ~32, 37, 43
Infant who became mentally retarded from being administered vaccine at age
of three months was entitled to damages to cover future medical expenses, to
reimburse him for future loss of wages, and to cover past, present and future
pain and suffering.
40. Damages ~135
Evidence established that $160,000 would be fair amount to insure adequate
future medical care for infant who became mentally retarded from administra-
tion of vaccine at age of three months.
41. Damages ~133
Infant who became mentally retarded from administration of vaccine at age
of three months was entitled to $50,000 as damages for loss of future earnings
even though he would be confined to institution during most of his life and would
not start work until age 21.
42. Damages ~132(3)
Infant who as result of being administered vaccine suffered from high fever,
underwent two spinal taps and craniotomy, was partially paralyzed and subject
to seizures and was mentally retarded was entitled tO $400,000 as damages for
pain and suffering.
PAGENO="0278"
4568 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY
Fuchsberg & Fuchsberg, New York City, Jacob D. Fuchsberg, Richard E.
Shandell, New York City, of counsel, for plaintiffs.
Costello, Ward, Tirabasso & Shea, New York City, Joseph M. Costello, New
York City, David C. Dethmers, Detroit, Mich., of counsel, for defendant.
TENNEY, District Judge.
This product liability case. w-hich was tried to this Court without a jury, in-
volves the ethical drug Quadrigen, made by defendant Parke Davis & Co., and
administered to the infant plaintiff herein. Quadrigen contains four antigens:
diphtheria toxoid, tetanus toxoid, pertussis (whooping cough) vaccine and
poliomyelitis vaccine. The action has been brought on behalf of the infant plain-
tiff by his father, and by the father individually, charging negligence in various
respects and breach of an express and implied warranty. There is no dispute
that the injuries suffered by the infant plaintiff are catastrophic.
The plaintiff, Eric Tinnerhoim, was born on August 30, 1959, in Huntington
Station, Long Island, New York. He was the third child born to his parents, the
plaintiff Carl F. Tinnerholm and Mrs. Tinnerholm, the other two children then
being five and four years of age. His birth was normal, as was his mother's preg-
nancy, and at the end of the first and second months of his life he was taken to
the family physician, Dr. Gerald Feinberg, for routine check-ups. The infant was
apparently a big, healthy boy who ate and slept well and was active and alert.
Some time between ii :00 AM. and noon on Saturday, November 28, 1959, Mrs.
Tinnerhoim, by prearrangement, took Eric to Dr. Feinberg's office for his first
immunization injection. She was informed that this immunization was not the
usual 3-in-i that her other children had received, but that it was a 4-in-i which
added poliomyelitis vaccine to the antigens with which she was already familiar.
Eric suffered no immediate side-effects following the injection and continued in
apparent good health through that Saturday and Sunday. On Monday he ap-
peared extremely quiet and seemed to look toward the wall most of the day,
although the parents apparently thought nothing of this at that time. On Tuesday
morning, December 1, 1959, at about 4 :00 A.M., the child was found tangled up in
his bedclothes and whimpering, but on being picked up and patted he quieted
down and presumably went back to sleep. There was no indication of temperature
at that time. However, some time later, between 6 :30 and 7:00 AM., the child
was found by his mother huddled under the covers, lethargic and bathed in per-
spiration. His temperature at that time n-as 108°, he was very white, his lips were
blue, arid he was limp. While Mrs. Tinnerholm gave the child an alcohol bath,
Dr. Feinberg was summoned by the boy's father.
When the doctor arrived around 7:30 AM. he confirmed the 108° temperature
which was shortly reduced to 106° by the alcohol bath. The doctor's examination
further disclosed a small amount of emesis and some coughing. The remainder
of the examination was negative.
Eric was admitted to Huntington Hospital at 8 :45 A.M. where he was again
examined by Dr. Feinberg, who found the child's neck supple, an absence of
masses, and a negative Brudzinski.° Dr. Feinberg's original diagnosis was fever
of unknown origin. Eric remained in Huntington Hospital until December 18th.
during which period he was cared for by two pediatricians, Doctors Gordon and
Kagan, and also examined by a neurologist, Dr. Sengstaken. Dr. Kagan examined
the boy on the day of his admission to the hospital and found him to be pale,
hyperpneic,3 the eyes dull and apathetic, with focal seizures and twitching of
the right side. There was a dullness and loss of landmarks in the ears and some
redness at the back of the throat. On the basis of his examination, Dr. Kagan
believed that the boy had either a bacterial infection of the bloodstream (sepsis)
or meningitis. However, subsequent laboratory testing ruled out both the sepsis
and meningitis, for a spinal culture revealed clear fluid with only three cells, a
normal finding, indicating the absence of infection. There was, however, an
elevated protein content of 10 milligrams percent, indicating some abnormality
attacking the brain. A repeat lumbar puncture ten days after admission again
showed an absence of cells and a protein content of 56 milligrams percent, lower
than the previous 100 milligrams percent, but still above normal. During this
first hospitalization Eric developed recurrent seizures, and on the fifth day a
flaccid paresis or paralysis of the right arm and leg was noted and which per-
1 An antigen is a substance which causes antibodies to be produced by the organism
into which it is injected.
2 A Brudzinski is a neurological test which includes tile forward flexion of tile neck
or the head on the neck, which, if done without resistance and without pain, indicates
there is no meningeal irritation.
Abnormally rapid breathing.
PAGENO="0279"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4569
sisted until his discharge on December 18, 1959. Since that time he has been
retarded in his mental development, being classified in the imbecile-4diot range.
He is unable to stand or walk or talk, is incapable of toilet training, and in order
for him to be able to sit he must first be propped up. There is a spasticity in
posturing of the right upper limb and the right lower limb, indicating a spastic
weakness of these extremities. He still suffers occasional seizures and has a
mental age in the range of five months.
Is it possible to determine, with reasonable medical certainty or reasonable
medical probability, that something peculiar to Quadrigen was the proximate
cause of the injuries suffered by the infant plaintiff? The question must be
answered affirmatively. Dr. Charash, one of plaintiffs' experts, concluded that
the child suffered a pertussis-vaccine encephalopathy,4 basing his conclusion on
the temperal relationship between the immunization and the onset of illness;
the unusual and spectacular sudden rise and subsequent rapid reduction in
temperature; the appearance of unilateral seizures and weakness; the essen-
tially extraordinary discrepancy between the very high protein and the absence
of white cells in the spinal fluid; and the flatness of the fontanel. For the same
reasons, he discounted the possibility of a viral encephalitis,~ one of the possible
alternatives raised by defendant. Likewise, the suggestion that the infant may
have developed a brain abscess from otitis media is not supported by the evidence.
What was it, then, that was peculiar to Quadrigen that it can be stated, with
reasonable medical certainty or probability, that it caused the injuries already
described? In order to answer this question it is necessary to discuss in some
detail pertussis and pertussis vaccine as incorporated in Quadrigen.
Pertussis, or whooping cough, is a communicable respiratory disease caused by
a bacterial organism. The disease may attack the brain to the extent that con-
vulsions, high fever, and occasionally hemorrhages in the brain are produced.
Sometimes this is accompanied by hemiplegia or paralysis of half the body, and
not infrequently there is a resultant mental retardation. The disease is particu-
larly dangerous for children during their first year of life, since little or no
maternal immunity is passively transferred to the newborn. Immunity, how-ever,
may be obtained through the injection of a vaccine.
A vaccine, by introducting an antigenic factor into the body of the recipient, is
intended to stimulate the production of antibodies, which antibodies confer
protection against the disease. In the process, lymphocytes, a form of cell con-
tained in the lymph glands, absorb the antigenic factor and produce an antitoxin
against the particular disease. With some infectious diseases, such as diphtheria
and tetanus, it has been possible in developing a vaccine to isolate the soluble
toxin or poison excerted by the bodies of these bacteria, and to inactive this
toxin with formaldehyde, thus converting the toxin into what is called a toxoid.
This toxoid preserves the ability to immunize against the disease by stimulating
the production of antibodies in the recipent, but it has lost its poisonous qualities.
The pertussis organism, however, is a unique, very complex one containing
many different factors. There is an exotoxin, an endotoxin, a protective antigen,
a factor that gives the Schwartzman phenomenon,6 a factor sensitizing to his-
tamine, yeast, protein extracts, vaccines and endotoxin, to infection by gram
negative bacteria and by influenza, to X-rays, pressure, the stress of cold, and
to a marked degree sensitizing to ceretonium, one of the important neuro-hor-
mones of the brain. The exotoxin in the pertussis organism is thermo labile,
i.e., it is destroyed by heat, and all vaccines with which we are concerned are
heated during preparation and the thermal labile exotoxin destroyed. However,
the endotoxins inside the cell are not destroyed by heat. It is this endotoxin,
also called a lipopolysaccharide, to which febrile reaction following administra-
tion of pertussis vaccine is usually attributed. In addition to the protective anti-
gen already mentioned, there are some fourteen or fifteen different antigens, and
nobody knows which, of all these antigens, is the one which stimulates production
of the antibodies conferring protection against pertussis (whooping cough).
By reason of the complexity and mystery of the pertussis organism it was
impossible to isolate the toxin conferring protective activity and make a toxoid
out of it, as in the case of diphtheria and tetanus. Therefore, it was necessary
to administer the entire bacteria organism, treating it in some way by heat or
otherwise to kill the organism but preserve the antigenicity. As a result, whereas
there were practically no reactions to diphtheria or tetanus toxoids, there were
Encephalopathy Is any degenerative disease of the brain.
Encenhalitis is an inflammation of the brain.
6 The Schwartzman phenomenon is the production of ulcers on injection under the skin
of a rabbit.
PAGENO="0280"
4570 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
not uncommonly reactions to pertussis vaccine such as a swollen injection area
and some fever. Occasionally, there was severe plain from the site of the injec-
tion, and on rare occasions convulsions, high fever and the neurological sequelae
of brain hemorrhage, hemip.legia and mental retardation, just as with the
disease itself. The cause of these neurological manifestations following the use
of pertussis vaccine is not definitely known either on a pathological, histological
or clinical basis. These manifestations, however, were first brought to the at-
tention of the medical profession in April of 1948. Thereafter there were devel-
oped additional controls over the production of pertussis vaccine. Under the new
regulations the encephalopathic type of reaction was minimized. The use of
phosphate adjuvants made possible a decrease in the amount of pertussis in the
formula; new maximum as well as minimum potency standards were set; and
the toxicity of the pertussis component was reduced by extra heating and by
the toxicity test. The potency test is performed by injecting groups of mice
with varying dilutions of vaccine, and, then, after a period of time, challenging
the mice with virulent organisms. The toxicity test was performed by injecting
a group of ten mice of specified weight with a specified dose of vaccine and
weighing the group at specified intervals. I will have further occasion herein
to discuss in greater detail the matter of tests as to their adequacy in the present
case. Mention has been made above of the use of phosphate adjuvants which
permitted a reduction of the amount of pertussis in the formula. Today, at least
in American vaccines, an aluminum salt is used as an adjuvant. An adjuvant
serves as a depot or button which will slow the release of the antigen rather
than having it released all at once when the vaccine is merely suspended in a
liquid. When aluminum phosphate was first used, there was some apparent in-
crease in toxicity and the amount of the aluminum phosphate was reduced ap-
proximately one-half with a resultant substantial reduction in toxicity. There-
after vaccines with the aluminum phosphate were no more toxic than other
adsorbed vaccines.
One other aspect of the manufacture of pertussis vaccine should be mentioned
at this time. All vaccines packed in multi-dose vials require a preservative to
keep them sterile (not to preserve their potency). In the development of pertussis
vaccines until the development of polio vaccine the universal preservative
used was Merthiolate. At the time there was no information that the Merthio-
late affected the vaccine for better or for worse, but it has recently been dis-
covered that Merthiolate acts as a stabilizer of the vaccine, that in its presence
the vaacine tends to decrease in toxicity in storage at the same time that its
potency is stabilized at a level at least for the first six months.
In the early 1940's, there was developed the method of combining pertussis
vaccine with diphtheria and tetanus toxoid into a combined antigen product
colloquially known as "DDT". No apparent decrease in toxicity or reactivity
was noted as a result of such combination. Defendant marketed such a product
under the trade name "Triogen".
After the Salk poliomyelitis vaccine had been developed, it was decided by do-
fendlant to attempt to mix the polio vaccine with the "Triogen" in order to develop
commercially a quadruple antigen product. In connection with the development
of polio vaccine it had been learned that Mertliiolate had a deleterious effect
upon the polio virus, caused by the action of released mercury ions. Eli Lilly
& Company incorporated Versene within its vaccine, which prevented the re-
lease of the mercury ions. However, Versene was incompatible with the aluminum
phosphate used as an adjuvant by defendant in Triogen, and since defendant
anticipated that it would want to develop a vaccine combining the polio vaccine
with Triogen. it decided to use benzethoniurn chloride, or Phemerol which was
defendant's trade name for this product.
Unknown to defendant the benzethoniurn chloride had an unusual effect on the
pertussis vaccine contained therein. It appears that there was a loss of potency,
a reduction in the protective activity of the pertussis vaccine when benze-
thonium chloride rather than Merthiolate was used as the preservative. This
loss occurred only when the vaccine was exposed to variations in temperature.
While there is no knowledge as to the manner in which benzethonium chloride
affects the unidentified protective antigen of the pertussis vaccine, considerable
knowledge has been accumulated as to the physical effects of benzethoniurn
chloride on pertussis bacteria placed in a solution including benzethonium
An adjuvant in immunology is any substance that, when mixed with an antigen, en-
hances the antigenicity and gives a superior response.
PAGENO="0281"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4571
chloride. It has been demonstrated that benzethonium chloride partially disap-
pears from the solution during storage, coming down from twenty-five parts
per million to only seven parts per million. Benzethonium chloride is a quate-
nary ammonium compound and has a positive charge, whereas the bacterial
cell wall has a negative charge. By attraction, the benzethonium chloride is ad-
sorbed to the cell. Such adsorption on the bacterial cell wall may cause its
denaturation and favors the leaching of the toxin from the bacterial cell, result-
ing in the leakage of the contents of the organism. Cei~tainly, it is reasonable
to conclude that the effect of the use of benzethoniurn chloride was to release
the endotoxin from the bacteria cell into the fluid that was injected. One such
endotoxin, the lipopolysaccharide, causes fever, and fever can produce con-
vulsions and brain damage. Indeed, fever is one of the recognized etiologies
or causes of post-pertussis vaccine encephalopathies.
[1, 2] It is reasonable to conclude, as I do, with reasonable medical certainty
or probability that the release of the endotoxin into the fluid injected into
the infant plaintiff was the cause of the unusually high fever which, in turn,
caused the severe and permanent brain daniage. I find defendant's suggestion
that the cause of such damage was a viral encephalitis caused by some unspecified
virus, a sepsis or meningitis, or an allergic reaction, totally unconvincing. It is
not plaintiffs' burden to disprove every possible ground of causation suggested by
defendant, nor must the findings of the Court meet the standards of the labora-
torian. Plaintiffs' experts have furnished impressive evidence to support the
conclusions reached herein, evidence which has clearly withstood the attack
of defendant's experts. Having found Quadrigen to have been the causative
factor, I turn now to the question of warranty, express and implied, and the
further question of negligence.
Warranty Generally.
[3, 4] Liability for breach of warranty arises where persons or property
are damaged because of a product's failure to live up to an express or implied
representation by the manufacturer or other supplier. It is distinguished from
negligence liability in that it is not based upon fault or upon the failure of such
manufacturer or supplier to exercise reasonable care. 2. Frumer & Friedman,
Products Liability § 16.01[1] (1967) (hereinafter referred to as "Frumer &
Friedman") ; cf. Rheingold, Products Liability-The Ethical Drug Manufac-
turer's Liability, 18 Rutgers L.Rev. 947, 977 (1964) (hereinafter referred to as
"Rheingold").
[5-8] An express warranty will arise where a manufacturer, supplier or other
seller positively represents a fact concerning the goods he sells. 2 Frumer &
Friedman § 16.02; cf. Uniform Commercial Code § 2-313. In the instant case,
plaintiffs allege that defendant warranted Quadrigen as "safe, effective and free
from harmful side effects °." Amended Compit. ¶ 20.8 An implied warranty,
on the other hand, is imposed by operation of law. 2 Frumer & Friedman § 116.02.
The implied warranties allegedly breached in the ease at bar are the warranties
of merchantability and fitness for a particular purpose. Amended Complt. ¶ 28.
The warranty of merchantability is that "the thing sold is reasonably fit for
the general purpose for which it is manufactured and sold." Henningsen v.
Bloomfield Motors, Inc., 32 N.J. 358, 161 A.2d 69, 75 A.L.R.2d 1 (1960) ; 2
Frumer & Friedman § 16.04[2] [d]; see Burr i~. Sherwin Williams Co., 42
CaL2d 682, 268 P.2d 1041 (1954) ; Twombley v. Fuller Brush Co., 221 Md. 476,
158 A.2d 110 (1960) ; Ryan v. Progressive Grocery Stores, 255 N.Y. 388, 175
N.E. 105, 74 A.L.R. 339 (1931) ; Rheingold at 978 (reasonable fitness for ordinary
purpose for which sold). The implied warranty of~ fitness for a particular pur-
pose is virtually self-explanatory, the major distinction from the merchantability
warranty being reliance on the particular seller's skill and judgment. 2 Frumer
& Friedman § 16.04[2] [dl; see Henningsen v. Blomfield Motors, Inc., supra.
Privity and Related Problems.
a. Privity.
The last decade has seen a vigorous frontal assault on the previously near-
impregnable "citadel of privity" so that in many states the insulation of the man-
8In paragraph 20 of the amended complaint, plaintiffs also claim that defendant ex-
pressly warranted that Quadrigen "was fit for the use as an immunizing agent against
various ailments and was of good merchantable quality." These are normally considered
to be implied warranties and do not appear to be expresly warranted in the Quadrigen
package insert or advertisements to the medical profession. Indeed, in paragraph 28 of
the complaint, plaintiffs make these same allegations in their cause of action for breach
of implied warranty.
PAGENO="0282"
4572 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
ufacturer of defective goods from direct liability for breach of warranty, express
or implied, is a thing of the past. See generally the excellent state~by-state
analysis of the privity problem in 2 Frumer & Friedman § 16.04; Kessler, Prod-
ucts Liability. 76 Yale L.J. 887 (1967) ; Prosser, The Assault Upon the Citadel
(Strict Liability to the Consumer), 69 Yale L.J. 1099 (1960).
The decision which provided the impetus for the collapse of privity was
Hennington v. Bloomfield Motors, Inc., supra, wherein the New Jersey Court
held that public policy demanded the extinction of the privity doctrine because
of mass marketing conditions causing the manufacturer to become remote to
the ultimate consumer, sales being accomplished through intermediaries, and
product demand being created by use of advertising media. It was obvious, in-
dicated the Court, that manufacturer contemplated the cultivation of the ulti-
mate consumer and that at least with respect to the purchase of a car, the
implied warranty of merchantability should extend to the ultimate purchaser of
such vehicle and those persons who would reasonably be anticipated to use it,
such as members of the purchaser's family and .those occupying or using the
vehicle with his consent.
[9. 10] Of course, no extended discussion is necessary to show that this Court
is bound by the New York law of warranty. And it is clear that if the
requirement of privity is not dead in this jurisdiction, it has at least been dealt
a deliberating blow by the New York Court of Appeals in Greenberg v. Lorenz,
9 X.Y.2d 195, 213 N.Y.S.2d 39, 173 N.E. 2d 773 (1961) ; Randy Knitwear, Inc. v.
American Cyanamid Co., 11 N.Y.2d 5, 226 N.Y.S.2d 363, 181 N.E.2d 399 (1962);
and Goldberg v. Kollsman Instrument Corp., 12 N.Y.2d 432, 240 N.Y.S.2d 592,
191 N.E.2d 81 (1963). See generally 2 Frumer & Friedman § 16.04 [2] [b] [xl.
In Greenberg v. Lorenz, supra, the Court held that a retailer impliedly warrants
the wholesomeness of food and household goods to all members of the buyer's
household since a presumption should arise that the purchase was made for
all such persons. Randy Knitwear, Inc. v. American Cyanamid Co., supra, dis-
ljensed with the requirement of privity in an express warranty case. Frumer
& Friedman point out that the real importance of Randy Knitwear was that it
paved the way for the New York Courts to abrogate privity as a requirement
in implied warranty cases since the Court noted (1) a trend away from privity;
(2) privity was an outmoded technical rule; (3) that the separate indemnity
actions required by the privity rule were a waste of time spent in litigation
(obviously both on the part of the courts and the various parties who would be
involved) ; and (4) that warranty was historically a tort action. Id. at § 16.04
[2] [b] [x]. Finally, in Goldberg v. Kollsman Instrument Corp., supra, the New
York Court of Appeals went about as far as Hennin.gsen by holding that an
airplane assembler could be liable for the death of an airplane passenger under
an implied warranty theory. It was held, however, that the manufacturer of
a component part was not liable since "adequate protection is provided for the
passengers by casting in liability the airplane manufacturer which put into the
market the completed aircraft." 12 N.Y.2d at 437, 240 N.Y.S.2d at 595, 191, N.E.
2d at 83.~ It is apparent that the refusal to hold the component part manufacturer
was not because of lack of privity. 2 Frummer & Friedman § 16.04[2] [b] [xl.
From the foregoing, it should appear obvious in the instant case that privity
presents no bar to recovery.'0
b. Necessity of a &iie
In Perimutter v. Beth David Hospital, 308 N.Y. 100, 123 N.E.2d 792 (1954), the
Court held that a hospital administering a blood transfusion is rendering only
a service and is not making a sale. Whether a sale is necessary to impose war-
ranty liability today is questionable (see 1 Frumer & Friedman § 19.02; Rhein-
gold at 974), but even assuming such a requirement, it is submitted that
Perimutter would not bar a recovery in the instant case. Faced with the argu-
For an apparent extension of Goldberg v.. Kolisman Instrument Corp., see Rooney
v. S. A. Healy Co., 20 N.Y.2d 42, 281 N.Y.S.2d 321, 228 N.E.2d 383 (1967), where the de-
fendant supplier sold used protective masks to the City of New York. The Court of Ap-
peals held defendant had breached the implied warranty of merchantability since the
defect was in design.
15 Gottsdanker v. Cutter Laboratories, 182 Cal. App. 2d 602, 6 Cal. Rptr. 320, 79 A.L.R.
2d 290 (1960), used a novel but valid approach to solve the privity problem. The reason-
ing of the Gottsdankcr Court was that both food and drugs are intended for human
consumption and that such consumption is one of the basic reasons for the food exception.
Therefore, the courts should extend the exception to drugs. Of course, in light of the New
York cases cited supra, there is no need to resort to the Gottsdanker reasoning herein. See
generally 3 Frumer & Friedman § 33.02 [2] [a] ; Rheingold at 978.
PAGENO="0283"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4573
rnent that cases such as Perirnutter would prevent recovery, in Gottsdanker V.
Cutter Laboratories, 182 Cal.App.2d 602, 6 Cal. Rptr. 320 (1960), the iive-polio
vaccine case, the California Court stated:
"Clearly it is the patient, and not the doctor, who is the ultimate consumer
of the vaccine. While a sale is essential to impose liability under the implied
warranties, the intial sale to distributor or retailer of pharmaceuticals is
sufficient to impose upon the manufacturer the responsibility of fulfilling the
implied warranties which run to the benefit of the persons whom the manu-
facturer intended to be, and who in fact became the `consumers'." Id. at 605,
6 Cal.Rptr. at 324.
[11] The Gutter rationale is a sound one. Moreover, the case at bar is dis-
tinguishable from Perimutter (as was clutter). Similarity would have been
present if the physician who had administered the vaccine to Eric Tinnerholm
had been sued for breach of warranty. See 3 Frumer & Friedman § 33.02[b].
Under the law as it existed at that time, plaintiffs would possibly have been
denied any recovery. But the later decisions of the New York Court of Appeals
in Greenberg v. Lorenz, Randy Knitwear, Inc. v. American Cyanamid Co., and
Goldberg v. Kolisman Instrument Co. would allow a direct recovery against the
manufacturer, a result not inconsistent with Perlin utter. Accordingly, I find that
even if the technical requirement of a sale is necessary, such requirement has
been fulfilled under the Gutter Laboratories decision and Perirnutter presents
no obstacle to recovery.
\~rith these hurdles cleared, I turn to a consideration of the warranty causes
of action.
Ewpress Warranty
The package insert (Plaintiff's Exh. 1) which was apparently sent to the
administering physician with his purchase of Quadrigen stated that:
When given in accordance with suggested methods, local and systemic
reactions following the administration of Quadrigen are usually mild. The
incidence is usually no greater than is normally experienced with trivalent
vaccine. Local reactions and fever of short duration may occur, however,
and parents should be cautioned not to apply local treatment, such as wet
dressings or heat. Any child who shows a febrile reaction should be kept
quiet, should be offered water repeatedly and may be given one or more
doses of aspirin as indicated. Occasionally, a residual induration or cir-
cumscribed nodule may persist for a week or more.
In instances of more marked reaction, the immunization may be completed
with monovalent antigens or other combinations of antigens.
Local reactions have been known to be more severe when the child is in
the incubative stage of pertussis. Encephalitic symptoms occasionally occur
with acute pertussis though rarely with the use of the prophylactic vaccine.
Such severe symptoms of the central nervous system include convulsions
and lethargy. They may be followed by mental or physical manifestations,
sometimes permanent, or even by death; but fortunately such reactions are
extremely rare.
Whether this statement establishes an express warranty and a breach there-
of need not be reached herein, for it is clear, as will be hereinafter developed,
that the defendant has breached a warranty implicit in the package insert. How-
ever, certain of the problems which need be considered in express warranty
causes of action will be briefly discussed. Discussion of the sufficiency of the
warning will be reserved for that portion of this opinion wherein the negligence
issues are considered.
The unique characteristic of drug-product-liability litigation is that while
the product is actually meant for the patient, the sales pitch is made to the
physician in an attempt to get him to prescribe a particular product or course
of treatment to the ultimate consumer. Rheingold at 976. Thus, advertising will
take the form, among other things, of promotional literature to the physician,
statements of "detail" men who solicit purchases by the physician, package
inserts, labels and the like, and/or articles in medical journals. Id. at 965. Can
liability of the manufacturer be sustained even though the consumer has not
relied on any representation? One New York decision has held that the physician
is an agent of the patient for the special purpose of receiving statements from
the manufacturer. Wechsler v. Hoffman-La Roche, Inc., 198 Misc. 540, 99 N.Y. S.2d
588 (Sup.Ct. 1050). A number of commentators have expressed the view that
the representation need not be made directly to the injured consumer. See, e. g., 2
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4574 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Frumer & Friedman § 16.04[04]; 2 Harper & James, Torts § 28.7 (1956) ; Rhein-
gold at 976-77. Nevertheless, if direct communication is dispensed with, it would
appear that a plaintiff must still prove reliance by the physiciall. See id. at
977.
Dr. Feinberg, the administering physician, testified that he had read the
package insert (TR 610, 616). According to him, it presented no more than
he had already been taught in his formal medical education and in his practice
(TR 460-63, 617). But, as will be discussed infra, the evidence clearly indicates
the greater incidence of febrile reactions resulting with the use of Quadrigen,
so that the statement as it appears in the package insert is incorrect. Moreover,
the statement regarding encephalitic reactions is, at the very least, an ambiguous
one (TR61O-18).
However, whether these statements can be properly characterized as express
warranties which were breached need not be reached in light of my subsequent
decision with respect to the implied warranty of merchantability.
Implied Warranty
In Picker X-Ray Corp. v. General Motors Corp., 185 A.2d 919, 922 (D.C.Mun.
Ct.App.1962), it was stated that:
Implied w-arranty recovery is based upon two factors: (a) The product
or article in question has been transferred from the manufacturer's pos-
session while in a "defective" state and (b) as a result of being
"defective" the product causes personal injury or property damage.
The critical problem, then becomes the meaning of the word "defective". One
commentator has attempted to distinguish between pure and impure drugs, the
former being "those sold as the manufacturer intended, but with the harm aris-
ing as a side effect because of some inherent quality" and the latter being defined
as "those sold other than as the manufacturer intended, and containing deleteri-
ous impurities." Rheingold at 970. According to this article, additional consiclera-
tions flow from a finding that the drug is pure. Id. at 983. The problem with this
definition is that in the instant case it is unclear whether a pure or impure drug
is involved. It can be argued that Quadrigen was pure because its ingredients
were as the manufacturer intended. On the other hand, it can be as persuasively
contended that the drug was impure because the endotoxiii that was released
from the bacterial cell into the fluid was "a deleterious impurity" and thus the
drug was defective.
Another commentator suggests a more reasonable test: "[T]he issue as to
whether a substance not intended to be present is natural or foreign is com-
pletely immaterial on the ground that a product is to be regarded as defective
if a reasonable man would not have sold it lied he hnown of the presence of the
substance in the product. Keeton. Products Liability-Liability Without Fault
and the Requirement of a Defect, 41 Texas L.Rev. 855, 861-62 (1963). (Em-
phasis added.)
The commentary to the Torts Restatement provides perhaps the best working
definition of a defect: "the product is, at the time it leaves the seller's hands,
in a condition not contemplated by the ultimate consumer, which will be unrea-
sonably dangerous to him." Restatement (Second) of Torts § 402A, commenting
at 351 (1965).
[12] Whatever definition is used, in my opinion the proof amply sustained
the fact that Quadrigen was defective and that time defect was the proximate
cause of the injury sustained by Eric Tinnerholm. Compare Stromsodt v. Parke-
Davis & Co., 257 F.Supp. 991 (D. N.D.1966). I need not discuss the evidence
with respect to the biological and clinical testing of Quadrigen by Parke-Davis
and the National Institutes of Health at this time although such matter has been
fully considered by me in reaching conclusions on the warranty issues. The
matter of testing will be amply discussed in the negligence portion of this opinion.
However, certain of the articles that have been written in the field and received
in evidence, the deposition of Dr. Margaret Pittman of the Division of Biologics
Standards (hereinafter referred to as "DBS") of the National Institutes of
Health (hereinafter referred to as "NIH"), and testimony elicited at the trial
are all important, have been coilsidered by me in reaching this conclusion and
will be discussed at some length herein.
[13] The occurrence of encephalopathics following administration of vaccines
containing a pertussis component has been long known but the specific element
that causes this explosive assault to the brain has not been discovered. See Berg,
Neurological Complications of Pertussis Immunization, British Medical Journal
24 (July 5, 1958); Byers & Moll, Encephalopathies Following Prophylactic
PAGENO="0285"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4575
Pertussis Vaccine, 1 Pediatrics 437 (1948). However, the fact that an encephalop-
athy can be caused by pertussis vaccine would not mean that liability would be
incurred for breach of warranty in the instant case. Rather, the finding of an
implied warranty breach is predicated on the fact that by manufacturing Quad-
rigen in the method chosen by defendant, the changes of contracting an encepha-
lopathy were enhanced.
Aside from the clinical and laboratory studies of the benzethonium chloride
preserved Quadrigen which, in my opinion, indicate a defect in defendant's
product, the earliest literature which noted a problem with Quadrigen was pub-
lished in 1960. Massachusetts Department of Public Health, Pertussis Immuni-
zation, 263 New England Journal of Medicine 410 (Aug. 25, 1960). The
investigation indicated by this group "established that the potency of the
pertussis-vaccine component in the quadruple antigen products * * was relatively
unstable." Pittman, Instability of Pertussis-Vaccine Component in Quadruple
Antigen Vaccine, 181 Journal of the Am. Medical Ass'n 113 (11162). It is interest-
ing to note this Pittman article points out that with the adoption of a unit of
potency in 1953 with an upper limit placed on potency, no cases of fatal encepha-
lopathy due to pertussis vaccine were reported to DBS although "occasional
nonfatal neurological reactions" continued to occur. Id. at 114~ Dr. Pittman
hypothesized that "the preservative and the tissue-cell enzymes present" in the
quadruple antigen vaccines "may be factors which contribute to instability."
Id. at 148.
In 1964, a study was made with bordetella pertussis cells which showed that
various substances influenced leakage from the bacterial cell. Niwa, Yamadeya
& Kuwajiina, Leakage of Cell Components of Bordetella Pertussis, 88 Journal
of Bacteriology 809-10 (1964). Although benzethonium chloride was not used
in that study, certain chemical substances similar thereto were employed
(TR 1529-30).
Finally, in 1965, in an article co-authored by Dr. Pittman, it was stated:
"Recent work has' shown that pertnssis vaccine in DTP-P[diphtheria-teta4ius-
pertussis-polio vaccine] preserved wit/b benzethoninm chloride is unstable in
potency * `~. This surface-acting preservative, no doubt, contributed to the
greater toccicity of DTP-P * * by favoring the leaching of the towin from the
bacterial cell. It is well known that alkalinity favors lysis and thereby promotes
toxicity." Pittman & Cox, Pertussis Vaccine Testing for Freedom-from-Toxicity,
13 Applied Microbiology 447,453 (1965). (Emphasis added.)
When testifying at her deposition, Dr. Pittman attempted to water down her
statement by contending that she considered this statment to be a mere hypoth-
esis (Pittman deposition of Nov. 17, 1967, at 83 (hereinafter referred to as
"Pittman I")), but that it was based on scientific experimental data (id. at 83-
84). The statement in her article, written when she was not involved in the
instant litigation, seems far more significant than her later attempt to diminish
its importance. Dr. Pittrnan, throughout her testimony, appears to consider the
instant litigation a personal attack and an indictment of DBS as well (Pittman
deposition of Nov. 27, 1967, at 214-15 (hereinafter referred to as "Pittman II")).
Dr. Pittman also testified that leakage would be immediately ascertainable in
the toxicity tests conducted by the defendant and DBS (Pittman I, at 79-80).
However, she later stated she bad absolutely no idea as to the extent of leakage
or how long it would take (Pittman II, at 79-81), so it is most difficult to see
how she could predict with any certainty that the toxicity tests would reveal the
leakage phenomenon.
The foregoing documents lend significant credence to the testimony of one of
plaintiffs' expert witnesses, Dr. Lapin, who stated that in his opinion Quadrigen
was toxic and that the administration of the vaccine to the infant plaintiff
caused the injury involved in this litigation. Coupled with this is the complete
failure of defendant to offer any reasonable alernative cause of Eric Tinnerholm's
injury.
The "defect" involved was, in my opinion and as already stated hereinbefore,
the leakage of endotoxins from within the bacterial cell and it has been shown
by a preponderance of the credible evidence that such defect was the proximate
cause of the injury.
Nor can defendant argue that this was a marked improvement over Triogen
so that it should be shielded from liability even if the above finding is correct.
I will state now, and will have occasion to reiterate later that no need justified
a risk of marketing Quadrigen at an early date. Other products which performed
the same function as the indicated vaccine without the danger involved were on
the market and readily available to the medical profession. Although there is
PAGENO="0286"
4576 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
testimony that it is beneficial to the patient and the medical profession to reduce
the number of infections, when balancing this with the tragic occurrence in the
case at bar and perhaps several other cases, the reduction of injections argument
pales into insignificance.
[4] Accordingly, it is my opinion that the defendant has breached its war-
ranty of merchantability to the plaintiff. In view of this discussion, the issues
involving liability for breach of the warranty of fitness for a particular purpose
need not be considered.
Negligence
[15-16] The finding of implied warranty liability does not preclude this Court
from finding the defendant liable in negligence. ~S~tromsodt v. Parks-Davis c~ Go.,
supra, 257 F.supp. at 995. However, it is fundamental law that plaintiffs will be
limited to one recovery.
[17] Defendant herein is chargeable w-ith negligence in failing to adequately
test its product, for thereafter releasing the product for commercial distribution
in the face of certain danger signs emanating from the test results, and in failing
to adequately warn the medical profession of the risks inherent in its use.
[18] It is established law that where a drug manufacturer develops a new
drug subsequently foimd to produce harmful side effects which the manufacturer
failed to discover in the course of testing the product, the manufacturer is
liable in negligence where it appears that the drug in fact was inadequately
tested or that the manufacturer failed to exercise due care in the development of
the product prior to its release on the market for commercial distribution.
3 Frumer & Friedman § 33.O1[2] ; Roginsky v. ftieltardson-Merrell, Inc., 378
F.2d 832 (2d Cir. 1967); Stromsodt v. Parke-Davis c~ Co., supra.
The tests which the various lots of vaccine had to undergo prior to their
release on the market were generally biological and/or clinical in nature. Not
only was it required that each lot fall within the acceptable standards of
potency and toxicity established by DBS, but also the reports from the doctors
in the field as well as those testing the vaccine under clinical conditions had to
indicate that the drug was safe for use and that it produced no untoward adverse
reactions in the recipients.
Both the potency and toxicity tests were first performed in the laboratories
of the manufacturer. Once satisfactory results were achieved, the manufacturer
would send the lot to DBS which, in turn, would conduct its own independent
study. If the DBS test results confirmed the manufacturer's report or protocol,
the lot would be approved for release on the market. If, on the other hand, the
DBS results conflicted with the results set forth in the manufacturer's protocol,
the lot would be returned to the manufacturer for re-testing.
As hereinbefore stated, the potency test was performed by injecting groups
of mice with varying dilutions of vaccine, and, after a period of time, challeng-
ing the mice with virulent organisms. The protective activity of the vaccine
w-as judged by the number of mice which survived the challenge at the various
dilution levels. In addition, it w-as required that the pertussis vaccine com-
ponent have no greater potency than 12 protective units per total human immu-
nizing dose (THD) .~ Because a standard deviation is inherent on a test of this
nature, a vaccine would be deemed satisfactory if the result of one test or an
average of the combined results of two or more tests indicated that the calcu-
lated protective activity of the vaccine fell within the allowable range of 8 to
36 protective units. Any result falling outside this range indicated that the par-
ticular lot was not fit for public use and consequently was unacceptable for
distribution.
The standard toxicity text was preformed by weighing a group of ten mice,
injecting them with a test dose of vaccine and weighing them again at the end
of periods of 72 hours and 7 days. A vaccine was accepted as being free from
toxicity if at the end of 72 hours the group weight of the mice was no less than
it had been at the initial weighing, and at the end of 7 days was greater than
it had been initially. A lot automatically failed the test if it w-as determined
that a mouse had died from the vaccine.
Although Parke-Davis found no problem in meeting the potency requirements
in the testing of its triple antigen vaccine, Triogen, it is apparent from the
11 "THD" is the total dose of vaccine, administered in a series of three separate inocu-
lations, that any one individual is required to be given in order to insure full immunizing
protectivity. The "12 protective units" standard represents the number of bacteria within
a total human dose which successfully immunizes the recipient from the disease without
itself causing harmful side effects.
PAGENO="0287"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4577
correspondence between Parke-Davis and DBS during the year 1959 that begin-
ning with the very first experimental lots of Quadrigen submitted to DBS for
testing, i.e., Lots X-7513 and X-7514, Parke-Davis was having difficulty obtain-
ing satisfactory potency values. On January, 9, 1959, Dr. Workman of DBS wrote
to Parke-Davis that:
"Our potency assays on the pertussis component of this lot (X-7514) showed
values of only 7.9 and 3.8 units per total immunizing dose and thereby suggest
the potency of the pertussis component is too low. In view of the extreme differ-
ence between your and our results, however, we would be willing to give further
consideration to this lot if you are willing to retest. * *" Plaintiffs' Exh. 3.
Letters of a similar nature were written concerning Lots 049033, 059294,
049032, 049034, 054044, 055961, 051639, 058836 and others, which lots initially
produced test results between 2.7 and 7.25 protective units per PHD. Some of
these lots were re-tested and eventually withdrawn from processing.
Evidencing Parke-Davis' dilemma, on March 5, 1969, only 4 months prior to the
time Quadrigen was commercially marketed, George D. Brigham, Director of
the Biological Division of Parke-Davis, wrote a letter to Dr. Workman regarding
Lot X-7514:
"As you know from recent reports, we have been having difficulties in obtain-
ing satisfactory potency values in our preliminary production lots of Quadrigen.
In view of these results, we are planning to increase the H. pertussis content to
20 opacity units instead of 15 opacity units as was originally intended." Plaintiffs'
Exh. 3.
In a follow-up letter dated March 13, 1959, from Dr. Brigham to Dr. Workman,
it was further stated:
"You indicate in your letter that you are concerned with the low values we have
been obtaining in the pertussis component of our multiple antigens. As far as we
are aware, our only problem seems to be with the quadruple antigens i.e. eacept
for an occasional lower than usual result, our other pertussis-containing products
are given satisfactory potency tests. Naturally, we have been concerned with the
low pertussis test results in Quadrigen and as indicated in earlier correspon-
dence, we plan to increase the concentration of organisms to a minimum of 20
opacity units per cc. as an immediate step to correct the situation." Plaintiffs'
Exh. 3D. (Emphasis added.)
It seems significant to this Court that Parke-Davis, realizing the inherent poten-
tial of the pertusis component for causing fatal reactions, and faced with the
unique problem of exceptional deficiencies in the potency values of its premarket
lots, simply sought to strengthen the pertussis component without considering
the possible existence of a defect in the combination itself. This proposed solution,
however, also presented problems. On June 4, 1959, Dr. Brigham wrote Dr. Work-
man with reference to Lot 52230, the first commercial lot:
"We noted the unusually high value obtained in the pertussis vacc~ine potency
test. In view of these high results we conducted a re-test on thi slot. A supple-
mental protocol summarizing the test is attached indicating 21.5 units per total
human dose. Phis confirms our thought that a re-test would probably show aver-
age results within an acceptable range." Plaintiffs: Exh. 3F. (Emphasis added.)
It appears clear to this Court that Parke-Davis in its rush to commercialization
of its product either overlooked or neglected to consider the possibility that
Quadrigen was too unstable a vaccine and therefore too unpredictable to be
released on the market at that time.
[19, 20] Parke-Davis was equally negligent in failing to test its product under
market conditions. Inasmuch as it was well known that variations in tempera-
ture could have marked effects on the safety and effectiveness of a vaccine, and
it was also known, as testified to by Dr. McLean of Parke-Davis, that many of
the lots could not be shipped under refrigerated or storage conditions, it was
incumbent upon Parke-Davis to subject their pre-release lots to those foreseeable
variations in temperature to which their product would be exposed prior to the
point of inoculation so as to insure that this exposure would not produce deleteri-
ous effects. This was not done. As it developed, tests taken in 1960 by the Massa-
chusetts Department of Health and subsequently by DBS, indicated that although
samples of the quadruple antigen vaccine which were held in storage under refrig-
erated conditions showed no perceptible loss of potency, those purchased on the
market revealed a loss of potency below the minimum requirements for a per-
tussis vaccine. Although events subsequent to the injury herein cannot be con-
sidered in determining the manufacturer's negligence, it could not have been
PAGENO="0288"
4578 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
clear during 1959 that tests under market conditions were necessary and that
the defects subsequently discovered in 1960 were foreseeable.12
Similarly, Parke-Davis was experiencing difficulty in its attempt to meet the
minimum standards of toxicity. Even as late as August 1959, one month alter
Quadrigen had been released to the commercial market, certain lots which had
been submitted by Parke-Davis to DBS for toxicity testing were being repected.
On August 25, 1959, a letter from Dr. Workman to Dr. Brigham, regarding Lot
054043, indicated:
"Our tests of the pertussis component for freedom from toxicity do not con-
form with the results reported in your protocol. Three tests were performed and
6 of 30 mice died by the end of 7 days." Plaintiffs' Exh. 3.
In a letter dated September 16,1959, Dr. Bringham replied that Parke-Davis'
own re-test of Lot 054043 resulted in the deaths of 4 of the 40 mice inoculated.
Defendant admitted that although this lot passed a 10-mouse test given earlier,
the lot "appears upon more extensive testing to have enough toxicity to fail to
pass the Minimum Requirements test in a certain percentage of cases." Plain-
tiffs' Exh. 3.
Clinical trials of Quadrigen prior to marketing were conducted by Dr. Clarence
D. Barrett, Director of the Division of Material and Child Health of the City of
Detroit, beginning in 1956 and terminating in 1959.12 Although these trials were
primarily designed to determine antibody response in children of various ages
and to determine the earliest age in infancy at which immunization with Quad-
rigen could be started, Parke-Davis used these trials in its license application as
a basis for the proposition that the clinical experience involving Quadrigen
yielded no greater local or febrile reactions than was experienced with the triple
antigen product.
[21] Because of the nature of the vaccine used in the Barrett study and the
lack of controls placed on the diagnostic and reporting procedures, it was negli-
gent for Parke-Davis to have used this study as its basis for making the above
representation. The pertussis component which Dr. Barrett used had been in
cold storage for the two-year period immediately preceding the inoculations. If
had been discovered that during this period of time the potency of the pertussis
component had fallen below the NIH's minimum requirements for an acceptable
vaccine. Nevertheless, it was used in the study. Although in the standard commer-
cial production lots the benzethonium chloride is combined with the pertussis
component at the point of manufacture and allowed to remain in combination
throughout the entire storage period, such was not the case with the vaccine used
in the Detroit study. There, the preservative was not combined with the pertussis
component until the time that the children were to be inoculated. Consequently,
the clinical trial could not validly test the extent to which the addition of the
benzethoniurn chloride (one of the few important changes being made in the
quadruple antigen product) increased the reactivity of the product. Although
the vaccine used may have been sufficient to determine the antibody response in
the children tested, never having been subjected to market conditions and rep-
resenting a quadruple antigen of lesser strength and of a different manufacturing
process than the one eventually to be released on the market, it should not have
been used as a barometer for judging local and febrile reactions.
Even had the vaccine used been an acceptable one for this purpose, the ab-
sence of controls over the diagnostic and reporting procedures made any con-
clusion with regard to the nature and extent of the reactions an invalid one.
Mothers, most of whom came from the lowest socio-economic stratum of urban
Detroit, had been asked to report, by telephone, all illnesses or reactions suffered
by the children following their inoculations. No doctor or medical assistant at
any time took the temperatures of the children either on the day that the vac-
cine was administered or subsequent thereto unless a mother, suspecting a re-
action, brought her child back to the clinic. Needless to say, it was somewhat
12 It must be noted that in 1059 there were no regulations requiring a drug manufacturer
to test its product under market conditions prior to releasing it for use to the general
public. It is the opinion of this Court, however, that although it would be negligent for a
manufacturer to disregard the regulations established by the National Institutes of Health
in the manufacture of its drug products, a manufacturer cannot exempt itself from
liability in negligence for failure to exercis due care in an area not covered by a specific
regulation. See Stromsodt v. Parke-Davis & Co., supra at 997; Frumer & Friedman
§ 3301[3].
12 Barrett, Timm. Molner. Wilner, Fahey & McLean, Multiple Antigen for Immunization
Against Poliomyelitis. Diptheria, Pertussis and Tetanus, 49 American Journal of Public
Health 644 (1959) ; Barrett, Timm, Molner, Wilner. Anderson, Carnes & McLean, Multiple
Antigen for Immunization Against Poliomyelitis, Diphtheria, Pertussis and Tetanus, 167
Journal of the American Medical Association 1103 (1958).
PAGENO="0289"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4579
presumptuous to assume the mothers' ability to recognize a "reaction", to as-
sume their possession of thermometers with which to determine whether their
children were experiencing febrile reactions, to assume the availability of tele-
phones with which to communicate the fact that a reaction had been suffered,
and hypothesizing the fact that telephones were available, to assume the depend-
ability of the mothers to make the requested reports. To allow any implication
to be derived from this study with regard to the incidence of reactions following
the inoculation of the children was negligence on the part of the defendant
herein.'4
[22] Quadrigen was then made available to selected members of the medical
profession who were requested to comment on their experience with the prod-
uct. Enough of the "field trials" indicated a marked increase in reactions among
the patients given Quadrigen over those being given the triple antigen product
with a separate inoculation of the pollomyelitis vaccine to have required Parke,
Davis to experiment further with their newly-developed quardruple antigen.
There were some reports indicating up to 75 per cent reactions in the children
tested whereas `other reports indicated that no reactions whatsoever had been
suffered. Some of these contrasting reports involved experiences with the same
lot of vaccine. In other reports which indicated reaction rates as low as 2 per
cent, the "Remarks" sections indicated that "slight fever" was not reported,
"high temperature" was designated "no reaction", and "103-degree tempera-
ture" designated as a "slight reaction". In one report, only temperature of 105
degrees qualified as a "reaction". Many of the reports which indicated un-
realistically low reaction rates were from doctors who, by the nature of their
covering letters, seemed primarily interested In obtaining more of the free vac-
cine. In addition, it is most significant that the deposition testimony of Dr. John
E. Gajewski, employed during 1959 in Parke-Davis' Department of Clinical
Investigation and thereafter as Assistant Director of Medical Correspondence,
indicated that during the period between July 1959 and September 1961 the re-
ported incidents of febrile reactions with Quadrlgen showed more frequent and
higher temperature elevations. Similarly, and in the face of the testimony of
Dr. Feinberg and Dr. Lapin that it was a rare instance when the triple antigen
vaccine produced a fever of 104 degrees, the results of a study conducted by
Dr. Sauer, the inventor of the original pertussis vaccine, su:bmitted for publi-
cation on June 10, 1959, and published in the fall of that year, evidenced that
of the large groups of infants inoculated with Quadrigen 5 per cent reacted
with temperatures of 104 degrees and as much as 2 per cent reacted with temper-
atures of 105 degrees. All in all, it appears to this Court that there existed a
sufficient number of both unrealistic and conflicting reports from the field to
have required Parke-Davis to take a serious second look at its product before
placing it on the market.
Of particular note was Parke-Davis' cursory attempt to investigate the cause
of a reported death attributed by the treating physician to his use of Quadri-
gen. Although the autopsy report, received subsequently by Parke, Davis, stated
that the immediate cause of death was bronchial pneumonia, the hospital recQrd
revealed that the patient had exhibited high fever, convulsions, opisthotonus,
vomiting and lethargy several hours after a Quadrigen inoculation. The con-
clusion of the autopsy report is not necessarily inconsistent with a finding that
the child experienced a pertussis encephalopathy prior to his death in that
although bronchial pneumonia may have been the immediate caus& of the in-
fant's expiration, such condition can frequently be brought about by some other
condition, which, in this case, in light of the small hemorrhages found in the
subarachnoid portion of the brain, could ~vell have been the vaccinal encepha-
lopathy as was originally diagnosed. Nevertheless, there should have been an
immediate and thorough investigation conducted by Parke-Davis into the pos-
sible connection between the Quadrigen inoculation and the infant's death two
days subsequent thereto, especially in view of the fact that the quadruple anti-
gen was soon to be released on the commercial market. This was not done nor
did Parke-Davis attempt to notify the NIH of the possible existence of a Quadri-
gen-related death."
U Although a separate study had been conducted by Dr. Barrett in 1958, using fresh
experimental vaccine and employing stricter controls over the diagnostic and reporting
procedures, this study showed increased febrile reactions with the use of Quadrigen, and
was not the principal study relied upon in support of the license application. To the con~
trary, It was the Detroit study discussed in the accompanying text which Parke-Davis
attached to its application and upon which it relied most heavily.
ii See note 12, supra.
81-280 0-69--pt. 11-19
PAGENO="0290"
4580 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
[23] In considering the above discussion, it should be understood that the
entry of Quadrigen on the market in July 1959 was not a response to a situation
in which an epidemic or need existed justifying the risk of premature market-
ing since products were already available to the medical profession w-hich satis-
factorily accomplished that which Quadrigen was designed to do. Stromsodt v.
Parke-Davis & Co., supra 257 F.Supp. pp. 996-997.
[24] In addition to defendant's negligence in failing to further test its prod-
uct in the face of evidence that the quadruple antigen w-as unstable, and in the
absence of a public need justifying its premature release on the market, de-
fendant was similarly negligent in not adequately warning the medical profes-
sion of the dangers inherent in its use.
25[-28] It is the opinion of this Court that a drug manufacturer is under a duty
to warn the medical profession of dangers inherent in its biological drugs which, in
the exercise of reasonable care, it knew or should have known to exist. Sterling
Drug, Inc. v. Cornish, 370 F.2d 82, 84-85 (8th Cir. 1960) ; Stromsodt v. Parke-
Davis & Co, supra, 257 F. Supp. at 997; Love v. Wolf 26 Cal.App.2d 378, 38 Cal.Rptr,
183 (1904); Alfieri v. Cabot Corp., 17 A.D.2d 455, 235 N.Y. S.2d 753 (1st Dep't
1962), aff'd, 12 N.Y.2d 1098, 240 N.Y.S.2d 163, 190 N.E.2d 535 (1963) ; Marcus
v. Specific Pharmaceuticals, Inc., 82 N.Y.S.2d 194 (Sup.Ct.1948); Frumer &
Friedman, supra ~ 33.01 [3]; Restatement (Second) of Torts § 388 (1965)
Rheingold at 993, 994. "Watering down" the substance of a warning so as to
give false assurance to the medical profession that a drug or biological can be
safely administered, thereby minimizing the danger which exists in the use
of a product, amounts to an inadequate warning. Love v. Wolf, supra, 38
CalRptr. at 193, 197; Alfieri v. Cabot Corp. supra; Rheingold at 993, 994. In-
asmuch as doctors have the right to and in fact do rely on the brochures sent
to them by the manufacturers regarding safety in the use of their products,
Gielskie v. State, 18 Misc.2d 508, 191 N.Y.S.2d 436, 439 (Ct.Cl.1959), rev'd on
other grounds 10 A.D.2d 471, 200 N.Y.S.2d 691 (3rd Dep't 1960), aff'd, 9 N.Y.2d
834, 216 N.Y.S.2c1 85, 175 N.E.2d 455 (1961), a manufacturer is negligent who,
after reporting the results of its tests to the FDA and on the strength of those
reports markets its products, discovers new- harmful side effects produced by the
drug, yet fails to send out warnings of this new- development to the foreseeable
users, i.e., doctors and dispensaries, Sterling Drug, Inc. v. Cornish, supra, 370
F.d at 85; De Vito v. United Airlines Inc., 98 F.Supp. 88, 96 (E.D.N.Y. 1951);
Gielske v. State, supra; Rheingold at 995.
Since the relevant portions of the warning which Parke-Davis issued in the
form of a package insert are specifically set forth in the express w-arranty por-
tion of this opinion, there is no need to recite them at this time:
Knowing that the only advantage in administering Quadrigen rather than the
trivalent vaccine was the reduction from two to one of the number of inocula-
tions required for each immunization, it is reasonable to assume that had the
doctors been informed that greater reactivity could be expected from the quad-
ruple antigen, they would not have subjected their patients to needless risk by
using this product. Fully realizing this, Parke-Davis, employing the technique
of ambiguity and a shrewd use of descriptive adjectives, was able to gloss over
those facts which would have dissuaded the doctors and dispensaries from using
their product, thereby lulling the medical profession into a false sense of security.
[29] The brochure states that "[t]he incidence [of reactions with Quadrigen]
is usually no greater than is normally expected with trivalent vaccine." (Em-
phasis added.) This statement is misleading in that it reasonably permits one to
conclude that the results from the studies conducted by the manufacturer have
shown that Quadrigen has produced no greater reactions in the recipients thereof
than did Triogen, with the exception of an insignificant number of isolated in-
stances. Of course, this was not true. If Parke-Davis thought that in this instance
it could legitimately use the word "usually" to mean "in a majority of the lots
tested", it was clearly in error, for under that interpretation the manufacturer
could conceal from the medical profession a 49 per cent increase in the reaction
rate of its products. For example, if Product A and Product B produce reaction
rates of 50 per cent and 60 per cent, respectively, in all the lots tested, it is con-
ceivable that a manufacturer could represent that there is "usually" no greater
reaction found to exist in Product B than in Product A, relying on the fact that
only 1 additional person out of every 10 tested reacted to Product B. This method
of linguistic distortion is grossly misleading. Clearly, any significant increase
found to exist in the reaction rate of a particular drug must be disclosed.
[30] As hereinbefore stated, a study conducted by Dr. Sauer, submitted for
publication in June 1959, revealed that 7 per cent of the children inoculated
PAGENO="0291"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4581
with Quadrigen suffered fevers of 104 degrees and above. Parke-Davis alleges
that the reason such study was not mentioned in its brochure was that the
Sauer report had not been published until after Parke-Davis had written its
package insert. However, it would appear from the evidence that Parke-Davis
was fully familiar with the contents of this report in light of Dr. Sauer's contin-
uing association with defendant since the early days in the development of the
pertussis vaccines. As the cases cited above hold, it was Parke-Davis' duty
timely to amend its brochure to inform the medical profession of any significant
new developments or information which could reasonably be expected to affect
a doctor's decision to use the product. Had Parke-Davis promptly amended its
literature to include the results of the study conducted by Dr. Sauer, the medical
profession would have been apprised prior to the day that the infant plaintiff
was inoculated of the unusual reactivity produced by Quadrigen.
[31] Having raised the possibility at trial that plaintiff's injury could have
been caused by an allergic reaction and therefore due to plaintiff's own particu-
lar hyper-sensitivity (a possibility rejected by me herein), it would appear
sufficient to note in passing that defendant was under a duty in 1959 to warn the
medical profession of this possibility, especially in view of the fact that such
an etiological theory had been recognized since 1947. Berg, Neurological Compli-
cations of Pertussis Immunization, British Medical Journal 26 (July 5, 1958).
Inasmuch as Parke-Davis did see fit to warn of a possible allergic reaction to
penicillin and streptomycin, the two antibiotic residuals from the poliomyelitis
vaccine, it similarly should have warned of that possibility with regard to the
pertussis component.
Finally, the warning that "[l]ocal reactions have been known to be more
severe when the child is in the incubative stage of pertussis" was ambiguous in
that it reasonably could have misled the members of the medical profession to
believe that only in cases where the child was in the incubative stage of pertussis
would encephalitic symptoms occasionally occUr. Stromsodt v. Parke-Davis &
Co., supra, 257 F.Supp. at 997. This was Dr. FeiUberg's interpretation and, in the
opinion of this Court, could reasonably have been followed by others.
After due consideration and for the reasons set forth herein, it is the opinion
of this Court that the defendant was negligent both in its failure to adequately
test its product prior to releasing it on the commercial market and for its failure
to adequately warn the medical profession of the dangers inherent in its use.
As stated by the late Justice Jackson, dissenting in Dalehite v. United States :16
"This is a day of synthetic living, when to an ever-increasing extent our
population is dependent upon mass producers for its food and drink, its cures
and complexions, its apparel and gadgets. These no longer are natural or simple
products but complex ones whose composition and qualities are often secret.
Such a dependent society must exact greater care than in more simple days
and must require from manufacturers or producers increased integrity and
caution as the only protection of its safety and well-being. Purchasers cannot
try out drugs to determine whether they kill or cure. * * Where experiment
or research is necessary to determine the presence or the degree of danger, the
product must not be tried out on the public, nor must the public be expected
to possess the facilities or the technical knowledge to learn for itself of inherent
but latent dangers. The claim that a hazard was not foreseen is not available
to one who did not use foresight appropriate to his enterprise."
[32] Finally, as to the damages claimed, I have been guided by the principle
enunciated by the New York courts that damages are compensatory, not punitive.
Little purpose would be served by further detailing the catastrophe irrevocably
visited on this infant child.
[33] The plaintiff father is, of course, entitled to recover for the loss of the
child's services and for medical attendance and expenses. Kalina v. General
Hospital, 31 Misc.2d 18, 20, 220 N.Y.S.2d 733,735 (Sup.Ct.1961), aff'd, 18 A.D.2d
757, 235 N.Y.S.2d 808 (4th Dep't 1962), aff'd mem., 13 N.Y.2d 1023, 245 N.Y.S.2d
a99, 195 N.E.2d 309 (1963). The parties have stipulated that his out-of-pocket
payment for hospital and medical expenses for the infant total $3,470.55 and
payments made by him to the State hospitals total $2,812.97, for which he is
entitled to recover herein. Eric has been confined to State institutions since Jan-
uary 30, 1962 and will require institutional care, either of a public or private
nature, for the rest of his life.
[34-36] Defendant suggests that since the infant plaintiff might be cared
for at State expense, the doctrine of Drinkwater v. Dinsmore, 80 N.Y. 390 (1880)
16346 U.S. 15, 51, 73 S.Ct. 956, 97 LEd. 1427 (1953).
PAGENO="0292"
4582 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
should be applied. Such `collateral source" doctrine, however, has been severely
limited in recent years in its application. Klein v. United States, 339 F.2d 512
(2d Cir. 1964); Feeley v. United States, 337 F.2d 924 (3rd Cir. 1964); Cunning-
ham v. Rederiet Vindeggen A/S, 333 F.2d 308 (2d Cir. 1964). Moreover, it is in-
applicable in the present case since liability for such expenses may be asserted
herein against plaintiff father and plaintiff infant. The present cost of maintain-
ing the infant at Suffolk State School is $6,000, wthich the State may recover from
the father. New York Mental Hygiene Law-. McKinney's Consol.Laws, c. 27, § 24.
Even though it has accepted lesser payments in past years, it may recover the
full reimbursement rates less the payments already made, § 24(9) (b), which
potential recovery for the past period of institutionalization is fixed at $33,000.
Such sum is subject to the lien of the State under § 24(5) (b). Defendant may,
for his own protection and if so advised, move to have such lien determined.
[37, 38] I have not included any amount to cover the nursing services ren-
dered by the infant's mother during the period from December 1, 1959 to Jan-
uary 30, 1962, for lack of proof that such survices were other than would norm-
ally have been rendered by a mother to her child. I do aw-ard the plaintiff father
$2,500 for the loss of the child's services during minority.
[39, 40] The damages properly awarded to the infant are to cover future
medical expenses, to reimburse him for future loss of w-ages, and to cover past,
present and future pain and suffering. With respect to future medical expenses,
it seems clear that Eric will require institutionalization for the rest of his life.
However, in view of the injury, I believe from the evidence that a present life
expectancy of 50 years is a reasonable approximation. Also, recognizing the
continuing rise in medical costs and the fact that Eric may well be entitled to
private nursing and therapy additional to what may be received under State
care, I believe that $160,000 would be a fair amount to ensure him adequate
future medical care. Loss of wages may also properly be awarded. Grayson v.
Irvmar Realty Corp., 7 A.D.2d 436, 184 N.Y.S.2d 33 (1st Dep't 1959).
[41] The defendant contends that since the infant will be permanently con-
fined to an institution he will have little need for damages attributed to loss of
earnings. The only authority cited for this proposition is Scolavino v. State, 187
Misc. 253, 263, 62 N.Y.S.2d 17 (Ct.Cl.) modified, 271 App. Div. 618, 67 N.Y.S.2d
202 (3rd Dep't 1946), aff'd. 297 N.Y. 460, 74 N.E.2d 174 (1947), and is clearly
inapposite since the condition of the infant in that case prior to the accident
made his future employment impossible, i.e., loss of future earnings was not
attributable to the accident. Accordingly, taking into account a 5-percent dis-
count factor and making the valid assumption that Eric would not have com-
menced to work until age 21, I award him $50,000 for loss of future earnings.
[42] To the out-of-pocket losses suffered by this infant must be added the
general damages for pain and suffering. Little purpose would be served in fur-
tiler dwelling on the various aspects of his past, present and permanent con-
dition. He has undergone two spinal taps and a craniotomy, is partially paralyzed
and subject to seizures. He is not comatose, however; he is not a vegetable.
Accordingly, after careful consideration of this case and of others in which
somewhat similar injuries were involved,1~ I consider an award of $400,000 for
pain and suffering reasonable and just.
In summary, I find as follows:
I. For plaintiff Carl F. Tinnerholm-
(a) Reimbursement for medical expenses paid $ 6, 283. 52
(b) For Past medical expenses for which liable 33, 000. 00
(c) Loss of Services 2, 500. 00
II. For the infant plaintiff Eric Tinnerholm-
(a) Future medical expenses 160, 000. 00
(b) Loss of future earnings 50, 000. 00
(c) Pain and suffering 400,000. 00
The foregoing represents the Court's findings of fact and conclusions of law-.
A judgment shall be entered for plaintiffs in conformity herewith.
(Whereupon, at 1 :40 p.m., the subcommittee recessed, to reconvene
at 10 a.m., on Tuesday, March 18, 1969.)
~ See, e.g., Christopher v. United States, 237 F. Supp. 787 (ED. Pa. 1965) (29-year old
man -paraplegic----$350.000) Schwartz v. United States, 230 F. Supp. 536 (ED. Pa. 1964)
(4S-year-old man-facial cancer-~over $600,000) : Wolfe v. General Mills Inc., 35 Misc.
2d 996, 231 N.Y. S.2d 918 (Sup. Ct. 1962) (30-year-old man-brain injury-$240,000).
PAGENO="0293"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
TUESDAY, MARCH 18, 1969
U.S. SENATE,
MONOPOLY SuBcO~IMIrrEE OF THE
SELECT Coi~IMIrrEE ON SMALL BusINEss,
Washington, D.C.
The subcommittee met, pursuant to reôess, at 10 :05 a.m., in the Cau-
cus Room, Old Senate Office Building, Senator Gaylord Nelson (chair-
man of the subcommittee) presiding.
Present: Senator Nelson.
Also present: Chester H. Smith, staff director and general counsel;
Benjamin Gordon, staff economist; Jay Cutler, acting minority coun-
sel; and Elaine C. Dye, clerical assistant.
Senator NELSON. This morning the Subcommittee on Monopoly re-
opens its hearings. We have as our witness today the distinguished
Dr. Edward Annis, past president of the American Medical Associa-
tion, and now one of the 15 trustees of the association.
*Dr. Annis, w-e are very pleased to have you here before the corn-
imttee this morning. Perhaps for the reëord, you should introduce
your associates.
STATEMENT OF DR. EDWARD R. ANNIS, PAST PRESIDENT OF THE
AMERICAN MEDICAL ASSOCIATION; ACCOMPANIED BY DR.
THOMAS HAYES, DIRECTOR, DEPARTMENT OF DRUGS, AND SEC-
RETARY, AMA COUNCIL ON DRUGS; AND BERNARD P. HARRISON,
DIRECTOR, LEGISLATIVE DEPARTMENT, AMA
Dr. ANNIS. Yes, Senator.
Mr. Chairman, members of the committee, I appreciate this oppor-
tunity and I would like now to introduce Dr. Thomas Hayes, director
of our department of drugs, secretary of the American Medical Asso-
ciation's Council on Drugs, and a member of the Department of Medi-
cine of the University of Illinois. The Senator in the past has expressed
his desire to Dr. Hayes to attend this hearing and we are very pleased
that he could be with us. With us also is the director of the Legislative
Department of the American Medical Association, Mr. Bernard
Harrison.
Senator NELSON. Doctor, you may proceed to present your state-
ment in any fashion you desire. Certainly at any time you wish to
elaborate or extemporize on any part of your statement for the record,
we will be happy to have you do so. Your statement will be printed in
full in the record, along with the appropriate, material that you have
submitted along with your statement. I assume if we have some ques-
tions in the course of your presentation, you will have no objection
4583
PAGENO="0294"
4584 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
to my asking them, but most of the questions, I will ask when you
finish.
Dr. ANNIS. Mr. Chairman, if it meets your approval, I will not
extemporize during my original presentation. This has been prepared
pursuant to your request so that we can have a record. We have con-
densed it as much as is possible. If I would be allowed to present our
entire statement first-I would like to withhold extemporaneous re-
marks and answers to the chairman until after that presentation, if
this meets with your approval.
Senator NELSON. Fine.
Dr. ANNIS. In correspondence between this committee and our as-
sociation, it has been requested that I include in my discussion these
topics:
1. The AMA itself.
2. The evaluation of advertising appearing in AMA publications.
3. Revenue of the association from advertising in its publications.
4. AMA views on a comprehensive drug compendium.
5. Prescription labeling.
All of these subjects are included in this statement, along with
exhibits of supporting data which I shall not read, but which will
be available for your further information. In addition, I will offer
some brief comments which I believe you will find pertinent.
I would like to hope that what I say here today is as carefully
reviewed in the Nation's press and in other communications media
as the testimony of earlier witnesses has been. If it is, I know it will
buttress the public's confidence in American medicine, which I feel
has been weakened by some statements this committee has heard.
This Nation is blessed with many hundreds of medical organiza-
tions and medical journals, along with hundreds of thousands of phy-
sicians and allied medical and health personnel, devoted to improving
the health care of the people.
Medicine in this country is already good. That fact can be attested
to by millions of men, women, and children who are helped by
physicians-and by drugs-every day.
The goals of this committee will not be achieved, and the best
interests of the Government and of the Nation's people are not served
by undermining confidence in the medical profession or any of the
other professions and occupations working to maintain or restore
good health.
Mr. Chairman, let me now turn to the topics I promised to cover.
THE AMERICAN MEDICAL ASSOCIATION
The AMA was founded 122 years ago in a nation and a world en-
tirely different from those we now know. In 1847, there were only 29
States with a combined total population less than the present popula-
tion of the New York and Chicago consolidated areas.
Three primary desires motivated the conscientious physicians and
medical school faculties of t.hat day to found a national professional
association in medicine.
One was the need to establish and maintain a code of ethics by
which physicians' behavior and professional performance could be
judged by their peers and the public.
PAGENO="0295"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4585
Second was the need to combat the flourishing trade in quackery
and nostrums which was endangering the health and lives of
Americans.
Third was the need to improve and accredit medical education
and to establish high standards which persons must attain before
being permitted to practice as physicians.
All three of these objectives are implicit in the purposes of the
association, first written into the AMA constitution when it was adopt-
ed May 5, 1847: "To promote the science and art of medicine and
the betterment of public health."
In 122 years, the association has grown into the world's largest
medical association, with 217,000 members-including members who
are in the Armed Forces or other Government service and some who
are not "active," such as physicians of other nations and dentists and
other scientists outside the M.D. discipline who have been accepted
into membership because of their contributions to health.
The AMA is a federation of 54 State and territorial medical asso-
ciations, each of which is autonomous. Remember, it was the State
and regional medical societies that existed in 1847 which created the
American Medical Association as their national voice; not the other
way around.
Each State association-one in each State plus the District of
Columbia, Puerto Rico, the Canal Zone, and the Virgin Islands-has
its own house of delegates as its policymaking body, made up of
representatives elected by the county, city, metropolitan or regional
medical societies within its geographical jurisdiction. All together,
there are 1,955 of these local medical societies in the United States.
The policymaking body of the AMA is its 242-member house of
delegates, of whom 215 are elected by the, State and territorial medi-
cal associations on the basis of one delegate for each 1,000 members.
Five other delegates represent the Army, Navy, Air Force, Veterans'
Administration and U.S. Public Health Service. The remaining 22
are from the AMA scientific sections, each representing a medical
specialty.
The wishes of the house of delegates-as expressed through the
adoption of resolutions or reports-are translated ito action by the
officers of the association; by the staff of the AMA; by one or more
of the committees, councils, or commissions; or by the State and local
medical associations and societies, according to their nature.
Limitations of time make it impratical-if not impossible-to list
all of the activities and projects of the AMA on a national scale. But
as just one example, the current inventory, of books and pamphlets
shows 676 designed primarily for physicians; and another 321 pri-
marily intended for public education. Those latter items most com-
monly are distributed to the public by the State and local associations
and by individual physicians. Mr. Chairman, what follows is a partial
list of these publications, exhibit A, and a recent brochure entitled
"The Search" containing the 1968 Annual Report of the American
Medical Association. I believe that both exhibits will be of interest
to the committee and I ask that they be iiiclu~1ed in the report at this
point.
Senator NELSON. They will be printed in the record.
Dr. ANNI5. Thank you.
(The documents referred to follow:)
PAGENO="0296"
4586 COMPETITIVE PROBLEMS IN THE DR1JG INDUSTRY
Exhibit A
A PARTIAL LIST OF AMA PUBLICATIONS
AVAILABLE FOR DISTRIBUTION
(Other Than Subscription Items)
Hard and Soft Cover Books
The Best of Law and Medicine (192 pp.)
U.S. Adopted Names for Drugs (150 pp.)
Manual on Alcholism (100 pp.)
The Physician's Career (100 pp.)
The Extended Care Facility (152 pp.)
Current Medical Terminology (976 pp.)
Standard Nomenclature of Athletic Injuries (158 pp.)
Emergency Department, A Handbook for the Medical Staff (144 pp.
Alcohol and the Impaired Driver, A Manual on the Medicolegal
Aspects of Chemical Tests for Intoxication (236 pp.)
Utilization Review, A Handbook for the Medical Staff (116 pp.)
Health Education (430 pp.)
School Health Services (414 pp.)
Healthful School Living (324 pp.)
Today's Health Guide (640 pp.)
Let's Talk About Food (148 pp.)
The Look You Like (144 pp.)
Chemical Tests for Intoxication (104 pp.)
Survey of Medical Groups in the U.S. (148 pp.)
Health Appraisal of School Children (56 pp.)
Continuing Medical Education (128 pp.)
New Drugs (591 pp.)
Pamphlets and Brochures
Keeping Healthy
A Letter To You, Mother, About Measles and Your Child
Allergies
Allergies from the Air and What to Do About Them
Anes thes iology
Arthritis
Blood Tests
Cancer: Facts You Should Know
Cons tipa tion
Diabetes
How to Prevent Heart Disease
Immunization
Old King Cold
Smoking: Facts You Should Know
TB Control: Prospects for Eradication
Tons us and Adenoids
Veneral Disease Is Still a World Problem
When Hearing Fades
Your Blood Pressure
PAGENO="0297"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4587
(A Partial List....
Pamphlets and Brochures - cont.)
Health Education
Education of Children for the New Era of Aging
Health Promotion for Adults
Mental Health and School Health Services
Suggested School Health Policies
Why Health Education?
Health Aspects of the School Lunch Program
Health of School Personnel
Quackery
Chiropractic: The Unscientific Cult
Did You Know That...? Chiropractic
Facts on Quacks
Health Quackery
Health Quackery-Arthritis
Health Quackery Devices
Mechanical Quackery
The Merchants of Menace
Health Quackery-Chiropractic
Health Quackery-Cancer
Alcoholism
How Teens Set the Stage for AlcOholism
The Illness Called Alcoholism
Test Your Alcohol Quotient
To Your Health (Alcoholism)
Diet and Nutrition
Can Food Make the Difference
The Healthy Way to Weigh Less
Vitamin Supplements and Their Correct Use
Your Age and Your Diet
Sex Education
Approaching Adulthood
A Story About You
Facts Aren't Enough
Finding Yourself
Infertility
Parents' Responsibility
Contraceptive Drugs and Devices
Skin Care and Groomj~g
The Aging Skin
Man's Oldest Fallout Problem: Baldness
The Case of the Sunburned Mannequins
Color Her Hair Beautiful
PAGENO="0298"
4588 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
(A Partial List.
Pamphlets and Brochures - cont.)
Skin Care and Grooming - cont.
Color Is Only Skin Deep
Common Sense About Moles
Dandruff
A Dermatologist Talks About Warts
Excess Hair-A Common Problem for Women
Housewife and Her Hands
Feminine Shaving Practices
Psoriasis: The Scaling Disease
Shaving Advice For Men
Something Can Be Done About Acne
Sunlight and the Skin
Time Out For Good Grooming
Vascular Birthmarks and Your Child
What to Expect from Your Deodorant
Cosmetic Surgery
Doctors and Patients
8 Ways to Cut Your Doctor Bills
How to Be a Good Patient
Let's Use Not Abuse Health Insurance
Medicines and How to Use Them
Surgery
What Is Hypnosis?
What to Look for in a Nursing Home
When A Mental Patient Comes Home
When To Call Or See Your Physician
Why Wait?
Your Family Health Record
Your Health Examination
The Human Body
The Miracle of Life
The Wonderful Human Machine
Safety and First Aid
Are You Fit to Drive?
Artificial Respiration Card
Danger Lurks
Emergency Medical Identification Card
Emergency Medical Identification Symbol
First Aid Manual
Protecting Your Home from Unlabeled Poisons
Safety Belts Save Lives
Tetanus-the Second Deadliest Poison
Child _Care
A Child in the Family
Prenatal Care
When Your Child Needs Glasses
PAGENO="0299"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4589
(A Partial List....
Pamphlets and Brochures - cont.)
Adolescent Years
Why Girls Menstruate
Why the Rise in Teenage Gonorrhea?
Why the Rise in Teenage Syphilis?
Your Teenager And Smoking
Fitness and Sports
The ABC's of Perfect Posture
Exercise and Fitness
First Aid Chart for Athletic Injuries
A Guide for Medical Evaluation of Candidates for School Sports
Height/Weight Folder for Boys
Height/Weight Folder for Girls
Johnny Makes the Team
Physical Fitness
Safeguarding the Health of the Athlete
Seven Paths to Fitness
Tips on Athletic Training
What Makes a Good Hobby?
What You Should Know About Saunas
Senior Citizens
Health Aspects of Aging
How the Older Person Can Get the Most Out of Living
A New Concept of Aging
Stay Young, Think Young
For Young Children
Your Friend The Doctor
Your Body and How It Works
Drug Dependence
The Crutch That Cripples - Drug Dependence
Amphetamines
Barbitura tes
Glue Sniffing
LSD
Mar ihuana
For Physicians
Mental Retardation Handbook
Patient's History Form
Who Helps the Physician Help the Retarded
Prenatal Record
Nursery Record of a Newborn Infant
Newborn Nursery Daily Worksheet
Labor Record
Summary of Labor and Delivery
Physician's Record of Newborn Infant
Obstetrical Discharge Summary
PAGENO="0300"
4590 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
(A Partial List....
Pamphlets and Brochures - cont.)
Timely Tip~
Buckle Down and Stay Safe
Pull a Switch to Exercise
How Are You Fixed for Poisons
Battling the Cold
Recipe for Family Feeding
Tune-Up for Motoring
The Better to See and Hear
Well Done is For Steak
Operation: Diet Right
Prognosis: Medical Career
Pick Your Shots
How to Be a Medical Watchdog
Key Facts About Tetanus
How's Your Medical ID?
Take Stock of Your Assets
Smarter Than Ponce de Leon
Operation Lift
How D0 You Shape Up?
Don't Test Your Poison Defense
Have You Checked on Health
Upstairs, Downstairs, All Through the House
Silent Killer
Let Breakfast Fight Your Battles
Badge of Safety
How To Be A Good Patient
Aid For Acne
Measles Vaccine
Handle With Care
Stock Up for First Aid
Partners for Better Health
Beware of Food
The Everyday Exercise-Walking
The Facts About Hay Fever
Night Driving - Double Trouble
Treat Your Feet Right
The Cigarette - A Dubious Companion
Two In Every Hundred
Building a Better Mousetrap
Also Spanish Language Series
PAGENO="0301"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4591
the
Search
EXHIBIT A-i
1968 ANNUAL REPORT
of the
AMERICAN MEDICAL ASSOCIATION
"The Death of Socrates," by Jacques Loais David (French, 1748-1825(, courtesy of The Metropolitan Museum at Art, Waite Fund, 1931.
PAGENO="0302"
4592 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
GENERAL OFFICERS
President
DWIGHT L WILBUR, MD
California
President-Elect
GERALD D. DORMAN, MD
New York
Immediate Past President
MILFORD 0. ROUSE, MD
Texas
Vice President
CARL A. LINCKE, MD
Ohio
Secretary-Treasurer
ALVIN J. INGRAM, MD
Tennessee
Speaker, House of Delegates
WALTER C. BORNEMEIER, MD
Illinois
Vice-Speaker, House of Delegates
RUSSELL B. ROTH, MD
Pennsylvania
TRUSTEES
EDWARD R. ANNIS, MD
Florida
JOHN M. CHENAULT, MD
Alabama
BURT L. DAVIS, MD
California
WESLEY W. HALL, MD
Nevada
IRVIN E. HENDRYSON, MD
Vice-Chairman
New Mexico
RAYMOND T. HOLDEN, MD
Washington, D.C.
ALVIN J. INGRAM, MD
Secretary
Tennessee
JOHN R. KERNODLE, MD
North Carolina
ROBERT C. LONG, MD
Kentucky
BURTIS B. MONTGOMERY, MD
Chairman
Illinois
MAX H. PARROTT, MD
Oregon
L. 0. SIMENSTAD, MD
Wisconsin
The President, President-Elect and
Immediate Past President
also are Trustees.
PAGENO="0303"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4593
FOREWORD
WHAT IS THE AMA?
It is the publisher of the world-famous Journal of the
American Medical Association (JAMA); ten medical
specialty journals; a family health magazine; a news-
paper for physicians and others interested in the socio-
economic aspects of medicine, and numerous books,
proceedings, reports and papers on medical science
and medical care.
It is the sponsor or co-sponsor of approximately a
thousand meetings, large and small, every year on a
host of scientific and non-scientific subjects of interest
to physicians and others in the health field.
It is a primary source of medical and health informa-
tion for the public, the government, schools and writers
of books, newspaper stories, magazine articles or
television scripts.
Alone, or jointly with other health and scientific
organizations, it is the accrediting body for hospitals,
extended care facilities, medical schools, internships,
continuing education programs for physicians, and edu-
cational courses for persons pursuing allied health
professions and occupations.
More than anything else, however, the AMA is a state
of mind . . . a state of mind that aspires to that of the
man honored on the cover of this report.
Socrates sought the truth, and in imparting it to his
generation, passed it to all succeeding generations.
Physicians, too, seek truth and impart it to their col-
leagues, to their professional successors and to society
so that mankind may live not only a longer life, but a
better, richer life.
As an organization, the AMA reflects the desire of
physicians to join together for the "maintenance of their
honor and respectability, for the advancement of their
knowledge and the extension of their usefulness-as
the Association founders said in 1846.
It also manifests the belief stated in the last two
years by the House of Delegates that "the health and
well-being of the patient has always been-and must
continue to be-the first concern of the physician," and
that "adequate health care should be available to all
who need it."
This report of some of the activities of the AMA for
the year 1968 is designed to highlight the diverse pro-
grams in which the AMA is engaged. I commend it to
your attention and I hope you will find it useful as a
source of information.
Burtis 8. Montgomery, MD
Chairman
Board of Trustees
PAGENO="0304"
4594 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
SEEKING MORE MEDICAL MANPOWER
PAGENO="0305"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4595
Nobody quarrels with the idea that there is a shortage
of health services. But a lot of arguments can be started
by asking, "Why?"
Is there a shortage in the supply, or an excess of
demand? Is the shortage only in patient care services,
or can it be traced also to areas of teaching, research
and the establishment and control of environmental
health conditions?
Where people are unable to get immediate medical
attention, is it because there is no physician nearby?
Or is the problem caused by lack of transportation, lack
of knowledge about how to get care, poverty which
inhibits some from seeking help, and insurance plans
that encourage hospitalization and crowd existing fa-
cilities?
How efficiently is today's medical and health person-
nel being used? How much time does a physician spend
doing things that don't require his professional knowl-
edge, judgment and skill? How often is the same thing
true of other professionals and technicians? Adding 10
per cent to the productivity of today's physicians would,
in effect, add 30,000 physicians to the nation's re-
sources, a figure approximately equal to the yearly
production of 300 additional medical schools. A similar
increase for all health workers would add the equiva-
lent of 350,000 skilled people.
Answers are being sought to two obvious questions:
How can more medical and health personnel be de-
veloped? How can today's workers best be utilized?
As one step in seeking the answers, the AMA and the
Association of American Medical Colleges issued two
joint statements in 1968 calling for expanded enroll-
ment in existing medical schools and establishment of
new schools; curricular innovations and other changes
in the educational programs which could shorten the
time required for a medical education; and innovation
in educational programs to encourage diversity in the
character and objectives of medical schools,
From a first-year enrollment of 9,479 in the nation's
94 medical schools in 1967, the figure has grown to an
estimated 9,930 in 99 schools in 1968; and it is expected
to reach 10,370 in 101 schools in 1969 and 10,930 in
102 schools in 1970, The five schools which opened for
the fall term of 1968 were the University of California
School of Medicine at Davis, the University of California
San Diego School of Medicine, the University of Con-
necticut School of Medicine in Hartford, Mount Sinai
School of Medicine of the City University of New York,
and the University of Texas Medical School at San
Antonio,
AMA also is working closely with the National Medi-
cal Association to attract more young men and women
from minority groups into medicine and to find ways of
providing both financial and educational help where
necessary.
In addition to its interest in the education of physi-
cians, the AMA also evaluates and approves educational
programs for nine groups allied to medicine-medical
technologists; x-ray technicians; medical record li-
brarians, and technicians; occupational, physical and
inhalation therapists; cytotechnologi~ts, and certified
laboratory assistants. Standards are currently being
developed for programs for radiation therapy tech-
nologists, nuclear medicine technologists and tech-
nicians, and medical assistants.
FIRST YEAR ENROLLMENT
PER MEDICAL SCHOOL
81-280 O-69-pt. 11-20
PAGENO="0306"
4596 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
"American" is AMA's first nsme, but its interests end
activities are by no means limited to these shores.
During the past year, for example, 229 foreign guests
from 47 nations visited the headquarters of the Ameri-
can Medical Association.
AMA is the largest of 29 national medical groups that
organized the World Medical Association in 1947, now
representing more than 700,000 physicians in 59 na-
tional associations. A member of the WMA governing
Council, AMA has played an important role in such
projects as the International Code of Medical Ethics,
the Declaration of Helsinki (ethical principles for clini-
cal research), and the Declaration of Sydney (organ
transplants).
In cooperation with the U. S. Agency for International
Development (AID), AMA organized and administers the
American Project of Assistance to Medical Education
in Vietnam, bringing together departments of the Uni-
versity of Saigon's Faculty of Medicine and counter-
parts in U. S. medical schools, now including Emory
University and the Universities of Louisville, Nebraska,
Washington, Missouri, Georgetown and Oklahoma.
American professors help Saigon's teaching program
and Vietnamese faculty and graduates are selected for
advanced training and observation of educational
methods here.
In three years of the Volunteer Physicians for Viet-
nam Program, more than 500 U. S. physicians have
contributed more than 80 man-years of voluntary medi-
cal service to South Vietnam's civilian population. Also
done in cooperation with AID, the program has at-
tracted.U. S. physicians from 49 states, the District of
Columbia, Canal Zone and seven overseas locations.
Through AMA's `Doctor-to-Doctor" program, 1,747
American physicians now are corresponding with 2,424
overseas colleagues, sending them medical journals
and exchanging information and knowledge.
Readers in 139 foreign countries subscribe for 32,000
copies of the Journal of the AMA, the 10 specialty
journals, The AMA News or Today's Health. Another
3,000 copies are sent free to 117 countries. A bimonthly
International Health Bulletin goes to 2,000 readers here
and abroad.
A Spanish edition of AMA's Current Medical Termi-
nology (CMT) is being prepared through a Barcelona
publisher. CMT is a reference book for selecting pre-
ferred medical terms, including certain synonyms and
generic terms, to provide maximum convenience in
usage and publication. AMA is working to make CMT
the international language of medicine.
AMA also-
has filled more than 300 requests from around
the world for free medical textbooks through its Medical
Missionary Program;
has named 22 AMA representatives to foreign
national medical meetings or international congresses
during the past year;
and maintains liaison with 90 per cent of the
73 volunteer foreign aid agencies recognized by AID.
The fourth AMA Conference on International Health
is being planned for the latter part of 1969.
.~
L
:1-- - --
PAGENO="0307"
COMPETITIVE PROBLEMS
IN
THE DRUG INDUSTRY 4597
EXPANDING MEDICINE'S HORIZONS
The Faculty of Medicine, University of Saigon.
PAGENO="0308"
4598 COMPETITIVE PROBLEMS IN THE DRuG INDuSTRY
In more innocent years past, the
natural desire of young people to
undergo new experiences-and to
horrify their elders-led to such
activities as goldfish swallowing and
telephone booth stuffing.
Today that same desire-appar-
ently coupled with greater sophisti-
cation, a social climate of conflict
and a disciplinary philosophy of per-
missiveness-is leading increasing
numbers of young people into drug
abuse.
Parents, physicians, educators,
lawmakers and others share grow-
ing concern about the problem and
ways to combat it.
As one step toward meeting the
challenge, AMA has launched a
nationwide educational program on
drug abuse.
The production and distribution
of a comprehensive educational
packet of materials aimed at both
physicians and laymen has laid the
groundwork for a program that can
be carried out at the community
level. In the packet, among other
things, are the AMA's basic booklet
on the subject, The Crutch That
Cripples (which ran in the Septem-
ber and October issues of Today's
Health), and a series of JAMA arti-
cles reviewing the latest scientific
findings on marihuana, other hallu-
cinogens, stimulants, sedatives and
narcotics.
The strategic position of physi-
cians as leaders of the health team
and their understanding of drug
abuse and its possible conse-
quences make state and county
medical societies and their mem-
bers best suited to implement such
a program, which already has been
well accepted by educators, civic
leaders, the military and allied med-
ical and health organizations.
Materials developed for the edu-
cational program are tailored to
community needs.
TELLING IT LIKE IT IS-DRUG ABUSE
PAGENO="0309"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4599
A pharmaceutical laboratory develops a flaw drug. It
is clinically tested and than approved by the federat
govarnmant tor marketing. tt is evailabte to patients on
preacription through licensed pharmacists.
How does the phyaician find out that this new drug
is available? Even more important, where can he get
accurate, unbiased information on exactly whet it wilt
do; what possible side effects can it cause; what con-
ditions within the patient forbid ita use?
There are a number of sources of such vital infor-
mal ion. An important one is AMA.
To provide timely drug information 10 practicing
physicians, the Journel of fhe AMA carries periodic
reports on new drugs based on an evaluation of the
published literature plus unpublished information re-
ceived from drug manufacturers-which includes phar-
macology and toxicology studies in animals. Before
publication, each report is reviewed by AMA and other
experts in the field.
AMA's annual book. New Drugs, has been en out-
standing source of drug information for practicing
physicians. II contains information on, and evaluations
of, new drugs made available during the previous
decade.
Novi in preparation is a new' publication, to be called
AMA Drug Eva/uafions fADEd, which will include every-
thing New Drugs contains plus date on commonly
prescribed older drugs, both single entities end com-
binations. Expected the letter pert of jggg, ADE initially
will nave more then 70 chapters covering as many as
1.500 drugs, with comprehensive indexes of names,
pharmacologic actions, therapeutic uses end adverse
reactions,
Staff soreicee for the United States Adopted Names
Council, w'hich names new drugs, are provided by
AMA, which also maintains a registry of edverse reac-
tions to drugs and is developing methods for surveil-
lance of drug usage in hospitals.
PAGENO="0310"
4600 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
PAGENO="0311"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4601
Television can sell products, person-
alities and ideas.
Can it sell good health practices?
AMA believes it can. So does the
television industry, which is coop-
erating by broadcasting one-minute
public service messages on the sub-
ject.
Produced and distributed monthly
by AMA, the health announcements
are used regularly by more than
600 television stations from coast to
coast. Many stations use them as
often as 90 times a month.
Purpose of the messages is to
stimulate awareness of how to stay has been one titled Faith. It urges
well by protecting one's own health viewers to "Let the faith that sus-
and safety. These spot announce- tains you grow strong," and reminds
ments are designed to relieve fear, them that "Faith, too, is a physician,
reinforce good health practices and with whose help you need never
discourage abuses. Subjects range fear." Since its production in 1963,
from the selection of a proper baby- Faifh has been seen by 50,000,000
sitter to drug abuse or the measles people.
vaccine. Certain messages are being ex-
The messages are animated to be panded to five minutes for use on
more attention-getting for adults children's programs. The first, Your
and more easily understandable for Body, has been seen across the
children, country on such programs as "Rom-
The most successful single an- per Room." A second, Your Friend
nouncement, in terms of, exposure, the Doctor, now is being distributed.
SERVING THE PUBLIC VIA TV
An AMA announcement for childrdns.televlsion
programs shows importance of a balanced meal.
PAGENO="0312"
4602 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
INTERPRETING LAW AND
LEGISLATION
Imagine a physician trying to keep
up with every recent court decision
related to health, medicine or phy-
sicians. Or imagine him finding time
in his busy practice to analyze every
piece of pending national or state
legislation to see if it would affect
his patients or medical practice.
Sound impossible? It is. Yet
America's physicians are extremely
nell informed on medicolegal mat-
ters because of the continuing ef-
forts of AMA.
Every bill in Congress that affects
health or medicine is analyzed, and
pertinent information is distributed
to medical societies. There were
1,600 such bills in the 89th Congress
and 1,435 in the 90th.
Hundreds of state bills also are
analyzed and indexed, providing a
valuable source of help for state
society legislative committees con-
sidering bills for physician support.
Every week a report on Law and
Medicine appears in the Journal of
the AMA. More than 80 of the arti-
cles that appeared between January,
1966, and February, 1968, were com-
bined in one publication in 1968.
Material on legal problems involv-
ing medicine or physicians also is
published in The AMA News.
The Citation, distributed every
other week, summarizes individual
court decisions involving physicians
or medicine. It is the only publica-
4 tion of its type in the country.
4 In addition, more than 200 printed
medicolegal items are available from
AMA, including model forms, acts
and agreements. AMA compiles in-
formation on taxes, corporate prac-
tice, professional liability, ethics,
blood transfusions and blood group-
`ing, hospital records and other sub-
jects pertaining to law and medicine.
AMA also oversees the mainten-
ance of medical ethics. It keeps
extensive files on health quacks and
helps collect evidence for their
`. .., prosecution.
PAGENO="0313"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4603
"In a split second, my life flashed before my eyes!"
The hero of a paperback novel describing a moment
of mortal danger? Not at all. Simply the comment of a
physician seeing AMA's computerized physician rec-
ords for the first time.
The visitor was seated in front of a television screen
as his code numbers were pressed by the operator. In
one fifth of a second-the time it takes to blink-his
complete record appeared on the screen, including
date of birth, medical education, type of practice,
American Board affiliations, specialty society member-
ships and other pertinent information. AMA keeps more
complete records on physicians than any other profes-
sion has on its members. To answer the approximately
200 requests a day for information, clerks formerly had
to go through files, find, remove and read the record
cards.
Now the computer-an IBM 360-40, known to the
key-punch operators, programmers, systems analysts
and operators as Mod-40-does the job for them in a
BRINGING RECORDS TO
LIFE
V
PAGENO="0314"
4604 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
tiny fraction of the time.
Keeping physician records-of AMA members and
non-members alike-is the computer's biggest job now.
However, Mod-40 is capable of serving every division
of AMA in addition to organizations affiliated with or
close to AMA, such as the Woman's Auxiliary and AMA-
ERF, component and constituent medical societies and
medical specialty organizations.
Mod-40's components include the console, through
which it is controlled; memory banks to store millions
of items of information for instantaneous retrieval; and
input-output devices that accept information for storage
and produce figures, charts or reports on the screen
or in printed form.
Data fed into the computer is stored on discs and
tapes. The full information on the nation's 318,000 physi-
cians is contained on six reels of tape. Information also
is stored in a "data cell," which can file 400,000,000
characters and symbols. The average physician's rec-
ord consists of 1,500 characters of information.
In addition to keeping statistics on physicians, Mod-
40 prepares mailing lists, survey and research reports
and AMA booklets and directories, It keeps statistical
records and makes weekly revisions of the AMA mem-
bership report.
New assignments are being sought for it. All account-
ing and budgeting operations are being computerized,
and additional work already is scheduled for other
departments or sections of AMA.
Computer technology is advancing at such a swift
pace that it is necessary for Mod-40's "keepers" to
undergo continual re-training. A new generation of
computers is developed every five years and each
innovation leads to changes, improvements, new uses
and new operating procedures.
The inner complexities of Mod-40 are somewhat a
mystery even to its highly trained programmers and
operators. "We know what goes into her," one said,
"and we know how to get what we want out of her. But
we really don't know how she does it."
0
PAGENO="0315"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4605
Put 25 scientists and MD's in a modern laboratory with
the latest equipment. Relieve them of all administrative
or teaching duties, allowing them to devote their full
time and energies to pure research. Give them the help
of some 35 research assistants, technicians, engineers,
secretaries and others, and permit them to call on the
facilities of AMA and AMA-ERF. And what do you have?
You have the Institute for Biomedical Research,
which, in its second full year of operation, has become
an increasingly visible landmark on the scene of bio-
medical research in this country and in the world.
It is not possible to hold up any one criterion of
productivity for an institute completely devoted to basic
research, but much of its impact and its worth can be
measured by published works in the most reputable
and influential scientific journals.
More than 80 scientific papers have appeared over
the names of Institute staff members in such journals as
the Proceedings of the National Academy of Sciences,
Journal of Biological Chemistry, Science, Virology,
Journal of Physical Chemistry, Archives of Biochemistry
and Biophysics and Experimental Brain Research. Thus,
the voice of the Institute is being heard in the forums of
the worldwhere basic biomedical research is reported
and discussed.
All of this is in keeping with the mission of the
Institute: to further the development of knowledge in
those fundamental aspects of biology which broaden
and deepen the foundations of an expanding science of
medicine.
The Institute now consists of an animal research
facility and laboratory departments of experimental
medical ecology, virology, molecular biophysics, regu-
latory biology and neurobiology.
With the approval of the House of Delegates, the
Institute will move to a location adjacent to the Uni-
versity of Chicago campus. George W. Beadle, PhD,
retired president of the University of Chicago and Nobel
prize winner in medicine and physiology, assumed
direction of the Institute December 1, 1968. No date has
been set for the move to the new location.
REACHING FOR KNOWLEDGE
PAGENO="0316"
4606 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
SUMMARY 1967 / ~? ~
/
1~' I.' ~
/ .,
- B'cnicdicst Reseasch.
PROGRAM
Schools-S 930396
Loan-350.800
Tobacco & Heaith-2,004.156
Medical Journalism-370
Biomedical Research-931 227
Unrestricted-304,21 0
Grants-3,758
$4,524,919
SOURCE
Physicians-S 798.059
Woman's Auxiiia~'-373,442
Companies-2.366.519
Medical Organizat'ons-535,874
Non-Medical Organizal~cna-6 351 ... - -
Foundations-131,032 ,
Laymen-10.642 -.--
$4,524,919 ` I
/ `p
/ _s~.c. _._...._e
- - --.~-.o8~'o -
M~s~ O'9ar"zaions . - - ~y~fl
-. -- - - ---:
Compantee
PUTTING MINDS AND
DOLLARS TO WORK
No dollar goes further or does more
good than one that supports re-
search. - - helps operate a medical
school - - . teaches physicians and
medical students journalistic skills
so they can communicate more
clearly with their colleagues . -
or makes loans available so a medi-
cal student, intern or resident can
go on with his studies,
And that's exactly what dollars do
when physicians and others con-
tribute them to AMA's Education
and Research Foundation,
AMA-ERF programs include loan
guarantees, the Institute for Biomed-
ical Research, contributions to medi-
cal schools, tobacco and health
studies, training in medical journal-
ism, and basic medical investigation
by independent researchers.
During the year, $959,000 was
contributed to medical schools by
AMA-ERF, providing a source of
unrestricted funds which may be
used as each dean sees fit. These
funds came principally from physi-
cians (68%) and their wives through
the Woman's Auxiliary to the AMA
(30%). The remainder came from
medical and non-medical organiza-
tions and laymen. In the past 15
years, physicians of the U. S. have
given almost $68,000,000 to medical
schools, both directly and through
AMA-ERF.
The Student Loan Guarantee
Fund so far has guaranteed 36,707
loans totaling $41,223,000. The guar-
anteed loans are made available by
commercial institutions to cover
only essential training and living
expenses. The borrower does not
start repaying until he has com-
pleted his training.
The Woman's Auxiliary, which
carries out many fund-raising pro)-
ects, has contributed $3,268,000 in
16 years to AMA-ERF, increasing its
gift every year-from $15,700 in
1951-52 to $389,800 in 1967-68.
About 80 independent investi-
gators in 50 institutions in this coun-
try and abroad are studying the
effects of tobacco on health, sup-
ported by grants allocated through
AMA-ERF.
PAGENO="0317"
IN THE DRUG INDUSTRY 4607
Current Assets
Cash . 2,794,108.68
Notes & Accounts
Receivable 1350,450.59
Inventories 1350,946.52
Total Current Assets
Deferred Charges
Deposits 112,233.75
Prepaid Expenses 309,941.27
Total Deferred Charges
Fixed Assets
Land 1,126,047.14
Building less Accumu-
lated Depreciation... .7,234,976.95
Furniture & Equipment
less Accumulated
Depreciation 899,785.08
Total Fixed Assets
Investment-Securities
U.S. Government
Securities 1,138,935.96
Common Stock 5,895,427.22
Total Investment-Securities
Other Assets 1,310,715.99
Total Assets 23,523,569.15
Liabilities and Reserves
Current Liabilities
Aàcounts Payable 1,618,743.03
Accrued Taxes - 293,311.91
Total Current Liabilities 1,912,054.94
Deferred Income
Dues & Subscriptions 2,599,903.96
Total Liabilities 4,511,958.90
422,175.02 Reserves
Reserves for Replace-
ment of Building and
Equipment 15,894,766.81
Reserves to finance
anticipated needs in
the future 3,116,843.44
Total Reserves 19,011,610.25
Total Liabilities & Reserves 23,523,569.15
BALANCE SHEET-DECEMBER 31, 1967
COMPETITIVE PROBLEMS
Assets
5,495,505.79
9,260,809.17
7,034,363.18
PAGENO="0318"
4608 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
It is the responsibility of the Ameri-
can Medical Association, as the rep-
resentative of the American medical
profession, to continue to foster the
advancement of medical science
and the health of the American
people.
Its continuing purposes are to
meet this responsibility through the
following means:
1. By encouraging the further de-
velopment of medical knowledge,
skills, techniques and drugs; and
by maintaining the highest stand-
ards of practice and health care.
2. By creating incentives to attract
increasing numbers of capable peo-
ple into medicine and other health-
care professions.
3. By advancing and expanding the
education of physicians and other
groups in the health-care field.
4. By motivating skilled physicians
who have the art of teaching to
apply themselves to developing new
generations of excellent practi-
tioners.
5. By fostering programs that will
encourage medical and health per-
sonnel to serve voluntarily in the
areas of need for medical care.
6. By developing techniques and
practices that will moderate the
costs of good medical and health
care.
7. By seeking out and fostering
means of making all health-care
facilities-physicians' offices, hos-
pitals, laboratories, clinics and
others-as efficient and economical
as good medical practice and atten-
tion to human values will permit.
8. By combining the utilization of
the latest knowledge for prevention
and treatment with the vital healing
force of the physician's personal
knowledge of and devotion to his
patient.
g~ By maintaining the impetus of
dedicated men and women in pro-
viding excellent health care by pre-
serving the incentives and effective-
ness of unshackled medical practice.
10. By maintaining the highest level
of ethics and professional standards
among all members of the medical
profession.
11. By continuing to provide leader-
ship and guidance to the medical
profession of the world in meeting
the health needs of changing popu-
lations.
THE PURPOSES AND REPONSIBILITIES OF THE
AMERICAN MEDICAL ASSOCIATION
I ~ -
`
PAGENO="0319"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4609
Dr. ANNIS. And a moment ago, I mentioned the committees, coun-
cils and commissions of the AMA. There is one whose responsibilities
are most pertinent to this presentation. It is the council on drugs. I
would like to take a few moments to describe some of its functions and
achievements.
THE COUNCIL ON DRUGS
In 1847-the year of its founding-the AMA House of Delegates
passed a resolution calling for regulation of pharmaceutical matters
and patent medicines.
In 1905, the `board of trustees of the A-MA established the council
of pharmacy and chemistry to consider medicinal preparations offered
to physicians for use in the prevention, diagnosis, or treatment of
disease.
`The `primary purpose of the council has been to encourage the prac-
tice of what physicians call "rational therapeutics," which simply
means prescribing drugs on the basis of knowledge of the disease and
knowledge of the actions of the proposed remedy.
Since its beginning, the council has engaged in programs of drug
evaluation leading to the publication of authoritative, unbiased infor-
mation on drugs and drug therapy. And as the scope of drug therapy
has changed, the council has enlarged and revised the scope of its
evaluation programs.
In 1957, after the use of single-entity drugs had become dominant
and individually compounded prescriptions had declined, the council
changed its name to the council on drugs.
As you can see, the AMA's drug evaluation program is the result
of more than 60 years of experience and has taken many forms, of
which I shall mention only a few.
From 1907 through 1957, the association published an annual `book-
this is the one that I received when I was in medical school-"New
and Nonofficial Remedies." That was followed from 1958 until 1964 by
"New and Nonofficial Drugs," which reflected the need for more clini-
cally oriented in'formation.
An improved annual book first appeared in 1965, called "New
Drugs." It provided, for the daily use of the physician, authoritative
information on single-entity drugs introduced during the previous
10 years, plus comparative reviews of oldei~- drugs in a particular thera-
peutic group.
A roster of the members of the `Council on Drugs is included in this
statement as exhibit B. I request that it be made a part of the record
at this point.
Senator NELSON. It will `be made part of therecord.
Dr. ANNIS. Thank you.
(The exhibit referred to follows:)
PAGENO="0320"
4610 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Exhibit B
COUNCIL ON DRUGS
AMERICAN MEDICAL ASSOCIATION
ROSTER
Adriani, John, M.D. New Orleans, Louisiana; Specialties -
Chairman Anesthesiology, Surgery, Certified by
American Board of Anesthesiology; Profes-
sor of Surgery, School of Medicine, Tulane
University; Member of Subcommittee for
Anesthesia and Surgery Committee; National
Research Council.
Azarnoff, Daniel L., M.D. Kansas City, Kansas; Specialty - Internal
Medicine; Associate Professor of Medicine
and Pharmacology and Director of Clinical
Pharmacology of the Department of Medicine,
University of Kansas, School of Medicine;
Research Interests - Clinical Pharmacology;
lipid metabolism and atherosclerosis.
Bass, Allan D., M.D. Nashville, Tennessee; Specialty - Pharma-
cology; Professor and Chairman, Department
of Pharmacology, Vanderbilt University
School of Medicine; Research Interests -
Cancer chemotherapy, Mechanism of steroid
action, Autonomic pharmacology.
Cluff, Leighton E., M.D. Gainesville, Florida; Specialty - Internal
Medicine, Certified by American Board of
Internal Medicine; Professor and Chairman,
Department of Medicine, University of
Florida College of Medicine; Member, Com-
mittee on Infections, American Hospital
Association; Recipient, Cancer Research
Award NIH, 1962.
Curry, John J., M.D. Silver Spring, Maryland; Specialties -
Cardiology, Internal Medicine, Certified
by American Board of Internal Medicine;
Associate Clinical Professor of Medicine,
Georgetown University School of Medicine;
Research Interests - Pulmonary physiology,
Hemodynamics in cardiovascular field,
Allergy.
PAGENO="0321"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4611
David, Norman A., M.D. Portland Oregon; Specialty - Pharmacology;
Professor and Head, Department of Pharma-
cology, University of Oregon Medical School;
Research Interests - Chemotherapy of ame-
biasis, Pharmacology of sedative and hypno-
tic drugs, Chronic effects of opium drugs
and synthetic analgesics, others.
Freis, Edward D. M.D. Washington, D.C.; Specialty - Internal
Medicine (Cardiovascular Disease), Certi-
fied American Board of Internal Medicine;
Professor of Internal Medicine, Georgetown
University, School of Medicine; Chief,
Cardiovascular Research Lab, University
Hospital Georgetown University, Washington,
D.C., 1949; Senior Medical Investigator,
Veterans Administration Hospital, Washing-
ton, D.C.,~ 1959; Research Interests - Clini-
cal evaluation and hemodynamic analysis of
hypotensive drugs, blood and fluid volume
changes in disease, cardiovascular physiology
in man.
Moser, Robert H. M.D. Washington, D.C.; Specialty - Internal
Medicine; Chief of Medicine, Walter Reed
Hospital; Editoral Staff, Archives of
Internal Medicine.
Paulsen, Charles A., M.D. Seattle, Washington; Specialties - Internal
Medicine, Endocrinology; Associate Profes-
sor of Medicine, University of Washington;
Member of Endocrinology Society, American
Society of Internal l4edicine.
Rogers, Daniel, M., M.D. Wenham, Massachusetts; Chairman, Board of
Health, Wenham, Massachusetts; Massachu-
setts Chapter, American Heart Association;
Governor's Task Force on Mental Illness;
Member of American Academy of General
Practice.
Shirkey, Harry C., M.D. Honolulu, Hawaii; Specialty - Pediatrics,
Certified by American Board of Pediatrics;
Professor and Chairman, Department of
Pediatrics, Professor of Pharmacology,
University of Hawaii; Research Interests -
Pediatric-Pharmacology, Therapy, Toxicolo-
gy Drug Standardization.
81-280 0-69-pt. 11-2l
PAGENO="0322"
4612 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Smith, Donn Le Roy, M.D. Louisville, Kentucky; Dean and Professor
of Physiology, Louisville University,
School of Medicine.
Woods, Lauren, M.D. Iowa City, Iowa; Specialty - Pharmacology;
Professor and Chairman of the Department
of Pharmacology, University of Iowa; Re-
search Interests - Metabolism of Drugs,
CNS compounds.
Hayes, Thomas H., M.D. Chicago, Illinois; Specialties - Adminis-
Secretary trative Medicine and Internal Medicine;
Director, Department of Drugs, American
Medical Association; Clinical Associate
of Medicine, Department of Medicine, Uni-
versity of Illinois, College of Medicine.
PAGENO="0323"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4613
ADVERTISING EVALUATION
Dr. ANNIS (reading).
Earlier in this statement, I mentioned the 997 books and pamphlets
produced by the AMA for distribution to physicians and the public.
None of those contain advertising. At that time, I did not include the
regular publications of the association, saving them for my discussion
of the criteria used by the AMA to determine the acceptability of ad-
vertising. This is the second of my maj or subjects.
The AMA publishes the "Journal of the American Medical Associa-
tion"-known as JAMA and recognized to be the outstanding medical
journal in the country.
In addition, the association regularly publishes 10 specialty jour-
nals. They are the "American Journal of Diseases of Children." "Ar-
chives of Environmental Health," "Archives of General Psychiatry,"
"Archives of Internal Medicine," "Archives of Otolaryngology," "Ar-
chives of Ophthalmology," "Archives of Dermatology," "Archives
of Pathology," "Archives of Surgery," and "Archives of Neurology."
Besides the scientific journals, the AMA publishes "Today's
Health," a monthly consumer magazine of articles on family health
and safety; "The AMA News," a weekly newspaper containing items
of general interest to physicians; and a large number of special
publications.
JAMA, the specialty journals, "Today's Health" and "The AMA
News" all contain advertising. The scientific publications restrict their
adverti~ing to products that are germane to, effective and useful in the
practice of medicine. The advertising of certain products, such as to-
bacco and alcoholic beverages, is specifically excluded.
The AMA has a department of advertising evaluation which reports
directly to Dr. Hugh H. Hussey, director of the AMA Division of
Scientific Activities. Dr. Hussey is a former dean of Georgetown
University School of Medicine.
It is important to note that administratively, the department of
advertising evaluation is not answerable to the advertising depart-
ment. It is a separate function, responsible only to the member of the
AMA staff charged with directing the association's activities in sci-
entific areas.
The wording and illustrations of advertising, to be acceptable in
JAMA or the specialty journals, must meet standards estthlished by
the "Principles Governing Advertising in the AMA Scientific Pub-
lications." Advertising for "Today's Health" or "The AMA News"
must meet written principles and policies governing their acceptance
for those publications.
The principles I have referred to are attached to this statement as
exhibits C, D, and E. I ask that they be inserted in the record at this
point.
Senator NEL50N.They will be printed in the record.
Dr. ANNI5. Thank you.
(The exhibits referred to follow:)
PAGENO="0324"
4614 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
EXHIBIT C
PAGENO="0325"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4615
THE AMERICAN MEDICAL ASSOCIATION seeks to promote the
science and art of medicine and the betterment of public health. In
serving these aims, the AMA communicates regularly with the mem-
bers of the medical profession, with professional persons in allied
fields, and with the public. A substantial part of this communication
is carried on through the regular production and distribution of its
publications.
In keeping with its avowed purposes, the Association will do all it
reasonably can to insure the accuracy, comprehensiveness, timeli-
ness, and relevancy of the advertising content of these publications.
The evaluation of advertising copy will be based on the considera-
tion of available data concerning the product or service. It will not
be based on tests conducted by the AMA.
The appearance of advertising in AMA publications should not be
construed as a guarantee or endorsement of the product by the
Association. The fact that an advertisement for a product, service,
or company has appeared in an AMA publication shall not be
referred to in collateral advertising without specific, written authori-
zation from the American Medical Association.
As a matter of policy, the AMA will sell advertising space in its
publications when (1) the buyer believes purchase of such space
represents a sound expenditure, (2) the inclusion of advertising
material does not interfere with or seriously detract from the purpose
of the publication, and (3) the advertising copy meets the standards
established for that publication.
Office of Advertising Evaluation
American Medical Association
PAGENO="0326"
4616 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
general
principles
These general principles are applied by the American Medical Associ-
ation in determining the eligibility of products and services for adver-
tising in AMA scientific publications-The Journal of the American
Medical Association and the ten specialty journals. The Association
reserves the right to change these principles in the light of develop-
ments in medicine or in industry.
ELIGIBILITY FOR ADVERTISING
1. Products or services eligible for advertising shall be germane to,
effective in, and useful in the practice of medicine and shall be com-
mercially available.
2. Pharmaceutical products will not be eligible for advertising until a
New Drug Application has been approved by the Food and Drug
Administration.
3. "Institutional~type" advertising germane to the practice of medicine
and "public service" messages of interest to physicians may be con-
sidered eligible for appearance in the scientific publications.
4. Alcoholic beverages and tobacco products are not eligible for ad-
vertising.
5. The Association may decide that certain products or services are
not eligible for advertising in AMA's scientific journals if advertise-
ments for these specific products or services in other media consistently
or significantly depart from the standards set forth in the following
sections.
PAGENO="0327"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4617
Data
Requirements
1. DRUGS-For convenience, advertisements for drugs (including vac-
cines and biologicals) may be separated into four categories, as follows:
(a) J~1ew Drugs or Jfew Claims for Drugs Which Have J'Iot Previously
Been Advertised in AMA Publications. A new drug is here defined as any
pharmaceutical product which has not been advertised previously in
AMA scientific journals. Example of a new claim: use of an established
antimalarial drug, such as chloroquiné phosphate, in rheumatoid
arthritis. In all such cases, the Office of Advertising Evaluation will
require supportive scientific evidence for, review. It is suggested that
clinical and laboratory data on new drugs be submitted to the Office
of Advertising Evaluation at the time a New Drug Application is filed
with the~ Food and Drug Administration. This will make it possible, in
many cases, to obtain product and advertising clearance prior to the
introduction of the drug. However, the Association will not grant final
clearance of advertising until notified that the New Drug Application
has been approved by the FDA.
(b) Drugs Which Represent an Additional Brand of a Product That is
Already Eligible. The advertisement alone may be submitted. Sup-
portive data are not required.
(c) Drugs Which Represent a Modification of an Eligible Product. Ex-
ample: Some modification of a previously eligible drug, such as a new
salt or ester. All pertinent clinical and laboratory data should be sub-
mitted to the Office of Advertising Evaluation.
(d) Mixtures of Drugs. Clinical and laboratory data should be sub-
mitted for review by the Office of Advertising Evaluation. Clearance
depends primarily on showing justification for the rationality of the
combination.
2. APPARATUS, INSTRUMENTS, AND DEVICES-The Office of Ad-
vertising Evaluation determines the eligibility of products and the suit-
ability of claims for medical equipment intended for preventive, diag-
nostic, or therapeutic purposes. Advertisements for products which
have not been advertised previously in AMA scientific journals, and
new claims for eligible devices should be accompanied by complete
scientific and technical data concerning the product's safety, operation,
and usefulness. The data should include the results of clinical and
PAGENO="0328"
4618 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
laboratory examination. The data may be either published or unpub-
lished. Samples of apparatus, devices, equipment, or instruments should
not be submitted unless specifically requested by the Office of Adver-
tising Evaluation.
3. FOOD PRODUCTS AND VITAMIN PREPARATIONS-Advertisements
for food products and vitamin preparations may be separated into four
categories as follows:
(a) General Purpose Foods. Those foods promoted for use by the popu-
lation in general. Examples are bread, processed meats, fruits, and vege-
tables. Advertisers of such products should submit descriptive literature,
labels, and a statement of composition where pertinent.
(b) Special Purpose Foods. These are foods for special dietary uses sub-
ject to the labeling conditions imposed by section 403j of the Federal
Food, Drug and Cosmetic Act. Examples are foods manufactured and
promoted for use by certain specific segments of the population, such
as infants, invalids, as well as others requiring foods with certain proper-
ties, e.g., foods for carbohydrate-restricted diets, sodium-restricted
diets, and other therapeutic diets. Advertisers of such products should
submit copies of labels, statements of composition, and analytical data.
When pertinent, they should be supported by data demonstrating the
effectiveness of the product for its intended use. If new claims are made
for a previously advertised product, clinical data substantiating such
new claims must be submitted.
(c) Supplemental Vitamin Preparations. Rational mixtures of the vita-
mins recognized to be essential in human nutrition or metabolism in
amounts not differing greatly from the recommended dietary allow-
ances are eligible. However, with the exception of iron-containing and
calcium-containing preparations that are intended for use during preg-
nancy, vitamin mixtures to which minerals are added (as contrasted
to trace minerals which are inherent in the manufacturing process)
are not eligible for advertising.
(d) Therapeutic Vitamin Preparations. Rational mixtures of the vitamins
recognized to be essential in amounts not greater than five times the
recommended dietary allowances are eligible. However, preparations
containing a mixture of all or most of the following antianemic factors-
vitamin B,2, folic acid, intrinsic factor, iron, ascorbic acid, and copper-
are not eligible for advertising. If claims not generally recognized are
made for any of the vitamins, such claims must be substantiated by
clinical studies in support of such claims.
4. BOOKS-A book may be requested for review so that its eligibility
for advertising can be determined.
5. MISCELLANEOUS PRODUCTS AND SERVICES-Products or services
not in the above classifications may be eligible for advertising if they
satisfy the general principles governing eligibility for advertising in AMA
scientific publications.
PAGENO="0329"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4619
advertising
copy
After a product or service has been declared eligible to be advertised
in the scientific publications of the AMA, the Office of Advertising
Evaluation must approve each advertisement. The AMA's decisions will
be guided in all cases by the following principles:
1. The advertisement should clearly identify the advertiser and the
product or service being offered. In the case of drug advertisements, the
full generic name (including salt and ester designation) of each active
ingredient must appear in eight-point type or larger.
2. Advertisements should not be deceptive or misleading. Layout, art-
work, and format should be such as to avoid confusion with the editorial
content of the publication. The word ~`advertisement" may be required.
3. Unfair comparisons or unwarranted disparagements of a competi-
tor's products or services will not be allowed.
4. Claims for superiority must be supported by evidence acceptable to
the Association. Unsubstantiated superlatives or extravagantly worded
copy will not be allowed.
5. Quotations or excerpts from a published paper are acceptable only
if they do not distort the meaning intended by the author. Claims made
within quotations must conform to the same standards as unquoted
claims.
6. Advertisements will not be accepted if they conflict with the prin-
ciples of medical ethics.
PAGENO="0330"
4620 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
procedures
of the AMA
office of
advertising
evaluation
(SCIENTIFIC JOURNALS)
The AMA Office of Advertising Evaluatio~
is responsible for applying the foregoing
principles and standards to advertising copy
submitted for inclusion in AMA scientific
journals. It will do so in accordance with the
following procedures:
1. Submission of Data-The Office of Ad-
vertising Evaluation requires that scientific
data be submitted to substantiate claims made
for new products (such as drugs, devices,
and foods) or new claims for products which
have appeared previously in AMA scientific
journals.
2. Type of Data )~eeded.-Data should in-
clude pertinent reports-published and un-
published, favorable and unfavorable-of clin-
ical and laboratory investigations covering
the efficacy and relative safety of the product
under consideration. These data should be
based upon sound studies and should be
sufficiently comprehensive to permit a critical
evaluation of the subject matter. While the
quantity of the scientific data required will
depend on the type of product, the nature of
the medical problem involved, and the claims
made in the advertising copy, the quality of
the evidence is regarded as highly important;
in this respect, the importance of suitable
controls is emphasized. Compilations of sub-
jective individual case reports and testimoni-
als are not considered acceptable evidence.
The unpublished portions of all submitted
data will be regarded by the Office of Adver-
tising Evaluation as confidential, and con-
sultants will be requested to treat them ac-
cordingly.
ions of consultants and recognizes the state-
ments formulated by AMA Councils and
Committees in determining the eligibility of
products and the suitability of claims. The
consultants to the Office of Advertising Evalu-
ation are persons who have been selected for
their competence in the specialties involved.
The names and affiliations of the consultants
are not made available.
Time Requirements of the Office of
Advertising Evaluation
Although the Office of Advertising Evalua-
tion cannot guarantee adherence, in all cases,
to a fixed time schedule, every effort will be
made to expedite completion of AMA con-
sideration in the following time intervals:
Advertisements for Eligible Products with Xo
Xew Claims-From the time copy is re-
ceived, 5 working days should be allowed for
AMA consideration.
Advertisements Involving )Vew Claims for, or
Modifications of Currently Eligible Products,
Or Both-From the time copy and, if neces-
sary, supportive data are received, 10 work-
ing days should be allowed for AMA con-
sideration.
Advertisements for )Vew Products-From the
time copy and supportive data are received,
15 working days should be allowed for AMA
consideration. Unless accompanied by sup-
portive data, proposed advertisements for
new products cannot be considered by the
Office of Advertising Evaluation.
In those cases in which AMA consideration
cannot be completed prior to the expiration
of the foregoing time intervals, the advertiser
or agency will be so informed.
As a matter of policy, the AMA periodically
will review its advertising principles with the
view of keeping pace with changes that may
occur in the industry and in the profession.
It is hoped by this practice of continuous
review and reevaluation to insure and im-
prove the timeliness, relevancy and appro-
priateness of the advertising content of AMA
scientific publications.
Correspondence, proposed advertisements,
supportive data, etc. should be addressed to:
I Office of Advertising Evaluation
American Medical Association
535 North Dearborn Street
Chicago, Illinois 60610
3. Consultation.-The AMA Office of Adver-
tising Evaluation frequently seeks the opin-
PAGENO="0331"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4621
EXHIBIT D
NON-HEALTH
ORIENTED
PRODUCTS
AND SERVICES
principles
governing
advertising
in
©àrtllhIILR
©~1I1
PAGENO="0332"
4622 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
advertising in tc -~ health
TODAY'S HEALTH, published monthly by the
American Medical Association, provides interest-
ing and authoritative information to the public
concerning the care and well-being of the readers
and their families. It is distributed to physicians
for their office reception rooms and to persons
who wish to subscribe.
The acceptance of an advertisement for
TODAY'S HEALTH by the American Medical
Association does not constitute in any way an
endorsement or guarantee by the Association.
The evaluators will make every reasonable effort
to ensure the accuracy, timeliness, and relevancy
of the advertising content of the magazine. No
laboratory testing of products is done by the
A.M.A. In no case may the appearance of an ad-
vertisement for a product, service, or company in
TODAY'S HEALTH be mentioned in collateral
advertising unless specific written authorization
has been obtained from the American Medical
Association.
The following principles are used to determine
the eligibility of products and services and the
suitability of advertising copy. The American
Medical Association reserves the right to change
its principles governing advertising in accord with
current developments. The Association also re-
serves to itself all final decisions regarding the
eligibility of any products and services and the
acceptability of proposed advertisements.
PAGENO="0333"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4623
eligibility
Products and services that are offered by
responsible advertisers and which, when used
properly, contribute to the general welfare of the
consumer are eligible for advertising in TODAY'S
HEALTH.
Products or services NOT eligible for adver-
tising in TODAY'S HEALTH include:
1) Products (e.g., tobacco and alco-
holic beverages) or services which,
in the opinion of the Association,
may be detrimental to the user, and
any products related to the use of
such a product or service;
2) Product or service claims which can
not be supported by data accept-
able to the Association;
3) Products or services that are adver-
tised in other media in a manner
inconsistent with the following prin-
ciples.
PAGENO="0334"
4624 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
advertising principles
Each presentation of advertising copy of an
eligible product or service must be approved in-
dividually by the American Medical Association,
which shall make the final decisions regarding the
suitability of copy, artwork, and format.
The following principles will be utilized to eval-
uate advertisements:
1) The advertisement must clearly
identify the advertiser and the prod-
uct or service.
2) The message, text, and artwork
must be in good taste and in harmony
with the purpose of the magazine.
3) The advertisement should present
the positive merits of the product or
service and not discredit or dispar-
age those of competitors. Fair
comparisons based on substantial
evidence are acceptable.
4) The advertisement shall be de-
signed to avoid deceiving or mis-
leading the reader in any way.
5) The format should be such as to
avoid confusion with the editorial
content of the magazine.
6) Claims made within quotations must
conform to the same standards as
unquoted claims.
PAGENO="0335"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4625
EXHIBIT D-i
TODAY'S
HEALTH
PAGENO="0336"
4626 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
PAGENO="0337"
COMPETITIVE PROBLEMS IN THE DRIJG INDuSTRY 4627
ADVERTISING IN
TODAY'S HEALTH ADVERTISING
io~ ~ ~ I I~ ~1e ~ ~ ~ ~ ~ d ~ e ~ ~ ~ ~ ~ PRESEN TAT ION
~) the ~ihIic conc ~rci~:i~' th~ he~ Ith and \\~1far~ of th.. ~ du~~ ~ ~ , ~ ~ ~ ~ ~ ~
rind socicty It is dis~ributd to ph~cid~n~ o~ }u~ir ~ reep ~ ~ ~, ~ ~ ~ ~ ~ ~ ~ ~
t1C),fl rooii~c ~ to )(1S()flc ~ ~O ~ ~h UbSCnb( ~ ~ ~ ~ ~ ~ ~ ~ ~
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American Medical Association c/ne' not r onstr/utr in ar's as as flnOi des c rd n t~ a tzh4tc c
an enaiorrcmen, or guarantee by the \mna ration, although hr 00 5000 and orma
eva/uators cdli make every o asonabte snort to ensure tire ass a
r "s 55rr h s'' 0
race, tirneirness and rekvanrv ol he adser tr mn contort or tire ~
magazine. No /abntrtorc testing of produc I' r~ done by the tO /~ Irate ads" Ii' morn' a mraisan
AMA. In no case mae tire appearans e sA an ado's ti,emerrt ~ he///t / rrms
a prodarcl service, or norrrpartc in r slam a //ms sit/s be rrrtsrrtis',mem/
in co/l,rteral ads es ti/inc urriess ngm i/is cc rmtten autlrrrrr!atrcrn has 1 kho adc'er'rs' nrcnt nrust ci, arts rderrtrrs
heert ohir/ned front lire American Meclms al Association the ads `rtisrr arrri the p'ocatmr m or rs ir e
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trroduc/s and mrs ices frrr cc /rtch It `a/lit claims re made attn hr cm rrntsr rsmea/rc,stkrrrs must hr rrlrr'i, 4
suitability of advertisirsg crrpv. The Amrrericarr \tcdmcrt As'ociatrcrrr to lime (Nc,' ot Ar/s enlrbn" by irrr/mrar
reserves tire right to charrge ste tsnirrciln/es goes ruing ads ertr rri~' kuçlt infoisratiors nraer/ ma 1 ise ira/mm/cl
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n'ligib/lil/ rrt any products anti sercrcs', rmmnl tire acr epta/ailitc ri a nary larr aurpc'ses or in nt/ri atin"r
proposed ardverticesta'rtls,
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81-280 0-69-pt. 11-22
PAGENO="0338"
4628 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
THE AMA NEWS ExhibitE
ADVERTISING ACCEPTANCE POLICIES
The acceptance of advertising to be carried in The AMA NEWS is governed by the
following policies:
A. ELIGIBILITY FOR ADVERTISING
1. Products or services eligible for advertising in The AMA NEWS must be
of interest to physicians and their families as consumers.
2. Products or services directly involved in the prevention, diagnosis or
treatment of disease or which involve copy claims pertaining to health
of people are NOT eligible for advertising in The AMA NEWS.
3. In addition to the above limitations, advertising will be accepted only
from responsible business firms which guarantee to stand back of claims
made in their advertising copy.
4. Advertisements which offer the reader information concerning investment
opportunities must comply with the above standards and, in addition,
must avoid reference to a specific security issue.
5. Advertisements for alcoholic beverages and products to be smoked are not
acceptable.
3. SUITABILITY OF ADVERTISING COPY
1. The advertisement should clearly identify the advertiser and the product
or service being offered.
2. Advertisements should not be deceptive or misleading to physicians or
their families.
3. Layout and format should be such as to avoid confusion with editorial or
news items.
4. Unfair comparisons or the disparagement of a competitor~5 goods will not
be allowed.
5. Advertisements will not be accepted if they appear to violate the principles
of medical ethics, are indecent or offensive in either text or art work,
contain attacks of a personal, racial or religious character.
6. Claims made in advertisements for insurance coverage must conform to the
above standards and, in addition, must conform to the following specific
criteria:
(a) Claims relating to policy benefits, losses covered, or premiums must
be complete and truthful.
(b) Claims made shall include full disclosure of expectations, reductions
and limitations affecting the basic provisions of the policy
(c) Claims incorporating quoted testimonials must meet the same standards
as unquoted claims.
(d) Each advertisement for insurance must include a statement indicating
the number of states in which the company is licensed.
PAGENO="0339"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4629
Dr. ANNIS. All proposed advertising is screened through the ifiter
of the appropriate written principles. If the product is found ineligi-
ble, the advertising is rejected. If claims in the proposed ad are ques-
tionable, substantiating data are requested and the material is reviewed
again in the light of the new information.
Finally, the advertisement is reviewed: for clarity; that it makes
no unwarranted comparisons or claims of superiority; and that it
does not conflict with the principles of medical ethics.
On the whole, we believe that no publication surpasses our own
standards for acceptable advertising. However, it should be remem-
bered that the AMA does not attempt to substitute its principles for
the advertising surveillance authority vested in the FDA by Congress.
We evaluate prescription drug advertisements to make sure the Jour-
nal of the AMA continues to fulfill its scientific purposes and remain
acceptable to the profession. In making these decisions, we are aware
of the ever-changing world of medical science. As new knowledge
becomes available, our judgment factors, must change accordingly.
ADVERTISING REVENUE
The third subject I promised to cover logically comes at this point.
It is the advertising revenue received by the AMA.
Your correspondence indicated that the committee is interested in
the income received by the AMA from pharmaceutical manufacturers
who advertise in JAMA. We do not have a breakdown purely for
pharmaceutical advertising. However, I can give you figures for total
advertising revenues for JAMA and the specialty journals.
I want to preface these figures by making it clear that they repre-
sent gross income-not net. To obtain a net figure, it would be neces-
sary to substract the expenses of producing the journals, including
salaries and wages for the staffs; buying the paper; printing; mailing;
and other items. I can assure you the costs are substantial.
For the years 1963 through 1968, gross advertising revenues for
JAMA ranged from a low in 1963 of $7,831,000 to a high of $10,605,000
in 1966. The revenue in 1968 was $8,643,000. For the specialty journals
combined, the gross figure for those years ranged from $1,413,000 in
1963 to $2,234,000 in 1968.
(Gross advertising revenues follow:)
GROSS ADVERTISING REVENUES
Year
JAMA
SpecialtY
journals
1963
1964
1965
1966
1967
1968
$7,831,000
7,968,961
9,983,795
10,605,625
10,546,000
8,643,000
$1,413,000
1,563,702
1,710,510
1,725,695
1,978,000
2,234,000
Dr. ANNIS. Advertising rates for medical journals are expressed
most commonly in cost per page of advertising and the cost per thou-
sand copies of the journal according to its total circulation.
For JAMA, the rate for one black-and-white page rose from $1,600
in 1963 to $2,120 in 1967 and 1968. The cost per thousand was $8.05 in
1963; fell to $7.89 in 1964; and reached $9.89 in 1968, having dropped
2 cents from 1967.
PAGENO="0340"
4630 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
(Advertising rates for JAMA follow:)
Year
Rate for 1
page, black
and white
Cost per
thousand
1963
1964
1965
1966
1967
1968
$1,600
1,600
1,840
1,840
2,120
2,120
$8.05
7.89
8.88
8.65
9.91
9.89
Dr. ANNIS. I have already referred to the association's substantial
expenses. I think it is of interest that the AMA has more than
$12 million budgeted for scientific programs in 1969; and more than
$6 million for medical service programs. Most of the medical service
programs are directed toward health education of the public and
community health planning.
Almost another million dollars is budgeted for support of other
medical organizations such as the World Medical Association, the
Joint Commission on Accreditation of Hospitals, and the National
Health Council.
Two million dollars is earmarked for international health pro-
grams; and mamtenance of complete biographical records on all phy-
sicians in the United States takes another million and a half dollars a
year.
The programs of the AMA Education and Research Fouiidatioii
receive $1 million a year from the association.
Mr. Chairman, I have attached as exhibit F a copy of the associa-
tion's 1969 budget, which lists major program expenditures. I ask that
it be inserted in the record at this point.
Senator NELSON. It will be printed in the record.
Dr. ANNIS. Thank you.
(The exhibit referred to follows:)
ExmBn~ F
American Medical Association, 1~6~ Bvdget
1. Scientific programs $12, 357, 903
2. Medical service programs 6, 058,459
3. Communications programs 1,232, 687
4. Support to other medical organizations 759, 700
5. Support to noiimedlical organizations 23,625
6. International health programs 2,031, 757
7. Legislative programs 299, 228
8. Professional ethics 89, 919
9. Medicine and reiigion program 148,907
10. Archive-Library service 238,431
11. Public affairs 1, 230, 100
12. Legal services 397, 528
13. Physician records 1, 422, 962
14. AMA-ERF programs 1,003, 300
115. Adminirtrative costs 6, (105, 1)41
Total 33, 899, 547
Dr. ANNIS. The American Medical Association's programs and
policies have never been, are not now, and will never be shaped by any
PAGENO="0341"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4631
dependence on the drug industry. And to insure that there is no "con-
thct of interest," the AMA has consistently separated the editorial
management, advertising acceptance, and business management of each
of its scientific publications.
The editorial staff of JAMA is in one division; the advertising
acceptance responsibility is in a separate division; and business man-
agement and sales are in still another.
The editorial content of a journal must be objective if it is to be
acceptable to members of our profession. If that content were shaped
or influenced by commercial considerations, the profession would
quickly reject the publication.
COMPENDIUM
Turning to my fourth topic, legislative proposals have been made
regarding publication of a drug compendium which would, in effect,
contain information presently included in package inserts for all
available prescription drugs.
The purpose of the compendium is to compile in one volume corn-
plete information on those drugs. It is intended to be, in fact, the single
authoritative source of readily accessible drug information for the
physician. Under most proposals, drugs would be identified both by
their generic and their brand names.
You will recall that during my earlier discussion of the AMA
Council on Drugs, I mentioned annual publications in the drug field-
specifically, New and Nonofficial Drugs, and New Drugs.
Today, an important activity of the council is to create a publication
that is expected later this year, to be called AMA Drug Evaluations,
or ADE.
We agree wholeheartedly that the medical practitioner needs an-
other source of reliable, unbiased, and current information on drugs
and new developments in drug therapy. It is necessary also that the
source be in a form that makes the facts he needs available with a
minimum of effort and in a minimum of time.
ADE will identify various diseases, disturbances, and conditions
for which drugs are prescribed.
Drugs used in the treatment of the conditions will then be listed
alphabetically by their generic names, along with other necessary
information, such as actions, uses, principal adverse reactions, dosage,
available dosage forms, and the names of manufacturers.
In addition-and this is a most important feature-will be informa-
tion providing a comparison of the therapeutic effectiveness of drugs
having similar uses.
A mere compendium, in the sense that it wOuld be a listing of drugs,
would leave significant information gaps. Our drug evaluation publi-
cation would not.
Evaluations are now being prepared for essentially all marketed
therapeutic agents that are new, single entity drugs; official in the
IJ.S. Pharmacopeia or National Formulary; frequently used or pre-
scribed; or otherwise notable. For example, they. might be otherwise
notable either because of their therapeutic nature or their unusual
toxicity.
PAGENO="0342"
4632 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
The book will be thoroughly cross-indexed, including listings by
drug name, by pharmacologic and chemical factors, by therapeutic uses
and by adverse reactions. It will be revised and updated regularly.
And because it will contain special information on newer products,
it will, in effect, absorb the earlier publication, New Drugs, by mak-
ing that same information available in a more usable form, along with
substantial amounts of other infonnation.
We believe sincerely that AMA Drug Evaluations will be the
most useful publication in the physician's library regarding drugs.
And that is not only our opinion. A sample chapter of the publica-
tion, on anticonvulsants, was published in JAMA May 20, 1968. I offer
it with this statement and ask that it be included as exhibit G at this
point in the record.
Senator NELSON. It will be printed in the record.
Dr. ANNIS. Thank you.
(The exhibit referred to follows:)
PAGENO="0343"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4633
Council on Drugs
Reprinted From The Journal ci The American Medical Association
May 20, 1968, Vol. 204, pp. 702-710B
Copyright 1968, by American Medical Association
Exhibit G
A new publication of the Council on Drugs will
provide authoritative, unbiased information on
drugs in a new format designed to meet the every-
day needs of the practicing physician. The Coun-
cil herewith presents a sample chapter of the new
book, and invites physicians to comment on the
book's usefulness by completing the question-
naire following p 710.
AMA Drug Evaluations
A New Book on Drugs
The American Medical Association's Council on
Drugs announces a new publication on drugs
designed to provide an improved service to the
medical profession. From its inception in 1905, the
Council on Drugs (originally called the Council on
Pharmacy and Chemistry) has encouraged rational
therapy by providing authoritative and unbiased
information on drugs. Throughout its long history,
the Council has modified its drug evaluation pro-
grams in accordance with new developments in the
drug field, and it has continued to alter the con-
cepts and format of its publications to reflect the
changing needs of the physician. Its earlier evalua-
tion program had been limited to those drugs con-
sidered to have well-established clinical usefulness,
but in 1955 this program was expanded to con-
sider all commercially available, newer single-entity
drugs. The older books published by the Council-
New and Nonofficial Remedies, New and Non-
official Drugs, and, more recently, New Drugs-
are now being replaced by AMA Drug Evaluations
(ADE), a comprehensive reference book that will
include information on- both old and new single-
entity drugs and mixtures. The book is being pre-
pared through a joint effort of the Council, the staff
of the AMA Department of Drugs, drug evaluators
outside the Department working part-time, and
many voluntary expert consultants; as with New
Drugs, the cooperation of much of the pharma-
ceutical industry will continue to be sought for the
furnishing of data relevant to some parts of ADE.
The design calls for continuing the practice of
having in each chapter an introductory statement
that discusses the overall therapeutic category, fol-
lowed by brief descriptions and evaluations of all
drugs in the class, old or new, if they fall within a
very broad priority list. The more detailed mono-
graphs on newer agents will be included as an ap-
pendix, which will represent a continuation of New
Drugs.
The priority list of drugs, including mixtures,
that will have individual evaluations includes vir-
tually all therapeutic agents in official compendia,
U$P and NF; the drugs most commonly pre-
scribed or used by physicians in the United States;
and, as in New Drugs, all single-entity prepara-
tions introduced during the past ten years. In ad-
dition, other selected drugs will be evaluated if
they are judged to be of particular importance be-
cause of such qualities as notable value, unusual
toxicity, notoriety, or need for notoriety. Many
nonpriority drugs that are not individually evalu-
ated will be listed in the book if they are distributed
nationally; these will be listed and indexed to give
information on their therapeutic category and avail-
ability. To make the information readily accessible,
ADE will be extensively indexed; comprehensive in-
dexes on drug names (nonproprietary and trade-
marks), pharmacologic actions, therapeutic uses,
and important adverse reactions are planned.
The evaluations of the older drugs and mixtures
will often contain fewer details than the mono-
graphs on newer, single-entity drugs. Nevertheless,
an effort will be made whenever possible to give
comparative statements on relative effectiveness
and relative safety and to inform of notable hazards
and necessary precautions in the use of the drugs.
The inclusion of a particular drug in the book will
not imply endorsement by the Council; an evalua-
tion may be favorable toward a drug, unfavorable,
or a combination of both, depending on the merits.
Whenever, the facts clearly warrant, a drug will be
described as an agent of first choice, reserve choice,
or last resort.
The evaluative or interpretive information in the
book, particularly on controversial matters, must
necessarily disagree with the opinions of some other
sources. Statements will be based on the convergent
trend of the best information available from such
sources as scientific literature, unpublished data,
and advice of consultants. Reportorial information
will be selective and condensed to represent what
the Council regards as the most useful to the phy-
sician in his selection and use of the drugs. Ac-
cordingly, such information as rare, relatively
minor, or uriconfirmed reactions, precautions that
relate to clearly obvious or highly remote situa-
tions, and unusual or speculative uses of a drug
Reprint requests to Secretary, Council on Drugs, American
Medical Association, 535 N Dearborn St, Chicago 60610.
JAMA, May 20, 1968 * Vol 204, No 8
PAGENO="0344"
4634 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
AMA DRUG EVALUATIONS
may be omitted. It is hoped that ADE thus will
provide a convenient reference from an authorita-
tive source to give the practicing physician the most
important information to help in his prescribing
practices. For other details, for basic data, and
even for varying points of view, the physician is
encouraged to consult and compare the many
sources of information on drugs he uses: journal
articles, standard textbooks, official compendia,
manufacturers' labeling, prominent bulletins and
periodicals on drugs and therapeutics, and sym-
posia.
The sample chapter that follows is presented
both to familiarize the physician with the Council's
plans and to invite comments and recommendations.
Most of the book is in a stage of preparation that
still permits flexibility in content and design, and
subsequent editions are intended to follow. There-
fore, since the Council's aim is to meet the needs
of its physician readers, responses to the attached
questionnaire can have an important influence on
the further development of the book. The book is
expected to be published in approximately one year.
The accompanying chapter on "Anticonvulsants"
is not completely a self-contained unit. The reader
will notice several cross-references that presently
are only hypothetical, as the associated material is
still to be published; nevertheless, they are included
to help illustrate the design of the forthcoming
book.
After reading the sample chapter, please fill out
the questionnaire following page 710 and return it
to the AMA.
Chapter 29
ANTICONVULSANTS
Anticonvulsants are used to terminate certain
acute convulsive episodes, but their principal use is
prophylactic to reduce the number and severity of
seizures in patients with epilepsy. Seizures may be
classified in various ways; for therapeutic purposes,
the following is convenient: major motor (grand
mal or focal), petit mal (absence), minor motor,
and psychomotor.
Although their specific modes of action are not
fully understood, a number of drugs have anticon-
vulsant activity and are effective in preventing or
reducing the frequency of seizures in most patients
with epilepsy. The objective of therapy is to con-
trol the seizures and at the same time maintain the
patient in as normal a physiologic state as is pos-
sible. Drug therapy must be individualized for
every patient; within the limits of adverse effects
and toxicity, the correct dosage of any drug or
combination of drugs is that which is "enough" to
accomplish the stated purpose. The choice of drugs
depends upon the type of seizure. Further, many
patients with epilepsy have more than one type of
seizure, and drugs effective for one of these types
may not help or may even unmask another. The
most common causes of failure of treatment are
703
improper classification of type of seizure, failure to
recognize a progressive neurologic disease, failure
to use the proper drugs or proper dosages, too fre-
quent changes in drug therapy, premature with-
drawal of drugs, poor indoctrination of patients,
and failure to recognize the social and economic
needs of patients. With the exception of patients
who do not adhere to their prescribed regimen, the
largest group of failures is related to the admin-
istration of insufficient dosages of appropriate drugs
and failure to use two or more of them concomi-
tantly when they are needed.
The patient should be started on a small or
moderate dosage of the drug that is considered to
be suitable. This dosage should be increased grad-
ually at intervals until the seizures are controlled
or until the appearance of minor toxic symptoms
makes further increases inadvisable. If more than
minor toxic phenomena develop, the medication
should be withdrawn and another substituted.
When the drug used initially is well tolerated but
only reduces the frequency of the seizures, another
compound should be added. The dosage information
given with the subsequent discussions of individual
drugs falls within the ranges given in official com-
pendia, those recommended by one or more man-
ufacturers, or those considered reasonable by other
authorities. However, the size, age, and condition of
the patient, his response to treatment, and the pos-
sible synergistic or antagonistic effect of concomi-
tant medication must always be considered. Reduc-
tions in dosages of anticonvulsants for children in
comparison with adult dosages are not always as
great as would be expected from the difference in
age and size.
Phenobarbital is still considered the mainstay of
anticonvulsant therapy; it is among the safest of
the available drugs and is useful in the management
of most types of seizures. The other long-acting
barbiturates, mephobarbital [MEBARAL] and meth-
arbital [GErooNIL], are alternate drugs, the actions
of which, with proper dosage adjustment, closely
resemble those of phenobarbital. Primidone [MY-
SOLINE], which is chemically related to the barbi-
turates and has similar action, is frequently useful
in refractory epilepsies, especially of the major
motor and psychomotor types.
The hydantoins, such as diphenylhydantoin
[DILANTIN], mephenytoin [MESANTOIN], and etho-
tom [PEGANONE], are used primarily in major motor
and psychomotor seizures; they are usually not ef-
fective in treating petit mal. They may be effective,
as may the barbiturates, in certain nonconvulsive
epileptic equivalents, a syndrome of recurrent au-
tonomic symptoms associated with an abnormal
electroencephalogram. Diphenyihydantoin is con-
sidered the drug of first choice among the hydan-
toins; it is safer than mephenytoin and more
effective than ethotoin. However, each of these
alternative hydantoins may be considered for trial
in special circumstances (see the individual drug
evaluations following this introductory statement).
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4635
AMA DRUG EVALUATIONS
types may be used alone or in combination. The
minor motor seizure syndrome of infancy or child-
hood sometimes responds to corticotropin or adreno-
cortical steroid therapy or to a ketogenic diet
program. Recent experience with various ben-
zodiazepine derivatives indicates that some of the
compounds in this group have effectiveness in
minor motor epilepsy; of the benzodiazepine de-
rivatives currently marketed in this country, die-
zepam [VALIUM] has given the most favorable re-
sults.
Sometimes, epileptic seizures that apparently
are under good control by drugs will escape from
control. When a barbiturate or hydantoin is in-
volved, the escape may result from a physiologic
adjustment in which the patient's metabolism of
the drug is increased. With these particular drugs,
an increase in dosage will ordinarily reestablish
control, and once this is accomplished, there is no
reason to expect a repetition of the escape unless
the disease itself happens to worsen. Trauma or
emotional stress may cause an increase in the
dosage requirement, which should be borne in mind
if a patient requires surgery.
Spontaneous remissions, particularly of petit ma!
seizures, are common if convulsive disorders have
begun during childhood but are rare if they have
begun during adulthood. Anticonvulsant therapy
therefore must be prolonged; as a rule, drugs are
continued until the patient has been completely
free of seizures for two to four years. When a de-
cision is made to discontinue their administration,
the dosage of one drug at a time should be reduced
gradually, since sudden withdrawal of any of these
drugs may precipitate a recurrence of seizures or
even status epilepticus. However, when a serious
adverse reaction to a drug occurs, the agent should
be discontinued immediately and another anticon-
vulsant should be given to protect the patient dur-
ing this period.
Status epilepticus is a serious emergency that
requires prompt and vigorous treatment to prevent
permanent harmful effects or death. It may be
terminated by the intravenous administration of
phenobarbital. This drug is preferable to shorter
acting barbiturates, since its effect is practically as
rapid but lasts longer. The full calculated anticon-
vulsant dose should be given initially since the use
of fractional doses may result in the paradoxic situ-
ation of drug-induced depression but continued
status epilepticus. Dipheny!hydantoin [DILANTIN]
may be given intravenously or intramuscularly, but
its onset of action is delayed for 5 to 15 minutes. It
has the advantage of usually not depressing res-
piration, but intravenous administration must be
slow to avoid serious hypotension. Recently dia-
zepam has been shown to be effective when given
parenterally. Paraldehyde given parenterally is still
used occasionally. When anesthetic agents are nec-
essary, they should be given under the supervision
of an anesthesiologist, when possible, and resuscita-
tive equipment should be available.
The hydantoins are cumulative in effect; therefore,
the dosage schedule must be adjusted gradually
over a long period to obtain control without pro-
ducing toxic reactions. Ordinarily, a hydantoin
should be added to a regimen after an initial trial
with the relatively safer phenobarbital has not pro-
vided adequate control. Alternatively, many clinics
and some of the Council's consultants prefer
diphenylhydantoin as the initial drug. The Coun-
cil's moderate preference for phenobarbita! is based
on considerations of relative safety, although this
drug does introduce the inconvenience of drowsi-
ness for many patients. Other drugs can be added
if a combination of a hydantoin and phenobarbital
do not completely control the seizures. Primidone
[MY50LINE] ordinarily should not be added to this
regimen, but it may be substituted for the pheno-
barbital in refractory epilepsy of the major motor
and psychomotor types. Also, psychomotor epilepsy
may respond to methsuximide [cEL0NTIN]. Phen-
acemide [PHENURONE] may be effective in con-
trolling psychomotor or various other seizures, but
since it is extremely toxic, it is only of limited
usefulness and should be used only if other medi-
cations are ineffective. Inorganic bromides(eg, so-
dium bromide, potassium bromide) also have anti-
convulsant activity against grand ma!, but because
of their toxicity, interest in them is chiefly histori-
cal. However, they may have a limited place in the
treatment of children with grand mal.
Methsuximide [CELONTIN], phensuximide [MI-
L0NTIN], ethosuximide [zAR0NTIN], trimethadione
[TRIDI0NE], and paramethadione [PARADIONE] are
useful primarily in the treatment of petit ma!.
Ethosuximide is the drug of choice in this group,
but phensuximide may be considered for initial
treatment in mild cases because it is moderately
safer. Acetazolamide [DIAM0x], and perhaps keto-
genic diets, control petit ma! in some patients. Re-
cently, selected new benzodiazepine derivatives,
particularly diazepam [VALIUM], have also shown
promise and relative safety. Among the remaining
drugs, trimethadione is probably the most likely
to be effective, but it is also the most dangerous.
Petit ma! rarely responds to phenobarbita! alone;
nevertheless this drug, because of its broad anti-
convulsant spectrum, should be tried initially un-
less there is convincing evidence, including a char-
acteristic electroencephalogram, that the patient
has classical petit ma! uncomplicated by any other
type of seizure. Less satisfactory agents like mepro-
bamate [EQUANIL, MILTOwN], quinacrine [ATAII-
SINE], or the amphetamines may be tried if other
medications do not control petit ma!. For patients
who have petit ma! and other seizure types, drugs
effective in controlling those other types must be
combined with the drugs selected for the treatment
of petit ma!.
Minor motor seizures are akinetic and myoclonic
types that are often refractory to drug therapy.
They may occur alone or in. association with petit
mal or grand mal. Drugs effective for both seizure
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4636 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
AMA DRUG EVALUATIONS
705
Major motor seizures, usually with severe, pro-
tracted, clonic convulsions, are sometimes associ-
ated with the withdrawal syndrome in persons with
physical dependence on barbiturates, alcohol, or
certain other sedative drugs. Barbiturates will often
help prevent these dangerous convulsions; the by-
dantoins are usually of little value.
Adverse Reactions and Precautions
Many minor reactions to anticonvulsant drugs
may be overcome by reducing the dosage of the re-
sponsible agent, which may, however, necessitate
the addition of another anticonvulsant agent to the
regimen.
Most anticonvuisants produce gastrointestinal
disturbances in at least some patients, especially
during the early stages of treatment. The symptoms
may be reduced either by administering the drugs
after meals or by decreasing the dosage.
Many of the anticonvulsants have sedative ef-
fects, and drowsiness is sometimes a significant
complaint. Again, this effect is most noticeable dur-
ing the early period of treatment; if it persists, a
reduction of dosage may be indicated. Sedative
drugs may cause alterations in mood, which- oc-
casionally are serious (see the chapter on Sedatives
and Hypnotics).
Other anticonvulsants also can cause mental dis-
turbances. Phenacemide [PHENURONE] is particu-
larly prone to cause serious personality changes
including psychoses and suicidal depressions.
Ataxia occurs commonly with the hydantoins
and, if persistent, requires reduction in dosage.
There is evidence that the hydantoins can cause
cerebellar damage if a dosage that produces ataxia
is administered for a prolonged time. For practical
purposes, however, this danger appears remote
since the reaction is so troublesome in itself that it
demands correction by dosage adjustment. Very
young patients can present an exception, as drug-
induced ataxia may be confused with the natural
unsteadiness of the toddler. Ataxia also may occur
with the use of barbiturates.
Many anticonvulsants commonly cause skin
eruptions, which are usually morbilliform or acne-
like and may disappear when the dosage is reduced
or the drug is temporarily discontinued and cauti-
ously readministered. However, a skin reaction may
herald the development of a severe reaction that
may warrant withdrawal of the drug. Lupus erythe-
matosus, Stevens-Johnson syndrome, angioneurotic
edema, serum sickness, and polyarteritis have been
associated with anticonvulsant medication. Anaphy-
laxis is extremely rare. Other reactions that occa-
sionally have been noted with some anticonvulsants
include alopecia and hypertrichosis.
Because the barbiturates are particularly prone
to aggravate porphyria, their use should be avoided
in patients with that disease.
Several of the anticonvulsant drugs may cause
reversible visual disturbances such as diplopia and
nystagmus; one of the most notable, hemeralopia
(defective vision in a bright light), occurs with the
oxazolidinediones, trimethadione [TRIDI0NE] and
paramethadione [PARADIONE].
Certain untoward effects are frequently char-
acteristic of a particular anticonvulsant and may
not occur with a chemically related drug; for e~-
ample, diphenyihydantoin [DII.ANTIN] frequently
causes gingival hyperplasia, but this reaction sel-
dom occurs with mephenytoin [MESANTOIN], and
apparently never with ethotoin [PECANONE] -
Lymphadenopathies simulating malignant lym-
phomas have occurred with several of the anticon-
vulsant drugs. Hydantoins have been implicated
most frequently. Although it is questionable whe-
ther diphenylhydantoin is as prone to cause these
pseudolymphomas as is mephenytoin, it is responsi-
ble for a greater number of reactions since it is
more widely used. The signs and symptoms may
show a temporary progression but usually begin to
disappear within one to two weeks after therapy is
stopped. A few cases of true lymphoma and of
Hodgkin's disease have been reported in which a
causal relationship to hydantoin therapy seems
possible.
Megaloblastic anemias, which respond to folic
acid or leucovorin (folinic acid) therapy, also have
been reported with several anticonvulsants. Ac-
cordingly, periodic blood studies are indicated when
such drugs are taken. Usually, the drug may be
continued if the anemia responds well to treatment.
However, because of the possibility that folic acid
may interfere with the anticonvulsant action, rou-
tine prophylactic treatment with folic acid in pa.
tients without anemia is not suggested.
Among the most dangerous reactions that de.
velop during therapy with anticonvulsant drugs
are those that result from damage to the marrow,
liver, and kidneys. Severe blood dyscrasias have
sometimes been associated with phenacemide
[PHENURONE], mephenytoin [MESANTOIN], para-
methadione [PARADIONE], trimethadione [TRIDI-
ONE], and less frequently with other drugs. Base-
line blood counts should be made before initiating
treatment with these drugs. Although periodic
blood studies during treatment will detect mild
leukopenias of uncertain clinical significance, they
cannot be relied upon to predict the more serious
reactions that ordinarily occur precipitously (eg,
agranulocytosis, thrombocytopenia, aplastic ane-
mia). There is some chance that an aplastic anemia
might be detected early, before symptoms develop,
if one were so fortunate as to have a hemoglobin
determination at a time during its beginning de-
cline, but even moderate expectation of such de-
tection would require an impractical frequency of
blood studies in view of the extreme rareness of the
reaction with most drugs. Since early recognition
of the presence of a dyscrasia and discontinuance
of the offending drug are essential, the patient
should be advised to report promptly such symp.
toms as sore throat, fever, easy bruising, petechiae,
epistaxis, or other signs of an infection or bleeding
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4637
tendency. Clinical and laboratory evaluation is
necessary if such symptoms occur. Although the
risk of dyscrasias is diminished after the first year
of treatment with these medications, the physician
should be constantly alert to their possible occur-
rence at any time. The mortality rate from aplastic
anemia is particularly high and, if the patient does
survive, recovery is slow. Except for mephenytoin
and phenacemide, however, this reaction is fortun-
ately very rare with the anticonvulsants that cause
it at all.
Severe liver disease, sometimes fatal, has occur-
red with phenacemide [PHENURONE] and more
rarely with some of the other anticonvulsants,
including hydantoins. Before treatment with these
drugs is begun, it is advisable to make baseline liver
function studies, and patients should be instructed
to report promptly any symptoms of hepatitis such
as jaundice, dark urine, anorexia, abdominal dis-
comfort, or other gastrointestinal symptoms. Since
this drug-induced hepatitis is probably idiosyn-
cratic, the monitoring of treatment with periodic
laboratory studies in asymptomatic patients is of
doubtful reliability in predicting a reaction. Phena-
cemide may present an exception, as there is some
evidence that hepatitis can develop insidiously with
its use; liver function abnormalities, eg, decreased
prothrombin activity, may herald serious disease.
Nephropathies have developed occasionally dur-
ing treatment with anticonvulsants, especially in
patients receiving the oxazolidinediones, trimetha-
dione and paramethadione. Unlike the blood dys-
crasias and hepatitis, these reactions may develop
insidiously without producing symptoms in the
early stages. Therefore, urinalyses should be made
before treatment and periodically during treatment.
The development of any significant renal abnor-
mality is an indication for discontinuing the drug.
From the preceding discussion, the question
arises of just what type of laboratory monitoring
is advisable for patients taking anticonvulsants
who have no symptoms suggesting marrow, hepatic,
or renal damage. As noted, baseline studies of the
functional state of these organs are needed before
initiating treatment with drugs known to cause
damage even occasionally. Tests should be repeated
and perhaps extended if signs or symptoms of a
reaction develop. Periodic urinalyses and evalua-
tions for anemia are of value with drugs known to
cause nephropathy or megaloblastic anemia, as
these conditions may occur well in advance of their
symptoms. The problem is whether to subject pa-
tients to frequent testing for idiosyncratic blood
dyscrasias and hepatitis when nothing suggests the
presence of these disorders. The Council's con-
sultants have expressed widely divergent views on
whether such testing is of any significant medical
value with most anticonvulsants. It is known that
various minor laboratory abnormalities may appear
and cannot be relied upon to herald the develop-
ment of a serious reaction. Moreover, when a dan-
gerous idiosyncratic reaction does occur, signs or
symptoms will probably appear about as soon as
a diagnosis can be made reliably by laboratory
methods (with the possible exceptions of hepatitis
from phenacemide, and aplastic anemia from me-
phenytoin and phenacemide). Accordingly, and
with due respect to those consultants who disagree,
the Council regards routine laboratory monitoring
with most drugs as optional, rather than man-
datory, if the only issue is whether an asympto-
matic patient is taking a drug that rarely produces
a blood dyscrasia or hepatitis by some apparently
idiosyncratic mechanism. This is in contrast with
the situation where a drug has a direct toxic action
on the marrow or liver.
A frequently cited paradoxic effect of anticon-
vulsants is the tendency of agents effective for one
type of seizure to aggravate or precipitate seizures
of another type. However, epileptic disorders tend
to be mixed as to seizure type and, very probably,
the apparent aggravation of one type is a mani-
festation of the natural course of the disease and
merely reflects the therapeutic ineffectiveness of
the particular drug for that type of seizure. Caus-
ally related precipitation of seizures by anticon-
vulsant drugs probably is rare, and some consult-
ants doubt that it occurs. There is no question,
however, that abrupt withdrawal of anticonvulsants
can precipitate seizures. Thus, when a drug is to
be discontinued, the dosage should be reduced
gradually unless rapid withdrawal and substitution
of another drug is mandatory because of a serious
adverse reaction.
In general, there has been little systematic in-
vestigation of the anticonvulsant drugs for terato-
genic effects, but a lack of reported teratogenicity
after extensive use provides some circumstantial
evidence of probable safety. Thus, whenever prac-
tical, it would seem prudent to use older and more
extensively used anticonvulsants if it is necessary
to treat epilepsy in a pregnant woman.
As a general rule, the more toxic compounds
should not be used if an equally effective and less
potentially toxic preparation is available. However,
minor adverse effects should be expected and ac-
cepted with any drug. The anticonvulsant drugs in
frequent current use, and a few that are rarely used,
are listed and briefly described in the individual
evaluations that follow. Not every known adverse
reaction is mentioned, but an effort has been made
to include those that are notable because of danger
to life, unusual frequency of occurrence, proneness
to cause significant discomfort, or peculiarity to a
particular drug.
Barbiturates
Phenobarbital
Most broadly useful anticonvulsant. Initial
therapy of choice in most epilepsy (see general
statement). Principal effectiveness is in major
motor and psychomotor seizures. Sedative-hypnotic
effect, as well as ataxia, may present problems.
Produces hyperactivity in some children instead of
706 AMA DRUG EVALUATIONS
JAMA, May 20, 1968 * Vol 204, No 8
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4638 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
sedation. Amphetamines, which do not interfere
with anticonvulsant action, sometimes useful for
relieving drowsiness. Occasional skin eruptions;
rare progression to exfoliative dermatitis. Abrupt
termination in epilepsy may cause withdrawal
convulsions, but true addiction and barbiturate in-
ebriation unlikely in usual doses for epilepsy. Con-
traindicated in patients with porphyria.
Usual Dosage-Oral: Adults: Usually 120 to 200
mg daily in divided doses. Range: 50 or 100 mg at
bedtime to 300 mg in divided doses. Children: 1 to
6 mg per kilogram of body weight per day in di-
vided doses.
Preparations-Various, including: Elixir 20 mgI
5 ml; tablets 16, 32, 50, 64, and 100 mg. Many
manufacturers.
Phenobarbital Sodium
Used parenterally in status epilepticus, but may
depress respiration. Parenteral diphenyihydantoin
may be given concomitantly.
Usual Dosage.- (Status epilepticus) Intramus-
cular, Slow Intravenous: Adults: 200 to 320 mg.
Children: 3 to 5 mg per kilogram of body weight
represents a reasonable guide.
Preparations-Various, including: Powder 120,
130, and 320 mg; solution 130 mg/ml in 1 ml con-
tainers; 160 mg/mlin 2 and 10 ml containers; tablets
(hypodermic) 60 mg. Many manufacturers.
Mephobarbital [MEBARAL]
Metabolized to phenobarbital and has effects
similar to phenobarbital, but larger doses are used.
Usual Dosage-Oral: Adults: 200 mg at bedtime
to 600 mg daily in divided doses. Children: Under
5 years, 16 to 32 mg three or four times daily;
over 5 years, 32 to 64 mg three or four times daily.
Preparations.-Mebaral (Winthrop): Tablets 32,
50, 100, and 200 mg.
Metharbital [GEM0NIL]
Similar to phenobarbital, but less potent on basis
of weight. Dosage adjustment can compensate for
this difference. Has same relation to barbital as
mephobarbital has to phenobarbital.
Usual Dosage-Oral: Adults: Initially, 100 mg
at bedtime to 300 mg daily in divided doses. In-
crease to as much as 600 to 800 mg daily if re-
quired. Children: 5 to 15 mg per kilogram of body
weight daily in divided doses.
Preparations.-Gemonil (Abbott): Tablets 100
mg.
Primidone [MYSOLINE]
Not really a barbiturate by traditional classifi-
cation, but closely related chemically. However,
larger doses are needed. Principal usefulness is as
substitute for barbiturates in patients not respond-
ing adequately to regimen of barbiturate and hy-
dantoin. No compelling reason why it may not be
used as initial anticonvulsant in major motor and
psychomotor epilepsy, but it is more commonly
reserved for refractory cases because it often causes
marked sedation. Sedation often diminishes with
707
continued administration. Dosage build-up should
be gradual to avoid incapacitating drowsiness.
Ataxia and various relatively minor reactions re-
semble those of barbiturates. Skin eruptions oc-
casionally occur. Megaloblastic anemia may occur;
responds to folic acid.
Usual Dosage-Oral: Adults: 250 mg to 2 gm
daily in divided doses. Children under 8 years:
One-half adult dosage.
Preparation.s.-Mysoline (Ayerst): Suspension
250 mg/S ml; tablets 50 and 250 mg.
Hydantoins
Diphenyihydantoin Sodium [DILANTIN]
Drug of choice among the hydantoins. Often
used in conjunction with phenobarbital. Used in
major motor and psychomotor epilepsy. Has little
or no sedative activity in usual doses. Ataxia oc-
curs with larger dosages; if persistent, it indicates
overdosage, and the dose must be reduced. Ocular
signs and symptoms such as nystagmus and di-
plopia may also necessitate reduction of dosage.
Skin eruptions rather frequent; only rarely serious.
Gingival hyperplasia common, and often is severe
in children; scrupulous oral hygiene helps prevent
it. Hirsutism and excessive activity are less com-
mon but do occur, especially in the young. Rare
hut serious idiosyncratic reactions include hepatitis,
marrow depression, megaloblastic anemia, lupus
erythematosus, Stevens-Johnson syndrome, and
lymphadenopathy resembling malignant lymphoma
(see general statement).
Useful parenterally for control of status epilepti-
cus. Unlike barbiturates, seldom depresses respira-
tion. However, onset of action is slower than bar-
biturates. Also, if intravenous administration is too
rapid, dangerous hypotension may occur.
Usual Dosage-Oral: Adults: Initially, 100 mg
three times daily; most common maintenance dose
is 300 to 400 mg daily but may reach 600 mg.
Children: 3 to 8 mg per kilogram of body weight
daily in divided doses.
Intramuscular, Intravenous: (Status epilepticus)
Adults: 150 to 250 mg. Inject intravenously no
faster than 50 mg per minute. Children: Reduce
dosage according to weight or body surface area.
Preparations.-Dilantin (Parke, Davis): Oral:
Capsules 30 and 100 mg. Injection: Powder 50
mg/ml when properly diluted with special solvent
provided in 100 and 250 mg vials.
Diphenyihydantoin [DILANTIN]
See Diphenylhydantoin Sodium.
Preparations.-Dilantin (Parke, Davis): Oral:
Capsules (delayed action) 100 mg; capsules (Di-
lantin in oil) 100 mg; tablets (pediatric) SO mg;
suspension 100 mg/4 ml.
Ethotoin [PECANONE]
Moderately effective in grand mal and slightly
so in psychomotor epilepsy, but usually unsatis-
factory if used alone. Toxicity resembles that of
diphenylhydantoin but incidence of at least some
AMA DRUG EVALUATIONS
JAMA, May 20, 1968 . Vol 204, No 8
PAGENO="0349"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4639
and possibly all reactions is lower. In summary, the
drug is less toxic but also less effective than di.
phenylhydantoin.
Usual Dosage-Oral: Adults: Initially, 1 gm
daily in divided doses; for maintenance, 2 to 3 gm
daily in four to six divided doses. Children: 0.5 to
1 gm daily in divided doses.
Preparateons.-Peganone (Abbott): Tablets 250
and 500 mg.
Succinimides
Ethosuximide [ZARONTIN]
Drug of choice for petit mal. Also effective for
minor motor seizures in some patients, but gener-
ally ineffective for psychomotor or grand mal epi-
lepsy, or in patients with considerable organic brain
damage.
Major untoward effects appear to be less fre.
quent than with trimethadione or paramethadione;
the most frequent are gastrointestinal disturbances.
Drowsiness, ataxia, headache, dizziness, euphoria,
hiccup, skin eruptions, and psychologic or psychi-
atric aberrations have been reported. Aplastic ane-
mia, thrombocytopenia, leukopenia, pancytopenia,
and eosinophilia have been reported rarely. See the
monograph in the New Drugs section for further
details.
Usual Dosage-Oral: Adults and Children over 6:
500 mg daily initially; increase daily dose by 250
mg every one to two weeks until seizures are con-
trolled or untoward effects develop. Dosages ex-
ceeding 1 gm per day are seldom more effective
than smaller dosages. Children under 6: Initial
daily dosage is 250 mg.
Preparations.-Zarontin (Parke, Davis): Cap-
sules 250 mg.
Methsuximide [CELONTIN]
May be helpful in petit mal and minor motor
seizures, especially when used with other anticon-
vulsants. Also may be used as the second or third
drug to reduce the incidence of psychomotor at-
tacks. Grand mal, if present, must be controlled
with other medication. Untoward effects occur fre-
quently and may be of minor or major consequence.
These include gastrointestinal disturbances and re-
actions affecting the central nervous system (drowsi-
ness, headache, dizziness, diplopia, and ataxia).
Hypersensitivity reactions, such as skin eruptions,
fever, hiccup, and periorbital hypsremia, occur only
rarely. Many minor untoward effects may disappear
spontaneously or be controlled by reducing dosage,
but a rash may herald a more serious reaction.
Severe mental depression may occur, and patients
who have psychomotor seizures particularly should
be watched closely for behavioral changes, for these
may progress to an acute psychosis unless the drug
is discontinued. Renal and hepatic damage may
occur. Hematologic reactions, including aplastic
anemia, although rare, have also been reported.
Usual Dosage-Oral: Adults and Children: Ini.
tially, 300 mg daily; this may be increased at
weekly intervals until a daily dose of 1.2 gm, given
in divided amounts, is attained. The optimal dose
is the minimal amount that will control seizures
without causing serious untoward effects.
Preparattons.-Celontin (Parke, Davis): Cap-
sules 150 and 300 mg.
Phensuximide [MILONTIN]
Used in control of petit mal seizures. Less ef-
fective and less potent than ethosuximide and
trimethadione. However, it is the safest of the
succinimides. Its relative lack of serious toxicity
justifies its inclusion among drugs that may be
considered for initial trial in petit mal (see general
statement), although substitution of a more effec-
tive agent usually will be necessary. Adverse effects
may inolude nausea, weakness, drowsiness, and
skin eruptions. The confirmed reaction of greatest
concern reported to date is nephropathy, particu-
larly in children, which apparently is reversible on
withdrawal of the drug. Agranulocytosis, if indeed
it is caused by this drug, has been very rare.
Usual Dosage-Oral: Adults and Children: 500
mg to 1 gm two or three times daily.
Preparations.-Milontin (Parke, Davis): Cap-
sules 250 and 500 mg; suspension 250 mg/4 ml.
Oxazolidinedjones
Trimethadione [TRIDI0NE]
Principally effective in control of petit mal sei-
zures. Although among the more effective agents
for this purpose, should be reserved for refractory
cases because of toxicity. Serious reactions, some
of them fatal, include skin eruptions that may
progress to exfoliative dermatitis or erythema mul-
tiforme, nephropathy, hepatitis, and marrow de-
pression with aplastic anemia, neutropenia, or
JAMA, May 20, 1968 . Vol 204, No 8
708 AMA DRUG EVALUATIONS
Mephenytoin [MESANTOIN]
Effective in major motor and psychomotor epi-
lepsy, but more dangerous than diphenylhydantoin
and thus should be reserved for cases refractory to
the drugs of choice. Has a sedative effect usually ab-
sent with diphenylhydantoin; otherwise lacks or has
lower incidence of some of the more minor adverse
effects of diphenylbyclantoin (eg, ataxia, gingival
hyperplasia, hirsutism, gastric distress). However,
life-threatening and other serious reactions are con-
siderably more common: severe skin eruptions,
blood dyscrasis (eg, aplastic anemia, leukopenia,
agranulocytosis, thrombocytopenia, megaloblastic
anemia), liver damage, lupus erythematosus, and
pseudolymphoma.
Usual Dosage-Oral: Adults: Initially, 50 to 100
mg daily, with weekly increases of the same
amount until maintenance dose, usually 200 to 600
mg, is established. Further increases to 800 mg or
more occasionally required. Children: Initially as
for adults; maintenance dose usually 100 to 400
mg, depending on age of patient and severity of
seizures.
Preparattons.-Mesantoin (Sandoz): Tablets 100
mg.
PAGENO="0350"
4640 COMPETITIVE PROBLEMS IN THE DRTJG INDuSTRY
agranulocytosis. Pseudolymphomas, lupus erythe-
matosus syndrome, and myasthenia gravis-like syn-
drome also have been reported. Drowsiness may
occur. Reversible visual disturbances, particularly
hemeralopia, are quite common. Hiccup sometimes
occurs during early treatment. Hair loss may occur.
Usual Dosage-Oral: Adults: 0.9 to 2.1 gm daily
in three or four divided doses. Children: Reduce
initial dosage in proportion to age and weight.
Preparotions.-Tridione (Abbott): Capsules 300
mg; solution 150 mg/4 ml; tablets 150 mg.
Paramethadione [PARADIONE]
Similar to trimethadione and has similar indica-
tion, ie, petit mal that is refractory to safer drugs.
Somewhat less toxic than trimethadione but also
less effective. Reactions that occur tend to be the
same as with trimethadione, but some occur less
frequently. A few (eg, pseudolymphoma, lupus
erythematosus) have not yet been reported with
paramethadione.
Usual Dosage-Oral: Adults: 0.9 to 2.1 gm daily
in three or four divided doses. Children: Reduce
initial dosage in proportion to age and weight.
Preparations.-Paradione (Abbott): Capsules 150
and 300 mg; solution 300 mg/mI.
Miscellaneous
Bromides
Usually as sodium bromide or potassium bromide.
Historically of interest as the first antiepileptic.
Moderate anticonvulsant activity against grand mal.
Routinely cause sedation. Skin eruptions are fre.
quent. Of greatest importance is cumulative poison-
ing that causes severe toxic psychoses. Bromides are
regarded as obsolete for routine use, although they
may still have a role in grand mal in children in
whom other drugs, for various reasons, prove un-
suitable.
Usual Dosage-Oral: Recommendations have
varied. The following are reasonably consistent
with several suggestions: 20 to 60 mg per kilogram
of body weight per day in divided doses up to 1 gm
three times daily total.
Preparations-Common preparations are tablets
or elixirs of various strengths. Many manufacturers.
Phenacemide [PHENuR0NE]
An effective anticonvulsant that ma~' be useful
in refractory psychomotor, grand mal, petit mal,
and mixed seizures. However, it is a very dangerous
drug and should be used only when adequate con-
trol of seizures cannot be achieved with other
drugs. Potentially fatal reactions include hepatitis.
blood dyscrasias (aplastic anemia, agranulocytosis),
and toxic psychoses, often with suicidal tendencies.
Nephropathy occasionally occurs. Rashes and gas-
trointestinal symptoms are rather common.
Usual Dosage-Oral: Adults: Starting dose, 250
to 500 mg three times daily. If necessary, an addi-
tional 500 mg daily may be added at weekly inter-
vals. Usual maintenance dose is 2 to 3 gm daily in
divided doses. Children: Age 5 to 10, approximate-
709
ly one-half adult. dosage.
Preparotions.-Phenurone (Abbott): Tablets 500
mg.
Acetazolamide [DIArtlox]
Has been reported useful in children with petit
mal, but effectiveness declines with continued ad-
ministration. See chapter on Drugs Used in Glau-
coma for properties and other uses.
Usual Dosage-Oral: Adults and Children: 8 to
30 mg per kilogram of body weight daily in divided
doses.
Preparations.-Diamox (Lederle): Capsules (sus-
tained release) 500 mg; tablets 125 and 250 mg.
Meprobamate [EQUANIL, MILTOWN]
May be helpful in some cases of petit mal. When
used alone, seldom controls any but the mildest
cases. See chapter on Antianxiety Agents for prop-
erties and other uses.
Usual Dosage-Oral: Adults: 400 to 800 mg
three times daily. Children: Age 3 and older, 100
to 200 mg two or three times daily increased as
needed to as much as 2.4 gm daily in older children.
Preparations.-Equanil (Wyeth): Suspension 200
mg/S ml, tablets (uncoated) 200 and 400 mg, tab-
lets (coated) 400 mg, capsules (sustained release)
400 mg; Miltown (Wallace): Tablets 200 and 400
mg; Meprospan (Wallace): Capsules (sustained re-
lease) 200 and 400 mg; Meprotabs (Wallace): Tab-
lets (coated) 400 mg. Other manufacturers.
Paraldehyde
Effective in status epilepticus, but should be re-
served for cases in which phenobarbital has failed.
Beware of decomposed drug. Intravenously, should
be given slowly in a drip; otherwise, it induces
severe coughing that, at best, makes administration
difficult, and at worst, can cause pulmonary hemor-
rhages. Some fatalities have occurred. Compatibil-
ity with blood has been questioned. Intramuscular
injection, though often very irritating, is reason~
ably safe if adequate care is taken to avoid periph-
eral nerves. The Council's consultants have divided
sharply on whether this agent should be used par-
enterally, and if so. by which route. Bronchopul-
monarv disease is a relative contraindication. The
sedative effect mas' he intensified and prolonged in
the presence of liver damage.
Usual Dosage.- (Status epilepticus) Intro tnu~rii-
tar. Intrarenous: Suggestions have varied, a~d
available recommendations of manufacturers are
vague. However, dosage for status -epilepticus fe-
quently exceeds that given for more benign :-o:'dr-
tions. About 0.15 ml per kilogram of body v-ei-'ht
is reasonable; sometimes a moderate additional
dose will he needed, especially for smaller children.
Intravenous injection must be slow, preferably by
drip, with the drug diluted by physiologic saline,
and with caution to avoid extravasation.
Preparations.-Paral (Fellows-Testagar), Paral-
dehyde (Tilden.Yates): 2, 5, and 10 ml containers.
Quinacrine Hydrochloride [ATABRINE]
May he effective in petit mal, but should be used
AMA DRUG EVALUATIONS
JAMA, May 20, 1968 . Vol 204, No 8
PAGENO="0351"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4641
only if other drugs have failed. Its toxicity is se-
vere and its effectiveness is not great. See the chap-
ters on Antimalarial Agents, Anthelmintics, and
Antineoplastic Agents for properties and other uses.
Usual Dosage-Oral: Adults: 100 mg daily. Chil-
dren: 1 to 2 mg per kilogram of body weight per
day.
Preparations.-Atabrine Hydrochloride (Win-
throp): Tablets 100 mg.
Diazepam [VALIUM]
This drug was introduced as an antianxiety
agent, but like other benzodiazepine derivatives, it
has anticonvulsant properties. Eventually, it prob-
ably will not prove the best anticonvulsant of this
group, but it is the l)referred one of these now mar-
keted in this country. Conflicting reports of effec-
tiveness in various epildpsies have appeared. The
drug has shown much promise in petit ma!, but
perhaps of greatest importance is it.s value paren-
terally in terminating status epilepticus and its fre-
quent effectiveness in minor motor epilepsy, which
is so often refractory to the conventional anticon-
vulsants. Its greatest drawback in maintenance
therapy is the eventual tolerance that develops to
the therapeutic effect. However, this problem also
occurs with other agents in minor motor epilepsy.
The most common adverse effects with oral use are
drowsiness, dizziness, fatigue, and ataxia, all dose
related. Paradoxic excitement or stimulation some-
times occurs. Parenteral administration for status
epilepticus requires observation for respiratory de-
pression and hypotension, and the slight possibility
of cardiac arrest must be borne in mind; however,
from the limited information available, the overall
safety of the drug appears to compare favorably
with other agent.s used for this life-threatening
emergency. See the monograph in the New Drugs
section for other properties ant! uses.
Usual Dosage-Oral: Adults: 4 to 40 mg daily in
divided doses, beginning with a low dose and in-
creasing it gradually. Consider starting with only
2 mg in elderly or debilitated patients. The effect
of the drug is cumulative. Children: Somewhat re-
duced dosage, beginning with 2 to 4 mg daily in
divided doses.
Intravenous: (Status epilepticus) Adults: 5 to
10 mg injected slowly. Children: 2 to 5 mg injected
slowly. Intramuscular injection may be substituted
if the convulsions make sloic intravenous injection
impossible. The drug should not be mixed physical-
ly with other agents or diluted with intravenous
solutions.
Preparations-Valium (Roche): Solution (injec-
tion) 5 mg/mI in 2 ml containers; tablets 2, 5, and
10 mg.
Corticotropin and Various Adrenal Corticosteroids
Of value in minor motor epilepsy. See the chap-
ter on Adrenal Corticosteroids for detailed discus-
sion of these agents.
Dosage varies with the agent used.
Mixtures
Several fixed combinations of anticonvulsants are
marketed. They are listed below only to acknowl-
edge their availability and not necessarily to en-
courage their use. The usefulness of such fixed
combinations is limited since, in the management of
epilepsy, the dosage of each drug used concomi-
tantly should be established individually. After this
has been done, if the doses present in an available
mixture happen to correspond to the ratio and
quantities required liv the patient, the use of such
a combination product would seem justified, for the
convenience of the patient, unless a subsequent ad-
just.ment of dosage becomes necessary. However,
some available ,ombinations are unrealistic, since
the usual dose of one ingredient carries with it only
a trivial dose of the other. Some others contain
irrational ingredients that are not effective thera-
peutic agents for epilepsy. Still others contain more
than two ingredients and appear to be entirely too
cumbersome for practical use in view of the impor-
tance of individualizing the dosage of every drug
the patient receives.
ALEPSAL (Fougera): phenobarbital 97 mg, bella-
donna powder 20 mg. caffeine 26 mg/tablet
5ARBA-NIACEN (Cole Pharmacal): phenobarbital 32
mg, niacin 16 mg/tablet
BARRA-NIACIN FORTE (Cole Pharmacal): phenobar-
hits! 97 mg. niacin 46 mg/tablet
DILANTIN with PHENOBARBII'AL (Parke, Davis): di-
phenylhydantoin sodium 100 mg, phenobarbital
16 or 32 mg/capsule
ELMALOIN with PHENOBAISB1TAL (Elder): diphenyl-
hydantoin 50(1mm 10(1 nig. phenobarbital 15 mg/
capsule
HYDANTAL (Sandoz): mephenytoin 100 mg, pheno-
barbital 20 mg/tablet
MEBROIN (Winthrop): mephobarbital 90 mg, di-
phenylhydantoin 60 mg/tablet
NEO-SEDAPHEN (Smith, Miller & Patch): pentobar-
hital sodium 30 mg. phenobarbital sodium 10 mg,
sodium bromide 300 mg, potassium bromide 200
mg. calcium bromide 100 mg/S ml
PI-1ELANTIN (Parke, Davis): diphenylhydantoin 100
mg, phenobarbital 30 mg, methamphetamine hy-
drochloride 2.5 mg/capsule
QIJADRA-SED (Smith, Miller & Patch): pentobarbita!
sodium 15 mg, phenobarbital sodium 15 mg,
hutabarbital sodium 15 mg, secobarbital sodium
15 mg/5 ml
SEDAI.IXIR (National): pentobarbital sodium 8 mg,
phenobarbital 16 mg/S ml
SEDAPHEN (Smith, Miller & Patch): phenobarbital
sodium 20 mg, sodium bromide 300 mg, potas-
sium bromide 200 mg, calcium bromide 100 mg/
Sm!
SEDOBARR ~ 1 (Whittier): phenobarbital 16 mg,
pentobarbital sodium 32 mg/tablet
SE000ARB !=2 (Whittier): phenobarbital 32 mg,
pentoharbital sodium 65 mg/tablet
JPMA, May 20, 1968 * Vol 204, No 8
710 AMA DRUG EVALUATIONS
PAGENO="0352"
4642 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Dr. ANNIS. This advance chapter was run in JAMA for good rea-
son. To find out if we were heading in the right direction to meet the
physician's need for usable drug information, we asked physicians
who received the ADE chapter to give us their reactions.
To summarize the results, 96 percent said a drug evaluation book
like the one in the sample chapter would supply the type of informa-
tion needed in their practice; 96 percent said the information in the
sample chapter was presented in a readily accessible. form; and 91
percent said the extent of information presented ii4 the sample chapter
was "about right" rather than "inadequate" or "ex~sive."
Details of that study are included in this statemei. u and I request that
they be included in the record at this point as "exhibit H."
Senator Nni~soN. They will be printed in the record.
Dr. ANNIS. Thank you.
(The exhibit referred to follows:)
ExIrn3rr H
An,aZys~s of ADE Questionnaire
(Total Number, 3,761)
The questions and results were:
1. Would a book containing evaluations of all drugs that are commonly pre-
scribed, as illustrated in the accompanying sample chapter, supply the type of
information you need in your practice?
Yes ~ 622
No 110
No comment
Percent favorable response 96.3
2. As a reference on drugs, is the information in the sample chapter presented
in a readily accessible form?
Yes 3, 6G1
No 116
No comment
Percent favorable response 95.7
3. An effort has been made to present the most useful information for most
circumstances in which a drug may be used. In view of this intention, do you
believe the extent of information presented is: inadequate, about right, excessive?
Inadequate 165
Excessive 137
About right 3,418
No comment 41
Percent favorable response 90. 6
4. Do you have a copy of New Drugs?
Yes 1, 243
No 2,677
No comment
Percent having new drugs 31.9
PAGENO="0353"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4643
PRESCRIPTION LABELING
Dr. ANNIS (reading). Also in connection with drugs and drug in-
formation, my fifth subject is labeling prescription drugs.
The AMA Council on Drugs has considered the question of labeling
prescription drugs many times. The council's recommendations last
appeared in JAMA in 1965. Mr. Chairman, I ask that the article,
which is attached to this statement, be included in the record at this
point as "exhibit I."
Senator NELSON. .t will be printed in the record.
Dr. ANNIS. ThaI~; you.
(The exhibit referred to follows:)
81-280 O-69----pt. 11-23
PAGENO="0354"
4644 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
Repeisted Frov& the Josroot of the Ac -ass Slnbeot ~
Deeee,ber 20, 1965, Va!. 194, page 1311
Cepycight 1965, by Aeoeiess 5! od:col A,vs3st:s::
Exhibit I
To-~Labe1 or
In a less sophisticated era, when the art of medical
practice outweighed scientific knowledge, physicians
did not tell their patients the identity of the medications
they prescribed. Today, this practice is being gradually
abandoned, and increasi,,g numbers of physicians ask
pharmacists to indicate or the label the names and
strengths of the drugs they prescribe. The Council on
Drugs believes that all physicians should adopt this policy,
and make an exception only when such disclosure would
be detrimental to the welfare of the patient. In a prior
discussion of this subject,' the Council made a number of
the following points:
The patient has the right to be informed about his ill.
ness and the medications prescribed.
In emergency situations, such as accidental poisoning,
overdosage, or attempted suicide, immediate identification
of a prescription drug from the label may be lifesaving.
The information is invaluable when the patient changes
physicians, moves to another locality, or contacts the pre.
scribing physician at a time when his records are not
readily available.
The information on the label is of value in group prac.
tices in which the patient may not always have the same
attending physician.
It is advisable that patients with allergies know what
is being prescribed.
This specific information on the label helps to prevent
mix-ups between two or more drugs being taken concur-
rently, or between medications being token by different
members of the family.
Should it become necessary to issue a warning against
the use of a particular drug, the name on the label serves
as a danger signal to thsse who have been given prescrip.
tions for the product.
In its earlier consideration of this subject, the Council
on Drugs passed the following resolution':
The Council resolves that it favors labeling oi prescriptaons as
a general practice, and furthermore, it is recommended that pre-
scription pads contain hoses for a "yes" or "no" on whether to
label; if these hoses are not filled in by the physician, thr pre-
scription will be labeled.
That resolution was received favorably by many. How-
ever, pharmacy organizations and several state medical
societies have opposed the nsethod that the Council aug.
gested for implementing its recommendation. The Profes-
sional Relations Committee of the American Pharmaceu'
tical Association agreed with the position expressed by
Apple and Abrams,5 who concluded that unless a pre-
scriber specifically requests labeling, ". . - a pharmacist
should not by himself, or upon request by a patient, dis-
close the ingredients in the prescribed medication by
labeling." This reflects the feeling of the pharmacist that
he needs a directive to label from the physician, who alone
has the authority to make such a decision.
Physicians and pharmacists who are opposed to labeling
as a routine measure and feel that it may create or ac-
centuate various problems have the following objections:
The practice may lead to self-medication and to "pa-
tient-prescribing" for others.
A patient who knows the drug name may compare
prices at different pharmacies, and thus tempt pharmacists
to bid for business on a price basis rather than on a basis
of professional service.
The information may only co,,fuse and trouble the
patient.
Not to Label
The practice reduces the stature of the physician and
lowers the status of the prescription to practically that of
an over-the-counter item.
Patients may put other drugs into bottles labeled with
the previous co,,tests, which may then lead to charges
that a pharmacist dispensed the wrong medication.
Labeling could make it easier to channel drugs into
illegal markets.
The Council believes that the advantages of labeling
outweigh these objections in almost every instance; the
Council always has recognized that there are occasions
when such labeling is inadvisable for psychological or
other reasons, and that the physician is the one who must
decide.
However- only in exveptior:al circumstances is it desir-
able not to reveal the identity of prescribed drugs under
today's conditiot,s. Moreover, the physician's explanation
to his patient regarding thc purpose of a prescribed drug
and what may be expected from it, together with the
public's growing awareness of the effects of drugs-both
beneficial and harmful-will help to minimize problems
that may occur occasionally
After consultation with officers of the national phar-
macy organizations and after further deliberation, the
Council on Drugs strongly reaffirms its position that in
the best interest of the patient the prescription container
should, as a rule, be labeled with the name and strength
of the drug. To implement this recommendation, the
Council suggests that the physician use two sets of pre-
scription blanks, one of which is for routine use and is
imprinted with an order to label. This procedure is con-
sonant with tl- - ethics of medicine and pharmacy, and
with the physician's responsibility to decide whether the
prescription label should or should not identify the drug.
The Council further urges that the physician always
designate the number of refills he wishes the patient to
have, and that he prescribe only the number of doses
usually required in any specific condition, since adjust-
ments in dosage are often necessary to obtain the desired
result in individual cases. The Council also recommends
that any prescription that does not indicate the number
of refills, or that is labeled "p.r.n." or "ad lib," not be
refilled.
The Drug Abuse Control Amendments that were recently
passed by the Congress regulate the refilling of prescrip-
tions for stimulant and depressant drugs. No prescription
for drugs in these cl.isses can be renewed more than five
times, or more than six months after the date of issue un-
less the physician gives additional authorization for re-
filling.
The physician's responsibility for the medication regi-
men of his patient is clear, and he should therefore heed
the pharmacist's requests for specific instructions on cc-
The Council hopes that this statement will clarify its
position on the question of labeling and refilling of pre-
scription drugs, and earnestly solicits the cooperation of
physicians, pharmacists, and other health personnel in
implementing these irnpurtaist public health recommenda-
References
1. Lnbctisg of Picsenptis" Drags, editorial, JAMA 185:316 Jaty 27)
ions.
2. Apple, W.S., and Ah:aoe-. Rn.: Problems in Presenpt:sn Order
Conossasimtiont, JAMS 185:291-293 (Jaly 27) 1963.
JAMA, Dec 20, 1965 . Vol 194, No 12
Pr:oted is U.S.A.
PAGENO="0355"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4645
Dr. ANNIS. May I summarize the council's views? It recommends
that in most instances the physician should request that the prescrip-
tion label indicate the name and strength of the drug prescribed.
Some of the reasons given are these:
The patient has the right to be informed about his illness and the
medication prescribed.
The information is invaluable when the patient changes physicians.
It is advisable that patients with allergies know what is being
prescribed.
Specific information on the label helps to prevent mixups between
two or more drugs being taken at the same time; or between medica-
tions being taken by different members of the family.
However, the council also offered the fact that there are situations
when the physician might determine that such information should not
be contained on the label. Those situations usually involve psycholog-
ical considerations for specific patients.
Mr. Chairman, I would now like to add some further remarks that
the AMA considers of importance to these hearings.
Almost at the beginning of this statement, I listed the three primary
reasons for which the American Medical Association was founded 122
years ago; to established a code of ethics; to combat quackery; and to
improve medical education.
That last point-education-includes the entire spectrum of training
and education necessary to produce and maintain a competent
physician:
Premedical education.
Medical school.
Postgraduate education through internship or residency training.
Continuing education of practicing physicians.
The proper use of drugs is a vital part of all medical education, be-
ginning with medical school.
A survey of medical schools by the AMA in 1~966 revealed that an
average of 173 classroom hours was: devoted to pharmacology during
the sophomore year. The range was from a low of 62 hours to a high
of 396 hours.
In the junior and senior years, instruction in drug therapy is pre-
sented as a part of each clinical service and through clinical pathology
conferences which all students are required to attend.
It is not possible to give the total hours of drug therapy instruction
received by the student because there is continuous education in that
area throughout medical school arid during the internship and resi-
dency years.
The same observation can be made about continuing medical educa-
tion courses. The AMA publishes a list of such courses each year. The
latest list, and I have with me a copy for the committee, shows 1,922
courses offered to physicians by 372 institutions and organizations. I
will leave it with the committee. This is, I think, the 11th or 12th-the
14t.h consecutive year which this has been made available, so physicians
anyplace in the country will know where they can go for continuing
education.
Senator NELSON. Thank you.
Dr. ANNIS. While there are no courses titled "Drug Therapy," with
very few exceptions, each course necessarily includes information and
PAGENO="0356"
4646 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
discussion of the therapeutic agents used in the treatment and control
of the problems being covered by the course.
The medical profession has great respect for the results of drug
research. It recognizes that a great number of the specific medical ad-
vances of the last three decades have been in the area of chemother-
apy-of drugs.
These advances have come about becausc of the varied support of
research and development-by the private drug industry, through aca-
demic contributions supported by private and Federal grants and
directly from the Federal Government.
If financial support for research and development were confined to
only one of those sources, it is possible-even probable, I think-that.
the research would be directed into whatever approach was of most
interest to the sponsoring body. That could mean fewer innovative dis-
coveries and applications.
Speaking of the application of drug discoveries, the American
Medical Association has always advocated the rational use of thera-
peutic agents by physicians in treating patients and has consistently
expressed its firm belief that the physician should have for his patient
the very best drug available for the patient's condition.
At the same time, the AMA has urged that physicians be aware of
the economic factors connected with the use of drugs.
In this regard, I would like to present the essence of a position
adopted by the AMA House of Delegates:
Physicians should be free to use either the generic or the brand name in pre-
scribing drugs for their patients; and physicians should supplement medical
judgments with cost consideration in making this choice.
A copy of the report is included as exhibit J and I ask that it be
inserted in the record at this point.
Senator NELSON. It will be printed in the record.
Dr. ANNIS. Thank you.
(The exhibit referred to follows:)
PAGENO="0357"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4647
Exhibit J
Excerpt From
Proceedings of the AMA House of Delegates
November 1966
Prescribing and Dispensing of Drugs
This report is intended to state the position of the American Medical
Association regarding the considerations which are pertinent in determining
under what circumstances the physician should prescribe generically or by
brand name.
The present policy of the American Medical Association is that physi-
cians should be free to prescribe drugs generically or by brand name for ~j,
of their patients, whether they are paying, medicare, or indigent patients,
the primary consideration being the best interests of the patient. Medical
considerations must be paramount in the selection of drugs. In addition,
the physician also has an obligation to be mindful of the economic conse-
quences of the treatment he prescribes.
The issue of cost is not simply a matter of prescribing drugs generi-
cally as opposed to brand name prescribing. Often there will be~substantial
variations in the cost of the same drug marketed under differentbrand names
by a number of reputable manufacturers. However, gene~ric prescribing
alone will not assure that the least costly brand will be dispensed or that
the savings will be passed on to the patient. Nor will generic prescribing
alone assure the physician that his patient is receiving the product of a
manufacturer in whom he has confidence.
If the physician prescribes by;brand name, he designates the source
of supply. If the physician prescribes generically without naming a manu-
facturer, the pharmacist or some other third party chooses the source of
supply.
The attending physician should not delegate this choice, that is,
he should not prescribe generically, unless he is convinced that he can
rely upon the quality and purity of the drug that will be dispensed to his
patient. If this is not the case, then the physician himself should desig-
nate the source of supply by prescribing by brand name or by adding the
name of his choice of supplier to the generic name of the drug.
Cost Considerations
If medical considerations lead the physician to the conclusion that
he should not delegate the choice of supplier to anyone else, then he must
make the decision. And in doing so he should supplement medical considera-
tions with considerations of cost to his patient.
PAGENO="0358"
4648 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
It is a fact that, in many cases, drugs prescribed by physicians in
the United States are available from more than one dependable supplier.
They are also available to patients from a large number of retail phar-
macies. Thus, in selecting a dependable supplier of the drug of his choice,
the physician has an opportunity to serve his patient at the lowest possible
cost. The physician should inform his patient of the medical considera-
tions which have led him to the decision to prescribe a particular brand.
He should also encourage the patient to be cost conscious in having the
prescription filled.
If medical considerations lead the physician to the conclusion that
he can safely delegate the choice of a supplier to a pharmacist, a hospital
formularly committee or some other third party, he does not abrogate his
responsibility to protect the economic as well as the medical interests of
his patient. Just as it does not follow that generic prescriptions automati-
cally ensure therapeutic effectiveness, it is also a fact that generic pre-
scriptions do not automatically ensure the lowest possible cost. If the
third party filling a generic prescription does not reflect the same concern
as the prescribing physician, his patient may be charged a higher price
than would have been the case given a brand name prescription. Thus, in
choosing to prescribe generically, the physician should be assured that
whoever actually makes the choice of supplier can and will take into
account not only the medical needs of his patient but will protect the
patient's economic interests as well.
With this clarification of the medical and the economic consequences
which can flow from the physician's decision to prescribe by generic or by
brand name, the Board of Trustees recommends that the House of Dele-
gates:
(1) Reaffirm the present policy of the Association which states
that physicians should be free to use either the generic or
brand name in prescribing drugs for their patients; and
(2) Encourage physicians to supplement medical judgments with
cost considerations in making this choice.
PAGENO="0359"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4649
Dr. ANNIS. This committee has heard testimony that drugs should
be prescribed by their generic names only. That recommendation
usually is founded on the assumptions that drugs of the same generic
name are therapeutically equivalent; and that a prescription written
by generic name will automatically save the patient money. Neither
assumption is necessarily true.
The AMA believes firmly that no : system of prescribing drugs
should be compulsory for a physician. instead, a full range of drugs
must be available so he can select for his patient the one he believes
will achieve the best response.
To cope with differences among some patients in their responses
to drug therapy, the physician must be allowed the greatest possible
freedom in prescribing from a supply~ of drugs that is as large and
as flexible as possible.
It takes more than laboratory testing-more than just chemistry-
to prove therapeutic equivalence among drugs. it takes proper clinical
testing.
Even assuming equivalence of chemical composition among drugs,
other factors are involved. Among these are crystalline size, nature of
incipients, flavors, coloring agents, tableting pressures and the num-
ber, thickness, and orientation within the tablet of coating films.
The physician who prescribes a drug needs to know what to expect
from that drug. A generic prescription, filled by a drug the pharma-
cist selects, may be filled with any drug within that generic classifica-
tion. If the prescription is refilled, the product of a different manufac-
turer may be used. As a result the physician may be unable to evaluate
fully the patient's response to that course of drug therapy.
Mr. Chairman, and members of the committee, that completes the
statement of the American Medical Association before these hearings.
I have tried at least to touch on, if not to discuss in elaborate detail,
subjects that we believe are important both to this committee and to
the medical profession. If there are any questions at this time, I shall
be glad to do my best to answer them.
I will be glad to `be assisted by both Dr. Hayes and Mr. Harrison.
We appreciate this courtesy.
Senator NELSON. Thank you very much, Dr. Annis. We appreciate
this statement of the American Medical Association.
You made some reference in the beginning to statements by some
witnesses that may reflect in a fair way on the profession. Let me say
that in my judgment based upon some natural `bias, coming from a
medical family, I consider the medical profession the finest of the pro-
fessions, though I am a lawyer. And though we have highly motivated
people in all professions and we have some who are not, I think my
own unscientific estimate from experience is that there is a higher
percentage of highly motivated people in medicine for a very simple
reason, that I think more people go into this profession because they
want to do something for people. That has been the history of medicine
more than perhaps any other profession.
I want to say, too, that the fact that Congress conducts hearings of
various kinds involving all aspects of the social structure of the coun-
try and the economic structure and the professions does not mean that
the hearings which may bring out testimony critical of some indus-
tries, some profession, or something else, does not mean that that is a
PAGENO="0360"
4650 CO~ETITWE PROBLEMS IN THE DRUG INDUSTRY
general indictment of the industry or the profession or that the Con-
gress feels that that industry or profession or economic or social
group is not making a very fine contribution to society.
I have introduced a fair amount of consumer legislation involving
pesticides and the chemical industry, the tire industry, tire safety
standards, the auto industry, and a number of others. I remember
when I introduced the tire and auto safety bills, I was attacked in
some quarters as being against the auto industry, which it could be
said is the greatest, at least in terms of its size, of any industry in
the country. I had to point out repeatedly that the fact that I thought
there were some things wrong in that industry in terms of the work
they are doing in safety, and in terms of the quality of tires the auto
industry was using, this is not a general indictment of the industry.
There is not any group in the country that has a relationship with
the public that is perfect~ The purpose of this hearing is to raise is-
sues in which the public has an interest. The problems and issues
raised before this committee have not been raised by the members, by
me, or the members of the committee. They have been raised by wit-
nesses who come before the committee, and, like anybody else, I could
agree with some and disagree with others, based upon what they
have to say.
But in the last 2 years there have been a large number of very
reputable witnesses who have been critical of certain practices in the
medical profession, of the medical journals, and of the drug indus-
try. They have been very distinguished men who have been willing to
come before the committee and express their opinions about these
various matters.
Of course, there have been others who have come before the commit-
tee to respond or to criticize those who have criticized. We have made
it a point in this committee, which I think we must, to be fair, when
we are discussing anything involving the drug industry, and that
has been the main thrust of these hearings, that any company that was
criticized would have an opportunity forthwith to respond to that crit-
icism and whenever they have asked for the opportunity, we have set
up the earliest possible date in order to let them respond to anything
that was said before the committee.
We also have made it .the policy of this committee to hear from all
viewpoints respecting any issues raised. And we have been trying to
do that. We cannot hear from everybody at once, of course, because
we would have to hold the hearing in a stadium.
But anyway, the fact that these questions are raised before the com-
mittee, as you well appreciate, puts me in an adversary position, in the
view of many, since that is the kind of issue that is being raised here.
In other words, it is a. hearing to raise public questions of importance
which are critical of certain practices in the drug industry.
Many times, it has been said, "Well, you are just hearing the bad
things about the drug industry." Well, we know a great deal about the
good things. However, that is why we have always been happy to per-
mit the drug industry or the Pharmaceutical Manufacturers Associ-
ation to appear, or anybody else, and delineate in a great detail as they
desire the contributions, the work of the particular organization they
represent.
While we will be pleased to have your summary of the vast amount
of work the American Medical Association does-I realize it is, just
PAGENO="0361"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4651
as you have said, a concise, short presentation of an organization that
has a long and distinguished history in this country. Nevertheless,
since it is the function of this committee to probe these very questions,
I necessarily have to ask the hardest questions I can think of. Some-
times they are not very hard. And some of the questions I ask may not
be very perceptive. In fact, some may be considered foolish. That is
because nobody on this committee, particularly myself, poses as an
expert on any aspect of this field or as an expert in the issues before
this committee. The committee conducts hearings and hears testimony
of experts who have conflicting views so that the whole story will be in
the hearing record, so that it may be read and evaluated and so that
the Congress sitting in the position, so to speak, of a jury, may make
some kind of evaluation as to what the testimony means and whether
or not legislation is required in some area respecting the public interest.
Now, I try, as I said, to make my questions as tough and probing as
possible. Som,e witnesses even think, if you can imagine it, that som.e
of my questions are offensive, and some people even think the question-
er is offensive. That is not my intent.
I want to say also that I try to ask the most probing questions I can,
affecting all the issues that have been raised here. I note that very
frequently I am quoted as advocating some position because of the
questions I ask.
Dr. ANNIS. I can `appreciate that, Senator, I have had that directed
toward me a. few times, too.
Senator NELSON. I ask questions that occur to me, saying why is this
not a good idea, and then I am put in the paper as saying I advocate
doing such and such, and then there will be an editorial someplace, in
one of the medical publications, saying how foolish `the proposal I ad-
vocated was when, in fact, I did not advocate anything. I am just ask-
ing for information. I may conclude after hearing all the testimony
that I agree with the proposition implicit in the question I asked. Or
I may not.
Now, having said that, I would like to ask some questions.
First, on the continuing question of generics versus brand names
~and labeling of drugs and so forth, it seems to me, after 2 years of
listening to testimony, and after reading the arguments made by
the drug manufacturers, that there is a continuous and very successful
attempt by the manufacturers to convince the medical profession that
you cannot ever trust generic drugs, and that you have to prescribe
brand names, particularly the brand name of a particular company. We
have not received any adequate `testimony from either sid&-when I
say adequate, I mean we have not had any conclusive testimony that a
brand name is better than a generic. The FDA is presently testing a
whole series of very commonly used drugs to try to settle this question.
The test I refer to, a previous test made by the FDA, is of some 4,600
drugs, of which 2,600 were generic drugs and 2,000 brand name, and
they tested them only for potency. On that particular test., `the generics
came out slightly better than the brand names.
Pharmaceutical manufacturers attacked it on the grounds that it
was not accurate and the FDA, after reexamining it., conceded that
there were six instances, I think, out of the 4,600, that. were erroneous.
In any event, as I recall, about 8.8 percent of the brand names failed
the potency test; that is, they: were slightly under or `above the TJSP
standards, and 7.7 percent of the generics failed that test.
PAGENO="0362"
4652 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
So the prcthlem continues, and the drug companies have been very
persuasive in trying to make.sure that generics are not trusted by much
of the medical profession. However, we have had a number of dis-
tinguished witnesses who simply say that they prescribe by generic
name-that if the drug meets TJSP standards, there is no evidence, of
any consequence, that they are not therapeutically equivalent.
First, let me ask you about the question of labeling which you re-
ferred to in the latter part of your statement. You recommend that the
doctor use the generic name in prescribing, I believe, is that correct?
Dr. ANNIS. My recommendation, Senator, is that `a physician `be
given the opportunity to prescribe generically as he will do in some
instances. -
Senator NELSON. I was referring to labeling; I am sorry.
Dr. ANNIS. But if he so prescribes, or by brand name, if he feels that
he is a little more certain. The recommendation for labeling is one that
has come as a result of long discussion by many of the a:ble members on
our council on drugs, supported by many others in the profession.
With the growth of new drugs with the expanding names, whether
they are generic and hard to decipher, to spell, or to pronounce; or
whether a simple brand name, it is increasingly difficult, with the tre-
mendous mobility of our population-people moving around-to know
what they are taking. So the recommendation for labeling is that in
most instances, except for a few where for psychological reasons it is
not good for a patient to realize what you are giving him is acetylsali-
cylic acid-plain aspirin-when they think they need an exotic one-
except in those rare instances-for the most part the physician would
be wise and it would be safer, and therefore better for the patient who
is moving around, and `better for another doctor, should they be travel-
ing or should they move, to know exactly what they are getting.
So that if, for example, you write a prescription for a tol'butamide
for a diabetic, you might write "Tolbutamide" with the name of a
producer. You might write it, as I often do, one or the other producer,
whichever the pharmacist may have on hand. But label itso that it will
say tol'butamide, whatever company. I do not treat diabetes, but if I
did, the patient would know ihe drug.
Then if they are visiting on a weekend, or if they have a reaction-
because they ate inadequately, or because of an upset stomach and
their diabetes the effect of the medicine to control their diabetes is too
great and. they have a reaction from `the `drug, any doctor can t'ake a
look at it and know what the patient is getting. This is a protection
for the patient. It gives more information. They know what they are
treating, they know what drug is `being used and it helps immeasurably.
I `have many patients from out of town, who come down to Miami.
They will come in and bring two or three bottles with them, with `a
prescription number. Not infrequently, I have had my secretary call
various parts of the country to find out from the druggist what the
prescription for Mrs. Jones is. Then I will know.
For some people, you can't tell them what they are taking. They will
not only think it is good for them, but they will prescri'be it for Aunt
Lillie when she is visiting.
We think it is good practice, it gives greater information and shares
with the patient a little of the responsthility in their own care ~nd it
will give tremendous aid for our increasingly mobile population in
being immediately able to let the doctor know what they are taking,
PAGENO="0363"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4653
and the dosage they are taking. This is so important in many drugs,
how frequently they take it, and also, how long they have been taking
it. Many drugs are not considered dangerous if taken for a week. The
same drug you might give for a week, you would not want anybody to
refill, and you sure do not want them taking it for a month or two or
three. This basically is the summary of the philosophy behind this
recommendation.
Senator NELSON. I think we have had a number of distinguished
physicians testify on this precise point. No one so far as I know, has
testified to the effect that the physician should not have a choice of
whether it is a brand name or generic, but in order to accomplish this,
is it not necessary to have some legislation that would require that the
label carry the generic name, and then, of course, the doctor may de-
cide that it should he Lilly or Parke, Davis or Merck or something
else. It may very well have t.hat on the label, also.
Do you see any other way to secure, without legislation, a require-
ment that the label shall bear the generic name excepting in those
cases where the doctor notes that he: does not wish a patient to have the
drug identified?
Dr. ANNI5. Well, Senator, in most instances compulsory labeling
would cause no hardship. But, especially in the field of psychiatry,
sometimes in other fields, for psychological or emotional reasons-if
you were to tell someone who is disturbed-an exception must be
provided. This is one of the fields that I have to listen to my colleagues.
Let me cite an example. There are meprobamates, Miltown or Equanil.
These patients will say, "I read about that Miltown, I tried that years
ago, and it is of no value." Yet the prescribing physician, the psychia-
trist, the internist, the obstetrician, would be very reluctant to let this
patient know she is being given Miltown, so lie might prescribe
meprobamate made by someone else or meprobamate TJSP.
There are many reasons why physicians will not tell the whole
story. Psychiatrists dealing with children are totally reluctant to dis-
close all to their patients.
This is the reason that our recommendations, following the Council
on Drugs, with the concurrence of most of these very distinguished
men who have been before your committee in the field of physiology
and medicine, recommend st.rongly an increase in the. practice of label-
ing, but they still leave to the physician the discretion. If it became a
matter of law, it is mandatory, then we overcome the part of treatment.,
the mysticism, for example, that some physicians in certain areas of
medicine-in psychiatry-feel is part and parcel of good treatment.
This is where the objection comes.
In my practice I cannot conceive of but very few 1nstances where
a compulsory labeling would make any difference.
Senator NELSON. It has been the testimony of a number of distin-
guished witnesses that it ought to be described generically on the
label, with the caveat that if a doctor does not think it should be, i.t
will not be put on the label. So I am wondering why legislation re-
quiring it., except when the physician directs otherwise, is not the only
way you are really going to accomplish this.
Dr. ANNI5. I would not have too strong au opinioii against that as
long as the physician-this is the only thing-as long as the physician
taking care of this patient. has the right to discriminatory judgment
in the interest of the patient. This is all we ask for.
PAGENO="0364"
4654 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. I would call upon the AMA to support legislation
to that effect, as I say, with the freedom of the physician to decide
if he does not wish to have the generic label on it.
I have a letter from Dr. John Adriani, who is chairman of the
council on drugs, endorsing that himself. He said, referring to an
educational television program he was on, "I was the participant who
expressed the opinion that all drugs should be sold by the generic
name, that the generic name should appear in large print and the
trade or brand name be put in smaller type below it, or the generic
name in parenthesis."
Dr. ANNIS. I am acquainted with Dr. Adriani and also this tele-
vision show. Dr. Adriani is an anesthesologist and a very capable one
in a umversity in Louisiana. There are many people who concur with
this basic approach. The thing that they are fearful of is anything
that makes it mandatory that physicians prescribe in only one way or
that they always label in one way. This is where you take away from
the physician his opportunity to discriminate.
Senator NELSON. Thus far, we have not had any one who advocated
that you not reserve that right to the doctor.
One of `the problems raised continuously to which I referred a bit
back, is the brand name versus generic name. A year or so ago two
drug chains, People's and Gray's, involving, if my memory is correct,
about 300 pharmacies, announced that they were stocking across the
board generic drugs supplied by Strong, Cobb & Arner, and that the
average price of prescriptions would be about one-half of the brand
name. Everybody testifying and appearing before the committee has
been familiar with that company and spoken very highly of it.
The question I am getting at is it seems we have to have adequate
legislation, adequate personnel in the FDA, to guarantee inspection
and quality control so that we can forever get rid of this argument
about brand name being always better, which has never been proven.
Would the American Medical Association support, before the Con-
gress, legislation that would furnish adequate inspectors for the FDA
so that they could sample, check the producers on a regular basis, so
that we can have assurances that adequate quality control exists at
each producing plant, so that once and for all we can say that these
plants are inspected, they do meet USP or NF standards, so that the
doctor can be assured that what he is buying meets these standards?
Would the AMA support that?
Dr. ANNI5. I am under the impression that the F'DA already has
that authority. They need a little more money to implement it and to
carry it out.
I would like to say, however, that I do not think either I or the
American Medical Association can be put in a position that we have
ever stated that the brand name is always preferable to the generic
term. There are many excellent drugs available generically that come
from responsible manufacturers who have built-in quality controls
to put out good drugs. There are many generic drugs that actually
come from these same manufacturers. Again, our point is that pre-
scribing generically does not in itself assure that you are going to get
what you expected.
It has been about 21,4 or 3 years ago, Senator, that I read an article
repeated in many of our medical journals about an instance that took
place in the Province of Ontario. I am sure that is where it was, wherein
PAGENO="0365"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4655
tolbutamide, a drug taken by mouth to control diabetes rather than
injections of insulin, had been purchased in large quantities ty virtue
of its price. It was the low priced generic drug purchased. Subse-
quently many physicians who were using this drug in government hos-
pitals and in that area began to have patients go into diabetic coma
or show other evidences that their diabetes was not controlled. Subse-
quent investigation found and traced the trouble to the generically
purchased drug, tolbutamide. Chemical examination proved that the
tolbutamide was in fact what it was supposed to be; it was tolbuta-
mide. However, in putting it together, the manufacturer who supplied
it compressed it in such a way that it was not properly absorbed. It
was not properly utilized.
Senator NELSON. We had testimony-
Dr. ANNI5. May I continue? I was waiting to see whom you were
going to listen to, because this is an important point.
The drug was not absorbed. Many people passed it out of their
intestinal tract in the same state they took it in. It was a good drug.
They got what they bouo~ht. But itdid not have the quality of absorp-
tion so the patient would'get the result desired by the physician.
About a year and a half ago I had an opportunity to speak in
Toronto before a drug trade meeting. On that occasion I raised this
question: I said:
It is the first time I have been in Canada and I read this a year or two ago.
I would like to know more about what really happened.
The president of the association said:
Gee whiz, I wish you hadn't asked me. I was the main supplier for the drug.
He went on to say that when they purchased it, it was purchased by
virtue of its price from a supplier, and the chemical ingredient was
exactly what it was supposed to be. It did not have the other built-in
changes which would come from a quality product of those who had
made longer examinations as to its ability to be absorbed and properly
utilized.
I think this is why a number of physicians feel in prescribing many
drugs that they will prescribe it with the brand name with reference
to a particular manufacturer. I know this is true of many of my
physician colleagues who treat diabetes. They will not just depend on
one, but they will prescribe tolbutamide and then put two-either one
or the other of two producers. What they want is to be certain that
the pharmacist can supply it. from whichever source is the cheaper of
three or four sources.
The main thing the physician wants is that whatever the source
that produces it generically, it comes from a source that also can assure
a product that has the other necessary qualities which will make it
absorbable and usable by the patient.
Senator NELSON. We had testimony on that exact case, and the
record will speak for itself. I am simply going by memory. This case
was discussed on pages 1340 and 1341 of part 4 of our hearings-
Dr. ANNI5. There were a number involved.
Senator NELSON (continuing). That is not valid to prove the par-
ticular point, because, as I recall it, it did not meet Canadian stand-
ards. Whether they use TJ.S.P. I am not sure.
Dr. ANNIS. It was generically equivalent. I would not say whether
PAGENO="0366"
4656 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
it met any other standards, because I do not know where it was
purchased.
Senator NELSON. We have a constant instance involving generic
and brand names where somebody will testify that it proves that the
generic is not as good, because here is a case in which it did not do
such and such. Every single case we checked is the case of a drug that
did not meet U.S.P. standards. Of course, when that happens, that is
front page in all the medical press and the pharmaceutteal manufac-
turers naturally say, "Here is another case that you cannot trust it."
We have cases in the files from the last hearing in which exactly the
same thing happened to the brand names, so you might as well say
you cannot trust brand names. In the cases I mentioned of the 4,600
drugs tested, with 8.8 percent of the brand name not being able to
meet potency standards, that proves the case that you had bettter stick
with generics, because generics meet it more often.
Dr. ANNIS. My point was just the opposite-that the mere generic
equivalence in itself is not sufficient. If we were talking about build-
ing in additional safeguards, as I indicated earlier, many generic
drugs prescribed come from satisfactory suppliers. We are not opposed
to these. All we want is to be sure that when a physician prescribes a
drug, he gets the drug that he prescribes and one that has the other
qualities over and above its chemical constituency that are essential
to its proper and expected action.
Senator NELsoN. The point is made very frequently by lISP, manu-
facturers and so on, that if the drug meets NF or lISP standards,
they are equivalent. Then the other side argues that they are not and
they use chloramphenicol as one of their cases, in which there is no
proof that there was any theraputic difference between the Chioromy-
cetin and the other two in the marketplace. They just reached differ-
ent blood levels in a different period of time, but the, FDA decided
that they would make them uniform. They could have made them
uniform to the other drug as far as any clinical knowledge of the
therapeutic efficacy of either one of them is concerned.
But the problem is that every time you find a generic t.hat fails a
test-and the brand names appear to fail them just as often-that is
publicity to all the doctors, who then say, "Well, you cannot trust the
generic."
Now, the thing that we have to resolve, it seems to me, is how do we
get adequate testing to assure the medical profession, whether it is
brand or generic, that it does meet the DSP or NF standards.
It seems to me there are two things: One of them is to give enough
personnel to FDA so that they can make adequate quality control in-
spections. You will not get this unless distinguished groups such as
the AMA appear before Congress and say this is critical to America.
Not just say this in the journal but appear before the Appropriations
Committee and say that it is going to be critical to the health and
pocketbook of the consumer, and, therefore, we think you ought to
give FDA more inspectors.
Would the AMA appear before the Appropriations Committee
when the issue arises in support of inspection?
Dr. ANNIs. Senator, we would be happy to appear before the Ap-
propriations Committee or anybody else to assure increasing quality
standards for all these products made for the benefit of the American
people.
PAGENO="0367"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4657
The Senator may be aware of the fact that the AMA is one of the
three financial supporters of the Drug Standards Laboratory here
in Washington, D.C. We pay one-third of the budget to supply speci-
fic research and standardization of these drugs. Few people realize
that. But this is just one other area, that indicates our long desire for
quality drugs. We will be very happy to testify.
We have long felt that the Food and Drug Administration-and
the record will show it came into being many years ago with a strong
continued support of the American Medical Association-we have
no battle with these men who are trying to assure quality products.
The only time that we come into conflict with anyone is when they say
that by virtue of a chemical similarity the drugs are the same. These
other standards are absolutely essential. We would support such a
stand for more dollars to enable the FDA to do an ever-better job.
Senator NELSON. Are you saying that you disagree with the testi-
mony of a representative of the USP and the NF that if a drug meets
TJSP standards, it is therapeutically equivalent?
Dr. ANNIS. No; I did not say that, Senator.
Senator NELSON. Oh, I see.
Dr. ANN'S. I did not read their testimony, and if this is indeed
their testimony, I would suspect that it would deserve serious con-
sideration. I have not seen it.
My point is that the general continuing argument has been against
brand as opposed to generic, with the assumption that if a drug is
generically the same, it therefore has therapeutic equivalence. If the
valuations referred to by USP and: NF include these other standards,
the absorbability in certain areas Of the intestinal tract within a cer-
tain period of time, so that when I give a drug I know it is going to be
absorbed within the person's body, I have no quarrel. But this is shown
by clinical testing. This will not show up sometimes in the laboratory.
What is true in a guinea pig, or a dog, a cat, or rabbit is not necessarily
true in a human.
So in many cases the laboratory alone, the chemist, the pharma-
cologist cannot give the whole answer. So our position is that we must
look at the drug in its whole spectrum-from the standpoint of how it
is compounded, its basic purity and the rest, including its reaction
within the body-so that we can assure a physician when he prescribes
the drug generically~ nothing will be supplied his patient that falls
short of these desirable physiological reactions and he will know the
end result, then I am sure we would be on common ground.
Senator NELSON. But the position of the DSP is, and it has been the
position of a number of witnesses, including distinguished pharma-
cologists and clinicians, that if a drug meets DSP standards, then it
is therapeutically equivalent to any other drug that meets that stand-
ard and that in the whole history of this debate there have been-there
has been I think one proven case where that was not the situation.
That would be a case when all the distinguished people who set the
standard happen to have missed the point-the clinicians, the chem-
ists, and so forth-in evaluating the drug have established the stand-
ard and missed some point. But in the whole history of drug testing,
there has been a proof of one or maybe two cases. Therefore, if we
are going to use any standard at all, it would seem to me the DSP
standard is the one that we should use. If clinical evidence is developed
PAGENO="0368"
4658 COMPETITIVE PROBLEMS IN THE DRUG INDuSTRY
that the two drugs with the sam~ compound did not have the same
clinical result and they discovered that some different excipient was
used in one and that caused it and lISP had missed that point,
that would be an exception to the rule. But when we have never been
able to find more than one or two such cases in history. It would seem
to me that this is the standard to rely on.
Dr. ANNIS. Senator, here is an area I would like to ask Dr. Hayes
about. He is much more knowledgeable in this area. Do they set up
TJSP standards after the extensive basis of clinical testing?
Dr. }IA1~s. Of course, this is a problem which has engendered a
great deal of discussion amongst interested parties. In fact, several
learned bodies have spent considerable time studying it. Two come to
mind, the Academy of Pharmaceutical Sciences and the Drug Research
Board of the Nationai Research Council. They have recently, as a
result of their study of the problem, called for some improvement of
the standards for assuring physiological availability or biological
equivalence, as it were, of all drugs reaching the market. I believe that
both the lISP and NF at the present time are reevaluating their
testing procedures in order to develop tests which will more properly
evaluate the biological equivalence of all drugs reaching the market.
So I do not think it is possible to say that the existing standards-
although I know the people in the NF and the lISP, that they are sin-
cere, dedicated scientists, and the fact that they question their own
testing procedures and look to improve them-that the matter can be
settled as to whether, under existing standards of the lISP and the
NF, that they, in themselves, will assure biological equivalence. I think
that more work has to be done. I think that work is being done.
Dr. ANNIS. Senator, may I add, too, that in this connection-I
thought this was true, but I was not certain enough to testify. Recently
the Drug Standards Laboratory had to come back to us; they needed
more money. They are suffering from something known as inflation,
too. The American Medical Association feels so strongly about this
kind of testing that you are referring to that, without hesitation, when
the Council recommended to the Board that additional appropriations
be made, we did so.
This is an area where we are concerned. But we are even more con-
cerned that it goes beyond what can be done in that chemical or phar-
maceutical laboratory, because ultimately the laboratory of a drug for
a person who is ill is in that patient's body. This is why that biological
testing that Dr. Hayes refers to and other groups apparently feel must
be upgraded, too, is so important. Here again is an area where we
would want to be assured before testifying along that line.
Senator NELSON. I just want to say on this point that Dr. Miller of
the lISP and a representative of the NF have not testified that their
standards were perfect. They have testified that they are the best
standards existent in the world today and that they can be improved,
and, of course, they will be. But the question arises, after accepting the
lISP standard or NF standard in some clinical .testing we find out a
year later that the standard omitted something, then they would cor-
rect it. But as of the date that standard is there, it is the best standard
there is. Therefore, if a generic drug meets that standard and a brand
name meets that standard, on what basis does an individual practitioner
say or the PMA, in particular, say that one is better than another?
Dr. ANNIS. I would agree if standards are all the same they could
PAGENO="0369"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4659
not say "Ours is better." As the Senator is well aware, about a year
and `a half ago I had requested, through Senator Smathers the oppor-
tunity to come to these hearings and speak as a private physician.
At that time I did not realize that I was going to be elected to the Board
of Trustees and have an opportunity to serve the American Medical
Association.
When I went into the practice of medicine, we did not have all these
drugs. When I talk to medical students `today, I remind them that
90 percent of the drugs they learn about were not in existence when
I went into medical school. I have two sons in medical school, and what
they study, what they learn, was not known when I was there. I grew
up knowing `that I lost a young brother who died of an infectious
disease because what he had could not be controlled. I lost a father
at the age of 22 from a ruptured appendix. So I know as a clinician
what these drugs mean. I `have seen what they mean. I have seen
people and children die of diseases that now we prevent and control.
I am one of those who has grown up with great respect for `the
pharmaceutical indus~ry.
Over this same period of time, with the constant addition of all
these new drugs, naturally others have come in with the idea of pro-
ducirig. But, though I prescribe generically on occasion and I prescribe
generically with the name of two or three producers following, I
lean heavily on the reputable, responsible, long-term members of a
great industry because I believe that, in most instances, I can depend
upon their reliability.
There is a second reason. There are only, out of some 1,700 or 1,800
drug manufacturers-~only about 130 or 140 do any significant `amount
of research. It is from this group that have come some 95 or 97 percent
of all these `drugs that I have seen produced in my 30 years as a
physician. So, naturally, I feel obligated as a physician-as an indi-
vidual practitioner, for what it has done for me and the tools that they
have given-to support that segment of the pharmaceutical industry
that is more than just a business, that segment which also does the
research and has come up with one tool after another-first to control
infection and diseases and then put into the hands of doctors in the
field of anesthesiology, upon whom surgeons are dependent, some of
the tools that have made possible modern surgery as we know it. So
when I prescribe a drug-I do not care what it is-I generally will
support that segment of this great industry that continues research,
that continues to seek out other and better ways to solve the problems
that we have not solved.
In my personal experience, it goes beyond just generic or trade
mark drugs. It also goes to support that segment of the industry-
I do not know what percentage it is, but I would guess 10 percent or
less of the total industry-who are doing this great amount of research
which I think is a boon to America and to medicine.
Senator NELSON. I have some more on this, but Senator Dole has a
question.
Senator DOLE. First, I apologize for being late. I have been at an-
other committee hearing.
I am a new member of this committee and I have not had the benefit
of the extended hearings held in the past 2 years. I do not want to
spend a lot of time covering old ground, but I have a question or two.
I am a great believer in drugs. I do not know whether they are
81-280 0-69-pt. 1i-24
PAGENO="0370"
4660 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
generic or brand name. Several years ago I was the recipient of
streptomycin when it was in the guinea-pig stage, as a part of World
War II, and also lived on streptomycin and Dicumarol for quite a
while and became a great believer in drugs and the wonders they
perform.
I had a letter last week asking me whether I was a generic or brand-
name Senator, and I have not decided, yet, which; so I huve not an-
swered the letter. But it poses a problem with us, of course. There is
a feeling, as you know, Dr. Annis, from your present and past ca-
pacity, among some members of the public that there is a sort of con-
spiracy or unholy alliance between the AMA and the pharmaceutical
industry. This is a matter of concern to all of us. I do not know if you
can answer that generally, but I would appreciate your comment. I
know it is ground that has been gone over time and time again, but
not in my presence. So if yoti could just comment on that, then I have
two or three questions I would like to ask.
Dr. ANNIS. I know of no conspiracy. If you will look at the de-
liberations of our council on drugs, and their evaluation of drugs, and
how they have spoken out against drugs that have had bad side ef-
fects, the abuse of drugs, the overuse of dangerous drugs, constantly
reminding physicians, you would see no such conspiracy exists.
I have been raised in the school of therapeutic nihilism. I do not be-
lieve in drugs. The next moment, I say they are tremendous. I lean
on them.
My point ~s that I refuse, and over the years have refused, to let
my patients tell me when they should get a pill or a shot or something
else. All drugs have a potential for harm. All drugs are dangerous.
The medical profession as a whole has spoken out repeatedly on this.
Drugs, whether they are aspirin or any of the other more potent drugs
of today, all have a real potential for harm.
Aspirin has been a great boon. It is a great drug. But it still kills
children every year.
Penicillin has changed the whole complexion of medical practice,
since my early years of practice. Yet penicillin kills people every
year.
There is no such thing as a truly safe drug. They all have potential
danger. I think this is the message that the medical profession has
continued to spread. We have no alliance with the industry.
If you think so, I would welcome you to come to some of the meet-
ings of our house of delegates to hear physicians discuss these con-
tributions to medicine, absolutely milestones in our progress, and yet,
like so many great things, that also carries a.long with it built-in
hazards that are very serious.
Had we such an alliance with the pharmaceutical industry, I am
sure we would not have carried the thousands and thousands of pages
of critical and analytical discussion on drugs that should be elimi-
nated, drugs that are dangerous, drugs with a serious potential, and
we would not have constantly advised physicians to carefully evaluate
the therapeutic use and the necessity for their use before prescribing
any drug.
Senator DoLE. Does a generic prescription automatically assure
thwt the patient is going to save money?
Dr. ANNIS. No; there is no automatic assurance that that is the
case. A generic prescription leaves to the pharmacist the decision as
PAGENO="0371"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4661
to what drug he will prescribe. Assuming it is a neighborhood pharma-
cist with some good generic drugs from a good supplier, as opposed to
a brand name, and he supplies it on a generic basis, knowing of the
background-here, in this instance, a patient could conceivably save
dollars.
If, on the other hand, a physician prescribed a certain drug without
mentioning the name of the supplier, another kind of pharmacist, not
of the neighborly, friendly variety, could supply him with the highest
priced drug from a generic source. So it is not essentially so. It could
be.
Senator Doiai. How much influence, in your opinion, does drug
advertising have on a physician's decision to prescribe any particular
drug? Do you have time to read the Journal of the American Medical
Association-do you have time to read this monthly publication or just
how much does advertising, whether it is written or verbal, influence
your decision?
Dr. ANNIS. The journal I have an opportunity to review every week,
the Archives of Surgery every month, and many other publications.
I have made it a practice for over a year to ask physicians, wherever
I have gone, to what extent does advertising or the detail man deter-
mine their choice of a drug? You know what? I have yet to find one
physician-and I have asked hundreds in medical schools, medical cen-
ters, in small cities and large cities-who makes his judgment on them.
What they do is remind physicians of many drugs in the field.
I run into this frequently, where I will, having read in an ad about
a new drug for a certain condition, or a drug that is supposed to be of
value in, say, the field of orthopedics or medicine or in areas that I do
not know anything about, I will ask doctors, what about this; I read
about it in the last few days. Twice in the last week, I have phoned
medical centers to find out, to be: brought up to date on the medical
use of Dopra, dihydroxyphenyl, something or other. I can't remember
the long term hooked up with it. But it is being used now, experimen-
tally, under limited circumstances in the research of Parkinson's
disease. Now, as a surgeon, I have read about it. I knew that it was
taken off the market for a while :because of its dangerous side effects,
but allowed back in for experimental use because it had been proven
that despite its danger and toxicity, it also has a great potential for
good in conditions where we do not have much in the way of treatment.
Now, what I read in the journals merely reminded me that there are
drugs that are treating this. So when I had a personal request from a
friend of mine because his mother is afflicted with this disease, I got
on the telephone and called four of my good friends in different parts
of the country in the field of neurology and neurosurgery and spoke
to a man in one of our large research centers that is working on it. So
the advertising in the journal often will remind me of advances in
other fields.
But as far as having an ad ever determine for me to initiate and
to use a drug without further checking it with-I often will write to,
as many physicians do, the AMA. Our mail runs at the moment some-
thing like 15,000 or 18,000 letters a day. We get requests for informa-
tion all the time.
I also would check it with medical men in my area who know men
who deal with these things all of the time, as well as the pharmacist
PAGENO="0372"
4662 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
and the pharmacologist. I know of no physicians with clinical experi-
ence and no physicians educated in the Nation's medical schools today
who would prescribe a drug on the basis of what they read in an ad.
Their attention might be called to it so that they look into it. But,
gee whiz, you never think of prescribing it on that basis.
We have a number of copies of the journal if for any reason you
would like to review some of them or some of their various ads.
This is a part of advertising. It is like Coca Cola. We have known
about it for years, yet wherever we go in the world, you see a sign,
Coca Cola. It is a sign that reminds you something is around if you
need the pause that refreshes. Even a 5-year-old will tell you that. It is
the way America has commercialized its products around the world.
But it would be dangerous if we bought drugs like we buy Coca Cola.
They just remind you that they are there.
I do not know of any physician, and I have asked hundreds, who
will prescribe a drug on the basis of what they have seen in ads of any
kind. I have yet to know one.
Mr. GORDON. Dr. Annis, may I interrupt here?
According to the study which was done for the American Medical
Association in the town of Fond du Lac, Wis.-are you acquainted
with that particular study?
Dr. Ai~is. I am acquainted with the city but not with the study.
I went to school with some men from Fond du Lac.
Mr. GORDON. That study showed that around 50 percent~-that may
not be the exact figure, but it is around 50 percent-of the doctors pre-
scribed on the basis of advertising and detail men; as a matter of fact,
it is mostly the detail men. With respect to certain indMdual items,
like Achromycin, a trade name drug, and others, it went as high as 80
percent.
Dr. ANNIS. This is a different matter. Had you asked me to what
extent the detail men or advertising has called my attention to drugs,
that is a different matter. My first years, in my first 8 years in practice
of medicine, I was in general practice in the capital city of Florida,
Tallahassee. Those were days when transportation was not very good.
We didn't have airplanes in and out. I think after a couple of years,
Eastern went once a day north and south and National once a day east
and west. Transportation was not good. We had no television in those
days; radio certainly was not a medium for education. Only the pub-
lications of the American Medical Association, the medical journals,
and the detail men kept me informed.
This was during the time that sulfanilamide, sulfamerazine, sulfa-
suxidine, sulfathiazine, right on down the line of the sulfas, that gave
us control over gonorrhea, a previously uncontrollable disease, were
developed. The sulfas gave us control of pneumonia and kept lives
going. But they had side effects. People would be getting sick. They
would be nauseated. Half of them would go down.
Now, the important point is the detail man or the ad would call my
attention to the fact that he have a new derivative that eliminated the
side effects, the nausea and vomiting. Very often it would be the detail
man who would call it to my attention. You would not start off on a
drug or prescribe on that basis initially. These people, however, kept
us informed-in those days of a different kind of communications than
we have today-as to what is new and reasons to look into these drugs
and what they were doing. So their role was there as an initiator, as
PAGENO="0373"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4663
a stimulus to look, but certainly they were not the deciding factors as
to whether or not we prescribe the drug.1
Senator NELSON. I did not mean to or intend to open up this whole
question at this moment involving the drug chloramphenicol, upon
which I have some questions to ask later. But I might pose this ques-
tion: We have had Dr. Goddard appear before the committee, and to
quote him, he said, "I am at wits end on how to dissuade doctors from
misprescribing chloramphenicol"-in this case, Parke, Davis' chloro-
mycetin. We had Dr. Dameshek, Dr. Best, Dr. Lepper, and two others,
all of these whom you know, estimating that between 90 and 99 per-
cent of the patients receiving this drug were receiving it for nonindi-
cated cases. This was their estimate. It has not been refuted by
anybody. A week or so ago, Dr. Ley appeared before the committee
and estimated that still 90 percent of the cases are receiving it for
nonindicated cases.
The medical journal, the literature have all stated what the indi-
cated cases are. If advertising and detail men are not important in
determining what the doctor prescribes, how do you account for the
fact that contrary to all the expertise and all the literature, including
articles in the AMA, doctors continue to prescribe this drug for hang-
nails, upper respiratory diseases,~ sore throats, infected toes, infected
gums, a whole miscellaneous list of cases for which it is not indicated?
Dr. ANNIS. Senator, I share with the distinguished array of scien-
tists who have been before this committee their concern for the misuse
of any drug. I am concerned about the use of a drug with great poten-
tial for harm when other drugs with less potential are available and
about the use of a dangerous drug for minor conditions, especially
when other drugs are available. We are in accord with this. This is
a long record of the American Medical Association. I am sure that the
Senator is aware that we have agreed and our council on drugs is
happy to serve and work with Dr. Ley, and others to increase our
efforts to further educate more physicians.
What I keep looking for in the records, and what I have yet to find
and am hopeful of finding, i's who is prescribing these drugs, where
do they fall, for example, in age groups-not just age chronologi-
cally-and how long have they been practicing and where are they
practicing?
Many physicians in the earlier days, before we knew the side effects
of this and other drugs, leaned upon it as a drug that was found to be
effiective in many conditions. It has been a number of years since the
AMA testified that our clinicians, as well as our researchers and ad-
vertisers and teachers were finding some of the very serious side effects
from the use of chloramphenicol.
I suspect two things, but I canot prove ether of them. One, if we
could look and see a spectrum of physicians who prescribe the drug,
I think we will find that they fall, I would expect, on the basis of my
experience with the profession, into two areas. One, the physician in
practice a number of years, as I have been, who has gotten into my
habit, I have never been a' great prescriber of new drug's. You learn
six, eight, 10 or 12 well that serve your purposes and that is generally
where you stay. I suspect that some of these, will be found in physi-
1 See app. XII for excerpts of affidavits submitted to FDA by doctors who prescribed
Thaliomide on basis of statements by detail nien, pp. 4857-4862, 1nf~ra.
PAGENO="0374"
4664 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
cians as old as I am, 30 years in practice, who many years ago began to
use this drug and because it did give good results. Even in the records
presented to you, the fatality is one in 20,000, something of this kind.
Too many. One in a hundred thousand is too many unnecessarily.
That is not my point.
My point is a physician could have been using it for 15 or 20 years
and never himself have had a fatality. So they are not persuaded
against it. I would suspect that we find a great number in this category.
I doubt seriously if you will find many of the medical students of
the past 10 years misusing it. I have already talked to my sons and
some of those in school with them. They have all been forewarned.
The second group includes physicians who work in areas far removed
from a medical center, physicians who are often far removed from a
hospital where they could run sensitivity tests, where they do not have
the chemist and the pharmacologist and the pathologist, to assist them,
and where they are dealing with diseases often associated with poverty,
with lack of nutrition and other factors. On high temperature diseases,
sometimes of a gastrointestinal nature, where they are not quite sure
what is the maatter with the youngster or with the patient, and know-
ing its broad spectrum applications and that it is readily absorbed,
and again on the basis of experience, they will often lean on this drug.
Now, again, I am not citing this to justify it, because we share with
your witnesses the very serious concern for the use of a good drug in
too many instances. But I would not be at all surprised if this is where
we are going to find them.
Now, we have to increase our efforts to educate these physicians that
even though they have not gotten in trouble themselves, or they are
not aware of it, the danger is there, the record is there, the potential
is there, and that `the use of this drug, like others of tremendous poten-
tial, should be limited to strict areas where it is the only drug of choice
or where it is preferable because of other conditions of sensitivity or
otherwise on the part of the patient. I have to admit to you frankly,
Senator, I have never prescribed Chloromycetin. One reason, perhaps,
was that Harry Beekman at Marquette, where I went to school, was
one who educated me and my colleagues to be very wary of any kind
of drugs. So I cannot speak from personal experience.
But I have talked to physicians around the country who use the
drug. I talked to them especially this past year or so. In every instance,
the physician who continues to insist on it has not been persuaded.
So I agree with you. This is why the American Medical Association
is anxiously awaiting a meeting that had to be postponed twice in
the last couple of weeks. Dr. Ley was tied up with other problems of
the Food and Drug Administration. We are most anxious to expand
our effort to bring the total message to all of our physicians.
We feel that the drug itself has proven in the minds and in the
experience of every qualified clinician to have a very worthwhile and
a very definite place in the armamentarium of drugs. but it is one that
should be limited in its use to definite indications. We go along with
this completely.
Senator NELSON. The issue that was raised, however, is the extent
to which doctors base their prescribing upon advertising, promotion,
and detail men vis-a-vis the literature-
Dr. ANNIS. I think the success of the advertising was 15 or 20 years
ago, Senator. I do not think it has continued success today.
PAGENO="0375"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4665
Senator NELSON. I do not think that is shown by the record. When
it was taken off the market back in 1952 or 1953 it dropped way down
in its usage. Then-Dr. Hayes can answer more accurately, but I
think this is roughly correct-it was off the market. The indications
for its use were drafted some 15 years ago, very limited for some dis-
ease, for limited use in other cases where no other drug was effective
and where this drug was effective against the particular organism
causing the problem. That has been the indicated use for~ I think,
15 years and it came right back up again and continued to rise.
Now, that was against all the medical literature, against all the
authorities. Yet it continued to rise and be widely misprescribed.
Now, once it dropped, but then people starting using it again-I do
not think you can say that the advertising and promotion is not
effective.
Here you have a case where, since 1954 or 1955, the indicated uses
were very limited, and yet it is being widely misprescribed according
to the testimony we have had. The AMA Journal carries ads. It used
to have lots of reminder ads which simply said, "Chloromycetin,
when it counts." In fact, the JAMA ad carried a picture of a broncho-
scope. Now, the Drug Council and the AMA knew very well that
it is not indicated for bronchial diseases, but the AMA allowed the
ad to be run.
Now, I think the fact of the matter is that just from a commonsense
viewpoint, contrary to all the education, contrary to all the articles
in medical journals, contrary to all the expertise in this country, the
drug company successfully promoted it and continued to get doctors
to use this. I do not know how you explain it.
Dr. ANNI5. Senator, I presented to you two theoreticals from my
own experience and guessing, because I do not use it. However,
Wisconsin is known for its good physicians. I used to do a little
fishing in Michigan, where I was born and reared. And for some
time, your fine lures are off the market and you cannot use them
because they are off the market. But if you hear they are on the
market again, you go back to that fine lure with which you caught
good bass and pike years back.
What I am saying is that the man who built his confidence earlier
for whatever reason may be the area where we are going to have to
concentrate our education. I do nbt believe it is being prescribed in
these ways to which you referred. I doubt if this is prescribed by
today's young generation of educated physicians.
I doubt if the advertising is educating new physicians to its use.
I would have to give a point and indicate and admit to you that if I
were a doctor who was persuaded some years ago that it was a good
drug, and then it was taken away by what I might call an arbitrary
decision of somebody and it : upset me, the advertising might remind
me that it is back again.
The advertising accepted by the AMA-and I have to absolve the
Council of the bronchoscopic ad because the Council itself would
not have seen this ad prior; to its being published-I think it was a
reflection back to the older days when it was used on children. I have
heard pediatricians who used it extensively-
Senator NELSON. I do not think it was ever indicated for any
bronchial infection.
PAGENO="0376"
4666 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Dr. ANNIS. One of the cases has been hemophilus influenza and
there are still physicians today who still feel it is the drug of
choice in hemophilus influenza or pneumonia.
Senator NELSON. That is contrary to the National Academy of
Sciences-National Research Council, who said it is no longer "the"
drug of choice for any reason.
Dr. }ik~rEs. As far as respiratory infections are concerned, there
are some who believe that treatment in specific instances of cystic
fibrosis, involving the lungs, that chloramphenicol is effective in reduc-
ing the possibility or potentiality for serious respiratory infection. I
certainly would agree that in a.ny pneumonitis bacterially caused,
there may well be other as effective antibacterial agents as chlorain-
phenicol. It would be unlikely that you would prescribe chlorampheni-
col unless it became a life-threatening situation and for one reason or
another other antibacterial agents could not be used, such as
sensitivity of the bacteria, itself or possibly in the matter of some
reaction of the patient to other drugs that might be used. It would be
a rare instance where it might be used.
Senator NELSON. Has it ever been indicated in general for upper
respiratory diseases, bronchitis, or any other thing like that?
Dr. HAYES. Not that I know of as a general indication. However, you
must take into account that irrespective of the hazards of chlora.m-
phenicol, and they are very real and I think that every physician
is aware of them-I do not condone the misuse of the drug in the face
of these hazards at all-it is a very effective broad spectrum anti-
biotic. In fact, at the institution where I do some volunteer teaching,
they `occasionally post a summary of the sensitivities as determined by
their routine testing of `bacterial sensitivities to a number of orga-
nisms. It is surprising that chloramphenicol in the vast majority of
the organisms that they encounter will turn out to be most effective
antibacterial agents in and under those tests. I do not say on the basis of
those that you would use the drug, but I merely say that to emphasize
that it is an effective antibacterial agent and in the face of a life-
threatening situation, a physician might elect to use chloramphenicol
if he was not certain of the offending organism or organisms. And
that is the situation that he might encounter if he is remote from a
medical center where all of the sophisticated facilities might be avail-
able to him.
Again, I would not condone the use of chioramphenicol or possibly
any other antibacterial agent for a `hangnail or some incidental infec-
t~on.
Senator NELSON. I am sure you know better than I do that the indi-
cations have been stated as very, very, very limited. As I stated before,
according to the National Academy of Sciences, it is not the drug
choice for any disease.
Dr. ANNIS. I understand that has `been very recent. I do not know
how recent, `but I heard it the first time 2 or 3 days ago.
Senator NELSON. It was last October. But for 15 years, correct me
if I am wrong, it was indicated for ricketsia.l diseases, it was indicated
when the disease was serious-it always had to be serious-when no
other drug `was effective against the organism and when c.hloramphen-
icol was effective `against it.
PAGENO="0377"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4667
So now on the question of advertising and promotion, if I under-
stand the experts correctly here, it has never been generally usu'able as
a broad-spectrum antibiotic, at least since the first side effects were
found in 1952 or 1953. it is not indicated for general upper respiratory
diseases, as I understand it.
On the question of which is the most effective, the articles of the
journals as to its indicated use or drug advertising promotion and
detail men, it seems to me that the ad in the AMA Journal with the
bronchoscope picture is not saying: "We are ruiming this broncho-
scope to indicate that you might use Chioromycetin if there is cystic
fibrosis." What they are doing with the bronchoscope is saying, gentle-
men, if there is `anyhing in that area, use Chioromycetin when it counts.
So obviously, that is an improper ad, making a claim on its face that
I do not think any scientist who has testified here would defend.
It obviously must have had effect, because it is vastly and widely
prescribed for upper respiratory problems. We have had letters of
deaths in the files that it was used for that purpose.
So on the question of which is effective, just again using horse sense,
I would say vis-a-vis the articles by Dr. Dameshek and others in the
journal cautioning against it and vis-a-vis the effectiveness of the ad,
I think the ad and the detail man run away with the case.
So I raise the question, one, I think it is effective, and, two, why
would the AMA run an ad with a bronchoscope in it when they know
very well it is not indicated for that use?
Dr. ANNI5. Mr. Chairman, I would not plead that we do not have
human error in judgment. I suspect that in this particular instance, the
evaluation of the bronchoscope and the rest, from the standpoint of its
implied suggestion that it would alleviate the need for bronchoscopics
and conditions of that kind, this undoubtedly was inappropriate. I
would think so as I review the record and what is there.
But I still would like one of these days to have someone, if we can
find out from the records, find out the age of the doctors prescribing it.
Are we, in effect, getting new prescribers in the last 5 or 6 years, or, in
essence, are we still getting prescriptions coming primarily from the
same sources?
Or as indicated by Dr. Hayes, from those in medical centers where,
on sensitivity tests, it is indicated?
These are some of the other perplexing areas that are involved in
this drug `and its advertising and we are seriously concerned `about the
effects of this or any other drugs that have `similarly serious effects.
This is why I reiterate the welcome participation that we will ~-
ceive from Dr. Ley in an effort to expand our efforts to inform those
segments `of the profession that still use this very dangerous drug that
its limitations are even greater than they used to be `by virtue of newer
and more effective drugs to take care of conditions that in the past were
treated by chioramphenicol.
Senator NELSON. But it seems to me the facts in the case scream
rather loudly. They use the advertising device very widely. They `have
sophisticated advertising, a powerful group of creative minds
involved.
Dr. ANNIS. It was cleverly done; no question about it.
Senator NELSON. And they have been able to get doctors to pre-
scribe it. If I can use the expert testimony, they misprescribe it 90 to
PAGENO="0378"
4668 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
95 percent of the time. Now, the best estimates are that this involves 4
million people who were receiving tha.t drug in 1967, but anywhere
from 90 to 95 percent were for nonindicated cases. Does it not indicate
obviously that the precautions of the profession itself and all the ex-
perts have just not prevailed, and is that not an indictment on three
counts-the doctors who are prescribing it, continuing to prescribe it,
and the company who will continue to promote it, and the journals
that accept the ads despite the fact that they know it is being widely
misprescribed.
Dr. ANNIS. May I remind the Senator that today, under the rule of
the law, the content of the ads has to meet the many and rather strin-
gent requirements of the Food and Drug Administration. But here is a
drug, as you indicated, that was taken off the market and a. drug re-
turned to the market. The content of what they say in their ads is re-
latively controlled by the Food and Drug Ad.ministration. So what
you are suggesting is that we had better take a look at some of the
regulations and controls there.
But again, I see no evidence-4 will not argue, I can't, one way or
the other-that the ads in today's journal are increasing the numbers
of new prescri'bers of this drug.
Now, we do not take ads, for example, of the most dangerous drug
in the United States, the drug that contributes toward more deaths
than chioramphenicol and all the rest of them put together. And I
cite alcohol.
Now, here again, we educate all of our public a.gainst the dangers
of alcoholism and driving while under the influence. Yet the records
of the National Safety Council indicates that it is involved in 50 or
60 percent or more of the accidents: 52,000 Americans last year were
killed in automobile accidents. A million nine hundred thousand were
injured sufficiently to require doctors.
Now, a drug was involved, the most dangerous drug we have. Edu-
cation of the masses of the people has `been inadequate and we have to
step up our efforts.
Senator NELSON. It is not a prescription drug.
Dr. ANNIS. In the field of medicine, we have another drug, ex-
tremely dangerous, nowhere near as dangerous in its effect on the
numbers of people, nor even in its lethal effect, `but one, nevetheless,
that poses a very serious and continuing problem. I would again re-
assure you of our desire to use every reasonable means to get the
message to more physicians. Admittedly, this is an area where the
message has not gotten through to everybody. What I question is an
indictment on the basis of an ad or a particular drug company's ad
about a certain drug when the content basically is controlled by the
Food and Drug Administration. What I question is the effectiveness
of this or any other ad to `be the prime reason for a physician practic-
ing medicine. This is what's not in accord. They have never persuaded
me to prescribe it. But perhaps I have not had the indications of
others.
My only point is that an ad alone is inadequate. I would like to
know if the physicians who are prescribing it today are the same ones
who were prescribing it 10 or 15 years ago, or with the rare exceptions
Dr. Hayes has indicated by virtue of sensitivity tests. This is merely
raising a question, Senator.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4669
Senator NELSON. Well, I have no doubt about that, but the facts
are there that the medical profession-the AMA is the leadmg
organization-
Dr. ANNIS. What would you suggest that we do, Senator?
Senator NELSON. Well, I `would not run an ad, if I were in control,
with a bronchoscope in it. I think it was an outright fraud. I think
it was intended to be a fraud; it was intended to mislead. We received
letters about people who died from it. Therefore, why should the
AMA Journal be a part-
Dr. ANNIS. I have indicated that human fallibility is a part of our
structure, too. We `build in as many filters as we possibly can. In th1s
particular ad, I would agree with you. This was a good Madison Ave-
nue effort that slipped through the screen.
Senator NELSON. It has been slipping through for 15 years.
Dr. ANNIS. Oh, no. I do not think this ad has been slipping through.
Senator NELSON. I think so. As a matter of fact, if we go back--
Mr. HARRISON. Senator, perhaps I can add just a little bit to place
this in somewhat its proper perspective.
Senator NELSON. I thought I had.
Mr. HARRISON. I just want to add something that I think will be of
interest to the committee.
Looking through our records, I find that in the past 5 years, AMA
journals have carried a total of about 84 pages of chloramphenicol
ads. Since we publish 52 issues a year, or a total of 260 issues in 5 years,
we have had a total of about 65,000 pages of paper. I would say tha.t
the total advertising with respect to this drug is something like less
than three-tenths of 1 percent. At least here, it is indicated that we are
not speaking of an advertising campaign. We have only some 85 pages
over a total of 5 years, out of a total of 260 issues, and perhaps some-
where in the neighborhood of 65,000 pages.
Senator NELSON. I do not really think that answers much. If it
is 85 pages in 5 years, you are talking about what, 18 pages of adver-
tising a year-19?
Mr. HARRISON. This publication, you know, is weekly. That is 52
issues per year, with approximately 250 pages in each issue. So it is
a relatively small number and I have computed it to be about 0.3
percent.
Senator NELSON. But do you think the percentage is relevant? It
is 19 times a year that the ad for Chloromycetin has been in the maga-
zine during the whole period. Experts all over this country have
been tearing their hair out about the misuse of this drug and the pro-
motion, the company has won the battle against the AMA and the
medical profession consistently and continuously until they were
prescribing 42 or 43 million grams in 1967. It took these hearings
and wide exposure to drop that in 1968 down to I think 18 million
grams. As I said before, this committee is not the expert on it. Where
was the medical profession? The public is entitled to say, my heavens,
the AMA carried ads and promotion of it but very, very little about
how bad it was.
We cannot. find very much in the last 2 or 3 years. There was
very little material on our hearings. We found two or three little
notes, but it would seem to me it would call for a front-page editorial,
just saying, Doctors, are you off your rocker? It seems to me it would
PAGENO="0380"
4670 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
call for the AMA to say to all its people, call meetings in your State,
right now, people are dying from this, have a public meeting, get
to the doctors, get it on the front page, tell them they are mispre-
scribing these drugs, and that the AMA would do the same. The great.,
responsible medical profession, did not. And it took these hearings
to expose it.
Mr. HARRISON. We take strong objection to the statement on wheth~
er or not the AMA has been doing something in this regard. I think
Dr. Hayes can respond with respect to what the Council on Drugs
is doing. I have here some adverse drug comments taken from the
Journal of AMA, very consistent and in great detail. The AMA News
which is distributed free of charge to all physicians, members or not,
just over a period of recent weeks, and even more so in prior months,
has consistently included comments with respect to the discovery
of adverse reaction on chloramphenicol, and the statements made by
this committee or by others with respect to the dangers involved. The
Association is very much concerned and very much aware.
Now, we have also accepted advertisements with respect to the
drug-that is correct-recognizing that the Food and Drug Admin-
istration has not seen fit to take the drug off the market. The AMA
has scrutinized these ads and, as Dr. Annis has suggested, it is pos-
sible that this one particular ad did carry some background of a pic-
ture which slipped by and, perhaps on reflection, should not have
been included. But in the overall picture, Senator, I think it can be
seen that the Association has been very much concerned, and I would
ask Dr. Hayes, if he would, to add to this comment with respect to
the activities of the Council on Drugs.
Senator NELSON. May I respond just a moment on that? We had
the Library of Congress check every single edition of JAMA and of
the AMA News since this issue was raised by the committee. As I
look through the material, and we have photostats here, I consider
it a pitiful effort in terms of notifying the profession about what was
wrong. I raise this point again: the medical profession, the AMA has
the health of America in its hands. We want to have confidence in it.
One can examine these and see how pitifully small these articles are.
Dr. ANNIS. Senator, this is just one publication. We have county
and State medical societies across the country. We have medical meet-
ings where this is presented to physicians. I outlined to you we have
100 pages of medical programs to physicians where there is repeated
by physician teachers. This is consistent with the medical profession.
You have a drug which our own Food and Drug Administration
of this country took off the market and they put it back on the market
and allowed it again to be sold. If this is the case-
Senator NELSON. For limited application.
Dr. ANNIS. If this is the case, they have given tacit approval to the
drug. We have always, in accepting advertising, repeatedly told the
profession, this is a drug with ever-increasing evidence of its danger-
ous side effects and that it. should be used on a limited scale. If further
information is demanded by virtue of the facts, these then should
come from the Food and Drug Administration.
Senator NELSON. Of course, it is interesting to note that the FDA
is attacked time after time by various members of the medical
profession-
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4671
Dr. ANNIS. Everybody is attacked. We are attacked, too, Senator,
Senator NELSON (continuing). For regulating too much. But 1
think, Doctor, in all fairness-we will look through these ads-the
fact is that whatever the AMA did, it did not work. That is a fact.
Now, what this committee did-
Dr. ANNIS. The facts are, Senator, that Moses brought 10 little
messages down from Mount Sinai and that message has not gotten
through yet. The fact that the message gets out does not mean that it
is received on the other end. It takes two people to absorb a message,
those that send it out-and we have put effort after effort to get it.
out-and those who are to receive it. I have admitted to you that.
there is a segment of the profession that has not gotten the message
and does not understand it. This does not mean that we have failed
to send it out. It has failed to fall on receptive ears. We are willing
to meet with you, or with the Food and Drug Administrator, or
anybody else in an effort to increase the recep:tivity of these ears that
it has not fallen upon.
But do not accuse us of not. trying. You can say what we have done
has not been enough. We will do more. But this is in keeping with
what we have been doing.
Senator NELSON. I look at the ads and we can examine them later.
There is not much in them.
Dr. ANNI5. May we have Dr. Hayes give you at least a summary
of what we know we have done?
Senator NELSON. Of course. The point I want to make is whatever
you have done it is not effective, and then I suppose if you have done
all that you think it is feasible to do, you ought to concede that a con-
gressional subcommittee, with no experts on it, has been 100 times
more effective in telling the doctOrs the story than the AMA, because
we got it reduced in 1 year from 43 million grams to 18 million.
Dr. ANNIS. This is great. We: are happy about it. But may I give
you an example of what was even more effective than your drug hear-
ings? That is the conquest of polio. But why? Here is an area of a
serious disease.
Senator NELSON. What's the analogy?
Dr. ANNIS. The analogy is the mechanisms, the communications
media, the overwhelming use of press, radio, television, civic
clubs, everyone, to tell the story. We had everyone telling the story
on this. And it. was tremendous what we were able to do, not just
because we had a drug that could solve the problem, but that the great
pharmaceutical industry could manufacture it by the millions of
doses. Then the story was told to everybody, come, not just with your
doctor and your nurse, but with grandma, grandpa, mother and dad
and everybody. Here is an example of an overwhelming approach with
every communications media available. And it got to the American
people.
In some instances where the education was poor, buses were sent out
into the areas and the kids were given lollypops and balloons and
physicians joined with vohinteers all over the country in a massive
effort to tell the story.
Now, these are the two extremes, one that is undoubtedly tremen-
dously effective, and it. was quickly so, and an effort through us to use
every kind of medical communication, from publications, meetings at
hospitals, medical centers, county and State societies. And we still
PAGENO="0382"
4672 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
have not gotten the message through to some members of the profes-
sion. I still do not know whether it is the same ones that were using it
because they were happy with it 10 or 15 years ago.
My point is we have to step up the means of communication. My
analogy with the polio effort is merely what can happen when every
medium of communication is concentrated and where what they are
selling has merit, where the problem we are facing is a serious one,
and where those who are the potential victims a*s well as those who
are their protectors share a common interest.
And this, I am satisfied, is what you are seeking. TI1at is better medi-
cal care, better drugs, safer drugs. And in the instance of a drug that
may have to be kept available for its very limited use, what you want
to do is to see to it that all physicians get this message, that they are
motivated by it, having received it, and that in the future, they pre-
scribe this drug only when it is needed. We are in total accord.
Now, the question is what's the best way to do it? But do not say
what we have done wrong 5, 10, 15 years ago. Many of the drugs that
are in here were not available 5, 10, 15 years ago. We are not carrying
an ad today that has not carried the tacit approval of the Food and
Senator NELSON. I might say that in the past 2 years, you have
carried 10 for which a remedial "Dear Doctor" letter was written.
We will look at those later-the FDA forced the company which
misrepresented the drug in your publication, as well as in others, to
write a letter to every doctor in the country.
Dr. ANNIS. But you just admitted, Senator, that there is a contract
by regulation between the FDA and the company. You admitted,
to, that the ad that was carried was a violation of that contract on
the part of the company. And if we carried it, and I willingly admitted
that we have human error occasionally on matters of this kind, too,
where things get through occasionally that we would not want to
have gotten through had we had all of the facts-but I think you will
have to admit that if there is an understanding between the Food and
Drug Administration and any producer, this, in effect, esta;blishes
through that company and their advertising agency the basic princi-
ples that they should not violate.
Senator Nr~soN. The question was raised, and as you will recall,
it was raised around the question of whether advertising or promotion
is effective. Something is effective.
Dr. ANNIS. I do not think anybody in America can deny the im-
portant role of advertising in any area.
Senator NEr~soN. My committee counsel advises me-this does not
have a date on it; we will recheck it to see if it is correct-but this is
a 1968 ad.
Dr. ANNI5. I would not be surprised, and I have already
indicated-
Senator NELSON. This was carried in 1968.
My point again is what you said in your articles did not work. It
seemed to me that there should have been a meeting, a public meeting
in every State in the Union saying that this company's drug is being
misused.
Dr. ANNIS. Senator, I just asked Dr. Hayes how long we have car-
ried the contraindications on chloramphenicol, and he said since 1952.
What you and I agree on is that some doctors either do not read it
or having read it, they do not comprehend it, or having comprehended
PAGENO="0383"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4673
it, they do not believe it and do not accept i~. But this is not the fault
of a failure on the part of the AMA to attempt `to properly inform its
members.
Senator NELSON. Well, `I think, DOctor, arid I think you will agree
with this, that the medical profession, the AMA, has a peculiar
responsibility.
Dr. ANNI5. I would agree.
Senator NELSON. It is not like all ad for a piece of machinery or
something else which may be deceptive. It may fall apart and it may
do all kinds of things. The AMA is highly regarded by the medical
profession and by the public. it seems to me they have to do much
more in terms of their responsibility than just saying-
Dr. ANNI5. And we do-
Senator NELSON (continuing). Than just saying FDA approves.
Dr. ANNIS. I agree with you, and we do.
Senator NELSON. Let me ask you a question: The AMA Journal is
still running the ad: "W]ien it counts, Chloromycetin."?
Dr. ANNIS. That is still true. When it counts, it is the drug. When
it is indicated, it is the `drug.
Senator NELSON. But you and I know what they mean by that.
Dr. ANNIS. What do they mean, Senator? You read into it some-
thing that some of our doctors `obviously do not. I agree with you,
let's get the `message to those who do not..
Senator NELSON. Let me ask you a question: The medical profes-
sion does have a peculiar, very important responsibility to the public.
Why should they not insist that in big print, right here, it says "The
National Academy of Sciences says this drug is not `the' drug of
choice for any disease"?
You might say, well, this drug passes the FDA. I do not think you
can shift your responsibility to the FDA. If you are willing, I have
some laws I would like to pass and have your support on. But it is
serious enough and they are not reading fine print any more. If it
is correct, as you say-and I have no information one way or another,
hut I doubt it-I think there are plenty of young doctors prescribing
this.
Dr. ANNIS. I do not say there are not. I am asking you. I would
love to know, too. I do not know any young ones that are.
Senator NELSON. I do not know, either. But if it is true that lots of
of them, and I think that is correct, that lots of them are people who
have been prescribing it for many, many years, therefore, they do not
read the new contraindications-
Dr. ANNIS. It could be.
Senator NELSON. They see the reminder. That helps remind them.
They have been using it. It is being widely misused, `and because of the
AMA's, the medical profession's peculiar responsibility, why do they
not say, this just is not working and it is being overused and if you are
going to run this ad in our~ Journal, I want to be sure that the doctor
who reads it sees in big print, "Not indicated as the drug of choice
for anything" and some other precautions, plus the editorials that are
big and displayed prominently in the Journal.
Dr. ANNIS. The editorials and all these approaches `there, our coun-
cii on drugs and the ranking members of the elected representatives of
the association share your concern. I have repeated this over and
PAGENO="0384"
4674 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
over again. This is an area of real concern to us. When it comes to
advertising, I have specifically raised this question with some of our
people. We also have fair trade problems involved in discriminating
against one company as opposed to another. If we are talking about
broad spectrum antibiotics and we except three or four companies,
when they comply to certain other requirements, then we are in this
position, too. I do not attempt. to know whether or not this applies in
this instance by virtue of the other side effects of chloromycetin,
chloramphenicol, its generic name. However, this is an area where
we admit there is a real problem. It is one we have tried to solve. And
again, I would like to ask Dr. Hayes if he can give a summary at
least of what we have done in this area. -
Senator NELSON. Of course.
Dr. HA~i~s. Well, the first statement on chioramphenicol that the
council on drugs published was in 1951. That original statement in-
dicates the peculiar and dangerous hazard of chloramphenicol. Since
that time, in all of the statements of the council and its publications,
the message has been very clear and consistent that there is a peculiar,
dangerous hazard to the use of chloramphenicol as regards bone
marrow depression, and that as time has gone on and other effective
antibacterial agents have appeared for use by physicians, the indica-
tions for chloramphenicol have become fewer. Those statements have
clearly indicated that.
In addition to those statements in the formal publications, the coun-
cil has periodically published in JAMA statements firmly enunciating
the proper perspective of chloramphenicol as regards its uses and its
hazards.
Now, I might just say in addition that in JAMA itself over the past
20 years that chloramphenicol has been available, the Journal itself has
published some 285 articles on chioramphenicol, of w-hich,. as I recall,
55 were directly related to its toxicity. In the specialty journals, there
were some 30 articles published-that is, the 10 specialty journals-
of which 20 or more related to its toxicity.
But most important, in 1953, recognizing the seriousness of the
hazards of chloramphenicol as a cause of aplastic anemia, the council
established a Committee on Blood Dyscrasia to look into the matter.
They established a registry of blood dyscrasia which collected case
reports on all drugs causing blood dyscrasia, but it was generated by
the problem involving chloramphenicol.
In 1963, the council expanded that r~gistry on blood dyscrasia to
include the reporting of adverse reactions of all types on all drugs.
And that activity continues to this day.
We recognize that in spite of this consistent effort which, when
added up, is quite considerable, in my opinion, we need to get our
message across in a more effective way.
In 1963, we approached the Joint Commission on Hospital Accredi-
tation and asked the commission to include in their standards the
reporting of adverse reactions to drugs. The commission at that time
was not amenable to do that.. They did agree to publish in their bulletin
statements encouraging hospitals, through their hospital and pharmacy
therapeutics committees if they did exist, to report. adverse reactions.
We have continued those conversations, and I am happy to say that
it looks as though we are making a little bit of progress. The joint
PAGENO="0385"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4675
commission is rewriting some of their standards and we are hopeful
that they will actually get into it, into the standards, the need for
drug usage surveillance programs.
Now, we recognize that there is a great limitation to the effectiveness
of a registry which involves voluntary reporting of adverse reaction
to drugs by physicians. A physician for some reason or another, and
I am not prepared nor at `any time would I be prepared to say why,
is reluctant to report, but the sad fact is that they do not report read-
ily. So now, `and for the past year and a half, what we have been doing
is developing a plan to establish dru:g usage surveillance programs
in hospitals, so that those programs would develop the data, the firm
data, reliable data, so we would have some indication of the overall
usage of chloramphenicol and `all other drugs used in a hospital and
be able to get firm d'ata on their `adverse actions. We would know who
is prescribing them-~that is, the local hospital would know who is
prescribing them, for what conditions and what the effects were. Out
of that, we would have, instead of estimates, we would have firm
reliable data.
At the same time, the governing body of the hospital, in situations
where there was evidence of misuse or overusage of a drug, would be
able to take some remedial action against those who'might be misusing
or overusing drugs.
So we recognize our deficiencies. We are trying to do something
about it. I think that over the course of years, the posture of council
has been one of progressive deliberation. We are not sticking our
heads in the sand; we are trying to `do something about it. I think that
we enjoy a considerable amount of success.
Senator NELSON. I have some more questions on this, but it is 12:30.
Let me ask you, Doctor, I have not covered but a fraction of the ques-
tions and areas I want to cover. How much time will you have this
afternoon?
Dr. ANNIS. I made the whole day available to you, Senator, because
I am just as anxious as you are tO present our position and our will-
ingness to cooperate toward the end of better drugs and better therapy.
Senator NELSON. If it is not possible to finish, can we set another
date in the future to finish?
Dr. ANNI5. Yes, we could in the future. It would not be in the im-
mediate future, but I imagine your schedule is just `as tight as mine.
Senator NELSON. Yes. I ask you that because I do not think we can
get to all the material today.
Dr. ANNIS. I would be very happy to come back.
Senator NELSON. Thank you. Why not come back at quarter to 2?
That will be 1 hour. Is that all right?
Dr. ANNIS. Very good.
(Whereupon, at 12:35 p.m., the committee recessed, to reconvene
at 1 :45 p.m., this same day.)
AP1~RNOON SESSION
Senator NELSON. I had not intended this morning, or at that mo-
ment, to get off on the chloramphenicol thing, but since we did it, I
did have `a couple of questions to ask just to finish what we had before
we left. `
81-280-69--pt. 11-25
PAGENO="0386"
4676 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
On the continuing dialogue we had on the defectiveness of advertis-
ing, did JAMA or the AMA News carry the story, and to what extent,
on the National Research Council of the National Academy of Sci-
ences' recommending filing with the Federal Register that chioram-
phenicol was not the drug of choice for any disease?
STATEMENT OP DR. EDWARD R. ANEiS ET AL-Resumed
Dr. ANNIs. Do you know, Tom, whether they did or not?
Dr. HA~s. No, I do not know whether they did or not.
Dr. ANNIS. Was it given general currency?
Senator NELSON. On October 19, 1968, the FDA published in the
Federal Register the results of the National Academy of Sciences'
study on chloramphenicol. Copies of the reports-
Dr. ANNIS. I must admit, I did not see it in the medical or the lay
press. That is the reason I did not know about it until just recently.
Senator NELSON. Well, the drug coimcil of the AMA is advised
forthwith of whatever goes in on drugs, is it not?
Dr. HA~s. No, we ordinarily do not receive any special notification
from the Food and Drug Administration of its publication. We do,
of course, review its pronouncements as published in the Federal
Register.
Senator NELSON. I assume you review them on a regular basis, do
you not?
Dr. II~ri~s. Not entirely. It depends on the substance of the an-
nouncement; also, in relation to what is our immediate concern a.t the
time. We have taken this into account, that we are reviewing the
background information on chloramphenicol for this book that was
mentioned, and we are aware of the announcement and are awaiting
further developments on it.
Senator NELSON. Here is a drug which has been receiving lots of
publicity for better than a year, and the National Research Council
of the National Academy of Sciences states its indicated use which is
filed in the Federal Register, and the AMA knows the publicity all this
has had and all this took place 5 months ago.
Dr. ANNIS. This might be a good example, of better publicity from
some of these ftndings, Senator. I understood this morning, you said
December.
Senator NELSON. October 19, 1968.
Dr. ANNIS. When was it published, do you know?
Senator NELSON. It was published in the Federal Register on Octo-
ber 19, 1968, according to the information I have.
Dr. ANNIS. My only point is, this is another good example that we
had better step up lines of communication, especially on matters that
are vital. I was not aware of it.
Senator NELSON. I would assume that any filing with the Federal
Register by the FDA on a drug would be of great interest to the AMA.
Mr. HARRISON. May we see the notice?
Mr. GORDON. We do not have the notice here.
Senator NELSON. We just have the date on which it was filed.
Is there any question about that?
Mr. GORDON. No, no question about that.
Mr. HARRISON. I thought if we had a copy of the notice, we could
see the purpose of the notice itself. As you know, some are just pub-
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4677
lished as official notice to the manufacturer so they can submit com-
ments with respect to the action that is proposed to be taken, or what-
ever would be involved. That is official: notice.
I thought if we had a copy of it, we could look to see what is involved
in this particular instance.
Dr. ANNIS. Merely as a citizen, I am a little surprised, Senator, that
after all the publicity that has redounded from your investigation on
this drug, a finding of this kind, if it were a final decision, would not
have gained more currency if it were: really put into the distribution
channels.
In other words, here is an essential finding that is very important
to the Food and Drug AdministratiOn. We find when they begin to
investigate mixed drugs like Panaiba, and Mysteclin and others-this
we found in the medical press as well~ as other press, so someone made
it immediately available.
I must admit I may be derelict, but I read a great deal and it has
only come to my attention in the last few days.
Senator NELSON. I think it was in the public press.
What I am curious about is when the National Academy of Sciences
issues an evaluation of the drugs in some detail, and the FDA an-
nounces it in the Federal Register, does not the American Medical
Association get these fflings and look at them?
Dr. ANNIS. In this particular instance, without seeing it, I would
not know.
Mr. hARRISON. If you are asking,,, Senator, whether we review the
Federal Register as to items that are and should be of interest to medi-
cine, the answer is "Yes," we review the Federal Register on a regular
basis. I `am inclined to `believe that the notice you are speaking of,
and I do not recall it, may have been notice to the manufacturer with
respect to some finding and an opportunity for the manufacturer to
provide some additional information. I do not know.
Senator NELSON. No, this wss an evaluation, a new evaluation of
the drug by `the National Academy of Sciences, the National Research
Council, Division of Medical Studies. It is a drug efficacy study. It
was a formal study done on it. They: reached their conclusion and this
is an 11-a lOi/2-'page evaluation of' the drug. It is then made public
by a filing in the Federal Register.
Mr. HARRIsON. This is with respect to the changes agreement that
may be required in labeling?
Mr. GORDON. Yes.
Senator NELSON. That would be part of it.
Mr. hARRISON. Most likely it was intended to provide notice to the
manufacturer for the purpose of, giving him an opportunity to
comment.
Senator NELSON. But it evaluates' the drug for all purposes. Staphy-
lococcal infections-it makes a statement about that, evaluates it "p05-
sibly effective." It gives documentation; ricketsial diseases, and the
evaluation is "effective, but * * ~ Evaluation of typhoid fever, "ef-
fective, but * * ~" and so on.
The NAS-NRC review of cliloramphenicol is filed in the public rec-
ord. AMA reviews it, you tell me. I would assume you would. The
Federal Register is a public record, Of public notice.
PAGENO="0388"
4678 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Mr. HARRISON. Yes, we review the Federal Register, no question
about it.
Senator NELSON. Then my question is, since this has been an item
of such importance and with so much discussion in the past year, and
there is such a failure on the part of somebody to convince the doctors
not to overprescribe, why did not the AMA Journal, which carries all
the ads, give prominent play to the fact that the National Academy of
Sciences says it is not the drug of choice for any disease?
Mr. HARRISON. I would have to review exactly what is stated there-
what is stated in the Register. You do not happen to have a copy of
the Register at the moment?
I would only say to you, Senator, that we would need to look again
at the Register and see what action was taken by the AMA pursuant
to it. It would be through the mill to effect the implementation.
I cannot respond at the moment, first, because I do not recall the
specific situation, except to say as to what it likely must have been,
and second, because we do not have a copy of the Federal Register on
hand. If you would like further information on that, we shall be glad
to supply it to you.
Senator NELSON. I would, but do you not agree that this raises a
question. Here is a very important document on a very important is-
sue, the leading medical organization of America is directly involved
in this. It carries ads in the area, carries articles about the drug, is
concerned about the misprescribing of the drug, and apparently, no
prominent story is run-we could not find any.
Dr. ANNI5. Senator, could you get somebody to get a copy of the
Register so that we could have some people review it. It might be a
good idea for us to know what we are talking about.
Senator NELSON. We will see if we can get it upstairs. But I would
have thought it was just routine for everybody-
Mr. HARRISON. Routine would not be sufficient, Senator. If it is of
that importance, it should not be handled in a routine manner. We
receive the Federal Register on a regular basis. We also receive copies
of the Congressional Record on a regular basis and your daily calen-
dar on a regular basis. There are a thousand bills of health interest that
are introduced in every Congress we review on a regular basis.
I think in the last Congress there were 1,500 health bills. There are
many things important to medicine, and the health of the Nation, that
the AMA is interested in. On a routine basis, we take these matters
and process them through the various councils and committees of the
AMA directly concerned with these subjects, and again on a routine
basis, give them an opportunity to comment and provide their expert
opinion.
This may have been in the nature of a routine matter. If so, a copy
of that article or a copy of that notice would have been sent to the
Council on Drugs to be considered in its usual course of business-when
they next meet again. If it was more than routine, perhaps other action
would have been taken. At this moment, it appears that this was a
notice to manufacturers with respect to changes in labeling. Until
some further comment is made and the picture develops, we would be
unable to provide further information.
Senator NELSON. Well, I did not mean that it is routine in the
sense that it was unimportant. I meant that I would assume that it
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4679
would be routine to the American Medical Association in a matter as
important as this, that it would be automatically acted upon.
Dr. ANNIS. It would have been, Senator, if it had come to attention
of the right people. But we are talking about something that we do
not even know what was printed in the Register.
Senator NELSON. I understood the witness to say that they did regu-
larly review the Register.
Dr. ANNIS. They do.
Mr. HARRiSON. Yes. I do not know the particular item at the
moment. I do not know what it was about in the Register.
Senator NELSON. I beg your pardon?
Mr. HARRISON. I am saying that,: as a routine matter, we do go
through the Federal Register and `a number of other publications that
come from Washington and the Federal Government. I would assume
then that as a routine matter, we would have seen this particular item.
I am not familiar with the contents of the item at this moment.
Senator NELSON. I would be concerned about two things: one, if the
drug evaluation efficacy study, and there is a big one going on as, of
course, you are well aware in the medical profession
Dr. ANNI5. Many of them all over the country. We are very proud
of it.
Senator NELSON. Yes, and it is being reported to the Food and Drug
Administration. One, is the communication so bad between the
National Academy of Sciences, the FDA, and the distinguished medi-
cal societies that 5 months would go by on an important issue like this
without the societies knowing it? That would be the first question.
The second question is, if that is not the case, if attention were
called-I mean, if the AMA reviews the Register, why was not the
publicity given by AMA? That would be the second question.
Dr. ANNIS. I would be able to answer that question when we know
what we are talking about.
Mr. GORDON. There is an official from the Food and Drug Adminis-
tion present. I just asked him what was in the Federal Register.
Mr. Schneider would you step forward for just a moment, please?
What was in the labeling?
Mr. Scimeider is with the Food and Drug Administration.
Senator NELSON. Would you, identify yourself, please, and give
your agency and title?
STATEMENT' OF MORTON M. SCHNEIDER, CHIEF, CONGRESSIONAL
SERVICES, FOOD AND' DRUG ADMINISTRATION
Mr. SCHNEIDER. My name is Morton M. Schneider; I am Chief of
Congressibnal Services for the ,Food and Drug Administration.
Mr. GoI~oN. What was in the Federal Register?
Mr. SCHNEIDER. The Federal Register announcement contained a
statement to the effect that, based upon the NA'S-NRC report, the
following labeling is recommended for the drug. It then set forth the
complete labeling for the drug.
Senator NELSON. The new labeling?
Mr. SCHNEIDER. Yes, sir.
Senator NELSON. Did it recite the National Academy of Sciences'
efficacy study?
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4680 COMPETITIVE PROBLEMS fl~ THE DRUG INDUSTRY
Mr. SCHNEIDER. The statement is based upon the report. It did not
copy it.
Mr. GoI~oN. Did you say copies were available?
Mr. SCHNEIDER. Yes, that is true. Copies were available from our
office, and the address where it could be obtained was given in the Fed-
eral Register announcement.
Senator NELSON. This was ified with the Federal Register?
Mr. SCHNEIDER. Yes, sir.
Senator NELSON. Did it give the reason for the revised labeling?
Mr. SCHNEIDER. Yes, based upon the NAS-NRC report.
Mr. HARRISON. Did that FDA publication, or the publication in the
Federal Register, contain the statement that it is not the drug of
choice?
Mr. SCHNEIDER. In the labeling you are talking about, are you talk-
ing about the disease typhoid?
Mr. HARRISON. I am talking about the presentation in the Register
of which you are speaking.
Mr. SCHNEIDER. It gave the labeling as recommended.
Mr. HARRISON. Did it contain the statement that this is not the drug
of choice?
Mr. SCHNEIDER. For typhoid?
Mr. ILuuusON. Does the labeling state it is?
Mr. SCHNEIDER. The labeling states that the `article is a drug of
choice in typhoid.
Mr. HARRISON. It does not state that it is the drug of choice-
Mr. SCHNEIDER. It restricted its use for severe salmonellosis and
typhoid.
Mr. HARRISON. This appears to be substantially different from what
was just stated here.
Senator NELSON. What is substantially different?
Mr. HARRISON. There apparently is no statement-again without
having the Federal Register available-that there is a labeling re-
quirement for a statement that this is not the drug of choice.
Mr. SCHNEIDER. You see, the labeling was oriented not toward
specific illnesses as much as it is designed or oriented toward specific
organisms. You see, that is the difference.
Mr. HARRISON. I understand.
Dr. ANms. But am I correct that this basically is the information
of the Food and Drug Administration on the basis of which regula-
tions will be instituted to insist on change of labeling?
Mr. SCHNEIDER. This is the labeling that is required, based upon the
NAS-NRC review.
Dr. ANNIS. And you give the manufacturer 30 days-
Mr. SCHNEIDER. I don't know if we gave 30 days to anyone that was
adversely affected by the statement in this case.
Dr. ANNIS. This automatically would affect the subsequent adver-
tising and labeling for us, because the company, in making up its
advertising for our publication or any other publications would have
to bring about the changes. Is this not correct?
Mr. SCHNEIDER. That is correct.
Dr. ANNIS. So it is an automatic thing as it pertains to their ad-
vertising to the profession. These are their changes that they would
therefore institute and would come into subsequent ads submitted to
the AMA or any other source.
PAGENO="0391"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4681
Senator NELSON. Let me ask another question.
What kind of distribution is given to the studies made by the Na-
tional Academy of Sciences?
Mr. SCHNEIDER. Once it becomes public, anyone who wants it can
ask for it and receive it. We do not distribute it per Se. Our press rela-
tions office has it available to anyone who is interested.
Senator NELSON. That was stated in the Federal Register?
Mr. SCHNEIDER. Yes, sir, that is correct.
Senator NELSON. Thank you.
What puzzles me about it is, here is a very important matter and
apparently, there has been no report in JAMA, and 5 months have
gone by. Now, I feel like this, where there is an independent press
that is reportincr to consumers on things all the time, the moment the
Federal Trade dommission says something about the tire or about this
or that, there are big stories about it in a number of magazines.
STATEMENT OP DR. EDWARD R. ANNIS ET AL-Resumed
Dr. ANNIS. I am surprised they did not pick up this one.
Senator NELSON. They might have. What surprises me is that the
medical journals did not. This brings up a question that people have
raised, as you are well aware, over the years, regarding the tie-in be-
tween the drug industry and the medical profession-and the large
amount of advertising.
Dr. ANNIS. Senator, this might be a good place to raise this ques-
tion: Has anybody testified as to the percent of drug advertising that
is spent with the American Medical Association and our fine profes-
sional journals? I think you will find, and this is prescription adver-
tising, that we get approximately 13 percent of the total budget
expended in this area.
Senator NELSON. Thirteen percent of whose budget?
Dr. ANNIS. Thirteen percent of the moneys expended for medical
drug advertising is spent in our journal. This is where we get our
professional readers.
Senator NELSON. You mean 13 percent of the total amount of money
spent by the industry-
Dr. ANNIS. Right.
Senator NELSON (continuing). Is spent by the-
Dr. ANNIS. No, spent by the industry in advertising drugs. The rest
of itis Spent in other competitive publications.
Senator NELSON. I do not have that statistic.
Dr. ANNIS. My only point is that we are not alone in exposing the
profession to this kind of advertising. And if, in truth, as you indicate,
there has been advertising that has slipped through our screens, that
in retrospect, at least, might better not have been accepted, we plead
guilty of human frailty.
My point is that in this particular instance we are only-13 percent
is a good percentage, but it is certainly not an overwhelming percent-
age of the recipients of drug advertising. So that if changes are to be
made by the medical association~alone and no change is instituted in
other areas, you will not accomplish the desired objective.
Senator NELSON. Let me say, Doctor, that I intend to raise the
question with all recipients of prescription drug advertising.
PAGENO="0392"
4682 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Dr. ANNIS. We are going to assist ~ ou in your efforts to zero in on
those who unwisely use an admittedly double-edged sword as it
pertains to particular drugs. We are not in disagreement on this.
Senator NELSON. Actually there is a very, very brief reference in
the AMA News.
Dr. ANNIS. You mean we said something about it.
Senator NELSON. Yes, we expose everthing here.
On August 26, 1968, there is a very, very brief reference in an article
on chloramphenicol with brief reference to this in which it said that,
as you may recall, chioramphenicol was decertified and then, after
examination and study, put back on the market, and those that did
not meet the Chloromycetin blood level-time spectrum were required
to meet it. This is about that.
It says that the Food and Drug Administration, as expected, an-
nounces that it will resume certification of chloramphenicol sodium
succinate.
The National Research Council reported to the FDA, according to
this, that the drug is effective only for the limited applications, and
it lists them.
So there was that-
Dr. ANNIS. When was this published?
Senator NELSON. August 26.
Dr. ANNIS. This is even before it appeared in the Register?
Senator NELSON. Of course, there was publicity to the effect-
Mr. HARRISON. Which publication is that?
Senator NELSON. This is the AMA News.
Mr. HARRISON. Which is a publication that goes to every physician
in the country.
Dr. ANNIS. Whether he is a member of the AMA or not.
Senator NELSON. This demonstrates my point that it did appear.
Dr. ANNIS. A few minutes ago you were being counseled that we
did not have it.
Senator NELSON. Correct.
Dr. ANNIS. That was in August. That is when I was on vacation
with my kids, up in camp in Michigan, enjoying fishing.
Senator NELSON. The National Academy of Sciences/National Re-
search Council reported to the FDA that the drug is effective only
for the limited indications in the drug's new labeling. It does not say
what it is. It does not say what the National Academy of Sciences said
about it. If that is all that is in here, the point I am making, I think,
is still valid, considering what is going on in the drug misuse around
the country, considering all the publicity about it, and considering
that the AMA News and ~JAMA take a lot of advertising from the
company. It would seem to me that those magazines ought to have a big
headline to emphasize the fact that the National Academy says it is not
the drug of choice for anything. This is my point.
Dr. ANNIS. Senator, when we discussed this particular drug with
its limited use, and its side effects which-Dr. Dameshek indicated
this-side effects and bad reactions are rare, but it is when they occur
that they are so serious. We admit this. In this context, maybe we
should have put it in the front page of the journal. But if we talk
to the National Safety Council, they think we ought to put the over-
use of alcohol and "Don't drive when you are drinking" on the front
PAGENO="0393"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4683
page of the journal. It kills more people each year than chloramphen-
icol in its whole history.
I think your point is that we, in reviewing the Federal Register,
have not given this information the circulation it deserves. May I ask
Dr. Hayes how we handle such routine things-I do not want to say
this is routine-how we handle such matters when they appear in
the Federal Register, whether it is chloramphenicol or any other drug.
Although I am not aware of it myself, I know that they have a regular
way of handling reports of this kind. It may be helpful in clarifying
the point that has been raised.
Senator NELSON. I shall be glad to have him respond to that, but
let me say, you raise the question of alcohol. Alcohol is not advertised
in JAMA. The point is that chloramphenicol is.
Dr. ANNIS. Correct.
Senator NELSON. And it is a-
Dr. ANNIS. I am talking about putting on the front page of JAMA
the dangers inherent in a drug.
Senator NELSON. This is actually what puzzled me about the whole
thing. I cannot find in journals, in the medical newspapers, big head-
lines emphasizing what has happened here. That is why I think
Dr. Goddard had to say, "I am at wits' end on how to handle this."
But it raises the question then, one, is the medical association being
effective in informing the doctors; and, two, what question does that
raise about heavy advertising in these journals when there is a big
criticism to be made of a drug which is advertised there? That ques-
tion has been raised by distinguished doctors in this country. Dr.
Console raised it in his statement to the committee this week.
Mr. HARRISON. Senator, the Register statement indicated that this
drug had some limited uses and that some labeling changes would be
required. That was the extent of it. It did not contain the other infor-
mation that you speak of, except that perhaps it contained some infor-
mation that other documents were available upon resquest.
From that, to draw any implication with respect to influence, or
undue influence by advertisers would appear to me, at the very least, to
be unwarranted. Nor could the public accept such an assumption.
Earlier I stated that the amount of Ohloromycetin ads-and if you
are going to be influenced, there has to be a substantial amount-repre-
sents something like 0.3 of I percent. That was the figure over a
period of 5 years.
Now, when we start looking for conflicts of interest, Senator, I
think we have to recognize that they have to be of some merit or of
some substance.
So, first, I do not believe that the implication is warranted at all,
because all the Federal Register contained was some changes in label-
ing and we would examine the ads to see if they complied with our
own requirements for advertising; secondly, we are talking about an
ad that appeared in the Journal over 5 years at such infrequent times
that perhaps to infer that the public would draw an inference of con-
flict, even with all other things not being known, would be totally
unwarranted.
Senator NELSON. I do not say there is necessarily any intention
about it. I just say it is, I think, recognized as implicit in the case, that
newspapers are very reluctant to run critical attacks on their biggest
advertisers. Everybody knows that.
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4684 COMPETITIVE PROBLEMS fl~ THE DRUG INDUSTRY
Dr. ANNIS. They do not have any compunctions about the medical
profession, because we are not very many.
Senator NELSON. Well, the medical profession does not advertise in
newspapers, either.
Dr. ANNIS. That is right.
Senator NELSON. This is only one of a whole spectrum that we in-
tend to explore, of the drug companies starting out with gifts to the
students in medical school, the promotion of their drugs in various
ways, and their advertising.
Dr. ANNIS. What would you suggest that we substitute? We have
so many different avenues, Senator, whereby physicians are educated.
I just indicated that only about 13 percent of the advertising dollars
spent for advertising drugs is spent with the AMA for advertising
in its journal.
Senator NELSON. But is that the question? The question is what
percentage of that advertising comes in as a percentage of the total
AMA income. That is a better question; 13 percent or 1 percent of
somebody's advertising could be my total income.
Dr. ANNIS. On the contrary, your commenting on the advertising
as carried in our journals as, in effect, carrying with it an implied
endorsement whch affects the physicians that you are talking about,
who continue to use chloramphenicol where it is not indicated. We
have repeatedly indicated, and our publications show this, that we
have, time and over again, in many publications attempted to reach
physicians to let them know of the potential hazards of using a drug
where other drugs, less toxic, equally effective, are certainly prefer-
able. We admit we have not been successful in reaching all of our phy-
sicians, and we will put forth every effort to continue.
Mr. HARRISON. And as Dr. Annis indicated earlier, we have in the
works, or we are attempting to work out at the present time, recogniz-
ing the problem, Senator, to meet with the Commissioner of the Food
and Drug Administration for the purpose of providing further
information through our communications media.
We anticipate, for example, an interview with Dr. Ley and a release
in the AMA News on this subject as soon as it can be arranged. Then
we will carry on beyond that.
Senator NELSON. An interview on what?
Mr. HARRIsoN. On the subject of chioramphenicol and its danger-
ous side effects and its proper use. In other words, we recognize the
problem. There are more things that can be done and we are seeking
means of getting that information out even more than it has been
in the past.
So we are not trying to say that we are not interested in providing
this kind of information or we are not seriously concerned about it.
We plan more things. It is just that it appears to be unfair to warrant
a conclusion on the part of anybody, and in the public's mind espe-
cially, that because some limited ads have appeared with respect to
a drug that has been approved by the Food and Drug Administration,
in our scientific journals as well as in many others, that because of
the appearance of these ads, there is some kind of unholy alliance.
Senator NELSON. Well, I did not use the words "unholy alliance."
But-
Dr. ANNIS. Senator, would you suggest that we deliberately sup-
pressed this information? I hope this is not a part of the implication
PAGENO="0395"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4685
of your questions. Assuming that the: FDA announcement said more
than it did, are you assuming that we deliberately suppressed
dissemination of this information?
Senator NELSON. No; I have not said that, either. Although I will
say that I think that most people would recognize that if somebody
is a very good friend, you are unconsciously more considerate-
Dr. ANNIS. Why have we been so inconsiderate in our publica-
tions-where we have called attentipn to these side effects repeatedly
in JAMA and the other publications, as pointed out by Dr. Hayes?
There were several hundred occasions.
Senator NELSON. Yes; I am glad to get into others, but we are just
on one that has been a big story.
For example, what kind of stories did JAMA run in the News; what
kind of play did they give to the very dramatic statements of
Dr. Dameshek, Dr. Lepper, Dr. Best, and the others who testified
on this?
Dr. ANNIS. As I recall, they were given pretty good currency. This
is where it was first brought to the attention of many physicians.
Senator NELSOI~. Could you send those to us? 1 We could not find
many in the past year. We have xeroxed what we have found in the
past year on chloramphenicol, and I went through it yesterday. I
thought it was quite minor. We shall put it in the record and it shall
speak for itself. But it certainly was not commensurate with the
dramatic situation.
Now, I do not know how you fairly evaluate that, but I think you
can certainly say that on a dramatic, important issue in which the
responsible custodian of the public welfare, in terms of health, the
medical profession failed dramatiôally in this case.
Dr. ANNIS. Senator, the profession deals with drama and death
every single day, many times a day. If you deal with some of the
more serious areas, some of your decisions, affecting life and death,
occur many times in one day. In that context, all things have to fall
into their proper perspective as they are presented to the public. This
is the reason that I did ask if we may have Dr. Hayes indicate to you
what happens, not just for this one drug, but how we handle matters
that appear in the Federal Register that are of importance to the
profession, and. by virtue of drug connections, important to our
council on drugs. It is through these methods that basic changes, as
well as continuing education, are presented to the physician.
Senator NELSON. I shall be glad to hear from him. I am just raising
one part of the iceberg. We shall have at a later date extensive testi-
mony; we have had some from some distinguished pharmacologists
and clinicians about how the~ drug industry has successfully over-
promoted dru.gs so that one of our distinguished witnesses, Dr. Fred-
erick Wolff, research director of the Washington Hospital Center and
professor of medicine, George Washington University, said that he
thought that 60 to 70 percent,~ of the drugs taken by people were not
indicated; they did not need them at all.
Dr. ANNIS. I have read some of those, Senator. There are other
people who do not take the medicine that is prescribed, some of them
made fearful of drugs by virtue of some public utterances, as reported.
1Material not received.
PAGENO="0396"
4686 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
The drug not taken often results in a greater tragedy than the drug
that is prescribed could cause.
Senator NELsoN. There are statistics available that I do not have
here on the number of patients in hospitals who are there for drug
reactions-
Dr. ANNIs. No question about it.
Senator NELSON. (continuing). From drugs that were not mdi-
cated. They should not have had the drugs. This is what we are talk-
ing about as just one item in the whole picture. The reason I have
taken chioramphenicol is that it is a very dramatic case that has
persisted for 15 years without the medical profession successfully
convincing the physicians, and there must be a lot of them, because
estimates are that some 4 million people received the drug in 1967.
Dr. ANNIS. Its life history is very short alongside of morphine
and other opiates. Neither the medical profession of the world nor
the legal and law enforcement agencies of the world have been able
to control them very well, either. This does not mean that they do not
continue to try and continue their efforts.
Senator NELSON. I do not know whether that is overprescribed
or not.
Dr. ANNIS. Let us say it is overused.
Senator NELSON. That is not the issue we are on here. We are on
the issue that has lasted for 15 years.
Dr. ANNIS. Oh, yes, that is part of the issue. A lot of these drug
reaction cases are drugs that are purchased over the counter. Prob-
ably 40 or 50 percent of all drugs are purchased over the counter.
Reactions come from these just as much as from the prescribed drugs.
Senator NELSON. Some day we intend to have hearings on over-the-
counter drugs. But we are at this moment on prescription drugs. What
I am saying is, reviewing what we have had in testimony for over
a year, this a dramatic case of the medical profession failing its
responsibility over a 15-year period, and I am wondering how much
longer it would have gone on if we had not had the dramatic testi-
mony we had a year ago, before this committee.
Then that raises the question whether the profession is derelict
in its responsibilty here. I would say yes. I do not know what you
would say.
Dr. ANNIS. I would say that is a matter of opinion. What you
are saying is that the educational efforts of the organized profession
to use its regular channels of communication have been unsuccessful
in dissuading some members of the profession from the use of a drug
when other drugs could perhaps have been better and more safely
used. This is a question of the failure of education.
Again I come back to alcohol and the failure of education. Here
is another drug that has many good and profitable uses as a drug.
It has uses in other areas in our social structure. Yet here again,
although we have all been educated that it, like most other drugs,
if abused, can result in troubles, we have failed to get that total story
to physicians, to lawyers, to lawmakers, the people at home that vote
for them, and to our patients. This does not indicate a failure on the
part of someone to try to tell the story, but rather a failure, as I in-
dicated this morning, on the part of the message recipient. What is
true in one area is equally true in another as long as we continue to
be humans and fallible.
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COMPETITIVE PROBLEMS IN THE DRUc' INDUSTRY 4687
We agree with you totally ~ts far as the dangers of the misuse of any
drug, and we are doing everything we can. We have made appoint-
ments with Dr~ Ley; he has had to cancel them on a couple of occa-
sions because of other, more pressing business. But we will continue
our efforts.
And he has agreed, as quickly as possible, to meet with our council
on drugs and our representatives toward this end of improving the
effort of communication that you feel is so essential. We are in
agreement.
Senator NELSON. Let me say I respectfully suggest that alcohol is
not analogous. You say the recipient has to listen.
Dr. ANNIS. He has to be sold, too.
Senator NELSON. But the recipient in the chloramphenicol case
does not know, has no option of his own.
Dr. ANNIS. The recipient of the message is the doctor ~who still
overprescribes or unwisely prescribes. We are talking about getting
a message to the physician who prescribes the drug.
In this instance we agree with you, we have to get more messages
to more physicians who unwisely prescribe it.
Senator NELSON. The issue I am raising, Doctor, concerns promo-
tion of drugs by the drug industry..
Dr. ANNI5. This is a part of education.
Senator NELSON. I think it appears clearer and clearer to me as I
read the past hearings, as I read the testimony that comes here, that
in fact, we have a case in which the drug industry, by its advertising
promotion directly to the doctor .~ and through the medical journals,
is so persuasive and effective that it persuades doctors to use drugs
for purposes that are not indicated. It seems to me this clearly demon-
strates something wrong with the whole method of bringing drug
information to doctors. Chloramphenicol is just one dramatic example
of the total picture. I do not claim to know the answer.
I would think it ought to be a matter of such concern to the profes-
sion that it would reexamine the whole relationship with the drug
industry and the whole relationship in terms of advertising, in terms
of drug promotion, because it is pretty clear that the drug mdustry is
outpacing the drug experts in the profession by a country mile day
in and day out.
Dr. ANNIS. Senator, I would not agree with the premise. I have
seen what drugs have done to change the whole face of medicine.
Senator NELSON. I am not arguing about that, Doctor. I am not
objecting-
Dr. ANNIS. But I would object, I would object strenuously when
you give the impression that doctors are dolts; that they do not know
what they are doing-that they are persuaded by some advertising
and the rest, and that this is the only basis on which doctors are
acquainted with the drug and upon which they made a decision for a
drug.
This is only one part of the overall educational process.
Senator NELSON. Nobody is saying that the drug industry has not
made a great contribution. All I am saying is that there are distin-
guished people in the medical profession who have testified already,
there will be more who will testify, who say that the influence of the
drug industry on the medical profession is far greater than it ought
to be. ,
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4688 CO~PETITWE PROBLEMS IN THE DRUG INDUSTRY
Dr. Ars. Senator, may I ask a question?
Senator NELsoN. Surely.
Dr. ANNIS. If this influence is so great, and I have not counted all
the antibiotics that compete with chioramphenicol or even all of the
broad-spectrum antibiotics, they are all advertised, too-why is this
one particular product used in a relatively small, circumscribed area,
even to the extent that it is used, in proportion-
Senator NELSON. Chloramphenicol, you mean?
Dr. ANNI5. We have 200 million people in this country, so even in
the proportion that they are used, why are not all these other manu-
facturers of antibiotics equally persuasive in being able to persuade
physicians that their product is better?
Senator NELsoN. We have had testimony to that effect here and we
shall have more. I think you, as a doctor, are quite aware of the fact
that there are plenty of your distinguished colleagues who will tell
you that doctors frequently prescribe a broad-spectrum antibiotic for
sore throat and other such ills.
I have had them prescribed over the phone for my own family, for
my kids. The doctor did not look to see if there was an organism
involved, of any kind.
There are plenty of doctors who say: Well, a sore throat, this and
that, takes a broad-spectrum antibiotic. This goes on extensively and
the organism has not been identified, but it is very handy, a broad-
spectrum antibiotic, and ready to go.
Dr. ANNIs. Yes; patients will call you up and say I want a shot of
penicillin or thus and so. They read the publications that are non-
medical oriented, that are not directed to physicians, but only to the
consuming public, the women's magazines, the weekly magazines, the
monthly magazines and all the rest, including feature articles by
science writers and newspapers.
This is not only because of the drug advertising by the drug manu-
facturer.
Senator NELSON. Many of the articles you talk about are induced
by the manufacturers themselves, time after time after time. Some
of them are already in the record.' The manufactures get an article
written on their drug to popularize it.
That is again part of the influence of the drug industry on the
medical profession.
I do not draw any specific, direct conclusion.
Dr. ANNIs. Should we eliminate all advertising, Senator?
Senator NELSON. I think there is a serious question, under all the
circumstances, whether the medical journals should accept advertising.
I think there is a serious question. If they do, I think there is a very
serious question about the kind of advertising they accept.
Dr. ANNI5. If we eliminate from medical journals advertising of
drugs-there has been, for many years, a little joke among physicians
that they imve to buy the Reader's Digest in order to keep up on the
latest drugs. Sure enough, a patient will walk in and ask him: How
about getting me a prescription for thus and so?
Are you going to propose that such articles also be eliminated?
Senator NELSON. No; I do not think you could eliminate them. The
advertising, as I read it and look at it in the journals, time after time,
1 See article on Indocin (indomethacin) from Pageant magazine, pt. 8, pp. 3177-3181.
See also app. V, "The MER-29 Case," pt. 10, pp. 4202-4296.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4689
is cleverly slanted to promote it for a purpose for which it is not in-
dicated. And it is accepted time after time.
Dr. ANNIS. Then you are suggesting that the advertising copy
itself should be of a different kind?
Senator NELSON. I think that the journals in general-I am not just
talking about JAMA-just default to the drug companies. When you
consider the impact of advertising-doctors are not any different
from lawyers and engineers. Publici relations, promotion, advertis-
ing-clever people in promotion clearly have an impact on busy
people.
I think that these chloromycetin ads are disgraceful, myself. I
think it has been clear for a long time that if you run one bronchoscope
and "when it counts" and then a whole bunch of fine print that you
know is not going to be read, but you are required to print it, it has
an impact that the journals do not have. You would not accept that
stuff as an article in your magazine.
I think there is something wrong with what is accepted in the
medical journals. I am just saying this as a layman. I have looked at
a few hundred ads now, and I see that in 29 instances, better than once
a month for the past 2 years, there has been a drug advertised in one
of the medical journals in which the company made a claim which
was absolutely not justified, and the company was forced to write let-
ters to some 300,000 doctors, corrective "Dear Doctor" letters.
Now, as I said, there were 10 of those in your journal. The next
time we have another journal, I shall just take that as an example.
But take the AMA Journal. In the 10 cases in 2 years, in which
ads were carried in the JAMA which the FDA said were misleading,
some of them grossly misleading, and in which they were required to
send a letter to every doctor in the United States, we cannot find a
single occasion where the journal said: This ad was misleading, we
regret we ran it; they made claims for it that are not justified; we
think that is bad advertising practice: we should not have done that.
And emphasize it. After all, the doctor is looking at that ad.
Dr. ANNIS. You have indicated, Senator, that the drug company
has been called to task by the FDA, and rightly so, because they
violated that which has been spelled out by the FDA. We admit that
the advertising, especially these past couple of years, basically is that
which is in accord with the inserts demanded by rules and regulations
of the FDA. We admit this. We admitted this earlier this morning
as well.
Senator NELSON. The point I am making here is a little different.
That is that in 10 cases where they made illegal claims, improper
claims, they were required to spend a lot of money to send 300,000
letters to all the doctors in America, this ad was carried in JAMA
and we cannot find any case-noW, I shall stand corrected if there is-
we cannot find any case where' JAMA made a big point, because the
ad is big, a big point of saying: This company was guilty of
misleading the doctors in its ad.
Dr. ANNIS. `Senator, this morning we indicated `that the reason we
stopped the seal of acceptance of the American Medical Association
is because, in the minds of too many, it carried implied approval of
the safety, efficacy, and reliability of the drugs accepted. One of the
reasons we discontinued it was because of the absolute inability to
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4690 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
have an organization of sufficient strength-of sufficient scientists,
chemists, pharmacologists, and the rest-to examine every drug to
be certain as to its efficacy and safety that we could put a stamp of
approval on. This was taken over by the Food and Drug
Administration.
Admittedly, we also agreed that if the Food and Drug Administra-
tion, and we have testified to this repeatedly-has inadequate and
insufficient funds to do so properly, they should say so.
But we cannot be in a position to evaluate every drug that is made
available.
Now, when we have a department of our Government well financed,
or at least it should be, to carry out a certain job, when they make out
the rules a.nd the regulations for information to be provided to a physi-
cian and when the essence of an ad is in accord with what has been
spelled out by the FDA, we feel that as the ad pertains to safety and
efficacy, which have been the main role of the FDA in recent years,
we feel that they have the means, or should have; have the personnel,
or should have; have the finances, or should have, to see that this job
is accomplished.
There is no such ability on the part of any professional organization.
Senator NELSON. Yes, but Doctor, tha.t does not, I think, address
itself specifically to the question I raised, which is that 10 times in the
last 2 years, ads have been run in JAMA which made false claims,
29 times in all publications.
Dr. ANNIS. Some part of which, as you indicated, has been not in
accord with the facts; that is correct. The producer violated the regu-
lations of the FDA.
Senator NELSON. This is the point, though. It made important
claims, and if a doctor reads it and it is the official position of the
AMA that the ads are educational, so the company makes a false claim,
pays for the ad, puts it in JAMA-
Mr. HARRISON. Are there instances where we have continued to run
these ads. after the "Dear Doctor" has been sent, or after we. have
been notified that portion of the ad is unacceptable.?
Senator NELSON. I shall give you another example. The point I am
trying to get at-I thought I was making myself clear-is that you
have a paid ad. A claim was made that was important for the drug.
The AMA claims the ads are educational.
Dr. ANNIS. Which claim are you talking about?
Senator NELSON. The claim of the general counsel of the AMA
before the Tax Committee in the House of Representatives.
Dr. ANNIS. No, you aren't talking about an ad containing claims
that are in error.
Senator NELSON. We have a number here. I do not know whether
this is the toughest one or not. But it makes my point clear that the
claim was made and it is an important claim that is educational to the
doctor. He reads it. The FDA says it is false and misleading and forces
the company to send a "Dear Doctor" letter.
My question is: Whiy does not the AMA feel obligated to run a big
story right then, saying, this company misled you? Maybe that doctor
would be a little bit more cautious the next time about believing the
claims of these brand-name companies that he stands on so firmly. Why
does the AMA not do that?
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4691
Mr~ HARRISON. Let us take the claim that is made and is subse-
quently found to be inaccurate. From my own limited experience, what
happens is that the FDA comes back and finds that a particular state-
ment, one of many statements that is made, is inaccurate; or that a
statement which should have been iiicluded was omitted. In other
words, I do not believe that we are speaking about a complete fabrica-
tion. FDA may find that one of the contraindications is not noted in
the ad.
I believe that we would find in most instances, or in all instances,
that the fault found by the FDA is the failure to include a contraindi-
cation that should have been included, or perhaps a misstatement of
one fact which is only one of the many facts that must be included in
the advertisement. It is of a limited nature in that respect, and I'
wonder whether or not it would warrant the kind of communication
you indicate is needed by way of advertising.
But going back to my own schooldays, Senator, I recall when `we dis-
cussed advertising as such, we found that the best way to communicate,
the most effective way, was on a pers'on-to-person basis, and that as you
went down the ladder, the next best way to communicate was by direct
mail, because that went to everybody, and we assumed that everybody
opened up their letters and read the communication. Down the line
somewhere was the advertisement in a periodical or newspaper, which
might or might not be seen by the individual.
Now, apparently, here, the Food and Drug Administration has com-
municated with every one of the physicians in the country by way of
a "Dear Doctor" letter, or has required the company to communicate
by way of a "Dear Doctor" letter. It seems to me, Senator, that a very
effective mechanism has been established to provide that physician,
even if he never saw the ad `originally-which is probably the case in
most instances-with the information that has been required. I do not
think anybody can improve upon that situation unless we got on the
phone and called all 300,000 doctors in the country.
Senator NELSON. I would say to that' `two things: one, I have had
several doctors say they never bother to read them.
No. 2, that does not relieve the AMA of its responsibility to the
profession. It would seem to me that AMA could be quite dramatic
and effective in two ways: one; convey to the doctor that you had a
brand name company advertising in your' publication `that' lied to
you, and they were required to `reform their ad or cut it out; that they
were required to write a letter to every doctor in America. That would
take a little gloss off of what all the doctors are saying, that you can-
not trust anything but the brand-name company.
Secondly, I do not know how the doctors are going to keep up with
this reading two "Dear Doctor" letters a month, 29 over the past 2
years.
Dr. ANNIS. The mail is measured by inches on this, Senator.
Mr. HARRISON. The publications are measured by feet.
Dr. ANNIS. First-class letters are in that pile. And the publications
are measured, as Mr. Harrison said, by the foot. ` `
We have indicated that we are a fallible organization, as `are those
who review our advertising, and if there are necessary changes by
virtue of the facts, these will be instituted.
Senator DOLE. How many persons; other than doctors, receive the
journal? What is the total? ` , . ` . ` `
Si-280----69-pt. il-26
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4692 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
Mr. HARRISON. The circulation is in the neighborhood of 215,000,
I believe. I have the exact figure here.
Senator DOLE. How many of those are doctors?
Dr. ANNIS. 212,000 are members.
Mr. HARRISON. Except for libraries, Senator, and other recipients
of that nature, almost all the direct recipients are physicians.
Senator DOLE. If they have all gotten the letter, I do not know why
you would need to run an ad in the journal, unless you get it twice.
Mr. HARRISON. They all receive the letter. Also, the other hundred
thousand or so physicians who do not receive the journal also receive
the letter.
Senator NELSON. I would submit that there is a moral obligation
involved. If you run an ad that misleads and it is seriously misleading,
as a number of these were, in the place where the ad occurred, you
ought to, and are morally obligated to tell the doctor that the com-
pany that advertised in here was wrong. If that is not a moral obliga-
tion of the AMA, I do not think the AMA has one.
My heavens, Doctor, if I ran a publication in which the health of
the people-
Dr. ANNIs. Senator, we are guided, as I have repeatedly told you,
in the basic content by the regulations of the Food and Drug Adminis-
tration. Many of these rules have emanated as a result of hearings, such
as yours, in an effort to tighten up this situation. If we are going to
castigate any organization because they occasionally make an error-
because unless you are going to accuse them of deliberate falsification-
even those who have testified before your commitee as to the severity of
the com~ilications, and Dr. Dameshek is a good example, have recog-
nized this. One of his earliest statements was that this drug is rare in
its complications.
Senator NELSON. Which?
Dr. ANNIS. Chloramphenicol. He indicated that it is rare that it
event has side effects and that its absorption in youngsters was and is
great. So many pediatricians used it. It is the rare thing that does
occur that is tragic. There is not any question about this. There is no
argument about this. But the point is that even these men have not
held that the drug, for example, should be abolished. It still has limited
but nevertheless essential uses. For this reason, the manufacturers have
a legitimate right for it to be advertised.
Do not forget, as I indicated this morning, there is no question in
my mind that many of the physicians who have used this drug `are
among physicians, such as myself, who have learned to use and depend
upon a few basic drugsin the past. If a drug that I used for 4,5,6,8 or
more years was consistently successful, was consistently giving me
good results, and I never had a bad effect-and that could easily be in
a drug that has had a bad effect in one in 20,000, or up to one in
200,000-I would continue to use it. I can easily see if `a drug is pulled
off the market, when it comes back, a physician could say, in effect,
that the FDA is saying, "look, after we have looked into this, we find
this is still a good drug, and once again we will allow it to be sold,
and the `advertising to be done."
And once again, it comes on the market, and the content of that copy
is contained in the inserts, as prescribed by the Food and Drug Ad-
ministration. I maintain that we have not been derelict because we
have not read fine print or taken occasional exceptions.
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COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4693
When you get to this point, you ran into disagreements between
physicians. For example, the one who may have used the drug for
years and who has never had a side effect, the other who, by virtue of
scientific, laboratory and other facilities available, and greater expo-
sure to literature7 is well aware of them.
These are basically conflicts. There is no reason on the basis of a
difference of opinion to castigate anyone or told them up as though,
by virtue of this, they deliberately misled the profession.
They are still advertising a product that our Government's FDA
admits is acceptable for manufacture, sale, and distribution. So if
there are objections to certain of the facts t.hat are contained in ads, the
Food and Drug Administration has full authority at the present time
to bring about any necessary changes. This is neither the responsibility
nor the prerogative of the medical profession.
Senator DoLE. In other words, the FDA could require-
Dr. ANNI5. They could require, in big red letters on the front page,
if they so desire, "This is a dangerous drug except under certain cir-
cumstances." Even its danger may be ignored because it is the only,
or one of the only treatments available for certain conditions.
Anything they could put in there. All they have to do is do it by
regulation, and they have the authority right now.
Senator DOLE. But instead, they: require a letter, as I understand it.
Dr. ANNIS. No, they set up certain standards. Then, if the advertis-
ing that we receive and the rest of the drug advertisers receive, they
put it in print, assuming it meets the basic requirements of the law.
The FDA, after reading it, says to the manufacturer, "look, you have
exceeded what we have allowed or, you have failed to comply with the
law; you must send out a `Dear Doctor' letter." And the FDA requires
it to be in a special envelope.
I do not care how busy you are, these envelopes doctors have come
to recognize and they read them. Because whether you prescribe these
drugs or not, the drug may come to your `attention and you want to
know which ones are involved.
Senator NELSON. I repeat, Doôtor, at the risk of `being boring, that
I am talking about the case where the ad was misleading. I will find
an example or two here for you.
Dr. ANNIS. I am satisfied you could find these, Senator. You have
indicated that.
Senator NELsoN. When you carry an ad and it is educational; it is
intended to convince the doctor of something.
Dr. ANNIS. Senator, here are six or seven publications. You see how
thick they are. If you would pick them up, you would see how heavy
they are.
I do not doubt that we have errors in there. But they are not errors
of coimmission; they are not errors deliberately made. They are errors
*inherent in human beings, and by virtue of our desire to bring up to
date knowledge in an obviously changing area of communication and
knowledge. What appears to :be true today experience will prove is
not true 6 months from now, even in the use of other drugs.
Senator NELSON. I am not saying that it is an error of commission
for the Journal not to notifi~ its readers that false claims have been
made in an ad in its Journal. It is an error of omission. All I am say-
ing is, since doctors to a large extent do prescribe on information they
get out of the ads, the Journal has the obligation immediately to cor-
PAGENO="0404"
4694 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
rect that misleading ad in the same place, in the same way, something
similar to the way in which the claim was made.
Do you not think so?
Dr. ANNIS. I would suggest that you give the Food and Drug Ad-
ministration enough money to do the job for which they are author-
ized and which they are qualified to do.
Senator NELSON. What is your obligation in JAMA? You are a
private, independent, publication in an area that has run a false and
misleading ad that was paid for-
Dr. ANNIS. Not deliberately.
Senator NELSON. I did not say that.
Dr. ANNIS. May I ask how long Dr. Goddard said it required the
Food and Drug Administration to review one ad for approval?
Senator NELSON. I do not recall.
Dr. ANNIS. I do not, either, but it was 11, 12, 13 days or more. I am
talking about reviewing each ad on this basis.
Senator NELSON. No, I am not talking about that. I am talking
about the case where you ran the ad, you did not know that they were
making false claims. FDA discovers they were making false claims.
Dr. ANNIS. Maybe they do not know it.
Senator NELSON. We have seen enough of it, so we do not think there
is any question of it. It happens all the time. They are leading to-
ward getting wider use of the drug than the FDA thinks-
Dr. ANNIS. As an attorney you are better at this than I am, but if
there is evidence that they are deliberately trying to get around the
law, they should be called to task on.
Senator NELSON. They rim a bronchoscope in one of your ads. If
that is not fact, I do not know what it is. If that does not indicate that
that is to be used for general use in that area, I do not know how any
other person in the world would interpret that, "When it counts," and
a bronchoscope.
Dr. ANNIS. No, they said, "When it counts, think of Chloromycetin."
Senator NELSON. You and I are sophisticated enough to know what
it means.
Dr. ANNIS. I have told you I have never used it. But my point is
that many physicians still feel, and have testified before your com-
mittee, that there are indications for it.
Senator NELSON. We know that. But it is being used 90 percent of
the time, 90 to 95 percent, in nonindicated cases.
Dr. ANNIS. These are guesses, and the men who testified admitted
this. I do not know what the figure is. If somebody else says 20 per-
cent, I would say, could be. I do not know that, either.
But the essential point is to get the message. It would seem to me
that this should be the main point of what you are driving at; that is,
that more physicians get notice of the potential side effects of this drug
so that they are critical in their appraisal of the need and justification
for its use.
And again, I would agree with you-we are m total agreement.
I believe the records will show that since you have started this in-
vestigation, many physicians have paid attention. In fact, I believe,
according to Dr. Ley, there has been a decrease in the use of chloram-
phenicol to a considerable degree.
Senator NELSON. From about 41 or 42 million grams in 1967 to 17
or 18 million grams in 1968.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4695
Dr. ANNIS. Then I would say we must be on some proper wave-
lengths; let us increase the speed with which we use them to accom-
plish an objective that both of us desire.
Senator NELSON. But I think a major share of the credit comes from
what the committee did with it.
Dr. ANNIS. My point is we are not in disagreement with you.
Senator NELSON. But I still cannot~ quite get an answer to the point
that I-apparently you do not think; is important. You say the FDA
can correct any of this.
Dr. ANNIS. They have troubles, too.
Senator NELSON. I think the FDA had some problems with the in-
dustry and with the medical profession.
Dr. ANNIS. They do.
Senator NELSON. I think that since Dr. Goddard and I hope in the
future, the FDA has done a superb job compared with what has been
done in the past. I would be sure that Dr. Ley and Dr. Goddard would
say that they would do a lot bettei~ and will hope to and try to. But
I would have quarrels with them about what they permit in ads.
Dr. ANNIS. And they have the same problems we do.
Senator NELSON. But you have no problem at all, it seems to me.
Dr. ANNIS. Oh, yes, we do.
Senator NELSON. In this respect: the company runs an ad and it
is found to be -false and misleading. I still have not got an answer
to the question, why do you not feel as a custodian, a most important
custodian, with a special relationship to the people as custodian of
the health of the people of this country, why you do not feel a moral
obligation to run a prominent story saying that the claim made in X
issue on this drug was false and misleading, according to the FDA,
and here is their language; this claim was made and it is not in-
dicated for that.
Dr. ANNI5. Probably because there are some reaJ sharp lawyers in
this country that have arranged the laws in such a way that we had
better be careful what we put in print, especially any indication of
malicious intent.
Senator NELSON. You would just report the news.
Dr. ANNIS. Well, that is all right. To say that they have made an
error, that is all right. A lot of people make errors. I do not know
anybody who does not.
Senator NELSON. I did not say malicious intent.
Dr. ANNIS. But you said lied to them.
Senator NELSON. False and misleading.
Dr. ANNIS. That is lying to them.
Senator NELSON. I think I could use the language of the FDA, but
I would go further than that, Doctor.
Since the responsibility of the profession to the American people
is special, I think you could make an agreement, if that is what is
worrying you, with any company that advertised, that you intend to
run a story on any misleading advertising as found by the FDA, you
intend to run it prominently. T do not think there is anybody, and if
any manufacturer says, we would not advertise with you on that basis,
that is about the time they ought to be kicked Out of your pages.
I am saying you have a moral obligation.
Dr. ANNIS. We will take it under advisement.
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4696 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. I was asked whether it was intentional. I can oniy
repeat what the FDA said. This is a July 8 memorandum of the FDA.
Here are three ads that ran in JAMA on June 29, 1964.
Dr. A~is. Senator, we do not deny that we have ads that you have
indicated. In retrospect, I can think of a lot of things that have been
wrong in the past.
Senator NELSON. Let me just read here. You raised the question of
whether there was ever any intent. I shall just read what was said.
These are on Pree MT. This is just one, June 8 and June 29, 1964.
This is a July 8 memorandum, 1964.
To the Bureau of Regulatory Compliance, Joseph F. Sadusk, Jr., M.D., Medical
Director-
Through him from Robert S. McCleery, M.D., section on adver-
tising and promotional labeling-
1. We believe the faults-
What happened here was that they ran two ads, the first two. When
they got to contraindications, they printed in the ad, "None known."
Then when they got the complaint, they ran one on the 29th and they
did not put contraindications in at all. They left it blank. So they had
"None known," and there were contraindications, and they knew it.
Then on the third ad, they did not put in the contraindications.
Dr. A~is. Were they prosecuted by the FDA?
Senator NELSON. Counsel advises me that the company was prose-
cuted and found guilty.
1. We believe the faults of the ad and the attached mail pieces are significant
and that we can help you support any action you deem advisable. We are deeply
concerned that the action chosen might also have as a consequence the immediate
cessation of this type of promotion which can mislead the reader into using the
drug in a manner that could jeopardize the safety of his patients.
2. An interesting and disturbing event has occurred since our interest in the
Pree MT ads began on June 9. (See attached copies of June 8 and June 22 issues
of Modern Medicine and June 8 and June 29 issues of J.A.M.A.)
Note that the heading "Contraindications" has disappeared from the June 22
and the June 29 ads.
The June29 ad was in JAMA.
This kind of change is very easy to accomplish technically. It could have been
handled by a telephone call from the company or the agency to the printer. In
a few minutes the printer could knock off the offending type, without the need
to produce new plates. The only difference is that the J.A.M.A. printer was not
an expert. As a consequence, he also damaged the type for the word "Dosage."
a. The fact of the change is an obvious admission by the company that it had
been wrong.
That is leaving out the contraindications entirely.
b. The cynicism of the company is disclosed by its willingness to continue the
ad and merely change an error of commission to one of omission.
c. Since Section 502(n) of the Act requires a true statement of contraindica-
tions, they have not really removed the basis of our complaint. Further, the
other errors, pointed to in our June 10 memo, still stand.
d. The act of the J.A.M.A., re: the June 29 issue, raises an important point.
Its Council on Advertising could be perhaps excused, on the basis of ignorance,
in accepting the June 8 ad copy. However, their agreement to delete the line,
"Contraindications: None Known," makes it appear that the Council became a
knowledgeable participant in an act of omission contrary to law.
This is FDA speaking. Now, I suppose somebody in JAMA might
have an argument to respond to that. But again, they run an ad that
is important. They run one in June-
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4697
Dr. ANNIS. Whose letter was that, Senator?
Senator NELSON. It was a memorandum from Robert S. MeCleery,
M.D., section on advertising and promotion, to Joseph F. Sadusk, Jr.,
M.D., Medical Director/BM.
Mr. HARRISON. Dr. Sadusk, I now believe is with Parke, Davis &
Co.
Senator NELSON. Yes, he is.
Mr. HARRISON. I have some statements here with respect to the
promotion, or lack of overpromotion, of Chloromycetin. The point I
make is he has made some references here as to whether he believes-
Senator NELSON. Whom is he with now?
Mr. HARRISON. Parke, Davis.
Senator NELSON. And who manufactures Chloromycetin?
Mr. HARRISON. Parke, Davis.
All I am saying is there are some other statements here.
Dr. ANNIS. I hear proper action was taken, Senator.
Senator NELSON. Yes, but again; I raise the point that an ad has
been run in JAMA in which it tells all about Pree MT, and then it
runs nothing on contraindications. Again, a doctor reads that and
looks and says, great ad. I think I will use that because there are no
contraindications.
Now, it seems to me-
Dr. ANNIS. Your point is that, we should have the same kind of
check that FDA has.
Senator NELSON. No, my point is, I don't know what you ought to
have m advance. In your brochure that you submitted today, you say
that you require evidence of efficacy and various other things.
Dr. ANNIS. And satisfaction of the requirements of FDA.
Senator NELSON. We have a case or so that I will show you where
there was not any evidence at all. But let us stick with this one. This
is a case where they were found guilty by the FDA. They left out con-
traindications. A doctor relying upon your ad may be prescribing this
and no doubt is prescribing it, and he says, it is great, there is no con-
traindications, but there are.
it seems to me that there is a moral obligation on the part of the
AMA when something like this is done to report that ad was incor-
rect. And here is what the FDA has done about it. I do not understand
how you can shirk that responsibility.
Dr. ANNIS. Senator, we are not shirking any responsibility. But I
recall one trip up here a few years ago when our mutual friend, Sen-
ator Smathers, returned at noon from the White House where, as a
representative of the southern Senate group, he had had bheakfast.
I recall, too, that he came in and he said, "Ed, you think you guys
have problems. I just came from the President's, and you think that a
President of the United States has unlimited power."
And he said, "But during most of breakfast this morning he was
talking that he will give an order and, by the time it goes down through
various people, nobody knows who makes the changes along the way,
but ultimately, it comes out-if it comes out-totally different from
what was intended."
I think he used the illustration that it is like somebody standing on
the end of the line and passing a handful of salt or sugar, one to an-
other. When it gets to the end of the line, nobody knows how much
was lost or by whom, but there is not as much there.
PAGENO="0408"
4698 COMPET1TTVE PROBLEMS IN THE DRTJ~ INDUSTRY
The fact that you can find errors occasionally, omissions occasion-
ally, yes, nobody would deny that these things occur in medicine, in the
AMA, in all publications, or in Government. What I am saying is that
these are contrary to our basic intent, to our aims, to our procedures,
to what we try to do in bringing to the American physician, as best we
can, constant and continuing exposure to new drugs which are essential
to the armamentarium of medicine.
By the same token, because the Government has taken over an im-
portant role, and in this the FDA has had strong support from the
medical profession. They have taken over this role and have assumed
responsibility not only for safety and purity, but also for efficacy. We
feel that they have helped us immeasurably.
Now, within the confines of our organization, the manner in which
we operate-I am satisfied that you can pick instances where we have
failed to live up to that which we desire.
I would plead guilty of failing to reach that goal in many instances.
But this is not a failure because of the lack of desire or because of an
unwillingness on our part to direct our efforts toward these things. If
it requires a change in our policies or our procedures, we will do so.
This is my point.
Senator NELSON. The issue I am raising here is not that complicated
a question as the President and unlimited power.
Dr. ANNIS. It makes no difference. I bet you give orders in your
office sometimes and they do not quite come out the way you intended
them to.
Senator NELSON. If it were a policy issue and it happened 10 times
in my office, I would have a new employee.
Dr. ANNI5. You are impatient. I do not know .that we would last that
long.
Senator NELSON. Well, there are about 10 ads here; that is the reason
I use the figure 10.
But I still get to the point of the obligation of the American Medical
Association. You do not have a policy at all. It is not a question of
giving an order as a President might on something and all of a sudden
it goes through a lot of hands and is not executed the way he liked. It is
something I know happens.
Dr. ANNIs. But we have a policy-
Senator NELSON. There is no policy as to this.
Mr. HARRISON. What you are saying, Senator, in summation, I
guess, is that when it is found that an advertisement carried by the
American Medical Association publications-
Senator NELSON. Or any other.
Mr. HARRISON (continuing). Or any other, but of course ours would
only be with our own publications. When it has been found to contain
information which the FDA subsequently feels inappropriate and,
after negotiations with the company to issue a "Dear Doctor" letter,
AMA should again, with full prominence, say, "look, there was
one point here that should have been included," or "something was
omitted."
Perhaps there is some merit in saying that we could be doing some-
thing beyond that which ire are doing. But we should recognize that
these letters, again, go out to all physicians, that they were a com-
plete sta tement as such. Having iust engaged a bit in some community
PAGENO="0409"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4699
politics, on a very local level, I have come to know that sometimes you
you give more notoriety than it had when it was read the first time.
I am not quite sure, Senator, that it would be appropriate, in all in-
stances certainly, to place in large prominence full-page ads with
respect to some omission or some mistake that was made in the ad, as
subsequently determined by the FDA.
However, you have a point there and I think we can review our
present policy with respect to that point, and see if we should be doing
something more.
But I wish the committee would keep in mind that we are speaking
here of perhaps an omission which may be only one statement among
a number of statements that were included.
Perhaps it took the FDA a couple of weeks to review that ad. The
manufacturer may have been required to come in and discuss the prob-
lem, and then reach an agreement as to what should be done with
respect to the way the ad was worded, and how it was in conflict with
the statement made in the package insert.
And after all this is done, finally, it is agreed, perhaps in this one
instance, that a "Dear Doctor" letter should go out to the physicians
across the country-all of that. Then the question is, should the AMA
in a large-page ad also say, "there is one other statement that should
have been made there!" We cannot see that, but perhaps something
should be done and, again, we shall take this under consideration,
perhaps to improve our communication on this point.
Senator NELSON. Well, this is part of the whole context in which
these hearings have been conducted, part of it, about the t.remendous
influence of the drug industry in promoting the sale of drugs. It seems
to me that the AMA's journal is not an ordinary publication, and that
when a false claim is made that can and will mislead the doctor to
improperly prescribe for his patients, there is a moral obligation of
JAMA to say right off the bat-and if every medical publication did
that every time it happened, you will see some more honest adver-
tising.
But if every time something like that happens, the publishers who
receive the ads say nothing about it, why should they reform?
Mr. HARRISON. I think they are seriously hurt by these "Dear Doc-
tor" letters, seriously hurt, because here is a communication that, ~n
effect, again goes to every single physician and which states that they
have done something in error and done something improperly. And I
think this seriously affects them.
So I think there is a very pertinent and powerful restraining influ-
ence here.
Senator NELSON. You are saying after all this discussion that you
do not think that the American Medical Association has an obligation
to correct misleading advertising in its journal. Is that the conclusion?
Mr. HARRISON. We are not saying that at all, Senator. I think I have
made the point that certainly we will look at this again, but the ques-
tion is whether you use a sledgehammer here to kill a flea. We would
have to look at the particular: statement that was made, the context in
which it was made, the advertising, and I would say ~.o you that on
the basis of what has been related here and more recently through the
committee, we would have to evaluate again the procedures involved
and perhaps effect some change.
PAGENO="0410"
4700 COMPETITIVE PROBLEMS L~ THE DRUG INDUSTRY
But to just make a comment that the American Medical Association
has failed to do something in this respect when these "Dear Doctor"
letters go out to all the physicians and when we do not run the ads
again when we are aware of their defects-I think this is the point
that is unfair.
Senator NELSON. I shall be glad to see the FDA do these things, but
I quite frankly say if the doctor read that ad and believed it and mis-
prescribed to his patient on account of it, and the journal had not run
a correction, the journal has defaulted in its moral responsibility. That
is my opinion.
I would just like to spend a minute to find another example or two
here.
Senator DOLE. While the chairman is looking, I might ask a few
questions.
Senator NELSON. Yes, of course.
Senator Don~. Does the journal ever make any reference to these
"Dear Doctor" letters? Do you ever rerun the letter or anything of
that kind?
Dr. ANNIS. I was just asking Dr. Hayes. I know I have seen them,
either in the journal or the AMA News, but I do not know if they
are run as a regular procedure. I have had my attention called to an
AMA News article after I had received the letter, so that I know that
it has occurred on occasion.
I know, for example, and Dr. Hayes feels the same way, that there
was a reminder in the AMA News following the "Dear Doctor" letter,
on chloramphenicol. 1?\Thether or not it is the regular procedure, this
is one of the matters that we will look into and will take up with our
Council on Drugs.
Senator DOLE. I think the record probably is clear on how many ads
have been run in a period of time, total ads, and how many have been
in the category suggested by the chairman. Do you have the figures on
how many total ads you may run in a year and how many have been
"false and misleading"? Is that information available?
Mr. HARRISON. How many false and misleading?
Senator DOLE. Out of the total? Is it 5 percent, 1 percent?
Mr. HARRISON. The Senator has indicated some 10 ads which have
been subsequently found to require corrections through a "Dear Doc-
tor" letter, appeared in the AMA Journal, I believe he said over a
period of a year.
Senator NELSON. Twenty-nine over a period of 23 months.
Mr. HARRISON. Of which 10 were with AMA publications?
Senator NELSON. And others, but 10 of the 29 did appear in the AMA.
Journal.
Mr. HARRISON. So that would be 10 advertisements, and I can tell
you the number of pages that we have. It is such an insignificant num-
ber-that we are talking about something like one-thousandth of 1
percent for just the journal itself, and we have 10 specialty journals.
The journal is published once a week. That would be 52 issues during
the course of the year.
In a period of 2 years, we would have more than 100 issues. There
are approximately 100 pages of advertising, somewhere m that area,
in each issue. I do not know where that takes us, but the percentage
is obviously small.
PAGENO="0411"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4701
Senator DOLE. As a matter of practice, do you screen ads that come
toyou?
Mr. ILUmISON. Yes, we have a department which evaluates drug
advertising and it does so in accordance with the principles included
in our testimony.
Senator DOLE. Yes, I read the principles here.
Dr. ANNIs. The screening is there, but when it comes to such things
as the drug content, the pharmacology, the chemistry, the efficacy, the
safety, these are matters that the Food and Drug Administration is
responsible for. Essentially, if they meet the FDA requirements and
our requirements-advertising critical of others, or pricewise, saying
we are better than someone else's, and all of the other things that are
there, plus the keeping of medical ethics, they are acceptable.
That is what we screen basically for, but the basic contents, since the
FDA has been given that authority by the Congress and has assumed
the authority and are doing a good job with a difficult chore, we leave
this matter to them, because we do not have the mechanism or the means
to go into these details.
Admittedly, out of either their screen or our screen, occasionally
there are errors.
Senator DOLE. The FDA has made errors, too, I assume.
Dr. ANNIS. Well, yes. Everybody has. A good example is thalido-
mide, a safe drug. You could buy it over the counter in Europe. The
main reason it was so popular was that one could not commit suicide
with it. One could take a barrel of it and it would not kill.
But looking back, for a young: woman in her first 6 or 7 weeks of
pregnancy, it created problems. Researchers could not find them in
test after test on animals. They only found it in a certain species of
rabbits. You have a drug that is safe. Old people take it, young people
take it, it has minimum toxicity.
People take it for sleeping. If they take too many, it will not kill
them. Think what a great thing this was. They could even buy it over
the counter in Europe. It was never used in this country, not because
of the drug effect on the unborn child, but because it had peripheral
side effects-numbness in the fingers and toes, a sort of tingling.
But the research group, Richardson-Merrill, continued its research
on it. Then we began to hear of the trouble they were having in Europe
with this drug. Then, as a result of what happened, they saw the dan-
ger. From then, you could set a ëlear course.
Chloramphenicol has not been the same, but similar. It is a drug
that has not been widely used, a drug with an admitted broad spec-
trum, a drug that came along with other drugs at a time when we
were looking for something extraordinary. So in the minds of many
physicians, older physicians, particularly, of 15 or 20 years ago, here
was a great tool.
Now even its severest critics-and we are among those-admitted
that its side effects are rare. But when they occur, they can be tragic.
But a man could have used it for 15, 20 years without any trouble. So
when he hears that other people have had trouble, he says, "I have had
no trouble."
Then the FDA took it off the market. Then, for a while, he could not
get his favorite broad-spectrum antibiotic. Now, it is back on the
market. He can get it again. And in the mind of this fellow, not one
PAGENO="0412"
4702 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY
who has kept up with things, but one who had been getting good
service from a drug over a number of years, he begins to use it again.
I suspect that a number of users of this drug will fall into that cate-
gory, where they have never had any trouble with it and it is the same
old deal. It has long been a human saying, and it is dangerous in drugs,
I will admit, but the saying is "When you have something that works
well for you, do not be the first to jump to the new."
I suspect-I cannot prove it, but I suspect this from physicians with
whom I have had discussions in the last year and where I have zeroed
in on this drug. But over the years, I have pointed out the many side
effects that have occurred in rare instances.
Now, what has happened is that our recognition of it and the safe-
guards that Senator Nelson is referring to have not yet, at least in his
mind, caught up to today's knowledge. It is different today. We are
more secure, more certain.
Even the references he made this morning about the National
Research Council-even these final pronouncements that apparently,
for the first time, indicate that there is no indication left for chioram-
phenicol-that other drugs do as well or are better and safer-even
this is only a result of today.
So we have several years where apparently, it was a pretty good
drug with minimal side effects. Then we began to see some side effects.
Then we began to see an increasing number of serious side effects-not
often, but when they occurred, very serious indeed.
Now, the record begins to lay out.
So as we look back over those years, the Senator is amazed. Why did
you not do something sooner? Well, of course, if we had known about
thalidomide-they were not researching defects in children, but
researchmg something else. That is the way research has been made.
Some of these are just as dangerous as flights in space. We are so
proud of what we have accomplished, and it has been tremendous, it
has been exhilarating as a nation. But we lost three men.
These are the hazards that come with progress, as we move forward.
In retrospect, we now fix it so that we will not lose them that way
again. But we lost three men.
The same is true here. Now, we can ask: should we not have recog-
nized this earlier? Perhaps. Perhaps the safeguards we build in now
will make it possible for use to recognize other and similar potential
tragedies in the future, before they occur.
These are some of the very real problems that are the practical prob-
lems of medicine. You have a disease, you have a condition that is
difficult to deal with. Som~body comes along and says, here is an
answer. You begin to use it and you say, "gee, this is great," Then all
of a sudden, you realize that the side effects that go with it can be very
serious indeed.
We have a number of drugs which solve many problems, but they
produce deafness, total deafness. One of my good friends, one of the
outstanding otolaryngologists in this country, has a patient I met one
day. This man is totally deaf from a drug, dihydrostreptomycin, given
to him for something else. As we look back, we are adding to our
knowledge, and as we keep people alive who used to die, we find that
the same drug that saved life produced deafness or inability to see.
Aralen-a great drug in the control of malaria, was found by acci-
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4703
dent to help arthritis. It was prescribed for arthritis only to find that,
though it is great for arthritis, if it is taken over a period of time,
it begins to affect your ability to see.
This is the progress of medicine.
If you look backward, you can find many errors that we have made.
But they are not errors that have come because of failure on the part
of our researchers, our scientists, our drug manufacturers, to whom we
owe so much, or the physicians who use the drugs. These are the
human failures.
Admittedly, criticism highlights our appraisal of these facts. If,
from a hearing of this kind, some of the criticisms can redirect our
efforts toward a closer scurtiny, toward a more effective scrutiny, I can
assure you that this will be one of the side effects, at least, that will
make our appearance a justifiable one and a good investment of time.
Senator Don~. Thank you, Mr. Chairman.
I have to go to another meeting.
Senator NELSON. I would just like to say, Doctor, though, on this
question of acquiring new knowledge about a drug, the indications
for using chloramphenicol, have been quite limited, according to the
testimony before the committee.
Dr. ANNIS. According to our publications. We agree with you,
Senator.
Senator NELSON. For 15 years.
Dr. ANNIS. Correct.
Senator NELSON. And then along has come tetracyclines, and that re-
duced again its indications. But they have been quite limited. And the
point here is that the profession was not successful in that 15 years.
I am not going to go through all that again. But let me refer to
something.
The committee has a stack of letters. This is the kind of thing that
is so dramatic and so important.
Dr. ANNIS. Our medical literature will have a bigger pile than that,
Senator.
Senator NELSON (reading). "Our eight-and-a-half-year-old daugh-
ter, Judy Dianne, was given intermittent doses of Chioromycetin
frOm August 1964"-that is recent-"through February 1966 for rea-
sons varying from minor ear infections, respiratory infections, and
an abscessed tooth."
Now, we have lots of them like this. Here is one from a doctor say-
ing that just recently, "A lady came into my office"-this is a doctor
from Florida-no; I be~ your pardon, these are attorneys. I guess
there will be a lawsuit. `A lady came into my office stating that this
drug had been prescribed for her only child for acne."
Here is one for a common cold.
When I raised the issue with Dr. Goddard and others who have
been here, that since the failure to convince the profession has been so
complete, why should we not do as Dr. Dameshek recommended, and
several others-I would have to check the record to be sure that was
his recommendation. This was a year ago. But I believe he was the
one who recommended that the FDA simply require that the drug
be prescribed only in a hospital.
Dr. ANNIS. I think that was Dr. Dameshek.
Senator NELSON. Subsequently we have had others say the same
thing.
PAGENO="0414"
4704 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Well, Dr. Goddard said he was "at wits' end" about what to do
about this problem. I have a high respect for him and I think I know
what his problem was. Dr. Goddard said that restricting its use to
hospitals would be an interference with the doctors' practice of
medicine.
Do you think that would be interference in a doctor's practice, if
you have a case of this kind, where little kids like this are dying and
4 million people are getting it, and we have been unable to persuade
the doctors. This is a way to guarantee that in most instances it would
call the doctor's attention to the fact that it should be used only in a
hospial. Besides, in any good general hospital, you have some exper-
tise on the drug there.
Do you agree or disagree that that would be a good proposal?
Dr. ANNIs. Again, Senator, you will recall, as I said before, I am
not speaking as a user nor a defender of the drug. But I do know
that there are many physicians in this country of ours who practice
many miles away from a hospital. One of the real problems is to get
physicians to practice in rural areas, in sparsely populated areas, in
areas far removed from medical centers and often far removed from
hospitals. I suppose that some, at least, of the rather consistent users
of the drug fall into that category. If it becomes necessary, if the cir-
cumstances justify it, if there are no other drugs, if we fail in our
education along other lines, then this, too, would have to be, as with
anything, have to be considered.
I would suggest, however, that even in some of the testimony that
has been presented before this committee, there have been indications
that one need not have taken chioramphenicol over a long period of
time if one is sensitive to it. One dose in itself can set up the mechanism
that ultimately results in the depression of bone marrow production,
aplastic anemia, and death.
I would also suggest-and I recite these not as arguments but as
reasons for a continued dialog in this particular area-that one of
my good friends in Miami had his wife take their little girl to the
hospital and request a shot of penicillin for an infection a couple of
years ago. She went into the hospital to the outpatient department
and requested it. The physician who was in attendance agreed that it
was all right, and Andrea, the little girl, was given her injection of
penicillin. She was dead within a few minutes; they were unable to
resuscitate her.
So the mere fact that a patient is brought to a hospital for treat-
ment or as an outpatient does not necessarily protect him. The theory
is, of course, that if they are in a hospital, they are under better care,
you can watch their blood count, do other things. If, however, we are
dealing with hypersensitivity for any one of a number of reasons, be-
ing in a hospital would not protect.
I think, ultimately, the point arises that it is not a question of the
location at which the drug is given, it is a question of trying to edu-
cate our doctors wherever they practice as to hazards, as to new knowl-
edge, as to the fact that whatever their experience has been in the past,
there are other drugs today that can satisfy their needs much more
safely. I still say that the answer to this, like most areas in the field of
medical practice, where human beings are dealing with human beings,
we should improve one's education to as great an extent as possible.
But not forget that a physician may be dealing with people where
PAGENO="0415"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4705
they are often far removed from medical centers, far removed from
the ability to get the tests and everything necessary, and where his
practice or experience over the years with various diseases has led
him to use drugs which, in his mind, have saved lives.
That is the other angle to this that must not be overlooked.
If we want to concentrate on the few with dangerous side effects,
including those ending in fatalities, we must also, in fair appraisal
of any drug, not just this one that we are talking about, take a look
at in how many instances is the evidehce there that it saved lives,
prolonged lives, terminated illnesses quickly, protecting against fur-
ther complications? .
I do not know all these answers, but I do think so far, in reviewing
the record of many distinguished physicians who have testified before
your committee, and I share their concern about this drug, I am not
yet convinced, nor are some of your other witnesses of equal promi-
nence yet convinced, that confining or restricting the use of the drug
to a hospital will solve the problem we all want solved.
I am not opposed to it, but neither am I a proponent of it. I would
want to hear more from others in circumstances where its use is
dictated by conditions beyond those to which I personally have been
exposed.
Senator NELSON. But here you have a case in which it is really
catastrophic, if Dr. Dameshek and the rest are correct, that this drug
is being widely misprescribed and that we have deaths like this. Now,
I assume that the person who got the penicillin in a hospital got the
penicillin for an indicated case.
Dr. ANNI5. I would hope so.
Senator NELSON. But here is a case where 90 percent, if it is 90 per-
cent, are getting it for nonindicated cases, and the fact that you re-
quire it to be administered in a hospital immediately reduces that
percentage.
Presumably there is somebody there who asks if this disease is
serious enough for this and is there another drug that will do the job?
Also, is the organism susceptible to chioramphenicol? You would
save quite a few lives that way.
I believe it was Dr. Dameshek and some of the others, too, who
advocated this and said, if they are sick enough to have chiorampheni-
col, they ought to be in a hospital. But it seems to me that Dr. God-
dard's answer that it interferes with the practice of medicine is hardly
a justification in a case where the medicine is being practiced
incorrectly.
Dr. ANNIS. I think Dr. Darneshek's exposure has been in a great
medical hospital where we have up-to-date tools and many qualified
people around. He works in a totally different envorinment than those
to which I have reference, and I suspect to which Dr. Goddard has
reference. But I did indicate, indirectly perhaps, that even the use
of chloramphenicol in a hospital would not protect that person, where-
in one exposure is adequate to set off the very dangerous and ulti-
mately destructive mechanism. Again, I am merely quoting some of
the testimony before this committee that it does not have to be pro-
longed administration in a certain percentage of people for one reason
or another. A very small amoñnt of the drug, just like a small amount
of tetanus toxin-antitoxon, I should say-can be sufficient to result
in a fatality. This is merely an area where I do not believe that we
PAGENO="0416"
4706 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
have had sufficient discussion or have had an opportunity to hear from
all parts of the profession as to the limitation of any therapeutic a.gent
just to a hospital.
In my earlier years of practice, I did a little of what they used to
call barehanded practice when I was in Wisconsin. I was out in the
country many times. I have seen patients where, if it were a necessity
to send them to a hospital, they would rather stay home and die.
I do not know, maybe people have changed since that time. How-
ever, I am not quite sure. I know of instances in the past couple o±
years, at least of two people who have died following automobile acci-
dents in Miami because the family, the patient who was dying, and
the family, refused to allow the physicians to give blood transfusions,
where there was massive hemorrhage as a result of the accident. It was
impossible to treat the patient without blood, and there was refusal.
In one instance, the mother of two children died.
There are these tragedies. We can go on through tragedy after
tragedy for the want of proper medication.
In another case, the giving of a drug under ideal circumstances
results in fatality.
In a third, ignorance and unwillingness to allow modern trained
physicians to use a therapeutic agent that could be life saving, re-
sults in a fatality.
All of these are merely examples of the constant problems that face
physicians. But many of them face physicians who are far removed
from a hospital or medical center. And there I would not attempt
to come to a conclusion. I would be reluctant and hesitant to tie the
hands of any physician with a therapeutic agent that might, under
some circumstances, be the difference between his offering his patient
an opportunity to survive a serious or perhaps fatal illness, or de-
priving him of any such treatment by virtue of there being no other
tool available at that time in that situation, and the inability to get
into a hospital.
I do not know, and I gather from other testimony that others are
not yet persuaded, including Dr. Goddard.
Senator NELSON. But the National Academy of Sciences has in-
dicated these drugs are for very limited cases, that, in fact, it should
not be used until no other drug would work, and since we have tetra-
cyclines and other drugs-the doctor would then try those first. If
you compare what is happening all over this country with the wide-
spread misuse of this drug compared with the limited number of rare
cases for which it is indicated-well, the doctor would say "I cannot
use chloramphenicol in this case for acne or hang-nail or sore throat
or a nonspecific high fever." He would say "I shall try out one of the
other antibiotics" and I submit you would avoid this kind of tragedy.
Then after a year or 2, I believe you would find the drug would be
limited to the uses for which it is indicated-which is very small,
according to all the experts we have heard.
Dr. ANNIS. I think the record is becoming increasingly clear, Sen-
ator. I do believe that as a result of the testimony of very distinguished
people before your committee, you have enhanced the effort of the
American Medical Association to spread this message.
I have indicated earlier that we intend to expand it, that our Coun-
cil on Drugs has already indicated its willingness to meet with Dr.
Ley and to cooperate and work with him in its behalf.
PAGENO="0417"
COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4707
As Mr. Harrison indicated, Dr. Ley has agreed to an interview
with AMA News, for the specific purpose of a full disclosure of the
most up-to-date information on chloramphenicol and its side effects.
All this has already been done in the sense of establishing the rapport,
the agreement for cooperation.
The only reason that it has not been done as the moment is because
of the many responsibilities on the shoulders of Dr. Ley. He has made
a couple of appointments to meet which have had to be postponed. I
anticipate that much of the desired effects indicated by the Senator
today will be accomplished, and the message will be gotten through
various channels to more and more physicians.
In so doing, perhaps we shall get it down to the rare usage of this
or any other drug. Their use will be limited to occasions when all
indications are that it and only it is the weapon of choice against the
invader of infection.
Senator NELSON. Thank you, Doctor. As I said earlier, I had not
expected that I would cover as small an amount of the material I
wanted to explore, and I made some other commitments. I think
probably it would be helpful if I jotted a note on some of the other
areas that I would like to have you comment on whenever we can
arrange a future date that is agreeable with you.
I think 4 hours-more than 4 hours-is enough time for 1 day, any-
way. So if it is all right with you, I shall not pursue any of the other
questions I have, and we will work out some future date that is con-
venient to both of us.
Dr. ANNIS. Fine. If you will indicate the areas, Senator, as we
have attempted to do in this presentation today. I do hope that you
will have an opportunity to review some of the exhibits and the other
material that we have. I do want to leave with you one we are very
proud of. As I indicated, with a little prompting, I do not know for
how many years, but for 14 years, we have had these continuing
educational courses for physicians.
In all of these, we are dealing with these and similar problems. But
these reflect, and I will see that it is given to the Senator, the continuing
effort of the medical profession. We want to cooperate in every way
possible to inform you and your committee as to what we are doing,
what we are trying to do, our willingness to cooperate, as Dr. Ley well
knows, with the Food and Drug Administration.
If there are particular areas which were not covered in the presenta-
tion, we will be very hapyy to :provide answers.
Senator NELSON. I have a number and I will jot them down in a
letter to you.
I want to thank you very much. I read all the exhibits and all your
testimony this weekend. I always try to read in advance, so your effort
at least was not wasted on me.
Thank you very much for coming here today. We appreciate your
taking time to do so. I realize it is an imposition on you with your
busy practice, but it is a valuable contribution to the record.
Thank you.
Dr. ANNIS. Thank you, Senator.
Senator NELSON. The committee is recessed until next Tuesday,
March 25, at 10 a.m.
(Whereupon, at 4 p.m. the hearing was recessed, to reconvene on
Tuesday, March 25, 1969, at 10 a.m.)
Si-280-----69-----pt. 11-27
PAGENO="0418"
PAGENO="0419"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
TUESDAY, MARCH 25, 1969
U.S. SENATE,
MONOPOLY SUBCOMMITTEE OF THE
SELECT COMMITTEE ON SMALL BUSINESS,
Washington, D.C.
The subcommittee met, pursuant tO recess, at 10: 10 a.m., in the
caucus room, Old Senate Office Building, Senator Gaylord Nelson
(chairman of the subcommittee) presiding.
Present: Senator Nelson.
Also present: Chester H. Smith, staff director and general counsel;
Benjamin Gordon, staff economist; and Elaine C. Dye, clerical
assistant.
Senator NELSON. Our witness this morning is Dr. Marvin Pollard,
who is president of the American College of Physicians.
Dr. Pollard, we are very pleased to have you appear with us this
morning. We appreciate your taking time from your busy schedule
to come here and testify.
Did you sumit some biographical data?
Dr. POLLARD. Yes, before.
Senator NELSON. The biographical: data will be printed in the record
prior to your statement. Your statement will be printed in the record
in full.
You may proceed to present the statement in any fashion you de-
sire. And if you wish to depart from it at any time to elaborate on
anything you have said in your statement, feel free to do so. And I
assume if we have some questions as we go along you don't object to
being interrupted?
Dr. POLLARD. Not at all.
Senator NELSON. Go ahead.
(The biographical sketches follow:)
BIOGRAPHICAL SKETCH OF H. MARVIN POLLARD, M.D.
ACP PRESIDENT HEADS VAST TASK OF KEEPING INTERNIST INFORMED
PHILADELPHIA, PA.-HOw to help the internist remain stimulated and keep fully
informed of the continuing changes in medical knowledge and practice is the job
facing the American College of Physicians (AOP), its new president maintains.
H. Marvin Pollard, M,D., Ann Arbor,, Mich., who has taken the lead in many
new continuing education programs in : the specialty field of internal medicine,
was installed as President of the College in April and will serve until the Col-
lege's 50th Annual Session in Chicago, April 20-25, 1969.
As President, Dr. Pollard will be taking an official part' in a major, 35-year-old
program for continuing education of internists-the annual ACP regional meet-
ings at which leading research investigators, including internists, present scien-
tific papers on clinical studies. Dr. Pollard will attend some of these meetings as
both scientific participant and ACP official.
4709
PAGENO="0420"
4710 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
"The internist must realize his great responsibility in keeping himself thor-
oughly informed with medical progress," Dr. Pollard believes. "He must cope
with the enormous amount of research information pouring out of the various
institutions, as well as with the problems brought about by government-spon-
sored programs such as the Regional Medical Programs, Medicare and Medicaid,
in addition to his concern over family practice and community health."
Dr. Pollard is Professor of Internal Medicine at the University of Michigan
Medical School and Head of the Section of Gastroenterology at the University's
Medical Center.
I)uring the past decade, the 61-year-old internist has served five years as
Chairman of the subspecialty Board of Gastroenterology; served as Secretary-
General of a World Congress of Gastroenterology, and spent two years as chair-
man of the senior staff at the Medical Center's University Hospital.
Dr. Pollard helped organize the first postgraduate course sponsored by the ACP
in South America a few years ago. In 1963 he was made chairman of the ACP
International Medical Activities Committee, which has organized and presented
five subsequent courses in various cities of South America. These courses are
designed for the young teachers in medical schools as well as for practicing
internists.
In this country, Dr. Pollard and his Section on Gastroenterology at the Univer-
sity of Michigan Medical Center have organized and held three postgraduate
courses for the AUP on gastroenterology. These courses have been part of the
ACP's on-going program of continuing education for internists, a program which
provides 20 concentrated, formal postgraduate courses on different subjects dur-
ing each academic year. The courses are held at medical centers throughout the
country.
Dr. Pollard has been "a Michigan man" since the start of his medical career,
having received his medical degree from the University of Michigan Medical
School in 1931. A native of Lamar, Cob. (born, Dec. 7, 1906), he attended school
there and took his premedical course at the University of Colorado.
Dr. Pollard rose through the medical school ranks to become professor of
internal medicine, his present academic title, in 1951. He is certified to practice
internal medicine by the American Board of Internal Medicine and to practice
his subspecialty by the American Board of Gastroenterology.
Among organizations in which he holds memberships are the American Gas-
troenterological Association, the American Endoscopic Society, the American
Federation for Clinical Research, the American Medical Association as well as its
local and state medical societies, the American Association for Cancer Research,
the American Association for the Study of Liver Diseases, the Central Society
for Clinical Research and the Central Clinical Research Club.
He has published more than 100 articles on various subjects in internal medi-
cine with special emphasis on gastroenterology.
Dr. Pollard is a Director-at-large (1966-68) of the American Cancer Society
and Treasurer (since 1962) of the World Organization of Gastroenterology.
Among offices he has held are President (1951-52) of the Washtenaw County
Medical Society and President (1959-60) of the American Gastroenterological
Association. He has also served the ACP as Governor for six years and as Regent
for six years. _______
BIOGRAPHICAL SKETCH OF EDWARD C. R05EN0w, Ja., M.D.
COLLEGE ExECUTIVE DIRECTOR KEEPS IN TOUCH WITH CLINICAL MEDICINE
PHILADELPHIA, PA.-The Executive Director of the American College of Physi-
cians (ACP) is one of a special breed of administrative physicians-the M.D.
executive who likes to keep in touch with clinical medicine.
Edward C. Rosenow, Jr., M.D., who practiced internal medicine for 17 years
before becoming the ACP's Executive Director in 1960, holds the title of Adjunct
Clinical Professor of Medicine at the University of Pennsylvania. Among projects
by which he keeps in touch with the practice of medicine are teaching assign-
ments on the University of Pennsylvania's services at Philadelphia General Hos-
pital and Pennsylvania Hospital.
He serves his specialty also as a member of the Joint Commission on Accredita-
tion of Hospitals, the AMA Residency Review Committee in Internal Medicine
and as secretary of the Council of Medical Specialty Societies, all of which are
involved in improving standards of medical practice. Dr. Rosenow is also on
PAGENO="0421"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4711
the advisory committee for CARE-MEDICO, the international organization of
medical services.
Playing such an active role in the many facets of his specialty has been a habit
with the 58-year-old executive director since his graduation from Carleton Col-
lege, Northfield, Minn. in 1931. He received his medical degree from Harvard
Medical College in 1935 and went on to the Mayo Clinic where, from 1936-40,
he fulfilled his residency requirements in internal medicine. His father, the late
Edward Carl Rosenow, Sr., M.D., was a distinguished physician-bacteriologist on
the original staff of the Clinic.
While at Mayo, Dr. Rosenow received a Master of Science in Medicine degree
in 1939 from the University of Minnesota (Mayo Foundation). His formal edu-
cation completed, Dr. Rosenow moved to Pasadena, Calif. in 1940 to begin his
nearly two decades of private practice. During this time, he undertook many ac-
tivities that provided excellent background for his position as Executive Director
of the College.
He taught at the University of Southern California School of Medicine from
1940 to 1959, attaining the position of Clinical Professor of Medicine. He was
also appointed to the same post at the University of California at Los Angeles
and at the College of Medical Evangelists, both in 1958-59.
From 1951 to 1959, Dr. Rosenow was chairman of the Postgraduate Activities
Committee of the California Medical Association and became Editor-in-Chief of
Audio Digest, non-profit subsidiary of the association, in 1954.
In 1957, Dr. Rosenow retired from active practice to become Executive Director
of the Los Angeles County Medical Association, a position he held until moving
to the American College of Physicians.
Thus, Dr. Rosenow came to the ACP equipped with a well-rounded career of
private practice, medical school teaching and medical society administration. In
addition, he became acquainted with research medicine as President, from 1955
to 1959, of the Charles Cook Hastings Home in Pasadena, Calif., an institution
for tuberculosis research.
Among other organizational offices he has held are presidencies of the Los
Angeles County Medical Association, the Los Angeles Society of Internal Medi-
cine, the Los Angeles County Heart Association, the Huntington Memorial Hos-
pital Staff, Pasadena, Calif., the Alumni Association of the Mayo Graduate
School, the American Medical Writers' Association and the Association of Medi-
cal and Allied Publications.
Currently, he serves as President of the Carleton College Alumni Association
and of the Commission on Professional and Hospital Activities.
Dr. Rosenow is a Fellow of both the American College of Physicians and the
College of Physicians of Philadelphia; a Diplomate of the American Board of
Internal Medicine, and a member of the American Association of Medical Society
Executves and the Professional Convention Management Association. He belongs
to the Philadelphia County, Pennsylvania State and American Medical Associ-
ations.
His honorary memberships include the American Society of Internal Medicine,
the Los Angeles County Medical Association, the American College of Chest
Physicians, the Los Angeles Society of Internal Medicine and the American
College of Gastroenterology.
Among honors and awards are an honorary degree of Doctor of Science granted
in 1967 by Carleton College; the Distinguished Alumnus Award of the University
of Minnesota, given in 1965 and the 15th Peter Bohan Lectureship of the Univer-
sity of Kansas School of Medicine, delivered to the 1966 graduating class.
He has written papers on blood groups in China, published in the National
Medical Journal of China; "Extreme Cardiac Hypertropy," published in Mm-
nesota Medicine, "Cahicification of Renal Pappillae," published in the Journal
of Urology and "Septicemia," published in the Proceedings of the Staff of Mayo
Clinic.
Dr. Rosenow, who resides in Philadelphia, is married and has two children.
He is a member of St. Christopher's Episcopal Church in Gladwyn, Pa., the
Merion Golf Club, the Racquet Club and the Faculty Club of the University of
Pennsylvania.
PAGENO="0422"
4712 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
STATEMENT OP DR. H. MARVIN POLLARD, PRESIDENT, AMERICAN
COLLEGE OP PHYSICIANS; ACCOMPANIED BY DR. EDWARD C.
ROSENOW, JR., EXECUTIVE DIRECTOR
Dr. POLLARD. I think to open with I will read this prepared state-
ment word by word, and then we will proceed from there if there are
any questions.
My name is Dr. H. Marvin Pollard, and I am the president of the
American College of Physicians. I am also a professor of medicine
at the University of Michigan School of Medicine. With me is Dr.
Edward C. Rosenow, Jr., the executive director of the American
College of Physicians. He holds a faculty appointment at the Uni-
versity of Pennsylvania School of Medicine as a clinical professor of
medicine. The comments I wish to make are my own.
STATEMENT OF FACTS
The American College of Physicians is a corporation organized
under the State laws of Delaware in 1915 for educational and scientific
purposes and except under section 501 (c) (3) of the Internal Revenue
Code. The college has, at the present time, approximately 15,000 mem-
bers throughout the United States and Canada, with a few members
located in Mexico and the Central American countries. All of the
members are specialists in internal medicine and allied specialties.
The headquarters office is in Philadelphia. Pa.
The object of the college, as stated in its constitution, is to maintain
an organization of qualifIed in the field is to maintain an organization
of qualified physicians in the field of internal medicine and its allied
specialties for the following purposes:
1. Maintaining and advancing the highest possible standards in
medical education, medical practice, and research.
2. Preserving the history of perpetuating the best traditions of
medicine and medical ethics.
3. Maintaining both the dignity of internal medicine and the
efficiency of its function in relation to public welfare.
All of the educational activities of the college are open to non-
member physicians as well as members and all of the financial aid
programs such as scholarships, fellowships, and residency loans are
available only to nonmember. The ultimate beneficiary of all of these
programs is the general public.
In order to carry out these functions, the college conducts numerous
seminars and postgraduate courses. These are presented throughout
the year and are held at various locations in the United States and
Canada. There are numerous regional meetings during the year, con-
ducted for the benefit of the college members and nonmember physi-
cians. Once each year a large national scientific meeting is held, which
lasts for 5 days, with four large scientific sessions going on simultane-
ously. The meeting last year, in Boston, in April of 1968, attracted
3,159 college members and 2.073 nonmember physicians.
The college publishes a monthly medical journal, called the Annals
of Internal Medicine which contains scientific articles and reports of
new developments of importance to its readers. This outstanding mecli-
cal journal is distributed all over the United States and, in fact, all
PAGENO="0423"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4713
over the world. In addition to college members, the journal is mailed
to over 32,000 nonmember physicians, students, hospitals, and medical
libraries.
Included in the journal are advertisements for pharmaceuticals,
medical equipment, and medical textbooks. All advertisements are
carefully screened by a special committee to insure that they are con-
fined to products related to the care of patients by specialists in in-
ternal medicine or in allied specialties.:
Senator NELSON. May I interrupt a moment.
Dr. POLLARD. Yes.
Senator NELSON. Do you have some established principle that the
ad must conform to?
Dr. ROSENOW. Yes; Senator. You~ have there this folder that is in
blue. That is the policy statement and the code for advertising that
we use for our advertising. The committee consists of four members,
physicians, who screen each ad that comes along. We establish gen-
eral policies as to how they should be done. And briefly, that is our
primary concern at the present time. It is somewhat easier than it used
to be because of the requirement of Food and Drug that you have to
put in the information that is in the informational leaflet. But our job
is to see that the ad does not exceed the claims in this product in-
formation brochure. And also that it refers to internal medicine or
the allied medical specialties. We don't take anything that does not
relate to our specialty.
Senator NELSON. Thank you.
Dr. POLLARD. In a recently released report by the Government Task
Force on Prescription Drugs it was pointed out that physicians rely
to a considerable extent upon advertising by the pharmaceutical
manufacturers for their knowledge of drugs. The advertising carried
in the Annals of Internal Medicine compliments the other educational
activities of the college. Attached hereto is a copy of the December
1968 issue of the Annals of Internal Medicine, to be made a part of
this report, as exhibit A.'
I think you have a copy there before you.
Mr. GORDON. May I ask you a question at this point?
Dr. POLLARD. Yes.
Mr. GORDON. Do you have any idea how many ads you rejected in
the last couple of years?
Dr. ROSENOW. I could get accurate information as to that. I would
say many less than we did 4 or 5 years ago before the new regulations
came along, because at the present time the ads are a little bit more
stereotyped. But I know now that we have turned down at least
several. One that I can remember is one of the penicillin agents in
which the statement was made that this should be the doctor's first
thought in infection. Our committee felt that it should be about the
second thought in an infection. The first thought should be to prove
the infection was due to an organism that would be susceptible to
this agent, and we wanted them to put it this way. And at that time
they decided that they would not do it. So we did not run the ad
for a couple of years. As a matter of fact, this company canceled all
of its penicillin advertising in the annals for several weeks. And I
think they felt that this w~ould make us feel pretty bad. And it did
Exhibit A has been retained In committee files.
PAGENO="0424"
4714 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
not. And I notice that just recently they have submitted copy which
includes our recommendations. This is one that I can remember.
Senator NELSON. What company was that?
Dr. ROSENOW. I would have to rely on my memory for this, but I
can furnish this for you. I really would prefer to go and look it up
and submit it to you.
Senator NELSON. Would you submit it for the record?
Dr. RosExow. Yes. And I would be glad, if you would like, to give
you information about any other ads that we have ref used.1
Senator NELSON. Thank you.
Dr. POLLARD. There are other activities of the college worthy of
note, all intended to make physicians better able to administer to
the health requirements of the public. Teaching and research scholar-
ships are granted for a period of 3 years. The 1969 budget contains
$116,500 for this purpose. A residency loan fund of over $~OO,OOO
is used to assist young physicians to pursue graduate training in
accredited mstitutions. Annual appropriations are made to the Joint
Commission on Accreditation of Hospitals, by the American College
of Physicians in cooperation with other national medical associa-
tions, to underwrite the administrative costs of this organization
which seeks to assure the general public of receiving highest quality
medical care when hospital confinement is necessary. The appropria-
tion for 1969 is $43,253.
An innovation in medical education was started by the college 2
years ago. The medical imowledge self-assessment program is a very
comprehensive examination of approximately 700 questions covering
the entire field of internal medicine. The physician, on a purely volun-
tary basis, answers the questions, then takes the correct answers out of
a sealed envelope and marks his own answers. The confidential nature
of the assessment encouraged 11,000 physicians, both members and
nonmembers, to participate.
Senator NELSON. May I ask a question there?
Dr. POLLARD. Yes.
Senator NELSON. How many members did you say are affiliated with
the American college?
Dr. RosENow. Just under 15,000.
Senator NELSON. And how many of your own members took the
self-assessment examination?
Dr. ROSENOW. 6,375.
Senator, I might qualify this a little bit by stating this, that we have
about 4,000 of our members who are in allied medical specialties who
might not take this examination. For example, dermatologists, neu-
rologists, phychiatrists, radiologists, and pathologists belong to our
college and are a part of the total number, so they would not be expected
to. I think the 6,375 realistically represents a little more than 60 per-
cent of the ones who would benefit by taking this one.
Senator NELSON. I notice that a couple of clinics with which I am
familiar require their physicians to take the self-assessment exam. Is
this a widespread practice?
Dr. POLLARD. I will answer that. I think that it will be increasingly
widespread. As I go on in this description here you will find that it is
being adopted not only in this country but in areas overseas. So I
~ See information beginning at p. 4734, infra.
PAGENO="0425"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4715
am sure that it will be utilized. It is utilized in many ways in this
country by the young individuals preparing for examinations, and by
older individuals who want to reassess their own knowledge. And I
would not be at all surprised but what on an individual basis clinics
may well require it.
Senator NELSON. Thank you.
Dr. POLLARD. This idea has since been adopted by several other
national medical organizations and the American College of Physi-
cians' medical knowledge self-assessment program is now being trans-
lated into the German language for the use of the German medical
community. We were recently informed that the program is being
used in South Africa, in their education program.
Dr. RosENow. May I interrupt here, please. On this test translated
into German-and this is very appropriate to the hearing that you
are having. As you know, many foreign countries depend even more
for their educational efforts in medicine on pharmaceutical companies.
I am not absolutely sure that we are going to go through with this,
because I have not yet gotten from the German colleagues that want
to do this conformance to what our agreement with them was. One of
the agreements that we made was that they would have to distribute
this exactly as we printed it originally. And what they want to do with
it is send it out in serial form, cooperating with a drug company that
wants to put some ads in it. And we have refused to do this. So we
may not do it, because we do not want to get mixed up in a kind of
gimmick for selling drugs.
Senator NELSON. Thank you.
Dr. POLLARD. There are other programs that the college uses to fulfill
its purpose. Unlike many educational organizations, it makes no public
appeal for gifts, neither does it receive support from the Government.
The principal sources of funds are dues, subscriptions and advertising
from the Journal, exhibits at the annual scientific session and income
from investments.
Senator NELSON. May I interrupt? Doesn't the breakdown, I think it
is your exhibit B, show the specific sources, that is, how much of the
income is from journals, exhibits, investments? Do you have that
figure?
Dr. RosEwow. Yes, Senator, I can give it to you in more detail later
if you like. At the present time-let us take 1968. When you first told
us what you wanted, you wanted the breakdown between advertising
revenue. And we have given you this. But in addition to the break-
down in. the other total revenue, other than the Journal, the largest
amount is $370,438 in dues, $33,000 in initiation fees. We have a total
of about $160,000 of income from our endowment investment. And we
have $187,000 of income from postgraduate tuition fees. This is al-
most-they go right out on the other end as expenses, so we do not
really make anything on this. The medical knowledge self-assessment
program, when we originally handled it we estimated a deficit of $90,-
000 and now we-I hate to use the word profit-but an excess over ex-
penses of about $50,000.
Exhibit income is $121,000. Guest fees are $22,000.
This, however, I must also tell you, is not an even balance, but on our
annual session we go in the hole about $48,000 over this income.
Senator NELSON. The income from what kind of exhibits?
PAGENO="0426"
4716 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY
Dr. ROSENOW. This is for what we call our technical exhibits, which
is the place where the pharmaceutical companies, the instrument people
like electrocardiogram machinemakers, and other diagnostic things
that are used in our profession, and book publishers.
Dr. POLLARD. Textbooks.
Dr. ROSENOW. There are about 200 exhibits at our annual session.
Senator NELSON. And these are the only exhibits? Do you have re-
gional sessions?
Dr. RosENow. We have regional meetings but not regional exhibits.
Senator NELSON. And what amount of the exhibits is income from
pharamceutical manufacturers exhibits?
Dr. RosExow. Versus the others?
Senator NELSON. You gave a total on the exhibits. What amount was
pharmaceutical?
iDr. IROSENOW. I would have to go back and actually count that up.
But I would imagine it is about two-thirds.
Senator NELSON. Would you submit that for the record, also?
Dr. ROSENOW. Yes, sir.
Senator NELSON. And on the income from advertising, as I under-
stand the testimony of Dr. Pollard, it is advertising from-
Dr. ROSENOW. Internal medicine advertising.
Senator NELSON. From pharmaceuticals, books, scientific instru-
ments. What amount of the subscription revenue is pharmaceutical
advertising?
Dr. ROSENOW. I would have to look this up. I can submit this to
you.' I would suppose it is about the same.
Senator NELSON. Two-thirds?
Dr. ROSENOW. I would think so.
Senator NELSON. You used the figure subscription revenue on ex-
hibit B, subscription revenue net of commission. What do you mean
by that?
Dr. ROSENOW. Excuse me, I did not get it.
Senator NELSON. In exhibit B you used the figures subscription
revenue net of commission, and then you have advertising revenue.
Dr. RoSExow. Right. I would suppose that more than half of our
subscriptions for the Journal which come from nonmembers comes
through an agency that takes up subscriptions. This is quite common
in medical publications, that a man puts all of his medical journal
subscriptions through one agency. And I believe the discount there
is 15 percent.
In the advertising revenue the same thing. Very few of the phar-
maceutical companies, for examples, put their ads in with us direct,
but go through an agency. And this is what that is called. And the
discount is 2 or 3 percent if they pay by the end of a certain period
of time.
Senator NELSON. So what you are referring to, then, is the adver-
tising revenue received by the publication after payment of the fee,
15 percent of whatever it may be to the advertising agency that places
the ad?
Dr. ROSENOW. That is right. It is money that we can use.
Senator NELSON. I have one more question. What kind of invest-
ment? Do you have any pharmaceutical investments?
I See p. 4734, infra.
PAGENO="0427"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4717
Dr. ROSENOW. We do not restrict-we do not ordinarily take phar-
maceutical ads, investments, but wo do not say that we cannot. I
would say at the moment that we do not have any, but I am not ab-
solutely sure. We had Smith Kline & French a few years ago, but we
do not have that any more. We do not have a policy against it. This
is run by an investment company we work with, Drexel, Harriman &
Ripley Investment Counselors. We are a little bit touchy about to-
bacco investments; we do not take those. But we have no firm rule
against it. So that essentially I would say that we would have to be
a little extra persuaded that a pharmaceutical company was a good
investment for our college.
Senator NELSON. If you have an investment in pharmaceuticals now,
would you notify the committee as to what they are?
Dr. RosENow. Yes.
Dr. POLLARD. I believe it is true that there are none in pharma-
ceutical houses at the present time.
Senator NELSON. Thank you.
Dr. ROSENOW. You asi~ed the total amount of our investment
account.
Senator NELSON. Yes.
Dr. RosENow. I would also have to furnish this. But I think at its
mark value it is somewhere around: $3 or $31~ million.
Senator NELSON. Please go ahead.
Dr. POLLARD. Because of increased activities, additional office space
is required. We are in the planning stages of plant expansion which
could cost up to $1 million. The funds to pay for this addition must
come from the sources mentioned above.
A committee on diagnostic and therapeutic agents has been ap-
pointed recently under the chairmanship of Dr. Carter Smith, of At-
lanta, Ga. They plan a continuing study of all aspects of these agents.
Although no specific policy statements have been developed on some
of the matters of concern to your committee, such policy statements
will be forthcoming from time to time. 1-lowever, the following gen-
eral comments I believe fairly represent what would reflect the atti-
tudes of a majority of our members:
COMPENDIUM
Physicians must have accurate, up-to-date information about drugs.
A number of methods are helpfulin this regard. Physicians' Desk Ref-
erence is a convenient source of information about the drugs included,
but is incon'iplete. The objection raised that there is no editorial review
of what goes into PDR has been corrected by requiring that the FDA-
approved package insert information be included.
Senator NELSON. The FDA doesn't require the PDR to print the
whole package insert. I think it requires that it conform to it, however.
Dr. ROSENOW. That is right. But PDR has adopted, I believe, that
they put in the product insert as their writeup.
Senator NELSON. In toto?
Dr. RosENow. I believe so.
Senator NELSON. I did not realize that.
Dr. POLLARD. That is essentially what the PDR is.
Senator NELSON. From some that I have looked at in the past, it was
PAGENO="0428"
4718 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
my impression that they were condensations of the package insert or
that the requirement was that they conform and not conflict.
Dr. ROSENOW. I am not absolutely sure of that, either. I have been
told that the PDR editors themselves are requiring this.
Senator NELSON. The committee counsel reminds me that there
have been recent corrective "Dear Doctor" letters based on the advertis-
ing in the PDR which did not conform to FDA regulations in the last
2 years.
Dr. ROSENOW. I believe that is correct. I think my information ~
this is that it is only very recently that they are doing this.
Dr. POLLARD. I have the impression it was in the last 2 years.
Senator NELSON. We will check it. Please go ahead.
Dr. POLLARD. The AMA's Council on Drugs has announced a new
publication, "AMA Drug Evaluation." When available, this should be
a very useful reference book. We are impressed by the preliminary
chapters which have been circulated.
Probably the most useful source of information is the advice and
counsel of a physician's colleagues. Very few physicians prescribe a
new drug for the first time without discussion with colleagues or hav-
ing read about it in a first-class journal article, or having heard about
it at a medical meeting.
Direct-mail advertising, journal advertising, exhibits at medical
meetings, and the work of detail men are all important sources of in-
formation. It must be recognized, however, that the latter, though giv-
ing the doctor accurate information, are primarily directed to selling
products. We believe our physicians accept advertising for what it is
in our free enterprise system and judge it accordingly.
We would have no objection to a compendium, and certainly would
approve the inclusion of generic and trade names. Probably the in-
clusion of the chemical name should also be included. We are not
convinced that inclusion of prices would necessarily reduce the cost
of drugs to the consumer.
Senator NELSON. Why do you think that?
Dr. POLLARD. I think largely because the actual pricing is out of
the hands of these people-because the actual pricing is out of the
hands of anything that is listed in the book.
Senator NELSON. I do not follow that.
Dr. POLLARD. It is not the responsibility of the book to dictate the
final selling price.
Senator NELSON. But might it not make a difference if the price
were stated, in other words, if the doctor had a choice between several
companies, and the drug of one of them was a fraction of the price
of the other, might that not affect the price to the consumer?
Dr. POLLARD. I can seen where that should influence it, or it could
influence it.
GENERAL PRESCRIBING
In general, our view would be that each physician should use his
own judgment about how lie prescribes a drug. It has never been
shown that generic prescribing necessarily insures comparable quality
or a lower price. The experience with chioramphenicol and Chioro-
mycetin is an example much cited. A sutcly in Chicago by the AMA
indicated no relationship existed between prices of drugs ordered
generically even in the same drugstore chain.
PAGENO="0429"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4719
Senator NELSON. May I interrupt a moment, Doctor? If the brand
name is the only drug that the drugstore has stocked, because that is
the name the doctor is prescribing most frequently, then when the
pharmacist receives a prescription using the generic name, he can sub-
stitute any brand name he wishes. Therefore, in the AMA study, the
patients probably got the same drugs, whether they were prescribed
by the brand or generic name. And many drugs that are cheaper may
not be stocked at all simply because~ the doctor is prescribing them
by brand name, and under the law in some 40-odd States a pharmacist
cannot substitute another brand or another generic name. So the test
that was used by the AMA in my judgment was not a fair test of the
issue. The fact that the drug was ordered by generic name didn't
mean that it was supplied on that basis.
Dr. POLLARD. I have not any great comment on that.
Senator NELSON. I might add that a year ago the Peoples Drug
Stores and the Gray's Drug Chain, one out in Ohio and the other
here, announced that they were going to stock a line of generic drugs
manufactured by Strong, Cobb & Arner, and that in their public
statements the price of the generic would average one-half of the
brand name, which I think is a pretty convincing case to demonstrate
that you could get a lower price from the generic. And Strong, Cobb
& Arner, of course, is a very distinguished generic manufacturer.
Dr. POLLARD. Well, I am impressed with that statement.
Senator NELSON. Please continue.
Dr. POLLARD. We are told by pharmacologists that equivalency is
sometimes variable merely by the physical methods of drug prepara-
tions. In some hospitals, where it is possible to have a committee of
physicians review all drugs, purchasing drugs by generic titles can
save considerable sums of money. Physicians sometimes prefer to order
certain drugs by trade name merely because they can identify the
various pills they have prescribed for a patient who might call by
telephone to ask question about his medication. Most physicians really
believe they can be more confident their patients will get reliable, con-
sistently potent drugs if they prescribe products made by firms in
which they have confidence.
Senator NELSON. Why do doctors believe that?
Dr. POLLARD. I think in most instances they believe it because of past
experience.
Senator NELSON. What experience could they have had that would
indicate otherwise? Most of them prescribe brand names anyway.
How would they get the experience? Wouldn't the experience be
testimonial?
Dr. POLLARD. Sometimes when a drug house comes out with a drug
product in the beginning they look upon that as being a dependable
drug, as with any new product that comes on the market. And I am
afraid that they then get into the habit of prescribing that drug be-
cause they have learned how to use it and depend upon it.
Senator NELSON. But your statement is that physicians believe that
they can be more confident that their patients will get reliable, con-
sistently potent drugs if they prescribe products made by firms in
which they have confidence. I do not quarrel with your statement. I
think that is probably what they do believe. But my question is, What
scientific foundation is that belief based on?
Dr. POLLARD. It is just based on their past experience.
PAGENO="0430"
4720 CO~ETITIVE PROBLEMS ~ THE DRUG INDUSTRY
Senator NELSON. The one large test that we have had that I am
aware of in the last 2 years was the FDA report on 4,600 drugs re-
leased October 15, 1966, from 250 manufacturers in which 2,600 were
generic drugs that they had tested and 2,000 were brand names. And
the generics had a better potency, consistently met the standard for
potency better than the brand names. In fact 7.8 percent of the generic
products were not of acceptable potency, they varied from the TJSP
standard, the established standard, 7.8 percent of the time. But with
the brand names, 8.8 percent varied from the potency standard. I just
raise this question because I think the fact is-it is my judgment from
looking at this over a period of 2 years of hearings-that what has
happened is that the brand name companies have convinced the physi-
cians of this, but there is no scientific basis for that.
Dr. ROSENOW. Senator, this statement in itself is true.
Senator NELSON. I do not doubt it. I said I did not quarrel with
that.
Dr. RosENow. When we wrote this up we recognized that it is prob-
ably possible and susceptible of proof that they should not believe this
way. But I think it is a fact that they do believe this way. And it is a
little bit like everything that you buy in this country, some people
have confidence in one kind of product because it is made by a certain
company. Even though your experience might be different from this,
you may have a lot of different things that you do this way.
I would also say that part of it is-I think what you do is sort of-
let me take the drug digitalis, for example. I am a physician who likes
to use the whole leaf digitalis. I always used the Davis Rose digitalis,
not because I really thought it was a lot better, but because as far as
my treatment of this patient was concerned I could do it better by
knowing that I always prescribed this same kind of pill. For one
thing, it was easily identified, because it was a kind of a round pill
instead of an oblong one, and when they called up and wanted to know
whether they should take one less pill or one more-digitalis is a pretty
toxic drug-I felt more confident if I knew they had this. I recognize
that there are many good products of digitalis, including generic ones,
that I could have used. We are just trying to make a point that this is
one of the reasons why doctors are opposed to not being permitted to
prescribe by brand names.
Senator NELSON. I could not in any way differ with you in your
statement. I think it is absolutely correct. A substantial percentage,
maybe a large percentage, of the medical profession are more con-
fident of the consistency and potency of the brand name drug than the
generic even though the tests do not come out that way, and perhaps
the generics are better. The reason I raised the questioii is that it does
involve the issue we have been raising over the past few years, that is,
the very powerful influence of the propaganda of the manufacturers
upon the medical profession. And consistently that statement is made
before this committee-the same statement that Dr. Pollard says they
believe in, which I think is an accurate statement. Many of these who
testified and commented on it simply asserted flatly that it is a fact.
And this committee has been raising the issue of the effectiveness Of
the promotion by the companies of their products under their brand
names versus generic names, and so forth. And that is why I raise
the issue here, that so far as testimony before this committee, we have
PAGENO="0431"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4721
not been able to find any evidence that demonstrates that the generic
or the brand, either one, was any better than the other, consistently or
otherwise.
Thank you.
Dr. POLLARD (reading).
DETAIL MEN
Many detail men offer the physician useful information about a
product lie is selling. Many times he renders a real service in getting
a supply of a medicine his company makes in small amounts for rare
diseases. If he is the kind of man who is poorly trained or a pressure
type of salesman, his chances of getting to see the doctor again are
pretty slim. In other words, there are detail men both good and bad
and most physicians have no difficulty telling the difference.
TESTING DRUGS
Drugs should be treated by someone who knows about testing drugs.
Many of our members are superb clinical investigators and do in fact
carry on a lot of the clinical testing of drugs. With the kind of regula-
tions being required by FDA, it would seem logical that the experts in
a pharmaceutical company should continue to test drugs. Any good
company would be as interested as anyone else in the quality uniform-
ity and effectiveness of its products.
RELATION OF DRUG INDUSTRY TO THE MEDICAL PROFESSION
It would seem obvious that such a relationship would be a close one,
because the therapeutic agents developed by the pharmaceutical com-
panies can only be used for patient care upon order of a licensed physi-
cian. Probably the physicians exert more control over the industry
than vice versa. In any case, we will attempt to delineate what rela-
tionship exists between the American College of Physicians and the
pharmaceutical industry.
As we have already stated, the college's only function is to pro-
vide its members and other physicians with adequate educational op-
portunities in our specialty. One part of this educational activity re-
lates to educating the physician about drugs and other therapeutic
agents. Although the college's educational program is much broader
than offering only information about drugs, we will outline at this
time the ways in which we help educate physicians about drugs.
The college publishes the Annals of Internal Medicine which is
the leading journal in our specialty. Its circulation is 47,000, of which
approxmiateiy 15,000 are members of the American College of
Physicians.
In this journal, as you can see, we display advertisements for a
variety of products, including drugs, instruments, books, and educa-
tional opportunities. The policy of the college is that advertising
pages will occupy no more than 40 percent of the total. Usually the
percentage is less than this. Each advertisement is subject to review
by a committee of four physicians. The work of this committee has
been considerably lessened since the FDA rules on advertising copy
have been adopted. However, the committee does look carefully at
PAGENO="0432"
4722 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
the copy and determines whether claims or emphasis are in keeping
not only with the FDA required information but in addition conform
to good medical practice. If one member of the committee Votes against
an ad, it is reconsidered by the committee and the ad agency is noti-
fied and requested to make changes. Usually the required changes are
made and the ad is approved. If changes are not made, the ad is de-
clined. And we will supply you with the number that we have declined
in the past 2 years.
The decisions are based upon adherence to the code which is fur-
nished to all advertisers-copies are herewith included.'
The college has resisted all efforts by the advertisers to incorporate
ads within the editorial pages of the journal. As a matter of fact, we
separate the editorial pages from the ads even more by having the
executive director be in charge of the advertising and publishing of
the journal and by restricting the two physician editors' responsibil-
ities to the editorial pages.
The income we derive from journal advertising is considerable and
one of the principal sources of income. However, it can in no way
be considered of such importance that the college would change any
of its policies in order to maintain this income. Furthermore, the
percentage of advertising income related to total journal income (sub-
scriptions plus advertising) is probable smaller than comparable fig-
ures from newspapers, nonmedical magazines, and medical journals
published by commercial publishers. The controlled circulation jour-
nals such as Modern Medicine, MD and Medical Economics depend
entirely on journal advertising revenue.
Our percentage of advertising income related to the total income
of the college for the past 5 years is attached, labeled exhibit B.'
Inasmuch as this income is used completely in the total continuing
education program for physicians, we feel it offers a way in which
physicians may participate in our programs at a lower cost. If
the physician has to assume the entire cost of his educational activi-
ties, the costs would be passed on to the public in higher fees. In any
case, the public benefits by this arrangement through the education
of physicians.
The college sponsors an exhibit at its annual session. The same rules
apply to screening the exhibits to be sure they are of high quality and
have relevance to our specialty. Last fall, we surveyed physician atti-
tude about our annual session. Of interest to you should be the fact
that 86.4 percent of the respondents voluntarily visited the exhibits
regularly and 86.7 percent of these found them to be informative and
useful. The total physician registration at the Boston annual session
was 5,232. The net income incidentally from this activity falls far
short of paying the entire cost of the annual session.
We do have a few other activities sponsored jointly with drug com-
panies. You should be interested in the general policy of our college
regarding good will support of an activity by a drug company. It is as
follows:
The college does not solicit drug companies for financial support of any of its
activities but will consider accepting any grants offered on an individual basis.
See pp. 4730-4733.
PAGENO="0433"
COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4723
The following are important activities supported in part by phar-
maceutical companies:
1. Smith Kline & French has for 20 years operated sophisticated
color television equipment in order that we can conduct hospital clinics
at the time of our annual session and bring these conveniently to the
doctors at the site of the session. All parts of the program are planned
by the American College of Physicians. Smith Kline & French is re-
paid solely by acknowledgement in the program that the technical pro-
duction of the TV program is sponsored by them.
2. Mead Johnson & Co. furnishes the college with 14 fellowships
which the college grants to young men during their training. Inci-
dentally, prior to 1962, this company furnished $3,500 for entertain-
ment at our annual banquet. In 1962, we declined further support of
this activity and suggested increasing the number of fellowships ac-
cordingly. Thus, $4,000 more was granted for this purpose by Mead
Johnson.
3. The Wyeth Foundation for Postgraduate Medical Education
has over the years helped finance new parts of our annual session pro-
grams. A new section devoted to basic science lectures was given fi-
nancial support. Recently a part of our program called "Meet the Pro-
fessor" was given support.
4. Merck Sharp & Dohme recently offered to support several of our
postgraduate courses in South America. Several years ago, they fi-
iianced a film which one of our committees planned. The title of this
is "Portrait of an Internist." It is an excellent educational film which
depicts for the public what a specialist in internal medicine really does.
It has had widespread appeal and we are told it has been shown to
approximately 10 million people over public television and at public
meetings. No products are mentioned and only a line of credit is given
to the company.
5. The Eli Lilly Co. has offered some support to our postgraduate
courses in South America. Parke, Davis & Co. and the Kellogg Foun-
dation have also helped us start these important programs. The Kel-
logg Foundation incidentally has also provided financial support to
a Latin American fellowship activity which our college supervises.
In this program, young medical school teachers from South America
are brought to this country for a period of training after which they
return to their own countries. : Of interest also is the fact that all of
these 200 teachers have remained in their own countries.
Each year the college awards two honorary fellowships. These are
made to distinguished medical scientists from other countries. They
are brought to our annual session where they give lectures and receive
their honorary fellowship. Eli Lilly supports the cost involved in
bringing one of these and the college finances the other. Both are se-
lected independently by the Committee on Awards of the College of
Physicians.
We think all of these activities are manifestly in the public interest
and indicate a wholesome and worthwhile relationship between our
college and the drug industry. We remind you again, however, that
what we have just described is only one small part of our entire edu-
cational program.
Senator NELSON. *Thank you very much, Doctor.
Do you recall an article or a study that was made by Upjohn last
fall? Sometime in November of 1968 Upjohn released a study they had
81-280-69-pt. 11-28
PAGENO="0434"
4724 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
made on tolbutamide. They are the only manufacturers, and they took
the standards of DSP which were, in fact, the standards of th~ coin-
pany, because it was the only product in the market. And they set up
a comparison making some variances in the production of the drug
product, yet staying within the DSP standards which, as I say, were
the standards of the company, a.nd those were the only standards there
were. They came out with a result which showed that the two drug
products were not equivalent. And the Journal of the American Medi-
cal Association on November 18, 1968, ran an article entitled "The
Generic Inequivalence of Drugs."
Did your publication treat with that at that time?
Dr. RosENow. I don't know without looking. You mean on this
same subject?
Senator NELSON. In other words, did your journal report this find-
ing which was reported in the American Medical Association?
Dr. RosENow. It would be unlikely, Senator. If the article was
published in another journal, they would not submit it to us as well.
It is seldom that an original article is submitted-it may be submitted
to several journals, but the editors do not particularly like to publish
it. They have a little pride of ownership, as they call it. So I do not
think there would be any likelihood that it would be published in two
places. The one thing that might happen in our journal is-and I do
not know whether it did in this instance-is that someone else might
refer to this article in, say, Clinical Notes, or something like that. But
it would not be an original article.
Senator NELSON. And you do not know whether your publication
commented on that editorially or otherwise?
Dr. RosExow. No; I do not.
Dr. POLLAED. I am not familiar with it if they did.
Senator NELSON. That occurred November 18 in JAMA. Would
you mind just checking since November to see what coverage your
publication gave to it, if any?
Dr. ROSENOW. Yes; I would be glad to.'
Senator NELSON. I want to thank you very much for your testimony.
I just make this point. You have been raising the point here, and others
who testified have expressed the view that the relationship between
the pharmaceutical manufacturers and the medical profession is not
an unhealthy one. I think there is some question to be raised about
that. But we notice in the testimony we have had that you have phar-
maceutical manufacturers starting out at the medical school level
and supplying various things to the students, stethoscopes, medical
l)ags, research grants, and so forth; most of the journals receive sub-
stantial support in advertising from the pharmaceutical manufac-
turers; they provide income from exhibits at conventions; that they,
in fact, in some instances-in one instance that we know of, paid part
of the cost across the board in sponsoring of conferences, the medical
conference itself, that there are free samples directly to doctors; that
detail men see the physicians regularly, and $4,000 to $~,000 per year
is spent in advertising per physician in the country; that the medical
press, as contrasted with the journals, many of them are 100 percent
supported by advertising by the pharmaceutical manufacturers; that
you almost never see a critical editorial of the pharmaceutical manu-
~acturers themselves.
1See p. 4734, infra.
PAGENO="0435"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4725
I have never seen one. I do not say there have never been any, I
have never seen one; news stories about the industry, especially when
there have been conspiracies as to prices, seem to have played them
down in the medical press if covered at all; that the AMA itself gave
wide prominence to tolbutamide IJSP which Dr. Miller of the USP,
destroyed by his analysis of it; that the task force report of the FDA
found a significant difference in generic and brand names does not
seem to be covered in the medical press very prominentl,y at all; that
the 4,600 drug tests do not seem to be publicized widely if at all; and
that the testimony before this committee-I am not referring specif-
ically to anything in particular to any of yours, I am just referring
generally-by representatives of medical groups and by individual
doctors recites consistently exactly the same arguments that the phar-
maceutical manufacturers made; that you cannot trust the generics,
that they are not equivalent, that brand-name companies do research,
and therefore they are entitled to our support, that in general, as I
said, the one group of people whO are qualified in the profession to
make criticisms of practices in the profession-practices by the man-
ufacturers-is, I think, effectively silenced by the close information
check.
Now, there have been very distinguished individual physicians,
pharmacologists, clinicians, and experts of various kinds who have
made some very strong criticisms~ of the practices of the pharmaceuti-
cal manufacturers in relationship to the subject, but we did not find
that, at least I did not, in the journals I look through or in the medical
press. So does it not really raise the question that there is a very close
relationship here, just in the nature of it, and everybody is so friendly
that everybody ends up by not criticizing anybody else; is not that the
kind of thing we get?
Dr. POLLARD. Well, Senator, if I may express my own reaction to
your comments, my information and my knowledge about this prob-
lem is really not in keeping with your comments.
Senator NELSON. Pardon?
Dr. POLLARD. I said my reaction and my knowledge is not in keeping
with the comments which you have just made.
And let me tell you why I say that. Your one comment was that there
were very few if any critical comments about drugs or pharmaceutical
products appearing in medical journals. Is that-that has not been my
experience. In medical journals-and I brought with me a group of
programs of regional meetings throughout the United States just the
past 12 months, and I ticked off in here the papers that were presented
in all of these relative to drug intolerance, drug sensitivity, damage to
the liver, damage to the stomach-
Senator NELSON. Were these papers delivered at medical confer-
ences?
Dr. POLLARD. Oh, yes. These are regional meetings of the American
College of Physicians-and by region I mean usually a State or, in
some instances, two or three States together. Now, these are just our
ways and means of educating our physicians. And all I am doing is
pointing out that I think we attempt to keep the doctor educated by
meetings. By publications, by articles in the annals, and by our annual
scientific sessions, plus our postgraduate courses on all of the complica-
tions that go along with it. And then for that reason, while we must
PAGENO="0436"
4726 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
maintain close cooperation with the drug conwanies-I would not deny
that 1 single minute, because we are dependent upon drug companies in
a great way for the development of new products and for the refine-
ment of products-yet we are totally independent in our opinion and
decision as to how effective those products are.
Senator NELSON. I wasn't suggesting that at medical conferences the
profession did iiot call upon its most distinguished members to present
the best possible papers on all aspects of medicine. I don't suppose
you could find experts who would be willing to say anything other than
what they believed in at these conferences, and I could not expect that
anyone in the profession would think that any other presentation ought
to be made in medical conferences. I was raising the question as to what
the publications themselves really say about practices in the industry.
For example, what kind of prominence did your publication give to
the FDA findings on 4,600 drugs in which the generic caine out bet-
ter in terms of potency than brand names?
Dr. ROSENOW. May I try to clarify a little bit how this operates.
If a physician or a clinical investigator interested in that report would
send to our journal an article that lie wanted to put in here about that,
then our editors would do this.
Now, sometimes our editors look for these things themselves, and
would write au editorial about this. I am quite sure that in this par-
ticular instance this was not done. And we do not have a mechanism
where we screen every single release that comes out from the Food
and Drug or from any of these other agencies. But our editors would
not hesitate to put this in if they felt and their editorial staff felt that
this was important information for our members to get.
Senator NELSON. The point I am making is that the argument-that
you must rely upon brand names, that you cannot trust generics, that
generics are not as good as brand names-that that argument is widely
spread to all the medical journals in this country, it is advertised
and widely spread to physicians in promotion. And here comes a study
that is a significant one, it is a very significant study by the FDA of
great importance to the medical profession. My point is-I have not
looked at your journal, you may have run something, I am not address-
ing myself specially to your journal on this question-but this finding
was rather massively ignored so far as I was able to determine. And all
I am saying is that if you have this kind of relationship, don't you
end up, because of the closeness of such a relationship, as a matter of
human nature, muting the criticism of the indepeiident industry whose
relationship is so close? It seems to me that through years and years
and an expenditure of millions of dollars, that doctors have been con-
vinced, as Dr. Pollard said in the beginning of his statement, that they
can rely upon the consistency and the potency of the brand name more
than the generic, that all the journals ought to have a positive moral
responsibility to run big editorials saying, it has been found that the
claim made by the brand name people does not stand up.
Now, if it were a separate, completely separate situation-for ex-
ample, when we introduced the legislation involving tire safety, a
number of journals hit the issue real hard with editorials, big stories
about the tires being put out by the automobile manufacturers. It is
a shocking story, they ran it big, but they are not relying upon their
support from the independent industry. But here is a case where
PAGENO="0437"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4727
there is faith by the profession, as stated by Dr. Pollard, that the con-
sistency and the potency of the brand named drug is better, and sud-
denly a finding by a massive study is made, and most all the journals
who have ads are silent, or play it down. This is the question I am
raising.
Dr. RosENow. May I make one other comment about the Food and
Drug Administration, and what we try to do. This was over 4 or S
years ago. And we have repeated it over, that any time the Food
and Drug would like to reach the members of the American College
of Physicians-I have made this as a personal offer, and also as a let-
ter from our colleagues-if they will send us information that they
want published to go to our doctors, we will publish it. The first time
I made this offer it was very quickly that I got on apparently nine
different mailing lists. And I got piles of material, and, I did not
really personally have the time tO go through every one of these
things to find out what I wanted. And I had made the offer that I
did not have time if they did not have time to state exactly what they
wanted in, not just give me-everything came with no selection what-
ever, volumes this big [gesturing]. And you probably have some
problem getting through the mail, too. I finally wrote them, I said, I
would really like to get just one copy of everything.
The girl said I would have to tell her which mailing list I was on.
And of course I did not know.
We have made this offer many times, and we will still make it, that if
FDA wanted to make an announcement they could reach our 15,000
members within the next publication date.
One other time, I might add-you will recall the thalidomide episode
several years ago. The first notice to the professional public was
made at our annual session, it was at on.e of the meetings-I am not
quite sure whether it was-where we rearrange the program to have
announcement made at our meeting about this.
Dr. POLLARD. It was in San Francisco.
Dr. ROSENOW. This was the first notice to this company. So I am not
quite sure-the thing that I would like to assure you of, I really do
not think it is always kind of a conspiracy of silence so much as it is
poor communictions as to how we get this information from that re-
port you have, how it gets to our editors.
Senator NELSON. I would assume that every medical journal in
this country has somebody who is responsible for keeping track of the
major pronouncements by the FDA. We do not quarrel with that.
Dr. RosENow. I was tyring to explain how we keep track of it.
We do not have enough people on our staff so that we can read all the
material they send us.
Senator NELSON. There was a major drug report by the National
Academy of Sciences.
Dr. RosrNow. This was done by the Committee on Drug Efficacy.
Senator NELSON. This was done by the FDA itself, and the Corn-
mittee on Drug Efficacy of the National Academy of Sciences/
National Research Council, made another report in which they
observed, paraphrased, that there did not seem to be any significant
difference between the generic drugs and the brand name drugs. But
I am simply raising the questions that these are major issues-this was
a task force report-these are major issues that directly affect the drug
PAGENO="0438"
4728 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
industry and the medical profession. And I just wonder how vigorous
anybody can be in raising this kind of an issue when the relationship is
so close. I do not know of any circumstance in human relations where
the relationship is close financially and socially or otherwise in which
the parties are inclined to be as vigorous in their criticism of each
other as they are if there is no relationship. It is just in the nature
of the human animal. And I think it will always be so. This is one of
the questions we are raising. When the drug industry makes such a
major point of this lack of equivalency between generic and brand
names, they have been able apparently for one reason or another-
the reason I think is that the relationship is too close-for one reason
or another they get by without having the major authoritative inspec-
tive body in this country, the American physicians, and their journals
and their spokesman, rising up and saying, they have been pushing this
phony propaganda for 20 years. And now we find a study which
shows that they have been fibbing to us. I would think that this would
be a major, important point right off the bat. The whole profession
ought to be told that they have been living by a propaganda pitch
which the drug industry has promoted for years, and here is an
answer to it. Why not?
Now, I say that the inclination is to draw the conclusion that the
relationship is so close that criticism by the profession of the industry
has not occurred in the past and will not occur in the future. Individ-
uals, yes, we have had them before the committee. But that is the
problem that this relationship raises, I think.
Dr. POLLARD. Senator, if I interpret your point, it is whether or
not generic versus trade names is the answer to the whole drug prob-
lem. And I am not sure that even you believe that.
Senator NELSON. I am not saying that is the answer to the whole
drug problem, I am just saying that the assertion has been made for
years by the drug manufacturers-and now here is a scientific report
of major consequence which refutes the claims that have been made
for years by the brand-name companies. And the general profession is
quite silent about the matter.
Dr. POLLARD. Let us interpret that with a little bit of caution. Be-
cause this comment that the profession has said nothing about it, I
will still go back to the point that I mache, that where we spend our
time in the medical Profession is evaluating drugs and reporting upon
their complications in our scientific meetings. Now, perhaps we have
not touched on generic versus trade name as the key to the whole drug
problem. And I still think what we have attempted to do is to keep
the doctor educated about his drugs, what they are, and what their
applications are in a very fair and open way. And that is where we
have been beating our drums, as it were. And maybe we have not made
a great issue about the brand name versus the trade name. Frankly,
I do not think we have any strong feelings about it one way or the
other. There probably are other studies that would take generical
named drugs, make studies of them and find disturbances there. Just
because one chooses one or the other I do not think necessarily will
resolve the whole drug problem. It may help it, but I do not think
it will resolve it. And I think what the medical profession is after,
what we in the college of physicians prefer, is that the physician be
left to make his own choice.
PAGENO="0439"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4729
Senator NELSON. In the 2 years that we have had the hearings, we
have announced publicly on several occasions that we will hear all
viewpoints and that anybody who manufactures drugs is entitled to
first preference to appear before this committee. In that period of time
we have not had any scientific testimony that proves the claim that the
industry consistently makes, that the brand name is better than the
generic name. The assertion by the DSP and the National Formulary
and the distinguished pharmacologists before the committee is that if
two drugs meet the official compendium standards they are equivalent.
And there are rare exceptions, which do not even count up to one, and
they are not even certain of that. But the profession becomes con-
vinced that that is not the case. My point is that the profession believes
what you stated in your opening remarks, I agree-I think that is
exactly what they believe. But what responsibility do the journals and
the medical press have for pointing out that the claim that is being
made consistently to the profession is not true, it has not been true?
That is my point.
Dr. POLLARD. Senator, may I just comment on this recent publication
of the AMA drug evaluations. This, I believe, is their first chapter on
this, published May 20, 1968. As you go through the listing of all of
the drugs they are listed by generic name in bold type, and in very
small parenthesis is the trade name. I think that is a little along the
line that you are talking about.
Senator NELSON. Yes.
Dr. ROSENOW. Senator, may I ask a question?
If your feeling is that doctors should prescribe by generic name,
would you have objection to them including also the brand name or
the manufacturer?
Senator NELSON. First let me say, doctor, that I would not make any
independent judgment of my own about what a physician ought to do.
I have not decided what some of the authorities would do because I do
not have any independent expertise of my own. The testimony of
experts before the committee consistently has been that doctors ought
to prescribe by generic name, but the doctor would have complete
freedom to designate the brand that he wants. No one has testified
before this committee that the doctor must prescribe by generic name
and not indicate the manufacturer or brand. All of our testimony has
been that he should be able to select the company if he desires to do
so. So we have introduced legislation based upon the testimony of a
number of highly regarded pharmacologists and physicians that the
label should contain the generië name, and if desired by the physician,
the brand name or the manufacturer himself. What is your view of
that?
Dr. RosENow. I personafly~ would have no objection-in fact, I
would say over 30 years my attitude is changed about how much you
should let the patient know anyhow. I think they ought to know as
much as they can. That is as I get older. It is harder and harder to
find out how to take care of people anyway. But I think with the
American public traveling as much as they do and moving from place
to place it is really a good idea to have on the label what the drug
is, what drug he is taking, and what the dosage is. And preferably,
I think I would like to know not only the generic name of that drug
PAGENO="0440"
4730 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
but I would like to know which company makes it to see whether
it is the one I am used to or not. I would have no objection to this.
Dr. POLLARD. Senator, in our own institution, the University Hos-
pital in Ann Arbor, we have required our pharmacy there that fills
the prescriptions for any patient that we write prescriptions for to
put on the label specifically what the product is and what the dosage
is, and how many grains or milligrams, and what each tablet contains.
So that is required, unless one ticks off a little area and indicates that
this is not to be noted. Otherwise every prescription going out of
there for at least, I think, the past 7 years has had written on the
prescription exactly what it is.
Senator NELSON. By official name or generic?
Dr. POLLARD. I would have to check that to be sure. I think they
write it merely the way the doctor has written it. And I say, in keeping
with your comments, that the Chairman of our Department of Inter-
nal Medicine encourages openly and constantly when the residents
write their prescriltiOns, when they are ordering drugs, that they use
the generic term. He prefers that.
Senator NELSON. Thank you very much. We appreciate your taking
the time to come here and present your very valuable testimony.
Dr. POLLARD. Thank you very much, Senator, for this privilege.
Dr. ROSENOW. Thank you very much.
Senator NELSON. We are pleased to have you.
Dr. ROSENOW. And I will send the information that you have
requested.
(The supplemental information submitted by Dr. Pollard follows:)
THE AMERICAN COLLEGE OF PHYSICIANS
ADVERTISING IN THE ANNALS OF INTERNAL MEDICINE-EXHIBITING AT
THE ANNUAL SESSIONS
The following criteria will be used in screening product advertising
to be carried in the Annals of Internal Medicine publication and for
exhibition of the Annual Sessions of the American College of Physicians.
The Committee on Advertising makes the final decision regarding the
acceptability of all products and services to be advertised and exhibited
and gives final approval of the advertisement or exhibit. The Commit-
tee reserves the right to change these standards in the light of develop-
ments in medicine or in industry.
A. Eligibility for advertising and ewlii biting
I. Products or services.-Only those products or services relevant to the prac-
tice of internal medicine or in allied specialties shall be eligible for advertising
and exhibiting.
2. New drug applications.-No pharmaceutical products will be eligible for
advertising or exhibiting until a New Drug Application from the Food and Drug
Administration has become effective.
3. Institutional-type advertising.-Only that copy which is relevant to the
practice of internal medicine and "public service" messages of interest to our
physicians will be considered eligible for appearance in the ANNALS OF IN-
TERNAL MEDICINE.
4. Special-purpose foods-Foods which are used by certain specific segments
of the population who have specific diseases or conditions requiring foods with
certain properties, are permitted.
PAGENO="0441"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4731
B. Products not acceptable for advertising and exhibiting
1. General purpose foods.-Foods promoted for use by the population in gen-
eral; Examples-Fruits, meats, eggs, bread, processed fruits and vegetables.
2. Beverages.-Alcoholic Beverages.
3. Miscellaneous products.-Tobaccos, cosmetics, patent drugs, automobiles,
etc.
C. Detailed information required on modified old and new products
1. New drugs.-A new drug is defined as follows: As a single active ingredient
(e.g. reserpine, deserpidine), or an extract from a single source (e.g. alseroxylon,
rauwolfia).
2. Modification on drugs of approved products.-A drug previously approved
must be re-submitted for review if a modification of the drug has been made
subsequently, for example such as a new salt or ester.
3. Combination of one or more drugs.-Combination of one or more drugs a~-
ready considered acceptable-clearance will depend on rational grounds for justify-
ing such a new combination.
4. Additional brand of product.-An additional brand of a product already
considered acceptable (copy of proposed advertisement only need be submitted).
In order for a pharmaceutical manufacturer to become eligible to advertise the
products in the ANNALS OF INTERNAL MEDICINE, or to exhibit them at the
annual meetings, the following data concerning a product must be submitted to
the Committee for review before acceptance. This ruling applies to new products
and on established drugs or equipment which have been modified.
(1) Five copies of the currently approved package insert be forwarded to
the American College of Physicians and addressed to the attention of the
Advertising Manager.
(2) Indicate whether approved by FDA.
(b) Indicate whether approved by AMA or other publications.
The Advertising Committee frequently seeks the opinions of consultants in
determining the eligibility of products and suitability of claims. The Advertising
Committee expects that the medical department of the pharmaceutical company
has approved not only the product but the advertising copy before its submission.
Drugs introduced before 1961 should include if available the package insert and
other data supporting the efficacy, instructions of uses and relative safety of the
product. Evidence of such medical department approval must be furnished on
request.
D. Advertisements for specific types and classes of products and services
1. Apparatus, instruments and devices.-The eligibility of medical equipment
intended for preventive diagnostic or therapeutic purposes is determined by the
Advertising Committee. Advertisement for new products and new claims should
be accompanied by FIVE COPIES of information, presenting full and adequate
scientific and technical data concerning the products' safety, operation and use-
fulness, including the results of laboratory and clinical examination. These data
may be either published or unpublished. Samples of apparatus, devices, equip-
ment or instruments should not be submitted unless requested by the Committee.
2. Books.-A book may be requested for review so that its eligibility for ad-
vertising may be determined.
PAGENO="0442"
4732 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
(3) Miscellaneous products and services.-Products or services not in the
above classifications may be eligible for advertising provided they are closely
related to the practice of internal medicine and can meet all requirements.
E. Advertising or eahi bit copy
After a product or service has been submitted for advertising in the AN-
NALS OF INTERNAL MEDICINE, the Advertising Committee makes the final
decisions regarding the acceptability of new copy. The Committee's decision in
this regard will be guided by the following principles:
(1) Advertisements should not be deceptive or misleading. The layout, art
work and format of the advertisement should be such as to avoid confusion
with the editorial content of the publication and be in good taste. The Com-
mittee reserves the right to reject the format of the advertisement as it
would appear in the ANNALS. It is understood this would be at a stage be-
yond the approval of ordinary advertising copy.
(2) The Committee reserves the right to. reject the format of any exhibit.
(3) Advertisements should clearly identify the advertiser and the prod-
uct being serviced or offered.
(4) Unfair comparisons or offensively forward and unwarranted depre-
ciation of a competitor's products or services will not be permitted.
(5) Advertisements will not be accepted if they appear to, conflict with
the principles of medical ethics.
(G) Exaggerated or extravagantly worded copy will not be allowed. Any
claims for superiority must be supported by evidence acceptable to the
Committee.
(7) Excerpts or quotations from published papers are acceptable provid-
ing they do no,t distort the meaning intended by the author. Claims made
within quotations must conform to the standards as unquoted claims.
All exhibitors are prohibited from using any of the following tactics for pro-
moting their products at our meetings:
(1) Exhibitors shall not use any gimmicks, door prizes, lucky number
drawings, etc.
(2) There shall be no-button-holing doctors in the aisles.
(3) High pressure "pitch" of any kind will not be permitted.
(4) All exhibitors must conduct their exhibits, at all times, in a clean and
dignified manner and at no time display a side-show atmosphere.
Those exhibitors not abiding by the above regulations while attending the
meeting will be immediately expelled.
DEADLINE DATES
Receipt of material for committee review
Proposed advertising copy on pharmaceuticals or biologicals not previously
advertised in the ANNALS, and NEW advertising copy only, on products already
approved for advertising or exhibiting, must be submitted for Committee review
at least two weeks before the Closing Date for advertising in the scheduled issue.
It is imperative that FIVE COPIES each of currently approved package inserts
and proposed advertising be submitted. Indicate whether approved by FDA,
AMA, or other publications.
Closing date
The Closing Date for insertion orders is the 20th of the second month preced-
ing publication.
PAGENO="0443"
0
t~j
EXHIBIT B
ANNALS OF INTERNAL MEDICINE
1964 1965 1966 1967 1968
Amount Percent - Amount Percent Amount Percent Amount Percent Amount Percent
Subscription revenue net of Commission $221 688 16 4 $244 511 17 3 $272 056 16 5 $291 078 15 6 $343 278 15 7
Advertising revenue net of Commission and discount 374, 060 27. 6 432, 597 30. 7 602, 802 36. 5 719, 747 38. 4 796, 947 36. 5
Total revenue from annals 595, 748 44. 0 677, 108 48. 0 874, 858 53. 0 1, 010, 825 54. 0 1, 140, 225 52. 2
Total revenue including annals 1, 353, 489 100. 0 1, 409, 301 100. 0 1, 649, 617 100. 0 1, 872, 455 100. 0 2, 184, 286 100. 0
FF2
PAGENO="0444"
4734 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
(The subsequent supplemental information submitted by Dr. Rose-
now follows:)
THE AMERICAN COLLEGE OF PHYSICIANS,
Philadelphia, Pa., April 7, 1969.
MONOPOLY SUBCOMMITTEE OF THE SENATE SMALL BusINEss COMMITTEE,
U.S. Senate,
Washington, D.C.
(Attention of Mr. Gordon)
This letter is to give you additional information in response to Senator Nel-
son's questions asked of Dr. Pollard and me recently.
First of all the following is a breakdown of Exhibit B of our report to show
what percentage of Advertising Revenue w-as represented by pharmaceutical
advertising in the annals.
1967
1968
Amount
Percent
Amount
Percent
Pharmaceutical
Instruments
Books
Other (miscellaneous)
Breakdown for exhibit revenue:
$823, 738
21.296
13,250
4, 160
95. 5
2.5
1.5
. 5
$898, 019
34,470
13,020
5, 670
94. 41
3.62
1.37
. 6
Pharmaceutical
Instruments
Books
Other
58, 011
15, 795
11,391
11,091
60. 0
16.0
13. 0
11. 0
65, 350
27, 950
11,325
19, 100
53
23
10
14
A second question concerned our endowment fund and whether w-e had any
stock in a pharmaceutical company. At the present time our total portfolio in
invested capital is as follows:
Market, as of
Cost Feb. 28, 1969
Operatisg fund $307,912 $426,416
Endawment 3,524,830 3,945,303
Building fund 889, 835 1, 051,064
Total - 4,722, 577 5, 422, 783
Holdings in pharmaceutical stock: -
Baxter Laboratories convertible 4 percent, Mar. 1, 1987__ 49,688 56,400
Rorer-Amchum 60, 788 54, 000
Total 110,476 110,400
Psrcent 2. 3 2.0
It can be seen that 2% of the total invested capital is in pharmaceutical com-
panies. I remind you that we invest our funds upon advice of Drexel, Harriman
and Ripley.
I have checked with our Editors and we have not commented on the AMA
journal article November 18, 1968 on Generic Inequivalence of Drugs by Alan B.
Varley, M.D.
During the past couple of years we have rejected a number of ads which were
so totally unsuited to a journal devoted to Internal Medicine that we did not
circulate to the committee. The following represent those we would have re-
jected if the agency did not comply with our request to make certain changes.
1. Stuart Company-Ad submitted by Sudler & Hennessey Company for Myli-
con (brand of simethicone). We asked that the statement "This liberating action
of Mylicon is unlikely to mask organic disease-And side effects and seldom re-
ported-even during prolonged use." They dropped this and the ad appeared in
the August, 1967 issue of Annals of Internal Medicine.
2. Rowell Laboratories-Agency Barickman & Shelders Advertising, Inc.
Product-Cortenema.' Attached is copy of our letter dated October 4, 1967. The
company did not submit further ads for this product.
PAGENO="0445"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4735
3. A. H. Robins Company-Agency Martin & Woltz, Inc. Product-Robitussin
DM, Entozyme, and Exna-attached is copy of o~ir letter of December 28, 1966.
None of these have run as ads in our journal.
4. Pharmacia Laboratories Inc.-Agency Paul Klemtner & Company-Product
Azulfadine. Attached is copy of our letters of December 14, 1966 and December
20, 1966 indicating their willingness to comply.
5. Organon, Inc.-Agency Erwin Wasey, Inc.-Product Accellerase. Attached
note dated December 15, 1966-Did not comply with suggestion so agency can-
celled contract.
6. Massengill Laboratories-Agency Ramsdell Buckley & Company-Product
Obedrin LA. Attached is letter of November 23, 1966 speaks for itself.
7. Lederle Laboratories-Product Levoprome submitted for exhibit. Rejected
by committee because no reprints were submitted to substantiate claims made.
8. Key Pharmaceuticals-Product Nitroglyn. See attached letters dated Jan-
uary 13, 1967, to the company and letter of January 24, 1966 making changes
requested.
9. Bristol Laboratories-Product Prostaphlin-Agency Sudler & Hennessey.
This is the one I mentioned at the hearing. I was in error at the time this oc-
curred and also that they cancelled all ads with us. They only cancelled the ads
for Prostaphlin but continued advertising other products namely, Kantrex-Jan-
nary to June, 1967 and April to November, 1968-Polycillin-all of 1967 and Jan-
uary, 1968; May & October to December, 1968. Attached letters explain our im-
passe over Prostaphin.
Memo to me October 18, 1963
Letter to Mr. Phillips, A.C.P. Advertising Manager from Mr. Wilkins.
Letter, October 28, 1963 to Mr. Wilkins from Mr. Phillips.
Intermittently we had inquiries about again considering a Prostaphlin ad-
My letter of March 18, 1968 is self explanatory.
Finally my letter of March 19, 1969 resolves the problem because the company
has submitted copy satisfactory to the committee.
If there are other questions we can answer please write me.
Sincerely,
EDWARD C. ROSENOW, Jr., M.D.,
Eceecutive Director.
Memo to: E. C. Rosenow, Jr., M.D.
From: Andrew P. Phillips.
Date: October 18, 1963.
Re Bristol Laboratories, Prostaphlin advertisement scheduled for the November
issue.
In reviewing the November proofs sent from Lancaster Press I noted that the
changes which the committee requested has not been made. The changes are
as follows:
The heading of the advertisement reads "Whenever You Suspect Staff",
the committee suggested that this copy be changed to read "In Staff Infec-
tions." Also the word "suspected" appearing on the first line in the first
paragraph would be changed to the word "present" and that the asterisk
appearing in the close of the first sentence and foot note at the bottom of
the page be deleted.
I immediately called the agency regarding these changes. After a lengthy con-
versation, the agency called Bristol Laboratories and they had informed us that
no change would be made in the copy as it is a repeat of the October advertise-
ment. Their interpretation of our letter was that they felt this being a repeat
would not require a change. However, they are aware that all future advertise-
ments must be approved by the committee before they precede in preparing
plates.
The complete issue is at Lancaster Press and locked-up to run. If we cancelled
this spread it would have meant using College ads, which unfortunately we can-
not supply. Therefore, I informed the agency and client that we would run this
advertisement for this issue.
I realized our instructions could be interpreted as future copy as opposed to
New Copy, to future advertisement which could be repeats of previous insertions.
PAGENO="0446"
4736 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
SUDLER & HENNESSEY, INC.,
iVew York, October 21, 1963.
Mr. ANDREW P. PHILLIPS
Advertising Manager,
The American College of Physicians, Philadelphia, Pa.
DEAR Mn. PHILLIPS. Regarding your letter to Mr. Rich of October 18th, we in-
tend to rerun the present Prostaphlin ad "Whenever you suspect staph" in the
December issue of the Annals of Internal Medicine. We do not intend to change
this ad at this time or in the foreseeable future.
As I believe I mentioned to you before, the decision to accept or reject the ad
is yours. Bristol supports this position.
Sincerely,
WALTER K. WILKINS.
OCTOBER 28, 1963.
Mr. WALTER K. WILKINs,
Sudler c~ Hennessey, Inc.
New York, NY
DEAR MR. WILKINS. Thank you for the reply to my letter regarding the copy
revisions for your client's Prostaphlin advertisement, scheduled to run in the
December, 1963 issue of the Annals of Internal Medicine.
Unfortunately, there seems to have been a misunderstanding on the accept-
ance of our request for copy changes. We understood from Dr. Kitto's conversa-
tion with our Executive Director, Dr. Rosenow, that your client knew the
October and November advertisements were accepted on the premise that the
revisions would be made in all forthcoming advertisements on this product. The
copy changes though slight were important, e.g. quoting one of the Committee
members, "I do not like the statement, `whenever you suspect staph-start with
Prostaphlin". One should never start treating staph just on suspicion and an
A-i physician would consider the best drug. In other words this advertisement
constitutes poor teaching".
The word "suspect" in the caption of the advertisement was to be deleted and
"suspected" in the body of type to be changed to "present". The caption would
read "In staph Infections". Also, the asterisk at the end of the first sentence
and the footnote to be deleted.
I have referred your letter to Dr. Rosenow and he feels inasmuch as the ruling
for copy changes requested by authorized members of our Committee, applies
to all of our advertisers, the Prostalphin advertisement could not run in our
journal without being revised.
Sincerely,
ANDREW P. PHILLIPS,
Advertisement Man~ager.
JANUARY 13, 1966.
Mr. BERNARD FRIEDLAND,
Assistant Medical Director,
Key Pharmaceuticals, Inc., Miami, Fla.
DEAR MR. FRIEDLAND: While "Nitroglyn" may be a fine product the Committee
on Advertising feels the copy is ambiguous and misleading when you state
"Gives 24-hour protection against attacks *and possible myocardial damage".
This claim is not substantiated in the material forwarded to us, if it was please
indicate where or submit additional information which will prove this statement.
It will, therefore, be necessary for you to substantiate this claim or revise
your ad copy before this ad can appear in the Annals of Internal Medicine.
Sincerely yours,
EDWARD C. RosENow, Jr., M.D.
Ewecutive Director.
KEY PHARMACEUTICALS, INC.,
Miami, Fla., Jan/u ary 24, 1966.
ANNALS OF INTERNAL MEDICINE,
The American College of Physicians,
Philadelphia, Pa.
(Attention of Edward C. Rosenow, Jr., M.D.).
GENTLEMAN: In reply to your letter of 13 January concerning the advertising
copy for our product Nitroglyn®, we have studied your comments, and wish to
PAGENO="0447"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4737
submit the following change in the copy which you brought to Our attention.
Item 1. has been amended to read "Give 24-hour protection against attacks,
taken twice or three times a day ;"
We trust that this change now meets with the approval of the Committee on
Advertising, and will be satisfactory for the desired insertions.
Sincerely yours,
BERNARD FRIEDLAND,
Assistant Medical Director.
NOVEMBER 23, 1906.
Mr. FRANK HENSOHEL,
Ramsdell, Buckley c~ Go., Inc.,
Philadelphia~ Pa.
DEAR Mn. HENSCHEL: This is to confirm our telephone conservation of yester-
day regarding the advertisement your client wishes to run in the January, 1907
issue of the Annals of Internal Medicine.
As I mentioned the members of our committee feel "Holy flabbergast-it's
Fatman," does not lend itself to our journal.
At the present time I understand you will repeat the "Jim Nathans sat here"
advertisement which ran in the December : issue. I would like to mention, how-
ever, several members of the committee have told me they feel the "Jim Nathans"
ad is more in keeping with our journal and an eye-catcher.
I will assume that a revised insertion order will follow shortly.
Sincerely yours,
ANDREW P. PHILLIPS,
Advertising Manager.
DECEMBER 14, 1960.
Mrs. LORRAINE MoonE,
Space Bvyer, Paul Klerntncr i Go., Inc.,
New York, N.Y.
DEAR MRS. MOORE: I have submitted the "Azulfidine" advertisement #4700
one drug has distinguished itself by having a place in the treatment of almost
any patient with ulcerative colitis-Azülfidine, the mainstay of therapy for
colitis. The following, therefore, is an excessive claim.
"But, to achieve the ultimate aim of restoring normal intestinal function, one
drug has distinguished itself by having a place in the treatment of almost
any patient with ulcerative colitis-Azulfidine, the mainstay of therapy for
ulcerative colitis."
Unless this is revised we will not be able to run this advertisement in our
journal.
Sincerely yours,
(Miss) BARBARA RAIJSCH,
Secretary to Mr. Phillips, Advertising Manager.
DECEMBER 15, 1906.
Dn. RosENow: Organon, `Accelerace' #4706 Rev, has been submitted to appear
in the February, 1967 Issue. The following comments were made regarding this
product:
Dr. Rosenow.-"We have no objection to Accelerase but do object to combin-
ing with P-B. Therefore, they should remove that from ad."
Dr. Frost.-"This product is no different from numerous others in our adver-
tising. If we are not going to accept this product then I think we should review
our position entirely and eliminate all products that are not scientifically proven
to be effective. Believe Committee should establish a few guidelines and princi-
ples that are consistent rather than saying as was the old procedure of "it isn't
valuable but won't do harm."
Dr. Rouse.-"No clinical material included. It appears to me to be `shot gun'
therapy."
Dr. Wise.-"See letter from Dr. Franz Goldstein."
Please advise.
PAGENO="0448"
4738 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
DECEMBER 20, 1966.
Mrs. LORRAINE MOORE,
Space Buyer, Paul Klemtner ~ Co., Inc.,
New York, N.Y.
DEAR MRs. MOORE: This is to confirm our telephone conversation of today re-
garding the "Azulfidine" advertisement #4706 which has been revised to read:
"Many patients-many measures-from the use of simple antispasmodics
to intensive psychotherapy. But one drug has consistently proven its value
in the treatment of each and every stage of ulcerative colitis-Azulfidine
(salicylasosUlfaPYridifle) the mainstay of therapy of ulcerative colitis."
The Committee has approved the above for insertion in the Annals of Internal
Medicine. Your insertion order was received in this office yesterday.
Sincerely yours,
(Miss) BABBARA RAuscM,
Secretary to Mr. Phillips, Advertising Manager.
REVISED CoPY FOR PHAi~MACIA LABORATORIES "AZTJLFIDINE"
Many patients-many measures-from the use of simple antispasmodics to in-
tensive psychotherapy. But one drug has consistently proven its value in the
treatment of each and every stage of ulcerative colitis-Azulfidine (salicylazo-
sulfapyridifle) the mainstay of therapy of ulcerative colitis.
DECEMBER 28, 1966.
Miss HELEN R. LLoYD,
Martin ~ Woltz, Inc.,
Richrnoiid, Va.
DEAR Miss LLOYD: Earlier this month you sent material to us for Committee
review on "RObit~55ifl-DM," "Entozyme" and "EXNA" for your client, A. H.
Robins Company. These products have been submitted to our Committee, however,
they feel that no evidence has been given to show that adding DM to Rohitussin
does anything more than Robitussin alone.
"EXNA" has been approved but ad copy was not submitted and must be in
the future before it appears in the Annals, as I am sure you are aware.
Regarding "Entozyme", although there is no advertising copy presented this
product is acceptable as a pancreatic substitution therapy but is unrelated to the
relief of functional gastrointestinal disorders and any copy should not include
such an inference.
I would appreciate it if you could send addditional information on the Robitus-
sin DM product and ad copy on all of these ads for further consideration by our
Committee.
I will be looking forward to hearing from you in the near future.
Sincerely yours,
ANDREW P. PHILLIPs,
Advertising Manager.
OCTOBER 4, 1967.
Miss ELAINE SKJELSTAD,
Barickman ~ S/i elders Advertising, Inc.,
Minneapolis, ]Iinn.
DEAR Miss SKJELSTAD This is to inform you that the "Cortenema" advertise-
ment for your client, Roweli Laboratories, Inc., has been approved by our College
Committee and was scheduled to appear in the October and November, 1967 issues
of the Annals of Internal Medicine as per your instructions received in this office.
Our Committee feels, however, that the advertisement should state that signifi-
cant absorbtion occurs. They also feel it is an exaggeration to say "an absorbable
steroid is safe and should be used in most cases of chronic ulcerative colitis".
They feel it w-ould be better to say "in cases of chronic ulcerative colitis in which
steroids would be indicated".
We would appreciate your revising this advertisement before it reappears in
the Annals. Thank you so much for your cooperation in this matter. If you
should have any questions regarding this revision please feel free to contact me.
Sincerely yours,
ANDREW P. PHILLIPs,
Advertising Manager.
PAGENO="0449"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4739
MARCH 18, 1968.
Mr. WILLIAM W. GORDON,
Product Advertising Manager,
Bristol Laboratories, Syracuse, N.Y.
DEAR Mit. GORDON: Referring to your letter to Mr. Phillips, you do not inter-
pret his letter of March 8th correctly. I can understand why you interpreted it
as you do, however, the long standing objection goes back to 1003 and the objec-
tion we have is to the statement which you have put in the middle of the second
page in bold print which states "Start therapy immediately with Prostaphlin".
The members of the Committee feel that this is generally bad advise and is
not acceptable unless it is agreed by a clear statement that a staphylococcus or
other suitable infection has been diagnosed.
Until you are willing to change this statement the Committee will not accept
the ad as proposed.
In January of 1007 Dr. Robert Wise wrote a long letter to your President,
Mr. J. D. McNitt, explaining in detail our feeling about this type of advertising
statement. I would be happy to discuss this further with your medical department.
Sincerely,
EDWARD C. RosaNow, Jr., M.D.
Eceecutive Director.
MARcH 14, 1069.
Mr. JOHN L. ROBINSON,
Director of Promotion,
Bristol Laboratories, Syracuse, N.Y.
DEAR MR. RoBINSoN: I am pleased to inform you that the College Committee
on Advertising has approved ad #8433 for your product Prostaphlin. Also ap-
proved is "Kantrek" advertisement #8345.
These ads will be scheduled to appear in the May, 1969 issue of the Annals
of Internal Medicine upon receipt of your further instructions.
Sincerely,
(Miss) BARBAB4 RAnSOM,
Secretary to Mr. Phillips, Advertising Manager.
Senator NELSON. Senator Hruska of Nebraska is here, I believe, to
introduce our next witness. We are very pleased to have the distin-
guished senior Senator from Nebraska appear here this morning.
STATEMENT OP HON. ROMAN L. HRUSKA, A U.S. SENATOR PROM
THE STATE OP NEBRASKA
Senator HRUSKA. Thank you, very much.
It is my happy privilege today to introduce your next witness, a
constituent and good friend of mine, and a long-time practitioner in
the city of Omaha. He is Dr. Robert S. Long.
He got his doctor of medicine degree in the University of Nebraska.
He served as intern and resident of the Harvard Medical Service
City Hospital, and was a fellow in internal medicine at the Lehigh
Clinic in Boston.
He served as a major in the Medical Corps of the U.S. Army, and
has engaged in the practice of internal medicine in Omaha since 1947.
He is a fellow of the American College of Physicians, and currently
president of the American Society of Internal Medicine.
I would ask unanimous consent, Mr. Chairman, that a biographical
sketch a little more detailed in character be inserted in toto in the
record.
Senator NELSON. Senator, Dr. Long has submitted a biographical
sketch. And it will be printed in the record immediately prior to Dr.
Long's statement.
81-280-69--pt. 11-29
PAGENO="0450"
4740 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator HRUSKA. And now, Dr. Long, I turn you over to this very
generous and distinguished chairman of this subcommittee.
Dr. LONG. Thank you very much, Senator.
Senator RRUSKA. And with your permission I will go back to the
Appropriations Committee where I have a hearing.
Senator NELSON. On the way out you may get into some argument
about the use of that word "generous".
Thank you, Senator.
We will place Dr. Long's biographical statement in the record at
this point.
(The biographical sketch follows:)
BIOGRAPHICAL SKETCH OF ROBERT S. LO~cG, M.D., OMAHA, NEBR.
1. President, American Society of Internal Medicine.
2. Diplomate, American Board of Internal Medicine.
3. Fellow, American College of Physicians.
4. Associate Professor Internal Medicine (Volunteer Faculty), University of
Nebraska College of Medicine.
5. Associate Medical Director and Consultant on Medicare for Mutual of
Omaha.
6. Member, Medical Relations Committee Health Insurance Council of
America.
7. Member, Public Relations Committee Medical Section American Life Con-
vention.
8. Chairman, Insurance Committee Omaha Douglas County Medical Society.
9. Member, Coding and Relative Values Committee, Nebraska State Medical
Association.
10. Member, American Therapeutic Society, American Rheumatism Associa-
tion, American Heart Association, American Medical Association, and other
medical scientific societies.
11. Clinical Investigation of New Drugs prior to release Cortisone, ACTH,
Diuril, Orinase, Tapazole, Decadron, Prostaphlin, Valium, and others.
12. Past-President Medical Staff Nebraska Methodist Hospital.
13. Private practice of Internal Medicine in Omaha, Nebraska since 1947.
14. Major, Medical Corps, AUS, World War II with overseas service as As-
sistant Chief of Medical Service, 98th General Hospital.
15. Born Cowles, Nebraska, February 25, 1916. B.Sc. and M.D. University of
Nebraska, Intern and Resident Harvard Medical Service City Hospital, Fellow
in Internal Medicine The Lahey Clinic, Boston, Massachusetts, Married, 2 chil-
dren.
STATEMENT OP DR. ROBERT S. LONG, PRESIDENT OP THE
AMERICAN SOCIETY OP INTERNAL MEDICINE
Dr. LONG. Senator, I brought with me some items which I would
like for you to see. And I brought some extra copies of the memoran-
dum which will illustrate my statement.
One of my organizations I represent here today does in general
deal with internal medicine. And I have here some specific data that
you requested in your letter that I did not have available before.
Senator NELSON. Thank you very much, Doctor.
Do you have an extra set of these memorandums?
Dr. LONG. Yes, I have it here.
Senator NELSON. May I ask at the beginning, does this memorandum
that you submit have a breakdown of the advertising by source, that
is, drug manufacturers and other sources?
Dr. LONG. The advertising in the Internist, of which you have a copy
in that little bundle right in front of you, is almost entirely drugs.
PAGENO="0451"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4741
Occasionally I have an advertisement for an instrument. But I have
no breakdown, sir.
Senator NFi.soN. It is almost entirely pharmaceutical.
Dr. LONG. Pharmaceutical products, yes.
Senator NELSON. This memorandum will be printed in the record at
this point.
(The document referred to follows:)
MEMORANDUM
AMERICAN SOCIETY OF INTERNAL MEDICINE,
$an Francisco, Calif., March 11, 1969.
rfo: Robert S. Long, M.D.
From: W. R. Ramsey.
Subject: ASIM finances-5 year period.
The following figures are provided in accordance with your request:
Donations
Advertising
Period Dues income income
Cash
Services I
1968-69 2 $401,046.50 $4,275.83
1967-68 3 363, 200. 00 10. 113. 84 $5, 000. 00 $476. 09
1966-67 ~261, 505. 00 8, 558. 90 500. 00 619. 54
1965-66 233, 790. 00 5. 830. 80 b. 711. 15 338. 10
1964-63 225, 600. 00 3, 941. 76 6 3, 216. 20 497. 54
7200.00
1963-64 152,105.00 1,606.45 64,3.0.00
7700.00
1 Binders for house of delegates meeting and plastic briefcases for delegates.
2 Dues increased to $50 per year.
3 Dues increased to $40 per year.
4 Exhibits: Our records indicate exhibits were discontinued after the 1966 annual session.
1 Dues increased to $30 per year.
6 Exhibits.
7 Grants.
Senator NELSON. Dr. Long, we are very pleased to have you take the
time to come here today to present your testimony. You may present
it in whatever fashion you desire. If you wish to depart from it and
elaborate on any aspect of it, feel free to do so.
Dr. LONG. Thank you, Senator Nelson.
I think my statement is relatively shOrt and it will take me only a
few minutes to read it for the record. I think our best interest would
be served timewise and otherwise if I might read this first. This will
then perhaps give you a clue as to any questions you might wish to ask
subsequently.
Senator Nelson and members of the committee, I am grateful for
this opportunity to appear before your committee to present my views
regarding some of the matters you have~ under consideration~ particu-
larly the responsibilities of practicing physicians in the prescribing and
administration of drugs, biologicals, and chemical agents in the treat-
ment of patients, and the relationships between physicians and organi-
zations of physicians and the drug industry.
I am the president of the American Society of Internal Medicine, an
organization of approximately 10,500 specialists in the field of internal
medicine.
Senator NELSON. What is the total number of internists in the
country?
Dr. LONG. This would be a little hard to judge. There are some 40,000
physicians who are self-designated internists in the AMA Directory
PAGENO="0452"
4742 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
of some 300,000 physicians. A sizable percentage of those are not men
whom those of us who took the additional training would categorize
entirely as specialists in internal medicine. By that designation I think
they mean to indicate that they restrict their practice to the field, in
other words, they do not do surgery, let us say, or deliver babies, and
so forth, whereas in our organization, as I will indicate in a moment,
our 10,500 specialists who must meet certain requirements of training
in order to belong.
I think a realistic figure, in answer to your question, as close as he
could get it, would be somewhere in the neighborhood of 25,000, per-
haps, 20,000 to 25,000.
Senator NELSON. Who are internists?
Dr. Loxc. Who are qualified specialists in the field; yes.
On February 4, 1969 I mailed to you. a copy of the bylaws of our
organization, several copies of our monthly Newsletter, a pamphlet
entitled "Aims and Purposes of ASIM", and a brief biographical
sketch of myself, I have brought with me today a few of the pamphlets
and other publications of our society as well as a roster of our member-
ship and a list of our committees and councils.1
All our active members are doctors of medicine who have completed
an internship, three years of special training in internal medicine and
2 years of practice in the specialty. Our basic goal is to assure that high
quality medical care is rendered to all. We are especially concerned
with the working domain of medical practice, and with the profes-
sional, socioeconomic and political conditions under which such prac-
tice is carried out, whether in the hospital, the physician's office, the
patient's home or elsewhere. Our efforts have to do primarily with the
practical aspects of how to translate medical science and knowledge
into the day-to-day care of sick patients in the most efficient, effective,
and economical way possible without sacrificing any of the quality of
such care.
Inasmuch as the specialty of internal medicine has to do with the
diagnosis and treatment of diseases and disorders by nonsurgical
means, you would know that my training, experience, and interest
have been in the use of drugs and related materials in the practice of
medicine. While I have had some experience in the clinical investiga-
tion of drugs both in my private practice and in connection with my
teaching of students at the University of Nebraska College of Medi-
cine, my principal knowledge and experience have been gained in the
study and use of drugs and related materials in the day-to-day prac-
tice of medicine with private patients.
I served for many years on the pharmacy committee of the Nebraska
Methodist Hospital in Omaha, Nebr. on the executive committee for
10 years, and was chief of staff for 2 years. In these positions I gained
some knowledge as to the practical problems involved in operating
a pharmacy in a large, private, general, metropolitan hospital.
My father was a pharmacist, so I know something, too, of the private
druggist's problems from his side of the counter.
I have been active in several organized medical societies for many
years, including the American Therapeutic Society, an organization
which has to do with the scientific study and practical application of
~ Material retained In committee files.
PAGENO="0453"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4743
the use of drugs in clinical medicine, the American Diabetes Associa-
tion, the American Rheumatism Association, the American Heart As-
sociation and others. These activities have naturally brought me in
contact with many pharmaceutical companies and their representa-
tives in scientific matters as well as in business matters having to do
with arrangements for meetings, contributions for clinical research
and similar joint projects.
With respect to the internal organization and operation of medical
societies themselves, I have had experience as an officer in many of
them at the State and local level. For the past 6 years I have been a
member of the board of trustees of the American Society of Internal
Medicine and president this past year.
In this position I have necessarily become familiar with the financial
as well as all other aspects of the operation of these organizations. As
the principal liaision officer. I have spent a great deal of time with the
officers of other professional organizations in the health care field as
well as with governmental agencies having to do with health care
matters both at the national and State level.
I have been interested and active in the health insurance field for
many years. This, of course, involves the insurance considerations
related to the use of drugs as well as other matters pertaining to
health care insurance. I am associate medical director of Mutual of
Omaha and their consultant on medicare. Mutual is one of the fiscal
intermediaries for the Department of HEW in this program as well
as for the Department of Defense in the CHAMPUS program,
formerly known as military medicare. I will be in Baltimore at SSA
headquarters the next 2 days for a regional meeting of medical direc-
tors and consultants of the fiscal intermediaries for the medicare pro-
gram. One of the important subjects wewill discuss is the use of drugs
and related materials in the program.
I have read many of the press releases and some of the official
testimony given to this committee. If I can make any contribution
which might be of help to you I believe it would be in the area of the
relationships between the drug industry and organized medical
societies and in the areas involved in the practical translation of
medical scientific knowledge to the care of patients. I will be glad
to answer any questions that I can.
PHYSICIAN EESPONSIBILITY
With respect to the prescribing drugs, I believe it is the physician's
responsibility to be fully informed about any of the drugs he
prescribes_-the dose, the expected pharmacologic effects, side effects,
toxicity and all similar matters. It is equally important for him to
know his patient because the identical drug may produce an entirely
different pharmacologic effect in one person than another. Dosage
requirements and tolerances may vary widely in different patients and
even in the same patient at different times. Treatment with drugs,
as with all other modalities, should be highly individualized.
Physicians have an economic responsibility to their patients too,
and some consideration should be given to the cost of drugs prescribed
so long as cost is not the sole determining factor. If a cheaper drug
will not accomplish the desired result, then obviously it is not cheaper
PAGENO="0454"
4744 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
at all but really more expensive and the delay in obtaining the desired
result might be harmful to the patient. Naturally, no prescribing
physician should have any secondary financial gain in prescribing one
drug or one brand as compared with another. He should always be
guided by what he believes to be best for his patient.
Senator NELSON. In what way does the sole practitioner decide to
prescribe one drug at a certain price and not another which may be
equivalent?
Dr. LoNG. In the final analysis, Senator, it is not the advertising
or the claims of the pharmaceutical houses that determine what we
prescribe. Myself and all the physicians whom I know, and have known
over the years, decide what kind of a drug to prescribe and which drug,
based upon our examining our patient, and talking with our patient,
and prescribing for the patient, and then reexaminating, reevaluating,
and assessing the results obtained.
When we start out initially to prescribe a new drug for the very first
time, this, of course, happens. Then we depend upon information we
have obtained about this drug from reading in the scientific medical
literature, from hearing about it at medical meetings as previously
described this morning by Dr. Pollard, or by talking with our col-
leagues formally and informally as we meet together.
Senator NELSON. What I was getting at, if you have a cheaper drug
which would not accomplish the desired result, then obviously it is
not cheaper at all?
Dr. Loxo. Yes.
Senator NELSON. To use the example I have used here before be-
cause it is based on the medical letter on prednisone, the price to
pharmacies is $17.90 for Meticorten and $17.80 for Paracort. It drops
down to $2.45 for Merck, and then to $1.80 and 50 cents for Wohns.
And then the Letter said that the laboratory testing was done for
them and all met lISP standards, and that in their consulting with
clinicians they found they were equivalent. On what ground would the
doctor, the sole practicing physician, decide that, say, Meticorten, at
$17.90 to the pharmacist, was better than Merck's Deltasone at $2.20?
How does a. physician practicing on his own make that decision?
Dr. LONG. A practitioner practicing alone makes a decision based
on his results and his experience with the drug. And if he prescribes
a certain drug, and in his hands it works well, and in his hands he
can predict with reasonable accuracy how his patients will respond to
it to given dosage levels, and can predict with reasonable accuracy,
when, a.t what levels, and what periods of time he may be in trouble
with side effects or complications or unwanted effects from the drugs,
if he becomes, then, thoroughly familiar, I think it is understandable
that lie might be hesitant to change on the basis of price alone, unless
and until the time comes that someone-and this does come to all of
us in some instances-and I think prednisone is a good example-
unless and until it can be shown and demonstrated to him on the basis
of the experience of people in whom he has confidence, on the basis
of reports in medical journals in which he has confidence, if then it
can be demonstrated that an equivalent product at a lower price is in
fact therapeutically equivalent, not just lISP, which does not really
mean much.
Senator NELSON. Pardon?
PAGENO="0455"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4745
Dr. LONG. I think therapeutic equivalency is an entirely different
matter than chemical equivalency.
Senator NELSON. Do I understand you to say that the USP standard
did not mean very much?
Dr. LONG. It does not mean very much with respect to therapeutic
results. Let us take the old common aspirin, for example, aspirin
grains five, TJSP. You can find on the market lots of different kinds
of aspirin, some at 9 cents a hundred, if you will, and some at 49
cents a hundred. And in some instances there is no difference, perhaps,
between the 9 cents and 49 cents. But in other instances there is. Be-
cause there is a difference in the way the tablet is compounded, the dis-
integration rate, the permissible-even under lISP standards the
permissible variations in quantities of something other than pure
acetylsalicylic acid may be permitted up to certain tolerances of
purity. So that, therapeutically, equivalency is a good deal more im-
portant to the physician than the term lISP alone. So I think perhaps
I should change my statement to say that lISP does not mean any-
thing. It means a good deal, of course, because it does tell you about
the chemical quantities that are in there, and the tolerance limits that
are permitted for impurities, if you will, within a given product. lISP
does provide for that. But in addition to that, one needs to know some-
thing about biologic or therapeutic equivalency, which may be affected
by many many things, as you know.
Senator NELSON. It is the position of the lISP as well as many others,
including Dr. Modell who testified here, that if a drug meets TJSP
standards it is therapeutically equivalent until they find some evi-
dence to the contrary. In other words, the best knowledge that the pro-
fession has, physicians as well as pharmacologists, is put into the lISP
sLandards, they may not have all the knowledge, but when something
new is discovered they put it into the standard. So their position is that
if it meets the standard it is therapeutically equivalent according to
the best available expertise.
I notice you are shaking your head.
Dr. LONG. I do not agree, Senator.
Senator NELSON. Do you have a specific example of a case where two
drugs meet the tTSP standards and were proven not to be therapeuti-
cally equivalent?
Dr. LONG. Oh, yes. FDA has that, for example, in chloramphenicol.
Senator NELSON. As an example, the FDA does not say they were
not therapeutically equivalent. They just did not reach the same blood
level. Dr. Ley will tell you that they did not have any test to find Chlo-
romycetin vis-a-vis the two that did not meet the Chloromycetin level.
There is no test to say that they are not therapeutically equivalent.
So apart from that, FDA simply says there is no proof on therapeuti-
cally equivalency. Do you have another example?
Dr. LONG. I think there are many examples. I did not research this
subject because I did not come prepared to testify on that particular
line of testimony, Senator. But I can tell you, on the basis of my own
experience, `and on the basis of experience of many of my colleagues
with whom I visited, that there are situations in which there is not
therapeutical equivalency.
Senator NELSON. You say in your own experience. Do you have a
case in which you had the drugs assayed, two drugs, and they both met
tJSP standards, and they were not equivalent?
PAGENO="0456"
4746 COMPETITIVE PROBLEMS ]i~ THE DRUG INDUSTRY
Dr. LONG. That is correct.
Senator NELSON. Testimonial proof or clinical proof?
Dr. LONG. This is clinical proof. In the final analysis, Senator-and
this is really the only point I want to make-in the final analysis it is
iiot what it says in the drug manufacturers' advertising. It is what
does the patient tell you about how he feels after he has taken this drug
or that. And it is the clinical examination of the patient by physical
means, physical examination, and examination of the patient by labo-
ratory means, if you will, in addition, the total evaluation of the pa-
tient. This to me is the therapeutic result. This is what happens to the
guy who is sick.
Senator NELSON. Do I understand you to be saying that if you pre-
scribed a particular drug-
Dr. LONG. Let us take a common one like aspirin. I treat a lot of
people with arthritis. And I have over the years had many patients
who on a given kind of aspirin-I cannot even tell you the name of
it-let us say a cheap aspirin, if you will, or let us say a low-cost
aspirin, if you will-and these patients with rheumatoid arthritis,
for example, will take a dozen tablets a day, and do badly, they are
just not comfortable, their joints are still stiff and painful and swollen,
and then they will change to a different brand of aspirin-both of
them plainly labeled IJSP-and they will immediately get relief from
their symptoms on the same dose.
Senator NELSON. Did they meet TJSP standards, is the question.
You recognize-
Dr. LONG. Let us say they are plainly labeled USP in both in-
stances.
Senator NELSON. That is not the question, because we know that
brand names and generic name drugs go into the marketplace lacking
adequate quality control and supervision and they cannot meet TJSP
standards. The testimony before the committee by lISP and other dis-
tinguished pharmacologists is that if they meet lISP standards they
are therapeutically equivalent. I am asking did they, in fact, meet US?
standards?
Dr. LONG. I have to assume so, if the manufacturer is following the
labeling law. I have the impression that he isviolating the law if he
labels it lISP and it is not TJSP.
Senator NELSON. Correct, and that is what is happening in both
brand and generic names. And many of them are pulled off the mar-
ket every year. But the real question we are getting at is-do you have
a case? We have been seeking one. The reason I raise this, Doctor, is
that we have been seeking one publicly in this forum for 2 years,
and I would think that the manufacturers themselves would come up
with an example. But they do not. And all I am saying is, do you
have an example of two drugs meeting lISP standards and not being
therapeutically equivalent? I do not mean testimonials, because I do
not think that means much. Do you have a case in which you have
done double blind testing with an adequate sample and proved that
the 20 drugs that were assayed to meet USP standards are not
therapeutically equivalent? That is the case that we have not been
able to get.
Dr. LONG. Well, as I say, I did not research this scientifically or in
the medical literature. I am persuaded on the basis of my nearly 30
years of experience as a. practicing physician, and my contacts with
PAGENO="0457"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4747
hundreds and thousands of physicians, I am persuaded that there is
something else besides chemical equivalency that has to do with thera-
peutic results in the treatment of patients.
Senator NELSON. I think the TJSP will say that. Of course chemical
equivalency-that includes coating and~ tablet pressing and all that?
Dr. LONG. That is what I mean.
Senator NELSON. But TJSP insists, they take all the best available
knowledge, based upon all of their consultants, and put into the
standard, the best knowledge that is known today. They will concede
that some better knowledge may come later, and then they will put
it into the standard. But as to the standard today, until additional
evidence is produced they say that if drugs meet TJSP standards
they are therapeutically equivalent. And only in the rarest of cir-
cumstances has this not been true.
Dr. LONG. I wonder why the statement is always put that way?
Why would you not say that they are not therapeutically equivalent
until it is proven that they are?
Senator NELSON. The experience of the consultants and clinicians,
pharmacologists, and authorities when they establish the standard is
that if they meet the standard, they are equivalent.
Dr. LONG. I think this is not the consensus of the opinion in my
experience, or in my contacts with practicing physicians who have
been taking care of sick people day after day and week after week
and month after month. That consensus of experience is that thera-
peutic equivalence and chemical equivalence are not always identical,
that with the same dose of a given drtig in the same patient for the
same disease, that brand X, let us say, the therapeutic results are not
the same as with brand Y, if you will. Now, this may be true in many
instances, that X and Y will result in the same. But I think there are
many other instances in which this is not true.
Senator NELSON. You see, the drug companies will argue, well, the
coating will make a difference, the excipient will make a difference,
the size of the granule will make a difference, how hard the tablet is
pressed will make a difference. Everybody knows that.
Dr. LONG. Yes.
Senator NELSON. Including the TJSP. So they set a standard for
dissolution, and the excipient, and so forth. And the amount of the
active ingredient can only vary, depending upon again the consulta-
tion with the experts, it has to have X percentage of the active in-
gredient, and in aspirin it is 95 to 1O5~percent pure aspirin. And their
consultan.ts advise that if you get within that tolerance you get the
same result. All I am saying is, we have been asking for proof of in-
stances where they meet the standard and were not equivalent, and we
have received testimonials, but we have received nothing scientific
from the drug industry or from any clinician or anybody ~lse, except
what they stat.e what their personal experience has been. Well, in that
kind of case it might be very well true that maybe they did not meet
[TSP standard. None of the testimonials we have had, in the case
where the drug was assayed to see whether it met [TSP standards
first-that is our problem, trying to get that kind of a case.
Dr. LONG. I think maybe if I read a little further I may answer
your question in part, and then perhaps we will come back to it if you
wish.
PAGENO="0458"
4748 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
RELATIONSHIP OF PROFESSIONAL MEDICAL ORGANIZATIONS
TO THE PI-IARMACEUTICAL INDUSTRY
It is not only natural and inevitable but highly desirable that there
be a c-lose relationship between the pharmaceutical industry and the
medical profession. This is essential in the public interest and neces-
sary in order for us to provide the best care and treatment that we- can
for our patients. That is what we all want in the final analysis with
the best care a-nd treatment that we can get for our patients. We are
providing professional services for our patients in the course of which
we use drugs, biologicals, instruments, and supplies of various kinds.
We need to know something about the companies that provide these
materials.
At the same time, the drug, instrument, appliance, and other pro-
ducers of materials used in health care need to know a good deal about
the problems we practicing physicians have in usmg these materials
in the care of patients. They need to know how and when and under
what circumstances we use their products, and what the results are~
both good and had.
Th~re is no way for us to find out what we need to know from each
other without a continuing dialogue and exchange of information
between us, in person as well as in writing. This necessarily takes place
at an individual level, such as between the individual physician and
the individual manufacturer's personal representative, and at an orga-
niZational level. The latter is particularly important because of the
complex matter of logistics. There are more than 300,000 physicians
and several hundred manufacturers. To provide the necessary exchange
of information on an individual basis obviously would be impossible.
To try to do it on the basis of a single publication or even a few would
be as impractical as to try to do it on the basis of a single meeting.
Each of us has to get our message to the other in many different ways.
The science of medicine, particularly as related to drugs and instru-
mentation as well as techniques, has advanced so far and so rapidly in
the pa-st 20 years that no one method of disseminating information,
acquiring information, or translating it to the care of sick patients can
suffice. It has become necessary for many different techniques and
many different organizations to be developed to do the job.
Just as we are all dependent on each other in the philosophic and
scientific sense in the pursuit of our common goal, it necessarily fol-
lows that there is a certain amount of financial interdependence too.
It costs money to do research, to produce a drug or an instrument, to
publish literature, and to have a meeting. It seems natural and logical
that a manufacturer of drugs would provide information about his
products in a magazine or journal published and read by physicians. In
the same journal, of course, medical scientific information is trans-
mitted from one physician to others. So long as the advertising a-nd
the medical scientific information in the articles written by the physi-
cia-n-authors is ethical, accurate, and honest t-hen the best interests of
the public are being served.
It is not t.he advertising campaign of the drug manufacturers, nor
their contributions to medical organizations for scientific or social
affairs that convinces the practitioner of the virtues or safety of a new
or old drug, but only his own personal experience gained from listen-
PAGENO="0459"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4749
ing to and examining his patients and his knowledge of the experience
of his colleagues.
I hope that this very sincere and dedicated committee will not be
diverted in its efforts to help identify and solve some of the trouble-
some socioeconomic problems related to the health care field by those
few persons who presume to see some sort of collusion between the
drug industry and practicing physicians which they believe exists to
take unfair advantage of the public. Believe me, gentlemen, there is
no exchange of material goods or servièes or money that I know of
which is contrary to moral or statutory law or ethics.
NATIONAL DRUG COMPENDIUM
The matter of publication of a national drug compendium has been
discussed at length and in detail by medical, governmental, and other
organizations for several years. The consensus of opinion of practicing
physicians generally is, I believe, that such an effort would not be de-
sirable, practical, useful, or in the public interest. If such a book were
to be all-inclusive, several volumes more than 3 inches thick would be
required. It would have to be loose leaf and updated regularly and fre-
quently. It would have to be compartmentalized for the best use of the
different medical specialties, yet there is sufficient overlap in all that
there would have to be some duplication of entires. It would, indeed,
be difficult to find any agency or group of physicians, however knowl-
edgeable, who could put such a mass of information together in read-
ily usable form.
By the time it was published and distributed, much of the informa-
tion would be outdated. The editors would not dare put in anythin
too new, yet much of the new is very, good and useful as time an
experience later prove. It would be difficult to leave out some of the
old, yet much of it is outdated or so very well known generally that
it would be in the way.
However much disclaimed, if published by or with the approval of
the Government, the material contained in it would be interpreted as
having legal Federal sanction. Then if a drug were used in the treat-
ment of a condition not listed in "the book," or in a different dosage
range, the physician might be presumed guilty of malpractice.
Conversely, if a drug were listed as useful for a certain condition
and the attending physician did not use it even for very good and
acceptable reasons, then he might also be presumed guilty.
A further disadvantage would be its use as a lever to impose com-
pulsory prescribing by generic name. This simply cannot be, in my
opinion, handled by the majority of practicing physicians. All of us
prescribe some drugs by generic name, but we cannot possibly remem-
ber all of the generic terms for all the drugs we are accustomed to
prescribing. To be required to look them up in "the book" would use
up too much valuable time and would further aggravate our existing
health-manpower shortage.
Further, and more importantly, a compendium would further con-
fuse the question of generic equivalence. 1~Ve have already found out,
as has the FDA, that drugs identified as being the same generically
are not always the same clinically.
Senator NELSON. I am not familiar with what the FDA found on
that point.
PAGENO="0460"
4750 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Dr. LONG. I do not have the citation with me. All I can tell you is
that I have read this. And as I say, I did not come prepared to discuss
that in detail. But I have read this in what I consider to be a reliable
and authoritative publication.
Gentlemen, the last book on therapy has not yet been written. What
person, or committee, or agency is to say with finality that this or that
vitamin is better than another, that this or that antibiotic should or
should not be used, that the dosage range of this or that drug
is from here to there but no less and no more, that this or that
drug is very good for this condition but must never be used for that?
I can think of nothing worse for the health and care of the American
people than for individual physicians to be compelled, directly or by
implication, to treat their patients according to a majority vote of
a committee of other physicians or scientists, however honest, capable,
and sincere the members of that committee might be.
Treatment must be individualized and scientific areas where precise-
ness of measurement is almost nonexistent should not be highly regu-
lated. Pharmacology, toxicology, absorption factors, excretion factors,
blood levels, bacterial sensitivity studies in the test tube and the like
fail to inform us really of what drugs do at the cellular level. Until we
have better methods for making such determinations, these studies,
while necessary and important, are only gross guides for drug therapy.
There are no "standardized" patients and I do not believe there can
be any "standardized" drugs to meet their needs.
Previous testimony before this committee indicates that more than
90 percent of prescriptions ifiled called for a product by brand name or
the product of a particular manufacturer in whom the physician had
placed his confidence. It also has been stated here that 86 percent of
the dollars spent by the Federal Government went for the purchase of
products of brand name manufacturers when all the testing and elabo-
rate screening procedures were completed.
Physicians, depending on manufacturer integrity to secure the high-
est quality medicines for their patients-and Government, refusing to
accept anything except scientific proof of quality-both arrived at the
same drug counters to secure healing agents for those for whom they
were responsible.
DRUG LABELING FOR PATIENT
The matter of labeling prescription drugs dispensed to a patient is
a highly individual matter and often involves medical judgment which
only the attending physician who knows his patient should exercise.
I hold no brief for the physician who labels a bottle of medicine "take
as directed," unless those directions are given in writing to the patient
by the. physician. This is necessary in certain situations. It is my own
practice to identify the name of the drug, the dosage schedule, and the
purpose for which it is prescribed in most instances. Even here, there
are exceptions. For example, there are certain patients who develop
so much anxiety from seeing the name of a drug on the bottle when the
possible harmful side effects of that drug have been discussed in re-
cent newspaper and magazine articles, that it is better for them just
not to know the name of it.
Again, the doctor has to know his patient and act accordingly. A pa-
tient should almost never he given the usual "package insert" to read.
They already have enough anxiety about their condition without be-
PAGENO="0461"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4751
ing frightened by reading information which they cannot possibly
interpret properly without a medical background.
One other item that I do not have in this written statement. Some-
times when medicines are labeled to exactly what they are, ~t IS quite
surprisnlg sometimes how often patients prescribe for other patients,
or they exchange medicine, when the name of it is on the bottle. And
there has been an article by one of the columnists in the newspaper
telhiilg how, for example, some friends, neighbors, grandma, a rela-
tive, or someone else, say, you have got some of that so-and-so medi-
cine, I should take some, and how in that respect sometimes people
take drugs that they should not be taking because their friend has it
and they saw the name of it and recognized it from some article in the
lay press.
So that is one disadvantage. I think there are many advantages, but
there is occasional disadvantages that I have run into.
From the testimony given here previously as I have read it, I believe
most witnesses and also this committee recognize the advantages and
disadvantages of generic prescribing and everyone is generally agreed
that the attending physician has the privilege and the duty to prescribe
what lie believes to be best for the particular patient in the particular
circumstances which exist at tIme time the decision must be made and
that dispeilsing pharmacists should never make substitutions for the
specific preparation prescribed.
I will be glad to answer any questions I can. Thank you for your
kind attention.
Senator NELSON. Just so that it will be clear, I think, no witness
that has testified here has suggested that the physician should not be
able to designate the manufacturer or the brand.
Dr. LONG. Yes, I read your staternentin the testimony to that effect.
Senator NELSON. Thank you very much, Doctor, for taking time
from your busy schedule to come here and testify. It has been very
helpful to the committee. Thank you.
Dr. LONG. Thank you, sir.
Senator Nelson. The committee will meet at 10 o'clock tomorrow
morning in room 4221, the Foreign Relations Committee room.
(Whereupon, at 12:10 p.m., the subcommittee was recessed, to me-
convene at 10 a.m., Wednesday, March 26, 1969.)
PAGENO="0462"
PAGENO="0463"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
WEDNESDAY, MARCH 26, 1969
U.S. SENATE,
MONOPOLY SUBCOMMITTEE OF THE
SELECT COMMErTEE ON SMALL BusINir~ss,
Washington, D.C.
The subcommittee met, pursuant to recess, at 10: 10 a.m., in room
4221, New Senate Office Building, Senator Gaylord Nelson (chair-
man of the subcommittee) presiding.
Present: Senators Nelson and Dole.
Also present: Chester H. Smith, staff director and general counsel;
Benjamin Gordon, staff economist; and Elaine C. Dye, clerical as-
sistant.
Senator NELSON. Our witness this morning is Dr. Maynard I.
Shapiro, president of the American Academy of General Practice.
Dr. Shapiro, the committee is very pleased to have you take time
from your busy schedule today and appear before the committee.
STATEMENT OP PETER CHUMBRIS, CHIEF MINORITY COUNSEL OF
THE ANTITRUST AND MONOPOLY SUBCOMMITTEE, COMMITTEE
ON THE J~UDICIARY, U. S. SENATE
Mr. CHUMBRIS. Good morning.
My name is Peter Chumbris, I am chief minority cot~nse1 of the
Antitrust and Monopoly Subcommittee of the Senate Judiciary Com-
mittee, and I am appearing here this, morning on behalf of Senator
Dirksen and Congressman Annunzio to introduce to you the witness,
who is from the State of Illinois, Dr. Maynard Shapiro, president
of the Academy of General Practice.
Dr. Shapiro is a very highly professional gentleman and highly re-
spected gentleman in his community. And it gives me great pleasure
to introduce him to you this morning.
Senator NELSON. Thank you very much; He comes here with very
distinguished credentials and we are pleased to have you, Doctor, why
don't you introduce your associates for the purposes of the record,
and then if either of them wishes to ôomment, see that they identify
themselves so that the record will be straight.
STATEMENT OF DR. MAYNARD I. SHAPIRO, PRESIDENT OP THE
AMERICAN ACADEMY OF GENERAL PRACTICE; ACCOMPANIED BY
MAC F. GAHAL, EXECUTIVE DIRECTOR AND t+ENERAL COUNSEL;
AND WALTER KEMP, SECRETARY, COMMISSION ON PUBLIC
POLICY
Dr. SHAPIRO. With me today on my right is Mr. Mac F. Cahal,
executive director and general counsel of the academy. And on my
left, Mr. Walter Kemp, secretary of its Commission on Public Policy.
4753
PAGENO="0464"
4754 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. Your statement will be printed in full in the record.
Did you submit a separate statement of biographical data, or did
you wish to present anything in that regard?
Dr. SHAPIRO. That can be submitted, Mr. Chairman.'
Senator NELSON. If you wish, we would be pleased to print it in the
record preceding your statement.
Dr. SHAPIRO. Thank you.
Senator NELSON. You may proceed to present your statement in any
way you desire. If you wish to depart at any time to elaborate on any-
thing you have said, feel free to do so. I assume you have no objection
if we interrupt occasionally with questions, and if your associates wish
to comment at any time, they are free to do so.
Dr. S~&PIRo. We have abbreviated this statement to the maximum
extent, Mr. Chairman, and possibly the flow of our prepared testimony
would be best uninterrupted. However, I have no objection if it is
necessary for clarity to stop at any time.
Senator NELSON. Very well.
Dr. SHAPIRO. Mr. Chairman, I am Dr. Maynard I. Shapiro, a family
physician with offices at 7531 Stony Island Avenue in Chicago. I am
also clinical associate professor of medicine at Chicago Medical School
and director of medical education at Jackson Park Hospital. I am a
member of the Medical Assistance Advisory Council of the Depart-
ment of Health, Education, and Welfare. I am here today as president
of the American Academy of General Practice. The academy is the
Nation's second largest medical association and presently has more
than 31,000 members.
I have not read all or even most of the testimony presented since your
committee hearings started almost 2 years ago. I will not pose as an
expert on all health care matters but I can and do speak as a practicing
family physician who is primarily concerned with people-be they
healthy, ill, injured or infirm.
Your letter asked for information about the academy, its member-
ship, its admission requirements, its publications, it advertising accept-
ance criteria, its advertising revenues and its other financial relation-
ships with the drug industry. The letter closed with a suggestion that
I comment on drum compendium proposals. I will attempt to give you
the information you have requested and then add a few comments-in
my official capacity as president of the academy.
To become an active member of the academy, a physician must be
engaged in the general practice of medicine, be a graduate of an
approved medical school, be duly licensed to practice medicine and be
a member of his State medical society. But, to remain a member, he
must complete 150 hours of academy-approved postgraduate study
every 3 years. The academy is the only national medical association
which requires continuing postgraduate study.
This should adequately illustrate the academys continuing deter-
mination to maintain high health care standards. As another example,
most recently, the academy, in conjunction with the section on general
practice of the American Medical Association, has been successful in
its determined efforts to establish an examining board for family
practice. This board will certify to the competence of family physi-
~ See pp. 478~-478S, infra.
PAGENO="0465"
COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 4755
cians who render the major portion of medical services delivered in
this country today. We believe this latest development will swell the
ranks of family physicians, an increase which is sorely needed in order
to assure the availability of continuing comprehensive health care for
the people of America.
The academy publishes two journals, both primarily scientific.
Senator NELSON. Would you name the two, Doctor?
Dr. SHAPIRO. GP and the American Family Physician.
Senator NELSON. I do not recall that you recite any place in your
statement the circulation of each-or do you?
Dr. SHAPIRO. GP is circulated to members on a subscription basis.
The American Family Physician is circulated to all nonmember gen-
eral practitioners in the country.
Senator NELSON. Is that by subscription?
Dr. SHAPIRO. No, sir.
Senator NELSON. Is the GP by subscription?
Dr. SHAPIRO. Yes, sir.
Senator NELSON. And the one that is circulated to all family physi-
cians is the American Family Physician?
Dr. SHAPIRO. Yes, sir.
Senator NELSON. And that is in the form of a newspaper?
Dr. ShAPIRo. No, sir; it is a journal.
Senator NELSON. The circulation is a total of how much, just in
round figures?
Mr. CAHAL. It is about 40,000. And GP is about 32,000.
Senator NELSON. Thank you.
Dr. SHAPIRO. Mr. Chairman, the American Family Physician con-
tains the leading scientific articles from GP. But the difference in the
two magazines is that GP contains much Academy information.
Senator NELSON. Much Academy information?
Dr. SHAPIRO. Yes, sir.
Senator NELSON. What do you mean by that?
Dr. SHAPIRO. Reports from chapters,reports on postgraduate courses
for Academy members, things of that type.
Senator NELSON. Are they separately edited and printed?
Mr. CAHAL. Mr. Chairman, GP is the official journal of the Ameri-
can Academy of General Practice, and as Dr. Shapiro stated, it goes
on a subscription basis to all Academymembers 31,000 and about 1,500
nonmember subscribers, including libraries, et cetera.
American Family Physicians is actually a reprint of the leading
scientific articles which have appeared in GP magazine. American
Family Physician goes to all general practitioners in the United States
under age 65 who are not members of the Academy, who have not main-
tained the 150-hour postgraduate training requirements. The combined
circulation, therefore, is around 70,000.
GP contains internal business matters pertaining to the organiza-
tion. American Family Physician does not.
Senator NELSON. On that point, the GP is supported by subscrip-
tions. Is the American Family Physician supported by advertising?
Mr. CAHAL. It is not self-sustaining. It takes advertising, but it is
i~ot fully supported by that revenue. The Academy subsidizes it from
its general revenues.
Senator NELSON. What percent is the subsidy?
81-280-69-pt. il-30
PAGENO="0466"
4756 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Mr. CAHAL. Well, we have lost about $100,000 a year on it in recent
years.
Senator NELSON. That is what percent of the total cost of getting it
out?
Mr. CAJIAL. I am afraid, Senator, I would only hazard a guess, but
I would be glad to look that up and communicate with the committee
secretary if you wish. I would say roughly its total revenues are prob-
ably $300,000, and it costs approximately $400,000 to publish. But this
is a hazardous guess on my part.
Senator NELSON. Could you submit that for the record?
Mr. CAHAL. I shall be glad to, sir.'
Senator NELSON. Thank you. You may continue, Dr. Shapiro.
Dr. SHAPIRO. One magazine goes to American AOademy of General
Practice members, the other goes to nonmember family physicians.
Advertising is screened by a group of physicians, all of whom we
considered qualified to perform their task. We do not list the names
of these physicians in our magazines because we believe they prefer a
degree of anonymity. All are medical school faculty members and all,
in our opinion, are well qualified to screen pharmaceutical advertising.
In your letter, you asked about Academy income from pharmaceu-
tical advertising. Exact figures would take substantial digging be-
cause our advertisers include equipment companies, book publishers,
and so forth. However, it would not be far off to say that our drug in-
dustry advertising income has run between $1 million and $1.5 million
a year since 1962.
Our total advertising revenues-from both publications and includ-
ing nondrug advertising-are as follows:
1962, $1,155,000; 1963, $1,236,000; 1964, $1,493,000; 1965, $1,587,000;
1966, $1,725,000; 1967, $1,538,000; for 11 months, because the fiscal year
ended on November 30, 1968.
Senator NELSON. But your books do not show a breakdown by
source?
Mr. CAHAL. Yes, Mr. Chairman, our annual financial statements
show the revenues from subscription versus advertising. This is only
advertising revenue, though, that Dr. Shapiro has given.
Senator N~soN. That is what I was inquiring about. What amount
is pharmaceutical industry, what amount is books, and what amount
is surgical instruments, and so forth?
Mr. CAnAL. As a matter of fact, our financial records do not segre-
gate those classifications.
Senator N~soN. We have a breakdown done by the Library of
Congress, but it is only for the American Family Physician. I will
submit it for the record. We did not get it from them on the UP. This
one shows that in terms of space, we do not know what the dollars are,
but in terms of space-drug advertising-as a percent of all adver-
tising in 1967, was 91.5 percent.2
Mr. CAHAL. That would be my guess also.
Senator NELSON. Do you have a figure on what percent of total
income all advertising is, percent of total income for the Academy?
Dr. SHAPIRO. Approximately 50 percent.
`See pp. 4781-4786, infra.
2 See app. XIII, "A Study of Pharmaceutical Advertising in Selected Medical Journals,"
pp. 4863-4998, infra.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4757
Senator NELSON. Fifty percent of the total income of the Academy
is advertising?
Dr. SHAPIRO. Yes, sir.
Senator NELSON. And the rest is-
Dr. SHAPIRO. Dues.
Senator NELSON. Do you have, as a number of the other organiza-
tions, have, revenue from displays at conventions, for example, by the
drug industry?
Dr. SHAPIRO. We do have, but our conventions are always a loss.
Senator NELSON. But you do have have an income from that source
from the pharmaceutical industry?
Dr. SHAPIRO. There is an income for exhibit space which only partly
displaces the cost of our meeting.
Senator NELSON. Do you have a figure on the amount of that
income?
Mr. CAHAL. It approximates in recent years $108,000, the gross rev-
enue from the sale of exhibit space at our annual convention. As Dr.
Shapiro has pointed out, this is about half of the annual convention.
Senator NELSON. And what percentage of that $108,000 would be
pharmaceutical advertising?
Mr. CAI-IAL. I would guess, Mr. Chairman, that ratio would be
lower than the one for advertising in the journals. And I would
estimate that the revenues for exhibit space for drugs is 70 percent at
the annual convention, the balance being other classifications.
Senator NELSON. The figure we discussed a moment ago from the
Library. of Congress, 91.5 percent for advertising in the American
Family Physician, is that roughly an equivalent percentage of the
advertising in the GP.
Mr. CAnAL. I would imagine, sir.
Senator NELSON. Apart from advertising and exhibits, are there
any other. funds from the drug industry?
Mr. CAI-IAL. No, sir; there are no other revenues from any source
except the sale of supplies to members.
Senator NELSON. Any other from the drug industry of any kind?
Mr. CAHAL. No other sales to the drug industry.
Senator NELSON. Or any other grants or scholarships or research,
and that sort of thing from the drug industry?
Mr. CAHAL. Occasionally, Mr. Chairman, there are grants from
pharmaceutical companies to endow a speaker at a meeting. Or, for
instance, Mead Johnson & Co. makes a grant to the Academy which is
used to subsidize preceptorships, medical students who go out and
spend a portion of their time with practicing family physicians. This
is a grant from Mead ,Johnson & C., a pharmaceutical company. We
have had occasionally grants of that nature.
Senator NELSON. Thank you.
Go ahead, Dr. Shapiro.
Dr. SHAPIRO. Mr. Chairman, in this next paragraph we have `some
changes in the arithmetic which are substantial. This was our error
in calculating. I will read them correctly.
If our drug advertising income averaged out at $11/4 million per
year, it is then reasonable to state that the pharmaceutical industry
suppOrts our publishing efforts to the extent of approximately $18
per family doctor per year.
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4758 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Senator NELSON. This is in place of the figure $41?
Dr. SHAPIRo. Yes, sir.
Senator NELSON. And when you say family doctor, are you talking
about all fainil doctors in the country?
Dr. SHAPIRO. Yes, sir.
Senator NELSON. What is the total of the family doctors by that
mathematics?
Dr. SHAPIRO. 68~000.
Senator NELSON. And your publications go to about 40,000 of those?
Dr. S~IRo. No, sir. We cover them all. G-P goes to 32,000 and the
American Family Physician goes to the remainder.
Senator NELSON. There is no duplication?
Dr. SHAPIRO. No, sir.
With this $18, what can we do for the individual doctor? We can
deliver, to the door of his office or his home, about 84 original scien-
tific articles and 240 well-edited abstracts. We can also tell him about
the government medical programs and about hundreds of postgradu-
ate study programs. In short, we can provide him with more useful
information than we could if we sent him a first-class letter every
day. We think it is $18 well spent-by both the Academy and the
pharmaceutical industry.
Allow me to touch on another point which involves liaison between
the Academy and the pharmaceutical industry. In January, we started
publishing a six-installment course on the "Diagnosis of Diabetes."
The course was programed to our specifications by a firm in New
York City. However, it was made possible by a no-strings grant from
jhe Upjohn Co.
What does Upjohn get for its money? A small credit line, a letter
of appreciation, hopefully some satisfaction-and that is about all.
Please note that the course is concerned only with the diagnosis of
diabetes-not the treatment of diabetes.
Senator NELSON. May I ask a question at this point?
Dr. SHAPIRO. Yes.
Senator NELSON. What would your view be of the reason for Upjohn
sponsoring such a progra.m if there is not any credit in doing that?
Dr. SHAPIRO. As an important cog in the health team, the pharma-
ceutical industry feels that this is necessary. They are totally involved
in continuing education.
Senator NELSON. The only question I would raise-and I do not say
that there are no public spirited people in all industries, I am sure
there are-but tolbutarnide is Orinase, is it not?
Dr. SHAPIRO. Yes, sir.
Senator NELSON. And that is the only drug of its kind in the market-
place, is it not? There is no other tolbutamide but Orinase?
Dr. SHAPIRO. Not to my mind.
Senator NELSON. So would it be fair to say that there is a benefit in
the promotion of their drug Orinase?
Dr. SHAPIRO. There would be an indirect long-range benefit to them
as well as to all other manufacturers of oral antidiabetic drugs, or
insulin. Basically we are hopefully uncovering unfound diabetics who
must be treated, not necessarily by Upjohn's product.
Senator NELSON. I know. But Orinase is the only tolbutamide in
the market, and it is under patent, and it is only made by Upjohn.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4759
And is it not correct that if they can establish the name Orinase widely
in the mind of the physician in the 17-year period of the patent pro-
tection then there is an expectation on their part that when the pat-
ent runs out the doctor will continue to prescribe under the brand
name of Orinase.
Dr. SHAPIRO. But Orinase is only one of the antidiabetic agents.
Senator NELSON. But it is the only tolbutamide?
Dr. SHAPIRO. Yes, sir.
Senator NELSON. So if the doctor wants to use tolbutamide and the
company has established it under its brand name Orinase, and the
doctors have been writing Orinase for 17 years, and the patent runs
out, isn't it the hope of the company and the expectations based on
experience that the physician will continue to write Orinase even after
the patent has run out? That is my point.
Dr. SHAPIRO. Possibly, yes. But my point, then, is that this will not
alter the percentage of the number of diabetics that are being treated
by their medication. There is also Diabinese, or DBI, and other agents
available to us.
Senator NELSON. I realize that. But isn't there expectation-that
is part of the advertising program-that when any doctor desires to
use tolbutamide, after 17 years of advertising and prescribing by the
name Orinase rather than by the name tolbutamide, that when the
patent runs out and competition comes into the marketplace they
could maintain a better position than they otherwise could, because
the doctor will continue to write the name Orinase, or at least a good
percentage would; isn't that the expectation?
Dr. SHAPIRO. I believe so, yes.
Senator NELSON. I just wanted to point that out, that there certain-
ly are additional reasons other than the desire to promote continuing
education. There is a very good, sound selfish reason for this kind of
program.
Dr. SHARPIRO. However, Mr. Chairman, this sales pitch for their
product will not be included in this series.
Senator NELSON. Upjohn is identified with the product, and every-
body there will know it is Orinase, won't they?
Dr. SHAPIRO. There is no product. This is on the diagnoses of
diabetes.
Senator NELSON. But it is Upjohn that sponsors it?
Dr. SHAPIRO. Yes, sir.
Senator NELSON. All right.
Mr. CAIIAL. Mr. Chairman, it is not Upjohn that sponsors it. The
articles are prepared by the medical~ editorial staff of GP magazine.
A company is employed in New York to structure this in programed
learning. This is an innovation in medical teaching of the American
Academy of General Practice. The series is not sponsored by Upjohn.
Senator NELSON. I meant paid for, rather.
Mr. CAHAL. A small portion of the total cost is paid for with the
grant, no strings grant from Upjohn. There is no reference to it in the
article.
Senator NELSON. How much is the grant?
Mr. CAHAL. Mr. Kemp?
Mr. KEMP. $36,000.
Senator NELSON. Did you say this is a four-part program?
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4760 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
Dr. SHAPIRO. Six installments.
Senator NELSON. Over a period of how many months?
Dr. SHAPIRO. Six months.
Senator NELSON. Please go ahead.
iDr. SHAPIRO. There will be no "plugs" for Upjohn products, no
waving of banners, no coupons, no sales pitch, nothing commercial at
all. Is the cost of this program part of the $3,000 per doctor that the
pharmaceutical industry is supposed to spend each year? I do not
know. Also, I do not know if it is always possible to draw a line be-
tween a (a) the educational and (b) the advertising efforts of the
pharmaceutical industry.
To my personal knowledge, there is no other industry that spends
a larger share of its dollars not only on research but on professional
education.
Senator NELSON. How much do they spend on research?
Mr. CAHAL. Are you referring to the industry?
Senator NELSON. Yes.
Mr. CAHAL. This figure has been produced in testimony before this
committee, I believe, but I do not have it at my fingertips.
Dr. SHAPIRO. Not on research alone.
Senator NELSON. We have never been able to get from the companies
a real breakdown on research. We do not know whether they consider
detail men part of the research and promotion and advertising. We
really have not been able to get that. And the assertion is made con-
tinually by the industry that they spent more on research than any-
body else. And then we have distinguished people like you appearing
and saying they spend more on research than everybody else, but we
cannot get anybody to tell us exactly what it is and what kind of
research. That is our problem. I wonder where you got the information
that they spend more on research than anybody else?
Dr. SH~u?mo. I do not have any figures on this, Mr. Chairman. But
having visited many varied industries, including the pharmaceutical
industry, I am very much impressed myself on the amount of their
plant that is earmarked for research.
Senator NELSON. The only witness we have had who would have
reason to have knowledge was Mr. George Squibb, who said it was
about 6 percent. And that is not a tremendous percentage.
Dr. SHAPIRO. You raised the point yourself, Mr. Chairman. If we
were to follow their annual financial reports, they show the portion
of their income that is earmarked for research. But as you mentioned,
we do not know where they draw the line, where research ends.
Senator NELSON. That is right. We have had other independent in-
dustries claim they are doing great things in research, but when you
go to breaking it down we found out that it really does not qualify as
research. I would be very pleased to have the industry-I guess we will
have to ask them again-come in and just say, here are the dollars, and
here is the breakdown, and here is the kind of research, and here is how
much we spent. But as many hearings as we have had I do not think
either the late distinguished Senator Kefauver or anybody else ever
got from the industry anything other than this assertion.
I notice that the very authoritative and distinguished Task Force
on Prescription Drugs Final Report states on page 8:
Since important new chemical entities represent only a fraction-perhaps
10 to 20 per cent-of all new products introduced each year, and the remainder
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4761
consists merely of minor modifications or combination products, then the Task
Force finds that much of the drug industry's research and development activities
would appear to provide only minor contributions to medical progress. We
likewise find that to the extent the industry directs a share of its research
program to duplicative, noncontributory products, there is a waste of skilled
research manpower and research facilities, a waste of clinical facilities needed
to test the products, a further confusing~ proliferation of drug products which
are promoted to physicians, and a further burden on the patient or taxpayer
who, in the long run, must paythe costs.
Doesn't that strike you as a rather powerful indictment of the claim
for the research by the independent industry?
Dr. SHAPIRO. It sounds very condeinning
Senator NELSON. That is the Task Force on Prescription Drugs
composed of some very distinguished people. And this was issued
on March 16, 1969.
Dr. SHAPIRO. I have no knowledge of .this report, Mr. Chairman.
It comes to my mind that possibly something that you read is a
little out of context, and could be qualified. I do not know the report,
I am very sorry.
Senator NELSON. This is the summary. And we would be entitled to
go back, of course, and check the basis of their finding. But this is
the finding that they made.
The thing that is disturbing to me, just as an observer, is how often
it is asserted by representatives of the medical profession that no
other industry in the United States invests more in research than
the drug industry, which is the drug industry line, yet no one from
the medical profession can ever explain how they came to that con-
clusion except that they are repeating what the pharmaceutical manu-
facturers said. Doesn't that bother you a little bit?
Dr. SHAPIRo. In that context, yes, Mr. Chairman. But having been
out of school now for a little over 30 years, and watching the great
innovations and the changed health care so completely, this came
from some place.
Senator NELSON. The statement came from the pharmaceutical
manufacturers.
Dr. SHAPIRO. I mean the progress that we have enjoyed. It did
not just grow like Topsy, someone had to do it. We know it has been
done.
Senator NELSON. No witness before the committee of which we have
had a large number, has ever said that~ the industry has not made a val-
uable contribution in terms of research, and neither has any member of
this committee said that. The committee is concerned about overdrawn
claims. And when we have tried to chase this one down we never can
get the answer. But the task force, which is a very distingmshed group,
makes a rather telling indictment of some of the kind of research and
dissipation of money and presumed valuable research that the indus-
try makes. That is my point.
Dr. SHAPIRO. We have no further information. As a matter of fact,
you have more information than we have.
Mr. GORDON. Mr. Chairman, may I; interrupt for a moment?
Dr. Goddard on April 6, 1966 at Boca Raton, Fla., at the annual
meeting of the Pharmaceutical Manufacturers' Association said this:
Let me begin with investigational new drugs. I can say that I have been shocked
at the quality of many submissions to our IND staff. The hand of the amateur
Is evident too often for my comfort. So-called research and so-called studies are
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4762 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
submitted by the cartonful, and our medical officers are supposed to take this all
very seriously.
This confirms what the task force says about the quality of research.
Dr. SiIAPnio. That is, I believe, why we have regulations to control
the releases. And they are good.
Senator NELSON. Please continue.
Dr. SHAPIRO. Allow me to comment on drug compendium proposals
and make a point that perhaps has been overlooked in previous pro and
con discussions. Think for a moment, please, about the use to which
physicians put drug compendia. The drug compendium is not a cata-
log and thus does not serve the purpose that a catalog serves.
When you and I consult a catalog, mail order or otherwise, we ex-
pect to find that each item comes m a variety of shapes, sizes and
colors-and we choose the one we want. On the other hand, a doctor
does not normally use a drug compendium to help choose between prod-
ucts A, B, C and D. Instead, he uses it to check out a drug he already
expects to prescribe; to review, if necessary, the contraindications, et
cetera. This does not mean that he never changes his mind after con-
sulting a compendium but this happens only occasionally.
In short, the compendium is a reference book-not a catalog. In this
connection, let me make one more point quite clear: If a physician
knows nothing a.bout a drug, he is most certainly not going to prescribe
it simply on the basis of compendium listing-no matter how many
compendia are available or who published them. As an aside, I hope
that my own health and well-being are never entrusted to a physician
who feels he must consult a drug compendium every time he writes a
prescription. So a compendium is a reference volume-nothing more.
How, then, do we learn about drug products? We read, listen,
observe-and discuss. I read many scientific articles-not all of them
but as many as possible of the ones that I consider of value to a
physician in active family practice. I attend medical symposia and
other meetings and I talk to my colleagues and detail men-about
whom I will comment in a moment.
In other words, gentlemen, drug compendia are not an integral
part of my drug therapy education. The scientist has his book of
mathematical functions, the physician has his compendium. Both are
useful, both are valuable-but neither is a substitute for knowledge.
I hope I have made this point clear because perhaps you will then
understand why I see no urgent need for still another compendium.
Senator NELSON. Do we have an authoritative, objective compendi-
um available now?
Dr. SHAPIRO. I believe I touch on this further on in the testimony,
Mr. Chairman, I make reference to the AMA. May I continue?
Senator NELSON. Yes, sir.
Dr. SHAPIRo. In the months that have passed since the compendium
proposal was first mentioned, I have iiot had a single colleague tell me
that he thinks we need another compendium. So if there is no demand,
isn't it then a bit unfair to suggest that the drug industry spend $6
million for an item that physicians do not seem to really want or need?
Senator NELSON. I might. say on that, Doctor, that the proposal
that Dr. Goddard made was that the $6 million that was spent on the
package insert, be used for the compendium, and that the package
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COMPETITIVE PROBLEMS IN THE DRLTG INDIJSTRY 4763
insert not be required, since the physician does not see the package
insert very often; it goes to the pharmacist.
Dr. SHAPIRO. The package insert has not done a great deal for me,
Mr. Chairman. I can read everything I want to except the package
insert, and that is why I got these glasses. The printing is so fine and
everything is so piled on a thin piece of onionskin that it is difficult to
handle.
If the Government does decide to publish its own compendium, I
am afraid that the printed product will not be of substantial value or
use to the practicing physician. It will be little more than a collection
of package inserts, neatly bound together but almost unreadable. When
you start listing every adverse reaction to every listed drug-such
as one minor skin lesion in 10,000 patients-you cannot emerge with
anything but a tome.
Senator NELSON. Doesn't the doctor when he checks on the drug want
to know all adverse reactions? If the doctor is going to prescribe a
drug, doesn't he want to know all indications and all adverse reactions?
Dr. SHAPIRO. Yes, sir.
Senator NELSON. Then what is his objection to having it in the
compendium?
Dr. SHAPIRO. You are assuming that a doctor will prescribe a drug
from a compendium. And my assumption is that he will not, he will
have the information that he needs before he will consider using a
drug.
Senator NELSON. Where does he get the information on all the drugs
that he might need?
Dr. SHAPIRO. He does not use all the drugs.
Senator NELSON. Where does he get the information on all of those
that he does need?
Dr. SHAPIRO. As I have covered already in this testimony by reading
proper scientific articles, attending meetings, symposiums, discussions
with colleagues, hospital staff meetings.
Senator NELSON. You have been told by a number of physicians that
a lot of them rely on PDR, for example?
Dr. SHAPIRO. To that extent, I question very much. I use PDR for
one specific function. In being cost conscious for my patients, I usually
check PDIR to see what the trade size package is, and I usually pre-
scribe that amount. This enables the pharmacist to merely add a lable
to the trade size package, and not use another bottle. I have found that
if a liquid item is supplied in, say, 60 cc. form, and I write for 40 cc.,
the patient will be charged with the full 60 cc., and I am cost con-
scious for all my patients. This is the major use that I put to the PDIR.
Senator NELSON. I do not know what the compendium would answer,
I am not an expert in that, of course, or anything in this field. But I
quote from the final report of the Department of Health, Education,
and Welfare's Task Force:
We find that few practicing physicians seem inclined to voice any question
of their competency in this field of therapeutics. We also find, however, that the
ability of an individual physician to make sound judgments under quite confusing
conditions is now a matter of serious concern to leading clinicians, scientists
and medical educators. A distinguished pharmacologist, for example, has stated
that lack of sophistication in proper use of drugs is perhaps the greatest defi-
ciency of the average physician today.
PAGENO="0474"
4764 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Do you have any comment on that? In other words, they are saying
that there is something wrong here.
Dr. SHAPIRO. There is a need, Mr. Chairman, for continuing educa-
tion in therapeutics and drug use. We in the Academy are attempting
to do this through a section in our journal called Practical Thera-
peutics. The results that appear in print are not always complimen-
tary to the drug or the pharmaceutical house. We attempt to give the
doctor basic information that he can use. We have run editorials on
drugs-the thing that sticks in my mind right now is that we had run
advertising for Merrell and MER-29, and of course when this thing
blew up and it was known in the market, we were one of the first
journals to run a full editorial on this and bring all the information
to the physician, those who had not possibly read the letter that was
mailed out. The need for continuing education is great here, this I will
not question at. all. . .
You are aware that the American Medical Association is publishing
a compendium for physicians. I do not know when copies will be avail-
able but I would want to examine it in detail before planning still
another compendium.
Senator NELSON. But there is not now a general compendium.
Dr. SHAPIRO. I believe Some portion of this has already been pub-
lished, I have not seen it.
Senator NELSON. You mean a total compendium?
Dr. SHAPIRO. Not yet.
Perhaps prices should be included, hut this is not necessary, because
when the doctor needs price information, he can obtain this informa-
tion from a pharmacist. To satisfy this need and obtain information
on actual costs, I keep a copy of the pharmacists' Red Book in my
office. In short, there seems to be no real need or demand for another
compendium of the kind that has been proposed.
Please also remember that most physicians do not prescribe on a
strict cost basis-for the same reason you do not shop around for a
bargain-basement doctor. It is not my intention to become involved in
the generic-equivalency debate because I am not a pharmacologist, but
as a practicing family physician I am certainly quality-conscious.
Allow me to give you an example. A doctor knows that product X
is manufactured by the ABC company, a first-line pharmaceutical
firm that each year spends millions of dollars on research. He has read
two or three articles by eminent physicians who have used product X
and found that it is effective. He has also talked to colleagues who
have prescribed product X for patients with similar conditions.
On the basis of the results they have obtained, which correlate with
his findings, he determines the best product to prescribe. Would you
then expect him to prescribe product X-or a so-called generic
equivalent that is supposed to be "just as good" or "almost as good"?
If the. patient happened to be your wife--or one of your children-
would you want your doctor to prescribe a product in which he has
less than complete confidence? Medicine does not lend itself to either
production lines or bargain-basement economics and I would certainly
not want anyone to tell me when to prescribe, how to prescribe, or
what to prescribe. I would call your attention to the words of John
Ruskin who wisely pointed out that "there is hardly anything in the
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4765
world that some man cannot make a little worse and sell a little
cheaper, and the people who consider price only are this man's lawful
prey."
A moment ago I mentioned detail men and I would now like to
add a comment or two. Detail men are often referred to as salesmen
and in a sense, they are. But I must again urge you to think of the
detail man's function and his relationship with the individual
physician.
He-the detail man-is a source of information. I said earlier that
I would not prescribe a drug just because it is listed in a compendium
and by the same token, I would also not prescribe a drug just because
a detail man has listed its indications, contraindications, et cetera.
I have read some of the newspaper stories generated by these hear-
ings and it seems to me that one important point has been almost
entirely neglected. Medicine, and thank God this is true, is practiced
by physicians-not by detail men, not by advertising agency copy-
writers, not by the Food and Drug Administration and not, with all
clue respect, by the Congress of the United States. To get an M.D.
degree, you need 4 years of pre-med, 4 years of medical school and
at the very least, a 1-year internship. You do not have to be a mental
giant to be a doctor but most of us are not witness ninnies ready to
be gulled by a sharp-tongued detail man or a clever copywriter. So
instead of pointing one finger at the detail man, another at the copy-
writer and a third at the fellow who mans an exhibit, take a look at
the composite and remember that most physicians are involved in a
series of 1 to 1 relationships with people-people who are sick, ill,
injured, or infirm. When I see a sick child or a pregnant woman or an
elderly diabetic, I am Dr. Maynard Shapiro and that person is my
patient and I am his doctor. Whatever you do, please do not destroy
or impinge upon that relationship.
Health legislation, or related legislation, has enjoyed fantastic
popularity in recent years. Such legislation has a certain emotional
and political appeal and I would be the last to claim that the Nation's
health care structure is perfect. But as it is not all good, it is not all
bad-and I would urge you nOt to destroy the good while seeking to
improve the bad.
Senator NELSON. May I ask a question here?
Dr. SHAPIRO. Surely.
* SenatOr NELSON. 1 do not understand these general statements,
"Whatever you do please do not destroy or impinge upon that relation-
ship," and the sentence, "I would urge," meaning the committee-
"not to destroy the good while seeking to improve the bad."
What is the basis of those statements, something the committee has
done?
Dr. SHAPIRO. No, sir. This is referring more to a tendency, not the
committee specifically. If you will notice in what I have presented
just now, I did not refer to a health care system, I referred to a health
care structure, It is my contention that we do not have a system in this
country for the delivery of health care;
Senator NELSON. So you were not~ referring to issues raised before
this committee?
Dr. SHAPIRO. No, sir.
Senator NELSON. Please go on.
PAGENO="0476"
4766 CO~ETITWE PROBLEMS IN THE DRUG INDUSTRY
Dr. SH~rnio. I think we could all agree that the pharmaceutical
industry has been raked over some pretty warm coals in recent years
and let me again emphasize that I am in no way wedded to the indus-
try. However, I have many patients-perhaps literally hundreds of
patients-who are alive today because pharmaceutical industry
research came up with the drug they needed. And where is most of
this research being done? Right here in America. The Russian phar-
maceutical industry, for example, cannot hold a candle to the American
industry.
This is why I shudder when someone suggests that we impose rigid
controls on drug industry prices or profits.
Senator NELSON. May I ask a question?
Dr. SHAPIRo. Yes, sir.
Senator NELSON. What do you refer to there? Nobody before this
committee has suggested that.
Dr. SEAPIRo. The excess profits that have been discussed so widely
in the newspapers, supposedly from this committee hearing.
Senator NELSON. But nobody, if I recall, has suggested imposing
rigid proposals on the drug industry prices or profits, have they? They
have been criticized for the profits and for the pricing structure, and
I have criticized them myself.
Dr. Su~pmo. The unions have suggested this in some of their releases
to the press. I am not referring to the committee or testimony. We are
here trying to give you our
Senator NELSON. I just thought that you might be referring to
some comments that have been made by the committee suggesting rigid
controls.
Dr. SHAPIRO. I do not believe that anyone will deny that lower
profits will mean less research and although drug industry profits are
certainly substantial, I know of no industry more committed to
research. Drug industry research will not put men on the moon or
speed up an SST but it will save a great many young and not-so-
young lives. I firmly believe that the relationship which now exists
between the individual physician and the drug industry is essentially
healthy and I hope it will not be stifled.
Thank you.
Senator NELSON. Thank you very much, Doctor.
Your last statement raises a question that has been discussed before
the committee, as you well know, by a number of witnesses, including
representatives of some of the other distinguished medical organiza-
tions before this committee, AMA and the American College of
Surgeons in the past week. So I will just raise with you some of the
same questions that I raised with them. This involves the relation-
ship between the drug industry and the medical profession, which,
as I say, we have raised with every representative of medical organiza-
tions appearing before the committee as well as with the drug industry
itself, so that we can explore it and see what the relationship is and
see whether or not it is a relationship that is not healthy for either the
profession or the country as a whole. And pursuant to that line of ques-
tions, I would like to ask some of the same ones that I have asked of
other organizations.
In 1967 you published a brochure called "News and Views of Interest
to the Pharmaceutica.l Industry." As you know, this brochure is made
PAGENO="0477"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4767
up of editorial comments that occurred in,~ the GP, or American Family
Physician. I am puzzled by the purpose of it. It says, "News and Views
of Interest to the Pharmaceutical Industry."
Why would you be interested in publishing a brochure that recites
a group of editorials, all of which, as I read them one way or another,
defend the pharmaceutical industry position? What is the purpose of
the brochure?
Mr. CAHAL. Dr. Shapiro has asked that I comment on that, Mr.
Chairman.
This brochure was published for the very reason you stated, sir, that
we thought it would be of interest to the, pharmaceutical industry, the
things we had to say about this matter. By the same token, the phar-
maceutical industry sends to our office many of its publications. The
pharmaceutical companies regularly send us their annual reports, be-
cause the pharmaceutical industry and the medical profession and the
nursing profession and the hospital profession are all engaged on the
same team, and I think have a natural and healthy interest in each
other.
Senator NELSON. Did the PMA distribute this?
Mr. CAIJAL. No, they did not distribute the original.
Senator NELSON. Did they reprint it and distribute it?
Mr. CAnAL. I would not know. I doubt it without our permission.
Senator N~soN. What was the circulation of it? It is printed, and
it is the views of the pharmaceutical industry-how many did you
print?
Mr. CAHAL. I cannot answer that at this moment, Mr. Chairman. A
few hundred, I presume.
Senator NELSON. And it was sent to the pharmaceutical manufac-
turers?
Mr. CAnAL. Yes, sir.
Senator NELSON. You don't know whether the PMA circulated it
themselves or reprinted it and circulated it?
Mr. CAnAL. Of my own knowledge I do not, sir.
Senator NELSON. Does anybody?
Mr. Ki~n~ir. I do not believe that they did, sir, I do not know that
they did.
Senator NELSON. I am still puzzled by the purpose. The editorials
appeared in G-P and the American Family Physician. They all defend,
directly and frankly, right down the line, the manufacturer's position
on every issue that is discussed. And looking at it as an outsider, if I
were in business, I would say that it is a direct and blatant appeal to
the industry for more advertising. What other purpose does it have?
Mr. CAnAL. Mr. Chairman, it has been some time since this was pub-
lished, and I do not remember all the editorials that were in it. I would
like to repeat what Dr. Shapiro said in his direct testimony, that our
journals, GP and American Family Physician, have from time to time
published articles and editorials quite critical of the industry and of
individuals in the industry. And I would like to report to you, sir,
and for the record, that some of these editorials have resulted in a
cancellation of heavy advertising schedules.
Senator NELSON. Who has canceled because of some editorials?
Mr. CAnAL. One that I specifically recall is Wallace Laboratories.
Another, I think, was Pfizer-for editorial comments we made, as a
PAGENO="0478"
4768 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
result of the editorial comments we made critical of them or the in-
dustry, they have canceled out.
Senator NELSON. When was this?
Mr. CAnAL. Well, they were at different times, different occasions.
Senator NELSON. For how long did they cancel them?
Mr. CAnAL. I think Wallace is still canceled.
Senator NELSON. When did they cancel?
Mr. CAnAL. I think about 2 years ago.
Senator NELSON. Do you have file copies of the editorial comments
that caused them to cancel?
Mr. CAHAL. I shall be glad to send them to you, sir.1
I remember one editorial of ours which offended some of our friends
in the industry. It was one in which we stated that we were suspect of
any pharmaceutical company which manifested an interest in a
scientific article we were preparing to publish in our journal, that we
were sacrosanct in our scientific and editorial material and we did not
want any pharmaceutical company to have any interest in it, and if
they manifested one, it would put us on guard that they had an
interest.
Senator NELSON. Did some company cancel based on that, do you
know?
Mr. CAnAL. I suspect they did. I do not know that they told us,
frankly, that they were canceling because of that editorial attitude of
ours, but I know that it resulted in critical and complaining comment
in the industry.
Senator NELSON. How many times has any drug industry, any manu-
facturer canceled, based upon critical material in the publication?
Mr. CAHAL. Well, Mr. Chairman, we were not always certain of the
reason for the cancellation of advertising, or a failure to buy adver-
tising. But from our intimacy in the field we have reason to believe that
sometimes our editorial posture has resulted in a loss of advertising
sales in our journals.
Senator NEI~soN. But do you have any specific case that you know
of where the industry did cancel because of a specific adverse editorial
comment in either of your publications?
Mr. CAnAL. Yes, sir. I refer to Wallace Laboratories, which advised
us that they were canceling because of an editorial.
Senator NELSON. Pfizer and Wallace?
Mr. CAnAL. Yes, sir.
Senator NELSON. Are those the only two specific cases?
Mr. CAHAL. That I can recall at this moment, sir.
Senator NELSON. And they were how recent?
Mr. CAHAL. Wallace was 2 years ago, at least 2, maybe 3.
Mr. KEMP. Closer to 3, I think, on Wallace. I do not remember when
Pfizer did.
Mr. CAHAL. The two had no relation to each other, they were two
different episodes.
Senator NELSON. The point that this whole issue continues to raise,
it seems to me, and I am saying this not just as to your publications,
but with regard to all journals and all medical news publications,
some of which are 100 percent supported by advertising from phar-
1 See pp. 4779-4781, infra.
PAGENO="0479"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4769
maceuticals, and some of which are substantially supported, such as
yourself and other distinguished medical associations-the point it
continues to raise is that, since there is a heavy dependence on adver-
tising, do the respective journals of the respective professional medi-
cal organizations pursue as vigorously a policy of criticism when it is
appropriate as they would if there was no dependence on advertising?
It seems to me that that is the issue that is continually raised here.
And in looking at a large number of the publications I rarely find
anything critical of the industry itself, even though there are critically
important issues that are raised. For example-maybe you can tell me
about your publication, I do not know about this-but I cannot find
any publication that ran big strong stories pointing out the misuse of
chloramphenicol. Did your publication?
Mr. CAHAL. Mr. Chairman, I cannot speak for all publications, but
I have just tried to make it clear to you, sir, that the journals of the
American Academy of General Practice are independent editorial
spokesmen, and are not the slave of their advertisers any more than
the Washington Post is the slave of its advertisers. I shall be glad
to furnish for your committee, Mr. Chairman, copies of editorials
which have appeared in GP magazine critical of individuals and of
the industry. As for the misuse of chloramphenicol, we have from
time to time had articles in GP written by distinguished authorities
about the dangers of abuse in antibiotic therapy, and I do know that
we reported fully the antitrust action.
Dr. SHAPIRO. Some of the members of the industry-
Senator NELSON. The problem, it seems to me, of the medical publi-
cations is that as contrasted with a large daily newspaper, their de-
pendence is on two things: One, the dependence of the journal upon
a single industry source, that is, pharmaceuticals, is very high. In
the case of American Family Physician, 911/2 percent of the advertis-
ing is pharmaceuticals. A publication that accepts advertising from
a single source is quite a different case from one that accepts advertis-
ing from many sources.
Secondly, it seems to me that there is a very special relationship
and responsibility toward the public on the part of the medical pro-
fession as the custodians of the public health, so to speak, a very
special ethical responsibility that I think is unique. That is why I
think this poses a serious question. In~ reading through this brochure
"News and Views of Interest to the Pharmaceutical Industry," and
I read it through. twice last night and once this morning, it seems
to me it raises some very serious questions. I made some notations
on it as I went through.
For example, on the next-to-the-last page of the brochure, "News
and Views," it says:
From time to time and with increasing frequency we get weary of
listening to au the flack which relates, however remotely, to pharmaceutical
prices. We hear that company A sells a particular tablet for 8 cents apiece, but
company B charges only 3 cents for its version of the same product. In the first
place, let there be no mistake about this, most of the people who make noises
about "generic equivalents" do not know an aspirin tablet from a jelly bean.
They will shout that frozen tutti-fruitti pies "are not as good as mother used to
make" and then turn right around and claim that generic and trade name prod-
ucts are like two peas in a pod. You can buy a cow for $25-or $250. A local
jeweler tells us that we can buy a one carat diamond for $300 or $2300. In other
words, we are always required to make decisions based on the qualtiy of the
merchandise and this axiom applies to anyone who wants to buy anything.
PAGENO="0480"
4770 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
We are a bit amused by acquaintances who will go out of their way to consult a
high-priced specialist-and then complain when he gives them a prescription
which costs $3.50. The average retail prescription charge is $3.48-on which the
manufacturer nets 18 cents. We have made these same statements, perhaps more
diplomatically, in earlier "Publishers' Memos." We may be compelled to repeat
them again-perhaps even less diplomatically. Our parting plea is this: When
you run across what seems to be an outrageous fact concerning prescription drug
prices, consider t.he source, consider that the statement may have been made with
ulterior motives-and remember that a bargain basement price almost always
bespeaks bargain basement quality.
Now, this is a strong direct plea, really, for the brand-named drugs.
But let me recite a case which we have used a number of times before
and will continue to use. We could give you a dozen, but this one is
based upon the conclusion of the Medical Letter, and it would not be
subject to the same kind of attack that another example might be.
But referring to the prices now, a cow for $25 or $250, the Medical
Letter of June 1967 published an analysis on prednisone tablets. And
referring to the paragraph in here which says:
Our parting plea is this: When you run across what seems to be an outrageous
fact concerning prescription drug prices, consider the source, consider that the
statement may have been made with ulterior motives-and remember that a
bargain-basement price almost always bespeaks bargain-basement quality.
The Medical Letter concluded from testing done by an independent
lab and in consultation with clinicians around the country that all
these drugs, all 22 prednisones by 22 different companies were thera-
peutically equivalent. The prices have changed since our hearings on
this, but Meticorten, which was the original `and most widely pre-
scribed, was $17.90 a hundred to the druggist, and Paracort, $17.88.
And it got down to Merck at $2.20, and McKesson at $2.25, down to
Upjohn $2.25, and finally to Wolins at 59 cents a hundred. Now, here
they are, with a price differential of 30 times. What is your conclusion
about that?
Dr. SHAPIRo. Mr. Chairman, I think this committee has won its
badge on this particular instance. You were successful in having the
prices brought within a range of reality. And I would say nothing to
support this 30-times price differential.
Senator NELSON. But the problem that your editorial, which went
to about 60,000 physicians, raises is that it tells them the pharmaceu-
tical manufacturers' line. And this is a national refutation of it. This is
just one of many examples. I use the Medical Letter repeatedly, since
I do not find anybody in the medical profession or pharmacy or phar-
macology who does not highly regard the integrity and the quality of
the letter. If I used another ekxample they would say "Yes," but
Wolins' is no good, or McKesson's product is no good, or they aren't
as good as Meticorten. Schering claimed before us, that they respected
the Medical Letter, but some were not as good-
Dr. SHAPIRO. In this particular instance I believe that the therapeu-
tical equivalence was proven, not the generic equivalency, of the
cheaper products. And I believe that across the country every doctor
who has read anything at all in the journals regarding the corti-
costeroids is aware of this.
Senator NELSON. But the same thing on prices goes across the board.
We have lots of examples. When the editorial takes the position that
when you run across what seems to be an outrageous fact concerning
PAGENO="0481"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
4771
a lower price, consider the source. Well, what I do not understand is
then why-for, example, you take Serpasil, reserpine. Ciba sells this
to the pharmacies for $39.50 a thousand. Now, American Pharmaceu-
tical sells it to New York City for 72 cents a thousand. Now, there is
the low price, 72 cents. Thirty-nine dollars is 50 times as high. How
does that fit in with the statement here that the price is low, consider
the source? You just have dozens of examples which absolutely refute
the editorial claim made in your magazine.
Dr. SHAPIRO. As a practicing physician and not as a pharmacologist,
I would not like to use this particular example of an extract of rauwol-
fia Serpentina, because each company has purified a different fraction
of the alkaloid. And in my practice I have found that a trade name
made by Lilly, Sandril, gives me better results than generic rauwolfia.
Senator NELSON. As you know, New York City, the Defense Supply
and the Veterans' Administration use their own independent testing
to see that the drug meets the appropriate NF or IJSP standards. Well,
then let me ask you this one on prices, again referring back to this
paragraph. How would you explain why Ciba's Serpasil is sold to the
pharmacist at $39.50, but when they wanted to sell to New York City
in competitive bidding they bid a $1.10 a thousand?
Dr. SHAPIRO. I cannot. defend it.
Senator NELSON. As I understand this editorial, it is an across-the-
board defense of the prices.
Dr. SHAPIRO. I believe the words ai~e "usually," or "most of the
time," toward the end.
Senator NELSON. It says:
Our parting plea is this: When you run across what seems to be an outrageous
fact concerning prescription drug prices, consider the source, consider that the
statement may have been made with ulterior motives-and remember that a bar-
gain-basement price almost always bespeaks bargain-basement quality.
Dr. SHAPRIO. The sense of it seems to be-there was something before
that, I believe. I may be mistaken.
Senator NELSON. The article starts out "Attacking generic equival-
ence," and ends with this conclusion. All I am saying is, you can take
their own products, you can take Ciba Serpasil, and they are charging
this outrageously high price, and then when they bid in New York City
in competition, they bid $1.10. Well, that is one-thirtieth as much. Now,
that is outrageously low compared with what they are charging the
pharmacist.
All I am saying is this editorial is really a defense of the drug
industry, they are saying you pay for what you get when you see the
big price differential, and what they are really trying to say is that
generics are not as good. They start out with that. If it is not a brand
name, then you had better watch out, you are getting what you pay
for, whether it is cows or diamonds. All I am saying is that that
same company will come in with $1.10 when they have to bid honestly
in competition, but $39.50 when they are running on their brand
name to the pharmacist. Now, you say you cannot explain that. I
simply say your editorial defends the pricing structure. If it defends
the pricing structure right across the board as it does here, what is
your comment about this aspect of the pricing structure?
Senator Dor~. He does not write the editorial.
8l-280-69-pt. 11-31
PAGENO="0482"
4772 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Dr. SiI.AIIRo. No, this editorial was written by the staff, I had
nothing to do with it.
Senator NELSON. Dr. Shapiro is the president of the organization.
But we are on the whole question here of the close relationship
of the drug industry. I give you a dramatic example of an all-out
defense of the pricing structure and the attack on generic drugs, and
a caution to watch out:
When you run across what seems to be an outrageous fact concerning prescrip-
tion drug prices, consider the source, consider that the statement may have
been made with ulterior motives-and remember that bargain-basement price
almost always bespeaks bargain-basement quality.
Well, I can give you dextroamphetarnine, I can give Thorazine
and Compazine, all the same pattern here. And all I am saying is that
it seems to me that each one of the representatives of the medical
profession who appear here and defend the pricing structure and the
cost of drugs ought to be prepared, then, to discuss the pricing struc-
ture, you must be prepared to defend it. If you cannot defend the
pricing structure, then it seems to me that it is hardly justifiable to
run an editorial like that and then claim that you are not influenced
by the drug industry.
This is the whole problem.
Mr. CAHAL. Mr. Chairman, I think the thrust of that editorial, if I
understood it correctly, is directed toward another situation. During
the past couple of years, I think doubtlessly as a result of the hearings
conducted by your distinguished committee, there has been a rash of
articles appearing in lay magazines and newspapers which tended to
frighten the consumers of medical care, or to convey the idea that they
are being gouged by their pharmacists or drug manufacturers. And
I think the thrust of that editorial is directed toward this. I am sure
you have seen such square headlines and articles in lesser consumer
magazines, "Are you paying too much for drugs?" "Are you being
gouged by your druggist?" "Can you afford for your parents to be
sick ?"-I recall such editorials. And I think that was the thrust of that
point.
Senator Nelson. You are correct that articles have appeared saying
in one way or another that the public is being gouged. I have said that
the pricing structure is inexplicable by any rational competitive stand-
ard in a free enterprise system.
You talk about being gouged. I think there is a reason for it. Let me
point something out which I do not think the medical profession as
a general rule is familiar with. For example, if you are going to use
the word "gouging," let us take a look. Ciba sells reserpine, its brand
name is Serpasil, a thousand 25-milligram tablets for $39.50 to the
pharmacist. They bid $1.10 to New York City the same day, across
the State in city hall, they bid $1.10 to New York City, and they lost
it to American Pharmaceutical for 72 cents. But now they package it
overseas and they sell it~ not for $39.50, but in Bonn, Germany, for
$10.53 a thousand versus $39.50 here; in Berne, Switzerland, $11.09,
and in London, $11.20-in every case less than a third of the price they
are charging the American pharmacist. Take prednisone. Schering
ships it overseas. They sell it for $170 a thousand for 5-milligram
tablets to the pharmacists in this country. They offered to sell to New
York City at $12. They sell to the pharmacist at $170, but in competi-
PAGENO="0483"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4773
tive bidding they dropped to $12, which is $1.20 a hundred, and they
lost it to Lannett, which bid not $170 but $4.58 a thousand. That is
45 cents a hundred. On prednisone they go overseas, and they charge
not $170, as they charge the American pharmacist, but $43.70 a thou-
sand in Berne, $53 in Rio, and $70 in Australia. One of them is one-
fourth the price, and one of them is less than a third the price, and.
one of them is less than half the price.
Then another distinguished company, Smith Kline & French-for
Thorazine they charge the American pharmacist $6.06. This drug is
sold in Paris for $1.18; in London for $1.08; and in Bonn for $2.40.
This is why the stories appeared in the paper saying that the public is
getting gouged. There has been no explanation from the industry as
to why they will charge a third and a fourth as much .to a foreign
pharmacist after shipping it overseas as they charge the American
public. If that is not gouging I cannot think of a better word for it.
But the medical profession is appearing here with considerable
regularity defending the pricing structure of the industry. The indus-
try is the heaviest support of all the professional organizations. The
professional organizations defend the structure and claim that they
are not influenced by the industry.
I think that is a fair question to raise. I raised it with everybody
else. What is the answer?
Dr. SHAPIRO. To what?
Senator NELSON. What is the answer tO the proposition that you are
influenced by the industry because you accept and use their line of prop-
aganda while at the same time we can give you examples of all these
discrepancies in the pricing structure.
Mr. CAHAL. Mr. Chairman, if I may, 1 have pointed out that our
publication is not a captive of the industry, and we are prepared to
submit evidence to your committee to prove that.
I have also stated that it seems to me understandable and reason-
able that those two members of the health team would be close to-
gether, have mutual understanding. They are engaged in the same
business, the same as the lumber industry and the nail industry.
Senator NELSON. I would be attacked all over this country in all the
medical journals if I compared the medical profession and the drug
industry with the lumber and nail industry, but it is your comparison.
I would have thought that the-~
Mr. CAHAL. I did not say which was the nail.
Senator NELSON. Or who was getting nailed. As I said to the AMA,
I have raised as tough a question as I can think of, and you are entitled
to answer as extensively as you please. But I think, if I sat on a jury,
the physical facts would lead me to believe as a juror that the tie be-
tween the industry and the profession is close, and very close, too
close, and that the profession is too dependent upon the money
from the industry, that the industry is too influential with the
profession, and that the profession defaults substantially in its re-
sponsibility to put the industry under the kind of critical view that
the public is entitled to have them do in terms of industry practices
in the promotion of the drugs and in prices they charge. If you look
through the record, I would think it would be an embarrassment. But
it is true that doctors who have appeared here and the representative
of every organization that has appeared has in one way or another
PAGENO="0484"
4774 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
given every single argument that the industry itself gives in behalf
of its research and in behalf of its prices, and in behalf of the generic
brand name argument. You could not tell the presention of the medi-
cal profession in terms of content from that of the pharmaceutical
manufacturers. I would think that that would give one pause-unless
you are prepared to say that the industry is right on every single
claim they make.
Now, let me turn to something else. I will read something here.
This is from an article by Morton Mintz. Mr. Mintz is probably the
most; distinguished writer in this field in the lay press. In his article
"Medical Press Shifts News for Physicians," let me read something:
Another case in point is the handling of an October 13 hearing by the gen-
eral practitioners, GP, the witness was Richard M. Furlaud~ President of E. R.
Squibb & Sons. He came before Nelson's subcommittee with a lengthy pre-
pared statement defending the system of dual prices under which a medicine
prescribed by brand name can be very expensive, but prescribed under its gen-
eric or chemical name can be quite inexpensive. An editorial in the New York
Times found Furlaud's case unpersuasive. But GP was so impressed that it
turned over four and one-half glossy pages in its February 1968 issue to ex-
cerpts from Furlaud's text. GP did not, however, tell its 30,000 doctor readers
of a development at he hearing that was not in Squibb's script. This was the sub-
committee's introduction of documents which the FDA had prepared in recom-
mending criminal prosecution of Squibb. They recited a long history of "mix-
ups, recalls and warnings," that Indicated in the agency's view that the firm
had "failed to understand its responsibilities as a drug manufacturer." In
March 1967 Squibb pleaded no contest to the charges in that case, although it
has sweepingly rejected the FDA allegations at the hearing.
How do you account for the fact that you select four and a half
pages to write a praiseworthy defense of Squibb, but neglect inform-
ing your readers about the long history of mixups, recalls and warn-
ings? This is a pattern of-I want to emphasize, I am not trying to
select your publication, but this is a pattern that runs all through the
medical press, the criticism that ought to come, comes but rarely.
Dr. SHAPIRO. Mr. Chairman, it is not our duty or thought to defend
an industry and say that everything they do is perfect. On the question
of influence, I believe there is a reciprocal influence. We would be less
than honest not to admit that ads have some impact, and we are carry-
ing ads in our journal. At the same time, the industry generally, and
specifically certain companies that I could not possibly mention with-
out research, are influenced in what they are doing by our needs, by
our stated needs. As far as the major question that you are posing,
I have no expertise in this purely business matter, and I watch what
the committee accomplishes with great interest. I have no defense for
these things, nor am I trying to present a defense for the industry. As
for prednisone, I believe every doctor to my knowledge is ordering.
it without even a manufacturer's name after it. And this is all due to
the good efforts of this committee.
Senator NELSON. The questions I have been raising, though, with the
distinguished spokesman of the various professional medical organiza-
tions is this very question, that there is heavy reliance upon advertis-
ing. And it does not seem to me there is almost total absence of the kind
of critical analysis and comment about industry practices that would
be made by purely independent journals. And the pattern runs so
clearly, the continuous praise and promotion of the industry. Then
when a dramatic case occurs, the medical journals, medical press in
general, ignore it. That is what disturbs me.
PAGENO="0485"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4775
Dr. SHAPIRO. No, sir; we do not ignore it. I mentioned earlier our
section on practical therapeutics which is serving for drug therapy
education to our readers, and which is written by medical faculty
members. And they may be laudatory or they may be critical. And we
do not have editorial privilege on these, we print them. And we have
many critical practical therapeutics articles.
Second, the advertising we are carrying is not only the business as-
pect of what a corporation is selling, but it is a service to our members
to bring them more detailed information than they may have on a visit
from a detail man, if you will, or present some use of a drug in an
article where the actual total insert is not printed. So we are using this
as a service to our members.
Senator NELSON. But the point raised in this one, Doctor. President
Richard Furlaud of Squibb made a presentation to the committee in
defense of the system of dual prices under which a medicine prescribed
by brand name can be very expensive, but~prescribed under its generic
or chemical name can be quite inexpensive. On this economic issue-
which is critically important, the point is critically important to the
manufacturers-your publication gives them four and one-half glossy
pages. Have you ever run four and a half glossy pages on what they
charge overseas and what they do at the Defense Supply Agency,
and how they offered to sell at one-tenth, one-twentieth the price to
Defense Supply in competitive bidding versus what they are charg-
ing the pharmacies where the doctor's patient goes? If you can run Fur-
laud's stuff, why not the other?
Dr. SHAPIRO. I have asked Mr. Kemp4-it seems to me that we did
run something on Defense Supply prices, ~ut I cannot be certain. Edi-
torially I would state that our editorial staff could easily work up such
a presentation. And I would be most happy to bring this up before
the board of directors and see if we will direct them to do so.
Senator NELSON. I think that would be laudable. But the point I
am making is that this pattern of treatment of the drug industry is
the same throughout, roughly the same throughout all the publica-
tions, the medical journals, and the medical press. And that is a his-
torical fact right up to this day. That certainly leaves unresolved the
question of the effect of the close relationship I do not think any
body has suggested that they are directing, or dictating. It is just the
question of-if I have just like you-a good personal friend, and he has
some faults, they "ain't" half as bad as the same faults in someone I
don't like. And if I am economically dependent upon somebody-that
is human nature-I am not as critical of the person I am economically
dependent upon as I am of one I am not dependent upon. I think that
that is recognized universally among human beings, and that is why
you have independent audits in Government and in industry, the board
of directors is not permitted by the stockholders to audit their own
books, because they are pretty friendly to each other, and the errors
and mistakes would not be exposed. And in exposing what is wrong in
C overnment, if you left it up to the Congress or the Legislature to
tell the country what is wrong with what they are doing, you would
never hear about it. Because there is a special interest in not exposing
what is wrong. It strikes me that this is the kind of case this presents.
When you look at what happens editorially and in the news within the
journals themselves, that kind of picture shows up, does it not?
PAGENO="0486"
4776 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Dr. Sii~pruo. Yes, sir. We are dealing with the third largest in-
dustry in our country. I think the Secretary of HEW says 50 billion,
and growing at the rate of 5 billion per year. It is peculiar and
different from any other industry that we can consider, in that the
frontline men like myself are involved with life and health and the
well-being of the people. I am sure that the pharmaceutical industry
at the other end feels some of the pressures that must pass over to
them because they are the suppliers to us. And I hate to say "lumber
and nails," because in a great way they are involved with the health
and well-being of the people.
Senator NELSON. Let me cite another one here along the same line.
I do not know whether you commented off the cuff on that or not.
But on page 3 here in your brochure-do you have this there ~
Dr. S~pruo. No, sir.
Senator NELSON. This is a question again involving the dispute over
generics and bra.nd names, and referring back to the fact that your
editorials have taken the side, I think, quite clearly, of the brand
name companies on this argument. In June of 1967-first, the FDA
did a study of 4,600 drugs that were in a miscellaneous way collected
from 245 manufacturers. And 2,000 of these were generic and 2,000
were brand names. That study by FDA was solely for potency-did
the drug meet the USP-NF standards of potency. The variance out-
side the range established by the official compendium was that 7.7
percent of the generics did not meet the standard for potency, and
8.8 percent of the brand names did not meet it. So here is a case of
a substantial size study-which did not claim to be a scientific selec-
tion-it was just a selection from 245 companies, I believe, but the
generic came out better in that test than the brand name.
Now, it says in this June 1967 editorial:
Four days prior to the date set for the opening of the Nelson subcommittee
hearings, the Pharmaceutical Manufacturers Association issued a stinging and
factual rebuttal of an earlier FDA study on the potency of prescription drug prod-
ucts. Mr. 0. Joseph Stetler, PMA president, said that the FDA study contained
"gross inaccuracies" and demanded that the FDA "repudiate the survey out-
right." Stetler said that four PMA member firms have already received letters
from the FDA, admitting that the FDA erred when it claimed that their products
were below acceptable potency limits. Said Stetler: "Isn't it fair to require that an
agency which. demands the truth delivers the truth?" The FDA claimed that 7.8
percent of the products studied "deviated to a material extent from the declared
potency," but followup studies, done by the firms and often reconfirmed by inde-
pendent laboratories, showed that only 1 percent were out of line with acceptable
potency limits. Furthermore, of the 42 firms which reputedly sold subpotency
products, only six were so advised by the FDA during the seven months after the
survey was completed. The other 36 were not told of the source of the samples
checked or given a reasonable opportunity to check on alleged potency violations.
Well, this is a pretty strong rejection of the FDA report. I do not
have everything that you have written on it, but I raise this question.
Did you publish the answer made by Dr. Goddard to Mr. Stetler's
charge? Dr. Goddard said:
There were 245 manufacturers represented in these 4,575 samples examined.
And then he goes on to say:
In six samples involving five firms, six samples out of 4,573 involving five firms
after the review of the original data, we did concede that we had made an error.
Now in three of these six samples involving two firms the NDA potency limits
were incorrectly tabulated. In the other three samples the examining laboratory
PAGENO="0487"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4777
had not followed the prescribed methodology, and the letter acknowledging the
error was sent to five firms.
Now, the other original findings I still say are correct. We stand behind them.
Did you run this answer in as prominent a way. as you ran Mr.
Stetler's attack on the `FDA study? I would think that six samples out
of some 4,600 on the tabulation error is avery small computation error
on the part of the FDA.
Mr. CAI-JAL. Mr. Chairman, subject to~ correction, to the best of my
recollection we did make mention of Dr. Goddard's refutation of that
statement. I think it can be found.
Senator NELSON. Then why would it not be in this publication?
Mr. CAHAL. It probably was after that was published.
Senator NELSON. Would you-so that the whole record would be
clear then-would you send for the record what you published and on
what date, and we will print it in the record at this point?
Mr. CAETAL. To whom do we direct those, to Mr. Gordon?
Senator NELSON. Yes.
(Material not received.)
Senator NELSON. If there is anything you would like to respond to in
what I have raised or said, we would be happy to hear you.
Just one more point to make. There is an editorial in September 1967
on prescription policies, and it recites an AMA study which was not
scientific, to say the least, the AMA study of price of generics versus
brand names in the drug industry. And~ I will not get into an elabora-
tion on that, except to say that, of course, if you go to the drugstore
and you have a generic-name prescription, and the drugstore only is
carrying one brand name, you are going to pay the same price, because
you can substitute as you would for the brand name. But it states here:
"The AMA study showed that generic-name prescriptions are filled
with brand name 63 percent of the time," that obviously would be be-
cause that is what is stocked and that is what is prescribed.
But I would just like to make one point for the record here, and that
is on the question of whether, contrary to the conclusion of AMA on
the price of generic versus brand names, Gray's drug chain and Peoples
announced a year ago that they would put in stock a line of generic
drugs made by Strong, Cobb & Arner, which I guess everybody recog-
nizes as a distinguished manufacturer of generics, and that the aver-
age prescription price would be one-half the average brand-name price.
But again here in the editorial is support of the brand-name com-
panies. If there is anything you would like to add to the question I
raised, I want to be fair and be glad to have you answer it. But it
disturbs me to see how consistently the professional groups support the
industry and how rarely they put them under tough criticism.
Is there anything you want to add, Doctor?
Mr. Ki~ip. I would only say this, Mr. Chairman, not in a full defense
of what you are saying, but I do think that sometimes our liaison or
our communications with, for example, the Food and Drug Adminis-
tration, is not what it might be. I believe you were reading a few
moments ago from some remarks made by Dr. Goddard after the
earlier study or `after the comment by the PMA. I do not know. I have
no reason to know or have no way of knowing at the moment whether
we received these. I would call your attention, sir, to the fact that the
"Dear Doctor" letters, if you will, whiCh are being mailed periodically
to members of the medical profession-we do not receive them.
PAGENO="0488"
4778 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
Senator NELSON. You do not receive copies of the "Dear Doctor"
letters ~
Mr. Ki~n'. No, sir. I have often thought this would be a good idea.
Senator NELSON. I agree with you, you ought to receive them, and
I think it would be a good idea to print them.
Mr. Ki~ip. That is my thought, too, sir.
Senator NELSON. Well, thank you very much. I appreciate your tak-
ing the time from your busy schedule to come here and testify today.
Thank you.
(Subsequent information follows:)
AMERICAN ACADEMY OF GENERAL PRACTICE,
Kansas City, Mo., April 9,1969.
BENJAMIN GORDON,
Staff Economist, Subcommittee on Monopoly, Senate Select Committee on Small
Business, U.S. Senate, Washington, D.C.
Dear Mr. GORDON: In obedience to the request made by Senator Nelson at the
time Dr. i\Iaynard Shapiro testified on March 26 before Senator Nelson's com-
mittee, I am sending by parcel post today the following:
(1) A biographical sketch of Dr. Maynard Shapiro, myself and Mr. Walter
Kemp, who accompanied us.
(2) Annual financial statements of American Family Physician showing the
losses incurred on that publication.
(3) Copies of representative editorials appearing in GP and APP.
(4) Copies of "Practical Therapeutics" series which have appeared in GP
magazine.1
It was a pleasure to make your acquaintance.
Sincerely,
MAC F. CAHAL.
ITS. SENATE,
SELECT COMMITTEE ON SMALL BusINEss,
Washington, D.C., April 22, 1969.
MAC F. CAHAL, J.D.,
Executive Director and General Counsel, American Academy of General Practice,
Kansas City, Mo.
Dear Mr. CAHAL: During your appearance before our Monopoly Subcommittee
on March 26, you stated: ". . . that our journals, GP and AMERICAN FAMILY
PHYSICIAN, have from time to time published articles and editorials quite
critical of the industry and of individuals in the industry." You also stated that
you would supply us with copies of these editorials and articles.
Since the editOrials and articles you have sent us are not responsive to the
Chairman's request, we would appreciate your sending us the relevant material
as soon as possible.
Sincerely,
BENJAMIN GORDON, Staff Economist.
AMERICAN ACADEMY OF GENERAL PRACTICE,
Kansas City, Mo., April 25, 1969.
Mr. BENJAMIN GORDON,
staff Economist, U.S. Senate,
Select Committee on Small Business, Washington, D.C.
Dn~n Mn. GORDON: The material we sent you may not, by your standards, be
considered critical of the pharmaceutical industry but you may rest assured
that this view was not fully shared by the industry.
May I respectfully point out that we do not normally index material by the
degree to which it is favorable or unfavorable to the drug industry and we
1 "Practical Therapeutics" series has been retained in committee files.
PAGENO="0489"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4779
have thus not perused every page of every issue. (GP was first published in
April, 1950.) However, if members of my staff turn up additional material, I
will see that copies are sent to Senator Nelson.
Sincerely,
MAC F. CAnAL.
[From American Academy of General Practice, January 19651
Vivz LA DIFFERENCE
Another instance has recently come to our attention in which members of the
"weaker sex" have demonstrated a superiority over their masculine counterparts.
Exeprimental work both in dogs and in rabbits has indicated that the female
of the species is more resistant to digitalis cardiotoxicity than the male. This
extra tolerance seems to be due to estrogen and related steroid compounds.
A survey of hospitalized patients under age 40 with rheumatic heart disease
indicated that approximately 20 percent of the male patients receiving digitalis
develop signs of digitalis intoxication at some time during hospitalization. In the
group of females, only 10 percent of those receiving digitalis develop digitalis-
induced arrythmias (American Heart Journal, September 1964).
Because of the limited size of the series, the results are not of high statistical
significance and there are other weaknesses which the authors appreciate in a
retrospective study.
However, digitalis preparations are frequently, if not usually, administered
as a "standard" dose. Therefore, the finding of a lesser incidence in the some-
what smaller group of patients (the females) presents added weight to the valid-
ity of the study. This new piece of information, coupled with the relatively high
rate of toxicity noted particularly among male patients in the study, would in-
dicate that there is still much for us to learn about the actions and usage of digi-
talis preparations. As for the plus on the female scoreboard, we are becoming used
to that.
[From American Academy of General PractIce, June 1965]
PHENACETIN AND THE NEPHROLOGISTS
A Food and Drug Administration ruling still requires a printed warning label
on over-the-counter preparations containing phenacetin, stating that these prod-
ucts may damage the kidneys when used in large amounts. Despite such official
warnings, evidence pointing to the nephrotoxicity of phenacetin is still largely cir-
cumstantial.
(Incidentally, the great strides in the understanding and the management of
medical renal disease have brought into great prominence the medical sub-
specialty now called "nephrology." To be sure, the functional unit of the kidney
is the nephron. However, one might consider~ some of the other terms that would
seem equally suitable for labeling this field of study. Why not "renology"? Of
course, "urology" does not seem acceptable to the "salt and water" doctor.)
Back to phenacetin. Several years ago, Schreiner queried many nephrologists
on the relationship of phenacetin to kidney disease. More than half of 74 ne-
phrologists reported that they had never seen a case of nephritis related to
phenacetin.
Now, Strickler suggests that phenacetin may have been singled out unjustly.
He cites the conflicting findings in the clinical investigative literature. It is pos-
sible that "phenacetin nephrits" is in reality chronic pyelonephritis. The problem
still has not been studied in systematic fashion.
[From American Academy of General Practice, September 19671
Dnua REMOVAL
Suicidal or accidental ingestion of potentially lethal drugs continues to rep-
resent an important clinical problem. Two recent trends have been of interest in
this regard. The first is the variety of new drugs involved in overdosage situa-
PAGENO="0490"
4780 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
tions. Tranquilizers and antibiotics of various sorts are a case in point. The clini-
cal pharmacology and, indeed, methods for measuring blood levels are not avail-
able in every instance. The second trend deals with improved methods of drug re-
moval, particularly by hemodialysis.
Maher and Schreiner have recently reviewed some of these methods in the
Transactions of the American Society for Artificial Internal Organs for 1067.
Several drug removal rates are given, using the well-established figures for hemo-
dialysis into an aqueous bath as the basis of comparison. For example, in the case
of lipid soluble poisons, e.g., glutethimide (Doriden®), it is possible to greatly
accelerate removal by hemodialysis against a lipid (soybean oil) bath and this
has been sucessfully used clinically. A newer development is hemoperfusion
through an activated charcoal column which appears to be superior even to lipid
dialysis in removing glutethimide from experimentally poisoned animals. Pen-
toneal dialysis with various modifications of the dialyzing fluid is appropriate
for certain barbiturate poisonings. Further, there may be a significant increase in
the rate of drug removal in the patient's own urine by alkalinization and forced
diuresis.
Drugs of the same class, e.g., barbiturates, differ from one another in response
to these therapeutic measures and the clinician must acquaint himself with their
individual characteristics. Calcium can be removed by hemodialysis but if the
stimulus to hypercalcemia is strong enough, e.g., hyperparathyroidism, there may
be no change in blood level. The phenothiazines and chlordiazepoxide (Librium®)
illustrate two types of nondialyzable poisons for which no removal procedure is
yet available. Information on drug removal is slowly accumulating and will con-
tinue to be important as long as chemical or physiologic methods of treating a
poisoned patient remain unavailable.
[From American Academy of General Practice, April 1969]
Aonoss THE MEDICAL EDITOR'S DESK
ANOTHER LOOK AT IMMUNIZATIONS
Mass immunization programs have become a way of life in this country within
the past few years. When the oral poliovirus vaccine first became widely avail-
able, many communities instituted programs for administering the vaccine to any
citizen desiring it. In a number of localities, the development of a successful vac-
cine against measles was the signal for another mass immunization program for
school-age children. The pattern may be expected to continue. New vaccines are
appearing on the scene almost yearly-this year, mumps vaccine; next year,
rubella vaccine, and so on.
Operation Head Start provides a further example of how long-standing im-
munization programs (DPT) are coming in for their share of popularity. Par-
ticularly in this socioconomic group, parental recollection of past immuniza-
tions is often hazy. In any socioeconomic group, many families which frequently
change residence do not take records with them.
Whether speaking of mass immunizing programs or those directed toward
patients seen in private practice, the proved efficacy of most vaccines and the
relatively low incidence of adverse reactions often have led private and public
medical resources into some rather slipshod practices. Is it too much to inquire
whether the child has had measles before administering the vaccine? Should we
not have immediate prior evidence of a negative tuberculin test?
Recent examples from the medical literature further highlights the problem:
Children who have received inactivated measles vaccine, when subsequently
exposed to measles, may develop a severe illness characterized by high fever,
prostration and a maculovesicular rash beginning on the lower extremities and
progressing cephalad. Other children who have received inactivated vaccine,
when subsequently given live attenuated vaccine, may develop severe local re-
actions at the site of injection (Nader et al., Journal of Pediatrics, January
1968, p. 22).
In this country, morbidity from smallpox vaccination now exceeds that from
the naturally occurring disease. In one survey of reports from more than 4,000
physicians in four states, generalized vaccinia and eczema vaccination occurred
at a frequency of 238 and 80 per million primary vaccinations respectively (Neff
et al., Pediatrics, June 1967, p. 016). Complications occurred disproportionately
during the first year of life, suggesting that vaccination should be deferred be-
yond this period.
PAGENO="0491"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4781
Current recommendations call for booster doses of tetanus toxoid at 3, 6 and
12 years of age, despite evidence indicating that 96 percent of children receiving
a primary immunizing series have tetanus antitoxin titers well above the pro-
tective level after 12 years. In older individuals receiving repeated injections of
tetanus toxoid, a 1 to 3 percent morbidity may be expected, consisting of urticaria
with or without angioneurotic edema or localized vascular injury (Steigmara,
Journal of Pediatrics, May 1068, p. 753).
Still unresolved are questions of subtle, long-term hazards of "overimmuniza-
tion." In addition to local Arthus-type reactions resulting from tetanus toxoid
injections, for example, there is evidence that a delayed hypersensitivity can
occur. This involves the toxoid antigen portion of the complex with its homol-
ogous antibody.
These are early straws in the wind. American medicine increasingly is moving
from a curative to a preventative approach. As one consequence, the underlying
mechanisms of patient morbidity from immunizing procedures will need con-
tinual reassessent.
Period ending
Nov. 30,
Month of
November
1968
1968
Circulation:
Postage 37,.992. 18 3, 188. 58
Directory service 7, 183. 85 588.07
45,176.03 3,776.65
Production:
Authors alterations and plate changes 837 35 30 76
Composition 6, 124.61 511.83
Electrotypes and foundry 6,399.85 417.02
Freight and express 1, 615.76 134.91
Paper 61,142.15 4,113.70
Printing and binding 170, 432.47 12, 403.27
Salaries 12,808.34 1,091.66
Total, production 259, 360. 53 18, 703. 15
General expense:c~pyrightfee 72.00.. 6.00
Total expense 307,476.40 22,788.48
Profit or (loss) - 24,821. 96 8, 277. 27
AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, NOV. 30, 1968
Income:
Gross advertising sales
Less:
Discounts to advertising agencies (15 percent)
Discounts to advertising agencies (2 percent)
Net advertising sales
Other income:
Subscription income
Single copy sales
Total income
Expense:
Editorial:
$407, 623. 00 $37, 121. 50
68, 955. 85 5, 568. 29
6,857.05 525.18
331, 810. 10 31, 028. 03
422.66 27.72
65.60 0
Engraving
Total, editorial
Total, circulation
332, 298. 36 31, 065. 75
1,761.07 190.91
1,106.77 111.77
2, 867. 84 302. 68
PAGENO="0492"
4782 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, NOV. 30, 1967
Year ending Month of
- Nov. 30, 1967 November 1967
Income:
Gross advertising soles
Less discounts to advertising agencies (15 percent)
Net advertising sales
Other income:
Subscription income
Single-copy sales _____________ ____________
Total income
Expense:
Editorial:
Art
Engraving ___________
Total editorial
Circulation:
Postage
Directory service
Total circulation
Production:
Authors' alterations and plate changes 3,294. 38 49. 49
Composition 4, 403. 17 539. 70
Electrotypes and foundry 12, 515.21 421. 30
Freight and express 3, 106. 68 494. 84
Paper 77,805.61 7,954.89
Printing and binding 203,624. 10 19, 302. 67
Salaries 5, 000. 00 1, 000. 00
Total production 309,749.15 29,762.89
General expense: Copyright fee 66. 00 6. 00
Total expense 370, 138.92 36, 298. 75
Profit or (loss) (1,368. 00) (1,216. 67)
AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, DEC. 31, 1966
Period ending Year ending
Dec. 31, 1966 December 1966
Income:
Gross advertising sales
Less discounts to advertising agencies
Net advertising sales
Other income:
Subscription income
Single copy sales _____________ ___________
Total, income -
Expense:
Editorial:
Art
Engraving __________
Total, editorial
$541, 802. 00
173, 376. 65
368, 425. 35
263.64
81.93
368, 770. 92
$51, 536. 00
16, 491. 52
35,044.48
33.72
3.88
35,082.08
1,516.59
1,133.87
2, 650. 46
167.61
113.42
281. 03
49, 867. 22 4, 622. 41
7, 797. 09 1, 626. 42
57,673.31 6,248.83
$345, 291. 50
110,190.68
235, 100. 82
232. 84
4.09
235,337.75
$40,659.50
12, 922. 64
27,736.86
21.64
27,758. 50
2,012.12
1,344.92
3,357.04
397.53
117.50
515.03
40, 824. 10
7,252.55
48,076.65
Circulation:
Postage
Directory service
Total, circulation -
Productinn: -
Authors' alterations and plate changes
Composition
Electrotypes and foundry
Freight and express
Paper
Printing and binding
Total, production -
General expense: Copyright fee -
Total, expense -
Excess expense over income
4, 217, 67
0
4,217.67
2,884. 34 203. 55
2,087.55 291.85
15,344.02 1,770.15
914.08 41.27
59, 630. 21 6, 044. 13
197, 837. 89 17, 094. 94
278,698. 09 25,445. 89
72.00 6.00
330, 203. 78 30, 184. 59
94, 866. 03 2,426. 09
PAGENO="0493"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4783
AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, DEC. 31, 1965
Period ending Month of
Dec. 31, 1965 December 1965
Income:
Gross advertising sales
Less discounts to advertising agencies
Net advertising sales
Other income:
Subscription income
Single-copy sales
Total income
Expense:
Advertising: Advertising promotion
Circulation:
Postage
Directory service
Total circulation
$303, 559. 50 $24,313. 00
97,139.04 7,780.16
206, 420.46 16, 532. 84
213.06 67:32
109.00
206,742. 52 16, 600. 16
1,036.76 (246.54)
40,912. 83 3, 087. 05
8, 806. 01 851. 72:
49,718.84 3,938. 77
Income:
Gross advertising sales $241, 382. 50
Less discount to advertising agencies 76,983. 15
Net advertising sales 164,399. 35
Other income:
Single-copy sale
Subscription income
Total other income --
Total, income
Expense:
Advertising: Advertising promotion -
Circulation:
Directory service
Postage
Total, circulation
Production:
Art
Engraving
Paper
Printing and binding
Composition
Authors' alterations
Freight and express
Electrotypes and foundry
Total, production
General expense:
Copyright fee
Fees and dues
Total, general expense -
Total, expense
Excess expense over income -
18.85
18.85
163.31
64.91
Production:
Art
Engraving
Paper
Printing and binding
Comnosition
Authors' alterations
Freight and express
Electrotypes and foundry
Total production
General expense: Copyright fee
Total expense -
Excess expense over income
1,655.69 162.47
1,637.34 107.210
60, 185. 93 4,696. 98
199,964. 20 15, 538. 66
2,626. 87 467. 810
2, 190. 13 223. 50
878. 91 65.64
10,621.60 714.30
279,763. 67 21, 976. 55
50. 00 6. 00
330, 566. 27 25, 674. 78
123, 823.75 9, 074. 62
AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, DEC. 31, 1964
Period ending Month of
Dec. 31, 1964 December 1964
$25,807.50
8,201.45
17,606. 05
182.16 83.76
164, 581. 51 17,689. 81
1,441.00
2,732. 41 2,732. 41
35, 017. 19 3, 651. 57
37,749. 60 6, 383. 98
2,240.43 395.96
1,813.20 1,455.29
53, 257. 01 5, 210. 21
170, 201. 82 16, 161. 19
2, 092. 45 296. 50
2, 332. 33 223. 86
849.11 152.73
8,491.52 751.53
241,277. 87 24, 647. 27
48.00 4.00
100.00
148.00 4.00
280,616.47 31,035.25
116, 034. 96 13,345.44
PAGENO="0494"
4784 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, DEC. 31, 1963
Period ending Month of
Dec. 31, 1963 December 1963
Income:
Gross advertising sales $205, 668. 40 $12, 563. 50
19~ Less discounts to advertising agencies 66,376. 72 3,972,28
~1Net advertising sales 139, 291. 68 8, 591. 22
Subscription income 151. 69 12. 56
Single copy sales 8. 36
Total income 139,451. 73 8,603.78
Expense:
Advertising
Sales promotion 69 69
Advertising promotion 1,356. 88
Market research service 3, 000. 00
Total advertising 4,426. 57
Circulation:
Printing and office supplies 39. 78
Postage 77.76 5.25
Mailing 29,912. 77 2, 657. 50
Total circulation 30, 030. 31 2,662. 75
Production:
Art 2,369. 10 223.37
Engraving 1,754.68
Paper 51, 528. 53 4,413. 45
Printing and binding 166, 135.84 13, 146. 25
Composition 2,287.90 276.75
Alterations and plate changes 1, 806. 64 173. 80
Freight and express 963. 17 70. 06
Electrotypes and foundry 7,413.21 477. 67
Total production 234,259. 07 18,781. 35
General expense:
Printing and office supplies 285. 26
Copyright fee 48. 00 4. 00
Fees 80. 00
Total general expense 413. 26 4. 00
Total expense 269, 129. 21 21,448. 10
Excess expense over income 129,677.48 12, 844. 32
PAGENO="0495"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4785
AMERICAN FAMILY PHYSICIAN INCOME AND EXPENSE ANALYSIS, DEC. 31, 1962
Period ending Month of
Dec. 31, 1962 December 1962
Income:
Gross advertising sales
Less discounts to advertising agencies
Net advertising sales
Subscription income
Single copy sales
Total income 75, 252. 73
Expense:
Advertising:
Sales promotion 167. 41 69. 18
Printing and office supplies 196. 50
Dues and subscriptions 500. 00
Advertising promotion 6, 552. 84 62. 63
Market research service 545. 24
Total advertising 7,961.99 131.81
Circulation:
Circulation promotion
Printing and office supplies
Postage
Mailing
Total circulation ______________________________
Production:
Art
Engraving
Paper
Printing and binding
Composition
Authors' alterations
Freight and express
Electrotypes and foundry
Total production 203, 844. 68
General expense:
Printing and office supplies
Copy right fee
Total general expense 1, 000. 04
Total expense 241,290.83 22,436.49
Excess, expense over income 166, 038. 10 15, 872. 01
$8, 143. 24
2,493.97
i~ingraving 2,568.19
Paper 18, 137.62
Printing and binding 68,200. 62
Composition 3 428. 75
Authors' alterations 478. 85
Authors' reprints 433. 04
Freight and express 529.27
Electrotypes and foundry 3,910.36
Printing and office supplies 345.72
108,669.63
$109,947. 00 $9, 663. 00
34,777. 90 3, 092. 32
75, 169. 10 6, 570. 68
76. 63 (6. 70)
7.00 .50
6,564.48
161.29
125. 97 72.93
171.46 6.12
28, 025. 40 2,541.96
28,484. 12 2,621. 01
2,936. 81 481.99
1,949.97 217.64
45, 189.81 4,388. 84
141,811.76 14,018.36
2,857.77 295. 35
1,855.28 189.64
1,771.53 51.85
5,471.75
19,643. 67
960.04
40.00 40.00
40. 00
Production:
Salaries
Art
Family physician income and eopense analysis, January through December 1961
Total
PAGENO="0496"
4786 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Family physician income and eapense analysis, Ja~wary through December
1961-Continued
General:
Printing and office supplies 2, 655. 29
Office equipment 617. 10
Total 3,272.39
Total expense 161, 144. 94
Excess expense over income 113, 169. 92
Income:
Gross advertising sales-981/2 pages 62, 189. 19
Less: Discounts to advertising agencies 14,217.49
Net advertising sales 47, 971. 70
Subscription income 2. 82
Single copy sales . 50
Total income 47, 975. 02
Expense:
Accounting:
Salaries 1,359.42
Printing and office supplies 9.38
Total 1, 368. 80
Administration and publishing: Salaries and commissions 1, 000. 00
Advertising:
Salaries and commissions 4,225. 73
Printing and office supplies 470.49
Market research 3, 638. 29
Sales promotion 3, 852. 31
Advertising promotion 7,975.28
Total 20, 162. 10
Circulation:
Salaries 1, 427. 35
Mailing 11, 856. 90
Postage 28. 12
Promotion 1, 000. 00
Printing and office supplies 2, 395.39
Part time personnel 537. 00
Total 17,244. 88
Editorial:
Salaries 9,374. 64
Printing and office supplies 52.50
Total 9,427. 14
BIoGRAPHICAL SKETCH OF MAYNARD I. SHAPIRO, M.D.
DR. SHAPIRO TAKES HELM
Dr. Maynard Irwin Shapiro of Chicago will be installed tonight as the Aca-
demy's 21st president, during his 20th anniversary year as an AAGP member.
The 53-year-old Chicago native becomes chief spokesman for the Academy after
a steady rise from the ranks which triggered his election to the Board of Direct-
ors in 1903.
While a director, Dr. Shapiro served as chairman of the Commission on Mem-
bership and Credentials and the Commission on Education. Upon completing a
three-year term on the Board, he was elected vice president and then became
PAGENO="0497"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4787
president-elect last year in Dallas. This past year he has been on the Executive
Committee, the Residency Review Committee for General Practice and the
Family Health Care Services Committee.
Many key honors have come to Dr. Shapiro during the year. He was named
a member of the HEW Medical Assistance Advisory Council and a trustee of
the Family Health Foundation of America. In Illinois, he became a member
of the Task Force on Health Manpower of the Illinois Regional Medical Pro-
gram and a consultant in the Family Health Care Project of Illinois Masonic
Hospital.
In his home state, Dr. Shapiro has held every elective office of the Illinois
chapter, culminating in the presidency in 1961-62. He has been on innumerable
committees and commissions and continues to serve in the Illinois Congress of
Delegates.
He has served his regional chapter in many capacities and was president in
1955. He was co-chairman for the inception of the postgraduate school which
has continued to be recognized as a model.
Dr. Shapiro also has remained active in the Cook County Medical Society, in-
cluding his local branch, and the Illinois State Medical Society. Currently, he
is chairman of the industrial committee of the South Chicago Branch of the
COMS, on the committee on careers in medicine and allied sciences of GUMS and
on ISMS advisory committee to the Illinois Medical Assistants Association. He
is a consultant to the ISMS advisory committee to the Health Careers Council of
Illinois, and continues as a member of the house of delegates of the ISMS.
Dr. Shapiro has worked as a member or co-chairman of several committees
of the AMA and currently is serving as alternate delegate from the Section on
General Practice and as a member of the Council on Health Manpower. He also
is a national advisor to the Student American Medical Association.
He is on the active surgical staff of Jackson Park Hospital, where he also is
director of the Department of Physical Medicine and Rehabilitation, director of
medical education and director of the Summer Student Program, as well as a
member of the Executve and Credentials committees.
Previous hospital affiliations were as clinical assistant in surgery at Mt. Sinai
Hospital and as medical-surgical consultant to the Neurological Hospital in
Chicago.
In addition to teaching both undergraduate and graduate medical students in
the community hospital setting, he is a visiting lecturer in the graduate program
in hospital administration in the Graduate School of Business of the University
of Chicago.
He is a fellow of the Industrial Medical Association, Central States Society
of Industrial Medical and Surgery, Academy of Psychosomatic Medicine and the
American Geriatrics Society. He also holds memberships in the Chicago Society
of Industrial Medicine and Surgery (he is a past member of the board of
governors), American Congress of Rehabilitation Medicine, Mid-America Society
(and Illinois division) of Physical Medicine and Rehabilitation, Association of
Hospital Directors of Medical Education and the Association of American Medi-
cal Colleges.
His civic activities have been equally varied. He served in the city and state
venereal disease campaigns, as well as on a medical advisory committee to the
city, culminating in the presentation of a citation of service plaque. He currently
is president of the Health Careers Council of Illinois (he was elected to an un-
precedented third term), on the advisory board of the Health Improvement
Foundation of the Illinois Health Improvement Association, a director of the
Illinois Social Hygiene League and a member of the professional advisory coun-
cil of the National Easter Seal Society for Crippled Children and Adults.
Dr. Shapiro is a life member of Phi Delta Epsilon medical fraternity, a mem-
ber of Scottish rite and Medinah Temple (Shrine) and a member of Beth Am
Synagogue and Men's Club.
He was born in Chicago on December 18, 1914. He has remained there, with
his residence currently at 8911 South Chappél Ave., and office for full general
practice in the Jackson Park Hospital.
Dr. Shapiro received his premedical training at Crane Junior College and
Central YMCA College, Chicago. He was graduated from the University of Illi-
nois College of Medicine in 1939 and served his internship and residency at Mt.
Sinai Hospital in Chicago.
81-280-69-pt. 11-32
PAGENO="0498"
4788 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
His military service was with the Army Medical Corps on active duty from
1941-46 in the South Pacific, rising in rank to lieutenant colonel.
Dr. Shapiro and his wife, the former Lenore Martha Gold of Providence, RI.,
have one daughter, Jull Ann, 16.
BI0GnAPHICAL S~ToH OF MAC P. CAnAL, J.D.
Mac F. Cahal, Executive Director and General Counsel of the American
Academy of General Practice, Publisher of the Academy's medical publications,
GP and the American Family Physician, and Secretary-Treasurer of the AAGP
Foundation, Kansas City, Missouri; born March 28, 1907, Kiowa, Kansas; son
of Frank B. and Carrie (Fullerton) Cahal; A.B. University of Kansas School
of Journalism, 1931; J. D. (Doctor of Jurisprudence) Be Paul University College
of Law, Chicago, 1935; attended Northwestern University 1937-38; married
Wilma Marshall, June 1, 1935; one daughter Caroyln, and son William Marshall.
Doctor Cahal began his work with organized medicine as Executive Secretary
of the Sedgwick County Medical Society (Wichita), Kansas, in 1932. In 1937
he became Executive Secretary and General Counsel of the American College
of Radiology. During a leave of absence in 1944 he served as Executive Vice-
President of the Southwestern Medical Foundation in Dallas. In 1948 he resigned
from the American College of Radiology to become General Counsel and Execu-
tive Secretary of the American Academy of General Practice.
He is an associate Fellow of the American Medical Association, a member
of the American Bar Association and the Chicago Bar Association, an Honorary
Member of the Sedwick County Medical Society, and a member of numerous
clubs and societies.
Doctor Cahal was founder and president in 1948 of the Medical Society Execu-
tives Association. He is a past president of the Association of Medical and Allied
Publications, and serves on the Board of Directors of the American Society
of Association Executives. He is the author of numerous monographs on the
social, economic, and legal aspects of medicine, published in both the medical
and legal literature. He has been a frequent speaker before medical and lay
audiences on the above subjects and has testified on several occasions before
government boards and committees in Washington.
His home is at 6610 Indian Lane, Mission Hills, Kansas.
BIoGI~s.iHIcAL SKETCH OF WALTER H. KEMP
Mr. Kemp is managing editor of GP and American Family Physician maga-
zines, both published monthly by the American Academy of General Practice.
He is also secretary of the Academy's Commission on Legislation and Public
Policy and has previously served as advertising sales manager, director of pub-
lic relations and director of the Communications Division. He holds B.S. and
B.A. degrees in psychology and economics from Northwestern University and
is the son of Dr. and Mrs. Howard M. Kemp (both deceased) of Greenfield and
Shelburne, Mass.
Mr. Kemp was earlier employed by Armour Research Foundation and the
American Medical Association in Chicago. He was a police reporter and special
features writer on the Greenfleld (Ma~ss.) Recorder-Gazette. He is a member
of Beta Theta Pi, DERU (seniormen's honorary society) and Sigma Delta Chi.
During World War II, he served in the airborne infantry and was honorably
discharged after being wounded during the Normandy and subsequent cam-
paigns.
Mr. and Mrs. Kemp have three children and reside at 9332 Catalina Drive,
Shawnee Mission, Kansas 66207.
(Whereupon, at 12 o'clock, the Subcommittee on Monopoly of the
Select Committee on Small Business was adjourned, to reconvene sub-
ject to the call of the Chair.)
PAGENO="0499"
APPENDIXES
APPENDIX I
[From the Virginia Medical Monthly, vol. 94, Feb. 1967, pp. 110-114]
THE IMAGE OF THE DRUG INDUSTRY, AS SEEN BY TOWN AND GOWN
(By William J. Hagood, Jr., M.D., Clover, Virginia, John A. Owen, Jr., M.D.,
Charlottesville, Virginia)
(Presented before the Public Relations Section of the Pharmaceutical Manufacturers
Association, Sixth Annual Meeting, Hot Springs, Virginia, October 4-7, 1964.-From the
Division of Clinical Pharmacology, Department of Internal Medicine, University of Vir-
ginia School of Medicine, Charlottesville. Aided by Training Grant HE 5544 from the
U.S. Public Health Service.)
Results of a questionnaire with regard to the pharmaceutical in-
dustry and products are presented.
During the last several years the pharmaceutical industry has repeatedly
made headlines-not always to its advantage. Perhaps for this reason, the
Public Relations Section of the Pharmaceutical Manufacturer's Association in-
cluded in its 1964 convention program a panel discussion on the industry's image
in the eyes of the physician. In preparing our independent presentations for this
program we distributed two questionnaires: one to 200 general practitioners
in the rural areas and small towns of Virginia and the other to the medical
students, interns, and residents of the University of Virginia Medical Center.
The contrasting responses from the two grOups have given rise to some discus-
sion and conclusions which may be of interest.
THE GENERAL PRACTITIONERS' QUESTIONNAIRE
There were five general questions on this list, as follows:
1. What is your impression of the pharmaceutical industry? Why do you
have the opinion you have expressed?
2. What influences you to use a drug company's product? Why do you
think the influences you have expressed `are important?
3. Do you favor the continuing use of the medical service-representatives
or "detail men" `by the drug companies? Why?
4. Do you think the cost of drugs is too high, too low, or about right?
What would you suggest the pharmaceutical industry do to better inform
the patients why drugs cost what they dO?
5. What is your opinion of the `apparently growing practice of physicians
gaining a financial interest in pharmacies and drug distribution firms?
Why do you have this opinion?
Of the 200 physicians queried, 80 (40%) responded; these 80 resided in 55
of Virginia's 99 counties and had practiced medicine from three to 61 years in
offices located either in open rural country or in villages ranging in population
up to 4200. In the following paragraphs, percentage figures will be based on the
80 responses.
In reply to the first question, 64 physicians (80%) affirmed that they have
a good impression of the pharmaceutical "industry, based primarily on the in-
dustry's extensive research programs and high ethical relations. Another 9% were
non-committal. Only nine physicians (11%) actually criticized the industry be-
cause of exorbitant prices, pushy and garrulous detail men, or excessive adver-
tising.
As reasons for using a `specific company's product, 40% claimed to be guided
mainly by previous results with the product, 33% by the positive influence of de-
4789
PAGENO="0500"
4790 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
tail men, 28% by the over-all integrity of the company, 21% by medical jour-
nals, and 14% each cited the research behind the drug and the relative cost of
the drug as being crucial to their decision. There were in all 17 reasons given
the least popular (1 physician, 1%) being the evaluation of the drug by the
Medical Letter.
Regarding the utility of the detail man, 85% of general practitioners gave him
a strong vote of confidence, because his new drug information was valuable to
them and he could order drugs directly for dispensing physicians. The other
15% felt that in view of the abundant available literature his services could be
eliminated and the resultant savings be passed on to the patient.
Questioned about drug prices, 51% of general practitioners thought that they
were "about right," and 45% thought that they were "too high"; none con-
sidered them "too low." Furthermore, 24% urged a better public relations at-
tempt to help the layman understand why drugs cost what they do. However,
one physician urged the opposite course: "reduce the cost instead of spending
more money to tell the patient why drugs are expensive."
Finally, the general practitioners were definitely opposed (75%) to the prac-
tice of physicians gaining a financial interest in pharmacies and drug distribu-
tion firms.
TIlE MEDICAL CENTER QUESTIONNAIRE
Questions 1 and 2 required a listing of material gifts from drug companies
and stock ownership in them. Questions 3-5 asked for a graded evaluation of the
pharmaceutical industry on its (1) record in the development and testing of new
drugs, (2) margin of profit in prescription drugs, and (3) performance in dis-
seminating information about new drugs. Questions 6 and 7 tried to assess the
impact of the new Food and Drug Administration regulations concerning clinical
trials in terms of general awareness and reaction. In question 8, each person was
asked to compare and rate the following over-all sources of comprehensive in-
formation about new drugs: faculty and house staff, scientific meetings, scien-
tific articles, advertisement in medical journals, mail literature from drug com-
panies, detall men, the "Physician's Desk Reference," the Medical Letter and
drug inserts. Question 9 asked for a correct matching of both the generic names
and the therapeutic effects to the trade names of twenty common drugs.
Question 10 was multiple choice: "The pharmaceutical industry could bet-
ter serve the medical profession by (1) continuing just as it is; (2) cutting
prices; (3) developing more new drugs at a faster rate; (4) sponsoring more
post-graduate courses; (5) distributing more educational material; (6) chang-
ing its advertising policy as follows; (7) changing its drug development policy
as follows; (8) changing its detail man program as follows; (9) changing its
drug sample policy as follows; or (10) other." Question 11 asked each person to
assign a grade rank to the following factors as strongly affecting his opinion
(good or bad) of a specific drug company: "(1) advertisements; (2) experience
with its products; (3) gifts and services to you; (4) research support; (5) as-
sistance in post-graduate and medical educational programs; (6) detail men;
and (7) other."
Returns from this questionnaire were scattered, ranging from a 7% response
from the second-year class to a 30% response from the fourth-year class. There
were 73 questionnaires completed and returned from the 384 persons polled,
an over-all 19% response.
Almost everyone had received some sort of gift from one of the drug com-
panies. Eli Lilly and Company had donated 57 pen lights, 46 medical bags, 45
percussion hammers, 35 stethoscopes, 30 pocket notebooks, 28 tuning forks, 19
pen knives, and 18 tape measures, as well as sundry other diagnostic aids, to
the 73 persons polled. Burroughs Welcome & Company had given 18 pocket
notebooks, Ciba Pharmaceutical Company had distributed 11 subscriptions to
the Ciba Symposia, and Wyeth Laboratories had given 10 pen lights. In all, 19
drug companies were listed as donors, some only once, of generally minor and
inexpensive gifts.
Of the 73 polled, six owned stock in one or more drug companies and 58 of
the nonowners considered such stock to be a good financial investment.
Most answers rated the pharmaceutical industry's record in development and
testing of new drugs as good (41, or 56%), its margin of profit in prescription
drugs as wide (35, or 48%), and its performance in disseminating information
about new drugs as good (39, or 54%). Most of the other answers were equally
divided between the two evaluations nearest the mode ("very good," and "fair").
PAGENO="0501"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4791
Knowledge of the current Food and Drug Administration regulatioins regard-
ing clinical drug trials seemed to be greater among residents than medical
students: 26 out of 35 students had at most a vague cognizance of them; 17
out of 32 residents had a fairly good or exact knowledge. Most medical students
felt they were "necessary and reasonable", but the residents were divided
equally between this viewpoint and "necessary and unreasonable". In addition,
five residents felt them to be "unnecessary and unreasonable", and three "highly
commendable and long over-due".
The ratings of best sources of comprehensive information about new drugs
are shown in Table I. The influence of faculty and house staff rises to a peak
during the intern year and then progressively declines. Articles in medical
journals appear to be the most consistently~ respected authority throughout,
with the Medical Letter running a close second during the post-graduate period.
Advertisements, mailed literature and the detail man are usually at the bottom
of the list, although the latter performs better during senior residency years.
TABLE I
Q. 8. Which do you believe to be the best overall source for comprehensive information about new drugs?
M.S.2 M.S.3 M.S.4 I. R.l R.2 R.3 R.4
Insert
P.D.R.
Journ.
FaclIS.
Journ.
Journ.
Journ.
Journ.
Journ
Journ.
FacHS.
Journ.
MedLet
MedLet
MedLet
MedLet
FacHS.
FacHS.
P.D.R.
P.D.R.
FacHS.
FacHS.
Insert
Meets.
Meets.
MedLet
Insert
MedLet
Meets.
Insert
Fad-IS.
FacHS
P.D.R.
Meets.
MedLet
Meets.
P.D.R.
P.D.R.
Detail
Detail
Ads
Mail
Meets.
Insert
Insert
Meets.
P.D.R.
P.D.R.
Insert
Mail
Ads
Ads
Mail
Meets.
Detail
Ads
Mail
Detail
Ads
Mail
Ads
Detail
Detail
Mail
Detail
Ads
Legend: MS-medical student; 1.-intern; R.-resident. Numbers indicate years of training. Abbreviations for sources
self-explanatory.
In the matching quiz, some generic names were almost as familiar as their
corresponding trade names but there were some impressive discrepancies: 60
persons correctly described Elavil (Merck Sharpe and Dohme) as a mood eleva-
tor but only 14 of these knew that its generic name was amitriptyline; 60 persons
knew the therapeutic action of Dulcolax (Geigy) but only 23 knew its generic
name.
The last two questions produced the most spontaneous responses. The sugges-
tions for the pharmaceutical industry are summarized in Table II. The same
general sentiments are reflected in the responses to the last question, illustrated
in Table III. The same three sources of dissatisfaction (detail men, advertise-
ments, and gifts) are again apparent.
TABLE II
Q. 10. The drug industry could best serve the medical profession by-
Sponsoring more post-graduate courses -
Distributing more educational material
Cutting prices -
Changing its advertising policy -
Changing its drug sample policy -
Changing its detail man policy
Developing more new drugs at a faster rate. -
Changing its drug development policy -
Continuing just as it is -
TABLE III
Q. 11. Your opinion (good or bad) of a specific drug company is most strongly affected by:
Factor
Total response
Favorable Unfavorable Either
Experience with products
Detail men
57
32
9 1
1 12 1
Advertisements
Personal gifts, etc
Postgraduate education support
Research support
23
19
17
14
2 7 3
6 3
8
8
18
18
16
15
15
14
7
7
5
PAGENO="0502"
4792 COMPETITIVE PROBLEMS IN THE DRtIG INDUSTRY
COMMENT
It would be imprudent to attempt multiple interpretations of the responses to
two different questionnaires, distributed to two different and heterogeneous
groups, with such a variable percentage of replies. However, the following sim-
ilarities deserve emphasis.
1. There is general appreciation for and satisfaction with the over-all per-
formance of the pharmaceutical industry.
2. A feeling that drug costs are too high or profits too wide is evident in 45% of
the answers from the general practitioners and in 48% of those from the Medical
Center.
3. Most doctors judge a drug company by the efficacy of its products, with the
activities of the detail man receiving second place in consideration.
In addition, one may ask what is the comparative efficacy of the three forms of
advertising: direct mailing, medical journal ads, and the detail man? The
physician has a built-in bias against them all, knowing that none is likely to
give him what he wants: a carefully balanced comparison of the product vs. (a)
older, simpler substances, (b) new products of competitors, and (c) no treatment
at all. Also, to make best use of his limited reading time he glady dispenses with
all save the most authoritative sources of information. So it is unlikely that mail
literature and journal advertising have any lasting impact; both could probably
be curtailed completely without much effect on the practice of medicine.
This is true because in their absence the detail man could serve the same
functions. Conversely it is hard to see how impersonal mailings and glossy ad-
vertisements could take the place of an ideal detail man: cheerful, helpful, dis-
armingly proprietary, willing to listen and happy to debate. Although the
physician spends time with him, be spends it as he chooses; he can in effect carry
on a conversion with a person, with a drug company, or with the entire phar-
maceutical industry.
If the ideal detail man exists, he is clearly outnumbered by his imperfect
brethren who reportedly interrupt the office routine, parrot stereotyped en-
coniums, hawk their wares in a truculent manner, and talk without listening.
This confrontation destroys the one thing the physician wants: a chance to learn
some valid information. Since the physician is unlikely to change his attitude,
the pharmaceutical industry must become more information-oriented. This
metamorphosis cannot occur spontaneously but requires active and vocal effort on
the part of the physician. The following avenues of information have been worked
out at many teaching medical centers:
1. A hospital policy for detail men requires that any "detail visit" (five min-
utes) to any physician be scheduled through a central office.
2. A similar policy encourages drug companies to work through a central office
in arranging clinical trials of new drugs, thus bringing together the mOst promis-
ing drug and the best-qualified investigator.
3. Books, films or other educational material can be useful in both medical and
post-graduate education; courses and lectureships, research fellowships and hon-
oraria for visiting speakers have been deeply appreciated gifts from the phar-
maceutical industry.
4. Occasionally the drug company may support an entire laboratory or clinical
research area, where patients are hospitalized for study by all the. newer tech-
ñiques of clinical pharmacology.
Implicit in all of these programs is the presence of a professional person or
persons who maintains a liaison with the drug house representatives and ar-
ranges these collaborative efforts. At every opportunity such a person works to-
ward one specific goal-to help bring the best information available from the
drug houses to the physicians.
Whenever the physican works actively in cooperation with the pharmaceutical
industry in these areas, he appreciates anew its sceintific contributions and puts
aside his built-in resistance to its commercial aspects. Thus these possible ap-
proaches to a closer working relations, while sometimes apparently restrictive,
cannot fail to increase the physician's appreciation of the industry-a reservoir
of good will which is a powerful reality and capable of even greater enhance-
ment. The medical profession and the pharmaceutical industry, working together,
should bend themselves to that task.
PAGENO="0503"
COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 4793
APPENDIX II
[From the Virginia Medical Monthly, vol. 93, August 1966, pp. 459-461]
TEACHING THE EVALUATION OF DRUG ADVEIITISING TO MEDICAL STUDENTS
(By D. R. H. Gourley, Ph. D., professor of pharmacology, University of Virginia
School of Medicine, Charlottesville, Va.)
Physicians until the present have developed their own methods for
evaluating the advertising of pharmaceutical manufacturers. Now a
course is being given in medical school to prepare the student for
this task.
From time to time, spokesmen for the pharmaceutical industry have attempted
to justify the expenditure of heavy sums for the advertising of prescription
drugs to a limited group as "postgraduate education of the doctor." The charac-
ter of drug advertising in the United States today under regulation by the Food
and Drug Administration(6) has improved considerably since the abuses de-
scribed by May (5) and others. However, there is reason to believe that many
physicians in private practice have been introduced to a large proportion of the
drugs they are now prescribing by communications from the pharmaceutical
manufacturers. Baehr (1) noted that many general practitioners and specialists
in his experience were motivated to shift from one drug to another by the per-
suasive propaganda of advertising literature and by visiting representatives of
manufacturers.
It is clearly desirable for the~ physician to have a set of guidelines by which
*he can evaluate the claims that will be made for drugs introduced to the thera-
peutic scene in the years following graduation from medical school. The course
in pharmacology appears to be a logical place to begin to introduce such guide-
lines and studies of the evaluation of drug adyertising ha\ e been initiated in the
pharmacology courses in some medical schools. (2, 3) Typically, a program of
drug advertising evaluation is modified in some details from year to year, but
the principles can be illustrated by a description of the program most recently
undertaken with second year medical students in the Department of Pharma-
cology at the University of Virginia School of Medicine
The objectives, of the evaluation of drug advertising (EDA) program were:
(i) to develop in the medical student a skeptical attitude towards advertising
claims for new. drugs; (2) to provide the medical student with training and ex-
perience in the evaluation of these claims and with some knowledge of the relia-
bility of various authorities. The practical exercise of the EDA program was
limited to direct mail advertising although it is recognized that this is only
one of several channels through which drugs are advertised. To obtain the neces-
sary material, three cooperating physicians saved all of the drug advertisements
and samples received through the mail during the three-month period immedi-
ately preceding the project. The program was scheduled during the latter part
of the pharmacology course after the students had completed their study of drugs
which affect the central nervous system, autonomic nervous system, cardiovas-
cular system and kidney. The mass of accumulated mail was gleaned for material
advertising drugs in these general categories. Most of the drugs were relatively
new but a few older agents were included for balance. Advertised material that
included literature references was selected in preference to poorly documented
brochures. Although this bias favored the advertising material, it was a neces-
sary concession in order to provide the students with certain leads.
The class was divided into 18 groups of four students each. Therefore, 18 drugs
were chosen. All of the available direct mail advertising for one drug was given
to one group for their analysis.
At a preliminary session, the students were given their assignment and in-
structions for the program. The peculiar features of drug advertising and the
relative role of direct mail advertising in overall drug promotion were discussed.
The volume of drug samples received through the mail during the collection pe-
riod was dramatized by emptying a large galvanized can containing the drug
N0VE.-Numbered references at end of article.
PAGENO="0504"
4794 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
samples on the lecture table. A considerable portion of the introductory session
was devoted to methods for assessing reports of drug trials. The criteria outlined
by Mahon and Daniel(4) were emphasized. The method consists of the stepwise
application of the following criteria: (1) the presence of adequate controls, in-
cluding the effects of a placebo preparation as well as standard therapy; (2) ran-
domization of treatments; (3) objective assessment of drug effects, including
the principle of the double-blind trial to avoid biased evaluation; and (4) sta-
tisical analysis of results. The students were instructed to determine how many
of the cited references were actually available in the Medical Library (which
has 1250 scientific journals on the subscription list) and what proportion of
those available were adequate according to the above minimal criteria. Attention
was also directed to other source material such as the Medical Letter, the
A.M.A. Council on Drugs reports, New Drugs, etc.
it was not an objective of this program to criticize or rate individual drug
manufacturers. The important role of the pharmaceutical industry is emphasized
in many ways in this course. During the EDA program, for example, a one-day
visit to a nearby pharmaceutical firm was arranged. In addition to seeing the
excellent pharmacological and medicinal chemical research and the manufac-
turing and packaging functions of this firm, the students were addressed by an
executive officer of the firm who, by prearrangement, presented much valuable
additional material on drug advertising from a viewpoint somewhat different
from that of the instructors.
Each group of students was assigned a clinical advisor, usually a physician
who had had considerable clinical experience with the assigned drug. The
students were instructed to discuss their assignments with their advisor follow-
ing the introductory session and from time to time during the progress of the
program in regard to questions relative to the evaluation of the drug, the other
drugs available for comparable therapy, and the state of knowledge in the field
for which the particular drug is intended. They were urged to obtain as many
opinions on these questions as possible by also consulting other clinical instruc-
tors and to consult several pharmacists regarding available preparations and
relative costs to the patient of equivalent doses of the assigned drug and of
other comparable drugs. Students were offered secretarial assistance if they
wished to write to pharmaceutical firms for additional information.
The students were allowed eight hours of laboratory time over a three-week
period to work on the EDA program. At the end of the program, each group
submitted a written report of their study and each member of the group was
prepared to present an oral 10-minute report. The oral reports were presented
to the class and discussed by the class advisors and departmental staff. The
person chosen from each group to present the oral report was not announced
in advance.
The staff of instructors and the clinical advisors report that the students
rapidly developed a skeptical attitude towards the particular advertising claims
which they studied. The students were particularly impressed with the number
of quoted "references" which were not available even in a good medical library.
Many groups found that of the references they could find in the literature only
about 5% fulfilled all of the criteria for a satisfactory clinical trial of a new
drug, which is in general agreement with results of the large study reported
by Mahon and Daniel. (4).
At the end of the pharmacology course, student opinion of various aspects of
the pharmacology course was polled in an unsigned questionnaire. The class
was unanimous in its belief that a study of drug advertising belonged in a
medical pharmacology course. Ninety-five per cent of the class thought that the
project outlined in this report was a valuable learning experience and 85%
thought that the time allotted to the project was "about right". Further polls of
the same class will be sought just before graduation and after a period of time
in practice to determine whether attitudes towards drug advertising and reports
of clinical trials of new drugs developed as a result of this teaching exercise
have been maintained. In the meantime the enthusiasm of the students and the
members of the faculty who participated is ample justification for continuing
the project with modifications designed to improve the attainment of the objec-
tives or to better suit further developments in drug advertising and regulations
of the Food and Drug Administration.
PAGENO="0505"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4795
Acknowledgements: It is a pleasure to acknowledge the contributions to the
success of this program of the A. H. Robins Co., Inc., Richmond, and the follow-
ing members of the faculty of the University of Virginia School of Medicine:
Drs. A. J. Bollet, E. D. Brand, G. Goldstein, C. D. Green, J. I. Kitay, C. M.
Kunin, D. N. Mohier, J. A. Owen, Jr., L. E. Rudolf, 0. A. Thorup, Jr., and F. B.
Westervelt, Jr.
REFERENCES
1. Baehr, G.: Drug Costs and the Consumer in Drugs in Our Society. Ed. by
Talalay. The Johns Hopkins Press, Baltimore, 1964, p. 179.
2. Daniel, E. E.: Are Laboratories in the Basic Medical Sciences Necessary?
Canad. Fed. News 7: 69, 1965.
3. Garb, S.: Teaching Medical Students to Evaluate Drug Advertising. J. M.
Educ. 35: 729, 1960.
4. Mahon, W. A. and Daniel, E. E.: A Method for Assessment of Reports of
Drug Trials, Canad. M. Assoc. J. 90: 565, 1964.
5. May, C. D.: Selling Drugs by "Educating" Physicians. J. M. Educ. 36:
1, 1961.
6. Sadusk, J. F.: Planning in the Food and Drug Administration for Regula-
tion of Prescription Drug Advertising. Current Therap. Res. 7: 332, 1965.
APPENDIX III
APRIL 22,1969.
Dr. W. J. HAGOOD, Jr.,
Little Retreat Clinic,
Clover, Va.
DEAR Dn. HAGOOD: When you appeared before our Subcommittee on February
19th, you stated that you had prescribed the drug combination, Signemycin to one
of your patients.
I am enclosing copies of two drug efficacy studies by the National Academy of
Sciences which may be of interest to you. The NAS/NRC appraisal of this drug
applies to every dosage form.
I would appreciate any comments you might have.
Sincerely,
GAYLORD NELSON,
Chairman, Monopoly Subcommittee.
(No reply was received from Dr. Hagood.)
PAGENO="0506"
4796 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL
Division of Medical Sciences
DRUG EFFICACY STUDY
Farm A
(To be submitted in duplicate by applicant)
Reg. No. 146c.23].
I. NSA N.mb.r_._-_- 2. Dcc. Ocgrclly Appccr.d 4/21/SR * 3. Cc ~ OTC Q
4. t~d Nsm._-__Si em~tcin_Cap.sza1e.s_125._tog.._.and 250 tog.., Signemy~--3-G.op&u~ee------------9---
3. Applksric Ncr. Chas. Pfizer 8z.Co., Ioi~.
erd Add.,, 235 East 42nd Street, New York, New York 10O17 -
6. Quantitative Formula
cct.blichcd tN.e.Pr.p,i,~.ryt Noac .1 Acti,. lmgr,dl.ets lit s.c.. .,cmcr tcb.II A.ucc par tablet, p.r act,,
Signetoycin Capsules 125 tog.
Signenyciro 125 tog. (83 tog. of tetracycline hydrochloride, 42 tog. `of oleandornycin
as triacetyloleandotoycin)
Signetoycin Capsules 250~~g.
Signetoycin 250 tog. (167 tog. of tetracycline hydrochLoride, 83 tog. of oleàndoonycin
as triacelyloleandotoycin)
~4gn~pycin 375 Capsules
Signeroycin 375 tog. (250 tog. of tetracycline hydrochloride, 125 tog. of oleandotoycin
as triacetyloleandotoycin)
7. D..co. F.... licbI.I,, .15.1 Capsules
~ :z:::~:: ~ ~
9. Th.rcp.u.s Ctcim,-Aitc,P. to -`--i. --4 10 pc,keu, r,.tc lit cc.dt to crigir.t Form A tbtu.) acid 1 copy to duplloot. Focvs A leNtil.
to Li., ci I., tar..,,, i.c.r pcrri..c.it to cci ccc luclic,, ci it,. eff.,Ii,.cicsc ci the dmg icr .... purp~scs f.r mht,t. it is .,cad Ii, the fob,F,
it.. p.ockcg. ir..,t. ci b,,,hcr.. Appic.imotctm 5 to to t.,9 r.t.r.rc.s ci. r.qu.cl.d, it oroilcbto. (Attoch 10 oopi.s cc eriginot For,. A (big.)
c'd t copy to dupliict. Form A tmhii.i.t
t. it.. cppl.,c'i ic .`-.t.d. it 5. cc dccin.c. I. ibbacit c.yunpu blich.d .,ctutict hot is p.nilir.nt to ih. .,otuoliocs .1 h. drug by cbs Ai.dam~'-.
i,,.or,t. Cccn,iI. Thi, ccppl.m,itory cot.ti~t should b. pockcg.d ellb Form A tsNtcl. A slngl., ocpy *tthlc material ii rcqesotcd,
2. Ii It.. p.,.. pl.e,. ci end d.cor.b. bni.Fy Iha scppl.ni.nlory ,.sl.tict that is scbmill.d mitt, Form fr (chit,),
PANEL ON ANTI-INFECTIVE DRUGS (III)
INDICATIONS
I. Signemycin is indicated in the therapy of acute severe infections caused by
susceptible organisms and primarily by bacteria more sensitive to the combina-
tion than to either component alone.
Evaluation: Ineffective as a fixed combination.
Comments: Although either tetracycline or oleandomycin is effective in the
treatment of some infections, there are serious objections to the use of the
combination as formulated. Oleandomycin is present in insufficient amounts for
effective treatment. If sufficient oleandomyci.u is administered for effective
treatment, tetracycline overdosage results.
The Panel is not aware of infections caused by bacteria more sensitive to this
combination than to either of its components.
PAGENO="0507"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4797
Establishing efficacy would involve demonstrating that the clinical response
to the combination is greater than to either agent used alone. No such evidence
is available. In vitro studies of this combination have given variable results. The
effects may be antagonistic, additive, or synergistic, and are unpredictable for
any particular organism.
Thus, there is no evidence that each of the active ingredients contributes to the
effect as claimed.
Documentation:
1. Jones, W. F., Jr., B. L. Nichols, and: M. Finland. Development of resistance
and cross resistance in vitro to erythromycin, carbomycin, spiramycin, oleando-
mycin and streptogramin. Proc. Soc. Exper. Biol. & Med. 93:388-393, 1956.
2. Jones, W. F., and M. Finland. Antibiotic combinations. Tetracycline, erythro-
mycin, oleandomycin, and apiromycin, and combinations of tetracycline with
each of the other three agnts.-Comparisôn of activity in vitro and antibacterial
action of blood after oral administration. New Eng. J. Med. 257:482-491, 536-547,
1957.
3. Fofar, J. 0., and A. F. Maccabe. Erythromycin, spiramycin and oleando-
mycin. Brit. Med. J. 1 :581, 1957.
4. Editorial. Erythromycin, oleandomycin and spiramycin-and their combina-
tions with tetracycline. New Eng. J. Med. 257:525-526,1957.
II. Favorable clinical response to Signémycin has been Observed in the follow-
ing categories and indications: infections of the respiratory tract and related
structures and the genitourinary system, ~: surgical infections, and miscellaneous
(amebiasis and lymphogranuloma venereum have been found responsive to Sig-
nemycin). Dental infections caused by susceptible organisms are candidates for
Signemycin therapy.
Evaluation: Ineffective as a fixed combination.
Comments: There is no evidence that each of the drugs present in this combi-
nation contributes to the effect as claimed. Although case reports can be found
indicating favorable response, this response is similar to that expected follow-
ing administration of tetracycline alone or, more rarely, oleandomycin.
Documentation: Informed judgment of the Panel.
III. In streptococcal infections, therapy should be continued for 10 days to
minimize the possibility of the development of rheumatic fever or glomerulo-
nephritis.
Evaluation: Ineffective as a fixed combination.
Comments: The Panel is not aware of convincing evidence that treatment
with Signemycin will prevent either of these conditions, regardless of the dura~
tion of therapy. More effective drugs are available for therapy of streptococcal
infections.
Documentation: Informed judgment of the Panel.
Approved by WM. KIRBY,
Chairman.
PAGENO="0508"
4798 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
NATIONAl. ACADEMY OF SC)ENCE~-.NATIONAI. RESEARCI~ COUNCIl.
DMsion of Medical Scionce;
DRUG EFFICACY STUDY
Form A 2r4~fj
(To be submitted in~dtSIic~)~eb~pPPIicanl)
P4DA fdusb.: JA6c'.23]. ~. Dotc'Od;toIIy Approred October I~, 1956 3:RO ~ .CTC Q
4. Ocard N~.- Sinezycin (Si~carn)Capsu]&a..1Q~.1QO ant 250 m~.
5. Apphoort's Nose Chas. Pfizer & Co. Inc. (EcTEREATIO1iAL) .
- 235 East 42nd Street, Ne~' York, New-York 1O~O17
6. Quootit~tivo Formula
f,tcbHshad )Pder.Pt.pri.tarp) f4.s. .5 Aot.o. )rvodi.ttt. (!r order shoot lob.!) Asousc (p.r tobI.t, p.r st. etc.)
Tetracycline (Hcl) 33.3 ~z~*
Oleandoaycin (phosphate) 16.7 ong.
100 rag.
Tetracycline (HC1) 66.7 ui5.
Oleandomycin (Phosphate) 33.3 mg.
250 mg.
Tetracycline (sd) 167 mg.
Oleando~rcini (Phosphate) 83 zig.
7. O*sog. Pots (tobl.tc. Capsules
S. ,.ut. .5 Ads, 0,.!. etc. WI'... a to. drug oppkoototooc.r.
dfet.st cult, ot od ticttotOt sep-.rc!. tots. .hocld be used.) Oral
9. Thetop..c~.c Cloktc-Aysch tO oh.!, s.d tO pookoge tced~ (5 used) to o:k,itot F.t.t A bk,.) cod 5 copy to Juptroot. Peter A (ottO.).
(0. List at ta..cr.... ,ctet.soe, sect peditest to on ctclu.tlos of the .t'.at.cete,. .f:th. drug for A.. purpo.m fir which fit .a.r.d to tb. label,
4.. p-echo;. c~err, or br.chom. Approsieo!.ly 5 to 10 boy a.t.r.eo.s ore t.qv..t.d, it oteil,btc, (Attach 10 c.p.a to .r!girot Purrs A )btu.tt
ord I copy to dcp!kete huts A )r.kit,t.)
tt~ The eppkcest I, itoSod, it he .o dosres, a ,ebeit sty stpublish.dt.r.tetk,t thor is pec'fit.tt to (ho .rotcotk,s of ha drug by the Aood.sy..-
O.st~roh Cosecil. Tb!. eoppteeettory *et.t,o) shostd be psok.g.d `alA. form A (oNto). A sir;!, copy of this rstet(ol Is re~o.et,d.
12. to ks .p.c., pt..sc Sct .sd d.scribe br,efy ho soppl..,ttory treterig) th.( is subtr!tt,d with Pot's A (oNto).
PANEL ON ANTI-IN~scTIvE DRUGs (III)
INDICATIONS
I. Sigmamycin -is indicated in the therapy of acute severe infections caused by
susceptible organisms and primarily by bacteria more sensitive to the combina-
tion than `to either component alone.
Evaluation: Ineffective as a fixed combination.
Comments: Although either tetracycline or oleandomycin is effective in the
treatment of some infections, there are serious objections to the use of the com~
bination as formulated. Oleandomycin is present in insufficient amounts for effec..
tive treatment. If sufficient oleandomycin is administered for effective `treatment,
tetracycline overdosage results.
PAGENO="0509"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4799
The Panel is not aware of infections caused by bacteria more sensitive to this
combination than eo either of its components.
Establishing efficacy would involve demonstrating that the clinical response to
the combination is greater than to either agent used alone. No such evidence is
available. In vitro studies of this combination have given variable results. The
effects may be antagonistic, additive, or synergistic, `and are unpredictable for
any particular organism.
Thus, there is no evidence that each of the active ingredients contributes to the
effect as claimed.
Documentation:
1. Erythromycin, oleandomycin and spiramycin-and their combinations with
tetracycline. New Eng. J. Med. 257: 525-526, 1957. (Editorial)
2. Forfar, J. 0., and A. F. MacCabe. Erythromyein, spiramycin, and oleando-
mycin. Britt. Med. J. 1: 581, 1957. (Correspondence)
3. Jones, W. F., Jr., and M. Finland. Antibiotic combinations; tetracycline,
erythromycin, oleandomycin, and spiramycin, and combinations of tetracycline
with each of the other three agents-comparisons of activity in vitro and anti-
bacterial actions of blood after oral administration. New Eng. J. Med. 257: 482-
491; 536-547, 1957.
4. Jones, W. F., Jr., R. L. Nichols, and M. Finland. Development of resistance
and cross-resistance in vitro to erythromycin, carbomycin, spiramycin, oleando-
mycin and streptogramin. Proc. Soc. Exp. Biol. Med. 93: 388-393, 1956.
II. Favorable clinical response to Sigmamycin has been observed in the follow-
ing categories and indications: infections of the respiratory tract and related
structures and the genitourinary system, surgical infections, `and miscellaneous
(amebiasis and lymphogranuloma venereum have been found responsive to Sig-
mamycin). Dental infections caused by susceptible `organisms are candidates for
Sigmamycin therapy.
Evaluation: Ineffective as a fixed combination.
Comments: There is no evidence that each of the drugs present in this com-
bination contributes to the effect as claimed. Although case reports can be found
indicating favorable response, this response is similar to that expected follow-
ing administration of tetracycline alone or, more rarely, oleandomycin.
Documentation: Informed judgment of the Panel.
III. In streptococcal infections, therapy should be continued for 10 days to
minimize the possibility of the development of rheumatic fever or glomerulo-
n~phritis.
Evaluation: Ineffective as a fixed combination.
Comments: The Panel is not aware of convincing evidence that treatment with
Sigmamcyin will prevent either of these conditions, regardless of the duration of
therapy. More effective drugs are available for therapy of streptococcal infections.
Documentation: Informed judgment of the Panel.
Approved by WM. KIRBY,
Chairman.
APPENDIX IV
[From the New England Journal of Medicine, vol. 261, No. 26, Dec. 24, 1959, pp. 1318-1321)
FATAL CIRCLATORY COLLAPSE IN PREMATURE INFANTS REcEIvING
CHLORAMPHENICOL *
(By Lafayette E. Burns, M.D.,~ Joan E. Hodgman, M.D.4 and Alonzo B. Cass,
M.D.,~ Los Angeles, Calif.)
A survey was made of premature infants born twenty-four hours or longer
after spontaneous rupture of the fetal membranes, because of a higher mortality
*From the Premature Center of the Los Angeles County Hospital and the departments of
Pediatrics, University of Southern California School of Medicine and College of Medical
Evangelists School of Medicine.
tAssistant in pediatrics, University of Southern California School of Medicine.
tAssistant professor of pediatrics, University of Southern California School of Medicine.
~Associate clinical professor of pediatrics, College of Medical Evangelists School of
Medicine.
PAGENO="0510"
4800 COMPETITIVE PROBLEMS tN THE DRUG INDUSTRY
in this group than in the premature infants whose membranes had ruptured at
birth. Routinely, these infants had been placed on antibiotics shortly after birth
because of assumed exposure to infection. The role of antibiotics in this higher
mortality was questioned. A comparative study of these infants on different
treatment schedules was conducted from March, 1958, to February, 1959. This
is a report of that study.
METHOD
All premature infants delivered in the birth suites of the Los Angeles County
Hospital after spontaneous rupture on the fetal membranes for twenty-four hours
or more were assigned to one of four groups according to the time of admission to
the premature center. Group 1 received no antibiotics. Group 2 received chioram-
phenicol,~J 100 to 165 mg. per kilogram of body weight per day intramuscularly.
Group 3 received procaine penicillin, 150,000 to 600,000 units per day, and strep-
tomycin, 50 mg. per kilogram of body weight per day. Group 4 received all three
antibiotics in the same dosage previously mentioned. Half of the daily dose of
each antibiotic was given intramuscularly every twelve hours.
RESULTS
Table 1 lists the results of the study. The mortality rates in the nontreated
group and the group treated with penicillin and streptomycin are similar. The
mortality in both groups given chloramphenicol is strikingly higher than that in
the groups not receiving it. The higher mortality is most obvious in the infants
weighing 2001 to 2500 gm., that of the babies given chloramphenicol being 45 per
cent and that in those not given it 2.5 per cent.
TABLE 1.-COMPARISON OF MORTALITY
Group 1
(no treatment)
Group 2
(chioramphenicol)
Group 3
(penicillin and
streptomycin)
Group 4
(penicillin and
streptomycin and
chioramphenicol)
Percent-
Percent-
Percent-
Percent-
Total age
Birth weight (grams) infants who died
Total age
infants who died
Total age
infants who died
Total age
infants who died
<1,000 1 100.0 0 0 3 100 1 100
1,001-1,500 5 40.0 5 100 2 0 4 100
1,501-2,000 9 22. 0 9 67 4 75 11 90
2,001-2,500 17 5. 9 16 50 24 0 15 40
Total 32 30 33 31
Average 19.0 60 18 68
The general care of the babies in this study followed the established routine for
the nursery. All babies came from the socioeconomic group cared for by the county
hospital. All babies had ruptured fetal membranes for twenty-four hours or longer
before delivery. Analysis for sex and race showed no significant difference among
the groups.
CLINICAL STUDY
The clinical histories of the infants were reviewed. Figure 1 lists the common
physical signs and symptoms and presents the percentage in each group who were
symptomatic. The two groups given chloramphenicol were similar and were
combined to simplify the presentation. All the signs and symptoms but jaundice
were present in markedly increased numbers in the babies receiving chloram-
phenicol. The higher number of gastrointestinal symptoms in the infants treated
with penicillin and streptomycin as compared to the nontreated group should be
noted. The clinical courses of the chcloramphenicol-treated babies who died were
strikingly similar. The symptoms appeared in a typical order. Figure 1 lists the
overage age at onset of each symptom for the chloramphenicol-treated groups.
¶In the form of Chioromycetin Intramuscular, Parke, Davis and Company, Detroit, Mich.
PAGENO="0511"
COMPETITIVE PROBLEMS IN
THE DRUG INDUSTRY 4801
SYMPTOMS
AVE.D~O~ON5C
GROUPS 2 & 4
JAUNDICE
3.6
VOMITING
I2~L~L~
4
ANOREXIA
-
~
RESPIRATORY
DISTRESS
/
~
ABDOMINAL
DISTENTION
/
~
-~
-
CYANOSIS
-
GREEN
STOOLS
~~~_~____
LtTHARGY
-
w
~-
~__
5
ASHEN
COLOR
DEATH
-
-~ --~
5.7
EJ~J~ATMCNT ~ ~E?~C~L~UN& ~
FIGURE 1._Comparison of Symptoms.
Treatment was started in all cases within twelve hours of birth. The infant's
condition at forty-eight hours of age was generally satisfactory. The first evil-
dence of toxicity was vomiting or regurgitation of feedings, which appeared from
two to nine days after the start of treatment, with an average onset at four
days of age. Refusal to suck followed shortly. Respiratory distress, manifested
by irregular, rapid respirations, appeared within a few hours, followed by
abdominal distention, periods of cyanosis and passage of loose, green stools.
By twenty-four hours after the onset of symptoms these infants were seriously
ill. Progression of symptoms continued rapidly, with the appearance of flac-
cidity, ashen color and a drop in temperature during the next twelve hours.
Death usually occurred late in the fifth day of life. Fifty-eight per cent of the
babies who survived ran a similar course, recovering twenty-four to thirty-six
hours after the chloramphenicol was stopped. These infants appeared normal
at the time of discharge.
Of the 126 infants studied, blood cultures were taken on admission to the
nursery in 99, and again at death in 27. In no case was there any agreement
between the admission and terminal blood cultures. The pathological findings
at autopsy correlated with the organism recovered from the blood culture in only
1 case. This infant had a negative blood culture on admission to the nursery.
Escherichia coli was recovered from the terminal culture. He received no treat-
ment, becoming sick on the fifth day and dying three days later. Autoposy re-
vealed subarachnoid hemorrhage and meningitis.
Cultures of the gastric contents were taken on admission to the nursery in 89
infants. Thirty-nine of the cultures showed no growth. From the remaining
cultures, the following organisms were recovered: Staphylococcus albus, 17;
Bacillis subtilis, 12; Esch. coli, 6; coliform organisms, 10; gamma-hemolytic
streptococcus, 5; beta-hemolytic streptococcus, 3; Staph. aureus, 1; and diph-
theroids, 1. There was no correlation between the organisms recovered and the
clinical course of the infants. Random throat, urine and stool cultures were
equally nonspecific.
Blood chemical studies were done in some of the infants. All the infants studied
had an elevated non-protein nitrogen. As their condition deteriorated, the serum
carbon dioxide fell, and the serum potassium rose. Spinal-fluid chemical findings
in 2 of the infants were normal. White-cell counts ranged from 6000 to 30,000.
Autopsies were done on 34 infants, or 68 per cent of the deaths. Gross findings
were not remarkable in 25 of them, the cause of death being obscure. Of the
remainder 2 had bronchopneumonia, 5 had cerebal hemorrhage, and 2 died after
surgical correction of a tracheoesophageal fistula and a duodenal stenosis. Micro-
scopical findings will be reported in detail in a later paper.
Chloramphenicol blood levels were obtained in 2 of the infants. The levels
were determined by testing for aromatic nitro compounds after the method of
PAGENO="0512"
4802 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Glazko et al, (1, 2) which includes both the active and the inactive metabolites
of chloramphenicol. Figure 2 shows the levels in the babies. Both infants died
within four hours of the last blood level indicated. Autopsy showed intraventricu-
lar hemorrhage in baby E. No autopsy was done on baby J.
WUOLE-TIT.OOD LEVZLS
OF TOTAL NITRO COMPOUNDS
inicrogrn./ml.
I8O~
IBABYC
170r ~ ~
`60r
/
14O~
`4
1~~'*
I'
~rL0RAMPH~1C01~
0* ~ *.+-,.~--~4 2 +3 444
AGE
days
FIGURE 2.-Chloramphenicol Blood Levels.
Although the groups were small, there was no increase in mortality in infants
who received 140 to 165 mg. of cliloramphenicol per kilogram of body weight as
compared to those given 110 to 140 mg. per kilogram per day.
DISCUSSION
Physiologic studies have shown that liver and kidney functions are poor in the
premature infant as compared to the adult. Potter and Thierstein (3) found his-
tologically immature kidneys in almost all premature infants weighing 2000 mg.
or less. The volume of urine excreted is small, and the ability to concentrate it is
poor. Glomerular filtration, as measured by urea and mum clearance, and tubu-
lar excretion, as measured by iodopyracet compound and para-amino-hippurate
excretion, are markedly reduced. (4-6) Deficiency in the glucuronide conjugation
of bilirubin in the premature liver has been well established. (7-9) This deficiency
is thought to be due to a lack of conjugating enzyme. (10) In adults, Glazko and
his associates (11) demonstrated that chloramphenicol is detoxified in the liver
and excreted by the kidney. They found that detoxification is mainly by glucuro-
nide conjugation. They were able to recover 90 per cent of a given dose from the
urine of adults. (12) The bulk of the excreted drug was in the form of an inactive
glucuronide conjugate. Less than 10 per `~ent was excreted unchanged. Renal
plasma-clearance studies in adults suggest that the active form is filtered by the
glomerulus, and the inactive form is excreted by the tubules.
The toxicity of chloramphenicol has been extensively studied in animals. Smith
et aL (13) found that the LD50 for chloramphenicol given by mouth to adult mice
was 245 mg. per kilogram of body weight. Smaller doses caused tremors and pros-
tration followed by recovery. They also found that dogs given chloramphenicol
intravenously responded with a fall in blood pressure. With the use of high doses,
the bloodpressure fall was followed by respiratory failure and death.
Several reports in the European literature describe fatal circulatory collapse
in patients with typhoid fever treated with chloramphenicol, the shocklike state
appearing three to five days after the start of medication. (14-18)
Norz.-Numbered references at end of article.
PAGENO="0513"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4803
Sutherland and his co-workers (19, 20) recently reported 5 cases of fatal cir-
culatory collapse in newborn and premature infants that they believed to be
due to chioramphenicol toxicity. (19, 20) Their findings clinically and at autopsy
were similar to our findings. They postulated that the high blood levels demon-
strated were due to poor absorption, poor excretion or failure of conjugation.
Porn and Smith (21) reported prolonged blood levels in the newborn and the
premature infant after a single dose of chioramphenicol.
SUMMARY AND CONCLUSIONS
Premature babies delivered after rupture of the fetal membranes for twenty-
four hours or longer were assigned to one of four treatment groups. Group 1 re-
ceived no antibiotic, Group 2 received chloramphenicol alone, Group 3 received
penicillin and streptomycin, and Group 4 received all three. The mortality of the
group treated with penicillin and streptomycin was the same as that of the un-
treated group, but a higher number of the treated babies had gastrointestinal
symptoms.
The mortality rates of the two groups given chloramphenicol were significantly
higher than those of the other two groups.
The babies receiving chloramphenicoi followed a typical clinical course. Gastro-
intestinal symptoms appeared first, followed by circulatory collapse and death.
Blood levels of chloramphenicol showed a continuous rise. Removal of the drug
stopped the progession of symptoms. Recovery left no sequelae.
Since the administration of chioramphenicol was the only factor common to
the two groups having the high mortality, and the absence of chioramphenicol
the only factor common to the two groups with the low mortality, chlorampheni-
col in the dosage used must have been responsible for the increase in mortality
observed. Poor liver function, especially in the glucuronide conjugation system,
as well as decreased kidney function, allowed normally safe doses to accumulate
to toxic levels. This toxicity manifested itself by a characteristic picture of cir-
culatory collapse.
If toxicity is partially due to failure of glucuronide conjugation, other drugs
using this pathway of metabolism should be evaluated for use in the premature
infant.
No benefit to the infants from administration of penicillin or streptomycin
could be demonstrated. Since there were more symptoms in the group treated
with penicillin and streptomycin than in the non-treated group, these drugs may
not be harmless. Therefore, the use of prophylactic antibiotics has been discon-
tinued in this nursery.
We are indebted to the Pediatric Attending and House Staff of the Los Angeles
County Hospital for help with this study, to Dr. Frederick Moore, who prepared
the statistical analysis, to Drs. Charles F. Weiss and A. J. Glazko, Parke, Davis
and Company, who did the assays on blood levels, and to Mary Finley, R.N., and
the nursing personnel of the Premature Center.
REFERENCES
1. Glazko, A. J., Wolf, L. M., and Dill, W. A. Biochemical studies on chioram-
phenicol (Chloromycetin) I Colorimetric methods for determination of chloram-
phenicol and related nitro compounds Arch. Biochem. 23 :411-418, 1949.
2. Glazko, A. J. Personal communication.
3 Potter, E. L., and Thierstein, S. Glomerular development in kidney, as index
of fetal maturity J. Pediat. 22: 695-706, 1943.
4. McCance, R. A. Renal physiology in infancy. Am. J. Med. 9:229-241, 1950.
~. Barnett, H. L. Kidney function in young infants Pediatrics 5 :171-179, 1950.
6. Barnett, H. L., and Vesterdal, I. Physiologic and clinical significance of im-
maturity of kidney function in young infants. J. Pediat. 42:99-119, 1953
7. Lathe, G. H., and Walker, M. Synthesis of bilirubin glucuronide in animal
and human liver Biochem. J. 70:705-712, 1958.
S. Billing, B. H., Cole, P. C., and Lathe, G. H. Excretion of bilirubin as di-
glucuronide giving direct van den Bergh reactions Biochem. J. 65 :774-~784, 1957.
9. Schmid, R. Direct-reacting bilirubin, bilirubin glucuronide, in serum, bile,
and urine. $cience 124:76 1956.
10. Driscoll, S. G., and Hsia, D. Y.-Y. Development of enzyme systems during
early infancy Pediatrics 22 (4) :785-845, 1958.
11. Glazko, A.. J., Dill, W. A., and Rebstock M. C. Biochemical studies on chlor-
amphenicol (Chlormycetin). III. Isolation and identification of metabolic prod-
ucts in urine J. Biol. Uhem. 183 :679-691, 1950.
81-280-69-pt. ll-33
PAGENO="0514"
4804 COMPETITIVE PROBLEMS IN THE DRUG ~DUSTRY
12. Glazko. A. J., Wolf. L. M. Dill, W. A. and Brattan A. C. Jr. Biochemical
studies on chloramphenicol (Ohloromycctin) : tissue distribution and excretion
studies J. Pharmacol. ci E3Jper. Therap. 96 :445-459 1949.
13. Smith, R. M., Joslyn, D. A., and Gruhzit, 0. M. Chioromycetin: biological
studies. J. Bact. 55 :425-448 1948.
14. Stephens, P. R. Unsuccessful treatment of typhoid fever with chiorampheni-
col Lancet 1 :731, 1950.
15. Patel, J. C., Banker, D. D., and Modi, C. J. Ohioramphenicol in typhoid
fever; preliminary report of clinical trial in 6 cases. Brit. Al. J. 2 :908, 1949.
16. Farinaud, M. E., and Portes, L. La chioromycetine a doses progressive dans
le traitement des fievres typhoides a forme hypertoxique. Presse med. 59:3, 1951.
17. Izar, G. Collasso acuto di circolo da cloroamfenicolo. Riforma med. 64:1237-
1240, 1950.
18. Chatterjee, P. K., and Roy, B. B. Vasomotor collapse after chioramphenicol.
Brit. 211. J. 2:1334, 1950.
19. Sutherland, J. M. Fatal cardiovascular collapse in infants receiving large
amounts of chioramphenicol. J. Dis. Child. 97:761-767, 1959.
20. Sutherland, J. M., et al. Toxicity of chloramphenicol for newborn infant.
Presented at twenty-ninth annual meeting of Society for Pediatric Research,
Buck Hill Falls, Pennsylvania, May 8 and 9, 1959.
21. Dorn, A., and Smith, M. Blood levels of palmitate ester of chioramphenicol
in infants and children. Presented at twenty-ninth annual meeting, Society for
Pediatric Research, Buck Hill Falls, Pennsylvania, May 8 and 9, 1959.
APPENDIX V
{From American Journal of Diseases of Children, vol. 101, February 1961, pp. 140-148]
SAFE AND EFFECTIVE CHLORAMPHENICOL DOSAGES FOR PEEMATUItE INFANTS
(By Joan B. Hodgman, M.D. and Lafayette E. Burns, M.D., Los Angeles)
Infections are a significant cause of death in premature infants. Arey and
Dent(1) reported, in 1953, a survey of 102 neonatal deaths of which 84 were pre-
mature. They listed infection as the major cause of death in 13 (15.4%) of the
prematures. Six years later Branton, (2) in a report of 176 consecutive newborn
deaths, of which 136 were prematures, attributed death to infection in 20
(14.7%) of the prematures. He reported gram-negative coliform bacilli in 5 of 6
positive blood cultures. Infection also plays a significant role in the mortality at
the Premature Center of Los Angeles County Hospital, which cares for over 1,200
premature infants yearly. The main organisms cultured from infections have been
gram-negative coliform bacilli,' particularly E. coil and Klebsiella aerogenes
group. Studies have indicated that these organisms are most consistently sensi-
tive to chloramphenicol. The toxicity of chioramphenicol to premature infants in
doses over 100 mg/kg is well documented(3-6). Reported studies have correlated
this toxicity with high blood levels of chloramphenicol. Prophylaxis with chioram-
phenicol as well as other antibiotics has been discontinued at the Premature
Center, since in a controlled study they did not lower the mortality rate (3).
Chloramphenicol would still be useful for the treatment of infected prematures
if a safe dosage schedule were established.
This paper is a report of studies of blood-level responses to intramuscular and
intravenous chloramphenicol made to determine whether lower doses would give
therapeutic blood levels without toxicity.
METHOD
Premature infants of varying weights and ages were given microcrystalline or
the succinate ester of chloramphenicol intramuscularly and intravenously, ac-
cording to planned dosage schedules. Blood levels of total nitro compounds were
Accepted for publication Oct. 27, 1960.
1200 N. State St. (33).
Supported by a grant from Parke, Davis & Company, Detroit.
From the Premature Center of the Los Angeles County Hospital and the Department of
Pediatrics, University of Southern California School of Medicine, Assistant Professor of
Pediatrics (Dr. Hodgman) and Instructor in Pediatrics (Dr. Burns).
N0TE.-Numbered references at end of article.
PAGENO="0515"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4805
determined by analyzing capillary blood according to the method of Glazko(7).*
This method measures both active and inactive metabolites of chioramphenicol as
total nitro compounds.
Timed urine specimens were collected by plastic bags from some of the in-
fants. These were analyzed for chioramphenicol content by microbiologic assay
against Shigella sonnei (8), as well as by chemical determination for total nitro
compounds.
Microchemical analyses for serum sugar, BUN, and potassium levels were
performed at the start of treatment, at 24 hours, and at 96 hours in the group of
infants receiving chloramphenicol 25 mg/kg/day. Serum bilirubin determinations
were done on any infant who developed jaundice.
MICROCRYSTALLINE CHLORAMPHENICOLt
Figure 1 shows the average blood level of total nitro compounds obtained in
premature infants 1 to 6 days old given microcrystalline chioramphenicol, 10
mg/kg every 12 hours intramuscularly. The average level is low and probably
inadequate for 12 to 24 hours after the start of treatment. From then on, it
gradually rises as the nitro compounds accumulate. A tendency for the level to
plateau may be noted during the fourth~ day of treatment. Of the 13 babies
studied, 11 reached therapeutic levels of 10-20~g/cc(9), and showed no toxic
symptoms. One infant failed to reach a therapeutic blood level. One infant ac-
cumulated nitro compounds to high levels and developed symptoms of chioram-
phenicol toxicity.
This infant was 3 days old at the start of treatment and weighed 1,980 gm. On
the third day of treatment, he was noted to be voiding very little. During the next
24 hours he became limp and lethargic, at which time his blood level of nitro com-
pounds had risen to 78~g/cc. Following the omission of one dose, the blood level
fell to 52, and his symptoms became less severe. Treatment was continued for 3
more days, during which time he was anorexic and somewhat listless. His
symptoms disappeared 3 days after treatment was stopped.
Figure 1 also shows the average blood level of nitro compounds in 5 premature
infants 12 to 67 days old on the same dosage schedule, 10 mg/kg every 12 hours
intramuscularly. Of the 5 infants, 4 had been tested previously in the 1- to 6-day-
old group. The absence of accumulation in this group is clearly demonstrated.
None of these infants reached adequate blood levels on this dosage.
* AGE 16 DAYS / \
~,, ~.._..RANGE. / \
c~~O WEIGHTS / \
1001- 1501- 2001-
D ~n-* `500 2000 2500
~i 2 3 8 /
/
/
`.
o~
/
P-i /
Z4g- /
._J I
/
*~35~-.
L/~J'~..T
~V-' :...
~ /..~
0
/ U1CKA~
~
TICK N
~.
E
-S--.
~_AVERAGE 5 PREMATURES AGE 2-67 DAYS
~.L. - - RANGE
WEIGHTS: 1001-1500 1501-2000 2001-2500
2 3
.~
~` ,~ *zo~. so io so. ~ io~ so 90.'r ~ *~ ~ ~ .7. ~.
TIME INHOURS
FIGURE 1.-Blood levels during treatment with microcrystalline chiorampheni-
col iO mg/kg every 12 hours i.m.
*Analyses were done by the Parke, Davis & Company Laboratories.
tCbloromycetin Intramuscular.
PAGENO="0516"
4806 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
The average blood level for 15 premature infants, 1 to 2 days old, given a
single injection of microcrystalline chloramphenicol, 50 mg/kg intramuscularly,
is shown in Fgure 2. Adequate blood levels were attained within 7 hours in all
but 2 infants. The peak was reached at the 23-hour sample, followed by a grad-
ual fall. The half-life of the administered dose was 28 to 44 hours as compared
to a half-life in adults of 15 to 24 hours. (10) Two premature infants 8 and
9 days old were given the same dose. The blood levels as shown in Figure 2 were
lower than in the younger babies, and the fall in level was more rapid. The
birth weights of the infants tested are grouped on the charts. There was no
correlation between birth weights and blood levels.
Further studies were carried out on week-long dosage schedules. Premature
infants, ages 1 to 4 days. were given microcrystalline chloramphenicol, 50 mg/kg
intramuscularly, every 48 hours. Of 12 infants tested, 8 had adequate levels but
with marked fluctuations. Only 1 of 4 prematures, ages 13 to 27 days, similarly
tested, had adequate levels. Using a schedule of 25 mg/kg given once daily, all
of 12 infants tested had adequate levels in the 1- to 6-day-old group, but only 2
of 8 in the 14- to 23-day-old group. Given 50 mg/kg once daily to premature in-
fants 9 to 36 days old produced adequate levels in all 8 infants tested without
toxic symptoms.
FIGURE 2.-Blood levels following a single dose of microcrystalline chloram-
phenicol 50 mg/kg I.l~J.
CHLORAMPHENICOL SODIUM SUCCINATE~
Chloramphenicol sodium succinate is a recently introduced ester of chloram-
phenicol which is highly water soluble `and hence more readily absorbed than the
micronized form. (11) Figure 3 shows the average blood level of nitro com-
.t~
do
>~
~:i
00,
3x.
S_i ~
I.J
S_i
......../~/ERAGE 15 PREMATURES AGE 1-2 DAYS
- ~RANGE
wEIGHTS: 001-1500 1501-2000 2001-2500
1~~ - -i 5
/ S
/
*/
4
.3
.3
_8 DAY PREMATURE WEIGHT 560 oms
...~9 DAY PREMATURE WEIGHT 350 ~ms.
IN
`~s~ .; ~
7//I//I
////4~/T~~ ~ 7/
.19 ~Q ~Q 3~ 49 TO 4~) 90 0 20 30 ~0 50 40 70 CV 90
TIME IN HOURS
AVERAGE.15 PREMATURES.I~4 DAYS
Sr~~t RANGE ~5
";:.wEIGHTS:Ioo-500 1501-2000 200F2500~
°~r1 ~ 2 6 * 7
.45
-siil \~--.
* "~ ..~._.AVERAGE 5 PREMATURES 10-19 DAYS
~.. RANGE
~. WEIGHTS 1001-1500 l50I~ 2000 2001-2500
0 4 I
i-I \
TIME' IN HOURS
FIGURE 3.-Blood levels following a single dose of chloramphenicol sodium sue-
cinate 50 mg/kg I.M.
~Ch1oromycetin Succinate.
PAGENO="0517"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4807
pounds following a single 50 mg/kg intramuscular injection of the succinate
ester in 15 prematures 1 to 4 days old. Peak levels were obtained within 3 hours,
clearly showing rapid absorption. Adequate levels were present for over 48 hours,
but fell more rapidly, the half-life being 24 hours, as compared with a half-life of
28-44 hours with the microcrystalline form. Levels fall even more rapidly in
older children, the half-life being 4 hours in 5-year-olds given the succinate ester.
(1,10) Figure 3 shows the average blood level found in 5 prematures, 10 to 19
days old, given the same dose. Absorption was again rapid, and here, too, excre-
tion was more rapid than with the younger prematures. The half-life was 14
hours with adequate levels maintained for 12 to 18 hours.
Eight premature infants, 2 to 4 days old, given chloramphenicol sodium suc-
cinate, 25 mg/kg intramuscularly once daily, after an initial dose of 50 mg/kg, had
adequate levels for the week they were treated. One infant accumulated nitro
compounds on this schedule, the blood level on the third day reaching 5G~g/cc.
At this time the infant's abdomen was distended; he had liquid stools and grunt-
ing respirations. The infant recovered, and the blood levels dropped without
stopping the drug. Although the symptoms disappeared while treatment was
continued, they may represent a toxic reaction.
Three prematures, 12 to 22 days old, had inadequate levels when given 25
mg/kg/day intramuscularly. Five prematures, ages 10 to 18 days, had good levels
on 50 mg/kg/day without toxic symptoms. Again, no correlation between birth
weights and blood levels was found.
Chloramphenicol sodium succinate given intravenously to premature infants
was also slowly excreted, as shown in Figure 4. Three 1-day-old infants were
given 25 mg/kg in 50 cc. 5% glucose in water over a 5-hour period. Blood levels
remained in the therapeutic range for 18 to 24 hours following completion of the
infusion; the half-life was 15 to 22 hours. Two infants, 13 and 23 days old, were
given 50 mg/kg over a 3-hour period. Again, adequate levels persisted for the
succeeding 12 and 21 hours, with a half-life of 8 and 15 hours, respectively. One
infant developed ashen gray pallor and lethargy within 1 hour after starting the
infusion, when his blood level was 72~g/cc., The symptoms disappeared in the
next 3 hours coincident with the fall in blood level to 53pg/cc.
: ~ ~ ~)5O m9m/k(~ In 50cc of 50~1o ~1L5~ i~
cc ~ AGC I DAY 25 rngm/Icg ~n 50 cc of 57* 913ic03e ~n H~
z -~I.V.RUNNING
I ~ .. .1..., ~ ~ ~ i h ~ .
0 a ~ ~ io 11. ~ 20 22 2+ 2~ 28 30 Ia 44 46 48 50
TIME IN HOURS
FIGURE 4.-Blood levels following I.V. administration of chioramphenicol sodium
succinate.
PAGENO="0518"
4808 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
URINE STUDIES
Twenty-four-hour excretion studies of microcrystalline chioramphenicol were
made. In a study of 19 premature infants under 7 days old, an average of 20%
of the daily dose was recovered (range 5%-52%). A higher average, 33%, was
recovered from 5 infants over 10 days old (range 1.4%-50%). In similar studies
on adults Glazko (12) was able to recover 90% of the daily dose, of which 5%-
10% was excreted as the active form. In our studies on 8 premature infants under
7 (lays old, 7.7% of a dose was excreted in the active form, in older prematures,
0.2%.
BLOOD CHEMISTRIES
Blood chemistry determinations taken at the start of treatment, 24 hours later,
and at 96 hours, w-ere studied in 32 1- to 2-day-old premature infants on chioram-
phenicol injections of 25 mg/kg daily. BUN levels ranged from 8 to 30 mg%, ex-
cept for 3 infants w-hose levels were 37, 53, and 89 mg%. The 2 infants with levels
of 37 and 53 mg% had the low-est levels of nitro compounds in their respective
test groups. The remaining infant, whose blood urea nitrogen level at the start
of treatment was 89 mg% and at 24 hours was 85 mg%, gradually accumulated
nitro compound levels to 56~ig/cc at 72 hours.
This infant, who weighed 1,162 gm. at birth, was 4 days old and in apparently
good condition at the start of treatment with 25 mg/kg/day of microcrystalline
chloramphenicol. Except for mild dehydration, his clinical condition remained
good until the fifth day of treatment when he developed lethargy, respiratory
distress, and abdominal distention. The chloramphenicol was discontinued, but
the baby's symptoms progressed until death 48 hours later. A. white blood cell
count on the day before death was 29,500, with 74 segmented forms, 5 band forms,
and 21 lymphocytes. A blood culture before death grew E. coli, sensitive only to
polymyxin. Autopsy revealed pulmonary hemorrhage.
With the exception of the infant mentioned above, there was no consistent
correlation between the BUN and nitro compound levels. Of 8 infants who had
BUN levels betw-een 25 and 30 mg%, 7 had nitro compound levels similar to
others in their test groups. BUN levels below 10 mg% were not accompanied by
low nitro compound levels.
Serum potassium levels were under 7 mEq/L in all except 3 infants. Two of
these had low blood nitro compounds levels. The third w-as the infant mentioned
above with elevated BUN levels, who died.
Blood sugar levels ranged between 26 and 107 mg%, except for the infant
described above w-hose level was 144 mg% initially, and 126 mg% at 24 hours.
There was no correlation between serum bilirubin levels and levels of nitro
compounds in 30 infants tested. For example, one infant had high blood nitro
compound levels and a bilirubin level of 17 mg%. Another had a bilirubin of
16.8 mg% and low nitro compound levels. Infants receiving chlorampbenicol
had no increase in incidence of jaundice.
MORTALITY
Tests were performed on 126 premature infants. Six infants died during or
after treatment. In general, infants in good condition were selected for study,
making the mortality rate in this group meaningless. The clinical course of one
of the infants who died is outlined above. A brief résumé of the histories of
the remaining 5 infants follows:
Baby, birth w-eight 2,180 gm., demonstrated webbing of the neck and minor
skeletal anomalies, but was in good general condition at the start of treatment
with 50 mg/kg/48 hours of microcrystalline chioramphenicol. At 10 days of age,
following 7 days of treatment, the infant died suddenly. Autopsy revealed
infantile coarctation of the aorta. Blood levels of nitro compounds were con-
sistently low.
Baby, birth weight 1.280 gm., died at 2 days of age after 1 injection of 50
mg/kg. Blood level at 24 hours was 40~mg/cc. Autopsy revealed intraventricular
cerebral hemorrhage.
Baby, birth weight 1,920 gm. was in good condition at 4 days of age when
treatment with mg/kg/48 hours of microcrystalline chloramphenicOl w-as started.
The baby developed lethargy, cyanosis, abdominal distention, and apnea at the
start of treatment. Blood and spinal fluid cultures grew an organism of the
Klebsiella-Aerobacter group, sensitive to chioramphenicol. Treatment was con-
tinued `but the infant died at 6 days. Autopsy confirmed the diagnosis of puru-
lent meningitis.
PAGENO="0519"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4809
Baby, birth weight 1,420 gm., was started on treatment of 50 mg/kg/48 hours
of microcrystalline chioramphenicol at 4 days of age. Forty-eight hours later,
the infant developed vomoting, followed by loose yellow stools, lethargy, ashen
gray pallor, apnea, and death at 8 days of age. Blood levels reached a peak at
5~g/cc 24 hours following the start of the treatment, dropped to 40kg/cc at 48
hours when symptoms appeared, fellow to 25jig/cc at 72 hours, and rose again to
5Qag/cc at 96 hours. Death occurred 14 hours after the last blood level noted.
Blood culture drawn at death was sterile. No autopsy was permitted.
Baby, birth weight 1,990 gm., was started on treatment of 50 mg/kg/48 hours
of microcrystalline chloramphenicol on the first day of life. Respiratory distress
was present from birth. Tremors appeared on the third day, followed by dis-
tention of the abdomen, lethargy, ashen gray pallor, apnea, and death on the
sixth day. Blood levels were 41kg/cc at 24 hours, and 38pg/cc at 48 hours. Blood
culture drawn at death was sterile. No autopsy was permitted.
COMMENT
The normal metabolic pathway for chloramphenicol is absorption, conjuga-
tion with glucuronic acid in the liver, and excretion by the kidney tubules. (12)
Some active chloramphenicol is removed from the circulation by glomerular
filtration. (13) Aecumulation of chloramphenicol in the premature infant must be
due to differences in one or more of these factors.
Single-dose studies of the microcrystalline form of chloramphenicol clearly
demonstrate its slow absorption, the peak level not being attained for 24 hours.
Considering the low solubility of this form of the drug, a depot effect could be
anticipated. Single-dose studies of chloramphenicol sodium succinate showed
rapid absorption with a peak within 4 hours, but also gave prolonged levels with
half-lives 2 to 3 times those of adults. Half-lives of the succinate ester given intra-
venously were much longer than those reported for adults, eliminating sldw
absorption as the explanation for the prolonged levels. Decreased kidney func-
tion in the premature is well established. (14-16). The glucuronide conjugated, or
inactive, chioramphenicol is excreted by the renal tubules while the active form
is filtered by the glomerules. Tubular excretion is quantitatively the most im-
portant excretory pathway, as 90% of the chloramphenicol in the urine is in the
conjugated form in both the adult and premature. (12). However, the adult ex-
cretes 90% of a daily dose, in contrast to 1.4%-52% in the premature. Therefore,
a decrease in tubular excretion in the premafture must be one of the factors ac-
counting for prolongation of blood levels~
A deficiency in conjugation by the liver must also be present to explain the
prolonged levels of active chloramphenicol. If hepatic conjugation were normal
with poor kidney function, only the inactive form would accumulate. This is seen
clinically in anuric adults, where a renal defect only is present, the conjugated
form alone accumulates to high levels and patients exhibit no toxicity. (17) In
the premature, however, only 35% of the circulating ehloramphenicol is in the in-
active form. (5,10) A deficiency of the glucuronidase in the liver of the newborn
has been documented. (18,19). The accumulation of active chloraphenicol in
the premature can be explained by this deficiency. The finding that blood levels
plateau on the third and fourth day, plus the correlation of levels with chrono-
logical age rather than birth weight, lend support to the idea that enzymatic
deficiencies, which improve as the infant matures, are responsible for the pro-
longed blood levels.
As chloramphenicol and bilirubin apparently follow the same metabolic path-
w-ay, some correlation between blood levels of bilirubin and chloramphenicol
could be expected. No correlation was demonstrated. In a previous study, there
was no increase in the incidence of jaundice among premature infants receiv-
ing chloramphenicol compared with a similar group not receiving it. (3) In the
same study, autopsies on infants who died with chloramphenicol toxicity did not
reveal kernicterus. V
There was no correlation between the levels V of nitro compounds and a BUN
of 53 mg% or less. One infant with a BUN of 89 mg% at the start of treatment
accumulated nitro compounds, as did another V infant with a low renal output
for 24 hours. Infants with a BUN above 60 mg%, or other signs of defective
renal function should be treated cautiously with a reduced dosage.
Premature infants were tested in all weight groups over 1,000 grams. No
correlation between birth weight and blood levels was found. A definite correla-
tion between age and blood levels was demonstrated. Tendency to accumulate
nitro compounds in the blood stream was most marked during the first 4 days
PAGENO="0520"
4810 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY
of life. None of the infants tested after 7 days of age showed accumulation of
nitro compounds in the blood. The majority of these older infants failed to
maintain levels in the therapeutic range on 25 mg/kg/day, whereas doses of
50 mg/kg/day produced therapeutic levels without toxic symptoms. Premature
infants over 1 week of age can be treated with 1 daily dose of 50 mg/kg of
chioramphenicol with reasonable safety.
The young infants also showed greater variability of levels on a given dosage
than did prematures over 7 days of age. This is well demonstrated in Figure
1, representing 1-4-day-old infants given microcrystalline chloramphenicol, 10
mg/kg every 12 hours. On this dose, one infant accumulated nitro compounds
to toxic levels, while another failed to reach therapeutic levels.
The young infants tested on low doses of microcrystalline chloramphenicol
given twice daily accumulated nitro compounds more rapidly than when a
larger dose was given once a day; Since adequate levels are maintained for
24 hours after a single injection of both types of chloramphenicol tested, the
total dose should be given once daily.
The symptoms of chloramphenicol toxicity in the premature infant have been
reported by several authors. (3-6) The time necessary for symptoms to appear
depends on the dose used. When 125-165 mg/kg/day were given intramuscularly,
the earliest symptoms appeared from 48 to 96 hours after the start of treatment
and involved the gastrointestinal tract. (3) The infants refused to nurse, began
to regurgitate formula, their abdomens became distended, and they developed
loose green stools. Within 24 hours after the appearance of toxic symptoms, they
became ashen gray, lethargic, and developed rapid, shallow respirations. Death,
when it occurred, followed within an additional 24 hours. The infants who
recovered had no demonstrable sequelae on discharge from the nursery.
Of the 126 infants tested during this study, 6 developed symptoms similar to
those described. One infant was receiving intravenous medication, and the
correlation between symptoms and blood levels seems clear cut. Lethargy and
grayish pallor appeared within an hour of starting the intravenous medication,
when the blood level was 72pg/cc. and the symptoms disappeared rapidly
coincident with a fall in level to 53~g/cc. The accumulation of nitro compounds
in this baby was caused by too rapid an intravenous infusion, and the symptoms
could have been prevented by slower administration. This is a precaution that
must be carefully observed when giving chloramphenicol intravenously.
Two infants, both under 4 days of age, developed symptoms of chlorampheni-
col toxicity on intramuscular medication, but recovered. In both of these infants
the symptoms appeared on the third day of treatment, when their blood levels
were over 50j~g/cc. and the symptoms disappeared as the levels fell. In the
3 surviving infants, toxic symptoms seemed to be correlated directly with
elevation in blood levels of nitro compounds. The blood levels varied from
53jig/cc to 73~tg/cc at the time symptoms appeared.
Three infants died while receiving chioramphenicol, with symptoms similar to
those described above. The symptomatology of septicemia is very similar to that
of chloramphenicol toxicity. One case had abnormal blood chemistries at the start
of treatment, and a chloramphenicol-resistant organism was grown from blood
culture taken before death. Symptoms appeared after 5 days of treatment, when
the infant was 9 days old. This death was probably due to infection, but may
represent a toxic reaction to chioramphenicol. Autopsies were not performed on
the remaining 2 infants, and blood cultures taken at the time of death were
sterile. The levels of chloramphenicol in these infants were never over 54kg/cc.
A definite cause of death could not be determined on the basis of the clinical
findings. Unexplained deaths, particularly without autopsy, are too common on
a premature service to definitely assign these deaths to chioramphenicol toxicity;
however, it is possible that these 3 infants represent a toxic reaction at relatively
low blood levels. It is perhaps important that these babies were under one
week of age at the start of treatment.
If chioramphenicol is used for young premature infants, it should be given in a
dosage of 25 mg/kg once daily. If toxic symptoms appear, the drug should be
discontinued immediately and blood levels determined where possible. Blood
levels can be determined by following the method of Glazko et al. (11) .~ The
determination requires 0.2 cc. of whole blood, which can be obtained from a heel
puncture. The method is a relatively simple colorimetric comparison, which could
be performed by the average hospital laboratory.
§Detailed procedure available from Parke, Davis & Company.
PAGENO="0521"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4811
Of the 5 infants exhibiting toxicity on intramuscular medication, 4 were given
microcrystalline chioramphenicol. This preparation has the disadvantage of slow
absorption, resulting in low initial blood levels and greater tendency to accumula-
tion with repeated dosage. In tratment of the premature infant, the more rapidly
absorbed chloramphenicol sodium succinate would be preferred.
SUMMARY
Recent investigations have documented chioramphenicol toxicity in premature
infants given doses over 100 mg/kg/day. Toxicity was shown to have a correlation
with elevated blood levels of chloramphenicol. In order to establish whether lower
doses would result in therapeutic levels without toxicity, we determined blood
nitro compounds in premature infants after intramuscular and intravenous
administration of 20 to 50mg/kg/day.
Initial levels were lower and toxic reactions occurred more commonly with
microcrystalline chloramphenicol than with the sodium succinate ester. The
latter form should be preferred for treatment of the premature infant. A tendency
to accumulate chloramphenicol in the blood was observed only in the young in-
fants, regardless of birth weight.
Two infants under 4 days of age accumulated blood levels over 5Opg/cc and
developed toxic symptoms after daily dOses of 25 mg/kg intramuscularly. Two
infants died with blood levels below50~tg/cc without clinical explanation of their
death. Two of the infants with toxic symptoms had clinical or laboratory evidence
of reduced renal function. Such infants should be treated cautiously with a
smaller dose.
Premature infants 7 days of age or less maintained blood levels in the thera-
peutic range when given 25 mg/kg of chioramphenicol sodium succinate intra-
muscularly once daily. Premature infants over 7 days of age failed to maintain
thereapeutic levels on this dose, but developed adequate levels without toxic
symptoms when given 50 mg/kg intramuscularly once daily of the same drug.
The same doses of chloramphenicol sodium succinate in each age group, given
intravenously, gave adequate levels for 24 hours. This form of the drug must
be infused slowly over a period of 3 to 5 hours to prevent accumulation of
chioramphenicol to toxic levels.
All premature infants, especially those in the first week of life or with evi-
dence of reduced renal function, should be carefully watched for the development
of abdominal distention, lethargy, respiratory distress, and gray cyanosis. The
drug should be discontinued promptly if these symptoms appear.
We wish to thank Alonzo Beecher Oass, M.D., Chairman of the Newlnrn
Committee, for his help and encouragement.
We are indebted to Miss Maxine Wertman and Miss Leola Westover for tech-
nical help.
The cooperation of Mary Finley, R.N., Head Nurse, and the Nursing Staff of
the Premature Center was essential to the completion of this study.
REFERENCES
1. Arey, J. B., and Dent, J.: Causes of Fetal and Neonatal Death with Special
Reference to Pulmonary and Inflammatory Lesions, J. Pediat. 42:1-25 (Jan.)
1953.
2. Branton, L.: Neonatal Mortality with Special Reference to Infectious
Causes of Death, Am. J.M. Sc. 238 :760-771 (Dec.) 159.
3. Burns, L. E.; Hodgman, J. E, and Cass, A B.: Fatal Circulatory Collapse
in Premature Infants Receiving Chloramphenicol, New England J. Med.
261:1318-1321 (Dec.24) 1959.
4. Sutherland, J. M.: Fatal Cardiovascular Collapse of Infants Receiving
Large Amounts of Ohlorampehnicol, A.M.A. J. Dis. Child. 97:761-767 (June)
1959.
5. Sutherland, J. M.; Michael, A F; Giesel, R G.; Keller, W. H., and Beber,
B. A.: Toxicity of Ohloramphenicol for the Newborn Infant, presented at 2~ith
Annual Meeting of Society for Pediatric Research, Buck Hill Falls, Pa., May
8-9, 1959, A.M.A. J. Dis. Child. 98 :648-649 (Nov.) 1959.
6. Kent, S. P. and Widemann, G L.: Prophylactic Antibiotic Therapy in Infants
Born After Premature Rupture of Membranes, J.A.M.A. 171 :1199-1203 (Oct. 31)
1959.
PAGENO="0522"
4812 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
7. Glazko, A. J.; Wolf, L. NI., and Dill. W. A.: Biochemical Studies of Chior-
amphenicol. I. Colorimetric Methods for the Determination of Chioramphenicol
and Related Nitro Compounds, Arch. Biochem. 23 :411-418 (Oct.) 1949.
8. Joslyn, D. A., and Galbraith, NI.: A Turbimetric Method for the Assay of
Antibiotics, J. Bact. 59:711-716 (June) 1950.
9. Bliss, E., and Todd, H. P.: A Comparison of Eight Antibiotic Agents in
Vivo and in Vitro, J. Bact. 58:61-72 (July) 1949.
10. Weiss, 0. F.; Glazko, A. J., and Weston J. K.: Physiological Disposition
of Chloramphenicol in Newborn Infants, New England J. Med. 262 :787-794 (April
21) 1960.
11. Glazko, A. J.; Carnes, H. E.; Kazenko, A.; Wolf, L. NI., and Reutner, T. F:
Succinic Acid Esters of Chloramphenicol, in Antibiotics Annual, edited by H.
Welch and F. NIarti-Ibdflez, New York, Medical Encyclopedia, Inc., 1958, Vol. 5,
pp. 792-802.
12. Glazko, A. J.; Wolf. L. NI.; Dill, W. A., and Bratton, A. C., Jr.: Biochemical
Studies on Chloramphenicol. II. Tissue Distribution and Excretion Studies, J.
Pharmacol. & Exper. Therap. 96:445-459 (Aug.) 1949.
13. Glazko, A. J.; Dill, W. A., and Rebstock, NI. C.: Biochemical Studies on
Chloramphenicol (Chrioromycetin). III. Isolation and Identification of Metabolic
Products in Urine, J. Biol. Chem. 183 :679-691 (April) 1950.
14. Barnett, H. L.: Kidney Function in Young Infants. Pediatrics 5 :171-179
(Feb.) 1950.
15. Barnett, H. L., and Vesterd'al, I.: Physiologic and Clinical Significance of
Immaturity of Kidney Function in Young Infants, J. Pediat. 42:99-119 (Jan.)
1953.
16. MeCance, R. A.: Renal Physiology in Infancy, Am. J. Med. 9 :229-241
(Aug.) 1950.
17. Kunin, C. NI.; Glazko, A. J., and Finland, NI.: Persistence of Antibiotics
in Blood of Patients with Acute Renal Failure II. Chroramphenicol and Its
Metabolic Products in the Blood of Patients with Severe Renal Disease or
Hepatic Cirrhosis, J. Olin. Invest. 38:1498-1508 (Sept.) 1959.
18. Driscoll, S. G. and Hsia, D. Y-Y.: The Development of Enzyme Systems
During Early Infancy, Pediatrics (Supp.) 22:785-845 (Oct.) 1958.
19. Vest, NI.: Insufficient Glucuronide Formation in the Newborn and Its Re-
lationship to the Pathogenesis of Icterus Neonatorum, Arch. Dis. Childhood
33 :473-475 (Oct.) 1958.
EDITORIAL COMMENT
This report documents the considerable variability of chloramphenicol blood
levels achieved in individual prematures even when the intravenous or intra-
muscular route of administration is used. Observe that several less than week old
infants showed signs and symptoms of toxicity while receiving doses currently
recommended. Also note the frequent failure to achieve blood levels claimed to
be therapeutic when the "cautious" dose is used after the first week. The sus-
pected inability of newborns to absorb adequately the palmitate form of the
drug when given by mouth is not dealt with here.
APPENDIX VI
[From Annals New York- Academy of Sciences, 1967, pp. 488-498]
BAc~rEnIAL MENINGITI5*
(By Paul F. Wehrle. Allen W. Mathies, John NI. Leedom and Daniel Tyler,
Departments of Pediatrics and Medicine, University of Southern California
and the Communicable Disease Service, Los Angeles County General Hospital,
Los Angeles, Calif.)
INTRODUCTION
Bacterial infections of the central nervous system still constitute serious medi.
cal emergencies, despite the availability of numerous effective antimicrobial
agents. Death occurs in at least 10% of these patients, and serious sequellae are
frequently seen among those who survive. In spite of the serious nature of these
*Supported in part by the Hastings Foundation Fund National Institutes of Health
Grant 5 TO1-AI-00275 and Contract ~DA-49-l93-MD2874 from the U~S. Army Research
and Development Command, Office of the Surgeon General, Department of the Army.
PAGENO="0523"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4813
infections and the significant disability among many of those who survive, the
various therapeutic regimens proposed have not been evaluated as thoroughly
as is desirable.
Some of the problems that complicate analysis of the various therapeutic
routines advocated in the past are readily apparent. The incidence of bacterial
meningitis infections is not great, and the relative etiologic importance of par-
ticular bacterial species varies with the age group considered. Rates of bacterial
meningitis approach 1 :1000 live births during the neonatal period. The rates fall
rapidly during infancy and childhood. This progressive decline in age specific
rates continues until the fifth decade. Itthen rises slightly with the increase in
pneumococcal infections among older persons. Because of these low rates, rela-
tively few patients are available for study in any single hospital. In addition,
the diagnosis of these infections is often made in hospitals other than those pro-
viding definitive treatment. Referral for definitive treatment may be made after
some form of treatment has been initiated. This referral is usually to other hos-
pitals on the basis of age group, economic status, or other selective determinants.
These factors make the interpretation of experience within a single hospital,
unless carefully controlled, subject to serious errors. It is also obvious that
experience in different hospitals with different routines cannot be compared, yet
several attempts to do so have been made. As yet, no well controlled cooperative
study has been attempted, involving several large institutions, to evaluate the
management of this type of infection, although such an effort might yield useful
data. If such a study were contemplated, these and still other factors must be
properly controlled.
The severity of the illness and the progressive nature of the disease often intro-
duce additional variables with respect to supportive therapy. This support, de-
pendent upon experienced nursing and medical personnel, is necessary if the
patient is to survive long enough for an antimicrobial drug to have any benefit.
This situation is further complicated by a fixed and mystical belief that if one
antimicrobal agent is good, two must be better, and three even more efficacious,
despite evidence to the contrary. (1)
It is the purpose of this paper to examine some of the characteristics of bac-
terial meningitis and the factors important in survival. In addition, the results
of treatment with ampicillin alone and ampicillin plus chloramphenicol sup-
plemented by two days of streptomycin therapy will be presented.
If one examines the case fatality rates for a particular type of bacterial
meningitis on our service during successive years, it is interesting to note the
substantial variation in mortality. If one contrasts selected years, this varia-
tion is greater than expected by chance alone. As yet, we have no explanation for
these variations. This pattern is clearly illustrated by meningococcal infections
treated on our service during the past six years. as shown in Table 1. During this
time, Type B meningococci have been predominant, and approximately one-third
of the strains tested have been resistant to sulfadiazine (MIC»=10 mg/100
ml). (2)
NATURAL VARIATION IN CASE FATALITY RATES
TABLE 1.-MENINGOCOCCAL DISEASE, CASE FATALITY RATIOS BYYEAR, LOS ANGELES COUNTYGENERALHOSPITAL
Outcome of patient
Case fatality
Year of treatment Survived Died Total cases (percent)
1961 34 4 38 10.5
1962 64 6 70 8.6
1963 67 6 73 8.2
1964 85 14 99 `14.1
1965 88 3 91 `3.3
19662 86 6 92 6.5
Total 424 39 463 (8. 4)
1 X2=6.74; p2 months ol age, 15; unusual organisms, 15; error in treatment assignment, 9; en-
docarditis, mechanical defect. 6; total exclusions, 45 with 11 deaths.
Additional data from our most recent study of the treatment of meningitis
in patients older than 2 months of age are shown in Tables IV.2, IV.3, and IV.4.
Therapy consisted of ampicillin alone in an initial intravenous push dose of
50 mg. per kg., followed by 150 mg. per kg. per day in six divided push doses at 4-
hour intervals, and contrasted ampicillin alone with ampicillin plus two other
drugs. Alternate patients received therapy consisting of a combination of the
same dose of ampicillin plus chioramphenicol at 100 mg. per kg. per day, to a
maximum of 4 gm. each day for the total duration of therapy, and streptomycin
at 40 mg. per kg. per day (to a maximum of 2 gin.) for the initial 2 days of
treatment. Administration of chloramphenicol was delayed until 30 mm. after
ampicillin had been administered in an effort to avoid antibiotic interference.
As noted in Table IV.2, the response to ampicillin was excellent, with only five
deaths among 129 patients treated or an over-all mortality of 3.9 per cent. Mul-
tiple antibiotic treatment yielded 13 deaths among 111 patients, a mortality rate
of 11.7 percent. The difference is statistically significant (w2=5.33; p7 days)
Subdural effusion
Prolonged hospital stay (»=19 days)
Complications of therapy (rash, eosinophilia, phlebitis, etc.)
Hematological
27 20. 0 23
6 4.5 6
47 35.0 36
38 27. 6 30
0 0 3
21. 6
5.4
32.2
27. 0
2.7
TABLE 3.-TIME OF DEATH
AFTER INITIATION OF THERAPY BY TREATMENT GROUPS IN 2 SEPARATE
PATI ENTS WITH BACTERIAL MENINGITIS
SERIES OF
Source of data
Single drug Combination of drugs
Death Death
All Total All
»=48 hr. >48 hr. deaths cases »=48 hr. >48 hr. deaths
Total
cases
Lepper and Dowling (11)
Percent
9
69
4
31
Present report
Percent
4
66. 7
2
33. 3
3
8
11
14
27.2
72.8
100
4
9
13
124
30.8
69.2
100 --
PAGENO="0542"
4832 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
DISCUSSION
The data presented support the thesis that antibiotic interference or antago-
rdsm can be observed in a clinical situation. The interference of one antibiotic with
another may be expressed clinically in several ways, as illustrated in Table 4.
As previously mentioned, Lepper and Dowling (11) observed an increased case
fatality rate in patients with pneumococcal meningitis treated with penicillin
plus clilortetracycline. A similar observation was made by Olsson, Kirby, and
Romansky (16) in patients with the same diasease. In comparing various treat-
meats regimens, excessive mortality was present only in the treatment group
which combined penicillin and a tetracycline (16). Increased case fatality rates
are not the only manifestations of antibiotic interference. Lepper, Wehrle, and
Blatt (12) observed a slower response to therapy in patients with H. i~nfivenzae
meningitis who received multiple drug therapy; in that series, penicillin was not
used, although chlortetracycline was common to each treatment group. Strom (18,
19) reported apparent interference of chlortetracycline and erythromycin with the
action of penicillin in streptococcal disease. Antimicrobial antagonism may
occur in the treatment of infections with gram-negative enteric bacilli, as illus-
trated by the report of McCabe and Jackson (13). These authors (13) clearly
showed a relationship between in vitro antagonism and clinical outcome, as meas-
ured by failure to eradicate bacteriuria. Bacteriological correlations are less
apparent in patients with meningitis. Excepting neonates, almost all patients
who die with meningitis have negative post-mortem cultures.
TABLE 4.-CLINICAL STUDI ES DEMONSTRATING ANTI BIOTIC ANTAGONISM
Reference Disease Manifestation Combination therapy
Lepper and Dowling (li) Pneumococcal meningitis~ Increased mortality Penicillin+chlortetracycline.
Olsson et at. (16) do do Penicillin+a tetracycline.
Lepper et at. (12) Haemophilus influenzae Slower response Chloietracycline+streptomycin±
meningitis. sulfisoxazole.
Strom (18) Scarlatira Persistence of organism - - - Penicillin+chlortetracylcine.
Strom (19) do Slower response Penicilin+erythromycin.
McCabe and Jackson Urinary tract infection Relapse Various.
(13).
Present study Bacterial meningitis Increased mortality and Ampicillin+chloramphenicol±
residua. streptomycin.
TABLE 5.-PERSISTENCE OF VIABLE ORGANISMS IN CEREBROSPINAL FLUID AFTER 24 HOURS OF ANTIMICROBIAL
THERAPY
Patient Age Complications Initial therapy Organism Outcome
C. V 26 yr None Chloramphenicol+peni- Haemophilus influenzae._ Successful.
cillin G.
D.D 3yr do do do Do.
M.W l6months do do do Do.
D. 0 2 yr do do do Do.
T. P 18 months do do do Do.
P. H 7 months Subdural Chloramphenicol do Reaidua.
J. A 64 yr None Penicillin G Pneumncocci Death.
J. M 32 yr do do do Do.
What factors are responsible for the apparent antagonism in bacterial menin-
gitis and its seeming absence in other severe infections requiring antiliotic
therapy? The difference probably is due to the lack of surface phagocytosis and
other host defense factors which act together with antibiotics to effect recovery
(17). In meningitis, a "test-tube" situation is more nearly approximated. Wallace
et al. (21) have clearly shown interference of chioramphenicol with the rapid
bactericidal action of penicillin in experimental pneumococcal meningitis in dogs.
That this situation may pertain in humans is suggested by the data in Table 5.
The eight patients listed were observed in a previous study (15) ; all had viable
organisms in the cerebrospinal fluid after 24 hr of antibiotic therapy. One might
speculate that the host defenses in patients J.A. and J.M., who died 3 days
after admission with pneumococcal meningitis, were totally inadequate because
PAGENO="0543"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4833
of age or underlying illness such as alcoholism. Likewise, the persistence of
organisms in patent P.R., who had a subdural effusion, might be explained by a
drug diffusion problem. In the other five patients, there were no obvious explana-
tions for persistence of viable organisms other than antibiotic interference. These
five patients received a rapid intravenous infusion of penicillin and chlorampheni-
col on admission, followed by a continuous intravenous infusion containing the two
antibiotics in our standard dosage (15). In contrast, no ampicillin-treated pa-
tients with the usual types of meningitis have had positive cultures after 24 hr
of therapy. Similar observations, after 12 to 36 hr of therapy, have also been
made by Fleming et al. (7) in a controlled study of the treatment of meningitis.
Lepper and Dowling (11), in comparing the two regimens which they em-
ployed, noted that the majority of deaths in the penicillin-treated group occurred
within 48 hr of admission, whereas only 3 of the 11 patients who died while re-
ceiving combination therapy did so during the first 48 hr. An analysis of our
patients revealed the same distribution (Table 3). Our observations would tend
to substantiate the view that the effective single-drug and multiple-drug regimens
both failed to effect recovery in a certain number of patients. In addition, mul-
tiple-drug herapy seems to have failed in, potentially salvageable patients, pre-
sumably because of antibiotic interference.
It is somewhat surprising that in our study the only obvious difference be-
tween the single- and multiple-therapy groups was disability or death. One would
have expected other differences, which might have been manifested in cerebro~
spinal fluid findings, days of fever, or hospital stay. Although no differences were
apparent in the large groups, more detailed analyses of subgroups may be
fruitful.
CONCLUSIONS
Many investigators have demonstrated the phenomenon of antibiotic antagon-
ism in vitro and in experimental animals. Clinical examples of this phenomenon
are restricted to a few situations in which the rapid bactercidal acton of an anti-
biotic is apparently necessary for a good response. Bacterial meningitis, par-
ticularly that which is severe on admission, appears to be one of the situations
in which a combination of bacteriostatic and bactericidal agents is undesirable.
ACKNOwLEDGMENTS
These studies were supported by the Hastings Foundation Fund; contract
#DA-49-193-MD-2874 from the U.S. Army Research and Development Corn-
mand, Office of the Surgeon General, Department of the Army; and Public Health
Service grants of 5 T1-AI-275, 5 RO1-AI-06346, and 1 K3-AI--23,479.
REFERENCES
1. Ahern, J. J., J. M. Burneil, and W. M. M. Kirby. 1952. Lack of interference
of chioramphenicol with penicillin in a hemolytic streptococcal infection in mice.
Proc. Soc. Exptl. BioL l\Ied. 79 :568-571.
2. Ahern, J. J., and W. M. M. Kirby, 1953, Lack of interference of aureomycin
with penicillin in treatment of pneumococcic pneumonia. Arch. Internal Med.
91 :197-203.
3. Barrett, F. F., W. A. Eardley, M. D. Yow, and H. A. Leverett, 1966.
Ampicillin in the treatment of acute suppurative meningitis. J. Pediat. 3 :343-353.
4. Dowling, H. F. 1965. Present status of therapy with combinations of anti-
biotics. Am. J. Med. 39 :796-803.
5. Dowling, H. F., M. H. Lepper, and G. G. Jackson, 1953. When should anti-
biotics be used in combination. J. Am. Med. Assoë. 151 :813-815.
6. Elek, S. D., G. R. F. Hilson, and P. Jewell. 1953. Laboratory aspects of com-
bined antibiotic treatment. Brit. Med. J. 2 :1298-1300.
7. Fleming, P. C., J. D. M. Murray, M. W. Fujiwara, J. S. Prichard, and G. A.
McNaughton. 1967. Ampicillin in the treatment of bacterial meningitis. Antimicro-
bial Agents and Chemotherapy-1966, p. 47-52.
S. Ivler, D., L. D. Thrupp, J. M. Leedom, P. F. Wehrle, and B. Portnoy. 1964.
Ampicillin in the treatment of acute bacterial meningitis. Antimicrobial Agents
and Chemotherapy-1963, p. 335-345.
9. Jawetz, E., J. B. Gunnison, J. B. Bruff, and U. R. Coleman. 1952. Studies
on antibiotic synergism and antagonism. J. Bacteriol. 64:29-39.
10. Jawetz, E., J. F. Gunnison, R. S. Speck, and U. H. Coleman, 1951. Studies
on antibiotic synergism and antagonism. The inteference of chloramphenjcol
with the action of penicillin. Arch. Internal Med. 87:349-359.
PAGENO="0544"
4834 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
11. Lepper. M. H., and H. F. Dowling. 1951. Treatment of pneumococcal
meningitis with penicillin compared with penicillin pins aureomycin. Arch.
Internal Med. 88:489-494.
12. Lepper, M. H., P. F. Wehrle, and N. Blatt. 1952. Treatment of Hemophilus
influenzae meningitis: Comparison of aureomycin alone versus aureomycin,
streptomycin and gantrisin. Am. J. Diseases Children 83 :763-768.
13. McCabe, W. R.. and G. G. Jackson. 1965. The treatment of pyelonephritis.
Bacterial, drug and host factors in success or failure among 252 patients. New
Engl. J. Med. 272 :1037-1044.
14, Manten, A., and M. J. Wisse. 1901. Antagonism between antibacterial drugs.
Nature 192 :671-672.
15. Mathies, A. W., Jr., J. M. Leedom, L. D. Thrupp, D. Ivler, B. Portnoy, and
P. F. Wehrle. 1966. Experience with *ampicillin in bacterial meningitis. Anti-
microbial Agents and Chemotherapy-lOGS, p. 610-617.
16. Olsson, R. A., J. C. Kirby, and M. J. Romansky. 1901. Pneumococcal
meningitis in the adult. Clinical, therapeutic and prognostic aspects in forty-three
patients. Ann. Internal Med. 55 :54~-549.
17. Smith. M. R., W. D. Perry, J. W. Berry, and W. B. Wood, Jr. 1951. Surface
phagocytosis in nyU. J. Immunol. 67 :71-74.
18. Strom, J. 1955. The question of antagonism between penicillin and
chiortetracycline, illustrated by therapeutical experiments in scarlatina. Antibiot.
Med. 1 :6-12.
19. Strom. J. 1961. Penicillin and erythromycin singly and in combination in
scarlatina therapy and the interference between them. Antibiot. Chemotherapy
11 :694-697.
20. Thrupp, L. D., J. M. Leedom, D. Ivler, P. F. Wehrle, J. F. Brown, Jr.,
A. W. i~Iathies, Jr., and B. Portnoy. 1964. H. influenzcie meningitis: a controlled
study of treatment with ampicillin. Postgrad. Med. J. (Suppl.) 40 :119-125.
21. Wallace, J. F., R. H. Smith, M. Garcia, and R. G. Petersdorf. 1967. Studies
on the pathogenesis of meningitis. VI. Antogonism between penicillin and chloram-
phenicol in experimental pneumococcal meningitis. J. Lab. Clin. Med. 70:408-418.
22. Wehrle, P. F., A. W. Mathies, J. M. Leedom, and D. Ivier. 1967. BacteriaJ
meningitis. Ann N.Y. Acad. Sci. 145:488-498.
APPENDIX IX
[From the Journal of Pediatrics, September 1966, vol. 69, No. 3, pp. 343-353]
Al~rPIcILLIN IN THE TREATMENT OF ACUTE SUPPURATIVE MENINGITIs1
(By Fred F. Barrett, M.D., Warren A. Eardley, M.D., Martha D. Yow, M.D., and
Howard A. Leverett, Houston, Tex.)
During 1903 and 1964 in vitro sensitivity studies indicated that
ampidillin was effective against the three common etiologic agents
of bacterial memningitis in children. Blood and cerebrospinal fluid
studies revealed high blood levels and detectable cerebrospinal fluid
levels of ampicillin in patients with and without meningeal disease
but the mean cerebrospinal fluid/serum ratio was significantly
higher in patients with bacterial meningitius. Twenty-eight chil-
dren with acute bacterial meningitis were treated with ampicillin
alone. No significant differences in mortality or complications were
noted when the results of this therapy were compared with those in
two groups of patients treated with conventional "triple therapy."
Ampicillin, alpha-aminobenzyl penicillin, became available in England in
1961. This semisynthetic penicillin is of particular interest since it is bactericidal
against both gram-positive and grain-negative bacteria. Ampicillin has been
found to be highly effective in vitro against Diplocoecvs 2)neumo?~iae, Neiescria
meningltidi$. and Hcniopiiilus in flnenzae, to achieve good blood levels when
administered by oral and parenteral routes, and to have a low incidence of side
1From the Department of Pediatrics, Baylor University College of Medicine and Ben Taub
General Hospital. Address, Department of Pediatrics, Baylor University College of Medi-
cine. Houston, Texas 77025.
This study was supported in part by the Bristol Laboratories, Syracuse, New York, and
by Public Health Service Training Grant iT 1 AI-258-O1.
NoTE-Numbered references at end or article.
PAGENO="0545"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4835
effects. (1-7) These characteristics suggested that ampicillin might be an ideal
single drug for the treatment of acute suppurative meningitius due to D. pneu-
moniae, N. nceioingitidis, or H. influenzae. The parenteral form of ampicillin was
released for clinical trials in the United States in 1963. During 1963, Tyler and
his associates (8) published a preliminary report of in vitro studies and clinical
experiences, in the management of 31 patients with purulent meningitis due to
various organisms, including D. pneumoniae, N. meningitidis, and, H. intluenzae.
A more detailed report of the treatment of H. inflnenzae meningitis with am-
picillin was presented at the International Conference on Therapy With the New
Penicillins (9) in 1964. These investigators found that 126 strains of H. inlluenzae
isolated from the cerebrospinal fluid were sensitive to ampicillin. Ninety-one
per cent of the strains were killed by 0.4 meg. per milliliter and only one strain
required as much as 1.6 meg. for bactericidal activity. Ampicillin and penicillin
G were both bactericidal at 0.4 meg. per milliliter for greater than 90 per cent
of 72 strains of N. meningitidis and 37, of D. pneurnoniae. Tyler, Thrupp, and
co-workers (8, 9) found that ampicillin was comparable to chloramphenicol and
equal to penicillin G in efficacy for the treatment of bacterial meningitis. Ampi-
cillin did not appear to have any definite advantages over chloramphenicol other
than freedom from hematologic depression.
During 1963 and 1964 similar laboratory and clinical investigations were con-
ducted at the Texas Medical Center in Houston. This report summarizes the
results of these investigations. Since the majority of the laboratory studies were
performed as a base home for the clinical stt~dies, the laboratory data are presented
as Part I and the clinical studies as Part II.
PART I. LABORATORY STUDIES
In vitro sensitivity tests. Prior to the initiation of clinical studies, strains of
D. pneumoniae, N. meningitidis group C, and H. inftuenzae Type B freshly iso-
lated froni patients with meningitis in the Houston area were tested for suscep-
tibility to ampicillin,~ tetracycline, chloramphenicol, and penicillin G. The two-
fold serial tube dilution technique using tryptose phosphate broth and an mo-
culum of approximately iO~ organisms was employed for the determination of
the minimal bactericidal concentration (MBC) of pneumococci and ineningococci.
Agar diffusion plates were used in determining the minimal inhibitory concen-
tration (MIC) of H. influenzae. Oasman's agar base with 10 per cent heated
blood was employed as the medium. The plates were inoculated from a 24 hour
culture in 5 per cent blood and brain-heart infusion broth with a standard 5 mm.
wire loop. All of the strains tested during the preliminary phase of investigation
were sensitive in vitro to all four of these antibiotics. Since the results of sen-
sitivity tests of organisms isolated from patients enrolled in the later clinical
trials were similar to those obtained in the preliminary studies, the cumulative
results are presented in Table I.
TABLE I-MINIMAL INHIBITORY CONCENTRATIONS OF AMPICILLIN, CHLORAMPHENICOL, PENICILLIN G AND
TETRACYCLINE AGAINST HEMPOHILUS INFLUENZAE AND MINIMAL BACTERICIDAL COCENTRATIONS OF
THESE SAME DRUGS AGAINST DIPLOCOCCUS PNEUMONIAEANDNEISSERIA MENINGITIDIS STRAIN~ SOLATED
FROM PATIENTS WITH MENINGITIS
Antibiotic concentration
Number
of 0. 012 0. 025 0. 05 0. 01 0. 20 0. 39 0. 79 1. 56 3. 12
strains (mcg./ (mcg./ (mcg./ (mcg./ (mcg./ (mcg./ (mcg./ (mcg./ (mcg./
Antibiotic tested ml.) ml.) ml.) ml.) ml.) ml.) ml.) ml.) ml.)
Hemophilus influenzae:
Amipicillin 41 2 10 26 3
Chioramphenicol 24 4 6 4 10
Penicillin G 15 2 9 1 3
Tetracycline 27 2 7 7 11
Diplococcus pneumoniae:
Ampicillin 12 2 6 4
Chloramphenicol 11 3 8
Penicillin G 12 s 7
Tetracycline 11 5 3 2 1
Neisseria meningitidis:
Ampicillin 15 1 8 5 1
Chloramphenicol 7 3 4
Penicillin G 13 1 4 7 1
Tetracycline 7 3 4
°Polycillin (Bristol Laboratories).
81-280-69--pt. 11-35
PAGENO="0546"
4836 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
A total of 41 strains of H. injiuenzae, 12 of D. pneumoniae, and 15 of N. menin-
gitidis were tested for their sensitivity to ampicillin. Varying numbers of these
same strains were tested for their sensitivity to chioramphenicol, penicillin G,
and tetracycline. All of the strains of H. influenzae were inhibited by anipicillin
in a concentration of 0.78 mc. per milliliter or less, the majority by a concentra-
tion of 0.39 mcg. per milliliter. The MBC of ampicillin and penicillin G for
pneumococci and meningococci were similar and ranged from 0.012 to 0.05 mcg.
per milliliter for pneumococci and from 0.025 to 0.20 for meningococci.
Serum and spinal fluid ampicillin levels. Thirty eight simultaneous serum and
spinal fluid samples were obtained one hour after a parenteral dose (intra-
venously or intramuscularly) of ampicillin. Eight of the paired specimens were
from patients with no evidence of meningeal disease, 10 from patients with viral
meningitis or encephalitis, and 20 from patients with bacteria meningitis. Am-
picillin levels in the serum and spinal fluid were assayed by Bristol Laboratories
using the cup-plate method with Sarcina lutea as the test organism. The rela-
tionship between the dose of ampicillin and the cerebrospinal fluid and serum
levels could not be assessed in this series of patients because of variations in
dosage and route of administration. However, data are presented to demon-
strate the ratios between simultaneous cerebrospinal fluid and serum levels
(Tables II and III). The dose employed varied from 25 mg. per kilogram (150 mg.
per kilogram per day divided into 6 doses) to 50 mg. per kilogram (250 mg. per
kilogram per clay divided into 6 doses). The paired samples were obtained one
hour after administration of the dose and all patients had been on the drug for
a period of ito 4 days at the time of sampling.
Satisfactory serum levels were obtained in all instances and ampicillin was
detectable in each spinal fluid specimen. However, there w-as a striking differen-
tial between the simultaneous cerebrospinal fluid and serum levels. The highest
mean cerebrospinal fluid-to-serum ratio (expressed as percentage) was obtained
in patients with bacterial meningitis (ii per cent) while the ratio in the patients
with viral meningitis was 9 per cent and in patients without evidence of menin-
gitis was 4 per cent. Although the mean cerebrospinal fluid ampicillin levels in
the patients with `bacterial meningitis and the group without evidence of menin-
gitis, 1.9 mg. per milliliter and 0.8 mg. per milliliter, are not significantly differ-
ent (p=>0.1), the mean ratios in those two groups of patients, 11 and 4 per cent,
respectively, are significantly different (p=1O5~ F., symptoms >5 days, or complicating disease.
1+ None of the above.
TABLE VI.-SEVERITY OF ILLNESS: STUDY AND MATCHED CONTROL PATIENTS
Number of matched control
Number of study patients patients
Severity of illness 1 4+ 3+ 2+ 1+ 4+ 3+ 2+ 1+
H. influence 8 2 4 2 7 2 2 1
N. meningitidis ~ 1 3
D. pneumoniae 1 1 1 2
Unknown etiology 3 1 1
Total patients 3 1 1
Total patients 12 3 10 3 10 4 4 7
I See text.
PAGENO="0549"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4839
As can be seen in Table VI, the severity of the illness was comparable in the
study and matched control groups.
The duration of fever prior to admission to the hospital was used as a rough
index of the stage of illness (Table VII). There were no outstanding differences
in the three groups except for a wide variation in the duration of illness in the
"unknown" category.
Bacteriologic studies. Cerebrospinal fluid and blood cultures were obtained from
all the study, matched control, and 5 year review patients on admission to the
hospital. Repeat spinal fluid cultures were performed on all patients. In the
ampicillin-treated and matched control groups the repeat cultures were obtained
within 24 to 48 hours after the original culture. Additional cultures were obtained
at suitable intervals and prior to discharge. Repeat cultures were also performed
on all patients in the "5 year review group"but the time interval was less uniform
than in the former two groups. The antibiotic sensitivity tests are described in
the previous section on laboratory studies.
TABLE VII.-MEAN DURATION OF FEVER PRIOR TO ADMISSION: STUDY, MATCHED CONTROL, AND 5-YEAR REVIEW
PATIENTS
Study
patients
(days)
Matched
control
patients
(days)
5-year
review
patients
(days)
H. influenzae
4 9
3 5
3. s
N. meningitidis
D. pneumoniae
1. 1
2. 0
1. 6
2. 3
2. 0
4. 2
Unknown etiology
2.3
8.5
5.2
Antibiotic management. The study patients received ampicillin, 150 mg. per kilo-
gram per day divided into 0 intravenous doses for at lear 48 hours. The ampicillin
was diluted with 5 c.c. of 0.85N saline and given over a period of 60 seconds.
Unused portions of ampules were discarded so that each dose was freshly pre-
pared. After 48 hours the intramuscular route was employed except in instances
where patients exhibited a slow response to treatment. In these cases, intravenous
therapy was continued for longer periods of time. The average total duration of
ampicillin therapy was 2 weeks.
The matched control patients and the 5 year review patients received penicillin,
chloramphenicol, and sulfadiazine until an etiologic agent had been identified.
Thereafter, the appropriate antibiotic was continued and the unnecessary oneS
discontinued. The dose of penicillin was 4 to 12 million units per day depending
on the size of the child, chloramphenicol, 100 ing. per kilogram per day, and sulfa-
diazine, 150 mg. per kilogram per day.
RESULTS
A susumary of the results of treatment in the three groups of patients is pre-
vented in Table VIII.
Seventeen of the 28 ampicillin-treate'd patients recovered completely (01 per
cent), 2 died (7 per cent mortality), subdural effusions were demonstrated in 4
(14 per cent), 1 (4 per cent) had severe neurologic sequelae, and 4 (14 per cent)
had minor neurologic sequelae which subsequently disappeared.
TABLE VIII.-RESULTS OF THERAPY: STUDY, MATCHED CONTROL, AND 5-YEAR REVIEW PATIENTS
Study patients Matched control patients 5-year review patients
Number Percent Number Percent Number Percent
Satisfactory course
Deaths
17
2
61
7
12
3
48
12
123
18
64
9
Severe sequelae
Subdural effusion
1
4
4
14
1
5
4
20
24
25
13
14
Minor sequelae
4
14
4
16
(1)
Total
28
100
25
100
190
100
I Unknown.
PAGENO="0550"
4840 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Twelve of the 25 matched control patients recovered completely (48 per cent),
3 died (12 per cent mortality), subdural effusions were demonstrated in 5
(20 per cent), 1 (4 per cent) had permanent neurologic sequelae, and 4 (16
per cent) had minor neurologic sequelae which subsequently disappeared.
The mortality in the 5 year review group (9.5 per cent) was strikingly similar
to that of the other two groups. Twenty-five of the 190 patients (14 per cent)
had subdural effusions. The incidence of permanent neurologic sequelae in this
group of patients (13 per cent) was not significantly different from that of the
other two groups (p - < 0.1). Minor neurologic sequelae could not be adequately
evaluated in the 5 year review patients.
All of the deaths in the study and matched control groups occurred in patients
who were in coma and/or shock on admission to the hospital. Four of the 5 deaths
took place during the first 48 hours of hospitalization. The cerebrospinal fluid
was sterile at the time of death in all 5 patients. Table IX presents the mortality
figures in relationship to the etiologic agent. The incidence of subdural effusion
and severe neurologic sequelae according to etiologic agent is shown in Table X.
TABLE IX.-MORTALITY RATE: STUDY, MATCHED CONTROL, AND 5-YEAR REVIEW PATIENTS
H. influenzae
N. meningitidis
D. pneumoniae
Unknown etiology
Overall mortality
1/16
1/8
0/1
0/3
2/28
3. 5
3.5
0
0
7
2/12
1/7
0/4
0/2
3/25
8
4
0
0
12
9/88
0/8
7/35
2/59
18/190
4. 7
0
3.7
1. 1
9.5
TABLE X.-INCIDENCE OF SUBDURAL EFFUSION AND SEVERE NEUROLOGIC SEQUELAE ACCORDING TO ETIOLOGY:
STUDY, MATCHED CONTROL, AND 5-YEAR REVIEW PATIENTS
Study patients
Matched con
trol patients
5-year revi
Subdural
ew patients
Severe neuro-
Subdural
Severe neuro-
Subdural
Severe neuro-
effusion
sequelae
effusion
sequelae
effusion
sequelae
Num- Per-
Num- Per-
Num- Per-
Num- Per-
Num- Per-
Num- Per-
Etiologic agent ber cent
ber cent
ber cent
ber cent
ber cent
ber cent
H. influenzae
N. meningitidis
D. pneumoniae
Unknown etiology
3/16
0/8
1/1
0/3
19
100
1/16
0/8
0/1
0/3
6
4/12
0/7
1/4
0/2
33
25
1/12
0/7
0/4
0/2
8
14/88
0/8
7/35
4/59
16
20
7
8/88
0/8
7/35
9/59
9
20
15
Total
4/28
14
1/28
4
5/25
20
1/25
4
25/190
13
24/190
13
TABLE XI.-MEAN DURATION OF FEVER AFTER INITIATION OF THERAPY: STUDY, MATCHED CONTROL, AND
5-YEAR REVIEW PATIENTS
Study
patients
(days)
Matched
control
patients
(days)
5-year
review
patients
(days)
H. influenzae
6. 9
8. 5
7. 0
N. meningitidis
D. pneumoniae
Unknown etiology
6. 3
5.0
3. 0
6. 3
2.5
2. 0
4. 0
5.2
- 9
Study patients Matched control patients 5-year review patients
Number Percent Number Percent Number Percent
PAGENO="0551"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4841
a STUDY
~ 200f ~ MATCHED CONTROL
~ l8Ot~~
z 160
~~L1 ~`
I 2-6 7-Il 12-16
DAY OF THERAPY
FIGURE 1.-Mean cerebrospinal fluid cell counts of study irnd matched control
patients.
RANGE OF CEREBROSPINAL FLUID PROTEIN VALUES IN MILLIGRAMS PERCENT
Day 1 Days 2-6 Days 7-11 Days 12-16
Study group 13-480 30-970 14-76 23-120
Control group 22-684 34-571 21-1, 400 20-140
~ STUDY
0 MATCHED CONTROL
w
U)
0
0)
-J
L~.
U)
U
DAY OF THERAPY
FIGURE 2.-Mean cerebrospinal fluid glucose values of study and matched control
patients.
RANGE OF CEREBROSPINAL FLUID GLUCOSE VALUES~ IN MILLIGRAMS PERCENT
Study group 10-92 20-98 50-94 30-80
Control group 10-78 20-95 35-75 28-58
PAGENO="0552"
4842 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
E
-J
-J
w
U
1-
z
0*
U
-j
-J
w
U
U)
U
FIGURM 3.-Mean cerebrospinal fluid protein values of study and matched control
patients.
RANGE OF CEREBROSPINAL FLUID CELL COUNTS PER CUBIC MILLILITER
Studygroup
Control group
90-19,500
52-11,000
3-6,000
3-4,150
2-237
0-182
0-103
0-115
In addition to mortality figures and neurologic sequelae, other criteria used
to assess the efficacy of antibiotic therapy were: duration of fever after initiation
of therapy; eradication of bacteria from the spinal fluid, and return of the spinal
fluid cell count, sugar. and protein to normal values. The duration of fever in the
ampicillin-treated patients, the matched control patients and the 5 year review
patients is show-n in Table XI. There does not appear to be any significant differ-
ence in the time of defervescence in the three groups. The bacterioligoc response
to antibiotic therapy was rapid in the groups of patients studied in 1904 and
1965 (study and matched controls). There were no positive cultures within 48
hours after initiation of therapy in either of these two groups. There were in-
sufficient data to evaluate the rapidity of bacteriologic response in the 190 patients
receiving conventional therapy during the last 5 years~
The cerebrospinal fluid findings of the study and matched control groups are
presented in Figs. 1 to 3. No significant differences in the initial cerebrospinal
fluid cell count, protein, and sugar values are apparent in the two groups. These
values returned to normal at the same rate in the two groups. The difference in
protein values at 7 to 11 days may be a reflection of the small number of lumbar
punctures done during that phase of the illness. There were insufficient data to
evaluate the cerebrospinal fluid findings in the 5 year review group.
The incidence of drug hypersensitivity and toxicity could be evaluated in the
study and matched control patients but not in the 5 year review group. No skin
manifestations of hypersensitivity developed in the ampidillin-treated patients.
Eosinophilia was observed in 8 patients. The serum glutamic oxaloacetic trans-
aminase (SGOT) was slightly elevated in 8 patients. Three patients developed
mild diarrhea which may have been related to ampicillin therapy. The eosin-
ophilia and diarrhea cleared spontaneously in every case, usually without dis-
continuation of drug therapy. The 8GOT returned to normal after cessation of
therapy in all patients in whom repeat values were obtained. No hematologic
abnormalities developed in the study patients. None of the patients in the matched
control group developed evidence of penicillin allergy. Four patients with
STUDY
D MATCHED CONTROL.
DAY OF THERAPY
PAGENO="0553"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4843
Heniophilus influenzae meningitis developed anemia and/or absolute neutropenia
while on chlorarnphenicol therapy. One patient with pneumococcal meningitis
developed anemia while on triple antibiotic therapy. In all instances the anemia
and neutropenia resolved spontaneously with cessation of chloramphenicol
therapy.
SUMMARY AND CONCLUSIONS
During 1963-1965, strains of H. iaftuen,zae, D. pneunumiae, and N. meningitidis
isolated from patients with purulent meningitis were tested for in vitro sensitivity
to ampiciflin, chloramphenicol, penicillin G, and tetracycline. These studies indi-
cated that, in vitro, ampicillin was as effective or slightly more effective than
chloramphenic'ol, penicillin G, and tetracycline against H. influenzae and was
equally effective in vitro as penicillin G against D. pneumoniae and N. menin-
fTjitidis.
Simultaneous serum and cerebrospinal fluid ampicillin levels were determined
in 8 patients with no evidence of meningeal disease, 10 patients with viral menin-
gitis or encephalitis, and 20 patients with bacterial meningitis. High blood levels
were achieved in all three groups. The drug was detectable in the cerebrospinal
fluid of patients with normal meninges as well as patients with inflamed men-
inges. The mean cerebrospinal fluid/serum ratio, however, was significantly
higher in patients with bacterial meningitis than in those with no evidence of
meningeal disease.
Twenty-eight patients admitted consecutively to Ben Taub General Hospital
from July, 1964, to April, 1965, with the diagnosis of acute bacterial meningitis
received single drug therapy with ampicillin (study group). Twenty-five patients
admitted from April, 1965, to July, 1965, received conventional antibiotic therapy
and served as a matched control group. In order to establish a base line of
mortality and morbidity of bacterial meningitis in our hospital, the charts of 190
children (2 months to 14 years of age) who received conventional antibiotic
therapy for bacterial meningitis from 1959 through 1963 were reviewed (5 year
review group).
The mortality rate and the incidence of severe neurologic sequelae were not
significantly different in the three groups of patients studied. The incidence of
subdural effusion was approximately equal in the three groups of patients, and
the incidence of minor neurologic sequelae was approximately the same in the
study and matched control groups.
The rapidity of response to therapy as measured by: (1) the duration of fever
after the institution of antibiotic treatment in the three groups studied and (2)
the return of the cerebrospinal fluid values to normal in the study and matched
control groups indicated no significant difference betwen therapy with ampicillin
and conventional drugs.
No serious drug reactions occurred in the ampicillin-treated patients. Eosino-
philia, diarrhea, or slight elevation of the SGOT were encountered in a few-
patients but these often subsided without cessation of therapy. Five patients in
the matched control group developed anemia and/or absolute neutropenia while
on chioramphenicol therapy. In all instances, the anemia and neutropenia re-
solved with cessation of chioramphenicol therapy.
Ampicillin appears to be an excellent drug for the- treatment of acute bacterial
meningitis due to D. pneumoniae, N. nieningitidis, and H. influenzac in children.
It is as safe and as effective as conventional triple therapy and in addition has
the following advantages: (1) simplicity of administration, and (2) apparent free-
dom from hematologic and renal complications encountered with chloramphenicol
and sulfonamides, respectively.
REFERENCES
1. Brown, D. M., and Acred, P.: "Penbritin"-a new broad-spectrum antibiotic.
Preliminary pharmacology and chemotherapy, Brit. M. J. 2: 197, 1961.
2. Knudsen, B. T., Rolinson, G. N., and Stevens, Shirley: Absorption and excre-
tion of "Penbritin," Brit. M. J. 2: 198, 1961.
3. Stewart, G. T., Coles, H. M. T., Nixon, H. H., and Holt, R. J.: "Penbrithi":
An oral penicillin with broad-spectrum activity, Brit. M. J. 2: 200, 1961.
4. Rolinson, G. N., and Stevens, Shirley: Microbiological studies on a new-
broad-spectrum penicillin, "Penbritin," Brit. M. J. 2: 11, 1961.
5. Klein, J. 0., and Finland, M.: Ampicillin, activity in vitro and absorption
and excretion in normal young men, Am. J. Med. Sc. 245: 544, 1003.
6. Quinn, B. L., Cox, F., Jones, D., and Farns, L.: Clinical experience with
parenteral ampicillin, Antimicrobial Agents & Chemother. 226, 1964.
81-280 0-69-pt. 11-36
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4844 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
7. Turck, M., Anderson, K. N., McKee, W. M., Shulman, J. A., Smith, R. H. and
Petersdorf, R. G.: Further studies with ampicillin, Antimicrobial Agents &
Chemother., 220, 1964.
8. Ivier, D., Thrupp, L. D., Leedom, J. M., Wehrle, P. F., and Portnoy, B.:
Ampicillin in the treatment of acute bacterial meningitis, Antimicrobial Agents
and Chemother., 335, 1963.
9. Thrupp, Lauri D., Leedom, John M., Ivier, Daniel, Wehrle, Paul F., Brown,
John F., Mathies, Allen W., and Portnoy, Bernard: H. inflvenzac meningitis: a
controlled study of treatment with ampicillin, "Therapy with the new penicillins,"
Proceedings of a Conference held at the Apothecaries' Hall, London, 119. 1964.
APPENDIX X
[From Post Graduate Medical Journal, December 1964, pp. 119-125]
H. INFLIJENZAE MENINGITIS: A CONTROLLED STUDY OF TREATMENT WITH
AMPICILLIN
(By Lauri D. Thrupp, John M. Leedom, Daniel Ivler, Paul F. Wehr.le, John F.
Brown, Allen W. Mathies and Bernard Portnoy)
From the Communicable Disease Service, Los Angeles County Gen-
eral Hospital, and the Infectious Disease Laboratory, the Depart-
ments of Medicine and Pediatrics, University of Southern California
School of Medicine
THE case fatality rate in Hemophilus inlluenzae meningitis has been reduced
to 5-10% by present methods of anti-bacterial and supportive therapy. As this
rate is still far from optimal, the incidence of both early and late neurological
sequelae is appreciable, and the antibiotics presently employed have definite and
occasionally serious toxicity, new approaches to therapy must be evaluated.
Preliminary in vitro studies performed in our laboratory (Ivler, Thrupp, Lee-
dom, Wehrle `and Portnoy, 1963) indicated that 126 strains (118 type B) of H.
influenzae isolated from cerebrospinal fluid (C.S.F.) were sensitive to ampicillin.
Bacteriostatic and bactericidal levels did not differ significantly, and 91% were
killed by 0.4 ~g./ml. Only one had a bactericidal level as high `as 1.6 yg./ml. In
addition, sensitivities of meningococci `and pneumococci to ampicillin were simi-
lar to those to penicillin G. These data, in conjunction with the apparent low
toxicity of ampicillin suggested the trial of ampicillin as `a single drug treatment
for bacterial meningitis, in contrast to control groups treated with conventional
therapy. The present report summarizes the experience to date with H. influen.zac
meningitis. Eighteen of these 70 patients were included in a preliminary report
(Iveret al., 1963).
MATERIALS AND METHODS
(1) Selection of Patients: All patients more than two months of age with
bacterial meningitis admitted to the Communicable Disease Service of the Los
Angeles County General Hospital were included in the ampicillin study. Chart
numbers assigned at the hospital central admitting office, and not subject to
control of the ward physicians, were used to insure proper randomization. Pa-
tients with even (2, 4, 6, etc.) numbers were assigned to the ampicillin group
while patients with chart numbers ending 1, 3, 5, etc., were given conventional
therapy. During the period considered (June, 1963 to March 1964) a total of
72 patients were admitted with H. in/luenzac meningitis. Of these, 44 with odd
chart numbers were assigned to the control group, and 28 with even numbers
were eligible for ampicillin therapy. The difference in the size of the two groups
was unexpected, although within the limits of chance variation. Tw-o of the 28
patients were excluded from the ampicillin group, one by error in assignment
and the other because of concomitant severe facial cellulitis following a dog bite
where additional therapy was indicated. These two patients w-ere not tabulated
with either group. Most of `the patients had received some antibacterial therapy
prior to admission, usually subtherapeutic dosages, ineffective drugs, or both.
NOTE.-References at end of article.
PAGENO="0555"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4845
No attempt was made to evaluate this, since it was assumed to provide an equal,
and probably negligible, effect in both treatment groups.
(2) Administration of antibacterial therapy: Sodium ampicillin was reconsti-
tuted in 0.85 per cent NaCl and administered rapidly (15-20 minutes) at four
hour intervals in a total daily dose of 150 mg./kg. of body weight. (The first
seven patients treated received 100 mg/kg. per day intravenously at six hour
intervals). The intravenous route was used invariably for at least the first 48
hours, w-hile after adequate initial clinical response many patients were given
the same daily dose by intramuscular injection at four hour intervals during the
remainder of the period of treatment.
Ohloramphenicol was given by continuous intravenous infusion in a total
daily dose of 100 mg./kg. In some patients in whom the diagnosis of H inflaenzw
was not certain on admission, sulfisoxazole and penicillin G (150 mg./kg./day
of each drug) were also given until isolation and identification of the organisms
were completed.
(3) Duration of therapy: Treatment was continued until the patient was
afebrile for at least five days, the spinal fluid contained less than 40 cells per
cmm. with few or no polymorphonuclear leukocytes, and the C.S.F. sugar was
normal.
(4) Evaluation of response to therapy: Response to therapy was evaluated
by the usual clinical criteria, including duration of fever, improvement in neuro-
logical status, decrease in peripheral blood leukocyte count with a return of the dif-
ferential count toward normal, and improvement in C.S.F. finding, including pres-
sure, cell count, percentage polymorphonuclear leukocytes and glucose and protein
content.
Subdural taps were performed whenever indicated (Platou, Rinker and Der-
rick, 1959). In this report the outcome of therapy was evaluated according to
the patient's course in the hospital and status at the time of discharge from the
hospital. Untoward findings during the course of treatment in the hospital and
any neurological abnormalities were recorded. "Delayed resolution clinically, but
no squelae at discharge" is a descriptive category which included patients with
one or more findings such as: (a) transients subdural effusions, (b) convulsions
persisting beyond the first 24 hours in the hospital, (c) persistence of a positive
C.S.F. culture the day following admission to the hospital, (d) persistence or
recurrence of O.S.F. pleocytosis, (e) documented persistence of nuchal rigidity or
neurological findings such as cranial nerve palsies beyond five days even though
resolution has occurred by the time of discharge. An additional "slow response"
category incorporated the above plus other patients with no abnormality but
fever persisting beyond five days of treatment.
(5) Bacteriological methods: Isolation and identification of the organisms
were accomplished by conventional methods utilizing blood and chocolate agar,
serum and thioglycollate broth and both aerobic and CO2 incubation. Quellung
was done in C.S.F. if adequate numbers of organisms were present. Bactericidal
levels of ampicillin and chloramphenicol were determined using serial tube
dilution techniques in GC medium containing 1% supplement B. (Difco).
RESULTS
Bacteriologic confirmation of the diagnosis of H. influenzw type B infection
was complete in 68 of the 70 patients in the study group. Blood and O.S.F. cul-
tures were both positive in 34 patients and organisms were cultured from the
C.S.F. alone in the remaining 34. Two patients admitted with partially treated
purulent meningitis had no positive cultures; they are included in this series on
the basis of organisms seen of Gram's stain of the C.S.F. The cultural recovery
of H. influ~uzw from 68/70 patients supported the assumption that antibiotic
therapy given prior to admission had little effct on the course of the illness. To
date, 164 strains of H. influenzw isolated from C.S.F. have been tested for i~v `i~itro
sensitivity to ampicillin. Ninety-one per cent of the strains were killed by 0.4
~g./ml., and only two had bactericidal end points as high as 1.6 and 3.1 ~ig./ml.
respectively.
The age and sex distribution of the patients studied is indicated in Table I.
Two of the patients were more than 15 years of age. It should be noted that 14
of 26 patients in the ampicillin group were two years of age or older, and 13
of 44 patients in the control group were in this age group. This was believed to be
an unimportant difference, since the distribution of severity of illness, accord-
ing to the criteria in Table II, was similar within each age group and apparently
PAGENO="0556"
4846 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
was not related to age. The expected male predominance was found in both
study groups.
The duration of illness prior to admission was similar in both groups. In
Table II the patients in each group are recorded by severity of illness on ad-
mission. There was no difference between the two groups.
The duration of fever after therapy was instituted as indicated in Table III.
No significant difference is apparent between the two groups. Sixty-four per
cent of the chloramphenicol treated patients were afebrile by the fifth hospital
day, while 72% of the ampicillin group were in this category.
The C.S.F. was re-examined within one or two days following admission in 24
ampicillin and 38 control patients. Cultures of these follow-up C.S.F. samples
were positive in three of 31 specimens from the ampicillin patients and three of
46 samples from controls. These six positive specimens were all obtained less
than 18 hours after the start of therapy; no positive C.S.F. cultures were ob-
tained from either treatment group later than 18 hours after admission. The
similarity of response in the two treatment groups is further emphasized in
Figs. 1 and 2, in which changes in O.S.F. cell count and glucose are shown dur-
ing the period of therapy. In addition to the data shown, the rate of decline in
percentage of polymorphonuclear cells in the O.S.F. during the period of treat-
ment was similar in the two groups.
TABLE I-H. INFLUENZA MENINGITIS, AGE AND SEX DISTRIBUTION OF PATIENTS BY THERAPY GROUP
Therapy group and sex
Less than 1
year
1 year
2 to 4 years
5 to 29 years
Total
Control:
Male
Female
Total
Ampicillin:
Male
Female
Total
10
9
7\
5
3
5
3
2
23
21
19
12
8
5
44
7
2
3
0
6
6
0
2
16
10
9
3
12
2
26
TABLE 11.-H. INFLUENZA MENINGITIS, CLINICAL STATUS ON HOSPITAL ADMISSION ACCORDING TO TREATMENT
GROUP
Severity
group
*
Findings
Control
Number Percent
Ampicilli
Number
n
Percent
4+
3+
2+
1+
Coma,shock,semicoma,hypoteflsiOn1
Convulsions without coma or shock
Temperature of 105° R. or more, symptoms 5 days or more,
complicating disease, marked lethargy 1~
None of above
Total patients
8
10
15
11
18
23
34
25
3
7
9
7
12
27
34
27
44
100
26
100
11 or more of the findings listed.
TABLE 111.-H. INFLUENZAE MENINGITIS, DURATION OF FEVER IN HOSPITAL BY TREATMENT GROUP
INumber (percent distribution) of patients with maximum temperature > 100° Fl
Therapy group
Days
in hospital
0-I
2-3
4-5
6-7
8-9
10+
Total
Control
3
11
11
8
2
4
1 39
(100)
Ampicillin
(8)
6
24
(28)
3
(12)
(28)
9
(36)
(21)
1
(4)
(5)
2
(8)
(10)
4
(16)
2 25
(100)
Total
9
14
20
9
4
8
64
1 4 fatalities and 1 case with incomplete temperature record excluded.
2 1 fatal case excluded.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4847
TABLE IV.-H. INFLUENZAE MENINGITIS COMPLICATIONS AND SEQUELAE BY TYPE OF TREATMENT
Control
Number Percent
Ampicillin
Number Percen
Death
4 9
1 4
Neurological residual `
5 11
3 12
Severe
Mild or questionable
Subdural effusions
1
4
4 9
2,
1
4 15
Required surgery
Mild neurological residual
Nosequelae
Seizures persistent 2
Delayed resolution clinically 3 but no sequelae at discharge
Temperature of 100° F. or more for 6 days but without any of the
above findings
Good response (none of above findlngs).
0
1
3
1 2
13 30
5 11
18 41
2
1
1
2 8
8 31
1 4
13 54
1 At hospital discharge.
2 Some seizures persistent 24 hours or more after admission.
3 Tabulation includes patients with slight subdural effusions which cleared without surgery or neurological sequelae.
TABLE V.-H. INFLUENZAE MENINGITIS, STATUS ON DISCHARGE FROM THE HOSPITAL
Slightorno
residual with
Serious
Age group-Treatment group
No residual
satisfactory
response
minor
subdurals or
slow response
neurologic
residual
or death
Total
Less than 12 months:
Control
9
9
1
19
Ampicillin
Total
12-23 months:
0
6
3
9
9
15
4
28
Control
7
3
2
12
Ampicillin
Total
2ormoreyears:
Control
2
1
0
3
9
4
2
15
6
5
2
13
Ampicillin
Total
All ages:
Control
12
2
0
14
18
7
2
27
22
17
5
44
Ampicillin
14
9
3
26
Total
36
26
8
70
TABLE VI.-H. INFLUENZAE MENINGITIS (POSSIBLE REACTIONS OR COMPLICATIONS OF THERAPY)
Type of reaction
Control (44 patients)
Number Percent
Ampicillin (26 patients)
Number Percent
Anypossible reaction
Phlebitis
Skinrash
Gastrointestinal
Miscellaneous
Eosinophilia I
Hematologicdepression
Leukopenia3
Rel. granulocytopenia4
Thrombocytopenia5
Anemia°
20 (45)
9 (20)
4 (9)
3 (7)
6 (14)
3 (7)
10 (23)
5
5
2
3
16 (62)
10 (38)
5 (19)
1 (4)
1 (4)
1 (4)
22 (8)
0
1
1
1
I >10 percent eosinophils in peripheral smear.
2 1 patient failed to respond to Ampicillin, and developed mild anemia and thrombocytopenia 14 days after the substi-
tution of chloramphenicol.
<4,000 per cmm. (or <5,000 if other hematology abnormal).
<15 percent polys and bands.
Marked reduction in platelets on smear.
Drop in hemoglobin of >2 g./100 ml.
PAGENO="0558"
4848 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY
Complications seen are recorded in Table IV by type of sequehe and method
of therapy. Again, it is apparent that no significant difference is present between
the two groups. A strong association was found with coma, shock and/or con-
vulsions on admission and fatal outcome or serions neutrological residual. This
was the case in both therapeutic groups. None of the 42 patients admitted
without the above serious clinical signs had a fatal outcome or neurological
sequehe of consequence. Among the 28 patients admitted with coma, shock or
convulsions, four of 18 treated with chlorampheMcol died and one had a serious
residual. One of 10 in the ampicillin series died, and an additional two patients
had severe residual involvement (hydrocephalus).
The status of the patients at the time of discharge by age group and type
of therapeutic response is recorded in Table V. A Ithough minor differences were
noted among the various age groups, the numbers were small and of doubtful
significance. In the total group, the proportion with entirely satisfactory re-
sponse was 22 of 44 control patients and 14 of 26 ampicillin patients. These pro-
portions may be regarded as nearly identical.
Possible drug reactions or complications of therapy are listed in Table VI.
These findings were not proven to be due to the specific antibiotic therapy in any
instance. The high incidence of local phlebitis in both groups accompanied the
frequent use of polyethylene, indwelling, venous catheters. Twelve patients with
some evidence of hematologic depression are also listed in Table VI, although
the findings were minimal in most. Eleven cases accompanied the administra-
tion of chloramphenicol. One three-month-old patient treated with ampicillin
had a peripheral white blood cell differential count of 15% polymorphonuclears
and no bands on the seventh day of therapy. This finding was of doubtful sig-
nificance in view of the age of the patient, lack of accompanying anemia or
leukopenia, and a reticulocyte count of 1.6%. The other patient with hemato-
logic depression included in the ampicillin group was treated initially with am-
picillin with prompt sterilization of O.S.F. However, the pleocytosis failed to
clear, and subdural effusions and hydrocephalus were noted. The marrow de-
pression appeared two weeks after chloramphenicol had been substituted.
Pf. .INFI.UENZAE MENINGITIS
.0.
U
..1~
U
~n.
U.
FIGuuz 1.-C.S.F. cell counts during the treatment period.
H. INFLUENZAE MENINGITIS
~ co~ 6SF. CLUCOS~
~ ~7OI:
*. 60 ~ (0) CM
~
~ 40 ,p.~?%~1) (2) (19) (~ (24) (23)
D~ 30 ~ ,`AIG)
U 20 ~ MEDIAN' 0 f~OPJIl1OL
* ..(2oMr.% * AMPIGILLIN
10 (2!) C ) M~MuCR OF PATIENTS TESTED
0 I 1 I ...~q -
ADM I 2 3 4.5 6.7 U-Il 12.15 16+
GDASE DAYS AFTER HOSPITAL ADMI~SION
FIGUBE 2.-C.S.F. glucose levels during the treatment period.
NEDIAN CFI.1. i-... AM?ICILLIK
COUNT lo....o CONTROL
RANGE
I'2~3 4.5
DAYS AFTER HOSPITAL ADMISSION
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4849
DISCtJSSION
The patients with H. infIuenzw meningitis in this study comprised a group
similar to series previously reported (Haggerty and Ziai, 1964). 90% of the
patients were between two months and four years old. This age distribution
followed the characteristic pattern which, as shown by Fothergill and Wright
(1933), reflects inversely the age prevalence of bactericidal serum antibody.
Three per cent (two cases) were young adults, a proportion similar to the 2.7%
of patients more than 20 years of age reëorded in Dolphin and Popham's (1951)
review of 915 cases. There was the expected male predominance.
Analysis of the results of therapy with ampicillin and chioramphenicol in
these two comparable groups of patients failed to elicit any clear-cut differences.
General clinical criteria such as mortality, neurological sequeloe, duration of
fever, subdural effusions, sterilization of the C.S.F. rafes of reduction in the
number of cells, per cent polys and protein content in O.S.F. and rise in C.S.F.
sugar, were similar in both groups. The C.S.F. cell counts and sugar levels showed
no differences on the first and the third days after admission, or afterwards
Among small numbers of observations on the second day, the larger variation in
in values for the ampicillin patients resulted in differences in distributions of
values about the medians for that single day of bordering significance (Figs. 1
and 2). However, in view of the data for the days prior to, and following, this
second day of treatment, it is doubtful that these differences were meaningful.
Although all nine ampicillin patients less than one year of age manifested at
least some deficiency in response to therapy, nine of 19 controls in this age group
had satisfactory responses (Table V). A trend toward fewer unsatisfactory
responses with ampicillin than chioramphenicol was observed in patients two
or more years of age. As stated previously, neither therapeutic group was
weighted with disproportionate numbers of, severely ill or moderately ill patients
at any age. Disregarding age, the proportion of satisfactory responses in both
therapeutic groups was almost identical. The apparent minor differences in
response to ampicillin and chloramphenicol by age group would probably dils-
appear if more patients were tested. Consideration of these data emphasizes the
difficulty of being certain that every important variable is known in any clinical
study.
The one patient in the ampicillin group who died and the two who survived
with major residua were all severely ill on admission. Nevertheless the clinical
findings in these two survivors were of interest in that C.S.F. pleocytosis with
polymorphonuclear predominance persisted in one, and both developed subdural
effusions and hydrecephalus eventually requiring neurosurgical correction. None
of the patients in the control group required neurosurgery, although it should
be noted that four deaths occurred in this group.
Several studies have demonstrated the in vitro effectiveness of ampicillin
against H. influenzae (Rolinson and Stevens, 1961; Klein and Finland, 1963)
including type B strains isolated from C.S.F. in our hospital (Ivler et al., 1963).
Although ampicillin displayed significantly more activity in vitro than penicillin
G against C.S.F. H. Influenzae isolates, the differences were small and of ques-
tionable clinical significance (Ivler et al., 1963). Nevertheless, the pverall response
of patients with H. influenzae meningitis treated with ampicillin ~vas comparable
to the results observed with chloramphenicol. These favourable results with
ampicillin stand in contrast to the reported experience with penicillin G even
when patients treated with the latter drug had meningitis due to H. influenzae
strains sensitive to penicillin G, and C.S.F. penicillin G levels were maintained
by intrathecal therapy (Drysdale, McIntosh and Brodie, 1946; Zinnemann, 1946;
Thomson, Bruce and Green, 1947). Perhaps qualitative differences in the activity
of ampicillin and penicillin G against H. influenzae account for the more effective
results with ampicillin.
Ampicillin levels in the O.S.F. samples studied to date have been variable,
ranging from 0.1 to 1.0 ~ig./ml. with average C.S.F.-to-seruin ratios of 20 to 30%.
These C.S.F. levels seem rather low in view of the overall satisfactory clinical
response to ampicillin. Indeed, C.S.F. levels of 0.1 to 1.0 pg./ml. barely approxi-
mate the in vitro minimum bactericidal concentrations (Ivler et al., 1963) and
clinical responses have not correlated well with C.S.F. levels. For example, a
C.S.F. sample from an eight month old patient who developed subdural effusion
and hydrocephalus contained more than 7.0 ~zg./ml. of ampicillin, one of the
highest levels found in any patient.
The peripheral blood differential count of 15% neutrophils noted in a three
month old in the ampicillin group on the seventh day of therapy could not be
PAGENO="0560"
4850 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
considered definitely abnormal. The anemias, leukopenias granulocytopenias and
thrombocytopenias observed in the control patients on chloramphenical therapy
all subsided after the drug was discontinued. One control patient who developed
anemia, thrombocytopenia and leukopenia, concurrently developed staphylococcal
pneumonia and extensive phlebitis and cellulitis at the site of an intravenous
polyetheylene catheter. However, as the patient's differential count remained
normal, and the lowest total white blood cell count recorded was 3,100 per cmm.
the superinfection was not necessarily related to the mild leukopenia.
SUMMARY
Overall results of treatment of H. influenza meningities with ampicillin or chlor-
amphenical appeared comparable, but no definite advantages were demonstrated
in the use of ampicillin other than the freedom from hematologic depression.
While one death occurred among the ampicillin group and two additional patients
required neurosurgical procedures for correction of hydrocephalus, four control
patients died and one had severe neurological residual. Further study, perhaps
with higher dosage, is indicated.
This study was supported in part by the Hastings Foundation, and a grant
from Bristol Laboratories, Syracuse, New York, TJ.S~A.
John M. Leedom is an Epidemic Intelligence Service Officer, Epidemiology
Branch, Communicable Disease Center, U.S. Public Health Service.
Dr. Bernard Hanes provided statistical advice.
We should like to thank Robert A. Murray for technical assistance and Drs. A.
Burckin, A. Christiansen, P. R~bbie and V. Spilotro for assistance in reviewing
clinical data and *the house staff of the Communicable Disease Service, Los
Angeles County General Hospital for their co-operation and excellent care of the
patients.
The diagnostic bacteriology was directed by Margaret Parrish and Patricia
Hagen, in the Communicable Disease Section of the Microbiology Laboratories,
Dr. Robert Cleliand, Director, Los Angeles County General Hospital.
Ampicillin assays were performed by Bristol Laboratories, Syracuse, New
York.
REFERENCES
DOLPHIN, A., and POPHAM, R. P. (1951) : Lancet, ii, 472.
DRYSDALE, 0., MCINTOSH, D., and BRODIE, J. (~1946): Brit. med. J., ii 223.
FOTHERGILL, L. P., and WRIGHT, J. (1933): J. Imnwnol., 24, 273.
I~AGGERTY, It. J., and ZIAT, M. (1964) : Advanc. Pediat., 13, 129.
~ivi~, P., Tmiupp, L. D., LERDOM, J. M., WEHBLE, P. F., and `PORTNOY, B. (1963):
Antirnierbial Agents ansi Chenwtlierapy-1963 p. 335, American Society of Micro-
biology.
KLEIN, J. 0., and FINLAND, M. (1963) : Amer. J. med. Set., 245, 544.
PLATOV, R. V. RncKER, A., and DERRICK, J. (1959) : Pediatricts, 23, 962.
ROLINSON, G., and STEVENS, S. (1961): Brit. med. J., ii, 191.
THOMSON, J., BRUcE, L., and G~sic, M. (1947): Brit. med. J.. ii, 414.
ZINNEMANN, K. (1946) : Brit. medJ., ii, 931.
APPENDIX XI
[From Antimicrobial Agents and Chemotherapy, 1965, pp. 610-617]
EXPERIENCE WITH AMPICILLIN IN BACTERIAL MENINGITIS
(By Allen W. Mathies, Jr., John M. Leedom, Lauri D. Phrupp, Daniel Ivier,
Bernard Portnoy, and Paul F. Wehrle)
Departments of Pediatrics, Medicine, and Microbiology, and the
Hastings Foundation Infectious Disease Laboratory, University of
Southera California, and the Communicable Disease Service, Los
Angeles County General Hospital, Los Angeles, California
ABSTRACT
The mortality of bacterial meningitis is 10 to 15% in large contemporary
series and prompts continuing search for effective, nontoxie therapeutic agents.
PAGENO="0561"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4851
Ampicillin was highly effective in vitro against Haenzophilus influenzae, Neis-
seria meningitidis, and Diplococens pneurnoiviae, and, being a penicillin, would
be expec:ted to have low toxicity. Therefore, ampicillin as a single drug treat-
ment for bacterial meningitis was contrasted with "conventional" therapy. From
1 July 1963 to 30 April 1965, 541 bacterial meningitis patients over 2 months
of age were assigned to ampicillin therapy or to conventional therapy with peni-
cillin, chloramphenicol, or both, according to chart number. Error in drug assign-
ment, fulminant meningococcemia, unusual organisms, or concomitant disease
requiring other therapy excluded 88 patients. The severity of illness on admission
was comparable in both treatment groups. Overall mortality rates in the am-
picillin (A) and control (C) groups were 8.3 and 11.8%, respectively. Case
fatality rates varied slightly according to etiological agent, i.e., H. influenzac
(6.0 with A versus 9.3 with C) ; N. meningitidis (5.3 with A versus 9.1 with C);
D. pneumoniae (22.0 with A versus 28.7 with C) ; purulent meningitis, no isolate
(0 with A versus 5.7 with C). The overall incidence of neurological residua
was 12.5% with A and 10.7% with C. Duration of fever and cerebrospinal fluid
abnormalities were comparable. Possible complications of therapy were more
frequent in the control group, primarily because of hematological changes with
chloramphenicol. The data indicate that ampicillin is effective as a single drug
for the three major causes of bacterial meningitis and purulent meningitis of
unknown etiology, and also illustrate the difficulties inherent in naming a
"regimen of choice" when two effective modes of treatment are compared.
Although serum therapy, sulfonamides, and subsequently the use of various
antibiotics have substantially reduced the mortality of bacterial meningitis,
the total case fatality rate remains between 10 and 15% in many large series.
Current therapeutic recommendations for the most frequent types of bacterial
meningitis include one or more of several different antimicrobial agents. Of the
drugs most frequently recommended, only benzylpenicillin lacks major pharma-
cological toxicity. A new 6-amino-penicillanic acid derivative, ampicillin, demon-
strated marked bactericidal activity against Haemophilas injluenzae in vitro and
resembled benzylpenicillin in potential toxicity and efficacy against organisms
customarily penicillin-sensitive (Ivler et al.. 1964). Therefore, it seemed desir-
able to evaluate this antibiotic in the therapy of H. inflnenzae and other types
of acute bacterial central nervous system (CNS) infections.
After treatment of a small nuntber of patients seemed to indicate clinical
efficacy and no toxicity, a controlled clinical evaluation of parenteral ampicillin
in comparison with groups treated with penicillin or chioramphenicol or both,
was started at the Communicable Disease Service of the Los Angeles County
General Hospital in 1963. A preliminary report of this study (Ivler et al., 1964)
and some of the data concerning patients with H. inf1~ei~zae have been presented
previously (Thrupp et al., 1964).
MATERIALS AND METHODS
$election of patients. The Gemniunicable Disease Service of the Los Angeles
County General Hospital is the major referral center for the entire County for
patients with ON1S infections of all ages and from all socioeconomic groups.
Patients were included in the present study in accordance with the following
criteria. All patients 2 months of age and older who were admitted to the Com-
municable Disease Service of the Los Angeles County General Hospital with
bacterial meningitis were in~luded in this study. Patients were assigned to the
ampicillin or control groups on the basis of hospital chart numbers. Ch!art num-
bers were obtained by telephoning the central admitting office, which obviated
physician bias in assignment of patients to one group or another. Patients with
even chart numbers were assigned to the ampicillin group, and those with odd
chart numbers, to the control group.
Administration of antibiotic therapy. One-third of the 24-hr dose of the re-
spective antibiotic was given by' rapid intravenous infusion on admission to
the service. Sodium ampicillin was given in a daily dose of 150 mg/kg, intra-
venously, in equally divided doses at 4-hr intervals. Each dose of ampicillin was
dissolved in 0.85% sodium chloride and was administered as, a rapid infusion.
Reconstituted drug was stored in a `refrigerator at 4 C for not more than a 24-hr
period. After a minimum of 2 or 3 days of intravenous therapy, the antibiotic was
given intramuscularly, at the same dosage, on `a 4-hr schedule. Control therapy
consisted of penicillin G in `doses approximating 150 mg/kg for patients with
NOTE-References at end of article.
PAGENO="0562"
4852 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
Neisseria nwningitidis or Diplococous pneurnoniae infections. For those with H.
influenzae, chioramphenicol was used as a single drug dosage of 100 mg/kg,
for 24 hr. Both of the latter antibiotics were administered by continuous intra-
venous infusion. As with ampicillin, after 2 or 3 days of therapy, these drugs
were given in the same dosage intramuscularly. Control group patients with
meningitis of unknown etiology received both aqueous penicillin G at 150 mg/kg
and chloramphenicol at 100 mg/kg. As outlined above, the initial 24-hr dosage
of ampicillin or penicillin G was therefore approximately 200 mg/kg and for
chioramphenicol was 133 mg/kg. Sulfisoxazole was added to the regimen of a
few patients in the control group at the beginning of the study. In control patients
in whom no organisms were seen on the initial direct examination of the spinal
fluid, but who had subsequent isolation of an organism, either penicillin or
chloramphenicol was discontinued, depending upon the organism identified.
The response to therapy was evaluated by the usual clinical criteria, including
duration of fever, improvement in the mental and neurological status, and im-
provement in the cerebrospinal fluid (OSF). Treatment was continued until:
the patient was afebrile for at least 5 days; the spinal fluid cell count was less
than 30 cells, with less than 10% polyrnor-phonuclear cells; the OSF sugar w-'as
normal: and the protein approached normal. Subdural taps were performed when-
ever indicated.
Bacteriological methods. Gram-stained sediment of spinal fluid was examined
both by the admitting physician and by laboratory personnel. The quellung test
for specific confirmation of H. inftuenzae infections was used if adequate num-
bers of organisms were present. Isolation and identification of the causative
organisms were accomplished b~ conventional methods, including both aerobie
and 002 incubation techniques. In vitro data concerning ampicillin, chioramphen-
icol, and penicillin G sensitivities have been presented previously (Ivler et al.,
19~4).
TABLE 1-TOTAL MENINGITIS PATIENTS STUDIED, LOS ANGELES COUNTY GENERAL HOSPITAL,
JULY 1963 TO APRIL 1965
.
Bacterial etiology
Treatment regimen
Ampicillin Control
Patients
excluded
Total
patients
Haemophilus influenzae
Neisseria meningitidis
Diplococcus pneumoniae
Unknown
Other organisms
66 107
56 77
41 42
29 35
16
23
22
9
18
189
156
105
73
18
Total cases
192 261
88
541
TABLE 2--IDENTIFICATION OF ORGANISMS FROM MENINGITIS PATIENTS BY TREATMENT GROUPS 1
.
Etiology and regimen
Sourc
e of organisms
Total
Smear2
Total
cases
included
CSF
Blood
CSF plus
blood
Haemophilus influenzae:
Ampicillin
Control therapy
Neisseria meningitidis:
Ampicillin
Control therapy
Diplococcus pneumoniae:
Ampicillin
Control therapy
Total
60
94
39
55
34
30
35
51
7
12
21
17
32
42
5
7
20
13
63
103
41
60
35
34
3
4
5
6
6
8
66
107
o 56
77
41
42
312
143
119
336
32
389
1 Total cases studied 453, 81 percent with known etiology (88 exclusions).
2 Direct examination only.
Includes 10 clinical diagnoses.
Includes 11 clinical diagnoses.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4853
RESULTS
Distribution of patients. During the period from 1 July 1963 through 30 April
1965, a total of 541 patients with bacterial meningitis were admitted to the
Communicable Disease Service. The distribution of these patients by etiological
agent is shown in Table 1. The 88 total exclusions comprise patients who were
inadvertently assigned to the inappropriate therapeutic group (43), or were
subsequently discovered to have nonpurulent meningitis (7). Those with under-
lying disease [brain abscess (4) or bacterial endocarditis (7)] were also ex-
cluded, as were those with dual infection (1), unusual organisms (10), and those
patients known to be hypersensitive to penicillin (6). Within the meningococcal
category, those considered by the admitting physician to have fulminant menin-
gococcal disease were also excluded. Five patients who would have received
ampicillin and five patients w-ho might have been assigned to the control group
were thus excluded. All received penicillin G, and two deaths occurred among
these 10 patients, one in each category should they have been included.
Source of organisms. Of the 453 patients suitable for analysis, precise bacterial
etiologies were determined in 368, or 81%. Although many of the patients had
received at least some antibacterial therapy prior to their admission, this was
not a reason for exclusion, since, despite previous antibacterial therapy, the
organism was recovered on culture from the great majority of patients, as is
noted in Table 2. In 32 instances, organisms were identified on direct examina-
tion of spinal fluid or petechiae without subsequent growth in culture. Twenty-
one patients with purulent meningitis and a petechial-purpuric rash were in-
cluded in the meningococcal category on clinical grounds.
Severity of illness. To properly categorize patients for comparative purposes,
they were divided into four groups according to the severity of illness at the
time of admission to the hospital. Included in the 4+ (severe) category, were
patients who were comatose or semicomatose, in definite shock, or with signifi-
cant hypotension. The 3+ (moderate) category included patients with convul-
sions, but who were not hypotensive or comatose. The 2+ (mild) category had
patients in whom either the temperature was greater than 105 F rectally on
admission, or symptoms had been present for more than 5 days; also included
were those with a complication already present on admission or with marked
lethargy. The 1+ (mild) category was reserved for those patients with none of
the above findings but with definite bacterial, meningitis. Since the 2+ and 1+
categories were associated with low mortality and few complications, these grades
have been combined and are presented for allgroups in Table 3. As is apparent,
the distribution of severe and lesser grades of illness was essentially the same
for the ampicillin and the control groups. The method of randomization was
effective, although minor differences in proportions of patients in moderate and
severe categories were seen.
In the pneumococcal severe category there was an apparent difference in the
assignment of excess patients in the severe group to penicillin therapy. This
difference is not statistically significant (X2=3.28; P=0.077), and is explained
by the difference in age distribution for pneumococcal cases (Table 4). Fewer
control patients appear in the 1 to 15-year group, and an excess is apparent in
the 30 to 44-year and 60 to 74-year groups. The slightly lower mortality in
pneumococcal disease with ampicillin therapy may be explained entirely by the
age and severity distributions in this study.
TABLE 3.-TYPES OF MENINGITIS BY SEVERITY ON ADMISSION
Clini
cal estimate on severity
Severe
Moderate
Mild
Total
Etiology and regimen
Number
Percent
Number Percent
Number
Percent
cases
Haemophilus influenzae:
Ampicillin
Control therapy
Neisseria meningitidis:
Ampicillin
Control therapy
Diplococcus pneumoniae:
Ampicillin
Control therapy
Unknown:
13
18
13
23
22
31
20
17
23
30
54
74
10 15
20 18
10 18
4 5
3 7
2 5
43
69
33
50
16
9
65
65
59
65
39
21
66
107
56
77
41
42
Ampicillin
Control therapy
3
5
10
14
5 17
0 0
21
30
73
86
29
35
PAGENO="0564"
4854 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
TABLE 4.-PERCENTAGE DISTRIBUTION
OF MEN
INGITIS PATIENTS BY AGE AND TREAMENT GROUP
Regi-
Etiology men 1
Age group in years
Less
than 1
1-4
75 or
5-14 15-29 30-44 45-59 60-74 more
Total
cases
Haemophilus influenzae A
C
Neisseria meningitidis A
C
Diplococcus pneumoniaa A
C
Unknown A
C
Total
241
41
12
14
15
16
28
25
50
51
39
29
19
5
28
20
9
5 2 1
14 11 9 11 4
22 18 9 4 3 1
12 5 8 17 19 5
5 5 19 19 26 5
14 14 6 10
20 6 17 6 6
66
107
56
77
41
42
29
35
26
35
12 7 7 6 6 1
453
1 A=ampicillin; C=control therapy.
2 Percentage of total group.
Therapeutic response. Over 85% of the patients were afebrile or had a tempera-
ture lower than 100 F rectally by the 7th day in both the ampicillin and control
groups (Table 5). Five H influenzae patients who received ampicillin had sub-
dural effusions, and 3 of these required surgery, whereas 12 of the control group
had effusions, and 1 required surgery. The CSF was re-examined 1 or 2 days
after admission. No positive cultures were obtained from H. influenzae patients
later than 24 hr after admission in the ampicillin group, whereas 6, or 5.6%.
of the 107 patients had positive cultures after more than 24 hr of treatment
in the group treated with chloramphenicol. It was somewhat surprising that one
and three positive cultures after 24 hr were also seen in meningococc'al and
pneumococcal categories, respectively, during penicillin G therapy.
The data conceiming sequelae and mortality are presented in Table 6. As noted,
4 deaths occurred among 66 patients with H. influenzae infection in the ampicillin
group, giving a case fatality rate of 6.0%. There were 10 deaths, or 9.3% among
107 patients in the control group. With respect to neurological residua, the figures
are similar, since 6 of the 66 patients had neurological residua in the amipicillin
group, `and 11 of the 107 patients had neurological residua in the chioramphenicol
group.
The slight increase in residual rate and decrease in fatal outcome in the
meningocoecal patients treated with ampicillin can be explained by a single pa-
tient recovering with sequelae. This difference is not significant.
TABLE 5.-PERCENTAGE DISTRIBUTION OF COMPLICATIONS OF DISEASE AND RESPONSE TO THERAPY BY
TREATMENT GROUP
Problems observed
Subdural effusions
Regi-
Etiology men I
CSF posi-
Persistent Require tive at 24
fever 2 Total surgery hrs.
Total
number of
patients
Haemophilus influenzae A
C
19.4 7.6 4.5
12.3 11.3 .9 5.6
66
107
Neisseria meningitidis A
C
Diplococcus pneumoniae A
C
5.3 3.6 1.8
11.4 2.6 1.3 1.3
12.4 7.3
26.2 4.7 7.1
56
77
41
42
Unknown A
10.3
29
C
8.6 2.9
35
Total A
12.5 5.2 2.1
192
C
13.5 6.5 .8 3.8
261
1 A=Ampicillin; C~=control group.
2Temperature >100° F; (R) >7 days.
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COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4855
TABLE 6.-STATUS ON DISCHARGE FROM HOSPITAL BY ETIOLOGY AND TREATMENT GROUP
Cat
egory of patients studied
No apparent
defect
Recovery with
sequelae
Fatal outcome
Total
number
of
Etiology and regimen
Number Percent
Number Percent
Number
Percent
patients
Haemophilus influenzae:
Ampicillin
Control groups
Neisseria meningitidis:
Ampicillin
Control groups
Diplococcus preumoniae:
Ampicillin
Control groups
Unknown:
56 85.0
86 80.4
~
45 80.4
63 82. 0
24 58.5
22 52. 5
6 9.0
11 10.3
8 14.3
7 9. 1
8 19.5
8 9. 0
4
10
3
7
9
12
6.0
9.3
5.3
9. 1
22.0
28.7
66
107
56
77
41
42
Ampicillin
Control groups
Total:
27 93.1
31 88. 6
2 6.9
2 5.7
0
2
0
5. 7
29
35
Ampicillin
Control groups
Grandtotal
152 79.2
202 77.5
354 78.1
24 12.5
28 10.7
52 11.5
16
31
47
8.3
11.8
10.4
192
261
453
Both the case fatality rate and the frequency of sequelae upon recovery were
extremely high in the pneumoccocal category. This can be expected, since many
of the older patients were alcoholics and in poor nutritional state, and, at times,
substantial delay was encountered before hospitalization. The slightly decreased
fatality rate in those receiving ampicillin is without significance, since, as was
noted earlier, a slight excess of patients' in the older, poor-risk category received
penicillin G. The neurological sequelae in this category represented major defects,
including mental retardation (1), hearing loss (2), definite weakness or paresis
involving one or more extremities (2), expressive a'phasia (1), and other similar
defects. The types of residual defects noted were similar in both control and
ampicillin groups, since three patients in the ampicillin category had definite
hearing loss, one a spastic hemiparesis, and others had defects as noted above
with penicillin G.
No differences in sequelae or fatality rates were seen among patients in the
purulent unknown category. This iS particularly interesting in view of the fact
that the randomization of the patients in this category yielded almost identical
age and severity distribution figures. Patients receiving both chloramphenicol
and penicillin G in large doses had similar responses with ampicillin alone.
With respect to the overall figures, 47 deaths occurred among the 453 patients
treated for purulent meningitis in the various categories. Although this was a
10.4% case fatality rate, it must be remembered that our Service accepts all age
groups, and a substantial portion of our patients come to us with delayed diag-
noses, are severe alcoholics, or are persons found in their residence by an inter-
ested neighbor who has not seen them for sometime. All patients with detectable
heart sounds on admission to the hospital have been included in this report,
whether or not respiratory aids were required. It is of particular interest to note
that there is no significant difference with regard to either fatality or number
and type of sequelae between the ampicillin and contol categories.
TABLE 7.-POSSIBLE COMPLICATI ONS OF THERAPY
Category considered
Ampic
Number
illin
Percent
Contro
Number
I
Percent
Total
Number
Percent
Total treated
Phlebitis
Rash
Local
Eosinophilia 10 percent
Other hematological 1
Other
192
32
18
4
20
7
8
100
16.7
9.4
2.1
10.4
3. 6
4.2
261
39
20
5
18
23
14
100
15.0
7.7
1.9
6.9
8. 8
5.4
453
71
38
9
38
30
22
100
15.7
8.4
2.0
8.4
6.6
4.9
1 Depression of reticulocytes<0.1 percent, or marked reduction in platelets on smear, or 4,000 white blood cells/cm,
or <15 percentpolymorphonucleocytes and bands.
PAGENO="0566"
4856 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
The neurological residua tabulated were those present at the time of discharge
from the hospital, and may or may not have persisted. It is possible that in some
instances additional defects will be found on careful follow-up study during sub-
sequent years. It is important to note that there do not appear to be significant
differences in proportion or severity of residual defects in any category between
the study groups.
Evaluation of the side effects of therapy reveal no significant differences in
the frequency of phlebitis, rash, eosinophilia >10%, or local reactions (Table 7).
There was, however, a substantial difference (12=5.26; P= <0.05) in the fre-
quency of signs of heinatological toxicity. The most frequent change was a depres-
sion of reticulocytes, although granulocytopenia, and thrombocytopenia were
also observed. Only I of 66 patients who received ampicillin for H. infiuenzae
meningitis had a transient depression in granulocytes, whereas 17 of 107 who
received chioramphenicol had hematological abnormalities. All of the hema-
tological changes observed have been reversible, although in two patients in the
chloramphenicol group granulocytic depression persisted for more than 2 months.
DISCUSSION
During the early period of the development of effective antimicrobial agents,
it was apparent, without equivocation, that several caused substantial decreases
in mortality and sequelae in bacterial meningitis. At the persent time, with num-
erous effective and relatively safe drugs available, selection of specific antibiotic
agents for clinical use becomes more complex. These studies were conducted to
determine whether it would be possible to simplify the therapy of acute bacterial
meningitis, so that only a single compound could be used with results equivalent
in safety and effectiveness to currently accepted therapy. Multiple drug therapy
increases the hazards to the patient, as well as the expense of therapy, and, in
addition, complicates nursing care. Since H. influen~rae infection is often difficult
to identify on direct examination of the spinal fluid, even by experienced person-
nel, it has been necessary frequently to administer either tetracycline (with at-
tendant phlebitis with initial intravenous therapy or local reactions on subsequent
intramuscular administration) or chioramphenicol (with a definite hematolo-
gical hazard) to be certain that proper therapy is provided prior to confirmation
by culture. It would appear that these studies demonstrating the efficacy of
ampicillin offer an escape from this dilemma.
As one of the indices used in determining the response to an antibacterial
regimen is the ease fatality rate, it should be noted that this was 8.3% for the
ampicillin group versus 11.8% in patients treated with conventional antibiotic
routines. This difference was not significant, however, and may have been due
entirely to the difference in age distribution of the pneumococcal group.
As noted above, all patients with detectable heart sounds on admission were
included, whether or not aids to respiration were employed in transit, and whether
or not cardiac arrest occurred within minutes. If one adjusts the overall mortality
rate to exclude deaths occurring within the 12 hr immediately after admission,
the corrected case fatality rate in the ampicillin group is 6.3% and among controls
is 9.2%.
With regard to evidence of neurological residua, the rates were also similar
in the two groups. Excluding fatalities, the pro~)ortions with residua at the
time of hospital discharge was 13.6% among ampicillin-treated patients and
12.2% for the control group.
Ampicillin, although appearing to be somewhat more effective than chlor-
amphenicol in vitro (Ivler et al., 1964), did not have a substantially greater clin-
ical therapeutic benefit than chloramphenicol in H. inftvcnzac meningitis. It is of
interest, however, and consistent with the in vitro data, that six patients with
H. inflt~~enzae meningitis had positive spinal fluid cultures 24 hr or more after
initiation of chlorainphenicol therapy, whereas none had similar positive cultures
in the anipicillin category. The in vitro differences between benzylpenicillin and
anipicillin against pneumococci and meningococci, were even less marked, but
ainpicillin appeared slightly more active (Ivler et al., 1964). It is interesting to
note that three patients with pneumococcal meningitis and one with meningococcal
meningitis had positive OSF cultures after 24 `hr of therapy with benzylpenicillin,
whereas none had positive cultures after 24 hr of ampicillin therapy.
While no significant differences were noted between the treatment groups with
regard to phlebitis, skin rashes, local reaction, or eosinophilia, 17 patients (16%)
who received chloramphenicol alone had evidence of hematological depression.
Bone marrow examinations presented the classic picture of chioramphenicol tox-
PAGENO="0567"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4857
icity. Fortunately, none of the reactions was permanent, although two patients
had persistent and marked hematological depression for more than 2 months.
Although ampicillin is not significantly more effective than penicillin G or
chloramphenicol in the treatment of the common types of bacterial meningitis, the
advantages of a single drug and the absence of significant toxicity suggest that
this agent be considered as the drug of choice for the initiai treatment of bacterial
meningitis in patients more than 2 months of `age. It should be emphasized, how-
ever, that, with definite confirmation of the infection as either due to pneumococci
or meningococci, penicillin G provides a less expensive and equally effective mode
of therapy.
ACKNOWLEDGMENTS
This investigation was supported by the Hastings Foundation Fund, Bristol
Laboratories, Inc., Syracuse, N.Y., and by Public Health Service grant
5-PI-AI-275 from the National Institute of Allergy and Infectious Diseases.
We thank Pat Hagen for the primary isolation and identification of bacteria.
REFERENCES
Ivler, D., L. D. Thrupp, J~ M. Leedom, P. F. Wehrle, and B. Portnoy, 1964.
Anipicillin in the treatment of `acute bacterial meningitis. Antimicrobial Agents
and Ohemotherapy-1963, p. 335-345.
Thrupp, L. D., J. M. Leedom, D. Iv'ler, P. F. Wehrle, J. F. Brown, A. W.
Mathies, and B. Portnoy. 1964. H. infiuenzae meningities: a controlled study of
treatment with ampicillin. Postgrad. Med. J. 40:119-125.
APPENDIX XII
EXCERPTS OF AFFIDAVITS SUBMITTED TO THE FOOD AND DRUG ADMINISTRATION
FROM VARIOUS PHYSICIANS RE PRESCRIBING OF DRUG THALIDOMIDE BASED ON
INFORMATION GIVEN BY DETAIL MEN
D. Scott Bayer, M.D., 2122 West E~id Avenue, Nashville, Penn., Obstetrician-
Gynocologist, signed an affidavit which states in part, "About November 1, 1960
I was approached by a representative of the Wm. S. Merrell Company
regarding the use of Kevadon. This representative told me that Dr. Jere C.
Robertson had agreed to use the product in St. Thomas Hospital where he
was a resident physician in OB-GYN. . . . This representative told me that
the firm just wanted a clinical impression based upon our use and testing or
laboratory work were not necessary.. . . Because of the safety representation made
by the representative at that time and because it was my understanding that no
real clinical experimentation or reporting was required, but that only a clinical
impression was wanted, I agreed to sign a statement of investigation for the
representative in order to allow Dr. Jere C. Robertson to use the product.
It was my understanding that Kevadon would very shortly be available as a
prescription item
Bernard A. Bercu, M.D., Wayne County General Hospital, Eloise, Michigan,
Internist, signed an affidavit stating in part, "The detail man on first visit
concerning Kevadon asked me if I would like to try some on patients. I decided
to use Kevadon as a sedative for sleep for some of my patients on the basis
of the representation made to me by the detailman and the preliminary medical
brochure that Kevadon had a very low toxic effect as compared with the other
sleep inducing agents such as barbiturates.. .. I have submitted no reports of any
kind to Wm. S. Merrell Company or to its representatives concerning Kevadon.
I do not consider my use of Kevadon as part of an investigational program to
determine safety. I did use it for familiarization. I had not planned any clinical
trial. I was not prepared to study the drug
Jack B. Brants, M.D., 751 E. 63rd Street, Kansas City, Mo. Internist, signed
an affidavit quoted in part, "In October or November 1960 I was approached by
Frank Johnson, a detailman for Wm. S. Merrell Company, concerning the drug
Kevadon. He presented the drug as a non-barbiturate, non-narcotic, safe sleep
PAGENO="0568"
4858 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
inducing drug. . . . The claims for safety and non-habit forming characteristics
of the drug were largely responsible for my using the drug. . . . I submitted
no written reports on the use of this drug, and the drug was given to me with
this understanding. I did not pretend to do any research on drugs used in my
regular practice. My agreement with Mr. Frank Johnson was that I would
submit no written report but would give oral reports to him. I made it clear that
I was not a research man and that I would want the safety of the drug deter-
mined before I would give it to any of my patients. . . . In my opinion this
drug was made available to me to familiarize me with its use."
John D. DeIlIott, M.D., 1440 Professional Bldg., Kansas City, Mo., Psychiatrist,
signed an affidavit stated in part. "Just prior to November of 1960 I had dis-
cussions with Frank Johnson, detailman for Wm. S. Merrell Company,
regarding my use of the drug Kevadon. I also talked to Dr. T. L. Jones, of
Wm. S. Merrell Company by phone, concerning this same drug and its use.
I decided to try the drug largely because of its claims regarding efficacy and
safety which are of great importance in my type of practice. When arrange-
ments were made for my using the drug, I understood that a clinical report
was to be submitted after I had used the drug for a period. I signed no par-
ticular agreement but drugs were to be supplied to me in the amount that
I requested. The drug was supplied to me to allow me to evaluate its ef-
fectiveness . . . I have not submitted any written reports to Win. S. Merrell
Company but I have given verbal reports to the firm's detailman, Frank John-
son concerning the use of the drug . . . I have received a number of pieces of
literature from the home office of Win. S. Merrell Company and Inspector
Souder made copy of this literature as follows:
"1. Dated August 21, 1962 from Thomas L~ Jones, M.D. giving a current status
report on the use of Kevadon .. ."
Milton Ende, M.D., 121 S. Market Street, Petersburg, Va. Internist, signed
an affidavit stated in part, "The representative contacted me at my office dur-
ing the latter part of 1960 at which time he offered to supply me with Kevadon
for my use as a sedative. The representations made indicated that the drug
was safe for use as a sedative. I do not recall any direct claims for the drug
other than its safety as a sedative. Information supplied me concerning the
drug was of a casual nature with no specific details concerning the drug ex-
cept that I had obtained the impression from the representative that the drug
was completely safe. This drug was represented to me in a manner similar to
the manner in which detailmen or medical representatives present me with
physicians samples of commonly marketed drugs. I was persuaded to accept the
drug for use due to its apparent safety and due to the fact that it was a free
sample for which I would not have to charge my patients . . . I have not
submitted any written reports to Merrell Company but may have filled out any
investigator statement. I do not recall if this statement was supplied by Mer-
roll Company . . . In my original contact with the medical representative con-
cerning this drug I was lead to believe that written reports concerning my use
of this drug would not be necessary, however, I do not recall any positive
statements indicating the need for or non-necessity of written reports and
records . . ."
Ray Firestein., M.D., 416 Sherland Bldg., So. Bend, Indiana, Internist, signed
an affidavit which is quoted in part "The detailman stated or else there were
statements in the literature supplied by Merrell to the effect that Kevadon
had been carefully studied in Europe. I was impressed by the claim that no
lethal dose was known for Kevadon. This alone would have made the use of
Kevadon highly desirable as a hypnotic . . . I did not submit any written
reports to Wm. S. Merrell regarding my use of Kevadon. I did not consider
my use of Kevadon as part of an investigational program to determine safety.
I considered that the manufacturer had supplied me with the drugs so that
I could familiarize myself with its use. I w-as not testing safety. .
PAGENO="0569"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4859
John V. Hummel, M.D., 273 S. Bellevue, Memphis, Tennessee, Obstetrician and
Gynecologist, signed an affidavit which he first wrote out himself and which is
quoted in part, "I was first approached about Kevadon in the winter of 1960 when
Mr. James M. Walker, representative for the Wm. S. Merrell Company was
visiting our office. . . . He was our friend and called on us often. He told us of a
new drug called Kevadon that Merrell had and was waiting to get approval
before putting this drug on the market. He wanted to know if we would like to
have some to try to see if we liked it, how the patients liked it, and so we could
be using it by the time it came on the market. He told us the fundamentals of the
drug. We said that we would try the drug. He sent us a large folder containing a
full account of the drug and stressed how safe it was, that it was of the same
strength as the barbiturates and there was no contraindications that I can
remember. . . . This was not done as a clinical investigation, but as a friendly
personal basis so that we would get an impression of the drug before it was put
out on the market as a sleeping pill
S. Bruce Kepart, M.D., 303 S. Main Street, Bluifton, Indiana, Obstetrician-
Gynecologist, signed an affidavit which is quoted in parts, "I did discuss Kevadon
with Mr. Brenner on/or about November 28, 1960. Probably at that time, I was
supplied with the Wm. S. Merrefl Company's statement of investigator which I
signed. Inspectors Glassner and Maclejewski showed me a copy of this signed
statement. The phraseology under the sectiOn `Brief description of proposed inves-
tigation indicating facilities namely evaluation of above' . . . facilities is not
mind. Under the section animal and human experiments appears the type response
`animal.' I had no intention of conducting any animal experiments on Kevadon nor
do I have experimental animals available. . . Regarding the safety of Kevadon,
I received the aforementioned letter from Mr. Brennan dated November 19, 1960
which indicated that the drug had no fatal dose, that fatal toxicity was not known.
Also, the preliminary medical brochure described above stated that Kevadon was
not addicting and was not habit forming; that tolerance had not been a problem;
that no withdraw-al symptoms had been experienced; that very large dosages had
not produced respiratory depressions; that Kevadon had been administered to
expectant and nursing mothers and that all of the babies were born or nursed
without any abnormality or harmful effects from the medication; that Kevadon
resulted in a very low in side effects; that Kevadon produced no measurably
impairment of the functions of the vital organs.
"As a result of the representa tion made to me as described above, I concluded
that I would try Kevadon in my practice, because (1) it would not be a hazard in
the medicine cabinet in the patient's home in the event of accident ingestion of
over-dosage and because of its non-habit forming property. (2) Its reported
effectiveness in producing normal sleep and not a deep sleep from which a nursing
mother would not be easily aroused to nurse her baby. (3) Because it was as
effective as the most active barbiturate. (4) I was told either by the Merrell
detailman in the fall of 1960 or by Mr. Brenner on/or about November 28, 1960
that Kevadon was soon to be made commercially available and that it was already
being sold in Canada.. . I was not aware at an~y time of instructions from Wm. S.
Merrell Company or its representative that reports from me were unnecessary,
similarly I did not have the impression that the reports from me were required.
In my use of Kevadon, I was not testing its safety; I was not condu~ting a basis
testing program. I was determining its efficacious application so as to be able to
report my experience with its use..
Richard W. Miller, M.D., 1265 Union Avenue, Memphis, Tennessee, Surgeon,
signed an affidavit which is quoted in part, "When first approached, the Mer-
rell representative supplied me with both verbal assurances and literatures at-
testing to the safety of Kevadon. The majority of this literature comprised re-
prints of clinical studies, information as to dosage, contraindications, etc. .
It was my distinct impression that Kevadon w-as not considered an experimental
drug since it had been tested and widely used in Europe and since the literature
and verbal assurances of the Merrell representative pointed up the safety of
the drug. I definitely feel that the manufacturer sought my participation in this
program not to supply clinical evidence but to familiarize myself with Kevadon
and to test the patient acceptance of the drug. It was these verbal and written
81-280 0-69-pt. 11-37
PAGENO="0570"
4860 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
assurances furnished by the Merrell representative which persuaded me to use
Kevadon. . . . When first approached by the Merrell representative with regard
to my trying out Kevadon, I made it clear to them that I was not going to keep
any records or furnish them with any written reports. I was informed that re-
ports would not be necessary.
I explained that I was not setup to do research or provide clinical data because
I deal with paying patients in a private practice. I urged the representative to
seek their data from a clinical which had the personnel, equipment and facili-
ties to do justice to a valid research program. It was my impression that reports
were not required. . . - To reiterate, I felt that verbal and written assurances
on the safety of Kevadon were valid, or else I would never have used the drug.
It is my practice to use experimental drugs. The manufacturer never asked that
I pay for any Kevadon which I received. With this in mind, I felt that the Wm. S.
Merrell Company wanted me to participate in a program which was not to supply
data as to the safety and efficacy of Kevadon since such had already been dem-
onstrated in Europe, but to familiarize myself with the drug and test patient
acceptance. . . ."
Donald J. Nenno, M.D., 490 McKinley Parkway, Buffalo, New York, Obstetri-
cian-Gynecologist, signed an affidavit quoted in part "Mr. Rose represented Keva-
don as being absolutely safe in that according to him it had been proven safe
through wide spread use in Europe and was superior to other hypnotic drugs such
as barbiturates and that it was impossible to be used for suicidal purposes and was
not habit forming. However, Wm. S. Merrell Company advised me not to give the
drug before administering anesthesia as the effect of the drug with anesthesia had
not been documented even though they were certain it was safe. I accepted the
drug on these representations. From our discussion with Mr. Rose, I had no idea
that Kevadon was an experimental drug, the safety of which had not been cleared
by the U.S. Food and Drug Administration. I thought it was simply for clinical
comparison study. I have many drugs offered to me by pharmaceutical companies
for my determination if their effects are superior to competitive products on
the market. Kevadon was represented to me as just another one in that category.
To the best of my knowledge I never signed a clinical investigator statement.
Mr. Rose supplied me with the evaluation forms on which the attending nurse
could record how the patient felt about the drug. Mr. Rose said that these forms
were provided to keep the information on, but it was not necessary to return
them
~1?. C. John Pearson, D.O., 3416 S. W. Webster, Seattle, Washington, General
Practitioner, signed an affidavit which is quoted in :part "The Merrell detailer
stated that he had a new sedative preparation named Kevadon. He strongly indi-
cated a human lethal dosage had not yet been determined and even gross amounts
consumed in suicidal attempts had not been fatal - . . that this was an important
drug since it was a highly effective sedative yet non-toxic. . .. During Mr. Cowles'
visit of 11/3/60, I agreed to evaluate Kevadon in my hospital practice to learn if
the drug was as effective a sedative as indicated by the detailer and the above
brochure. The studies were undertaken on the basis that it was an effective seda-
tive and non-toxic. From Mr. Cowles approach, I considered the use of Kevadon
as an opportunity to determine its efficacy and not to determine its safety since
I had no facilities for this type of study... I gave him my verbal report. . . I do
remember receiving a letter dated August 21, 1961 from the Wm. S. Merrell Co.
where it states among other things `Nulsen administered Kevadon to expectant
mothers with a sleep problem without effects on the newborn infants.'
Roy J. Phillip, M.D., 44 W. Main Street, Carbondale, Illinois, Internist, signed
an affidavit which is quoted in part, "Mr. Howard informed me his firm had a new-
sedative, a drug name Kevadon arid gave me a brochure on the drug. He in-
formed me to note in this brochure that the drug had no LD5O. He also stated
that he would have his firm send me an investigator's statement to sign. He made
no representations as to safety of the drug and other claims except that I should
note or read the information under the safety data. . . But after reading
the brochure I was impressed with the statement under the caption of safety
data that LD5O could not be determined. This specifically persuaded me to under-
PAGENO="0571"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4861
take the use of this drug as a sedative. . . . That I consider the use of the
Kevadon drug as a means to familiarize myself with it and not as part of an
investigational program to determine the safety of the drug."
Jere .C. Robertson, M.D., 1110 S. Main Street, Hopkinsville, Ky., signed an
affidavit which is quoted in part "I was approached by a Wm. S. Merrell detail-
man and asked if I would like a new type of sleeping pill to use in the clinic
known as Kevadon. I remember specifically that the detailman stated that he
could take as much as two bottles and not commit suicide. . . . I recall that
the detailman emphasized the drug's safety. It was my understanding that the
drug Kevadon was due to be marketed momentarily. . . . I believe that the
detallman showed me charts and brochures to emphasize the safety and use of
Kevadon. Because of this I did not believe it was an experimental drug which
required clearance from Dr. D. S. Bayer, Head of the OB-GYN Section of the
St. Thomas Hospital. I am almost positive that I did not sign an investigator
statement before use of the drug. Any experimental drug or drug for investiga-
tional purposes require clearance from Dr. Bayer. I was lead to believe that this
drug, Kevadon, was not in that category. No records of any kind were kept on
the use of this drug and no reports concerning its use were rendered to the firm
as it was my understanding that this was not necessary. I would not have been
persuaded to use this drug had it not been for the assurances given me by this
detailman that it was completely safe and had been thoroughly tested
George P. Roseinond, M.D., 3401 North Broad Street, Philadelphia, Pa.,
Surgeon, signed an affidavit which is quoted in part, "The Merrell representa-
tive told me that this product Kevadon was not yet available for general use.
He told me that his firm was interested in obtaining my opinion of the product.
He told me that Kevadon had been studied quite extensively in Europe and
that its safety had been well established. The latter point of established safety
was well stressed. As I recall, he called to my attention to certain statements
in a product brochure which stressed the safety of Kevadon. He left a copy
of this brochure with me but I no longer have it available. As a result of this
initial meeting, I decided to undertake the use of Kevadon tablet as a hypnotic
convinced by the detailman that the safety of Kevadon had been well estab-
lished by oral representations and statements made in the firm's brochure. The
detailman had me complete a statement of investigator dated November 2,
1960, . . . a copy of a letter from Wm. S. Merrell Company dated August 21,
1962 addressed to me which states Nulsen administered Kevadon to expectant
mothers with a sleeping problem without effects to the newborn infant. I believe
I did receive this reference letter although I do not have my original copy.
I have not submitted any written or verbal reports covering my use of
Kevadon to Wm. S. Merrell Company during the period of my use of the prod-
uct. I had been told by the detailman during his initial contact that such
reports were not necessary. It was my understanding that Kevadon was given
to me to familiarize me with the product and was in no way associated with
or considered as part of an investigational program. I am familiar with the
procedures to be followed for clinical investigations of new drugs. Had I been
told by the Merrell detailman that Kevadon was an investigational new drug
I would have maintained more adequate recOrds covering its clinical use. . . ."
Herbert F. White, M.D., 4741 Broadway N. E., Knoxville, Tenn., Internist,
signed an affidavit which is quoted in part, "Mr. Hurley advised me that
Kevadon was an excellent sedative with no side effects which had been used
extensively in Europe. I was given to understand that Kevadon would be re-
leased in this country for general use very shortly and that Kevadon was the
Merrell name for thalidomide. I was lead to understand that the drug had
been thoroughly tested and was safe and at this time clinical evaluation was
all that was being requested. It was my understanding that Kevadon was not
to be considered an experimental drug in the true sense and that controlled
experiments with laboratory testing was not required. Mr. Hurley had litera-
ture which he showed me during this first presentation which confirmed the
above statement on the drug's efficacy. I agreed to use the product because of
PAGENO="0572"
4862 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY
the above representations and because I had a number of elderly people in
the hospital with a sleep problem on whom I expected to use the drug.
I did receive a letter from Wm. S. Merrell dated August 21, 19G1 which stated
among other things `Nulsen administered Kevadon to expectant mothers with
a sleep problem without effect on the newborn infants.' This letter also requested
that I fill out a brief summary report of my clinical experience with Kevadon.
I did not complete or return these forms because of the extremely limited use
I had made of the drug because I had initially not been asked for any reports
and understood that such were not necessary. . . ."
H. Glenm Williams, M.D., 273 South Bellevue, Memphis, Tenn., Obstetrician-
Gynecologist, signed an affidavit which is quoted in part "Mr. Walker told me
about Kevadon and stressed both the safety of the drug and the fact that it had
about the same potency as barbiturates. Mr. Walker also stated that it was
almost impossible to take an overdose of Kevadon. He said that his firm wanted
physicians with private practices such as mine to try the drug. He said that this
was to be done both to acquaint the doctor with Kevadon and to test patient
acceptance of the drug. Mr. Walker said that the drug had already been proven
safe in Europe and this program which was promotional in nature was to be
accomplished prior to the formal release of Kevadon early in 1~61. . . . I cannot
recall whether or not I signed a Statement of Investigator for Merrell. In any
event I made it quite clear that I did not plan to do further research on the
drug. . . . To reiterate, I did not furnish the Wm. S. Merrell or their repre-
sentative with any written reports. I told them from the beginning that I did
not have time to keep records. If they still wanted me to try their drug out
I would do just that. It was my impression that reports would not be required.
I recall at least one instance on an undetermined date where the Merrell rep-
resentative possibly Mr. James M. Walker asked me informally how I liked
the drug. I told him I liked it fine. There was no detailed questioning, and as far
as I remember my answer was confined to how I like Kevadon. I do not know
whether this impression of Kevadon was to be considered as clinical data. I did
not give it as such as I had not agreed to enter into an investigational program.
From the beginning it was my impression that Kevadon was not an experi-
mental drug. I was lead to believe from both the clinical reports and by verbal
assurances from the Merrell representative that Kevadon was safe. I actually
thought the drug had been released by FDA. I even wrote several prescriptions
for the drug which bounced, of course. I felt from the very first that the Wm.
S. Merrell Company wanted physicians with private practices to become familiar
with Kevadon and test patient acceptance. It was my impression that my par-
ticipation in this program was promotional in nature and was to precede formal
introduction of Kevadon to the American market early in 19f31
Uknsde H. Workman, M.D., 273 S. Bellevue, Memphis, Tenn., Obstetrician-
Gynecologist, signed an affidavit which is quoted in part "When Mr. Walker
approached me about Kevadon in late 1960, he told me that the drug was safe.
Mr. Walker did not seem to know much else about the drug but he said that he
would send me some literature which contained all of the necessary details.
To the best of my knowledge Mr. Walker wanted me to try Kevadon to see how
I liked it. I interpreted the program to be promotional rather than investiga-
tionaL To the best of my knowledge I did sign a statement of investigator. I told
Mr. Walker that I did not plan to enter into a formal investigation of Kevadori.
I was informed that Merrell just wanted me to try the drug. It was my impres-
sion that the drug had been proven safe and would be on the market in a few
months. . . . During the period in which I was trying Kevadosi, I did not `submit
any written reports to either Wm. S. Merrell Company or to any of their repre-
sentatives. I do recall giving a verbal report on at least one instance to Mr.
James M. Walker, Merrell representative. He asked me informally how I liked
the drug, I told him it was the best sedative that I had run across. . . . It is
my firm belief that the Wm. S. Merrell asked me to enter into this Kevadou
program for promotional investigation reason
PAGENO="0573"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4863
Appendix XIII
A Study of Pharmaceutical Advertising in Selected
Medical Journals
(I-~ ~
THE LIBRARY OF CONGRESS
WASHINGTON, D.C. 20540
10~~
~
LEGISLATIVE REFERENCE SERVICE
March 6, 1969
TO: Senate Subcommittee on Monopoly, Select Committee
on Small Business
FROM: Education and Public Welfare Division
SUBJECT: Study of Pharmaceutical Advertising in Selected
Medical Journals
This is in reply to a request from the Chairman of the Sub-
committee asking the Legislative Reference Service to undertake a de-
tailed study of the patterns of pharmaceutical advertising appearing
in selected medical journals over the last several years. The Chair-
man also asked that we ascertain to what degree such advertising con-
stitutes a source of revenue for these journals and the medical or-
ganizations which publish then. We were also asked to proyide the
Subcommittee staff with other m;terials showing the relationship be-
tween the organizations which publish the journals analyzed in this
report and the manufacturers who advertise in the journals studied.
1. The Advertising Survey Design
At the direction of the Subcommittee staff, the Legislative
Reference Service undertook a survey of the pharmaceutical and other
advertising which appears in four medical journals, each of which is
published by a different professional association of medical practi-
tioners. The journals selected for the survey were: The Journal of
the American Medical Association, published by the American Medical
Association; The Journal of Abdominal Surgery, published by the Ameri-
can Society of Abdominal Surgeons; The Annals of Internal Medicine,
published by the American College of Physicians; and the American
Family Physician, published by the American Academy of General Practice.
The survey period covered a span of five years for each pub-
lication, from January 1963 through December 1967. Each issue of each
magazine was reviewed by the staff, except for four issues of ~
Journal of Abdominal Surgery during 1967 and the six issues of the
PAGENO="0574"
4864 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
LRS-2
American Family Physician for 1963, and one issue of the Journal of the
American Medical Association for 1963, which were unavailable for review.
The review was made from the collected sets of these journals maintained
by the Library of Congress and the National Library of Medicine.
The data contained in this report were obtained fron a review
of the advertising pages found in each journal and, in part, fron a re-
view of the advertising index which each of these journals publishes in
each issue. Where the advertising indices were used, careful exanination
of the particular index was nade to assure that the information contained
therein accurately reflected advertising copy appearing in the publica-
tion. Where the indices were deemed unreliable, a page-by-page review
was made of the issues under study. For some journals, a page-by-page
review was necessary for every issue.
The advertising copy found in the four journals was studied in
sufficient detail in order to obtain information on the firms which ad-
vertise in particular issues, the trade-names of the products advertised
by these firms, the frequency with which some products appeared, and the
volume of advertising copy devoted to the promotion of each product.
Summary data were compiled for each journal, for each year,
showing the journal page-to-advertising ratios of the magazine studied,
and the distribution of pharmaceutical advertising to other advertising
appearing in each magazine throughout the study period. In addition to
the summary data, a detailed manufacturer and product survey for each
year of each journal is contained in this report to the Subcommittee.
In the case of the Journal of the American Medical Association and the
Annals of Internal Medicine, the data gathered are so extensive, that
additional summary data have been prepared showing the ten leading firms
by volume of advertising for each year, the ten most frequently advertised
products for each year, and the ten most heavily advertised products for
each year, for each of these two journals.
2. The Survey Criteria
Certain criteria were employed in carrying out the survey in
order to determine which products would be specifically identified in
the study. These criteria were adopted to select out that advertising
in the four journals which could not properly be termed "pharmaceutical
advertising." Advertising copy not satisfying the criteria used in the
study are excluded from the detailed data representations appearing here-
in, but are accounted for in the aggregate under the term "other journal
advertising."
Each page of each journal was classified into one of three
categories: journal pages, pharmaceutical advertising, and other journal
advertising. Journal pages represent the residual number of pages
PAGENO="0575"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4865
LRS-3
remaining in any particular issue after pharmaceutical and other journal
advertising are accounted for. Pages so counted are those devoted to
articles, papers, indices, announcements, tables of contents, classified
advertising, and other pages not otherwise counted in either of the other
two categories.
The term "other journal advertising", is used to account for
non-medical trade advertising such as advertising copy promoting soaps,
coffee, soft drinks, foods, and other similar products. Also included
in this category are advertisements for medical devices and instrumen-
tation, books, educational opportunities and courses, employment oppor-
tunities except when they involve placement bureaus, and other service
promotions. Institutional promotions, even for manufacturers whose prod-
ucts may be otherwise included in the detailed survey, are also shown in
this category.
The term "pharmaceutical advertising" is intended to apply to
prescription-legend drug products and to certain non-legend or over-the-
counter items, including for example certain antacids, topical prepara-
tions, and so on. Vitamin products and certain contraceptive agents are
also identified in this category. Persons desiring to limit the detailed
data to prescription-legend items only could do so simply by eliminating
other products in the detailed analysis and by adding the number of pages
for such products to the category of "other journal advertising."
For the purpose of this study, any page which contains a com-
mercial advertisement is considered a page of advertising, rather than a
journal page. And, where two or more commercial advertisements are found
on the same page, each is counted as a distinct page of advertising. This
apportionment of advertising pages, however, does not alter substantially
the conclusions from the survey, since the overwhelming majority of com-
mercial advertisements are full-page promotions. To further test the
validity of this method, a comparison was made between the results of the
Anerican Medical Association's own study of advertising-to-editorial page
ratio in their Journal with the results of this survey for the same time
period. In a report found in the Journal, the following statement was made:
The editorial-to-advertising pages ratio was
~/ Journal of the American Medical Association, Vol. 202, No. 1,
October 2, 1967.
PAGENO="0576"
4866 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
LRS-4
55:45 based upon the total of 6,864 pages
published during this period [first 6
months of 1967].
Findings from the LRS survey, using the assumptions and criteria set
forth above, produce a ratio of 56.2:43.8. We believe, therefore, that
the data contained in this report fairly represent the volume and dis-
tribution of advertising in the medical journals studied.
3. Organization of Report
The summary and detailed data given in this report are arrayed
by the particular journal surveyed. The Journal of the American Medical
Association which is the largest of the four publications, in terms of
volume of pages and circulation, is discussed in Part I of the report.
Parts II, III, and IV are devoted to the Annals of Internal Medicin~
the American Family Physician, and the Journal of Abdominal Surgei~y, in
that order.
Each Part in the report begins with summary data covering the
entire period of the survey for each journal studied. Among the data
sunmiarized are the total pages published for each year, the total jour-
nal pages, total advertising pages, total advertising pages classified
as pharmaceutical advertising, and the total of other advertising pages.
The data are also represented as percentages for each of these cate-
gories for each year studied.
Following the summary data, a detailed product survey for each
year is given, showing the names of the manufacturers, the trade-names
of the products advertised, the frequency of the products advertised,
and the volume of copy devoted to each product. In the case of the
Journal of the American Medical Association and the Annals of Internal
Medicine, special annual summaries are given showing the leading firms
which advertise in these two journals, the most frequently advertised
products, and the most heavily advertised products appearing in the two
journals.
4. Income from Advertising Revenue
The Chairman asked that we attempt to ascertain to what degree
advertising revenue constitutes a source of income for the nedical asso-
ciations which publish the four journals surveyed in this study. We have
obtained data showing this relationship only for the American Medical
Association. Other publications by the remaining three organizations,
insofar as they are available for review in the Library of Congress,
PAGENO="0577"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4867
LRS-5
produced no usable data in this area. The staff of the Subcommittee
has been advised of this finding, but we understand that sone of the
data needed by the Subcommittee has been subnitted by the organizations
thenselves. We have, therefore, included in this report only the infor.-
nation on the American Medical Association. Should it be necessary to
obtain comparable information for the other three organizations, direct
inquiry to the associations probably will be required.
Table 1 on the next page shows the total incone and income from
advertising of the American Medical Association for the period 1961-1967.
Table 2 shows the total income and income from exhibit space sales for
the sane period. Income from exhibit space sales is'in~luded since many
of those organizations which purchase such space are pharmaceutical manu-
facturers who also advertise extensively in the publications of the Asso-
ciation. Table 3 shows the sources of income of the American Medical
Association by each source of income, including that obtained from adver-
tising revenue. Table 4 gives the A.M.A.'s financial status for the six-
year period 1962-1967.
If there are any questions in connection with this report,
please let us know.
Glenn Markus
Joe Licata
Attachment
Table I - Total Income, Income from Advertising, A.M.A., 1961-1967
Table II - Total Inoome, Income from Exhibit Space Sales, A.M.A.,
1961-1967
Table III - Sources of AMA Income During 1961-1967
Table IV - American Medical Association Financial Position 1962-1967
Survey of Pharmaceutical Advertising in Selected Journals
PAGENO="0578"
4868 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
LRS-6
TABLE 1
TOTAL INCOME, INCOME FROM ADVERTIS ING, A. M. A., 1961-19671/
ADVERTISING AS
% ALL INCOME
YEAR
TOTAL INCOME
ADVERTISING INCOME -
1961
$17,589,537
$ 8,906,993 51.0%
1962
19,524,435
9,017,383 47.0%
1963
22,516,013
10,122,065 45.0%
1964
23,110,239
10,356,640 44.8%
1965
27,772,879
12,770,825 46.0%
1966
27,759,623
13,290,714 47.9%
1967
31,677,215
13,565,106 42.8%
TABLE 2
TOTAL
INCOME, INCOME FROM
EXHIBIT SPACE SALES, A.M.A., 1961-19671/
INCOME FROM EXHIBIT EXHIBIT INCOME
YEAR
TOTAL INCOME
SPACE SALES AS % ALL INCOME
1961
$17,589,537
$664,753 2.0%
1962
19,524,435
605,104 3.0%
1963
22,516,013
577,092 2.6%
1964
23,110,239
638,471 2.8%
1965
27,772,879
832,341 3.0%
1966
27,759,623
782,680 2.8%
1967
31,677,215
730,646 2.3%
1/ Fron Reports of Annual or Clinical Conventions of the American
Medical Association for each year.
PAGENO="0579"
SOURCES OF AMA INCOME DURING 1961-19671/
C
t~j
H
1965 ~t-4
At ____ ____ H
1961
Amount
1962
Amount
1963
Amount
1964
Amount
Advertising $
Subscriptions
Membership Dues
Directory Report Service...
Exhibit Space Sales
Investments
Miscellaneous Publications.
Other Gross Income
8,906,993 (51)
6,475,289 (37)
.~J
749,839 (6)
664,753 (2)
410,372 ~2)
382,291~ (2)
.~
$
9,105,636 (47)
2,533,995 (13)
5,483,388 (28)
776,615 (4)
605,104 (3)
666,320 (2)
353,377.~I(2)
±1
$10,122,065 (45.0)
2,713,269 (12.0)
7,210,680 (32.0)
822,089 (3.7)
577,092 (2.6)
597,086 (2.6)
473,7322.1(2.1)
.~I
$10,356,640
2,279,444
7,337,043
1,054,787
638,471
670,760
441,384
331,710
(44.8)
(9.9)
(31.7)
(4.6)
(2.8)
(2.9)
(1.9)
(1.4)
Total $17,589,537
$19,524,435
$22,516,013
$23,110,239
C
H
H
Advertising $12,770,825(46.O)
Subscriptions 2 316 535 (8 4)
Membership Dues 7,446,612 (26.8)
Directory Report Service... 1,241,980 (4.4)
Exhibit Space Sales 832,341 (3.0)
Investments 1,001,338 (3.6)
Miscellaneous Publications. 1,862,024 (6.7)
Other Gross Income 301,224 (1.1)
Total $27,772,879
1966
Amount
$13,290,714 (47.9)
2,436,550 (8.8)
7,508,058 (27.0)
1,451,451 (5.2)
782,680 (2.8)
824,739 (3.0)
1,144,254 (4.1)
321,177 (1.2)
$27, 759, 623
1967
Amount
$13,565,106 (42.8)
2,726,217 (8.6)
11,547,120 (36.5)
1,538,139 (4.8)
730,646 (2.3)
589,393 (1.9)
822,386 (2.6)
158,208 (.5)
$31,677,215
L/ From Reports of Annual or Clinical Conventions of the American Medical Association for each year.
Figures in parentheses are percentages of total income.
2/ Amount of Income from Membership Dues included in Subscriptions.
3/ Shown only as "miscellaneous income" for the years 1961-1963.
4/ No "other income" reported for 1961-1963.
PAGENO="0580"
AMERICAN MEDICAL ASSOCIATION FINANCIAL POSITION 1962-19671/
1962
ASSETS
Cash $ 600,973
Accounts and notes receivable 876,274
Inventories and prepaid expenses.... 691,316
Building and equipment 4,489,752
Investments and other assets 8,367,660 ___________ ___________
TOTAL $15,025,975
LIABILITIES
Accounts Payable $ 967,623
Income Received but not yet earned.. 1 684 823 ___________ ___________
TOTAL $ 2,652,446
NET WORTH $12,373,529
ASSETS
Cash $ 271,206
Accounts and notes receivable 856,402
Inventories and prepaid expenses.... 1,704,330
Building and equipment 8,946,458
Investments and other assets 6,424,119 __________ __________
TOTAL $18,202,515
1963 1964
$ 109,794
844,605
741,584
5,237,299
10,636,581
$17,569, 863
$ 1,112,914
1,721,021
$ 2,833,935
$ 117,989
953,021
890,900
7,420,071
8,688, 685
$18,070,666
$ 1,650,682
1,920, 765
$ 3,571,447
********* **
1965
$14,735,928 $14,499,219
1966 1967
Co
$ 353,652
1,151,498
1,550,382
9,275,467
7,095,887
$19, 426,886
$ 234,524
1,150, 304
1,498,944
9,260,808
11,102,365
$23,246,945
LIABILITIES
Accounts Payable $ 1,844,057
Income Received but not yet earned.. 2,051,124
TOTAL 3,895,181
NET WORTH $14,307,334
$ 1,715,381 $ 1,909,609
2,030, 126 2,325,726
$ 3,745,507 $ 4,235,335
$15,681,379 $19,011,610
1/ From Reports of Annual or Clinical Conventions of the American Medical Associa-
tion for each year.
PAGENO="0581"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4871
SURVEY OF PHARMACEUTICAL ADVERTISING IN SELECTED JOURNALS
TABLE OF CONTENTS
Part I The Journal of the American Medical Assotiation pages
1. Summary Data: 1963-1967 1
2. Year: 1963
a. 10 Leading Firms, by Advertising Volume 2
b. 10 Most Frequently Advertised Drugs 2
c. 10 Most Heavily Advertised Drugs 2
d. Detailed Product Data 3
3. Year: 1964
a. 10 Leading Firms, by Advertising Volume 15
b. 10 Most Frequently Advertised Drugs 15
c. 10 Most Heavily Advertised Drugs 15
d. Detailed Product Data 16
4. Year: 1965
a. 10 Leading Firms, by Advertising Volume 27
b. 10 Most Frequently Advertised Drugs 27
c. 10 Most Heavily Advertised Drugs 27
d. Detailed Product Data 28
5. Year: 1966
a. 10 Leading Firms, by Advertising Volume 40
b. 10 Most Frequently Advertised Drugs 40
c. 10 Most Heavily Advertised Drugs 40
d. Detailed Product Data 41
PAGENO="0582"
4872 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
6. Year: 1967 pages
a. 10 Leading Firms, by Advertising Volume 52
b. 10 Most Frequently Advertised Drugs 52
c. 10 Most Heavily Advertised Drugs 52
d. Detailed Product Data 52
Part II The Annals of Internal Medicine
1. Summary Data: 1963-1967 62
2. Year: 1963
a. 10 Leading Firms, by Advertising Volume 63
b. 10 Most Heavily Advertised Drugs 63
c. Detailed Product Data 64
3. Year; 1964
a. 10 Leading Firms, by Advertising Volume 71
b. 10 Most Heavily Advertised Drugs 71
c. Detailed Product Data 72
4. Year: 1965
a. 10 Leading Firms, by Advertising Volume 79
b. 10 Most Heavily Advertised Drugs 79
c, Detailed Product Data 80
5. Year: 1966
a. 10 Leading Firms, by Advertising Volume 87
b. 10 Most Heavily Advertised Drugs 87
c. Detailed Product Data 88
PAGENO="0583"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4873
6. Year:, 1967
a. 10 Leading Firms, by Advertising Volume 96
b. 10 Most Heavily Advertised Drugs 96
c. Detailed Product Data 9.7
Part III The American Family Physician
1. Summary Data: 1963-1967 104
2. Year: 1963 105
3. Year: 1964 107
4. Year: 1965 110
5. Year: 1966 113
6. Year: 1967 116
Part IV Th.e Journal of Abdominal Surgery
1. Summary Data: 1963-1967 120
2. Year: 1963 121
3. Year:, 1964 122
4. Year: 1965 123
5. Year; 1966 12~
6. Year: 1967 125
iii
PAGENO="0584"
*Based on review of 5lof 52 issues published in 1963.
JOURNAL OF AMERICAN MEDICAL ASSOCIATION
SUMMARY DATA
Advertising, 1963 through 1967
4874 COMPETITIVE
PROBLEMS IN
THE DRUG INDUSTRY
Volume in Pages
Total
Pages
Year Magazine
Total
Pages
Journal
Total
Pages
Advertising
Total Pages
Drugs
Advertising
Total Pages
Other
Advertisi'~
1963* 12,418
6,548
5,870
4,526
1,344
1964 12,702
6,863
5,839
4,650
1,189
1965 13,438
7,244
6,194
5,149
1,045
1966 14,286
7,664
6,622
5,354
1,268
1967 13,332
Total... 66,176
7,501
35,820
5,831
30,356
4,964
24,643
867
5,713
Percentag~
Year
Percent
Total
Pages
Percent
Journal
Pages
Percent
Advertising
Pages
Drug Advertising
as Percent
All Advertising
as Percent
All Advertising
1963*
100.0%
52.7%
47.3%
77.1%
22.9%
1964
100.0%
54.0%
46.0%
79.6%
20.4%
1965
100.0%
53.9%
46.1%
83.1%
16.9%
1966
100.0%
53.6%
46.4%
80.8%
19.2%
1967
Total...
100.0%
100.0%
56.2%
54.1%
43.8%_
45.9%
85.1%,
81.1%
14.9%
18.9%
1
PAGENO="0585"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4875
THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
SUMMARY DATA
1963*
10 Leading Firms, by Volume of Advertising
RANK
FIRM NO. DRUG ADVERTISING PAGES
1
2
Wallace Laboratories
Merck, Sharpe, & Dohme
524
457
3
Warner-Chilcott
239
4
Abbott Laboratories
192
5
Lederle Laboratories
174
6
Upjohn
163
7
Wyeth Laboratories
158
8
Burroughs-wellcome
157
9
Lilly
145
10
Pfizer
144
RANK
1
2
3
4
5
6
7
8
9
10
10 Most
Frequently Advertised Drugs
ISSUES IN WHICH ADVERTISED
DRUG NO.
Deprol (Wallace)
Miltown Wallace)
Meprospan (Wallace)
Appertrol (Wallace)
Sums (Wallace)
Capla (Wallace)
Aldomet (Merck)
Miltrate (Wallace)
Tepanil (National)
Orinase (Upjohn)
so
so
48
40
38
34
33
33
33
31
RANK
1
2
3
4
S
6
7
8
9
10
10 Most
Heavily Advertised Dr~~
DRUG NO.
Peritrate (Warner-Chilcott)
Aldomet (Merck)
Miltown (Wallace)
Deprol (Wallace)
Diuril/Hydrodiuril (Merck)
Capla (Wallace)
Orinase (Upjohn)
Orenzyme/Parenzyme (National)
Neprospan (Wallace)
Darvon (Lilly)
PAGES
ON WHICH ADVERTISED
97
96
93
89
67
64
64
54
49
48
*Based on a review of 51 of 52 issues published in 1963.
2
81-280 0-69-pt. ll-38
PAGENO="0586"
4876 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
19 63*
COMPANY PRODUCT NO. ISSUES NO. PAGES
Abbott Laboratories
1. Compocillin-VK 8 16
2. Desbutal 11 21
3. Desoxyn 12 24
4. Enduron 2 8
5. Enduron/Eutonyl 2 10
6. Erythocin 13 28
7. Eutonyl 8 28
8. Nembutal 4 8
9. Norisodrine 10 14
10. Placidyl 3 3
11. Quelidrine 2 2
12. Radio pharmaceuticals 9 9
13. Selsun 3 3
14. Surbex-T 13 13
15. Various 1 1
16. Vi-Daylin 2 4
Total... 192
Arch Laboratories
1. Dicarbosil 10 Total... 10
Armour
1. Acthar 6 6
2. Chymar 10 10
3. Chymoral 12 26
4. Listica 4 5
5. Thyroid 4 6
Total... 53
Ayerst Laboratories
1. Gristactin 6 12
2. Mesulf in 1 2
3. Premarin 6 10
4. Thiosulfil 5 14
Total... 38
Breon Laboratories
1. Bronkometer - 12 12
2. Bronkotabs 11 _J:~;L_~
Total... 23
* Based on review of 51 of 52 issues published in 1963.
PAGENO="0587"
COMPANY
CIBA Pharmaceutical
Davies, Rose, Hoyt
De~itin Chemical
1. Kantrex
1. Aerosporin
2. Antepar
3. Cardilate
4. Cardilate-P
5. Empirin
6. Lanoxin
7. Leukeran
8. Mantadil
9. Migral
10. Nyleran
11. Narezine
12. Perazil
13. Purinethol
1. Esidrex/Esidrex-K
2. Doriden
3. Ismelin
4. Serpasil
5. Vioform
1. Digitalis
2. Quinidine sulfate
1. Come-dab
2. Cort-Dome
3. Cor-Tar-Quin/others
4. Neo-Domeform
1. Desitin ointment
4 Total... 8
8
20
10
8
15
24
12
6
4
12
23
3
12
Total... 157
30
34
24
23
13
Total... 124
3 3
3 3
Total... 6
4 4
6 6
3 3
2 2
Total... 15
COMPETITIVE PROBLEMS IN
THE DRUG INDUSTRY 4877
PRODUCT
Bristol Laboratories
Burroughs-Wellcome
NO. ISSUES NO. PAGES
8
20
7
7
12
12
11
6
4
11
23
3
11
19
23
11
21
12
Dome
11 Total... 12
4
PAGENO="0588"
4878 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Eaton Laboratories
1. Furacin 27 29
2. Furadantin 21 25
3. Tricofurcn 12 12
Total... 66
Endo Laboratories
1. Coumadin 26 43
2. Hycodan 10 10
3. Numorphan 22 22
4. Percodan 10 10
5. Valpin/Valpin-PB 16 24
Total... 109
Flint, Eaton, & Co.
1. Synthroid 9 Total... 9
1. Butazolidin 10 10
2. Persantin 6 18
Total... 28
Glenbrook Laboratories
1. Bayer Aspirin 7 7
2. Philips Milk of
Magnesia 6 6
Total... 13
Hynson, Westcott, & Dunning
1. Broniosulphalein 4 4
2. Lactinex 1 1
3. Lutrexin 6 6
Total... 11
Holland-Rantos
1. Nylmerate 6 Total... 6
Ives Laboratories
1. Cyclospasmol 16 19
2. Isordil 12 16
Total... 35
Johnson & Johnson
1. Liquiprin 5 Total... 5
PAGENO="0589"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4879
COMPANY PRODUCT NO. ISSUES NO. PAGES
~y Pharmaceuticals
1. Nitroglyn 7 Total... 7
Lakeside Laboratories
1. Imferon 14 Total... 14
Leeming, Thomas
1. Metamine 8 Total... 8
Lederle Laboratories
1. Achromycin 16 25
2. Aristocort 14 28
3. Bainadex 10 15
4. Declomycin 20 40
5. Ferro-Sequels 10 10
6. Hydromox 14 28
7. Orimune 4 8
8. Pathibamate 11 21
Total... 175
Lilly, Eli
1. Anhydron/w/K, KR 2 8
2. Darvon 26 48
3. Haldrone 12 40
4. Ilosone 16 18
5. Novrad 5 17
6. Quintess 2 2
7. V-Cillin-K 9 12
Total... 145
1. Doxidan 4 Total... 7
Mallinkrodt Chemical
1. Codeine 12 Total... 12
Mead Johnson
1. Beta-Chlor 13 15
2. Mucomyst 1 3
3. Quibron 9 18
4. Vasodilan 16 16
Total... 52
McNeil Laboratories
1. Butisol 14 Total... 27
6
PAGENO="0590"
4880 ~o~jpETITIvE PROBLEMS I~ THE DRTJG INDUSTRY
C0MP~ANY PRODUCT NO. ISSUES NO. PAGES
Merck, Sharpe, & Dohme
1. Aldomet 33 96
2. Aldomet/Rubeovax 1 2
3. Aldoril 11 21
4. Aramine 7 14
5. Benemid/Colbenemid 5 20
6. Codeine 1 1
7. Cuprimine 4 4
8. Decadron 21 34
9. Decagesic 25 30
10. Diuril/Hydrodiuril 20 67
11. Diupres 13 17
12. Elavil 13 26
13. Hydropres 15 20
14. Mephyton/Aquamephyton 9 11
15. Periactin 7 7
16. Redisol/AipharedisOl 16 16
17. Respihaler some WI
Xylocaine 24 47
18. Rubeovax/Gaminagee 11 19
19. Urecholine 5 5
Total... 457
Merrell, Wm. S.
1. Bentyl 4 8
2. Tenuate 13 13
Total... 21
National Drug
1. Orenzyme/Parenzyme 27 54
2. Parenzyme 3 6
3. Tepanil 33 41
4. Vaccines (various) 13 13
Total... 114
1. Hexadrol 6 Total... 6
Ortho
1. Ortho-Novuni 4 Total... 4
7
PAGENO="0591"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
4881
Parke-Davis
Pfizer, Chas.
Purdue-Frederick
1. Benadryl
2. Chioromycetin
3. Dilantin
4. Elase
5. Norlutate
6. Pitocin
7. Povan
1. Diabinese
2. Renese
3. Terramycin~
4. Vistaril
1. Jefron
2. Novahistine DH
3. Novahistine Elixir
4. NovahistineLp
5. NovahistineMelet
6. Novahistine Singlet
1. Silain/Sibel
2. St. Joseph's Aspirin
1. Mudrane
2. Trocinate
3. Synirin
4. Solfoton
1. Cardioquin
2. Paremycin
3. Senokot
20
44
17
1
9
12
4
Total... 107
22 44
16 32
21 44
12 24
Total... 144
16
11
4
11
4
5
Total... 51
2
12
Total... 14
14 15
4 4
1 1
7 7
Total... 27
4 4
5 5
16 16
Total... 25
COMPANY PRODUCT NO. ISSUES NO. PAGES
10
25
9
1
9
12
4
Pittman-Moore
Plough, Inc.
Polythress, Wa. P.
9
7
2
7
2
3
2
12
8
PAGENO="0592"
4882 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMRANY PRODUCT NO. ISSUES NO. PAGES
Radium Chemical
1. Radium 12 Total... 12
Riker Laboratories
1. Medihaler-Duo 11 22
2. Norflex 8 16
3. Rauwiloid 2 4
4. Ulo 4 7
Total... 49
Robins, A. H.
1. £Ambar 3 3
2. AllBee w/C 6 6
3. Dimetane 10 13
4. Donnatal 12 15
5. Naclex 4 8
6. Robaxin 11 18
7. Robaxisal 3 5
8. Robinul/Robinul-PH 7 11
9. Skelaxin 5 10
Total... 89
Roche Laboratories
1. Alurate 1 1
2. Gantrisin 6 6
3. Gantanol 1 4
4. Librium 17 26
5. Nestinon 2 4
6. Nadribon 2 4
7. Roniacol 1 1
8. Taractin 11 11
9. Tigan 4 4
10. Valium 2 10
Total... 71
Roerig, J. B. & Comp~
1. Atarax 7 15
2. Antivert 14 14
3. Enarax 7 15
4. Narax 12 12
5. Tao 12 32
Total... 88
9
PAGENO="0593"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4883
COMPANY PRODUCT NO. ISSUES NO. PAGES
Rorer, Wa. H.
Sandoz Pharmaceutical
Schering Corporation
Searle, G. D.
Schmid, Julius
Sherman Laboratories
1.
Ananase
13
22
2.
Maalox
5
5
Total...
27
1.
Cafergot/Cafergot-PB
6
6
2.
Fiorinal
4
4
3.
Mellaril
19
19
4.
Sansert
26
Total...
26
55
1.
Celestone
4
8
2.
Chlortrimeton
16
16
3.
Coricidin
7
7
4.
Fulvicin
6
9
5.
Meticorten
2
2
6.
Naqua
9
9
7.
Naquival
9
9
8.
Rela
10
10
.
Total...
70
1.
Aldactazide/Aldactone
6
6
2.
Dramamine
6
6
3.
Enovid
9
14
4.
Flagyl
8
14
5.
Lomotil
10
10
6.
Nilevar
1
1
7.
Pro-Banthine
23
Total...
23
74
1.
Imolin
5
5
2.
Vagesic
8
Total...
8
13
1.
Elixophyllin
9
Total...
13
10
PAGENO="0594"
4884 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
CONPANY PRODUCT NO. ISSUES NO. PAGES
Smith, Kline, & French
1. Compazine 9
2. Dexedrine 6 6
3. Parnate 18 18
4. Stoxil 4 8
5. Thorazine 12 12
6. Various 2 2
Total... 55
Squibb
1. Delautin 7 12
2. Delestrogen 6 12
3. Deluteval 3 6
4. Feramel 3 3
5. Fungizone 5 5
6. Kenalog 2 2
7. Mycolog 6 6
8. Mysteclin 10 10
9. Naturetin 8 12
10. Noctec 6 6
11. Pentids 6 6
12. Prolixin 15 17
13. Rautrax-N 10 10
14. Raudixin 4 4
15. Theratuss 8 10
16. Theragran 7 19
Total... 140
Strassenburgh Laboratories
1. Biphetamine/lonamin 12 22
2. Biphetamine-T 5 6
3. Metropine 4 8
4. Omnituss 12 16
5. Tussionex 9 9
Total... 61
Stuart
1. Dialose 2 2
2. Mulvidren 3 3
3. Mylanta 14 14
4. Mylicon 3 3
Total... 22
11
PAGENO="0595"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4885
COMPANY PRODUCT NO. ISSUES NO. PAGES
Syntex
1. Synalar 12 Total... 25
Trent Pharmaceuticals
1. Tocosamine 12 Total... 12
Upjohn
1. Didrex 1 1
2. Depo-Medrol 5 11
3. Depo-Provera 13 13
4. Medrol Veriderm 16 47
5. Medrol 7 12
6. Orinase 31 64
7. Provera 15 15
Total... 163
U.S. Vitamin & Pharmaceutical
1. Arlidin 8 8
2. Aquasol 4 4
3. Dexemeth 8 13
4. DBI-TD 10 10
5. Emivan 6 6
Total... 41
Towne
1. Various 2 Total... 2
Wallace Laboratories
1. Appertrol 40 40
2. Capla 34 64
3. Caplaril 8 32
4. Deprol 50 89
5. Meprospan 48 49
6. Milpath 28 31
7. Milprem 18 18
8. Miltown 50 93
9. Miltrate 33 33
10. Soma 38 42
11. Soma Compound 17 17
12. Somacort 16 16
Total... 524
12
PAGENO="0596"
4886 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
CONPANY PRODUCT NO. ISSUES NO. PAGES
Wampole
1. Vo-Sol 11 Total... 11
Warner-Chilcott
1. Amphocortrin 6 18
2. Colymycin 16 36
3. Gelusil 17 22
4. Nandelamine 12 24
5. Papase 15 30
6. Peritrate 26 97
7. Tedral 6 12
Total... 239
White Laboratories
1. Asperguin 22 22
2. A&D 23 23
3. Cod Liver Oil Tabs 14 14
4. Disophrol 1 2
5. Gitaligin 24 24
Total... 85
Winthrqp
1. Creamalin 2 2
2. Isuprel 9 9
3. Neo-Synephrine 6 6
4. Nebaral 5 5
5. Telepaque 1 1
6. Trancogesic 11 11
7. Trancopal 6 6
8. Winstrol 11 11
9. WTZ 1 1
Total... 52
Wyeth Laboratories
1. Bicillin 10 19
2. Cyclamycin 7 14
3. Equagesic 13 23
4. Equanil 12 35
5. Equanitrate 8 8
6. ~1epergan 5 7
7. Pen-Vee-K 8 11
8. Polymagna 3 3
9. Phenergan 3 3
10. Prozine 1 1
11. SMA 10 18
12. Sparine 8 13
13. Zactirin 3 3
Total... 158
13
PAGENO="0597"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4887
1. Aininophylline
2. Histadur
3. Nuina
4. Quinaglute
2 2
6 6
8 8
22 22
Total... 38
CONPANY
~ynn Pharmacal
PRODUCT NO. ISSUES NO. PAGES
14
PAGENO="0598"
4888 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
Summary Data
1964
10 Leading Firms, by Volume of Advertisip~
No. Drug Advertising ~
Wallace Laboratories 585
Merck, Sharpe, & Dohme 522
Warner-Chilcott 267
Upjohn 214
Roche Laboratories 189
CIBA 154
Schering Corporation 152
Abbott Laboratories 148
Burroughs-WellcOme 145
Lederle 145
Firm
Rank
1
2
3
4
5
6
7
8
9
10
Rank
1
10 Most Frequently Advertised Dr~g~
No. Issues in which
Advertised
Miltown (Wallace) 52
2
Meprospan (Wallace) 51
3
Deprol (Wallace) 50
4
Soma/Soma Compound (Wallace) 49
5
6
Diuril/Hydrodiuril 37
Neggram (Winthrop) 34
7
Valium (Roche) 34
8
Elavil (Merck) 32
9
Vioform (CIBA) 31
10
Miltrate (Wallace) 29
Rank
1
10 Most Heavily Advartised Dr~gR
No. Pages on which
Advertised
Soma/Soma Compound (Wallace) 129
2
Diuril/Hydrodiuril (Merck) 119
3
Miltown (Wallace) 110
4
Deprol (Wallace) 100
5
Peritrate (Warner-Chilcott) 97
6
Neggram (Winthrop) 79
7
Valium (Roche) 68
8
Elavil (Merck) 67
9
Celestone (Schering) 61
10
Thyroid (Armour) 61
15
PAGENO="0599"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4889
THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
1964
PRODUCT
1. Desbutal
2. Descixyn
3. Enduron/Eutonyl
4. Eutonyl
5. Erythocin
6. Nembutal
7. Rad:to pharmaceuticals
8. Selsun
9. Surbex-T
10. Triosorb
1. Dicarbisol
1. Chyinoral
2. Thyroid
___________________________ Inc.
IXylocaine
____________________ 1. Mesulfin
2. Penbritin*
3. Premarin
4. Spartocin
5. Thiosulfil Forte
_____________________ 1. Polycillin
*Distributed by Ayerst for Beecham Laboratories,
16
Inc.
10 21
9 18
3 13
10 30
16 32
11 11
6 6
2 2
12 12
3 3
Total... 148
12 Total... 12
3 6
15 61
Total... 67
3 Total... 6
7 14
4 18
16 17
3 9
3 6
Total... 64
15 Total... 41
CONPANY
NO. ISSUES NO. PAGES
Abbott Laboratories
Arch Laboratories
Armour Pharmaceuticals
Astra Pharmaceutical Products,
1.
Ayerst Laboratories
bristol Laboratories
PAGENO="0600"
4890 COMPETITIVE PROBLEMS fl~T TEE DRuG INDUSTRY
COMPANY PRODUCTS NO. ISSUES NO. PAGES
Burroughs Weilcome and Co., Inc.
1. Antepar 12 12
2. Aerosporin 10 10
3. Alkeran 7 7
4. Cardilate 13 13
5. Cardilate-P 9 9
6. Cortisporin 3 3
7. Empirin 5 5
8. Lanoxin 13 22
9. Leukeran 10 10
10. Mantadil 5 5
11. Marezine 20 20
12. Myleran 10 10
13. Nigral 2 2
14. Neosporin 4 4
15. Perazil 3 3
16. Purinethol 10 10
Total... 145
CIBA Pharmaceutical 1. Esidrex/Esidrex-K 17 34
2. Doriden 7 7
3. Pyribenzatnine 13 13
4. Ritalin 19 26
5. Serpasil 26 34
6. Vioform 31 40
Total 154
Davies, Roae-Ro~t and Co.
(Division of Kendall)
1. Quinidine/Digitalis 2 2
2. Quinidine sulfate 1 1
Total... 3
Dome Chemicals, Inc. 1. Doinol 1 1
2. Cort-Dome 7 7
3. Cor-Tar-Quin 2 2
4. Domeboro 2 2
Total... 12
17
PAGENO="0601"
Endo Laboratories
Rynson, Westcott, and Dunning
1.
2.
Ives Laboratories
1. Furacin
2. Furadantln
1. Coumadin
2. Hycodan
3. Nutnorphan
4. Percodan
5. Valpin/Valpin-PB
BSP
Lactinex
1. Cyclospasinol
2. Isordil
NO. PAGES
17
30
Total... 47
36
8
16
11
6
Total... 77
12
13
Total... 32
7 7
6
Total... 13
2 2
11
Total... 13
16 16
13 13
Total... 29
4 Total... 4
14 14
12 12
3 6
Total... 32
COMPETITIVE
PROBLEMS IN THE DRUG INDUSTRY 4891
Eaton Laboratories
COMPANY PRODUCT NO.
ISSUES
15
15
18
7
16
11
6
7
6
13
Geigy Chemical Corporation
Glenbrook Laboratories
1. Butasolidin
2. Preludin
3. Regroton
1. Rayer Aspirin
2. Philips Milk of Magnesia
Key Pharmaceuticals
Lakeside Laboratories,
1.
Inc. 1.
2.
3.
Nitroglyn
Cantil
Imferon
Norpramin
18
81-280 0-69-pt. 11-39
PAGENO="0602"
4892 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Lederle Laboratories 1. Achromycin 1 2
(Division of American 2. Aristocort 12 24
Cyanimid) 3. Amicar 3 16
4. Bamadex 10 18
5. Declomycin 17 24
6. Perro Sequels 9 9
7. Hydroniox 17 24
8. Orimune 2 4
9. Pathibamate 13 14
Total... 145
Lilly, Eli & Compai~y 1. Anhydron 12 16
2. Darvon Compounds 18 21
3. Dymelor 5 5
4. Ilosone 14 16
5. V-Cillin K 14 14
Total... 72
1. Doxidan 4 Total... 6
Mallinkrodt Chemical 1. Codeine 1 Total... 2
McKesson Laboratories 1. Various 1 1
2. Tetracycline 2 2
Total... 3
McNeil Laboratories 1. Butisol 25 25
2. Tylenol 14 14
Total... 39
Nead Johnson 1. Nucomyst 1 2
2. Vasodilan 21 21
Total... 23
Nerrell, William 5. 1. Bentyl 10 10
2. Bendectin 10 10
3. Tenuate 9 9
Total... 29
Miles Products 1. Alkaseltzer 12 Total... 12
(Division of Niles
Laboratories)
19
PAGENO="0603"
COMPETITIVE
PROBLEMS IN THE DRUG INDUSTRY
4893
1. Aldomet
2. Aldoril
3. Aramine
4. Benemid/Colbenemid
5. Codeine~
6. Cyclex
7. Decadron
8. Decagesic
9. Diuril/Hydrodiuril
10. Diupres
11. Dornavac
12. Elavil
13. Hydrodiuril-KA
14. Hydropres
15. Hydropres-KA
16. Mephyton
17. Periactin
18. Respihaler Decadron
19. Redisol/Alpharedisol
20. Rubeovax
21. lJrecholine
1. Orenzyme
2. Tepanil
1. Durabolin
2. Deca-Durabolin
3. Hexadrol
1. Ortho-Novum
20
NO. ISSUES NO. PAGES
12 27
22 43
12 22
25 38
2 2
6 6
21 39
13 13
37 119
17 17
3 6
32 67
10 10
12 12
5 5
19 20
18 18
12 22
15 15
5 9
12 12
Total... 522
4
12
Total... 16
17 17
3 3
8
Total... 28
5 Total... 8
PRODUCTS
COMPANY
Merck, Sharpe, & Dohme
National Drug
Organon
Ortho
4
10
PAGENO="0604"
4894 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY
CONPANY NO. ISSUES NO. PAGES
Parke-Davis 1. Adroyd 3 3
2. Benylin expectorant 1 1
3. Benadryl 23 36
4. Chloromycetin 2 2
5. Dilantin 26 38
6. Norlestrin 18 36
7. Nidicel 3 3
8. Pitocin 5 5
Total... 124
Pfizer, Chas. 1. Daricon 9 18
2. Desitin* 7 10
3. Diabinase 10 26
4. Terra-Cortil 5 10
5. Terramycin 10 22
6. tJroscreen 2 4
7. Vistaril 22 44
Total... 134
Pittman-Hoore Company 1. Jefron 4 8
2. Novahistine DH 14 20
3. NovahIstine LP 1 1
4. Novahistine TMelet 4 5
5. Novahistine Singlet 5 6
Total... 40
Plough Inc. 1. St. Josephts Aspirin 12 Total... 12
Polythress.. Wa. P. 1. Nudrane 6 7
2. Solfo-Serpine 10 10
Total... 17
Purdue/Frederick 1. Otalgine 4 4
2. Parelixir 4 4
3. Senokot 10 10
Total... 18
Radium Chemical 1. Radium 12 Total... 12
21
PAGENO="0605"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4895
1. Medihaler-Duo
2. Norflex
3. Norgesic
4. Titralac
1. Ambar 6
2. AllBee W/C 9
3. Dimetane 9
4. Dimetapp 1
5. Donnatal 12
6. Exna 5
7. Robaxin 7
8. Robinul 4
9. Robinul.Vorte/Forte-PH 4
10. Quinidex 13
11. Skelaxin 2
12. Robaxisal 3
1. Gantanol
2. Librax
3. Librium
4. Roniacol
5. Taractin
6. Valium
1. Atarax
2. Antivert
3. Enarax
4. Narax
5. Tao
NO. PAGES
18
6
16
8
Total... 48
6
9
14
1
15
10
11
8
8
13
4
6
Total... 105
30
21
38
18
14
68
Total... 189
13
6
4
12
22
Total... 57
24
4
Total... 28
COMPANY PRODUCTS NO. ISSUES
9
4
7
4
Riker Laboratories
Robins, A.H.
Roche Laboratories
Roerig, J.B. & Company
8
18
15
9
14
34
6
6
4
8
11
11
4
Rorer, Wm. II., Inc. 1. Ananase
2. Naalox
22
PAGENO="0606"
4896 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCTS NO. ISSUES NO. PAGE~
Squibb 1. Feramel 2 2
2. Fungizone 1 1
3. Kenacort 12 16
4. Kenalog 6 10
5. Medotopes 2 4
6. Mycolog . 4 4
7. Mysteclin-F 7 7
8. Naturentin w/K 4 4
9. Noctec 9 9
10. Pentids 400 6 6
11. Prolixin 10 10
12. Raudixin 10 22
13. Rautrax-N 6 9
14. Theragran 6 15
15. Theratuss 6 6
Total... 125
Strassenburgh Laboratories
1. Biphetamine-T 7 9
2. Biphetamine/Tonamin 6 12
3. Omnituss 6 8
4. Tussionex 7 7
Total... 36
Stuart 1. Nylanta 18 24
2. Softab 2 2
Total... 26
Syntex 1. Norinyl 18 Total... 43
Trent Pharmaceuticals
1. Tocosamine 3 Total... 3
U.S. Vitamin & Pharmaceuticals
1. Aquasol-A 1 1
2, Arlidin 12 12
3. DBI/DBI-~TD 13 14
4. Dexameth 4 4
5. Emivan 6 7
Total... 38
23
PAGENO="0607"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4897
CONPANY PRODUCTS NO. ISSUES NO. PAGES
Sandoz Pharmaceutical 1. Belladenal 1 1
2. Fiorinal 17 17
3. Mellaril 25 25
4. Sansert 14 14
Total... 57
Schering Corporation 1. Afrin 13 26
2. Celestone 24 61
3. Chlortriiñeton 15 15
4. Coricidin 5 9
5. Demazin 5 5
6. FulvIcin 14 22
7. Rela 7 14
Total... 152
Schmid, Julius, Inc. 1. Candeptin, 1 2
2. tmmolmn 4 4
3. Vagesic 5
Total... 11
Searle,G.D. 1. Anavar 7 14
2. Aldactazide 10 10
3. Dramamine 5 6
4. Enovid 6 6
5. Enovid-E 11 15
6. Enovid/EnovJd-E 6 8
7. Flagyl 7 8
8. Lomotil 9 9
9. Pro-BanthIñe 17 20
Total... 96
Sherman Laboratoriec 1. Exlisophyllin 11 Total... 12
Smith, Kline, & French. 1. Dyrenium 12 23
2. Parnate 3 3
3. Stelazine 17 17
4. Thorazine 18 18
Total... 61
24
PAGENO="0608"
4898 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCTS NO. ISSUES NO. PAGES
Upjohn 1. Depro-Nedrol 4 8
2. Didrex 13 26
3. Medaprin 13 26
4. Nedrol 13 26
5. Neo-Nedrol Veridem 10 21
6. Orinase 24 46
7. Provera/Depo-Provera 17 33
8. Provest 5 18
9. Painine 2 4
10. Solu-Nedrol 3
Total... 214
Wallace Laboratories
1. Capla 13 21
2. Caplaril 17 41
3. Deprol 50 100
4. Neprospan 51 51
5. Niltown 52 110
6. Miltrate 29 29
7. Nilpath 23 41
8. Nilprem 16 16
9. PreeMI 20 - 29
10. Soma/Soma Compound 49 129
11. Somacort 13 18
Total... 585
Warren-Teed 1. Meprobamate 3 Total... 3
Warner-Chilcott 1. Amphocortrin 6 6
2. Colymycin 20 40
3. Gelusil 18 27
4. Mandelamine 17 57
5. Papase 2 4
6. Peritrate 26 97
7. Sinutab 13 22
8. Tedral 11 14
Total... 267
Wampole 1. Vosol 9 Total... 9
WTest~-Ward 1. Meprobamata 3 Total... 3
25
PAGENO="0609"
COMPETITIVE PROBLEMS IN
THE DRTJG INDUSTRY 4899
COMPANY PRODUCTS NO. ISSUES NO. PAGES
White Laboratories
1. Disophrol
2. Permitil
10
7
13
14
Total... 27
Winthrop
Wynn Pharniacal
1.
Isuprel
10
10
2.
Mebaral
4
4
3.
Neggrani
34
79
4.
Neo-Synephrmne
5
5
5.
Phisohex
2
2
6.
Telepaque
3
3
7.
Trancogesic
10
10
8.
Trancopal
8
16
9.
Winstrol
7
Total...
7
136
1.
Bicillin
7
14
2.
Cyclamycin
2
2
3.
Equagesic
11
20
4.
Equanil
9
17
5.
Nepergan
2
2
6.
Oxaine N
5
12
7.
Pen-Vee-4C
2
2
8.
Phenergan
4
5
9.
Polyinagna
3
4
10.
Sparine
4
8
11.
lJnIpen
9
26
12.
Zactirin Coinp.
4
Total...
122
1.
Aininophylline
7
7
2.
Numa
9
9
3.
Quinaglute
23
23
26
PAGENO="0610"
4900 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
Summary Data
1965
10 Leading Firms by Volume of Advertising
Rank Firm No. Drug Advertising Pages
1 Merck, Sharpe & Dohme 609
2 Warner-Chilcott 590
3 Wallace Laboratories 381
4 Roche Laboratories 295
5 CIBA 208
6 Wyeth Laboratories 189
7 Upjohn 172
8 Lilly 144
9 Lederle 128
10 Robins, Burroughs-Wellcome 121
10 Most Frequently Advertised Drugs
No. Issues in which Advertised
No. Pages
Rank
1
Pre-Sate (Warner-Chilcott)
159
2
Peritrate (Warner-Chilcott)
145
3
Miltown/Meprospan (Wallace)
107
4
Valium (Roche)
95
5
Indocin (Merck)
82
6
Diuril (Merck)
77
7
Soma (Wallace)
73
8
Polycillin (Bristol)
62
9
C-Quens (Lilly)
56
10
Pyribenzamine (CIBA)
56
Rank
1
2
3
4
5
6
7
8
9
10
Miltown (Wallace)
Soma (Wallace)
Milpath (Wallace)
Diuril (Merck)
Elavil (Merck)
Neggram (Winthrop)
Pre-Sate (Warner-Chilcott)
Polycillin (Bristol)
Pyribenzamine (CIBA)
Gelusil (Warner-Chilcott)
10 Most ~
50
41
39
39
35
33
32
32
31
29
~ Dru~
on which Advertised
27
PAGENO="0611"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4901
THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
1965
Arch Laboratories
Armour Pharmaceuticals
1. Desbutal
2. Desoxyn
3. Enduron
4. Erythocin
5. Eutonyl
6. Eutron
7. Nembutal
8. Radio pharmaceuticals
9. Surbex-T
NO. PAGES
24
12
6
15
15
5
24
12
14
104
13
12
Astra Pharmaceutical
Products, Inc.
Ayerst Laboratories
1. Xylocaine
1. Penbritin*
2. Premarin
3. Thiosulfil
4. Riopan
Forte
1. Polycillin (injectables and
oral)
2. Tegopen
3. Tetrex
*Distributed by Ayerst for
Beecham Laboratories, Inc.
28
COMPANY -
Abbott Laboratories
NO. ISSUES
12
6
6
3
5
2
12
12
14
Total...
13 Total...
3 Total...
1. Dicarbosil
1. Thyroid
Bristol Laboratories
5
8
10
6
7
32
22
4
Total... 8
24
10
12
11
Total... 57
62
37
8
Total... 107
PAGENO="0612"
4902 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Burroughs Wellcome and Co., 1. Actidil 2 2
Inc. 2. Aerosporin 9 9
3. Alkeran 5 5
4. Antepar 10 10
5. Cardilate 17 17
6. Cortisporin 11 11
7. Empirin 8 8
8. Emprazil 3 3
9. Lanoxin 17 17
10. Leukeran 6 6
11. Nantadil 4 4
12. Marezine 9 9
13. Myleran 9 9
14. Neosporin 11 U
Total... 121
CIBA Pharmaceutical 1. Esidrex 26 54
2. Esidrex-K 2 4
3. Ismelin 14 28
4. Pyribenzanine 31 56
5. Ritalin 26 39
6. Vioform 18 27
Total... 208
Davies, Rose-Hoyt and Con- 1. Digitalis 13 13
pany (division of 2. Quinidine 13 13
Kendall)
Total... 26
Dome Chemicals, Inc. I. Cortarquin 4 4
2. Cort-Dome 6 6
3. Neo Cortdome Octic 4 4
Total... 14
Eaton Laboratories, Inc. 1. Puradantin 7 14
2. Furoxone 7 13
3. Tricofuron 6 12
Total... 39
29
PAGENO="0613"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4903
COMPANY PRODUCT NO. ISSUES NO. PAGES
Ives Laboratories
Lederle Laboratories
` (Division of American
Cyanamid)
1. Butazolidii~
2. Dulcolax
3. Hygroton
4. Persantin
5. Preludin
6. Regroton
1. Bayer Aspirin
2. Philips Milk of Magnesia
1. Cyclospasmol
2. Isordil
1. Akineton
1. Imferon
2. Norpramin
1. Amicar
2. Aristocort
3. Aristocort Tabs
4. Bamadex
5. Declomycin
6. Hydronox
7. Pathibamate
8. Stresscaps
9. Varidase
Total... 52
15
12
8
10
16
24
Total... 98
7 7
6 6
Total... 13
8 8
3 3
Total... 11
4 Total... 4
10 10
16 32
Total... 42
7 7
7 14
7 6
18 26
26 38
2 3
12 12
6 6
16 - 16
Total. . .128
1. Coumadin
2. Numorphan
3. Percodan
Endo Laboratories, Inc.
Geigy Chemical Corpora
tion
Glenbrook Laboratories
32
10
10
16
10
10
15
12
4
5
8
12
Knoll Pharmaceutical
Lakeside Laboratories, Inc.
30
PAGENO="0614"
4904 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Lilly, Eli & Company 1. Anhydron 2 2
2. Aventil 6 24
3. Darvon 17 17
4. Darvon Compound 1 1
5. Darvon Compound-65 1 1
6. Dymelor 11 11
7. C-Quens 14 56
8. Ilosone 2 2
9. Keflin 9 21
10. V-Cillin K 9 9
Total... 144
1. Surfak 7 Total... 7
McNeil Laboratories, Inc. 1. Butiserpine 26 26
2. Butisol 26 26
3. Tylenol 26 26
Total... 78
Nallinkrodt Chemical 1. Codeine 1 Total... 2
Mead Johnson 1. Vitamin series 6 18
2. Dracon 22 55
Total... 73
Merrell, William ~. 1. Bendectin 6 6
2. Bentyl 6 6
3. Cepacol 1 1
4. Tenuate 14 14
Total... 27
Miles Products (Division
of Miles Laboratories) 1. Alkaseltzer 12 Total... 12
31
PAGENO="0615"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
4905
Merck, Sharpe, & Dohme
(Division of Merck &
Company)
National Drug
1. AVC/AVC Dienestrol
2. Tepanil
NO.
3 6
4 4
Total... 10
*Merck Chemical Division ot Merck & Uompany
32
COMPANY PRODUCT
NO.
ISSUES
PAGES
1.
Aldomet
10
20
2.
Aldoril
19
37
3.
Aramine
10
20
4.
Benemid
.15
18
5~
Codeine*
2
2
6.
Cosmogen
2
2
7.
Cuemid
2
2
8.
Cosmogen/Cuemid
2
2
9.
Cremomycin/Cyclex
7
13
10.
Cyclex
2
4
11.
Decadron
25
52
12.
Decagesic
11
18
13.
Diuril
39
77
14.
Diupres
10
20
15.
Diuril/flydrodiuril
1
2
16.
Dornavac
4
8
17.
Dronactic/Periactin
5
5
18.
Elavil
35
75
19.
Elavil/Diuril
6
12
20.
Hy~1odiuril
1
2
21.
Hydropres
6
10
22.
Hydrodiuril MA
7
14
23.
Hydropres MA
7
7
24.
Indocin
9
82
25.
M~phyton
11
11
26.
Periactin
11
11
27.
Rubeovax
6
6
28.
Respihaler
12
24
29.
Triavil
6
30
30.
Urecholine
12
21
.
Total.. .
609
PAGENO="0616"
4906 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Organon, Inc. 1. Hexadrol (and injection) 22 23
2. Maxibolin 2 6
Total... 29
Ortho 1. Contraceptive products 3 Total... 8
(Ortho-Novum)
Philips Roxane Laboratories 1. Measles vaccine 4 Total... 11
Pittman-Moore Company 1. Lirugen 13 16
2. Novahistine DH 13 19
3. Nova LP 3 3
4. Nova Singlet 5 5
Total... 43
Polythress, Wm P. 1. Solfo-serpine 5 5
2. Trocinate 3 3
Total... 8
Purdue Frederick Company 1. Otalgine 3 3
2. Senokap 1 1
3. Senokot 1 1
4. Sulfabid 4 6
Total... 11
Parke-Davis 1. Benadryl 24 25
2. Dilantin 24 39
3. Measles virus vaccine 1 1
4. Nidicel 3 3
5. Norlestrin 10 22
6. Pitocin 13 13
Total... 103
Pfizer, Chas. 1. Daricon 4 8
2. Desitin Ointment* 10 10
3. Renese 13 36
4. Vistaril 16 46
Total... 100
*Leeming Division of Pfizer.
33
PAGENO="0617"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4907
COMPANY PRODUCT NO. ISSUES NO. PAGES
Plough, Inc. 1. St. Joseph's Aspirin 10 Total... 10
Radium Chemical 1. Radium 13 Total... 13
Riker Laboratories 1. Medihaler Duo 4 8
2. Norgesic 12
Total... 32
Robins, A. H. 1. AllBee W/C 9 9
2. Dimetapp 8 8
3. Dimetane 9 18
4. Donnatal 7 14
5. Phenaphen 6 6
6. Quinidex 12 12
7. Robaxin (and Robaxin 750) 12 32
8. Robaxisol 4 8
9. Robinul 11 22
Total... 121
Roche Laboratories 1. Gantanol 8 24
2. Gantanol Suspension 8 23
3. Gantrisin 6 12
4. Librax 9 24
5. Librium 17 42
6. Librax/Librium 10 45
7. Roniacol 13 26
8.Tegan 1 2
9. Valium 35 95
Total... 295
Roerig, J. B. & Company 1. Atarax 6 12
2. Antivert 6 6
3. Enarax 4 4
4. Marax 5 10
5.Tao 5 21
6. Tetracyn 8 16
Total... 69
Rorer, Wm. H., Inc. 1. Ananase 13 Total... 13
34
81-280 0-69--pt. 11-40
PAGENO="0618"
4908 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Sandoz Pharmaceutical 1. Bellergal 19 19
2. Cafergot 27 27
3. Fiorinal 17 17
4. Mellaril 25 30
5. Sansert 3 3
Total... 96
Scherer, R. P. Corporation 1. Hydrospray 1 Total... 1
Schering Corporation 1. Afrin 6 12
2. Celestone 6 12
3. Celestone Soluspan 11 22
4. Celestone Solutab 1 2
5. Chlortrimeton 6 12
6. Coricidin 1 4
7. Denazin 2 2
8. Rela 2 4
Total... 83
Schmid, Julius, Inc. 1. Candeptin 8 9
2. Vagesic 5 5
Total... 14
Sherman Laboratories 1. Elixophyllin 13 Total... 13
Strasenburgh Laboratories 1. Biphetamine 10 21
(Division of Wallace & 2. Biphetamine T 3 3
Tiernam, Inc.) 3. Oinnituss 5 5
4. Tussionex 10 11
Total... 40
Stuart Company (Division 1. Mylanta 18 Total... 38
of Atlas Chemical)
Syntex 1. Norinyl 12 17
2. Synalar 3 7
Total... 24
35
PAGENO="0619"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4909
COMPANY PRODUCT NO. ISSUES NO. PAGES
Searle, G. D.
1. Aldactazide 5
5
2. Aldactazide A 2
2
3. Dramamine 3
3
4. Enovid 11
19
5. Enovid-E 20
30
6. Enovid/Enovid-E 1
3
7.Flagyl 5
9
8. Lomotil 7
7
9, Pro-Banthine 16
16
10. Pro-Banthine/w Dartal 1
1
Total...
95
Smith, Kline, & French
1. Compazine 15
2. Cytomel/Compazine 4
3. Cytomel/Parnate 1
4. Cytomel/Stelazine 1
5. Dexamyl 5
6. Dyazide 1
7. Dyrenium 12
8. Dyrenium Caps 4
9. Parnate 10
10. Stelazine 11
11. Thorazine 7
15
4
1
1
5
1
13
4
10
11
7
Laboratories
Total...
72
Squibb
1. Kenacort 2
2. Kenalog 3
3. Kenalog IM 7
4. Kenalog/Mycolog 1
5. Mysteclin-F 10
6. Naturentin 7
7. Noctec 6
8. Pentids 7
9. Pentids 400 1
10. Prolixin 8
11. Raudixin 6
12. Rautrax-N
13. Theragran
4
6
16
1
10
7
6
7
1
14
12
12
4
Total...
100
36
PAGENO="0620"
4910 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY
CONP~NY PRODUCT NO. ISSUES NO. PAGES
U. S. Vitamin & Pharmaceu- 1. Arlidin 11 11
ticals 2. Aquasol 3 3
3. Aquasol-A 3 3
4. Dexameth 5 5
5. DBI (DBI-TD) 16 16
Total... 38
Upjohn 1. Depo-Nedrol 1 2
2. Didrex 14 28
3. Lincocin 12 37
4. Medaprin 1 2
5. Medrol 13 26
6. Medrol/Veriderm 9 18
7. Panalba 14 20
8. Provest 22 39
Total... 172
Wallace Laboratories 1. Deprol 25 46
2. Milpath 39 39
3. Milprem 10 16
4. Miltown (Meprospan) 50 (24) 107
5. Solacen 21 46
6. Soma 41 73
7. Soma Compound 16 16
8. Somacort 18 33
Total... 388
Warner-Chilcott 1. Anusol 1 2
2. Colymicin Injectable 19 40
3. Colymicin Octic 13 17
4. Gelusil 29 30
5. Mandelamine 18 64
6. Peritrate 24 145
7. Pre-Sate 32 159
8. Proloid 11 24
9. Papase 17 34
10. Tedral (Tedral SA) 9 45
11. Sinutab 19 30
Total... 590
37
PAGENO="0621"
COMPETITIVE PROBLEMS IN THE
DRUG INDUSTRY
4911
COMPANY PRODUCT NO. ISSUES NO. PAGES
Warren-Teed Products Compapy~
1. Chymolase
2.Kaon
6
3
6
3
3. Ventussin
1
1
Total...
10
Winthrop Laboratories
1. Isuprel
2. Mebaral
3. Neggram
4. Neo-Synephrine
5. Radiologics
6. Trancogesic
7. Trancopal
8. Trancopal/Trancogesic
9. Winstrol
6
7
33
11
6
14
2
1
1
6
7
38
11
6
14
2
2
1
Total...
87
Westward, Inc.
1. Meprobamate
12
Total...
12
Wampole Laboratories
1. Vosol
9
Total...
9
White Laboratories
1. Permitil
2. Permitil Chronotab
6
2
12
4
Total
16
Wyeth Laboratories (Division
1. Bicillin
2. Equagesic
3. Equagesic/Mepergan
4. Equanil
5. Mepergan
6. Phenergan
7. Pen-Vee K
8. Polymagna
9. Sparine
10. Serax
11. SMA
12. Sulfose
13. Unipen
14. Zactirin Compound
8
10
1
9
3
3
1
6
7
15
10
3
14
4
8
18
2
18
3
6
1
12
14
44
20
3
28
12
of American Home Products)
Total...
189
38
PAGENO="0622"
4912 COMPETITIVE PROBLEMS ]~ THE DRUG INDUSTRY
1. Ainnophyllne
2. Nanna
3. Quinaglute
8 8
8 8
20 20
Total... 36
COMPANY
wynn Pharnuacal Corp.
PRODDCT NO. ISSUES NO. PAGES
39
PAGENO="0623"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4913
THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
Summary Data
1966
10 Leading Firms, by Volume of Advertising
Rank Firm No. Drug Advertising Pages
1 Wallace Laboratories 623
2 CIBA 559
3 Merck, Sharpe, & Dohme 496
4 Warner-Chilcott 365
5 Lilly 290
6 Upjohn 200
7 Wyeth Laboratories 186
8 Squibb 164
9 Pfizer 152
10 Lederle Laboratories 144
Rank
1
10 Most Frequently Advertised Dr~gs
No. Issues in which
Advertised
Miltown (Wallace) 50
2
Doriden (CIBA) 48
3
Sotna (Wallace) 48
4
Milpath 47
5
Deprol (Wallace) 46
6
Mandelamine (Warner-Chilcott) 39
7
Solacen (Wallace) 39
8
9
Pyribenzamine (CIBA) 35
Gantanol (Roche) 35
10
Neggram (Winthrop) 31
Dialog (CIBA)
Rank
1
10 Most Heavily Advertised Drug~
No. Pages on which
Advertised
Deprol (Wallace 107
.
2
Doriden (CIBA) 106
3
Miltown (Wallace) 105
4
Ser-Ap-Es (CIBA) 91
5
Terramycin (Pfizer) 84
6
Darvon (Lilly) 83
7
Solacen (Wallace) 77
8
Diuril (Merck) 74
9
C-Quens (Lilly) 72
10
Dialog (CIBA) 72
40
PAGENO="0624"
4914 COMPETITIVE PROBLEMS 1N THE DRUG INDUSTRY
THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
1966
COMPANY PRODUCT NO. ISSUES NO. PAGES
Abbott Laboratories
1. Desbutal 1 2
2. Desoxyn 1 2
3. Desbutal/Desoxyn 6 24
4. Erythocin 5 18
5. Eutron 8 26
6. Placidyl 13 13
7. Radio pharmaceuticals 12 12
8. Surbex-T 2 2
9. Vercyte 4 8
Total... 107
Arch Laboratories
1. Dicarbosil 18 Total... 18
~yerst Laboratories
1. Penbritin* 19 38
2. Premarjn 12 12
3. Riopan 16 17
4. Thiosulfil 5 6
Total... 73
Bristol Laboratories
1. Polycillin (oral & inject.)2O 40
2. Polycillin-N 1 2
3. Prostaphlin 4 8
4. Tegopen 14 24
5. Tetrex 10 20
Total... 9~4
*Distributed by Ayerst for Beecham Laboratories, Inc.
41
PAGENO="0625"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
4915
Burroughs-Wellcome and Co., Inc.
COMPANY PRODUCT NO. ISSUES NO. PAGES
CIBA Pharmaceutical
Davies, Rose-Hoyt and Co.
1.
Actifed
4
8
2.
Aerosporin
7
7
3.
Alkeran
2
2
4.
Antepar
6
6
5.
Cardilate
26
26
6.
Cortisporin
8
11
7.
Einpirin
7
10
8.
Lanoxin
24
24
9.
Leukeran
Lidosporin
9
9
10.
4
4
11.
}~yleran
6
7
12.
Neosporin
11
13
13.
Zyloprin
2
Total...
6
133
1.
Dialog
31
72
2.
Doriden
48
106
3.
Esidrex
27
65
4.
Esiinii
19
64
5.
Ismelin
17
34
6.
Pyribenzamine
35
51
7.
Ritalin
26
59
8.
Ser-Ap-Es
20
91
9.
Vioform
~
9
Total...
17
559
1.
Ipsatol
1
1
2.
Luride
9
9
3.
Pil-Digis
20
20
4.
Pil-Digis/Davoxin
1
1
5.
Quinora
13
Total...
13
44
42
PAGENO="0626"
4916 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Dome Chemicals, Inc.
1. Cor-Tar-Quin 3 6
2. Cort-Dome 6 6
3. Domeboro 3 3
4. Lidaform 4 4
5. Neo Cort-Dome 8 8
6. Uval 1 1
Total... 28
Dorsey Laboratories
1. Triaminic 3 Total... 9
Eaton Laboratories, Inc.
1. Furadantin 13 26
2. Nitrofurans 4 4
3. Tricofuron 4 4
Total... 34
Endo Laboratories, Inc.
1. Coumadin 30 33
2. Nurnorphan 13 13
3. Percodan 4 4
Total... 50
Geigy Chemical Corporation
1. Butazolidin 8 8
2. Dulcolax 7 7
3. Pertofrane 5 10
4. Persantine 16 35
5. Preludin 12 24
6. Regroton 6 6
7. Tanderil 6 12
Total... 102
Glenlirook Laboratories
1. Bayer Aspirin 7 7
2. Measurin 8 21
3. Philip's Milk of Magnesia 6 6
Total... 34
Hoechst Pharmaceutical
1. Doxidan 4 4
2. Lasix 5 44
Total... 48
Hyland Laboratories
1. Hemophilia-A 1 Total... 1
43
PAGENO="0627"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4917
COMPANY PRODUCT NO. ISSUES NO. PAGES
1. Cyclospasmal
2. Isordil
1. Nitroglyn
1. linferon
2. Norpramin
1. Butiserpine
2. Butisol
3. Grifulvin
4. Tylenol
30
48
Total... 78
3
12
Total... 15
18
26
13
15
Total... 72
Ives Laboratories
Key Pharmaceutical
Lakeside Laboratories. Inc.
16
27
3 Total... 3
Lederle Laboratories
Lilly, Eli, & Co.
McNeil Laboratories
1. Aristocort
2. Bamadex
3. Declomycin
4. Rydrinix
5. Levoprome
6. Pathibamate
7. Stresscaps
8. Varidare
1. Aventyl
2. C-quens
3. Darvon
4. Keflin
5. Ilosone
6. V-Cillin--K
3
12
5
12
28
5
1
6
12
15
13
10
29
20
9
5
18
26
13
15
10
23
46
22
4
12
12
15
Total... 144
42
72
83
56
27
10
Total... 290
44
PAGENO="0628"
4918 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Mead-Johnson
1. Oracon 10 Total... 40
McKesson
1. Kessodrate 1 1
2. Kessotetra 1 1
3. Various 4 4
Total... 6
Merrell, William S.
1. Tenuate 3 Total... 3
Miles Products
1. Alkaseltzer 13 Total... 13
Merck, Sharpe, & Dobme
1. Aldomet 12 24
2. Aldoril 2 4
3. Arainine 5 10
4. Benemid/Colbenenijd 15 30
5. Codeine* 5 5
6. Cyclex 12 24
7. Decadron 18 34
8. Decagesic 8 16
9. Diuril 27 74
10. Diupres 10 20
11. Dornavac 3 6
12. Elavil 23 44
13. Hydrodiuril 3 6
14. Hydropres 9 18
15. Hydrodiuril-KA 2 3
16. Indocin 24 60
17. Nephyton 11 11
18. Periactin 11 11
19. Respihaler 8 16
20. Triavil 18 42
21. Triavil/Hydropres 3 6
22. Tr~avil/Urecholine 4 8
23. tjrecholine 12 24
Total... 496
*Merck Chemical Division of Merck & Co.
45
PAGENO="0629"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4919
COMPANY PRODUCT NO. ISSUES NO. PAGES
National Drug
1. AVC 6 7
2. AVC/Dienestrol 2 2
3. Avcen 7 7
4. Tepanil 11
Total... 36
Organon, Inc.
1. Hexadrol 10 Total... 10
Parke-Davis
1. Benadryl 21 30
2. Cholormycetin 17 17
3. Dilantin 16 28
4. Elase 3 6
5. Norlestrin 27 37
6. Pitocin 10 10
Total... 128
Philips-Roxanne
1. Duphaston 3 Total... 3
Pittinan-Noore
1. Novahistine Singlet 11 13
2. Novahistine DG 6 12
3. Neo-Polycin 4 8
4. Lirugen 13 13
Total... 46
Pfizer, Chas.
1. Daricon 6 6
2. Desitin* 6 6
3. Rondoniycin 12 56
4. Terramycin 28 84
Total. .. 152
Plough, Inc.
1. St. Joseph's Aspirin 10 Total... 10
Polythress, Wa. P.
1. Nudrane 2 2
2. Trocinate 3
Total... 5
46
PAGENO="0630"
4920 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Purdue-Frederick Company
1. Senokot
1 Total... 1
Radium-Chemical
1. Radium
13 Total... 13
1. Gantanol (various)
2. Gantrisin
3. Librax
4. Librium
5. Menrium
6. Valium
70
14
28
12
12
7
Total... 143
1. Atarax
2. Antivert
3. Marax
4. Signemycin
5. Tao
6. Tetracyn
12
24
10
4
15
8
Total... 73
Roerig, J.B. & Company
Roche Laboratories
Robins, A.H.
Rorer, Wa. H.
6
24
5
2
15
4
35
7
6
10
6
7
8
8
1
4
13
1
8
1. AllBee w/C
2. Dimeta~,p
3. Donnatal
4. Exna-R
5. Phenephan
1. Ananase
2. Maalox
8
8
2
10
13
Total... 143
1
12
Total... 13
47
PAGENO="0631"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4921
COMPANY PRODUCT NO. ISSUES NO. PAGES
Sandoz Pharmaceutical
1. Bellergal 4 4
2. Caf ergot 12 19
3. Piorinal 17 17
4. Nellaril 18 36
Total... 76
Schmid, Julius, Inc.
1. Candeptin 3 3
2. Vagesic 11 JL
Total... 14
Schering Corporation
1. Chlortriineton 5 10
2. Etrafon 14 28
Total... 38
Searle, G.D.
1. Aldactazide 8 9
2. Enovid-E 2 4
3. Flagyl 13 13
4. Lomotil 10 10
5. Mutamucil 2 2
6. Ovulen 13 33
7. ProBanthine 12 12
Total... 83
Sherman Laboratories
1. Exlisophyllin 9 Total.. 9
Smith, Kline, & French
1. Combid 13 17
2. Dyazide 10 23
3. Dyrenium 10 10
4. Teldrin 3 3
5. Thorazine 10 15
6. Stelazine 16 27
Total... 95
48
PAGENO="0632"
4922 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Sguibbs, E.R.
1. Kenacort 10 10
2. Kenalog 14 14
3. Kenalog IN 7 14
4. Nycolog 10 10
5. Mysteclin-F 9 18
6. Noctec 7 8
7. Naturetin 17 20
8. Pentids 13 21
9. Prolixin 12 16
10. Raudixin 14 14
11. Rautrax-N 14 19
Total... 164
Strassenburgh Laboratories
1. Biphetamine 5 5
2. lonamin 6 6
3. Omnituss 4 4
4. Tussionex 8 8
Total... 23
Stuart Company
1. Nylanta 12 Total... 24
Syntex
1. Synalar 4 Total... 10
1. Depo-Nedrol 11 22
2. Depo-Nedrol/Nedrol 1 1
3. Lincocin 20 48
4. TMedrol Dosepak 13 24
5. Orinase 24 39
6. Panalba 20 26
7. Provera 2 4
8. Provest 11 21
9. Tolinase 8 15
Total... 200
49
PAGENO="0633"
COMPETITIVE PROBLEMS IN
THE DRUG INDUSTRY
4923
COMPANY PRODUCT NO. ISSUES NO. PAGES
Aquasol
Arlidin
DBI-TD
Dexameth
Vaponefrin
1. Capla/Caplaril
2. Deprol
3. Neprospan
4. Nilpath
5. Niltown
6. Milprem
7. Miltrate
8. Solacen
9. Soma
10. Soma Compound
4
15
3
2
8
4
15
3
2
8
Total... 32
30
107
55
55
105
54
27
77
59
54
Total... 623
Wampole
1. Vosol
6 Total...
1. Choledyl
2. Colyinycin
3. Gelusil
4. Mandelamine
5. Peritrate
6. Pre-Sate
7. Proloid
8. Papase
9. Sinutab
10. Tedral
8
42
35
54
48
70
14
18
36
40
Total... 365
6 Total... 6
U.S. Vitamin & Pharmaceutical
1.
2.
3.
4.
5.
Wallace Laboratories
15
46
24
47
50
25
9
39
48
30
Warner-Chilcott
Warent-Teed
White Laboratories
8
20
29
39
21
14
7
9
18
15
1. Chymolase
1. Disophrol chrobotabs
5O~
3 Total...
82-280 0-69-pt. ll-41
PAGENO="0634"
4924 COMPETITIVE PROBLEMS ll~ THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Winthrop Laboratories
1. Isuprel 11 11
2. Mebaral 4 4
3. Neggram 31 46
4. Neo-Synephrine 10 10
5. Phisohex 9 9
Total... 80
West-Ward, Inc.
1. Meprobamate 3 Total... 3
Wyeth Laboratories
1. Bicillin 1 2
2. Equanil 12 25
3. Equanil/Equagesic 2 4
4. Equanil/Phenergan-VC 1 2
5. Equagesic 8 15
6. Nepergan 9 12
7. Omnipen 10 20
8. Pee-Vee-K 7 14
9. Phnergan 6 10
10. Polymagna 5 10
11. Serax 10 21
12. SMA/S-26 3 6
13. Sparine 6 12
14. Sulfose 2 4
15. Unipen 9 18
16. Zactirin 6 11
Total... 186
Wynn Pharmacal Corporation
1. Arninophylline 7 7
2. Numa 11 11
3. Quinaglute 23 23
Total... 41
51
PAGENO="0635"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4925
THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
Summary Data
1967
10 Leading Firms, by Volume of Advertising
Firm No. Drug Advertising Pagç~
Rank
1
Merck, Sharpe, & Dohme
747
2
CIBA
405
3
Warner-Chilcott
359
4
Wallace Laboratories
355
5
Lilly
279
6
Roche Laboratories
262
7
Squibb
210
8
Upjohn
207
9
10
Parke-Davis
~
150
144
--
10 Most Frequently Advertised Drug~
No. Issues
Rank
in which Advertised
1
Indocin (Merck) 50
2
Esidrex (CIBA) 43
3
Doriden (CIBA) 43
4
Ritalin (CIBA) 39
5
Ser-Ap-Es (CIBA) 38
6
Miltown (Wallace) 37
7
Elavil (Merck) 36
8
Triavil (Merck) 36
9
Peritrate (Warner-Chilcott) 35
10
Diupres (Merck) 32
Rank
1
10 Most Heavily Advertised Dru~g~
No. Pages on which Advertised
Miltown (Wallace) 90
2
Indocin (Merck) 84
3
Esidrex (CIBA) 82
4
Maolate (Upjohn) 80
5
Peritrate (Warner-Chilcott) 80
6
Triavil (Merck) 78
7
Elavil (Merck) 72
8
Ritalin (CIBA) 69
9
Ser-Ap-Es (CIBA) 69
10
Darvon (Lilly) 69
52
PAGENO="0636"
4926 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
1967
COMPANY PRODUCT NO. ISSUES NO. PAGES
Abbott Laboratories 1. Desbutal 1 4
2. Desbutal/Desoxyn 8 32
3. Enduron 7 7
4. Placidyl 14 14
Total... 57
Ames 1. Glucola 1 Total... 1
Arch Laboratories 1. Dicarbisol 13 Total... 13
Ayerst Laboratories 1. Atromid-S 5 20
2. Penbritin* 24 48
3. Premarin 11 11
Total... 79
Bristol Laboratories 1. Polycillin 31 68
2. Prostaphlin 14 28
3. Tegopen 4 8
4. Tetrex 14 28
5. Tetrex-F 4 4
6. ~etrex-B 2 4
Total... 140
Bristol-Meyers 1. Bufferin 2 Total... 2
Burroughs-Wellcome and 1. Aerosporin 8 8
Co., Inc. 2. Actifed 8 16
3. Antepar 6 6
4. Cardilate 26 30
5. Cortisporin 6 10
6. Empirin 4 8
7. Leukeran 10 10
8. Lanoxin 22 22
9. Lindosporin 2 2
10. Neosporin 5 5
11. Zyloprim 8 27
Total 144
*Distributed by Ayerst for Beecham Laboratories.
53
PAGENO="0637"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4927
NO.
NO.
COMPANY
PRODUCT
ISSUES
*
PAGES
CIBA Pharmaceutical
1.
Dialog
1
2
2.
Doriden
43
54
3.
Esidrex
43
82
4.
Esimil
16
48
5.
Ismelin
11
32
6.
Otrivin
11
11
7.
Ritalin
39
69
8.
Ser-Ap-Es
38
69
9.
Vioform
19
38
Total...
405
Cutter Laboratories
1.
Hyper-Tet
5
Total...
9
Dome Chemicals, Inc.
1.
Cort-Dome
1
Total...
1
Dupont
1.
Symmetrel
8
Total...
30
Eaton Laboratories
1.
2.
3.
4.
5.
Chioraseptic
Furacin
Furadantin
Nitrofurans
Tricocuron
11
7
14
8
12
Total...
11
7
28
8
24
78
Endo Laboratories
1.
2.
3.
Coumadin
Numorphan
Valpin
20
12
3
Total...
35
12
3
50
Flint Laboratories
1.
Choloxin
8
Total...
17
Frost Laboratories
1.
Chlorazene
11
Total...
11
Geigy Chemical Corporation
1.
2.
3.
4.
Dulcolax
Hygroton
Preludin
Tandearil
6
6
6
6
Total...
6
15
12
13
40
54
PAGENO="0638"
4928 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Glenbrook Laboratories 1. Bayer Aspirin 7 7
2. Haley's NO 8 8
3. Measurin 1 2
4. Philip's Milk of Nag- 6 6
nesia Total... 23
Hoechst~ 1. Doxidan 1 1
2. Lasix 13 74
3. Surfak 4 4
Total... 79
Ives Laboratories 1. Cyclospasmol 12 18
2. Isordil 16 16
Total... 34
Key Pharmaceutical 1. Nitroglyn 9 Total... 9
Knoll Pharmaceutical 1. Akineton 2 2
2. Dilaudid 13 13
3. Metrazol 8 23
4. Quadrinal 19 20
5. Theokin 18 18
Total... 76
Lederle Laboratories 1. Achromycin 2 2
(Division of American 2. Aristocort 5 10
Cyanamid) 3. Bamadex 7 14
4. Declomycin 17 21
5. Diamox 6 6
6. Hydromox 5 11
7. Leverprome 4 8
8. Pathibamate 2 4
9. Stresscaps 10 10
Total... 86
Lakeside Laboratories 1. Imferon 11 11
2. Norpramin 14
Total... 25
55
PAGENO="0639"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4929
COMPANY PRODUCT NO. ISSUES NO. PAGES
Lilly, Eli, & Co. 1. Aventyl 20 57
2. C-Quens 21 61
3. Cordran 8 8
4. Dymelor 7 21
5. Darvon 23 69
6. Keflin 17 63
Total... 279
Mallinkrodt Chemical 1. Codeine 1 Total... 2
McKesson 1. Amphicol 1 1
2. Kessorate 1 1
3. Kessotetra 2 2
4. Meprobamate 1 1
5. Various 1 1
Total... 6
Mead-Johnson 1. Oracon 7 14
2. Questran 2 2
Total... 16
Merrell, Wm. 5. 1. Tenuate 3 Total... 9
McNeil Laboratories 1. Butisol 24 24
2. Butiserpine 15 15
3. Grifulvin 15 15
4. Haldol 8 40
Total... 94
Miles Products 1. Alkaseltzer 5 Total... 5
56
PAGENO="0640"
4930 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Merck, Sharpe, & Dohme 1. Aldomet 24 48
2. Aldoril 15 45
3. Aramine 4 8
4. Benemid 18 36
5. Codeine 2 4
6. Cuprimine 7 7
7. Diuril 8 16
8. Duipres 32 64
9. Elavil 36 72
10. Edecrin 17 67
11. Hydropres 27 54
12. Indocin 50 84
13. Mephyton 15 15
14. Periactin 19 19
15. Respihaler 23 46
16. Triavil 36 78
17. Turbinaire 11 33
18. Urecholine 8 16
19. Vivactil 7 35
Total... 747
National D~pg 1. Tepanil 9 Total... 9
Neisler Laboratories 1. Rynatuss 5 Total... 5
(Division of Union
Carbide)
Organon, Inc. 1. Hexadrol 8 16
2. Monosticon 6 6
Total... 22
Parke-Davis 1. Benadryl 26 32
2. Chloromycetin 18 36
3. Dilantin 12 17
4. Elase 12 24
5. Norlestrin 12 34
6. Pitocin 7 7
Total... 150
Pfizer, Chas. 1. Bondornycin 22 53
2. Terraniycin 23 61
3. Vibramycin 5 22
Total... 136
57
PAGENO="0641"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4931
Roche Laboratories
Rorer, Wm. H., Inc.
PRODUCT
1. Lirugen
2. Novahistine
3. Tussend
1. St. Joseph's Aspirin
1. Senokot
1. Radium
1. Dimetapp
2. Donnatal
3. Phenaphen
4. Robitussin
5. Tybatran
1. Antivert
2. Atarax
3. Navane
4. Marax
5. Signemycin
6. Tao
1. Azo Gantanol
2. Gantanol
3. Librax
4. Librium
5. Libritabs
6. Menrium
7. Roniacol
8. Tigan
9. Valium
NO. PAGES
9
25
6
Total... 40
Total... 7
Total... 9
6 Total... 6
7 7
12 24
11 11
6 12
7 28
Total... 82
9 9
4 8
2 6
2 6
4 8
6 6
Total... 43
4 4
29 45
21 51
11 28
9 18
19 38
13 26
7 8
26 44
Total. . .262
4 Total... 4
NO. ISSUES
9
22
3
COMPANY
Pittman-Moore
Plough, Inc.
Purdue-Frederick
Radium Chemical
Robins, A. H.
Roerig, J. B., & Company
1. Maalox
58
PAGENO="0642"
4932 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Sandoz Pharmaceutiç~,l 1. Cafergot 6 6
2. Fiorinal 16 16
3. Mellaril 18 44
4. Sansert 8 8
Total... 76
Schaid, Julius 1. Candeptin 16 16
2. Vagesic 12 12
Total... 28
Schering Corporation 1. Chlortrimeton 17 17
2. Etrafon 5 16
Total... 33
Searle, G. D. 1. Ovulen 15 25
2. Ovulen-2l 11 14
3. Aldactazide 7 7
4. Enovid-E 1 1
5. Lomotil 8 8
6. Flagyl 11 12
7. Probanthine 10 10
Total... 77
Sherman Laborator~~es~es 1. Elixophyllin 1 Total... 1
Smith, Kline, & French 1. Diazide 3 6
2. Stelazine 3 6
3. Thorazine 4 7
4. Vontrol 3 9
Total... 28
Stuart Co~p~pj 1. Mylanta 2 Total... 2
1. Kenalog 26 51
2. Mycolog 24 24
3. Mycostatin 27 27
4. Mysteclin 1 1
5. Noctec 20 30
6. Pentids 12 24
7. Rauzide 14 42
8. Sumycin 11 11
Total... 210
59
PAGENO="0643"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4933
Syntex
Unimed, Inc.
U. S. Vitamin & Pharmaceu
tica].
Upjohn
1. Otnnituss
2. Tussionex
1. Synalar
1. SERC
1. Arlidin
1. Depo Medrol,
2. Medrol
3. Medrol Dosepak
4. Maolate
5. Orinase
6. Orinase/Tolinase
7. Panalba
1. Deprol
2. Capla/Caplaril
3. Meprospan
4. Miltown
5. Miltrate
6. Milpath
7. Milprem
8. Sotna
9. Soma Compound
1. Colymycin Injectable
2. Colymycin Octic
3. Gelusil
4. Mandelamine
5. Neba ir
6. Papase
7. Peritrate
8. Pre-Sate
9. Proloid
10. Pyridium
11. Tedral
NO. PAGES
3
10
13
8
42
3 Total... 3
13 26
3 3
4 8
26 80
15 25
16 46
19 19
Total... 207
26 58
9 18
7 19
37 90
14 31
27 54
7 20
22 44
7 21
Total... 355
7 45
8 8
19 19
16 44
3 14
11 21
35 86
12 67
3 7
16 16
16 32
Total... 359
COMPANY PRODUCT
Strassenburgh Laboratories
NO. ISSUES
3
10
Total...
1 Total...
30 Total...
Wallace Laboratories
Warner-Chilcott
60
PAGENO="0644"
4934 COMPETITIVE PROBLEMS LN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Warren-Teed 1. Chyinolase 1 Total... 1
Winthrop Laboratories 1. Isuprel 16 16
2. Neggram 23 31
3. NeoSynephrine 4 4
4. Phioshex 2 2
5. Talwin 8 22
Total... 75
Wyeth Laboratories 1. Bicillin 2 3
2. Equagesic 3 6
3. Equanil 6 12
4. Omnipen 5 10
5. Pen-Vee-K 5 10
6. Phenergan 8 16
7. Polymagna 3 6
8. Serax 6 12
9. Sparine 8 16
10. Unipen 4 8
11. Wyanoids 4 4
Total... 103
61
PAGENO="0645"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4935
ANNALS OF INTERNAL MEDICINE
SuMMARY DATA
Advertising, 1963 through 1967
Volume in Pages
Total Total Total Total Pages Total Pages
Pages Pages Pages Drugs Other
Year Magazine Journal Advertising Advertising Advertising
1963 4,228 2,392 1,836 1,402 434
1964 4,372 2,565 1,807 1,511 296
1965 4,764 2,637 2,127 1,695 432
1966 4,598 2,830 1,768 1,439 329
1967 4,701 2,940 1,761 1,426 335
Percentages
Percent Percent Percent Drug Advertising Other Advertising
Total Journal Advertising as Percent as Percent
Year Pages Pages Pages All Advertising All Advertis~rc~
1963 100% 56.5% 43.5% 76.3% 23.7%
1964 100% 58.6% 41.4% 83.6% 16.4%
1965 100% 55.3% 44.7% 79.6% 21.4%
1966 100% 61.5% 38.5% 81.3% 18.7%
1967 100% 62.5% 37.5% 80.9% 19.1%
62
PAGENO="0646"
4936 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
ANNALS OF INTERNAL MEDICINE
SUMMARY DATA*
1963
10 Leading Firms, by Volume of Advertisip~
Rank Firm No. Drug Advertising Pa~
1 Wyeth Laboratories 106
2 Wallace Laboratories 101
3 Pfizer 94
4 Merck, Sharpe, & Dobme 89
5 McNeil Laboratories 80
6 Roche Laboratories 79
7 Lederle Laboratories 62
8 Mead-Johnson 52
9 Smith, Kline, & French 48
10 CIBA 46
10 Most Heavily Advertised Drugs
Rank Drug~ No. Pages on which Advertised
1 Equanil (Wyeth) 32
2 Aldomet (Merck) 26
3 Benemid (Merck) 26
4 Aristicort (Lederle) 24
5 Daricon (Pfizer) 24
6 Librium (Roche) 24
7 Parafon (McNeil) 24
8 Butisol (McNeil) 23
9 & 10 Diabinase, Miltown, Terramycin 22
* Frequency table not given.
63
PAGENO="0647"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
ANNALS OF INTERNAL MEDICINE
1963
4937
PPflT~1T(~T -
1. Desbutal
2. Eutonyl
3. Norisodrine
4. Optilets
5. Placidyl
6. Tridione
1. Alphalac
2. Andercid
1. Chymoral
1. Mesulfin
2. Riopan
1. Kantrex
2. Prostaphlin
3. Salutensin
5
18
10
4
2
1
Total... 40
4 8
3 3
Total... 11
7 Total... 7
2 4
1 1
Total... 5
3 6
2 4
8 16
Total... 26
COMPANY - --
NO. ISSUES NO. PAGES
5
7
7
4
2
1
Abbott Laboratories
Anderson
Armour
~yerst Laboratories
Bristol Laboratories
Burroughs-Wellcome
1.
Empirin
2
2
2.
Lanoxin
1
1
3.
Leukeran
3
3
4.
Methedrine
3
3
5.
Myleran
4
4
6.
Purinethol
2
Total.
2
.. 15
64
PAGENO="0648"
4938 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
CONPANY PRODUCT NO. ISSUES NO. PAGES
Burton & Parsons
1. Neutra-Carb 2 Total... 2
CIBA
1. Doriden 12 19
2. Ismelin 11 18
3. Ritalin 6 9
Total... 46
Cutter Laboratories -
1. Peridial 8 8
2. Polysal 1 1
Total... 9
Chic~g~
1. Urised 2 Total... 2
Davies, Rose,~y~
1. Pil-Digis 1 Total... 1
Endo Laboratories
1. Coumadin 10 16
2. Percodan 12 12
Total... 28
Paugera
1. Digitoxin 3 Total... 3
Geigy Pharmaceutical
1. Butazolidin 12 12
2. Tofranil 6 12
Total... 24
Ives
1. Isordil 11 Total... 15
Glenwood
1. Patoba 3 Total... 3
Dome
1. Decholin 3 Total... 3
65
PAGENO="0649"
1. Butibel
2. Butisol
3. Butiserpine
4. Parafon
5. Tylenol
1. Aldomet
2. Aramine
3. Benemid
4. Decadron
5. Dornavac
12
23
12
24
9
Total... 80
11 26
7 14
8 26
9 11
12 12
Total... 89
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
4939
COMPANY
NO. ISSUES NO. PAGES
PRODUCT
1.
Dilaudid
6
6
2.
Quadrinal
5
Total...
14
1.
Aristocort
12
24
2.
Declomycin
8
13
3.
Hydromox
9
9
4.
Pathibamate
~
8
Total...
16
62
1.
Cordran
3
3
2.
Cytellin
4
4
3.
Darvon
7
19
4.
Haldrone
3
3
5.
Ilosone
3
3
6.
Novrad
2
2
7.
V-Cillin-K
2
2
Knoll Pharmaceutical
Lederle Laboratories
Lilly, Eli & Co.
McNeil
Mead-Johnson
Merck, Sharpe, & Dohme
12
12
12
12
9
9
9
2
8
11
1. Beta-Chlor
2. Colase
3. Mucomyst
4. Quibron
5. Vasodilan
10
9
6
16
11
Total... 52
66
81-28~ 0-69-pt. 11-42
PAGENO="0650"
4940 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
C0NP~ANY PRODUCT NO. ISSUES NO. PAGES
Merrell, Win. S.
1. Bentyl 5 10
2. TACE 5 10
3. Tenuate 9 9
Total... 29
Or~anon
1. Cotazym 4 4
2. Deca-Durabolin 2 2
3. Hexadrol 4 4
Total... 10
Parke-Davis
1. Adroyd 4 4
2. Benylin 7 8
3. Chloromycetin 3 3
4. Carbrital 11 11
5. Dilantin 6 11
6. Ther-Combex 2 2
Total... 39
Pfizer, Chas.
1. Booms 12 12
2. Daricon 12 24
3. Diabinese 11 22
4. Niain.id 5 10
5. Terratnycin 11 22
6. Tetracyn 4 4
Total... 94
Pharinacia
1. Azulfidine 12 Total... 12
Purdue-Frederick
1. Senokot 1 Total... 1
Biker Laboratories
1. Estomul 2 4
2. Norflex 7 14
3. Rauwiloid 3 6
Total... 24
67
PAGENO="0651"
COMPETITIVE PROBLEMS IN
THE DRUG INDUSTRY
4941
CONPANY PRODUCT NO. ISSUES NO. PAGES
Robins, A. H.
Reed & Carnick
Roche Laboratories
Rorer, Win. H.
Sandoz Pharmaceutical
Schering Corporation
1.
AllBee w/c
4
4
2.
Diinetane
7
7
3.
4.
Donnagel
Donnatal
4
3
4
6
5.
6.
7.
Donnazyme
Phenaphen
Robaxin
2 *
4
3
2
4
3
8.
9.
Robaxisal
Robinul
2
3
2
3
10.
Robitussin
3
3
11.
Skelaxin
4
Total...
4
42
1.
Phazyme
5
Total...
5
1.
Gantanol
8
16
2.
Librax
12
12
3.
Librium
12
24
4.
Roniacol
6
6
5.
6.
Tigacol
Tigan
.
12
9
Total...
12
9
79
1.
Maalox
5
Total...
5
1.
Belladenal
3
3
2.
3.
4.
Bellergal
Cafergot
Fiorinal
.
.
12
4
1
12
4
1
5.
Nellaril
12
12
6.
Sansert
12
Total...
12
44
1.
Meticorten
3
3
2.
3.
Naqua
Sigmagen
5
12
Total...
5
12
20
68
PAGENO="0652"
4942 COMPETITIVE PROBLEMS ll~ THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Searle, G. D.
1. Enovid 12 18
2. Pro-Banthine 6 6
Total... 24
Smith, Kline, & French
1. Conbid 6 6
2. Cytomel 12 12
3. Compazine 6 6
4. Eskatrol 6 6
5. Parnate 12 12
6. Thorazine 6 6
Total... 48
~q~ibb
1. Benograf in 1 1
2. Cholorgraf in 2 2
3. Mysteclin 6 6
4. Noctec 5 5
5. Pentids 5 5
6. Oragrafin 2 2
7. Pronestyl 5 5
8. Rautrax-N 4 4
9. Renografin 3 3
10. Retrografin 3 3
11. Raudixin 5 5
Total... 41
Syntex
1. Synalar 7 Total... 7
Upjohn 1. Orinase 10 20
2. Solu-B 7 7
Total... 27
U.S. Vitamin & Pharmaceutical
1. Arlidin 6 12
2. DBI-TD 5 10
Total... 22
69
PAGENO="0653"
PROBLEMS IN
PRODUCT
1. Capla
2. Deprol
3. Meprospan
4. Milpath
5. Milprem
6. Miltown
7. Miltrate
8. Soma
1. Nicalex
2. Uticon
1. Trancogesic
2. Trancopal
3. Winstrol
1. Bicillin
2. Equanil
3. Equanitrate
4. Mepergan
5. Oxaine
6. Pen-Vee-K
7. Prozine
8. Sparine
9. Thiomerin
1. Quinaglute
70
10
13
12
10
10
22
12
12
Total... 101
4 4
1
Total... 5
12 Total... 12
7
1
9
Total... 17
16
32
8
3
20
5
3
13
6
Total... 106
12 Total... 12
COMPETITIVE
THE DRUG INDUSTRY 4943
COMPANY
NO. ISSUES NO. PAGES
5
10
12
10
10
12
12
12
Wallace Laboratories
Walker
Warrent-Teed
Winthrop
Wyeth Laboratories
1. Kaon
7
1
9
4
12
8
3
10
5
2
8
6
PAGENO="0654"
4944 COMPETITIVE PROBLEMS Th~ THE DRUG INDUSTRY
ANNALS OF INTERNAL MEDICINE
Summary Data*
1964
10 Leading Firms, by Volume of Advertising
Rank Firm No. Drug Advertising Pages
1 Pfizer 115
2 Wyeth Laboratories 106
3 Merck, Sharpe, & Dohme 105
4 Wallace Laboratories 93
5 Warner-Chilcott 77
6 Sandoz Pharmaceutical 72
7 CIBA 69
8 Bristol Laboratories 54
9 Mead-Johnson 51
10 Parke-Davis 43
10 Most Heavily Advertised Drugs
No. Pages on which Advertis
1 DBI (U.S. Vitamin) 40
2 Unipen (Wyeth) 26
3 Deprol (Wallace) 24
4 Diabinese (Pfizer) 24
5 Furadantin (Eaton) 24
6 Gelusil (Warner-Chilcott) 24
7 Vistaril (Pfizer) 24
8 Equanil (Wyeth) 22
9 Polycillin (Bristol) 22
10 Aldomet, Colymycin,
Aquinitrate 20
* Frequency table not given.
71
PAGENO="0655"
1. Formatrix 10
2. Mesuif in 7
3. Premarin 3
1. Kantrex
2. Polycillin
3. Salutensin
1. Doriden
2. Esidrex
3. Forhistal
4. Ismelin
5. Ritalin
6. Reg~itine
7. Serpasil
10
11
3~
Total... 24
3
4
5
2
Total... 14
14
22
18
Total... 54
18
8
6
10
9
16
2
Total... 69
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
4945
COMPANY -
ANNALS OF INTERNAL MEDICINE
1964
PRODUCT
1. Opilets 10
2. Placidyl 2
3. Surbex-T 12
1. Dicarbosil 8
NO. ISSUES NO. PAGES
* 10
2
* 12
Total... 24
Total... 8
Abbott
Arch
Ayerst
Bourroughs
Bristol
CIBA
1. Alkeran
2. Empirin
3. Leukeran
4. Migral
3
1
5
2
7
8
9
12
4
6
5
5
8
1
72
PAGENO="0656"
4946 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
CONPANY PRODUCT NO. ISSUES NO. PAGES
Cutter
1. Polysal-M 12 12
2. Perdial 5 5
Total... 17
Davies
1. D.I. Digitalic 6 Total... 6
Eaton
1. Furadantin 12 24
2. Furoxone 7 7
Total... 31
Endo
1. Percodan 12 12
2. Coumadin 7 14
Total... 26
Glenwood
1. Potaba 9 Total... 9
1. Butazolidin 6 6
2. Persantin 3 6
3. Preludin 7 14
4. Tofranil 12 12
Total... 38
Ives
1. Isordil 7 Total. .. 7
Kenwood
1. Papavatral 6 Total... 6
Knoll
1. Delaudid 6 6
2. Quadrinal 6 6
Total... 12
Lederle
1. Aristocort 4 8
2. Declonycin 7 14
3. Hydromox 9 9
4. Pathibamate 11 11
Total... 42
73
PAGENO="0657"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4947
COMPANY PRODUCT NO. ISSUES NO. PAGES
1. Co-Pyronil 3 3
2. Cytellin 2 2
3. Darvon 6 13
4. Haldrone 2 2
5. Keflin 2 8
6. Novrad 2 2
7. Mi-Cebrin-T 3 3
Total... 33
McNeil
1. Butibel 12 12
2. Butisol 11 17
3. Tylenol 12 12
Total... 41
Mead-Johnson
1. Colace 12 12
2. Mucoinyst 7 14
3. Peri-Colace 9 9
4. Quibron 1 2
5. Tribute 1 2
6. Vasedilan 12 12
Total... 51
Merck, Sharpe, & Dohme
1. Aldomet 9 20
2. Aramine 7 11
3. Diupres 8 8
4. Diuvil 8 18
5. Dornavac 8 12
6. Elauil 9 18
7. Hydropres 8 8
8. Mephyton 10 10
Total... 105
Merrell
1. Bentyl 10 10
2. Tace 1 2
3. Tenuate 12 12
Total... 24
74
PAGENO="0658"
4948 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Organon
1. Durabolin 6 12
2. Hexadrol 6 6
3. Wigraune 4 5
Total... 23
Parke-Davis
1. Benylin 4 4
2. Carbrital 12 12
3. Dilantin 12 12
4. Norlestrin 5 11
5. Thera-Cambex 4 4
Total... 43
Pfizer
1. Bonine 12 12
2. Daricon 10 18
3. Desitin 8 8
4. Diabinese 12 24
5. Renese 5 11
6. Terramycin 9 18
7. Vistaril 12 24
Total... 115
Pharinacia
1. Azulfidine 7 Total... 7
Pitman-Moore
1. Phenoxene 12 Total... 12
Riker
1. Norflex 2 4
2. Norgesic 7 16
3. Titralac 3 6
Total... 26
Rob ins
1. Albee 5 5
2. Dimetane 6 6
3. Donnagel 4 4
4. Donnazyrne 2 2
5. Phenaphen 6 6
6. Quininidex 5 5
7. Robaxisal 2 4
Total... 32
75
PAGENO="0659"
THE DRUG INDUSTRY 4949
COMPANY
NO. ISSUES NO. PAGES
Roche
Rorer
Sandoz
Searle
COMPETITIVE PROBLEMS IN
PRODUCT~
1. Gantanol
1. Ascriptin
2. Maalox
1. Belladenal
2. Caforgot
3. Fiorlnal
4. Mellaril
5. Sansert
6. Torecan
1. Aldactazide
2. Anavar
3. Enovid
4. Pro-Banthine
1. Compazine
2. Cytomel
3. Eskatrol
4. Dyrenium
5. Feosol
6. Parnate
7. Thorazine
1. Chlorografin
2. Kenacort
3. Mysteclin
4. Noctec
5. Pentids
6. Raudixin
7. Rautrax
8. Renograf in
9. Retrograf in
10. Oragraf in
76
Smith, Kline, & French
12
12
10
12
12
12
12
12
3
2
12
2
3
4
2
3
4
2
3
1
9
5
7
1
5
1
2
1
1
Total... 12
12
12
Total... 24
10
12
12
14
12
12
Total... 72
3
4
18
2
Total... 27
3
4
2
6
5
2
3
Total... 25
1
9
5
7
1
10
1
3
1
1
Total... 39
Squibb
PAGENO="0660"
4950 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Stuart
1. Mylanta 4 Total... 4
U.S. Vitamin
1. D3I 10 Total... 40
Upjohn
1. Pamine 4 4
2. Unicap 1 1
3. Solu-Cortef 12 12
Total... 17
Walker
1. Nicalex 6 Total... 6
Wallace
1. Capla 4 8
2. Deprol 12 24
3. Meprospan 12 12
4. Miltown 12 14
5. Milprem 2 2
6. Miltrate 12 12
7. Preemt 7 9
8. Soma 12 12
Total... 93
Warner-Chilco tt
1. Anugesic 3 4
2. Anusol 12 12
3. Coly-Mycin 10 20
4. Gelusil 12 24
5. Mandelamine 8 17
Total... 77
White
1. A&D 7 14
2. Permitil 5 10
Total... 24
Warren-Teed
1. Ilopan 2 2
2. Kaon 6 6
3. Modane 2 2
4. Ventussin 3 3
Total... 13
77
PAGENO="0661"
COMPANY
COMPETITIVE PROBLEMS IN THE
PRODUCT -
1. Trancopal
2. Trancogesic
3. Winstrol
1. Bicillin
2. Cyclamyciñ
3. Equagesic
4. Equanil
5. Equanitrate
6. Mepergan
7. Pen-Vee-K
8. Phenergan
9. Purodigin
10. Sparine
11. Thiomerin
12. Unipen
13. Zactirin
4 6
3 3
12 12
Total... 21
4 4
2 2
2 2
11 22
12 20
8 8
2 2
2 2
2 2
2 4
2 2
9 26
4 10
Total... 106
1. Quinaglute
78
12 Total... 12
DRUG INDUSTRY 4951
Winthrop
NO. ISSUES NO. PAGES
PAGENO="0662"
4952 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
THE ANNALS OF INTERNAL MEDICINE
SUMMARY DATA*
1965
10 Leading Firms, by Volume of Advertising
Rank Firm No. Drug Advertising Pages
1 Merck, Sharpe, & Dohme 134
2 Wyeth Laboratories 120
3 CIBA 100
4 Pfizer 95
5 Bristol Laboratories 66
6 Lilly 64
7 Wallace Laboratories 63
8 Warner-Chilcott 60
9 Robins 59
10 Geigy 58
10 Most Heavily Advertised Drugs
Rank Drug No. Page on which Advertised
1 Darvon (Lilly) 26
2 Diabinese (Pfizer) 26
3 Keflin (Lilly) 25
4 Decadron (Merck) 24
5 Diuril (Merck) 24
6 Dornavac (Merck) 24
7 Quinidex (Robins) 24
8 Tetrex (Bristol) 24
9 Mylanta (Stuart) 23
10 Robinul (Robins) 23
* Frequency table not given.
79
PAGENO="0663"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4953
THE ANNALS OF INTERNAL MEDICINE
1965
COMPANY PRODUCT NO. ISSUES NO. PAGES
Abbott
Arch Laboratories
Ayerst Laboratories
Bristol Laboratories
Burroughs-Wellcome
CIBA
1.
Fero-Grad
11
11
2.
Optilets
6
6
3.
Surbex-T
12
Total...
12
29
1.
Dicarbosil
5
Total...
5
1.
Forinatrix
11
11
2.
Mesulf in
4
8
3.
Premarin
1
Total...
1
20
1.
Kantrex
11
22
2.
Polycillin
10
20
3.
Tetrex
~
12
Total...
24
66
1.
Alkeran
5
5
2.
Leukeran
3
3
3.
Migral
3
3
4.
Myleran
3
3
5.
Purinethol
3
Total...
3
17
1.
Doriden
11
11
2.
Esidrex
9
18
3.
Ismelin
7
14
4.
Regitine
11
11
5.
Ritalin
9
18
6.
Ser-Ap-Es
6
18
7.
Serpasil
5
Total...
10
100
80
PAGENO="0664"
4954 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
NO. ISSUES NO. PAGES
COMPANY
PRODUCT
Dorsey Products
1.
Trest
2
Total...
4
Davies, Rose, H2y~
1.
Pil-Digis
12
Total...
12
Eaton Laboratories
1.
Puradantin
6
Total...
12
Endo Laboratories
.
1.
2.
3.
Couxnadin
Hycodan
Percodan
10
4
11
Total...
17
4
11
32
1.
2.
3.
4.
5.
Butazolidin
Pertofrane
Persantin
Regroton
Tofranil
8
10
3
11
9
Total...
13
22
3
11
9
Ives Laboratories
1.
Isordil
9
Total...
18
Kenwood
1.
Papavatral
11
Total...
.
11
Knoll Products
1.
Dilaudid
12
Total...
12
Glenwood
1.
Potaba
9
Total...
9
Lakeside
1.
2.
Nercuhydrin
Norpramin
6
9
6
18
81
PAGENO="0665"
1. Bentyl
2. Kolantyl
3. Tenuate
10
3
12
82
10
6
12
Total... 28
THE DRUG INDUSTRY 4955
COMPANY
NO. ISSUES NO. PAGES
8
7
10
6
12
8
10
4
7
1
8
14
10
12
12
Total... 56
8
26
4
25
1
Total... 64
COMPETITIVE PROBLEMS IN
1. Artane
2. Aristocort
3. Diamox
4. Declomycin
5. Pathibamate
1. Anhydron
2. Darvon
3. Dymelor
4. Keflin
5.. V-Cillin-K
1. Obedrin-LA
1. Butibel
2. Butisol
3. Tylenol
1. Sustagen
1. Aramine
2. Aldomet
3. Benemid
4. Decadron
5. Dornavac
6. Elavil
7. Diuril
8. Mephyton
9. Hydropres
Lederle Laboratories
Lilly, Eli & Co.
Massengill Company
McNeil Laboratories
Mead Johnson
Merck, Sharpe, & Dohme
Merrell, William S.
10 Total... 10
12 12
12 12
11 11
Total... 35
8 Total... 8
10 20
1 2
5 5
12 24
12 24
8 16
12 24
12 12
4 7
Total... 134
81-280 O-69--pt. 11-43
PAGENO="0666"
4956 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPMW PRODUCT NO. ISSUES NO. PAGES
Neisler Laboratories
1. Dainite-KI 8 8
2. Diutensen 11 22
Total... 30
National
1. Nicalex 5 5
2. Quinamm 2 2
Total... 7
Parke-Davis
1. Benylin 7 7
2. Carbrital 11 11
3. Dilantin 8 8
4. Thera-Combex 3 3
Total... 29
Pfizer, Chas.
1. Bonine 11 11
2. Daricon 10 20
3. Diabinese 12 26
4. Desitin 5 5
5. Renese 8 20
6. Vistaril 5 13
Total... 95
Pharinacia Laboratories
1. Azulfidine 7 Total... 7
Purdue-Frederick
1. Senokot 3 Total... 3
Riker Laboratories
1. Nedihaler-Duo 10 20
2. Norgesic 1
Total... 22
Robins, A. H.
1. Diinetane 12 12
2. Quinidex 12 24
3. Robinul 12 23
Total... 59
83
PAGENO="0667"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4957
COMPANY PRODUCT NO. ISSUES NO. PAGES
Roche Laboratories
1. Librium 9 18
2. Tigan 6 12
Total... 30
Rorer, Wm. H.
1. Ascriptin 12 13
2. Maalox 12 21
3. Parepectolin 3 3
Total... 37
Sandoi Pharmaceutical
1. Belladenal 12 12
2. Cafergot 11 11
3. Fiorinal 11 11
4. Nellaril 12 14
5. Sansert 1 1
Total... 49
Schering Corporation
1. Signamycin 3 3
2. Soluspan 2
Total... 7
Searle, G. D.
1. Aldactazide 8 8
2. Anavar 3 6
3. Enovid 10 19
4. Flagyl 2 2
5. Pro-Banthine 1 1
Total... 36
Smith, Kline, & French
1. Combid 9 9
2. Cytomel 7 8
3. Ecotrin 6 6
4. Esketrol 1 1
5. Dexedrine 3 3
6. Dyrenium 8 9
7. Spansule 9 9
8. Thorazine 3 3
Total... 48
84
PAGENO="0668"
4958 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Squibb
1. Kenacort 6 6
2. Medotopes 2 2
3. Nysteclin 3 3
4. Noctec 11 11
5. Oragrafin 2 2
Total... 24
Stuart
1. Dialose 3 3
2. Mylicon 9 12
3. Mylanta 10 23
Total... 38
U.S. Vitamin & Pharmaceutical
1. Arlidin 5 20
2. DBI 5 20
Total... 40
Upjohn
1. Solu-Medrol 9 Total... 9
Wallace Laboratories
1. Capla 2 2
2. Deprol 11 21
3. Meprospan 2 2
4. Milprem 8 8
5. Miltrate 5 5
6. Miltown 11 22
7. Soma 3 3
Total... 63
Warner-Chilcott
1. Anusol 12 12
2. Colymycin 9 14
3. Gelusil 12 12
4. Peritrate 11 22
Total. ~. 60
Warren-Teed
1. Ilopan 10 10
2. Kaon 9 19
3. Modane 9 9
Total... 38
85
PAGENO="0669"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4959
COMPANY NO. ISSUES NO. PAGES
1. A&D 11
2. Permitil 3
3. Disophrol 9
1. Isuprel
2. Winstrol
1. Aldurox
2. Equagesic
3. Equanil
4. Equinitrate
5. Mepergan
6. Oxaine
7. Serax
8. Unipen
9. Zactirin
1. Quinaglute
8
10
Total... 18
1
17
20
17
4
17
14
18
12
Total... 120
12 Total... 12
White
Winthrop
Wyeth Laboratories
22
22
Total... 50
7
7
1
10
10
9
4
6
5
9
4
86
PAGENO="0670"
4960 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
ANNALS OF INTERNAL MEDICINE
Summary Data
1966
10 Leading Firms, by Volume of Advertising
Rank Firm No. Drug Advertising Pages
1 Smith, Kline, & French 78
2 Geigy 73
3 Lilly 73
4 Stuart 70
5 Wyeth 70
6 Robins 68
7 Squibb 62
8 Merck, Sharpe & Dohme 61
9 Bristol Laboratories 55
10 Mead-Johnson 49
10 Most Heavily Advertised Drugs
Rank No. Pages on which Advertised
1 Dymelor (Lilly) 36
2 Vasodilan (Mead-Johnson) 32
3 Kantrex (Bristol) 25
4 Darvon (Lilly) 24
5 Librium (Roche) 24
6 Mylanta (Stuart) 24
7 Quinidrex (Robins) 24
8 Pertofrane (Geigy) 23
9&lO Isordil, Ritalin, Roniacol 22
87
PAGENO="0671"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4961
COMPANY
Abbott Laboratories
Burroughs-Wellcome
1. Actadil
2. Alkeran
3. Empirin
4. Lukeran
5. Various
6. Zyloprim
NO. PAGES
12
4
8
24
8
11
2
8
6
Total... 14
25
21
9
Total... 55
4
2
3
2
1
6
Total... 19
Total... 7
ThE ANNALS OF INTERNAL MEDICINE
1966
Amf re-Grant
Arch Laboratories
Armour
Ayerst Laboratories
Bristol Laboratories
PRODUCT
NO. ISSUES
1.
Fero-Grad
12
2.
Surbex
4
3.
Vercyte
4
1.
Neo-Corovas
5
1.
Dicarbosil
11
1.
Pentritol
1
1.
Formatrix
8
2.
Thiosulfil
3
1.
Kantrex
11
2.
Polycillin
10
3.
Tetrex
6
Total...
Total...
Total...
Total...
Chesebrough-Pond, Inc.
4
2
3
2
1
4
1. Measurin
88
PAGENO="0672"
4962 COMPETITIVE PROBLEMS ll~T THE DRUG INDITSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
CIBA Pharmaceutical Company
1. Doriden 9 11
2. Regitine 6 6
3. Ritalin 10 22
Total... 39
Cutter Laboratories
1. Peridial 12 12
2. Polysal-M 12 12
Total... 24
Davies, Rose-Hoyt Pharmaceutical Co.
1. Pil-Digis, Davokin,
Myodigin 4 4
2. Pil-Digis 8 8
Total... 12
Dome Laboratories
1. Aniinet 6 Total... 6
Dorsey
1. Trest 1 Total... 2
Eaton Laboratories
1. Furadantin 9 Total... 12
Endo Laboratories
1. Coumadin 4 8
2. Hycodan 3 3
3. Percodan 12 12
Total... 23
1. Anturane 2 4
2. Hygroton 4 8
3. Persantin 4 8
4. Pertofrane 7 23
5. Preludin 7 14
6. Tandearil 4 8
7. Tofranil 4 8
Total... 73
89
PAGENO="0673"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4963
CONP~NY PRODUCT NO. ISSUES NO. PAGES
Hoechst
1. Lasix 2 Total... 20
Glenwood
1. Myocholine 1 1
2. Potaba 6 6
Total... 7
Ives Laboratories
1. Isordil 11 Total... 22
Knoll Pharmaceutical Co.
1. Dilaudid 12 Total... 12
Lakes ide
1. Norpramin 4 Total... 5
Lederle
1. Aristocort 6 12
2. Artane 1 1
3. Declomycin 5 10
4. Hydromox 1 2
5. Pathibamate 6 12
Total... 37
Eli Lilly & Company
1. Darvon 12 24
2. Dymelor 12 36
3. Keflin 4 13
Total... 73
S. E. Massengill Company
1. Obedrin-LA 9 Total... 9
McNeil Laboratories
1. Butisol 12 12
2. Tylenol 1 1
Total... 13
90
PAGENO="0674"
4964 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Merck, Sharpe, & Dohme 1. Aramine 3
6
3
2
2. Benemid 10
3. Decadron 6
4. Diuril 14
5. Dornavac 6
6. Elavil 14
7. Hydropres 2 2
8. Mephyton Total... 61
5
5
Mead-Johnson 1. Colace 6 32
12
2. Muconiyst
3. Vasodilan Total... 49
11
11
Merrell 1. Bentyl
10
2. Kolantyl 10 18
3. Tenuate Total... 39
National 1. Tepanil
6 Total... 12
5
5
Neisler 1. Dainite 10
2. Diutensen Total... 15
4
2
Organon 1. Durabolin 10 11
2. Hexadrol 12 12
3. Wigraine Total... 27
3
3
Pfizer 1. Daricon 1 2
2. Terramycin Total... 5
91
PAGENO="0675"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4965
COMPANY PRODUCT NO. ISSUES NO. PAGES
Parke-Davis
1. Benylin 8 8
2. Carbrital 12 12
3. Dilantin 9 9
Total... 29
Pharmacia
1. Azulfidine 12 Total... 12
Purdue-Frederick
1. Senokot 5 Total... 5
Riker
1. Duo-Medihaler 1 Total... 2
Robins
1. Dimetane 12 12
2. Dimetepp 11 11
3. Phenaphen 9 9
4. Quinidex 12 24
5. Robaxin 6 12
Total... 68
Roche
1. Librium 12 24
2. Roniacol 11 22
Total... 46
Roerig
1. Tao 1 Total... 1
Rorer
1. Ascriptin 11 11
2. Maalox 12 20
3. Quaalude 1 1
Total... 32
Sandoz
1. Belladenal 10 10
2. Belergal 4 4
3. Cafergot 12 12
4. Mellaril 6 12
Total... 38
92
PAGENO="0676"
4966 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Schering
1. Celestone 5 Total... 15
Searle
1. Aldactazide 5 16
2. Enovid 1 1
3. Lomotil 1 1
4. Ovulen 2 2
5. Probanthine 9 10
Total... 30
Sherman
1. Elixophyllin 5 Total... 9
Smith, Kline, & French
1. Combid 10 12
2. Cytomel 11 11
3. Dexedrine 6 6
4. Dyazide 8 20
5. Dyrenium 10 10
6. Eskatrol 4 4
7. Feosol 1 1
8. Stelazine 10 10
9. Thorazine 4 4
Total... 78
Squibb
1. Kenacort 5 5
2. Kenalog 7 14
3. Medatopes 2 3
4. Naturetin 4 7
5. Noctec 8 8
6. Pentids 1 1
7. Prolixin 2 4
8. Pronestyl 3 6
9. Raudixin 5 5
10. Rautrax 7 9
Total... 62
Stuart
1. Dialose 12 12
2. Mylanta 12 24
3. Mylicon 12 18
4. Stuartinic 11 16
Total... 70
93
PAGENO="0677"
1. Orinase
2. Tolinase
1. Arlidin
2. DBI-TD
3. Vaponefrin
1. Deprol
2. Miltown
3. Soma
1. Quinainm
2. Nicalex
1. Anusol
1. Kaon
2. Modane
1. Isuprel
2. Tranco-Gesic
3. Winstrol
1. A&D
2. Disophrol
7 14
5 10
Total... 24
4 7
4 9
4 4
Total... 20
3 6
3 6
2 3
Total... 15
1 1
1 1
Total... 2
1
10 20
8 14
Total... 34
3 3
7 7
3 3
Total... 13
8 9
2 3
Total... 12
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4967
COMPANY PRODUCT NO. ISSUES NO. PAGES
~pj~hn
U.S. Vitamin
Wallace
Walker
Warner-Chilcott
Warren-Teed
Winthrop
White
Total... 1
94
PAGENO="0678"
4968 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
1. Equagesic 6 13
2. Equanil 9 18
3. Equanitrate 1 2
4. Mepergan 5 10
5. Oxaine 3 6
6. Serax 3 9
7. Unipen 1 2
8. Zacterin 5 10
Total... 70
1. Quinaglute 12 Total... 12
95
PAGENO="0679"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4969
ANNALS OF INTERNAL MEDICINE
Summary Data
1967
10 Leading Firms, by Volume of Advertising.
Rank Firm No. Drug Advertising Pages
1 Merck, Sharpe, & Dohme 96
2 Geigy 94
3 Head-Johnson 93
4 Lilly 91
5 CIBA 87
6 Lederle Laboratories 74
7 Ayerst Laboratories 63
8 Robins 60
9 Squibb 57
10 Abbott Laboratories 47
10 Most Heavily Advertised Drugs
Rank No. Pages on which Advertised
1 Vasodilan (Mead-Johnson) 48
2 Dymelor (Lilly) 39
3 Lasix (Hoechst) 36
4 Aventyl (Lilly) 28
5 Atromid-S (Ayerst) 25
6 Darvon (Lilly) 24
7 Roniacol (Roche) 24
8 Ritalin (CIBA) 23
9 Tofranil (Geigy) 23
10 Zyloprim (Burroughs-Wellcome) 23
96
PAGENO="0680"
4970 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
ANNALS OF INTERNAL MEDICINE
1967
COMPANY PRODUCT NO. ISSUES NO. PAGES
Abbott Laboratories
1. Ferro-Grad
2. Nacroscan
3. Pertscan
4. Surbex-T
5. Vercyte
l~
8
12
12
11
1
11
12
12
Total... 47
Arch
Armour
1. Dicarbosil
1. Letter
2. Pentritol
3. Thyrar
11 Total... 11
8
8
1
16
16
2
Total... 34
Ayerst Laboratories
1. Atromid-S
2. Penbritin
3. Riopan
4. Thiosulfil
5
6
6
7
25
12
12
14
Total... 63
Breon Laboratories
Bristol Laboratories
1. Bronkometer
1. Kantrex
2. Polycillin
6 Total...
6
10
6
18
20
Total... 38
Burroughs-Wellcome
1.
Actidil
3
4
2.
Alkeran
3
3
3.
Empirin
1
1
4.
Leukeran
3
3
5.
Myleran
3
3
6.
Purinethol
3
3
7.
Thioguanine
3
3
8.
Zyloprim
9
Total.
1L
.. 43
97
PAGENO="0681"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4973
COMPANY PRODUCT NO. ISSUES NO. PAGES
Merck, Sharpe, & Dohme
1. Aldomet 9 18
2. Diuril 1 1
3. Elavil 3 6
4. Hydrodiuril 8 18
5. Hydropres 8 16
6. Indocin 11 22
7. Mephyton 9 9
8. Triavil 2 6
Total... 96
Merrell, Wa. S.
1. Bentyl 5 10
2. Kolantyl 5 10
3. Tenuate 10 22
Total... 42
National
1. Tepanil 9 Total... 13
Neilser
1. Diutensen 3 Total... 5
Ortho
1. Ortho-Novum 2 Total... 4
Parke-Davis
1. Benylin 4 4
2. Carbrital 10 10
3. Eldec 9 13
4. Thera-Combex 3 3
Total... 30
Pfizer, Chas.
1. Diabinese 2 6
2. Renese 6 12
3. Terramycin 2 4
Total... 22
Pharinacia
1. Azulfidine 9 Total... 9
100
PAGENO="0682"
4974 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Purdue-Frederick 1. Cardioquin 2 Total... 2
12
12
Robins, A. H. 1. Dimetapp 6
12
2. Donnatal 8 8
3. Entozyme
4. Phenaphen 12 19
5. Robaxin 1 2
6. Quinidex Total... 60
Roche Laboratories 1. Roniacol 12
24
18
9
2. Tigacol Total... 42
8
8
Rorer, Win. H. 1. Maalox 6
8
2. Quaalude Total... 16
Rowell Laboratories 1. Cortenema 2 Total... 4
12
Searle, G. D. 1. Aldactazide 2
6 2
2. Metamucil
3. Lomotil
4. Pro-Banthine Total... 24
4
Smith, Kline, & French 1. Combid 2
3
2. Cytomel
3. Dexedrine 11 21
4. Dyazide 1 1
5. Dyrenium 1 1
6. Eskatrol
7. Stelazine 2 2
8. Thorazine Total... 38
101
PAGENO="0683"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY .497 5
COMPANY PRODUCT NO. ISSUES NO. PAGES -
Schering Corporation
1. Celestone 3 6
2. Soluspan 3
Total... 12
Sherman
1. Elixophyllin 8 Total... 8
Squibb
1. Kenacort 9 9
2. Kenalog-IM 9 . 17
3. Medotopes 11 11
4. Pronestyl 10 20
Total... 57
Stuart
1. Mylanta 12 21
2. Mylicon 9 12
Total... 33
Unimed
1. SERC 2 Total... 4
U.S. Vitamin & Pharmaceutical
1. Emivan 6 10
2. Vaponef rim 6 10
Total... 20
Wampole
1. Theo-Organidin 1 Total... 1
Warner-Chilcott
1. Anusol 2 4
2. Mandelamine 3 6
3. Peritrate 4 9
Total... 19
Warrent-Teed
1. Kaon 4 11
2. Modane 1 2
Total... 13
102
PAGENO="0684"
4976 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
White Laboratories
1. Disophrol 6 Total... 9
Winthrop
1. Trancogesic 4 4
2. Winstrol 2 4
Total... 8
~z~a
1. Numa 4 4
2. Quinaglute 10 15
Total... 19
103
PAGENO="0685"
ANERICAN FAMILY PHYSICIAN
Summary Data 1963-1967
YEAR
TOTAL PAGES
MAGAZINE
TOTAL PAGES
JOURNAL
ADVERTISING
DRUG ADVERTISING
OTHER ADVERTISING
1963 (6 mo.)*
470
290
190
137
53
86
1964
1,058
602
456
370
88
1965
1,240
707
533
445
60
1966
1,261
677
584
70
1967
1,738
913
825
755
*Sjx issues unavailable for
review
0
0
~J2
H
0
~
Percent~~~
OTHER ADVERTISING
YEAR
PERCENT
TOTAL PAGES
.
PERCENT
JOURNAL PAGES
PERCENT
ADVERTISING PAGES
DRUG ADVERTISING
AS PERCENT
ALL ADVERTISING
AS PERCENT
ALL ADVERTISING
1963
lOO~
61.7%
38.3%
72.1%
27.9%
18.9%
1964
1965
1966
1967
100%
100%
100%
100%
56.8%
57.0%
53.7%
52.5%
43.2%
43.0%
46.3%
47.5%
81.1%
81.2%
89.7%
91.5%
~-__________________
18.8%
10.3%.
8.5%
PAGENO="0686"
4978 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
AMERICAN FAMILY PHYSICIAN
1963
COMPANY PRODUCT NO. ISSUES NO. PAGES
Abbott Laboratories
1. Calcidrine 3 3
2. Placidyl 1 1
3. Selsun 1 1
4. Vi-Daylin 3 3
Total... 8
Ayerst Laboratories
1. Mysoline 1 1
2. Premarin 6 6
Total... 7
Eaton
1. Furacin 2 Total... 2
Ernko
1. Enko Foam 1 Total... 1
Lilly
1. Haldrane 2 2
2. Ilosone 4 8
Total... 10
Mead Johnson
1. Natalins 3 9
2. Tacaryl 2 2
3. Tempra 2 4
Total... 15
Parke-Davis
1. Benadryl 5 5
2. Carbrital 5 5
Total... 10
Pfizer, Chas.
1. Bonine 6 6
2. Daricon 6 7
3. Renese 6 10
4. Tetracyn 4 4
Total... 27
105
PAGENO="0687"
COMPETITIVE PROBLEMS IN THE
DRUG INDUSTRY 4979
PRODUCT
1. Albee w/c
2. Dimetepp Extentahs
3. Donnagel
4. Phenaphren
5. Robavisal
6. Robaxin
7. Robihussin
1. Enovid
2. Lomatil
3. Pro-Banthene
NO. PAGES
5
2
2
2
3
3
2
Total... 19
2
1
4
7
3
2
1
12
7
6
Total... 25
COMPANY
Robins, A. H.
Searle, G. D.
Smith, Kline, & French
Syntex
Wallace Laboratories
wyeth Laboratories
NO. ISSUES
5
2
2
2
3
2
2
2
1
4
Total...
3 Total...
2 Total...
1 Total...
4
6
3
1. Daprisal
1. Synalar
1. Milltown
1. Bicillin
2. Equanitrate
3. Equagesic
106
PAGENO="0688"
4980 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
AMERICAN FAMILY PHYSICIAN 1964
PRODUCT
1. Placidyl
1. Chymer
2. Pentritol
1. Plegine
2. Preinarin
1. Asbran
1. Hycodan
2. Rycotnine
3. Percodan
4. Valpin-PB
1. Geyrite
2. PeritinIc
1. Butibel-Zynne
2. Butisol
1. Teinpra
2. -. ~oIy-vi-F1or
3. Trii-vi-sol
NO. ISSUES NO. PAGES
3 Total... 3
1 2
5 __~Q_
Total... 12
2 2
4 Total... 4
6
3 Total... 6
1 1
4 6
9 9
6 11
Total... 27
4 4
7
Total... 11
6 6
6 6
Total... 12
12 12
3 8
3 5
Total... 25
CONPANY
Abbott
Armour
Ayerst
Dorsçy
Endo
Lederle
McNeil
Nead-Johnson
107
PAGENO="0689"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4981
COMPANY PRODUCT NO. ISSUES NO. PAGES
Neisler
1. Di~tensen 6 12
2. Krem 4 6
3. Rynatan 10 13
4. Rynatuss 10 13
5. Synatan 9 14
Total... 58
Ortho
1. Ortho-Novvm 4 Total... 8
Parke-Davis
1. ABDEC 7 7
2. Adroyd 6 10
3. Benadryl 2 2
4. Carbrital 10 10
5. Dilantin 2 2
6. Elase 2 2
7. Thera-Cainbey 9 9
Total... 42
Pfizer
1. Oalmito 4 4
2. Darican 2 4
3. Signemycin 12 34
4. Terramycin 4 11
5. Vistaril 7 17
Total... 70
Robins
1. J~iiae1tepp Extentabs 10 13
2. Donnagel 6 6
3. Exna 2 4
4. Robitussin 6 6
5. Robinul 2
Total... 35
Roche
1. Valium 7 Total... 7
108
PAGENO="0690"
4982 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODU(~ NO. ISSUES NO. PAGES
6
3
Searle 1. ~
2. Enovid 2 2
3. Flagyl
4. LamotIl
5. Netamucil
6. Pro-Banthene Total... 18
Smith, Kline, and French 1
2
1. Chiorpromazine 6 6
2. Thorazine Total... 8
Syntex 1. Synalar
10 Total... 13
3
3
~~lace 1. Neprospan 3 6
2. Hiltown Total... 9
109
PAGENO="0691"
COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
DRUG
1. Chymar
2. Dentrital
3. Pentritol
1. Butazolidin
2. Persantin
1. Butthel-Zyme.
2. Butiserzapide
3. Buti~ol
4. Parafan-Forte
110
4983
PAGES
20
2
17
Total... 39
Total... 12
Total... 2
6
3
12
Total... 21
4
5
9
1
7
9
2
Total... 11
10
20
9
12
Total... 51
COMPANY
AMERICAN FAMILY PHYSICIAN
1965
NO.
-- NO.
1. Preniarin
1. Asbron
1. Hyconiine
2. Percodan
3. Valpin
Armour
Ayerst
Dorsey
Endo
Hankscraft
Lederle
Lilly
1'1cNeil
ISSUES
10
1
9
12
1
3
3
12
4
3
Total...
1 Total...
7 Total...
1. Zyinenol
1. Peritinic
1. Darvon
2. Tetra-Solgun
3
2
10
12
9
12
PAGENO="0692"
4984 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY DRUG NO. ISSUES NO. PAGES
Neisler
1. Dainite-KL 8 8
2. Diutensen 12 25
3. Rynatan/Rynatuss 9 32
4. Synatan 8 18
Total... 83
Ortho
1. Diutenstrol 5 5
2. Ortho-Novuin 12 29
3. Sultrin 5 5
Total... 39
Parke-Davis
1. ABDEC 6 6
2. Benadryl 8 8
3. CarbrItal 11 11
4. Nyadec 7 7
5. Thera-Coinbey 10 10
Total... 42
Pfizer
1. Bonine 10 10
2. .Calmetrol 3 3
3. Daricon 5 10
4. Diabinese 12 28
5. Meclezine-HCL 1 1
6. Vistaril 5 14
Total... 66
Robins
1. Albee 2 2
2. Donnatel 2 2
3. Entozyme 4 4
4. Robitussin 3 6
Total... 14
Riker
1. Duo-medihaler 6 Total... 12
111
PAGENO="0693"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4985
COMPANY DRUG NO. ISSUES NO. PAGES
Schering
1. Afrin 4 8
2. Metretan 2 2
3. Metriderm 1 1
Total... 11
Seozle 1. Enouid 5 9
2. Flagyl 3 6
3. Lamotil 1 2
4. Pro-Banthene 3 3
Total... 20
Smith, Kline, French
1. Stelazine 3 Total... 3
Winthrop
1. Negram 2 Total... 2
112
PAGENO="0694"
4988 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY
CONPM~Y DRUGS NO. ISSUES NO. PAGE~
Robins
1. Albee 3 3
2. Entozyme 11 11
3. Robaxin 6 12
4. Robitussin 4 12
Total... 38
Schering
1. Afrin 7 14
2. Celestine 5 13
3. Coricidin 3 3
4. Chlor-trimeton 2 2
5. Fluvicin 2 4
6. Baramycin 6 21
7. Polaramine 6 12
8. Tinactin 2 4
Total... 73
Searle
1. Aldactazide 3 6
2. Flagyl 3 6
3. Lomotil 2 4
4. Ovulen 4 20
5. Pro-Banthine 3 5
Total... 41
Smith, Kline, and French
1. Dexainyl 6 Total... 6
Warner-Chillcott
1. Peritrate 1 Total... 2
1. Bi-cillin 5 10
2. Omnipen 8 16
Total... 26
115
PAGENO="0695"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4989
AMERICAN FAMILY PHYSICIAN
1967
COMPANY PRODUCT NO. ISSUES NO PAGES
Abbott
1.
Compocillin
4
6
2.
Erythrocin
~
12
Total...
18
24
Cole
1.
2.
Asniinyl
Indo-~N1acin
1
3
Total...
2
6
8
Endo
1.
2.
3.
Hycomine
Percodan
Valpin
7
5
8
Total...
14
10
8
32
9~~z
1.
2.
3.
Pertofrane
Preludin
Tofranil
-
6
5
6
Total
16
10
10
36
Hankscraft
1.
Zymenol
5
Total...
5
1.
2.
3.
C-Quens
Ilosane
V-Cillin-K
2
11
11
Total...
6
28
28
62
McNeil
1.
2.
3.
4.
5.
6.
Butiserpazide
Butiserpine
Butisol
Butisone
Parafon
Tylenol
12
12
7
5
7
12
Total...
21
15
9
8
7
34
94
116
PAGENO="0696"
4990 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Mead Johnson
1. Oracan 2 Total... 16
Merck, Sharp, & Dohme
1. Benemid 10 20
2. Diuril 3 3
3. Indocin 8 16
Total... 39
Merrell
1. Bentyl 5 Total... 9
Organon
1. Accelerase 7 Total... 12
Ortho
1. Delfen 2 2
2. Ortho-Gynol 3 3
3. Ortho-Novum 11 39
Total... 44
Parke-Davis
1. Benylin 9 9
2. Carbrital 12 12
3. Cosanyl 4 4
4. Paladec 3 3
5. Pitocin 8 8
6. Povan 2 4
Total... 40
Pfizer
1. Diabines 2 5
2. Urobiotic 8 16
Total... 21
Pitrnan-Moore
1. Orifer 6 Total... 12
Riker
1. Estomul 7 Total... 8
117
PAGENO="0697"
4991
THE DRUG INDUSTRY
COMPANY -
NO. ISSUES NO. PAGES
Robins
Roche
Schering
Searle
Sherman
Smith, Kline, & French
Squibb
COMPETITIVE PROBLEMS IN
PRODUCT,
1. Albee
2. Entozyme
3. Robaxin
4. Robitussin
1. Gantanol
2. Gantrison
3. Roniacol
4. Tigan
1. Afrin
2. Celestone
3. Coricidin
4. Etrafon
5. Garamycin
6. Medilets
7. Polaramine
8. Tinactin
1. Flagyl
2. Lomotil
3. Ovulen
4. Pro-Banthene
1. Persisten
1. Stelazine
1. Delestrogen
2. Kenecort
3. Hematinie
4. Principen
5. Raudixin
6. Theragran
118
12 12
6 6
4 5
8 11
Total... 34
4 5
2 2
3 3
3 .3
Total... 13
12 14
8 20
2 2
3 5
12 24
1 1
4 8
1 2
Total... 76
5 8
4 8
1 2
2 4
Total... 22
5 Total... 5
2 Total... 2
4 8
5 5
4 4
2 2
12 12
12 23
Total... 54
PAGENO="0698"
4992 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
COMPANY PRODUCT NO. ISSUES NO. PAGES
Stuart
1. Dialose 4 8
2. Nylanta 9 18
3. Mylicon 9 12
4. Prenatal 11
Total... 49
1. Equanil 3 6
2. Oxaine 4 4
3. Phenergan 3 5
4. SMA-526 5 10
5. Sparine 3 6
6. Thiomerin 4 7
Total... 38
119
PAGENO="0699"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4993
JOURNAL OF ABDOMINAL SURGERY
SUMMARY DATA
Advertising, 1963 through 1967
Volume in Pages
Total Total Total Total Pages Total Pages
Pages Pages Pages Drugs Other
Year Magazine Journal Advertising Advertising Advertising
1963* 221 155 66 43 23
1964* 221 171 50 20 30
1965* 279 158 121 77 44
1966 626 397 229 162 67
451 298 153 110 43
* Bi-monthly
Percentages
Percent Percent Percent Drug Advertising Other Advertising
Total Journal Advertising as Percent as Percent
Year Pages Pages Pages All Advertising All Advertising
1963 100% 70.1% 29.9% 65.1% 34.9%
1964 100% 77.3% 22.7% 40.0% 60.0%
1965 100% 56.6% 43.4% 63.6% 36.4%
1966 100% 63.4% 36.6% 70.7% 29.3%
1/
1967 100% 66.0% 34.0% 71.8% 28.2%
1/ Data based on review of 8 out of 12 issues for 1967.
120
PAGENO="0700"
4994 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
JOURNAL OF ABDOMINAL SURGERY
1963
COMPANY PRODUUI NO. ISSUES NO. PAGES
Baxter 1. Cozyme 4 Total... 4
1. Darvon 4 10
2. V-Cillin-K 2 2
3. losone 2 2
Total... 14
Merck, Sharp and Dohme 1. Sulfathilidine 1 1
2. Neothalidine 2 2
3. Sulfasuxidine 2 2
Total... 5
~~anon 1. Cotazyme 2 Total... 2
Pfizer 1. Terramycin 6 Total... 12
1. Mepergan 4 Total... 5
121
PAGENO="0701"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4995
JOURNAL OF ABDOMINAL SURGERY
1964
COMPANY PRODUCT NO. ISSUES NO. PAGES
Merck, Sharp and Dohme 1. Sulfasuxidine 1 1
2. Aramine 1 1
3. Mephyton 1 `1
Total... 3
Robins, A. H. 1. Donnazyme 5 Total... 9
1. Mepergan 2 3
2. Oxaine 2 5
Total... 8
122
PAGENO="0702"
4996 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
JOURNAL OF ABDOMINAL SURGERY
1965
1. Surbex
1. Kantrex
2. Polycillin
3. Prostaphlin
ISSUES NO. PAGES
1 Total... 2
3 3
3 4
2 2
Total... 9
Knoll
Merck
Mead-Johnson
Roche
Upjohn
Warren-Teed
Warren-ChilcOtt
1. Dilaudid
1. Sulfasox
1. Sustagen
1. Librium
1. Solv-cortef
1. Ilopan
1. Coly-Mycin
1. Aludrot
2. Oxaine
3. Equ'inol
5 Total... 5
5 Total... 10
5 Total... 5
6 Total... 6
Total...
Total...
Total...
Abbot
Bristol
COMPANY PRODUCT NO.
5
6
2
1
5
3
5
13
2
1
11
7
Total... 19
123
PAGENO="0703"
COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4997
JOURNAL OF ABDOMINAL SURGERY
1966
Abbott
Bris tol
Knoll
Merck
Massengill
Robins, A. H.
Roche
Sandoz
Searle
Rorer
Upjohn
1. Surbex
1. Kantrex
2. Prostaphilia
1. Dilaudid
1. Neothialidine
1. Adrenosen
1. Albee w/c
1. Librium
1. Torecan
1. Metamucil
2. Dramamine
1. Argnase/maalox
1. Solv-Cortet
2. Gelfam
1. Winthrop/carbocaine
1. Coly-mycin
1. Ilopan
1. Oxaine
124
ISSUES NO. PAGES
5 Total... 7
6 6
6 6
Total... 12
11 Total... 11
8 Total... 16
3 Total... 12
12 Total... 12
12 Total... 12
12 Total... 12
6 6
5 5
Total... 11
5 Total... 5
12 12
1 1
13
1
19
12
6
Total...
1 Total...
10 Total...
12 Total...
3 Total...
COMPANY PRODUCT NO.
Winthrop
Warren-Chilcott
Warren-Teed
PAGENO="0704"
4998 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY
JOUBNAL OF ABDOMINAL SURGERY
1967 (8 Issues)
COMPANY PRODUCT NO. ISSUES NO. PAGES
Abbott Surbex 8 8
Ayerst Riopan 4 8
Bristol Kantrex 7 7
16
Darvon
Merck Neothalidine 12
Mead-Johnson Partagen 4 7
Robins Ailbee 4 4
Entozytne 4 4
Total... 8
Roche Librium 8 8
Rorer Maalox 4 4
Searle Metamucil 5 5
Dramamine 3 3
Total... 8
Warren-Chilçp~ Coly-Mycin 7 10
0
125