PAGENO="0001" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~ 70 &2 HEARINGS BEFORE THE SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS UNITED STATES SENATE NINETIETH CONGRESS FIRST AND SECOND SESSIONS ON PRESENT STATUS OF COMPETITION IN THE PHARMACEUTICAL INDUSTRY PART 6 NOVEMBER 29, 1967; FEBRUARY 6, 8, 27, 28, AND 29, 1968 Printed for the use of the Select Committee on Small Business U.S. GOVERNMENT PRINTING OFFICE 81-2800 WASHINGTON: 1968 Or-I q ~(77Lf For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 - Price $2.50 PAGENO="0002" SELECT COMMITTEE ON SMALL BUSINESS [Created pursuant to S. Res. 58, 81st Cong.] (90th Cong., first and second sess.) GEORGE A. SMATHERS, Florida, Chairman JOHN SPARKMAN, Alabama RUSSELL B. LONG, Louisiana WAYNE MORSE, Oregon ALAN BIBLE, Nevada JENNINGS RANDOLPH, West Virginia E. L. BARTLETT, Alaska HARRISON A. WILLIAMS, JR., New Jersey GAYLORD NELSON, Wisconsin JOSEPH M. MONTOYA, New Mexico FRED R. HARRIS, Oklahoma WILLIAM T. MCINARNAY, Staff Director and General Counsel JAMES H. GROSSMAN, Minority Counsel MONOPOLY SUBCOMMITTEE GAYLORD NELSON, Wnisconsin, Chairman HUGH SCOTT, Pennsylvania MARK 0. HATFIELD, Oregon JACOB K. JAVITS,* New York BENJAMIN GORDON, Staff Economist SUSAN H. HEWMAN, Research Assistant JACOB K. JAVITS, New York HUGH SCOTT, Pennsylvania NORRIS COTTON, New Hampshire PETER H. DOMINICK, Colorado HOWARD H. BAKER, JR., Tennessee MARK 0. HATFIELD, Oregon JOHN SPARKMAN, Alabama RUSSELL B. LONG, Louisiana WAYNE MORSE, Oregon GEORGE A. SMATHERS,* Florida *Ex officio member. II PAGENO="0003" CONTENTS Statement of- Best, Dr. William R., chief, Midwest Research Support Center, Page Veterans' Administration, Edward Hines, Jr., Hospital, Hines, I1l_ 2421 Blazey, Leland W., vice president, manufacturing, engineering and pur- chasing, McNeil Laboratories, Inc., Fort Washington, Pa 2374 Cutler, Lloyd N., special counsel, Pharmaceutical Manufacturers Association, Washington, D.C.; accompanied Leslie M. Lueck, Ph. D., director of quality control, Parke, Davis & Co.; A. E. Slesser, Ph. D., associate director of quality control, Smith Kline & French Laboratories; Dr. Hart E. Van Riper, vice president for medical affairs, Geigy Pharmaceuticals 2139, 2237, 2353 Dameshek, Dr. William, professor, school of medicine, the Mount Sinai Hospital, 5th Avenue and 100th Street, New York, N.Y 2390 Elfstrom, Edgar F., publisher, Daily News Tribune, 655 West Valencia Drive, Fullerton, Calif 2573 Farman, Dr. Franklin, 3928 Country Club Drive, Lakewood, CaliL - 2597 Goddard, Dr. James L., Commissioner, Food and Drug Administra- tion, U.S. Department of Health, Education, and Welfare, Crystal ,~ Plaza No. 6, 2221 Jefferson Davis Highway, Arlington, Va.; accom- panied by William W. Goodrich, General Counsel; and Dr. Herbert L. Ley, Director, Bureau of Medicine 2605 Goodrich, William W., General Counsel, Food and Drug Administra- tion, U.S. Department of Health, Education, and Welfare, Crystal Plaza No. 6, 2221 Jefferson Davis Highway, Arlington, Va.; accom- panied Dr. James L. Goddard, Commissioner 2605 Hewson, Dr. William C., physician and lawyer, 1405 Locust Street, Philadelphia, Pa 2535 iloeprich, Dr. Paul D., director, section of clinical microbiology and immunology, Department of Internal Medicine, School of Medicine, University of California, Davis, Calif 2509 Lepper, Dr. Mark H., vice president, professional and academic affairs, Presbyterian-St. Luke's Hospital, 1753 West Congress Parkway, Chicago, Ill 2443 Ley, Dr. Herbert L., Director, Bureau of Medicine, Food and Drug Ad- ministration, U.S. Department of Health, Education, and Welfare, Crystal Plaza No. 6, 2221 Jefferson Davis Highway, Arlington, Va.; accompanied Dr. James L. Goddard, Commissioner 2605 Lueck, Leslie M., Ph. D., director of quality control, Parke, Davis & Co., P.O. Box 118, Detroit, Mich.; accompanied by Lloyd N. Cutler, special counsel, Pharmaceutical Manufacturers Association, Wash- ington, D.C 2139 Scheele, Dr. Leonard A., president, Warner-Lambert Research* Insti- tute, Morris Plains, N.J 2289 Slesser, A. E., Ph. D., associate director of quality control, Smith Kline & French Laboratories; accompanied by Lloyd N. Cutler, special counsel, Pharmaceutical Manufacturers Association, Washington, D.C 2237 Van Riper, Dr. Hart E., vice president for medical affairs, Geigy Pharmaceuticals, Ardsley, N.Y.; accompanied by Lloyd N. Cutler, special counsel, Pharmaceutical Manufacturers Association, Wash- ington, D.C 2353 Watkins, Dr. Albe M., La Canada Medical Center, 1530 Foothill Boulevard, La Canada, Calif 2583 Weston, Dr. James T., State medical examiner, Utah State Division of Health, 44 Medical Drive, Salt Lake City, Utah 2469 In PAGENO="0004" IV CONTENTS APPENDIXES Page I. Articles from various sources re drug Chioromycetin (chioramphenicol) - 2653 II. Additional FDA submissions .2747 HEARING DATES* November 29, 1967 2139 Afternoon 2179 February 6, 1968 2387 February 8, 1968 2469 February 27, 1968 2521 February 28, 1968 2573 February 29, 1968 2605 *The 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, appears in pt 5 of these hearings. PAGENO="0005" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WEDNESDAY, NOVEMBER 29, 1967 U.S. SENATE, MoNoPorx SUBCOMMITTEE OF THE SELECT COMMITTEE ON SMALL BUSINESS, TTTashington, D.C. The subcommittee met, pursuant to recess, at 10:05 a.m., in room 318, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senators Nelson and Hatfield. Also present: Benjamin Gordon, staff economist; James H. Gross- man, minority counsel; Susan H. Hewman, research assistant; and William B. Cherkasky, legislative director, staff of Senator Nelson. Senator NELSON. The meeting of the subcommittee will come to order. The committee welcomes these witnesses representing the Pharma- ceutical Manufacturers Association. I understand the first witness will be Dr. Leslie Lueck; the second witness, Dr. Slesser; the third witness, Dr. Scheele; the fourth witness, Dr. Van Riper; and the fifth witness, Mr. Blazey.' Dr. Lueck, the committee welcomes your appearance today. Did you submit to the committee a biographical sketch? STATEMENT `OF LESLIE M. LUECK, PH. D., DIRECTOR OP QUALITY CONTROL, PARKE, DAVIS & CO., DETROIT, MICH.; ACCOMPANIED BY LLOYD N. CUTLER, SPECIAL COUNSEL, PHARMACEUTICAL MANUFACTURERS ASSOCIATION, WASHINGTON, D.C. Dr. LUECK. Yes, I did-a brief one. Mr. Cum~. It is at the beginning of Dr. Lueck's statement, Mr. Chairman. Senator NELSON. Dr. Lueck, we welcome your appearance today. The committee is aware of your distinguished record, including your association with the great State of Wisconsin and its university. You may present your testimony in any way you see fit. I assume you have no objection if we have questions during the presentation of your statement. Dr. LUECK. No, sir; I do not. Senator NELSON. The full statement will be printed in the record. If at any stage you feel it would expedite m~tters to extemporize in `Dr. Lueck, Dr. Slesser, Dr. Scheele, Dr. van Riper, and Mr. Blazey were originally sched- uled for appearance with Mr. C. Joseph Stetler, president, Pharmaceutical Manufacturers Association, hearing date, November 16, 1967, CompetitIve Problems in the Drug Industry, part 4. 2139 PAGENO="0006" 2140 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY order to summarize some material, you may do that, or you may read it m toto, however you see fit. Dr. LUEOK. Thank you, Mr. Chairman. With your permission, may I suggest that the first statement that was submitted on November 6 for presentation on November 16 be included in the record, and that we go on to the supplemental state- ment, which was submitted to your staff on the 13th of November and is labeled the supplemental statement. Senator NEI~soN. You are asking that the original statement be printed in full in the record? Dr. LTTEOK. Yes, sir. Senator NELSON. And you do not intend to comment or read any- thing from the original statement? Dr. L1TECK. No, sir; I am prepared to respond to any questions the chairman might have, however, on that statement. Senator NELSON. All right, then, we will probably have some ques- tions on the original statement, but we will let you proceed with the second statement and we can always jump back to the original statement.' Dr. LUECK. Thank you, Mr. Chairman. Then proceeding with the supplemental statement, it is relatively short and I think I may just read it for the record. In my prepared statement of November 16, 1967, to your subcom- mittee, I indicated that Parke, Davis & Co. had initiated a study to compare a product originated by the company with several products containing the same active ingredient now available from other firms by nonproprietary and brand names. Sufficient information has now been gathered to make the findings of these studies meaningful to the subcommittee. The technical information in this statement has been filed with the Food and Drug Administration. This report contains information derived from comparing several companies' chloramphenicol capsules with Chloromycetin capsules, Parke, Davis & Co.'s brand of chloramphenicol. The products studied are currently in commercial distribution in the United States and, * therefore, are available for use on a physician's prescription. Chloramphenicol, an antibiotic di-ug, is the result of the research and development efforts of Parke, Davis. Chloramphenicol, under the Parke, Davis trade name, Chloromyceti'n, was first made avail- able to the medical profession in 1949. In February of 1967, chloramphenicol capsules, from companies other than Parke, Davis, became available in the United States for commercial distribution. Shortly thereafter, it was called to our at- tention t.hat at least one of the competitive drugs did not disperse in water to the same degree as Chloromycetin, Parke, Davis. The above information suggested that it was advisable to carry out laboratory studies to compare some of the competitive chlorampheni- col capsules with the Parke, Davis product. To conduct these studies, Chloromycetin capsules, Parke, Davis, several other companies' chloramphenicol capsules were obtained from retail pharmacy stocks. The materials tested were, therefore, available and ready to be used on a ~hysician's prescription in the treatment of disease. `The complete prepared statement and attachments submitted by Dr. Lueck for pres- entation on Nov. 16, 1967, begins at p. 2225, infra. PAGENO="0007" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2141 It should be noted that the drug chloramphenicol and all its prod- uct forms are subject to a batch-by-batch certification pursuant to the antibiotic regulations of the Food and Drug Administration. There- fore, the capsules studied in this report, `which were all in commercial distribution, should have passed all the requirements contained in the antibiotic regulations, and the Food and Drug Administration should have certified that all those requirements were met. On each of the samples mentioned above, certain laboratory tests contained in the TJ.S. Pharmacopeia arid the antibiotic regulations were performed by Parke, Davis. None of the materials was found to be deficient in meeting the standards of those tests. However, as was mentioned in our earlier statement to the subcommittee, a reputable manufacturer frequently does more testing and has more expertise than is required to meet the minimum standards.. This is certainly true for Chlormycetin, Parke, Davis. It should be emphasized that Parke, Davis has defined the quality level of its Chioromycetin product in terms of clinically demonstrated efficacy. In fact, in 1964, before the Food and~ Drug Administration would certify batches of Chioromycetin manufactured by a new syn- thetic process, they required Parke, Davis to produce not only animal data supporting safety, but also blood level and clinical efficacy data in human subjects. Studies were performed to obtain this information and it was supplied to the Food and Drug Administration. Laboratory tests and standards in addition to those required by FDA and the IJSP were developed by Parke, Davis to maintain this built-in quality in each batch of Chloromycetin that is produced. To mention just one of the additional tests, Parke, Davis explored a dis- solution rate test on batches of chloramphenicol capsules. This test was performed on each sample of the chioramphenicol capsules obtained from the pharmacies. Dissolution rate is a test performed in the laboratory to measure the length of time required for the dosage form, such as a capsule, to re- lease the drug. The test was carried out using an official U.S. Pharma- copeia test solution, simulated gastric juice. The dissolution rate test is believed by experts to be a valuable tool to ascertain whether the manufacturing process produces a product which is readily absorbed into the bloodstream from the gastrointestinal tract of the patient.. Indeed, this is one of the tests required in the procurement of chior- amphenicol capsules by the Defense Supply Agency (DSA). This point we think is very important in oral antibiotic therapy be- cause without early and rapid absorption, the drug cannot be expected to reach the disease site sufficiently rapidly and in high enough con- centrations to carry out its therapeutic action. The results of the dissolution rate test are summarized in chart 1, which is attached, Mr. Chairman, to the supplemental statement.1 It is seen from the chart that none of the competitive chlorampheni- col capsules dissolved in simulated gastric juice as quickly or at the same rate as Chloromycetin, Parke, Davis. The Parke, Davis stand- ards for dissolution rate, which have been adopted by the Defense Supply Agency, are as follows: The capsules shall release not less `Charts 1 to 13 attached to Dr. Lueck's supplemental statement begin at p. 2i5i, infra. PAGENO="0008" 2142 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY than 85-percent chioramphenicol in 10 minutes, not less than 93 per- cent in 20 minutes, and not less than 98 percent in 30 minutes. None of the other ehioramphenicol products which we tested met these standards. Because the dissolution rate test is a laboratory test, in vitro and not in man, it alone cannot be considered to be sufficient to establish whether there was a lack of efficacy for these chioramphenicol prod- ucts. A question of efficacy can only be answered with established clini- cal data. Consequently, we applied to the Food and Drug Administra- tion for permission to conduct clinical studies on these same products to ascertain if human subjects would absorb the drug in a manner that could be correlated with the results of the dissolution rate test. The Food and Drug Administration granted Parke, Davis permis- sion to proceed with these clinical studies. The studies thus approved were to be conducted on normal human subjects, each of whom was to receive a single 500-mg. dose of one of the chloramphenicol. The tests of (1) the blood plasma levels of chloramphenicol and (2) the urinary excretion rate of chloramphenicol were to be determined for each subject. The first clinical study, designated on the charts as "Study 1," was carried out on five normal subjects who received FDA-certified Chloro- mycetin capsules and on five normal subjects who received presum- ably an FDA-certified sample of product A. Both samples, as previ- ously stated, were obtained from a retail pharmacy. Chart 2 shows the results of the blood plasma level tests. Senator NELSON. Do we have the names of the other companies in the sample comparative tests? Dr. LUECK. No, you do not, Mr. Chairman. The names and the lot numbers have been turned into the Food and Drug Administration. Senator NELSON. Do you object to giving the committee the names of the other companies? Mr. CUTLER. Mr. Chairman, Parke, Davis would certainly prefer not to furnish those names to the committee. But they have been fur- nished, together with all of the protocols and results of the tests, to the Food and Drug Administration. So they would be available to you, I assume, on a confidential basis, from the Food and Drug Admin- istration. Senator NELSON. Is there any reason why information of this kind should be confidential? Mr. Cumr~. Well, these are very serious charges addressed `to the other drugs, Mr. Ohairman, and Parke, Davis would prefer not to be naming the makers of the oLher products. It has turned its evidence over to the Food `and Drug Administration. The Food and Drug Ad- ministration will presumably seek to verify the results found by Parke, Davis and take~ whatever action it deems to be appropriate. Senator NELSON. Do any of the companies involved, without naming them, produce brand-name products? Dr. LUECK. Yes, sir. Senator NELSON. How many of them? Dr. LUECK. I think it would be divulging the companies' names if I went any further than my statement. Senator NELSON. Why would that divulge their names? PAGENO="0009" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2143 Dr. LUECK. Because I think they could decipher which products we had tested if I continued any further along that questioning. There are brand-name products. Senator NELSON. Are any of them companies that produce only generic drugs? Dr. L1JECK. Yes, sir. Senator NELSON. These are going to be public anyway. Dr. LUECK. Yes. Both types of products, both brand names and generic, are represented in the study. Senator NELSON. Are any of the brand-name companies that pro- duce an inadequate chioramphenicol tablet members of the Pharma- ceutical Manufacturers Association? Mr. CUTLER. I do not believe a.ny of them are, Senator Nelson. Dr. LUECK. To respond to that, I think one member is an associate member. Is that right? Mr. CUTLER. I don't know the answer to that, sir, `but we will find out and let you know. Senator NELSON. Well, all right, go ahead. It will become public at some stage, anyway. Dr. LUECK. Thank you, Mr. Chairman. Continuing on page 5, a plasma-level test consists of measuring the amount of the drug present in the blood at a given time. The plasma level of an antibiotic is considered by experts to be a measure of the amount of drug that has been absorbed `by the bloodstream `and, is therefore, indicative of the amount available for eliciting a therapeu- tic response. It is important to note that physicians require that an oral antibiotic product give as high and as rapid a blood level as possible per given dose. `This is because quick absorption of the anti- biotic into the bloodstream is necessary in order that the drug may be immediately transmitted to the site of `the infection. As can be seen from chart 2, the blood plasma levels of chloramphen- icol for the two products, `Chloromycetin and product A, are markedly different. To illustrate the significance of this difference, please note the following statement appearing in the labeling-pack- age insert-of both products: Ohloramphenicol adniinisterecl orally is absorbed rapidly from the intestinal tract, producing detectable concentrations in blood within one-half hour after administration and peak concentration in from one to three hours. Peak blood concentration is roughly proportional to the dose. It can readily be seen that product A is not absorbed as rapidly as Chioromycetin nor is the peak concentration in the blood as high as that found with Chioromycetin. The second test conducted in this study was the urinary excretion rate of chloramphenicol. `The test was performed on the same subjects `taking p'art in the `blood-plasma-level test.. The excretion rate of a `drug is determined by measuring the amount of `the drug in a sample of urine taken at various time intervals after administration of the product. It is pointed out that before a drug can be present in the urine, it must be absorbed from the gastrointestinal `tract into the bloodstream of the patient, `and `thence partially metabo- lized and found in the urine. This test, therefore, ascertains how much PAGENO="0010" 2144 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of the drug has been assimilated in the body to combat the infection being treated. As can be seen from chart 4, the urinary excretion rate data corre- sponds very closely to the blood-level data.. Thus the product A chior- amphenicol was excreted at a much lower rate than Chloromycetin, Parke, Davis. Particular note should be made of the fact that after 24 hours only 46 percent of the total chloramphenicol administered as product A could be accounted for by the urinary excretion rate test. This is in sharp contrast to Chloromycetin, Parke, Davis, where 76.4 percent of the drug was excreted in the same period of time. This point is especially significant because the Food and Drug Administration approved labeling for both products contains the statement that: Seventy to 90 percent of a single oral dose of 50 mg. of chioramphenicol is excreted in 24 hours in the urine of human subjects, with 5 to 10 percent as free chioramphenicol and the remainder as microbiologically inactive metabolites, principally the conjugate with glucuronic acid. Thus, in this test, product A was not excreted in the urine in the 70- to 90-percent range mentioned in t:he official labeling, see chart 4. The analytical procedures used in performing the blood-plasma level tests and the urinary excretion rate test for chloramphenicol were de- veloped by Parke, Davis. These procedures were published by Parke, Davis scientists and, of course, are available to anyone who wishes to use them. The plasma and urine samples were analyzed by the colorimetric procedure-Glazko, et al., Arch. Biochem. 23:411, 1949, modified as described in Antibiotics Agents and Chemotherapy-1966, page 655. A second study, designated in the charts as Study II, was conducted in precisely the same manner as described in Study I. Study II was done to verify the results obtained in Study I. The results of the blood plasma level test conducted in Study II can be seen in charts 5 and 6. The results of the urinary excretion rate test in Study II can be seen in chart 8. It can be observed from the charts that the blood plasma level tests and the urinary excretion rate tests of Study I and Study II are consistent. In addition to colorimetric or chemical test for chloramphenicol in the bh~~d, a microbioligica.l assay was also carried out in Study II. Senator NELSON. May I interrupt, Doctor? There has been a scheduled rollcall, so we will recess for 10 minutes. (Short recess.) Senator NELSON. The hearing will come to order. Dr. Lueck, you were where when we interrupted you? * Dr. L1JEOK. Mr. Chairman, I was on page 7 of the supplemental statement, the second full paragraph, starting on the second sentence of that paragraph. Senator NELSON. Fine, Doctor, proceed. Dr. LuEoK. The microbiological assay is important because it is a direct measurement of only the microbiologically active chlorampheni- col, and does not pick up any of the inactive metabolites which are measured by the chemical determination. This test, which was per- formed on the same blood samples previously used for the chemical test, is an actual measurement of the ability of the drug to inhibit PAGENO="0011" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2145 growth of a test microorganism. As can be seen from chart 6, product A demonstrated less inhibition of the microorganism, as measured in terms of micrograms of chioramphenicol per milliliter of blood sample tested, than did the Chloromycetin, Parke, Davis. At this point, it was evident that a significant difference did, indeed, exist between product A capsules and Chloromycetrn capsules, Parke, Davis. The `final clinical study, designated on the charts as Study III, was initiated to compare additional chlora.mphenicol capsule products with Chloromycetin, Parke, Davis. This study was performed in a manner identical to that described in Study I and Study II above. However, to improve the statistical significance of the study, 10 normal subjects were used per product in Study III. Samples of Chloromycetin capsules, Parke, Davis, and product A different batches, were again obtained from pharmacy stocks on the open market. Also, samples of product B and C, in commercial distri- bution by twb other companies, were obtained as above. Chart 9-and, Mr. Chairman, chart 9, for your convenience, is displayed over on your left. Number 5 you can see that product A and particularly product C showed very different dissolution rates as compared to Chloromy- cetin, the product depicted on the left. Senator NELSON. Did product A meet FDA standards? Dr. LtTEOK. Yes, sir; so far as we know, all of the products tested in these studies met the requirements of the antibiotic regulations or the laboratory tests of the antibiotic regulations. Senator NELSON. Is this a case where the FDA set the standard and DSP adopted it? Dr. LtleoK. No, sir. Senator NELSON. Does the DSP have a different standard from FDA? Dr. LiJEOK. No, sir; in this case, this is a certifiable antibiotic and the standards that prevail are the ones included in the Federal regu- lations on the antibiotic regulations. They supersede the DSP. - Senator NELSON. That is what I said, the DSP simply accepts the FDA standards. Dr. L1JEOK. Yes. Senator NELSON. This is not a case, then, of the DSP establishing a standard itself? Dr. LuECK. No, sir. Senator NELSON. When did the patient expire on Chioromycetin? Dr. Lu1~cK. The patent expired October 1966. Senator NELSON. October 1966? Dr. L1JEOK. Yes, sir. Senator NELSON. Did any representatives~ of Pa.rke, Davis partici- pate with the FDA in setting the standards to be met? Dr. L1JEOK. Yes, sir; initially, when Chloromycetin was approved for marketing, the standards were established on the basis of infor- mation submitted by Parke, Davis & Co., to the Food and Drug Ad- ministration. They, through the years, have been improved and changed, but standards were set largely on Parke, Davis information, corroborated by the Food and Drug Administration. Senator NELSON. At the time the patient expired and the FDA set PAGENO="0012" 2146 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the standards, did any representative of Parke, Davis participate with the FDA in establishing these standards? Dr. LiIEOK. No, sir; they did not change at that time. Senator NELSON. What do you mean? Dr. LUECK. There was no change in standards at the time the patent expired. Senator NELSON. In other words, the FDA accepted the standards that had been established `at the `time the New Drug Application was approved for Chloromycetin? Dr. LtJECK. Yes, sir; Mr. Chairman. Senator NELSON. What year was that, about 1949? Dr. LUECK. 1949, but I wish to point out again that those standards have changed `through the years and improved since 1949. Senator NELSON. And did FDA `adopt `the improved standards? Dr. LUECK. Yes. Senator NELSON. And was your company aware `that the standards adopted by FDA would not produce a product `that measured up to Parke, Davis' Chloromycetin? Dr. LUECK. No, sir. At that `time we were not in any position to ren- der `that judgment at all, except `to say, Mr. Chairman, that it has been our policy for many years that one can"t rely on laboratory tests to as- certain therapeutic efficacy. This is `the case in question, I think, of extreme interest to you and your subcommittee, whether laboratory testing alone can suffice to guarantee clinical effectiveness. In all cases, it certainly can't. Senator NELSON. I do riot think anybody disagrees wi'th `the proposi- tion that two drugs which meet USP standards do not always produce equivalent therapeutic results. I do not `think anybody before our committee h'as asserted `that it would in `all cases. What is at issue here is `that there are exceptions. Is `that not the case? And out of these rare exceptions, `the manufacturers like to make the rule. Dr. LUECK. I do not know if these exceptions are rare exceptions, Mr. Chairman. Exceptions come to our attention and `they have come to my attention in Parke, Davis & Co. When we are in the process of re- searching a new compound, we `have seen differences `that we can create in `the laboratory and we are cognizant of those differences. I do not know if these exceptions are rare. Senator NELSON. Well, the assertion by Dr. Miller of USP is that it is rare. The assertion `by Dr. Feldmann, of `the National Formulary, your classmate at `the University of Wisconsin, is `that they are rare. The assertion of Dr. Modell, a very distinguished pharmacologist and M.D., is that they are rare. The assertion by many witnesses before this committee who *are highly distinguished doctors, researchers, and professors, is that they are rare. Dr. Miller's assertion is that there are perhaps 15 or 18 cases known in all of the United States, versus all the drugs on the market where a drug meets USP standai~ds and does not produce `therapeutically equivalent results. And `this happens `to be one of them. And this is a case that does not include USP standards. If there is any fault, it is FDA in this case. But you are talking `about a drug whose patent expired in 1966 and you are able to select this one case to add to a list that involves 15 or 16 PAGENO="0013" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2147 drugs :ifl the whole history of `the business so far as `anybody has been able to prove. On each occasion, we have had witnesses before the com- mittee from the industry, we have asked for examples of cases where TJSP standards were met, but the drugs did not have therapeutic equivalency, and the industry has not produced them. Now, they can produce all kinds of cases where there was bad quality control and the product on the market did not meet TJSP standards and therefore was not therapeutically equivalent. But it is a rare case so far as this committee can find out, where drugs meet TJSP stand- ards, but are not equivalent. That is the crux of the whole matter. As a matter of fact, I `am sure you are aware that every formul'ary in America, both in public programs and private hospitals is based upon the assumption that if drugs meet TJSP standards, they are therapeutically equivalent. As I `am sure you are aware from the testi- mony in the record, time after time when we asked doctors who practice in hospitals using a formulary, whether `the generics included in the formulary produce results equivalent to the brand names, the answer was "Yes, they do." So what you are arguing against here is the common practice in the whole of the medical profession in the `finest of the hospitals in America where formularies are used on the assumption that if drugs meet USP standards, `they are equivalent `and experience has demonstrated that they are. Yet the industry has come in today and said, "Well, we have a case here where the standards are met but the generic is not equivalent. There is a problem with this drug, in part because it just came off patent.." Your company had the patent and the exclusive contrçil over the production, marketing, and use of this drug for 17 years. When it came on the market, FDA established a standard which your tests prove to be inadequate. But then to proceed, as the industry does, to propagandize the idea that, on the basis of one example, you cannot trust legal standards, s~ems to me to be a very weak case, frankly. I have said this to every witness who has appeared. Mr. CUTLTeR. Mr. Ohairman, the next witness, Dr. Slesser, is pre- pared to testify on the frequency of the occasions in which drugs that contain the same `active ingredients have been `scientifically demon- strated not to be therapeutically equivalent, and the fact that lISP itself specifically disclaims that meeting its standards results in thera- peu'tic equivalency. They specifically deny that in `the beginning of their own book. Dr. Lueck is prepared to testify about chloramphenicol. If we could have Dr. Slesser then discuss with you the frequency with which these occurrences take place I think that might be more orderly. Mr. GORDON. But, Mr. Cutler, although Dr. Lueck is discussing chloramphemcol, he is drawing `broad conclusions, from this one case only. One other thing, Dr. Lueck, is it not also correct that a patent on the process expired only in July of 1967, only a few months ago. Dr. LUECK. I can't be sure of that, Mr. Gordon. Mr. GORDON. Well, the Pink Sheet recently made a statement to the effect thatmany firms would be unable to manufacture Chloromycetin PAGENO="0014" 2148 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY because a very important process patent does not expire until July 1967. I was just wondering if you have any information on that. Dr. LUECK. I do know this, that it was, in terms of patent rights, legally possible for other companies to market and distribute chloram- phenicol in the United States from about October 4, 1966. Mr. GORDoN. But not if they needed the important process that you were using and had patented, and which expired, as I understand it, only a few months ago. Dr. LIJEOK. I think that chioramphenicol could have been produced by a procedure, chemical synthesis that would produce a certifiable product as soon as the patent on chioramphenicol itself ran out in October 1966. Senator NELSON. What was that? Dr. LUECK. I think that other companies legally could produce chioramphenicol and distribute it in the United States as far as any patent rights were concerned- Senator NELSON. So far as any what? Dr. LtTECK. Patent rights were concerned. They would, of course, have to have, to be legal, the approval of the Food and Drug Adniin- istration and the FDA would have to certify them batch by batch. Senator NELSON. What did your Chloromycetin patent protect, then? Dr. LUEOE. It protected the product, the fundamental scientific dis- covery of chioramphenicol as a chemical entity and therapeutic agent. Senator NELSON. But you are saying chioramphenicol could have been produced by anybody despite the patent? Dr. LUECK. No; only after October 4, 1966, after the patent ran out, Mr. Chairman. Senator NELSON. We will take this up when Dr. Slesser appears. I will just read one sentence on this question of TJSP standards and then submit it for the record in its entirety. Dr. Miller, in a statement dated November 29, 1967, states: We are aware of six proven cases of clinical difficulties with drug products which did or could have met U.S.P. standards. ~ * * Of these proven eases, one involves a product believed to have been distributed only in Canada. (The material referred to follows:) STATEMENT BY DR. LLOYD 0. MILLER, DIREOuoR OF REvIsIoN, OF THE U.S. PHARMA- COPRIA, NEW YORK CITY, NOVEMBER 29, 1967 The current U.S. Pharmacopeia lists about 900 drug substances or products prepared from them all for which suitable tests and standards are provided. The standards are sometimes questioned as being insufficient to insure that the products will give the full therapeutic effects expected of them. We dealt with this topic with a statement made to your subcommittee on June 27, but perhaps too briefly out of a desire to save time. Some specific supple- mentary comments may therefore be in order at this time. We are aware of six proven cases of clinical difficulties with drug products which did or could have `met the U.S.P. standards. These are: Approrimate date of Item: di8covery of problem Thyroid tablets Prior to 1940 Bishydroxycoumarin tablets 1957 Spiromolactone tablets 1960 Aspirin coated tablets 1960 Prednisone tablets 1962 Diphenylhydanto~n tablets 1967 PAGENO="0015" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2149 Of these proven cases, one involves a product believed to have been distributed only in Canada-namely Bishydroxycoumarin by Charles Frosst and Company. Even counting this case in, however, the "deficiency ratio" is six in 900 or less than 0.7%. It is U.S.P. policy to correct at once every form in inadequacy that is possible with the scientific information available. The U.S.P. Revision Committee is responsible for putting this policy into effect. The Committee consists :~f (30 mem- bers, each an expert in his ow~n field. The members charged with the revision of standards are mostly chemists who are associated with pharmacy schools xr phar- maceutical firms. At present, the number in each group is 17 and 12 respectively. It should be stressed that regardless of the nature of his bread-winning job, each member serves as an individual, not as a representative of his school or firm. The members consult other experts widely. For example, as a matter of long- standing policy no F.D.A. staff members serve on the U.S.P. Committee. How- ever, the closest sort of cooperation exists between the F.D.A. and the U.S.P., so the progress on drug standards is shared early and fully. In faet, Arthur F. Flemming, speaking as Secretary of the Department of Health, Education, and Welfare, observed in 1960, "I do not know of any organization that has a more interesting and significant relationship to the government of the United States than your organization." The same relationship exists with scientists within the industry. Avenues of contact with industries are kept open in many directions. It is always possible that thoe who produced the drugs will discover better ways of testing them. Although the U.S.P. standards are generally regarded as being the highest in the world, they are also looked upon as subject to improvemenit as technical advances from it. A good example is that of the standards for thyriod tablets which, as indicated above, have been known to be deficient for years. These standards are about to be made as exacting as those for any other drugs `through the application of findings made in the last few months and not yet published. In summary, U.S.P. standards form the bedrock upon which the quality of American drugs rest. But like any foundation, the standards can be made broader and stronger as science progresses. We trust that `these comments will be helpful. Senator NELSON. In any event, the insistence by USP and others is that there are rare cases where although these standards are met a drug may be produced that is not therapeutically equivalent. Ever~ybody Imows that you can coat a tablet so that it does not have any effect at all, even if you have the same active ingredients and the same excip- ients. But then it would not be within the lISP standards. If lISP set a standard that didn't guarantee absorption, they would correct it just as soon as the knowledge was available. Dr. LUECK. Mr. Chairman, I respect the gentlemen you mentioned, Dr. Miller, Dr. Feldmann, Dr. Modell. But I believe there is quite an element of opinion in their statements. Now, I respect their opinion, but I think that to prove the opposite, the products must `be tested side by side to prove the affirmative as well as prOve the negative. The fact is that there is an appreciable amount of information show- ing that products that meet certain chemical standards are not equiv- alent, and Dr. Slesser will cover that point; it is a long, laborious process to compare products. For example, the study that we are engaged in presenting right now, Mr. Chairman, required something like 8,000 analytical tests just for this small study. Senator NELSON. You say Dr. Slesser is going to address himself to thls precise question? Dr. LUECK. Yes, `and provide additional information in that area. Senator NELSON. I know he did from his prepared testimony, but PAGENO="0016" 2150 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY yours covers the same area. That is the reason I raised the question to you. Dr. LUECK. Yes. Senator NELSON. All right, go ahead. Dr. LUECK. The results of the blood plasma level tests, both chemical and microbiological, are shown in charts 10 and 11. May we have chart 10? Mr. Chairman, this chart refers to plasma levels as determined by the colormetric clinical test for Chiorornycetin, product A, product B, and product C. In a glance at the chart, it is readily discernible that differences `between these plasma levels, resulting from the administra- tion of the respective products, are quite different. May we have chart 11, please? Chart 11 depicts the blood levels as determined by the microbiologi- cal analytical technique and we see again that appreciable differences are noted between the products, and these results compare very favor- ably with the colormetric analytical results and corroborate the fact that the testing procedure is being followed accurately. Now, the results of the urinary excretion rate tests are shown in chart 13. May we `have chart 13, please? It again can `be seen that there is a significant variation between the products. I would like to point out that the official package insert for all these products reads that 70 to 90 percent of the `drug should be excreted in the urine over a 24-hour period. That 70 to 90 percent is depicted in the crosshatch area at the top of the figure. You can please note that Chloromycetin is the only product that reached those levels in this test.. Now, our clinical consultants believe that the difference shown in Studies I, II, and III would be very significant in the treatment of in- fectious diseases. The higher and earlier `blood plasma levels produced by `Chioromycetin capsules, Parke, Davis indicates that more rapid and thorough absorption of the dose occurred than with the competi- tive chioramphenicol capsules. Indeed, the blood plasma levels indi- cated for products A and B are low and product C is disturbingly low. Their clinical efficacy is open to question. The total urinary excretion of chloramphenicol and its metabolites was shown by the studies to be substantially less for the competitive chloramphenicol capsule products than that demonstrated by Ohioro- mycetin capsules, Parke, Davis. The Food and Drug Administra- tion approved labeling for all the chioramphenicol capsule products indicates that t.he chloramphenicol dosage should be absorbed into the human body so that 10 to 90 percent of the drug is excreted by the kidneys within 24 hours. It is evident from the urinary excretion data in chart 13 that none of the other companies' chioramphenicol capsules reached the proper degree of excretion as prescribed in the package insert which accompanies the drug. They all are below the labeled limits of 70 to 90 percent. PAGENO="0017" COMPETITIVE PROBLEMS IN. THE DRUG INDUSTRY 2151 It must be emphasized that when a physician prescribes an anti- biotic to be administered orally, he must assume that the drug will be absorbed rapidly and thoroughly from the product into the blood stream. A product which does not meet the above criteria may impair the recovery of a patient. In conclusion, it is evident that information obtained by laboratory and clinical studies is essential in determining the absorption, dosage range, duration of action, excretion rate, and so forth, of a drug. To put it another way, a manufacturer should not have the right to simply copy another company's package insert for a product which has been carefully studied in the clinic by the originator and then imply that the two drugs are therapeutically equivalent merely because his prod- u~t meets the minimum T5.S.P. and FDA laboratory test requirements. We believe we have demonstrated that laboratory tests alone which indicate that certain drugs contain similar chemical ingredients pro- vide no assurance that these drugs will behave in the same way in the human body. Thus, we have confirmed what experts have repeatedly said, that chemical similarity is not necessarily indicative of thera- peutic equivalency. Thank you, Mr. Chairman. That concludes my formal statement. (The charts attached to Dr. Lueck's supplemental statement follow:) STUDY I &fl PERCENT OFTOTAL DISSOLUTION RATE COMPARISON STUDIES OF DISSOLVED COMMERCIALLY AVAILABLE CHLORAMPHENICOL CAPSULES 907992992 ~r!4 2 OOA 60- 52.9 50 - 42.6 40- E 30 26.3 19.4 19.1 20~8~41I 10 20 30 10 20 30 10 20 30 0 20 30 tO 20 30 10 20 30 tO 20 30 TIME IN MINUTES CIILOROMYCETIN PRODUCT `A PRODUCT'S' PRODUCT `C" PRODUCT D PRODUCTE' PRODUCT `F CHART 1 81-280 0-68-pt. 6-2 PAGENO="0018" 2152 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY STUDYI PLASMA LEVELS OF CHLORP~MPHENICOL IN ADULT SUBJECTS FOLLOWING SINGLE ORAL DOSE OF 0.5 GM (MEAN OF 5 SUBJECTS PER GROUP) YPE OF ASSAY: COLORIMETRIC URIN~R\' EXCRETION RATE OF C~LORAMP~ENICOL IN ADULT SUDJECTS FOLLOWING SINGLE ORAL DOSE O~ 0.5 GM (MEAN OF 5 SUOJECTS PER GROUP) TYPE OF ASSAY: COLORIMETRIC COLOROMYCERN ,PARKE-DAVIS. TWO 250 MG KAPSEALS PRODUcT~K.TW0 250 MG CAPSULES 2 4 6 8 12 HOURS AFTER DOSE Original charts prepared in color; letters replace colors as follows: PD-red; product A-yellow - I - CHLOROMYCETIN, PARKE-DAVIS TWO 250 MG. KAPSEALS -- PRODUCT A TWO 250 MG. CAPSULES PLASMA LEVELS (McGfl~L) 10 6- 6 4 2 O~ MG CAIRO .MUEOCOL- EQUIVALETS P ER HOUR 50 - 40 - 30 - 20 - 10 i 4 e HOURS AFTER DOSE 1.4 12 CHART U STUDY I P-D A =~: P-D A P-D A TOTAL ~ CHLORAMPHENICOL ABSORBED AND EXCRETED 76.4 N24HOURS 46.0 Ti P000UCTK P-D A A 24 CHART 3 PAGENO="0019" EXCRETION ~X,TOTAL DOSE 100 CUMULATIVE PLP~SMA LEVELS OF CHLORAMPHENICOL IN ADULT SUBJECTS FOLLOWING SINGLE ORAL DOSEOFO.50M (MEAN OF S SUBJECTS PER GROUP) TYPE OF ASSAY: COLORIMETRIC ______ CHLOROMYCETI N PARKE-DAVIS TWO 250 MG. KAPSEALS 6.3 PRODUCT ~A TWO 250 MG. CAPSULES COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2153 STUDY I CUMULATIVE URINARY EXCRETION RATE FOR TOTAL CHLORAMPHENICOL IN ADULT SUBJECTS FOLLOWING SINGLE ORAL DOSE OF 0.6 CM (MEAN OF 5 SUBJECTS PER GROUP) - -- - CHLOROMYCETIN, PARKE-DAVIS,TWO 250 MG KAPSEALS PRODUCT A TWO 250 MG CAPSULES HOURS AFTER DOSE STUDYJI CHART 4 PLASMA LEVELS (MCG/ML.) 10 8 6 4 2 0 4.7 3.2 ~1.O O 12 HOURS AFTER DOSE 24 CHART PAGENO="0020" 2154 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY STUDYIE PLASMA PLASMA LEVELS OF CHLORAMPHENICOL 7 6.8 IN ADULT SUB~JECTS 6~ FOLLOWING SINGLE ORAL DOSE OF 0.5 GM 6 (MEAN OF 5 SUS~JECTS PER GROUP) TYPE OF ASSAY: MICROBIOLOGICAL HOURS AFTER DOSE CHART 6 STUDY U MG I CHLORA~PthNLtO~ URINARY EXCRETION RATE OF CHLORPMPHENICOL I IN ADULT SUDJECTS FOLLOWING SINGLE ORAL DOSE OF 0.5 GM * I (MEAN OF 5 SU3JECTS PER GROUP) 50 TYPE OFASSAY: COLORIMETRIC CHLOROMYCETIN, PARKEOAVIS,TWO 250 MG KAPSEALS PRODUCT'A TWO 250 MG CAPSULES P-D TOTAL% CHLORAMPHENICOL P-D ABSORBED AND EXCRETED 30 IN 24 HOURS sao 20 A A P-D CHL000MYCETIN PHODUCTA~ 10 A A A - P-D A ----A 2 4 3 8 12 * HOURSAFTER DOSE 24 48 Original chart prepared in color; letters replace colors as follows: CHART7 PD-red; product A-yellow. PAGENO="0021" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2155 PERCENT OF TOTAL DRUG DISSOLVED 100 90 80 70 60 50 40 30 20 10 EXCRETION %TOTAL DOSE 1 0 CUMULATIVE STUDY E 80 CUMULATIVE URINARY EXCRETION RATE FOR TOTAL CHLORAMPHEN~COL IN ADULT SUBJECTS FOLLOWING SINGLE ORAL DOSE OF 0.5 GM (MEAN OF 5 SUGJECTS PER GROUP) 70 18.6 CHLOROMVCETIN, PARKE-DAVIS,TWO 250 MG KAPSEALS PRODUCTW TWO 250 MG CAPSULES 24 43 CHART S STUDYIII DISSOLUTION RATE COMPARISON STUDIES OF COMMERCIALLY AVAILABLE CHLORAMPHENICOL CAPSULES 98.6 9LET - 88.7 48.7 28.2 r~1~'~F1 20.4 H~8 10 20 30 10 20 30 10 20 30 TIME IN MINUTES CHLOROMYCETIN PRODUCT~A~ PRODUCT ~ 10 20 30 PRODUCT CHART PAGENO="0022" 2156 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PLASMA STUDY 1t1 LEVELS (McGIML) 10 8 6 4- 2 0-~ 012 4 6 8 12 24 HOURS AFTER DOSE CHART 10 / STUDYIJI PLASMA ~ PLASMA LEVELS OF CHLORAMPHENICOL 7 IN ADULT SUBJECTS FOLLOWING SINGLE ORAL DOSE OF 0.5 GM (MEAN OF 10 SUBJECTS PER GROUP) 6- TYPE OF ASSAY: MICROBIOLOGICAL 5 4 S 2 0 PLASMA LEVELS OF CHLORAMPHENICOL IN ADULT SUBJECTS 9.1 FOLLOWING SINGLE ORAL DOSE OF 0.5 GM (MEAN OF 10 SUBJECTS PER GROUP) TYPE OF ASSAY: COLORIMETRIC 6.7 5.8 *~.7 - CHLOROMYCETIN,PARKE-DAVISTWO 250 MG KAPSEALS .*52 52 --- PRODUCT A~ TWO 250 MG CAPSULES 4.7\ PRODUCT ~S TWO 250 MG CAPSULES ~ PRODUCT ~C TWO 250 MG CAPSULES a .*. ~A. 2.3 :1 122 *~. ~ i.. 1.8'...., ~ .,,*,.1........ 10 ~ 06 0.6 C1ILOROMYCETIN,PARKE-DAVIS,TWO 250 MG KAPSEALS - - PRODUCTA TWO 250MG CAPSULES PRODUCT~B TWO 250MG CAPSULES PRODUCT'CTWO 250 MG CAPSULES 1~ 4 HOURS AFTER DOSE 8 12 24 CHART II PAGENO="0023" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2157 sTuDY]11 MG CHLORAM?HEBCOL URINARY EXCRETION RATE OF C~LORAMP:-IENICOL PEE HOUR IN ADULT SUSJECIS FOLLOt~JING SINGLE ORAL DOSE OF 0.5 GM (ME1~N OF 10 SUBJECTS PER GROUP) 50 TYPE OFASSPY: COLORI~ETRIC - CULOROMYCETIN, PARKE-DAVIS,TWO 250 MG KAPSEALS PR0DUCT~,TWO 250 MG CAPSULES 40 - PRODUCT'U,TWO 250 MG CAPOULES * - PRODUCTC~TW025OMGCAPSULES P-DJA * 246312 2448~C HOURS AFTER DOSE Original charts prepared in color; letters re place colors as follows: CHARTIE PD-red; product A-yellow; product B-blue; product C-green. STUDVIEC EXCRETION %TOTAL DOSE CUMULATIVE 90 80 76.1 /4~ 30 292/ /300 316 330 / *./ *..~2 - CHLOROMYCET1N. PARKE-DAVIS,TWO 250 MG KAPSEALS 20 /~j ..1~o --- PRODUCT A TWO 250 MG CAPSULES I /15.3 PRODUCT B TWO 250 MG CAPSULES i: i/f ~ PRODUCT C TWO 250 MG CAPSULES 2 4 6 8 12 24 48 HOURS AFTER DOSE TOTAL % CHLORRMPHENICOL ABSORBED AND EXCRETED 81.2 IN24HOURS Eh~~fl3~6 CUMULATIVE URINARY EXCRETION RATE FOR TOTAL CHLORAMPHENICOL IN ADULT SUBJECTS FOLLOWING SINGLE ORAL DOSE OF 0.5 GM (MEAN OF 10 SUBJECTS PER GROUP) CHART 3 PAGENO="0024" 2158 COMPETITIVE PROBLEMS IN THE D.RUG INDUSTRY Senator NELSON. Let me comment on your last statement: Thus we have confirmed what experts have repeatedly said, that chemical sim- ilarity is not necessarily indicative of therapeutic equivalency. I have never heard of anybody saying that it is. The statement is really, I think, Doctor, quite meaningless. Nobody says that. That is not the argument. The argument is, as you said earlier, whether or not in almost all cases, with a rare exception, if TJSP standards are met, the drugs a.re therapeutically equivalent. That is what the issue is. Now, Parke, Davis, which is the manufacturer of Chloromycetin, has had on the Committee on Revisions of the USP, Mr. F. 0. `Taylor, from 1950-1960---- Dr. LUECK. Yes, sir. Senator NELSON. And Mr. Marina from 1960 to date, is that correct? Dr. LUEOK. Yes, sir. Senator NELSON. Now, when the TJSP adopted FDA standards, did these representatives of Parke, Davis give them the benefit of their advice as to what standards had to be set in order to produce a thera- peutically equivalent or effective drug? Dr. LUEOK. I would like to comment on two things, with your per- mission, Mr. Chairman. I would like to state for the record that Parke, Davis & Co. feel that the lISP and NF and the FDA antibiotic regulations are the strongest standards in the world. Senator NELSON. Every witness from every company has agreed with that. Dr. LUECK. I would like to go on to say that this is evidenced by the distinguished people who have spent their entire careers in Parke, Davis who have contributed to the lISP and NF over the years and who will continue to do so. I would like to point out, though, for the chairman, that Chloromy- cetin or chloramphenicol is an antibiotic, Mr. Chairman, and is there- fore not covered in the standards in the U.S.P. It is covered in the antibiotic regulations. The antibiotic regulations cover chlor- amphenicol. Senator NELSON. I understand. Correct me if I am wrong about this: Does not the lISP adopt, then, the FDA standards? Dr. LUECK. No; they generally- Senator NELSON. Or do they just do nothing about it? Dr. LUECK. No; they just list the monograph, and in a few mo- ments, I will find it. They just list the monograph in the lISP and mention that this is under the antibiotic regulations. So Chloromy- cetin or chloramphenicol is not controlled by the monograph in the lISP. It is controlled standardwise by the antibiotic regulations. I would read from, Mr. Chairman, if you please, from the rubric of the lISP on chloramphenicol, page 114: Ohloramphenicol contatns not less than 90 percent- It gives the clinical formula: It conforms to the regulations of the Federal Fooil and Drug Administration concerning antibiotic drugs. See Antibiotics, page 768. PAGENO="0025" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2159 So it refers entirely to the standards in the antibiotic regulations. Senator NELSON. In this case, you had both a product patent and a process patent, is that correct? Dr. LUECK. I am sorry, I cannot comment on the process patent with certainty at the moment. Senator NELSON. I am reading from the Pink Sheet, April 25, 1966: Parke, Davis Chairman Harry Loynd at April 19 stockholders meeting pre- dicted another $70 million Chloromycetin year for 1966 despite the expiration in Odtober of the product patent, the first basic one on the drug. Even after October, it will be illegal for anyone to manufacture Chioromycetin in the U.S. A key process patent doesn't expire until July, 1967. Is that an accurate statement from the Pink Sheet? Dr. LIIEOK. I would have to presume, Mi' Chairman, that it is an accurate statement. Senator NELSON. So the record is clear, we have a case here which does not involve standards set by the U.S. Pharmacopeia at all. Dr. LuncK. Yes, sir. Senator NELSON. We have a case here in which the FDA set the standards under law. Dr. LtTECK. Yes, sir. Senator NELSON. Do you know whether or not your experts from Parke, Davis were consulted by FDA as to what those standards ought to be? Dr. LUECK. Yes, sir. Senator NELSON. And they agreed with the standards that the FDA established? Dr. LUECK. Well, the normal procedure, Mr. Chairman, was fol- lowed in the case of Chloromycetin, where the drug was discovered and researched and our information supplied to the Food and Drug Administration requesting permission to distribute the product for certain medicinal needs. Senator NELSON. No; I mean when the patent ran out. Dr. LUECK. Oh, no; when the patent ran out, there was no com- munication between Parke, Davis and the Food and Drug Adminis- tration on changing standards. Senator NELSON. Did the FDA then just adopt the standards that had been agreed upon between the FDA and Parke, Davis up until the expiration of the patent? Dr. LUECK. Yes; the same standards that applied before the patent ran out still applied after the patent ran out. They still prevail. Senator NELSON. Were the experts in Parke, Davis aware that if only those standards were met, the drug manufactured by another firm would not be therapeutically effective? Dr. LUECK. No, sir; we were not. We were only aware of the thera- peutic equivalency of our own product. Senator NELSON. Therapeutic effectiveness, you mean? Dr. LUECK. That is right. Senator NELSON. Because you did not have any equivalency test. Dr. LUEOK. I am sorry, I used the wrong word. Thank you for cor- recting me. Senator NELSON. So even the best experts in Parke, Davis that had been manufacturing this drug on an exclusive basis for 17 years did PAGENO="0026" 2160 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY not know that the standards adopted by the FDA would not produce a therapeutically effective drug. Dr. Lu~oK. We are not aware of any laboratory standards, Mr. Chairman, that will beyond any reasonable doubt, determine the thera- peutic equivalency or therapeutic effectiveness of the drug. This is the point in question, that you cannot rely on laboratory standards to do this job for you. Senator NELSON. But you did not know that the standards set would not do the job Dr. LUECK. No; by means of the standards set in the antibiotic regulations, plus the care and experience that Parke, Davis & Co. had with chlora.mphenicol and Chlorornycetin, and based on our clini- cal experience, we maintained a product of excellent quality through the years. We had in the United States no means or no way of com- paring Chioromycetin to another product. Senator NELSON. I am still getting at the point that your experts did not know that the standards established were not sufficient to du- plicate the same therapeutic effectiveness in chloramphenicol that Parke, Davis produced in theirs; is that correct? Dr. LUECK. That is correct, and we do not know of any laboratory standards at this moment, Mr. Chairman, that would provide that information for Chloromycetin that was not proven in the clinic. Senator NELSON. There is another rolicall on the Senate floor. (Short recess.) Senator NELSON. I apologize for the interruption. As I understand your last statement, it was that., in your view, a company should not be permitted simply to copy the drug of another company and put it on the market without performing additional clinical tests. Dr. LUECK. Mr. Chairman, I could probably clear up a few questions that you might have by just very briefly reviewing the information that Parke, Davis & Co. submitted to the Food and Drug Adminis- tration. I can do that very briefly and this may answer some fo your questions. Senator N~soN. Very well. Dr. LUECK. Back in 1947, 1948, and' 1949, when Chloromycetin was first discovered and researched, of course, Parke, Davis & Co. sub- mitted to the Food and Drug Administration clinical evidence of its safety and effectiveness. Tests were adopted at that time by the Food and Drug Administration to form the basis of a New Drug Applica- tion. The approval of the New Drug Application was on the basis of clinical effectiveness and adequate controls to maintain quality of the product in Parke, Davis' manufacturing facilities. Now, to illustrate further, in 1964, Parke, Davis & Co. changed the synthetic process for manufacturing Chloromycetin and at that time, we were requested by the Food and Drug Administration to run animaJ tests, human tests, and chemical tests to verify the safety and efficacy of our product.. We did all of these things at extreme lengths so that Chloromycetin has been of excellent quality at all times through the years. The controls established for Chloromycetin have been based on studies in human subjects, that the drug is effective. Now, in 1966, when the introduction of competitive products to Ohloromycetin was imminent, Parke, Davis & Co. suggested to the PAGENO="0027" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2161 Food and Drug Administration that before those products entered distribution in the United States, they, too, should be tested in the clinic, in human subjects. So we did correspond with the Food and Drug Administration in 1966 relative to effectiveness of possible competitive products, but there were no changes made in the specification or the standards for the antibiotic at that time. Senator NELSON. If a company licenses another company to produce its product, does the licensee have to do clinical testing before it can put the product on the market? Dr. LUECK. Frequently, yes. Senator NELSON. Do they always have to,? Dr. L1JECK. It would depend upon the situation, what was licensed. If it were just the license of a procedure, a chemical synthesis, for example, Mr. Chairman, to be followed, it would be necessary, in our opinion, to do clinical testing to make certain that the proper controls were placed on that chemical procedure. Now, if the company who owned the effective New Drug Applica- cation produced the product, it could be assumed that they would pro- duce the same quality product. In other words, if you sold the bulk chemical to the next company, it could be assumed that clinical test- ing was not required. But if the chemical process was moved to an- other operation, conducted by other people, other technicians, then efficacy should be proven, in our opinion, in human subjects. This is what Parke, Davis did with Chloromycetin. Senator NELSON. So that I understand you correctly, you are saying that if the bulk chemical itself were produced by the licensee holder of the New Drug Application, the firm who is granted the New Drug Application, and it licenses company A to produce the product and furnishes company A with the bulk product, this licensee may produce the tablet without conducting its own c.linical testing? Dr. LTJECK. No; I think I misled you slightly. It would not be nec- essary, in my opinion, to check the quality measures of the synthetic process. But in my opinion, it would be necessary to check the efficacy of the product form produced by the licensee if there indeed was any difference. Now, I would have to perhaps explain that a little further. The bulk chemical-suppose it was placed into a capsule with other diluent materials and so forth, it would be necessary, in my opinion, then, to perform sufficient clinical trials to prove that that product form, that capsule, was clinically effective. Senator NELSON. The present law? Dr. LUECK. It is up to the Food and Drug Administration, Mr. Chairman, to make that decision. Senator NELSON. Is it ever the practice for the company that has been granted the New Drug Application to license other companies and furnish them with all the information they have concerning the method of production? Is that a common practice? Dr. LUECK. It is my understanding that that has been done. I would like to remind the chairman that my concern in Parke, Davis & Co. does not include that area of our business and I am not the most familiar with it. But it is my understanding that arrangements like that have been made in the pharmaceutical industry. PAGENO="0028" 2162 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Do you have somebody here who can address him- self to that point? Dr. LUECK. I think we have members of the panel who can. Senator NELSON. Who here could answer my question? Mr. CUTLER. Mr. Chairman, I do not think we have anyone here who can answer that question for a variety of companies, but we can cer- tainly try to get you the answer. Senator NELSON. Is there anybody here who can answer it for any company as to what the law requires, and as to whether it is a practice that is followed by the industry at all. Mr. CUThER. I think I can answer as to the law, Mr. Chairman. There is nothing in the Food and Drug law or the patent law that would prohibit one company from turning all of its manufacturing and know-how information over to another company. It would then be up to the Food and Drug Administration, under the law, assuming the product is a new drug, to determine what evidence would be re- quired from the second company. Senator NELSON. Is there any reason at all why, after a patent has been granted by the public to a company for 17 years, that at the conclusion of the 17 years, all the processes, methods, and benefits accumulated by that. company from its experience and public pro- tection for 17 years should not be turned over to the FDA and then made a matter of public information? Mr. CUmER. Well, I believe all of the company's processing informa- tion is turned over to the FDA to the extent the FDA requires it. And, of course, all of the information that the company was required to disclose in order to obtain the patent is published in the patent itself. Dr. LUECK. I would like to comment if I may- Senator NELSON. But all the processes, I understand, are not. Mr. Cumi~ii. If it is a process patent-well, there is no proprietary know-how not subject to patent that is kept by companies, by indi- vidual companies, each for itself. But the information on which the patent was granted is, of course, published. Senator NELSON. What I am getting at is that the testimony re- peatedly heard from representatives of the industry is that even if you include the same active ingredients, maybe even if you include the same inert ingredients, even if you do all kinds of things the same way chemically, you may not get the same result. Mr. CUTLER. Right. Senator NELSON. What I am saying is, as a matter of public policy, we could pass legislation *to require the publication of all relevant production information. The American people have said, in order to encourage discovery, research, they will protect t.he patentable item in this field for 17 years. I do not. have any reason to quarrel with this policy. I think it has produced some good results. Now, once the 17-year period has expired and the company is deal- ing with a product which directly affects the public health, should not all the information on how- they produce the product be made available to any other company so that any firm, once the patent period is over, will be able to use the same processes and duplicate the drug if they wish? PAGENO="0029" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2163 Mr. CUTLER. You are raising, Mr. Chairman, a fundamental issue of patent law; that is whether the information disclosed and published in the patent is sufficient to confer the monopoly granted by the patent or whether the inventor should be compelled to disclose a lot of additional information in order to get his patent. It is an awfully complicated question and the job of the Patent Office is to see that the information disclosed is sufficient so that the benefits of the discovery will become available to the public after the monopoly period has expired. Senator NELSON. But the argument here is that a particular com- pany in such a case does some things better than anybody else does them. All I am saying is that after 17 years of protection, why should not., for example, the FDA make public all the information on the production of that product., and say to a firm, "If you want to produce this drug, following exactly the procedures followed by X company that has `had 17 years of experience, 17 years to make back its in- vestment and make a profit, we will furnish you all the production information, and you can go out on the market without further clinical testing. If, however, you want to do some additional experi- menting, may;be to refine the product, try to improve the product, then you have to do clinical testing becau'se we do not know what the result may be." I am just asking, as a matter of policy, why should not that be the practice? Mr. CUTLER. It seems to me it would be a much simpler policy to require the second company to do the clinical `testing. The point we are trying to make here is that there are some 40 or 50 chloramphenicol products on the market- Senator NELSON. What kind of products? Mr. CUTLER. There are some 40 to 50 chlorampherncol products on the market today and judging by tests that Parke, Davis has con- ducted on three of those product's in addition to its own clinical tests, the other products do not come up to the clinical effectiveness of the Parke, Davis product, Chloromycetin or, indeed, what is in their own labeling. It would be simple enough tQ require those companies to make the tests. Senator NELSON. We know in this case, a'ssuming your experiments are correct, that this is a case where the FDA standard is not ade- quate. I just repeat for the record `that we have hundreds of cases of drugs on the market that meet the FDA or TJSP standards which are adequate to produce an effective drug. I am just saying why should not a company that has had the benefit of the protection of a patent for 17 years then make public all the information that would allow another company to exactly duplicate that drug. Dr. LUECK. I would like to comment `briefly in regard to Ohioro- mycetrn in answer to your question. During the 17 years that Parke, Davis Co., was under the patent rights for Chloromycet.in, some more than 14,000 references or articles appear in the scientific literature on Chloromycetin. The very tests that we used to gather the information presented here today have been published by Parke, Davis scientists a number of years ago for anyone to use. It is our firm belief that the literature contains such information and the total amount of information that Parke, Davis & Co. has, PAGENO="0030" 2164 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY except experience. We cannot give another company experience. And to gain experience, it is my firm belief that a. fundamental thing that the company must do is clinically compare its product with the stand- ard that is in existence. In this case, the standard was clearly Chloro- mycetin. They could either make the product better or at least, they have to make it at least as good. Senator NELSON. Of course, you testified a while back that even though youi~ own experts helped develop the standard that FDA adopted, they either did not know or did not disclose to the FDA a sufficient amount of information to make it possible to produce a drug that would `be therapeutically effective. Dr. LUECK. No, sir, Mr. Chairman; I wish to correct one point. Parke, Davis & Co. made available to the Food and Drug Admin- istration all the information that we have on Chloromycetin and chloramphenicol. We recommended that clinical testing of the com- petitive products should be carried out before those products were allowed to go into distribution. Senator NELsoN. I know you recommended that. But is it not true that if a company took all your best experience and produced this tablet, using the same ingredients you do and following your proce- dures exactly, the company could produce the exact same product. Dr. LUEOK. No, sir; apparently that is not the case with Chloro- mycetin, Mr. Chairman. Senator NELSON. Has anybody exactly duplicated your tablet? You do not know what the problem is. It may be that the coating on that tablet does not dissolve ra~pidly enough. But, if the manufacturer had known your formula and followed it exactly, then he would be capable of producing anything your .company can produce, given the infor- mation, would he not? Dr. LUECK. I assume so if they do the proper testing. Yes; if they research the product- Senator NELSON. No; if you furnish them all the information. Dr. LUECK. If we furnish the information and produce the product, then I would stand behind that product as being similar. If they pro- duce the product in a. different procedure or different facility, even using the same procedure, then our products such as Chloromycetin, in our opinion, should be tested for clinical equivalence. As a matter of fact, we have to reject some of our own material that we manufacture, Mr. Chairman. We cannot manufacture this product perfectly each time ourselves. Senator NELSON. That is correct. Neither would any other company. Dr. LUECK. That is right. Senator NELSON. But you are testifying that if the best experts you have in your company advised any other high quality, brand-name company as to exactly how you produced a drug, that the other firm could not duplicate your product? It that what you are saying? Dr. LUEOK. `We have a prime example before us to answer that ques- tion, Mr. Chairman. In my opinion, when Parke, Davis changed the clinical process to produce Chloromycetin in 1964, we did exhaustive animal tests, we did exhaustive human tests in subjects with typhoid fever, comparing the old process with the new process. And we did not rely only on laboratory tests. PAGENO="0031" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2165 Mr. CUTLER. Senator, the point we are trying to make is that the second manufacturer may be able to do as well as the first, but that you cannot prove it is as good as the first without the chemical testing. And the fact is that these brands or products are on the market and that a generic prescription for chloramphenicol might have been filed with one of these other brands. That is the heart of the matter. Senator NELSON. The heart of the matter is, as you Imow, that every foimulary in America uses drugs which meet USP standards and then tests them out in the hospitals. They buy generic drugs and they buy brand names. They do not clinically test them before they use them and they have had good results with them. Mr. CUTLER. They often change as a result of their own clinical experience. Senator NELSON. Well, anybody might do that, You do it with your products or anybody else's product. That is not really the heart of the argument. Dr. Harry Williams of Emory University, Atlanta, Ga., and Grady Hospital testified here that- Prior to 1960, as I said, the hospital administration had watched its drug bill rise fairly steadily from $183,901 in 1935 to $470,000 in 1959. This rise could not be accounted for by an increase in prescriptions or patient care. The surveying drug purchase policies and prescribing habits at the hospital, the new formunary committee found that, except for a very few old drugs such as aspirin, drugs were being ordered by trade names rather than generic names; there were con- fusing duplications of drugs that had the same therapeutic action and that the pharmacy was in chaos attempting to keep multiple trade-name equivalents of the same drug in stock. In addition, the hospital was spending as much as $50,000 yearly for drugs which had no proved useful therapeutic action. A few examples, many could be cited. The hospital was paying $107 per thou- sand-these were wholesale costs-for a trade-name cortisone-type drug when a comparable generic product could be bought for $6 per thousand. I think this is prednisone, but I am not sure. Anyway, $167 per thousand versus $6 per: thousand. Senator NELSON. Then you did change in your formulary to the comparable $6 per 1,000 generic drug; is that correct? - Dr. WILLIAMS. Yes, we did; Senator NELSON. And have the physicians in the hospital observed any differ- ence in the therapeutic effect of the $6 per 1,000 versus $167 per 1,000 drug? Dr. WILLIAMS. None whatsoever. Mr. CUTLER. Well, Mr. Chairman, even- Senator NELSON. Let me finish: Those of us who had veen vaguely aware that trade named items were more expensive than non-trade-named items were nonetheless appalled when trade named items were found, as shown by the examples above, to be in many cases 20 to 30 times as expensive as their generic equivalents. Not 2, 5, or 10 percent more as might be expected in other areas of commerce, but 2,000 to 3,000 percent more. Now, the whole record is loaded with testimony from distinguished doctors who have worked in hospitals which use a formulary. Grady Hospital did not do clinical tests on this $6 a thousand drug versus the $167 product. They tested it chemically, if anything, to see if it met USP standards, they used it, and it worked. We have heard the same story from other witnesses as well. You would have to eliminate a part of every formullary in America if you were to follow your theory. PAGENO="0032" 2166 COMPETIT~\TE PROBLEMS IN THE DRUG INDUSTRY, Mr. CUmEi~. No, Mr. Chairman. In every one of those formularies from the Department of Defense on down, the hospital or procuring agent does not just say, "Give me prednisone, any old prednisone." Senator NELSON. Nobody ever says, "Give me any old prednisone," certainly. Mr. CUTLER. But in this committee, you are advocating that a doctor say on his prescription any old prednisone. Senator NELSON. When did this committee say that? Mr. CUTLER. Has not the thrust of this committee been that there should be `generic prescribing? Senator NELSON. I think you ought to read the testimony. Mr. Cm'i~R. I have, sir. Senator NELSON. Then you have not read it carefully. I have never said at any time, nor has anybody on this committee recommended, that a doctor prescribe any old prednisone. That is nonsense and you know it. We suggest that physicians ought to prescribe drugs of high quality. We suggest a doctor ought to prescribe by generic name and, if they want a brand name, that they should name the brand in addition. The doctors who testified here have said one of the problems in- volved here is the confusion caused by prescribing by trade name and not putting the generic name on the label. We had testimony by a very distinguished doctor here on thalidomide who said that deformed chil- dren were born because of this poor method of prescribing. You know this is true. Nc~body suggests prescribing any prednisone. But I would suggest to you that the Medical Letter tested 22 prednisones. One of them is Schering's at $17.90. One of them is Merck's `at $2.20. One of them sells at 59 cents. Another at 75 cents. The Medical Letter said they are all equivalent. Mr. Ctri~. They said there was no proof that they are not equivalent. Senator NELSON. That is correct. Mr. Cum~. Which is a double negative. Senator NELSON. Do you have any proof they are not equivalent? Mr. CUTLER. I do not; but you cannot prove a positive by a double negative. Senator NELSON. If you were a doctor in a hospital, looking at the medical aspects of prescribing, looking at the cost of running a hos- pital, on what method would you make the decision that you would use a drug that costs $17.90 versus Merck's $2.20 tablet? Mr. CUTLER. If I were satisfied there were two products that were therapeuticaly substantially equivalent, I would prescribe the cheaper one. Senator NELSON. How would you satisfy yourself on that? Mr. CUTLER. I am a lawyer, but doctors, I understand, do it on the basis of their experience. When there are hospital formularies or PAGENO="0033" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2167 Department of Defense formularies, they supplement that by the laboratory clinical tests of the entire medical organization. Senator NELSON. In order to make the selection in the first place, unless they have some clinical evidence to go on, and in many instances they do not, they go on the assumption that if it meets TJSP standards it is therapeutically equivalent.. That is the testimony before this committee. Mr. CUTLER. The DSP says right in its own introduction that meet- ing DSP standards does not assure pharmacological availability, which, as I understand it, is therapeutic equivalence. Senator NELSON. Dr. Miller of the DSP on page 508 of the hearing record, part 2 says: The important point, however, is that not more than a dozen drugs have presented problems with respect to physiological availability. Exactly your words. Thus, to damn the entire Pharmacopeia of some 2,000 drugs for the failure of a mere handful is unscientific in the extreme. This is Dr. Miller's direct, flat refutation of what you have just said. Mr. CUTLER. Here is page XVII of the preface of DSP: The term "physiological availability" connotes attribute of the dosage form of a drug that constitutes a measure of the extent to which the active ingredient is taken up by the body in a useful form. From a practical standpoint, the at- tribute is of useful significance only in respect to the dosage forms intended for oral administration. Progress has been slow in developing methods to measure physiological `availability that would be suitable for USP use. Con- ~equently, however desirable it is to give assurances of complete `availability' to every patient requiring a USP article, the problem of providing objective standards and methods remains in the exploratory stage at this time. Senator NELSON. Nobody argues with that. Let me quote to you from Dr. Goddard's testimony. The problem remains. There is no perfect chemical test to guar- antee physiological availability. The perfect test is in a human being. But listen to Dr. Goddard: I do not think anyone can provide absolute assurance that they are putting equivalent combinations for every drug in the marketplace. But by the same token, I have not seen any good evidence from `any firm, large or small, that their drugs are superior to anybody else's. I hear the statement made time and time again. I have challenged firms who have made this statement, show me evidence that their drugs are superior. The assumption when you design a formulary, according to the testimony before the committee, is that if drugs meet DSP standards they are equivalent. There are a handful of cases where evidence to the contrary has been shown. You have one of the handful before us, chioramphenicol, and we are going to get at the' question of how careful your testing was on that drug and the deaths that have been caused by your product. Now, Doctor, I understand `that your product, Ohloromycetin, has been responsible for deaths resulting from bone marrow disorders, is that correct~ 81-280 O-68-pt. 6-3 PAGENO="0034" 2168 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. LUECK. I do not know in what frame of reference you are phras- ing the question. If you mean Chloromycetin and all chioramphenicol products have official labeling approved by the Food and Drug Admin- istration, required statements on the labeling, that include indications for use, how to use the product, with warnings, actions, and side effects, that information is explicitly- Senator NELSON. Maybe you did not understand the question. I said I understand that your product, Chloromycetin, has been responsible for deaths from bone marrow disorders. Is that correct or incorrect? Dr. LUECK. I do not know in what reference you are phrasing that question. I know that Chloromycetin, the Parke, Davis brand of chioramphenicol- *Senator NELSON. Has never resulted in any deaths? Dr. LUECK. No, I did not say that. Senator NELSON. Maybe I did not put the question correctly. Some people have died from the administration of Chloromycetin, I understand. Will you tell me what you know about that? Dr. LUECK. I understand that Chloromycetin has been alleged to be related to or associated with some serious side effects, some serious reactions. Those things are related and detailed in considerable length in the package information, in the labeling, Mr. Chairman. Senator NELSON. You say you understand. You really are not sure that any deaths have resulted from this drug? Dr. LUECK. I think that there have been instances where some re- actions can be related to the use of Chloromycetin. Senator NELSON. Have you ever read the warning that your company now belatedly puts in its advertising for this drug? Here is an ad from the Journal of the American Medical AssoOiation, February 20, 1967: Warning: Serious and even fatal blood dyscrasias aplastic anemia, hypo- plastic anemia- And so forth- are known to occur after the administration of chloramphenicol. Were you aware of that? Dr. LUECK. Yes, sir. Senator NELSON. That was my question, Doctor: Do you know of any cases of fatal side effects occurring after the administration of Chloromycetin? Dr. LUECK. I was attemping to respond to your question by referring to this warning statement in the labeling, which is precisely identical to that in the advertising. I am sorry if I misled you. Senator NELSON. You did not mislead me. You are aware, then, that deaths have occurred in this case? S Dr. LUECK. Absolutely. Senator NELSON. What has Parke, Davis done about quality control to overcome that problem? Dr. LUECK. I would like to state, Mr. Chairman, that Chioromycetm, like many other drugs, is a very potent drug. As the packaging 1nfor- PAGENO="0035" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2169 mation, the labeling information, indicates, it is to be used in serious infections. In that regard, it is no different from many other drugs, and in many instances, safer than other drugs. The physician, every time he prescribes, must balance the risk of the bad against the risk of the good. Senator NELSON. You are saying that nothing done about quality control can affect the inherent danger of this drug, is that what you are saying? Dr. LUECK. So far as I know, that statement is correct. But in the case of the example we have before the committee today, Mr. Chairman, another point that can come into play is that a sub- potent therapeutic product can endanger the life of the patient by not treating t.he disease properly for which the drug is `being administered. Senator NELSON. I do not think there is any question about that. Are thcre any cases you know about of deaths resulting from the drug not being physiologically available? Dr. LtTECK. Not that I know of. Senator NELSON. But we do have cases of deaths occurring where it was physiologically available? Dr. LUECK. Yes; it is true of penicillin, true of streptomycin, true of a number of our famous drugs. I would like to review very briefly for the chairman the fact that Chloromycetin, at the request of the Food and Drug Administration, was reviewed in 1952 by the National Research Council and reviewed again in 1960 by that same body in terms of its safety and effectiveness. Senator NELSON. By what council? Dr. L1JECK. The National Research Council. Senator NELSON. What is the membership of the council, do you know? Dr. Lu1~oK. Just a moment, please. Senator NELSON. You can furnish it for the record. Dr. Lueox. The consultants used in preparing the opinion of the National Research Council were, in our opinion, among the great of our time in medicine. They include Dr. Cluff- Senator NELSON. How many, DQctOr? What organizations are repre- sented is what I was getting at? Is that a long list? Dr. LITEOK. Not too long. Drs. Connelly, Damashek, Dowling, Elbert, Finch, Finland, Keefer, Moore, Smadel, Spink, Wintrobe, and the Chairman, Dr. Cannan. Senator NELSON. Are they representative of various organizations, or just simply- Mr. CUTLru. Mr. Chairman, this is a branch of the National Acad- emy of Sciences. ~enator NELSON. Would you submit for the record their identifica- tion? Otherwise, one reading the record would not know who these physicians are. PAGENO="0036" 2170 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. CUTLER. These are the leading medical authorities of the coun- try in the National Academy of Sciences. Senator NELSON. Go ahead. Dr. LUECK. The National Academy of Sciences is recognized as the highest ranking scientific body in the United States. It might be of interest, Mr. Chairman, to note that it operates under Government funds. Now, the National Research Council has responded, as I said, on two occasions to inquiries from the Food and Drug Administration as to the place of Chloromycetin in the therapeutic armementarium of physicians. I might quote, on January 11, 1961, the Chairman of the Division of Medical Sciences of the National Research Council replied by letter and among other things, he commented as follows: Chloramphenicol is considered to be a valuable drug that should remain on the market. In fact in certain infections, it is a drug of choice. The newer anti- biotics that have appeared on the market since chloramphenicol was last evalu- ated by the National Academy of Science's National Research Council in 1952 can't replace satisfactorily in all cases. Point 2, and I quote further: A restriction of the usage of chloramphenicol to hospitalized patients is not deemed to be indicated. * * 3. A knowledge of the untoward side effects that may occur with this drug should be adequately known to all prescribers. The information should be dis- seminated as a warning on the drug label and elaborated in an enclosure in the drug package. Beyond this, there is need for the continuing education of the physician through the media of medical meetings and the medical literature. This, of course, is a responsibility of the leaders of medicine and not of the FDA. Point 6. Almost, if not all, potent therapeutic agents cause some undesirable side effects. Therefore, it should be pointed out that chloramphenicol is not the only antibiotic that may cause unfavorable reactions of a serious and sometimes fatal nature. In addition to the National Research Council review, the Food and Drug Administration in 1957 published comparative data of side effects comparing various antibiotics. Now, Mr. Chairman, let us look at this article in this publication, and let us look at the potential dangers of chioramphenicol in true perspective; in other words, comparing it to other anti-infective agents or other antibiotics. Let us take a look at disabling and death-dealing reactions that may occur with the other antibiotics. The last significant and overall review of severe reactions to antibiotics was communicated to the medical literature by personnel of the FDA in 1957. Now, it consisted of a nationwide study, including more than 800 hospitals and interviews with 1,600 physicians, and uncovered 1,070 severe antibiotic reactions that were life-threatening. Senator NELSON. Any deaths in that list? Dr. LUEOK. Yes. In a paper published in Antibiotic Medicine and Clinical Therapeutics, 1957, these authors brought out the fact that PAGENO="0037" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2171 penicillin was found to produce the greatest number and the most severe reactions of all antibiotics presently available. Mr. G0IUXN. This was when? Dr. Lusex. 1957. Mr. GORDON. And when did Chloromycetin appear on the market? Dr. LtTEOK. 1949. Further, in order of their frequency, the life-threatening reactions to antibiotics are anaphylactoid shock, super-infections, severe skin reactions, blood dyscrasias and anguineurotic edema, with respiratory- tract involvement. Please note, Mr. Chairman, that blood dyscrasias- which can be related to chioramphenicol therapy are-next to the last on the list of life-threatening reactions. These authors further noted that the tetracyclines account for most of the cases of super-infections. Mr. GORDoN. Excuse me, sir. What was the date of that particular report? Dr. LUECK. The specific date I don't know. It was 1957. Mr. GoRDoN. Are you aware of the fact, however, that the risk at that time was considered to be considerably less than it is today? For example, I think the risk at that time was considered to be one in 800,000. A recent report to the California State Assembly and Senate by the California Medical Association and the State Department of Public Health, has revealed that the risk, on the basis of an average dose of 7.5 grams, is 1 in 24,000. Dr. LUECK. Mr. Gordon, with your permission, I would like to com- ment on the California report and I will finish my brief review of the 1957 FDA publication in just a moment. Then I would go on to the California report. Mr. GORDON. But isn't it correct that considerably more is known today about the effects of chloramphenicol than was known, say, 12 or 13 years ago? Is that not correct? Dr. LtTECK. I do not know that we have a higher incidence of side effects now than we had in 1957. I will treat that subject in a moment, Mr. Gordon. But at any rate, the 1957- Mr. GoRDoN. Could you answer my question, Doctor? Dr. LUECK. I am sorry. Mr. GORDON. I asked the question: Is it not correct that we know considerably more today about the side effects and dangers of chloramphenicol than we did say 12 or 13 years ago when that par- ticular report was written? Dr. LUECK. No, sir; I do not believe we do. Mr. GORDON. You do not believe we know any more today than we did at that time? Dr. LUECK. I do not believe we know any more. The California report is largely the same as the National Research Council report. The recommendations are largely the same. PAGENO="0038" 2172 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GORDON. When was the National Research Council report written? Dr. LUECK. 1961. Mr. GORDON. That was how many years ago? Dr. L1IECK. The California report suggests that the occurrence of I think aplastic anemia may be one in 24,000 to one in 40,000, and we are not going to argue with that figure. Mr. GoRDoN. They also give the figure: one in 24,200. Dr. L1JEOK. That is what I thought I was trying to quote. I am trying to quote from memory now, Mr. Gordon. I thought they quoted one to 24,000 or 40,000. Mr. GORDON. Now, I want to get your answer absolutely clear in my mind. You say that we do not know any more today about the side effects and risks involved in the use of chioramphenicol than we did 12 or 13 years ago? Dr. LUEOK. Mr. Gordon, in my opinion, we do not. Mr. GoRDoN. Thank you, very much. Dr. LUECK. But I am not a medical person and I am not qualified in all of these areas, obviously. I am qualified, however, to read a report which is published on the drug, so that is what I am doing. Senator NELSON. So the record might be clear on that point, is there anyone here who is qualified to answer that question, one of the doctors? Do we know any more today about the side effects than we did 10 years ago? Dr. SGHEELE. I am president of Warner-Lambert Research Institute. We know more in the sense that there has been a longer experience. However, no new side effects have developed in the course of time. We know no more about this phenomenon which is in the patient who reacts to this particular drug, or even the sensitivity phenomenon that occurs in people who become sensitive to penicillin and have severe~ reactions and of even deaths. In a sense, we do not know any more. There has been a lot of experience. I do not think there has been any medical data that has turned up that suggests that the population at large has within it more susceptibility of having this idiosyncracy which leads them under treatment by this drug to develop aplastic anemia. Mr. GORDON. You knew that 8 or 10 years ago? Dr. SCHEELE. Yes. It was not known in the beginning. It was learned after the product was marketed. It continues. But I doubt that the incidence is higher now in the population-that is, the potential of this is any higher now than it was then. PAGENO="0039" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2173 Mr. GORDON. You mean the incidence per 1,000 treated? Dr. SOHEELE. That is right, but I mean the idiosyncrasy within the patients themselves to have this happen if he is given the drug. Mr. GORDON. So that the record may be clear, then, you have ac- cumulated additional information; but do I understand you to say that you do not have any more information about side effects now than you had 10 or 12 years ago? Dr. SCHEELE. That is correct, and the physician who uses it does it on the basis that the disease he is treating, the risk-that is, the need for the drug is greater than the hazard as far as he is con- cerned in prescribing the drug. Mr. CUTLER. Mr. Chairman, you might want to have the record show `that Dr. Scheele is the former Surgeon `General in the United States and not without experience in this. Dr. SOHEELE. I helped gather some of `the data for the FDA some years ago. Senator NELSON. The record will show that because I saw the re- porter writing it down. I would like to ask you a question about `something that puzzles me. You were aware of the occurrence of serious blood dyscrasias, even fatal blood dyscrasias 5 or 10 years ago. Your ad in 1960, an ad in the Antibiotics and Chemotherapy maga- zine, was a one page ad that we will submit for the record which says: "True broad-spectrum coverage, proved clinical efficacy, Chloro- mycetin, outstandingly effective against a wide range of p'athogens," and so forth. It compares various other antibiotics A, B, C, versus Chloromycetin. Then the written legend is: "Chloromycetin is a potent therapeutic agent and, because certain blood dyscrasias have been associated with its administration, it should not be used indiscriminately or for minor -infections. Furthermore, as with certain other drugs, adequate blood studies should be made when the patient requires prolonged or in- termittent therapy." There is nothing here `that would scare anybody. Your claim was for a potent therapeutic agent and because certain blood dyscrasias had been associated with its admin~strat.ion, you simply said that the drug should not be used indiscriminately. (The advertisement follows:) PAGENO="0040" 2174 COMP~TITIVE PROBLEMS IN THE DRUG INDUSTRY [From Antibiotics and Chemotherapy magazine, April 19G0] True broad-spectrum coverage11. proved clinical efficacy CH LOROMYCETIN OUTSTANDINGLY EFFECTIVE AGAINST A WIDE RANGE OF PATHOGENS IN VITRO SENSITIVITY OF GRAM-POSITIVE ORGANISMS TO CHLOROMYCETIN Aim TO THREE OTHER BROAD-SPECTRUM ANTIBIOTICS* CHLOROMYCETIN (254 strains) ANTIBIOTIC A (280 stralis) ANTIBIOTiC B (281 straIns) ANTIBIOTIC C (255 straIns) 89% IN VITRO SENSITIVITY OF GRAM-NEGATIVE ORGANISMS TO CHLOROMYCETIN AIBI TO THREE OTHER BROAD-SPECTRUM ANTIBIOTICS* CHLOROMYCETIN (244 strains) ANTIBIOTIC A (245 straIns) ANTIBIOTIC B (237 straIns) ANTIBIOTIC C (236 straIns) 55% 62% Ad~pwd horn Lemrng, B. If., Jr., & FIooig~o, C., Jr., Wrkh, If., & 5hrti-1b~ñn, F.: Anriboticr Arson 159.l955. New Yost. Medical Encyclopedia, Inc., 1959, p. 414. CH1.OROMYCF.TIN (chloramphenicol, l'arkc-l)avis) is available in various forms, including Kapseals~ of 250 ing., in bottles oF 16 and 100. CHLOROMYCETIN is a potent therapeutic agent and, bmatise certain blood dyscrasias have been associated with its administration, it should not be usetl indiscriminately or for minor mice' tions. Furthermore, as with certain other drugs, adequate blood studies should be made when the patient requires prolonged or intermittent tlterapy. I PARKE-DAV~7 PARKE, DAVIS & COMPANY. UETROIT32,MICH1GAS 46% 50% 79% 77% 73% PAGENO="0041" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2175 Senator NELSON. Now, on February 20, 1967 the Journal of the American Medical Association ran an ad which we will print in the record. I shall not read all of the fine print.. It reads: Because of its wide antibacterial spectrum and its ability to diffuse into infective foci, Chioromycetin may be of value in the treatment of selected severe respiratory tract infections due to susceptible microorganisms. And so on. Then it gets down to the boxed-in section here. I will read part of the warning: Warning: Serious and even fatal blood dyscrasias (aplastic anemia, hypo- plastic anemia, thrombocytopenia, granulocytopenia) are known to occur after the administration of chioramphenicol. Blood dyscrasias have occurred after both short-term and prolonged therapy with this drug. Bearing in mind the possibility that such reactions may occur, chloramphenicol should be used only for serious infections caused by organisms which are susceptible to its anti- bacterial effects. (The advertisement follows:) PAGENO="0042" 2176 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Journal of the American Medical Association, Feb. 20, 196fl Chioromyceti n~ (chioramphenicol) PAflKEDAVIS when it counts.. PAGENO="0043" COMPETITIVE PROBLEMS IN may be indicated in certain severe respiratory infections Because of its wide antibacterial spectrum and its ability to dittuse nto intective cci. CHL080MYCETIN may boot value in the treat- ment ot selected severe respiratory tract intections due tosuscep- tibte microorganisms. However, as with aey aetibacteriat agent, the administration of CHL080MYCETIN must be adjunctive to the over- all therapeutic approach to this family of diseases. Appropriately treated, good results can beeopec ted in bactesal pneumonia and empyema; in bacterial complications of bronchiectasis and bronchitis. alt of which ate severe disorders often chronic and ditficult to eradicate. The decision to choose CHLOROMYCETIN trom among a group of antibiotics suggested by in vitro studies lobe potentially effective against a specitic respiratory tract pathogen(s) should be guided by seventy of infection, relative susceptibility of the pathogen(s) to the various antibacterial drugs, relative efticacy of the various drugs in this family of intections. and the important additional concepts con- tained in the `warning box." Patients vvth respiratory tract infections usu ally become afebrile in 181072 hours on recommended doses; roentgenographic clearing may be slower. Neoplastic. fungat. and mycobacterial disease as a cause 01 persist- ing respiratory disease should be ruled out by appropriate means. - ~ Chioromycetin Detailed information, including indications and dosage, appears in he package inserts of CHLOROMYCETI N products for systemic use. Consult he appropriate package insert. CHL080MYCETIN. an antibiotic having therapeutic activity against a wide variety of organisms, must, in accordance with the concepts infhe "warning boo" above, be usedonly in certai oseve re infections. C~etrairrdicatfons: Chlaramphenicol is contraindicated in individuals with a history of previous sensitivity reaction to if. It must not housed in the treatment of trivial infections such as colds, influenza, or infections of the throat; or usa prophylactic agent lx prevent bacterial infections. THE DRUG INDUSTRY 2177 Precaufions and Side Ettects: Untoward reactions in man are infrequent; however, they have been reported with both short-term and prolonged administration of the drug. Among the reactions reported are blood dyscrvsias as mentioned in the warning. When, during the course of therapy, blood counts show uousuat deviations which may be attributable to the drug such as reticulocytopenia. lcukopeoia. or fhrombo- cytopenia, fherapy with chloramphenicol should be discon- tinued. Also reported are certain gastrointestinal reactions resultiog in glossitis and stomatitis, which are indications to stop the drug. On rare occasions, superiniposed infection by Candida albicano may produce widespread oral lesions of the thrush type. Diarrhea and irritation of perianal tissues have been reported. Pseudomembranouseo terocolitis has been reported in a few patients. Hypersensitivity reactions manifested by angioneurotic edema and vesicular and maculopapulur types of dermatitis have been reported in chloramphenicol-sensitive patieots. Urticaria and vesicu tar lesions have been observed. They are usually mild in character and ordinarily subside promptly up on cessation of treatmenf. Febrile reactions have been reported. A reaction of the Jarisch-Heraheimer type has been repoded following therapy in syphilis, brucellosis, and typhoid fever, Typhoid fever patients have echibited a `shock'type reaction" characterized by circulatory collapse attributed to sudden release of endotoxin. Neurotooic reactions, including optic and peripheral nevritides. headache, mild depression. "dazed feelings." internal ophlhulmoplegia, mental confusion, and delirium have been reported. Symptoms of peripheral neuritis or decreased visual acuity call for prompf withdrawal of he antibiotic and the possible use of large doses of oral or parenterul vitamin B complex. When prolonged high dosage is necessary. tooic side effects may occur which call for dosage reduction or discontinuance of chloramphenicof therapy. Adults and children with impaired liver or kidney function, or both, map retai neocessive amounts of the drug. to such instances, dosages should be adjusted accordingly, Tooic reactions, he signs and symptoms of which have been referred to as the `gray syndrome." with some fatalities, have resulted trom 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 having receioed chloramphenicol during labor. The following summarizes the clinical and laboratory sludies that have been made on these patients: 11) In most cases therapy with chloramphenicol had been instituted within the hrsf 48 hours of fife. 121 Symptoms first appeared after 3104 days of continued treatment with high doses of chloramphenicol. 13) The symptoms appeared in the following order: (a) abdom- inal disfenlion with or without emesis; (b) progressive pallid cyanosis; (ci vasomotor collapse, frequently accompanied by irregular respiration; and dl death within atew hours of onset of Ihese symptoms. (4) The progression of symptoms from onset to coitus was acceleraled with higher dose schedules, (5) Preliminary blood serum level studies revealed unusually high concentrations of ohtoramphenicol after repeated doses. 10) Termioarion of therapy upon early evidence of he associafed symptomatology frequently reversed the process with complete recovery. Precautfonst One "warning boo" for precautions, The use of this antibiotic, as with other antibiotics, may result in an overgrowth of nonsusceptible organisms, including fungi. Constanf nbservafion of the patient is essenfial. ft new infections caused by nonsosceptible organisms appear daring therapy, thn drug should be disconfinued and appro- priate measures should be taken, Monitoring of liver and kidney function should be accom- plished during therapy in patients with existing liver or kidney diseasn. Suppffedt CHLOROMYCETIN is available in a variefy of forms including Kapseals' of 200 mg. PARKE-DAVIS WarnIng: Serious and even fatal blood dyscrasias (aplasfic anemia. hypoplastic anemia, fhrxmbocytopenia, granulocy. topenia) are known to occur afterthe administration of chloramphenicol. Blood dyscrasias have occurred alter both shorl-term and prolonged Iherapywith this drug. Bearing in mind the possibility that such reactions may occur, chlor- amphenicol should be used only Icr serious infections caused by organisms which are susceptible to its antibacterial eflecfs, Chloramphenicol should not be used when other less poten- tially dangorous agents will be effective. If musl 001 be used in the treatmentof friviat infections such as colds, intluenza, or infections of the throat; onus a prophylactic agent 10 pre- vent bacterial infections. Precautions: It is essential that adequale blood studies be made during treatmenf with the drug. While blood studies may detect early peripheral blood changes such as leukopenia or granulocytopenia, before they become irreversible, such studies caneol be relied onto delect bone marrow depression prior 10 development of aplaslic anemia. PAGENO="0044" 2178 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. How do you explain that you kne~w how serious these effects could be 10 years ago and yet in 1960, you were running an ad that did not call this sharply to the attention of the doctor, but then suddenly, 7 years later, you are running tkc e~I ~ Dr. LUECK. Mr. Chairman, I would like to comment on the fact that since 1952, every ad, every advertisement that has appeared on Chloro- mycet.m, has first. been reviewed with the Food and Drug Administra- tion before that ad was ever submitted for publication in any journal. Senator NELSON. I am prepared to indict the FDA along with your company for that. Dr. LUECK. This was the opinion, the combined opinion, apparently, of the experts in Parke, Davis, the experts in the Food and Drug Ad- ministration, that adequate warning was included in those ads and in the labeling at any given time. We have diligently worked with the Food and Drug Administration a.nd disseminated the information to the best of our ability on any changes or improvements in that labeling through the years. And to carry the message to the physician, Mr. Chairman, each and every time. Senator NELSON. Do you really mean to tell me, Doctor, that you think this first ad says the same thing as the second ad? Do you really mean to say that? Dr. LUECK. I am not saying that they say the same thing. Senator NELSON. Do they give the same warning? Dr. LUECK. Yes; I think they give the essential warning. Senator NELSON. Let's read it again. I think that this is preposterous. Mr. ~J1TrLER. Mr. Chairman, I hope I will not sound impertinent, but may I ask what this has to do with the evidence Dr. Lueck has submitted with regard to the evidences of differences of therapeutic brands? Senator NELSON. I can give you several answers, but If will give you one that ought to satisfy you. If quality control is important, and I think it is as important as you say it is in the production of drugs for the marketplace, quality control of advertising is just as important. It does not do any good to have good quality control so the drug will do exactly what you expect it to do and then be outright dis- honest about what it will do. I think quality control in advertising is as important as quality control in the production of a drug. That is exactly what I am getting at. Now, I will read the two ads again. I will let the public judge this one. You tell me if t.hey both tell the doctor the same thing, and I am going to ask the doctors who testify what their opinion is. We will put into this record the opinion of distinguished doctors on this question. And, if you want me to, you can select. a number of doctors to appear on this question. The testimony has been that you knew as much about the dangers of this drug 10 years ago as you know now, and your ad stated in April 1960: Chioromycetin is a potent therapeutic agent and, because certain blood clyscrasias have been associated with its administration, it should not be used indiscriminately or for minor infections. Furthermore, as with certain other drugs, adequate blood studies should be made if the patient requires prolonged or intermittent therapy. If the doctor reads that, is there anything in there to alert him that there have been deaths indirectly attributed to this drug? PAGENO="0045" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2179 If you knew 10 years ago what you know today, why, in 1967, do you have a severe warning boxed in heavy print: Warning: Serious and even fatal blood dyscrasias (aplastic anemia, hypo- plastic anemia, thrombocytopenia- And so forth- are known to occur after the administration of çhloramphenicol. Blood dyscrasias have occured after both short-term and prolonged therapy with this drug. Bear- ing in mind the possibility that such reactions may occur, chioramphenicol should be used only for serious infections caused by organisms which are sus- ceptible to its antibacterial effects. Do you consider these to be eq~uivalent warnings? Dr. LUECK. The second warning is an exact duplicate of the package insert and, in my opinion, would be considered a stronger warning, Mr. Chairman. Senator NELSON. I bless you for that. Dr. LTJECK. I would like to repeat that all of the ads on Chloromyce- tin were reviewed by Parke, Davis & CO. with the Food and Drug Administration since 1952 before they were published or submitted to a journal or any advertising media. Also, I would like to- Senator NELSON. Let me say at this point, if I may, that I do not have any higher opinion of the FDA's judgment in permitting this kind of advertising then than I do of the company's running this ad. I do not think it protects you any to come up and say the FDA ap- proved of a lousy ad. Most of the industry is attacking the FDA most of the time, anyway. Dr. LUECK. Well, I think if Parke, Davis & Co. had improper ads, we would have been cited by the Food and Drug Administration, as some people have, and we have not. So our advertising of all our products- Senator NELSON. I am sorry, I have another vote. It is 12:45. Why not take 45 minutes for a long lunch? (Whereupon, at 1:45 p.m., the hearing was recessed, to reconvene at 1: 30 p.m., this same day.) AFTERNOON SESSION Senator NELSON. Doctor, would you resume? STATEMENT OP DR. LESLIE M. LUECK ET AL.-Resumed Dr. LUECK. So, Mr. Chairman, I think our advertising of all our products has been much in order with the keeping of the day and regulatory requirements appropriate to advertising the product and to inform the advertising. Senator NELSON. Well, my questions have been directed at the prop- osition that the evidence was available several years . ago that there were some major serious side effects, and that the ads did not indicate it. For example, there had already been known deaths-I think that. is indisputable-by 1954. The National Research Council in 1952 made statements which were brought to the attention of the industry and Parke, Davis, in particu- lar. You read some of the conclusions of the~~ Council, one of which PAGENO="0046" 2180 COMPETITIVE PROBLEMS IN THE: DRTJG INDUSTRY was tha.t certain cases of serious blood dyscrasias had been associated with chioramphenicol-that was 1952-and still an ad in the General Practitioner, in March 1954, did not mention this fact. Do you have a copy of that? This ad only said in 1954 that: Since its introduction over four years ago, Chioromycetin has been used by physicians in practically every country of the world. More than eleven million patients have been `treated with this important antibiotic, truly one of the world's outstanding therapeutic ~igents. That is all that is there. How do you explain that at that stage, even 2 years after the Na- tional Research Council's statement about side effects that there is no warning at all in the ad? Dr. LTJECK. Mr. Chairman, I would like to point out that the warn- ings and so forth on Chioromycetin were introduced into the official labeling and were delivered to practicing physicians by Parke, Davis and Co., following the first report from the National Research Council. Senator NELSON. I did not follow that. What about the physicians? Dr. LUECK. That the physicians, a major attempt was made to in- form the physicians of the information then included in a warning statement on Chioromycetin and it is our firm belief- Senator NELSON. In what way were the physicians informed? Dr. LUECK. Both by letters to the physicians- Senator NELSON. Every physician in the United States received a letter? Dr. LUECK. Yes. Senator NELSON. That was at the direction of the FDA? Dr. LUECK. With the cooperation of the FDA. Senator NELSON. Well, was it at their direction? Did they order it? Dr. LIJECK. I do not know whether they ordered it or not. It would not have made any difference to Parke, Davis whether they had ordered it or not. It is a means of communicating this information. Senator NELSON. .Do you have a copy of the information you sent? Dr. L1TECK. Just a moment, please. I have a copy of the letters that were sent to physicians in the country. I would be happy to submit it to the chairman for the record if he pleases. Senator NELSON. Do you have the date of the letter? Dr. LUECK. It will be all on the letter. Senator NELSON. You do not know the date? Dr. LIIECK. Just a moment. I think I can remember some of the letter. Mr. Chairman, there are three letters and the different letters are required for this purpose: One went to the medical profession, one went to the osteopathic profession, and the third to the pharmaceutical profession. The letters are dated February 15, 1961. They include a letter with the current package insert. Senator NELSON. A letter and what? Dr. LTIECK. And the package insert, the offigial labeling. Senator NELSON. That was in 1961? Dr. LIJECK. That is February 15, 1961. Senator NELSON. Those letters will be printed in the record. (The material referred to follows:) PAGENO="0047" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2181 ~Az~e4 RESEARCH LABORATORIES aeoo PLYMOUTH ROAD ANN ARBOR. MICHIGAN NORMANDY 3-7111 February 15, 1961 To the Medical Profession: The enclosed copies of recently revised package inserts required by new regulations of the Food and Drug Administration will accompany all oral and parenteral Chloromycetin products. This is our means of promptly placing this information into your hands. These inserts provide the latest essential information regarding warnings, precautions, indications and dosage for the proper use of this antibiotic. Sincerely yours, C' Director, Department of Clinical Investigation Enclosures PAGENO="0048" ~.C) ~ ono ~aE >`~5 ~.`-* ~ ~ ~ m~jZ ~- ZmD ~F+~ "!" ~i ml ~ h~ 0 0 H H 0 CI) H ci 0 ci CI) H n -~ 0 o.~ CD ~D ~2. In oR a a RD 9 PAGENO="0049" 0 0 02 0 C) ~ E~ ~ ~ 0 + ~ 8 U V PAGENO="0050" I. 0 ~rj 0 o~ -~ E~CD 0 CD~~ Q() ~ PAGENO="0051" Q 9- (~ ~-. 0 3 1~*oo0 ~1 Q 0 ~D 0 ~ 0 ci 0 t~i 0 Ci) PAGENO="0052" I, 0 LTI t:z1 0 w tTj 0) t~j ci ci 0) ~E° fl~ ~ 0-. ~ ~ ~ b .I1~ PAGENO="0053" c*i 0 o CI) CI) `-3 I. PAGENO="0054" 0 0 ~ 0 o~- 0~ 0 ~ ~0 0 z 0 C 0 0 x 0 a 0 0 ~0 P ~ crE~ P P p ~ ~ ~0~i ~Po ~0~p 0 ~ ~ P 0~i~ 3 0 P - CD 0 D~0 0 0 ~ g I~ a 0 H H 0 t~j Ci) H ~Tj Co H 0~0 ~`n (D~ In ~P0 o r ~D mui zm :i~1 no ~ O'i ~ PAGENO="0055" SD m a 0> 21< !~; *VL~~ 0, -u > z ~< Co C) 0 t~1 S S tn 0 tn CI) PAGENO="0056" 2190 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY e9~irAe, «=~/3avi~s tfl~/~e7fl~ RESEARCH LABORATORIES 2800 PLYMOUTH ROAD ANN ARBOR. MICHIGAN February 15, 1961 To the Osteopathic Profession: The enclosed copies of recently revised package inserts required by new regulations of the Food and Drug Administration will accompany all oral and parenteral Chloromycetin products. This is our means of promptly placing this information into your hands. These inserts provide the latest essential information regarding warnings, precautions, indications and 1 dosage for the proper use of this antibiotic. Sincerely yours, k.Q. Director, Department of Clinical Investigation 1 See package insert following letter to Medical Profession. PAGENO="0057" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2191 e~!4i~iei~e, ~a~n~frmny RESEARCH LABORATORiES 2800 PL.YMOIJTP-I ROAD ANN ARBOR, MICHIGAN February 15, 1961 To the Pharmaceutical Profession: The enclosed copies of recently revised package inserts required by new regulations of the Food and Drug Administration will accompany all oral and parenteral Ghloromycetin products. This is our means of promptly placing this information into your hands. These inserts provide the latest essential information regarding warnings, precautions, indications and dosage for the proper use of this antibiotic)' Sincerely yours, k,Q, (I Director, Dèpartment of Clinioal Investigation 1 See package insert follcwing letter to Medical Profession. PAGENO="0058" 2192 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Is that the first letter of warning that was sent to the phy~icians? Dr. LUECK. Mr. Chairman, I am informed tha.t in 1952, the report from the National Research Council and the conclusions drawn from this report by the Food and Drug Administration were disseminated to the' physicians in the United States, in 1952. Senator NELSON. What information was disseminated at that time, sir? Dr. LUEOK. The National Research Council report of 1952, plus the conclusions that the Food and Drug Administration arrived at as a result of that report.. Senator NELSON. I will go back to that in a moment. But now that you mention the report, are you aware of what notice Parke, Davis sent to its detail men at that time? Dr. LUECK. Am I aware of what, Mr. Chairman? Senator NELSON. What information on that point was sent to the detail men from Parke, Davis at that time? Dr. LUECK. No; I would not be specifically advised on that. Senator NELSON. From t.he 1961 report of June 27-the hearing of the Committee on the Judiciary of the U.S. Senate, Subcommittee on Antitrust and Monopoly, on page 196, it says: The third item contains the following passage which the detail man was in- structed to memorize and repeat verbatim to the physicians: "Intensive investigation by the Food and Drug Administration carried on with the assistance of the Special Committee on imminent specialists, appointed by the National Research Council, resulted in unqualified sanctions of continued use of Chioromycetin for all conditions for which it had been previously used." Do you see any warning there to the detail men to notify the physi- cian that there were serious blood dyscrasia problems associated with the drug? Dr. LUECK. Mr. Chairman, I would like to state a detail man would have these official labels with him and leave them when he talked to the physician. Mr. GolmoN. Dr. Lueck, I just tried to read it. You need a magnify- ing glass to read it. I could not read it. Senator NELSON. The real point is at that time, even though the de- tail man may have had the insert-whether or not he gives it to the doctor, I do not know-but the instruction was to say that this study by the specialists of the National Research Council "resulted in un- qualified sanction of continued use of Chloromycet.in for all conditions for which it has been previously used." Dr. LUECK. Which is ~l1 the labeling for the uses, Mr. Chairman, that are listed and described in the labeling. Senator NELSON. I hope I am not misinterpreting this Kefauver report, but the National Research Council said in item 1 that certain cases of serious blood dyscrasia had been associated with chloram- phenicol. The only point I am making is that in the instructions to the detail man, Parke, Davis did not say anything about that. They said the report resulted in an unqualified sanction of use of the drug. PAGENO="0059" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2193 It does not seem to me that that National Research Council state- ment is an unqualified sanction. Do you now think that would mis- lead a detail man? Dr. LUECK. I think what is unqualified in my opinion, Mr. Chair- man, is that the labeling qualifies the product and its users and what the detail man was saying is that those uses still remain, and they have. Senator NELSON. Do you really think that, when the detail man receives this kind of instruction about Chioromycetin, he is going to qualify this instruction from his own company. As the report says, the detail man was instructed to memorize and repeat the instructions verbatim to the physicians. Do you think the detail man is then going to say to the doctor, "There are really qualifications. If you will read the report of the National Research Council, you will see that there are serious blood dyscrasia associated with chloramphenicol." Do you think it is natural for the detail man to start emphasizing that when the company has told him something else? Dr. LTJECK. I do not think that the company told him something else. Along with that was this labeling that the doctor should read, which carried the warnings and which carried the uses and the recom- mended dosage, Mr. Chairman. This is official labeling. We do not want our detail men to paraphrase this. This is physician language and he must make the decision; the physician. Senator NELSON. Why does not the instruction to the detail man specifically say, not that there is unqualified sanction, but that there are serious blood dyscrasia and this ought to be called to the attention of the physician? Why should not the company have said that to the detail man? They did not. Dr. LIIECK. We have said that many times to physicians in our correspondence with them and the fact that millions of these package inserts or official pieces of labeling have been printed and `disseminated with every product of Chloromycetin in the history of that drug- Senator NELSON. Well, I am well aware of that. But the companies have testified repeatedly here that one of the responsibilities of the detail man is to be well informed and inform the doctor about what the drug is, `how it is to be used, and all benefits and risks involved in the use `of the drug so the doctor will be well informed. Yet what `was set out to the detail man in this case did not say that at all. Farther up on the page, on page 196, same reference, it reads, "An attachment to planned presentation 10," wthich under the heading "Suggested Details" suggests tlhe exact language to be used by the detail man in presenting his argument. The covering letter stated: So physicians are of the opinion that Ohioromycetin has been taken off the market or it `is just restricted. So physician's have formed the impression that this `autibiotic has been associat&I with the development of blood dyscrasias in large numbers of patients and will `be amazed when you point out the facts'. PAGENO="0060" 2194 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Now, is this not all calculated to instruct the detail men to play down the fact that there are blood dyscrasi'a at all and the fact that the National Research Council suggested some qualification-that is, cau- tion about how it is administered because of the blood dysc.rasia? Is that not your interpretation of that instruction? Dr. LUEOK. Our detail men, I will repeat again, Mr. Chairman, have instructions to leave with the physicians the official package insert that is current at that time. That is the document on which the physi- cian must make his judgment as far as Parke, Davis & Co. is con- cerned. He can render judgment on his own experience or other experiences gained from the literature or his own personal experience. But our detail men leave the packa~e `insert with the physician. It is the most effective and thorough way we know of, of informing the physician, which is one of the things that Council recommended that we do. Senator NELSON. I might say that, even with my brandnew glasses, I `have to concentrate very `hard to read the warning on the insert. Dr. LIJTEOK. I would like to comment on that. I personally have ch'an~ed that. That was the package insert that was current in 1961. This is the one that is current today. Senator NELSON. Can you read that more easily? Mr. CIrniE~R. Yes. Senator NELsoN. All right; to go back to reading from that report again. Dr. LUECK. Mr. Chairman, if I may, I would like to read to you or suggest that we did precisely in 1952, in the way of following up on the 1952 National Research Council report, that Parke, Davis & Co. followed out t'he instruction of the Food and Drug Administra- tion specifically and I have `a document here that is an FDA press release of August 14, 1.952, that we did intend following their instruc- tions to the letter. Senator NELSON. Well, I have no evidence that you did not follow any instructions. I think it is a rather sad commentary that the FDA at that period in history did not have any greater concern for the public interest than they demonstrated by what they did in this and other cases. It does not persuade me that there is not something the company ought to do itself regardless of the FDA. I have been familiar in my long period in politics that regulatory agencies are often con- trolled `by the `people they are supposed to regulate. I think if you will look at the history of this one, the FDA did not protect the public at `all. It `is a shocking case. The FDA's actions should not he the defense on which the company stands. The pharmaceutical industry has been a great American industry which has made a great contribu- tion to the `health and welfare of the people of this country and I trust will continue to d'o so. But if they continue with this kind of shoddy practice, I might say to you quite frankly, t:he industry is going to run into some tough regulations. It does not mean it is a bad PAGENO="0061" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2195 industry. It just means that the industry is doing things that are not in the public interest. I do not think anybody can read what the Kefauver report says about the instructions to the detail men without thinking that the company was doing its best to avoid giving the doctor the information that blood dyscrasias could occur as a cOnsequence of the use of this drug and that it should be used only in very serious cases. We have a document here which we will get to later whinh tells that Chioro- mycetin was administered to people who had sore gums, and `a lady died from it; to a 5-year-old with a little acne and a sore finger and somebody else with a sore throat, and they `both died. They should never have had the drug. It does not make `any sense at all. It ought to be the moral responsibility of the industry, the companies who know about this, to protect the public interest. But look at the instructions here, this same `letter that I was referrin'g to, and I qu'ote from the Kefauver hearings-these are not my words. This is a report made backin 1961: Parke, Davis perverted the permission for continued use under these restric- tions into a blanket "clearance of the drug." The same letter contains a highly misleading assertion: "Thus, Chioromycetin has successfully passed three in- tensive investigations originally by Parke, Davis Company, next `by officers of the Food and Drug Administration, then by a special committee of authorities in the field of hematology and chemotherapy and `the research by the National OounciL" I think all of these instructi'ons to the detail man were meant to con- vince him to peddle the story t'hat there are really not any serious side effects `here that the doctor ought to be worried about. I have to answer another vote. (Short recess.) Senator NELSON. I am sorry about the continual interruptions. I did not plan them. I realize that they are unfair to the witness, because it seems that every time I make a statement and ask a question, I leave. It is unintentional. Go ahead. I have finished what I had to say about that. Did you want to respond? Dr. LIJECK. Mr. Chairman, I did not remember quite where we were or if I had to respond. (Whereupon, the reporter read the record.) Dr. LTJECK. I think I have responded to that question a number of times for the record, Mr. Chairman. I think we could proceed. Senator NELSON. All right. - Just a couple more points on these ads before I conclude. There are, and I would ask that they be put in the record, a series of ads from 1951 through 1967. Give the witnesses copies of these so they know what I am referring to. I ask that they be put in the record. (The advertisements referred to follow:) PAGENO="0062" 2196 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Antibiotics and Chemotherapy magazine, Sept. 1951] three fo~ of Chioromycetin Chioromycetin Cream Chioromycetin Ophthalmic (powder for solution) Chioromycetin Ophthalmic Ointment* Extending its fields of usefulness, CHLOROMYCETIN (Chioram- phenicol, Parke-Davis) now provides topical therapy with the same outstanding advantages for which its systemic administra- tion is so well known: UNIFORMITY' RELIABILITY BROAD SPECTRUM `WELL TOLERATED Chioromycetin Cream, 1% CHLOROMYCETIN Cream contains 1% Chloromycetin in a smooth, non.irritatingwater-miscible base. Applied topically, CHLOROMYCETIN Cream is well tolerated and produces rapid clinical improvement in many superficial infections and dermatological conditions. Qiloromycetin Ophthalmic (powder for solution) Chioromycetin Ophthalmic Ointment CHLOROMYCETIN Ophthalmic preparations provide high local concen- trations - without irritation - for treatment of ocular infections. Otloromycetin is supplied in the following forms: Chloromycetin Kapseals,® 250 mg. bottles of 16 and 100. Chloro~nycetin Capsules, 100 issg.. bottles of 25 and 100. Chloromycetin Capsules, 50 mg.. bottles of 25 and 100. Chloromycetin Cream 1%. 1 ounce collapsible tubes. Chloromycetin Ophthalmic Ointment. 1%, Ii ounce collap- nible tubes. Chloromycetin Ophthalmic. 25 mg dry powder for solution. individual sia~wfthdroppera c A PARKE,DAVIS & COMPANY ~ ..,,a~ls* PAGENO="0063" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2197 [From Antibiotics and Chemotherapy magazine, Mar. 1952] Chioromycetin® "It has been demonstrated, in pregnant women at term, that chloramphenicol passes from the maternal to the fetal blood stream in one hour following its ingestion, that it there attains a concentration equal to three-fourths of that in the maternal stream, and that the blood concentrations of mother and fetus are relatively the same after two and one-half hours," Therapeutic concentrations of well tolerated CHLOROMYCETIN (chloram. phenicol, Parke-Davis) in the fetal blood stream are easily obtainable "by the simple oral administration of the drug to the mother."2 Investi- gators have suggested, therefore, the empiric use of CHLOROMYCETIN in such virus infections as atypical pneumonia, in an attempt to avoid fetal damage.3 Results with CHLOROMYCETIN in twopatients with typhoid fever during pregnancy were reported recently as "quite satisfactory." Bibliography: (1) Stevenson, C. S.: Gla,ko, A. J.: Gillespie. E. C., and Maunder. J. B.: J.A.M.A. 146,1100 (July 28) 1851. (2) Scott, W. C., and Warner, It. F.: J.A.M~A. 142:1331 (April 21) 1830. (3) Ross, S., and otl,ers: J.A.M.A. 141:1301 (April 29) 1930. cHL0R0MYcE'rr6 Is supplied In tl,e following forms: CHLOROMYCETIN Xapseals.® 230 mg, bottles of 10 and 100. CHLOROMYCETIX Capsules, ion mg, bottles of 25 and 100. CI-ILOROMYCETIN Capsules, 30 mg, bottles of 25 ansI 100. CHLOROMYCETG~ Ophtlsalmlc Ointment, 14~, %ounce collapsible tubes. CHLORoM1'cETn~ Ophthalmic, 23 mg. dry powder for solution, individual vials with droppers. ç, A ~ r ~ ~ I-IFS ~ Ib/*~ ~`i~' ~ V 7/~. w~,35 PAGENO="0064" 2198 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CHLOROMYCETIN produces prompt clinical response in the mixed infections commonly found in pelvic inflammatory disease. "In mixed infection [pelvic cellulitis and abscess] CHLOROMYCETIN appears to be superior to penicillin, strep- tomycin or sulfadiazine."1 "The clinical response to chloramphenicol consisted of marked symptomatic improvement, usually within 48 hours. "\Vomen who had large pelvic abscesses were treated so effectively with chloramphenicol that posterior colpotomy, with drainage of the abscess, was not necessary in effecting a rapid cure in any of our patients who were treated with this antibiotic from the start."2 CHLOROMYCETIN (chioramphenicol. Parke-Davis) is supplied in the following forms: CHLOROMYCETI~ Kapseals5~ 231) mg. bottles of 10 and 100. CHLOROMYCETIX CapsUles, 100 mg. bottles of 25 and 100. CHLOROMYCETI~ Capsules. 50 roe., bottles of 25 and 100. CHLOROMYCETI~ Ophthalmic Ointment. l~. %ounce collapsible tubes. CHLOROMYCETIN O~i:thalmie. 25 mg. dry powder for solutIon. lndl. vidual vIals wIth droppers. 1. Greene. C. C.: Kentucky M. .1. 50:8. 1821. 1. Stevenson. C. S.. et aS.: Am. J. Obst. & Gynec. 61:488, 1851. [From Postgraduate Medical magazine, July 1952] ~#Wi~ S® rapid response with Chioromycetin ç. A S ~ r:~ ~ ~ *i'~ ~ ~ ILl ~t PAGENO="0065" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2199 [From General Practitioner magazine, Jan. 1953] in the hands of the physician Often the critical evaluation of the drug to be administered is as im- portant to the patient's recovery as is the diagnosis of his condition. In each case correct procedures can be determined only by the physician. CHLOROMYCETIN is eminent among drugs at the disposal of the medical profession. Clinical findings attest that, in the hands of the physician, this widely used, broad spectrum antibiotic has proved invaluable against a great variety of infectious disorders. notably effective Chioromycetiri ~~Um antibiotic The many hundreds of clinical reports on CHLOROMYCETIN emphasize repeatedly its exceptional tolerance as demonstrated by the infrequent occurrence of even mild signs and symptoms of gastrointestinal distress and other side effects in patients receiving the drug. Similarly, the broad clinical effectiveness of CHL000MYCETIN has been established, and serious blood disorders following its use are rare. However, it isa potent therapeutic agent, and should not be used indis- criminately or for minor infectiom-and, as with certain other drugs, adequate blood studies should be made when the patient requires pro- longed or intermittent therapy. CHLOROMYCET1~' (chtona,aph~aka1. Pankn-Danh) is a%ailabk a a na,isiy at fanas. winding: cuL080MycErIx Kapssai,~6 250 ,ag.,bat,in af 10 and 100. CHL080MYCETIN Capaai~a. 100 sag.. baftiss af 25 and 100. CHL080MYCETIN capsain. sOng.. batti,s af 25 and 100. CHL000MYCETIN Ophthaiasin O:at,a~at. 1%. %aanpspaiiapnibiP tab,s. CHL080MYCETIN Ophthabnin. 25 ag. thy paaskn fan anh:tian indinidaaRiai,aiihdn:ppy,a. A ~ /~ ~/( J)(/, f) / 81-280 0 - 68 - pt. 6 - 5 PAGENO="0066" 2200 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From General Practitioner magazine, Mar. 1953] notably effective well tolerated broad spectrum antibiotic Chioromycetin®. - in the pneumonias Highly effective in a wide range of bacterial, rickettsial, and viral pneumonias, CHLORO- MYcE-rIN (chloramphenicol, Parke-Davis) is par- ticularly valuable in mixed infections and where the causative agent is not easily ascertained. Unusually active against staphylococci, CHLORO- MYCETIN reduces the likelihood of broncho- pulmonary staphylococcal superinfection, an in- creasingly common complication. Chioromycetin Is rapid in producing deferves- cence and recovery, according to recent com- parative studies. Exceptionally well tolerated, CHLOROMYCETIN is noted for the infrequent occurrence of even mild gastrointestinal and other side effects. Serious blood disorders following its use are rare. However, it is a potent therapeutic agent, and should not be used indiscriminately or for minor infections - and, as with certain other drugs, adequate blood studies should be made when the patient requires prolonged or inter- mittent therapy. CA ~ 0 2&1 ~ -. 1~ Chlornmyeetln (chioramphenleol, Parke-Davis) l~ available in a variety of forms, including: Chloromycetin Kapseals,® 230 mg, bottles of in and 100. Chioromycetin Capsules, 100 mg, bottles of 25 and 100. Chloromycetln Capsules, 30 mg.. bottles of 23 and 100. Chioromycetln Ophthalmic Ointment, 1%, %-ounce collapsible tubes. Chloromycetin Ophthalmic, 25 mg. dry powder for solution, individual vials with dropper,. PAGENO="0067" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2201 [From Antibiotics and Chemotherapy magazine, Nov. 1954] when resistance to other antibiotics develops... (hlorornycetiii Current reports'2 describe the increasing incidence of resistance among many pathogenic strains of microorganisms to some of the antibiotics commonly in use. Because this phenomenon is often less marked following administration of CHLOROMYCETIN (chloramphenicol, Parke-Davis), this notably effective, broad spectrum antibiotic is frequently effective where other antibiotics fail. Coliform bacilli-tOO strains up to 43% resistant to other antibiotics; 2% resistant to CHLOROMYCETIN.' Staphylococcus aureus-500 strains up to 73% resistant to other antibiotics; 2.4% resistant to CHLOROMYCETIN.2 CHLOROMYCETIN is a potent therapeutic agent and, because certain blood dyscra.. sias have been associated with its administration, it should not be used indiscriminately or for minor infections. Furthermore, as with certain other drugs, adequate blood studies should be made when the patient requires prplonged or intermittent therapy. References (1) Kirby, W. M. M.; Waddington, W. S., & Doornink, C. M.: Antibiotics Annual, 1953-1954, New York, Medical Encyclopedia, Inc., 1953, p. 285. (2) Finland, M., & Haight, T. H.: Arch, mt. Med. 91: 143, 1953. ~ PARKE, DAVIS & COMPANY ~ -~ DETROIT 32, MICHIGAN ~ PAGENO="0068" 2202 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Antibiotics and Chemotherapy magazine, Oct. 1955] less resistance encountered... ~ `0 0 S & a a B.coli b A. aerogenea a P. vulgaria d Staph. oureus 0 References (1) Altemeier, W. A.; Culbertson, W. R.; Sherman, B.; Cole, W.; Elstun, W, & Fultz, C. T.: J.A.M.A. 157:305, 1955. (2) Kutscher, A. H.; Seguin, L; Lewis, S.; Piro, J. D.; Zegarelli, E. V.; Rankow, R., & Segall, R.: Antibioticv& Chemother.4:1023, 1954. (3) Clapper, W. E.; Wood, D. C., & Burdette, 3. L: Anti- biotic: & Chemother. 4:978, 1954. (4)Sanford,J.P.; Favour,C. B.; Harrison, J. H., & Mao, F. H.: New England 1. Med. 251:810, 1954. (5) Balch, H. H.: MI!. Sur- geon 115:419, 1954. (6) Sanford, J.R; Favour,C.B.,&Mao,FH.: J. Lab. & Clin. Med. 45:540, 1955. (7) Felshin, C.: J. Am. M. Women's A. 10:51, 1955. (8) Jones, C. P.; Carter, B.; Thomas, .W. L, & Creadick, R. N.: Obst. & Gynec. 5:365, 1955. (9) Kass, E.H.: Am.J.Med. 18:764,1955. (10)Stein,M. H.,& Cechman,E.: New England I. Med. 252:906, 1955. (11) Yow, E. M.: Past grad. Med. 17:413, 1955. ~~5~~~~ /`~#lIi \~s~I \\ ~X, ~ /7 0 S #9 I- `-I Is $ 4~ `I' e.g d Chioromycetin® for today~ problem pathogens Recent in vitro tests and clinical studies again demon- strate the unsurpassed efficacy of CHLOROMYCETIN (chioramphenicol, Parke-Davis) against a wide variety of pathogens. For example, against urinary infections, now characterized by increased incidence of resistant- gram-positive and gram.negative strains, CHLOROMY- CETIN continues to provide outstanding antibacterial action.1-15 CHLOROMYCETIN is a potent therapeutic agent and, because certain blood dyscrasias have been associated with its administra- tion, it should not be used indiscriminately or for minor infections. Furthermore, as with certain other drugs, adequate blood studies should be. made when the patient requires prolonged or intermittent therapy. ;j~ FEZIS &ZY DETROIT MICHIGAN PAGENO="0069" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2203 [From General Practitioner magazine, Jan. 1956] more effective against gram-negative bacilli... Chioronyc etin® for today's problem pathogens SENSITIVITY or so GRAM.NEGATIVE BACILLI TO CHLOROMYCETIN AND THREE OTHER MAJOR ANTIBIOTICS TESTED BY THREE METHODS ANTIBIOTIC A j ANTIBIOTIC B ANTIBIOTIC C DISC 1 -~ CHLOROMYCETIN 14% TUBE ~ CHLOROMYCETIN 12% ANTIBIOTIC A ANTIBIOTIC B ANTIBIOTIC C 10 20 30 40 50 60 70 80 90 OR RESISTANT 0B MODERATELY BESISTANT fOR SENSITIVE * Breakdown of gram-negativc bacilli - Coli: 11; Proteus: 10; Klebsiella pneumottiae: 9; Aerobacter: 7; Pseuchlmonas: 7; Achrotnttbacter: 2; Paracolon: 2; Salmonella typhosa: 1; Bacterium anitratum: 1. Adapted traIn Branch, A.; Starkey, D. H.; Rodgers, K. C., & Power, E. E.: Antibio~cs Annual, 1954- 1955, New York, Medical Encyclopedia. Inc., 1955, p. 1125. CIILOIIOMYCETIN is 1011111 therapeutic agent and. because rrrtain blood dyscraslas have been associated with Its administratino, it should not he used indiscriminately or for minor infections. Furthermore, as with certain other drop, adeqllatl' blood stlldics should be made sshe,, the patient requires prolonged or intermittent therapy. ;J~~ ~,DAVIS&COM~NyDETRoIT,MIcHIG~ PAGENO="0070" 2204 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From General Practitioner magazine, Sept. 1956] Suspension Chioromycetin Pa ~ in tate p1easant~tasting broad spectrum antibiotic preparation I I for pediatric use When you prescribe SUSPENSION CHLOROMYCETIN PALMITATE for your young patients, therapeutic response is rarely marred by missed doses or spilled doses. Children really like the taste of this custard-flavored prepara- tion. And it slips soothingly down the sorest throat. SUSPENSION CHLOROMYCETIN PALMITATE keeps without refrigera- tion, a convenience appreciated by mothers. Its liquid form permits easy adjustment of dosage according to your directions. CHI.OROMYCETIN is a potent therapeutic agent and, because certain blood dyscrasias have been associated with its administration, it should not be used indiscriminately or for minor infections. Furthermore, as with certain other drugs, adequate blood studies should be made when the patient requires prolonged or intermittent therapy. supplied: SUSPENSION CHLOROMYCETIN PALMITATE, containing the equivalent of 125 mg of CHLOROMYCETIN (chloramplsenicol, Parke-Davis) per 4 cc., is available in. 60-cc. vials. ~ Parke, Davis & Company DETRO~, MICHIGAN they never make faces at. PAGENO="0071" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2205 [From Antibiotics and Chemotherapy magazine, Feb. 1957] SENSITIVITY OP COMMON PATHOGEN9 TO CHOROMYCITIN AND THREE OTHER MAJOR ANTIDIOTICS' -I greater antibacterial Chioromycetin efficacy... for today's problem pathogens (:IILOIIOMY(:ETIN is a patent therapeutic agent blood studies should he in ide when the patient aid. l)ecanse certaiii l)hX)d dyscrasias have beeti requires prolonged or intermittent therapy. .isSoCiat(d with its administration, it 5110111(1 not be Ibis g~aph is niapiml 1mm A1Iem~nr W A. Cnihmlsnn. `A~ ft. (C liii Sd 11010 It \ I)r II)! IflhIl( r 1111CC tioiis rtir Sh ft C 39 H I ~ & F' II C' T I S if A tiarmore. as ~sitli certaiii citlier clricgs. adequate 57:303 (Jan. 23) 193.5. ~ PARKE, DAVIS & COMPANY DETROIT 32. MICHIGAN PAGENO="0072" 2206 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From General Practitioner magazine, June 1958] THIS 5-YEAR STUDY SHOWS~I. CONTU$L~ED EFFICACY CII 10110 MYC ET1 N® COMBATS MOST CLINICALLY IMPORTANT PATHOGENS Recent reports comparing the effectiveness of various antibiotics against commonly encountered pathogens indicate that CHLOROMYCETIN (chlor- amphenicol, Parke-Davis) has maintained its high degree of effective- ness.'-~ It is still highly active against many strains of staphylococci,t-5 streptococci,2.7 pneutnococci,2 and gram-negative'.2-7-9.'0 organisms. REFERENCES: 1) Roy, T. F..; Coltios, A. M.; Codg, C., & Doocou, I. B. R.: Cuoud. .\!.AJ 77:844 (Nm.. 1)1957. (2) Setu ienuu, S. S. 3. .Stoottt Siooi Jlut~:. 25:52 (Jut-Fib.) 1958. (3) Koch. 8, & Doom.)), C.: Cobft(a Mid. 87:3t3 1937. (4) W ttctt, B. A., & 5tn1it~,,. C. L.: A Fi:,4i:o- 5tody of the Antibiotic Seootntt(ei nod Crust R;sistout,.i of Staphylococci iii a (`,yoyt:tI Itoi~;;t~). pipir pocoted at Fifth Aoo. Strop. or Antibiotics, Wathiogtoo, D. C., Oct. 2-4, 1957. (5) Dooigtr, D. F.. & Pm.nteoo. Sr. C. St.: J..tiuott M. A. 48:120, 1957. (6) Royce, A.: Ch.otgt.t it; Rtsiit:tocc to Vaticot Aubbiotius of St.rph~htcocci and Other M~nnbes, ptpcr pntstct;.d at Filth At;;;. Syutp. on Antibitti;.. Washington, D.C., Oct. 2.4. 1957. (7) lItnit, 11. F.: 1. Iwo Of. So. 47:130, 1957. (8) J;atphtan. J. F.., & Bather, B. W: Conad. M.AJ. 77:567 (Stpt. 15) 1957. (9) Rhooti, I'. S.: Puttgrad. Mid. 21:563, 1957. (10) Huhhooat, Sy J.. & Scott, E. C.: Dihttcttw MI. 29:159, 1957 PARKE, DAVIS & COMPANY. DETROIT 32, MICHIGAN ~Ti1b) 3 P. CHL.0R07'IYCETIN is a potent therapeutic agent, and because certain blood dyscrasias have been associated with its adt,tinistration, it sltould itot be used indiscriinittatelv or for minor infections. Furthermore, as wills certain other drugs, adequate blood studies should be made when the patient requires prolonged or intermittent therapy. PAGENO="0073" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2207 [From General Practitioner magazine, June 1958] IN VITRO SENSITIVITY OF FOUR COMMON PATHOCENS TO CHLOROMYCETIN FROM 1952 TO 1956* STAPHYLOCOCCUS PYOGENES 1956 (S1R STRAINS) ~ ~ 96% 1955 (1,249 STRAINS) .~. ~ 94% 1954 (749 STRAINS) 98% 1953 (455 STRAINS) --~~--------- _____9 99% 1952 (215 STRAINS) ~R~W~____ - 96% ESCHERICHIA COIl 1956 (11 STRAINS) ~ 1955 (12R STRAINS) -~ 1954 (105 STRAINS) ~___ ~ 98% 1953 (97 STRAINS) 100% 1952 (15 STRAINS) - - PROTEUS MIRABILIS 1956 (4$ STRAINS) ~- 89% 1955 (72 STRAINS) ~ 3 1954 (3$ STRAINS) -` 86% 1953 (39 STRAINS) 90% 1952 (14 STRAINS) 64% PSEUDOMONAS AERUGINOSA 1856 (55 STRAINS) 38% 1955 (113 STRAINS) ___________________ 25% 4 loss (102 STRAINS) 15% 1953 (7R STRAINS) _____________ 17% 1952 (51 STRAINS) - 29% 0 10 20 30 40 50 70 (0 90 100 `AI~p*dU~ II PAGENO="0074" 2208 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From General Practitioner magazine, Dec. 1958] ~ HICHLYI CHL Reports on studies of invitro activity of CHLOROMYCETIN over the past few years indicate that thisj antibiotic has maintained its effectiveness against most strains of staphylococci." "...Staphy1ococc~ do not acquire resistance to chiorampisenicol {cHLoRoxtYcETIN] as they do to other antibiotics, ii spite of heavy use of chioramphenicol [cHLonoxIYcETIN}." These in vitro studies are borne out isv excellent clinical results withcHLonoxIYcETIN in treatmrt of patients for severe staphvlococc'al infections, including staphvloc'occal pneumonia,5 postoperativc wound infections,6 postoperative parotitis, and Pterperal i)reast abscesses.' CLILOROMYCETIN (chiorampheisicol, Parke-Davis) is available in a varictv of forms, including Kapseals of 2.50 at in bottles of 16 and 100. CHL000MYCETIX is a potent therapeutic agent such, heca::s:' certain blood dvscra.sias have been associated wiS its administration, it should not bc used indiscriminately or for minor infections. Furthermore, as with certain nthc (ln:gs. adequate blood studies should bc macic' when the patient requires prolonged or intermittent therapy. REFERENCES: (1) Iteser, A., in Welch, 11., & Marsi-fl,aiicz, I: Antit,icties An,,,,.,i 1957-1938. New Y,,rk, Medical Encsdopedia, lv. l938,p.78.3.(2)Waisbron,B.A.,&Strelitaer,C.L.: Arc!,. Ins. Mc,!. 1O1::S'i7, 1958. (3) End,, lt.,& D,,,::,eli, C.: C,,lifcrni,: Sled. 87:31 19.57. (4) Bbs, T. E.; Calms, A. 11.; Craig, C.. & O,::,e:,n, I. B. 1).: C,,s,,,,!. 3!. A. 1. 77:844, 13257. (5) Cm:per, 21. L.. & K,ll,r, 11. 33 I. Din. Child. 95:245,1939. (6) Ca,ssell, I!. T., eta!.: SaW., Gyocc. & 0!,,:. 106:1, 1958. (7) Brawn,). V; Sed,sitc, J. L., & 11:,ooerJ. U. 5. Armed Forces 31. 1.: 9:161, 1939, (5) Samson, E. L., & Ba,,,,,a:,, S.: Sneg., Cyn,'c. & 0!,,:. 105:224, 1)57. Cab, PARKE, DAVIS & COMPANY* DETROIT 32, MICHIGAN PAGENO="0075" Upper respiratory Upper respiratory Upper respiratory 86.9% - OCTOBER. 1955MARCH. P956 JU9EOECEMBER 1953 91.5% 99.2% 91.8% 92.0% 86.0% 90.0% COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2209 [From General Practitioner magazine, Dec. 1958] .1 / 1/ S. IN VITRO SENSITIVITY OF STAPHYLOCOCCI FROM THREE FOCI OF INFECTION TO CHLOROMYCETIN FROM 1953 TO 1957° JANUARY-JUNE. 1957 fin fFI1~T1TUn . 98.7% 20 40 60 80 100 - PAGENO="0076" 2210 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Antibiotics and Chemotherapy magazine, Jan. 1959] EFFECTIVE AGAINST MOST STRAINS OF STAPHYLOCOCCI CHLOROMYCETIN COMBATS MOST CLINICALLY IMPORTANT PATHOGENS ~ VITRO SENSITIVITY OF PATHOGENIC STAPHYLOCOCCI TO CHLOROMYCETIN AND TO ANOTHER WIDELY USED DOAD*SPECTRUM ANTIBIOTIC FOR 1958, 1957. and 1955' 1958 (200 STRAINS) CHLOROMYCETIN 90.5% 1957 (200 STRAINS) CHLOR0MYCETIN 94.0% CHLOROMYCETIN 98.0% 100 `Adapted from ltollowav, W J.. & Scott. E. C.: Delaware .~f. 1. 30:173. 1958. In this study CIILOROMYCETIN and Antibiotic A wem used in identical strengths of 5 mcg. CHLOROMYCETIN (chloramphenicol, Parke-Davis) is available in a variety of forms, including Kapsealsb cii 250 mg., in bottles of 16 and 100. CHLOnOMYCETIN is a potent t):erapc'utic t~et:t and, becatise certain blood dyscrasias have been associated with its administration, it should not be usc-i) indiscriminately or for minor infections. Furthermore, as with certain other drugs, adequate blood studi(s should be made when the patient requires prolonged or inter- mittent therapy. Sc A PARKE, DAVIS a, COMPANY* DETROIT 32, MICHIGAN 1955 (42 TO 103 STRAINS) PAGENO="0077" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From General Practitioner magazine, May 1961] 2211 CHLO ROMYCETI K (chlsramphenicol, Parke-Davis) That the sensitivity patterns of "street" staphylococci differ widely from those of "hospital" staphylococci is a well-established clinical fact.'-5 Although strains of staphylococci encountered in general practice have remained relativelysensitiveto a number of antibiotics,° the problem of antibiotic-resistant staphylococci appears to be a threat to all patients in hospitals today. It is encouraging to note, however, "...that a relatively small percentage of strains develop resistance to chlsrarn phenicol, despite the consumption of large amounts of this antibiotic."7 In one hospital, for example, CHLOROMYCETIN"... was the only wieldy used antibiotic to which few of the strains were resistant."5 In another hospital, despite steadily increasing use of CHLOROMYCETIN sillce 1956, ". . - the pe,ct'tttage of chloramphenicol-resistant strains has actually been lowe,' in subsequent years." Elsewhere, insofar.as hospital staphylococci are concerned, it appeal-s that "the problem of antibiotic resistance can be regarded as mi,tinial for chloramphetticol-" CHLOROMYCETIN (shlorantphenieol, Parke-Davis) is available is vuricus fartss, isv1 isling Kapseals11 of 250 mg., in battles of IC on,l 100. See package insert for details of adntinistrutius and tlusuge. lIkening: Serious and sacs fatal ldeu,l lyvseasias (a~slautis ocr-asia, hvpu~~lasti,- aseesia, theus,l:sytspetl'. gronalonytopeniul see hess,, to areas aftr-r the aderisioteatius of shluraesphssiavl. lllrvd ,lyosrasias hos' occurred after ehert-tere, aol avith ts,,slesg,vt therapy svilt, this hug. lte:ri,sg is sied tt,r- psssilsility thaI such reactions nay ossar, shlarausp u-viral shsal,t l~- used esl~ foe serious infa-,lesv svause,l bc srgati"r-S ashieh are souseptil~le to its aetils:svte,i:l slIest,. C' hluraesphesisul eheald sit l.r- ascii ashes othur Ic" potentially duegerous sssetu a,ill `u- -11,-dive, se i,, the tsrut,ueet of teivial i,sD-vtiess sarIs as saId:, isila' viral infections of the throat, i.e as a peephylastis isgent. l'rcroatinec: It in rsceetiat that ,,da-,taate ldss'd sta,liss he ,,sude turisg tee:,t,ssst s,itl, the leug. While bait ntu,lies s~uy detest early peripheral bluest oh usges sash a, leukupe,sia or geasalucvtupenia. hefuec Ihey hecn,,se i ereseevible, earl, atadisa saseut be relied apou to detest buss ,ea eras, lsprssuiss peiue te developtnest of aptautis assnsia. inside as well as outside the hospital... staphylococci usually remain sensitive to PAGENO="0078" 2212 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From General Practitioner magazine, May 1961] IN VITRO SENSITIVITY 01" 250 STRAINS OF STAPHYLOCOCCI TO CHLOROSIY('I:TIN AND TO FOUR OTHER ANTIBIOTICS* CITLOROMYCETIN 78c Antibiotic A 68'; Antibiotic B 55', Antibiotic C 45'S _____________________ Antibiotic 1) 21 These Strains of coaculase-positive staphylococci were isolated front hospitalized patients at a Izege coo::ty hospital daring the year 195):. Sensitivity tests svere done by the disc nsethnd. 0d,,:el too,, Baser, Perry, & Kirby' (1) Baser, A. SC; Peers. 0.51.. & Kirby, SC 21. 21.: J..l..1t.A. 173:475, iWo. (2) Fisher. 21W: A':). fat. lied. 05:413. 1900. (3) (nhre, 0.: (i,,-::)::tj,,, 20:90, 1952. (4) Edsards, T. S.: ia:. J. OpOth. t,Part 11:19. 1959. (2: S:::i:h, 1.91.: 0:aphvloyoera) lnfyrtioes, (hirage. The Year Book Pobliohe,-,,, lee., 1(50, p. 148. (0) Peteysdoef, P. G.; P,n:e, 21. C.; Minnhro-. 11. B.; K reoc, SC B., & Ben,:ett, I. L., Jr.: lot. lIed, 05:39). 1900. (7) Kditori;;I: J.A..lI.5t. 173:544, 1900. (8) Fi::lon:I, 31.; Jnneo, SC }, Jr.. & ~ I. L., Jr.: ,l:'yI:. l::t. lIe,). 01:505, 1959. ________________________________________ `.`,/ !.;.*_*_ I PARKE-DAVIS] PAGENO="0079" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2213 [From Medical World News, Feb. 2, 1962] when urinary tract infections present a therapeutic challenge... CH LOROMYCETI N® (chloraniphenicol, Parke-Davis) Often recurrent.. . often resistant to treatment, urinary tract infections are among the most frequent and troublesome types of infections seen in clinical practice.2 In such infections, successful therapy is usually dependent on identification and susceptibility testing of invad- ing organisms, administration of appropriate antibacterial agents, and correction of obstruc. tion or other underlying pathology. Of these agents, one author reports: "Chloramphenicol still has the widest and most effective activity range against infections of the urinary tract. it is particularly useful against the coliform group, certain Proteus species, the micrococci and the enterococci."1 CHLOROMYCETIN is of particular value in the management of urinary tract infections caused by Escherichia coli and Acrobactcr aeroyencs.3 in addition to these clinical findings, the wide antibacterial range of CHLOROMYCETIN continues to be confirmed by recent in vitro studies.44 CIILOROMYCErIN )chloramphenicol, Parke-Davis) is available in various forms, including Kapseals5 of 250 mg, in bottles of 16 and 100. See package insert for details of administration and dosage. lVaruiog: Serious and even fatal blood dyscrosias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) are known to occur after the administration of chloramphenicol. Blood dyscrasias have occurred after both shoit-terns and prolonged therapy with this drug. Bearing in mind the possibility that such reactions may occur, chlorantphenicol should be used oniy for serious infections caused by organisms which are susceptible to its antibacterial effects. Chloraniphenicol should not be used when other less poten- tially dangerous agents will be effective, or in the treatment of triviül infections, such as colds, influenza, or viral infections of the throat, or as a prophylactic agent. I'r,',aotions: 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 or granulocytopenia, before they become irreversible, such studies cannot be relied upon to detect bone marrow depression prior to development of aplastic anemia. Refee,,:eo: (1) Mob:ee. E J., h.: .910. M,4. 125:956. 190:. (2) Mo:tio. W 3. Nieholo. 1). 11., & Cook, E. N.: ieee. Staff Meet. Slays Cite. 54:147. 1959. 3: tTIl:one, A.: l'eboooee .91. J. 32 :97, 1960. (4: Petceotoef, 11. G. 11:5.1:. N. W; t'oetio, 3. A.. & (c,s,h,s~. S. N.: lltd(. Jo!.ea llopki,, llo.~.. 108:48, 1961. 5) Jo)I:IT, C. 11.: Eegelhec'l, W. N.; Ohl:,,~, 3. it.; Hei:teiek, I. 3., & CeIn, 3. A.: o1,t:biotsce & (.hteothee. 10: PA - 634, 1960. (G~ lie:). 10. N.: A~. J. !`e.o,to(. 11:392, 1160. PAGENO="0080" 2214 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Medical World News, Feb. 2, 1962] L PAGENO="0081" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2215 [From General Practitioner magazine, June 1962] when postoperative infection complicates convalescence CHLOROM~CETIN (chioramphenicoi, Parke.Dauisl for broad antibacterial action The incidence of postoperative wound infections, particularly among debilitated patients, pre- sents a serious hospital problem.1 These infections are caused in many cases by strains of staph- ylococci resistant to most antibiotics in common use.'23 In such instances, CHLOROMYCETIN should be considered, since `.. the very great majority of the so-called resistant staphylococci are susceptible to its action."4 Staphylococcal resistance to CHLOROMYCETIN remainssurprisingly infrequent, despite wide- spread use of the drug.2.45-7 In one hospital, for example, even though consumption of CHLOROMYCETIN increased markedly since 1955, there was little change in the susceptibility of staphylococci to the drug.7 Characteristically wide in its antibacterial spectrum, CHL0ROMYCETIN has also proved valuable in surgical infections caused by other pathogens-both gram-positive and gram-negative.7'8 CHLOROMYCETIN (chloramphenicol, Parke-Davis) is available in various forms, including Kapseals.u of 250 mg., in bottles of 16 and 100. See package insert for details of administration and dosage. Warning, Serious and even fatal blood dyscrasias laplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenial are known to occur alter the administration of chloramphenicol. Blood dyscrasias have occurred alter both short-term and prolonged therapy with this drug; Bearing in mind the possibility that such reactions may occur, chloramphenicol should be used only for serious infections caused by organisms .vliich are susceptible to its antibacterial effects. Chloramphenicol should not be used when other less potentially danger- ous agents will be effective, or in the treatment of trivial infections such as colds, influenza, or viral infections of the throat, or as a prophylactic agent. Precautions, It is essential that adequate blood studies be made during treatment with the drug. V/hue blood studies may detect early peripheral blood changes, such as leukopenia or granulocytopenia, before they become irreversible, such studies cannot be relied upon to detect bone marrow depression prior to development of aplastic anemia. References: 11) Minchew, B. H., & Cluff, L. E.: J. Chion. Di,. 13:354,1961.12) wallmark, G., & Finland, M.: Am.J.M. Sc. 242:279, 1961. 131 Wallmark, G., & Finland, M.: J.A.M.A. 175:886, t96t. 141 welch, H., in welch, H., & Finland, M.: Antibiotic Therapy for Staphylococcal Diseases, New York, Medical Encyclopedia, Inc., t959, p. 14. 15) Hodgman, J. E.: Pediat. Clin. North America 8:1027, 1961. 161 Bauer, A. w.; Perry, D. M., & Kirby, .0. M. M.: J.A M.d. 173:475, t960. 17) Petersdorf, R. G., ci a).: Arch. nt. Med. 105:398, 1960. 18) Goodier, T. E. w., & Parry, W. R.: Lancer 1:356, 1959. LPARKE_DAVIS~1 I 81-280 0 - 60 - pt. 6 - PAGENO="0082" 2216 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From General Practitioner magazine, Sept. 1962] in urinary tract infections... the most common pathogens respond to C HLO ROMYC El N® lchtoran~henicot, ParkeDavis) That the urinary tract is especially vulnerable to invasion by gramnegative pathogens is an observation often confirmed. Also amply documented°'5 is the finding that many common offenders in urinary tract infections remain susceptible to CHIOROMYCETIN. In one investigator's eoperienco, chloramphenicol has maintained a wide and effective activity range against infec* tioos of the urinary tract. "It is particularly useful against the Coliform group, certain Proteus species, the micrococci and the enterococci."° Other clinicians draw attention to the "frequency for the need" of CHLOROMYCETIN inasmuch as "...a high percentage of Eucherichia coil and Klebsiella.Aerobacter are sensitive to it."l Moreover, enterococci, other streptococci, and most strains of staphylococci eohibit continuing sensitivity to CHLOROMYCETIN.' Successful therapy in urinary tract infections is dependent upon accurate identification and susceptibility testing of the invading organism, as well as the prompt correction of obstruction or other underlying pathology.6 CHI.080MYCETIN lchlonamphen;col, ParkeDavis) is available in various forms. including Kapseals' of 250 rig., in bottles of 16 and 100. See package insert for details of administration and dosage. Warning Serious and even fatal blood dyscrasias laplastic anemia. hypoplastic anemia, thrombocytopenia, granulocytopenial are known to occur after the administration of chloramphenicol. elood dyscrasias have occurred allen both short.ferm and prolonged therapy with this drug. nearing in mind the possibility that such eeactiors may occur. chlonamphenicol should be used only for serious infections caused by organisms which are susceptible to its antibacterial ef'ects. Chionamphenicol should not be used when other tess potentially dangerous agents will be effective, or in the treatment of trivial infections. such as colds, influenza, or viral infections of the throat, or as a prophylactic agent. Precantians: It is essential that adequale blood studies be made during treatment with the drug. While blood studies may defect early peripheral blood changes, such as teukopenia en granulocytopenia, before they become irreversible, such studies cannot bc relied upon to detect bone marrow depression prior to development of aplaslic anemia. References: itt Katz, y. j., & eoundo. S. R.: Pediat. cli. CuriA America 6:1259, 1961. 121 Malone, F. J.. Jr.: MU. Med. 125:836. t960. 131 OIlman, A.: Oeia ware HI.!. 32:97, 1060. 141 Petenndonf, 6. 5.; Hook, K. W.; Curtin, 3. A., & Grossbeng, S. K.: Buii. Jol:v' Hopkioa Hoop. 109:40, a96t. 151 Whitaker, 1,: canad. HI. A.!. 64.1022, 196t, 161 Martin, W. J.; flichols, 0. 0., & Cook, K. ft.: Proc. Staff Meet. Mayo Cue. 34~1t7, 1959. I PARKE-DAVi~J L I PAGENO="0083" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2217 [From Modem Medicine, Sept. 17, 1962] in urinary tract infections... the most common pathogen~ respond to CHLOROMYC ElI N~ ltotthcieyttootiocopeoity!o,toblo to ieo~yiye by goaeo-eegotioe p~thog,eo 0 an oboeooatio~ ftc, yonfitoned. 0100 aepty dooooteotnd' ioth~ boding that etany yotonton otf,ed,oa in ooieary tract efeotioesrceoin o~oooptibIn to CHIOR000CETIfL to one ieo,obgotoro eopnH~ry~, oh!oraetpheniyot boo eroteto?e,d a obdc and etTeotioe actiotty nange agocotntnotor0000heearytraot.ltopotoufulyoo,toIagorotth,colfor gtocp,oettainProtcuo 0,01,0th, miyr00000j rd the ,rterooooci.'° ~ to th, tceqcency too ho etc0 at C81ORTMYCE000 lea touch as `. a high pcrocrtoge of ooh,nloyla so,, and KtnboietaAyrybaoter ar,oeeoitiyeto it."° Moreooen.ent,rooocci, othcrotrep0000rri,andrnoytotrainsot staphylococci tohibit aotitinoingoenoitioity to CHI000MYCETIN. ooeoofulthetapyfrorinafytractinteytioy,isdep,nd,ntcponaoc,rat,j~,,ty,C~tjO,5,~ ousceptibitty tootrng otthe inoading arganionr as oct as the pronfpt correctiOn HI 050trortice or other under. ~Og pathology.' **0~~ PAGENO="0084" 2218 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Southern Medical Journal, Jan. 1963] in severe respiratory infections refractory to otber measures... CHLOROMYC Eli N® chloramphenicol Parke-Davis) for established clinical efficacy against susceptible organisms4 In Friedlander's Pneumonia313 * In Hemophilus Inf!uenzae Pneumonia3'4'""4 In Staphylococcal Pneumonia'8"3 * In Acute Epiglottitis4"°" * In Pneumonias Due to Gram-negative Bacilli9 * In Staphylococcal Empyema'2 CHLOROMYCETIN ct'.Toramphenicol. ParkeDavis' is available in various forms. including Kapseals of 250 mg.. in bottles of 16 and 100. See package insert for details of administration and dnsa~e. Warning: Serious and even fatal blood dyscrasias :aplastic anemia. hypoplastic anemia. thrombocylopenia. granulocytopenial are known to occur after the administration of chloraoiphenicol. Blood dyscrasias have occurred after both shorfterm and prolonged therapy with this drug. Bearing in mind the possibility that such reactions may occur. chlvrnmphenicot should be used only for serious infections caused by organisms which are susceptible to its antibacterial effects. Chloramphen:col should not be uoed when ether less potentially dangerous agents will be eftective, or in the treatment of trivial infections such as colds, influenza, or viral infections of the throat, or as a prophylactic agent. Precautions: tt is essential that adequate blood studies be made during treatment with the drug. Wnile blood studies may detect early peripheral blood changes. such as leukopeoia or granvlocytopenia. before they become irreversible, such studies cannot be relied upon to detect bonn marro's depression prior to development of aplasfic anemia. References Ill Thacher, H. C.. & Fiohman. 1.: J. Maine M. A. 52:84. 1961. 12) Hopkins, E. W.: Postgrad. Med. 29451, 1961. 131 Halt, W. H.: M. Clin. North America 43:191. 1059.141 Krugman. S.: Pedior. Clin. North America 8:1199. 1961. 51 Ede. 5: Davis, C. M., & Holmes, F. H.: i.A.M.,A. 170 638. 1959. 161 Wolfsshn, A. W.: Connecticut Med. 22:769, 1958. 171 Calvy, G. 1.: New England J. J I £ Med. 259:532, 1958. 181 Hendren. W. H.. lit. & Haggerty. R. I.: J.,A.M.A. 168:6, 1958. 19) Cufts. M. Rhode Island M. J. 43:388. 1960. 110) Berman, W. E., & Holtzman, A. E. California Med. 92:339, 1960. 1111 Vefto, B, R.: J.A.M.A. 173:990, 1960. 1121 Sia. C. C. J.. & Brainard. S. C.. Hawaii M. J. 17:339, 1958. 113) Rosenthal. I. M.: GP 17:77 lMarch) 1958. 1141 Gaisford. W.. Brit. M. J. 1:230, 1959. PARKE-DAVIS `I PAGENO="0085" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2219 [From the New England Journal of Medicine, Feb. 25, 1965] PARKE-DAVIS PAGENO="0086" 2220 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Southern Medical Journal, Apr. 1967] PARKE-DAVIS L ~--~-~~-w.iS I PAGENO="0087" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2221 Senator NELSON. None of the ads that you have referred to have very strong warnings in them. Mr. CUTLER. The only ads we have are the ones that are 15 and 16 years old. Senator NELSON. I was just about to refer to the ad of February 20, 1967, the ad that I spoke of before. Does the witness have a copy of that? Dr. LUECK. I believe so. Senator NELSON. It says, "When it counts, Chloromycetin"-on the front. Dr. LtncK. Yes, sir. Senator NELSON. Is it the intent of the company henceforth to pub- lish this kind of a warning in all of its ads? Dr. LUECK. Yes, sir. When the ad includes indications for usage, Mr. Chairman, and dosage schedules, we will include the full warn- ing statements, all the side effects, and so forth. Senator NELSON. You mean that you would still run an ad like the one you ran in the General Practitioner or some of these other ads, where there is no warning at all? Let me take one we talked about before, the January 1961. It says, "Resistant staphylococci among outpatients emerge less fre- c&uently, disappear more readily," and then the warning that is there simply says: Chloromycetin (chioramphenicol, Parke, Davis~ is available in various forms, including Kapseals of 250 mg., in bottles of 16 and 100. Chloromycetin is a potent therapeutic agent and, because certain blood dyscra- sias have been associated with its administration, it should not be used indis- criminately or for minor infections. Furthermore, as with certain other drugs, adequate blood studies should be made when the patient requires prolonged or intermittent therapy. You mean the company will run ads henceforth with that little warning in them? Dr. LUECK. Mr. Chairman, I do not have the ad you have in your hand, apparently, and before I respond to that question, I want to make certain what I am addressing myself to. Senator NELSON. This is the ad I read to you earlier, to contrast that with the much stronger warning in the February 20, 1967 ad. Is that warning in the 1961 ad adequate in view of what we now know about this drug from what you said in your February 20, 1967 ad? Dr. LUECK. Mr. Chairman, when Parke, Davis & Co. either cites an indication in the ad, an indication for use that physicians might elect to prescribe Chloromycetin for that, drug entity and/or if we include any dosage recommendations in any ad, the entire warning statement as depicted in this ad, the ad of February 20, 1967, pub- lished in the Journal of the American Medical Society, will be fol- lowed. Senator NELSON. Do you mean to say that you will run ads to phy- sicians urging their use of this drug, and omit the warning that says "serious and even fatal blood dyscrasias may occur"? Dr. LUTECK. No, sir; we are being misunderstood. I am merely saying that we will print what is in the package insert nearly vei~batim, as we have in the February 20, 1967 ad. Senator NELSON. Then take the ad I just gave you. You would not run that 1961 ad again, then? PAGENO="0088" 2222 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. LUECK. No, sir; we would not run that 1961 ad. Senator NELSON. You do not think that it is adequate? Dr. LUECK. No, sir; it does not meet the present requirements. Senator NELSON. Do you think these present requirements, in view of the history of this product, are justifiable? Dr. LUECK. Yes; I think they are. I think they are very adequate. Senator NELSON. Now, let me ask you another question: This ad was published February 20, 1967? Dr. LUECK. Yes, sir. Senator NELSON. I have here an ad from the British Medical ~iournal of February 11, 1967, just 9 days away from this very detailed ad. That British ad does not have any warning mit at all. It says: Olincally Unexcelled. Clinical use throughout the world has established Ohloromycetin (chloram- phenicol B. P. Parke, Davis) as an antibiotic of outstanding efficacy in a wide variety of bacterial, viral and rickettsial infections. Chiorornycetin possesses extremely high anti-microbial activity, crosses tissue barriers readily, diffuses widely and rapidly through nearly all body tissues and fluids, and is well toler- ated. It is rapidly absorbed and bacterial resistance is minimal. And because of these notable properties, therapy with Chloromycetin generally results in prompt response and rapid recovery. No warning at all in that ad. How do you explain that? Dr. LUECK. Mr. Chairman, is that the complete ad? Senator NELSON. Yes; do you not have a copy of it? Dr. LUECK. I only have one page. I did not know if t.hat was the corn- pleteadornot. Senator NELSON. Yes; I will show you the journal. Dr. LUECK. I would like to comment that the medical feeling and impressions on the warning requirements on Chloromycetin are dif- ferent in practically every country of the world. Parke, Davis & Co., has always met all the requirements, the legal requirements of what- every country we distributed our products in and we have met the necessity of the medical profession in that country. These ads, so far as I know, met all of those requirements. Senator NELSON. Well, the effect of the drug is the same on people in other countries as it is here; is it not? Dr. LUECK. Largely. Senator NELSON. Do you know of some differentiation? Dr. LUECK. Yes; there are some minor differentiations, but for the sake of this discussion, let us say they are the same. Mr. CUTLER. Mr. `Chairman, I think you will find that the point you are developing is true of every single ad in this magazine, which is a distinguished magazine of the British Medical Society and I assume it meets all of is~hat they consider to be appropriate requirements. Senator NELSON. I have not questioned whether or not it met their requirements. I have assumed that. There is a very serious moral ques- tion involved that ought to `be brought up. It sure shocks me. What the witness says is we will meet the standards of the country where the drug is sold. That means, of course, there is not a single under- developed country in the world that has any defense against the exploi- tation of their people for profit by an American corporation who does not warn them of the serious, mighty serious, possibly fatal conse- quences here. So you mean to testify that your company will stand PAGENO="0089" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2223 on the proposition that we will send drugs to Tanganyika, `we will send to Latin American countries, we will send drugs to all the under- developed countries in the world and since they do not have any standards, we will fool them all we can and make a great `big profit and never tell the doctors `that there is a risk of `serious blood clyscrasias. Is that what you are telling the committee,? Mr. CUTLER. No, sir. I think you know that, sir. This is a British Medical Society. The British doctors are sophisticated doctors, just as sophisticated as the doctors in this country. This meets all their require- ments. This is, of course, only a small part of the information that goes to a British doctor. Senator NELSON. That is not the testimony. Mr. CUTLER. Y'ou are indicting every drug company in Great Britain and the United States. Senator NELSON. Any company, drug company or any other kind of company, that would do that, I would be pleased to indict on moral grounds. I think they ought to `be indicted on moral grounds. Your testimony is that you will meet the standards of the country in which you are advertising, not the standards of safety which the witness has testified is a proper standard, the proper ad which gives this warning that is put in ads in this `country. But in~ countries where the people do not know any better, where the country is not protected by laws, you will tell us that you have no compunctiOn about running an ad that will fool a doctor, as you did in California hi 1961. I will read this to you. I would think you would not sleep at night, frankly, you or any drug company that would do that. On page 11 of "By Prescription Only," by Morton Mintz, it says that Dr. L. A. M. Watkins, La Canada, Calif., physician, prescribed ~3hlo- romycetin to his own son. In 1952, the boy died. In November 1961, the physician went before a California Senate committee and testified: "I do not know o'f one single victim who would not be alive today had `he only been permitted to get well `by himself; by nature without the use of antibiotics." Here is an American doctor. I do n'ot know what he read about chl'oramphenicol. But if he read these ads without any warning, he might very well prescribe it and lose his own son. I do not understand what standard of ethics would govern a great industry of this country that would find it satisfactory to finally, under compul- sion in this country, warn the public and warn the doctors about serious blood dyscrasias and then cavalierly advertise in anot'her country with- out telling those people about the risks. I should think you people would not be able to sleep. Mr. CUTLER. Mr. Chairman, I think you are reaching awfully far to criticize a witness and a company that brought you some evidence that you have been asking for, for months, about therapeutic equiva- lency of various drugs. It so happens that the pharmaceutical indus- try, as you know, has believed that advertisements of drugs are not the primary source of information on which the doctor relies. In 1962, this issue was fought out in this Congress and it was decided by the Congress that all advertisements should contain brief sum- maries, warnings, of complications and side effects, and the FDA was given power to regulate in that area. These cOmpanies have done their very best to live up to that law, the need for which they did not agree PAGENO="0090" 2224 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY with at the time. They have observed that law, and you are digging back to 1952, some 15 years ago, to whip this company which brought you some evidence. I must object to that, Mr. Chairman, most respectfully. This witness did not come to testify about advertising. Neither you nor Mr. Gordon said anything to him in advance to indicate you in- tended to question him about advertising. If you want to query Parke, Davis about its advertising, give them notice and they will produce a witness to reply to you. Senator NELSON. I am perfectly happy to have any statement you want to make in t.he record. I did not tell you what witnesses to bring. You are familiar with the questions that have been raised. Mr. CUTLER. You knew what they were going to cover. This wit- ness testified until 11 o'clock this morning on an issue you have been inviting the entire industry to bring in some evidence about; namely, therapeutic equivalency. He brought it in. You asked him perhaps half an hour of questions on that subject and ever since, you have been off on advertising as a way to harm this company. Senator NELSON. I have not been discussing advertising as a way to harm this company. And, I do not blame this witness. He does not run the advertising. But now that you mention it, you select the date, you bring in your advertising people, and we will stick to this one issue of ad- verti~ing and we will take 1 day or 2 days or whatever amount of time you need to explain this kind of advertising and what you do in this country versus what you do in underdeveloped countries or in England or elsewhere. Do you want to give me a datel I will cancel everything I have. Mr. CUTLER. I cannot act for the company, sir, but if you wish to have a Parke, Davis witness, they will be happy to supply one. Senator NELSON. We will be glad to have Parke, Davis come in at any time. We will set a date and we will go through all this advertis- ing with them. I have not been beating the company over the head unfairly. I think if you raised this issue on moral and ethical grounds before any ob- jective citizen in America, he is going to say it is shocking. Mr. CUTLER. Mr. Chairman, it is an issue that was fought and re- solved in 1962. Everything you have said here has been put into the record of the Congress before 1962. The law was passed, the companies are doing their level best. to comply with it. Parke, Davis, as this wit- ness said, has never since been accused by FDA of issuing any improper ad, as I understand it. We are on a different issue now: namely, the issue of generic equivalency. That is what you invited people to come and testify about. That is what. Dr. Lueck testified about and you do not have any questions to ask him about that. Senator NELSON. The issue was not. resolved in 1962. The. issue I am talking about right now is February 20, 1967, and February 11, 1967. I am talking about two ads run by the Fame company. I am talking about the witness' testimony as a professional person that he thinks that this warning should be in the ad. Mr. CUTLER. Speaking of warnings, Mr. Chairman, would it not have been appropriate for this committee to say to some representa- PAGENO="0091" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2225 tive of Parke, Davis or to us that you intended to `ask some question today about those ads and you would like have a witness qualified on that subject? Senator NELSON. We intend to ask questions about the whole spec- trum of issues related to the drug industry as we have of every other witness who has come here. You are the `first one to complain and you have not yet been `a witness. I can't predict every question we will think of as various issues arise. But if you think this is unfair, as I say, you can notify my office as to when Parke, Davis wants to go through these ads with us and we will pick out `a time very soon for Parke, Davis `to bring their `advertising people. Let them talk about the morality of this ad. But it shocks me that you do not even blush when you defend a company advertising drugs in another country without the warning required here when `the rea'son it is required in this coun'try is because the ad without the warning does mislead doctors, it does cause people to prescribe a dangerous drug for illnesses that are not serious. That is w'hy the `ad is run with `the warning. And you know it and every- body else knew it, too. I would like an answer to that. If this "is the standard of ethics by which the industry operates, I tell you, you fellows `are in for some sad trouble. I do not think this country will stand for it. I do not have any more questions of this witness. Thank you, Dr. Lueck. (The complete prepared statement and attachments submitted by Dr. Lueck for presentation on November 16, 1967, follows:) STATEMENT OF LESLIE M. LUECK, PH. D., DIRECTER OF QUALITY CONTROL, PARKE, DAvIs & Co. TOTAL QUALITY CONTROL OF MEDICINAL PRODUCTS Mr. Chairman and Members of the Committee: My name is Leslie M. Lueck. I am director of Quality Control for Parke, Davis & Company. I am representing the Pharmaceutical Manufacturers Association today to provide you and `members of the Subcommittee with an insight into the quklity control operations of rep- utable drug firms. I am a native of Wisconsin and a graduate of the University of Wisconsin having received a Ph.D in pharmacy from that school in 1954. After receiving my doctorate, I joined the Research staff of Parke, Davis & Company and spent the first seven years of my professional career in Product Development. Since 1961, I have devoted my efforts to Quality Control, becoming Director of Quality Control in April 1963. My interest in the quality of medicinal products, was, of course, first generated as a stuednt of the pharmaceutical sciences. However, it was enhanced to a great degree after joining Parke, Davis & Company for it was there, in Product Devel- opment, that I experienced firsthand the `true meaning of quality in a medicinal product. The philosophy of quality control of pharmaceutical products h~is changed a great deal since its inception in the late nineteenth century. There is often a tendency to associate the quality control of drugs with enactment of the first Food and Drug laws in 1906. This, however, is not thecase. Quality control was practiced by certain pharmacutical manufacturers before this law came into being and long before the term "quality control" was used to express the idea. For example, prior to about 1880, there were no standard tests applied to a medh~inai product. Compendia were primarily concerned with methods of prep- aration; recipe books, rather than books of standards. The first standardized pharmaceutical product was controlled by a determina- tion of the total amount of alkaloids present in various preparations. Subsequent PAGENO="0092" 2226 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY lots of the finished product were adjusted according to this specification; a crude method, indeed, in the light of present-day procedures. In the figid of control of the quality of medicinal products, it can be likened to the first Wright brothers' flight as compared to present-day aviation. Shortly thereafter, manufacturers of lesser quality products were forced, through the exercise of freedom of choice available to the prescribing physician to market standardized preparations. This, then, was the beginning of quality control. Quality control is not a term that is exclusive to the pharmaceutical industry. Most major industries maintain extensive quality control departments. Their philosophy of quality control, however, is often based on one-hundred percent inspection of the finished product. Inspection of every finished pharmaceutical product is not only impractical. but does not guarantee quality. Analysis is helpful, but cannot be done on all units of the product because it is destructive in nature and, of course, a one- hundred percent analysis would leave no product to administer to the patient. Therefore, since inspection and analysis cannot alone assure quality in a product, a new approach to checking quality w-as born, the concept of control rather than analysis. Control of the quality of a medicinal product `is based on preventive measures. That is, the establishment of control procedures, methods, and systems involving all the components, the methods of manufacture, and the package and labeling of a product. These measures reduce or prevent errors or defects from entering into product, and thereby assures its quality. Because of the advent of more and more complex pharmaceutical products with their diversified physiological actions, there has arisen a new concept in the realm of quality control-the theory and practice of "total quality control" as stated in the Principles `of Total Quality Control recently adopted by the Pharmaceutical Manufacturers Association. A copy of this statement is attached as Exhibit A for inclusion in the record. Guided by these principles, the function of the quality control division of a pharmaceutical company is to coordinate, integrate, and. provide an atmosphere within the company for total quality control. The term "quality" in a medicinal product can be defined as the assurance of safety, efficacy, and acceptability for the intended function of the product. The product must be safe when used according to directions for the indications recommended. In other words, when the product is administered according to the directions on the labeling, using the recommended dosage, observing the cautions cited, and monitored by medical experts when needed, the product is considered to be safe within the framework of medical judgment. The product must also be effective. It must do the job according to the claims which are made for it. The efficacy of a product must be determined prior to the time of submission of a new drug application. The monitoring process, however, does not stop there. One aspect of total quality control requires that the effectiveness of a marketed product be under continuous surveillance. This is especially true in the area of `individual patient responses, variations and tolerances, drug interaction, and long-term product stability. The product must of course be acceptable. This refers, among other things, to the selection of the product form, such as a tablet, capsule or ampoule, etc. Packaging is also important. The package must preserve and protect, `the product, be clearly and accurately labeled, and be convenient to the physician and patient. Mr. Chairman, now that we have briefly defined safety, efficacy, and accept- ability, I would like to consider `how these goals may be achieved in each product, batch after batch. We feel the first step of building quality into a product begins in the research or design phase. Design Phase (Please refer to Addendum I) It is in research that quality is designed into the product. As indicated by my associates, a new drug substance is first studied exxtensively in animals to establish toxicity, safety, and pharmacological activity. Chemists, bacteriologists, biologists, and pharmacists then design various dosage forms for the product. They establish standards of purity, methods of preparation, formulas, analytical specifications and collect stability data. In general, they find out all they can about the product prior to initiating clinical investigation studies concerning safety and efficacy in human subjects. PAGENO="0093" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2227 Finally, thousands of individual clinical tests are performed. Patient records obtained from these tests are painstakingly kept and analyzed and a summary of the studies is written. These investigations form the basis for a new drug application. The final labeling of the product is, of course, based on the results of the clinical trials. After establishing the safety and efficacy of the product, the design phase of building quality into the product is complete. Conformance Phase (Please refer to Addendum II) Now that a product exists, it must be manufactured in a way that duplicates the design phase of total quality control. This is called the conformance phase. This is the area in which the production, purchasing and quality control divi- sions of a pharmaceutical firm are most vitally involved. There are many systems by which pharmaceutical manufacturers can control their product during the conformance phase. I would like now to illustrate one of them. It starts by preparing an elaborate set of specifications for all the components that make up a product. These specifications include methods for determining the identity, purity, strength, physical characteristics, uniformity, quality, and many other param- eters, depending upon the requirements expected of the raw material. Package specifications and control procedures are also provided for such items as glass containers, bottle closurers, cap liners, filters, and even the glue used for labels. If the material is to be purchased, the purchasing agent is provided with a set of these specifications. Suppliers are selected on their ability to produce and deliver quality material. Quality control personnel often visit the suppliers, firsthand, to verify whether or not confidence can be placed in them. When the material from the supplier arrives in the plant, it receives an identifiying number. This number is never duplicated. The incoming raw material is then quarantined until it is sampled, inspected, tested, and approved according to the established specifications. Labeling the material also undergoes rigid inspection techniques. (Please see Addendum III) Samples of the labeling to be ordered are proofread by at least two qualified people before they are sent for printing. All labeling material received is 100% inspected for proper identity, lot number, and all regulatory requirements. The labeling material is counted and inspected by both quality control personnel and the label storekeeper. The labeling material is then stored in a secure manner to prevent any label mixups. All raw material must be approved by the quality control division before it is allowed to enter a product. The next step is control of the manufacturing, process. (Please refer to Ad- denda IV and V) Some of these points have already been covered by Mr. Blazey in his submis- sion for the record. The manufacturing process is very carefully detailed on manfacturing process cards. These cards are precisely controlled by a manufacturing identity number which is assigned to each batch production record. The entire history of a product, per batch, can be traced through a numbering system. The particular lot or batch number of every component and manufacturing aid involved in the production of a product must be traceable from the lot number on the final package. The quality control approved raw materials, clearly labeled, are then accu- rately weighed and checked for identity and accuracy of measurement by at least two qualified individuals at each dispensing step. The identification num- bers of the materials dispensed are recorded on the batch production card. All materials forwarded to a production department are very carefully labeled and quarantined by a system of control records. Upon arrival in the manufacturing department, the materials are checked for identity by at least two qualified persons. All material is then checked again for identity and quantity and verified by a qualified production control checker before it is allowed to be added to the product. PAGENO="0094" 2228 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The materials are then combined in the processing operation according to the specific instructions on the batch production card. During the manufacturing operation, each individual manufacturing process step is checked and endorsed by at least two individuals and their signatures entered on the batch production record. In-process product and equipment checks and verifications are made and re- corded during the processing operation, and production and control procedures are rigidly followed. Intermediate granulations or mixtures are often tested for homogeneity. The finished granulation or mixture is sampled, tested, analyzed, inspected, and the yield variation limits determined by the quality control division. Approval by quality control is given only when all the predetermined speci- fications and standards are met, and the records are complete. The approved blended powder mixture is now ready for further processing, such as into a tablet or capsule. The mixture is now carefully filled into its dosage form. The product is in- spected and tested to confirm the uniformity of composition of the active ingredients. After processing into a final dosage form, chemical analysis and identity tests are performed by the quality control divisions to reaffirm the quantity, quality, and uniformity of the product. Many firms identify their products by the use of an identity code written or stamped on each tablet or capsule. This aids the physician in identifying the medication being taken by their patients. It is also an aid in identifying the product as it proceeds through the manufacturing process. The quality control division will approve the bulic product (capsules, tablets, etc.) for further processing if the results of the testing, the final yield verifica- tion, the documentation, and the control procedures have all been properly carried out according to the established product specifications and standards. When an approved bulk medicinal product exists, the proper container, the cor- rect labeling, and the packaging materials are joined together to produce a finished product. Each of these items, along with their identifying numbers, are recorded on the finishing record. (Please refer to Addendum VII). Many checks, reconciliations, and identifications are made to control the fin- ishing operations. Included are the following: (1) A thorough cleaning and checking of the packaging line before the start of the operation. (2) A check of the identity, quantity and quality of the packaging material and labels. (3) In-process testing and control procedures on the product. (4) Complete label reconciliation and a physical evaluation of the final product. Finally, after all balances and reconciliations are made, product yield varia- tions determined, and all required government approvals are obtained, the product is given final approval by the quality control division. A reserve sample is removed and stored within the quality control division for reference. All the control documents pertaining to the batch are then filed in the quality control division. Now the product is ready for distribution. (Please refer to Addendum VII). Total quality control of a product does not stop here. A system of controlling the storage of the product in the warehouse, and also periodic inspections of the product of the pharmacy shelf, further assure its quality when it is dispensed to the patient. It is important to remember that the purpose of the conformance phase of total quality control is to duplicate exactly the product produced during the design phase. This does not jnst mean that each batch or lot of product should have the same physical and chemical characteristics as another batch or lot. It is far more important that each tablet, capsule or pill must perform both physi- ologically and pharmacologically in exactly the same manner. It is inconceivable to assume that merely analyzing a product for potency and purity will assure its quality. At this time, I would like to differentiate between the terms "analysis" and "control". Analysis is predicated on meeting minimum requirements after a product is manufactured. No degree of testing or analysis can change the quality aspects of the product after it is manufactured. PAGENO="0095" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2229 For example, in the case of a capsule ifiled with defects, it is obvious we can- not eliminate these defects by analyzing the final product. A surprisingly large number of individuals still regard analysis as the only basis for establishing and maintaining quality. Testing by official methods after the product is produced and after most products are in commercial distribution offers inadequate assurance of quality. Total quality control on the other hand uses analysis or testing only as a check to make sure that the manufacturing processes have been properly controlled. Testing merely indicates, in part, that minimum legal or other requirements have been satisfied. Testing does not show maximum levels of quality. What are these minimum requirements. They are the tests and requirements as set forth in the USP, NF, and FDA antibiotic certification regulations. It is important to note that industry considers the DSP, NF, and FDA anti- biotic regulations as essential and the tests and standards contained in them to be the strongest in the world. However, we must realize that these standards are not all-inclusive, and by no means should they be the sole basis for judging whether a product is suitable for use by a patient. Analysis of a product and adherence to the standards established by the official compendia does not mean that two products containing the same active ingredi- ent will necessarily perform the same way in the body. Unfortunately, technology has not yet provided adequate laboratory tests to assure the pyhsiological equivalence of drug products. Therefore, the gap must be filled with a complete program of strict adherence to the total quality control concept. As we started earlier, quality must be built into a product during its develop- mental stage. This must be followed by strict adherence to a system which assures that the quality which is built into a product will remain when it reaches the consumer. This is the ultimate goal of total quality control. An understanding of this inadequacy of official tests and standards to control a product completely can be best demonstrated by specific examples. One of the basic problems involved in relying strictly on chemical tests to ascertain the therapeutic equivalency of a drug is the nonspecificity of some of the tests. Many of the official monographs for the final dosage form Qf a drug utilize tests which detect a group or chemical class of drugs rather than a par- ticular molecular arrangement of the drug. The logical question evoked from this discussion is-why not develop new and more specific tests? Well, this is being done. The ethical pharmaceutical industry in conjunction with the official compendia and academic research laboratories is constantly looking for newer and better chemical and biological tests. However, `this is a slow and tedious job, requiring years, or even decades of work. Another example of the limitations of official standards can be seen in the latest revision of the United States Pharmacopeia. A statement in the general notices section reads as follows: "Variations in composition are undesirable and substantial differences in the content of active ingredients between individual capsules, tablets, and other dosage units are to be avoided." Yet, until just recently, most of the official monographs in the United States Pharniacopeia and National Formulary did not require tests to assure the uni- formity of composition of each dosage form. What does this mean? It means that some unit of a product could have 150 percent of label claim, others 50 percent of label claim, while still others may have no active ingredients present at all. The reason for this was that the assay required only that the average of a number of units fall within a range, for example, of 90 to 110 percent of label claim. Consequently, the product, though defective, would pass the official requirement. Another example is illustrated by the lack of standards established for the particle size of a drug substance. One of the big fallacies of the theory of "drug product equivalency" can be illustrated by the following example. Let me start by saying that the result of an assay of a product does not necessarily mean that the determined amount of active ingredients will be available to the patient upon ingestion. Thus, potency and purity of a product are not the only important characteristics of the quality PAGENO="0096" 2230 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of a drug. There are many other important factors involved, such as the method of granulation or mixing the drug, the choice of inert ingredients used in combi- nation with the active ingredient, and the product design which prevents impuri- ties and defects from entering into the final product. All the above factors may influence the final availability of the active ingredients to the patient. Physiological availability is, therefore, on essential quality characteristic that is not spelled out in any existing book of standards. Specific examples can be pointed out which substantiate the contention that adherence to official standards does not guarantee clinical efficacy. In testimony delivered earlier before this Committee by Congressman Dur- ward Hall, reference was made to a Department of Defense experience with a drug of "supposed generic equivalency". The drug mentioned was diphenyihydantoill which is used in the treatment of epilepsy. The Government had purchased at least three lots from three different producers other than Parke, Davis & Company. Documented com- plaints ensued from various military hospitals concerning the serious side effects elicited by patients taking the drug. Congressman Hall quoted a letter from the Chief Neurologist of one of the hospitals who recommended that: "It has been my experience that patient response is significantly more erratic with diphenylhydafltOifl supplied by other than Park-Davis. Therefore, all further procurements of this drug should be made from Park-Davis." Our product is now being procured by the Defense Supply Agency. This difference in therapeutic effect between supposedly equivalent products is one of the reasons which led the military medical procurement agency of the Defense Department to require clinical testing data on the physiologic and pharmacologic efficacy of products offered for contract. I believe that this testimony corroborates the stand we have taken. The firm I work for, Parke, Davis & Company, developed diphenylhydantoin, and through its many years of experience has been able to control the variables that are inherent in the production of this complex and useful medicine. The FDA in the "1966 Drug Potency Study" announced in a published list that Parke-Davis' Thyroid Tablets were assayed and did not fall within the United State Pharmaeopeia standard range. The company was deeply concerned, and since FDA did not at first disclose the particular lot number of thyroid sample tested, it was of even greater concern. However, through inquiries, the company was finally able to ascertain the 1~t number of the thyroid tablets that were tested by the Food and Drug Administration. As it turned out, the lot of thyroid tablets tested by the Food and Drug Administration was not the company's USP Thyroid Tablets, but rather was their Thyroid Strong Tablets, a product that is labeled to contain 11/2 times the USP potency. The particular sample of thyroid tablets, tested by the FDA was indeed within our labeled potency range. A letter of apology from the FDA was later sent to the company. Another example of failure of analysis in controlling the quality of medicinal preparations can be illustrated by the recall of a lot of tetracycline syrup distributed by a number of generic manufacturers a few years ago. Tetracycline, as you know, is an antibiotic and subjected to batch~by~batch testing and certification by the Food and Drug Administration. The recall of the tetracycline suspension involved a problem of subpotency. The question that arises here is-was the test performed by the Food and Drug Administration on the sample before distribution adequate to determine this lack of stability? On the other hand, if the product was potent when it left the manufacturer's plant, why did the product lose its potency in less than one year after distribution. The minimum shelfiife of this product, as established by regulation, is 18 months. Analysis at the time of manufacture, therefore, cannot assure that a product will be stable or retain its labeled and tested potency for an extended length of time. This is another important point which a total quality control program con- tains. Total quality control manufacturers test and study their products to determine the length of time that their products can be assured to maintain the labeled potency. PAGENO="0097" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2231 Ethical pharmaceutical manufacturers perform definitive stability studies of their products. Not only are they studied in a total quality control system during developmental research and manufacture, but also subsequent to distribution. Recently, Parke, Davis & Company initiated a study to compare a product originated by the company with several products containing the same active ingredient now available from other firms by nonproprietary and brand names. This study was undertaken to determine whether there are any significant differences between these products and the Parke-Davis product. Preliminary information on this study, available at the writing of this statement, indicates that differences were found between products in commercial distribution. More details on the study will be available shortly. They will be submitted as soon as they are received. The company which has developed a drug product knows it intimately and is continually learning and studying new information concerning it. Its systems of manufacture and quality control are designed to meet the' particular needs or requirements of the specific product. All the control procedures that are needed in duplicating the product as determined during the research phase are rigidly followed. These methods of control are what make the' drug clinically effective, batch after batch. In summary, Mr. Chairman, analysis has its limitations. There are many factors that can produce errors, and therefore, can produce varying results. Analysis of a drug product is useful, and in most cases essential, but it should only be used as a guideline in determining if the controls established for the manufacturing and the packaging operations are sufficient to insure the quality of the product. Analysis alone is insufficient to assure quality. Thus, a rigid program of totally controlling all the steps involved in producing a final product is the only way a manufacturer can assure the clinical effectiveness of his drugs. GENERAL PRINCIPLES OF TOTAL CONTROL OF QUALITY IN THE DRUG INDUSTRY (As approved by P.M.A. Board of Directors on June 22, 1967) INTRODUCTION AND DEFINITIONS The quality of a product is its degree of possession of those characteristics designed and manufactured into it which contribute to the performance of an intended function when the product is used as directed. The quality of medicinal and related products is the sum of all factors which contribute directly or indi- rectly to the safety, effectiveness, and acceptability of the product. Quality must be built into the product during research, development, and production. Total control of quality as it applies to the drug industry is the organized effort within an entire establishment to design, produce, maintain, and assure the specified quality in each unit of product distributed. The effort should not only establish specifications for product acceptance but should provide procedures and methods for achieving conformance with such specifications. The large variety of substances used in this industry, the complexity of its products, and the various types of company organization make it impossible to de- sign in detail a single universally applicable system for the total control of quality. OBJECTIVES The ultimate objective of a program for the total control of quality in a drug company is the attainment of perfection in meeting specifications for a product of high quality. It is a program designed to assure the professional user or ulti- mate consumer that every lot of a product conforms to specifications and that each dose distributed will fulfill the representationsmade in the labeling and will meet all legal requirements and such additional standards as the management of a firm may adopt. 81-280 O-68-pt. 6-T PAGENO="0098" 2232 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ADMINISTRATION Total control of quality is a plant-wide activity and represents the aggregate responsibility of all segments of a company. The responsibility for auditing the control system and for evaluating product quality is that of a specific group re- ferred to in this statement as Quality Control. A basic principle in the control of quality is that a production group should not have sole responsibility for final approval of products for distribution. The head of Quality Control should have the authority to release satisfactory lots of products, to reject unsuitable lots, and to recommend the recall from distribution of any lots subsequently found to be un- suitable. He should be responsible to a level of management which enables him to exercise independent judgment. His responsibilities and authority should be clearly defined by management. BASIC CONSIDERATIONS IN A TOTAL QUALITY CONTROL SYSTEM A system for the total control of quality should be designed to provide proper personnel, product design, specifications and procedures, facilities and equipment, materials, and records. Provision should be made for the audit, evaluation, main- tenance, and revision of the system. The failure of any component is cause for review of the reliability of the system. I. Personnel: Individuals involved in the research, development, engineering, production, and control of any medicinal and related product markedly influence its ultimate quality. These people should be competent in their respective fields of endeavor by reason of academic training, experience, or on-the-job training. Total control of quality can be achieved consistently only through quality-mind- edness in each employee and an understanding among all personnel of the part their performance contributes toward product quality. II. Product Design: The quality of a product must be built into it during re- search, clinical evaluation, development, and engineering. The formulation, the method of manufacture, the tests, the choice of materials, and the packaging and labeling should impart to the product or describe the desired quality character- istics. Effective quality control calls for a continuing quality evaluation and im- provement program. III. Specifications and Procedures: Specifications should state clearly the de- sired characteristics and acceptable tolerances for all raw materials, interme- diates, packaging supplies, labeling, and finished packaged products. Procedures should clearly state the necessary steps to evaluate sources, to obtain, receive, test, and accept purchased materials; to produce, store, test, and handle inter- mediates and products; to provide for checks and audits and such other functions that are necessary to assure products of the desired quality. Specifications and procedures should be recorded and dated to clearly designate the period of their use. IV. Facilities and Equipment: Facilities, buildings, and equipment for manu- facturing, testing, and storage should be of such design, size, and construction as to assure the desired quality characteristics of each product. Construction of facilities and equipment should take into account such considerations as ease of cleaning and maintenance and proper location in relation to surroundings in order to help avoid contamination or mix-ups. T7. Materials: Materials used in the manufacture of a product including raw materials, intermediates, packaging supplies, and labeling should be of a level of quality to assure that the final product meets specifications. The method of evaluation of quality characteristics in a material, including identification, sampling, testing, stability, and use in a particular manufacturing operation, should be predicated on the product's intended use and should be sufficient to assure conformance to specifications. VI. Records: The key element by which administrative control of each lot of product is maintained is the control numbering system and related docu- mentation. This is a system of identifying each product lot and includes marking of each distributed package of the manufactured lot so that the manufacturer can establish the history of the package and its contents, the source of each ingredient, the records of tests made on ingredients as well as on the final product, and the identity of the individual responsible for each of the steps in PAGENO="0099" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2233 the manufacturing process and the individual who checked each key step. Such control numbers and documentation should also relate to records of the packag- ing operations and the final audit for the total number of packages produced. The control number and documentation also provide a means to facilitate recalls, if necessary. ADDENDUM In the application of these general principles, consideration should be given, but not necessarily limited, to all of the items mentioned in the P.M.A. State- ment on Control of Quality dated May 3, 1961, which are listed below. 1. Buildings for manufacturing, testing, and storage operations are of ade- quate design, size and construction to: (a) provide for proper receipt and storage of raw materials. (b) allow proper segregation and identification of material during manu- facturing and packaging. (c) provide for ease in maintaining cleanliness and for avoiding contamination. (d) provide suitable sampling facilities. (e) provide adequate laboratory facilities. (f) provide proper storage for final products. 2. Equipment is: (a) properly located. (b) adequate for the required operations. (c) constructed to facilitate cleaning. (d) properly maintained. 3. Raw materials are controlled by: (a) establishment of suitable specifications. (b) development of adequate test procedures. (c) specific identification markings. (d) proper storage conditions. (e) adequate sampling. (f) appropriate testing. (g) requiring compliance with specifications. (h) providing for Quality Control release. (i) maintaining records and samples whenever appropriate. 4. Manufacturing operations are controlled by: (a) use of a suitable batch numbering system. (b) preparation of formula or batch records. (c) checking of ingedients; identity, weight and measure. (d) maintaining identity during processing. (e) checking quality during processing. (f) checking yield against theory. (g) adequate sampling and testing. (h) requiring compliance with specifications. (i) maintaining appropriate records and samples. 5. Packaging and finishing are controlled by: (a) establishment of specifications fOr packaging and packaging operations. (b) a formal procedure providing for the inspection *and issuance of packaging materials including labels and labeling. (c) providing for the proper disposition of unused label's and labeling. (d) use of suitable batch, lot or control numbers. (e) maintaining identity of product before and during packaging. (f) checking yield against theory. (g) sampling and checking for compliance with specifications. (h) providing for release `by Quality Oontrol. (i) maintaining `appropriate records and samples. 6. Finished stock quality in maintained by: (a) providing proper storage conditions. (b) collection and review of stability data. (c) investigation of all significant complaints concerning quality of products. (d) providing for the disposition of returned goods. PAGENO="0100" 2234 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DESIGN PHASE RESEARCH ORGANIC I ANTIBIOTIC BIOLOGICAL :1-IEMINTRY BIOCHEMISTRY I.IFECTIONS DISEASEA LABORATORY ~] LABORATORY CHEMICAL COHPQUNO5 E~MPOV~HQ5 IEA!WTIOMO. IMMUNIZING TOXICOLOG'i~1 L K _______ I ~ Li~ ~ _______ [~HLITY CO~i~j~] DEPARTMENT L!~!~Es _ PACKAGING MATERIAL QUARANTINE I ANULYTICA LABOR ADDENDUM I PRODIJCT ION PLANNING DEPARTMENT ADDENDUM II I QUALITY CONTROL NEW DRUG APPLICATION DEPT. ~i~TORY DEPARTMENT I L~ONTROL CONFORMANCE PHASE CONTROL OF INCOMING RAW MATERIALS TA NA TA C TORE PARC HA S INO DIVISION MANUFACTURER SUPPLIER S ~u~v CONTROL DEPARTMENT SUPPLIER K MANUFACTURER RECEIVING DEPT _____________________ RAW MATERIAL I ~~LIMAD~4 !t~.4PACKAOINGMATERIAL~ EL= PACKAGING STORES ovA~Ij [PRuNN~J L 1EGTI~l _______________ TORT RESERVE SAMPLE GIIIRED JORAGE GECTION CHEMICAL APPROVED RAW MATFRIAI RTOOAOF PAGENO="0101" 0 0 1~ 0 ~ 1~~ C7'1 ~fl C_o >IP V'1 0 LTj LTj 0 n~ LTj m r gm t'~. 0 I-I 4 ~ I z C PAGENO="0102" 0 1 -1 00 `~1 "I m P1 0 cPu ç~u' jfl 0 tn tn 0 tn 02 r:12 8 I z < PAGENO="0103" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2237 ADDENDUMVH COtJFORMAt'JCE PI-1ASE OUT- OF-PLAP~JT COK~TROL3 Senator NELSON. Dr. Slesser is the next witness, I understand. STATEMENT OF A. E. SLESSER, PH. D., ASSOCIATE DIRECTOR OF QUALITY CONTROL, &MITH KLINE & FRENCH LABORATORIES; ACCOMPANIED BY LLOYD N. CUTLER,' SPECIAL COUNSEL, PHAR- MACEUTICAL MANUPACTURERS ASSOCIATION, WASHINGTON, D.C. Dr. SLESSER. Mr. `Chairman, if it is satisfactory with you and the members of the subcommittee, I would like, in the interest `of saving time, to read a brief statement summary.', I had submitted to you in the fall a `statement for the record as of November 6. I certainly will entertain questions on that statement should you wish to ask them. On the other hand, this is a brief summary which is an excerpt, really, from that statement submitted earlier. I will be very happy to tell you what portion of the statement this relates to as I go along, if that is satisfactory to you. Senator NELSON. I want to do whatever will speed the hearing be- cause I know you were inconvenienced the' last time when we did not get through our agenda. I have promised Mr. Stetler that we would get through today. How long is your summary, how many pages? Dr. SLE5SER. About 10 or at the most, 20 minutes. Senator NELSON. Let's try it. Ordinarily that procedure does not shorten testimony, because I have to go back to the original testimony which I have marked and repeat portions of it, but I will try. PAGENO="0104" 2238 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. SLESSER. Mr. Chairman, first of all, I would like to express my appreciation for your permitting me to appear and giving me the opportunity to supplement Mr. Stetler's statement on the matter of therapeutic equivalency of drug products. Through my activities in the pharmaceutical industry, I know something about the factors that can affect drug performance. Senator NELSON. We will print in the record Dr. Slesser's full statement. Are we talking about the statement that is called supplementary? Dr. SLESSER. Mr. Chairman, I did not have one that says supple- mental testimony before the subcommittee. I think the original one had the wrong caption as far as committee identification is concerned. Mr. CUTLER. That was when he was going to supplement Mr. Stet- ler's. That is his original statement. Senator NELSON. What are we dealing with, then? Is this the one he is making an abbreviated statement on? Dr. SLESSER. Yes. I am trying to find a spare copy for you. Senator NELSON. I would ask that that statement be printed in full in the record. Then we will take his summary statement and we will ask questions. If you have a copy of the summary, I can probably follow you more easily.' Dr. SLESSER. I do have a copy of this brief summary, Mr. Chair- man, which I do not believe you have, which we will find very shortly. Senator NELSON. Go ahead while they are finding it. Dr. SLESSER. Control of the quality of the medicinals prepared from today's drugs is a complicated operation. It is simply wrong, in the light of the present state of the art and science of pharmaceutical manufacture and the inadequately manned FDA, to contend that all drug products of like generic name are equal. Even if we make the incorrect assumption that all manufacturers are capable of passing an FDA inspection, we are still in no sense out of the dilemma of therapeutic equivalence. There is the matter of conforming to USP or other standards. The question is not whether drug products should conform but whether each batch and each tablet, capsule and dose of every drug product does conform. The fact that standards exist and that companies put "lISP" or "NF" on drug labels does not establish that, in fact, the companies actually have adequate control procedures or that they fol- low them. In short, the real question is, do drug products conform to the standards they claim to meet? Now, I would like at this point to stress the fact that the lISP and the NF are indispensable compendia. There is no question about the importance of the standards that appear in these compendia. How- ever, this is only part of the story. Actually, the TJSP itself points out on page XVII that the problem of providing objective standards a.nd methods for lISP drug products to measure physiological avail- ability, which means the extent to which the active ingredient is taken up by the body in a useful form, "remains in the exploratory stage at this time" and adds, "Progress has been slow in developing such standards that would be suitable for U.S.P. use." 1 The complete prepared statement and attachments submitted by Dr. Slesser for pres- entation on Nov. 16, 1067, begins at p. 2271, Infra. PAGENO="0105" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2239 The NF, on page XLIII, echoes the essence of the TJSP state- ment under the caption "Therapeutic Authority Disclaimed," as follows: The inclusion of a drug in the N.F. is not iiltended as an endorsement of its therapeutic value. `Total quality control, Mr. Chairman, involves much more than any compendium can cover. Not too long ago, the chairman of the NF Committee of Revision, Dr. Edward G. Feldmann, discussed natural limitations of the compendia as follows-this is a direct quotation and we have copies here for you: Many people in pharmacy have the mistaken notion that if a product meets all the specific tests and requirements detailed for that article in the DSP. or N.F. monograph, then that particular product has to be perfectly satisfactory. The word "has" was italicized. To continue with the quotation: While I wish this were true, I am sorry to say it is not and the nature of the problem is such that we can never hope to develop compendia monographs which wifi give complete assurance of any product's absolute suitability. The detailed specifications that are needed to produce a quality drug product under good control procedures are so extensive and so all- encompassing as to defy inclusion in compendia of any sort. Quality control measures, records, and reports used in leading drug firms for each batch of even the simplest drug product are massive. These begin with the raw materials and end with the consumption of the product. Details of the manufacturing and control procedures utilized for only a few products of a capable manufacturer would constitute a book in itself. We all know that safety and effectiveness of a drug product are determined by well-designed, properly controlled and correctly ex- ecuted clinical tests. Such tests are run by the manufacturer on one, sometimes two, rarely on more than two batches of the product. Now, having proved the safety and effectiveness of the product, we must ask ourselves this question: To what factors are the product's safety and effectiveness due? For an answer to that question an~ an explana- tion of how quality control functions, I would like for this subcom- mittee to take a look at a chart; that I have prepared for this purpose. Before `doing this, however, let me state, Mr. Chairman, that con- trarv to common belief, the drug component in most tablet products comprises less than 10 percent of the makeup of the tablet and that the number of components other than the drug itself may vary from two or three to as many as 20 or more. I mention this because this should be taken into consideration when we are talking about a drug versus a drug product, which is the form of the drug which is marketed and administered to the patient. This is the area in which the effect of know-how or lack of know-how can be demonstrated in a very im- portant fashion. Senator NELSON. You just quoted Dr. Feldmann. In part 1 of these hearings of the Subcommittee on Monopoly of the Select Committee on Small Business, I quote from Dr. Feldmann: A good quality control system will minimize the differences between batches of the same drug product. The official compendia standards are designed to en- able the testing of the final product to ascertain that a given lot of a drug PAGENO="0106" 2240 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY product meets the appropriate criteria of identity, purity, quality and strength. Compliance with these standards constitutes generally reliable presumptive evi- dence that such a drug product will be clinically effective and safe. Clinically effective and safe. So I think Dr. Feldmann is saying the same thing about t.he issue with which we have been in dispute with the drug companies. If drugs meet the USP standards, it is presumed they will be clinically safe. That is the heart of the issue on which we differ, but a substantial body of authority in this country does agree with Dr. Feldmann's presumption. Dr. SLESSER. Dr. Feldmann presumes this to be true and certainly he has a right to make this presumption. I think the body of scientific evidence would take issue w~ith this presumption and I hope to bring that out more thoroughly as I proceed with the balance of my statement. Senator NELSON. I just wanted Dr. Feldmann's statement in the record in proper juxtaposition. That is a rollca.ll. Do you have any objection if Mr. Gordon sits and listens while you present your statement, or do you want to wait until I get back? Dr. SLESSER. I would be happy to wait. Senator NELSON. I have read your testimony so I know what is in it, and I have a few questions on it. I will do whatever you prefer. Dr. SLESSER. I prefer to wait. Mr. CUTLER. If it is just as short as the others, Mr. Chairman, why not wait? (Short recess.) Senator NELSON. The hearing will resume. Dr. Slesser, go ahead. Dr. SLESSER. Thank you, Mr. Chairman. Senator NELSON. It appears we will have a continuous series of rollcalls. So I guess we had better move along. Dr. SLESSER. That is perfectly all right. Senator NELSON. Is that going to be part of an exhibit you have in your testimony? Dr. SLESSER. Yes. Senator NELSON. When you get to it identify it for the record. Dr. SLESSER. This is chart No. 3, Mr. Chairman.1 Now, I think that a brief, a very brief presentation on how clinical effectiveness is established is probably worth while before going into the rest of the chart. The capable innovator manufacturer will make sure that for the research and development formula, the pilot, formula, or formulas, that all tests necessary are run to prove safety and effectiveness. The only way in which this can be done, of course, is by chnical triais on human subjects. So that sa.fety and effectiveness have been established by clinical tests on t.his particular product. Now, I think a great deal of misunderstanding about the sigrnfi- ca.nce of laboratory testing lies in this particular fact. It is presumed that-I am using tablets as an example, but they do 1 Charts 1, 2, and 3 appear as attachments to Dr. Slesser's prepared statement of Nov. 16, 1967, and begin at p. 2275, infra. PAGENO="0107" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2241 not constitute the only type of dosage form by any means-it could apply to any pharmaceutical product. It is presumed that by applying laboratory tests, whether they are USP, NF, or any other authority, tO a certain number of tablets from a batch, or to a certain number of bottles in a shipment of a batch, without knowing anything else, one can then, depending on the results of these analyses, state unequivocally that this product does have safety and effectiveness. Now, I hope to show wherein the fallacy of this line of reasoning lies. Quality control, Mr. Chairman, makes sure that what comes out here as a finished batch is a duplicate, insofar as safety and effective- ness is concerned, of what was tested at this particular point. In other words, I am suggesting that quality control has to be viewed as a chain, that it cannot simply be viewed as beginning and ending in an analytical laboratory, or a testing laboratory wherein, unfortunately, many people believe is the beginning and end of quality control. So if I may, I would like to show the factors which are responsible for the safety and effectiveness as determined by clinical tests on the prototype formulas. First of all, the specific components, both the drug and nondrug. Now, you will notice that I underline "specific" in each case, be- cause this is very important. The drug itself, we know that such matters as the fineness of the particles of the drug-most drugs are crystals or powders-depending on particle size-you may get differences in the rate of absorption, as well as the magnitude. There are other physical factors that can enter into the behavior of the drug in a drug product. One of them is described as polymorph- ism, which is simply a difference in the crystalline structure. If you were to analyze such a drug by the formal chemical tests, Mr. Chairman, you could not differentiate polymorphic form A from polymorphic form B or polymorphic form C. Special types of tests are necessary, such as infrared spectrometry or X-ray diffraction- and there again is a fallacy in relying upon simple laboratory tests. And, of course, the significance of this is polymorphic form A, B, or C may very well show differences in physiological availability of the drug and the drug product. Now, the nondrug components. They are also important. The capa- ble, qualified manufacturer is just as interested in who supplies these components as he is in how they test in a laboratory. And he takes precautions to make sure that he deals only with capable, reputable vendors, with whom he has had a history of successful quality in the past. Specific specifications are set up for drug and nondrug components. Written directions for sampling each incoming shipment exist. These are updated and precautions taken to make sure they are followed. The ratio of the drug to the nondrug components, and of the non- drug components to one another is important. `Then we are talking about a specific formula. TJSP clearly indi- cates that the formulas and methods for manufacturing the dosage PAGENO="0108" 2242 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY forms which are official in the TJSP are not a function and cannot be-included in the monographs for the official products that are listed therein. So that with a given drug, a manufacturer who may use the same drug or active ingredient-but then varies in some other respect, and does not use the specific formula-could alter the safety and effectiveness of the resulting drug product. Specific manufacturing procedure-this is extremely important. A statement has been made that it does not matter-or there is a feeling that exists, that it does not matter how a drug is made as long as it meets standards. This is certainly not true of the pharmaceutical industry. The pharmaceutical industry knows from experience, and the FDA knows, too, that you cannot rely upon the doctrine' I don't care what the kitchen looks like, as long as the soup tastes good. This is not at all valid, and there is a very definite relationship between the kitchen and how it looks-namely the pharmaceutical plant, the capability of the people who work there, the facilities with which they work, the know-how, the physical plant itself, and the quality of the product. Now, throughout the course of every batch, specific in process tests, assays, checks, and inspections are done. Mr. Chairman, these number literally in the hundreds for each batch, and sometimes may number a thousand or more. And it is important that these be done because these are an import;ant part of the chain of quality control which will insure that on a batch-to-batch basis, every batch will be the same in safety and effectiveness a the initial batches which were tested in the clinic. And finally, other specific in-process controls-one function of which is to make sure that these other four links in the chain have actually been executed, have been effective, have been properly con- ducted. One function takes the form of a stack of finished reports of data., results of inspections, tests, analyses, and so forth, which for even a single batch may number a great many pieces of paper. They show the complete history of the manufacture of that batch. Now, once a knowledge of the control of all these things-these links in the chain-is known, then and only then do the laboratory tests have meaning, because if the batch has been made with the links of this chain under control and unbroken, then we know that the finished batch will meet all the USP or NF or other required tests. So what I am trying to say, Mr. Chairman, is that if this chain has actually been effectuated, and has been capably applied, then the finished batch will meet TJSP tests. However, I want to emphasize this-the reverse is not necessarily true. In the absence of knowledge that this chain was in fact operative, capably applied and so forth, laboratory tests to establish `that the finished batch or a sample of it is safe and effective may not be meaningful. Now, that is the crux of the basis for the concept of total quality control. Lest there be any misunderstanding that this is solely some- thing which the industry is trying to use as a smokescreen, I would like to quote Dr. Earl Meyers who for many years was in the new drug branch of the Food and Drug Administration-in a speech that he made before the American Pharmaceutical Association, at the fifth PAGENO="0109" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2243 annual Federal Service Pharmaceutical Seminar here in Washington, on November 10, last year-Dr. Meyers made this statement: It also becomes important to establish the reproducibility of the dosage form of a drug from batch to batch if the clinical studies are not to be biased by an unknown variable. He says: A break in the control procedure- This is specifically an endorsement of what I have just presented- A break in the control procedures may be just as disastrous as the occurrence of unexpected toxicity~ Then finally-and I quote directly from his talk- Evidence establishing the safety and effectiveness of one or more batches of a drug under investigation has no significance- What he means is a drug product- with respect to the safety of subsequent batches of the drug unless they can be shown to be the same as to identity, strength, quality, purity, with. the batches studied. Dr. Meyers, more recently in an appearance on November 28, at the APhA, Academy of Pharmaceutical Sèience-made this statement: The active ingredient in a dosage form of~ a drug is probably not the sole determinant of its pharmacological effectiveness. And Dr. Meyers also said that the physiological response may be a function of the formulations of the dosage as well as the active component. Here is a very significant comment from this very experienced man in the Food and Drug Administration: Regulations and guidance do not establish product quality. Assurance of prod- uct quality begins in exploratory research when the future product is nothing more than a gleam in the chemist's eye. Mr. Chairman, what I am trying to portray in this chart, and with additive comments, is that generic equivalency does not necessarily denote therapeutic equivalency. I am reading from page 7: The importance of particle form and size in antibiotics, like chior- amphenicol, and in sulfadiazine and the anti-fungal agents, comes to mind. Variability in response to different formulations of the blood anticoagulant tablet, bishydroxycoumarin, are so significant that the choice of manufacturer source is clearly as important as the choice of the agent itself. The fineness of the drug in the tablet and how well the drug particlu size is controlled by one manufacturing source `as com- pared to another may very well determine whether dangerous clotting is prevented or serious internal bleeding occurs after ingestion of the usual dose. There are many examples of this sort. Mr. Chairman, I have a notebook here which contains 211 refer- ences, which relate directly to this matter of pharmacological equiva- lency, to the science of biopharmaceutics, which seeks to explore the ways by which physical and chemical differences in the drug and nondrug components in drug products can affect the therapeutic safety and effectiveness of the drug products. Now, the question has been raised, or the statement has been made PAGENO="0110" 2244 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY or has been implied, that because there are 18 or 20 known instances of so-called generic equivalent products, those which meet specifica- tions by USP or NF which are not therapeutically equivalent, that that number is the full total that is known about-and that for this reason we are talking about a small percentage of the total drugs in use. I disagree with that wholeheartedly. I think ~the fact that there are 211 references, that are related to factors, which, can affect the therapeutic effectiveness and safety of products scientifically, shows that there are many more than 18. The only reason the 18 have been acknowledged is in retrospect, because they were so dramatically obvious that it was unmistakable to over- look them. I think this whole problem is more like an iceberg, where nine-tenths of it is below the surface. And I think we have only scratched the surface. To the extent that we study this problem in more detail, more in depth, I think we will find there will be a lot more than 18. Mr. GORDON. Dr. Slesser, I would like to ask you a couple of ques- tions. With regard to your 211 references of published literature on the effect of drug formulation on therapeutic activity-one, how many are duplicate studies, two, do they cover 211 different drugs? And, three, over how long a period of time were the studies published? Dr. SLESSER. They do not cover 211 different drugs. Mr. GORDoN. How many drugs are actually discussed? Dr. SLESSER. I do not know exactly how many are discussed. I am going to make this availeble to the committee, a copy of these refer- ences, if it has not already been available to the committee. But the interesting thing about it, Mr. Gordon, is that one cannot help but be impressed by the effect on the activity, therapeutic activity of a prod- uct by differences which are rather suibtle_-particle size, crystalline structure, PH, additive materials of various kinds, and so forth. And I would like to use this as an example. You very often hear a negative statement made. "We have not in our experience found that there was any difference between a series of, let's say, generically eciuivaient products when we have used them." Here is a hypothetical situation ~ihich I think-I think anyone familiar ~with medicine knows that there are patients who do not respond to certain drugs. The body builds up a tolerance, or there is a certain idiosyncrasy, and they fail to respond. Let's create a situation here. We have a patient who is seriously ill, and he needs a certain medica- tion. That medication is supplied to him. The patient dies. Now, I think without question the verdict would be-even though the death may be due to a failure in the quality of that product, its inability to perform as it should-I think more than likely the verdict would be the patient failed to respond to the drug. Here is a case where it would not even be recognized for what it is. And I am sure the fact that this can happen, that we have seen dramatic instances where it has happened, certainly is good inference that it is very likely to happen and will continue to happen. Mr. GORDON. I do not think my question has been answered. Dr. SLESSER. If you repeat it, I will be glad to answer it, sir. PAGENO="0111" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2245 Mr. GolmoN. Are any of these duplicate studies? How many drugs are involved? You said, I think, that there are not 211 drugs involved although you refer to 211 studies. Now, they may be concerned with only one, two, three, or four drugs. Dr. SLES5ER. No-they are concerned with a lot more than one, two, three, or four. I do not know the exact nun~ber. But I can tell you they are not duplicate studies. They may be on the same drug in some instances. There may be some on the same drug, yes. But exploring different facets of this particular drug. In other words, there will not be two that `have to do with the fineness of division of drug X let's say in a particular product. Mr. GORDON. But you do not know offhand how many drugs are actually covered in the 211 studies? Dr. SLESSER. I have not counted them. Do you know, Dr. Adams? Dr. ADAMS. Well over 25. Mr. GoimoN. Now, how many are based on clinically controlled double blind studies? Dr. SLESSER. I do not know the number, Mr. Gordon. I will state this. It is not always necessary to run a so-called double blind study. If you are comparing a drug-for example, in the type of study that Parke, Davis conducted on their Chloromycetin versus so-called generic equivalent c.hloramphen'icol products, this need not be done in a double blind fashion. Mr. GORDON. You do not know how many are based on controlled clinical double blind studies. Is that correct? Mr. CUTLER. Could Dr. Van Riper answer that question? Mr. Goimox. Surely-anybody. Dr. VAN RIPER. Mr. Chairman, the importance of a double blind study depends on the drug that you have irnder study. `One does not do a double blind study in a situation where he may `have a fatal illness, where you would be giving a `plactho, a blank. Now, in this particular instance-I am not familiar with these studies, but the possibility and the probability is that these are run as therapeutic eqruivalents~one drug is studied against another, in a blind method, whereby the clinician who is doing the study is not aware of whether he is giving drug A or drug B. But lie does know that both drugs under study are active. Mr. GORDON. I can understand that. But I `am asking aibout the 211 studies. Do you know how many of those are of the type you just mentioned? Dr. VAN RIPER. I do not. Mr. CUTLER. Mr. Chairman, could we offer these 211 studies for the record? They are all from published medical literature, as I under- stand it. And then they will speak for themselves. Senator NELSON. All right. Depending upon how much value we determine there would be in printing them in the record as such. But you let us have them and we will decide that.1 Mr. CUTLER. At least the references could be printed in the record. (Subsequent correspondence between Senator Nelson and Dr. Feld- mann re 211 studies follows:) 1 RetaIned in committee files. PAGENO="0112" 2246 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MAaoH 5, 1968. Dr. EDWARD FELDMANN, Director, National Fornvulary, Washington, D.C. DnAR Dx. FELDMAN: During your testimony on June 8, 1967 before the Senate Small Business Committee's Monopoly Subcommittee you stated that you "would be hard pressed to name more than even a few-less than five-well-conducted clinically acceptable studies which have demonstrated significant differences be- tween two or more products clinically where they have met all the chemical and physical standards as provided by the official compendia." On November 29, 1967 Dr. A. B. Slesser of Smfth, Kline and French submitted a notebook containing 211 references which, he stated, "are related to factors which can affect the therapeutic effectiveness and safety of products," and which show that there are many more than the small number of cases you, yourself, mentioned. Dr. Slesser, however, was unable to tell the Subcommittee how many different drugs were involved in the 211 references; whether they meet DSP or NP standards; or to describe the scientific quality of studies which he was supplying. To complete the record on this subject, I am taking the liberty of sending you the material which Dr. Slesser gave us, and I should be extremely grateful if you would examine its contents to ascertain how valid is the documentation for his position.' Your assistance is greatly appreciated. Sincerely, GAYLORD NELSON, Chairman, Monopoly $nbcommittee. THE NATIONAL FORMULARY, Wash~ington, D.C., March 13, 1968. Hon. GAYLORD NELSON, U.S. Senate, Washington, D.C. Dn&a SENATOR NELsON: This will reply to your letter dated March 5, 1968 rela- tive to the notebook or compilation of 211 literature references and reprints entitled "A Measure of the Volume and Content of the Literature Pertinent to the pertinence of its content to its subject title. In response to your request to me, I have examined this compilation and have evaluated it in a general way from the standpoint of its scientific character and the pertinence of its content to its subject title. The preface statement in this compilation describes the division of the material contained therein into five sections identified as items A through B. From my examination of these five se~tions, it is my conclusion that items B, C, D, and E are largely supplemental to the information provided in item A. This conclu- sion can be drawn from the fact that item B principally draws upon many of the same retferences as those listed in item A. Item C is a chapter from a textbook, and as such is based principally upon information drawn from the literature- again largely information covered under item A. Item D is an annual review of all areas of research for a specific year in the `broad field of the pharmaceutical sciences. As such, the articles in item D of pertinence to this compilation already have been listed under item A. Finally, item B is simply a listing of all periodicals and journals dealing with pharmacy which are published throughout the world. On this basis then, it appears that greatest attention should be devoted to a consideration of the scientific aspects and pertinence of the material appearing under item A. As noted in the preface to the compilation, item A consists of a listing of 211 articles (along with the abstracts relating to some of them, and along with photo- copies of certain of the other articles). A detailed and thorough examination of these articles would constitute an enormous undertaking. My review of this ma- terial has been limited to a general examination of the material as presented in this listing. From this general review and survey, I believe that the following conclusions can be validly drawn: 1 Retained in committee files. PAGENO="0113" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2247 1. The literature covered by this survey ("item A") is sufficiently broad to indicate that it represents a reasonably comprehensive review of the subject fie1d~ It is rather unlikely that any significant areas have been overlooked in assembling this compilation. 2. The periodicals and journals which are cited as references constitute recog- nized and respected publications in the medical, pharmaceutical, and related professional or scientific fields. As such, they are appropriate sources for the col- lection of information on the subject topic of the compilation. 3. Of the 211 references, the first group of 102 references-according to the preface statement-pertain to in vivo clinical observations, which is the subject of greatest interest to the question that the compilation attemps to answer. On this basis, the succeeding observations will be limited to references fro~n this first groiip of 102. However, it appears that this first group of references is quite analogous to the second group of references in all other respects, so that the same general observations could be validly drawn regarding the source of the information, the applicability of the studies, the scientific veracity of the con- clusions, etc. 4. The absence of either abstracts or reprint cOpies of a substantial number of the references cited makes it difficult to evaluate the conclusions or pertinency of such articles without consulting the original literature. Certain of the articles listed by title only appear to be of questionable pertinency to the topic of this compilatiOn; for example, references number 37 and 71. 5. A nun~ber of the references appear to pertain to isolated case histories or other types of casual observations which were not conducted in a scientific manner-nor were they intended to be. Such articles are equivalent to testi- monials and while interesting, are usually regarded as almost meaningless by trained scientists and experienced clinical investigators. A few examples of this type include references number 13,14, and 19. 6. A few of the references do not appear to be appropriate for inclusion in this listing since the titles and/or abstracts of the articles indicate that the study involved is concerned only with the pharmacology of the drug under examination and not in any way with dosage forms or matters of formulations; for example, reference number 35. 7. Somewhat along the same vein, certain references appear only to compare entirely different routes of administration of a drug rather than different dosage forms or formulations to be administered by the same route. It is obvious to all that a drug administered by injection will be physiologically available more promptly than virtually any oral dosage form. Examples in this category include references number 24,25, and 97. 8. Many of the studies compare entirely different types of oral dosage forms- for example, a drug in the form of tablets or capsules in contrast to the drug substance in some liquid dosage form such as an elixir of suspension. Selection of the optimum dosage form is important and unquestionably can have an effect on the therapeutic effectiveness of the drug involved. However, I am unaware of any suggestion or claim that "therapeutic equivalency" exists between completely different types of dosage forms. This is quite anOther matter from comparing the tablets made by one firm with the tablets made by another firm. Therefore, references of this nature do not seem appropriate for inclusion in this compila- tion on "generic equivalency"; some examples include references number 7, 10, 12, 89, and 98. 9. By the same token, certain drugs are pnrposelij formulated in a manner to provide slow or gradual release of the drug. Studies comparing such timed-re- lease or sustained-release preparations with drug products intended for regular drug release should not be included in this listing. Since such products are pur- posely intended to have different properties or characteristics of drug release, it does not seem appropriate or valid to include such references in this listing. It is implied that the listing consists of references demonstrating differences observed in drug products where no such differences were intended. Examples of some of the references which should be excluded on this basis are numbers 4, 21, 32, 48, 70, 76, 84, 85, and 90. 10. Many of the articles cited appear only to compare completely different compounds. It is quite `obvious that formation of a water-soluble salt of a water- insoluble organic compound will result in a new compound which is more 81-280 0-68-pt. 6-8 PAGENO="0114" 2248 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY readily soluble in aqueous body fluids. For this reason, different salts and esters are regarded by the FDA, the official compendia, and the scientific community as entirely different drugs, since in fact they are entirely different compounds. It is inappropriate, therefore, to include in this listing studies which principally ap- pear to compare different compounds rather than different formulations of the same drug entity. This would exclude, for example, references number 27, 30, 34, 41, 72, 73,80, 86, and 96. 11. Certain references appearing on the list are duplicative of others already included on the list. The duplicative references include editorials, review articles, and general statements which are based on studies already included in the listing. Consequently, inclusion of these latter references could be misleading since their presence suggests a larger number of original reports in the literature than ac- tuafly exists in fact. References in this category which appear to provide no new data include, for example, numbers 22, 26, 38, 45, 51, 53, 58, and 66. 12. Several of the references referred to appear to be inconclusive or border- line regarding the conclusions which are drawn as to existence or nonexistence of therapeutic equivalency. Such references include numbers 5 and 31. 13. A number of the references cited indicate that current standards are satis factory to assure quality drugs. See, for example, references number 57 and 65. 14. Several of the references listed appear to constitute articles in which the conclusions of the respective authors show that drug product variation was not demonstrated on the basis of the particular study reported. The references which appear to support therapeutic equivalency include numbers 61, 62, 63, and 77. Moreover, references 61 and 77 specifically refute other articles appearing on this list which apparently report clinical `differences among drug products. 15. None of the examples of questionable references listed in the above paragraphs are duplicative. Furthermore, in each instance the references cited above are just some examples chosen at random to illustrate each of my points; hence, additional references probably could be similarly disqualified if a closer scrutiny were made. Consequently, significant question exists concerning the pertinency or appropriateness of including a large proportion of the references tabulated. Moreover, it appears that a substantial portion of the rem'aining ref- erences may in fact support the idea of "therapeutic equivalency" of drug prod- ucts rather than refute it. 16. After eliminating the above~mentioned questionable, inappropriate or refuting references, a limited number of references still remain which appear valid as `documentation to demonstrate instances in which "therapeutic equiva- lency" may not exist. It should be noted, however, that these remaining refer- ences do not all pertain to studies on different drugs. In other words, some of them constitute confirmatory studies regarding certain drugs discussed in other reports on this list. Hence, while it is appropriate to include these confirmatory references in this listing, the number of drugs concerning which non-equivalency of some sort has `been observed is substantially less than the total number of ref- erences which remain after excluding the invalid or inappropriate reports. For example, references 18, 32, 42, 43, 49, and 67 `all pertain to enteric coated aspirin tablets. 17. Your letter to me dated March 5, 1968, quoted a statement by Dr. Slesser explaining that the compilation contained references which "~ * * are related to factors which can affect the therapeutic effectiveness and safety of products." After eliminating the inappropriate studies, some of the remaining references do appear to provide some support to Dr. Slesser's statement. It should be noted, however, that his statement ~ays that these considerations are "related to factors," and that the factors "can affect" effectiveness and safety. This broad generalization does not really answer the basic question implied during the Subcommittee hearings; namely, "Does the scientific literature reveal many studies showing that a significant clinical difference (effectiveness or safety) has been demonstrated in comparing two drug products which meet applicable official compendia standards ?" In conclusion, it appears from the above point-by-point evaluation, that this compilation actually supports and substantiates the testimony presented by me and a number of other w-itnesses during the hearings of the Senate Subcommittee on Monopoly during 1967. In my testimony before your Subcommittee on June S. 1967, I stated under conclusion number 6: "Information available in the published literature reveals only isolated ease histories, and very few scientifically performed studies, which demonstrate sub- PAGENO="0115" COMPETITIVE PROI3LEMS IN THE DRUG INDUSTRY 2249 stantial differences in `therapeutic equivalence' between two comparable drug products (also referred to as generic or brand equivalence). Consequently, while we must recognize that this factor exists, currently available evidence indicates that only very seldom is there a difference in clinical performance if the official compendia standards are met by both drug products." In subsequent testimony both FDA Commissioner Goddard and USP Director of Revision Miller, among others, also commented to the effect that differences do exist in the case of some drug products, but that there are relatively few documented cases in literature references,, indicating tha:t from a clinical stand- point this problem has been greatly exaggerated. In your March 5, 1968, letter to me you also quoted from my statement made to your Subcommittee that: "* * * I would be hard pressed to name more than a few-tess than five- well-conducted clinically acceptable studies which have demonstrated significant differences between two or more products clinically where they have met all the chemical and physical standards as provided by the official compendia." The references which remain after eliminating those that are inappropriate may include a few such studies, hut the number certainly does not exceed five and probably is even smaller than five. Consequently, it appears that the above-quoted statement from my testimony is actually confirmed by a review of the compilation of references which you supplied to me, and concerning which you requested my evaluation and opinion from a scientific viewpoint. Sincerely, EDWARD G. FELDMANN, Ph. D., Director. Mr. GORDON. How many of the drugs in the 211 studies you cited did not meet the required standards set for them by the TJSP or the National Formulary? Dr. SLE5SER. Mr. Gordon, I do not know the answer to that question. But let me state this. The existence of DSP or NF standards does not by any means assure that every product on the market will meet them. The fact of the matter is there are products on the market that do not meet U.S.P. and NF tests, and there probably are a great number of them. The evidence is certainly in that direction There are products that do meet the DSP and NF tests which do not function properly therapeutically. And these are covered, of course, either directly or indirectly by scientific literature in these 211 references. Senator NELSON. Do you know of any drugs on the market that do meet DSP standards or NF standards and do not function appro- priately therapeutically which are not on the list of the 14 or 15 to which Dr~ Miller and other witnesses testified? In other words, do you know of more than the 14 or 15 that are cited as exceptions by Dr. Miller and other pharmacologists and experts in the field? In other words, if you know of some that ought to be added to the list, we ought to have the DSP advise us about them, because they are not aware of any more than 15 or so. Dr. SLESSER. Senator, perhaps in this connection you might be in- terested in inviting to some future session of this committee-I do not know whether he will consider this as an honor or not-my recom- mending him, I am talking about-not appearing before this com- mittee-but `Capt. Solomon Pflag who is Chief of the Technical Oper- ations Division, Director of Medical Materiel, the Defense Supply Agency. In a talk he made on November 20, a little over a week ago- perhaps you are interested in what the military feels about this par- ticular point. Let me read very briefly from his talk. PAGENO="0116" 2250 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. I assume when we get to the area of Government procurement of drugs, we will hear testimony from the appropriate person from the Defense Supply Agency. Go ahead. Dr. Sr~asseit. This on page 10, Mr. Chairman. Twill read his direct words. In our quest for quality pharmaceuticals, we found that we had to go one step further- He is talking about a 10-step program which he described nine steps of, one of them involving laboratory testing- we had to go one step further to complete our ten point quality assurance pro- gram. Therefore, a few months ago the Department of Defense approved the concept of requiring proof of pharmacological equivalency. The literature is replete with studies of factors, both biological and physiological, chemical, influ- encing the biological activity of drugs and drug products. This includes dissolu- tion rates, disintegration rates, comparison of dosage forms of the same drug, and particle size as they affect biological activity, and blood tissue levels, absorp- tion rates, and metabolism and excretion rates for drugs. This plus our complaint history on a score of select pharmaceuticals indicated a dire need for pharma- cological equivalency testing. In essence DPSO will formulate a proposed testing procedure with the cooperation of government personnel, universitieS, or in- dustry. This procedure will be submitted to the DMMB- Which is the Defense Medical Materiel Board- for profemional evaluation and approval. The DPSC will include the pharma- cological equivalency testing procedure in the specification. We will also docu- ment the bidders or offerors method of manufacture, specifications, procedures, and quality control for the production of the specific lot of materiel subjected to the testing required in the specification. Now, this, of course, is over and above U.S.P. or N.F., because I think you can easily see that no compendium, irrespective of its na- ture, can cover all those links in the quality-control chain-the essen- tial links- in order to make sure that each batch is safe and effective- when you consider the differences in the selection of nondrug com~o- nents, differences in formula, in manufacturing procedure-the quality control differences and so forth. Senator NELSON. If I understood correctly what the captain was saying, he was reciting careful procedures which must be followed to assure that TJ.S.P. standards were met, is that not correct? Dr. SLESSER. No. He was in effect stating the inadequacy of TJ.S.P. or N.F. standards, because he found it necessary to convince the DSA policymaking people that another specification was necessary-namely, proof of pharmacological activity. Senator NELsoN. This puzzles me a little bit. Today Dr. Lueck testified that the U.S.P. standards are the highest in the world, if I understood him correctly. Dr. SriussER. That is correct. Senator NELsoN. A week or so ago, the president of one of the major pharmaceutical corporations said that the U.S.P. was the highest standard in the world. Does this captain know of standards higher than those we have in this world? Dr. SLESSER. No standard, Mr. Chairman, can suffice in lieu of or instead of the test for safety and effectiveness on human beings in a clinical study. Senator NELSON. What we are talking about-the captam, and you- PAGENO="0117" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2251 in terms of quality control, I take it, are procedures to assure that T5.S.P. standards are in fact met. Isn't that what we are talking about? Dr. SLESSER. What we are talking about, Mr. Chairman, is this. That quality control, properly exercised, begins at the R. & D. stage, and that when properly exercised on a batch-to-batch basis-the only way a manufacturer can assure that every batch that he makes and every tablet and every capsule in that batch is as safe and effective as the original clinically tested batches, is by the implementation and the execution of this chain of quality control in the manufacture of each batch. So in effect, quality control serves as a substitute for the clinical test on a batch-to-batch basis. Now, this is really what quality control is, and what it does, after you have done clinical testing. If you have not done the clinical testing, I state it is a scientific fact that laboratory test results alone may mean absolutely nothing. Senator NELSON. Well, I hope we are not running around in a circle. But the T5.S.P. standards are the highest in the world, and the U.S.P. consults people from the industry, as well as the best clinicians in the country from all the various specialities2 to set the standards. It seem to me all you are talking about in quality control is that you must have a first-rate method of assuring that you really come out meeting those standards. If you know of some drugs that meet the T5.S.P. standards but are not therapeutically effective, I would like to have the names of them, because Dr. Miller has given us the names of all those he knows, 15 or so known among all the drugs on the market. Now, do you know of drugs in addition to those that Dr. Miller knows about that meet U.S.P. standards and are not therapeu- tically effective? Dr. SLESSER. Mr. Chairman, the fact of the matter is that there are such drugs on the market. Senator NELSON. What kind of drugs do you mean? Dr. SLEss]~n. There are two categories. There are drugs which do not meet U.S.P. and N.F. specifications. Senator NELSON. Those, we will all agree, should not be øn the market and are not at issue here at all. Dr. SLESSER. There is another category of drugs that do meet these specifications, but are not clinically effective. Now, the U.S.P.-Dr. Miller certainly has something to do with the TJ.S.P. On the page that I referenced, he stated that there is no-at the present state of knowledge, the monograph specifications cannot assure pharmacological availability. And that is what we are talking about. That is the guts of this issue. And~ the Defense Department recognizes this, and therefore they are going beyond TLS.P. or N.F. specifications. And I suggest that Captain Pflag could probably reveal reasons why they had to go to this particular kind of activity. Senator NELSON. There wouldn't be any reason for you to be aware of this, but I believe I have asked every industry witness that has appeared, "Do you know of any drugs that meet U.S.P. standards that are not therapeutically effective?" They do not give me any examples. Now, what amazes me, just absolutely astonishes me, is that I say this week after week after week, but witnesses merely give me a lot of other material that is peripheral. PAGENO="0118" 2252 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I will give you the names of the drugs that Dr. Miller gave us, and then will you give me a list of those proven cases that you know of where drugs meet U.S.P. standards but are not effective. Dr. Miller does not know of more than 14 or 15 cases. No witness from the indus- try knows of additional examples. I think I asked the PMA for examples when they testified for the first time and I did not get any. I am anxious to have it in the record. We are trying to do a fair job here. It would seem to me if you assert that certain drugs meeting U.S.P. standards are not therapeutically effective or equivalent, that you are bound to name them. Dr. Su~ssaa. Mr. Chairman, I would respectfully suggest that the reverse is true. Before we can market a drug, we must test to make sure- Senator NELSON. Just a minute, Doctor. You asserted tins yourself. Now, if you make such an assertion, you must base it on some knowledge. Will you give me the specific cases that you know, from your experi- ence, or anybody else's experience, of drugs meeting U.S.P. standards that were not therapeutically effective `beyond the list of drugs of a dozen or so that Dr. Miller and many other witnesses have talked about. You name me one. Dr. Sr~r~ssaa. Captain Pfiag refers to a score or so. - Senator NELSON. Does he name them? Dr. SLESSER. I think he can. Senator NELSON. Really, I must say, Doctor-this is your business, this is your industry. I have been asking this question for weeks. Dr. SLESSER. I will be happy to call him if you like. Senator NELSON. If you assert that it is the case that drugs meeting TJ.S.P. standards are not therapeutically effective, I would think you would be prepared to say on what basis do you draw that conclusion, and name the case, the drug, the example. You are a scientist. I am not. But just as an ordinary lawyer putting in evidence, I would not make that assumption if I did not have the evidence to back it up. I could not sit there and say "This is the case, and you people prove it is not true." Mr. `CumEn. Mr. Chairman, no one drug company has conducted these tests on every other product. Now the Defense Department has conducted a number of tests. Captain Pflag-they said he has found a score or more. He would cer- tainly respond to this committee. Senator NELSON. I did not hear him say, "I found a score or more that met TJ.'S.P. standards that were not therapeutically effective." Did he say that? Dr. SLESSER. What he said is, "This, plus our complaint history on a score of select pharmaceuticals, indicated a dire need for pharmaco- logical equivalence testing." Mr. CUTLER. In other words, testing that goes beyond the TJ.S.P. tests. Senator NELSON. Well, you did not answer the question I raised. Mr. CUTLER. Sir; we do not know how to answer that question. Dr. Goddard can help answer it, the Defense Department can help answer it. We have given you 211 medical literature references, some of which PAGENO="0119" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2253 refer to the dru~'s meeting U.S.P. tests. Those doctors are available to testify. And their findings are reported in medical literature. Senator NEr~soN. Name me one of the 211 that met TJ.S.P. standards and was found not to be clinically effective. Dr. SLESSER. Chioramphenicol. Senator NELSON. That is on the list. We know about that one. Name some in addition to the dozen or so that Dr. Miller has mentioned, and Dr. Feldmann has mentioned, and that have been in the literature. Dr. SLESSER. I do not know the ones they have mentioned. I have not seen them in the testimony. Senator NELSON. If anybody has combed that record better than the industry, I would be very surprised. Dr. SLESSER. I read their complete testimony before your committee, Senator, and I have not seen any names. Mr. GROSSMAN. Dr. Slesser, has the PMA ever made any efforts tO deal with the U.S.P. standards? Are you trying all the time to upgrade these standards? We have heard so much about how the standards may not be adequate. What are you doing about it? Dr. SLES5ER. The industry has been for many years, Mr. Grossman- the industry has been-PMA has been cooperating with the compen- dium officials, with Food and Drug Administration, through the quality control section, which meets twice a year, for the specific pur- pose of establishing standards and specifications for drug products. Mr. GROSSMAN. Let us pin this down a little bit. Do you think the TJ.S.P. standards are adequate, as far as quality control? In other words, we have heard so much talk-let us have a yes or no. Dr. SLEssm. They are adequate for pharmaceutical-in a pharma- ceutical sense, Mr. Grossman, not in a clinical sense. Mr. GROSSMAN. I am a lawyer. Could you explain that to me? Dr. SLE5SER. Well, there has to be some proof of biological effective- ness. If you look at any monograph in the U.S.P.-these are the tests and specifications for the TJ.S.P. and N.F. products-nnd if you examine each of the tests which are stipulated in those monographs, you will find, except for insulin, where there is a fasting rabbit blood sugar level lowering test-that there will be no test for therapeutic perform- ance. It is simply assumed, erroneously by many, because there are disclaimers in the U.S.P. and N.F. to this effect-nevertheless it is assumed that so long as a product meets these tests, ergo, TJ.S.P. or N.F. test-ergo it has to be therapeutically effective. This is disclaimed by the compendia themselves. If you are asking me do I know of a substitute for a clinical test, the answer is no. Mr. GROSSMAN. The T5.S.P., then, is not. doing enough. I mean yes orno? Dr. SLESSER. Insofar as therapeutic-I can only answer your ques- tion this way. I am not trying to be difficult., believe me. Insofar as spelling out clinical performance, there is no such sped- fication-except in the one instance that I mentioned, in the U.S.P. or N.F. Mr. GROSSMAN. Now, on another matter, you make a very, very strong allegation on page 11 of your testimony where you say, "The inability of the FDA to assure even the competence of all drug firms, PAGENO="0120" 2254 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY let alone the clinical quality of their products, is too longstanding tp. brush aside. And the possibility of that situation soon or e~er changing is extremely remote." Frankly, that is about as strong a charge as any- body could come before this committee and make. And then you come up here-and I was waiting for these 211 examples of doctors' re- ports-I don't know whether you have read them, but, when you are asked any questions about them, frankly you cannot answer them- do they meet TJ.S.P. standards. I would think you would come up here and have fairly accurate and detailed knowledge about these 211 cases, or at least be able to say of the 211 half of them did this or that. But it just seems like you are throwing 211 things that you want everybody to read, and you know nobody is going to read. Dr. SLESSER. Mr. Grossman- Senator NELSON. I have to answer another rolicall. You may con- tinue with your questions. Dr. SLESSER. Mr. Grossman, I would simply like to repeat a com- ment that I made earlier, and I think certainly it is one that is factual. And that is no matter what tests you may have in the tT.S.P. or N.F., you have many marginal and incapable manufacturers of pharma- ceuticals in this country today. And irrespective of the legal require- ments-after a product has failed to do a job it is supposed to do and there is a casualty as a result of the-in tolbutamide, it was easily recognized after the tablet passed through the GI tract without dis- solving it did not meet standards. The fact of the matter was it was on the market, available, prescribed and taken. The same thing, I am sure, happens many times. The fact that I personally do not know about them is simply an indication of the fact that this kind of a thing is not the kind of a thing you are apt to see in the scientific literature. Mr. GROSSMAN. I am assuming none of these firms are members of PMA that you are talking about. Is that safe to say? DT. SLESSER. They may be. I do not say being a member of PMA means one is perfect. I think PMA members make mistakes, too. But I think their batting average is far better than those who are much more poorly qualified. Mr. GROSSMAN. It just seems to me-and again I wafted to see what evidence you would present-that-and Mr. Cutler, as a lawyer- when you come into court or a committee, that if you have 211 cases, that they are just not thrown at us and say "Here are 211 cases." I would like to know what they all mean. When you were asked whether they were below U.S .P. standards and so on-there was no answer. Dr. SLESSER. Mr. Grossman, I said there were 211 papers that dealt with the subject of biopharmaceutics, which indicated the vast and profound effects that can occur in drug products depending on particle size of the drug, depending on t:he crystalline form of the drug, depend- ing on certain additives that are present, PH, and so forth. Mr. GROSSMAN. Have you yourself made efforts to study the various 211 articles, whatever they are, to decide how many say this and how many say that, and whether they refer to the same items, are they duplicative. Dr. SLESSER. They are not duplicative pieces of work. Some of them-more than one may involve a certain drug. But I would say some different aspect. PAGENO="0121" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2255 Mr. GROSSMAN. I want you to say that if you believe that the TJ.S.P. standards are not adequate, and that we should increase the minimum quality standards, why isn't the PMA pressuring the TJ.S.P. to do it. You have people on the TJ.S.P. that are members of PMA. Mr. CUTLER. Mr. Grossman, what we have tried to say, and what the TJ.S.P. itself says, and the publisher, the editor of the N.F. himself says, is that laboratory tests of the type~ that those two formularies or documents prescribe will not determine pharmacological availability or therapeutic effectiveness. Now, we cannot conjure up a test that will determine that in the laboratory. What we are trying to say is you can only determine that by clinical testing of the drug product itself. Mr. GROSSMAN. And the U.S.P. does not at present- Mr. CUTLER. The TJ.S.P. does not purport to establish clinical test- ing. It attempts to establish certain laboratory tests to detect the pres- ence of an active ingredient in a drug. Mr. GROSSMAN. Do you, as a consumer, feel safe when you take a drug that has a TJ.S.P. standard? Mr. CUTLER. The consumer does not select his drug. He goes to a doctor. Mr. GROSSMAN. You, yourself, sir-~are you concerned when you take a drug that has supposedly met TJ.S.P. standards, that you are not getting the proper quality control? Mr. CUTLER. I `don't have an idea in the world whether it met TJ.S.P. standards. I do not know how I would know. I get a prescription from a doctor on whom I depend, I go to a pharmacy that he recom- mends, and I get a drug. Mr. GORDON. On page 3 you discuss the great care exercised by manufacturers in insuring that the correct amount of ingredients is in each tablet. This is your statement. At this point I would like to insert into the record a list from the latest issue of Clin-Alert on recalls of products from major com- panies. I might mention Diamox Sustets, put out by Lederle Laborato- ries; Coumadin, put out by Endo Laboratories; Panwarfin, Abbott Laboratories. These are `all members of the PMA that produced drugs which could not meet TJ.S.P. standards. (The document referred to follows:) [From ClIn-Alert, Nov. 3, 1967] Dnua RECALLS LABELING ERRORS A. Diamoa, Sustets (acetazalamide-Lederle Laboratories): Approximately 700 bottles of 500 mg. Diamox Sustets (the export name for Diamox Sequels) were recalled due to a labeling error. According to FDA's weekly report of drug re- calls (Sept. 27 thru Oct. 3), the recall was initiated September 27, 1967 by telephone. B. Goamadim (warfarin sodium-Endo Laboratories): Approximately 30 mil- lion tablets recalled nationally. Tests showed that the tablets were above, and in some cases, below the stated potency levels on the labels. Variations were greater than those permitted to ensure safety. According to news releases (pub- lic announcement of the recall was made `by FDA's New York Office) a spokes- man for the food and drug agency warned that the overstrength tablets could be fatal to some patients. Later, Dr. Goddard, Commissioner of the U.S. Food and Drug Administration, was quoted as stating that lives would not `be tin- periled by taking the drug. PAGENO="0122" 2256 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY C. Panwarfla~ (warfarim sodium-Abbott Laboratories): Approximately 4 mil- lion, 5 and 10 mg. subpotent tablets recalled. This FDA-initiated action was an- nounced to retail pharmacists by letter dated October 10, 1967. Mr. GORDON. Also you remember that some time ago we put into the record a list of major recalls, some of them including millions of tablets, from Squibb, Abbott, Roche, Pfizer. I cannot understand why you are making such a big deal about going beyond TJ.S.P. standards, when many of your own companies cannot even meet TJ.S.P. standards. Dr. SLESSER. Dr. Scheele, are you going to talk about recalls? Mr. GORDON. Also, I would like to call attention to a list of recalls, which I will put in the record, where the following companies, mem- bers of the PMA, could not even meet the current good manufacturing practices provisions of the Kefauver-Harris Amendment of 1962. For example, Squibb & Sons, "Various drugs manufactured without satis- factory controls." Abbott Laboratories, "Various drugs manufactured without satisfactory controls." Wyeth Laboratories, "Aludrox manu- factured without satisfactory controls." Charles Pfizer & Co., Inc., "Several drugs mislabeled because of inadequate controls." (The document referred to follows:) [From the Pink Sheet, Tuly 26, 196~] (Excerpts-Drug Recalls-Oct. 1, 1962, to June 30, 1965, p. 18) ACTIONS INVOLVING "CURRENT GOOD MANUFACTURING PRACTICE-SECTION CITATION CASES Firm Charges Present status or case E. R. Squibb & Sons, New York, Various durgs manufactured with- Hearing held. Case placed in permanent abey- N.Y. out satisfactory controls. ance by FDA Headquarters on Mar. 11, 1965. Abbott Laboratories, Inc., North do Hearing held. Case placed in permanent abey- Chicago, Ill. ance by FDA's district office on Mar. 16, 1965. Wyeth Laboratories, Inc., "Aludrox" manufactured with- Hearing held. Case placed in permanent abey- Philadelphia, Pa. out satisfactory controls. ance by FDA's district office on Dec. 1, 1964. Chas. Pfizer & Co., Inc., New Several drugs mislabeled be- Hearing held. Case placed in permanent abey- York, N.Y. cause of inadequate controls. ance by FDA's district office on May 25, 1965 Mr. CUTLER. Mr. Gordon, you are only proving our point-that even the best companies make mistakes occasionally. If you go over those drug recall lists, you will find that the frequency of drug recalls for the non-PMA member companies that make only 5 percent of th~ drugs is far higher for any volume unit of production you want to take than the frequency of recalls of the PMA members who make 90 to 95 percent of the drugs. The fact that even the best companies are not perfect helps to estab- lish our point-that doctors simply must use their own experience and their own judgment based on what has happened to their patients when particular drugs of particular manufacturing sources were prescribed. Now, if, as Senator Nelson indicated earlier, he also favors identify- ing manufacturing source, I do not suppose we have any disagreement. That is all we are trying to say. Mr. GORDON. Now, on page 4, you stated: We all know that effectiveness and safety of a drug product are determined by well-designed, properly controlled and correctly executed clinical tests. PAGENO="0123" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2257 It is my understanding that most clinical tests are poorly executed. ,For example, in the Journal of the AMA, November 6, 1967, an a~rti~1e entitled "Studies of Drug Usages," pages 406 to 510, a review of over 200 papers reporting on the efficacy of many of these agents- that is, drugs most used in hospitals-revealed that very few studies were well controlled. This is on page 510 of the Journal of the AMA. I ask this article be inserted in the record at this point. (The article referred to follows:) [From the Journal of the American Medical Association, Vol. 202, No. 6, Nov. 6, 19671 STUDIES OF DRUG USAGE IN FryE BOSTON HOSPITALS (Ivan Borda, MD, Hershel Jick, MD, Dennis Slone, MD, Barbara Dinan, RN, Barry Oilman, and Thomas C. Chalmers, MD) A study of drug usage was conducted in five hospitals: two hospitals for patients with acute diseases, two for patients requiring long-term care, and one pediatric hospital. Partially due to the increased length of hospitalization, more drugs were used in long~term hospitals. The number of different drugs used to treat the same problem varied greatly. For some therapeutic indications, one particular drug was widely ac- cepted by most hospitals; in others, there was a wide variance. More than one drug of the same pharmacological action was often prescribed for the same patient. Older patients and women received more drugs. Antibiotics were used in a high percentage of all hospital patients. There were many incomplete prescriptions and discrepancies between drug orders written by doctors and records of medications administered by nurses. These results indicate the need for an epidemiologic approach to therapeutics. During the past few years the medical community has become aware of the aeed for more and better information concerning drug efficacy and adverse irug reactions. The importance of obtaining more data in these areas appears ~o be well recognized in England where the National Health Service has gathered statistics concerning the prescribing habits of British physicians over a four- year period (1959 to 1962). The British Ministry of Health is keeping records Df all general practitioners, and these records are periodically checked for "over- prescribing." (1, 2) Public health authorities in West Germany and Canada show an increasing interest in drug epidemiology and have established agencies responsible for studies on drug use and adverse reactions. (3-5) The great majority of publications as well as the structure~ of the existing programs in- dictate that investigators are focusing their attention mainly or entirely on the problem of adverse reactions to drugs. (6-10) However, an adverse reaction program requires the denomingtor factors for i meaningful interpretation of the numerator dat~i. (11) More specific informa- bion may be obtained if adverse drug reactions are correlated with the vital statistics (age, sex, race, etc) of the study population. In a hospital study, the recording of these factors together with characteristics of the hospital itself, such as whether the hospital cares for patients with acute or chronic diseases, whether it is a private or municipal hospital, the number of ordering physicians, md the type of hospital formulary will provide what may be called the "drug wofile" of a hospital. The prescribing habits of the physicians involved should also be studied. It s estimated that in 1963 between 700 and 800 million prescriptions were written Ln the United States, approximately 12.8 prescriptions for each family.12 This speaks for the enormous importance of collecting relevant data in regard to lrug usage. A drug survey was conducted in five hospitals in order to describe current drug raotices and to point out some aspects of drug use which require further investi- ration in depth. METHODS Randomly chosen records of patients who were discharged or who died between sept. 1, 1964, and Aug. 31, 1965, were studied in five hospitals in the Boston area. ~ total of 682 charts were reviewed. One of the hospitals cares for patients with ~hronic diseases (average stay, 307 days), one for patients requiring intermediate- PAGENO="0124" 2258 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY length care (average stay, 42 days), two are general hospitals for patients with acute diseases, and one is a pediatric hospital. Table 1 shows age data and diag- noses. TABLE 1.-AGE AND DIAGNOSIS Number of patients in hospitals Age group, years Chronic lnter- Acute 1 Acute 2 Pediatric Total mediate Lessthanl5 0 3 6 8 154 171 16to40 2 27 68 58 0 155 41to54 5 35 30 31 0 101 Morethan55 71 84 46 54 0 255 Total 78 149 150 151 154 682 DIAGNOSIS Diabetes 18 21 12 8 1 60 Stroke 24 10 0 6 0 40 Rheumatic heart disease 3 5 2 1 2 13 Hypertensive cardiovascular disease 9 5 Myocardial infarction 5 4 Heartfailure 4 4 6 5 5 3 3 5 1 26 0 17 2 16 Arteriosclerotic heart disease 12 15 6 9 0 42 Neoplasm leukemia 19 47 Upper respiratory tract infection 0 0 Chronic bronchitis emphysema 7 16 Pneumonia 2 3 Genitourinary tract infection 2 6 Meningitis 0 0 Abscess 1 1 8 3 4 4 7 0 1 8 1 3 2 1 3 1 0 3 4 86 3 3? 0 29 8 18 0 28 5 5 2 8 Peptic ulcer Headache Seizure disorders 0 1 0 0 0 2 4 1 1 4 5 0 0 9 0 6 6 9 Pregnancy Rheumatoid arthritis 0 0 2 7 0 24 0 1 0 0 Anemia 1 10 7 2 6 Skin diseases Cirrhosis 1 6 0 11 8 3 1 2 2 0 24 10 26 20 14 A study card was used for recording the following data copied from the phy- sician's order sheet, the nurse's notes, and the face sheet of the chart: (1) com- plete list of drugs ordered during the patient's last hospitalization; (2) dose, frequency, and route instructions for each drug ordered; (3) vital statistics; (4) admission and discharge dates; and (5) discharge diagnoses. Each drug was recorded only once. Neither orders to discontinue or restart nor changes in dosage or route were recorded. The data were transferred from the study cards to punch cards and were processed in a computer system. The output of this computer system was in the form of tabulations. RE5ULT5 Table 2 shows the basic working data in each hospital. More than twice as many orders were written per patient in the two long-term hospitals as in the two acute hospitals and almost twice as many orders in the chronic hospital as in the intermediate hospital. In order to estimate the role which length of hos- pitalization played in the observed differences between long-term and acute hos- pitals, a separate analysis was carried out. Since the average duration of hos- pital stay in the acute hospitals was ten days, we compared drug usage for this period in the two types of hospitals. Thirty randomly chosen records from each long-term hospital were examined. There was no significant difference between the number of drugs ordered in long-term and acute hospitals during the first ten days after admission. The frequency with which the various drug categories, ie, groups of drugs with similar pharmacological activity, were used is shown in Table 3. Only anti- cholinergic agents were used more frequency in the acute than in the long-term hospitals. All other drug categories were ordered more often in the two long-term ho~pitals. Order ratios of long-term to acute hospitals include the following: anti- biotics, 3:1; vitamins, 4 :1; tranquilizers, 2:1; diuretics, 4 :1; cardiac stimulants, 2:1, antihistamines, 3:1, ointments, 6:1, expectorants, 3:1; corticosteroids, 2 :1; antiseptics, 4:1; hematinics, 5 :1; and vasopressors, 5 :1. PAGENO="0125" -4 C) FTC C) m 0 0 -Ti -Ti m rrt 2 -I 0 C) C,) C,) 0 -I = 2 -I 2 rn 0 C, C, -I C, 0 C,) 3 ~ 3 ~ ~ C) DC ~ DC ~ 9:c~i-, CD 3 CD ~CD~ ~ 3 ~ DC ~.CD 3 ~.c' ~ ~o < ~ F~ `~cn~ ~ ~. ::::!::~H~H~HH~: DO (Ji-JOOC000 ~ ~JC~C~ -JCCJ C) C) C000CC)CCJ n~o~r~ r~- ~ c~ ~o, ~CJ C)C~C CO 00 C)-J t~)C) ~C~C)C,C 0i~J CJ1N) - 00F~ 01(00001 - F~3 F~ W 010 01-J C) F.)O) ~ -J (~) W ~-J~-~ 00 F~)~ ~ ~.j CCJC) 01~ ~ ~C) 00 *-4C) (OC)C)C)CO ~ ~CCJ F~3tl3t~3 F~C,J (&) C~ C) ~ 0)0)0)00CC C,) -- - - CCC CJ100~O) 01 (CC OiQi 0100C)C0 ~J (CCC) C) N)(CC CC) (TiC,) ~PCCFIC~)CCC CCC 01CC 0 CCC~1 ~J 010) 2 ~ -I o DC > - C) rn (Ti C) 00C)1~ (C) CC) 0CC) C) 010) C*) 3 NC C t~rj )0 ~ ~ C rn N ~ I LTj C) CI) C, 0 2 C) C) :0 -4 :0 CI) CCC 0)0) ~ 00~J ~ - C) ~NC 01 C)01-JNC ~0) CCC - ~CC) ~ 010) (0 ~C0 N) ~0)(C) 00 ~(0(0 0)-J C)~JNCNCC) C)~(oo)0oo1CC)(J1o01 ~00 - -~C) N) 01CC) F~ C) C) C)C)N) -C `~ PAGENO="0126" 2260 COMPETITIYE PROBLEMS IN THE DRUG INDUSTRY Table 5 indicates which particular drug within each category was used most frequently in each hospital. The data shows that in several categories the same drug was chosen most often in all adult hospitals. These were prochlorperazine (antiemetics), penicillin (antibiotics), atropine (anticholinergics), diphen- hydramine hydrochloride (antihistamines), digoxin (cardiac stimulants), pred- nisone (corticosteroids), aminophylline (therophylline ethlylenediamine) (bron- chodilators), ferrous sulfate (hematinics), milk of magnesia (laxatives), baci- tracin (ointments), and metaraminol bitartrate (vasopressors). PAGENO="0127" ci TABLE 5.-LEADING DRUGS IN EACH DRUG CATEGORY Chronic hospital Intermediate hospital Acute hospital 1 Acute hospital 2 Pediatric hospital Analgesics Meperidine hydrochloride Propoxyphene hydrochloride__ Propoxyphene hydrochloride_ Meperidine hydrochloride Morphine sulfate. Antacids Magnesium hydroxide-alum i- Dried aluminum hydroxide gel_ Dried aluminum hydroxide gel_ Magnesium hydroxide-alumi- Dried aluminum hydroxide gel. ~ num hydroxide mixture num hydroxide mixture. Antidiabetics Insulin in ection Tolbutamide Tolbutamide Insulin injection Insulin injection Antiemetics Prochlorperazine Prochlorperazine Prochlorperazine Prochlorperazine Prochlorperazine. Antibiotics Penicillin Penicillin Tetracycline Penicillin Penicillin. Anticholinergics Atropine Atropine Atropine Atropine Scopolamine hydrobromide. Antihistmines Diphenhydramine Diphenhydramine Diphenhydramine Diphenhydramine Dipoenhydramine. Antiseptics Hydrogen peroxide solution~ Hexachlorophene Hexachlorophene Hexachlorophene Hexachlorophene. Bronchodilators Aminophylline Aminophylline Aminophylline Aminophylline Phenylephrine hydrochloride. Cardiac stimulants Digoxin Digoxin Digoxin Digoxin Digoxin. Corticosteroids Prednisone Prednisone Prednisone Dexamethasone Prednisone Diuretics Mercaptomerin sodium Meralluride injection Hyrochlorothiazide Chlorothiazide Merallurideinjection. Expectorants Cough mxiture Glycerl guaiacolate White pine syrup Diphenhydramine Glyecryl gualacolate - - hydrochloride, Hematinics - - - - - Ferrous sulfate Ferrous sulfate Ferrous sulfate Ferrous sulfate Ferrous sulfate. Hyponotics Chloral hydrate Chloral hydrate Secobarbital Pentobarbital sodium Pentobarbital sodium. Laxatives Milk of magnesia Milk of magnesia Milk of magnesia Milk of magnesia Bisacodyl. Ointments Bacitracin Bacitracin Bacitracin Bacitracin Lanolin. Tranquilizers Promazine hydrochloride Chlordiazepoxide/ Chlorpromazine Chlordiazepoxide Hydroxyzine hydrochloride. ~ hydrochloride, hydrochloride hydrochloride. Vitamins Multivitamins Multivitamins Vitamin and Minerals Multivitamins Pyhtonadione. Vasopressors Metaraminol bitartrate Metaraminol bitartrate Metaraminol bitartrate Metaraminol bitartrate PAGENO="0128" 2262 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In all hospitals several drugs within a given category were often prescribed for an individual. Individual patients received as many as 12 antibiotics, seven analgesics, six diuretics, five hypnotics, seven laxatives, six tranquilizers, and 11 vitamin preparations. Table 6 shows the use of drug categories in different age groups. The data are expressed as a ratio of the observed (actual number of times the drug category was given) to the expected (number of times the drug category would have been given if the drug categories were equally distributed in each age group). In the adult hospitals drugs were prescribed most often for those over 55 years of age. Particularly striking were the ratios in the following categories: cardiac stimu- lants (70: 16), diuretics (58: 31), and vitamins (81: 49). Hypnotics, anticholiner- gics, and analgesics were given more often to patients in the middle-age groups. The youngest age group (0 to 15) presents higher observed than expected figures in decongestants (43: 32), antibiotics (65: 60), and anticholinergics (68: (30). TABLE 6.-USE OF DRUG CATEGORIES IN Age group, year Proximum <15 0.2507 16-40 0. 2273 41-54 0. 1461 >55 0. 3739 Analgesics Antacids Antibiotics Antidiabetics Antiemetics Anticholinergics Antihistamines Antiseptics Cardiac stimulants Corticosteroids Decongestants Diuretics Expectorants Hematinics Hypnotics Laxatives Ointments Tranquilizers Vitamins Vasopressors 23/95. 8 5/23.6 65/60. 4 2/12.5 2/22. 8 68/59.9 15/25.1 6/10.5 6/23. 3 12/16 43/31.6 6/20. 6 12/19.1 6/19. 1 68/129.6 22/89. 2 4/13 10/23. 3 21/33. 1 0/8 109/86. 8 20/21.4 34/54. 8 2/11.4 22/20. 7 71/54.3 16/22.7 7/9.5 3/21.2 6/14. 5 10/28.6 2/18. 6 9/17.3 1/17. 3 137/117.5 82/80.9 8/11. 8 17/21. 1 9/30 2/7. 3 84/56. 6 18/13.9 34/35. 7 7/7.4 18/13. 5 37/35.4 16/14.8 8/6.2 14/13. 8 10/9. 5 16/18.7 16/12. 1 15/11.3 5/11. 3 94/76.6 68/52.7 4/7. 7 15/13. 8 21/19. 5 6/4. 7 166/142. 8 50/35.1 108/90. 1 39/18.7 49/34 63/89.4 53/37.4 21/15.7 70/34. 8 36/23. 6 57/47. 1 58/30. 7 40/28.4 30/28. 4 218/193.3 184/133. 1 36/19. 4 51/34. 8 81/49. 4 24/12 1 The data are expressed as a ratio of the observed (actual number of times the drug category was given) to the expected (numberof times the drug categorywould have been given if the drug categories were equally distributed in each age group). Table 7 presents the different drug categories prescribed for male and female patients. The form of this table is similar to Table 6, i.e. observed figures are compared with expected (number of times the drug category would have been given if equally distributed by sex). In 15 of 20 categories orders were written more frequently for the female than for the male patients. BronchodilatorS, ex- pectorants, cardiac stimulants, hypnotics, and laxatives were used more often in males. TABLE 7.-DRUG CATEGORY ORDER DISTR!BUTION IN Proximum Males 0.570 Analgesics 95/120 Antacids 4/6 Antibiotics 68/76 Antidiabetics 10/11 Antiemetics 6/8 Anticholinergics 8/9 Antihistamines 3/6 Antiseptics 3/5 Cardiacstimulants 10/10 Corticosteroids 8/9 Decongestants and bronchodilators 31/27 Diuretics 12/17 Expectorants 12/10 Hematinics 2/5 Hypnotics-sedatives 119/114 Laxatives and stool softeners 68/69 Ointments 6/10 Tranquilizers -- - 12/16 Vasopressors 1/3 Vitamins 14/27 Total number of patients (682) 385 1 The data are expressed as a ratio of the observed (actual number of times the drug category was given) to the expected (number of times the drug category would have been given if the drug cateogries were distributed equally by sex). Females 0.430 117/92 6/4 65/57 10/9 8/6 8/7 8/5 5/3 8/8 8/7 17/21 18/13 5/7 6/3 80/85 53/52 11/7 16/12 4/2 34/21 297 PAGENO="0129" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2263 In the 682 patients reviewed, 585 antibiotic orders were written. The most fre- quently used antibiotics are shown in Table 8. Penicillin is followed in order of overall usage by sulfonamides, chloramphenicol, tetracyclines, and neomycin. TABLE 8.-USE OF ANTIBIOTICS Chloram- Neomycin- Type of hospital Tetracyclines Penicillins phenicol Sulfonamides paromomycin sulfate Chronic 6 78 20 22 0 Intermediate 13 41 13 14 8 Acutel 11 24 1 3 1 Acute 2 3 27 6 8 1 Pediatric 7 56 4 25 1 Total 40 226 44 72 11 We have found a high percentage of incomplete prescriptions in all four adult hospitals. Instructions for route of administration were missing in 35% to 60% of all prescriptions. In contrast, at the pediatric hospital only 29 (5%) of the prescrptions failed to specify the route o~f administration. Oomparing the physician's order sheet and the nurses' files, we frequently found that the drug order as written by the physician was not charted by the nurse as having been given as specified. Whether the nurse had forgotten to chart the medication given or the patient had actually not received it, could not be de- termined in retrospect. COMMENT This study is a descriptive one and is not intended to lead to any definite conclusion. It documents certain characteristics of therapeutics practiced in five hospitals. The following findings* merit emphasis since they help to de- fine areas which require study in depth. Our data confirm observations (10, 11, 15, 16) that the large quantities of drugs administered to patients are related to the length of hospitalization. Patients with chronic disease stay ~in the hospital longer than patients with acute disease and receive more drugs during hospitalization. Within any adult hospital, patients in the older age groups receive more drugs in almost all categories. These findings are not in themselves startling, but they serve to point out the need for careful evaluation of drug effects in older patients in general and in those with chronic disease in particular. More information is needed in such areas as drug interaction and drug effects in older patients. (13,14) Drug effects are not only related to age but also to sex. The fact that more drugs are ordered for women than for men may partially explain the ob- servations that more adverse reactions are reported in women than in men. (15) Other studies have shown a direct relationship between frequency of drug reactions and the number of drugs used. (10, 16) The proportionately greater use of bronchodilators, expectorants, and cardiac stimulants in men is probably accounted for by a higher incidence of chronic pulmonary disease in this sex. The use of antibiotics is exceeded only by analgesics and hypnotics in the study hospitals. Antibiotic orders were repeatedly changed in regard to both dose and specific drug. The same antibiotic was often ordered more than once for a given patient. Various antibiotic combinations were used. The leading antibiotic was penicillin in all hospitals. The usage frequency of other anti- biotics showed marked variation in the different hospitals. Overall, sulfona- mides were used more often and tetracyclines less often than chloramphenicol. The extraordinary frequency and variability of antibiotic drug practice points out the need and importance of further studies. The following four drug categories stand out in terms of usage frequency in the pediatric hospital: (1) antibiotics; (2) decongestants-bronchoclilators; (3) hypnotic-sedatives, and (4) anticholinergics.. Seizure disorders and surgical pro- cedures probably account for the frequent use of, hypnotic-sedatives and anti- cholinergics. Antibiotics are the most frequently used drugs in the pediatric hospital. 81-280 O-68-pt. 6-9 PAGENO="0130" 2264 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Certain specific drugs within their respective categories were preferred iii all of the adult hospitals as shown in Table 5. A review of over 200 papers re- porting on the efficacy of many of these agents revealed that very few studies were well controlled. Therefore, it would appear that general acceptance of a given drug is frequently based on personal experience. Muller has reviewed the importance of proper prescription writing. (17) Phy- sician~ who write prescriptions which lack precision and have poor style and in- complete instructions are unintentionally adding more variables to the prob- lems of drug usage. (18) The present study documents the fact that improper prescription writing included omission of route and frequency orders. While this study is descriptive and is not intended to lead to any objective con- clusions, it does document the need for more studies of multidrug therapy, and more care in the writing of drug orders. This investigation was supported by Public Health Service research grant HE-5616. Hugo Muench, M.D., PhD, and Rasma Klints gave blostatistical assistance. Generic and trade names of drugs Bisacodyl-Dulcolaz. Chiordiazepoxide hydrochloride-Librium. Chloramphenicol-Uhloromycetin, Gyiphenicol, Tega-Cetin. Ohlorpromazine hydrochloride-Thorazine Hydrochloride. Ohlorothiazide-Diuril. Dexamethasone-Decadron, Dea~ameth, Gamnuworten, Hexadrol. Di~henvldramine Hydrochloride-Blenadryi, Valdrenc. Dried aluminum hydroxide gel-Alkagel, Amphojel, Greamalin. Hexachlorophene-G-11, Germa-Medica, pHisoHea, Septisol. Hydrochlorothiazide-Esidris~, Hydrodiuril, Oretic. Hydroxyzine hydrochloride-Atarax, Vistaril. Meperidine hydrochloride-Demerol, Hydrochloride, Pro-Meperdan. Meralluride injection-Mercuhydrin. Mercaptomerin sodium-Thionzerin, Sodium. - Metaraminol bitartrate-Aranvine, Pressonea, Bitart rate. Paromomycin sulfate-Humatin. Pentobarbital sodium-Nembutal Sodium. Phenylephrine hydrochloride-Aquamephyton, Konakion, Mephyton, Mono-Kay. Prednisone-Deltasone, Deltra, Meticorten, Paracort. Prochlorperazine-Compazine. Promazine hydrochloride-Sparine. Propoxyphene hydrochloride-Darvan. Secobarbital-Seconal. Tetracycline-Achroen~ycin, Tetracyn. Tolbutamide-Orinase. References (1) Curran, W.J.: Legal Regulation and Quality Control of Medical Practice Under the British Health Service, New Eng J Mcd 274:547-557 (March 10) 1966. (2) Investigating the New Drugs, Letter to the Editor, Lancet 2 :1182 (Dec. 4) 1965. (3) Kaerber, G.: Arzneimittelschllden, ihre Erfassung und Dokumentation vom Standpunkt des bundesgesundeheitsamtes. Meth Inform Med 3:127-131 (No. 3-4) 1964. (4) Homann G.: Arzneimittelschäden, ihre Erfassung und Dokumentation C'~danken und Lösungvorschläge vom Standpunkt de Srztlichen Selbstverwaltung. iIetl, Inform Med 4:11-15 (March) 1965. (5) Reporting of Adverse Reactions to Drugs, Editorials and Annotations, Caned Med Assoc J 92 :476-477 (Feb 27) 1965. (6) Weston, J.K.: Adverse Drug Reaction Reporting and the Related Estab- lishment of a Registry of Tissue Reactions to Drugs, Med Ann DC 34:380-382 (Aug) 1965. (7) Weston, J.K., and Weston, K.: The Control of Drug Toxicity in the United States of America, Practioncr 194:16-21 (Jan) 1965. (8) DeUosaquo, N.: The Registry on Adverse Recation of the Americaii Medical Association, Meth Inform Mcd 4:15-21 (March) 1965. (9) Hennessey, RSF.: The Evaluation of Drug Toxicity, Practitioner 194 :9-15 (Jan) 1965. PAGENO="0131" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2265 (10) Schimmel, E.M.: The Hazards of Hospitalization, Ann Intern Med 60:100-110 (Jan) 1964. (11) Dunlop, D.: The Problem of Drug Toxicity. Practitioner 194:5-8 (Jan) 1065. (12) Krantz, J.C., Jr.: Evolution of the Prescription, Curr Med Digest 33:349- 352 (March) 1906. (13) Interaction Between Drugs, Annual Symposium at the Royal Society of Medicine, Lancet 1 :906-DOS (April 24) 1965. (14) The Interaction of Drugs, Lancet 1:82-84 (Jan 8) 1906. (15) Seidi, L.G.: Thornton, G.F.: and Cluff, L.E.: Epidemiological Studies of Adverse Drug Reactions, Amer. J. Public Health 55:1170-175 (Aug) 1965. (16) Cluff, L.E.: Thornton, G.F.: and Seidel, L.G.: Studies on the Epidemiol- ogy of Adverse Drug Reactions: I. Methods of Surveillance, JAMA 188:976-983 (June 15) 1964. (17) Muller, C.: Medical Review of Prescribing, J. Chronic Dis 18:689-696 (July) 1065. (18) Fogg, J.: Errors of Medication in Hospital, Lancet 2:31-32 (July 3) 1965. Mr. GORDON Now, in discussing the variability in response to dif- ferent formulations of bishydroxycoumariñ, you stated that the source of manufacture is as important as the chàice of the drug itself. Evi- dence already in the hearing record, which was brought out in an article by Dr. Gerhard Levy, shows that bishydroxycoumaTin tablets have shown a major variation in clinical response between two separate lots of that drug produced by the same manufacturer. Consequently, while there may be some evidence that a very few drugs such as this one you have mentioned are sensitive to variations in their formulation, even two lots from the same manufacturer may not be exactly the same. I would like this to be part of the record, too. (The document referred to follows:) (Excerpts from Competitive Problems in the Drug Industry, Part 1, Page 438) PHARMACEUTICAL FORMULATION AND THERAPEUTIC EFFICACY (Gerharci Levy, Ph. D., Buffalo and Elno Nelson, Ph. D., San Francisco) There is a mistaken belief among many that the active constituent as a chemical entity is the sole basis for the pharmacological effectiveness of a pharmaceutical product. It is. the purpose of this review to show that the physiological response to the administration of a given drug product is fre- quently a function of both the pharmaceutical formulation of the particular dosage form as well as of the active ingredient. Certain variables related to pharmaceutical formulation will be discussed with respect to the manner in which they may modify therapeutic response in the hope that the examples cited may lead to the recognition that the choice of dosage form and of brand can be just as important as the choice of the actual therapeutic agent. In general, differences in therapeutic efficacy among different generically iden- tical drug products, while sometimes caused by lack of stability or by con- tamination, are most frequently due to differences in the rate at which the active ingredient or ingredients become available for absorption. This may modify the onset intensity, and duration of the desired physiological response. Further- more, the efficiency, the biological availabliity (e.g., the completeness of absorp- tion), as well as the incidence and intensity of side effects and toxic reactions from he drug may be affected. A dramatic example illustrating differences in intensity of action of a drug as a result of dosage form modification has been given by Lozinski. His com- pany found it desirable to increase the physical size of their bishydroxycou- mann (Dicumarol) tablets to facilitate breaking the tablets for administration of half doses. Patients who switched from the smaller to the new larger tablets required larger doses in order to maintain prothrombin levels in the therapeutic range. Laboratory studies undertaken to explain this difference indicated that PAGENO="0132" 2266 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the dissolution rate of drug from the large tablets was slower than from the old tablets. The tablets were reformulated to increase this rate, and these were then used to replace the stocks of older tablets in retail and hospital pharmacies. A surprising turn of events occurred. It became apparent that some patients who had their prescriptions refilled with the newest tablets showed prothrombin levels below the therapeutic range and, in some, bleeding occurred. The company alerted all physicians concerning the more intense therapeutic effect of the new bishydroxycoumarin tablets and urged that all patients on anticoagulant therapy with their brand of bishydroxycoumarin tablets be retitrated for their require- ments. It is quite likely that no 2 manufacturers' brands of bishydroxycoumarin tablets will act alike in therapeutics, and it is conceivable that a change from a slow release brand to a fast release brand might even result in death if the necessity for retitration is not recognized. Mr. CUTLER. Mr. Gordon-are you in agreement that doctors would be well advised to identify the manufacturing source rather than sim- ply prescribing by a generic name? Mr. GORDON. I think so. I do not have any more questions. Mr. Ctrrr~ER. I do not have any more questions, either. Mr. GORDON. I would say I would go along with that. Mr. GROSSMAN. I do. Mtr. CUTLER. Then I think we have closed a very large part of the gap between us. Mr. GoRDON. This is only my opinion. Mr. CUTLER. Senator Nelson earlier disclaimed any recommendation that doctors should prescribe simply by the generic name, and leaving it to the pharmacist to pick out any old drug product meeting that generic name. If we are in agreement on that, I think we have closed the gap a good deal, and we might close in, then, on the next issue. Mr. GROSSMAN. I would like to turn to another aspect of this. Would you say that different PMA members-I assume you would- perform different quality controls? Dr. SLESSER. Yes; I think there are variations in the type. Mr. GROSSMAN. That you have mentioned here. Dr. SLESS~. You can have different approaches to accomplish the same thing. And I think the magnitude of the quality control system will be directly related to the number of products and the number of people, and things of that sort; yes. Mr. GROSSMAN. Would you say that some of your members are better at quality control than others? Dr. SLESSER. I think they all do the best job they can. I do not think they knowingly-any of them knowingly slight quality controls. Mr. GROSSMAN. But would you say probably that. the leaders-I won't define it, because we do not. define leaders-perform essentially similar quality controls? Dr. SLESSER. Yes. Mr. GROSSMAN. In other words, that the top firms would produce just about the same drug if they were given it from the beginning, if they had the same ingredients? Is that true? Dr. SLESSER. I think they would all make sure the product behaved in the clinic the way it was supposed to. and then do whatever is necessary to make sure each batch resembled in its clinical effective- ness the prototype clinically tested batch. Mr. GROSSMAN. Let me give you a hypothetical situation. Suppose, for example, that Squibb produces a brand-name drug, and PAGENO="0133" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2267 that Lilly produces a generic, the same drug. Would you say that the quality controls would be different? Dr. SLESSER. I don't think they would~ be. As I said, there may be minor differences in the approaches. But I think one would be as effec- tive as another, and they would both accomplish essentially the same thing. Mr. GROSSMAN. Are there, or do you know .of any examples, then, of drugs such as I have just mentioned where there is a trade name- a brand-name drug and a generic both produced by the leaders, so to speak, where there is a great deal of price differential between the two? I am not talking about- Dr. SLESSER. Mr. Grossman, I am not too well informed about prices. I have no price-determination function in my capacity with my company. Mr. GROSSMAN. Are there any of you that could answer that? Are there cases where a generic and a trade-name drug, both produced by leaders, the prices vary to a great extent ~ Mr. CUTLER. I do not have a specific answer for you, Mr. Grossman, but I think we can assume there are some such cases. Mr. GROSSMAN. I am informed we have prednisone $17 by Schering and $~ and some odd cents by Merck. Mr. CUTLER. Those are both sold under brand names. But still you can go ahead and make your assumption. There may be there are cases where they are sold under generic names. Mr. GROSSMAN. As a doctor, how would you make a distinction between those two? This is very basic-but~I think sometimes we have gotten away from the very basic. In other words, how is a doctor going to make his distinction? Dr. SLESSER. Mr. Grossman, since you brought up prednisone, and since the Medical Letter has been cited frequently in the course of these hearings-referred to, I should say-I would like to point out the significant statement that appears in this ery same Medical Letter that so far has not been aired. And I will read it: Disintegration test- Which is a T5.S.P. test- measures only disintegration and not physiological, availability. There is nothing, however, either in reports of clinical trials or in the experience of Medical Letter consultants to suggest that variations in formulation are causing any problems in the treatment of patients. Now, here again there is a double negative, which proves nothing. Mr. GROSSMAN. Would you be able to tell me, then, that a doctor should choose the Schering product as opposed to the Merck product, for any reason-except his own-for some reason he likes one? Mr. CtrrLER. Mr. Grossman, I think the only answer we can make to that is that if the doctor, based on his clinical experience with his patients or other clinical experience in which he has faith, concludes that those two drugs are substantially equivalent therapeutically, then as Dr. Slesser says, he ought to prescribe the cheaper one. And the AMA has urged doctors to take price into account. Mr. GROSSMAN. How does a doctor find out about price? Mr. CUTLER. About price? Mr. GROSSMAN. Yes. In other words, where does he find this out? Mr. CUTLER. The detail men inform him about price. Pharmacists will tell him, I suppose, if he asks about price. PAGENO="0134" 2268 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GROSSMAN. Would you agree that there should be something available to doctors to show priomg pMii~i~ of ~11 drugs~-m oth~ words, should there not be something? I think there should be some- thing that-so that a doctor would be able to look at something and say Merck is $2-some-odd cents, and Schering is $17, and maybe I better think twice before I do it. Mr. CUTLER. Mr. Stetler testified the other day that he thought a doctor should have whatever information, meaningful information, can be provided to them about manufacturers' prices. Now, you do have problems in equating manufacturers' prices, of course, because those are not the prices at which the drugs are sold in the drugstore. And it may be more meaningful for him to have drugstore prices. Mr. GROSSMAN. Is this ever going to be resolved? Are we going to continue to discuss this? Mr. Cumica. We would favor having it resolved. Mr. GROSSMAN. What steps are we taking to resolve it? Or are we going to resolve it? Mr. CUTLER. You now have directed HEW to make studies, at least with respect to the medicare problem. Mr. GROSSMAN. We discussed this at the end of Mr. Stetler's testi- mony last week. Aren't we faced with this unending process again? You know when FDA makes that study-I don't know-but there is going to be a lot of problems with the study, and you have the Parke, Davis study on the other side, and you can go on and on-this is with regard to equivalency. I am sure we can have the same dis- cussions about compendia. In other words, we can go on and on and on about all these things. Mr. Ctrrnu~. Mr. Grossman, I agree. But we suffer from some of the limitations of a trade association, one of which is that the member manufacturers cannot talk together about their respective price poli- cies, or how they will communicate prices to any class of customer. This may well be a governmentai function. Mr. GROSSMAN. Thank you. Senator NELSON. I have only a couple of questions, Doctor. How many companies would you guess meet, the stringent quality control procedures that you `suggest in your testimony should be followed? Dr. SLESSER. I wish I knew how many companiesthere were. Senator NELSON. I meant in the Pharmaceutical Manufacturers Association. Dr. SLEssen. How many of the PMA member firms? I would say most if not all of them-most of the time. I do not think any company is perfect. Senator NELSON. I do not mean that they always get that result, but how many follow a procedure that you approve of as an expert? Dr. SLESSER. I beg your pardon? Senator NELsoN. You testified very extensively about the kind of quality control procedures that you feel are necessary to produce a quality drug. In your judgment, how many companies in the PMA do you think meet this standard? Dr. SLE55ER. I think most of them do most of the time, Senator. Senator NELSON. Well, it is not really much of a problem, then, in this country, since PMA member firms produce 95 percent of the prescription drugs sold in this country. And if some of the 5 percent PAGENO="0135" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2269 that do not belong meet the standard, we do not really have much of a problem, do we? Dr. SLESSER. If we take 1,500 as a round number-and I think a part of this problem arises from the fact that no one actually knows how many manufacturers, and I am talking about manufacturers-there are, then you are talking about 1,364 firms, and only 136 of the 1,500 PMA member firms-5 percent of the drug supply in this country can be meaningful if the products are given to people who are seriously ill and need effective medication, and they 1~appen not to be. Senator NELSON. But in any event, as I understand it, the members of the PMA manufacture about 95 percent of the prescription drugs. If they meet the standards, we do not have a quality control problem as to 95 percent. Then of that 5 percent who do not belong to the asso- ciation, there are certainly some who meet the standards. So you are down to a situation where a very small percentage-it could be 2 per- cent, or 1 percent-of the drugs on the market are not meeting the quality control standards that you suggest. All I am saying is that this big problem is not nearly so big as it would appear from your testimony, is it? Mr. CUTLER. Senator, while you were over in the Senate just re- cently Mr. Gordon and I reached a meeting of the minds at least on one issue, I think- Senator NELSON. That probably means I won't agree with you. Mr. CUTLER. You agreed earlier-namely that doctors would be well advised to identify the manufacturing source of any drug prod- uct they prescribe. If we are all in agreement on that, I think we have narrowed the issues considerably. And our thesis is they should iden- tify those sources, because the sources vary in the therapeutic effective- ness of their products, and that is true among PMA members and as between PMA members and non-PMA members. Senator NELSON. All the expert testimony from pharmacists or pharmacolo~ists or doctors who have appeared and addressed them- selves to this question, has stated that prescriptions should all be written in the generic term, and that if the doctor has a preference for a particular brand, then he should name the company or the brand, if he wants. That is the testimony, as I recall it, from the experts we have had. Mr. CUTLER. How he should write the prescription is a second issue. But if we do agree that he should identify the manufacturing source, then that is something-we have moved that far along. That is really a condemnation or at least a critique of generic prescribing in the normally understood sense of the word, which is just to write the generic name and let the pharmacist pick any product of that generic- Senator NELSON. I do not know that is what the testimony is. I know they testified that the doctor should prescribe generically, and should be free to name the company or the brand in addition. I think there might very well be some argument from the pharmacists themselves as to their qualification, once you give them a generic name, for being able to sel~t a high-quality generic drug. They may very well be as qualified as a doctor in ordinary circumstances. Mr. GomoN. I want to make a correction. You asked me whether a doctor should write the manufacturer's name or identify it.. What I PAGENO="0136" 2270 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY meant was that the doctor should have the right to iclenvify l& ir ii~ desires to do so. That is only my opinion. Senator NELSON. I have a couple more questions and we can move along. (At this point in the hearing a short recess was taken.) Senator NELSON. We will resume the hearings. Dr. Slesser, on page 11 of your statement, you say, The inability of the FDA to assure even the competence of all drug firms, let alone the clinical quality of their products, is too long-standing to brush aside and the possibility of that situation soon or ever changing is extremely remote. I think you also recited some statistics showing that they made less inspections recently. Was that less inspections this year than last? Dr. SLESSER. Yes, sir. Senator NELSON. Would your company support expanded appro- priations for FDA so that the agency could do a better job of inspecting? Dr. Sr~ussER. Yes, Senator. We certainly have concurred as a member of PMA in the past. history of the PMA to do everything they could to encourage maximizing the budget for the Food and Drug Adminis- tration so that-so as to increase its staff, including inspectors. Senator NELsoN. Has your company ever appeared before `the Appropriations or other committees in behalf of more staff for the FDA? Dr. SLESSER. I do not know, Mr. Chairman. Dr. SCHEELE. If I can answer. It has not been the practice of the Appropriations Subconimit'tees of the House or Senate to hear outside witnesses on such matters. Mr. CUTLER. I am sure we `have written letters, Senator Nelson, supporting appropriations for FDA. Senator NELSON. I think it is a very serious matter that FDA does not have an adequate number of personnel in the field for better inspec- tion `and better enforcement to assure `higher quality. I am sure from all the testimony we have had that certainly there is no member of the PMA who objects to that. But in order to do something about it, I am wondering if the mem- bers of the PMA or the PMA itself is prepared to appear before Appropriation Committees and strongly endorse an expansion of FDA personnel for purposes of testing, inspection, and enforcement of higher standards in the manufacture of drug products. Can you answer that?~ Mr. CUTLER. I believe, Senator, we have supported all of FDA's requests for appropriations, and we are on record and were on record in 1962 as supporting more frequent FDA inspections. Senator NELSON. Good. I think that is very important. I am hope- ful that we will be able to do something constructive about it in the near future, because I do not think it is any economy to economize on quality in this field. One more question. We had testimony yesterday from Dr. Helen Taussig. She testi- fied in the same way as some other expert witnesses we have had re- specting the labeling of bottles that go to patient. from the pharmacist. This is not your responsibility, of course. She testified, as have some other witnesses, that she thought it was very important that the bottle that goes to the patient from the pharmacist have on the label PAGENO="0137" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2271 the generic name of the product, excepting, of course, in cases where a doctor has a specific reason for instructing that the generic name not be on the bottle. Does the PMA endorse that idea? Mr. CUTLER. That is the recomendation as I understand it of the AMA, and the PMA supports that proposal. The PMA also thinks that the manufacturing sources should be identified and the brand name when there is one in.addition to the generic name. Senator NELSON. You have no objectl9n to the appearance of the generic name? Mr. CUTLER. No, sir. Senator NELSON. That concludes all the questions I have, Doctor. I appreciate very much your testimony. It was very constructive, very informative, and useful to the committee. Dr. SLESSER. Senator Nelson, thank you so much for allowing me to appear. (The complete prepared statement and attachments submitted by Dr. Slesser for presentation on November 16, 1967, follows: STATEMENT OF A. E. SLESSER, PH. D., ASSOCIATE DIRECTOR OF QUALITY CONTROL, SMITH KLINE & FRENCH LABORATORIES Mr. Chairman and Members of the Committee, I am pleased to have the op- portunity to supplement Mr. Stetler's statement on the matter of therapeutic equivalence of drug products. Through my activities in the pharmaceutical industry 1 know something about the factors that can affect drug performance. There was a time when phar- maceutical manufacturing, like many other industries, was relatively simple. During that era there was a bare handful of drugs, few of them of known compo- sition or specificity in treatment of disease. However, now we have a great num- ber of highly sophisticated drugs, many of which are chemically complex and quite specific in disease treatment. As a consequence, the technology of manu- facturing consistently safe and effective medicines today is not simple. Control of the quality of the medicinals prepared from today's drugs is a com- plex operation. There was a time when quality control pretty much began and ended in an analytical testing laboratory. But, Mr. Chairman, that time is long past. It is simply wrong, in the light of the present state of the art and science of pharmaceutical manufacture and the inadequately manned government agency, to contend that all drug products of like generic names are equal. I submit we are not likely to have that assurance soon despite the efforts of all involved. Recent figures on FDA inspections, for example, do little to encourage optimism in this regard. The Agency made 3,651 inspections of drug plants in 1966; impressive as that figure may seem, it is 150 inspections less than the 1965 figure, and 341 less than the number for 1964. I do not recite these figures to criticize the FDA, Mr. Chairman. Their inspections of necessity are becoming more complex and time-consuming, and FDA personnel shortages are persistent. Nevertheless, fewer inspections are being made, not more. It seems to me, there- fore, that it would be imprudent to rely heavily or solely on this mechanism as "the method" of assuring drug quality. Even if we make the incorrect assumption that all manufacturers are capable of passing an FDA inspection, we are still in no sense out of the dilemma of therapeutic e~uiva1ence. There is the matter of conforming to USP or other standards. The question is not whether drug products should conform, but whether each batch and each tabTet, capsule and dose of every drug product does conform. The fact that standards exist-and that companies put "USP" or "NP" on drug labels-does not establish that in fact the companies actually have adequate control pro- cedures, or that they follow them. In short, the real question is, do drug products conform to the standards they claim to meet? In all candor, as one who has long followed and~ participated in the work of the USP and NE, I must also note that the standards of the USP and NP do not PAGENO="0138" 2272 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY pretend to include all the specifications and tests that a highly skilled, conscien- tions manufacturer requires his product to meet before he will put his name on it. Mr. Chairman, the chart which I have here (chart #1 attached) provides a dramatic illustration of the potency of some of the pharmaceuticals manufactured today and the importance of pharmaceutical know-how in manufacturing and quality control technology. It shows the proportionately small amount of drug that is contained in 100 tablets of this product. This small amount of drug creates a serious problem-that of making certain that each tablet in the batch contains exactly the correct fractional amount of the total quantity of drug used. This requires technological and control know-how. Furthermore, if an error occurs during manufacture and some tablets have too little drug while others have too much, the consequences to the patient could be serious-yet the cause of the error could not be identified by USP or NP tests. In other words, unless quality and uniformity are built into the batch, laboratory tests may very well not reveal the defect, nor can all the testing in the world of the batch after it is made instill quality into the batch. The fact is that the detailed specifications needed to produce a quality drug product under good control procedures are so extensive and so all-encompassing as to defy inclusion in compendia of any sort. Quality control measures, records and reports used in leading drug firms for each batch of even the simplest drug product are massive. These begin with the raw materials and end with the consumption of the product. Details of the manufacturing and control procedures utilized for only a few products of a capable manufacturer would constitute a book in itself. What I am saying is that conformance to compendial standards like those of the USP and NP, while of unquestioned importance, represents only part of the story. Total quality control involves much more. Mr. Chairman, with your kind permission I would like to call your attention to chart #2 (copy attached) to demonstrate what quality control is, what it does, and how it does it. We all know that safety and effectiveness of a drug product are determined by well-designed, properly controlled and correctly executed clinical tests. Such tests are run by the manufacturer on one, sometimes two, but rarely, on more than two, batches of the product. Having proved the safety and effectiveness of the product, we must ask our- selves this question: "To what facts are the product's safety and effectiveness due?" I have indicated the five factors on chart #2. First, the specific COMPONENTS used-drug and non-drug components. Let me state, Mr. Chairman, that contrary to common belief, the drug component in most tablet products comprises less than 10% of the makeup of the tablet and that the number of components other than the drug may vary from two or three to as many as twenty or more. The capable manufacturer makes sure that components all have pertinent, significant specifications and that these are in writing; that the components are purchased only from known, reputable vendors; that written, detailed in- structions describing the manner and method of sanipling incoming shipments of components exist and are followed; that all analytical test methods are written, are complete, up-to-date, available to the analysts, and are followed for establish- ing compliance with the written specifications. For example, an apparently trivial characteristic such as particle size of a component, whether the component is the active drug or not, may very well be a significant specification for which a test may be required prior to approving it for use in manufacturing a batch of the drug product. The second factor is the formula. Neither the USP nor the NP lists the formula of the products contained therein and for good reason as we shall see later. The formula must list each component and the amount that is to be used. The master formula should be checked by no fewer than two capable, com- petent people, independently and individually, for correctness. Each batch formula derived from this master formula is produced by a process which assures against errors in transcribing, so that each batch formula will have to be correct if the master formula itself is correct. The third factor is the Manufacturing (or Compounding) Procedure. Now, again, these are written, extremely exacting, detailed descriptions of every step of the manufacturing operation, including directions denoting the specific type of equipment to be used in each instance. Fourth, are the various Analytical Tests, Inspections and Cheeks that must be carried out at certain stages during manufacture of the batch. These are in- process controls and they are important; they must be written, they must be detailed; there must be a lot of know-how in deriving the tests, inspections and checks to be followed at the various stages of the manufacturing operation- PAGENO="0139" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2273 with respect to raw material components, intermediates, and at the finished product stage. Finally, we come to what can be called Other In-Process Controls, one impor- tant function of which is to assure that all of the preceding four factors were, in fact, operative and correctly so. Thus the required records, reports, data, signatures, analytical and inspection test results on each batch would comprise an important segment of this factor. Now, Mr. Chairman, let us assume that we have confirmed the safety and effectiveness of one or, at most, two or three batches of the product. However, when we get down to the matter of day-to-day, batch-to-batch production of the product, we obviously cannot clinically test each batch before releasing it to the marketplace. Such tests are extremely time-consuming and costly. Yet we must be sure that each batch is the clinical counterpart of the prototype batch(es). Here, Mr. Chairman, is where the capably exercised Quality Control function comes into play. Quality control, by locking into each batch manufactured sub- sequently to the clinically tested, prototype batch(es) the five factors respon- sible for the product's safety and effectiveness, services as a substitute for the clinical tests on a batch-to-batch basis! In other words, Mr. Chairman, quality control must be visualized as a chain, as shown in chart #3 (copy (copy attached). Thus, the manufacturer who has ca- pably applied the chain throughout the batch's~ manufacture can be reasonably certain that compliance with the laboratory test results at the end of the manufacturing operation assures the safety and therapeutic effectiveness of the batch. However-a'nd this is important-laboratory test results obtained on a sample of a batch or a shipment of tablets, without knowledge as to whether the quality control chain was applied at all or~ how effectively, may not be at all significant in evaluating the safety and therapeutic effectiveness of the batch or shipment. Dr. Lueck will present specific evidence to support the inadequacy of apparent compliance with typical laboratory specifications to assure therapeutic perform- ance. In other words, generic equivalency does not necessarily connote thera- peutic equivalency. The importance of particle form and size in antibiotics, like chiorampheni- col, and in sulfadiazine and the anti-fungal agents, come to mind. Variability in response to different formulations of the blood anti-coagulant tablet, bishydroxy- coumarin, are so significant that the choice of manufacturer source is clearly as important as the choice of the agent itself. The fineness of the drug in the tablet and how well the drug particle size is controlled by one manufacturing source as compared to another may very well determine whether dangerous clot- ting is prevented or serious internal bleeding occurs after ingestion of the usual dose. There are many examples of this sort. A few examples of the steps over and above standard procedures or official standards taken by a quality manufacturer to improve his product and distin- guish it from competing products are the following: (a) To lessen pain on injection. As you know, the injection of some drugs is painful. We are constantly striving to lessen such pain and some of us have learned that by the addition of certain ingredients we can produce a product that causes less pain on injection. This does not happen by accident. (b) To produce medications, particularly injections, which lessen the liability of allergic reactions, which are sometimes not just troublesome but, on occasion, fatal. Much can be done to exclude as far as possible in- gredients suspected of causing such- reactions. Again, such procedures are sometimes costly, but the manufacturer who values his identity and reputa- tion will constantly strive to attain higher levels of purity. The manufacturer who is interested only in "generic equivalency" may not. (c) To produce more prompt solution in the stomach and absorption in the blood where this is desired. Variations in manufacturing procedures, differences in the crystal structure or particle size of the active ingredient and its purity, differences in the combination of non-drug components-all may affect the time necessary for the drug to dissolve in the gastrointestinal tract and may distinguish one product from another. Such differences can have a crucial effect on the therapeutic efficacy of the product. (d) To retard solution in the stomach of a drug that is better absorbed in the intestinal tract, or which performs its function better if it is grad- ually released. All this is, and can be, influenced by different methods of compounding the product, or (if a tablet) by a different coating, or by the addition of other non-drug ingredients. PAGENO="0140" 2274 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (e) To mask bad flavor of an active ingredlient which not infrequently causes adults as well as children to resist and even refuse to take the med- icine. The problem is getting a child to take a prescribed and oftentimes extremely necessary medicine is something that every mother and every nurse is familiar with. Pediatricians and general practitioners choose their medicines carefully and by specification with this in mind. The importance of palatability, I should note, is important in geriatric medicine as woll Mr. Chairman. I am happy to submit for the record a PMA publication en- titled "The Importance of Manufacturer Identification" which includes addi- tional information on the points just covered. (Copy attached.) Recently we undertook a careful search of the published literature on the effects of drug formulation on therapeutic activity of drug products. We col- lected a total of 211 references. Many of them are reports on variations in therapeutic activity observed in human volunteers and patients; the others cover both in vivo and in vitro (laboratory) experiences. These articles, I should point out, are solely related to the subject of generic and therapeutic equivalence. In fact, much additional literature on pharmaceutical sciences, published in thousands of articles annually, bears on this question; much of it relates to corollary subjects, such as stability variations, effects of certain non-drug components on the drug's effectiveness or stability, particle size and form, and other significant factors that can and do affect quality. Gentlemen, there is a whole profession, international in scope, with thousands of practitioners who are dedicated to such scientific studies and, in fact, a new scientific discipline, called "biopharmaceutics" has recently arisen because of the importance of such work. The scientific literature output of these scientists has been estimated to be nearly 10,000 articles each year. Some witnesses who have appeared here would like to eliminate or to curtail therapeutic duplication of drug products. In my opinion, such a step would serve as a devastating setback to medical progress and deprive patients of es- sential medication. In illness, patients vary in their response to medication. Patients vary in their idiosyncrasies, sensitivities, allergies and tolerances to drugs. It is, for example, a well known fact that no one or two drugs are suitable for the treatment of all cases of epilepsy. The wide choice of drugs available for epilepsy exists solely because a half century of experience has shown that there is great variability in response by individual epileptics to available drugs. What we need is more and not fewer strings to our therapeutic bow. The same is true of almost every disease and disability. The broader the therapeutic armamentarium, the better our physicians can care fOr the sick and suffering. The harm of eleminating one necessary drug far outweighs the alleged burden of too many drugs. Mr. Chairman, the evidence of variability in drug product performance is too obvious to be ignored. The inability of FDA to assure even the competence of all drug firms, let alone the clinical equality of their products, is too longstanding to brush aside, and the possibility of that situation soon or ever changing is extremely remote. Of one thing I am certain: tying the doctor's hands, binding him in a kind of pharmaceutical straightjacket, will not answer the problem. It will compound it. It will be more constructive to work toward a Federal drug program that will take cognizance of all the realities of medicine and pharmacy today. And in that task we are most anxious to join you. BIOGRAPHICAL SKETCH OF Dn. A. E. SLE5SER, ASSOCIATE DIRECTOR, QUALITY CON- TROL, SMITH KLINE & FRENCH LABORATORIES Born: Lafayette, Indiana. Education: Purdue University, School of Pharmacy, B.S. in Chemistry M.S. and Ph. D. in Pharmaceutical Chemistry. Ea,perience: Four years with Burroughs Welicome & Co. as Chief Research Pharmacist in product research and development, followed by two years with Bristol Laboratories as Head of Production Development. Seven years with University of Kentucky College of Pharmacy as Professor of Pharmacy, Chairman. of the Department, and Assistant to the Dean. Thirteen years with Smith Kline & French Laboratories as Assistant Tech- nical Director, involved in Quality Control, production trouble-shooting, formula, process and packaging improvement in commercial products. Cur~ rently Associate Director Quality Control for SK&F. PAGENO="0141" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2275 Awards, Honors, Memberships: Eli Lilly & Company postgraduate Fellowship. Member Society of the Sigma Xi and Rho Chi Society. Past Chairman, Committee on Inter-Tablet Dosage Variation (a committee of the Quality Control Section of the Pharmaceutical Manufacturers Association). Author of textbook: "The Pharm-Assist Manual" (C'. V. Mosby & Co.-1953). Registered pharmacist (Indiana and Kentucky). Member American Pharmaceutical Association's Academy of Pharmaceutical Sciences (Drug Standards, Analysis and Control Section, and Industrial Pharmaceutical Technology Section). Senior Technical Advisor, Exhibit Committee, National Pharmaceutical Council. *~~`*øS1P'* lU -V CHART 1 PAGENO="0142" 2276 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FACTO[~S D~T~M!N!N~ SAFETY AN~ CT~V~N~ OF A ~UG PRODUCT I. Components (Drug. ~nd Non~1'ug) 2. Form~~ 3. Manu~cci~urinçj (Compounding) ProcQdurG 4. .A~ciy~, Tests, 1n~pGciori~, Chc~ct~ 5* Other tH~roco~s Contrc!s CHART 2 (SAFETY a EFFECTIVENESS BY CLINICAL 1I~IR) FINISHED t (LAB. TESTS ALONE CANNOT ASSURE 0G. CHAIN FOR SAFETY & EFFECTIVENESS WAS APPLIED) QUALITY CONTROL (SAFETY & EFFECTIVENESS) CHAiN CHART 3 PAGENO="0143" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2277 TEE IMPORTANCE OF MANTJFAOTTJRER IDENTIFICATION A review of the issue influencing the choice of drug products in the interest of more precise therapy and greater assurance of reliability (By the Pharmaceutical Manufacturers Association, October, 1965) I. INTRODUCTION AND BASIC POSITION The member firms of the Pharmaceutical Manufacturers Association (P.M.A.) believe that competition in prescription drug production and distribution, under a system whereby physicians' prescriptions and drug labeling and advertising prominently identify the source of products by~ company name or product trade- mark, accelerates the pace of drug discovery, and encourages the highest stand- ards of safety and effectiveness and the most economical medical care. This statement outlines the bases for this belief and discusses the public health importance of a drug identification system. As the statement will show, there are variations in finshed drug products result- ing from the different formulations and prOduction methods of individual manufacturers-differences that exist even though the pharmacologically active ingredients may be chemically identical. These differences are not necessarily related to product quality, but they may be. In any event they can affect the thera- peutic value and physician or patient acceptance of a given finished drug. The system of using trademarks or brand names is the best known and most effective means of providing responsible identification of finished products, thereby giving the greatest assurance of reliability and predictability in drug therapy. And, for the same reasons that prevail throughout all American industry, the trademark or brand name system fixes the responsibility and the reputation of the manufacturer, causing him to seek ever higher levels of excellence in his total performance. Modern medical care owes much to pharmaceutical advances. Medical and pharmaceutical scientists have turned one key after another in the search for specific remedies to treat the myriad ills responsible for suffering and premature death. P.1~LA. member firms alone have contributed more than $2 billion-worth of research to this quest since 1945. Thirty years ago, for instance, there was only, a small handful of drugs which would safely cure an infection in man. Today~ there are many, ranging from the broad-spectrum antibiotics to a compound so selective in its action that its use is restricted to a specific virus infection in the human eye. Around one billion prescriptions are written by the nation's physicians and dentists every year in the United States. Practically all of the products pre- scribed and used come from the nation's pharmaceutical manufacturing labora- tories. Precise dosage forms and formulations usually identified by trademark or brand name are made available to the physician and are dispensed by a pharmacist to his patient. The proposition that the use of drug trademarks or brand names is in the public interest is based on three principles that are fundamental to the con- tinuance of excellence in drug discovery, production, and therapy. They are: 1. Therapeutic Uontrol.-The physician responsible for the care of the patient must determine which drug product is needed in each case. Many important and widely used drug products do not have legal standards. Even when drugs are covered by such standards, there are difference among individual formulations of products of different manufacturers which can be significant for some patients. The physician must decide whether therapeutic precision, reliability, or convenience calls for a particular formulation for a given patient, or the extent to which the selection can be delegated to another member of the health team, e.g., the pharmacist. 2. Reliability of Product.-A. physician should be in a position to judge and select products on the basis of his knowledge of the reliability of the product and experience with the past performance of the producer. This method gives added protection to the patient-who should be assured that high standards of quality and reliability are being used in prescribing and dispensing pharmaceu- tical products for his use-and promotes high standards of production and con- trol that go beyond minimal enforceable levels. PAGENO="0144" 2278 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3. Company Total-Value Product.-The prescription pharmaceutical manu- facturing industry is in competition for excellence. Responsible pharmaceutical concerns, under the stimulus of our competitive system commb th~olTAa th expenditures and accomplishments in creative research, reliable production and marketing, and high standards of management. These organizations, who openly and widely identify their products by trademark or brand name, and in so doing identify themselves, are thus motivated to provide excellence in total quality of product and service. Such total control of quality of product and service is of significant value to dispensers and consumers of today's prescrip- tion medicines, exceeding by far the value of the product's ingredients. In. summary, patients, physicians, and pharmacists can best be assured of therapeutic control, reliability of product, and the value of total company service when the product is designated by trademark, brand name or other responsible identifloatkm~ of the people who stand behind it. II. NAMES, STANDARDS AND REOULATIONS The issues involved in drug prescribing and regulation cannot be approached intelligently unless certain terminology, references and practices are precisely defined and clearly understood. The following description of drug nomenclature, of the official reference guides to drug standards, and of government regulatory processes are presented here in brief summary. A. How drugs are named Most drug products have `three names: the chemical name, the established or generic name, and the tradenuirk or brand name. The first two names describe the same thing; that is, the chemical composition of the active therapeutic ingredient(s). The first is scientific and precise; the second is more convenient and concise. The re'lation~hip is analogous to that of `the scientific term, Homo sapiens, and the more common and usable term, man. The third name-the trademark or brand name, on the other hand, refers to a particular manufac- turer's formulation, and identifies the drug product with the originator or manufacturer. So, the completed analog would go like this: H'omo sapiens, man, John T. Jones. Chemical name A therapeutically active compound, like all other matter, is composed of a combination of basic chemical elements. Once created or identified, a drug molecule is named in the laboratory according to standard practice in the field of chemistry. Here is an example: 6-choloro-3,4-dihydro-7-suifamoyl-2H-1,2,4,benzotMadiaz- ine-1,1 dioo~ide. This is the chemical name of a product compound widely pre- scribed to decrease excessive fluid content in the body-a diuretic. While long and cumbersome, this name is also precise for it serves as a complete identifi- cation of the compound to any truined chemist. Established (or generic) name Obviously, a drug compound must also have a shorter, more usable name. Such a name is originated by research or medical authorities involved `in the possible therapeutic application of the chemical. The name is then submitted to review coirnuittees of the American Medical Association and of two standard drug references, the U.S. Pharma~copeia and the National Formnlary. These three groups function through a coordinating group called the United States Adopted Names Council. If there is any conflict with existng names, or disagreement as to the meaning suggested by the proposed name, further negotiation takes place with the initial sponsor of the name. The Food and Drug Administration has veto power over final selection. If entirely satisfactory, the name is then transmitted to the World Health Organization, which works with the official pharmacopelal organizations of many nations. Once a name for a drug compound has been approved `by `the Adopted Names Council, or by a regulatory body it is thereafter known as the "established" name, also referred to as the "generic," "offidial," or "nonproprietary" name; the most popular of these terms, and the one that will be used in the balance of this paper, being, "generic". In the case of the compound illustrated earlier, the established or generic name adopted is lzydrochlcrothiazide. Still quite a mouthful, but much easier than: 6-coloro-3,4-dihydro-7-swlfamoyl-2ff-1,2,4, benrothiadiazine-1,1 dienide. PAGENO="0145" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2279 The generic name is a shorthand way of referring to a specific chemical substance. It does not describe some of the therapeutically significant physical attributes of the substance; i.e., it does not tell if `it is amorphous, crystalline, coarse, or fine. Neither does it describe its' degree of purity beyond minimum legal standards. For these and other reasons, the often-used phrase "generic drug product" is no more than a misleading term. The term "generic name," properly used, refers only to the pharmacologically active chemical ingredient of a finished product, and not to the finished product itself. To be dispensed and used, the chemical ingredient must be combined with other carefully selected substances' and embodied in a finished product (dosage) form such as a tablet, an ampule, or a suppository. Therefore, in the case of finished drugs (dosage form), application of the same "generic" name to two or more products does not and cannot mean that they are necessarily identical. The brand name or trademark Pharmaceutical companies generally adopt `brand names or trademarks to identify their products. No official rules control this nomenclature. The objective is to coin a name which is useful, dignified, easily remembered, and individual or proprietary. After it is finally put into use in interstate commerce, the brand name is gen- erally registered with the U.S. Patent Office. To continue the example cited above, one manufacturer of a product based on hydrochlorothjazide gave its finished produce the brand name, HydroDiuril, sug- gesting partly the chemical name and partly its diuretic properties. Another manufacturer, for other reasons, chose to name its product containing hydor- chlorothiazide Esidrix; a third, Oretic. These names are quite different, which is proper since they are intended to identify different products produced by different companies. But in order to avoid confusion and simplify the physician's and pharmacist's `task of remember- ing the main therapeutic ingredient of the many products on the market, the generic name of the principal ingredient appears on product labels in advertising and in other communications about the product. Hence, the names mentioned above may be referred to this way in written communications. HydroDiuril (hydrochlorothiazide) Esidrix (hydrochlorothiazide) Oretic (hydrochlorothiazide) There is the alternate method of using the company name, initials, or synthol along with the generic name. The following examples, based on a fictitious John Doe Drug Co., illustrate the method: hydrochloroibhiazide, Doe or hydrochlorothiazide, DDO B. Legally acceptable and other standards For more than 100 years, drug standards established `by non-governmental bodies have played a major role in the continuing effort to o1~tain uniformity in therapeutic agents. Their existence, however, does not guarantee therapeutic uniformity of products from manufacturer to' manufacturer. But since these standards have frequently been cited as a readymade foundation for a system of so-called generic name prescribing, it is important to understand their exact coverage and function. The Pharmacopeia of the United States and National Formulary are "official" publications of the U.S. Pharmacopeial Convention and the American Pharma- ceutical Association respeCtively. They are recognized as registers of legal stand- ards to which drugs and some ingredients used in making medicines should conform. These lists are specified by the U.S. Government under the Food and Drug Act, as amended, as setting minimum standards. Lists are periodically compiled by other organizations, too, each designed to serve specific needs. Pharniacopeia of the United States (U.S.P.) .-~--This compendium was the first of two published in the 19th century covering the broad practice of pharmacy, to guide pharmacists and drug manufacturers. The first edition of U.S.P. was printed in 1820 under the auspices of the U.S. Pharmacopeial Convention, a pri- vate assemblage of physicians, pharmacists, chemiSts and others. It is an au- thoritative source of minimal standards for therapeutic substances "the utility 81-280 0-68-pt 6-1O PAGENO="0146" 2280 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of which is most fully established and best understood." IJ.S.P. is now revised every five years by a committee representing the naition's Schools of medicine and pharmacy, certain government agencies, medical and pharmaceutical socie- ties, and other professional organizations. National Farrnulary.-~Because the U.S.P. was selective in its inclusion of drugs, restricting its coverage of those drugs the utility of which the committee considered the "most fully established," many other valuable and widely-used drugs were not included. To cover these, the American Pharmaceutical Asso- ciation, a professional association of pharmacists, began publishing in 1888 the National Fornislary (N.F.). The N.F. also has served as a guide to drugs some- times before they appear in U.S.P., and frequently after they are removed from U.S.P. The monographs of the TJ.S.P. and N.F. have been recognized in every federal law pertaining to drugs, starting with the Food and Drug Act of 1906, as legal standards. Drug products containing ingredients conforming to the criteria in these compendia have permission to carry the designation "U.S.P." or "N.F." on their labels and packages. It is important then to understand just what these standards guarantee as well as what they do not guarantee: 1. In general, the information in these compendia is descriptive only of the chemical properties of active ingredients and a'djuvants and the laboratory pro- cedures required to demonstrate substance identity and allowable limits of purity. Significant as this information is, the chemical tests and specifications do not by themselves give full information on the pharmacologic or micro- biological activity of the substances listed. Additional studies of a given drug product are still necessary to reveal the presence of certain physical char- acteristics such as particle size, crystal form, surface properties and other attributes which influence the biological availability of the pharmacologically active compound in question. Only an extensive and integrated physical-chemical- biological research program can determine the ultimate pharmacological action of the compound along with the characteristics which must be controlled to guar- antee safety and efficacy. Moreover, it is rare to find an active drug compound used by itself in ther- apeutic treatment of a. patient. Frequently, the finished product will contain other materials to facilitate or augment the action of the principal ingredient Often the complete preparation contains more than one active ingredient. The selection of these active ingredients and ancillary materials-4n terms of their purity, function, concentration and appropriateness-is of central importance to achieve maximum efficacy and safety. In short, the complete formulation of a finished product for use by a patient inveives much more than is covered by the information in these compendia. 2. U.S.P. and N.F., stemming from an era in which the pharmaceutical formu- lation of active ingredients was largely performed by the local pharmacist, contain some occasional information on simple compounding. But they do not cover the complex processes of modern mass production, and they give relatively little guidance to standards in this area. Neither do they cover other considera- tions of great importance to modern production and distribution, such as long- term stability. Many of these things are not covered, because in fact they cannot be re- duced to precise standardization that would be meaningful with respect to all manufacturers alike. Production of quality pharmaceutical products is not en- tirely a science; it is also an art and craft involving experience and know-how and professional pride. The experienced industrial pharmacist calls upon skills and a background of knowledge unique to him. 3. Because of the prodigious effort required of so many authorities working on U.S.P. and N.F. revisions, these compendia are revised only at five year intervals with supplemental addenda published occasionally in the interim. However, numerous new drug products may be introduced without being included in either 4~ompilation for several years. The regulatory agencies, of course, do not depend solely on the compendia for establishing standards, and new products are monitored from the start on a product-by-product, company-by-company basis (see below). But, until a consensus is worked out within the TJ.S.P. and N.F. mechanism, there is no set of standards for these new items. AMA New Drugs.-In view of these limitations, it is understandable that reg- ulating bodies and large purchasing groups have set up other reference standards~ PAGENO="0147" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2281 The Council on Drugs of the American Medical Association began to publish in 1906 detailed information on the chemistry, pharmacology, clinical utility, and safety of some new drugs in a reference guide, until recently titled New and Non~-Ojfleka Drugs. This book has been redesigned, changed in form and text, and first published in 1965 as New Drugs (N.D.). The N.D. does not es- tablish standards at all, as U.S.P. and NJ?. do, but rather serves as an annual collection of monographs for the guidance of the practitioner. Like the U.S.P. and N.F., this volume does not provide criteria from the chemical-physical- pharmaceutical subtleties of drug product manufacture and control. Selected groups depend on other sources for guidance regarding drugs for use in their fields, for example the dental profession generally refers to Ap- proved Dental Remedies as a source of information. The Medicare Act (P.L. 89-97) accepts the above four compendia as well as the Homoeopathic Pharma- copoeja as lists of drugs qualifying, without further action, for reimbursement under the program. New Drug Application ~peeifications.-.The~ Federal Food and Drug Adimin- istration (FDA) requires that each new drug application (NDA) include de- tailed data on the process and control procedures under which the product is to be manufactured. Thus, the new drug application covers a broad range of information and standards not included in the U.S.P. and N.F. For obvious competitive reasons, much of this information is not published. But, even if it were, it is important to note that each manufacturer filing an NDA must in- clude his own production specifications. Therefore, approval of one company's product does not carry with it the assumption that a second or third company's version will be approved or will be identical. In point of fact, the techniques of production and complete formulation inevitably differ. This is further recog- riized by the Fl)A's requirement that clinical trials and data are required from each company for each product version as assurance that every formulation is safe and effective. So, even though all new drugs come under FDA control and there are detailed standards applied to the production of these products, these standards are not and cannot be regarded as general across-the-board standards, applying to a group of products with the same generic name. Purchaser Speoi/icationu.-Finally, standards are sometimes applied by pur- chasing groups having the facilities and staff to prepare and enforce specifica- tions in a more detailed way. Large hospitals, government agencies and other such volume purchasers may consult with suppliers and draw up detailed, but practical, specifications as a guide to competitive bidders for supplies of drug products. C. 1?egulation-Enforcement and "voluntary eompliaince" Regulation of any private enterprise in this country, of necessity, is composed of two elements-direct enforcement and voluntary compliance. It is impractical to expect the government or any outside agency to observe and then rule over every action of a large industry. Neither is it in the public interest to allow products affecting human health to be made and distributed without regulation. Obviously, the best situation consists of a proper balance, a harmony of purpose between official regulations and private initiative. Our brand name system actively serves to promote this goal, which has been called "voluntary com- pliance." As it is, the U.S. prescription drug industry is one of the most intensively regulated industries in the country. Numerous laws affecting the industry are administered by the U.S. Food and Drug Administration, the Division of Biologics Standards of the National Institutes of Health and other federal bodies, as well as state and local agencies. A proposed drug product is monitored by the government from the time an experimental project is designed through its emergence from the laboratory ready for trial and its marketing for treatment of human disease. Monitoring does not stop here. It continues as long as the product is on the market. A new drug cannot be offered for sale without express approval; its production, promo- tion and marketing methods must also be approved. These laws stem from the Pure Food and Drug Act of 1906, which was aimed at barring adulterated or misbranded foods and drugs from interstate commerce. The Food, Drug and Cosmetic Act of 1938 added provisions requir- ing that the FDA pass on the safety of new drugs before their commercial in- PAGENO="0148" 2282 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY troduction. The Kefauver-Harris Amendments of 1962 added the pre-marketing requirement of proof of product effectiveness, increase governmçnt control of production and quality control procedures, required the registration of all drug manufacturers, increased the inspection powers of FDA and gave FDA greater control of labeling and promotion. Despite increased legislation and regulation, both the Food and Drug Ad- ministration and the industry recognize that the principle of voluntary com- pliance has remained a key part of the philosophy of federal regulation. This principle gives rise to positive stimulation of responsibility within the industry, so that federal enforcement activities can be held to reasonable, workable limits. In the field of quality manufacture and control, the techniques and patterns set by pharmaceutical industry leaders have tended over the years to be codified into government regulations. But it is important to recognize that under our system of voluntary compliance, it is neither intended nor practical for a gov- ernment agency to assume the fundamental responsibilities of production and distribution. For instance, the law calls for inspection of every production facility at least o~nce every two years. Clearly, this infrequency places the greatest share of the burden of maintaining good manufacturing practice upon the producer. In this area, as in so many others, the competitive nature of American business serves the interests of the public well. For the reliable manufacturer there is a built-in desire to excel in product quality as a competitive measure. The FDA picks up products from distribuiton channels to spot-check contents and labeling. But there are thousands of products in interstate distribution, and hence there is a real responsibility of the manufacturer to guard against the distribution of sub-standard products. Furthermore, spot-checks of product con- tents and labeling are made after products have been in the channels of distribu- tion for some time. The services performed by brand name manufacturers supple- ment the regulatory activity of FDA. Their record-keeping, returned goods policies, and inventory checks by their sales representatives help to maintain fresh stocks of quality products on retailers' shelves. Then too, some FDA powers extend only to products in interstate commerce. In many states, separate regulations apply to intrastate commerce in drugs. Some states have statutes almost identical to the Federal Food, Drug and Cosmetic Act; in others, consideration is being given to laws comparable to federal provisions. Realistically, however, the state rules covering production and sale of drugs within a state's boundaries are, and are likely to remain uncertain and varied for years to come; and the capacity of state governments to carry out an effective enforcement program to back up their laws varies considerably. Here again, the importance of voluntary compliance is evident. In view of the limitations of enforcement, the public interest is well served by our system of trademark or supplier identification. The well-identified product and producer must excel in product quality as a matter of probity, as well as competitive necessity. By creating a proprietary interest in the performance, reputation, and hence usage of branded products, this system gives a strong stimulus to private responsibility, which together with practical regulation and enforcement, can provide the public with maximum assurance of safe and effective medicines. III. THERAPEUTIC CONTROL A fundamental principle enunciated by this paper is that the physician respon- sible for the care of the patient must determine which drug product is needed in each case. Many important and widely used drug products do not have legal standards. Even when drugs are covered by such standards, there are differences among individual formulations of products of different manufacturers which can be significant for some patients. The physician must decide whether thera- peutic precision, reliability, or convenience calls for a particular formulation for a given patient, or the extent to which the selection can be delegated to another member of the health team, e.g., the pharmacist. Finished pharmaceutical products can differ, even though their principal active ingredients are identical in the generic sense. For some patients these differences can have significant therapeutic consequences. Under a compulsory generic system, which would suggest that all products bearing the same generic designation are equal and could be interchanged, the PAGENO="0149" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2283 physician would prescribe by indicating, without regard to the producing source, only the generic name of the drug and the dosage form he wanted his patient to have. This would introduce the possibility of a number of variables which could affect the course of treatment of some patients. For one thing, the physician would not know, unless he made a later check, exactly which one of any number of preparations the patient actually received from the pharmacy. Since different products purporting to contain the same ingredients may have different effects, the physician could not properly judge the patient's responses. Not only may products which purport to contain the same active ingredients have therapeutically significant differences, there are significant differences between such products at least in terms of patient convenience and acceptance. If a medication is relatively pleasant and "easy to take", the patient is more likely to follow the regimen outlined by the physician. Then too, most patients and most physicians, under ordinary circumstances, prefer to avoid the potential uncertainties of generic prescribing. The long-range trend of drug therapy has been the search for precise treatment-matching the particular therapy to the individual patient and disease. Even with the same finished form of the same drug, there are variables in patient response. Further unnecessary variations in the drugs themselves only serve to reduce the control of the physician over the circumstances he seeks to correct or prevent. The members of P.M.A. do not contend that all patients would in every in- stance be adversely affected by "bline" generic name prescribing nor that the physician should never elect to govern his choiëe of product by price differences in cases where they exist. However, the fact that variations occur in products purporting to contain the same active ingredients makes it advisable that only in exceptional circumstances should the physician fail to designate by trade- mark or manufacturer's name the source of the product he intends for his patient. A. Product differences Here, in brief, are selected aspects of drug formulation that affect the action or patient-acceptance of drug products. Liquid&-Among drug preparations administered as liquids, by injection, ingestion, or application to sensitive tissue membranes, there can be distinct variations in particle size, stability, sterility, surface tenson (which determines wetting or spreadabifity), and viscosity (which controls resistance to flow, or adherence). ~olids.-Important variables among tablets include the maintenance and effec- tive release of potency; absorption characteristics of ingredients; tablet dis- integration and dissolution rate characteristics; uniformity and biological b& havior of delayed and sustained release compositions. Lotions, creams, ointments.-Factors important to therapeutic effectiveness and patient tolerance include skin permeability, ease of application and removal, and lack of local irritation. Other therapeutic variables.-For certain types of patients, specialized formu- lations provide significant elements of safety or tolerability. The allergenicity of the additive (filler or binder) substances in some brands of a pharmaceutical preparation may be reflected in undesirable reactions on the part of sensitive patients. Also, a quality manufacturer will design his formulation, if possible, to be compatible with other medications that may be added to it or taken with it. f~ubjective factors.-A patient's acceptance of a drug preparation is also important. If the product is in some way obnoxious or uncomfortable to the patient, he will tend to avoid taking the prescribed medication. Liquids require palatability, freedom from nausea, pleasant "feel", freedom from grittiness and ease of swallowing. Odor and flavor can be of considerable importance, particu- larly when medications must be used over long periods of time. Packaging.-Pharmaceutical products are frequently in direct contact with their containers for long periods of time. The choice of proper grades and types of glass, plastic~, meal, rubber foil and other materials to prevent interaction with the components of a drug preparation, and to provide adequate protection for the contents requires specialized tests and skills of the highest competence. 1~tability.-A drug product should be compounded to maintain its labeled potency throughout the expected period between its production and consumption by the patient. Care must be taken to assure reasonable shelf stability when PAGENO="0150" 2284 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the drug is at the pharmacy and in the patient's medicine cabinet. Responsible producers will generally accept for credit out-of-date goods returned by a pharmacist. B. Therapeutic consequences of product differences Clinicians, pharmacists and others have reported the significance-in some cases, the hazard-of changing to different brands or formulations of so-called generically identical drugs. No complete scientific study of the entire problem has been made, but published findings are persuasive indications of the risks involved in generic prescribing. The dissolution rate of a compound may be influenced by the finished formulation, as with dicumarol tablets reported by Levy-Nelson (Journal of the American Medical Association, September 9, 19(31) and others. Levy has also cited differences in absorption rate of spironolactone, leading to a fourfold overestimation of proper oral dosage. Similar experiences with formulations of, cortisone, prednisone, and other steroids have been reported, as well as with the antidiabetic tolbutamide in certain tablet preparations. Probably the most telling review of this issue was that recently published by Sadove, Rosenberg and Shulman of the University of Illinois Hospital and Hines VA Hospital (American Professional Pharmacist, February 1965). Their experi- ence is presented from the viewpoint of hospital staff members who are not always informed of changes made in the hospital's inventory of drugs, and who have found therapeutic variations later traced to switches among so-called "generic equivalents". They cite the marked irritancy resulting from switching to an erythromycin preparation containing a different salt; the decreased shelf life of a soluble barbiturate preparation using a different vehicle; the effect of buffering agents on local anesthetics, with marked differences in irritation, onset, and duration; the irritating consequences of a new container which used a closure high in heavy metal content; a case of idiosyncratic reaction to a test drug that unexpectedly caused a thrombophiebitis because of a different vehicle used in its preparation; and so on. In commenting on the proposal to obtain drugs from different sources at lower cost through "generic" prescribing, they say: "The specifications of. . . two products were identical. The clinical results were entirely different. . . in many instances it is physically `impossible to compare `two similar products without extensive, carefully-controlled laboratory and clini- cal trials. Though it is admirable to keep the cost of drugs to a minimum and `it is admirable to know and prescribe drugs generically, the generically-similar product exerts, in many instances, a very different reaction from the one anticipated. "It `is practicaily impossible for one not skilled in the area of clinical phar- inacology to know what is-and what is not-a real `equivalent'. "Above all, the lack of avai1a~ble data would preclude substitution without prior equation of the `many factors which could materially `alter apparent equivalency." Their conclusion was "that generic equivalency is frequently a fable without basis in fact; chemical equivalency of the primary agent or agents is not neces- sarily clinical nor pharmacologic equivalency". IV. RELIABILITY OF PRODUCT The Basic principle presented here is a physician should be in a position to judge and select products on the basis of his knowledge of the reliability of the product and experience with the past performance of the producer. This method gives `added protection to the patient-who should `be assured that high standards of reliability are being used in prescribing and dispensing pharmaceutical prod- ucts for his use-and promotes high standards `of production an'd control that go beyond `minimal enforceable levels. Except in large and exceptionally well-equipped institutions and consulting laboratories, facilities for providing independent and reliable assays of drug quality do not exist. The resources of the `average physician, pharmacist or hos- pital are not adequate `for comparing physical qualities of competing products. Under these circumstances, the system of responsible identification by trademark or brand name plays an important role. It enables the physician to judge quality of product on the basis of its producer's established reputation. And since respon- PAGENO="0151" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2285 sible producers know that their products are so judged, they strive to achieve and maintain the best possible reputation for quality. The physician and his patients obviously benefit greatly from this system in which the needs of medical care `are matched by the aspirations of the producer. Standards and legal enforcement, as a practical matter, can concern themselves only with certain major aspects of product specification. Only through the active desire and efforts of the producer to excel can the principle of "voluntary com- pliance" give the assurance of quality that the public must have. This desire to excel is a built-in feature of the responsible identification system. The P.M.A. defines quality control as follows: "Control of quality in the formulation, manufacture, and distribution of phar- maceutical, biological, and other medicinal products in the organized effort em- ployed by a company to provide and maintain in the final product the desired features, properties, and characteristics of identity, purity, uniformity, potency, and stability within established levels so that all merchandise shall meet profes- sional requirements, legal standards, and also such additional standaTds as the management of a firm may adopt." Testing a finished pharmaceutical product for quality is a difficult and com- plex laboratory problem, because quality is often a hard-to-trace feature that must be built in-during production, from raw materials to formulation, through in packaging and all intervening operations up to the delivery of the products to the consumer. As an example, long-range stability is a feature of quality made possible by careful research, formulation, and production. The only com- pletely valid test of this feature is time. Any short cut or lack of skill during manufacture that results in deterioration of the product months later often cannot be detected until the weakness appears. And only fortuitous spot-checking would pick up the inadequacy before many patients have received the faulty medication. For these reasons, federal regulations are now stressing standards of good manufacturing practice, even though such standards are difficult to enforce unless the company itself it motivated to meet them. The storage facilities for raw materials; the facilities for bulk formulation; the layout of the plant; the work-flow process; the precision of the equipment; the training and experience of supervisors and workers; the standards and dis- ciplines of internal quality inspectors; the attention to quality control technol- ogy; the searching for solutions to, rather than avoidance of troublesom,e prob- lems; the willingness to assume the costs of detecting and correcting error; the intelligence of information flow, and record keeping-these are among the ele- ments of responsible, quality production. These elements are recognized by most experts in drug production. However, they emphasize the difficulty encountered by an individual physician or pharma- cist in making quality judgments without the advantage of relying on the producer's known reputation. The drug standards regulatory system (see pages 7 to 14) is clearly not designed to replace private manufacturing responsibility. It is therefore clear that the system of competitive sthnuiation to quality, through responsible product identification, provides a service of inestimable value. V. THE VALUE OF TOTAL COMPANY PERFORMANCE The third positive value of the brand name system, which goes beyond reli- ability of product, has been expressed in this way: Company Total-Value Product.-The prescription pharmaceutical manufac- turing industry is in competition for excellence. Responsible and identified pharmaceutical concerns, under the stimulus of our competitive system commit themselves `to expenditures and accomplishments in creative research, reliable marketing and production, and high standards of management, personnel and comprehensive service. These organizations, who openly and widely identify their products by trademark or brand name and in so doing, identify themselves, are thus motivated to provide excellence in total quality of product and service. Such total control of quality of product and service is of significant value to dispensers and consumers of today's prescription medicines, exceeding by far the value of the product's ingredients alone. `General Principles of control of Quality in the Drug Industry, adopted by the Board of Directors of the P.M.A., May 3, 1961. PAGENO="0152" 2286 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Encouraged by the stimulus of a system built around responsible identifica- tion of products and their source, the private-enterprise method of drug de- velopment and supply impels companies to seek continually rising levels of total performance. Spurred by competition, and vulnerability to criticism if products or services are lacking on any count, companies seek constantly to surpass others and to improve their own record in quality performance that extends into all operations. The physician and pharmacist gain added assurance of excellence when a company undertakes quality performance, for dedication to quality is a long- term commitment. A quality operation requires the assembling of capital and skills and a background of experience that cannot be readily shifted from one business to another. Manufacturers without these long-term commitments are risking relatively little in producing cut-rate products of questionable quality. They can seek short-term gains, with little to prevent their shifting to a clif- ferent field when difficulties arise. And the consumer-patient also gains because commitment to quality generates what might be called "total quality." To provide top-notch facilities and per- sonnel for excellence in production and distribution, the company must make a commitment over the long4erm suffcient to attract investment money and high- caliber technical people. These factors stimulate pressures for growth in per- formance and service that motivate the other activities or potential activities of the company-enterprising marketing of products to new geographic areas or new fields of medical practice; enterprising search for products improvements leading often to totally new products and services; more efficient management and administrative and legal operations to back up the broadening product line and numbers of personnel. In short, quality performance in research, in development, in production and control generally does not operate in a vacuum, but accompanies or creates a broader range of company service that supplies the professional and consuming public with what can be termed "total-value product." This total value extends from the creation and marketing of the product to its productiun, distribution and service as part of an industrial organization with a broadening role to j~lay in the city's, state's, nation's or world's economic and social progress. Elements of total company performance Here, in brief summary, are some of the most important activities adding up to total quality performance in the prescription drug industry. Note that quality of product per se is not one of the items listed, since this has already been covered adequately. 1. The importance of research for new products is so obvious that it requires no explanation. It is enough to say that three-fourths of the drugs taken by patients today did not even exist in 1950, and that all too many diseases causing premature death and untold suffering today cannot yet be controlled. 2. The continued testing and improvement of existing products is another obviously necessary and ongoing activity of responsible pharmaceutical companies. 3. Availability of product, regardless of distance or population density, is im- portant in a nation such as ours which happily considers the health of a person in a remote rural area just as significant as that of a man living within easy distance of a major medical center. 4. The care and completeness with which records are kept can make a con- siderable difference in many situations. Being able to trace a suspected product problem throughout the entire distribution operation can ease the worry from an unexpected occurrence and provide a course of action otherwise less certain. 5. Under unusual circumstances, if recall of a shipment of products is neces- sary, a reliable company can perform the task with speed and thoroughness. 6. At any time, when a physician anywhere has questions concerning the use or effects of a drug a staff of experts is on hand to respond with all the available information. 7. A quality company provides complete product information to prescribing physicians and pharmacists; as well, it hires and trains professional representa tives who personally visit health professionals. 8. In addition to the above, quality companies contribute substantial sums to further the professional education of health professionals and to inform the gen- eral public on health matters. PAGENO="0153" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2287 9. Quality companies have the facilities and will to move quickly to meet emergency situations, which might involve massive shipments to disaster areas or the formulation of a special dosage of a product to treat rare individual cases. 10. Quality companies as a service to physicians and patients frequently stock lifesaving medicines for which there is no profitable market, medicines such as an anti-venom for the black widow spider bite. 11. With an established company, the public is assured that there will be con- tinuity of its high-quality products, an especially important point for persons with long-term chronic illness helped by a particular medication. 12. With no reference to its contribution to health, an established company usually represents a significant contribution to the economy, in terms of employ- ment, purchases, payments of taxes and general desirability of an entire area. VI. THE ALTERNATIVE TO ABSOLUTE GOVERNMENTAL REGULATION Earlier sections discussed the limitations of existing standards and government regulation of the pharmaceutical industry. The intent of these sections was to show why these measures alone cannot be reliedupon to provide the best medica- tion and the best therapy. Nevertheless, they are an indispensable part of our present productive system. On one hand, they provide restraints against gross actions contrary to the public interest. On the other hand, they represent a base from which competitive companies build toward ever higher levels of total quality performance in production and in service. In fact, it frequently happens that the companies in the vanguard introduce advanced standards and techniques that are later codified into the regulations. In this way, the regulations keep moving ahead. The ultimate effect of this proc- ess may be the virtual elimination of companies in which little or no effort is made to pursue the goal of total quality. For once a company makes a significant commitment to quality performance, as outlined in the preceding section, its course tends to move steadily upward. It might be argued that, if regulations and enforcement have this beneficial effect, why do we not upgrade all the regulations and increase their enforcement? To begin with, it has been shown in other sections of this statement that no amount of regulation could possibly cover all the important aspects of drug discovery, production and therapy. In addition to what has been said before, it should be recognized that the complexities of drug production make it not only impractical but completely unfeasible to develop such detailed standards and such complete enforcement as to oversee the the detailed operations carried out in the production process. For instance, raw materials and intermediates for the production of drug ingredients may be collected from a number of sources, the active ingredients manufactured in various stages and even in more than one plant, and incorporated in a number of products and a number of dosage forms of each product. During this process, literally hundreds of laboratory tests may be conducted. The most complete government regulation attempted to date has not been sufficient to oversee all details of production and testing. Govern- ment regulation simply cannot substitute for competition in stimulating the achievement of superiority in discovery and production. Unless 1egal standards set by the government permit the free play of competition such as that evidenced by the trademark system, it could easily result in higher economic costs without providing additional benefits. Instead of considering ways to place research or production of pharma- ceuticals, or any other consumer products, under airtight governmental domina- tion we should work toward further perfection of the present balanced and flex- ible system which is the foundation of the most inventive, productive and quality-conscious pharmaceutical industry in the world. It is clearly in the interest of everyone concerned to keep it that way. VII. SUMMARY In briefest summary, the position of the Pharmaceutical Manufacturers Asso- ciation with regard to the responsible identification of product and manufacturer in drug therapy, is as follows: Pharmaceutical products, even those with the same principal therapeutic in- gredients, differ from manufacturer to manufacturer in terms of quality and formulation, either of which may influence proper therapy. PAGENO="0154" 2288 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Existing standards, controls and enforcement measures contribute importantly to the protection of the public, but they would be inadequate to assure reliability without the incentives and dedication of responsible pharmaceutical companies. Moreover, generic identity of principal drug ingredients is a futile goal, for it does not guarantee uniform therapeutic effect of finished products in all patients. The quality-minded producer who identifies his products and promotes them under unique names or under his company name has an interest in furthering his reputation and his services to a point that goes far beyond any norms that could reasonably be established and enforced as a general system of govern- mental regulations, even under complete domination of the industry. The overall reputation and performance of a company serve as reliable indexes to the quality of its products. No measures should be instituted that might abridge the physician's preroga- tive and responsibility to determine the proper therapy and prescribe the type and quality of medication which in his opinion will best serve the needs of his patients. Senator NELSON. Who is your next witness? Mr. CUTLER. Our next witness, Senator, is Dr. Leonard Scheele. But before he begins, let me just add in response to a question asked earlier-there is at least one of the references in this book which specifically recites that the drug in question, which happened to be prednisone, did meet TJ.S.P. standards, and yet was found to be therapeutically deficient. And that is from the Journal of Pharmaceu- tical Sciences, volume 52, No. 5, June 1963. Senator NELSON. Mr. Cutler, I am sure you will be pleased to know that is one of the drugs named by Dr. Miller as one of the 15 examples. So you have not yet added to my list. Prednisone is also one. Mr. GORDON. Mr. Cutler, was that a clinically controlled study? Mr. CUTLER. It is a study done by Dr. Eino Nelson, and a number of other doctors experienced in this subject. Mr. GoiwoN. They are pharmacists, not medical doctors. Mr. CUTLER. Dr. Campagna, one of the four, is a physician. Mr. GORDON. Do you know if it is a double blind study? Mr. CUTLER. I cannot tell you, but I will be glad to hand you the study. Mr. GORDON. I have a letter on this subject by Dr. Harold Aaron that I would like to submit for the record' at this point. (The letter referred to follows:) JuNE 12, 1967. DR. J. A. CAMPBELL, Department of National Health and Welfare, Food and Drug Directorate, Tunney's Pasture, Ottawa, Ontario, Canada. DEAR DR. CAMPBELL: Many thanks for your comments on our preliminary draft of "Tests of Prednisone Tablets." Dr. Gerhard Levy made the same comments. If we turn to the articles cited by you and Dr. Levy we find the following: The article by Dr. Campagna cites one case in which a patient with paroxysmal peritonitis did not respond clinically to one brand of prednisone. The dissolu- tion time of tablets of this brand of prednisone was slower than that of the clinically effective tablets. However, there were no in vitro determinations of prednisone or its metabolites or conjugates in the blood, urine or other body fluids. Such determinations are generally required to confirm "physiologic avail- ability" and absorption of the drug. Clinical respouse as a test of adequate dissolution rate and absorption is usually unreliable because of spontaneous changes or remissions in clinical behavior. Such tests can be reliable only when they are double-blind and the numl)er of subjects is large. This is likewise true in the case cited in the second reference, in which a patient with "arthritic pain" failed to respond to one brand of prednisone. In a telephone conversation with PAGENO="0155" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2289 Dr. Levy on May 24, 1967 he agreed that dissolution time of a tablet should be correlated with plasma or urinary levels. It is also noteworthy that Dr. Campagna's study was reported in 1963 on tablets of undefined age and Dr. Levy's article was published in 1964. Finally, a Food and Drug Administration official was not aware of any sub- standard prednisone tablets reported to it or determined by the FDA itself. If your department has evidence of substandard prednisone tablets or other prep- arations we shall be grateful for the information. One unrelated point-iron and vitamins are considered to be absorbed only in the jejunum. Are any drugs absorbed chiefly in the ileuin or even in the colon? Sincerely, HAROLD AARON, M.D. Senator NELSON. Just so I have the record straight, did we put all of Dr. Slesser's statement and the summary in the record? Mr. CUTLER. Yes, sir. Senator NELSON. Now, did I put Dr. Lueck's full statement in the record? Mr. CUTLER. Yes, you did, Mr. Chairman. Senator NELSON. I thought Dr. Lueck's statement was very profes- sional and very valuable and informative. We are pleased to have it for the record. I did not know whether I had asked that it be printed in full. Mr. CUTLER. Thank you very much, sir. Senator NELSON. Proceed. STATEMENT OP DR. LEONARD A. SCHEELE, PRESIDEWF, WARNER- LAMBERT RESEARCH INSTITUTE, MORRIS PLAINS, NJ. Dr. SCHEELE. Mr. Chairman, my statement is very brief. With your permission, I will read it. First, I wish to make a very brief statement concerning my back- ground. I was a career medical officer in the U.S. Public Health Service for 23 years, serving as Surgeon General from 1948 until 1956. Since then, I have been a member of the staff of the Warner- Lambert Pharmaceutical Co. in Morris Plains, N.J., and have de- voted the last 5 years primarily to administration of the company's research programs. I shall devote my statement mainly to new drug research and de- velopment as conducted by the research-oriented companies in the pharmaceutical industry. A recent National Science Foundation study shows that industry supports about 96 to 98 percent of its own drug research. Facing un- known odds against success because the overwhelming majority of chemicals synthesized never become useful drugs, and being self- financed, each pharmaceutical company must draw new research and development money from its own financial resources. The key organizations for finding urgently needed new drugs for many unsolved medical problems are the research-oriented firms in the pharmaceutical industry. Currently research and development ex- penditures for a successful new single chemical entity drug product range from $500,000 to $10 million-wii h an average estimated cost per new drug discovery of about $7 millicn during the period 1957-66. From the point of discovery it takes from 4 to 10 years to develop and market a new drug product. Obviously, the successful product must pay for the hundreds of costly efforts that failed along the way. PAGENO="0156" 2290 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY At present the medical research expenditures of research-oriented drug companies average about 11 percent of sales, compared with an average of 2 percent for all types of industry in the United States. The total PMA member firm expenditures for research and develop- ment this year will exceed $460 million. For the 10 years 1958-67, these firms expended nearly $3 billion of their own funds in such activity. A report entitled "Ethical Pharmaceutical Industry Operations and Research and Development Trends-196O-66~'1 based upon PMA annual surveys of member firms, contains considerably more detail than I have briefly outlined in my statement. A copy of this report is attached for inclusion in the record. It should be noted that the research-oriented firms in the pharma- ceutical industry employ the highest ratio of scientists of all industries. A study done a few years ago by the National Science Foundation showed 156 scientists per 1,000 employees in the drug industry, com- pared with the next highest of 48 in the chemical industry, 32 in the petroleum industry, and an average of eight for all manufacturing industries. The large number of research scientists in pharmaceutical laboratories attests to the complex problems of biomedicine and funda- mental drug research in contrast to the more applied and technical nature of research in other industries. Drug research progress is complex and slow. The unfinished work hopefully leading to understanding of the biochemistry of health and disease and in new drug development is vast and needs to be pursued more intensively by all sectors of the research establishments in aca- demic and private institutions and in Government and industry. Mr. GoiwoN. You say 2 percent of all industry. Does that include manufacturing only, or does that include agriculture and mining? What does it actually include? Dr. SCBIELE. It is all manufacturing industries. Mr. GORDON. Only manufacturing, you say? Dr. SCHEELE. Yes, sir. Mr. GoRDoN. All right. Dr. SCHEELE. These elements of our research force are not separate. They have and need to continue to work together closely for maxi- mum achievement. For example, it was academic-industrial collabora- tion that brought about the discovery of cortisone and then made it available as a major drug of value in the treatment of arthritis. Later industrial research and good molecular modification led to the finding of other uses and the development of other steroids with new uses, such as treatment of skin problems. In more recent times, still other mo- lecular changes have led to progestational steroids and such steroids, combined with estrogens, provide a useful treatment of women's menstrual disorders. More recently, used together or sequentially, they have become important in spacing pregnancy-family planning. Al- though great strides have been made with the now classical 20-day regimes, it is certain that, in the not too distant future, altogether new concepts of hormonal modification may be expected, which will con- trol fertility in either sex with specificity and relative lack of side ef- fects. These developments will only be made possible by continuation of the reproductive physiology studies of the past 20 years. The cur- rent compounds are playing a role in attacking one of the world's 1 See p. 2293, infra. PAGENO="0157" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2291 greatest problems-the population explosion. In the future, even newer compounds and newer methods discovered by research-oriented phar- maceutical companies will play an even greater role in population control. Penicillin, and its availability for use on a mass production basis, and chloramphenicol, a widely used broad-spectrum antibiotic, were also the results of work in government, university, and industrial labora- tories. Today the search for soil samples that may contain micro-or- ganisms which will produce as yet unknOwn antibiotics, useful against viruses and cancer as well as against larger micro-organisms infecting man and animals, is an expensive research operation. The venture capital being plowed into it comes almost entirely from the research- oriented drug firms. In spite of continued large-scale efforts to find new antibiotics, few have emerged in recent years. Nevertheless it is important that these costly industrial research programs be continued. You have occasionally heard references to "molecular manipula- tion" and the implication that this is bad and wasteful. It is a rare instance when a company markets a product that doesn't have some superiority over existing ones. There are many instances where molec- ular modification has led to major advances in medicine. Sometimes the drugs have been useful in new diseases and in other cases new clinical values of such drugs turn up months or even years after they have been marketed. The discovery of aspirin as an analgesic was the result of attempts to improve the properties of a plant constituent, salicylic acid. The local anesthetic, procaine hydrochloride, was found in attempts to synthesize a simple molecule retaining the structural features of the complex alkaloid, cocaine. Studies in which attempts were being made to simplify the chemi- cal structure of quinine led to synthesis of Atabrine and other anti- malarials. Later studies of pharmacologic properties of the synthetic antimalarials led to observation of an unexpected, new effect which was interpreted as an antagonistic action to histamine. These observations culminated in synthesis of an important new class of drugs, antihista- mines. Later observation of the sedative effect of one of these on mental patients in France led to discovery of a very useful tranquilizer, chlor- promazine. This drug has played a major role in decreasing the num- ber of patient beds in use in mental hospitals for 11 consecutive years. Thus, antihistamines and tranquilizers can trace their history to an ancient remedy, quinine, and its molecular modification. Chance pharmacologic observations on existing drugs led to many important new drugs and to new uses for old drugs. Today's new drug research is complex. Industry chemists are en- gaged in large-scale chemical synthesis programs. Various members of the biomedical research team screen these compounds for activity in animals. The promising compounds are then tested for toxicity and if the mass of data from this screening suggests that the compound is safe and may have utility in the treatment of human illness, a "Notice of Claimed Investigational Exemption for, New Drugs" (IND) is filed with the Food and Drug Administration. I `do not want to take the time `here to describe `in detail the com- plicated processes of research that lead to new drugs; however, Mr. Chairman, with your permission I would like to submit for the record a chart describing the process. PAGENO="0158" 2292 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY If I may just make one additional-I should say this chart is one of the best graphic presentations I have seen of the flow of `activity in research, development, and preparation for manufacture of `a new drug and the preparation of a New Drug Application for submission to the Food and Drug Administration. It was prepared by Eli Lilly's research staff and presented at `a hearing of a House of Rep- resentaitives subcommittee studying drug safety, chaired by Congress- man Fountain in June 1964. The chart shows the great complexities faced in the creation of a new drug `and `the assembly of material submitted as a New Drug Application.1 I might point out here that the steps are complex, and they are variable. This chart is not the exact course of every drug. These things flow back and forth. A certain finding in one instance m'ay make it go back to something else and flow around. Nevertheless, it is a very complex process. Strange as it may seem, few new drug products that our industry makes `are ever "finished" `as far `as laboratory `and clinical research are concerned. New analytical techniques are continually developed and applied and other efforts to improve absorption, stability, and clinical effectiveness of many old drugs represent a way of life in re- search-oriented and quality-conscious companies. These usually in- clude more elaberate testing and specifications than appear in the U.S. Pharmacopei'a and National Formulary, which `are chemical descriptive documents. Clinical research continues to be sponsored by research-oriented companies on many old drugs even though the products `have been on the markets for years. The 1962 amendments to the Federal Food, Drug, and Cosmetic Act have h'ad the effect of increasing greatly the testing required before `a new pharmaceutical can be marketed, increasing substantially the risk connected with administrative decisions concerning the con- tinued investigation and marketing of products, and enlarging greatly the period between investments made in research and the beginning of *any monetary return-to keep the cycle of research trial going with its many failures and only `occasional successes. If we are to make additional progress, industry must be allowed to continue to fulfill the role it `has succesfully performed up to now- namely, synthesizing and experimenting, conducting the long and costly process of screening, the preclinicai testing, development of production `and quality control procedures, and finally the long clin- ical trials leading to accumulation of data showing the safety and effectiveness of drug products. I hope that we will always keep our academic-Government-industry science teams working together, because doing so will lead to major new health benefits. Dr. Van Riper will follow me and discuss clinical testing. This is his `area of specialty. Senator NELsoN. Thank you for your fine statement. I have some notes on questions to be asked. 1 think what we h'ad better do is get all the testimony in the record and if we have some time we will go back. (The attachments to Dr. Scheele's statement follow:) 1 See chart, p. 2352, infra. PAGENO="0159" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2293 ETHICAL PHARMACEUTICAL INDUSTRY OPERATIONS AND * RESEARCH AND DEVELOPMENT TRENDS 1960-1966 A Report BAsed Upon PMA * Annual Surveys of Member Firms Pharmaceutical Ma nufacturers Association Office of Economic Research PAGENO="0160" 2294 ?~OMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ETHICAL PHARMACEUTICAL INDUSTRY OPERATIONS AND RESEARCH AND DEVELOP- MENT TRENDS 1960 - 1966 This report encompasses key results of a number of PMA analyses of prescription drug manufacturers' operations. Surveys have been conducted annually since 1960, dealing mainly with sales and research and development activities of member companies. The last two reports in the series, "Manufacturers' Sales of Ethical Pharmaceuticals, 1965" and "Pharmaceutical Industry Research and Development Activity, 1965- 1966," were distributed to member firms in the fall of last year. The present study is designed to serve as a link between earlier trend data and projected studies. It summarizes previous findings and incorporates, for the first time, de- tailed analyses of quality control activities and fi e ld s of res earch. When used in conjunction with forthcoming PMA reports this study should be a useful tool to member com- pany executives in their planning and decision making functions. In preparation is a more detailed review of 1966 operations, scheduled for release within the next few months. Prepared by: Office of Economic Research Howard L. Binkley, Director M. Erol Caglarcan, Economist March 1967 PAGENO="0161" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2295 The ethical pharmaceutical industryhas experienced a faster growth than many other sectors of the economy. Between 1951 and 1965 dosage sales of ethical drugs grew 35 percent fa s t e r than the national output of all goods and services. New and therapeutically more effective drugs have paved the way for the ethical drug industry' s rapid growth. It is estimated that the industry has invested some $7 million in research and development c o st s for every new and significant drug that has reached the public in the past decade. The industry continually invests in the future. While sales doubled in the 15-year period shown in Chart 1, research and development expenditures in- creased sixfold. A significant portion of every sales dollar is d e v ot e d to drug research activities. For instance, in 1965 companies spon- soring research allocated 10. 5 percent of their U. S. domestic and export sales revenue to R&D activities directed toward the discovery and development of human-use and veterinary-use pharmaceuticals and biologicals. Chart 1 Growth Picture of Ethical Drug Sales and Research & Development R & D Expenditures Abroad 100 21 1951 52 53 54 55 56 57 58 59 60 61 62 63 E4 65 1956 i/Plotted on semi-logarithmic grid. ~./Estimated. INTRODUCTION $400 300 200 100 Global Dosage Sales (right scale) R & D Expenditures (left scale) SALES j illions) $4, 000 3, 000 2, 000 50 . 20 10 1, 000 500 200 81-2800-68-pt. 6-11 PAGENO="0162" 2296 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PART ONE: OPERATIONS HIGHLIGHTS SALES TAXES EMPLOYMENT QUALITY CONTROL MANUFACTURING PLANTS PAGENO="0163" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2297 HIGHLIGHTS OF 1965 OPERATIONS-U Sales: In 1965, global ethical pharmaceutical sales by U.S. fi r m s rose to $4. 2 billion, 13. 5 per c e nt more than in 1964. Sales in the United States increased 13 percent, while foreign sales of U. S. manufacturers increased 15 percent. Product Classes: Central nervous system drugs ranked first in dollar sales volume in 1965. This group also registered the greatest increase, $88 million, from the preceding year. Market Shares: No single company had as much as seven per- c e nt of domestic sales of prescription drugs. The 13 largest manufacturers accounted for only 62 percent of the U. S. market. Customer s: Manufacturers sold approximately half of their dosage form products directly to ultimate dispensing outlets and government agencies and the other half via wholesale channels. Taxes: Producers of ethical pharmaceuticals paid a record $559 million in taxes for 1965, 73 percent of whichwent to U.S. Fed- eral taxes Firms averaged an outlay of 13 cents in taxes for each sales revenue dollar. Employment: 1965 employment of the U. S. industry totaled one hundred ninety-three thousand, 120, 500 in the United States and 72, 500 abroad. H Quality Control: Quality control operations involved over 7, 000 full-time employees and at least $74 million in expenditures in 1965. Manufacturing Plants: Fifty-two PMA members operated 338 plants throughout the world, 232 abroad and 106 in the United States. The following data, unless indicated tb the contrary in the text, havebeen extrapolated torepresent the entire industry based on the estimate that PMA member companies account for 95 per- cent of the ethical drug i n d u s t r y s U. S. sales of dosage form products for human use. PAGENO="0164" 2298 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SALES Prescription product sales have increased annually for the past two decades. Between 1960 and 1965, worldwide sales rose 48 percent (see Chart 2). The increase in 1965 was 13. 5 percent. Chart 2 Domestic and Foreign Sales (billions) 1960 - 1965 $5 - : i_ 1~ ~ Foreign Dome stic PAGENO="0165" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2299 SIX YEAR GROWTH TREND, 1960-1965 The relatively steep upward trend has been dominated by sales abroad, going up 70 perc ent in the 1960- 1965 period. Thus, foreign sales continued to gain a more prominent share of U. S. companies' global sales, rising from 23 percent of the total in 1960 to 26 percent in 1965. The relative share of exports as p e r c e nt of total foreign sales declined in every one of the six years between 1960 and 1965, from 13 perc ent in 1960 to six percent in 1965. Table 1 MANUFACTURERS' SALES, 1960- 1965 (millions of dollarè) Destination 1960 1961 1962 1963 1964 1965 Domestic $2,201 $2,259 $2,480 $2,604 $2,763 $3,121 Private 2,111 2,147 2,354 2,468 2,614 2,876 Government 90 112 126 136 149 245 Foreign~ 646 733 756 865 955 1,098 Export 81 79 66 56 62 66 Abroad 565 654 690 809 892 1,032 TOTAL $2,847 $2,992 $3,236 $3,469 $3,717 $4,219 -~Intra-company exports to foreign subsidiaries (not shown sepa- rately in Table 1) are included in "sales abroad". Two-thirds of the 1965 total transfers of $115 million were in bulk form. PAGENO="0166" 2300 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PRODUCT FORMS AND END USE Global Sales: Ninety-three percent of manufacturers' 1965 sales were in products.int ended for human use. Veterinary drugs accounted for the remaining seven p e r c e nt. Ratios have re- mained relatively unchanged in the last several years. Ninety- four percent of the 1965 ethical drug sales for human use were in dosage form. Dosage-form and bulk-form products equally shared the 1965 veterinary drug market. U.S. Sales: Bulk sales made up 57 percent of the veterinary market in 1965. However, importance of veterinary sales in bulk form increased only in recent years. For instance, while in 1960 bulk products accounted for one-third of total veterinary sales, every year since then they have accounted for more than half. In contrast, during the same period dosage-form products for human use have consistently accounted for 95 percent. Chart 3 SALES (millions) $4, 000 3, 000 2, 000 1, 000 0 Global Sales of Ethical Drugs By Product Form and End Use Bulk Dosage PAGENO="0167" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2301 Foreign Sales: Sales abroad made up 94 percent of the foreign sales total in 1965. Exports from the United States accounted for the rest. In 1965, drug products for human use dominated the export sales as well as the drug sales overseas. Most of the 1965 foreign sales revenue was obtained from dosage-form products. Table 2 ETHICAL DRUG SALES, 1965 (millions of dollars) Product Form and End Use Domestic~?/ Foreign~' Total Dosage form: human $2, 779. 3 $ 929. 8 $3, 709. 1 Dosage form: veterinary 76. 6 55. 7 132. 3 Bulk: human 161. 1 68. 7 229.8 Bulk: veterinary 104. 1 43. 5 147. 6 TOTAL $3, 121. 1 $1, 097. 7 $4, 218. 8 ~`Sales are before deducting cash discounts and other marketing expenses, but a ft e r returns and allowances (domestic returns and allowances totalled $86.3 million in 1965). Export sales are f. o. b. port. The majority of the firms reported most sales were made f. o. b. purchaser' s location or equivalent. Domestic sales" are `gross" at invoice price. For `f. o. b. manufacturers' plant" totals, deduct $81. 7 million ($37. 2 mil- lion transportation out and $44. 5 million company branch or field warehousing). ~1"Foreign sales" refer to exports and sales in a foreign area by subsidiary or other corporate operations. PAGENO="0168" 2302 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PRODUCT CLASSES-~~ Growth: Fifty-eight PMA members, accounting for 90 percent of the industry's sales, reported a 12 percent sales increase in 1965, a growth rate considerably higher than the eight percent growth between 1963 and 1964. The detailed product data in Table 3 are based on an analysis of these firms' reports. From 1963 to 1964 the sales volume of drugs affecting neo- plasm s, endocrine systems and metabolic diseases increased 24 percent. However, the rate slowed down to 5. 6 percent from* 1964 to 1965. While sales ofrespiratorydrugs rose the fastest in 1965, the greatest increase in sales revenue came from central nervous system products and anti-infectives, $88 million and $65 million respectively. These two product groups accounted for almost half of total sales in 1965 (see Chart 4). Chart 4 1965 Sales, Product Group Percentages Drug Type Central nervous system 26% Antiinfectives 19% Neoplasms and endocrine system 12% Digestives and genito-urinary 12% Vitamins and nutrients 9% Respiratory system __________ 7% Others 15% Unlike most sections of this report, the following analysis does not represent the entire industry and is based on reports re- ceived from 58 PMA members. PAGENO="0169" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2303 Competition: For Pu r P 0 s e s of analysis the entire human use drug market was divided into 11 product classes. Not all firms were active in everyproduct market. The number of companies varied from a minimum of ten actively competing for the diag- nostics market to 50 for the digestive, genito-urinary and central nervous systems product classes. Approximately one half of the companies with annual sales in excess of $5 million depended upon one prpduct class for more than half of their an- nual sales revenues. Biologicals: Sales of biologicals forhuman use continued todrop in 1965. There had been a 30 percent decline inreportingmem- bers' biological sales between the end of 1963 and 1965. Only 15 PMA members reported continued production of biologicals for humanuse during 1965. In 1964the number of producers was 20. During 1965 five companies ceased production of bio- logicals altogether.. Volume of biological sales dropped from $98 million in 1963 to $74 million in 1964 to $68 million in 1965. B e tw e en 1964 and 1965 six companies experienced an $11. 3 million drop. When added to the $2. 6 million sales production on the part of the five firms that dropped biological productions this amounts to a sales decline of $13. 9 million for the year. However, this was par- tially offset by a $7. 8 million revenue gain sustained by s even other manufacturers. PAGENO="0170" Table 3 SALES BY PRODUCT CLASSES, 1963-1965 U. S. Sales o f Dosage Form Ethical Drugs for Human and Animal Use (millions of dollars) 0 For Human Use 1963 1964 1965 Growth 1964-65 Number of Firms Reporting 1965 data ~i (a) Drugs for central nervous system and sense organs (b) Drugs affecting parasitic and infective diseases (c) ~rugs forneoplasms, endocrinesystemandmetabolicdiseases (d) Drugs acting on digestive or genito-urinary systems (e) Vitamin, nutrients and hematinic drugs $ 534. 5 400. 0 226.6 288. 7 192. 3 $ 576. 6 424. 1 280.3 290. 3 215. 7 $ 664. 5 489. 1 296.9 294. 6 224. 1 15. 2% 15. 3 5.6 1. 5 3. 9 (50) (43) (41) (50) (46) 0 ~ ~ (f) Drugs acting on respiratory system 135.8 148. 1 173.9 17. 4 (45) (g) Drugs acting on cardiovascular system 135.0 143.4 168. 1 17. 3 (40) (h) Biologicals (i) Drugs acting on skin (j) Diagnostic agents (k) Other pharmaceutical preparations TOTAL 97.9 51. 4 ~ 28. 1 $2,090.3 74.0 40. 5 ~ 53. 5 $2,246.5 67.9 45. 5 26. 8 66. 8 $2,518.2 -8.2 12. 3 24.9 12.1% (15) (43) (10) (26) j~) For Animal Use (a) Pharmaceutical preparations (b) Biologicals TOTAL $ ** $ 65. 6 $ 52. 9 18. 3 $ 71. 2 $ 58. 2 18. 4 $ 76. 6 10. 0% 0.5 7. 6% (21) (13) ~ `~ * In 1963 and 1964 some diagnostic sales were included in other pharmaceutical preparations. ** No breakdown available. PAGENO="0171" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2305 MARKET SHARES The numb e r of leading ethical drug producers with individual global sales volume exceeding $100 million increased from 12 in 1964 to 13 in 1965. In 1962 this sales class consisted of only ten manufacturers. This e x pa n s i o n in number was re- flected in a larger share of the domestic market attributable to this group. Table 4 MARKET SHARES BY SALES SIZE GROUP, 1965 Perc entage Sales Sales Group U.S. Foreign-~' Total $100 million and over 61. 7% 87. 6% 68. 5% $30 to $100 million 21. 3 8. 7 18. 0 $5 to $30 million 13. 3 3. 5 10. 7 Less than $5 million 3. 7 0. 2 2. 8 TOTAL 100. 0% 100. 0% 100. 0% S. firms' sales abroad plus U.S. exports to other companies for sale abroad. PAGENO="0172" 2306 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In 1965 wholesalers accounted for 48 percent of manufacturers' d o m e s tic sales of ethical drug products in dosage form (see Table 5). The remainder was made directly to retailers, hos- pitals and other outlets (see Table 6). Table 5 SALES BY CLASS OF CUSTOMER, 1965 Manufacturers' Direct Dosage Form Sales in the U. S. Customers Wholesalers Retailers Private Hospitals State and Local Government Hospitals. Federal Government Hospitals Federal Government, Other Than Hospitals Practitioners, Private Medical and Dental Manufacturers and Repackagers All Other Direct Sales Value Percent (millions) of Total $1,344.5 48.4% 840. 4 30. 2 287.9 10.4 138.2 4.9 83.6 3.0 22.1 0.8 41.0 1.5 2.6 0.1 19.0 0.7 $2, 779. 3 100. 0% TOTAL PAGENO="0173" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2307 Table 6 DISTRIBUTION OF DIRECT SALES, BY SIZE OF FIRM, 1965 Customers Wholesalers Retailers Non- Federal Hospitals. Federal Government~~1. Practitioners Other TOTAL Sales Group over $30- $5- Less $100 $100 $30 than $5 million million million million _________ $ 35. 70 $ 65. 60 $ 72. 30 $ 66. 20 41. 70 14.40 9. 30 13.40 16. 40 15. 30 10. 90 12. 20 3. 70 4. 10 4.40 2. 20 1.40 0.50 2.70 5.40 1. 10 0. 10 0. 40 0. 60 _______ $100.00 $100.00 $100. 00 $100. 00 ________ Average, All Firms $ 48. 40 30. 20 15. 30 3,80 1.50 0.80 $100. 00 -1"Including federal hospitals. PAGENO="0174" 2308 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Distribution by Size of Manufacturer: There appears to be an inverse relationship between the size of the firm and its sales via wholesalers. Table 6 shows that in 1965, on the average a manufacturer in the $100 million and over yearly sales group distributed via w h o 1 e s a 1 e r s $35. 70 worth of drugs for every $100 of manufacturer's business. The remainder was sold di- rectly to various dispensing outlets. Smaller manufacturers sold a greater proportion of their products via the wholesaler (see Chart 5). Chart 5 Mar~ufactur er s Direct Sales Market For Each $100 Sold, By Size of Firm, 1965 Sales $100 90 80 70 60 50 40 30 20 10 0 Others Federal (~overnment - Federal Hospitals Retailers Wholesalers Average over Firm $100 $30 $30 $5 Size of Firm (millic~s) PAGENO="0175" COMPETITIVE PROBLEMS IN TAXES THE DRUG iNDUSTRY 2309 A total of $559 million was paid in taxes for 1965 by ethical drug producers. Of this sum nearly three-quarters was paid by the thirteen largest manufacturers who produce 62 p e r c e nt of the nation s total prescription drug output. The Federal Government received 73 percent of all the taxes paid by ethical drug manu- facturers for 1965. Local Other Chart 6 Manufacturers' Taxes and Excises, 1965 (nuillions) Federal Foreign State PAGENO="0176" 2310 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY EMPLOYMENT Global prescription drug manufacturing employment for U. S. corporations and the U. S. -based subsidiaries of foreign com- panies reached 193, 000 during 1965. Approximately one-third of the totalwas employed abroad. The industry employed 120, 500 persons in the United States - three percent over the 1964 fig- ure of 117,500. Production workers comprised 46,200 of the domestic working force. Table 7 EMPLOYMENT, 1965 United States 120, 535 Foreign 72,510 TOTAL 193,045 The 13 firms with more than $100 million in sales employed 60 percent of the working force. Eighteen percent was attributable to concerns grossing between $30 to $100 million in sales. Companies with sales under $30 million employed 22 percent. PAGENO="0177" Quality controlis a vital, continuous process to assure the de- sired result when the pharmaceutical product is used by the consumer. Quality control is the sum total of all the planning, testing and supervision involved in this process. Survey data pertaining to the control of physical product quality encompass all employees responsible for sampling and testing of materials as they are received, produced or stored. -~` In- vestigation of complaints, disposition of returned goods, selec- ting and weighing of components, proper sanitation, storage of raw and -finished materials, and inspection of labels, contents and packages are all fibers of the complex quality control pro- cedures that govern product excellence. under $5 $5-$30 $30-$l00 Size of Firm (millions) over $100 -~The analysis in this section was made on the basis of data re- ceived from 64 major PMA members with 1965 sales volumes in excess of $1 million. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2311 QUALITY CONTROL Chart 7 1 0( Quality Control Costs and Employment, 1965 80 60 40 20 Costs Employment 81-280 0 - 68 - pt. 6 - 12 PAGENO="0178" 2312 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The data reported here includes quality control in production. For a responsible firm, however, quality control goes well be- yond this to establish an excellence in quality of 9peration which has been called `company total-value product". -~ This repre- sents activities designed to assure quality of product and service which surpasses normal standards. Direct and In d i r e c t Quality Control: "Direct quality control" employment and cost data deal with full-time staff members of reporting companies' quality control departments. But since al- most all production employees have some quality control func- tions incidental to their primary assignments, estimates were solicited from member firms on "indirect quality control" em- ploy m e nt and costs. Employment data on such individuals is stated in terms of full-time equivalents, prorated by r e s p on- dents on the basis of hours devoted to quality control functions as a share of total labor time. Company Allocations: Table 8 shows that quality control costs during 1965 amounted to at least $73. 8 million. Primary quality control accounted for three-fourths of the total cost incurred by all firms. Companies with yearly sales exceeding $100 million were responsible for approximately two-thirds of all quality con- trol costs and employed a high e r proportion of quality control w o r k e r s - a ratio largerthan their share of the market (see Chart 7). Average Quality Control Costs: As Table 9 demonstrates, avei'- age quality control spending per company was $1. 2 million in 1965. However, quality control costs were much higher for the leading firms. On the average, responding firms allocated 2. 4 percent of their 1965 domestic sales revenue to quality control. However, quality control cost-to- sales ratios ranged up to 7. 5 percent. Responsible pharmaceutical concerns commit them s e lv e s to expenditures and accomplishments in creative research, reliable production and marketing, and high standards of management. These organizations are motivated toprovide excellence in total quality of product and service. Such total control of quality of product and service is of significant value to d i s p en s e r s and consumers of prescription medicines, exceeding by far the value of the product's ingredients. PAGENO="0179" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2313 Table 8 QUALITY CONTROL COSTS BY SALES GROUP, 1965 Number of Total Cost ____________ Firms Direct Indirect Total (thousands of dollars) 13 $38, 880 $10, 875 $49, 755 14 9,355 4,015 13,370 27 7,970 2,300 10,270 10 395 15 410 64 $56, 600 $17, 205 $73, 805 AVERAGE QUALITY CONTROL EXPENDITURES PER COMPANY BY SALES GROUP, 1965 of Expenditures Per Company ____________ Firms Direct Indirect Total (thousands of dollars) 13 $ 2,990 $ 835 $ 3,825 14 670 285 955 27 295 85 380 10 40 2 42 64 $ 885 $ 270 $ 1, 155 Sales Group $100 million and over $30 to $100 million $5 to $30 million Less than $5 million TOTAL Table 9 Number Sales Group $100 million and over $30 to $100 million $5 to $30 million Less than $5 million Average, All Firms PAGENO="0180" 2314 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Quality Control Employees: In 1965, sixty-four pharmaceutical manufacturers employed more than 7, 000 people in their efforts to maintain high product quality. Such duties were the principal concerns of 75 percent of these employees. The other 25 per- cent had additional responsibilities in c o nj unction with their quality control work (see Table 10). Table 10 QUALITY CONTROL EMPLOYMENT BY SALES GROUP, 1965 Number of Total Employment Sales Group Firms Direct Indirect Total $100 million and over 13 3, 695 1, 260 4, 955 $30 to $100 million 14 805 390 1, 195 $5 to $30 million 27 760 180 940 Less than $5 million 10 55 5 60 TOTAL 64 5,315 1,835 7,150 Ratio of Quality Control Employees to Total Employment: Table 11 indicates that one production employee in eight w a s directly engaged in the quality control process. Persons connected with this phase of production comprised 17 percent of the manu- facturing staff and six p e r c e n t of the U. S. employment total. The 13 largest firms had higher ratios. PAGENO="0181" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2315 Table 11 QUALITY CONTROL EMPLOYMENT AS PERCENT OF PRODUCTION WORKERS AND ALL EMPLOYEES BY SALES GROUP, 1965 Percentage of Production Percentage of All Workers Engaged in Employees Engaged Quality Control in Quality Control Number Direct Direct of and and Sales Group Firms Direct Indirect Direct Indirect 100 million and over 13 13. 6% 18. 2% 5. 1% 6. 8% 30 to $100 million 14 11.0 16.3 3.7 5.5 es s than $30 10. 3 12. 6 4.9 6.1 verage, All Firms 64 12. 5% 16. 9% 4. 8% 6. 5% Average Quality Control Employment: On the average, each of the reporting 64 PMA m em b e r s had in its employ 112 quality control workers, 83 of whom performed quality control activities as their primary assignments (see Table 12). On the average, a company with annual global sales exceeding $100 million em- ployed 284 full-time pers ons in direct quality control activities. Their activities Were supplemented by many other workers who attended to other responsibilities as well. When prorated, time s p e n t in quality control a c t iv it i e s by such part-time people meant an additional 97 full-time workers with quality c ont r ol functions. Table 12 AVERAGE QUALITY CONTROL EMPLOYMENT PER COMPANY BY SALES GROUP, 1965 Number of Employment Per Company Sales Group Firms Direct Indirect~ Total $100 million and over 13 284 97 381 $30 to $100 million 14 57 28 85 Less than $30 million 37 22 5 27 Average, All Firms 64 83 29 112 PAGENO="0182" 2316 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MANUFACTURING PLANTS Fifty-two PMA members, accounting for four-fifths of the in- dustry' s United States employment and a slightly higher ratio of total domestic and export sales, reported production plant loca- tions and related employment data for 1965. Domestic opera- tions were scattered throughout 27 states. Manufacturers re- ported 232 plants abroad-more than double the 106 U. S. - based plants. On the average, one out of every th r e e employees was located abroad. Domestic concerns averaged 345 production workers per plant as c o m pa r e d to 105 for each foreign plant. United States manufacturingplants averaged 625 total employees; over- seas plants employed an average of 170 persons. Foreign Manufacturing Plants: Respondent firms employed 90 percent of all persons working in the U. S. companies' ethical drug facilities abroad. An average of 60 percent of the personnel employed abroad worked in production plants. Chart 8 Regional Distribution of Foreign Plants and Employment, 1965 Plants Ep~p~oyment PAGENO="0183" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2317 Latin America a c c o un t e d for almost one-third of the foreign plants (see Chart 8). With 25 percent, Western Europe ranked second. Twenty-six plants were located in the Pacific and Far East region, accounting for 11 percent of thetotalabroad. Canada and Africa represented nine percent and three percent respec- tively. The remaining 21 percent is not classified (see footnote, page 26). LatinAmerica and Western Europe were the leaders in employ- ment among regions with a combined total of 25, 560 employees (amounting to 65 percent of the total abroad). The average num- ber of employees per plant in Latin America was 180 as com- pared to 220 for Western Europe. These averages exceeded the over-all overseas aver3ge of 170 per plant site. The Pacific and Far East region equaled the norm of 170. However, Canada with 105 and Africa with 60 employees per plant fell below the median. Of the individual countries, the United Kingdom had 19 plants and ranked highest for total number of, employees (6, 415), yet it had one plant less than third-ranking M ex i c o with total em- ployment of 3, 075. Brazil placed second in employment with 4, 275 persons, employed at eight plant locations. PAGENO="0184" 2318 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Table 13 FOREIGN MANUFACTURING PLANTS OF U. S~ FIRMS AND RELATED EMPLOYMENT, l'965~ Region Number 2 and of 3/ Employment Country Plants~ Production Other Total LATIN AMERICA Brazil 8 1,665 2,610 4,275 Mexico 20 1,525 1,550 3,075 Argentina 11 1, 670 1, 190 2, 860 Colombia 10 655 590 1,245 Venezuela 6 245 120 365 Peru 4 135 150 285 Chile 3 140 30 170 Panama 3 55 40 95 Puerto~JUco 3 510 70 580 Other-s 4 110 70 180 Regional Total 72 6, 710 6, 420 13, 130 WESTERN EUROPE United Kingdom 19 3,885 2,530 6,415 Germany 9 880 525 1,405 France 9 755 435 1, 190 Italy 8 645 490 1, 135 Spain 4 1,000 75 1,075 Belgiu~ 3 420 70 490 Other' 5 390 330 720 Regional Total 57 7, 975 4, 455 12, 430 PACIFIC & FAR EAST Australia 10 990 590 1,580 India 4 1,005 365 1,370 Pakistan 3 220 100 320 Philip%i7.nes 3 190 120 310 Other-1 6 530 325 855 Regional Total 26 2, 935 1, 500 4, 435 CANADA 20 1,025 1,090 2,115 AFRICA 7 270 135 405 UNCLASSIFIED~' 50 5,430 1,685 7,115 TOTAL 232 24,345 15,285 39,630-~' Footnotes for Table 13 on page 26. PAGENO="0185" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2319 U.S. Manufacturing Plants: Fifty- seven respondents, accounting for four-fifths of the industry employment within the United States, provided statistical information on plant locations and related employment. These firms reported 66, 500 employees located in 106 plants, an average of 625 workers per plant. It is estimated that there were an additional 20, 300 people employed in numerous smaller plants of companies that did not respond to this survey. Footnotes for Table 13, page 25: reporting companies. 3d Data deal only with respondent firms' employment within man- ufacturing plants.. Sixty percent of total drug industry personnel abroad work in plants. The other 40 percent are housed outside of plants. ~Countries are listed by region in descending order by number of employees with the exception of "other" and "unclassified". -~1Includes plants in Uruguay (1) and other Latin American coun- tries (3). ~Includes plants in Turkey (2), Netherl~nds (1), Ireland (1), and Austria (1). .Wlncludes plants in Japan (2), Thailand (1), New Zealand (2), and Taiwan (1). 3dlncludes 50 plants not specifically classified by country. It is estimated that there are at least 50 additional U. S. ow n e d ethical drug plants in various foreign countries. PMA received only limited data on these manufacturing facilities and was un- able to classify them in the above manner. .WAn additional 33, 000 people are employed in U. S. companies' ethical drug production plants and administrative offices abroad. PAGENO="0186" 2320 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Smaller firms concentrated e nt i r e operations in the manufac- turing plant. On the average 72 percent of the employees worked at the production facility locations. However, this ratio was in- v e r s e 1 y related to firm size. While firms with annual global sales exceeding $100 million maintained 69 out of every 100 em- ployees in production plants, firms with annual sales less than $5 million averaged 92 employees. Several multi- unit companies housed their marketing, res earch and other administrative staff outside of manufacturing extablish- ments. However, a large number of administrative personnel were 1 o c at e d in manufacturing facilities and accounted for 45 percent of total employment at the plant site. Chart 9 Regional Distribution of U. S. Plants and Employment, 1965 Plants 9y~ient PAGENO="0187" COMPETITIVE PROBLEMS IN THE~ DRUG INDUSTRY 2321 The responding companies repOrted 40 production plants in the Northeast region. An equal number of manufacturing facilities w a s located in the North Central region. Plants in the North- eastern states were relatively larger, and accounted for more than half of the total employment reported (see Chart 9). These establishments also had a higher average ratio (one to one) of administrative personnel to productiOn workers. On the average, a plant located in one of the Northeastern states employed 865 people. The average for the North Central region was 655. Pharmaceutical plants in the South and the West were relatively smaller - averages per plant were 275 and 170, re- spectively. Additionally, the s e plants concentrated mostly on manufacturing, employing a higher p e r c e n t a g e of production workers - 70 percent. In a separate survey (see Table 30) New Jersey and New York emerged as the leading industrial drug research centers of the nation. This survey indicated that New J e r s e y and New York were also the leading production centers of the country in 1965 and jointly accounted for two-fifths of all production and other employees. While Pennsylvania ranked third as a drug research center, it had a smaller number of productionworkers than each of the states of New Jersey, New York, Indiana, Michigan, and illinois. Footnotes for Table 14, page 29: reporting companies. ~Analys,is is based on data furnished by respondents on manu- facturing plant employment. -~States are listed in each Census Region in descending order by number of employees with the exception of "other". ~Includes plants in Connecticut (1), Massachusetts (1), and Rhode Island (1). -~`~`Includes plants in Kansas (1) and Minnesota (1). Includes plants in South Carolina (2), Mississippi (1), Tennes- see (1), Arkansas (1), Georgia (1), North Carolina (1), Mary- land (1), and West Virginia (1). -~It is estimated that the industry employs an additional 18, 000 - 20, 000 people in various other ethical pharmaceutical plants in the United States. PAGENO="0188" 2322 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Table 14 U. S. MANUFACTURING PLANTS AND RELATED EMPLOYMENT, Region and State _________ __________ _____ _____ NORTHEAST New Jersey New York Pennsy),vania Other-s ______ ______ _______ Regional Total NORTH CENTRAL Indiana illinois Michigan Ohio Missouri Wisconsin Nebra~a Other-1 ______ ______ ______ Regional Total SOUTH Virginia Texas 6 Other _______ _______ _______ Regional Total WEST California Other ______ ______ ______ Regional Total TOTAL Ernnlovrnent~~' Other Total Number of 3/ Plants -~ Production 16 6, 795 13 6,925 8 3,330 750 40 17,800 8 5,360 5 3,340 8 4,090 5 1,005 4 270 3 185 5 255 105 40 14,610 5 535 4 350 _2. 2, 120 18 3,005 7 880 85 8 965 106 _______ 8, 150 5, 710 2, 805 115 16, 780 5, 335 3, 390 1, 520 815 290 165 70 80 11,665 510 260 495 1, 265 14, 945 12, 635 6, 135 865 34, 580 10, 695 6, 730 5, 610 1, 820 560 350 325 185 26, 275 1, 045 610 2, 615 4, 270 355 1,235 40 15 395 1,360 36, 380 30, 105 66, 485-p Footnotes for Table 14 on page 28. PAGENO="0189" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2323 SECTION TWO: RESEARCH & DEVELOPMENT HIGHLIGHTS EXPENDITURES MANPOWER FACILITIES PAGENO="0190" 2324 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY HIGHLIGHTS OF 1965-1966 1 RESEARCH AND DEVELOPMENT ACTIVITY1 Expenditures: Seventy- seven PMA members, their subsidiaries and affiliates, spent $365 million for research and development during 1965. These firms bud g e t e d an additional $47 million for 1966, 13. 4 percent above 1965 expenditures. The firm with the largest company- financed research and development expendi- ture accounted for nine percent of the total. Capital Investment: The 1965 value of manufacturers' invest- ment in research and development equipment and facilities was $260 million. In 1965 alone manufacturers spent $60 million for purchases and construction of research and development equipment and facilities. Basic Research: PMA members allocated 15. 8 percent of their total research and development spending to basic research in 1965. Applied Research and Development: More than half of the applied research and development funds were directed toward the cre- ation of drugs to be effectiye inthree classes; (1) central nervous system and sense organ disorders; (2) parasitic and infective diseases; and (3) neoplasms, endocrine system and metabolic diseases. R&D Manpower: More than 16,400 research and development personnel were employed in 1965. Approximately one-fourth held a doctoral degree. On the average, firms spent $76, 700 to finance the activities of a doctoral-level research worker. Research and Development Facilities: The major portion of re- search activity was conducted in company research centers in 20 states and 20 nations. New Jersey, New York and Penn- sylvania were the three leading research centers in the United States. And the United Kingdom accounted for more than half of the industry's overseas R&D employment. The following PMA analysis is b a s e d on data obtained from 77 member firms. Not all 77 firms reported s tat i s t i c s for all parts of the survey questionnaire. Certain sections of the re- port are based on a smaller sample. This fact should be kept in mind when utilizing these findings in conjunction with fi g u r e s from Part One: "Operations", which generally relates to total industry operations. PAGENO="0191" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2325 (millions) $450 EXPENDITURES In the 16-year period between 1951 and 1966, the prescription drug industry's funds for research and development amounted to $3 billion. The 1951 expenditures totaled $50 m ill i o n, By the end of 1966 the annual level had reached $400 million, eight times the 1951 amount (see Chart 10). Chart 10 Industry Financed Research & Development Expenditures For Ethical Drug Products 1951 - 1966, 400 350 ~~~iii1 1951 2 53 54 55 56 57 !/Estimated PAGENO="0192" 2326 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY EXPENDITURES Company Financed Expenditures: In 1966 manufacturers spent over 92 percent of their funds within the boundaries of the United States. Two-thirds of the eight percent spent abroad was for work conducted within company facilities. Of the company fi- nanced 1966R&D expenditures of nearly $400million, 87.5per- cent was spent for work conducted within company facilities, both in the United States and abroad.(see Table 15). In 1966, $49million of company expenditures were for research c on d u c t e d by outside organizations. Of this $44 million was allotted for research contracted to various groups in the United States. Educational institutions, h o s p i t a 1 s and non- profit organizations accounted for $23 million of these funds. Next in importancew e r e private practitioners and consultants. Com- mercial laboratories and other performers made up the balance. Research and Development Abroad: While company financed research and development between 1964 and 1965 for the dis- covery of human-use prescription drugs increased 18 percent domestically, research and development spending abroad rose at a faster rate of 20 percent. Company budgets for foreign researchforecast a24percentincrease in 1966. Manufacturers' allocations for research and development activities in foreign laboratories amounted to $24. 5 million in 1965, accounting for 2. 6 percent of overseas sales of human-use pharmaceuticals. PAGENO="0193" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2327 Table 15 RESEARCH AND DEVELOPMENT EXPENDITURES, (millions of dollars) Company Financed or Conducted R&D ______ ________ Company Financed Expenditures for Human Use Drugs: (1) Amount spent within firms a. In the United States b. In foreign countries (2) Amount spent outside firms by a. In the United States b. In foreign countries TOTAL, Human Use R&D ______ ______ Company Financed Expenditures for Veterinary Use Drugs: (1) Amount spent within firms (2) Amount spent outside firms TOTAL, Veterinary Use R&D ______ ______ Government Grants and Contracts for Company Conducted Drug R&D _______ _______ TOTAL R&D EXPENDITURES -41The data recorded here represent 77 PMA member firm& R&D costs, accounting for practically all industry-conducted ethical pharmac eutical res earch. Proprietary drug res earch is excluded. Such ethical drug research and development work as is conducted by other industrial firms is estimated to be about $12 million. 1965- l966~~~ 1965 1966 Actual Budgeted $ 285. 8 266. 6 19. 2 $ 42.8 37. 5 5. 3 $ 328. 6 $ 21.9 $ 0.8 $ 22.7 $ 322. 3 296. 6 25. 7 $ 48.8 44. 0 4. 8 $ 371. 1 $ 26.7 $ 0.9 $ 27.6 $ 13.7 $ 14.1 $ 365.0 $412.8 81-280 0 - 68 - pt. 6 - 13 PAGENO="0194" 2328 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CAPITAL INVESTMENT~' To facilitate in-house research work, the responding firms spent $60 million for capital investment in 1965, increasing the value of total investment in research facilities and equipment to $260 million (see Table 16). With $36 million, construction of new buildings continued to account for the g r e a t e s t portion of physical research capital. In 1965, reporting PMA members also purchased $23 million worth of new scientific equipment. Table 16 CAPITAL INVESTMENT IN RESEARCH AND DEVELOPMENT (millions of dollars) Type & Cost of 1965 Total Capital Investment Additions Investment Land $ 0.7 $ 8.6 Building 36.0 225.6 Scientific & technical equipment 22. 6 127. 6 Other capital investment 7. 0 28. 9 TOTAL COST $ 66. 3 $390. 7 Less: Depreciation 5.9 131.0 Book Value $ 60. 4 $259. 7 This analysis was based on reports received from 49 member firms whose R&D spending accounted for 94 percent of the 1965 total. PAGENO="0195" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2329 DISTRIBUTION OF RESEARCH AND DEVELOPMENT EXPENDITURES Table 17 displays the breakdown by sales groups of expenditures for each major area of research, as sponsored or conducted by the firms and as allocated between the United States and foreign sectors. In 1965, the leading 13 firms sponsored two-thirds of the total research and development reported. These firms ac- counted for three-fourths of the research and development con- ducted in U. S. company laboratories abroad and nearly 90 per- cent of the total research funds directed toward the discovery of veterinary-use drugs. Table 17 RESEARCH AND DEVELOPMENT EXPENDITURES BY SALES GROUP SHARE, 1965 Sales Group Research & Development Expenditures Human Use Drugs over $100 million $30- $100 million Amount spent within firms 66. 2 64. 9% 25. 6% 24. 2 In the United States In foreign countries 65.4 24.5 8.8 1.3 Amount spent outside firms 55. 9 In the United States In foreign countries Veterinary Use Drugs 77.7 19.3 35. 0 58.8 31.0 35.8 62.8 $5 Less $30 than $5 All million million Firms 8. 4% 1. 1% 100. 0% 8.4 1.2 100.0 100. 0 3. 0 * 100. 0 8.4 0.7 100.0 9.5 0.7 100.0 1.2 / 0.2 100.0 4.8 1.6 100.0 5.0 1.6 100.0 0.9 1.8 100.0 Amount spent within firms 89. 7 Amount spent outside firms 93. 4 89.9 3.7 3. 7 3. 9 Government Grants &Contracts 76, 4 Average Distribution (Number of Respondents) 66.9% 24.0% 20.8 2.8 * 100.0 (13) (14) 8.0% (25) 1.1% 100.0% (25) (77) Less than . 05% PAGENO="0196" 2330 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Table 18 represents how a firm in a specific sales group typi- cally allocated its R&D dollar among the organizations perfor- ming research; whereas the preceding table indicated the pro- p o r t i on of R&D expenditures accounted for by groups of com- panies. The table depicts the typical' allocation of the firm's own R&D dollar for human-use drugs, excluding R&D funds for veterinary-use drugs as well as monies received from the gov- ernment. Manufacturers with global sales of $100 million and over per- form, intramurally, a larger percent of their research abroad, as compared with 0th e r sales groups. Medium-to- small pro- ducers direct a larger portion of their funds for projects con- tracted to outside organizations. Table 18 RESEARCH AND DEVELOPMENT EXPENDITURES BY COMPANY SALES, 1965 Sales Grouo Company Financed R&D for Over $30- $5- Less Avera Human Use Performing Drugs by Organization $100 million $100 million $30 million than $5 million All Firm~ Amount spent within firms In the United States In foreign countries Amount spent outside firms 88. 8% 82. 2% 81.8 77.7 82.2 7.0 4.5 2.5 84. 7% 86. 4% 86. 79 86.4 80.8 0 5~9 11.2 17.8 15.3 13.6 13.3 In the United States 10.3 13.8 15.0 13.2 11.6 Manufacturing & other companies 0. 1 0. 4 0. 3 0. 1 0. 2 Commercial laboratories 1. 2 1. 9 2. 8 1. 2 1. 5 Private practitioners, consultants 3. 1 4. 1 4. 5 3. 8 3. 5 Educational institutions & hospitals: Medical schools 2. 0 2. 5 2. 1 6. 0 2. 2 Other academic institutions 1. 0 0. 9 0. 6 0. 7 1. 0 Hospitals and clinics 2. 1 2. 8 3. 3 1. 0 2. 3 Non-profit research institutions 0. 6 0.2 0. 8 0.4 1. 3 0.1 0. 4 ~` 0. 7 0.2 Other In foreign countries, total TOTAL, Human-Use R&D (Number of Respondents) 0.9 4.0 0.3 0.4 1.7 100. 0% 100. 0% (13) (14) 100.0% (25) 100. 0% (25) 100. 09 (77) Less than . 05%. PAGENO="0197" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2331 SIZE DISTRIBUTION OF R&D BUDGETS Research and development spending was related to sales group in Table 18. It was observed that medium-to-small producers allocated a comparatively larger share of their R&D funds for projects delegated to outside organizations. In the following, spending patterns are analyzed on the basis of research andde- velopment budget size. In Table 19 companies are classified into seven groups on the basis of their research and development budgets, including monies received from the government: Group A -- $20 million and over; Group B - $10 to $20 million; Group C -- $5 to $10 million; Group D -$1 to $5 million; Group E- - $0. 5 to $1 million; Group F -- $0. 1 to $0. 5 million; and Group G -- less than $0. 1 million. Table 19 SIZE DISTRIBUTION OF R&D BUDGETS, 1965 Average Number Per .Company11 Classification of of Expenditures' R&D Budget Firms (thousands) A. $20 million and over 6 $24, 325 B. $10 to $20 million 7 14, 855 C. $5 to $10 million 8 8, 000 D. $1 to $5 million 16 2, 480 E. $0. 5 to $1 million 9 730 F. $0. 1 to $0. 5 million 18 250 G. Less than $0. 1 million 13 40 Average, All Firms $ 4, 745 ~`Total R&D outlays, including monies received from the govern- ment. PAGENO="0198" 2332 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Table 20 TOTAL RESEARCH AND DEVELOPMENT EXPENDITURES BY SIZE OF R&D BUDGET, 1965 (thousands of dollars) Average Research and Develooment Exoenditures Per Comoanv: Per company spending averaged $4.7 million. However, ap- proximately one-half of the respondents reported R&D budgets of less than $1 million. As Table 21 demonstrates, average expenditures for a Group "A" company exceeded $24. 3 million. The company financed most of its R &D work with its own funds. However, on the average, such a firm also received $1. 3 mil- lion in government funds for R&D contracts. Clas si- fication of R&D11 Budget-1 A B C D E F Veterinary Use Drugs $15, 530 Total Company Financed $138, 400 Number Human of Use Firms Drugs 6 $122,870 7 95,990 8 60,585 16 38,235 9 6,035 18 4,630 Government Financed $ 7,565 GRAND TOTAL $145, 965 5,080 101,070 2,920 103,990 670 61,255 2,745 64,000 955 39, 190 515 6,550 4, 630 G 13 _510 - TOTAL 77 $328, 855 $22, 750 485 39,675 6, 550 4, 630 510 - 510 $351,605 $13,715 $365,320 -~`Seepage39, Table 19. PAGENO="0199" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Table 21 AVERAGE RESEARCH AND DEVELOPMENT EXPENDITURES PER COMPANY, 1965 (thousands of dollars) Government Funds for Industry Research: Government finan- cingofindustryresearchaccounted for less than four percent of total research activity reported. No government funds were received by firms with budgets of less than one million dollars. More than half was accounted for by firms with budgets exceeding $20 million. About four-fifths was received by PMA members with annual research and development expenditures of $10 mil- lion or more. Research and Development to Sales Ratio: On the average, an R&D performer allocated 10. 5 percent of its 1965 sales volume of $40. 6 million to research and development. For companies with annual r e s e a r c h and development spending e xc e e d in g $500, 000 the ratio was nearly 11 percent. 2333 Classi fication of R&D11 Budget-' A Number of Firms 6 Human Use Drugs $20, 475 Veterinary Use Drugs $2, 590 Total Company Financed $23, 065 Government Financed_ $1, 260 Average, All Firms $24, 325 B 725 14,440 C 85 7,655 60 2,450 7 13, 715 8 7,570 D 16 2,390 E 9 670 F 18 250 G 40 415 345 30 Average, All Firms 60 730 -- 250 -- 40 14, 855 8, 000 2, 480 730 250 77 $ 4,270 - 40 $ 295 $~ 4, 565 $ 180 $ 4, 745 -~See page 39, Table 19. PAGENO="0200" 2334 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Table 22 RELATIONSHIP OF AN AVERAGE' COMPANY'S OWN RESEARCH AND DEVELOPMENT EXPENDITURES TO SALES BY SIZE OF R&D BUDGET Classification `Average" Company of R&D R&D 3/ R&D/Sales Budget-1 Expenditures-1 Sales1 Ratio (thousands of dollars) A $21,500 $190,110 11.3% B 13,040 128,990 10.1 C 7,155 57,955 12.3 D 2,390 27,320 8.7 E 685 7,580 9.0 F 250 5,460 4.6 G 40 1,295 3.1 Average, All Firms $ 4, 250 $ 40, 620 10. 5% -~See page 39, Table 19. -~Expenditures for company financed R&D work conducted in U. S. laboratories. Excludes monies received from the covernment. Also excluded are company funds spent abroad. -~Domestic sales plus all exports. PAGENO="0201" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2335 BASIC AND APPLIED RESEARCH AND DEVELOPMENTS Prescription drugmanufacturers allocated 15. 8 percent of their research and development funds to basic research in 1965 (see Chart 11). U.S. expenditur~p of firms responding to this section amounted to $231 million, -~ or 71 percent of the $327 million spent by all 77 firms analyzed throughout most of this report. Chart 11 Basic and Applied Research and Development, 1965 -~`Basedonresponses from 42member firms only. Datapresented in this section constitute neither the total number of R&D per- fo r m e r s nor total expenditures in the U. S. A more complete coverage of PMA membership comparable to earlier sections in this r e port would undoubtedly increase the num be r of firms allocating funds to basic and other types of research as well as total expenditures for such activities. For various r e a s on s, particularly related to the difficulty firms experience in care- fully identifying basic research operations and related costs within their research effort. There was a smaller response to this section of the research and development survey. -~Reporting 42 firms spent $36. 5 million for basic research and $194. 7 million for applied research and development. PAGENO="0202" 2336 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY BASIC RESEARCH1 Twenty~1nine companies spent$36.5millionforbasicre- search. ~ The ten largest respondents accounted for two- thirds of this total. Firms conducting or financing basic research allocated 19. 3 per- cent of their total r e s e a r c h and development expenditures for original investigations. A smaller ratio of 15. 8 percent is ob- tained when the additional 13 firms with only applied research and development programs are included in the analysis. The latter were mostly smaller firms (see Chart 13). Table 23 IMPORTANCE OF BASIC RESEARCH TO DIFFERENT SIZE FIRMS, 1965 Firms with & without Firms with Basic Basic Research Research Sales Group Number % Spent Number % Spent (millions of of for Basic of for Basic dollars) Firms Research Firms ..Research $100 & over 10 16. 5% 9 18. 8% $30-under $100 11 14.8 8 21.5 Less than $30 21 13. 8 12 19. 0 Average, All Firms 42 15. 8% 29 19. 3% -~`Based on responses from 42 member firms. -~Reporting companies' own funds spent for original investigations conducted within and outside of company facilities, excluding all government funds. PAGENO="0203" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2337 APPLIED RESEARCH AND DEVELOPMENT EXPENDITURES~ In 1965, more than half of the industry's applied research and development funds were directed toward the creation of drugs to be effective in three classes: (1) central nervous system and sense organ disorders; (2) parasitic and infective diseases; and (3) neoplasms, endocrine system and metabolic diseases. Table 24 is a breakdownby therapeutic purpose of the reporting firms' applied r e s e a r c h and development expenditures in the United States. Table 24 Number of Research for the Discovery and Development Firms For Human Use of: Drugs for central nervous system and sense organs (37) Drugs affecting parasitic and infective diseases . * . (21) Drugs for neoplasms, endocrine system and metabolic diseases (27) Drugs acting on cardiovascular system (36) Drugs acting on digestive or genito-urinary systems . (32) Biologicals (13) Drugs acting on respiratory system (26) Vitamins, nutrients and hematinics (17) Diagnostic agents (20) Drugs acting on skin (17) Other pharmaceutical preparations (25) Research for the Discovery and Development For Animal Use of: Pharmaceutical preparations (18) Biologicals (12) TOTAL Company Financed U.S. R&D Funds - $ 37.1 19.0% 33.9 17.4 32.8 16.8 18.8 9.7 15.1 7.8 8.4 4.3 5.5 2.8 4.6 2.4 4.0 2.1 3.4 1.7 18.5 9.5 DISTRIBUTION OF APPLIED RESEARCH AND DEVELOPMENT EXPENDITURES BY THERAPEUTIC PURPOSE, 1965 Expen- ditures (millions) Per- c entage 9. 9 2. 7 L~ $194. 7 5. 1 1.4 100. 0~ -~`Based on responses from 42 member firms. PAGENO="0204" 2338 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Company Size and Applied Research and Development: Table 25 shows the typical!t allocation of the applied research and de- v e lopm e n t dollar for a research-minded firm in a particular sales group. The largest funds were directed to discovery of drugs affecting parasitic and infective diseases by manufacturers with global sales of $100 million and over. Next in importance was research for the discovery of drugs acting on central nervous system and sense organs, a field equally important to the medium to smaller firms. Table 25 AVERAGE COMPANY APPLIED RESEARCH AND DEVELOPMENT DOLLAR ALLOCATION, BY SALES GROUP, 1965 Sales Group Research for the Discovery and Development $100 million $30- $100 Less than For Human Use of: and over million $30 million Drugs acting on central nervous system and sense organs 19. 3% 17.0% 23.4% Drugs affecting parasitic and infective diseases 21.1 13.5 3.1 Drugs affecting neoplasms, endocrine system & metabolic diseases 18. 6 16. 3 6. 3 Drugs acting on cardiovascular system . . . . 8. 1 12. 3 13. 0 Drugs acting on digestive or genito- urinary systems 6. 6 8. 3 14. 3 Biologicals 4. 8 4. 0 1. 7 Drugs acting on respiratory system 2. 7 2. 6 4. 3 Vitamins, nutrients & hematinic drugs . . . . 2. 4 2. 0 3. 6 Diagnostic agents 1. 1 1. 8 9. 6 Drugs acting on skin 1. 2 1. 4 6. 5 Other pharmaceutical preparations 5. 6 18. 5 9. 5 Research for the Discovery and Development For Animal Use of: Pharmaceutical preparations 6. 7 2. 0 3. 0 Biologicals 1. 8 0. 3 1. 7 TOTAL, Applied R&D 100. 0% 100. 0% 100. 0% Number of Firms Reporting: (42) (10) (11) (21) PAGENO="0205" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2339 MANPOWER-U Over 16,400 research and development personnel were em- ployed by the pharmaceutical industry in 1965. About one-fourth held doctoral degrees. Scientists constituted 54 percent of the research and development staff and, technicians and supporting personnel 46 percent. Relationship of Research and Development Expenditures to Scientific and Professional Staff: A National Institutes of Health analysis (see footnote below) states that, "the proportion of scientific and professional staff to the total research and develop- ment staff appears to be an inverse function of the total volume of s a 1 e s, with the larger organizations employing a relatively smaller percentage of scientific staff to the total research and development staff." PMA analyses of the relationshipbetween research anddevelop- ment manpower and research and development spending cor- roborate the National Institutes of Health fi n d in g s. Table 26 illustrates that the correlation between the size of the research and d e v e 1 o p m e n t budget and the ratio of scientific and pro- fessional staff to the total research and development staff is negative. Data in Table 27 give further credence to the afore- mentioned National Institutes of Health hypothesis. The t a b 1 e indicates that research and development performers with large budgets employ relatively a smaller percentage of doctoral level staff. -~No attempt is made in the current study to deal with R&D man- power in detail. A comprehensive analysis of this subject appeared in the Resources for Medical Research Report No. 8, March 1966, "Trends in R&D Manpower in the Pharmaceutical Industry 1959- 1965 and 1968," prepared by the National Insti- tutes of Health of the U. S. Department of Health, Education and Welfare based ondata provided by and in cooperation with PMA. The purpose of this section is to analyze the relationship be- tween R&D expenditures and R&D manpower. PAGENO="0206" 2340 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Table 26 U. S. R&D MANPOWER BY R&D BUDGET GROUP AND TYPE OF STAFF, 1965 Classi- Scientific Technicians Percent fication All and and Scientific of R&D11 R&D Professional Supporting of all R&D Budget-a Personnel Personnel Personnel Personnel A 6,110 3, 190 2,920 52% B 4,805 2,405 2,400 50 C 2, 795 1, 630 1, 165 58 D 2,050 1,305 745 64 E 320 215 105 67 F 325 180 145 55 G 35 20 15 57 TOTAL 16,440 8,945 7,495 54°lo Table 27 U. S. R&D MANPOWER BY R&D BUDGET AND EDUCATIONAL LEVEL, 1965 Classi- Less Percent fication All than Doctoral of R&D2J R&D Doctoral Doctoral of all R&D Budget-i Personnel Personnel Personnel Personnel A 6,110 1,430 4,680 23% B 4,805 985 3,820 20 C 2,795 610 2,185 22 D 2,050 525 1,525 26 E 320 105 215 33 F 325 95 230 29 G 35 15 20 43 TOTAL 16,440 3,765 12,675 23% -~See page 39, Table 19, ~!ibid. PAGENO="0207" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2341 Average R&D Expenditures Per R&D Staff Person: With a work- ing force of 16,44Oduring 1965, the industry spent $365 million for research and development activities. Thus, an average of $22, 200 was spent to finance the activities of each member of the R&D team, including all scientific, professional and sup- porting staff. The average is nearly double for each profes- sional or scientific individual -- $0, 800. A more significant figure may be the amount of money spent to support a doctoral- level scientist - $97, 000. The above averages were somewhat lowerwhencalculated solely on the basis of intramural spending. The over-all average1~1ropped to $17, 600; while the per scientist figure was $32, 300. -` Each doctoral-level scientist had nearly $76, 700 at his command (see Table28). Table 28 INTRAMURAL R&D EXPENDITURES PER R&D PERSON BY R&D BUDGET, 1965 Classi- Scientific fication All and of R&D21 R&D Professional Doctoral Budget-' Personnel Personnel Personnel A $19,300 $36,900 $82,300 B 16,700 33,400 81.900 C 17,000 29,200 77,700 D 16,100 25,200 62,600 E 16,500 24,500 51,300 F 13,500 24,700 45,600 G 13,000 22,400 30,800 Average, All Firms $17, 600 $32, 300 $76, 700 -~1The National Science Foundation average for 1964, latest year available, was $31,700. According to the National Science Foundation the ratio has inc r e a s e d every year s inc e 1957. 1963 -- $31, 100; 1962 -- $29, 200; 1961 -- $28, 100; 1960 - $26, 700; 1959 - $25, 900; 1958 -- $23, 300; and 1957 -- $21, 200. The National Science Foundation, Surveys of Science Resources Series, Basic Research, Applied Research, and Development in Industry, 1964", NSF 66-28, June 1966. -~~`See page 39, Table 19. PAGENO="0208" 2342 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Relationship of R&D Budget and Expenditures Per Sc i en t i st: Table 28 indicates that there is a d i r e c t relationship between the size of the R&D budget and expenditures per scientist. For instance, a doctoral-level scientist in a Group A or B company hadabout $82,000 at his disposal, including his staff's salaries.1 How e v e r, other scientists had les s to work with. A Group E company scientist with a doctoral degree was `allocated' about $51, 000. His colleagues with a G company received only $31, 000 each. The relationship between magnitude of the research and develop- ment budget and the per per s on expenditures is demonstrated equallywell by the "scientific and professional personnel" data. Here the range of variance is not as great. Nevertheless, per scientist allocations show a declining trend as we progress from Group A to Group G. The "all-persons" average does not show the same trend. In spite of this, the over-all average diminishes as the company research and development budget is r e d u c e d. Forexample, theaverage for GroupAwas thehighest- $19,300. Not much difference was observed among the averages for Groups B, C, D, and E; each of which was within the $16, 000 to $17,000 range. The two sma~est (F and G) groups averaged between $13, 000 and $13, 500.-~ Wages constitute 55 percent of total research and development costs (36 percent for scientists and 19 percent for research and development supporting personnel), according to the National Science Foundation. Material and supplies and other related re- search and development costs account for the remainder. -~`PMA observations regarding the relationship b e\tw e en the re- search and development budget and expenditures per scientist are in line with those of the National Science Foundation. The Foundation found "a direct relationship in the cost ratio and R&D program size." PAGENO="0209" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2343 FACILITIES The ethical pharmaceutical industry research laboratories pro- vided employment for 18, 600 people, 16, 500 in the United States and 2, 100 a b r o ad. Respondent PMA member firms reported 176 research and development facilities in 20 states and 20 foreign nations. Chart 12 Regional Distribution of Research and Development, 1965 R&D Facilities We~ Foreign United States Employment Foreign United States 81-280 0 - 68 - pt. 6 - 14 PAGENO="0210" 2344 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Foreign R e s e a r c h and Development Facilities: At the end of 1965 the United States ethical pharmaceutical industry had 85 research laboratories in 20 foreign nations. Most of these facilities were located at the manufacturing plant site. Only 16 were physically separate from manufacturing operations. Thirteen research laboratories were located in the United King- dom. This small segment accounted for more than half of the industry's combined research and development personnel in all foreign countries. Canada, with a larger number of research facilities but a smaller number of research and development personnel, was the second region of major concentration (see Chart 12). Drug research facilities abroad employed 2, 100 persons in 1965 (see Table 29). Research and development laboratories operating at a different address from that of the manufacturing plant em- ployed an average of about 15 scientists and supporting personnel. PAGENO="0211" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2345 Table 29 UNITED STATES RESEARCH AND DEVE~OPMENT FACILITIES ABROAD, 1965-' Number of R&D Facilities T0 Employment Outside Within TA in R&D Region & Country-' Mfg. Plant Mfg. Plant L Facilities WESTERN EUROPE United Kingdom 3 10 13 1, 135 France 2 5 7 60 Germany 1 5 6 35 Italy ~ - 3 3 10 Other~ 3 3 6 90 Regional Total 9 26 35 1, 330 CANADA 2 12 14 345 PACIFIC & FAR EAST AustraMa 1 5 6 Th Other-i 3 5 8 125 Regional Total 4 10 14 200 LATIN AMERICA Mexico 1 5 6 95 Argentina - 5 5 40 Brazil51 - 3 3 15 Other -` - 4 4 40 Regional Total 1 17 18 190 AFRICA 4 4 20 TOTAL 16 69 85 2,085 -~1Even though reported by only 19 PMA member companies with research facilities abroad, the following data is believed re- presentative of the general dispersion of the U. S. ethical drug i nd u s try foreign research facilities and related employment. Complete coverage of the industry would not appreciably increase the employment figures reported. ~Countries are listed by region in descending order by number of employees. ~`Includes facilities in Belgium (2), Switzerland (2), Netherlands (1), and an unspecified nation (1). ~`Includes facilities in India (2), Japan (2), Phillippines (2), Taiwan (1), and an unspecified nation (1). -~`Includes facilities in Colombia (1), Peru (1), and an unspecified nation (1). PAGENO="0212" 2346 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY United States Research and Development Facilities: At the end of 1965 the ethical pharmaceutical industry research and devel- opment facilities were lo c at e d in 20 states. However, more than four-fifths of the research and development facilities, and almost all of the scientists and supporting personnel were lo- cated in only half of these states (see Table 30). The major portion of the industry' s research facilities were lo- cated in three states of the Northeastern region. About one-half of the 91 major researchcenterswerebased in that area. These facilities also accounted for nearly 60 percent of the industry's total research and development personnel. The North Central region ranked second with 33 research facilities and 37 percent of the industrial staff engaged in research and related activities (see Chart 12). Three states included in the Northeastern area -- New Jersey, New York and Pennsylvania - were the leading drug research centers of the nation for 1965. Within the borders of these three neighboring states were included one-half of all research laboratories. New Jersey alone provided employment for 4, 650 scientists and supporting personnel. Onthe averagea research laboratorywas staffedwith 60 people. Average employment for a research facilityphysically separate from the manufacturing plant site was considerably high e r -- 150. However, a research facility located at the same address as the manufacturing operations averaged a smaller research staff of about 50. PAGENO="0213" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2347 Table 30 UNITED STATES RESEARCH AND DEVELOPMENT FACILITIES, l965-~' Number of R&D Facilities T0 Employment Outside Within T in R&D Region and State-1 Mfg. Plant Mfg. Plant AL Facilities NORTHEAST New Jersey 4 15 19 4, 650 New York 5 9 14 2, 490 Penns~1,vania 2 8 10 2,335 Other-1 - 2 2 355 Regional Total 11 34 45 9, 830 NORTH CENTRAL Indiana 2 4 6 2,265 illinois 1 8 9 1, 665 Michigan 2 3 5 1, 570 Ohio - 5 5 425 Nebras,,1~a - 3 3 30 Other ~ - 5 5 175 Regional Total 5 28 33 6, 130 WEST California - 7 7 330 Other - 1 1 5 Regional Total - 8 8 335 SOUTH-U 1 4 5 235 TOTAL 17 74 91 l6,S3O~~ -V 52 respondents. .WStates are listed in descending order by number of employees. ~Includes facilities in Connecticut (1) and Rhode liland (1). -~Includes facilities in Iowa (1), Kansas (1), Missouri (1), and Wisconsin (2). -~`1Includes facilities in Arkansas (1), Maryland (1), Virginia (2), and Texas (1). it includes a larger number of persons with R&D sup- porting functions, the total employment figure onthis page differs slightly from the R&D manpower data cited elsewhere in this report. PAGENO="0214" 2348 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SELECTED DEFINITIONS Basic Research: The National Science Foundation defines basic research as "original investigations for the advancement of scientific knowledge... which do not have specific commercial objectives, although they maybe in fields of present or potential interests to the reporting company." The National Science Foun- dation studies using this definition show the "drug industry" to be the leader among industries engaging in basic research. Bulk: For use as a pharmaceutical or medicinal product in further manufacture or in packaging, or for processing inanimal feeds (but not as nutritional ingredients), or in prescription compounding, etc. Company Financed Research and Development Expenditures: The total cost (worldwide) incurred for all pharmaceutical, bio- logical and medical research and development activity financed by PMAmember firms. These figures include cost of salaries, other direct costs, service, routine supplies, and supporting costs, plus a fair share of overhead (administration, depreci- ation, space charges, rent, etc.). Excluded are costs of drug or medical research and development conducted on grant or contract for other companies, government agencies, and so on. Conversely, total outlays for all research and development work contracted to others (manufacturers, in- dependent research laboratories, academic institutions, etc. are included. Company or firm is defined to include the parent company and affiliated, subsidiary or other related organizations under the same parent ownership. Domestic U. S. Sales to Governments: Sales or shipments made directly to federal, state or local government agencies, hospitals and clinics. Domestic U.S. Sales to Private Sector: Sales through regular marketing channels other than government agency administration or distribution. Employ~ment: Total number of full-time employees and full-time equivalent of those working part-time in ethical drug facilities. PAGENO="0215" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2349 ~pployment Abroad: Total numbé r of full-time employees, whether U. S. citizens or not, of PMA member firms or any wholly-owned overseas corporations, or corporations in which PMA member firms had a substantial or controlling i nt e r e s (ethical pharmaceutical manufacturing firms only). Employees Engaged Primarily in Production and Product Control: Workers up through theworking foreman level engaged in fabri- cating, processing, assembling, receiving, inspection, quality control, handling, packing, warehousing and storage, shipping, maintenance, repair, janitorial, watchman service, production development, record keeping, and other services associated with the production operations. Employees En g a g e d Primarily in Research and Development: Personnel engaged in research, research administration, din- cal evaluation and development; excludes pers onnel in promotion, sales, market research, business administration, production and quality control. Ethical Pharmaceuticals: Products,~ including biologicals and medicinal chemicals, used for the cure, alleviation, mitigation, treatment, prevention or diagnosis of disease in humans or ani- mals, and promoted primarily to the medical, pharmacy and allied professions; including products for "over-the-counter ethi- cal" sales as well as for ultimate dispensing "by prescription only". Government Grants and Contracts for Compai~y Conducted Dr~g Researchand Development: Includedaredollar amount of grants and contractual payments received by member firms from governmental agencies for drugand medical research and devel- opment. Manufacturing Plants: The definition of a plant is synonymous with that of the Bureau of the Census. By "production plant" is meant each location of a manufacturing, packaging or process- ing facility or group of such facilities geographically contiguous. Excluded are sales branches, administrative offices, research laboratories, w a r e ho u s e s, etc., which have no production, packaging or processing facilities. Employment figures for plants encompass all personnel, research and development staff, etc., as well as production workers. PAGENO="0216" 2350 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Quality Control: Encompasses: (1) Employment and cost data on direct quality control activities. Includes all full-time em- ployees responsible for sampling and testing of raw materials as they are produced, or while in storage; investigation of com- plaints; disposition of returned goods; selection and weighing of components; proper sanitation and storage of raw and finished materials; inspection of labels, contents, packages, etc.; main- tenance in the final product of the desired purity, uniformity, potency and stability; and (2) Employment and cost data on in- direct quality control activities. Includes the full-time equiva- lent of production workers and other employees who have in- spection or quality control functions incidental to their primary assignments; pro-rated according to hours, facilities, etc., de- voted to quality control functions as share of total labor time, and so on. Research and Development: The term includes basic andapplied researchas wellas development activities carried on or support- ed in the pharmaceutical, biological, chemical, medical and re- lated sciences, including psychology and psychiatry, if the purpose of such activities is concerned ultimately with the utilization of scientific principles in understanding human diseases or in im- proving health. Activity in pursuit of the following objectives is included: (1) Planned search for new knowledge, whether or not the search has reference to a specific application. (2) Application of existing knowledge to problems involved in the creation of a new product or, process, including work required to evaluate possible use. (3) Application of existing knowledge to problems involved in the improvement of a present product or process. For practical purposes, any scientific or technical activitywhich could result in a new drug, as defined in the Federal law, would certainly be considered research and development. Chemical synthesis of substances which might become drugs would be in- cluded in this definition and so would all clinical evaluation of new or old drugs. The question, `When does development end and production begin? is often asked. If the primary objective is to make further improvements on the product or process, then the work PAGENO="0217" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2351 comes within the definition of research and development. If, on the otherhand, theproduct or process is substantially "set, and the primary objective isto develop markets or to do preproduc- tion planning, or to make engineering changes in production equip.. ment, then the work is not defined here as res earch and develop- rnent. R o u tin e quality c o n t r o 1 activities are not included; figures or e stimates in d evelopment of quality control are included, where available. Research and Development Facilities: The R&D facility is defined in verybroad terms. It may be a five-man research laboratory within a manufacturing plantwith 5,000 employees, or a research building housing 300 research workers and physically separate from manufacturing facilities. If located at the same address and in the same building, regardless of the number of research laboratories within it, the facility is counted as one. Research facilities at different locations (addresses) are listed separately, even if several such facilities are administered from one central research building. Researchand Development Scientific and Professional Staff: In- cludes all persons whose work requires the application for re- search and development of knowledge, skills, and scientific techniques, in the life, physical, engineering, or mathematical sciences, acquired through the completion of a four-year college course (or its equivalent) with a major in these fields or in medicine or other health professions. Excludes per s on s who have formal training in the sciences but who are not actively en- gaged in research and development. Research andDevelopment Technicians and Supporting Personnel: Includes persons who may hold some academic degree at the bachelor's level or above. Technicians include persons actually engaged in technical work at a level which requires knowledge of the life, ph y s Ic a 1, engineering, or mathematical sciences comparable at least to that acquired through technical institutes, junior colleges, or other formal post-high school training less extensive than four-year college training, or through equivalent on-the-job training or experience. Supporting Personnel includes persons who provide literature, clinical, statistical, or o t h e r services specifically for R&D staff. Sales: Sales figures are reported as billed (before deducting cash discounts on sales and other marketing expenses), less returns PAGENO="0218" 2352 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and allowances. Includes sales value of products bought and re- sold without further processing or repackaging as well as the dollar value of products made from own m a t e r i a 1 s for other manufacturers' resale. Ex c 1 ud e d are all royalty payments, interest and other income. Sales Abroad: Actual sales consummated in foreign countries other than "Sales for Export to Other Firms". Such sales by affiliates, subsidiaries, distributors, sales offices, and other operations abroad are reported in dollars, computed at Dec- ember 31, 1965, rate of exchange (when possible). Where a par- tially-owned subsidiary or joint venture is involved, the firm's share is determined on a proportionate profit-sharing basis. Sale for Export: Reported `f. o. b. U. S. port": (a) To Other Firms: excludes intra-firm transactions; includes sales to third parties only. (b) Intra-Firm Transactions: includes "sales" and ship- ments to subsidiaries or affiliates for further han- dling, processing, or packaging by them. Reported as "net billed value", not end sales values. PAGENO="0219" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2353 Senator NELsoN. Dr. Van Riper, please proceed. STATEMENT OP DR. [ART E. VAN RIPER, VICE PRESIDENT FOR MEDICAL AFFAIRS, (~EIGY PHARMACEUTICALS, ARDSLEY, N.Y.; ACCOMPANIED BY LLOYD N. CUTLER, SPECIAL COUNSEL, PHAR- MACEUTICAL MANUFACTURERS ASSOCIATION, WASHINGTON, D.C. Dr. VAN RIPER. Thank you, Mr. Ohairnian. I have submitted a statement for the hearing on November 16, and to conserve time, I have eliminated certain sentences in the statement that I will read today, but you may follow the statement that I have submitted tin context.1 I am Hart E. Van Riper, M.D., vice president for medical affairs of Geigy Pharmaceuticals, division of the Geigy Chemical Corp., A*rdsley, N.Y. I was graduated from the University of Pennsylvania, being awarded a bachelor of arts degree in 1926 and a degree of doctor of medictine in 1930. After an intern~hip and residency in pediatrics, I was certified by the American Board of Pediatrics and pra~ticed my specialty in Madi- son, Wis., from 1~}33 to 1941. From 1941 to 1944, I served as Assistant Director for Maternal and Child Health, the Ohildren's Bureau, at that time a bureau in the Department of Labor. From 1944 to 1945, I was medical director of the Jackson Memorial Hospital, Miami, Fla. From 1945 to 1956, I ~was medical director at the National Founda- tion for Infantile Paralysis, and during this period was concerned with the researth that culminated in the field trials that established the safety and efficacy of the Salk pol'iomyeiitis vaccine. Since 1956, I `have been associated with Geigy Pharmaceuticals and for `T years, as medical director, I have been responsible for the clinical investigation of new drugs and the filing of new drug applications with the Food and Drug Administration. In my statement I would like to outline `briefly some of the activities of the research-oriented companies in the pharmaceutical industry in preparing safe and effective medicines for the treatment, cure, or pre- vention of disease~ 1 bope to give you some idea of the vast amount of time, effort, talent, and money expended in the clinical phases of drug researc,h. In an article entitled "The Evaluation of New Drugs," which ap- peared in the Archives of Internal Medicine, volume 119, Drs. Barron and Bukantz, authors of this scientific paper, state that "it is presently estimated that approximately 4 years will elapse between the time a drug is recommended for development by the corporation's ecien- tific advisory board and submitted as a new drug application (NDA) to the FDA for review and approval for marketing." This period may The complete prepared statement and attachments submitted by. Dr. Van Riper for pres- entation on Nov. 16, 1967, begins at p. 2360, infra. PAGENO="0220" 2354 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY be extended several additional years before a drug product is finally approved. The orderly progression in the development from a chemi- cal compound to a drug product; that is, from the early toxicity tests in a mouse to a safe and effective drug product in man, is.an extremely time-consuming and costly procedure. It is estimated that for each drug product that receives an effective NDA, in excess of 6,000 chemi- cal agents are investigated for their potential usefulness in the treat- ment or prevention of disease. The enactment of the Kefauver-Harris amendments to the Food, Drug, and Cosmetic Act in 1962 added a second basic statutory re- quirement, proof of therapeutic effectiveness, to the 1938 amendments. Prior to 1962 the statute was primarily concerned with a need to demonstrate safety of a drug product. Senator NELSON. What is the status presently of the question of the therapeutic effectiveness of the drugs that went on the market prior to 1962? Dr. VAN R.reei~. Mr. Chairman, those are currently under review by a committee of the National Science-the National Academy of Science, National Research Council. I understand approximately 20 of those drugs have had their final panel review and have been sub- mitted to the Food and Drug Administration for action. Senator NimsoN. To determine therapeutic effectiveness? Dr. VAN RIPER. Possibly effective or not effective. Senator NELSON. Twenty of them. How many more are there for review? Dr. VAN RIPER. I understand there are some 1,200 or more. They hope to have completed a review of about 400 by July 1, 1968. We were so advised about a month ago. Senator NELSON. Under the law as I understand it, there was n' requirement in the marketing of drugs prior to the Kefauver-Harris amendment in 1962 that proof of therapeutic efficacy be made; is that correct? Dr. VAN RIPER. That was not required under the law; no, sir. But I believe that most companies were not interested in the investment of marketing a drug that was not effective. Senator NELSON. I don't know about that. We don't know, as of this date, how many are on the market toda.y that are not therapeutically effective, do we? Dr. VAN RIPER. We do not. That is the purpose of this current review. Senator NELSON. So for a majority of the drugs on the market in America today, therapeutic effectiveness has not been formaily proved; is that correct? Dr. VAN RIPER. That is right-not under the law. There has been under the law, I think, clinical evidences Mr. Cha.irman~ that would indicate there are probably not many ineffective drugs. Now, in hear- ing the discussions by the review committee, they did indica.te that certain indications for some drugs might be questioned and might. require further clinical investigation to establish the claim that had been allowed until now. PAGENO="0221" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2355 Senator NELSON. I would assume, in any event, that there must be a mass of clinical evidence on widely used drugs that were discovered prior to 1962, is there not? Dr. VAN RIPER. That's right. And that was all submitted by the company that markets the drug at the time they made the informa- tion available for this review. Senator NELSON. This committee isn't attempting itself, then, to do independent clinical studies of these drugs. Dr. VAN RIPER. No. They are simply reviewing the clinical evidence that has been published, or it may be in the hands of the company that markets the drug, though it has not been published. Senator NELSON. Do they have any kind of a timetable on how soon they expect to report on the balance? Dr. VAN RIPER. We were told a month ago they hope to complete their reviews in about a year. Then those reviews will be submitted to the Food and Drug Administration who in turn will make a review and make final judgment as to whether the drug is effective, not effec- tive, or probably effective. Senator NELSON. Am I correct that if under the law any one of them turns out not to be therapeutically effective, it may be taken off the market? Is that what the law is? Dr. VAN RIPER. Dr. Leahy has advised us they would undoubtedly give the company time to conduct clinical research to determine its effectiveness. Mr. CUTLER. Senator, the law would require that the Food and Drug Administration at that point afford the company an opportunity for hearing. Senator NELSON. I am talking about the end result. What will be done if the FDA concludes that there is no proof. Mr. CUTLER. If FDA concludes-with the exception of a small class of grandfather drugs-if FDA should conclude that there is inade- quate evidence of therapeutic effectiveness, it could require the drug to be taken off the market. Senator NELSON. Have they grandfathered some drugs? Mr. CUTLER. You did grandfather some drugs. Senator NELSON. Not I. Mr. CUTLER. The Congress did~ Senator NELSON. Some old drugs that professional oldtimers can't get along without? Mr. CUTLER. It is a very complicated question and there is disagree- ment today as to just how many drugs are grandfathered. But it is a small number. Senator NELSON. OK. I don't want to catch my wife paying for any of them, that's all. Dr. VAN RIPER. The current regulations have placed under much closer scrutiny the evaluation of chemical substances employed in the treatment of human disease. The first phase of a drug's evaluation is confined to study in appro- priate species of animals. As much as a year may be required to estab- lish the systemic absorption, tissue distribution, metabolism and elimi- PAGENO="0222" 2356 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY nation as well as the pharmacologic action and toxic potentials in laboratory animals. The biochemist, the pharmacologist, and the toxi- cologist must establish the basic data that warrants the first administra- tion of the drug to man. It is unfort~unath that in the present state of the art that this information gained from animal experimentation can only be considered an indicator of its potential action in man. When the information that has been accumulated from the extensive animal research warrants the. trial of the potential drug in man, a spe- cial form (FDA Form 1571)1 is completed for submission to the Food and Drug Administration. A sample copy of a blank form is attached for your information. The assembly of the information required to complete this form may require as much as 2 months and constitutes a "Notice of Claimed Investigational Exemption for New Drug" (IND). The filing of this IND informs the FDA that the pharmaceu- tical company is prepared to initiate limited studies in man to deter- mine whether or not the information gained from the animal studies can be confirmed. The IND filed with the FDA represents a body of information gath- ered on a chemical entity or its combination products through animal experimentation. The cost involved in preparation and submission, however, reflects but a fraction of the total research expenditure to this point in the development of a marketable product. The man-hours of laboratory personnel, cost of animals, laboratory space, and equip- ment utilized in t.he screening of perhaps hundreds of compounds to discover a potentially safe and effective new drug product represents the hidden costs of drug research. Prior to the 1962 amendments to the Food, Drug, and Cosmetic Act, it was the sole responsibility of the manufacturer to exercise his judgment in establishing the reasonableness and safety of first admin- istering an entirely new drug product to man. Today, however, he shares tha.t decision with the FDA which has the added responsibility of reviewing t.he information set forth on form 1571 and concurring in the decision to enter into phase I in the process of drug development. The IND is a total profile, containing all information that is known with respect to the chemical structure of active ingredients, biologic activity, pharmacologic action, dosage form, that is, tablet, capsule, or liquid, detailed process of n~ianufa.cture and means of identifying in- gredients both qualitively a.nd quantitively, facilities for production, and a data sheet that provides all pertinent information for a prospec- tive investigator. The development of a drug product must necessarily be tailored to the chemical and physical nature of the active ingredients, anticipated therapeutic effects, the route of administration, the duration of action, a.nd the ratio of pharmacologic and physiologic action to toxic poten- tial. These developmental steps require a.n average of 12 months and are not instituted without the cautious control of persons experienced in the several disciplines that will influence the total procedure. 1 See attachments for FDA Forms 1571, 1572, 1573, and FD356H, beginning at p. 2364, infra. PAGENO="0223" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2357 The following table shows a representative time schedule detailing the several integrated steps that must transpire after 1 to 5 years of basic research from the time of selection of the potential clinical candi- date to the institution of the broadscale clinical trials. The same procedures and time schedule are involved in the case of a combination product containing a new drug substance. The spon- sor, in the majority of instances a pharmaceutical manufacturer, hav- ing already filed FDA Form 1571, is now required to obtain FDA Form 1572 from each investigator. The investigator in singing con- firms his understanding of the nature of the drug product he will study; guarantees supervision of every aspect of the study by him- self or one or more named associates who are directly responsible to him; describes the facilities available to him; and confirms his under- standing that the product will be administered only to volunteers or patients to whom he has made a full disclosure of its actions, the pur- pose of administering it, and the benefits to be derived from the study, and from whom an informed consent has been obtained for the admin- istration of the drug product. The investigator, in signing FDA Form 1572, accepts all of the limitations on the investigational use of the experimental drug product as set forth in the sponsor's brochure. He further agrees to report promptly any event of clinical importance which may be observed in the subjects included in the study whether or not, in his judgment, the event is related to the product's administration. It is the responsi- bility of the sponsor to report these events to the FDA with an evalua- tion of the observation. Phase I is a carefully restricted trial of the drug product in normal man, a relatively few volunteers who agree to take the drug product hopefully to confirm the information already established in a variety of animal species. Those qualified to investigate a drug product in this area of development must necessarily be carefully selected and knowledgeable in regard to drug action as it may affect all body systems and functions. This phase may involve no more than two investigators and perhaps 10 to 20 persons. Phase II studies are warranted when the probably working-dose range has been ascertained and the human tolerance to the product has been established. At this phase of the investigation, a few selected patients suffering from the illness for which the product may be indicated are given the drug. It is the customary practice in the industry that a single physician employee be assigned to monitor the investigations. He is responsible for the supplies of the investigational drug product, the filing of an FDA Form 1572 for each investigator, along with a protocol detail- ing the purpose of the particular study, its duration, and the numbers of patients expected to participate. Should an investigator, at any time or for any reason, elect to deviate from the protocol, the change must be reported to the FDA. Studies during this period are most critical. The drug product must PAGENO="0224" 2358 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY demonstrate that it is both safe and effective. Critical judgment gained through experience and knowledge of conditions for which the drug product is indicated is essential for a proper evaluation upon which will be based a decision to proceed with the extensive and expensive clinical trials required for the eventual submission of the New Drug Application. This monitoring of the investigation of an entirely new chemical for use in medicine demands the attention of a physician who possesses scientific curiosity, an in-depth knowledge of the clinical condition for which the drug product is being investigated, and clinical judg- ment in respect to the therapeutic agents already available to the practicing physician for the treatment or control of the clinical con- dition under investigation. An additional responsibility is an administrative chore, for it in- volves the constant attention to the details of drug supply and prepa- ration of progress reports to the FDA showing the continuing toxi- cological, teratological, and carcinogenic investigations are being cor- related and integrated with the studies in man. Indeed, it is a complex exercise not to be undertaken by the inexperienced or uninformed. Senator NELSON. May I interrupt for a moment? In this first full paragraph on the page you refer to the qualifications of the physician to monitor such an investigation. Are you referring to the doctor who does the experimenting? Dr. VAN RIPER. I was referring in that instance to the physician em- ployed by the pharmaceutical company. Senator NELSON. What qualifications do you seek for the perform- ance of clinical tests done pending approval of your application? Dr. VAN RIPER. You try to pick out individuals who have, through scientific qualification, established a reputation in a particular field. If you are investigating an analgesic, you certainly go to someone in the field. If you are investigating a drug in cardiology, you go to a cardi- ologist. It is a highly selective process. Senator NELSON. Is that a requirement of the law? Dr. VAN RIPER. It is not a requirement of the law. But it is essential to good clinical investigation. Senator NELSON. Does the FDA require, along with the submis- sion of your accumulated clinical testing, submission of the qualifica- tions of the doctor? Dr. VAN RIPER. Those are submitted before you ever are permitted to begin the investigation. Senator NELSON. They approve your proposal a.nd the physicians who are to participate prior to your starting a clinical test.? Dr. VAN RIPER. Mr. Chairman, they don't. actually give you writ- ten approval. But it does give them an opportunity-for instance, should they see you are using an investigator in whom they would have some doubts as to hisqualifications, it provides them an opportu- nity to at least warn you that they think you have made a bad choice. Sena.tor NELSON. But it is a practice in the industry to seek physi- cians who have expertise in the disease area with which the drug is concerned? Dr. VAN RIPER. That is right. PAGENO="0225" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2359 The ethical manfacturer of drug products, having established the safety and therapeutic action of the product under investigation, must make the final decision. Does this product represent a significant ad- vance in therapeutics? What makes this drug product a useful thera- peutic agent for the physician in his practice? What is the ratio of clin- ical effectiveness to the toxic potential? At this stage of development the producer of a new drug product has a very substantial financial investment that has resulted in only a minimum of information on which to predict the commercial value. Also, this one drug product containing an active ingredient which has shown promise among the thousands that have been synthesized, has alone progressed to this stage of development. Approximately 3 years after the decision to investigate a new drug product, plans are made for carrying out a phase III, broadly based, clinical trial. Prior to the initiation of this phase of the study, detailed analyses and review of the data derived from the phase II studies are completed. Any further modifications of the clinical data sheet, which are a consequence of new observations during the phase II period, are incorporated in a further revision of the clinical data sheet. At this point, a copy of FDA Form 1573 is sent to selected clinical investiga- tors throughout the country. (A sample copy of this form is attached for your information.) This study provides a wide experience of use in all ethnic and socioeconomic groups in the total population. This is *a broad test of the efficacy of the product in the specific clinical situations for which it is intended to be used. The sample of patients must be large enough to yield data upon which judgmentcan be made concerning the safety and efficacy of the product. As many as 150 (or more) clinicians may participate and the total number of patients under their observation will frequently exceed 1,500 and often 3,000. Although it is estimated that an additional 18 to 24 months will be re- quired for the completion of the phase JJJ: trial, it is likely that more than 4 years will pass between the initiation of clinical research on a product and the completion and filing of its NDA. During this period the monitor maintains close contact with each investigator so that he is informed of developments throughout the clinical trial and obtains periodic reports of the progress of the trials. A sample copy of the New Drug Application Form FD 356 H is included as an attachment. The detailed information required to complete this application can be appreciated in part by review of the form. FDA approval of an NDA does not terminate the monitor- ing of the drug product by the medical department of the sponsor- ing firm. Once the drug product is available on prescription, there is no way of preventing its being used in dosages and for indications not included in the approved labeling. A drug product may be used im- properly resulting in failure in therapeutic response or causing drug reactions. Both drug failures and adverse effects must be carefully investigated and reported to the FDA. These reports must be sub- mitted every 3 months for the first year of distribution, every 6 months during the second year, and once, a year thereafter. Any contraindication to use or toxic effect not already detailed in the 81-280 O-68-it. 6-15 PAGENO="0226" 2360 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY labeling must be investigated and reported within 15 days after such knowledge is available to the producers. No one has a greater interest or responsibility in the safety and effectiveness of a drug product than the manufacturer, who can ill afford to market a drug that will demonstrate a. toxic response not commensurate with its effectiveness. To insure the continuing flow of all essential information in respect to an FDA approved drug prod- uct the pharmaceutical manufacturers support the Armed Forces Institute of Pathology in its investigation of tissue reaction to pos- sible toxic drug effects and the American Medical Association's Coun~ cil on Drugs and its panel on hematology of the registry on adverse reactions. More than 700 doctors of medicine are engaged full-time by PMA member firms. There is a grave responsibility in the overall develop- ment of a new prescription drug product. Less than an honest ap- praisal of the product and constant surveillance of the claims made for it by its marketers could destroy a scientific reputation that was not obtained without great effort. Senator NELSON. Thank you very much, Doctor. We certainly ap- preciate your taking the time to come here and present your very valuable testimony to the committee. We regret the great imposi- tion on your time. (The complete prep~red statement and attachments submitted by Dr. Van Riper for presentation on November 16, 1967, follows:) STATEMENT OF DR. HART E. VAN RIPER, VICE PRESIDENT, GEIGY PHARMACEUTICALS THE CLINICAL EVALUATION OF NEW DRUGS Mr. Chairman and members of the committee, I am Hart E. Van Riper, M.D., Vice President for Medical Affairs of Geigy Pharmaceuticals, Division ~f the Geigy Chemical Corporation, Ardsley, New York. I was graduated from the Uni- versity of Pennsylvania, being awarded a bachelor of arts degree in 1926 and a degree of doctor of medicine in 1930. After an internship and residency in pedi- atrics, I was certified by the American Board of Pedi.atircs and practiced my specialty in Madison, Wisconsin from 1933 to 1941. From 1941 to 1944, I served as Assistant Director for Maternal and Child Health, The Children's Bureau, at that time a bureau in the Department of Labor. From 1944 to 1.945, I was Medical Director of the Jackson Meniorial Hospital, Miami, Florida. From 1945 to 1956, I was Medical Director at the National Foundation for Infantile Pai~a1ysis, and during this period was concerned with the re~earch that culminated in the field trials that established the `safety and efficacy of the Salk poliomyalitis vaccine. Since 1956, I have been associated with Geigy Phi rmaceutiicals and for seven years, as Medical Director, I have been responsible for the clinical investigation of new drugs and the filing of new drug applications with the Fo'od and Drug Administration. In my statement I would like to outline briefly some of the activities of the research-oriented companies in the pharmaceutical industry in preparing safe and effective medicines for the treatment, cure or prevention of disease. I hope to give you some idea of the vast amount of time, effort, talent and money ex- pended in the clinical phases of drug research. In an article entitled, "The Evaluation of New Drugs", whi~h appeared in The Archives of Internal Medicine, Volume 119, June, 1967, scientist,s not as~ociated with the pharmaceutical industry presented in con~iderthle detail the steps that must be taken in .the evaluation of a chemical compound from the chemist's laboratory to the finished pharmaceutical Product on the pharmacist's shelf. Drs. Barron and Bukantz, authors of this scientific paper, state .that "it is pres- ently estimated that approximately four years will elnpse between the time a PAGENO="0227" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2361 drug is recommended for development by the corporiition's scientific advisory board and submitted as a New Drug Application (NDA) to the FDA for review and approval for marketing". This period may be extended several additional years before a drug product is finally approved. The orderly progression in the development from a chemical compound to a drug product, that is, from the early toxicity tests in `a mouse to a safe and effective `drug product in man is an ex- tremely time consuming `and costly procedure. It is estimated that for each drug produce `that receives an effective NDA, `in excess of 6,000 chemical `agents are investigated for their potential usefulness hi the treatment or prevention of disease. The enactment of the Kefauver-Har.ris Amendments to the Food, Drug and Cosmetic Act in 1062 added a second basic statutory requirement, proof of thera- peutic effectiveness, to the 1938 amendments. Prior to 1962 the statute was pri- marily concerned with `a need to demonstrate safety of a drug product. The current regulations have placed under much closer scrutiny `the evaluation of chemical substances employed in the treatment of hum'an disease. The develop- ment of a new chemical entity for use as a therapeutic `agent h'as also become a much more complicated `and laborious process. The regulations `h'ave thu's added materially to the cost and the time required to develop a new drug product. The first phase of `a drug's `evaluation is confined to study in appropriate species of animal's. As much as `a year m'ay be required to establish the systemic absorption, tissue distribution, metabolism and elimination a's well as the phar- macologic action and toxic potentials in laboratory animals. The biochemist, the pharmacologist, and the toxicologist `must establish the basic data that warrants the first administration of the `drug to man. It `is unfortunate that in the present state of the art that this information gained from animal experimentation can only be considered an indicator of its potential action in man. The orderly pro- gression of drug development from "mouse to man" is `fraught with both difficul~ ties and disappointments. When the information that has been accumulated from the extensive animal research warrants the trial of the potential drug in man, a special form (FDA Form 1571) is completed for submission to the Food and `Drug Administration. (A sample copy of a blank form is attached for your information). The assem- bly of the information required to complete this form may require as much as two months and constitutes a "Notice of Claimed Investigational Exemption for New Drug" (IND). The filing of this IND informs the FDA that the pharma- ceutical company is prepared to initiate limited studies in m'an to determine whether or not the information gained from the animal studies can be confirmed. The IND filed with the FDA represents a body of information gathered on a chemical entity or its combination products through animal experimentation. The cost involved in preparation and submission, however, reflects but a fraction of the total research expenditure to this point in the development of a market- able product. The manhours of laboratory personnel, cost of animals, laboratory space, and equipment utilized in the screening of perhaps hundreds of com- pounds to discover a potentially "safe `and effective" new drug product, represent the "hidden costs" of drug research. Prior to the 1962 amendments to the Food, Drug and Cosmetic Act, it was the sole responsibility of the manufacturer to exercise his judgment in establishing the reasonableness and safety of first administering an entirely new drug product to man. Today, however, he shares that decision with the FDA which has the added responsibility of reviewing the information set forth on Form 1571 and concurring in the decision to enter into Phase I `in the process of drug develop- ment. The IND is a total profile, containing all information that, is known with respect to the chemical structure of active ingredients, biologic activity, phar- macologic action, dosage form, i.e., tablet, capsule or liquid, detailed process of manufacture and means of identifying ingredients both qualitively and quan- titively, facilities for production, and a data sheet that provides all pertinent information for a prospective investigator. The development of a drug product must necessarily be tailored to the chemical and physical nature of the active ingre'dients, anticipated therapeutic effects, the route of administration, the duration of action, and the ratio of pharmacologic and physiologic action to toxic potential. These developmental steps require an average of twelve months and are not instituted without the cautious control of PAGENO="0228" 2362 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY persons experienced in the several disciplines that will influence the total procedure. The following table shows a representative time schedule detailing the several integrated steps that must transpire after one to five years of basic research from the time of selection of the potential clinical candidate to the institution of the broad-scale clinical trials: Step I (4 to 6 months): Preparation of active ingredient, dosage form, animal toxicity, basic brochure, and filing of IND. Step II (3 to 6 months): Human tolerance (phase I). Step III (3 to 6 months): Refined dose range and efficacy (phase II). Concurrent studies: Toxicity, biochemistry, metabolism, blood levels, and formulation. Step IV (12 to 18 months): Controlled studies, potency, and safety determina- tion of possible claims. The same procedures and time schedule are involved in the case of a combi- nation product containing a new drug substance. The sponsor, in the majority of instances a pharmaceutical manufacturer, having already filed FDA Form 1571, is now required to obtain FDA Form 1572 from each investigator. (A sample copy of this form is attached for your information.) The investigator in signing confirms his understanding of the nature of the drug product he will study; guarantees supervision of every aspect of the study by himself or one or more named associates who are diredtiy responsible to him; describes the facilities available to him; and confirms his understanding that the product will be ad- ministered only to volunteers or patients to whom he has made a full disclosure of its actions, the purpose of administering it, and the benefits to be derived from the study, and from whom an informed consent has been obtained for the ad- ministration of the drug product. The investigator, in signing FDA Form 1572, accepts all of the limitations on the investigational use of the experimental drug product as set forth in the sponsor's brochure. He further agrees to report promptly any event of clinical importance which may be observed in the subjects included in the study whether or not, in his judgment, the event is related to the product's administration. It is the responsibility of the sponsor to report these events to the FDA with an evaluation of the observation. Phase I is a carefully restricted trial of the drug product in normal man, a relatively few volunteers who agree to take the drug product hopefully to con- firm the information alr~ady established in a variety of animal species. Those qualified to investigate a drug product in this area of development must nec- essarily `be carefully selected and knowledgeable in regard to drug action as it may affect all body systems and functions. This phase may involve no more than two investigators and perhaps ten to twenty persons. Phase II studies are warranted when the probable working dose range has been ascertained and the human tolerance to the product has been established. At this phase of the investigation, a few selected patients suffering from the illness for which the product may be indicated are given the drug. ITh is `the customary practice in the industry that a single physician employee be assigned to monitor the investigations. He is responsible for the supplies of the investigational drug product the filing of an FDA Form 1572 for each investi- gator, along with a protocol detailing the purpose of the particular study, its duration and the numbers of patients expected to participate. Should an investi- gator, at any time or for any reason, elect to deviate from the protocol, the change must be reported to the FDA. Studies during this period are most critical. The drug product must demon- strate that it is both safe and effective. Critical judgment gained through ex- perience and knowledge of conditions for which the drug product is indicated is essential for a proper evhluation upon which will be based a decision to proceed with the extensive and expensive clinical trials required for the eventual sub- mission of the New Drug Application. This monitoring of the investigation of an entirely new chemical for use in medicine demands the attention of a physician who possesses scientific curiosity. an in-depth knowledge of the clinical condition for which the drug product is being investigated, and clinical judgment in respect to the therapeutic agents already available to the practicing physician for the treatment or control of the clinical condition under investigation. PAGENO="0229" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2363 An additional responsibility is an administrative chore, for it invo~1ves the constant attention to the details of drug supply and preparation of progress reports to the FDA showing the continuing toxicological, .teratological and car- cinogenic investigations are being correlated and integrated with the studies in man. Indeed it is a complex exercise not to be undertaken by the inexperienced or uninformed. The ethical manufacturer of. drug products, having established the safety and therapeutic action of the product under investigation, must make the final deci- sion. Does this product represent a significant advance in therapeutics? What makes this drug product a useful therapeutic agent for the physician in his practice? What is the ratio of clinical effectiveness to the toxic potential? At this stage of development the producer of a new drug product has a very substantial financial investment that has resulted in only a minimum of infor- mation on which to predict the commercial value. Also, this one drug product containing an active ingredient which has shown promise among the thousands that have been synthesized, has alone progressed to this stage of development. Approximately three years after the decision to investigate a new drug prod- uct, plans are made for carrying out a Phase III, broadly based, clinical trial. Prior to the initiation of this phase of the study, detailed analyses and review of the data derived from the phase II studies are completed. Any further modi- fications of the clinical data sheet, which are a consequence of new observa- tions during the Phase II period, are incorporated in a further revision of the clinical data sheet. At this point, a copy of FDA Form 1573 is sent to selected clinical investigators throughout the country. (A sample copy of this form is attached for your information.) This study provides a wide experience of use in all ethnic and socio-economic groups in the total population. This is a broad test of the efficacy of the product in the specific clinical situations for which it is intended to be used. The sample of patients must be large enough to yield data upon which judgment can be made concerning the safety and efficacy of the prod- uct. As many as 150 (or more) clinicians may participate and the total number of patients under their observation will frequently exceed 1,500 and often 3,000. Although it is estimated that an additional 18 to 24 months will be required for the completion of the Phase III trial, it is likely that more than four years will pass between the initiation of clinical research on a product and the com- pletion and filing of its NDA. During this period the monitor maintains close contact with each investigator so that he is informed of developments throughout the clinical trial and obtains periodic reports of the progress of the trials. A sample copy of the New Drug Application Form FD 356 H is included as an attachment. The detailed information required to complete this application can be appreciated in part by review of the form. FDA approval of an NDA does not terminate the monitoring of the drug product by the medical department of the sponsoring firm. Once the drug product is available on prescription, there is no way of preventing its being used in dosages and for indications not included in the approved labeling. A drug product may be used improperly resulting in fail- ure in therapeutic response or causing drug reactions. Both drug failures and adverse effects must be carefully investigated and reported to the FDA. These reports must be submitted every three months for the first year of distribution, every six months during the second year, and once a year thereafter. Any con- traindication to use or toxic effect not already detailed in the labeling must be investigated and reported within fifteen days after such knowledge is available to the producers. No one has a greater interest or responsibility in the safety and effectiveness of a drug product than the manufacturer, who can ill afford to market a drug that will demonstrate a toxic response not commensurate With its effectiveness. To insure the continuing flow of all essential information in respect to an FDA approved drug product the pharmaceutical manufacturers support the Armed Forces Institute of Pathology in its investigation of tissue reaction to possible toxic drug effects and the American Medical Association's Council on Drugs and its Panel on Hematology of the Registry on Adverse Reactions. More than seven hundred doctors of mediCine are engaged full time by PMA member firms. There is a grave responsibility in the overall development of a new prescription drug product. Less than an honest appraisal of the product and constant surveillance of the claims made for it by its marketers could destroy a scientific reputation that was not obtained without great effort. 81-280 0-68-pt. 6-9 PAGENO="0230" 2364 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [Attachments]. FORM FD-157t 14/671' DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE FOOD AND DRUG ADMINISTRATION Name of Sponsor. Address Date ___________ NOTICE OF CLAIMED iNVESTIGATIONAL EXEMPTION FOR A NEW DRUG Bodgrt Norton Na. 57-RtO3n Name of Investigational Drug __________________________________________________________________________ To the Secretary of Health, Education, and Welfare For the Commissioner of Food and Drugs Washington, D.C. 20204 Dear Sir: The sponsor, , submits this notice of claimed investigational exemption for a new drug under the provisions of section 505(i) of the Federal Food, Drug, and Cosmetic Act and §130.3 of Title 21 of the Code of Federal Regulations. Attached hereto, in triplicate, are: 1. The best available descriptive none of the drug, including to the earent known the chemical name and structure of any new-drag sobstunce, and a statement of how it is to be administered. (If the drag has ooly a rode name, rnoogh information should be supplied to identify the doug.) 2. Complete list of components of the drog, including any reasonable alternates for inactive components. 3. Complete statement of qoantitotive composition of drug, including reasonable variations thot mop be enpecte during the investigational stage. 4. Description of source and prepurotion of, any new- drug substances csr d us components, including the rome ond address of each supplier or po cress or, other than the sponsor, of each nest-drag substance. 5. A statement of the methodR, facilities, and controls used f0t the manufacturing, processing, and packing of the new drug to establish and maintain appropriate standards of identity, strength, quality, and purity as needed for safety and to give significance to clinical investigations mode with the drug. 6. A state ment covering all information available to the sponsor derived from preclinicol investigations and any clinical stodies and enperieoce with the drug as fol- a. Adequate information about the preclinical investiga- tions, including studies made on loberotocy animals, on the basis of `nhich the sponsor has concluded that it in reasonably safe to initiate clinicol investigotions° with the drug: Such information should include identification of the person who conducted each investigation: identifi- cation and qualifications of the individuals whu evaluated the results on d concluded that it is teas onobly sufe to initiate clinical investigations with the drug and a state- ment of `chore the invesrigotions were conducted and where the records oar available for inspection; and enough de- tails obout the isreutigotiuns to permit scientific review. The poeclinical investigations uholl not be considered adequate to justify clinical testing unless they give pcnper attention to the conditions of the proposed clinical test- ittg. When this infoomation, the outline of the plus of clinical pharmacology, or any progress report on the clini- col pharmacology, mdi catesaneed foe full review of the preclinicol data before n clinical trial is undertaken, the Department will notify the sponsor to submit the complete preclinical dora and to withhold clinical trials until the review is completed and the sponsor notified. The Food and Doug Administration will be prepared to confer with the sponsor concerning this acta'on. b. If the drug bus been marketed commercially or in- vestigated (e.g. outside the United States), complete information oh out such distribution on investigation shall be uobmitted, along with a complete bibliography of any publications about the drag. c. If the drag is a combination of previously investi- gated or marketed drugs, an adequate summary of poe- misting information from prrclinical and clinical investi- gations and eaperiencr with its components, including all reports available to tb r sponsor suggesting side-ef- fects, contraindications, and ineffectiveness in use of such components: Such sammury should include an ade- quate bibliography of publications about the components and may incorporate by ref ereace any information concern- ing such components previously submitted by the sponsor to the Food and Drug Administration. lacludeostate meat rtf the enpecte d pharmacological effects of the crmbiaa- 7. A total of five copies of all informational material, including label and labeling, which is to be nupplird to each investigator: This shall include an accurate descrip- tion of the prior investigations and eaperie ace and their results pertinent to the safety and possible uuefulneus of the drug under the conditions of the investigation. It shall not represent that the safety or usefulness of the drag has been mstnblishrd f or the purposes to be investigated. It shall deucribe all relevant haaurds, contraindications, uide-effects, and precautions uuggesred by prior investiga- tions and eaperience `nith the drug under investigation and related drugs for the information of clinical investigators. 8. The ucienrific training and moperience considered appropriate by the sponsor to qualify the investigators as suitable eaperts to investigate the safety of the drug, bear- ing in mind what is known about the pharmacological action of the drug and tlse phase of the investigational program than is to be undertaken. PAGENO="0231" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2365 9. The names and a summary of the traininf and ex- perience of each investigator and of the individual charfed with monitoring the peogeess of the investigation and evaloating the evidence of safety and effectiveness of the deog as it is received from the investigators, together with a statemeot that the sponsor has obtained from each investigator a completed and signed form, as provided in subparagraph (12) or (13) of this paragraph, and that the investigator is qualified by scientific training and no- pen ence asanapprapriatreapert to undertake the phase of the investigation outlined in section 10 of the "Notice of claimed investigational enemption for a new drug." (In crucial situations, phase 3 investigators may be added and this form supplemented by rapid communication methods, and the signed form FD 1573 shall be obtained promptly thereafter.) 10. An outline of any phase or phases of the plumed investigations, as follows: a. Clinical pharmacology. This is ordinarily divided into two phases: Phase 1 starts when the new drug is first introduced into man-only animal and in vitro data are available-with the purpose of determining human toxicity, metabolism, absorption, elimination, and other pharnuucologicul action, preferred route of administration, and safe dosage range; phase 2 covers the initial trials ox a limited number of patients for specific disease con- trol or prophyluxis purposes. A general outline of these ph uses s hull be submitted, identifying the investigator or investigators~ the hospitals or research facilitien svhere the clinical pharmacology mill be undertahen, any expect committees or panels to be utilized, the maximum number of subjects to be invxlved, and the estimated duration of these early ph axes of investigation. Modification of the experimental design on the husis of experience gaiord need be reported only ix the progress reports on these manly phases, xc in the development of ihe plan for the clinical trial, phase 3. The first tea phases may overlap and, `ehex indicated, may require additional animal data before these ph axes can be completed or phase 3 can be undertaken. Such animal tests shall be designed to tube* into account the expected duration of adminixtrariox of the drug to human beings, the age groups and physical status, as for example, infants, pregnant women, pee- menopausal women, of those human beingu to whom the drug may be administered, unless this has already been dxxe ix the original aximul studies. b. Clinical trial. This phase 3 provides the assess- ment of the drug's safety and effectiveness and optimum dosage xchedules in the diagnosis, treatment, or prophy- lasis of geoups of xubjretx involving a given dixease xc conditiox. A reuxoxa ble protocol is developed on the basis of the bets accumulated ix the earlier phasns, ix- Very Only yoxro. eluding completed and submitted animal studies. This phase is corducted by separate groups following the some protocol (with reasonable variations and alternatives per- mitted by the plan) to produce mell-controllrd clinical d~ta. For this phase, the following data shall be sub- iTh e names and addresses of the investigators. (Ad- di,ixnal investigators may be added.) ii.. The npecific nature of the investigations to be con- ducted, together with ixfnemation or case report forms to show the scope and detail of the planned clinical ohserva - ti ons and the clinical laboratory texts to be made and reported. iii. The approximate number of nubjects (a reasonable range of sabjects is permissible and additions may be made), and criteria propoxed for subject selection by age, sex, and condition. iv. The estimated duration of the clinical trial and the intervals, xxt exceeding 1 year, at which progress reports showing the rrxaltn of the investigations will be submitted to the Food and Drug Administration. (The notice of claimed investigational exemption may be limited to any one or more phases, provided the outline of the additioral phase or phases is submitted before such additioxul phases begin. This does not preclude continu- ing a subject ox the drug from phase 2 to phase 3 without interruption while the plan for phase 3 ix being developed.) Ordinarily, a plan for clinical trial will not be regarded as reasonable unless, among other things, it provides for more than one independent competent investigator to main- tain adequate case histories of an adequate number of subjects, designed to record oh servo tiuns and permit evaluation of any and all di scerx ible effects a ttribotoble to the drug in each individual treuted, and comparable rec- ords on any individuals employed as controls. Tb cxc rec- ords shall be individual records for each subject main- tained to include adequate information pertaining to each, including age, sex, conditions treated, dosage, frequency of administration of the drag, results of all relevant clini- cal oh servotions and laboratury examinations made, ade- quate information concerning any other treatment given and a full statement of any adverse effects and useful results ohserved, tagether with an opinion as to wheth cc such ef- fects or results ure attributable to the drag under investi- Sa~i1on.1~ is understood thut the sponsor will notify the Food and Drag Administration if the investigation is dis- continued, aad th errasox therefor. 12. It is understood that the sponsor will notify each investigator if a new-drug application is approved, or if the investigatinn is discuntinard. 1). If thr drug in to be uold, a full roplonatiox why sale is required and should nut be regarded as the commercial- izarion of a new drag for which an ayplicarion is nor approved. (Spanner) Pee (inateate aaioortiy) (This noticr may be amended or supplemented from time to time on the basis of the exper inner gained with the new drag. Pnogresxre ports may be used to update the notice.) ALL NOTICES AND CORRESPONDENCE SHOULD BE SUBMITTED IN TRIPLICATE. PAGENO="0232" 2366 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FORM FD.1572 (8/64) STATEMENT OF INVESTIGATOR HEALTH EDUCATION, AND WELFARE (Clinical Pharmacology) TOSLICPLIER OFTOE DRUG (Nror~dAddeeru) 5AUE OFINVESTIGAIOR (P~iof an Type) Dear Sir: The undersigned, submils this statement as required by section 505(i) of the Federal Food, Drug, and Cosmetic Act and §130.3 of Title 21 of the Code of Federal Regulations anacaudition far rrceioisg and conducting clinical pharmacology -rnith a rem drag limited by Federal (or United States) lam to incestigatiassl use. 1. A STATEMENT OF THE EDUCATION AND TRAINING THAT QUALIFIES ME FOR CLINICAL PHARMACOLOGY. 2. THE NAME AND ADDRESS OF THE MEDICAL SCHOOL, HOSPITAL, OROTHER RESEARCH FACILITY WHERE THE CLINICAL PHARMACOLOGY WILL BE CONDUCTED. 3. THE EXPERT COMMITTEES OR PANELS RESPONSIBLE FORAPPROVING THE EXPERIMENTAL PROJECT. 4. THE ESTIMATED DURATION OF THE PROJECT, AND THE MAXDtUM NUMBER OF SUBJECTS THAT WILL BE INVOLVED-. 5. A GENERAL OUTLINE OF THE PROJECT TO BE UNDERTAKEN. (Madlllcttloo It prnmltlrdao Ihs basl. of enpmlrocr ~Rioed s'Ithoul rdcsoc. tubmiatlon at amendment, to the genrru I auttlo..) (Confinsmdan ncsonor) PAGENO="0233" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2367 B. THE UNDERSIGNED UNDERSTANDS THAT THE FOLLOWING CONDITIONS GENERALLY APPLICABLE TO NEW DRUGS FOR INVESTIGATIONAL USE GOVERN HIS RECEIPT AND USE OF THIS INVESTIGATIONAL DRUG: Th~ sps ~ qs:syd sspply h~ Sg~y, ~:th fsII s. D,sg Adsisi,~iss ss~ifiyd. Upss ths syqsyst isg hs psyyfisiysl :gs~ss h~st jssti- fiyslly usisyd ssd spyyifisslly hs,isyd plsyyy sf by slisiysl phsyslsgy. Dypsstyyst, ssssssbl~ i,sys, h~ iyigsss sill ssks sssh sssds ss~ilsbly Us i pys~iss ssd BSPY:sB. Thy b. Th~ ssy ,g~tss is qsi,yd s issis ,dyqs~ty ys:Js ~f by yf thy bjytssyyd so b~ disslgyd sslyss h~ s~cssds sf thy d:spssitiss sf sil sysyipts yf thy dog, sslBdisg doys, qsstity, ptisslss ssbjyyts syqttity soy dyoilyd stsdy sf h yyssys, ssd by ssbjyyts, ssd if thy slisiol ph stssslsgy is sslyss hy~y i s byliysy ho th~ s~sstds ds pysdyd st yssisstyd 5 yost s thy spssss, yyd sspply pysystsstto I stsdiys ds so pssttol sI h~ dog. sbtsisyd. Ths issystigstst is syqsi,yd s ptypsty ssd tsststsis sdyqtoty I. Thy iss~stigstst yy,tifiys ho by dog sill by tdytisistytyd histssiys dysigsyd t:: ysstd slI sb sysss tittss ssd stby ssly s bjyytsssdyt his pysssss I s ytsisiss st tsdy, tb~ dos pystisyst s th~ ylisissI phstsssslsgy. sspytsisiss sf by fsllsstisg issystiysttto syspsssibly s his:, d. Ths issyssigstss is syqsisyd s fosish his sypssss ts th ~spsssss shs is syspsssibly Is, ssllystisg ssd ys,tlsstisg th yyy~~ Its, ,,sd p,y,ystisg p,sg,yss ,ypots s th~ Fttttd ssd Dog Adtstststtss sppop,isty isty,tols, so ~ssyydisg 1 yyss. Asp sdsy,syy fyy, ,shiyh soy ,ysssssbly by ,ygodyd ,s ot,syd by, s pob' _____________________________________________________ shI yssssyd by, by sys-dog shsll by ,ypttst~d s thy spssss, pttttsp,ly; sttd if th y,,dsy,sy yffyy is sIsssisg p shsll by psnyd is:sydis,yly, As sdsqoty ty pot sf thy slisissI pl:ssso- stlttgy sbttt,ld by hssishyd s thy spssso shsuly Th~ issystigos, shsll tssistsis shy ,yys,ds sf disps,itiss sf by ds,g ssf thy sy,ypots dysy,ibyd tbssy fo .` py,isd sf 2 yys,s fsllssisg hy ds,y thy sys'dog sppliss,iss is ~pp,~syd st thy dog; if ys ~ppIiy,tiss is by filyd ,:t isspptstsyd ttstil 2 yyssfty, thy istystigttiss is disyss,issyd ,tsd by Fssd ,sd sod ho by dog sill by sttppliyd s ssy ohy, issys,igott, ,sssy slisis Itt, sdtsisis,,s,iss s ssbjyy,s. g Thy isssstigstts yy,tifiys ths, by sill isfs,ts ssy ks,, st ssy pyosssssyd ss sss,tsls, ,,hyi,,yp,ysyso isys, ho dogs bytsg sod U, tssystigstisssl pstpssys, ssd sill sbtsis shy ott- sf shy ssbjyy,s, st thyi,,ypt ysysts tisys, yssypt shy,y shis so fysstbly s, is btt issy,,igos,'s p,sfyssisssl ttdgtsys,, is ossttssytsthybys,is,y,ys,s,tfthyssbjyyts. Wry s,uly yotos, (N~st. of Isy.tofastor) PAGENO="0234" 2368 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FORM FD.1573 (8/64) HEALTH EDUCATION, AND WELFARE STATEMENT'OF INVESTIGATOR sabolits this statetoest as eeqaired by seotios 505(i) of the Federal Food, Drag, rod Costsetio Aot rod §130.3 of T:tle 21 of the Code of Federal Regalatioss osacosditioo for reoeisisg asd ooodaotiog olirioal iss'rstigatioss sith a se's' drag lirsitrd by Federal (or Uoited States) la's to iscestigatiooal ate. 1. THE FOLLOWING IS A STATEMENT OF MY EDUCATION AND EXPERIENCE: a. Colleges, roisertitiet, rod oedioal or other profestrosal sohool satteoded, sith datetaf atteodasor, degtees, asd dates degrees orte as'arded. b. Pottgradatte oedioal or other professiosal trairisg: Dates, races of ioetitatioos, asd satoteof ttaioisg. o. Teaohirg or ,esearoh eoperirooe: Dates, isstitrtio5t, brie) drsor:ptioo of eaperirose. 4. Etprtietoe is rtedioal ptaotioe ot other profettiosal eoprrietor: Dates, iottitatiosal aff:l:at:oos, satate of ptaorlor, at arhr, profets:osa e. Rrpreteota t:se l:st of pert:oest ord:oal or other toieotifio pablioatioss: Titles of artioles, races of pablioati ass as d oolaor paoe -- - satsber,aodda:e. (I) thfe foforrtetia,t f,rt rrerfaorfy beet eaboitted ta the aporrar, It r,tay be referred to rtd sty sdditiotte at~de to befog it op to date.) 2. IF ANY HOSPITAL, INSTITUTIONAL, AND CLINICAL LABORATORY FACILITIES, ETC., ARE AVAILABLE AND WILL BE EMPLOYED IN CONNECTION WITH THE INVESTIGATION, AN IDENTIFICATIONOF EACH FOLLOWS: Dear Sir: (If tttf. ioraer,stfair has preefaaely bee,, .abstftt.d to the epareor, ee)ereroe to the prerI raeeabtrf.efao e'fII be .deqaste.) PAGENO="0235" The innestinatan is qaited nn pnepate and nnaintain adrqaane and assatate sane hisnnaies designed ta nesnnd all nbnensa- inns and nthen data penninent ta the innentiganian an rash indinidaaltneated mith the dtag nt emplayed an sonnnol in d. The innesnigannn in neqained nn fannish bin nnpnnns tnnhe spnn- nf the dnag nthn in nespnnsible Inn snllensing and enalaating the tenalts nbtained by maninas innestiganntn. The spnnsnn neqaited a pnesent ptngness nepnnts a the Fnnd and Dnag Ad- at appnnpniane innennal nn~t~ncnnding 1 yean. Any ad nense rites t that nay neasnna bly be negatded as naasnd by, pnnbablynaased by, the nets dtag shall be tepntted a the spnnsnt pnmnptly, and it th eadnenseeltest is alanning, in shall be nepnnted innnrdianely. An adeqnate tepntt af the is- nestigatinn shaald be fatnished a nh nspannnn shantly attet sntnplrtine, af the innestigatian. The insentigatan shall maintain the necntds at dispasinian nt the dn.g and the sane hintanies desatibed abase Inn a pttind Very traly YOUtSt `(ThI. farm .hnald ha .tappt.ttn.nnt.d as' .nt.nd.d learn tint. a u.n. if n.m .abj.at..nn.dd.d as' if .tgntffaant nh.nj.. .s'. anadn inn the plant af ine.*tff.tfan.) (lVaasa at ine..ttg.tae) . (Adde...) COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2369 3. THE INVESTIGATIONAL DRUG WILLBE USED BYTHEUNDERSIGNEDOR UNDER HIS SUPERVISIONINACCORDANCE WITH THE PLAN OF INVESTIGATION DESCRIBED AS FOLLOWS: (Oatline the plan nl insentigatian, jaclnding apptnsimatinn at the sambet at sabjeans na be nneaned mith the dtag and the nambnn na be emplayrd as aanttals, it any;aliniaal attn ta be innettigated; chanannenisnias at tabjects by age, ten, and canditian; the kind at clinical absens'a inns and labntatnty tests ta be andennaken pnian a, dating, and atnen adnsinisttatian at the dtag; the estimated danatian at the insestigntinn; and a descniptinn atcnpien at nepant tatms a beaned na maintain as adeqaanr necatd af the ab sennatians and tests nesalts abtained. This plan may inclade neasnaa ble alnenaanen and maniatians, and shnald be sapplemennedan amended mhen any sign iti cant change in ditectian at snaps' at the innestigatian is andentaben.) 4. THE UNDERSIGNED UNDERSTANDS THATTHE FOLLOWINGCONDITIONS, GENERALLY APPLICABLE TO NEW DRUGS FOR INVESTIGATIONAL USE, GOVERN HIS RECEIPT AND USE OF THIS INVESTIGATIONAL DRUG: a. The spansat ns neqanned nn sapply the nnestigatnr mnth fall in' nf 2 yeats lallaming the date a senadnag applicatinn is ap- an cancena ing the ptecliaical innentigatians that jastify pnaned tan the dnag; nn if the applicatias i tsan appnaned, nnials, nagenhen mith tally intntmatins' matenial desctib- nntil 2 yeats attnt th~ innestt~gatian is discantinaed. Upan ng any ptnnt nnnesnigann ass and eapetnence and any pnssnbls' the neqaest at a scientifically nnained and pnnpenly aanhnn' haaatds, annttaindicatinnn, side'ettncts, and pts'aaatiass ta iced s'mplayee af the Department, an teasnnable times, the be taken ista accaaat nn the cantse nf the innestnga:ias. innesnigatan mill make sash necands atailable tan inspec' tins and anpying. The sabjeats' namesneed ant be di' b. The nncs'ntngatnn n teqanted a masntann adeqaate recnnds at nalged anless she necnnds at patticalat indinidaals teqssine the dispasitinn at all teceipts at the dnng, incliNing dates, a maie detailed snady af the casen, an anl ess nhene is qnantntnes, and ase by sablectn, and nt the nnestngatnan is neatan nn beliene that the recands da nan nepnenesn acnaal etmjnated a nenann a the spansan any anased sapply at the cases snadied, an da san neptesest actaa 1 nesalns abtained. The isnesniganan cettifies that the dnag mill be adminis- nenednsly na sabj eats an den his pennana I snpennnsias an ander the sapennisian at the fallaming inaestigatats spastible nn him, and that the dnag mill nan be sapplied na any anhen ianesni' gatan an na any clinic fan admini tnnan ins na snbjeans. g. The innesniganan centifies that he mill infants any sabje~ts, isalading snbj eats ased as aannnals, a tines, than dnagt ate being ased fan innesniganiasal pan- pases, and mill abnais th masses t af the snbiecns, an their neptesestatines, macpt mhene this is nan feasible at, is the isnesniganan's pnafestianal indgtnenn, is aasnnaty ta the best innmnesns at the sabjeans. PAGENO="0236" 2370 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FD-356H (REV. 5/67) DRUGS FOR HUMAN USE DEPARTMENT OF HEALTH, EDUCATION. AND WELFARE WASHINGTON, D.C. 20204 Name of new drug ~ Original application (regulation §130.4). ~jJ Amendment to original, unapproved application (regulation §130.7). ~ Supplement to an approved application (regulation §130.9). ~ Amendment to supplement to an approved application. The undersigned submits this application for a new drug pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Act. It is understood that when this application is approved, the labeling and advertising for the drug will prescribe, recommend, or suggest its use only under the conditions stated in the labeling which is part of this application; and if the article is a prescription drug, it is understood that any labeling which furnishes or purports to furnish information for use or which prescribes, recommends, or suggests a dosage for use of the drug will also contain substantially the same information for its use, including indications, effects, dosages, routes, methods, and frequency and duration of administration, any relevant hazards, contraindications, side effects, and precautions, as that contained in the labeling which is part of this application in accord with §1.106(b) (21 CFR 1.106(b)). It is understood that all representations in this application apply to the drug pro- duced until an approved supplement to the application provides for a change or the change is made in conformance with other provisions of §130.9 of the new-drug regulations. Attached hereto, submitted in the form described in §130.4(e) of the new-drug regulations, and constituting a part of this application are the following: 1. Table of contents. The table of costests should specify the volume numbeo and the page somber in which the complete and detailed item is located asd the volutse number asd the page number in which the summary of that item is located (if nny). 2. Sueonaey. A summary demonstrating that the applica- tion is well-organized, adequately tabulated, statistically analyzed (where appropriate), aod coherent and that it presents a sound basis foe the approval requested. The summary should inclode the following information: (In lieu of the outliot described belom and the es-nlaatioa described in Item 3, an- expanded snmmary and evaluation as outlined in § 130.4(d) of the new-drag regulations may be submitted to facilitate the resiew of this application.) a. Chemistry. i. Chemical structural formula or description foe any new-drug s~stance. ii. Relationship to other chemically or pharmacologi- cally related drugs. iii. Description of dosage form and quantitative com- b. Scientific rationale and purposenhe drug is to serve. e. Reference number of the investigotioanl drug no- tice(s) under which this drug was investigated and of any notice, acne-drug application, or master file of which any contents are beiog incorporated by reference to support this application. d. Preclinical studies. (Present all findings including all ad~eose enpetiences which may be interpreted as incidental or not drug-related. Refer to date and page notnber of the investigational drug notice(s) or the volume and page namber of this application where complete data andreports appear.) i. Pharmacology (pharmacodynarnics, endocrinology, metabolism, etc.). ii. Tonicology,and puthology: Acute tonicity studies; nubacatea ad chronic toaicity studies; reproduction und teratology studies; miscellaneous studies. e. Clinical studies. (All material should ref er spec ifi- cally to each clinical investigator and to the volume and page number in the application and any documents in- corporated by reference where the complete data and re- ports may be found.) i. Special studies not described elsewhere. ii. Dose-range studies. iii. Controlled clinical studies. iv. Other clinical stadies (for enumple, uncontrolled or incompletely controlled studie s) v. Clinical laboratory studies relnted to effectiveness. vi. Clinical laboratory studies related to safety. vii. Summary of literature and nnpublished reports uvail- able to the applicant. 3. Evaluation of safety and effectiveness, a. Sum- mation separately the favorable and unfavorable evidence for each claim in the package lubelinf. Include references to the volome and page number in the application and in any documents incorporated by reference where the com- plete data and reports may be found. b. Inclnde tabulation of all side effects or adverse experience, by age, sex, and dosage formulation, whether or not considered to be significant, showing whether ad- ministration of the drag was stopped and showing the investigator's name with a reference to the volume and page number in the application and any documents in- corporated by reference where the complete data and re- ports may be found. Indicate those side effects or adverse experiences considered to be drug-related. 4. Copies of the label and all other labeling to be used for the drug (a total of 12 copies if in final printed form, 4 copies if in draft form): Name of applicant Ar(drrss NEW DRUG APPLICATION (Title 21, Code of Federal Regulations, §130.4) Date Foen, Appeared Budget Bmrra No. 5P-RO0S3 PAGENO="0237" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2371 a. Each label, or other labeling, shoald be clearly identified ta show its pouitian on, or the wanner in which it accnrnpanies, the otanket package. b. If the drag in to be affered aver th ecoantee, labeling an at within the retail package should inclade ndequate directions far ase by the layntun ander all the conditinns far which the drug is intended for lay use or is to be prescribed, recommended, or saggesred in any labeling or advertising sponsored by or on behalf of the applicant and dieected to the luyrtun. If the drag is intended or offered for anon under the professional supervision of a practitioner ii ceased by law to administer it, the applica- tion should also contain labeling that includes ndeqaare information for all such uses, including all the purposes far which the over-the-counter drag is to be advertised to, or represented f or use by, physicians. c. If the drug is limited in its labeling to ase ander the professional supervision of a practitioner licease d by law to administer it, its laboling should bear information for use ander which such practitioners can use the drag far the purposes far which it is intended, including all the purposes for which it is to be advertised or repre- sented, in accord with §1.106(b) (21 CFR 1.106(b)). The application should include any labeling foe the drag intended to be made available to the layman. d. If no established name enists for a new-drag sub- stance, the application shall propose a sonproprietary name for use as the established name for the substance. Typewritten or other draft labeling copy may be sub- mitted for preliminary consideration of as application. As application will nut ordinarily be approved prior to the submission of the final printed label and labeling of the drag. /. No application may be approved if the labeling is false or misleading in any particular. (When mailing pieces, any other labeling, or advertising copy are devised for promotion of the new drug, samples shall be submitted at the time of initial dissemination of such labeling and at the time of initial placement of any such advertising for a prescription drag (see §130.13 of the new-drug regulations). Approval of a supplemental new-drug application is required prior to use of any pm- motionul claim snot covered by the approved application.) 5. A statement as to whether the drag is (or is sot) limited in its labeling and by this application to use under the professional supervision of a practitioner liceased by law to administer it. 6.Afull list of the articl en used as camposests of ~ This list should include all substasces use is the synthesis, eatraction, or other method of preparation of any oem-drug substance, and is the preparation nf the finished dosage form, regardless of whether they usderga chemical change or are removed is the process. Each substance should be identified by its established same, if any, or complete chemical same, us in g structura formulas when secessary for specific identificatios. If any proprietary preparation is used as a component, the proprietary name should be followed by a complete quas. titutive statement of composition. Reasonabl ealtemsa tives for any listed substance may be specified. 7. A fall statement of the compasitias of the drag. The statement shall set forth the same and amnuat of each ingredient, whether active or sot, coataised is a stated quantity of the drag is the form is which it is ta be distributed (for eaample, amount per tablet or per tail- liliter) asd a batch formula representative of that ta be employed for the manufacture of the finished dosage form. All camp onents shauld be included is the batch fnrmula regardless of whether they appear is the flaisbed product. Any calculated eacess of as iagredieat aver the label declaration should be designated as sach sad percent caress shams. Reasonable variations may be specified. 8. A fall description of the metho~s used in, and the facilities and controls used for, the manufacture, process- isg, and packing of the drag. Included in this description should be fall information wi'th respect to any new-drag substuace and to the new-drug dosage form, as fullows, is sufficient detail so permit evaluation af the adequacy of the described methods of manufacture, processing, and packing and the drscribed facilities and controls to determine and preserve the identity, strength, quality, and purity of the drug: a. A description of the physical facilities including building and equipment used in manufacturing, Pr cress ing, packaging, labeling, storage, and control operations. b. A description of the qualifications, includisg educa- tional background and esperience, of the technical and professional personnel who ace responsible for assuring that ~hr drag has the safety, identity, strength, quality, and purity it purports or is repres rated to p courts, and statement of their responsibilities. c. The methods used in the synthesis, ratruc tiou, isolation, or purification of any new-drug substance. When the specifications and controls applied to such aubstunce are inadequate in themselves to determine its identity, stresgth, quality, and purity, the methods should be described is sufficiest detail, including quantities used, times, temperatures, PH, solvents, etc., to determine these characteristics. Alternative methods or variations is methnds withia reasonable limits that do not affect such characteristics of the substance may be specified. d. Precautions to assure proper identity, strength, quality, and purity of the raw materials, whether active or not, including the specifications faa accept unce and methods of testing for each lot of raw material. a. Whether or sot each lot of raw materials is given a serial sumber to identify it, and the use made of such aumbers in subsequent plant operations. /. If the applicant does not himself perform all the masufactaring, paocess lag, packaging, labeling, and con- trol operations for any sew-drag substance ar the new-drug dosage form, his statement idostifying each person who will perform asy part of such operations and designating the part; asd a signed statement from each such person fully describiag, directly or by reference, the methods, facilities, and controls in his part of the operation. g. Method of preparation of the muster formula records and iadividaul butch recordu and manner in which these record sate used. h. The instructioss used in the manufacturing, process- ing, packagiag, aad labeling of each dosage farm of the sew drug, includiag asp upecial precautinas observed in the operations. i. Adequate isforatasion with respect to the character- istics of asd the test methods employed for the container, rlnsure, or other component parts of the drug package to assure their suitability fat the intended use. j. Number of individuals checking weight or volume of each individual ingrediest entering into each batch of the drug. k. Whether or sot the total weight or volume of each batch is determined at any stage of the musufucturing prac ens sabseqarat to makiag up a batch according to the formula card and, if so, at what stage and by whom it is 1. * Precautions to check the actual package yield pro- duced from a batch nf the drug with the theoretical yield. This should iacludeadescriptian of the accousting for such items as discards, breakage, etc., and the criteria used isaccepriag or rejecting batches of drags is the eveat ii aa ssesplaised discrepancy. ci. Precautions to assure that each lot of the drug is packaged with the proper label and labeling, including prneisiass for labeliag sturage and iaveatory control. PAGENO="0238" 2372 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The asulytical csntesls aced dosing the vacioun stages of the manufacturing; processing, packaging, and labeling of the drug, including detailed deacriptios of the collection of sae,plet and the analytical procedures to which they ace tabjected. The analytical pcoceduhes should be capable of determining the notice components scithin areas onable degree of accuracy and of assuring the identity of tuck components. If the article is one that is represented to he sterile, the same information with eegurd to the manufacturing, process ing, packagir.g, and the collection of samples of the drug should be given for sterility controls. Include the standards used for ac- ceptunce of each lot of the finished drug. o. An euplanurios of the enact significance of the butch control numbers used in the manufacturing, process- ing, packaging, and labeling of the drug, including the control numbers that appear on the label of the finithed article. State whether these numb era enable determina- tics of the complete manufocturinf history of the product. Describe any methods sued to permit determination of the distribution of any batch if its recall in required. p. A complete description of, and data ~ from, studies of the stability of the drsg, including information showing the nuitability of the analytical methods used. Describe any additional ttability studies underway or contemplated. Stability data should be submitted for any new-drug substance, foe the finished dosage form of the drug in the container in which it in to be marketed, in- cluding any proposed multiple-done container, and if it in to be pat into solution at the time of dispensing, for the solution prepared an directed. State the expiration date(s) that will be used on the label to prenerve the identity, strength, quality, and purity of the drug until it is sued. (If no eapiratios date in proposed, the applicant munt justify its absence.) q. Additional procedures employed which are designed to prevent contamination and other's-i Sr assure proper control of the product. (An application may be refused unless it includes adequate `information showing that the methodn used in, and the facilities and controls used foe, the manufacturing, processing, and packaging of the drug are adequate to preserve its identity, strength, quality, and purity in foemity with good manufacturing practice and identifies each establishment, showing the locatiss of the plant conducting these operations.) 9.Sumplen of the drug and articles used an c,p~py nentn, as follows: a. The following samples shall be sub- mitted wath the application or an uooa thereafter an they become available. Each tample shall consist of `four identical, separately packaged subdivisions, each cnn- raining at leant three times the amount required to per- form the laboratory tent procedures described is the ape pliration to determine compliance with its control speci- fications for identity and annayn: i. A representative sample or samples of the finished dosage form(s) proposed in the application and employed in the clinical investigations and arepeesentative sample or samples of each new-drug substance, as defined in §130.1(g), from the batch(en) emplayed is the productios of such dotage form(s). .` `, ii. A reprenentatt*ve sample Or samples of finished market packages of each dosage form sf the drug prepared for initial marketing and, if any such sample in not from a commercial-scale production batch, such a sample from a representative commercial-scale production batch; and a representative sample or samples of each new-drag nab.. stance an defined is §130.1(g), from the barch(es) em- played in the production rf such dosage firm(s). iii. A sample or samples sf any ref rrence nrandard and blnak used in the procedures described lb the applicarirn for assaying each new-drug substance and other assayed components of the finished drug: Provided, howeret, That samples of ref erence nrasdardn recognized is the rfficial U.S. Phurmacopeia or The National Formal ary seed nor be submitted unless requested. b. Additional samples shall be submitted on request. Each of the samples submitted shall be appropri- itely packaged and labeled to preserve its characteristics, to identify the material and the quantity is each sub- division of the sample, and to identify each subdivision with the name of the applicant and the new-drug applica- tics to which it relates. d. There shall be included a full lint of the samples submitted pursuant to Item 9a; a statement of the addi- tional samples that `s-ill be submitted an noun an avail- able; and, with respect to each sample submitted, full information with respect to its identity, the origin of any scm-drug nubntancr contained therein (including in the cane of ne's-drug subnrarcen, a statement whether it wan produced on a laboratory, pilot-plant, or full-production scale) and derailed results of all laboratory tents made so determine the identity, strength, quality, and purity of the batch represented by the sample, including assays. Include for any reference standard a complete description sf its preparation and sh cress Its of all laboratory tents on it. If the tent methods used differed from those de- scribed in the application, fall details of the methods employed in obtaining the reported results shall be tub- e. The requirements of Item 9a may be waived in whole or is part onrequen r of the applicant se otherwise when any such samples are nornecensory. f. If samples of the drug are neat under separate cover, they should be addressed to the attention of the Eureau of Medicise and identified on the outside of the shipping carton with the name of the applicant and the name of the drag an shown on the application. 10. Fall reports of preclinical investigations that have bees made to show whether or not the drug in tale £ crane and effective in use. a. An application may be refused unless it contains full reports of adequate preclisical tents by all method nrean onubly applicable rc a determina- tics of the safety and effectiveness of the drug under the conditions of ste noggented in the proposed labeling. ft. Detailed reports of the preclisical investigations, including all studies made on laboratory animals, the methods used, and the results obtained, should be clearly set forth. Such information should include identification of the person who conducted each investigation, a state- ment of where the investigations were conducted, and s-here the underlying data are available fcc inspection. The animal studies map act be considered adequate unless they give pro per amen tics so the conditions of ate recom- mended in the proposed labeling for the drug such an, for eaample, whether the drag is for shoot- or long-term ad- ministration or whether it in to be sued in infants, chil- dren, pregnnnr women, or women of child-bearing potential. c. Detailed reports of any pertinent microbiological and is s'ites studies. if. Summarize and provide a lint of literature refer- ences (if available) to all other preclinical informariss known to the applicant, whether published or unpublished, that in pertinent rs an evaluarics of the safety or effec- tivesess dthe drag. 11. List of investigators, a. A complete list of all invrarigar sea tsppli~d with the drug including the name and post office address of each,iavesrigator and, following each sane, the volume and page references to the in- vestigator's report(s) in thin application and is any docu- ments incorporated by reference, or she eaplanarirn of the omission tI any reports. b. The aserplained omission of any reports of is- `vestigatirns made with the new drag by the applicant, at PAGENO="0239" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2373 submitted to him by an investigator, or the stnexplained omission of any pertinent reports of investigations or clinicol roperiencerece ived or otherwise obtained by the applicont from published literature or other sources, whether or not it mould bias an evaluation of the safety of the drug or its effectiveness is use, may constitute grounds for the refusal or withdra~mal of the approval of an application. 12. Full reports of clinical investigations that have been made to show whether or not the drug is safe foruse and effective in use. a. An application may be refused unless it contains full reports of adequate tests by all method 5 reason ably applicable to show whether or not the drug is safe and effective f or use us suggested in the lubeling. 6. An application may be rrfusrd unless it includes substustiul evid ence consisting of ode qoute ond well- controlled investigations, including clinicul investiga- tions, by enperts qudlified by scientific training and ex- perience to evaluate the effectiveness of the doug in- volved, on the basis of which it could fairly nod respon- sibly be concluded by such experts that the doug will have the effect it purports or is represente d to have under the conditions of use perscribed, recommended, or suggested in the proposed labeling. Reports of all clinical tests sponsored by the ap- plicant or received or otherwise obtained by the applicant should be attached. Tb ese reports should include ade- quate information concerning each subject sneuted with the drug or employed us a coutrol, including age, sex, conditions treated, dosuge, frequency of administration of the drug, results of all relevant clinical observations and laboratory esuminutirns nude, full information con- cerning any other treatment giveo previously or concur- rently, and u full stutement of ad verse effects and useful results observed, together with an opinion us to whether such effects or results are attributable to the drug under investigation and u statement of where the underlying dutu are uvuiluble for inspection. Ordinarily, the reports of clinical studies will not be regarded us adequate unless they include reports from more than one inde- pendent, competent investigator who maintains adequate case histories of us ude quute number of subjects, de- signed to record oh servo ti non and peumit evaluation of any und all discern ible effects attributable to the drug in each individual treated and compurable records on any individuals employed an controls. An application fOr a combinutiox drug may be refused unless there is sub- stantial evidence that each ingredient designated as active mob mu contribution to the total effect claimed for the drug combination. Except when the disease for which the drug is being tested occurs with such infre- quexcy in the United States an to mube testing im- practical, some of the investigations shunld b,e performed by competent investigators within the United States. d. Attach asusepurute section u completed Form FD-l639, Drug Experience Report (obtainable, with in- structions, ox request from the Food and Drug Administra- tion, Department of Health, Education, and Welfare, Wash- ington, D.C. 20204), for each ad verse experience or, if feasible, for each subject or patient caperiexcing one or more ad verse effects, described in Item 12c, whether or not full information is uvuiluble. Form FD-1639 should be prapured by the applicant if the udverse experience was not reported ix such form by the investigator. The Drug Experience Report should be cross-referenced to any nurra tine description included in Item l2c. e. All information pertinent to an evaluation of the safety and effectiveness of the drug received or otherwise obtained by the applicant from any source, including information derived from other investigations or rum- merical murbeting (for example, outside the Uxited States), or reports in the scientific literature, involving the drug that is the subject of the application and related drugs. A x adequate summary may be acceptable in lieu of reprint of a published report which only supports other data submitted. Reprint 5 nrr notre quired uf reports in designated journals, listed in §130.38 of the new-drug regulations, about related drugs; a bibliography will suffice, Include any evaluation of the safety or effec- tivexess of the drug that bus been made by the applicant's medical department, exprrtc ommittee, or consultants. /. If the drug is a combination of previously investi- gated or murbered drugs, an adequate summary of pre- existing information from prrclinicul and clinical investi- gation and experience with its romponents, including ull reports received or otherwise obtained by the applicant suggesting side effects, contraindications, and ineffec- tivexes s in upe of such components. Such summary should include an adequate bibliography of publications about the components and may incorporate by reference informa- ti unconcern ing such rump onents previously submitted by the applicant to the Ford and Drug Administru~ion. g. The complete composition and/or method of manu- facture of the new drug used in each submitted report of investfgation should be shown to the cutest necess ury to establish its identity, strength, quality, and purity if it differs from the description in Item 6, 7, or 8 of the up- plicatiox. 13. If this is a supplemental application, full informa tion on each proposed oh unge concerning any statement made ix the approved application. Observe the pruvfsfons of §130.9 of the new-drug regulu- ri nns concerning supplemental applications. (Applicant) Per (Responsible official or agent) (Indicate authority) (Warning: A willfully false state mess is a criminal offense. U.S.C. Title 18, sec. 1001.) NOTE: This application must be nigned by the applicant or by an authorized attorney, agent, or official. If the applicant or such autho,ized representative does not reside or have a place nf business within the United States, the application must also furnish the name und post off3cr address of and must be counters igned by an authorized attorney, agent, or official resid- ing or muintuining a place of business within the United Staten. PAGENO="0240" 2374 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY STATEMENT OP T~LAND W. BLAZEY, VICE PRESIDENT, MANTJPAC- TURING, ENGINEERING, AND PURCHASING, McNEIL LABORA- TORIES, INC., PORT WASHINGTON, PA. Mr. BLAZEr. Mr. Chairman, I would like to have my statement which was submitted for presentation on November 16 made a part of the record. Senator NELSON. Your statement will be printed in full in the record. You may read from it or extemporize, or present it in any way you wish. Mr. BLAZEr. I would prefer, Mr. Chairman, to abstract some para- graphs from it, and I will let you know what pages I have deleted as I proceed through it.1 Senator NELSON. All right. Mr. BLAZEr. My name is Leland W. Blazey. I am vice president in charge of manufacturing, engineering, and purchasing for McNeil Laboratories, Inc. I am appearing today on behalf of the Pharmaceu- tical Manufacturers Association. Senator NELSON. Where is McNeil Laboratories' home office? Mr. BLAZEr. Fort Washington, Pa., just outside of Philadelphia. Senator NELSON. Is this where your manufacturing is done? Mr. BLAZEr. Yes. Senator NELSON. All of it? Mr. BLAZEr. Yes. Mr. GORDON. That is a subsidiary of what company? Mr. BLAZEr. Wholly owned subsidiary of Johnson & Johnson. Senator NELSON. There is another rollcall. I have to answer it. (Whereupon, there was a short recess.) Senator NELSON. Go ahead. Sorry about the interruption. Mr. BLAZEr. Since the early forties, I have worked with several pharmaceutical companies and have participated in some of our in- dustry's pioneering efforts in design and process procedures relating to antibiotics, medicinal chemicals and pharmaceutical products. As one who has been trained in the techniques of pharmaceutical manufacturing and engineering, I shall attempt to explain the great care which goes into the manufacturing operations of the research- oriented, quality-conscious companies in our industry. In particular, I shall try to point up how this dedication to quality is a distinguishing characteristic of the most respected prescription drug manufacturers in this country. To begin with, manufacturing facilities and equipment must be adequate for the highly technological science of making safe and effec- tive drug products. But more than that, it is essential that we have top-caliber personnel in sufficient numbers to do this highly complex job. Although the FDA's good manufacturing practice (GMP) regula- tions outline the general conditions under which prescription drugs are to be produced, there are wide differences in the actual operations of quality manufacturers and those of less responsible companies. The quality-conscious companies go well beyond basic FDA requirements. 1 The complete prepared statement and attachment submitted by Mr. Blazey for pres- entation on Nov. 16, i967, begins at p. 2377, infra. PAGENO="0241" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2375 As a matter of fact, many of these firms did not find it necesary to make significant changes `as a result of the 1962 amendments to the Food and Drug Act. Because of the `high standards they had set for them- selves over a period of many years, they were already in compliance with most of these new regulations. As new medicinal `agents have been discovered, our industry has recognized the need for constantly improving manufacturing methods and equipment. The advent of high-potency compounds, new formula- tion requirements, and more sophisticated medications has dictated change. Particularly during the last 10 to 20 years, the research- minded manufacturer `has modified his physical plant and updated facilities in order to produce `consistently safe and effective products. These companies in our business usually `are distinguished by stability of employment. Obviously, this is a most important factor in attracting good employees who are dedicated to the production of quality drugs. These workers `are well-trained people who understand the rules `and regulations under which the drug industry operates and who are proud of the part they play in their company's operations. Buildings in which drugs are manufactured must be of suitable size and construction to `house the necessary equipment and materials in such `a manner that cross-contamination Or mixup is avoided. In the better plants, provisions are made for cleaning the air and controlling temperature `and humidity. One example of the great care that is taken to assure the most sanitary conditions possible is the sterilization of areas used for the production of hypodermic drugs. Much of the equip- ment used in these plants is custom-designed, and considerable engi- neering ingenuity is required. Of paramount consideration are cleanliness and orderliness. For example, in my own company alone we have spent several hundred thousand dollars to separate operating equipment and functions, to provide a `high degree of air filtration and dust control, and to insure the sanitation qualities of floors, ceilings and walls. This is typical of what the research-oriented companies are Oontinuing to~ do `to improve their operating areas. Now, I should like to point out a few fundamentals about manu- facturing methods and procedures of the quality-minded drug manu- facturer. Our equipment must fulfill two important requirements: First, we must be able to produce batches of a drug product with uniform consistency day in `and day out. Second, the equipment must be compatible with the chemicals in- volved and suitable for thorough cleaning to eliminate the possibility of contamination from product to product. Clearly, maintenance of equipment is extremely imporbant. For example, in the case of a tablet compression machine, where close tol- erances are required, regular examination is essential to insure that each tablet produced meets the dose specified. Such care is part of the standard operating procedure of the quality-conscious, innovator-type of drug manufacturer. All-important considerations for every capable drug manufacturer are: (1) Quality of raw materials used in the manufacturing process, and (2) in-process controls. I should like to elaborate on bot'h of these points. 8i-280 O-68----pt. 6-16 PAGENO="0242" 2376 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY `To assure the quality of a raw material, the careful company first insists that the supplier guarantee the quality and purity of the ma- terial, then makes double sure by conducting its own extensive tests. This preoccupation with quality of raw materials applies to non- therapeutic as well as therapeutic substances: to nonofficial substances as well as those listed by the U.S. Pharmacopaeia is to assure the user of official medicinal substances of their identity, strength, quality, and purity, it is manifestly impossible to include in each monograph a test for every impurity or adulterant that might be present. In view of this undisputed fact, t.he quality-oriented pharmaceutical firm exerts additional efforts through the use of analytical know-how and in-process controls to give greater assurance of the identity. strength, quality, and purity of the ingredients which go into its products. Throughout the drug manufacturing process, from raw materials through finished product, careful control must be exercised at every step of the way. Every quality-minded manufacturer follows a stand- ing operating procedure which incorporates a system of checks and balances followed by quality audits. Our standard procedures cover such important considerations as product and container identity, quarantine provisions, and storage conditions. Each product is covered by an appropriate batch record, and throughout the manufacturing operation great care is exercised to assure accuracy of weight, volume, and yield of each batch. The packaging materials used are subjected to inspection, and par- ticular care is exercised in the issuance of labels, cartons, and package inserts. The warehousing of the finished product provides for proper stor- age, segregation, and identification by lot or `batch number, as well as systematic rotation and inspection of stocks at regular intervals. Another key factor in our standard procedures is the maintenance of records covering all manufacturing, packaging, and control opera- tions concerned with a product. These records must be prepared with such care as to provide a history of each batch of every drug product. The quality-conscious manufacturer continues his testing as long as a product is on' the market. Portions of each lot are retained and checks are made, even after the lot has reached the pharmacist's shelf, to make sure it measures upto the company's high standards. As an illustration of the importance of checks and balances exer- cised during pharmaceutical manufacturing by some firms, I think it is interesting to note that in one of our own company's routine manufacturing operations we conduct some 687 inspections and tests during the course of making a finished product. Among these are 215 different inspections and tests on raw materials, 395 checkpoints and tests during the actual manufacturing, and 75 inspections and counts during the packaging operations. The manufacturing principles I have discussed have been fol- lowed by the leading prescription drug companies of this country for many years. It is generally agreed by those who have firsthand knowl- edge of these research-minded pharmaceutical manufacturers that their plants stand out in their communities as models of modern in- dustrial facilities. PAGENO="0243" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2377 Control of air pollution and maintenance of waste treatment facili- ties are among the important contributions such companies make to- ward their environment. In concluding,. Mr. Chairman, I should like to emphasize that the manufacture of quality drug products is. a time-consuming and exact- ing process, requiring the best personnel and facilities. The reputable and responsible drug manufacturers of this country go as far as pres- ent-day technology permits in order to, provide the highest quality prescription drugs for the medical profession and the public. After all, it is not just the wood that makes the Stradivarius violin; it is the skill of the craftsman. It is not just the fabric that makes the fine suit; it is the skill of the tailor. So it is with prescription drugs. In the final analysis, differences in manufacturing process and con- trols can make the difference between good health and bad, .between comfort and pain, and even between life and death. Thank you. Senator NELSON. I thank you. (The complete prepared statement and attachment submitted by Mr. Blazey for presentation on November 16, 1967, follows:) STATEMENT OF LELAND W. BLAZEY, Vica PRESIDENT, MANUFACTTJRING, ENGINEERING, AND PURCHASING, McNirrr, LABORATORIES, INC. MANUFACTURING CONSIDERATIONS IN QUALITY DRUG PRODUCTION Mr. Chairman and members of the committee, my name is Leland W. Blazey. I am Vice President in charge of Manufacturing, Engineering and Purchasing for McNeil Laboratories, Inc. I am appearing today on behalf of the Pharmaceutical Manufacturers Association. Since the early 40's I have worked with several pharmaceutical companies on technical assignments in development, engineering and production. Together with other technical personnel, I participated in some of our industry's pio- neering efforts in design and process procedures relating to antibiotics, medicinal chemicals and pharmaceutical products. I have also been responsible for directing the planning, engineering and con- struction on many projects dealing with chemical, pharmaceutical and research facilities in the United States and in foreign countries. As one who has been trained in the techniques~ of pharmaceutical manufactur- ing and engineering, I shall attempt to explain the great care which goes into the manufacturing operations of the research-oriented, quality-conscious compa- nies in our industry. In particular, I shall try to point up how this dedication to quality is a distinguishing characteristic of the most respected prescription drug manufac- turers in this country. To begin with, manufacturing facilities and equipment must be adequate for the highly technological science of making safe and effective drug products. But more than that, it is essential that we have top-caliber personnel in sufficient numbers to do this highly complex job. Although the F.D.A.'s Good Manufacturing Practice (GMP) Regulations out- line the general conditions under which prescription drugs are to be produced, there are wide differences between actual operations of quality manufacturers and those of less responsible companies. The quality~conscious companies. go well beyond basic F.D.A. requirements. As a matter of fact, many of these firms did not find it necessary to make significant changes as a result of the 1962 Amendments to the Food and Drug Act and the subsequent promulga- tion of GMP regulations. Because of the high standards they had set for themselves over a period of many years, they were already in compliance with most of these new regulations. As new medicinal agents have been discovered, our industry has recog- nized the need for constantly improving manufacturing methods and equipment. PAGENO="0244" 2378 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The advent of high-potency compounds, new formulation requirements, and more sophisticated medications has dictated change. Particularly during the last ten to twenty years, the research-minded manufacturer has modified his physical plant and updated facilities in order to produce consistently safe and effective products. The research-oriented innovator type of company generally sets higher qual- ity standards for its products than does the non-innovator. Moreover, a manu- facturer of this type will not market a drug product until it has been clini- cally tested for safety and effectiveness. When one considers that there are many drug products which are classified by the F.D.A. as "old" drugs, for which no proof of safety and effectiveness is required prior to marketing, the extra care taken by the quality-conscious company can be more fully ap~preciated. For those drug products which do require F.D.A. approval for safety and effectiveness, the quality company establishes the conditions of manufacture and control which assure that each batch measures up in every respect to the initial batch on which the F.D.A. submission was based. The importance of this procedure cannot be over emphasized. The former Commissioner of the Food and Drug Administration, George P. Larrick, made some pertinent comments on the importance of manufac- turing control before the Senate Subcommittee on Antitrust and Monopoly in 1960. At that time he said: * It requires a great deal of technical knowledge as well as properly utilized procedures to produce modern drugs that will meet all the require- ments of modern medicine and of the law-. Our experience has demonstrated the soundness of that position and it is even more true today as the com- plexity of drugs and their dosage forms increase. Adequate and extensive control from the time the raw materials enter the drug plant to the tinie the finished drug reaches the patient is essential if both patient and clinicians are to have confidence in the drug prescribed." Mr. Larrick went on to say: "Our experience has show-n that those w-ho do not have proper controls are more like to produce substandard drugs. The point * * * is not whether drug manufacturers are large or small, but w-hether they have the scientific personnel and laboratory control to produce pure, re- liable and safe drugs". Assurance of quality in the manufacturing of drugs begins w-ith people. For this reason, the quality-minded companies are extremely careful in their selection of the personnel who devise the formulas, test the components and finished preparations, inspect the final product, and perform the many other tasks involved in drug production. These men and women must have a high degree of training, know-ledge, motivation and experience. The research-conscious innovator companies in our business usually are distin- guished by stability of employment. Obviously this is a most important factor in attracting good employees who are dedicated to the production of quality drug products. These workers are well-trained people who understand the rules and regulations under which the drug industry operates and who are proud of the part they play in their company's operations. Laws and regulations are no substitute for the care exercised by men and women of integrity. You simply cannot legislate quality into drug products. any more than you can eliminate traffic fatalities and injuries by making new law-s. There are many excellent traffic law-s already on the books-local, state, and federa~-yet the death toll on our highways continues unabated. In the final analysis, it's the human factor which counts. And so it is w-ith the production of quality drug products-the people a comj*ny employs make a big difference. As an example, in our own manufacturing plant, more than 33 percent of our employees have been with the company longer than fifteen years. They are with- out a doubt among our most valuable assets. In recognition of this fact, we invest in numerous fringe benefits and special progr~ams designed to demonstrate the high regard we have for our people. In addition, we strongly support safety pro- grams, provide tuition assistance to upgrade the education of employees, and conduct training programs to assure top-level performance. Because of the importance of employees in the production of top-quality drug products, the more responsible manufacturers go out of their Way to provide the best of working conditions. Particular attention is paid to buildings and equipment. PAGENO="0245" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2379 Buildings in which drugs are manufactured must be of suitable size and con- struction to house the necessary equipment and materials in such a manner that cross-contamination or mixup is avoided. In the better plants, provisions are made for cleaning the air and controlling temperature and humidity. One example of the great care that is taken to assure the most sanitary conditions possible is the sterilization of areas used for the production of parenteral products. Much of the equipment used in these plants is custom-designed and considerable en- gineering ingenuity is required. Of paramount consideration are cleanliness and orderliness. For example, in my own company alone we have spent several hundred thousand dollars to sep- arate operating equipment and functions, to provide a high degree of air filtration and dust control, and to insure the sanitation qualities of floors, ceilings and walls. This is typical of what the research-oriented companies are continuing to do to improve their operating areas. Now I should like to point out a few fundamentals about manufacturing meth- ods and procedures of the quality-minded drug manufacturer. Our equipment. must fulfill two important requirements: First, we must be able to produce batches of a drug product with uniform consistency day in and day out. Secondly, the equipment must be compatible with the chemicals involved and suitable for thorough cleaning to eliminate the pos- sibility of contamination from product to product. Clearly, maintenance of equip- ment is extremely important. For example, in the case of a tablet compression machine, where close tolerances are required, regular examination is essential to insure that each tablet produced meets the dose specified. Such care is part of the standard operating procedure of the quality-conscious, innovator type of drug manufacturer. All-important considerations for every reputable drug manufacturer are: (1) Quality of i~aw materials used in the manufacturing process and (2) In-process controls. I should like to elaborate on both of these points. To assure the quality of a raw material, the careful company first insists that the supplier guarantee the quality and purity of the material, then makes doubly sure by conducting its own extensive tests. Many companies even conduct their own inspections of suppliers' plants. This preoccupation with quality of raw materials applies to non-therapeutic as well as therapeutic substances; to non-official substances as well as those listed by the U.S. Pharmacopoeia and the National Formulary. In this connec- tion, the following statement is made by one of these official compendia: "While one of the primary objects of the Pharmacopoeia is to assure the user of official medicinal substances of their identity, strength, quality and purity, it is mani- festly impossible to include in each monograph a test for every impurity or adul- terant that might be present". In view of this undisputed fact, the quality- oriented pharmaceutical firm exerts additional efforts through thhe use of ana- lytical know-how and in-process controls to give greater assurance of the identity, strength, quality, and purity of the ingredients which go into its products. Throughout the drug manufacturing process, from raw materials through fin- ished product, careful control must be exercised at every step of the way. Every quality-minded manufacturer follows a standing operating procedure which in- corporates a system of checks and balances followed by quality audits. Included in these standard operations is a process for written procedures and specifications covering all raw materials and finished products. Items such as iiiethods of sampling and analysis, and criteria for acceptance, are specified. All manufacturing formulas and working directions are as explicit as we can make them. I - Our standard procedures cover such important considerations as product and container identity, quarantine provisions, and storage conditions. Each product is covered by an appropriate batch record, and throughout the manufacturing operation great care is exercised to assure accuracy of weight, volume, and yield of each batch. Special care is exercised in the production of sterile products to avoid micro- l)ial contamination. The packaging materials used are subjected to inspection, and particular care is exercised in the issuance of labels, cartons, and package inserts. The warehousing of the finished product provides for proper storage, segrega- tion, and identification by lot or batch number, as well as systematic rotation and inspection of stocks at regular intervals. PAGENO="0246" 2380 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Another key factor in our standard procedures is the maintenance of records covering all manufacturing, packaging, and control operations concerned with a product. These records must be prepared with such care as to provide a history of each batch of every drug product. One of the most important parts of our system of in-process controls is the testing required to assure the identity, strength, quality, and purity of all raw materials and finished products. Periodic checks are made even after it has reached the pharmacist's shelf to make certain it measures up to the company's high standards. The quality-conscious manufacturer continues his testing as long as a product is on the market. As a final step in this system of controls, the manufacturer must provide for the proper disposition of returned goods. As an illustration of the importance of checks and balances exercised during pharmaceutical manufacturing by some firms, I think it's interesting to note that in one of our own company's routine manufacturing operations we conduct some 687 inspections and tests during the course of making a finished product. Among these are 215 different inspections and tests on raw materials, 395 check- points and tests during the actual manufacturing, and 75 inspections and counts during the packaging operations. The manufacturing principles I have discussed have been followed by the leading prescription drug companies of this country for many years. It is gen- erally agreed by those who have first-hand knowledge of these research-minded pharmaceutical manufacturers that their plants stand out in their communities as models of modern industrial facilities. Control of air pollution and mainte- nance of waste treatment facilities are among the important contributions such companies make toward their environment. In 1965, the Pharmaceutical Manufacturers Association joined with the Food and Drug Administration and the University of Wisconsin in providing train- ing in the principles and procedures of modern drug manufacture. In his opening address, the Dean of the University's School of Pharmacy stated: "Today, this `know-how' (of drug making) exists and is constantly expanding as new, more complex and sophisticated drugs and dosage forms are introduced. Unfortunately, at the present time this know-how is confined to a relatively small segment of the total pharmaceutical industry." In concluding, Mr. Chairman, I should like to emphasize that the manufacture of quality drug products is a time-consuming and exacting process, requiring the best personnel and facilities. The reputable and responsible drug manufac- turers of this country go as far as present-day technology permits in order to provide the highest-quality prescription drugs for the medical profession and the public. LELAND W. BLAZEY Education: Hobart College, 1936, AB-Biology and Chemistry. Ohio State University, 1941, M. Sc.-Chemical Engineering. Graduate Studies, University of Rochester, Administration; Princeton Uni- versity Extension, Chemical Engineering. Experience: STice Principal and Instructor: Shortsville High School, 4 years. Merck & Co., Inc.-Positions from 1941-1958 in order, 17 years Supervisor in Pilot Plant and Chemical Engineering Division; Chemical Design Engineer; Manager Production Standards; Manager Industrial Engineer- ing: Manager Design and Construction. Merck Sharp & Dohme, Pharmaceutical Division: Chief Industrial Engineer. Merck & Co., Inc., Chemical Division: Assistant Director of Engineering. McNeil Laboratories, Inc. (1958 to present, 9 years) : Director of Engineer- ing, Vice President of Manufacturing and Engineering. Professional Organizations: American Institute of Chemical Engineers. American Chemical Society. Honorary Scientific: Society of Sigma Xi. Trade Associations: Member Production and Engineering Section, P.M.A., former Chairman. Member Parenteral Drug Association. PAGENO="0247" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2381 Other: Member of Board of Directors, Easter Seal Society for Crippled Children and Adults. Chairman of Montgomery County Business and Industry Campaign, Easter Seal Society. Senator NELSON. Nobody questions the importance, the great sig- nificance of research-oriented companies in the drug industry. I assume it is also true that a company that is not research-oriented may meet all of the same production standards as any research-oriented com- pany. Is that correct? Mr. BLAZEY. I think that is possible. Senator NELSON. I forgot to ask Dr. Van Riper-I notice in a report of the FDA before 1964 Geigy had contracted-out for the production of its entire line of drugs. One of the contractors was Strong Cobb Amer. I notice that Strong Cobb Amer produce drugs for a number of companies. And I notice that either Grays or Peoples-one of those two chains-has advertised that they are putting in a full line of Strong Cobb Amer's generic drugs. They also stated in their ad that the average cost of these drugs would be 50 percent or more below the average prescription cost for a trade name drug. Is there any doubt in your mind, for example, about the quality of the generic drugs produced by this company? Dr. VAN RIPER. I might say, Mr. Chairman, that Strong Cobb Amer no longer manufacture for Geigy. They did up to 1964. Senator NELSON. I think this was 1964. But it said, "still employ these contractors but will eliminate them entirely in 1 year's time." That was dated 1964. But this report states that at one period contract manufacurers produced Geigy's entire line of drugs. Dr. VAN RIPER. That is right, sir. Senator NELSON. There wasn't any doubt in your mind about the quality of the drugs that Geigy got from Strong Cobb Arner, or any of the other generic producers, was there? Dr. VAN RIPER. There was none, sir. But we maintained one of our personnel constantly in the production plant of Strong Cobb Amer. Senator NELSON. Did you find any difficulty in getting quality prod- ucts from them? Dr. VAN RIPER. Not as far as I know. Senator NELSON. The point I wanted to make is that certainly it ought to be clear that a company may produce high quality drugs un- der proper quality control without being in the research field, or with- `jut producing trade name drugs. Is that not correct? Mr. CUTLER. I think it is correct, Mr. Chairman. Strong Cobb Amer is a PMA member, and we are not trying to suggest in any way it does not have excellent quality controls and produce good quality drugs. It so happens that you need scientists to achieve good quality control, and the companies that have scientists, most of them like to do research. So, the two do tend to go hand in hand. Senator NELSON. Okay. Do you have anything else? Mr. CUTLER. No, sir. * Senator NELSON. At this time, I have an article that I will ask be put in the record at this point, by Dr. Mark J. Brauer and Dr. Wil- PAGENO="0248" 2382 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ham Dameshek on the occurrence of hypoplastic anemia and myelo- blastic leukemia. following chlorainp'henicol therapy. (The article above-referred to follows:) [From the New England Journal of Medicine, vol. 277, No. 19, Nov. 9, 19G7, pp. 1003-10051 HYPOPLASTIC ANEMIA AND MYELOBLASTIC LEUKEMIA FOLLOwING CHLORAMPHENI- COL THERAPY* REPORT OF THREE CASES (By Mark J. Brauer, M.D.,t and William Dameshek, M.D.f) Boston A pathogenic relation between aplastic anemia and myeloblastic leukemia has long been suspected. It is well known that certain agents capable of producing aplastic anemia in man can also induce leukemia. Prime examples are benzene' and irradiation.~4 In addition, cases of leukemia developing during the course of hereditary hypoplastic syndromes have been recorded.56 The broad-spectrum antibiotic chloramphenicol7° has become the most commonly cited cause of acquired aplastic anemia. To date, only 1 case report of acute myeloblastic leu- kemia following aplasia secondary to chioramphenicol administration has been published.10 The purpose of this communication is to present 2 additional cases of chioramphenicol-induced aplastic anemia of long standing that developed into acute myeloblastic leukemia. In addition, a patient in whom an indolent, pan- cytopenic myeloblastic leukemia followed the prolonged use of chioramphenicol for the treatment and prevention of head colds is reported. CASE REPORTS CASE 1. J.D. (N.E.M.C.H. 178-415), a 38-year-old woman, was initially in- vestigated 8 years before admission when, after a 0-week course of chloramphen- icol (total dose, 84 gm), marked pallor developed. The pretreatment `hemoglobin level was 12 gm per 100 ml, and the white-cell count 8000. Shortly after chioram- phenicol therapy the hemoglobin was 7.2 gm per 100 ml, the white-cell count 2200, and the platelet count 100,000. Peripheral blood examination showed a predominance of mature lymphocytes (69 per cent) with no primitive white-cell forms. In addition there was mild red-cell anisocytosis. Aspiration of the bone marrow produced a fatty `hypocellular sample with small spicules. The myeloid- erythroid ratio was increased, primarily owing to severe red-cell hypoplasia. Granulocytic precursors and megakaryocytes were also decreased in number. No vacuolization of bone-marrow elements nor increase in immature forms was apparent. Lymphocytes and reticular elements were relatively increased. A diag- nosis of chlorampheflicOl-iflduced hypoplastic anemia was made, but no specific therapy was initiated. Splenectomy was performed in 1959 because of worsening pancytopenia and bleeding. The spleen was of normal size and showed no abnormal features. Bone- marrow aspiration was not repeated. After splenectomy there was no marked change in the peripheral blood picture. The `hemoglobin values ranged between 6 and 8 gm per 100 ml, and the white-cell counts `around 2500. Treatment con- sisted of adrenocorticosteriods, androgens and occasional blood transfusion until 1903, when the patient gave birth to a normal male child. Thereafter, transfusion requirements rose sharply. This was attributed primarily to decrehsed red-cell production. Thirty-eight units of whole blood were given from March, 1965, until 1966. A hemogram performed in April, 1966, revealed a hemoglobin of 7.0 gm per 100 ml, a white-cell count of 15,000 and a platelet count of 50,000. The From the Blood Research Laboratory, New England Medical Center Hospital, and the Department of Medicine, Tufts University School of Medicine (requests for reprints should be addressed to Dr. Dameshek at the Mount Sinai Hospital, 100th Street and Fifth Avenue, New York, N.Y. 10029). Supported by a fund from the grant (CA 04168-09) from the National Cancer Institute, National Institutes of Health, U.S. Public Health Service. ~Attending physician and hematologist, New England Medical Center Hospital; senior instructor In medicine, Tufts University School of Medicine. ~ Attending hematologist, Mount Sinai Hospital; professor of medicine, Mount Sinai School of Medicine, New York City. NoTE-Numbered footnotes at end of article, p. 2385. PAGENO="0249" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2383 differential count showed a predominance of immature blast form's, some of which contained Auer reds. On clinical examination in May, 1966, the patient was extremely pale and in- coherent, with marked purpura. There was evidence of congestive heart failure and a severe neurologic deficit related to brain hemorrhage. The peripheral white- cell count was 37,900, with 15 per cent myeloblasts, Aspiration of the bone marrow produced a specimen almost totally replaced by myeloblasts. Shortly after admission the patient died. Permission for port-mortem examination was not granted. This patient with `chonic aplastic anemia after chioramphenicol was observed for eight years. The terminal development of ~cute myelobl'astic leukemia sug- gested a causal relation. CASE 2. L.R. (N.E.M.C.H. 169-853), a 57-year~old woman, was first seen 15 years before admission for recurrent attacks of dysuria diagnosed as "cystitis." Multiple urologic examinations gave no evidence of obstruction or intrinsic ab- normality. For 8 years before admission it `had been her custom to take chloramphenicol for her attacks~ Short courses taken ad lib always produced impressive clinical improvement. Over this period an estimated 500 to 700 capsules were consumed (approximately 175 gm). Routine blood counts performed during annual examinations were reported as "within normal limits." An anal fistula developed after hysterectomy in February, 1964. She was inter- mittently treated with chlorampheriicol until May, with little improvement. At that time the hemoglobin level was 8.4 gm per 100 ml, and the white-cell count 2500. No platelet count was recorded. A sternal puncture yielded a fatty specimen with marked hypocellularity. Erythroid precursors were almost totally absent. Granulocytic elements, although diminished, showed no "shift to the left" nor clusters of immature cells. No vacuolization of young forms was seen. Mega- karyocyteg were also markedly diminished. A diagnosis of chloramphenieol- induced bone-marrow hypoplasia was made. The patient was treated with `adrenocorticosteroids, androgens and `blood trans- fusions from August 1964, until February, 1965, without improvement of blood findings. On examination in February, 1965, she appeared chronically ill with marked pallor, widespread purpura and pulmonary `congestion. The liver and spleen were not enlarged. A major finding was a massive perirectal abeess. The hemoglobin was 7.3 gm per 100 ml, the white-cell count 5800, and the platelet `count 21,000. The differential count showed 25 percent myeloblasts. Bone-marrow aspiration revealed a hypercellular specimen completely replaced `by myeloblasts. Therapy with 6-mercaptopurine had no `beneficial effect, and she died in an- other hospital. No post-mortem examination was performed. In this case, chronic chlorarnphenicol ingestion was held responsible for the development of aplastic anemia. Acute granulocytic leukema was observed one year later. CASE 3., V.D., a 61-year-old woman, was first `seen on October 26, 1964. At a routine checkup on October 5, when she was asymptomatic and showed no physical abnormalities, a blood count revaled leukopenia and granulocytopenia. The history revealed further that the patient had been plagued by several "heavy colds" every year and that she had been advised by her family doctor in Au- gust, 1963, to take chloramphenicol, 4 capsules daily, "at the earliest sniffle." In the course of the past 14 months she had taken by actual count 60 capsules (15 gm) of the drug. There was no history of any other drug or chemical contact and no history of x-ray exposure except for a few single dental x-ray examina- tions. The family and past histories were noncontributory. On examination the patient looked very welL However, the liver edge was Palpable 3 fingerbreadths below the right costal margin, and a few ecchymoses were present. The hemoglobin was 11.5 gm per 100 ml, the red-cell count 3,890,000, the hernatocrit 37 per cent, reticulocyte count 2.2 per cent, and the platelet count 225,000; the white-cell count was 2200, with 15 percent neutrophils, 80 per cent lymphocytes; and S per cent monoeytes. The sedimentation rate was 10 mm per hour. Bone-marrow aspiration revealed hypocellularity to normocellularity. Large numbers of primitive pale-staining cells were present, and primitive monocy- toid cells were increased. The diagnosis of hypoplasia of the bone marrow, with primitive cell (myeloblastic) leukemia, was made. An alternative diagnosis of ~`niaturation arrest of the granulocyte series" induced by chioramphenicol was entertained. No therapy was advised except for discontinuance of the antibiotic. PAGENO="0250" 2384 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The patient was observed at intervals during the following year. During the first 6 months she continued asymptomatic. Gradually, increasing pancytopenia developed. Symptoms of gingival hyperplasia, bouts of diarrhea, and bouts of fever occurred in June and July, 1965. In mid-October, a severe nasopharyngitis, cellulitis of the left ear and rapidly progressive anemia appeared. The bone marrow was now almost completely replaced by myeloblasts and prornyelocytes. Therapy with 6-mercaptopurine was instituted, and antibiotics and transfusions were given. In early December, 1965, generalized sepsis due to a coagulase-positive staphylococcus was present, and the patient died on December 7. This woman of sixty-one, always in good health except for head colds, took 60 capsules of chioramphenicol during fourteen months as a prophylactic measure against further colds. This was successful, but pancytopenia and the indications in the bone marrow of hypoplasia and of primitive cell (myeloblast) leukemia developed. Chloramphenicol was discontinued. The patient was well for about six months, and then the various cliiiical manifestations of acute leukemia de- veloped and she died fourteen months after the diagnosis had been made. DISCUSSION Hypoplastic anemia has been defined in various ways by various observers. We prefer to reserve this .term for cases showing pancytopenia of the blood and well defined hypoplasia of the bone marrow. Those with increased cellularity of the marrow and blood pancytopenia may indicate other conditions ranging from maturation arrest to the DiGuglielmo syndrome or leukemia. In the aplastic anemia that follows the administration of chloramphenicol, 2 main forms may be discriminated. In the first the onset is acute, seemingly dose related and fre- quently associated with a normocellular bone marrow, which exhibits vacuoliza- tion of erythroblasts and granulocytic precursors. Moderate anemia, reticulo- cytopenia, increased plasma iron and delayed plasma iron clearance have been observed in this sitting.° Unless the dosage of drug has been inordinately high, this type is usually reversible when the drug is discontinued. Work in mam- malian cell-free systems suggests that prolonged exposure to chloramphenicol and high blood levels of unbound drug are both important factors in inhibiting protein synthesis through interaction with messenger RNA. Tills may help to explain the bone-marrow hypofunction.U The second form, or "late-onset type," may not be dose related. It is charac- terized morphologically by hypoplasia or severe aplasia of the bone marrow. In most patients manifestations of marrow depression develop after the drug has been stopped, often weeks or months later. In such cases, indications of marrow- injury remain long after the last trace of the drug have disappeared. Con- ceivably, injury to a large number of stem cells might explain such an effect. An interval would then be required before the stem-cell pool became depleted and cytopenia was manifest. That some patients, because of a metabolic abnor- mality or deficiency, may be more susceptible than others to the action of chlor- amphenicol or its degradation pro~lucts, is an attractive but unproved possibility. In fact, there is no ready explanation at present for the apparent susceptibility of some persons to the development of serious disorders of the marrow after chloramphenicol or other agents. The development of leukemia in the course of aplastic anemia is of con- siderable interest. Although most large series of acquired aplastic anemia 12-14 contain no such reports, examples may be found with benzene toxicity,"2 after radiation,3'4 after administration of phenylbutazone,15'16 during the hypoplastic phase of paroxysmal nocturnal hemoglobinuria and in hereditary hypoplastic syndromes."6 The development of paroxysmal nocturnal hemoglobinuria during aplastic anemia 18 is of additional interest. This may be but another example of the development of abnormal cell lines in a previously injured bone marrow-. The induction of leukemia by chemicals (including drugs) may be mediated through chromosomal injury. In line w-ith this is the recent observation by Castoldi and Mitus" of chromosomal vacuolization in patients receiving chlor- amphenicol. Inconstant chromosomal changes have been observed in several series of cases of acute leukemia.20" Similar changes have been found to follow radia- tion4 and benzene" and to occur in hereditary states." The chrornosomal vacu- olization seen after chloramphenicol may be a comparable lesion. Another pos- sible explanation is that the leukemia is a secondary, perhaps reparative. response to aplastic anemia. A tendency to neoplasia of hypoplastic tissues has PAGENO="0251" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2385 been recognized repeatedly in human pathology. Examples include atrophic gastritis and leukoplakia. Perhaps analogous to the potential of these disturbed tissues to transform into carcinoma is the eventual emergence of leukemia in the chronically aplastic bone marrow. Finally, another explanation for the development of leukemia in these cases deserves consideration. Aplastic anemia and leukemia may both be thought of as growth disturbances of the bone marrow (myeloproliferative disorders). Thus, they may occur either together or sequentially as phases of the same pathogenetic mechanism. Block et al.24 had the unique opportunity to observe 12 patients for as long as twenty-seven months before the development of acute myelogenous or `stem-cell leukemia. Most of the patients in this "preleukemic" phase displayed variable degrees of marrow hypoplasia as well `as peripheral cytopenias. Blair and his a'ssociates n reported a similar experience in 16 cases of "atypical leukemia." Thus, it may be hypothesized that in some cases aplastic anemia and leukemia simply represent different expressions of the same fund- amental disturbance. It is now reasonably clear that an "insult" to the bone marrow, as from chloramphenicol or another chemical, may either destroy totally or partially. Partial destruction of some cells may serve only to "knock out" one or two enzyme systems but not prevent cell reproduction. Under these cir- cumstances, a new self-perpetuating cell line (clone) may develop-that is, leukemia, when white cells are concerned, or paroxysmal nocturnal hemoglo- binuria with erythroblastic involvement. We have recently remarked upon the relation of paroxysmal nocturnal hemoglobinuria and aplastic anemi'a, particu- larly in association with chloramphenicol toxicity.28 The syndrome of aplastic anemia, regardless of cause, may lead to early death from hemorrhage or infection or may result in chronic bone-marrow mal- function. The development of leukemia and of paroxysmal nocturnal hemoglo- binuria has been associated `with the latter process. It is evident that chloram- phenicol can result in this `sequence of events. The continued widespread use of this drug, particularly in the less developed countries, and even among the high- est-income groups of this affluent country, often for trivial reasons, may be a factor in the causation of some forms of leukemia, particularly of the relatively in- dolent, hypoplastic type. SUMMARY AND CONCLUSIONS The development of myeloblastic leukemia during the course of chloram- phenicol-induced pancytopenia in 3 patients is described. Leukemia has been re- ported in a wide variety of clinical states commonly characterized by variable degrees of bone-marrow hypoplasia. Factors responsible for the development of aplastic anemia and drug-induced leukemia are considered. Chloramphenicol, by primary or secondary means, appears causally related to the blood dyscrasias in the cases presented. As stated so many times, indications for the routine or even common use of this drug in the treatment of infection mu'st always be care- fully scrutinized. REFERENCES 1 DeGowin, R. L. Benzene exposure and aplastic anemia followed by leukemIa, 15 years later. J.A.M.A. 185: 748-751, 1963. 2 Vigliani, E. C., and Saita, G. Benzene and leukemia. New Eng. J. Med. 271: 872-876, 1964. Cronkite, E. P., Moloney, W., and Bond, V. P. Radiation leukemogenesis; analysis of problem. Am. J. Med. 28: 673-682, 1960. Lawrence, J. S. Is there incriminating evidence for . . . Irradiation leukemogenesis. J.A.M.A. 199: 1049-1054, 1964. ~ Cowdell, R. H., Phizackerley, P. J. R., and Pyke, D. A. Constitutional anemia (Fan- coni's syndrome) and leukemia in two brothers. Blood 10 :788-801, 1955. 6 Garriga, S., and Crosby, W. H. Incidence of leukemia in families of patients with hypoplasia of marrow. Blood 14: 1008-1014, 1959. Registry on Adverse Reactions, Council on Drugs, American Medical Association. 8 Leiken, S. L., Welch, H., and Gui G. H. Aplastic anemia due to chloramphenicol. Win. Proc. Child. Ho8p. 17: 171-181, 1961. Yunis, A. A., and Bloomberg, G. H. Chloramphenicol toxicity: clinical features and pathogenesis. Progr. in Hemat. 4: 138-159, 1964. 10 Mukherji, P. A. Acute myeloblastic leukemia following chloramphenicol treatment. Brit. M. J. 1: 1286, 1957. "Weisberger, A. S., Wolfe, S., and Armentrout, `S. Inhl~ition of protein synthesis in mammalian cell free systems by chloramphenicol. J. Ea,per. Med. 12: 161-181, 1964. `~ Lewis, S. M. Course and prognosis in aplastic anaemia. Brit. M. J. 1: 1027-1031, 1965. 13 Mohler, D. N., and Leavell, B. S. Aplastic anemia: analysis of 50 1: 1027-1031, 1965. 14 Scott, J. L., Cartwright, G. B., and Wintrobe, M. M. Acquired aplastic anemia: analysis of thirty-nine cases and review of pertinent literature. Medicine 38: 119-172, 1959. PAGENO="0252" 2386 CO~tPETITWE PROBLEMS IN THE DRUG INDUSTRY ~ Bean, R. H. D. Phenylbutazone and leukemia: possible association. Brit. .11. J. 2: 1552-1555, 1960. 16Dougan, L., and Woodliff, H. J. Acute leukemia associated with phenylbutazone treat- ment: review of literature and report of further case. M. J. Australial: 217-219, 1965. ~` Hartman, R. C., and Jenkins, D. E. Personal communication. 18 Lewis, S. M., and Dacie, J. V. Aplastic anemia: paroxysmal nocturnal haemoglobinuria syndrome. Brit. J. Hadmat. 13: 236-251, 1967. 18 Castoldi, G.. and Mitus, W. J. Personal communication. 20 A. G., Jacobs, P. A., McBride, J. A., and Tough, I. M. Cytogenetic studies in acute leukemia. Brit. M. J. 1: 1564-1571, 1961. 21 Kiossoglou, K., Mitus., W. J., and Dameshek, W. Chromosomal abberations in acute leukemia. Blood 26: 610-641, 1965. 21Pollini, G., and Colombi, R. Ii donno cromosomico midollare nell' anemia aplastica benzolica. Med. d. lavoro 55: 241-255, 1964. 2~Bloom, G. B., Warner, S., Gerald, P. S., and Diamond, L. K. Chromosome abnormalities in constitutional aplastic anemia. New Eng. J. Med. 274: 8-14, 1966. ~ Block, M., Jacobson, L. 0., and Bethard, W. F. Preleukemic acute human leukemia. JIMA. 152: 1018-1028, 1953. ~` Blair, T. R., Bnyrd, E. D., and Pease, G. L. Atypical leukemia. J.A.M.A. 198: 21-26, 1966. ~° Dameshek, W. Riddle: what do aplastic anemia, paroxysmal nocturnal hemoglobi- nuria (PNH) and "hypoplastic" leukemia have in common? Blood 30: 251-254, 1967. Senator NELSON. We appreciate very much your taking the time to come here, gentlemen. I apologize for having to make some of you make an extra trip because we could not complete the testimony the last time. I realize that this was an irnDosition upon your time and I regret it. But I do appreciate your contributions to the record. I think that all of the prepared testimony presented was certainly well done, well prepared, and will be a. valuable asset to the record. Thank you very much. Mr. CUTLER. Mr. Chairman, we appreciate the time and attention you have paid to us. As you know, we do have a number of economic witnesses prepared to deal with such subjects as prices and profits, and I understand from Mr. Gordon that he will give us a date at some point in the near future for those witnesses. Senator NELSON. We certainly will. As I said the last time, if addi- tional time is needed we will take an additional day or two, or what- ever is required, for purposes of presenting for the record whatever yol.i desire to put into the record. With all your expertise, you are a very formidable group for me to contend with. Mr. CUTLER. Let's hope we are educating one another. (Whereupon, at 5 :35 p.m., the subcommittee was adjourned, sub- ject to the call of the Chair.) PAGENO="0253" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TUESDAY, FEBRUARY 6, 1968 U.S. SENATE, MONOPOLY StincoMMlrrsE OF THE SELECT COMMIrrEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to call; at 10:15 a.rn., in room 318, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; J~imes H. Gross- man, minority counsel; Susan H. Hewman, research assistant; and William B. Cherkasky, legislative director, staff of Senator Nelson. Senator NELSON. We will now open the hearings of t.he Monopoly Subcommittee. During the course of the Monopoly Subcommittee hearings on pre- scription drugs, the committee's attention has been called to a number of cases in which the administration of certain drugs has resulted in serious side effects. A short time ago an industry witness, in relating to the committee the effectiveness of the company's broad spectrum antibiotic, Chloro- mycetin, concurred in the statement that the drug had been the cause of serious blood dyscrasias, some of which have resulted in death. The "Physicians' Desk Reference" says that chioramphenicol "should not be used when other less potentially dangerous agents will be effective, or in the treatment of trivial infections, such as colds, influenza, or viral infections of the throat, or as a prophylactic agent," and so forth. Yet, the manufacturer of Chloromycet1in reported total domestic sales of $45,000,000 in 1966, and a total sales of $70 million worldwide. There is a growing mountain of evidence that Chloromycetin is being widely overprescribed. Dr. William Best, who has studied 408 cases of adverse reactions to the drug, has surfaced information on the indications for which doc- tors generally prescribe chloramphenicol. Tn 30 percent of the cases cited, he found that the drug had been ad- ministered for "relatively trivial indications for which the drug should never have been used." He says that many complications Oc- curred in patients who "should not have received chioramphenicol." Recently FDA Assistant Commissioner Theodore 0. Cron acknowl- edged that physicians in large numbers continue to ignore ]abel warn- ings about misuse of the drug. 2387 PAGENO="0254" 2388 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. William P. Cregar, addressing the San Diego Academy of General Practice, said that the drug "is the leading cause of" the often fatal aplastic anemia and that physicians "are using it far too much." One of our witnesses today, Dr. William Dameshek, has been quoted in a widely read book on drugs that: Promiscuous use of the drug should be avoided and use restricted to im- pelling circumstances; i.e., for conditions in which no other antibiotic is cur- rently effective. The American Medical Association Registry on Blood Dyscrasias, which provides reliable data on the subject, reported in July 1967 that in 96 percent of the 408 cases of aplastic anemia brought to its attention, it was strongly suspected that chloramphenicol was the causative agent-and its possible link in the remaining 4 percent was not ruled out. The report says the drug is believed to be the cause of death in 50 percent of these 408 cases. A physician, Dr. Albe M. Watkins, whose son died from aplastic anemia caused by chloramphenicol, stated: I do not know of one single victim who would not be alive today had he only been permitted to get well by himself, by nature, without the use of this antibiotic. In a case in March 1967, a Federal district court awarded the heirs of a California woman $180,000 in dan~ages because she was disfigured after taking the drug. A dentist had prescribed the drug for an in- fection which followed extraction of several teeth. The California woman claimed Chloromycet.in produced aplastic anemia and so disfigured her that friends could not recognize her. She said she had to shave daily, grew a `~buffalo hump," and developed severe acne. She later died of complications of the disease. On February 20, 1967, a two-page advertisement appeared in the Journal of the American Medical Association which described the use of Chloromycetin to the doctor. In 1,300 w-ords of warning and iii a large, black~bordered box, the ad warned `the physician that- Serious and even fatal blood dyscrasias (aplastic anemia, hypoplastic anemia *) are known to occur * * * chioramphenicol should be used only for seri- ous infections caused by organisms which are susceptible to its anti-bacterial effects. And it went on to warn against use for minor infections. I asked the quality control director of the Parke, Davis Co. if lie agreed that the warning w-as necessary and appropriate. He concurred that the warning was important and had to be an integral part of the ad; that the drug had dangerous side effects; that deaths had occurred which were directly attributable to the use of the drug. Then I showed him an advertisement for Chloromycetiii run by Parke, Davis in the British Medical Journal on February 11, 1967- 9 days prior to the American ad. Not a single word of warning appeared in the British ad. No men- tion was made of the drug's potentially fatal side effects to at least alert. the British physician. I asked the drug company representative why there was no warning. PAGENO="0255" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2389 His counsel replied that the company complies with the law of the country where it advertises, and the British do not require the warning. Because of the effect this lack of complete disclosure has on unfor- tunate victims in other parts of the world, on our trading partners, and on our friends in the underdeveloped countries, this committee has asked several distinguished authorities on blood diseases and dis- orders to testify to the committee about the uses and dangers of chioramphenicol. Our first witness this morning is Dr. William Dameshek, a very distinguished professor of medicine now at Mount Sinai School of Medicine in New York. Doctor, we appreciate your taking the time to come here today and the committee is well aware of your distinguished credentials. We will print prior to the printing of your statement, the biography which you have supplied to us. (The biography of Dr. Dameshek follows:) SHORT BIOGRAPHY William Dameshek, M.D. (New York, New York). Born: May 22, 1900. Harvard Medical School, 1923. Titles: Professor of Medicine, The Mount Sinai School of Medicine, N.Y.C. Attending Hematologist, The Mount Sinai Hospital, N.Y.C. Professor Emeritus, Tufts University Schoolof Medicine (Mass.) Editor in Chief (and Founder) of BLOOD-The Journal of Hematology. President of the International Society of Hematology, 1954-56. President, American Society of Hematology, 1964. Extraordinary Professor of Medicine, National University of Mexico. Professor, Honoris Causa, University of Santiago, Chile. Commander, Order of Carlos Finlay, Cuba. Awards: Certificate of Merit, American MedIcal Association, 1942. Billings Silver Medal, 1952, 1953. Premio Ferrata, 1958. Willard 0. Thompson Gold Medal American Geriatrics Society, 1968. Professional Societies: American Academy of Arts and Sciences. American Association of Immunologists. American College of Physicians. Fellow: American Society of Clinical Investigation. American Society of Hematology. New York Academy of Sciences. American Society for Experimental Pathology. Author of approximately 450 published articles, books and monographs on hematologic subjects. Books: The Hemorrhagic Disorders, Eds. I and II; Spleen and Hypersplenism. Chemotherapy of Leukemia and Leukosarcoma ; Hemolytic Syndromes. Leukopenia and Agranulocytosis; Leukemia. Eds. I and II. Family: Wife, Mrs. Williani Dameshek (Rose P.) Daughter, Mrs. Elinor D. Reichlin (wife of Dr. Seymour Reichlin of Rochester, New York ). Two grandsons. One grandaughter. Senator NELSON. Dr. Dameshek, we are pleased to have you here this morning. PAGENO="0256" 2390 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY STATEMENT OF DR. WILLIAM DAMESHEK, PROFESSOR, SCHOOL OF MEDICII~E, THE MOUNT SINAI HOSPITAL, NEW YORK, N.Y. Dr. DAMESHEK. Nice to be here, Senator. Senator NELSON. Go ahead, Doctor. Dr. DAMESHEK. What do you want me to do at this point? Senator NELSON. If you will proceed to read your statement and then, at any time when you wish to extemporize or elaborate, we will be pleased to have you to do so. I realize that attempting to reduce all you wish to say in a printed statement throws a considerable amount of effort on you, but we will be pleased to have you elaborate at any point. If we happen to have some questions which occur to us while you are giving your statement, I am sure you will not mind an inter- ruption. Otherwise, we will ask the questions at the conclusion of your statement. Dr. DAMESHEK. I would like to introduce my statement by saying I have no personal vendetta against any pharmaceutical house that might be implicated in the use of this drug. I realize that pharma- ceutical houses in this country are of considerable importance to the medical profession. They have done a great deal over the years in the research and development of drugs which we have used, as physicians, and I am fully aware of their importance and of their ethical respon- sibilities, and so on. Senator NELSON. Let me say, Dr. Dameshek, the committee agrees with that statement. We have no particular vendetta against anybody, either. We are attempting here to get the best professional testimony on certain problems in this area from the most authoritative people in the country. We think this will be, in the long pull, a benefit to the companies as well as to the public and the medical profession. Dr. DAMESHEK. I want to be, however, as objective as I possibly can. I realize that perhaps some of this objectivity may be lost in my own case possibly because I see the end results of some of the cases of chioramphenicol toxicity. I am in the special field of what is cafled hematology, disorders of the blood, and I see cases of aplastic anemia, many of which have been treated with chloramphenicol, and these cases are very serious cases. Most of them die. So that I ma.y be accused perhaps of looking through one end of t.he telescope whereas the cases of a.plastic anemia that de- velop with the use of this drug are certainly relatively few. Now, my statement here reads that chioramphenicol, or Chloromyce- tin as it is usually called, is a chemical or drug which was introduced as an antibiotic in 1948. It is a relatively simple compound and as such it was soon synthesized-a rare, if not unique, event in antibiotic studies, at least in soil antibiotics. Its formula is unique amongst anti- biotics in that one part of the molecule contains a benzene ring to which is attached an NO2 moiety. This means that the possiblity of injury might occur. At least we have been alerted to that idea since the time of Kracke, who was a hematologist and st.udent of drug reactions a good many years ago. This idea was early commented upon, notably by Smadel, who was an investigator of drugs, as indicating a possible risk to the bone marrow-the bone marrow is the factory that produces blood cells- PAGENO="0257" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2391 and the blood; as other nitrobenzene drugs had been previously incrimi- nated in the causation of toxic blood reactions.' The chloramphenicol story is an upsetting one from several stand- points: On the one hand, this drug is a great "broad-spectrum" anti- biotic; no question about it. It works just as well and perhaps better when taken by mouth than many other a~ntibiotics do when given by injection. On the other hand, it is at the same time a powerful anti- metabolite, which means a cell poison or a material which interferes with the growth of proteins, cells, and it has apparently a particular effect on the bone marrow which is the chief factory, as I have said here, of blood cell production. Thus, one must subordinate one's desire to use it because of the risk, it may do harm. In other words, great caution, great restraint, must be exercised by each individual physician when he prescribes Chloro- mycetin for a particular infection. It gets upsetting, too, that many times this restraint is not used by the physician and as a result great injury, sometimes irreversible, results-in the form of disorders of the whole marrow-aplastic anemia-or of one or another of its compo- nents; the red cells, the white cells, or the platelets. Those are the cells that are produced in the bone marrow and come out in the blood. Now, since the drug is often used withOut restraint, and especially in infectious states when either no drugs or less harmful drugs ca~ be used just as well, one must consider the possibility of restricting its use to certain well-defined conditions. This is something new, I must say, in my own thinking because some years ago we thought a simple warning would do the trick. Some years ago we thought that we could educate the medical profession by editorials, by articles, and so on. But, I must say this has not worked, and we see cases of aplastic anemia in which the drug need not have been used. Senator NELSON. Do you have any opinion as to why the warnings have not worked, as to why the cautionary statements about the limita- tions of this drug have not been effectively translated to a sufficient number of physicians who still do prescribe it ~ Dr. DAMESHEK. I have no real solid opinion about this. I think many warnings are honored in the breach rather than the observance. That is, people might look at them, either ignore them or just think that maybe this time it will not do any harm, because the severe reactions to this drug are relatively few. What is more, this antibiotic happens to be an exceptionally good antibiotic and can be given by mouth so that pediatricians like to use it. What is more, we have an affluent society, as has been said, in this country at least, and there seems to be an impelling need to use drugs even for minor infections. It is the thing to do because, if a doctor does not supply or does not prescribe drugs, a family thinks there is something wrong with him. So that, I suppose, there are many reasons why these warnings are perhaps ignored. Mr. GORDON. Dr. Dameshek, may I ask a question at this point? Why is the public so drug oriented? Could it be the large number of articles about drugs which appear in the lay magazines? Dr. DAMESHEK. Well, again I do not know. I have no solid answer. Advertising is an important feature here naturally. We know about a `See exhibit A, p. 2399, infra. 81-280 O-68----pt. 6-17 PAGENO="0258" 2392 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY lot of things from advertising. Word of mouth, the idea that every- thing responds nowadays to miracle drugs, that this has captured the public fancy and naturally people want something for an illness. The doctor who goes away from a patient without prescribing a drug is often thought to be a little bit unusual. The patient might then go to a doctor who does prescribe a drug. I think it is a rather complex, perhaps philosophical story. Well, I was talking about restrictions and we will take that up to- wards the end of my statement. What these restrictions might be, who is t.o do the restricting, can undoubtedly be worked out. Chioramphenicol, like most, if not all of the active medications we use in medicine, is associated with unwanted reactions particularly to cell systems which normally grow rapidly, as in the bone marrow. This drug, namely chioramphenicol, however, has particular value in serious or severe infections in which good, available antibiotics are hard to find. I should say in certain serious or severe infections. And one of them is typhoid fever, another is sudden severe septicemias in which interstinal organisms come out into the blood. This might. occur in shock or when the blood count is low. And in certain resistant severe urinary infections. Senator NELSON. Is chloramphenicol always indicated in every case of typhoid fever or would it depend upon the diagnosis of the condition of the partcular patient? Dr. DAMESHEK. I think we must say chloramphenicol is the best one for typhoid fever, although Ampicillin, a fairly recently introduced antibiotic related to penicillin, seems to be almost as effective and with- out the reactions of Chloromycetin. Senator NELSON. What I was getting at is whether typhoid fever is always so serious a. disease that a drug of some kind is always indicated? Dr. DAMESHEK. Yes. That is a serious disease and it does not re- spond to the ordinary tetracyclines or the sulfa drugs, et cetera, and Chloromycetin seems to have a particular iibility in controlling typhoid fever. Senator NELSON. Does the medical profession have any good edu- cated guesses as to how many cases of typhoid fever occur in this country annually? Dr. DAMESHEK. Well, I would sa.y it is a rare disease in this coun- try. Something in the neighborhood maybe of a few hundred cases occur a year. It. is a rare disease now.. Chloramphenicol is not indicated for colds, acne, that is pimples, grippe, influenza, and other common infections that are self-limited and in which either no treatment or such relatively harmless drugs as penicillin and the tetracycline drugs can be used. Senator NELSON. Is it 1ndicated for any of the upper respiratory infections? Dr. DAMESHEK. I would say it is not indicated. Senator NELSON. Not indicated? Dr. DAMESHEK. Not indicated. Either the upper respiratory infec- tions will get better themselves, which they do by and large, or else there are plenty of drugs around that could be used that do not. have the effects on the blood-building ma~hinery that this drug has. PAGENO="0259" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2393 So, I would say it is not indicated in the ordinary upper respira- tory infections. Large doses of the drug, for example, 6 grams a day, `will regularly result in well-defined injury to the bone marrow and to the blood. Now, it can he demonstrated in something like 18 out of 20 cases. In other words, if large doses of the drug are used, almost everybody, will develop well-defined effects which can be measured following the use of the drug, and here it is not a matter of sensitivity. It is a matter of dosage. The pharmacologic action of the drug is one in which the bone marrow is affected by the drug. Senator NELSON. And, are these effects usually permanent? Dr. DAMESHEK. These are ordinarily reversible, or self-limited. But, I must say this, that I do not like to see them. That is No. 1. And No.2, the possibility is present that once having had a reaction of this sort on the part of the bone marrow, that individual is, therefore, sensitized to future reactions, and finally there has not yet been a study made of those individuals who have developed reactions to 6 grams a day of the drug to see whether in the future they might have `developed severe drug reactions. Senator NELSON. Is 6 grams a day a program that is frequently prescribed? Dr. DAMESHEK. It has been rather frequently used by specialists in infectious diseases. I cannot say how frequently. But, I do know from personal observation that it has `been used by specialists in infectious disease for severe infection. Senator NELSON. Is that, in your judgment, usually or always an excessive amount to be prescribed in any event? Dr. DAMESHEK. No. The 6 grams may be effective whereas 2 grams may not be or 1 gram may not be. But, to say it is always effective, no. I do not think you can say it is always effective in clearing up any infection. Senator NELSON. In your judgment, would that be considered an excessive dosage in most cases? Dr. DAMESHEK. Well, to my way of thinking, it is an excessive dosage. I would say that. But, this is my own judgment. Unfortunately there is some evidence from case studies, that the continued use of even small doses of Chloromycetin, or in some cases even a single 5- to 7-day course of drug, may eventually lead to bone marrow damage, eventually, 6 months, a year, year and a half. Re- peated courses of drug at regular or irregular intervals has, in my ex- perience, been more regularly followed by severe reactions such as aplastic anemia than when only one course is given. This is in my own experience. Unfortunately, in most of the cases of severe aplastic anemia, that I have seen, Chloromycetin had been given for such infections as acne, upper respiratory disorders, mild urinary infections and, in fact, indiscriminately. Senator NELSON. These are all cases, in your judgment, where it should not have been given at all. Dr. DAMESHEK. Well, I would say this, that in most of the cases that I have seen, in fact, in most of the cases reported in the literature of severe drug induced reactions, the drug should not have been used. It PAGENO="0260" 2394 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY is as simple as all that because the indications for which the physician prescribed the drug were acne, upper respiratory infections, and the like, in which he could either have used no drug or have used a drug that does not cause these severe reactions. The side effects of the drug depend upon the fact that it is an anti- metabolite or cell poison. Evidences of injury to red cell growth, white cell growth, platelet growth, and lymphocyte growth have been demon- strated from a variety of careful studies. Now, the lymphocyte is not a bone marrow cell in the accepted sense. The lymphocyte is at the cen- ter of a special grouping of cells which is concerned with immunity or helping the body either to prevent an infection or to prevent an infec- tion from getting ahead. Now, it has been demonstrated from a number of studies that this drug also affects these cells concerned with immunity, that is, the lymphocytes. In general, the drug has demonstrated effects on the production of cell proteins, disturbance in transfer of the synthetic "message" from RNA to ribosome, that is, where proteins are produced within the cells. So that one can say in simple words that an actual "monkey wrench" has been thrown into the machinery of cell growth. Thus, with lymphocytes, antibody formation is greatly reduced: with red cells, hemoglobin synthesis is delayed and cell maturity greatly slowed down. Similar disturbances occur with white cells of the marrow and with the megakaryocyte platelets. Those are the big cells in the marrow that produce platelets. Sorry about these big terms. In most instances the entire marrow shows reactions and thus, all the elements of the blood are affected leading to the very serious condi- tion of aplastic anemia, which is frequently fatal. Senator NELSON. Would you describe aplastic anemia for the record? Dr. DAMESHEK. Yes. Aplastic anemia is fundamentally a disturb- ance of bone marrow growth in which the growth of cells normally in the marrow is greatly reduced so that the bone marrow is finally producing something like 1 percent, 2 percent, 10 percent, possibly 25 percent of the normal number of cells produced. This leads, there- fore, to a reduced number of red cells, a reduced number of white cells, a reduced number of platelets in the blood. The individual may be perfectly healthy in every respect but if his marrow is not working, lie has very little blood. So that. this becomes, then, a very important thing because without blood there can be no life. In some ways the blood is the central feature of life. Senator NELSON. What does the term aplastic mean? Dr. DAMESHEK. Lack of growth. Aplastic-plastic has to do with growth and "a" means lack of growth. Senator NELSON. And in what percentage of cases is the disease aplastic anemia fatal? Dr. DAMESHEK. Well, that. is a difficult question to define because it is hard to define what. is meant by aplastic anemia. If you say that aplastic anemia is a condition in which 75 percent of the bone marrow has been "knocked out," then I would say that the mortality rate for aplastic anemia varies between 50 to 75 percent, maybe more. Senator NELSON. In the cases that you have seen where aplastic PAGENO="0261" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2395 anemia has developed from the use of the drug chioramphenicol, what percentage of those cases were fatal? Dr. DAMESHEK. I would say something like 75 percent. Senator NELSON. 75 percent? Dr. DAMESHEK. Yes. I have seen mainly~t.he severe cases. Senator NELSON. One can live certain periods of time, I take it, then, with aplastic anemia depending upon the degree of inhibition of production of blood cells that has resulted. Dr. DAMESHEK. Yes; and depending also upon the amount of treat- ment., notably the use of transfusions, because if the individual de- velops lack of blood, lack of red cells, this can be substituted by the use of transfusions, at least to some extent. Senator NELSON. And what is the patient's condition even though he continues to live? Dr. DAMESHEK. Well, as a result of the aplastic anemia, the individ- ual becomes incapacitated as a rule. He cannot work, he cannot do his usual work. He is usually anemic. What is more, he is very apt to pick up infections because his white cell count is low. And the normal white cells which control infections are no longer there. He is apt to bleed from his nose, his gums, get black and blue marks and bleed internally because he has very few platelets which control bleeding. So that he is in a rather bad way. Now, in most instances the entire marrow shows reactions to the drug and thus all the elements of the blood are affected, leading to aplastic anemia which is frequently fatal. Overt or serious aplastic anemia de- velops only rarely in the wake of Chloromycetin therapy. Now, how rarely it develops is by no means known. We have no exact statistics on this subject at all. There is no need, there is no requirement about reporting drug reactions at this time. Senator NELSON. No requirement at all in the law? Dr. DAMESHEK. No. No requirement as far as I know in any State, municipal, or governmental law regarding~ the reporting of severe re- actions or drug reactions. Senator NELSON. To depart from your testimony, would it be feasible at least, to have a reporting system developed by all the hospitals? Would it be useful? Dr. DAMESHEK. Oh, I think it would. I see no great difficulties in- volved in that. If every hospital reported every case of aplastic anemia, and of every severe reaction to a drug or every severe possible or prob- able reaction to a drug, I think that would be quite feasible. I see no ob- jection to that. Senator NELSON. You would apply that to all serious reactions to all drugs? Dr. DAMESHEK. All serious reactions; yes, I would. I think it would be a very valuable educational thing to have and very valuable thing to have in general. Senator NELSON. If that were done by the hospitals, where would the best place be for the information to be accumulated so that it could be properly evaluated and disseminated? Dr. DAMESHEK. Well, I can see the possibility of the patient having a probable or well-defined reaction to a drug reported to the admin- PAGENO="0262" 2396 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY istrator's office, for example-to the administration office in the hospital. Senator NELSON. I am thinking that if this information would be valuable to the medical profession, where would hospitals ultimately report it? Dr. DAMESHEK. Well, at the present time there is a voluntary agency for picking up reports of drug reaction that is handled by the Amer- ican Medical Association, in their offices. That is one possibility. Another possibility would be that such reactions would be reported to the Food `and Drug Administration. That is `another possibility that might be more official, I suppose. Senator NELSON. As one who has had `a great deal of experience working in hospitals, if you had some defined requirement that serious reactions to drugs be reported by the hospital, what kind of a paper- work problem would this be? Dr. DAMESHEK. Oh, it would simply increase the paperwork which already is extremely high at hospitals. Some hospitals have more paperwork than others as I have found in my move from Boston to New York. So that this would simply increase the paperwork in New York by a very small fraction, in other places by a very large fraction. It could be d'one. I see no reason why it could not be done. Senator NELSON. It could be confined to reactions knowledge of which would be of some value. In `other words, there are drugs where I `suppose you have had enough experience so `that everybody in the profession knows about `all the possible reactions that could occur. I `suppose that is one kind of situation. Dr. DAMESHEK. I would think serious drug reactions-you take, for example, penicillin occasionally has drug reactions, that you are undoubtedly familiar with. You may get a skin rash or something of `that sort. I doubt that `anyone would want to `report `any more cases of drug rash with penicillin. But, when you talk about aplastic anemia or severe blood reactions, if I were `an admini~trator of' a hospital, I would like to know something about those reactions. Senator NELSON. Since `all the information is there in `the hospital records on every patient anyway, what you would be talking `about is that `at the conclusion of some period, 6 months or a year of the ap- propriate professional people and specialists in the hospital, would de- cide which of these reactions were reactions knowledge of which would be of `some value to medical knowledge and literature, and `they would then report those possibly to the FDA `and the AMA. Dr. DAMESHEK. Right. Most hospitals `already h'ave the machinery set up. They have `a drug committee which `in some hospitals, I believe, functions with respect to drug reactions. So that `the machinery is there in many hospitals and could easily be set up in other hospitals. Senator NELSON. And, do I understand it to be your judgment that, if this kind of information were collected and properly submitted to the right places, whether it be FDA and AMA or wherever, it would be a valuable contribution to medical knowledge? Dr. DAMESHEK. I would say it would `be valuable because one of the functions of dissemination of knowledge is development of facts first, accumulation of facts, and then one can draw conclusions from those facts, yes. PAGENO="0263" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2397 Senator NELSON. I suppose it would be most valuable when a new drug comes on to the market, during the first few years of experience with it? Dr. DAME5HEK. Yes; I would think so because a drug may be intro- duced, may get by all agencies as a fine drug without reactions, as this one did, and tihen in a few years case `after case begins to pile up. It is a curious thing. The reactions do not seem to show `themselves up for a ~hi'le. There can be no question that the continued widespread advertising of chloramp'henicol and of promotional activities by detail `men tend to increase the use of this drug. Although cautionary statements have been int~duced in the advertising literature and also in the medica- tion packet, there is no clear-cut evidence that these are heeded to `any degree. With access to an excellent antibiotic like Chioromycetin, the practicing physician is apt to reason that in this particular instance, and in view of the relatively few overt reactions to the drug, this par- ticular patient would probably `withstand any serious damage. As in cigarette smoking, the warning statements are honored more in the breach than in the observance. in some areas of the world, notably in less developed countries as in the Orient, Chioromycetin is used almost as freely as aspirin, from my experience there, and without the cautionary recommendations required in this country. Senator NELSON. Are these drugs manufactured in this country? Dr. DAMESHEK. As far as I know, they are. There may `be other sources, I do not know. But I know that Chloromycetin is used widely in various Oriental countries like the Philippine Islands and in Formosa and in many other foreign countries. Senator NELSON. Do you find a comparatively high incidence, then, of blood dyscrasias of various kinds in those countries where chlor- amphenicol is used extensively? Dr. DAMESHEK. Well, the physiciaiis I talked with in the `countries I visited seemed to think that the incidence of aplastic anemia in their respective countries is increasing, is unduly prevalent. I have a little statement here from an editorial I wrote a few months ago that talks about `this.~ I said: Thus, in Manila, the Philippines, Dr. Allen Oaviles, of the Philippines General Hospital- One of the largest `hospitals `in Manila~, "but only one o'f them, this is only `one hospital- informed me that he had observed 71 cases of aplastic anemia in 3 years, 53 of which had been the subject of followiip. One of these had developed another interesting disease that I have here. I call it here PNH, in abbreviation: In the same period nine cases of PNH had also been observed, five of them having previously been diagnosed as aplastic anemia. Another doctor, Dr. Hwang, in Taipei, Taiwan, reported that he had observed 10 to 14 new cases of aplastic anemia annually in one large hospital and he thought that the incidence had been going up year by year. Iii both these areas, Chloromycetin had been used very freely for about everything. See exhibit B, p. 2400, infra. PAGENO="0264" 2398 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Are the instructions about the precautions in us- ing it as widely disseminated there as here? Dr. DAMESHEK. I would be inclined to doubt that they were. I am not sure that they even have any cautionary statements itbout the use of chloramphenicol in these countries. Senator NELSON. In the- Dr. DAMESTIEK. In the literature or in the package. I am not sure about that. I do not believe they have, but I am not sure about it. Some of the disturbances which may be related to aplastic anemia, and which I have observed, are acute leukemia, which has been shown to develop in some cases of aplastic anemia after some time. And the peculiar disorder known as paroxysmal nocturnal hemoglobinuria, PNH, which I do not think I would go on and explain to you because it is rather complicated. But, a few months ago we did report in the New England Journal of Medicine three cases of myeloblastic leukemia following Chioro- mycetin therapy and in these two cases the patients had used the drug, had developed aplastic anemia which was followed by the develop- ment of leukemia. Senator NELSON. Were these cases in which the drug should not have been prescribed, in which it was not indicated? Dr. DAMESHEK. The first one I came in contact with was a woman from one of the most affluent families in this country. I will not men- tion the name. And her doctor in this elegant community had given her ChToromycetin for a head cold and had told her to use this drug for every sniffle that she might. get. in the future. She proceeded to follow this prescription regularly. Her colds disappeared. But later on she developed aplastic anemia and eventually leukemia. And, in the two other cases I have here, one had a urinary disturb- ance where she was asked to take-cyst.itis, so-called-she was asked to take the drug whenever she had a little burning of the urination. Eventually she developed aplastic anemia and then leukemia. The other one was a woman who had had simply a 6-week course of Chioromycetin for an infection. I do not have it. specified here what the infection was. I guess we did not know a.bout it. But., these are new- er developments in the foflowup of aplastic anemia. There was another case recently reported from California, the same sort of thing. Senator NELSON. Are each of these cases ultimately `fatal? Dr. DAMESHEK. Yes. This kind of leukemia is always fatal. Senator NELSON. Was the second case that. you mentioned one in which it should' have been prescribed for the condition? Dr. DAMESHEK. Well, this woman had a. urinary infection and a lot of people use this drug in urinary infections. Now-, whether it should not have been prescribed I am not sure, but she used it w-henever she ha.d a little burning of urination. I think she used it rather indis- c.riminately. That is about as `far as I can go on that. I discussed in an editorial of the Journal of the American Medical Association of a few years ago some of the problem's relating to respon- sibility and to precautionary measures.3 That is, who is responsible for this or whose responsibility is it? See exhibit C, p. 2401, infra. PAGENO="0265" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2399 Senator NELSON. You read from an editorial that you had written. Was that for the Journal of American Medical Association? Dr. DAMESHEK. Oh, that last- Senator NELSON. The first one you mentioned? Dr. DAMESIIEK. About the Far East? Senator NELSON. Yes. Dr. DAMESHEK. This was published in the journal "Blood." Senator NELSON. Would you mind supplying that to us so that it can be printed at this point in the record of your testimony? Dr. DAMESHEK. Yes. I have it here. Senator NELSON. And then, would you, suppiy for us the cases you just mentioned for printing in the record? Dr. DAMESHEK. Yes. Senator NELSON. We would appreciate `it if you would give us copies o'f each of the reports or editorials th'at you refer to. Dr. DAMESHEK. Fine. I think you have this one from "Blood," of which I- Senator NELSON. That is attached to the back of your statement and will be printed, yes. (The articles referred to follow:) [Reprinted from Blood, the Journal of Hematology, vol. VII, No. 7, July 1~52J EXHIBIT A.-EDITOBXAL CHLORAMPHENICOL (CHLOEOMYCETIN) AND THE BONE MARROW New drugs, miraculous as they often appear to be initially, not infrequently have their tarnish rubbed off as we come to know them better. More often than not, this is the result of reactions of the drug upon the bone marrow and blood. Since 1931 when Kracke' and others suggested `that agranulocytosis might be due to the administration of drugs such as aminopyrine, the medical profession has been alerted to the possibly deleterious effect of drugs containing the benzene ring, particularly when it is in combination with a nitrogen, amino, or nitrate group. In Denmark, agranulocytosis ceased to exist for all practical purposes when a complete prohibition was placed on the import and sale of Pyramidon (amino- pyrine) into that country. Later, when the first "miracle drugs" of present-day medicine, i.e., the sulfonamides were introduced, it was found that they too might result in various types of bone marrow reactions and thus in total or selective cytopenias. These reactions occurred with both the intermittent administration of the drug ("hypersensitivity?") or after long continued administration.2 With the advent of the soil antibiotics, this particular problem appeared to be solved, and in fact, penicillin administration soon became' the standard mode of therapy for agranulocytosis. Penicillin, remarkable though it was in quelling many gram positive infections, was ineffective in controlling such diseases as tuberculosis and the gram negative infections. This resulted in a wide search throughout the world for other thera- peutic molds, as a result of which streptomycin, aureomycin, terramycin and chloramphenicol (Chloromycetin) were found and developed. The latter three agents became known as the "broad spectrum" antibiotics since they prove to be active against both gram positive and gram negative bacteria, certain rickettsiae and even against some viruses. Of the group, chioramphenicol, originally derived from a soil bacterium found in Venezuela, had the `simplest formula and was the only one that could be synthesized. Isolated in 1948, it was introduced into medical practice the following year. The chemical formula of chloramphenicol is pictured (Merck Index, 1952) as: `Kracke, R. R. and Parker, F. P.: J. Lab. & Clin. Med. 19: 799, 1934. 2Dameshek, William: Leukopenla and Agranulocytosis, New York, Oxford, 1944. PAGENO="0266" 2400 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY F 11TH O2N-~.(~>._~. -C--CH2OH H~ Shortly after its introduction, at least one observer, Smadel,3 called attention to the nitrobenzene radical in the drug and warned of its possible toxic effects on blood-forming apparatus. Early reports indicating possible toxic hematologic reactions of Chloromycetin were largely minimized, especially since in the great majority of the cases in which the drug was used, no ill effects were noted. Furthermore, it was not clear in some of the cases whether Chloromycetin was the sole responsible agent. Recently, however, we have been apprised of a rapidly increasing number of cases from all parts of the country,4 and we ourselves have observed a striking instance of hypoplastic anemia following the long term ad- ministration of Chioromycetin for mild acne of the face. Although it is likely that a number of cases are in the process of publication5 there has been as yet only one ~ in 1952 dealing with aplastic anemia following prolonged ad- ministration of the drug. Many of the cases have been shown to be irreversible and therefore fatal. Although most of the reports are still in the status of "per- sonal communications," there seems to be no question as to their authenticity or their relationship on a circumstantial basis to chioramphenicol administration. It appears from the various reports that severe myelotoxic reactions have fol- lowed both the lengthy administration of the drug and its intermittent use. It seems increasingly clear that a real danger exists in the uncritical use of this drug by the medical profession. A recent pamphlet7 recognizes this possi- bility but places the emphasis upon the very large number of cases and the millions of administrations in which no harmful effects have apparently been observed. There can be no doubt regarding the relatively small proportion of severe hematologic reaction, thus indicating a possible allergic susceptibility on the part of some. However, to the luckless individual who develops panycyto- penia, the b-percentage figure means very little. In the instance of a valuable drug with potential toxic effects, the ultimate safety of the patient must transcend all other considerations. With the use of Chloromycetin the physician is assuming an admittedly small but nevertheless "calculated risk," and should, therefore, be on the watch for possible hemato~ logic reactions, particularly during long term administration. Chloromycetin appears to offer a potential hazard to the bone marrow, at least in some individuals, and it would, therefore, seem wise to use it only for short term administration and when there is a clear and impelling need for this partic- ular medication. Its indiscriminate use for trivial infections and as a household remedy must be deplored. It is unfortunate that no good method has yet been devised to measure in ad- vance the tendency of new drugs to cause hematologic reactions. Certainly in the case of chboramphenicol, careful animal and human studies on the meta- bolic disposition and toxicity of the drug gave no hint that it might induce severe bone narrow reactions. 1~Iuch thus remains to be done in the important field of drug sensitivity particularly as it relates to the bone marrow and blood. WILLIAM DAMESHEK. [Excerpt from editorial-Blood, vol. 30, No. 2 (August), 19&7} EXHIBIT B During a recent trip to the Far East where aplastic anemia appears to be unduly prevalent (perhaps because the use of chloramphenicol is relatively un- inhibited), it was evident that the incidence of PNH was also unduly high. Thus, in Manila, the Philippines, Dr. Allen Caviles of the Philippines General Hos- Smadel, J. E. : Am. J. Med. 7: 671, 1949. The U.S. Food and Drug Administration has collected about 40 cases (with 9 deaths) in which $evere hematologic reactions occurred following use of chioramphenicol. Smiley, R. K.. Cartwiight, G. E. and Wintrobe ,M. M.: J.A.M.A. In press. Wilson, L. E., Harris, M. S., Henstell, H. IL, Witherbee, 0. 0. and Kahn, Julius: J.A.M.A. 149: 231, 1952. Chloromycetin from the Hematologist's Point of View, Detroit, Parke, Davis, 1952. PAGENO="0267" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2401 pital informed me that he had observed 71 cases of aplastic anemia in three years, 53 of which had been subject to follow-up; one of these had developed PNH. In the same period, nine cases of PNH had also been observed, five of them hav- ing been previously diagnosed as aplastic anemia. Dr. Tien-tse Hwang in Taipei, Taiwan, reported that he had observed 10-14 new cases of aplastic anemia an- nually, as well as seven cases of PNH at the two hospitals where he worked, one of them the large National Defense Hospital. Among the first 10 cases of hypoplastic anemia he had seen in 1906, one of them subsequently developed PNH. From these several observations, the factor of coincidence for the two ap- parently disparate conditions of aplastic anemia and PNH seems unlikely. [Reprinted from J.A.M.A., vol. 174. No. 14; 1853-1854, 19601 EXHIBIT C.-CHLORAMPHENICOL---~A NEW WARNING In one month recently, I saw 4 new cases of aplastic anemia. Although they ranged in age from 3 to 63, and came from different sections of the country, they bad one common denominator: chloramphenicol had been used in the recent past for minor respiratory infections. There was no history of the use of other antibiotics or potentially toxic drugs and since the anemia and the other mani- festations appeared a few months after the last administration of chlorampheni- col, it seemed clear that this drug was responsible for the marrow aplasia. In our recently studied series of aplastic anemia (seen within the past 3 years) 8 of 30 had received significant amounts of chioromycetin, almost invariably for minor infections. Of the most recent 10 cases of aplastic anemia, 5 had followed therapy with chioramphenicol. The tragic thing about all these seriously ill cases, most of whom died, is that the drug need never have been given. It is becoming increasingly clear that chloramphenicol, an excellent broad- spectrum antibiotic, has antimetabolic effects aswell-that is, it may injure the intrinsic "machinery" of certain rapidly proliferating cells, notably of the bone marrow. Thus, Rubin and associates, using radioactive techniques, demonstrated a depressant effect of chioramphenicol on erythropoiesis; this occurred in 5 of 15 subjects receiving ordinary doses and in all of 4 cases with cancer who were given unusually large doses of the drug.1 In another study by Saidi and Waller- stein 2 10 of 22 cases treated with chioramphenicol for various infections devel- oped striking vacuolization of nucleated red cells in the bone marrow, associated with a maturation arrest phenomenon and marked reduction in blood reticulo- cytes. The possibility is present that these temporary changes could go on to complete or partially complete destruction of the bone marrow providing (a) that sufficient drug was used or (b) the patient became sensitized in some manner and was given a second course of drug therapy at another time. It is thus con- ceivable that both an immediate or direct effect as well as an indirect or hypersensitivity mechanism may be responsible for the marrow reactions seen. Following the introduction of chloramphenicol in 1948 and the reports of the first cases of aplastic anemia between 1950 and 1952, many editorials and reports of special ad hoc meetings appeared. Evidently the medical profession was pro- foundly influenced; in any event, the sales of chloromycetin declined sharply, reaching their lowest level in 1954. This lull was short-lived. By 1958, there was a five-fold increase in the sales of the drug and by 1960, enough chloramphenicol was being distributed, and presumably used, in the United States to supply 3,732,416 persons with 10 Gm. courses of the drug! (These data were supplied through the kind cooperation of Dr. Harry Carnés, Parke Davis & Co., Detroit, Mich.) To those of us who see cases of aplastic anemia following the use of various possible etiologic agents, chloramphenicol stands out as the most important single historical factor. To be sure, evaluation of histories and even of statistics relating to both the incidence of aplastic anemia and of chloramphenicol as an etiologic agent is difficult. Nevertheless the importance of the chloramphenicol-aplastic anemia relationship persists, and one must naturally be concerned with the possibility that an increased incidence in aplasti~ anemia may result as use of the drug increases so rapidly. Is the pharmaceutical house which introduced and for there can be no question that this respected company has gone to every effort popularized the use of chloramphenicol to be taken to task? This seems unfair to ferret out statistics of case reports, to carry out experimental work in various animals and even to note the effects of marrow transplantation in chemically induced aplastic anemia of monkeys. 1 Rubin, D.; Weisberger, A. S.; Botti, R. B.; and Storaasll, J. P.: Changes In Iron Meta- bolism in Early Chioramphenicol Toxicity,, J. Clin. Invest. 37: 1286-1292 (Sept.) 1958. 2 S~1di. P., and Walierstein, R. 0.: Effect of Chioramphenicol on Erythropolesls. To be published. PAGENO="0268" 2402 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Is it the physician, then, who is largely responsible? In a way he is, for with out his prescription, the drug would not be administered. Certainly, if he regards chloramphenicol lightly, to be dispensed like aspirin, for every minor cold and respiratory infection, he is not without blame. But are there certain mitigating factors? Some say that a person ill is a person to be treated! The urge to make a person comfortable and to cure his illness as quickly as possible is an urge each of us has. It follows then that a good antibiotic of the broad spectrum variety and which can be readily administered is something to be used at every opportunity. This is part of the mores in this affluent society of ours. We have potent medicines; the patient is ill; we must treat! The days of simple herb medicines and of simple galenicals have long since passed. More often than not, the newer synthetics, most of them composed of molecules with benzene rings and nitrogen, NH, NH2, or NO~ groupings-are used, and all of them, it should be said, are potentially harmful. What then can be done? A few suggestions may be offered: (1) Physicians must be warned, and in no uncertain terms by means of articles, editorials, meetings, announcements; not once, but repeatedly that chloramphenicol is riot only a potent antibiotic but apparently an antimetabolite as well, having effects noit only on bacteria but on the bone marrow. (2) By some means, whether by regulation or by self-discipline, promiscuous use of the drug should be avoided and its use re- stricted to inipeilisg circumstances, i.e. for conditions in which no other anti- biotic is currently effective. One realizes that this is more easily said than done, knowing the physician's individualistic nature. (3) The patient and the patient's family must be warned, either by the physician or by the druggist that this is a powerful drug; that it should be used only once; that its repeated use may result in serious blood reactions; that it should not be kept in the bathroom cabinet and used again if an apparently similar disorder supervenes. (4) The manufacturing drug house should instruct its detail men, our ubiquitous mentors, not to minimize the dangers of the drug, and to emphasize its value for certain specific conditions, and not for the whole gamut of infectious diseases. The journal advertising could be made more forceful regarding the necessity for guarding against use of the drug indiscriminately, and especially in minor infec- tions, or in repeated courses; or off the bathroom closet shelf. It might be wise for the patient or his family to have some knowledge of what antibiotic is being used in a given case. Perhaps we physicians might also con- sider, at least for many of the acute, self-limited infections, the more conser- vative course (radical by present-day standards) of giving no potent medications at all, but rather such symptomatic care as aspirin, fluids, and the like. After all, the body defenses are usually capable of handling most acute upper respira- tory infections. In any event, something must be done to reduce the incidence of grave insult to the bone marrow produced by some of the antibiotics. The practicing physician would do well to think twice before prescribing a potent antibiotic and to ask himself "Is this drug really necessary ?" WIu~IAM DAMESHEK, M.D. Dr. DAMESHEK. This is one on leukemia I did not put in. Senator i~ELSON. If you will furnish that to the reporter. Dr. DAMESHEK. Fine. (The article referred to follows:) [Reprinted from the New England 3ournal of Medicine, Z77: 10G3-1005 (Nov. 0), 1967] HYPOPLA5TIC ANEMIA AND MYELOBLASTIC LEUKEMIA FOLLOWING CHLORAMPHENICOL THERAPY*_REPORT OF THREE CASES Mark J. Brauer, M.D.,1' and William Dameshek, M.D.~ A pathogenic relation betw-een aplastic anemia and myeloblastic leukemia has long been suspected. It is well known that certain agents capable of producing *From the Blood Research Laboratory, New England Medical Center Hospital, and the Department of Medicine, Tufts University School of Medicine (requests for reprints should be addressed to Dr. Dameshek at the Mount Sinai Hospital, 100th Street and Fifth Avenue, New York, New York 10029). Supported by a fund from the grant (CA 04168-09) from the National Cancer Institute, National Institutes of Health, United States Public Health Service. tAttending physician and hematologist, New England Medical Center Hospital; senior instructor in medicine, Tufts University School of Medicine. ~Attending hematologist, Mount Sinai Hospital; professor of medicine, Mount Sinai School of Medicine, New York City. PAGENO="0269" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2403 aplastic anemia in man caii also induce leukemia. Prime examples are benzene1' and irradiation.8'4 In addition, cases of leukmia developing during the course of hereditary hypoplastic syndromes have been recorded.5'° The broad-spectrum antibiotic chloramphenicol7° has become the most commonly cited cause of acquired aplastic anemia. To date, only 1 ease report of acute myeloblastic leukemia following aplasia secondary to chioramphenicol administration has been published.10 The purpose of this communication is to present 2 additional cases of chioramphenicol-induced aplastic anemia of long standing that developed into acute myeloblastic leukemia. In addition, a patient in whom an indolent, pancytopenic myeloblastic leukemia followed the prolonged use of chioram- phenicol for the treatment and prevention of head colds is reported. CASE REPORTS CASE 1. J.D. (N.E.M.C.H. 178-415), a 38-year-old woman, was initially inves- tigated 8 years before admission when, after a 6-week course of chloramphenicol (total dose, 84 gm), marked pallor developed. The pretreatment hemoglobin level was 12 gm per 100 ml, and the white-cell count 8000. Shortly after chlor- emphenicol therapy the hemoglobin was 7.2 gm per 100 ml, the white-cell count 2200, and the platelet count 100,000. Peripheral blood examination showed a predominance of mature lymphocyites (69 per cent) with no primitive white- cell forms. In addition there was mild red-cell anisocytosis. Aspiration of the bone marrow produced a fatty hypocellular sample with small spicules. The myeloid~erythroid ratio was increased, primarily owing to severe red-cell hypo- plasia. Granulocytic precursors and megakaryocytes were also decreased in number. No vacuolization of bone-marrow elements nor increase in immature forms was apparent. Lymphocytes and reticular elements were relatively in- creased. A diagnosis of chloramphenicol-induced hypoplastie anemia was made, but no specific therapy was initiated. Splenectomy was performed in 1959 because of worsening pancytopenia and bleeding. The spleen was of normal size and showed no abnormal features. Bone- marrow aspiration was not repeated. After splenectomy there was no marked change in the peripheral blood picture. The hemoglobin values ranged between 6 and 8 gm per 100 ml, and the white-cell counts around 2500. Treatment con- sisted of adrenocorticosteroids, androgens and occasional blood transfusion until 1963, when the patient gave birth to a normal male child. Thereafter, trans- fusion requirements rose sharply. This was attributed primarily to decreased red-cell production. Thirty-eight units of whole blood were given from March, 1965, until 1966. A hemogram performed in April, 1966, revealed a hemoglobin of 7.0 gm per 100 ml, a white-cell count of 15,000 and a platelet count of 50,000. The differential count showed a predominance of immature blast forms, some of which contained Auer rods. On clinical examination in May, 1966, the patient was extremely pale and incoherent, with marked purpura. There was evidence of eonge~tive heart failure and a severe neurologic deficit related to brain hemorrhage. The peripheral white-cell count was 37,900, with 15 per cent inyeloblasts. Aspiration of the bone marrow produced a specimen almost totally replaced by myeloblasts. Shortly after admission the patient died. Permission for post-mortem examination was not granted. 1 DeGowin, R. L. Benzene exposure and aplastic anemia followed by leukemia 15 years later. J.A.M.A. 185: 748-751, 1963. 2 Vigllani, E. C., and Saita, G. Benzene and leukemia. New Eng. J. Med. 271: 872-876, 1964. Cronkite, E. P., Moloney, W., and Bond, V. P. Radiation leukemogenesis: analysis of problem. Am. J. Med. 28: 673-682, 1960. Lawrence, J. S. Is there incriminating evidence for . . . irradiation leukemogenesis. J.A.M.A. 199: 1049-1054, 1964. ~ Cowdell, R. H., Phizackerley, P. J. H., and Pyke, D. A. Constitutional anemia (Fan- coni's syndrome) and leukemia in two brothers. Blood 10: 788-801, 1955. o Garrlga, S., and Crosby, W. H. Incidence of leukemia In families of patients with hypoplasla of marrow. Blood 14: 1008-1014, 1959. Registry on Adverse Reactions, Council on Drugs, American Medical Association. 8 Leiken, S. L., Welch, H., and Gui G. H. Aplastic anemia due to chioramphenicol. Clin. Proc. Child. Hoop. 17: 171-181,1961. °Yunis, A. A., and Bloomberg, G. R. Chloramphenicol toxicity: clinical features and pathogenesis. Prog. in Hemat. 4: 138-159, 1964. 10 Mukherji, P. A. Acute myeloblastic leukemia following chloramphenicol treatment. Brit. M. J. 1: 1286, 1957 PAGENO="0270" 2404 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY This patient with chronic aplastic anemia after chioramphenicol was observed for eight years. The terminal development of acute myeloblas'tic leukemia sug- gested a causal relation. CASE 2. L.R. (N.E.M.C.H. 169-853), a 57-year-old woman, was first seen 15 years before admission for recurrent attacks of dysuria diagnosed as "cystitis." Multiple urologic examinations gave no evidence of obstruction Or intrinsic ab- normality. For 8 years before admission it had been her custom to take chlo- ramphenicol for her attacks. Short courses taken ad liii always produced im- pressive clinical improvement. Over this period an estimated 500 to 700 capsules were consumed (approximately 175 gm). Routine blood counts performed during annual examinations were reported as "within normal limits." An anal fistula developed after hysterectomy in February, 1964. She was inter- mittently treated with chioramplienicol until May, with little improvement. At that time the hemoglobin level was 8.4 gm per 100 ml, and the white-cell count 2500. No platelet count was recorded. A sternal puncture yielded a fatty speci- men with marked hypocellularity. Erythroid precursors were almost totally absent. Granulocytic elements, although diminished, showed no "shift to the left" nor clusters of immature cells. No vacuolization of young forms was seefl. Megakaryocytes were also markedly diminished. A diagnosis of chloramphenicol- induced bone-marrow hypoplasia was made. The patient was treated with adrenocorticosteroids, androgens and blood trans- fusions from August, 1964, until February, 1965, without improvement of blood findings. On examination in February, 1965, she appeared chronically ill with marked pallor, widespread purpura and pulmonary congestion. The liver and spleen were not enlarged. A major finding was a massive perirectal abscess. The hemo- globin was 7.3 gm per 100 ml, the white-cell count 5800, and the platelet count 21,000. The differential count showed 25 per cent myeloblasts. Bone-marrow aspiration revealed a hypercellular specimen completely replaced by myeloblasts. Therapy with 6-mercaptopurine had no beneficial effect, and she died in an- other hospitaL No post-mortem examination was performed. In this case, chronic cliloramphenicol ingestion was held responsible for the development of aplastic anemia. Acute granulocytic leukemia was observed one year later. CASE 3. V.D., a 61-year-old woman, was first seen on October 26, 1964. At a routine checkup on October 5, when she was asymptomatic and showed no physical abnormalities, a blood count revealed leukopenia and granulocytopenia. The history revealed further that the patient had been plagued by several "heavy colds" every year and that she had been advised by her family doctor in August, 1963, to take chioramphenicol, 4 capsules daily, "at the earliest sniffle." In the course of the past 14 months she had taken by actual count 60 capsules (15 gm) of the drug. There was no history of any other drug or chemical contact and no history of x-ray exposure except for a few single dental x-ray examinations. The family and past histories were noncontributory. On examination the patient looked very well. However, the liver edge was palpable 3 fingerbreadths below the right costal margin, and a few ecchymoses were present. The hemoglobin was 11.5 gm per 100 ml, the red-cell count 3,890,000, the hematocrit 37 percent, reticulocyte count 2.2 percent, and the platelet count 225,000; the white-cell count was 2200, with 15 percent neutrophils, 80 percent lymphocytes; and 5 percent monocytes. The sedimentation rate was 10 mm per hour. Bone-marrow aspiration revealed hypocellularity to normocellularity. Large numbers of primitive, pale-staining cells were present, and primitive monocytoid cells were increased. The diagnosis of hypoplasia of the bone marrow, with primitive cell (myeloblastic) leukemia, was made. An alternative diagnosis of "maturation arrest of the granulocyte series" induced by chloramphenicol was entertained. No therapy was advised except for discontinuance of the antibiotic. The patient was observed at intervals during the following year. During the first 6 months she continued asymptomatic. Gradually, increasing pancytopenia developed. Symptoms of gingival hyperplasia, bouts of diarrhea and bouts of fever occurred in June and July, 1965. In mid-October, a severe nasopharyngitis, (ellulitis of the left ear and rapidly progressive anemia appeared. The bone marrow- w-as now- almost completely replaced by mnyeloblasts and promyelocytes. Therapy with 0-mercaptopurine w-as instituted, and antibiotics and transfusions w-ere given. In early December, 1965, generalized sepsis due to a coagulase-posi- tive staphylococcus was present, and the patient died on December 7. PAGENO="0271" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2405 This woman of sixty-one, always in good health except for head colds, took 60 capsules of chloramphenicol during fourteen months as a prophylactic meas- ure against further colds. This was successful, but pancytopenia and the indica- tions in the bone marrow of hypoplasia and of primitive cell (myeloblast) leukemia developed. Chloramphenicol was discontinued. The patient was well for about six months, and then the various clinical manifestations of acute leukemia developed and she died fourteen months after the diagnosis had been made. D150U5510N Hypoplastic anemia has been defined in various ways by various observers. We prefer to reserve this term for cases showing pancytopenia of the blood and well defined hypoplasia of the bone marrow. Those with increased cellularity of the marrow and blood pancytopenia may indicate other conditions ranging from maturation arrest to the DiGuglielmo syndrome or leukemia. In the aplastic anemia that follows the administration of chloramphenicol, 2 main forms may be discriminated. In the first the onset is acute, seemingly dose related and frequently associated with a normocellular bone marrow, which exhibits vacuol- ization of erythroblasts and granulocytic precursors. Moderate anemia, retic- ulocytopenia, increased plasma iron and delayed plasma iron clearance have been observed in this setting.9 Unless the dosage of drug has been inordinately high, this type is usually reversible when the drug is discontinued. Work in mammalian cell-free systems suggests that prolonged exposure to chloramphen- icol and high blood levels of unbound drug are both important factors in in- hibiting protein synthesis through interaction with messenger RNA. This may help to explain the bone-marrow hypofunction.'1 The second form, or "late-onset type," may not be dose related. It is character- ized mnorphologically by hypoplasia or severe aplasia of the bone marrow. In most patients manifestations of marrow depression develop after the drug has been stopped, often weeks or months later. in such cases, indications of marrow injury remain long after the last trace of the drug have disappeared. Conceivably, injury to a large number of stem cells might explain such an effect. An interval would then be required before the stem-cell pool became depleted and cytopenia was manifest. That some patients, because of ,a metabolic abnormality or de- ficiency, may be more susceptible than others to the action of cliloramphenicol or its degradation products, is an attractive but unproved possibility. In fact, there is no ready explanation at present for the apparent susceptibility of some persons to the development of serious disorders of the marrow after chloram- phenicol or other agents. The development of leukemia in the course of aplastic anemia is of consider- able interest. Although most large series of acquired aplastic anemia ~ contain no such reports, examples may be found with benzene toxicity,"2 after radiation,3'4 after administration of phenylbutazone,15" during the hypoplastic phase of par- oxysmal nocturnal hemiglobinuria" and in hereditary hypoplastic syndromes.5'6 The development of paroxysmal nocturnal hemoglobinuria during aplastic ane- ~ is of additional interest. This may be but another example of the develop- ment of abnormal cell lines in a previously injured bone marrow. The induction of leukemia by chemicals (including drugs) may be mediated through chromosomal injury. In line with this is the recent observation by Cas- toldi and Mitus of chromosomal vacuolization in patients receiving chioram- 11 Weisberger, A. S., Wolfe, S., and Arementrout, S. Inhibition of protein synthesis in mammalian cell free systems by chioramphenicol. J. E'per. Med. 12: 101-181, 1964. 12 Lewis, S. M. Course and prognosis in aplastic anaemia. Brit. M. J. 1: 1027-1031, 1965. " Mohier, D. N., and Leavell, B. S. Aplastic anemia: analysis of 50 1: 1027-1031, 1965. 14 Scott, J. L., Cartwright, 0. E., and Wintrobe, M. M. Acquired aplastic anemia: analysis of thirty-nine cases and review of pertinent literature. Medicine 38: 119-172, 1959. "Bean, R. H. D. Phenylbutazone and leukemia: possible association. Brit. M. J. 2: 1552-1555, 1960. 16 Dougan, L., and Woodliff, H. J. Acute leukaemia associated with phenylbutazone treatment: review of literature and report of further case. 111. J. Australia 1 : 217-219, 1965. "Hartman, H. C., and Jenkins, D. E. Personal communication. 18 Lewis, S. M., and Dacie, J. V. Aplastic anemia: paroxysmal nocturnal haemoglobinurla syndrome. Brit. J. Haemat. 13: 236-251, 1967. `9Castoldi, G., and Mitus, W. J. Personal communication. PAGENO="0272" 2406 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY phenicol. Inconstant chromosomal changes have been observed in several series of cases of acute leukemia.20'2' Similar changes have been found to follow radia- tion4 and benzene 2' and to occur in hereditary states.23 The chromosomal vacuoli- zation seen after chloramphenicol may be a comparable lesion. Another possible explanation is that the leukemia is a secondary, perhaps reparative, response to aplastic anemia. A tendency to neoplasia of hypoplastic tissues has been recog- nized repeatedly in human pathology. Examples include atrophic gastritis and leukoplakia. Perhaps analogous to the potential of these disturbed tissues to transform into carcinoma is the eventual emergence of leukemia in the chronically aplastic bone marrow. Finally, another explanation for the development of leukemia in these cases de- serves consideration. Aplastic anemia and leukemia may both be thought of as growth disturbances of the bone marrow (myeloproliferative disorders). Thus they may occur either together or sequentially as phases of the same patho- genetic mechanism. Block et a1.~ had the unique opportunity to observe 12 patients for as long as twenty-seven months before the development of acute myelogenous or stem-cell leukemia. Most of the patients in this "preleukemic" phase displayed variable degrees of marrow hypoplasia as well as peripheral cytopenias. Blair and his associates 23 reported a similar experience in 16 cases of "atypical leukemia." Thus, it may be hypothesized that in some cases aplastic anemia and leukemia simply represent different expressions of the same fundamental disturbance. It is now reasonably clear that an "insult" to the bone marrow, as from chlorampheni- col or another chemical, may either destroy totally or partially. Partial destruc- tion of some cells may serve only to "knock out" one or two enzyme systems but not prevent cell reproduction. Under these circumstances, a new- self-perpetuating cell line (clone) may develop-that is, leukemia, when white cells are concerned, or paroxysmal nocturnal hemoglobinuria with erythroblastic involvement. We have recently remarked upon the relation of paroxysmal nocturnal hemoglob- inuria and aplastic anemia, particularly in association with chloramphenicol toxicity.26 The syndrome of aplastic anemia, regardless of cause, may lead to early death from hemorrhage or infection or may result in chronic bone-marrow malfunc- tion. The development of leukemia and of paroxysmal nocturnal hemoglobinuria has been associated with the latter process. It is evident that chioramphenicol can result in this sequence of events. The continued widespread use of this drug, particularly in the less developed countries, and even among the highest-income groups of this affluent country, often for trivial reasons, may be a factor in the causation of some forms of leukemia, particularly of the relatively indolent, hypoplastic type. SUMMARY AND CONCLUSIONS The development of myeloblastic leukemia during the course of chiorampheni- col-induced pancytopenia in 3 patients is described. Leukemia has been reported in a wide variety of clinical states commonly characterized by variable degrees of bone-marrow hypoplasia. Factors responsible for the development of aplastic anemia and drug-induced leukemia are considered. Chloramphenicol, by primary or secondary means, appears casually related to the blood dyscrasias in the cases presented. As stated so many times, indications for the routine or even common use of this drug in the treatment of infection must always be carefully scrutinized. Senator NELSON. I am sorry to interrupt you. Dr. DAMESHEK. Fine. I do not mind at all. 2°Baikie, A. G.. Jacobs, P. A.. McBride. J. A., and Tough, I. M. Cytogenetic studies in acute leukaemia. Brit. M. J. 1 : 1564-1571. 1961. 2'Kiossoglou, K., Mitus. W. J.. and Dameshek, W. Chromosomal abberrations in acute leukemia. Blood 26: 610-641, 1965. 22 Pollini, G., and Colombi. R. Ii donno cromosomico midollare nell' anemia aplastica benzolica. Med. d. lavoro 55: 241-255, 1964. 23 Bloom, G. E.. Warner, `S., Gerald. P. S.. and Diamond, L. K. Chromosome abnormalities in constitutional aplastic anemia. New Eng. J. Med. 274: 8-14, 1966. 24 Block, M., Jacobson, L. 0., and Bethard. W. F. Preleukemic acute human leukemia, J.A.M.A. 152: 1O18-102S, 1953. 2'Blair, T. R., Bayrd, E. D.. and Pease, G. L. Atypical leukemia. J.A.M.A. 198: 21-26. 1966.. `~ Dameshek, W. Riddle: what do aplastic anemia, paroxysmal nocturnal hemoglobi- nuria (PNH) and "hypoplastic" leukemia have in common? Blood 30: 251-254, 1967. PAGENO="0273" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2407 As I say, I discussed in an editorial of the Journal of the American Medical Association in 1960 something about the responsibilities in- volved. Who is responsible and whose responsibility is it in the use of this drug. Is it, I say, the pharmaceutical house which introduced and popularized the use of chloramphenicol to be taken to task? This seems unfair because there can be no question that this respected company has gone to every effort to ferret out statistics of case reports, to carry out experimental work in various animals, and even to note the effects of marrow transplantation in chemically induced aplastic ane- mia in monkeys. Is it the physician, then, who is largely responsible? In a way he is, because without his prescription the drug would not be adminis- tered. Certainly, if he regards Chloromycetin lightly, to be dispensed like aspirin for every minor cold and respiratory infection, he is not without blame. But are there certain mitigating factors, which I have already men- tioned? Some say that a person ill is a person to be treated. The urge to make a person comfortable and to cure his illness as quickly as pos- sible is an urge each of us as physicians has. It follows, then, that a good antibiotic of the broad spectrum variety and which can be readily administered is something to be used at every opportunity. We have potent medications. The patient is ill. We must treat him. The days of simple herb medicines and galenicals-that is, ordinary medications made from herbs and other sources-those days have long since passed.. More often than not the newer synthetics are almost invariably com- posed of molecules of benzene rings and nitrogen, .flH, NH2, NO2 groups and all of them it should be said are potentially harmful. So, I talked about these responsibilities hut I must say that since 1960 I have modified my stand a little bit. I say, in retrospect, this by no means set- tles the question. The numerous warnings regarding the indiscriminate use of Chioromycetin have been practically without effect. - Senator NELSON. The `printed warnings have been practically with- out effect? Dr. DAMESHEK. As I see it. It is now about time to consider more radical measures such as restriction of the drug for a few specific indi- cations. Should one stop its use altogether,? This would surely be a wrong thing to do because the drug is a potent antibiotic and has a well-defined usage. Should one simply continue with a warning state- ment in the advertising and in the package ? These seem to have little, if any, value. Should one attempt restriction of the use of the drug to various well-defined conditions? This, I would be in favor of, but who is to do the restricting? Should it be done by governmental means, either at National or State level? Should it be done by the practicing physician, or by whom? I would, myself, be in favor of including on the prescription blank for Chloromycetin a statement as to the diag- nosis of the condition. The druggist lookingat the prescription blank could then question, if need be, the physician. as to the indication. This might hold up some of the prescription writing. This is one way, of course, but you have already, Senator, pointed out another way, through the hospital, where many patients go. That is a possibility. And, of course, we as physicians do not like restrictions. We are highly individualistic. But, on the other hand, we do allow the Government 81-280 O-68-pt. 6-iS PAGENO="0274" 2408 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to restrict us in the use of opiates and other such materials through a registry, and one wonders whether this sort of thing might be appli- cable here, that certain drugs like Chloromycetin might have to be written under a specific ruling or registry where the druggist could then control, to some extent, the situation. Physicians are, of course, jealous of their prerogatives and perhaps rightly so. They are by nature individualists who object reflexly to restriction, but it is doubtful whether they would mind very much putting down the patient's diagnosis in general terms on the prescrip- tion blank. However, I am not so sure about that statement. To re- strict that drug solely to hospital practice, as you suggest; this is possible. It may be of some interest to say that about half the doctors in this country are in hospital practice one way or another. *Senator NELSON. About half? Dr. DAMESHEK. Yes; I would say so. About 100,000 of the 200,000 doctors, M.D.'s, in this country are in hospitals. That includes interns, residents, and the like; full-time physicians. Senator NEI50N. When you say limit it to hospital practice, do you mean limit it to administration to patients in a hospital? Dr. DAMESHEK. I suppose if in a hospital one of the rulings of the drug committee or of the administration were that Chloromycetin should be restricted to diseases one, two, and three, this might then cut. out some of the prescribing for this drug. This would cut out some of the prescribing for this drug for simple infections; but on the other hand, we realize that the simple infections-acne, head colds, grippe- are not treated in hospitals. They are treated on the outside. Senator NELSON. Dr. Barbara Moulton, a physician who was for- merly with the FDA, stated that in the case of a relatively small number of drugs, among which she included chloramphenicol, there should be established a special category of medicines that should be prescribed only with the written approval of a consultant except in emergencies or special circumstances. Would that. be feasible? Dr. DAMESHEK. Well, I think that is a bit unwieldy and I do not think that doctors by and large would like it. This would mean that every patient in a hospital or on the outside who has a disorder of an infectious type, and in which the physician wants to use the drug, would have to call in a consultant by law. I think that is a bit unwieldy. Senator NELSON. If it is the case as you state, and as I believe both Dr. Lepper and Dr. Best have w-ritten. that there are many cases where the drug is being prescribed w-here it just simply is not indicated, I as- sume that this occurs because the doctor is not really aware of the cau- tion which must be exercised, or for some reason does not believe that the warnings are very serious. Would it not be possible perhaps to have a. committee decide that there are some categories of drugs such as this one which produce very serious side effects in a certain per- centage of cases and that with regard to those drugs some special re- quirement be devised for the doctor in the prescribing of it to alert him that this drug is one in which there are serious side effects. You could probably notify all pharmacists so that there would be a couple of checks on the prescribing of these drugs. For example, prescription of such a drug could be limited to circumstances so that at least the doctor has a chance to take a second look if he is not aware of the PAGENO="0275" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2409 proper indications for the drug or has made a mistake. Would it be worth while to have some kind of control that would not be too cumber- some, but that still would control overprescription? Dr. DAMESHEK. Well, Senator, I think you are absolutely right. I have come to the reluctant conclusion in the last few years that some type of restriction is essential in the use of this drug. How that restric- tion is going to take place or should take place, I am not sure. Cer- tainly, physicians do not object to a registration number for the pre- scription of narcotics and, when they write morphine sulphate, they have to put their registration number down and they have to write out who it is being supplied for, and so on. The druggist then knows that this is a special type of prescription and he will not give it out for any- thing but a well-defined cause. He knows that. So there is restriction already in the medical profession with respect to certain drugs and I can see myself that this idea of a special registry for special drugs which have an undue proportion of serious reactions, I can see that such a registry could be begun and utilized. Exactly how, I do not know, either. Senator NELSON. Do the doctors find any particular difficulty in complying with the regulations applicable to the prescription of mor- phine or any other narcotic? Is it a particularly cumbersome proce- dure for them to have to follow? Dr. DAMESHEK. No. I do not think so. Once a year one has to make out a check for $1 to the U.S. Government on a blank furnished by the Government with respect to narcotics, and one has to put down on a prescription your registration number and the name and address of the patient and your own name and address. That is about it. And that is not much of a restriction, I do not think. Senator NELSON. Would you have any guess as to how many drugs ought to be in such a special category? You include chloramphenicol as one of those special drugs. Do you have any idea of what we are talking about in terms of numbers-half a dozen, a dozen-or any notion about which drugs you would include? Dr. DAMESHEK. I would think there might be half a dozen to 10 drugs or so that might come in this category. Senator NELSON. If the procedure followed with respect to certain other drugs like morphine is effective, why would not it be feasible, after appropriate consultation with members of the medical profes- sion and the FDA, to agree that there are a half dozen or more drugs which ought to be used with special caution and, therefore, they would be handled in the same way that morphine is handled? Would that be feasible, in your judgment? Dr. DAMESHEK. Well, I think there is something good that might be said about this. I personally do not think it would restrict any- * one's individual liberty to do this sort of thing and I think it might. be distinctly valuable. Senator NELSON. Would it have in your judgment, the effect of put- ting a doctor on notice that the prescription of such a drug has been considered a serious enough matter so that there is a `special require- ment with respect to this drug? Is it your judgment that he would then be alerted to examine the literature carefully, if he had not al- PAGENO="0276" 2410 COMPETITIVE PROBLEMS IN THE DRLrG INDUSTRY ready done so, to be sure that the drug was really indicated in the case for which he was prescribing it? Dr. DAMESHEK. I would think it would conceivably act as a brake on the practicing physician. I could conceive that.. If, in addition, the physician were asked to put down on the prescription blank the name of the disease, that might help even more. The two together, that is. Senator NELSON. I am just exploring this extemporaneously here. You mentioned that a doctor might be reluctant to write the diagnosis out so that the patient would see it. Is this something that a physician might be concerned about simetimes? Dr. DAMESHEK. No. I do not see how a doctor can be reluctant about putting the disease down if it is typhoid fever or a severe infec- tion. The only time I suppose he might be reluctant would be in the case of acute leukemia where infection, serious infection, may de- velop due to one cause or another. He might not like to put the diagnosis of acute leukemia down, but on the other hand, he could put down serious infection, I suppose. Senator NELSON. If the doctor followed the same procedure as he would with morphine so that pharmacists would also know that it was a special case, and at the time the pharmacist would make a specific record on a form as to the diagnosis, do you think that would be helpful? Dr. DAMESHEK. Yes. I think it would reduce-certainly it would stop, I would think, the use of the drug for cases of acne, colds, grippe, influenza, and minor infections in general. It seems to me it would. Now, the question of the mechanics of this I am not so sure about. I do not want to try to make any exact recommendations. That is not in my line really. Mr. GOImON. Dr. Dameshek, if the doctor would under ordinary con- ditions prescribe this drug, say, for a cold, why would writing it down on a prescription blank discourage him from doing what he had in- tended to do or would have done in the first place? Dr. DAMESHEK. Because I would think if the doctor knows that he should not be giving this drug for a cold, and, therefore, if he puts down a cold and the patient happens to be one of these rare birds that develops aplastic anemia, this prescription and the cold might be held against him in future times. Mr. GORDON. Well, are you saying, Dr. Dameshek, that the doctor frequently knows he should not be prescribing Chloromycetin for a particular illness and yet he still does so? Dr. DAMESHEK. I dislike to say anything against the medical profes- sion, being a member of that august profession myself. I doubt that the doctor is ignorant of all the statements that have been made over the years about Ohioromycetin. So that this is what I base my state- ment on. Senator NELSON. Might he not have been influenced by the adver- tising which is designed in such a way as to indicate that it is a mar- velous antibiotic and has over the years covered up the side effects to some extent? Unless the drug company wasted its money, then the advertising must have some influence. PAGENO="0277" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2411 Dr. DAMESHEK. Yes, I suppose so, but advertising might be con- strued as a form of brainwashing and I doubt that intelligent people, whether they are presidential candidates or doctors, should be brain- washed to that extent. Senator NELSON. But, they might be. Dr. DAMESHEK. Oh, yes. Senator NELSON. You were just near the end of your statement. Dr. DAMESHEK. Should a simple-I say here in my typed state- meat "to restrict the drug solely to hospital practice would not do very much because about half of the doctors in the country are in hospitals and they are apt to make as many errors of judgment in this regard as outside physicians." Well, I think it might do some- thing. We discussed this previously. Should a simple method such as including the diagnosis on a prescription blank not prove successful, then a more radical approach might have to be used-one which al- most completely restricts the drug to situations which are wholly ac- ceptable for chloramphenicol therapy and for chloramphenicol ther- apy alone, as determined by one or another agency or committee. `When lives are to be placed in jeopardy, even a few lives, one realizes, I should say this, that the reactions to this drug are few, relatively few, in comparison to the number of administrations, and this has been pointed up by many as an excuse for giving the drug. But in a democ- racy such as ours, every life is worth a great deal and the individual who does get this disease, aplastic anemia, is more apt to die than not, and, therefore, it seems to me that, even though the reactions are very few, the lives that are lost from this drug, whether they are 100 or 200 a year in this country-I do not know the statistics-those are well worth saving and since the great majority of drug reactions have occurred in the past in response to the use of the drug for minor in- fections, I think we could save some lives, and each life is worth a lot and when the person does develop aplastic anemia, it is a poor com- fort to that individual to say, well, 10,000 people took the drug and only you got it. Senator NELSON. Well, of course, if it is a case where it should not have been prescribed in the first place- Dr. DAMESHEK. Well, it makes it all the more binding, all the more upsetting. `When lives are to be placed in jeopardy, every precaution however frustrating, is desirable. Well, that is the end of my statement and I- Senator NELSON. Doctor, we appreciate very much your thoughtfu~ statement. I have a few questions I would like to ask. You, as well as a number of other experts in the field, have recited cases of serious side effects occurring in patients who should not have' received the drug in the first place. It has been estimated by some that approximately 3,700,000 people in this country are given chioram- phenicol annually for one reason or another. Considering the restric- tions under which you and many other experts believe the drug ought to be administered, do you have an educated guess as to how many people legitimately should be receiving chloramphenicol in their treat- ment annually? Dr. DAMESHEK. No. I think Dr. Best probably has some statistics. PAGENO="0278" 2412 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I would say no more than maybe 10 percent of the people receiving the drug should have ha.d it. I think Dr. Best in one of his articles takes this thing up and you might ask Dr. Best for a better-or best- answer to this. Senator NELSON. But, it is your belief or guess that of the some 3,500,000 or so who do receive the drug each year only about 10 percent should have received it? - Dr. DAMESHEK. I would think so, but I must confess that this is not a very-it is a guess. That is about it. And, if you want to say educated, all right. I `am agreeable to that. Senator NELSON. Pardon me. I did not understand that. Dr. DAMESHEK. If you want to say "educated" in front of a guess, that is all right. * Senator NET~SON. Doctor, I have here two package inserts on. chloram~ pherncol, in this case Chloromycet.in. One of them is a package insert that is used in this country now a.nd one is a package insert that is used in Great Britain. I would like to have one of the staff show these to you and get your comment as to the adequacy of the warning notices on these package inserts and then submit them for the record. Dr. DAMESHEK. Yes. The warning in the packet for use in this country is, I think, a pretty good warning. It is a direct outgrowth of an ad hoc committee of which I am a member, I think a committee of the National Academy of Sciences, or the National Sc.ience Founda- tion, and we had a meeting, I think, in 1952, and another meeting in, I think, around 1959, and we practically wrote this thing and it was accepted by the pharmaceutical house, Parke, Davis & Co., and it reads as follows, if I may read it: Serious and even fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopeina) are known to occur after the administra- tion of chloramphenicol. Blood dycrasias- Abnormalities of the blood- have occured after short-term and with prolonged therapy with this drug. Bearing in mind the possibility that such reactions may occur, chioramphenicol should be used only for serious infections caused by organisms which are suscep- tible to its antibacterial effects. Chloramphenicol should not be used when other less potentially dangerous agents will be effective, or in the tre~atment of trivial infections such as colds, influenza, viral infections of the throat, or as a prophylactic agent. And then, it says something about precautions: It is essential that adequate blood studies be made during treatment with the drug. While blood Studies may detect early peripheral blood changes, before they become irreversible, such studies cannot be relied upon to detect bone marrow depression prior to development of aplastic anemia. I think that is a very good statement. Mr. GoiwoN. Dr. Dameshek, does the ordinary practicing doctor read it and remember what it says? Dr. DAMESHEK. Now, now look, I cannot look into the minds of ordinary practicing physicians. There are no such things as "ordinary" practicing physicians in our country. There are practicing physicians and they are all people who have had an adequate training, it is hoped, and have passed all the various boards, it is hoped, and so on, aiid they PAGENO="0279" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2413 are all intelligent people, we believe. So that "does he read them?" I do Rot know. Does he bother with them? I do not know. Senator NELSON. Does he see them is, I su~ppose, another question, since, unless it is an injectible, the package insert goes to the drugstore and the doctor does not see it at all, does he? Dr. DAMESHEK. That is right. That may he. I had not thought of that. Yes, Senator. It is a possibility he~ may not even see it. Mr. GORDON. Most important of all, as you stated, he does not pay any attention to it. Dr. DAMESHEK. Now, look, do not lead me into this "does not even pay any attention to it." I do not know. I will not read his mind if you will excuse me on that. I cannot say. Now, you wanted me to read about the British thing, is that right? Senator NELSON. Yes. Dr. DAMESHEK. In the British statement-yes; it is, Parke, Davis & Co., Hounslow, London, England-I can see here no statement about such a warning. There is certainly no warning here, and then there is a statement about side reactions and toxicity, and this is what it reads: "Patients on treatment may complain of dry mouth and less often of nausea, diarrhea, or vomiting, although these are sldom sufficiently severe to justify withdraw.al of the drug. Drug sensitivity reactions are also sometimes encountered. Cases of optic and peripheral neuritis have been reported in patients receiving high total dosage during prolonged therapy. While the incidence of blood dycrasias associated with systemic Chloromycetin therapy is rare, cases of serious disorders including a~p1astic anemia have been reported. As with certain other drugs, adequate blood studies should be made when the patient re- ceives prolonged or intermittent therapy."~ Senator NELSON. Do you consider this as good a warning as the one used in this country, and is it adequate, in your judgment, as a warning? Dr. DAMESHEK. Well, I have not gone over the d:ata for drug sensi- tivity reactions due to chloramphenicol or drug reactions from chlor- amphenicol in England. I do not know if it has been adequate. I would say this is much less adequate than the American warning. And what is more, it takes up in a previous statement the idea that Chloromycetin is effective in a number of clinical conditions and lists a great many, which is true, hut the side reactions and the toxicity are not dilated upon, shall we say. Senator NELSON. Does it say in there that it should not he used for minor infections? I do not recall. Dr. DAMESHEK. No. Senator NELSON. It does not caution against that? Dr. DAMESHEK. No. Senator NELSON. Did you respond to my question: Would you con- sider that an adequate precautionary notice? Or maybe you have not had a chance to study it long enough. Dr. DAMESHEK. Well, to my way of thinking, it is inadequate. Senator NELSON. It is inadequate? Dr. DAMESHEK. Inadequate. (The material previously referred to follows:) PAGENO="0280" 00 00 or~' n0~ m - -iO 0* -u m z n 0 rn Ro 0 -u z 0 L*'i 0 w L~i cli ci ci Cl) PAGENO="0281" COMPETITIVE PROBLEMS Adults Adults should receive 50 mg./kg./day in divided doses at 6-hour intervals. Patients with infections due to moderately susceptible organisms or with severe infec- tions often require doses up to 100 mg./kg./day. 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., septicemia or meningitis), especially when adequate cerebrospinal fluid concen- trations are desired, may require dosage up to 100 mg./kg./day; however, dosage shoulli be reduced to 50 mg./kg./day as soonas clinical response occurs. When pro- longed high dosage is necessary, possible toxic side effects may occur. In this event the dosage should be immediately reduced or discontinued. Premature and Newborn Infants An initial close, of 25 mg./kg. may be given to rapidy achieve effective con- centrations in blood serum. This should be followed by administration of 25 mg./kg./ day in 4 equal doses at 6-hour intervals, which produces and maintains concentra- tions in blood and tissues adequate to con- trol most infections. Increased dosage in these individuals, demanded by severe Infections, should be given only to main- tain the blood concentration within a therapeutically effective range. Full term newborn infants ordinarily may receive from 25 to 50 mg./kg./day equally divided into 4 doses at 6-hour intervals. For comatose or gravely ill, patients, chioramphenicol is available in several forms for parenteral administration. These dosage recommendations are ex- tremely important because blood concen- tration of chioramphenicol in the prema- ture and newborn infant differs from that of an Infant over one month of age. This difference is due to variations in the meta- bolic disposition of this and other drugs in this age group which in turn depends on the maturity of the metabolic function and status of the liver and the kidneys. When these systems are Immature (or seriously impaired in adults) high con- centrations of the drug are found which tend to increase with succeeding doses. Toxic reactions and some fatalities have occurred in the premature and newborn age group, these being associated with higher than recommended dosages. The following summarizes the clinical and laboratory studies that have been made: (1) In most cases therapy with chioram- phenicol 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 chioramphenicol (100 mg/kg. daily or more). (3) The symptoms appeared in the fol- lowing order: (a) abdominal distension with or without emesis; (b) progressive pallid cyanosis; (C) vasomotor collapse, frequently accompanied by irregular res- piration; and (d) death within a few hours of onset of these symptoms. This has been referred to in some institutions as the "gray syndrome." 2 IN THE DRUG INDUSTRY 2415 (4) The progression of symptoms from onset to exitus was accelerated with higher dose schedules. (5) Preliminary blood serum level studies revealed unusually high concen- trations of chloramphenicol after repeated doses. (6) No characteristic pathological changes attributable to the use of chioram- phenicol were found in any of the organ systems, including the hemopoietic system. (7) Termination of therapy upon early evidence of the associated symptomatology frequently reversed the process with com- plete recovery. Infantè and Children with Immature Metabolic Processes In young infants (those between one month and one year of age) and others,in whom immature metabolic processes are suspected, a dose of no more than 50 mg./kg. but not less than 25 mg/kg/day, will produce therapeutic concentrations of the drug in the blood. In this group par- ticularly, the concentration of the drug in the blood should be carefully followed by available microtechniques. SIDE EFFECTS OF CHLÔRAMPHENICOL THERAPY Untoward reactions in man are in- frequent with chloramphenicol. Reactions attributed to chloramphenicoi may be con- sidered under the following headings: Blood Dyscrasias Aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia have been associated with the administra- tion of chloramphenicol. The following statement is quoted from NEW AND NONOFFICIAL DRUGS 1960, evaluated by A.M.A. Council on Drugs, page 82: "Although serious and even fatal blood dyscrasias are known to occur after the administration of chloramphenicol, cur- rent data seem to indicate that these reactions are rare. Blood dyscrasias have occurred with both short-term and pro- longed therapy with this drug. Bearing in mind the possibility that such reac- tions may occur, the physician may use chioramphenicol in the treatment of serious infections caused by organisms which are susceptible to its antibacterial effects. Chioramphenicol should not be used in treating colds, influenza, viral infections of the throat, or as a prophy- lactic agent to prevent bacterial respira- tory disease." When blood counts show unusual devia- tions such as leukopenia or thrombocyto- penia, chloramphenicol should be dis- continued. Gastro-lntestinal Reactions After several days of therapy, glossitis may occur. Stomatitis, when it occurs is generally mild and usually consists of con- gestion and tenderness of the buccal mucosa. This is an indication to stop the drug. On rare occasions, superimposed in- fection by Candida albicans may produce PAGENO="0282" 2416 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Neurotoxic Reactions Headache, mild depression, `dazed feel- ings," internal ophthalmoplegia, mental confusion, and delirium have been de- scribed in patients receiving chlorampheni- col for a variety of infectious diseases. Optic and peripheral neuritides as probable effects of prolonged chloramphenicol ther- apy have been reported. Analysis of these cases suggests that these neurotoxic reac- tions were related both to large total doses of cliloramphenicol and long periods of administration. The range ~f total dosages of chloramphenicol was from 190 to 1600 Gm. Toxic symptoms appeared between 42 days and 22 months after the start of therapy. Five patients had blurred vision as the most prominent symptom and in a sixth the initial complaint was blindness. This latter was the only one with permanent impairment of vision. Periph- eral neuritis resolved in all patients except one, who still had minor residual symptoms thirteen months after onset. If symptoms of decreased visual acuity or peripheral neuritis occur during therapy, prompt withdrawal of the drug is indicated and large doses of oral or parenteral vitamin B complex should be considered. Other Reactions The use of this antibiotic, as with other antibiotics, may result in an overgrowth of nonsusceptible organisms, particularly monilia. Constant observation of the patient is essential. If new infections CLINICAL USE OF CHLORAMPHENICOL Rickettsial Diseases The response of patients with rickettsial infections, including epidemic and murine typhus fevers, Brill's disease, scrub typhus fever, Rocky Mountain spotted fever, and rickettsial pox, has been dramatic with virtual elimination of mortality and marked shortening of the course of illness. Average length of the febrile period after adminis- tration of chioramphenicol is 2 days in patients with epidemic typhus fever and 3 days in those with other typhus fevers. Treatment should be given for a minimum of 6 days or 4 days after temperature returns to normal. Relapse may occur when treatment Is given only for 48 hours early in the disease. This can be prevented by giving additional doses on the fifth and sixth days after the initial course. Also, patients in relapse respond as readily to treatment as do those with primary infection. In patients with Rocky Mountain spot- ted fever, defervescence occurs about the fourth day after therapy is started. Treat- ment should be continued for 24 hours after normal temperature is attained. Other Salmonelloses While chloramphenicol has proved to be a useful therapeutic agent in ameliorating and shortening the clinical course of sal- monella infections other than typhoid, results are not as uniform. Recommended duration of treatment is the same as for typhoid fever. Urinary Tract Infections Treatment for infections of the urinary tract should be based upon sensitivity of bacteria and on anatomic factors con- tributing to the infection. The more com- mon organisms encountered in the urinary tract infections are Esch. coil, A. aerogenes, Ps. aeruginosa, Proteus sp., Staph. aureus and Strep. fecails. Chloramphenicol has been found effec- tive in treatment for about 70 per cent of urologic infections, particularly those caused by Esch. coil, Strep. fecails, and Proteus sp. Relief of symptoms and repeated bacteriological studies should be depended upon to indicate duration of treatment. widespread oral lesions of the thrush type. caused by nonsusceptible organisms appear Diarrhea and irritation of perianal tissues during therapy, appropriate measures have been reported after prolonged admin- should be taken. istration of chloramphenicoi and in pa- tients previously treated with the anti- biotic. These conditions are usually mild and disappear when chioramphenicol ther- apy Is stopped, although occasionally they are protracted. The pathogenesis of pseudomembranous enterocolitis of the Intestines Is not clear, but commonly staphylococci have been Implicated. This severe reaction occurs in patients already ill with pneumonia or peritonitis, or it may follow surgical opera- tion. Pseudomembranous enterocolitis has been reported in a few patients receiving chloramphenicol. Hypersensitivity Reactions Angioneurotic edema and vesicular and mftculopapular types of dermatitis have been reported in patients sensitive to chloramphenicol. Urticaria and vesicular lesions also have been observed. Dermal lesions, usually mild, ordinarily subside promptly when the drug is stopped. The .Iarisch-Herxheimer reaction has been reported after chloramphenicol ther- apy in patients with syphilis, brucellosis, and typhoid fever. In patients with typhoid fever treated with chloramphenicol, several Investigators have recorded a "shock-type reaction" characterized by circulatory col- lapse, attributed to sudden release of typhoidal endotoxin in an already weak- ened patient. Unlike the Herxheimer re- action, temperature is usually depressed, Typhoid Fever but exacerbation of fever has been reported. Recrudescense usually appears within 24 Chloramphenicol has been established hours of the start of chloramphenicol as the drug of choice for. this disease. therapy and persists from 24 to 48 hours. After therapy is started, fever subsides in 3 or 4 days regardless of age, severity of illness, or stage of disease. To lessen pos- sibility of relapse, it is important that therapy be continued for from 8 to 10 days after reaching the afebrile period. Close observation of the patient for complications of the disease, and for aforementioned side effects of the drug, is essential. Results of chloramphenicol treatment for the carrier state are equivocal. PAGENO="0283" COMPETITIVE PROBLEMS Surgical Infections Surgical infections such as post-opera- tive wound infections, cellulitis, infected sinus tract, and peritonitis or Intra-ab- dominal abscess from ruptured intestine, diverticulae, or appendix, usually are due to microorganisms sensitive to chioram- phenicol. The antibiotic is given, adjunc- tiveiy to surgical intervention, In the recommended dosage for an average of from 10 to 16 days. Respiratory Tract Infections Chloramphenlcol may be employed for severe infections of the respiratory tract due to susceptible microorganisms and in the presence of contraindications to other agents. Patients on recommended doses become afebrile in from 18 to 72 hours; roentgenographic clearing will be slower. Meningeal Infections Many microorganisms causing meningI- tis are susceptible to chloramphenicol. The drug's high diffusibility results in effective concentrations in the cerebrospinal fluid. Institution of therapy cannot be delayed until results of laboratory tests are known. Many clinicians consider chloramphenicol alone (or in combination with other effective agents) the drug of choice for meningitis caused by H. ~nfluenzae as almost all strains ate sensitive to this antibiotic. Parenteral dosage is recom- mended until the patient is afebrile, after which oral medication may be used. Medication should be continued for a minimum of seven days to avoid relapse. Miscellaneous Infections Chloramphenicol has proved to be useful and frequently effective in treatment for many diverse infections, including brucel- losis, bartonellosis, relapsing fever, granu- loma inguinale, plague, and ornithosis. Other effective therapeutic agents should receive consideration as the treatment of choice. Whenever definite contraindi- cations to t~iese are known, such as hyper- sensitivity, or clinical response Is poor, the Judicious use of chloramphenicol Is warranted, keeping in mind aforemen- tioned warnings, precautions, and side effects, particularly in patients requiring prolonged or Intermittent treatment. PACKAGE INFORMATION Kapseals No. 379, Chioromycetin, each contain 250 mg. chioramphenicol, sun- plied In packages of 16 and 100. Capsules No. 477, Chloromycetin, each contain 50 mg. chloramphenicol, sup- plied In packages of 25 ar.d 100. Capsules No. 480, Chloromycetin, each contain 100 mg. chloramphenicol1 sup- plied in packages of 25 and 100. SuspenAlon Chloromycetin Palmitate, each 4 cc. represents 125 mg. chloramphenicol, (each cc. contains chloramphenicol pal-* mitate equivalent to 31.25 mg. chioram- phenicol with 0.5 % sodium benzoate as preservative), in bottles of 60 cc. IN THE DRUG INDUSTRY 2417 ~CA4I~ PARKE, DAVIS i'D> & COMPANY DETROIT, MICHiGAN, U.S.A. Feb. 1961 AB PAGENO="0284" 2418 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY To the Medical Profession CHLOROMYCETIN* (chioramphenicol B.P., Parke-Davis) is a pure crystalline substance originally isolated from cultures of Streptomyces venezuelae and now synthesised. Each CHLOROMYCETIN Kapseal* contains O'25 G. CHLOROMYCETIN. CHLOROMYCETIN is effective in a number of clinical conditions, including typhoid fever and other salmonelloses; bacillary dysentery (shigellosis) and other entetin injections: pertussis: urinary tract infections; respiratory infections (bacterial and viral pneumonias~; peritonitis; brucellosis; ocular and aural infections; non-tuberculous meningitis; rickensial :utections (Q fever, typhus tever, scrub typhus fever), and venereal diseases. DOSAGE AND ADMINISTRATION General Dosage Schedule CHLOROMYCETIN is readily absorbed from the gastro-intestinal tract following oral administration, blood-levels increasing proportionally with increased dosage. Adults & Children: 50 mg. per kg. body-weight daily in divided doses at 6 hourly intervals (approximately equivalent to 3 G. [12 Kapseals] daily for a patient weighing 10 stone [63 kg.]). Patients with infections due to moderately susceptible organisms or with severe * Trade mark P.T.O. PAGENO="0285" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2419 infections often require doses up to 100 mg./kg. body-weight daily; in children however, this dosage should, be reduced to 50 mg./kg. body-weight daily as soon as clinical response occurs. In typhoid fever it is important that therapy be continued for 8 to 10 days after reaching the afebrile period. Administration of CHLOROMYCETIN to infants and young children is best accomplished by means of Suspension CHLOROMYCETIN Palmitate, a pleasantly flavoured suspension of a bitterless derivative of CHLOROMYCETIN containing in each teaspoonful (4 ml.) the equiva~nt of 125 mg. CHLOROMYCETIN. SIDE REACTIONS AND TOXICITY Patients on treatment may complain of dry mouth and less often of nausea, diarrhoea or vomiting, although these are seldom sufficiently severe to justify withdrawal of the drug. Drug sensitivity reactions are also sometimes encountered. Cases of optic and peripheral neuritis have been reported in patients receiving high total dosage during prolonged therapy. While the incidence of blood dyscrasias associated with systemic CHLOROMYCETIN therapy is rare, cases of serious disorders including aplastic anaemia have been reported. As with certain other drugs adequate blood studies should be made when the patient receives prolonged or intermittent therapy. Further literature on~ request PARKE, DAVIS & COMPANY HOUNSLOW, LONDON, ENGLAND No. 1188 T Senator NELSON. Doctor, I want to thank you very much for your very fine contribution to these hearings. We appreciate your taking the time to come today. Dr. DAMESHEK. Thank you, Senator. (Dr. Dameshek subsequently submitted the following informa- tion:) FEBRUARY 7, 1968. Dr. WM. DAMESHEK, Monnt Sinai Medical School, New York, N.Y. DEAR Dn. DAMESHEK: This morning, while in Milwaukee, Wisconsin, I read an article in the Milwaukee Sentinel concerning your testimony before a Senate subcommittee, concerning the Parke, Davis drug, Ohloromycetin. Frankly, this news release brought back to me all the unhappy memories and frustrations of the illness my daughter Marilyn, age five, suffered for nine weeks in 1955. The diagnosis was, of course, aplastic anemia, and the patient passed on May 3, 1955. Our physician, now deceased, had prescribed this particular drug for three years prior to Marilyn's final illness. Sore throats, colds, minor fevers were all handled with Chioromycetin. The drug, as you know, eventually destroyed totally her bone marrow, and the child's ability to manufacture proper blood was de- stroyed. PAGENO="0286" 2420 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The latter was confirmed by autopsy, and cause of death was confirmed as "Chloromycetal Intoxication." I brought the foregoing to Parke-Davis' attention; guilt was admitted, and blame was placed at the door of the doctor. I then asked Parke-Davis `to show me brochures and sales techniques that brought to the medical profession proper in- formation concerning the pros and cons in the use of the drug. In other words, I conceded that the drug certainly had great value in the treatment of spinal meningitis, nephritis, nephrosis, typhoid, etc., but I wanted to see that said drug was not oversold as a cure-all, but was used only for major problems. This in- formation was denied me. My next logical step was to call on the U.S. Pure Food and Drug Administra- tion in Detroit. I was informed at that time that Chloromycetin bad been with- drawn from the market sometime earlier than 1955, as a result of a rash of com- plaints resulting from its use. The Government had checked the drug for a year, while no sales were allowed, but had been unable to pinpoint a real connection between aplastic anemia and Chloromycetin. To me this was a typical conclu- sion of our unbelievable bureaucracy. Perhaps, at this point, you may be wondering why I am writing you about something that happened in 1955. `I will tell you why. Mrs. Lenox and I were desolate at the death of our child. The only reason we were able to continue without undue rancor was that we hoped, by bringing our situation to the attention of Parke-Davis plus the U.S. Food and Drug Adminis- tration, that future mistakes of this sort would be obviated. Thirteen years later I see that not only has the situation not been corrected, but that there is actually an increase in this sort of thing. Sincerely, HARBY LENOX, Jr., Detroit, Mich. P.S.-If ~ou wish to read this letter in future sub-committee hearings, you have my full permission to do so. FEBRUARY 8, 1968. t)EAR DR. DAMESHEK: Upon reading an article in the Daily News, Wed., Feb. 7th, I have some information which may be of some help. About 5 years ago our little boy took sick. Our Doctor at that time kept saying what he had was a virus, cold, sore throat, and kept giving him the drug chloro- mycetin as an antibiotic. Finally when the child appeared after many months with black and blue marks on his body, `the Dr. finally took a blood count. We then found out the dreadful news that our `boy had leukemia. He lasted 8 months after this. I for one think that there was some connection with this drug that brought on Leukemia on our child. If there are any further questions you may wish td ask me please feel free to contact me. I hope you continue your research in this field and maybe soon we can find a cure or some sort of vaccine. I remain, NAME WITHHELD. Mr. GORDON. Mr. Chairman, the subcommittee has some articles on this subject which I ask be put into the record.1 Senator NELSON. They will be put in the record. Materials submitted by the witnesses in the course of their testimony or at a later date will also be accepted for the record. Our next witness is Dr. William R. Best. Dr. Best is with the Vet- erans' Administration. The committee is very pleased to have you here today. As I said to Dr. Dameshek, we would be happy to have you elaborate on any of the points you make if you feel it would be helpful to an understanding of your statement or if it would be enlightening for the record. So, you may proceed t~o present your statement as you please. 1'See appendix I, p. 2653, infra. PAGENO="0287" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2421 STATEMENT OF DR. WILLIAM R. BEST, CHIEF, MIDWEST RESEARCH SUPPORT CENTER, VETERANS' ADMINISTRATION, EDWARD HINES, JR., HOSPITAL, HINES, ILL. Dr. BEST. Thank you, Senator Nelson. I have been asked to discuss chioramphenicol and some of the prob- lems involved in its use in medicine. As Dr. Dameshek has indicated, this was originally isolated and came on the market back in 1948. Parke, Davis & Co. has been the principal supplier. It was early proven to be very effective against a wide variety of bacterial, rickett- sial and viral infections. It was only after about 3 years of wide use that it became evident that rare susceptible individuals would develop aplastic anemia, an extreme depression of the bone marrow, as Dr. Dameshek has said. Since this complication is often fatal, this knowledge led to a reassess- ment of the indications for its use and, in 1953, the American Medical Association established a central registry of drug-associated blood dyscrasias. "Blood dyserasia" means "blood diseases." Before discussing these issues further, however, it is pertinent for me to outline my qualifications for appearing before you on this issue. I received my M.D. degree from the University of Illinois College of Medicine, Chicago, in 1947, and after this pursued 4 years of post- graduate training at its principal teaching hospital; the Illinois Re- search & Educational Hospital. My training was in the general field of internal medicine, and in the subspecialty of hematology, diseases of the blood. After 2 years of military service, I joined the faculty of the University of Illinois as an assistant professor of medicine at 90 per- cent time. The remainder of my time w~s as an attending physician at the Veterans' Administration Hospital, Hines, Ill., and as a hema- tology consultant in private practice. I have functioned in several roles in these particular settings. As `a physician in general medicine I have been responsible for treating a variety of patients in both outpatient and hospital settings and on many occasions in outlining the treatment of infections I have had to weigh the relative likelihood of good versus harm in the selection of antibiotic agents. In hematology, as Dr. Dameshek will attest, the choice of anti- biotics is terribly important because of the low levels of natural re- sistance characteristic of many patients with leukemia `and similar * conditions. On `a number of occasions chloramphen'iool ~l'one or in combination has appeared to be the drug of choice in my patients, despite the known risks of adverse reactions. No serious side effects have occurred in any patient to whom I have prescribed this drug. As a hematologist, `however, I have also been consulted in relation to patients who develop bone marrow depression as a result of medi- cations given by other physicians for other diseases. Over the years the number of oases of apl'astic `anemia due to ~hloramphenicol for which I have been personally consulted is not large. My knowledge of this `condition comes more from another `avenue which I `shall outline in a few moment's. As `assistant professor and later associate professor of medicine, my responsibilities have included not only direct patient care, but PAGENO="0288" 2422 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ai~o medical research and the teaching of medical students, interns, and residents. Much of my research has been direeted to ward clinical and laboratory studies in leukemia, pernicious anemia, and other blood diseases. I have been author or coauthor of more than 100 scientific publications, `including articles in journals, chapters in books, and abstracts of presentations for professional meetings. In recent years my research interests have turned from hemactologic topics to- ward the `applications `of statistics, mathematics, `and computers to general medical research `and practice. In keeping with these changing interests, on August 1, 1967, I became chief of the Midwest Research Support Center at Hines, Ill., one of four such regional centers es- tablished by `the Veterans' Administration to offer consultation `and support in experimental design, computer anaiysis `and related `areas to `any medical investigator `affiliated with the VA system. I have. re- tiaiiied my appointment `as `associate professor of medicine at the Uni- versity of Illinois on `a nonsalaried basis. I have given up `a partial consulting practice in hematology which I had up to that time. Because of my dual interest in biostatistics as well as hematology, I was asked several years ago to become a men~ber of the study group on drug-associated blood dyscrasias of the American Medical Associa- tion Council on Drugs, a group of volunteer hematologists. This group was concerned with the inferences which might reasonably be drawn from data submitted by diverse physicians to the previously men- tioned registry. During my period of membership with this group, 1961-67, I played a major role in attempting to analyze and interpret various types of data which had been submitted to the registry. A principal study in this regard, prepared at the request of the study group, culminated in an article entitled "Chloramphenicol-Associated Blood Dyscrasias," published in the Journal of American Medical Association, volume 201, pages 181 through 188, July 17, 1967. I have a copy here and I believe that copies have been distributed to those present. Senator NELSON. That is the one entitled "Chloramphenicol-Asso- ciated Blood Dyscrasias"? Dr. BEST. That is correct. Senator NELSON. That will be printed at the conclusion of your testimony in the record.1 Dr. BEST. Fine. Much of what I shall say here will be based on that study of 408 patients who developed blood cell depression within 1 year of receiving this drug and who were reported to the registery during the years 1963 through 1964. Senator NELSON. What was the source of these reports to the registry? Dr. BEST. These are cases that are voluntarily submitted by physi- cianS. The registry went through several phases. At the beginning there was a limited group of hematologists, about 50 over the country, who knew- about the registry and w-ho were contributing the cases they saw to it. After a period of time it was opened up and the attempt was made to get all physicians who would see a case to report it to the registry. 1See article, p. 2433, infra. PAGENO="0289" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2423 The registry is an iceberg peak of unknown proportion. We do not know what percentage of all cases occurring are represented. All we can say is that these are the cases that were reported to the registry. Undoubtedly, there are biases involved in this process. Some physi- cians have not known about the registry; others perhaps might feel that one reaction is too mild to bother repOrting or that another reac- tion to a particular drug is so well known that it does not need further documentation. I am sure all sorts of biasing considerations like this go into it. Although we would like to draw inferences from this data, there is always a question as to just how much the trends we see in the registry reflect what the across-the-board experience is. Senator NELSON. So this was a total of 408 cases. What period of time does this cover? Dr. BEST. 1953 through 1964. Senator NELSON. These were cases voluntarily submitted? Dr. BEST. Actually, there are two sources of cases. One which ac- counted for the vast majority, something like 75 or 80 percent, were voluntarily submitted. Some of the people on the AMA staff also screened literature that came in through their library and whenever they found a report in the literature that would bear on this, they would add that to the registry, too. Some of these are culled from the literature, about 20 percent; about 80 percent were voluntary reports submitted by the physicians. Senator NELSON. Those 80 percent, were they submitted by the orig- inal prescribing physician or a mix of the original prescribing physi- cian and the specialist at the end of the line? Dr. BEST. I would say the latter is the case most often, although I do not think we actually have figures on this. The impression I have is that a majority are physicians who took care of the patient after this complication developed. Probably in most cases this was a different physician than the one who had prescribed the drug originally. Senator NELSON. So, we have no notion as to how many other cases there are? Dr. BEST. No. The registry itself gives us no way of estimating that. Senator NELSON. May I ask one more questions? Of the specialists who would be called upon to diagnose or treat a patient subsequent to the onset of the problem, do you have any notion of what percentage of those in the United States have cooperated in sending in cases? Dr. BEST. I do not think I have any way to say. I do not know. To continue with my prepared Statementr-it is in relation to the details of chloraanphenicol-associated bone marrow depression that I should be considered most expert. The statements I would make in terms of the use, indications for use, other side effects and impressions with regard to promotional activity would reflect more my knowledge and judgment as a board-certified internist with a particular interest in these topics. In making these statements I wish to make it clear that I am speak- ing on the basis of my independent judgment and not as a spokesman for the Veterans' Administration, for the University of Illinois College of Medicine or for the American Medical Association. When should chloramphenicol be prescribed? A universal rule for making therapeutic decisions is to balance the likelihood of benefit Si-280 0-68-pt. 6-19 PAGENO="0290" 2424 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY against the likelihood of harm, in terms of both frequency and degree, for all reasonable courses of action or inaction. That course which seems to offer the best balance should then be implemented. The phy- sician must then periodically evaluate the apparent effect of his ther- apy on the course of the disease, making a new decision as to mode of treatment if the initially chosen method seems to be ineffective or detrimental. While this general principle is quite clear, details of implementation may be muddy. Exact figures often are not. known regarding the likelihood of benefit or harm; optimal methods of bal- ancing potential good against potential harm have usually not been spelled out. The type of balance which has appeared to make most sense to those concerned about bone marrow depression following chioramphenicol is based on the following observations: (1) Rare individuals, probably somewhere between 1 in 20,000 to 1 in 100,000, who receive courses of chloramphenicol will develop sig- nifica.nt bone marrow depression. This is a rather broad range of esti- mates. Dr. Dameshek, if I remember, threw in a figure of maybe 1 in 10,000. It is a reflection of our ignorance that we do not really know what the exact figure is. There have been a couple of attempts made to outline just how frequently this occurs and the truth appears to be somewhere in this general range. It is not an extremely frequent thing, but it does happen. (2) There is no known way of determining beforehand whether or not a given individual is likely to develop this complication from chlora.mphenicol. (3) When bone marrow depression does occur, it is serious, carrying a mortality rate of about 50 percent. There is no really good method of treating this complication. Some who do not die of it suffer prolonged disability. Dr. Da.meshek mentioned 50- to 75-percent mortality and I think that 75 percent would probably come closer for the severe cases. The so recent figure is based on an across-the-board estimate, including some mild as well as severe cases. (4) Careful attempts to detect the early stages of marrow depres- sion with the idea of stopping the drug and preventing death are doomed to failure in many cases. The first evidencee of marrow de- pression has most often appeared after the drug was stopped, a.nd in many cases has been seen weeks or months later. In it minority of cases periodic blood counts during therapy may permit a more favorable outcome through early detection. (5) Thus, under our present knowledge, there is no way to prevent fatalities due to this complication in rare cases if the drug is to be used at all. (6) However, chioramphenicol can be a very effective drug in com- bating a. variety of infections. In some life-threatening infections it. will be clearly superior to all other available agents. Based on these propositions, the following conclusions appear war- ranted: (a) When the greatest likelihood for control of a serious infection appears to be through use of chloramphenicol, it should be used. More lives will be saved through superior therapy than will be lost through adverse reactions to the drug. PAGENO="0291" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2425 (14 However, even an occurrence rate of one in 20,000 to one in 100,000 is too great a risk to take in relation to trivial infections or conditions which a less risky agent might better be expected to control. Given a group of patients representing a wide range of infections, most informed physicians would agree on a subgroup corresponding to (a) in which chioramphenicol should be used. Typhoid fever and severe paratyphoid infections would certainly be included. Many would also name Hemophilus influenza meningitis. Life-threatening infections, such gram-negative septicemia in patients with leukemia, if there is laboratory evidence suggesting the superiority of chloram- phenicol, would also be included. Mr. GORDON. Dr. Best, if I am not mistaken, you are saying here, are you not, that even in these serious cases, chloramphenicol should not be given perfunctorily but only after there is evidence showing that other therapeutic agents are ineffective or are contraindicated? Dr. BEST. This is the implication of what I have said. However, I feel that situations will rarely arise in which I would give the drug even before I had the laboratory evidence. If the patient was dying and my hunch was that chloramphenicol would be the best drug, I would give it even before the laboratory reports were returned. If there is not this urgency, then I would certainly say that you should have definite laboratory evidence that it is the superior drug to use. At the other pole, there would be agreement that corresponding to the trivial conditions of (14 one might name the common cold, viral infections, and many bacterial or rickettsial infections for which other effective agents with lesser toxic potentiality exist. There would inevitably be a gray zone, in which some physicians would consider the drug indicated; others, not. This would include various acute and chronic infections of lungs, urinary tract, bowel, and elsewhere involving `variable organisms, variable laboratory sensi- tivities, and variable prior therapeutic histories. Since medicine is not an exact science, I do not believe this gray zone can be meaning- fully resolved by law or pontification. The individual physician must remain free to exercise his judgment within a general framework of principles such as I have outlined. This is not to say that such discretion has necessarily always been the rule: Information on why chloramphenicol was originally given was available for 71 percent of the registry cases which I studied. The most frequent reasons together with corresponding percentages of this subgroup are: Lower urinary tract infectidns (14 percent), the com- mon cold (12 percent), pneumonia (8 percent), kidney infection (6 percent), typhoid fever (4 percent), septicemia (3 percent), chronic bronchitis (3 percent), and ear and sinus~ infections (3 percent). I might add-not necessarily the next in line, but Dr. Dameshek did mention it-acne. Approximately 2 percent were treated for acne. Senator NELSON. Is there any conceivable case where you could jus- tify using chloramphenicol for acne? Dr. BEST. I cannot see it myself. Maybe somebody could defend it but I certainly could not. In 26 percent of cases there was a serious acute or subacute infection fitting the (a) criteria for use of chioramphenicol, or, at the least, falling into the gray zone. Thirty percent of cases fit the (b) criteria, PAGENO="0292" 2426 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY relatively trivial indications for which the drug should not have been used. In the remainder of cases, there is not adequate information to say whether (a) or (74 would best fit, though one suspects that (74 would predominate. It should be pointed out that 26 percent of reports were from outside the United States, and that a number of the more serious infections such as typhoid fever are from this subgroup. Thus, in this country many of these complications have occurred in patients who, according to the criteria I have outlined, should not have received chlora.mphenicol. Senator NELSON. It appears from your statistics that, eliminating the gray zone, the higher percentage of those given the drug should riot have received it. Dr. BEST. I am sure that this is true. It is difficult, with the amount of information sent to the registry, to always say whether th\ere was a good indication or not. I gave the prescribing doctors the benefit of the doubt in any borderline case. I am sure that if you really examined each case with a fine-tooth comb, it would be a very significant majority in which you would say the drug should not have been used. Senator NELSON. And these are all cases where serious blood dycrasias occurred? Dr. BrsT. Yes, serious enough for them to be reported. Now, some are more serious than others. Something like 75 percent of these, I would say, were of a very definitely serious nature. Maybe 20 to 25 percent tended to be a milder variety of the same thing. Mr. GORDON. I notice in the circular chart on page 183 of your article that in only 6.~ percent of the reported cases was chloramphenicol the drug of choice. Dr. BEST. These are the cases of typhoid, paratyphoid, and hemo- philis influenza, where, just by knowing the name of the infection, you could say, "All right, we will say that chloramphenicol is indicated." In getting the 26 percent figure, giving the physician the benefit of the doubt, I decided that in a serious acute or subacute infection, evidence was adequate to say, "Yes, this was a good drug to use in that instance." But, I could be wrong. Here again it is a matter of working with, in many cases, a sketchy sort of information that is submitted with the report to the registry. Mr. G0IWON. Well, in those cases where it was not the drug of choice, was there any follow up to see whether it should have been used? Was there any indication in the reports to the registry? Dr. BEST. I might say that the policy of the registry has been gen- erally to receive the reports and unless they are grossly inadequate in information, to not try to seek further followup information. This policy was designed to obtain continued cooperation of the physicians by minimai paperwork harassment. Thus, there are very few of these cases where an attempt was made to find out further information other than that which was submitted in the original report. Despite periodic reminders in the medical literature of toxic poten- tiaht.ies, it is apparent that some physicians treat this possibility lightly. In some cases the attitude is, "I have never seen such a case; therefore, I do not have to worry about it." Being as rare as it is, the average physician could well treat many patients with chloramphenicol over a number of years and never see a resultant aplastic anemi. How- PAGENO="0293" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2427 ever, he takes a finite risk with each new patient given the drug, and for the patient who develops a fatal complication, it is 100 percent. What pact has advertising to the medical profession played m the ways in which physicians prescribe this drug? Here I can only give my casual observations and opinions. Chloramphenicol has apparently been one of the major products of Parke, Davis & Co., for many years, and they have continued to keep its name before the medical profession. In thumbing through recent issues of the Journal of the American Medical Association, I find a two-page spread on Chloro- mycetin in about every third issue. I find similar spreads in many other professional magazines, both those obtained on subscription and those which are sent to physicians unsolicited. Two similar, two-page ad- vertisements are used in their present campaign. I have these ads here. The first of these says, "When it counts-Chloromyctein may be indi- cated in certain severe respiratory infections." The second begins, "When it counts. . . Chloromyctein can be useful in uninary tract infections." These advertisements are similar in that the left-hand page is designed to catch the eye; about one-quarter of the right-hand page cautiously outlines the indications for chloraan- phenical in the particular type of infections; and the remaining three- quarters of a page is used in discussing dangers, precautions, and side effects. For example, there is a prominent area surrounded in black. I will not read what it says, because it repeats in detail, almost verbatim the precautions that Dr. Dameshek read as part of the package insert. It is my opinion that these advertisements do represent an honest and informative appraisal of the problems related to consideration of this antibiotic for these types of infections. If the physician heeds the admonitions, he will be following the principles I outlined earlier. Parke, Davis & Co. have sponsored `a second campaign, an adver- tisement appearing as recently as July 1967 in MD magazine, Hospital Physician, and other places as well. These are one-page advertisements depicting the physician in various hospital settings. I have three ex- amples here. The headlines are "When it Counts," "Among the Most Significant Drugs in Use Today," and "A Name You Can Count On When It Counts." These are followed by the word "Ghloromycetin," other identification items relating to the company, and then the phrase is given: "Com- pleite information for usage available to physicians upon request.." That is all. These advertisements give no hint as to either uses or adverse reac- tions. They serve only to keep the product's name in the mind of the physician. While not misleading, they are certainly in no way informa- tive. Senator NELSON. There are no warnings or precautions in these ads ? Dr. BEST. No warnings. It just says "complete information is available." It does not say what it is good for but it does not say what harm it may cause either. Senator NELSON. Well, since the idea, I~ assume, is to promote the use of the drug, would you not think that they ought to be required to list what it should be used for and to include cautionary statements inthead? Dr. BEST. I would think so. PAGENO="0294" 2428 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I also turned to the 1960 Physicians' Desk Reference, a yearly com- pilation of pharmaceuticals which the various drug companies wish to bring to the attention of physicians. The writeups for particular drugs are usually abbreviated versions of the product package inserts. I chose 1960 as a year during which the possibility of toxic marrow depression was well imown but which was prior to the recent tightening of controls by the Food and Drug Administration. The writeup says: "Chloromycetin is a potent therapeutic agent and, because certain blood dyscrasias have been associated with its administration, it should not be used indiscriminately or for minor infections. Furthermore, as with certain other drugs, adequate blood studies should be made when the patient requires prolonged or intermittent therapy." Though not as detailed as the precautions mentioned in recent advertising, this description did point to the danger of marrow depression. So far, the only adverse effects to Chioromycetin which I have mentioned are those related to bone marrow depression. This is be- cause it is the area with which I am most familiar and because it is the type of reaction most frequently associated with a fatal outcome. As an aside, I might mention that in the Registry on Blood Dyscrasias, chloramphenicol has been associated with a plastic anemia more com- monly than has any other group of drugs. Nonetheless, there are a variet.y of other types of reactions which can occur to this ant.ibiotic. These include, in addition to minor symptoms such as fever, diarrhea, or minimal skin reactions, the following: (1) A naphylactic reactions. (2) The "gray syndrome" in newborn infants. This is characterized by a distended abdomen, shock, and a bluish-white skin color. It can be fatal. (3) Severe skin reactions. (4) Optic neuritis with loss of vision, usually reversible. (5) Overgrowth of nonsusceptible bacteria or fungi. Most such complications are readily reversible on stopping the drug. Some can be fatal or permanently disabling. None occur very often. It should be pointed out that no antibiotic is 100 percent safe. All have potential side effects, some fatal. Penicillin and its variants probably constitute the most widely used group of antibiotics. Fatal anaphylactic reactions to the penicillins have undoubtedly been more numerous than have deaths from aplastic anemia following chlor- amphenicol. Unfortunately, we do not have adequate information to precisely evaluate the relative risks of such reactions under standard regimens of therapy. In regard to penicillin, I might say that one estimate has been that there are somewhere from 100 to 300 fatalities a year due to anaphylactic reactions to penicillin. I am sure this far exceeds the number of fatalities due to chloramphenicol. Of course, penicillin is much more widely used than chloramphenicol. A recent study in Boston hospitals showed the order of use of some of the more common antimicrobial agents. Penicillin and its analogs were far and away the No. 1 drug. The sulfa drugs occurred next in line among the drugs to be mentioned. The sulfa drugs can also cause severe and even fatal side reactions. Chioramphenicol was the third in this group, and the tetracyclines were No. 4. Tetracychnes have PAGENO="0295" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2429 much less serious types of side reactions, and in many cases the spectrum of activity is quite similar to that of chloramphenicol. In summary, chloramphenicol is a very useful drug in a variety of serious infections. In rare patients it may produce fatal bone marrow depression or other serious reactions. Since there is no way to predict or prevent these reactions in individual patients, the phy- sican must exercise judgment in weighing the possible benefits against the possible deleterious effects of therapy with chloramphenicol as with any other agent. There appears to be continued need for re- emphasis of potential dangers to the medical profession. However, I believe that attempts at legislative controls on the prescription of this drug would in the long run do more harm than good. Senator NELSON. Is not the real issue here, however, that there is a clearly defined group of cases which you, as well as Dr. Dameshek and other distinguished authorities have testified to, in which the drug just simply should not be used. And in a substantial percentage of cases that you have studied from the registry, the drug was in fact improperly used and serious as well as fatal consequences were the result? Is that not correct? Dr. BEST. That is true. Senator NELSON. So, an important part of the problem here is that the drug is being prescribed in cases where it just simply should not be prescribed. Dr. BEST. Yes; this is true. The danger I foresec is that controls would prevent it from being prescribed in cases where it should be prescribed. Senator NELSON. You heard the discussion with Dr. Dameshek indi- cating that there ought to be some method at least of effectively com- municating the warnings to the doctor or perhaps controllmg the use of the drug. As to the possible method we discussed-that is, setting aside a group of drugs to be in a special category, and following the procedure used, say, in the prescribing and dispensing of morphine, would you find that to be a procedure that might be feasible? Dr. BEST. I think so. Perhaps my summary statement against con- trols is a little too strong. Certainly, I would hate to see the pendulum swing over to the point where the drug could not be used. Let us put it this way: I think a certain amount of reasonable controls might be a good thing and acceptable. It depends on just how much of what one might interpret as harassment would be involved. A type of con- trol parallel to that on the prescription of, narcotics would seem to me reasonable; yes. Senator NELSON. Well, the history of cases that have been called to your attention, as well as those reported, your study indicates that 30 percent of those you studied concerned people who should not have received the drug. So you do have specific cases where patients are either made seriously ill for the balance of their life or suffer a fatal disease as a consequence of inappropriate prescription of the drug. As I mentioned earlier, when Dr. Danieshek was testifying, it ap- pears, both from your statistics and considering the amount of the drug sold, that a large number of the people to whom the drug is being administered, should not have it. Do you have any estimate or any guess to make as to how many people in this country ought to be receiving this drug annually? PAGENO="0296" 2430 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. BEST. Well, the best thing I can do is guess. I do not have any really solid figures on which to make such a statement. As stated in my article there is somewhere in the neighborhood of 30 percent who you could probably make a reasonably good case that they should have had the drag. Senator NELSON. Should have had the drug? Dr. BEST. Should have had it. Another about 30 percent where they should not, and then the remaining middle 40 percent we do not know, and my guess is that most of the middle one should not have had it, either. Obviously, there are some biases involved in those who were reported to the registry, and the chances are the bias would be towards reporting the cases where the drug was given for more serious diseases rather than less serious ones, so that just to kind of reach into the air and pull out a figure, I think the one that Dr. Dameshek mentioned of perhaps 10 percent of all that is given as having a good reason to be given is probably as good a guess as I would want to make but I do have to say that it is a guess. Senator NELSON. That would mean, then, that the guess is also that 90 percent- Dr. BEST. Ninety percent, probably some other drug or no drug at all would have been the better thing to use. Mr. GROSSMAN. Doctor, can I just ask you one question about the ramifications of this failure of the warning system. For example, Dr. Dameshek says that the numerous warnings regarding the indiscrimi- nate use of Choloromycetin have been practically without effect. With regard to our entire drug system, do you think that we have a failure of our warning systems to work and do we need some kind of a change? Dr. BEST. I do not agree with his statement in that case. I think it has not been without effect, to use a double negative. I think it has had an effect. I do not think it has had nearly as much effect as we would like it to have, but I think it has had an effect. I believe we would see a much worse situation if we did not have the warnings. This is based on conversations I have had with individual physicians. I know many who are very reluctant to use chloramphenicol because they are aware of these warnings. It is just that we have not hit 100 percent of physicians as far as this philosophy is concerned. So, we would like to do better. But I would not say that we have had no effect as far as our warnings are concerned. Mr. GROSSMAN. Would you say it is a minority of physicians or smaller group of physicians? Dr. BEST. It is hard to say whether it is a minority or a majority. Certainly, among those that I am personally familiar with, and these tend to be those who are academically oriented, I would say the vast majority are aware of this danger and tred very lightly in the use of chioramphenicol. Mr. GROSSMAN. What are the ramifications as far as other drugs are concerned? In other words, are warnings being heeded on other drugs? Is the same true in most of our other drugs? If it is not being done here to some degree, how can we believe that warnings are really effective at all on any- Dr. BEST. I am sure they are only partially effective. I am sure none- theless that the average physician when he uses a drug does become PAGENO="0297" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2431 aware of what the reported side effects are, what the possible dangers are. This brings us again to the question of considering and balancing the odds as to various possible outcomes. Many people would like to believe that the physician has a certain omnipotence, that everything is black and white; but it ends up that in making decisions he is always balancing odds. Mr. GROSSMAN. Would the reporting system that has been talked about here this morning-would that tend to restrict the use of danger- ous drugs to properly indicated conditions? Dr. BEST. Would you repeat that question, please? Mr. GROSSMAN. Well, Senator Nelson and Dr. Dameshek were talk- ing about a reporting system. Do you think this would have a beneficial effect on limiting improper usage? Dr. BEST. I am not sure how much effect the reporting system would have itself. It would produce-if a universal reporting system were involved-it would produce figures that would have a little more mean- ing than the ones that I have written about that are related to a voluntary reporting. In other words, we would have a better feeling for what the total number of cases are. I think that we still would not have the whole picture. I know that in a recent study in Philadel- phia, for example, five of the medical-school-affiliated hospitals tried to set up their own reporting system to catch all of the adverse reac- tions occurring in all of these hospitals. People being people the way they are, when they went back to check and see how complete the re- porting system was, even though the chief of each service told all of his residents and interns to report every case that came through, I think they reported somewhere in the neighbrohood of 5 percent; about 95 percent still did not get reported even though this was the rule of the particular hospital. Mr. GROSSMAN. Can I ask you how would you grade our warning system, then, today, not just this particular drug, but generally? Is it the best thing we can come up with? Is there a way you would specifi- cally recommend to improve our system? Dr. BEST. You mean by warning system, putting the warnings on the package inserts, putting them on the advertising, et cetera? Mr. GROSSMAN. I am talking about the way we are doing it now. In other words, is this adequate? Dr. BEST. Well, I think that-my own personal opinion is-Dr. Dameshek did not want to commit himself on it, but my position on it is that-the vast majority of physicians rarely read a package insert but they do read some of the material that comes through the mail- and there is a flood of it that comes to every physician. They do read some of the ads in the journals, and so on. 1 think that very many of them turn to things such as the Physicians' Desk Reference for infor- mation. If all of these sources stress the important side effects, the physician should become aware of them. What use they make of this information is another question, but I think the information will get to them through these avenues. If you speak about only giving this information in the package insert, however, I think it will be missed by many. Mr. GROSSMAN. Thank you. PAGENO="0298" 2432 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. I realize that both you and Dr. Dameshek were makrng what YOU conceded was a guess as to the percentage of cases in which chioramphenicol was prescribed and was indicated. You both were guessing about 10 percent, but even if it were 20 or 30 or 40 per- cent, it does obviously indicate that there is some breakdown in proper communication to the physician as to the proper use of this drug; does it not? Dr. BEST. Yes, I think so. Mr. GORDON. Dr. Best, I have one question. In a case in Californiar- I think it was Love against `Wolfe and Parke, Davis-the, court held that even though the warning is given, it could be regarded as can- celed out if a vigorous promotional campaign was being waged. How do you feel about that? Dr. BEST. Well, I have trouble responding to that. That seems like a legal question. Mr. GORDON. Well, do you feel that a vigorous promotional cam- paign, say especially by the detail men, could cancel out the effect of the written warning on the packages or at least mitigate it? I told you that the court found tha.t there is substantial evidence that it did wash out the warnings. How do you feel about that? Dr. BEST. Well, it seems to me that if all of this promotional activ- ity included the warning on each particular aspect of the promotion, I cannot say that that would necessarily negate it. On the other hand, the reason they put on a strong promotional campaign obviously is to sell more drugs and I can see a grain of truth in the court's point of view in that the more somebody is brainwashed, the more they are apt to think of this particular drug without necessarily thinking of the warnings; but it is a hard thing to give an absolute answer to. Senator NELSON. The report of the Kefauver hearings, dated June 27, 1961, comments on this exact point about chloramphenicol. I will just read briefly from it. The report says, starting on page 198: "Despite the `obvious importance of providing the physician on whom this responsibility rests with full and accurate information on side effects, the drug companies in their `advertisements `have tended to handle the matter in either one of two ways: ignore side effects en- tirely or note and then dismiss the subject with some sort of reassurring phrase. When the latter teclmique is employed, the physician i's com- forted with `such language," and these are quotes from the `advertising, "virtually free from side effects"; "with few significant side effects"; "with low incidence of side effects"; "minimum `side effects"; "unex- celled freedom from major `as well as minor `si'de effects." That, obviously, would not be correct. "With no irreversible side effects." "Fewer and less severe side ef- fects"; "absence `of serious side effects speci'ally noted"; "accompanied by fewer and milder reactions"; "incidence of `side effect's is lowest ever rep'orted"; "by adherence to recommended dosages `side effects will `be generally infrequent, mild, transient"; "without clinically `significant side effects"; "side effects minimal"; "serious reactions have been prac- tically nonexistent"; "no serious side effects noted"; obviously incorrect. "Relative freedom from untoward reactions"; "side effects are fewer and milder"; "fewer old and no alarming new side effects"; "fewer PAGENO="0299" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2433 and milder classic side effects"; "with minimal side effects"; "minimum incidence of certain side effects"; "relatively nontoxic"; "untoward re- actions infrequent and minimal"; "undesirable reactions are seldom encountered or are minor in degree"; "lower incidence of severe side effects"; "virtually free from side reactions"; "side effects minor"; "side effects generally miled and can be overcome by adjustment in dosage"; "fewer side effects", et cetera. I realize that these statements are out of èontext without the full ad, but are some of these statements `the kind yOu, `as a specialist, certainly would not endorse? Dr. BEST. I would certainly agree; some Of those statements I would consider very misleading. One of the problems in this whole business of `studying the side effects of drugs is the question of confusing how frequently `something occurs with `how serious it is when it occurs, and- Senator NELSON. And how unnecessary it is in those instances where it should not be used in the first place. Dr. BEST. Yes. Senator NELSON. Like the story of the fellow who, I think it was in the Philippine campaign where `a soldier came back and everybody was `saying, "We'll, it was not a very big war," and he said, "No, `but it was `awfully big for those fellows that got killed." That is as big as it can get for the man. Mr. GORDON. Doctor, on page 8 of your statement you refer to head- lines like: "When it counts," "Among the most significant drugs in use today," `and "A n'ame you can count on when it counts." Now, if I were to suggest that these slogans tend to play down the danger of the drug, would you accept th'at as a reasonably accurate statement? Dr. BEST. Yes. I would consider these `ads as being inadequately documented as to the `dangers, and as I say, these were last summer. 1 do not know whether they still are putting these out anywhere or not but I looked through a pile of journals in the library and these I found. Senator NELSON. Thank you very much, Doctor, for taking the time to come here and for your very useful contribution to these hearings. (The article by Dr. Best referred to previously, follows:) [From the Journal of the American Medical Association, July 17, 1967, vol. 201, No. 3, pp. 181-188] CHLORAMPHENICOL-ASSOCIATED BLOOD DYscaAsIAs-A REVIEW OF CASES SuBMITTED TO THE AMERICAN MEDICAL ASSocIATIoN REGISTRY (By William R. Best, M.D.) From the Research Resources Laboratory, University of Illinois, College of Medi- cine, Chicago, and Biostatistics Research Support Center, Veterans Adminis- tration Hospital, Hines', Illinois. This report has been prepared at the request of the Panel an Hematology of the Section on Adverse Reactions of the AMA Department of Drugs. Reprint requests to' Secretary, Council on Drugs, Ameri- can Medical Association, 535 N. Dearborn St., Chicago 60610. Ohloramphenicol, an effective broad spectrum antibiotic, was introduced in 1948. Only after three years of extensive use did it become evident that this drug was capable of seriously depressing bone marrow activity in rare recipients. It was in response to the delay in recognizing the toxic potentialities of this drug PAGENO="0300" 2434 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY that the American Medical Association established the Registry of Blood Dyscra- sias, hoping, among other things, to recognize such effects early when they occurred for other new drugs. The Registry and its study group have since accu- mulated data on a large number of drugs, have issued periodic tabulations and resumes of cases submitted, and have authored commentaries on various asso- ciated problems.1~ During this period, chioramphenicol has been implicated in more reports to the Registry than has any other single drug. It appeared that useful information could be obtained through a more thorough review of Registry reports. Included in this study were 408 cases, reported to the Registry from 1953 through 1964, who were known to have received chloramphenicol during the year preceding a non-neoplastic depression of blood cell formation. Generalizations from this experience would be most valuable if cases reported to the Registry represented an unbiased sample of the condition as it occurred throughout the world. However, there are unavoidable and, no doubt, unidenti- fiable biases in this coliection of cases. For example, most cases have been vol- untarily reported from selected sources, and the composition and attitudes of these sources have changed from year to year. Some cases were abstracted from the medical literature. Nonetheless, this appears to be the best data available for study. The Registry contains a total of 298 US reports, 25 known to be published, 273 not; plus 110 foreign reports, 70 known to be punished, 40 not. Yunis and Bloomberg reviewed much of the literature on this disorder, sum- marizing data on 94 cases.6 Twenty-one US and eight foreign literature cases are common to their review and to the Registry; their other cases are not in the Registry. The Registry contains 1 US and 65 foreign literature cases which were not covered in their review. There have been additional published case reports which appear neither in the review by Yunis and Bloomberg nor in the Registry. METHODS OF ANALYSIS During the years of existence of the Registry, the report form has gone through several different versions, more recent ones tending to call for more complete information. In general, no systematic attempt has been made to obtain more detailed clinical information or late follow-up of cases. Reports were coded and punched on 80-column computer programming cards, using from 4 to 36 cards per patient, under the direction of Norman De Nosaquo, MD, and Mrs. Helene Weston of the AMA staff. Data transformation, reduction, tabulation, and analysis were performed by the author using computers and over 30 special computer programs. GENERAL CHARACTERISTICS OF CASES Age and Sew.-Females accounted for 62% of 407 cases. There was a wide distribution of cases by age with a rate of 0.5% to 1.5% of total cases per year of age from the teens through the 70's, occasional cases in older age groups, and a striking peak occurrence of about 5% per year of age in the 3- to 7-year age group. There was some difference in sex distribution at different ages: females accounted for 69% of 113 patients 0 to 9 years of age, 69 (73%) of 94 patients 10 to 39 years of age, but only 47% of 150 patients 40 years of age or older. The percentage of females was essentially the. same for cases reported from the United States as compared to reports from elsewhere; however, there is a much less striking peak of occurrence for the 3- to 7-year age group in the latter series (Fig 1). 1Motulsky, A. G.: Drug Reactions, Enzymes, and Biochemical Genetics, JAMA. 1&5: 835-837 (Oct. 19), 1957. 2 De Nosaquo, N.: Development and Purpose of the Registry on Blood Dyscrasias, JAMA 170: 1925-1926 (Aug. 15), 1959. Huguley, C. M., Jr., Erslev, A. J.; and Bergsagel, D. B.: Drug-Related Blood Dyscrasias, JAMA. 177 : 23-26 (July 8), 1961. 4Erslev, A. J., and Wintrobe, M. M.: Detection and Prevention of Drug-Induced Blood Dyscrasias, JAMA 181: 114-119 (July 14), 1962. Best, W. R.: Drug-Associated Blooid Dyscrasias: Recent Additions to the Registry, JAMA 185: 286-290 (July 27), 1963. 6 Yunis, A. A. and Bloomberg, G. R.: Chioramphenicol Toxicity: Clinical Features and Pathogenesis, Prog Hemat 4: 138-159, 1964. PAGENO="0301" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2435 The smaller 3- to 7-year age peak in the non-US cases might represent either different patterns by which this drug is prescribed for various age groups, dif- ferent biases in the reporting of cases, or different hereditary patterns of age susceptibility to this complication as related to ethnic origin. The last of these possibilities seems unlikely, for 84% of the non-US cases are from Europe or European-colonizeij countries, and a similar background is claimed for most white patients from the United States. In addition, 14% of US patients are non- white whereas only 9% of foreign cases are nonwhite, and nonwhites had a lower peak of occurrence at ages 3 to 7 than did whites. AGE, SEX, AND REASON FOR RECEIVING CFILORAMPHENICOL Indication for chioramphenicol Age group Oto9 Number of patients years ~ Number of females 20 to 39 years Number Number of of patients females 60-plu - Number of patients syears Number of females Upper respiratory tract or ear infections Lower respiratory tract infections Urogenital infections Other indications 29 7 10 31 19 6 10 20 4 2 6 5 11 9 32 22 7 21 21 19 4 7 5 9 Total 77 55 53 38 68 25 The Table presents data on some of the more common indications for use of the drug in relation to age and sex. Upper respiratory tract or ear infections were the indications in 29 (almost 40%) of 77 patients, in the under 10-year age group but in only 7 (about 10%) of 68 patients in the older age groups; lower respiratory tract infections and urogenital infections, on the other hand, each accounted for almost a third of indications in the elderly, but only about a tenth of childhood indications. A comparison of US with other reports in this regard reveals similar patterns of indications for most age group except that there appears to be a slightly lower percentage of childhood eases corresponding to each of the three specific listed indications in the non-US group. Race and Ethnic Origin.-Of the 346 patients whose race is known, 28 (8%) were Negro, 10 (3%) were Oriental, 3 were American Indian, and 2 were East Indian. Negroes accounted for 11% of the US group but were not present in the Age distribution and geographic origin ~ USA~ (249 cases) o..--o Elsewhere (109 cases) 3. Age in years 1. Age distribution of cases of chloramphenicol.associ. ated blood dyscrasia as related to geographic origin. PAGENO="0302" 2436 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY non-US group. Only 18 (43%) of 43 nonwhite patients were female, whereas 191 (63%) of 303 white patients were female. Ethnic origin was indicated for 144 white patients. Of these, 79% were north European, 6% Jewish, 6% east Europeans, 5% Spanish-American, and 4% south European. Other Genetic Infornu~ticm..-4n a written communication to the Registry (March 1, 1900), D. J. Fernbach, MD, called attention to a set of identical twins, both of whom developed blood dyscrasias related to chloramphenicol; a pub- lished report of these cases appeared subsequently.7 These identical twins, who were white males 3 years of age, had been given seven- to ten-day courses of cliloramphenicol on several occasions during the preceding two years for severe upper respiratory tract infections. Twin A had six to ten such courses, the most recent being about a month before diagnosis, at which time trisulfapyrimidines was also given. Purpura developed characterized by thrombocytopenia and a hypoplastic marrow, which, over the course of about two months, developed into pancytopenia. Three mar- row transplants were attempted from twin B during the next two years, but without apparent improvement. Hemoglobin returned to normal after 11/2 years of corticosteriod and anclrogen therapy. The bone marrow became less hype- cellular, but thrombocytopenia and modern leukopenia still persisted six years after onset. Twin B had received only four courses of chloramphenicol, the most recent course (this drug only) being given two weeks prior to diagnosis, at about the same time that purpura appeared in twin A. Isolated thrombocytopenia asso- ciated with a hyperplastic marrow, including normal numbers of megakaryocytes, became evident when he was being worked up in prepartion for the first marrow transplantation. He received no therapy and `completely recovered within two weeks after chloramphenicol was discontinued. BLOOD AND BONE MARROW The reporting physician in each case indicated his diagnosis of the type of dyscrasia utilizing his usual criteria plus the admonition on the report form that leukopenia would consist of leukocyte counts of 3,000/cu mm or less. Further documentation was usually not present, and only rarely did members of the hematology panel find it necessary to change a diagnosis on the `basis of such documentation when present. All three major types of peripheral blood cells, erythrocytes, leukocytes, and platelets, were jointly depressed in 75% of 358 cases; two cell types were depressed in 6%; and a single cell type was depressed in 19% (leukocytes in 9%, erythrocytes in 6%, and platelets in 4%). Isolated erythroid cell depression was more common at ages 20 to 59 years (15% of 134 cases) than in younger (2% of 144 cases) or older (two [3%] of 80 cases) age groups, `but no other age trends were apparent. Depression of granulocytes was the most striking component of leukopenia in most instances, but because the report forms did not always call for specific details in this regard, a more complete statistical break- down is not given. Bone marrow findings were available in 129 cases. In ~% of these, the marrow showed increased cellularity and in 7%, normal cellularity, often with other changes such as maturation arrest of the granulocytic series or vacuolation of erythrocytic precursors. Depression in number was noted for precursors of one of the major types of blood cell in 12% of cases; of two types in 5%; and of all three types (eg, hypoplastic or aplastic anemia) in 74%. Two marrows in the last category showed increased numbers of marrow lymphocytes, but on follow-up this apparently did not represent leukemia or lymphoma. Of 24 patients with only one or two cell types depressed in the blood, 2 (8%) showed a normal to hyperplastic marrow, 15 (62%) had one or two cell types depressed in the marrow, and 7 (29%) showed general marrow hypoplasia. Of 105 patients with all three cell types depressed in the blood, 10% showed a normal to hyperplastic marrow, 6% showed depression of one or two cell types in the marrow, and 84% showed general marrow hypoplasia. 7Fernbach, D. J., and Trentin, ~. J.: "Isologous Bone Marrow Transplantation in an Identical Twin With Aplastic Anemia" in Proceedings of the Eighth International Con- gress on Hematology, Tokyo: Pan-Pacific Press, 19a2. vol. 1, pp. 150-155. PAGENO="0303" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2437 Clinical manifestations were not reported in detail for most cases, but those which were given conformed with what one might expect: manifestations of anemia, propensity to hemorrhage, and increased susceptibility to infection. DETAILS OF DRUG ADMINISTRATION General.-The reason that chioramphenicol had been given (for the most part infection or prophylaxis against infection) was cited in Ti~% of the 408 cases (Fig.2). Reasons drug was given Some specific conditions for which chioramphenicol given Lower 0 U. infections *.. .. Common cold ~ Pneumonia, bronchopneumonio ___________ Pyelooephrutis. . .. _ Typhoid fever Septicemia Chronic broochilis - . . . . . . . Ear and sinus infections Severe tonsillitis, pharyngitis. , - Cellulitis, boils Subacute boct.endocorditis. . .. Acne Paratyphoid infections - H. influenza meningitis 1,11,1. .1.1. 0 5 0 15 - Per cent of cases 2. Reasons why chloramphenicol given. Left, General nature of indica. tions. Right, Specific conditions; all those accounting for 3% or more of known indications plus selected conditions with lower percentages. Ohioramphenicol was the only known drug administered during the prior six months to 40% of patients. One other drug was mentioned for 19%, two for 13%, and three or more for 28%. In one case, 17 other drugs were listed. In ~% o-f all cases, the only o-ther drugs mentioned were members of what the study group considers to be generally "innocent" drugs-aspirin, the barbiturates, chioral hydrate, digitalis glycosides, the penicillins, and the tetracyclines; in 37% of a-li cases, drugs other than "innocent" ones were administered, but no "toxic" drugs were given; in 9%, another toxic drug was ad-ministered, -but suspicion was cast most strongly on chlora.mphenicol; and in 4% -suspicion was cast most strongly on another toxic drug. Thus, in 96% of cases, `there is str-ong suspicion that chioramphenicol was the causative agent, and in the remaining cases, this possibility cannot be ruled out. Since elimination of those patients receiving another t-oxic -drug ha-d virtually no effect on outcome of the -dyscra-sia, all cases were included in the analysis. Duration and Dosage of Chloramphenicol.-It is known that 9% of patients received thi-s drug at least `once -prior to the course i-n question. The dashed line of Fig 3 presents a cumulative plot of average daily dose in milligrams per kilogram per day and `a type of graph paper having logarithmic an-d probability scales. If the log-dose were distributed in gaussian fashion, -such a plot should approximate a -straight line. Central portions o-f such curves are generally more accurate than the extremes. In this case there is some deviation from a -single straight li-ne, but the fit is not bad. At any rate, interpolation will provide -estimates of dosage level-s defining selected percentiles. It is seen that 10% of patients received less than 8 -mg/kg/day, 50% received less than 23 mg/kg/day, and 10% received greater than 60 mg/kg/day. This i-s to b-c contrasted with a manufacturer's recommendations for a starting dose of 50 mg/kg/day in adults and 50 -to 100 mg per kilogram per day in children beyond infancy. Either smaller doses tend to be given to susceptible patient, o-r el-se the general trend in use of this drug i-s to administer smaller average amounts than recommended for initial therapy. The latter possibility seems, more likely. There appears to be slight -differences in pattern-s -of daily dose administration for different age groups. Thus, the median doses were: 33 mg/kg/day for patients 0 to 9 yea-ru of age, 24 mg/kg/day fo-r those 10 to 39 years of age, and 18 mg/kg/day for those 40 years of age and older. PAGENO="0304" 2438 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY (s".) Daily dose,milligrams per kilogram per day (244 cases) 2 5 0 20 50 100 200 I ```1 99. 0 0 0~ 95 0) ~, 90 04- U, ~) o ~ 80 -~ ci) C 4- i .E 60- -~ 40- U, a) U) a) 8 ~ 20- a) I0- C a) U a) 20 50 100 200 500 1,000 2,000 5,000 (c~.~) Total dose, milligramsperkilogram body weight (280 cases) 3. Daily dose of chloramphenicol in milligrams per kilogram per day and total dose in milligrams per kilogram. Distribution of values for each curve is indicated cumulatively on log-normal coordinates. The number of days of therapy is similarly plotted as one of the curves in Fig 4. There is a concavity to the cumulative plot line. Although various interpretations are possible, a tendency of physicians to use either short courses or prolonged courses of therapy depending on the nature of the infection seems to be the most reasonable explanation for this nonlinearity. In 10% of cases, development of a blood dyscrasia was related to four days or less of therapy with ~hlorarnphenicol; in 50% it was related to 13 days or less; and in 10% to 150 days or more. In a few instances the drug was administered on only one occasion. Median duration of therapy by age group was: 11 days for patients 0 to 9 years, 13 days for those 10 to 39 years, and 15 days for those 40 years and over. Time from first to last dose is similarly Shown in Fig 4. This time amounted to four days or less in 10% of cases, 38 days or less in 50%, and 200 days or more in 10%. The main difference between these two curves, seen at their middle, is due to instances in which the drug was taken intermittently. Of the 329 patients on whom such information was available, 39% received the drug intermittently. The small crossover of these two curves at their extremes reflects the fact that slightly different subsamples were suitable for each and that each curve is only an estimate rather than a precise indication of the curves which would be obtained from a much large population of similar cases. The total dose of chioramphenicol received by various patients is plotted cumulatively in Fig. 3. The cumulative plot closely approaches a straight line using these coordinates. In 10% of cases the total dose amounted to GO mg/kg or less, in 50% to 280 mg/kg or less, and in 10% to 1,300 mg/kg or more. One would expect the 50% intercept to agree fairly well with the product of 50% intercepts for average daily dose and number of days of therapy, and indeed the figure of 299 mg/kg obtained in this fashion is riot far from the value of the other curve of Fig. 3, 280 mg/kg. There appears to be essentially no dif- ference in total doses in milligrams per kilogram as related to age. Dosages of ChloramphenicoJ received .1,,,! 11111 I,.,cl ill PAGENO="0305" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2439 Time of Reaction a~ Related to Therapy.-One tends to think of adverse reac- tions as occurring during drug administration or shortly after discontinuation. Such a relationship proves to be the exception for chioramphenicol-associated blood dyscrasias. Among the 284 patients for which such information was avail- able, only 22% showed manifestations of the dyscrasia while the drug was still being given as shown by the appropriate curve of Fig. 4. The median time from discontinuation of the drug until clinical evidence of the dyscrasia appeared was 38 days, and in 10% of cases this time was 130 days or longer. There is a definite downward bending of this curve, and one wonders whether time from first dose to reaction might not more nearly approach a log-normal distribution. This curve has also been aharted in Fig. 4, and it shows an incomplete tendency to straight- ening. The reaction developed 10 days or less following initial dose in 10% of cases, 11195 days or less in 50%, and in 260 days or more in 10%. 99 .2 ~. Various time trends o - : ~ 95 : Survival curve, life table method Delay, last Na. of cases dose to reaction, `) Known dead I 08 284cosesfl ~ / Recovered 96 L~ °`y~ `~-&~ Alive with sequelae. .75 Totol...279 ~ 60 >c ~ 4Q 20- o ~, Number of days drug actually, 0 received, 204cases g'o ~ 5- 8) - 0 8) - a- I Ilitli Ill 0 2 5 0 20 50 00 200 Number of days 4. Number of days chloramphenicol received; elapsed time of chioramphenicol course; time from first dose to reaction; time from last dose to reaction; and survival time. Distribution of values for each curve is indi- cated cumulatively on log-normal coordinates. The survival curve is based on life-table analysis. None of the patients in this series are known to have been continued on or rechallenged with the drug after the dyscrasia was diagnosed, and we would not recommend that this be done. SURVIVAL AND COURSE Life Table Survival Curve.-Construction of a survival curve for a fatal disease on the basis of a series of patients, all of whom have not yet died at time of analysis, is best performed through the life table method.8 The present stitua- tion differs from that of a uniformly fatal disease in that, in addition to a trend towards mortality, there is also a trend towards recovery. Patients who have recovered are not known to have relapses unless the drug is administered fur- ther. In this instance, a satisfactory method of accounting for recoveries in life table analysis is to consider all patients who have recovered to be still alive at a relatively long period following onset of the dyscrasia, regardless of the actual length of follow-up. The top curve of Fig. 4 shows the results of this anal- ysis. Because of recoveries, the curve approaches an asymptote rather than describing a straight line on a log-probability plot. The overall mortality ap- proached is approximately 50%; 10% of the patients in the entire series have died within two weeks of onset of the dyscrasia. The 75% intercept (i.e., median survival for those with fatal outcome) is about 50 days. Rare cases may have a fatal outcome a year or more after diagnosis. 8Merrefl, M., and Schulman, L. B.: Determination of Prognosis in Chronic Disease, Illus- trated by Systemic Lupus Erythematosus, J. Chronic Dis 1: 12-32 (Jan.) 1955. 81-280 O-68-pt. 6-20 `J 500 PAGENO="0306" 2440 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Jourse.-It was specifically reported in several instances that recovery fol- lowed withdrawal of the drug, and it was presumed that this occurred within a few weeks. Most of these instanëes were associated with depression of a single blood cell type. On the other hand, of the 75 patients known to be alive with persistent evidence of the dyscrasia despite cessation of the drug, 20 (27%) were alive 100 to 299 days after onset, and 11 (14%) were alive 300 or more days after onset. Recoveries have sometimes been noted after relatively long periods of disease. Death is known to have occurred in 186 cases, 95% from complications of the dyscrasia. Performance of an autopsy was noted for 24% of these cases; however, details of this examination were not usually reported. Therapeutic measures directed against the marrow depression were usually not reported, and no attempt was made to evaluate these. PROGNOSIS Detailed studies on prognosis have been submitted for publication elsewhere (W. R. Best). The most important clinical findings are that improved survival is associated with fewer cell-types depressed, shorter delays in onset, larger daily doses, and occurrence in Negroes. COMMENT Yunis and Bloomberg have reviewed various types of evidence bearing on the pathogenesis of those hematologic reactions to chloramphenicol which occur in rare cases at commonly employed dosage levels. They found no convincing evidence to support an autoimmune process, and the current data. cannot be construed as adding such. Abnormal susceptibility due to some biochemical abnormality seems more likely, but the exact nature of such a disorder remains to be determined. Yunis and Bloomberg suggest that a defect in localization, metabolism, or excretion of chloramphenicol, or an enzymatic or other biochemical deficiency involving a metabolic pathway that becomes essential in the presence of this drug, could account for these reactions. One suspects that there is an underlying hereditary difference between individuals who do and those who do not develop this reaction to chloramphenicol. The occurrence of dyscrasias in both members of a set of identical twins is one of the most interesting findings in the Registry relative to the genetic question. It is reasonable to suppose that many close relatives of Registry patients have received courses of chloramphenicol com- parable to those of corresponding affected family members, and that a high percentage, if not all instances of multiple cases in a single family would have been called to the attention of the Registry. Yet, so far as we have been able to determine, the only instance in the Registry or the medical literature in which more than one member of a family has developed such a dyscrasia is this par- ticular one involving the relatively rare sib combination of identical twins. One could reasonably expect several nontwiu sibling pairs in the total experience to date if this susceptibility to chloramphenicol required a homozygous state relative to a single recessive gene. Simultaneous exposure to some unusual environmental factor or the fact that the only known sibling pair developing this defect share an identical genetic constitution strongly suggests that an unusual combination of genetic factors must he present in a homozygous form before this abnormal susceptibility becomes manifest. Unusual racial or ethnic patterns of occurrence or course would be consistent with genetic disorders, but would not provide conclusive evidence thereof. Con- sidering the racial composition and patterns of medical care of populations about whom the Registry is most likely to receive reports, one has no compelling reason to suspect that members of one race are more likely to develop this reaction, given a similar drug exposure, than are those of another. However, a striking difference in clinical course seems to be related to race in this series. Nonwhite patients tend to have a much more benign course than whites, a trend not previously noted. Unusual patterns of occurrence relative to age or sex, if not otherwise ex- plained, would tend to implicate developmental, degenerative, or hormonal factors as being of at least secondary importance. Females accounted for 54% of cases surveyed by Yunis and Bloomberg and 62% in the current report. Some of the age-sex patterns noted can reasonably be assumed to reflect dif- ferences in occurrence rate for various diseases for which chloramphenicol in PAGENO="0307" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2441 often given (Table), but in addition, it seems likely from case data that there is an increased susceptibility to this complication in females prior to the meno- pause. A peak occurrence rate was noted at 6 to 10 years of age by Yunis and Bloomberg and at 3 to 7 years of age in the present series, the differences being in part due to different tabulation intervals. The marked difference between US and non-US reports in this regard suggests that there may be different national medical trends in the approach to use of chloramphenicol. Upper respiratory tract infections are frequent in this age group and account for a high proportion of uses. Thus, one can neither confirm nor refute at this time the possibility that children at this age may be more susceptible to chloramphenicol-induced marrow depression. Clinical Uharaoterization~-yunis and Bloomberg interpret the data of their review as indicating that chloramphenicol produces two types of marrow toxicity. They state that the first of these usually occurs during therapy, is associated with a larger total dose, demonstrates a normocellular marrow, shows anemia with or without leukopenia or thrombocytopenia, and is reversible on withdrawal* of the drug. The second type shows a delayed onset, is not necessarily dose-related, demonstrates an aplastic marrow with associated pancytopenia, and usually has a fatal outcome. A majority of cases in the current report conform in most re- spects to the second class, and there is another cluster which fits fairly well into the first class. However, a number of cases fall between or overlap these two groups. For example, nine of 60 patients in the present series who had at least two weeks delay between the last dose and development of the reaction showed a normocellular marrow or one with only isolated cellular depression, whereas Yuni:~ and Bloomberg found no such cases. All combinations of blood cell de- pression were seen in association with nonaplastic marrows, and half of the cur- rent series showing pancytopenia in contrast to a more limited spectrum seen in the series reviewed by Yunis and Bloornberg. Patients with hypoplastic mar- rows tend to have received a smaller dose of drug, but there is an appreciable overlap. Thus, the 10%, 50%, and 90% intercepts of a cumulative dosage curve for 48 current cases with marrow hypoplasia were 5, 20, and 54 mg per kilogram per day, respectively; whereas for 28 cases with lesser degrees of marrow in- volvement the corresponding figures were 16, 31; and 88 mg per kilogram per day. These doses are well within usual recommendations. Curves for the dura- tion of therapy were very similar for the two degrees of marrow involvement with a median of 11 to 12 days. The cases reviewed by Yunis and Bloomberg on the other hand, show a median duration of therapy of about 35 days for patients with hypoplastic marrows, and about 20 days for those with nonhypoplastic marrows. Unidentified biases in the reporting of cases may account for this difference between the two series. The implication of these authors in dividing chioramphenicol-associated blood dyscrasias into two groups is that there may be two separate mechanisms in- volved. The current study would indicate that the cases as they occur are not always so sharply divisible, and that the possibility of a single pathogenic mechanism is by no means ruled out. Findings in the identical twins reported here would speak for a single mechanism, for the patient with the greater number of prior courses developed typical aplasia, whereas his twin showed a readily reversible, isolated cytopenia. Preventive Aspects.-The best educated guess as to frequency of this com- plication, probably an underestimate of true occurrence, is that of Leikin et al.9 in which it would appear that less than one case of serious marrow toxicity occurs for every 100,000 courses of therapy. The data presently available are not appropriate for further speculation in this regard. This study does, however, present a good deal of quantitative information relative to the types of drug course which have been associated with this complica- tion. Marrow toxicity has been seen after low doses and high doses, chloram- phenicol alone and in combination with other drugs, short courses and long courses, continuous therapy and intermittent therapy, and single courses and repeated courses. Most patients have received chloramphenicol in dosage and duration commensurate with best clinical practice. Unfortunately, however, it cannot be stated that indications for use always conformed to optimal standards. Most experts would consider chloramphenicol the treatment of choice in °Leikln, S. L.; Welch, H.; and Gum, G. H.: Aplastic Anemia Due to Chioramphenicol, Gun Pro Chil Hosp Wash 17: 171-181 (July) 1961. PAGENO="0308" 2442 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY typhoid and paratyphoid infections, and some would include Haenu~philua in- fl~en~ae meningitis. These three conditions accounted for 6.6% of indications in the current series, most of these being from non-US sources. Chioramphenicol is also indicated in certain other serious acute and ,chronic infections depending on in vitro sensitivities and particular features of a patient's course. The report forms did not request sufficient data for further evaluation in this regard. The drug is inactive against common viral and upper respiratory tract infec- tions, but these conditions accounted for a significant percentage of stated indications in this series. Thus, the most powerful preventive tool available is the use of this agent only for serious infections in which the balance of risks of adverse reactions against the risks of inadequate therapy tend to favor use of this antibiotic over alternative methods of treatment. It should be recog- nized that the risk of occurrence in any case treated with chloramphenicol is quite slight, but the risk of a fatality in that patient who develops this reaction is great. Some physicians have belittled this complication because they have seen no hint of a blood dyscrasia in `the many courses of chioramphenicol therapy which they have directed. One should not be surprised at such an experience, for it is a rare complication; however, this is little consolation to the future patient under such a physician's care who dies of aplasia because chlorampheni- col was given when it need not have been. Most patients develop manifestations of marrow depression after the drug has been stopped, often weeks or months later. It thus appears that monitoring blood counts during therapy would be of little or no value in preventing mor- bidity and mortality in the majority of cases. However, there is a minority of reactions, usually isolated cytopenias, which may become apparent during ther- apy and respond to withdrawal of the drug. It is for the recognition of such cases that we recommend the occasional performance of blood counts during chloranphenicol therapy. Under the assumption that an isolated cytopenia rep- resents a basically different and less dangerous type of toxicity. Yunis and Bloomberg do not feel that therpay need be stopped in such cases. We do not agree. No cases in which chioramphenicol was continued after the development of a cytopenia have come to our attention, and one would seem ill advised to continue therapy on the basis of this unproven theory. SUMMARY AND CONCLUSIONS This review involves 408 cases of chloramphenicol-associated non-neoplastic depression of one of more blood cell types that were reported directly to the AMA Registry on Blood Dyscrasias or abstracted from the medical literature. Various quantitative features of the occurrence of this dyscrasia and relation- ship to drug administration have been delineated. The dyscrasias noted range from readily reversible, isolated cytopenias occur- ring during therapy to delayed, progressive aplastic anemia. This range is not considered as necessarily indicative of more than one fundamental type of drug reaction. It is apparent that blood dyscrasias may occur in relation to conven- tional and even brief courses of therapy, and that signs of such reaction may not be seen until long after the course has been completed. The best approach to prevention thus lies in a sound appraisal of possible benefits and dangers when- ever use of this drug is contemplated. The occasional monitoring of blood counts may prove worthwhile in rare cases, but its expected value in the usual case is sufficiently small that one cannot substitute such a practice for good judg- ment in deciding when the drug should or should not be used. A more complete bibliography indicating where previously published cases appear, together with other supplemental information, including rules and trans- formations used to estimate desired parameters from partial data, may be ob- tained by ordering Document No. 9515 from American Documentation Institute, Library of Congress, Washington, D.C. 20540, remitting $2.50 for photoprints or $1.75 for 35-mm microfilm. GENERIC AND TRADE NAMES OF DRUG Chloramphenicol-Chloromycetin, Cyiphenicol, Tega-Cetin. Senator NELSON. Our next witness is Dr. Mark H. Lepper. Doctor, the committee appreciates your coming here today. Your PAGENO="0309" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2443 biographical material will be printed in full, so would you mind stat- ing for the record a summary of your biographical and professional background. STATEMENT `OP DR. MARK H. LEPPER, VICE PRESIDENT, PROFES- SIONAL AND ACADEMIC AEFAIRS, PRESBYTERIAN-ST. LUKE'S HOSPITAL, CH.ICM+O, ILL. Dr. LEPPER. I would be happy to, Senator. In connection with my background, I would also like to put in a disclaimer similar to that Dr. Dameshek used to point out that this is an attempt to be as objective as possible. It is quite clear that objec- tivity is something that none of us really achieves. I do have a somewhat different point of view than the previous witnesses simply because my background was in infectious disease, probably as much responsible for my being here today as anything was in support of the drug industry throughout my career in the field of infectious disease research, particularly in therapy of infectious diseases. We have, therefore, been interested in the problems of the treatment of infection from the days of the sulfanomides. Following this, I became professor of preventive medicine at the University of Illinois. Many people in infectious diseases-as control became the dominant activity-became more and more interested in preventive medicine. This is the gradually expanding interest in the biometric statistical approach to medicine, the so-called epidemio~ logical approach, and finally, tied into medical care and medical care research. I am vice president for professional and academic affairs at the Presbyterian-St. Luke's Hospital, which is an affiliate of the Univer- sity of Illinois, and I continue to carry my title of professor of preven- tive medicine at the university. I, too, am speaking as an individual. My opinion does not necessarily reflect the agencies which I have just mentioned. (The biographical material submitted by Dr. Lepper follows:) CURRICULUM VITAE-MARK HUMMER LEPPER, M.D. Born: June 12, 191'T-Washtngthn, D.C. Edv~cation George Washington University, A.B.-1938, M.D.-1941. Hospital Appointments Intern, Sibley Memorial Hospital, 1941-1942. Assistant Resident in Medicine, Gallinger Municipal Hospital, 1943-1944. Consultant in Internal Medicine, Walter Reed General Hospital, 1948-1950. Medical Superintendent, Municipal Contagious Disease Hospital, Ohicago, Illinois, 1950-1952. Attending Physician, Presbyterian-St. Luke's Hospital, 1952-1962. Consulting Physician, Presbyterian-St. Luke's Hospital, 1962- Executive Vice President, Prof. & Academic Affairs, Pre~byterian-St. Luke's Hospital, 1966- Following Appointn~ents and Fellowships Fellow in Medicine, George Washington University, 1942-1946. Clinical Instructor in Medicine, George Washington University (part time), 1946-1948. PAGENO="0310" 2444 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Clinical Instructor in Medicine, George Washington University (full time),, 1948-1949. Clinical Associate Professor of Preventive Medicine, University of Illinois, 1950-1952. Associate Professor of Medicine in charge of Preventive Medicine, University of Illinois, 1952-1965. Professor of Preventive Medicine and Head of the Department, University of Illinois, 1965-1966. Professor of Preventive Medicine, 1966- Military Service U.S. Army Medical Corps, Platoon Leader to Station Hospital, Commander. Rank following discharge, Major, 1944-1946. Certification by Specialty Board American Board of Internal Medicine, 1950. Membership in Professional Societies American Society for Olinical Investigation. Association of Teachers of Preventive Medicine, President, 1965-1966. American Federation for Clinical Research. Central Society for Clinical Research, Council, 1965-1968. Central Clinical Research Club, President, 1965-1966. Chicago Society of Internal Medicine. Chicago Society of Allergy. Fellow, American Public Health Association. Fellow, American Medical Association. Illinois Public Health Association. Medical Society of the District of Columbia. New York Academy of Science. Fellow, American College of Physicians. Sigma Xi, Scientific Society. American Society of Miero~iologists. Infectious Disease Society of America, Council, 1964-1968. Planning Committee Interscience Conference on Antimicrobial Agents and Chemotherapy, 1961-1963. Membership in Honor Societies Phi Beta Kappa. Alpha Omega Alpha. Membership in Community Societies Board of Governors, American Heart Association. Epidemiology Council, American Heart Association. Study Section on Bacteriology and Mycology, National Institutes of Health, 1962-1964. Surgeon General's Task Force on Tuberculosis, 1963. Advisory Board to Director Communicable Disease Center, 1963-1967. Advisory Board on Treatment Center Grants to National Foundation, N.Y. Committee in Human Reproduction, A.M.A. Advisory Committee, Mental Health Section, Board of Health, Chicago. Poliomyelitis Technical Advisory Committee, State (Illinois) Health De- partment. Board of Directors, Tuberculosis Institute of Chicago. Medical Advisory Board, Suburban Cook County Tuberculosis Control. Chairman, Community Service Council, Chicago Heart Association. Board of Directors and Executive Committee, Chicago Heart Association. Northeastern Illinois Air Pollution Technical Advisory Board. Medical Board, Visiting Nurses Association, Chairman, 1960-1965. Public Health Committee of.Welfare Council. Medical Advisory Council, Asthma and Allergy Foundation for Greater Chicago. Advisory Committee, Heart Disease Control Program, Chairman. Member, Editorial Board of Applied Microbiology. Technical Committee on Infant Health Study of Welfare Council. Medical Advisory Board, Chicago Committee on Alcoholism, Chairman. Member, Board of Directors, Chicago Committee on Alcoholism. Member of the Veterans Administration Research Program Advisory Board. Food and Drug Committee on Veterinary Medicine and Non-medical Use of PAGENO="0311" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2445 Antibiotics, Chairman. Advisory Board on Grants to National Arthritis Foundation. Board of Trustees, Bishop Anderson Foundation, Vice Chairman, 1965. Editorial Board, American Review of Respiratory Disease. Research Committee, American Thoracic Society. Editorial Board, Applied Microbiology. BIBLIOGRAPHY-MARK H. LEPPER, M.D. 1. Dowling, H. F. and Lepper, M. H. Toxic Reactions Following Therapy with Sulfapyridine, Sulfathiazole and Sulfadiazine. JAMA, 121, 1190-1194, (April) 1943. 2. Lopper, M. H., Sweet, L. K. and Dowling, H. F. The Treatment of Mening- ococcic Infections with Sulfadiazine and Sulfamerazine. JAMA, 123, 134-138, (Sept.) 1943. 3. Lepper, M. H. and Dumoff-Stanley, E. Method of Treatment of Meningococcic Meningitis with Sulfadiazine and Sulfamerazine; Results in 140 Cases. Med. Ann. Dist. of Columbia, 13, 54-57, (Feb.) 1944. 4. Dowling, H. F. and Lepper, M. H. "Drug Fever" Accompanying Second Courses of Sulfathuiazole. Sulfadiazine and Sulfapyridine. Am. J. Med. Sd., 207, 349-353, (Mar.) 1944. 5. Sweet, L. K. and Lopper, M. H. Acute Serous Meningitis in Scarlet Fever. J. Ped., 24,295-309, (Mar.) 1944. 6. Dowling, H. F., Dumoff-Stanley, E., Lepper, M. H., and Sweet, L. K. Rela- tive Toxicity of Sulfamerazine and Sulfadiazine. JAMA, 125, 103-105, (May) 1944. 7. Sweet, L. K., Dumoff-Stanley, E., Dowling, H. F. and Lepper, M. H. The Treatment of Pneumococcic Meningitis with Penicillin. JAMA, 127, 263-267, (Feb.) 1945. 8. Dowling, H. F., Hirsch, H. L. and Lopper, M. H. Toxic Reactions. Accom- panying Second Courses of Sulfonamides in Patients Developing Toxic Reactions During a Previous Course. Aim. mt. Med., 24, 629-633. (April) 1946. 9. Dowling, H. F., Lepper, M. H., Sweet, L. K. and Brickhouse, R. L. Studies on Serum Concentrations in Humans and Preliminary Observations on `the Treatment of Human Infections with Aureomycin. Ann. N.Y. Acad. Sci., 51, 241-245, (Nov) 1948. 10. Zelleir, W. W., Lepper, M. H., Robinson, J. A., Hirsch, H. L., and Dowling, H. F. The Effect of Caronamide on the Blood Concentration of Peni- cillin Following Oral and Intramuscular Administration of Penicillin. Ann. Tnt. Med. 30, 398-407, (Feb) 1949. 11. Dowling, H. F., Sweet, L. K., Hirsch, H. L., and Lepper, M. H. Specific Therapy of Bacterial Infections of the Central Nervous System. JAMA, 1:39, 755-758, (Mar) 1949. 12. Lepper, M. H., Dowling, H. F., Brickhouse, R. L. and Caldwell, E. R. Blood and Cerebrospinal Fluid Concentrations of Aureomycin After Oral and Intramuscular Admiinstration. J. Lab. and Olin Med., 34, 366-371, (Mar) 1949. 13. Dowling, H. F., Lepper, M. H., Caldwell, E. R. Jr., Whelter, R. L. and Sweet, L. K. Aureomycin in Various Infections: Report of One-hundred-eighty Cases and Review of the Clinical Literature. Med. Ann. D.C., 18, 335~-345, (July) 1949. 14. Brickhouse, R. t., Lopper, M. H., Stone, H. E., and Dowling, H. F. The Treatment of Pneumonia and Other Infections with Soluble Sulfonamide, Cantrisan (NU-445; 3,4-Dimethyl-5-Sulfanilimido-Isoxazole). Am. J. Med. Sd., 218, 133-137, (Aug) 1949. 15. Lopper, M. H., Dowling, H. F., Robinson, J. A., Stone, T. E., Briekhouse, R. L., Caldwell, E. R. Jr. and Whelton R. L. Studies on Hypersensitivity to Penicillin 1. Incidence of Reactions in 1303 Patients. J. Clin. Invest., 28, 826-831, (Sept) 1949. 16. Dowling, H. F., Lepper, M. H., Caidwell, E. R. Jr. Whelton, R. L. and Brickhouse, R. L. The Concentration of Aureomycin in Urine and Cerebro- spinal, Pleural and Ascitic Fluids after Oral and Intravenous Adminis- tration. J. Clin. Invest., 28, 983-986 (Sept) 1949. 17. Whelton, R. L., Caldwell, E. H. Jr., Lepper, M. H., Sweet, L. K. and Dowling, H. F. The Treatment of Poliomyelltis with Phenosulfazole. J. Ped., 35, 447-450, (Oct) 1949. PAGENO="0312" 2446 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 18. Dowling, H. F., Lopper, M. H., Hussey, M. H., Caidwell, E. R. Jr. and Spies, H. W. The Treatment of Pneumococcic Pneumonia with Aureomycin. J. Lab. and Olin. Med. 35,215-219, (Fob) 1950. 19. Dowling, H. F. and Lepper, M. H. Recent Advances in Antibiotic Therapy with Special Reference to Aureomycin and Cliloraphenicol. So. Med. J., 43, 190-195, (Mar) 1950. 20. Zeller, W. W. and Lepper, M. H. Meningitis Due to Pasteurella Other than Pasteurella Tularensis and Pasteurella Pestis. Am. J. Med., 9, 701-7~1X3, (Nov) 1950. 21. Lepper, M. H., Caidwell, E. R. Jr., Smith, P. K. and Miller, B. F. Effects on Anaphylactic Shock of Salicylates, Aminopyrine and Other Chemically and Pharmacologically Related Compounds. Proc. Soc. Exptl. Biol. and Med. 74, 254-258, (June) 1950. 22. Dowling, H. F., Lepper, M. H. and Hirsch, H. L. The Treatment of Pneumo- coccic Pneumonia with Large Doses of Repository Penicillin Compared With Lower Doses of Penicillin: A Study of 686 Patients. Am. J. Med. Sd., 220, 17-22, (July) 1950. 23. Dowling, H. F., Lepper, M. H., Caidwell, E. R. and Spies, H. W. Terramycin in the Treatment of Pneumococcic and Other Bacterial Infections. Ann. N. Y. Acad. of Sd., 53,433-436, (Sept) 1950. 24. Caldwell, E. R., Spies, H. W., Wolfe, C. K., Lepper, M. H. and Dowling, H. F. The Treatment of Various Infections with Terramycin. J. Lab. and Olin. Med., 36, 747-753, (Nov) 1950. 25. Bunn, P., Caldwell, B. R., Adair, 0., Lopper, M. H. and Dowling, H. F. Absorption and Clinical Use of Penicillin Preparations Given in Large Oral Doses. JAMA 144,1540-1543, (Dec) 1950. 26. Spies, H. W., Dowling, II. F., Lopper, M. H., Wolfe, 0. K. and Caidwell, B. R. Aureomycin in the Treatment of Bacterial Endocarditis. Arch. mt. Med., 87, 66-78, (Jan) 1951. 27. Wehrle, P. F., Lepper, M. H. with cooperation of Bundesen, H. N. Aure- omycin Treatment of Pertussis. J. Ped., 39, 435-441, (Oct) 1951. 28. Dowling, H. F. and Lepper, i~I. H. The Effect of Antibiotics (Penicillin, Aureomycin and Terramycin) on the Fatality Rate and Incidence of Com- plication in Pneumococcic Pneumonia. A Comparison with Other Methods of Therapy. Am J. Med. Sd., 222, 396-403 (Oct) 1951. 29. Lepper, M. H., Wolfe, C. K., Zimmerman, H. J., Caldwell, B. R., Spides, H. W. and Dowling, H. F. Effect of Large Doses of Aureomycin on Human Liver, Arch. Int. Med., 88, 271-283, (Sept) 1951. 30. Lepper, M. H., Zimmerman, J. H., Carroll, G., Caidwell, B. R., Spides, H. W., Wolfe, C. K., and Dowling, H. F. Effect of Large Doses of Aureomycin, Terramycin and Ohlorainphenicol on Livers of Mice and Dogs. Arch. Int. Med., 88, 284-~5, (Sept) 1951. 31. Lopper, M. H. and Dowling, II. F. Treatment of Pneuniococcie Meningitis with Penicillin Compared with Penicillin Plus Aureomycin: Studies Including Observations on an Apparent Antagonism Between Penicillin and Aureomycin. Arch. Int. Med., 88,489-494, (Oct) 1951. 32. Dowling, H. F. and Lopper, 11. H. Practical Problems in the Use of Anti- biotics. Med. Cl. N. Am., 36, 247-262, (Jan) 1952. 33. Lepper, M. H., Rodriguez, J., Blatt, M. and Spides, H. W. Use of Dibenzyl- enediamine Penicillin Administered Orally in Bacterial Infections. Anti- biotics and Chemotherapy, 11, 175-178, (April) 1952. 34. Dowling, H. F., Lepper, M. H., Caldwell, B. R., and Spies, H. W. Staphy- lococcic Endocarditis: An Anlysis of 25 Cases Treated With Antibiotics, Together with a Review of the Recent Literature. Med., 31, 155-176, (May) 1952. 35. Lopper, M. H., Wehrle, P. F. and Blatt, N. H. Treatment of Hemophilus In- fluenza Meningitis. Comparison of Aureomydin Alone Versus Aureomy- clii, Streptomycin and Gantrisin. Am. J. Dis. Child., 83, 763-768, (June) 1952. 36. Wolfe, C. K., Lopper, M. H., Caidwell, B. R., Spies, H. W. and Dowling, H. F. Treatment of Nontuberculous Bacterial Pleural Space Infections with Aureomycin: Results of Treatment in Nine Patients; Concentration of Aureomycin in Pleural and Pericardial Fluid in Seven Patients. Ann. mt. Med., 37, 164-171, (July) 1952. PAGENO="0313" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2447 37. Lepper, M. L., Dowling, H. F., Wehrle, P. F., Blatt, N. H., Spies, H. W., and Brown, M. Meningococcic Meningitis: Treatment with Large Doses of Penicillin Compared to Treatment with Gantrissin. J. Lab. and Clin. Med., 40 891-900, (Dec) 1952. 38. Lepper, M. H. and Dowling, H. F. Management of the Patient with Men- ingitis. G.P., 7,47-52, (Feb) 1953. 39. Dowling, H. F., Lepper, M. H. and Jackson, G. G. When Should Anti- biotics be Used in Combination? J. Am. Med. Assoc., 151, 313-815, (March) 1953. 40. Lepper, M. H., Blatt, N. H., Wehrle, P. F. and Spides, H. W. Treatment of Bacterial Meningitis of Unusual Etiology and Purulent Meningitis of Unknown Origin. Am. J. Dis. Child., 85,295-302, (March) 1953. 41. Lepper, M. H., et al. Round Table Discussion: Antibiotics. Pediatrics, 11, 270-279, (March) 1958. 42. Jackson, G. (1, Lepper, M. H., Seto, J. and Dowling, H. F. Antagonism and Addition from Combinations of Aureomycin and Penicillin in the Treatment of Pneumococcic Infections in Mice. Am. J. Med. Sd., 225, 525-534, (May) 1953. 43. Lepper, M. H., Jackson, 0. 0., Dowling, H. F. and Seto, J. Comparison of Results of Treatment of Pneumococcic Infectious in Mice with Multiple Doses of Aureomycin and Penicillin Combined, Compared with Each Drug Alone. Am. J. Med. Sci., 225, 648-656, (June) 1953. 44. Lepper, M. H., Dowling, H. F., Jackson, 0. 0. and Hirsch, M. M. Epidemiol- ogy of Penicillin and Aureomycin-Resistant Staphylococci in a Hospi- tal Population. Arch. Int. Med., 92, 40-50, (July) 1953. 45. Dowling, H. F., Lepper, M. H. and Jackson, G. 0. Observations on the Epidemiological Spread of Antibiotic-Resistant Staphylococci with Measurements of the Changes of Sensitivity to Penicillin and Aureo- mycin. Am. J. of Pub. Health, 43, 860-868, (July) 1953. 4(1 Blatt, N. H. and Lepper, M. H. with cooperation of Bundesen, H. N. Reac- tions Following Antirabies Prophylaxis. A Report on Sixteen Patients. J. Dis. Child., 86, 395-402, (Oct) 1953. 47. Lepper, M. H., Moulton, B., Dowling, H. F., Jackson, 0. 0. and Kofman, S. Epidemiology of Erythromycin.Resjs~n~ Staphylococci in a Hospital Population. Effect on Therapeutic Activity of Erythromycin. Antibiotic Annual, 308-312, 1953-54. 48. Seto, J. T. and Lepper, M. H. The Effect of Chlortetracycline, Oxytetracy- dine and Tetracycline Administered Intravenously on Hepatic Fat Con- tent. Antibiotics and Chemotherapy, 4, 666-672, (June) 1954. 49. Spies, H. W., Lepper, M. H., Blatt, H. W. and Dowling, H. F. Tuberculous Menegitis. Treatment with Streptomycin, Para-Aminosalicyclic Acid and Promizole, Isoniazid and Streptomycin, and Isoniazid. Am. Rev. Tuberc., 69, 192-204, (Fob) 1954. 50. Jackson, G. G., Dowling, H. F. and Lepper, M. H. Bacteriophage Typing of Staphylococci. I. Technique and Patterns of Lysis. J. Lab. and Olin. Med., 44, 14-28, (July) 1954. 51. Jackson, G. 0., Dowling, H. F. and Lepper, M. H. Bacteriophage Typing of Staphylococci. II. Epidemiologic Studies Among Patients, Household Contacts and Hospital Personnel. J. Lab, and Olin. Med., 44, 29-40, (July) 1954. 52. Jackson, 0. G., Dowling, H. F. and Lopper, M. H. Bacteriophage Typing of Staphylococci. III. Relationship to Antibiotic Sensitivity and Resistance. J. Lab, and Olin. Med., 44, 41-50, (July) 1954. 53. Lepper, M. H., Kofman, S., Blatt, N. H., Dówling, H. F. and Jackson, 0. 0. Effect of Eight Antibiotics Used Singly and in Combination on the Tra- cheal Flora Following Tracheotomy in Poliomyelitis. Antobiotics and Chemotherapy, 4, 829-843, (Aug) 1954. 54. Wood, W. S., Kipnis, 0. P., Spies, H. W., Dowling, H. F., Lepper, M. H. and Jackson, 0. 0. Tetracycline Therapy. Olinical and Laboratory Observa- tions on 184 Patients Treated with Tetracycline, Arch. Int. Med. 94 351-363, (Sept) 1954. 55. Kofman, S., Lepper, M. H., Jackson, 0. 0. and Dowling, H. F. The Effect of Proteolytic Enzymes on the Physical and Chemical Characteristics of the Tracheobronchial Secretions of Patients with Poliomyelitis. Am. J. Med. Sci., 228, 426-431, (Oct) 1954. PAGENO="0314" 2448 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 56. Kofman, S., Lepper, M. H. Jackson, G. G. and Dowling, H. F. The Use of Trypsin or Streptokinase-Streptodernase for the Therapy and Preven- tion of Atelectasis. Am. J. Med. Sci., 228, 432-439, (Oct) 1954. 57. Lopper, M. H. latrogenic Disease. General Practice, 10, 66-72, (Oct) 1954. 58. Louis, J., Best, W. B., Lepper, M. H. and Limarzi, L. R. Bone Marrow Find- ings on Infectious Disease. Acta llaema., 12,293-304,1954. 59. Lopper, M. H., Jackson, G. G. and Dowling, H. F. Usefulness of Minimal Inhibitory Concentrations of Antibiotics to Identify Strains of Micro- coccus Pyogenes var Aiireus. Antibiotic Annual, 1037-1045, 1954-55. 60. Lepper, M. H. and Spies, H. W. Hydrabamine Penicillin G, and Penicillin Salt of a Rosin Amine Used Orally in the Treatment of Infections. Anti- biotics Annual, 137-143, 1954-55. 61. Dowling, H. F., Lopper, M. H. and Jackson, G. G. The Clinical Significance of Antibiotic-Resistant Bacteria. Amer. Med. Assoc., 157, 327-331, (Jan) 1955. 62. Lepper, M. H. and Spies, H. W. Treatment of the Acute Stages of Bul- bospinal Poliomyelitis. Med. Olin. of N. Amer., 39, 95-109, (Jan) 1955. 63. Moulton, B., Blatt, N. H. and Lepper, M. H. Use of Erythromycin in the Treatment of Common Respiratory Infections, Soft Tissue Infectious, and Complications of Exanthematous Fevers. Antibiotics Annual, 229- 241, 1954-55. 64. Spies, H. W., Lepper, M. H. and Dowling, H. F., Use of Tetracycyline Hydro- chloride Intramuscularly. Antibiotics Annual, 619-624, 1954-55. 65. Dowling, H. F. and Lopper, M. H. Die Antibiotikatherapie and ihre prob- leme. Therapalewoche, 642, 23-24, 1955. GO. Jackson, G. G., Dowling, H. F. and Lepper, M. H. Pathogenicity of Staphy- lococi. A Ooniparison Alpha-Hemoclysin Prodution with the Coagulase Test and Clinical Observations of Virulence. New Bug. J. Med., 252, 1020-1025, 1955. 67. Lepper, M. H., Jackson, G. G. and Dowling, H. F. Characteristics of the Micrococcal Uasal Carrier State Among Hospital Personnel. J. Lab, and Olin. Med., 45, 935-942, (June) 195. 68. Fofman, S., Lepper, M. H., Jackson5, G. G. and Dowling, H. F. Bacteriologic Studies of Pulmonary Infections in Patients with Poliomyelitis. J. Dis. Child., 90,51-57, (July) 1955. 69. Lepper, M. H. Microbial Resistance to Antibiotics. Ann. Int. Med., 43, 70. Lepper, M. H., Szanto, P. B., Kofman, S., Jackson, G. G. and Dowling, H. F. Pathogensis of Pulmonary Infections in Patients with Poliomyelitis. Am. J. Med. Sci., 320, 270-275, (Sept) 1955. 71. Pearson, J. Z., Somberg, A., Rosenthal, L., Lopper, M. H., Jackson, G. G. and Dowling, H. F. A Clinical Bacteriologic Evluation of Novobiocin in 75 Patients. Arch. lilt. Med., 98, 273-283, (Sept) 1956. 72. Wood, W., Rosenthal, I. ?~I., Spies, H. W. and Lepper, M. H. A Clinical Evaluation of Oral Penicillin V Therapy. Antibiotic Med. and Olin. Therapy, III, 38-42, (June) 1956. 73. Lepper, M. H., Spies, H. W., Kellow, W. F., Rosenthal, I. M. and Plaut, S. Spiramycin in the Treatment of Infection. Antibiotics Annual, 658-666, 1955-56. 74. Lopper, M. H. and Pearson, J. Z. A Study of the Effect of Tetracycline plus Nystatin on Aerobic Fecal Flora as Compared to Tetracycline Alone. Antibiotics Annual, 221-227, 1956-57. 75. Lopper, M. H. and Spies, H. W. A Clinical Study of the Use of Cortisone, Hydrocortisone and Corticot.rophin in the Treatment of Seriously Ill Patients with Infectious. Antibiotics Annual, 447-454, 1956-57. 76. Lopper, M. H., Dowling, H. F., Jackson, G. G., Spies, H. W. and Mellody, M. The effect of the Routine Use of Novobiocin and Spiramycin in Combina- tion on the Antibiotic Sensitiveness of Hospital Staphylococci. Antibiotics Annual, 640-647, 1956-57. 77. Lopper, M. H. Spiramycin. The Practitioner, 178, 363-368, (March) 1957. 78. Samter, M., Lopper, M. H. and Montgomery, M. M. Teaching of Internal Medicine. The Evaluation of Loctures `and Lecturers: A Discussion of Re- suits of a Study by Faculty and Students at `the University of Illinois College of Medicine. Ann. Tnt. Med., 46, 568-589, (March) 1957. 79. Grayston, J. T., Lepper, M. H. and Youmans, G. P. The Host in Infection. Ill. Med. J., III, (Feb) 1957. PAGENO="0315" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2449 80. Lopper, M. H. The Newer Antibiotics. Transactions Amer. Acad. Ophth. and Otolaryn., 61, 577-583, (Sept-Oct) 1957. 81. Lepper, M. H., Simon, A. J. and Marienfeld, C. J. Use of Sulfamethoxypyrida- zine in the Prevention of Streptococcal Infections in Rheumatic Patients. Ann. N. Y. Acad. Sci., 69,485-492, (Oct) 1957. 82. Vosti, K. L., Pearson, J. Z., Lepper, M. H., Dowling, H. F. and Jackson, G. G. Paper Electrophoretic Partition of Serum Protein and C-Reactive Protein in Patients with Bronchiectasis with a Preliminary Report on the Effect of Prolonged Antibiotic Treatment. Am. J. Med. Sc!., 234, 656-662, (Dee) 1957. 83. Lepper, M. H. and Spies, H. W. The Use of Intravenous Hydrocortisone as Supplemental Treatment in Acute Bacterial Meningitis. Antibiotics An- nual, 336-349, 1957-58. 84. Lopper, M. H. Recent Developments in Antibiotics Treatment. Wis. Med. J., 157,207-215, (May) 1958. 85. Lopper, M. H., Lockwood, J., Spies, H. W. and Rubenis, M. Studies on the Epidemiology of Strains of candida in Hospital Wards. Antibiotics Annual, 666-671, 1958-59. 86. Lepper, M. H., Spies, H. W. and Rubenis, M. Use of Amphotericin to Elimi- nate can4ida from the Stools of Infants Treated with Tetracycline. Anti- biotics Annual, 672-676, 1958-59. 87. Lopper, M. H., Pearah, G. and Blatt, N. H. An Epidemiological Study of the Implantation of Bacteria in the Respiratory Tracts of Patients with Bulbospinal Poliomyeliti.s. Antibiotic Med. and Olin. Therapy, VI, 224-231, (April) 1959. 88. Cherniack, N. S., Yost!, K. L., Dowling, H. F., Lepper, M. H. and Jackson, G. G. Loug-derm Treatment of Bronchiectasis and Chronic Bronchitis. Arch. Int. Med., 103, 345-353, (Mar) 1959. 89. Cherniack, N. S., Yost!, K. L., Saxton, G. A., Lepper, M. H. and Dowling, H. F. Pulmonary Function Tests in Fifty Patients with Bronchiectasis. J. Lab. and Olin. Med., 53, 693-707, (May) 1959. 90. Lopper, M. H. and Riley, H. D., Jr. Antimicrobial Agents. Pediatrics, 23, 1192-1198, (June) 1959. (Panel Discussion) 91. Lepper, M. H. and Spier, H. W. Treatment of Pneumococcic Meningitis. Arch. Int. Med., 104, 253-259, (Aug) 1959. 92. Lepper, M. H. Staphylococcal Infections in Newborn Nurseries. Syinp. Prob. Inf. and Control in Gen. Hosp., md. State Board of Health, 1959. 93. Lepper, M. H. and Spies, H. W. Results of Treatment of Tuberculous Menin- gitis with Several Regimen. Trans 18th Conf. on Chemo. Tuberc., 183-191, 1959. 94. Lepper, M. H., Priest, J. H. and Simon, A. Studies of the Staphylococcus in the Upper Respiratory Tract of Patients Receiving Antibiotics in a Rheu- matic Fever Convalescence Home. Antibiotics Annual, 744-754, 1959L~60. 95. Ross, S., Sprunt, D. H., Goodman, S., High, R. H., Lepper, M. H. and Weiss, C. The Chemotherapy of Acute and Chronic Pediatric and Geriatric In- fections. Antibiotics Annual, 1001-1019, 1959-1960. (Panel Discussion) 96. Dowling, H. F., Lepper, M. H. and Jackson, G. G. Important Guides in the Recognition of Viral Diseases of the Respiratory and Central Nervous Systems. Med. Clin. N. Amer., 44, 5-16, (Jan) 1960. 97. Dowling, H. F., Mellody, M., Lopper, M. H. and Jackson, G. G. Bacteriologic Studies of the Sputum in Patients with Chronic Bronchitis and Bron- chiectasis. Am. Rev, of Resp. Dis., 81, 329-339, (Mar) 1960. 98. Lichter, E. A., Sobel, S., Spies, H. W., Lepper, M. H. and Dowlirig, H. F. Demethylchlortetracycline Therapy in Pneumonia, Scarlet Fever, and Other Infections. Arch. mt. Med., 105, 601-606, (April) 1960. 99. Poth, F). J., Lopper, M. H. and Smith, M. B. Resistant Staphylococcal In- fections. Postgradua~ Med., 500-508, (April) 1960. 100. Lattimer, A., Simon, A. J. and Lopper, M. H. Use of Sulfadimethoxine in the Prevention of Streptococcal Infections in Rheumatic Patients. Am. J. Med. Sci.,239,548-553, (May) 1960. 101. Lepper, M. H. Antimicrobials: The Two-edged Sword. J. International Col- lege of Surgeons, 34, 22-29, (July) 1960. 102. Priest, J. H., Simon, A. J. and Lepper, M. H. Aerobic Bacterial Flora of the Throat of Children Given Prophylactic Antibiotics. Am. J. Dis. Child., 100, 74-84, (July) 1960. PAGENO="0316" 2450 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 103. Anderson, A. J., Lepper, M. H. and Winzler, R. J. Studies on Urine Culloids. II. Production of an Antibody to the Insoluble Organic Matrix of Renal Calculi and a Determination of a Soluble Antigen in the Urine of Patients with Polimyelitis. 104. Anderson, A. J., Lepper, M. H. and Winzler, R. J. The Fractionation of Urine Colloids on Anion-Exchange Cellulose. Biochem. J., 77, 581-591, 1960. 105. Weisman, S., Goldsmith, B., Winzler, R. and Lepper, M. H. Turnover of Plasma Orosomucoid in Man. J. Lab. and Olin. Med., 57, 7-15, (Jan) 1961. 106. Kessner, D. M. and Lopper, M. H. A Comparative Study of Hospital and community Gram-Negative Rods. J. Lab. Olin. Med., 58, 835-836, (Nov) 1961. 107. Buzdygan, D., Lepper, M. H., Neuhauser, I. and Rosenthal, I. M. Extensive Cutaneous Moniliasis. Treatment with Amphotericin B. Am. J. Dis. Child., 102, 168-179, (Aug) 1961. 108. Lepper, M. H. The Use and Misuse of Antibiotics and Other Chemo- therapeutic Agents. Med. Clinics of No. Amer., 45, 1663-1676, (Nov) 1961 109. Lepper, M. H. Two More Years with the Antibiotics. Industrial Medicine and Surg., 30, 476-481, (Nov) 1961. 110. Steblay, R. W. and Lepper, M. H. Some Immunologic Properties of Human and Dog Glomerular Basement Membranes. I. Isolation of Human Glome~ular BaSeflient Membrane: Similar or Identical Complement- fixing Antigens in Human and Dog Glomerular Basement Membrane Preparations. J. of Immunology, 87, 627-635, (Dee) 1961. 111. Steblay, R. W. and Lepper, M. H. Some Immunologic Properties of Human and Dog Glomerular Basement Membrane. II. Nephritis Produced in Dogs by Rabbit Antihuman Glomerular Basement Membrane Sera. J. Immunol., 87, 636-646, (Dcc) 1961. 112. Lepper, M. H., Dowling, H. F., Jackson, G. G., Lichter, E., Sobel, S. and Davis, J. C. Prolonged Administration of Antibiotics in Patients with Chronic Bronchial Disease. Antimicrobial Agents and Chemotherapy, 308-316, (i~Iay) 1961. 113. Leedom, J. II., Kennedy, R. P., Leeper, M. H., Jackson, G. G. and Dowling, II. F. Changes in Nasal Flora in Patients and Contacts When Methictillin was Used Extensively on Hospital Wards. Antimicrobial Agents and Chemotherapy, 683-692, (May) 1961. 114. Lepper, M. H., Dowling, H. F., Jackson, 0. G., Lichter, E. A., Sobel, S. and Davis, J. C. Effect of Various Antibiotic Regimens On Symptoms and Bacterial Flora of Sputum in Patients with Chronic Bronchial Disease. Transactions of the 21st Research Conference in Pulmonary Diseases, 273-280, (Jan) 1962. 115. Lepper, M. H. and Spies, H. W. Nontuberculous Bacterial Infections of the Nervous System. General Practice, 25, 83-93, (Feb) 1962. 116. Lepper, M. H. Prophylaxis in Patients Receiving Adrenal Steroid Therapy. J. Chron. Dis., 15, 691-711, (Feb) 1962. 117. Sobel, S., Lichter, E. A., Davis, J. C., Dowling, H. F., Lepper, M. H. and Jackson, G. G. Adverse Reactions to Tetracycline Penicillin and an Oleandomycin-Penicillin Mixture Used in the Long-Term Therapy of Chronic Pulmonary Disease. Am. J. Med. Sd., 243, 341-352, (March) 1962. 118. Lepper, M. H. and Lattimer, A. 0. Effect of the Usage of a Combination of Novobiocin and Erythomycin on the Susceptibility of Nasal Staphylococci. Antimicrobial Agents and Chemotherapy, 160-170, (May) 1962. 119. Lopper, M. H., Chomet, B. and Karklys, E. Mixed Infections with Staphylococcius Aureus and Gandida Albicans. Antimicrobial Agents and Chemotherapy, 114-122, (May) 1962. 120. Lepper, M. H., Dowling, H. F., Jackson, G. 0., Spies, H. W., and Norsen, J. Effect of Antibiotic Nasal Ointments on Carrier States in Patients and on the Antibiotic Pattern of Organisms from Personnel Caring for These Patients. Antimicrobial Agents and Chemotherapy, 140-149, (May) 1962. 121. Gotoff, S. P. and Lopper, M. H. Assay of Oolistin in Focal Specimens. Antimicrobial Agents and Chemotherapy, 447-454, (May) 1962. 122. Lopper, M. H. Evaluation of Antibacterial Agents. Clinical Pharmacology and Therapeutics, 3,392-396, (May-June) 1962. 123. Dowling, H. F., Lepper, M. H. and Jackson, 0. 0. Commentary: Supnressive Therapy of Chronic Bronchial Infections. Clinical Pharmacology and Therapeutics, 3, 564-579, (Sept-Oct) 1962. PAGENO="0317" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2451 124. Nahamias, A. J., Lepper, M. H., Hurst, V. and Mudd, S. Epidemiology and Treatment of Chronic Staphylococcal Infections in the Household. J. Public Health, 52, 1828-1843, (Nov) 1962. 125. Lepper, M. H. Prevention is the Only Therapy. Bulletin of the Atomic Scientists, 18, p. 29, (Dec) 1962. Review of Article, The Medical Con- sequences of Thermonuclear War, New Eng. J. Med., 266, 1126-1155, 1962. 126. Lopper, M. H., Hubbard, J., `Spies, H. W., Somberg, A., Wolfe, C. K. and Dowling, H. F. Treatment of Staphylococcemia. Ten Years' Experience With Several Regimen Including the Use of Combinations of Two Anti- biotics. Chemothe.rapia, 4, 361-385, 1962. 127. Bennett, I. L., Jr., et al. Cooperative Study Group. A Double-Blind Study of the Effectiveness of Cortisol in the Management of Severe Infections. Transactions of the Assoc. of Amer. Physicians, 75, 198-207, 1962. 128. Bennett, I. L., Jr., et al. Cooperative Study Group. The Effectiveness of Hydrocortisone in the Management of Severe Infections. A Double-Blind Study. J. Amer. Med. Assoc., 183, 462-465, (Fob) 1963. 129. Lopper, M. H. Drug Treatment of Chronic Bronchitis. Geriatrics, 18, 98-106, (Fob) 1963. 130. Lopper, M. H. and Spies, H. W. The Present Status of the Treatment of Tuberculosis of the Central Nervous System. Ann. N.Y. Acad. Sci., 106, 106-123, (Fob) 1963. 131. Lopper, M. H. as collaborator with the author, Robert W. Miller. Down's Syndrome (Mongolism), Other Congenital Malformations and Cancers Among the Sibs of Leukemic Children. New Eng. J. Med., 268, 393-401, (Feb) 1963. 132. Lopper, M. H. Metabolic Effects of Tetracycline. Ann. Tnt. Med., 58, 553-556, (March) 1963. (An Editorial). 133. Toigo, A., Imarisio, J. J., Murmall, H. and Lepper, M. H. Clearance of Large Carbon Particles from the Human Tracheobronchial Tree. Am. Review of Resp. Dis., 87, 487-492, (April) 1963. 134. Lopper, M. H. Opportunistic Gram-Negative Rode Pulmonary Infections. Dis. of the Chest, 44, 18-26, (July) 1963. 135. Paul, 0., Lopper, M. H., et al. A Longitudinal Study of Coronary Heart Disease. Circulation, XX VIII, 20-431, (July) 1963. 136. Lopper, M. H. and Ostfeld, A. Preventive Medicine `and Mental Health. Epidemiology of Sociopsychologic Variebles. Arch. Environmental Health, 7,331-336, (Sept) 1963. 137. Devetski, R., Vygantas, C. and Lopper, M. H. Subacute Bacterial Endo- earditis. Preliminary Observations on the Efficacy of a New Utilized Parameter in Its Differential Diagnosis. Pres.-St. Luke's Hospital Med. Bull., 2, 153-158, (Oct) 1963. 138. Gotoff, S. P., Lopper, M. H. and Fiedler, M. A. Antibody Response as an Adjunct in the Investigation of an Outbreak of Shigellosis. Amer. J. Hygiene, 78, 261-268, (Nov) 1963. 139. Lepper, M. H., Chomet, B. and Karklys, B. Experimental Mixed Infections in Mice. Arch. Environmental Health, 8, 570-583, (April) 1964. 140. Dowling, H. F. and Lepper, M. H. Hepatic Reactions to Tetracycline. J. Amer. Med. Assoc., 188, 307-309, (April) 1964. 141. Lopper, M. H. The Treatment of Medical Shock, Pediatric Clinics of North America, 11, 465-481, (May) 1964. 142. Devetski, R., Tiliman, P., Norsen, J. and Lepper, M. Emergence yf Antibiotic- Resistant Eschericia Coli in a Closed-Population When Ohloramphenicol Was Used Extensively. Antimicrobial Agents and Chemotherapy, 714-720, 1964. 143. Lopper, M. H. Research Needed to Learn How to Cope with Airborne Infec- tion. Amer, J. Public Health, 54, 1683-1688, (Oct) 1964. 144. Lepper, M. H. Cook County is County in the United States with `Second Largest Number of Tuberculosis Cases, Says Dr. Mark H. Lepper. `Chicago Medicine, 67, p. 1016, (Nov) 1964. 145. Lepper, M. H., Dowling, H. F., Jackson, G. G. and Carton, R. W. Natural History of Placebo-Treated Patients with Chronic Bronchial Disease Observed for 7 Years. Antimicrobial Agents and Chemotherapy, 4, 692- 698, 1964. PAGENO="0318" 2452 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 146. Su!hs, R. H. and Lepper, NI. H. Relationship of the Antigenic Structure of Sputum and Tracheobroncliial Mucosa. Amer. Rev. Resp. Dis., .91, 59-63, (Jan) 1965. 147. Suhs, R. H. and Lepper, NI. H. Induction of Cutaneous Hypersensitivity to Tracheobronchial Mucosa in Rabbits. Amer. Rev. Resp. Dis., 91, 64-66, (Jan) 1965. 148. Lepper, NI. H. and Penman, D. Antimicrobial Agents and Chemotherapy, Science, 147, p. 522, (Jan) 1965. 149. Sharp, J. T., Paul, 0., Lepper, NI. H., NIcKean, H. and Saxton, G. A. Prev- alence of Chronic Bronchitis in an American Male Urban Industrial Population. Amer. Rev. Resp. Dis., 91, 510-520, (April) 1965. 150. G~otoff, S. P., Lepper, NI. H. and Fiedler, NI. A. Treatment of Salmonella Carriers with Golistin Sulfate. Amer. J. Med. Sd., 249, 399-403, (April) 1965. 151. Fried, M. A. and Lepper, NI. H. Endemicity of Enteropathogenic Eschenichi Coil. Studies of Screening Procedure. Arch. Environmental Health, 10, 742-746, (May) 1965. 152. Lepper, NI. H., Paul, 0., Espey, H. S. and Sondag, R. F. Report of Recom- mendations-Illinois Second National Conference on Cardiovascular Dis- ease. (Illinois Committee) May 23, 1965. 153. Leedom, J., Kennedy, R., Lepper, NI. H., Jackson, G. G., Dowling, H. F. Observations of the Staphylococcal Nasal Carrier State. N.Y. Acad. Sci., 128, 381-403, (July) 1965. 154. Lepper, NI. H., Tiliman, P. and Devetsky, R. PatternS of Transmission of Staphylococci. N.Y. Acad. Sci., 128, 401-427, (July) 1965. 155. Lepper, NI. H. Antibiotics in 1965. Illinois Med. J., 128, 323-330; (Sept) 1965. 156. The Control of Fertility. The Committee On Human Reproduction, Raymond T. Holden, Chairman. JAMA, 1944. 462-470 (Oct) 1965. 157. Lopper, NI. H. University Relationships. J. Med. Education, 40, Chapter 7, 79-91. Workshop Summary, 91-93. (Oct) 1965. 158. Gotoff, D. S., Boring, J. R. and Lopper, NI. H. An Epidemic of Salmonella Saint-Paul Infections in a Convalescent Home. Am. J. Med. Sc, 251, 16-22, (Jan) 1966. 159. Gotoff, D. S., Lepper, M. H. and Fiedler, M. A. Immunologic Studies in an Epidemic of Salmonella Infections. Amer. J. Med. Sci., 251, 23-28, (Jan) 1966. 160. Baitch, A. L., Lepper, NI. H. and Lolans, V. T. Influence of Gorticosteroid Therapy on Serum Complement, Agglutinins, Free-boundary Elcetropho- resis, Royal Protein and Blood Counts in Dogs with Staphylococcal Bac- teremia. J. ImmunoL, 96, 149-158, 1966. 161. Report of the Committee on the Veterinary Medical and The Non-Medical Uses of Antibiotics. William W. Wright, Exec. Sec. Washington, D.C., May, 1966. 162. Fried, NI. A., Hafermann, D. R. and Lepper, NI. H. In TTitro Comparison of Fluorescent Antibody Technique with Culture and Slide Agglutination for the Detection of Enteropathogenic Eschenichia Coli. Am. J. Med. Sd., 252, 75-77, (July) 1966. 163. Lopper, NI. H. Discussion. Bacteriological `Reviews, 30, 548-550, (`Sept) 1966. 164. Lashof, J. and Lepper, M. H. Health and Medical Cane in Poverty Ar~as of Chicago. Presbyterian-St. Luke's Hospital Med. Bull., 5, 188-195, (Oct) 1966. 165. Lopper, NI. H. President's Message, Assoc. Teachers Preventive Med., News Letter, 13, Winter, 1966. 166. Kessner, D. NI. and Lapper, NI. H. Epidemiologic `Studies of Gram-Negative Bacilli in the Hospital and Community. Amer. J. of Epidemiology, 85, 45-60, 1967. 167. Control of Fertility. An Evaluation of Intrauterine Contraceptive Devices by the Committee on Human Reproduction, and an Evaluation of Oral Contraceptives by the Council on Drugs. JANIA, 199, 647-653 and 660-661, (Feb) 1967. 168. Streeter, S Dunn, H. and Lepper, NI. H. Hospital Infection-A Necessary Risk? Am. J. Nursing, 67, 526-533, (Mar) 1967. 169. Lopper, NI. H. Treatment of Infection in Diabetes Mellitus. Forecast, 20, 1-5, (May-June) 1967. Am. Prof. Pharm. 70-73 (Oct) 1967. 170. Lapper, NI. H., Lashof, J. C., Lerner, NI., German, J. and Andelman, S. L. Approaches to Meeting Health Needs of Large Poverty Populations. Amer. J. Public Health, 57, 1153-1157, (July) 1967. PAGENO="0319" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2453 ABSTRACTS 1. Lepper, M. H., Spies, H. W. Blatt, N. H. and Dowling, H. F. Treatment of Tuberculosis Meningitis in 17 Patients with Isonicotinic Acid and Hydra- zicle (isoniazid). Clin. Res. Proc. 1, 11, (April) 1953. 2. Lepper, M. H., Dowling, J. F., Jackson, G. G., Moulton, B. and Spies, H. W. Effect of Antibiotic Usage in the Hospital on the Incidence of Antibiotic- Resistant Strains Among Personnel Carrying Staphylococci. Central Society for Clinical Research. J. Lab. Clin. Med., p. 832, (Nov) 1953. 3. Wood, W. S. and Lepper, M. H. Antibody Response of Persons Who Have Re- ceived Rabies Vaccine. J. Lab. and Clin. Mccl., 44, 958, (Dee) 1954. 4. Steblay, R. W. and Lepper, M. H. Some New Immunologic Studies on Puri- fied Human Glomerular Basement Membrane and Dog Glomerular Base- ment Membrane in vitro. Clin. Res. Proc., 3, 211 (Nov) 1955. 5. Louis, J., Limarzi, L. R. and Lepper, M. H. Fever and Infection in Leukemia. J. Lab. and Olin. Med., 48,921, (Dee) 1956. 6. Lepper, M. H., Dowling, H. F., Jackson, G. G., Spies, H. W. and Mellody, M. S. A Comparison of the Effect of Two Antibiotics (Novobiocin and Spiramy- cm) Used in Combination with That of Spiramycin Alone on the Antibiotic Sensitivity of Microccoccus Pyogenes. J. Lab. & Olin. Med., 48, 920, (Dee) 1956. LECTURES, PAPERS, SEMINARS Lepper, M. H. The Tuberculosis Problem in Chicago and Cook County. Paper Presented at the Inter-Organization Committee on Tuberculosis Nursing, at the AMA Auditorium, Dec. 11, 1963. Lepper, M. H. and Wolfe, Elwood K. (Consultant Editors) Second International Conference on Aerobiology (Airborne Infection) Bacteriological Reviews, 30, 485-698, (Sept) 1966. Discussion, Mark Lepper, pp. 548-550. Lepper, M. H. Health Planning for the Urban Community: The Neighborhood Health Center. Presented at the 1st National Congress on the Socio-Economics of Health Care. AMA, Jan. 23, 1967, Chicago, Illinois. Lepper, M. H. Scientific Issues and Research Needs Concerning Microbial Eco- ology and the Use of Drugs in Feed. Study on Animal Population, National Research Council, Washington, D.C., June 7, 1967. Lepper, M. H. (Technical Advisory Committee) Managing the Air Resource in Northeasern Illinois. Technical Report No. 6, August, 1967. Northeastern Illinois Planning Commission. BOOK REVIEWS 1. Lepper, M. H. Hospital Infection by R.E.O. Williams, R. Blowers, L. P. Gar- rod and R. A. Shooter. Year Book Publishers, Inc. The Modern Hospital, 96, 6-8, (June) 1961. BOOKS AND BOOK CONTRIBUTIONS 1. Lepper, M. H. "Meningitis", Method of Mark H. Lepper, pp. 34-37. "Tuber- culosis Meningitis", Method of Mark H. Lepper, pp. 147-148. In Current Therapy, edited by Howard F. Conn. W. B. Saunders, Philadelphia, Pa., 1954. 2. Lepper, M. H. "Aureomycin" (Chiortetracycline). New York Medical Ency- clopedia, 1956. (Antibiotics Monograph). 3. Lepper, M. H. "Meningitis". In Current Therapy, pp. 24-27, edited by Howard F. Conn. W. B. Saunders & Co., Philadelphia, Pa., 1958. 4. Wood, W. S. and Lepper, M. H. "Drug Reactions". In Disease-a-Month, Year Book Publishers, Inc., Chicago, Illinois, August, 1958. 5. Lepper, M. H. "Tularemia, Method of Mark H. Lepper". In Current Therapy, edited by Howard F. Conn. W. B. Saunders, Philadelphia, Pa., pp. 60, 1962. 6. Branham, S. B., Alexander, H. A., FaUc, C. R., Lepper, M. H. and Weinstein, L. "Bacterial Meningitis". In Diagnostic Procedures and Reagents, edited by Harris and Coleman. American Public Health Assoc., Inc., Chapter 16, pp. 426-461, 1963. 7. Lepper, M. H. "Treatment of Meningitis". In Modern Treatment. Hoeber Medical Div., Harper & Row, 1, 956-974, 1964. PAGENO="0320" 2454 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 8. Lepper, M. H. "Pneumococcal Infections". In Current Pediatric Therapy, edited by, Gellis & Kagan. W. B. Saunders, Philadelphia, Pa., pp. 522- 523, 1964. 9. Lepper, M. H. "Chemotherapeutic and Antibiotic Agents". In Communicable Infectious Disease, edited by, Franklin Top. Mosby, St. Louis, Chapter 6, pp. 101-167, 1964. 10. Lepper, M. H. "The Prophylaxis in Patients Receiving Adrenal Steroid Therapy". In Prophylaxis of Infection. A Collection of Articles from the Journal of Chronic Disease, 15, 691-711, 1962. Edited by, R. D. Peters- dorf, Pergamon Press, 1964. 11. Lepper, M. H. "Current Status of the Chemotherapy of Bacterial Infection with the New Penicillins". Third International Congress of Chemother- opy. Edited by, Georg Thieme Verlag, Stuttgart, Germany, July, 1964. International Society of Chemotherapy, II, 1268-1285, 1964. 12. Stamler, Jeremiah, Chairman: Anderson, 0. W., Breslow, L., DeBoer, L., Getting, V. A., Lepper, M. H. and Stiles, M. H. "Atherosclerosis". Com- munity Service, Heart and Circulation. Chapter 6, Federation of Ameri- can Society for Expti. Biol., Washington, D.C., 1965. 13. Lepper, M. H. "Growth and Development". In Preventive Medicine, edited by Duncan W. Clark and Brian MacMahon, Little Brown and Co., Boston. Chapter 10, pp. 163-185, 1967. Dr. Li~ppi~. As one can see, I, too, have wrestled with the problem of the balance of good and harm which we always do in therapy. The problems of the use of chloramphenicol is one of the best examples of the many ramifications and difficulties inherent in establishing a clini- cal therapeutic index. I would emphasize there "clinical," because that is what we are talking about. The concept of a therapeutic index, was originally stated by the father of chemotherapy, Ehrlich, early in this century, his concept was that the higher the ratio of therapeutic effective dose to toxic dose, the better the compound. This, however, was thought of primarily in terms of the experimental animal, and in them relatively easily handled on a statistical basis. Thus, it has become a routine to find the protec- tive dose in an experimental infection and the lethal dose for toxicity in other animals of the same species. The most common statistic used is the dose that is 50-percent ef- fective on the one hand, and 50-percent lethal on the other. Thus, a drug that cures 50 percent of a group of animals at a dose level of 10 milligrams per kilogram and is lethal at a dose level of 500 milli- grams per kilogram, in 50 percent of a group of similar, but unin- fected, animals would have an index of 1/100. That is a very favor- able therapeutic ratio, I might add. If these doses were 10 and 20, respectively, however, the index would be one-half. That is not a very favorable ratio. Certainly, this relatively simple laboratory guide has been quite a useful guide, but because of the many difficulties of going from a species, such as mice, with an artificially induced infection, to man with a naturally occurring infection, assures us that it is just a guide. The clinical investigator, therefore, is faced with the problem of developing a somewhat similar ratio for naturally occurring infections in a rather heterogeneous population from the toxicity point of view, as has been emphasized by the previous speaker. Needless to say, the estimates of these ratios are much less precise and involve more than an arbitrary endpoint because we want 100- percent survival if we can get it, and obviously not a 50-percent lethal dbse. However, there is a hierarchy of not necessarily mutually ex- PAGENO="0321" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2455 elusive effects that are, on the positive side: (1) the ability to pre- vent death; (2) the ability to maintain the permanent integrity of tissue, that is, the arrest of the process before irreversible and, there- fore, crippling conditions have occurred, and this has to do with em- piric use of drugs; and (3) the ability to shorten the duration of essentially reversible processes and limit morbidity. Similarly, there are several endpoints for toxicity in their order of importance; (1) fatalities and the available countermeasures for their prevention; (2) permanent damage from the drug; and, (3) production of reversible disability and morbidity. Now, obviously, in making these ratios, one tends to equate the cate- gories and it is hard to equate a lethal toxicity with prevention of morbidity, for instance. It is a different order of magnitude in the equation. Chloramphenicol is one of the early antibiotic discoveries, hence much information has accumulated for it. I think this is quite clear in the testimony and much of what we are talking about is the way the drug was developed, and in talking about relative indications, the way they came about, and whether they are still current. Most of the information that reaches the profession really is about new agents. Once they are establishd, the amount of knowledge dis- seminated is relatively small. Hence, much of what is said about chloramphenicol indications come from the early years and are not well stated in terms of competitive new drugs. Senator NELSON. I didn't understand that last statement. Dr. LEPPER. Changes in indications have not been well emphasized in terms of competitive new drugs as we shall see later on when we come to the staphylococci. This was a lifesaving drug in the late fifties. It is no longer indicated as such, so that when you look at indications, you have to realize that this is a constantly changing field and the physician doesn't really get a reevaluation of old drugs and their rela- tive role nearly as thoroughly as he gets an evaluation of the new drugs and their potential toxicities in relative roles. Chloramphenicol has wide antibacterial activities and, therefore, may be considered for use in many infections. This has already been indicated. As a matter of fact, from the package insert, one can pick out 17 groups of infections which are mentioned or listed, and some of these groups, such as salmonellosis, which includes typhoid fever, have hundreds of organisms of different species involved. Most of the indi- cations have more than one species of organism involved. Hence, the range of potential specific indications isquite great. Second, because of this, the empirical use has often been ordered without prior diagnosis, either because of urgency, which may be considered an indication or a feeding that the condition is not serious enough to warrant the expense of the work-up. In this situation they are used because potentially you can treat a lot of things, hence you do not need do a work-up. This is not a valid indication for chloram- phenicol, although it is one that undou~btedly is the heart of the use in minor respiratory illnesses which is still going on. Moreover, we have to consider the prophylactic use because this is one of the big uses of antibiotics. Senator NELSON. In what kind of situation is a prophylattic use of èhloramphenicol indicated? 81-280 0-68-pt. 6-21 PAGENO="0322" 2456 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. LEPPER. I discuss this a little later. It might be more appropriate there. But, for instance, to prevent postoperative infections in persons who have had, say, a ruptured appendix. This is a use that some people would recommended because the enteric organisms are involved. And we know people who have had a ruptured appendix are most apt to get a postoperative infection. This is not a valid indication in our opinion. There are better prophylatics and, as a matter of fact, the whole area of prophylaxis is a debatable one, but it is the kind of situation in which chioramphenicol is quite frequently used. Senator NELSON. That is what I was getting at. What kind of clearly specified instances are there in which chloramphenicol is in- dicated for prophylactic use? Dr. LEPPER. In my opinion, there is no justifiable prophylactic use for chloramphenicol, but there are other opinions. It is used extensively in this way more in some hospitals than in others. Another area, for instance, might be in prevention of infection after an indwelling urinary catheter. I think, (a) prophylaxis here is not well proven, and (b) if it is done at all, there are probably equally good agents which are less toxic which meet the criterion of the warning on the package insert. On the other hand, it is still used by some in this area because of the early emphasis on the breadth of the spectrum. The fact that you could treat so many different things, makes it logical that, if you are trying to prevent a wide variety of things, you use the agent that will prevent the widest variety and hence the emphasis on chloramphenicol in this regard. Now, as I say, I do not believe these are justifiable indications but they are indications and I would suspect in Dr. Best's gray zone. They are indications which some people have used and have recommended its use, and it is still being used in these situations in very many hos- pitals. In fact, I would be quite surprised if you went in a major hospital and did not find that some people were still using the drug in this respect because I know of none that I have looked at in which it is not being done. Senator NELSON. Your judgment is that it is not indicated in most of these cases. Dr. LEPPER. It is not indicated prophylactically at all. I think in the first place the whole area of prophylaxis of this kind is difficult to document. In general, when it is documented, it is documented for a few months and then the propagation of resistant organisms in the hospital, is such that it loses whatever effectiveness it had originally, and hence, there is considerable debate over the whole concept in the first place. Now, when you add to that the fact that cliloramphenicol is more toxic than many of the other drugs which can be used similarly, in- cluding tetracyclines and some of the newer penicillins, it becomes clear that chloramphenicol really has no such indication at the present time. Mr. GORDON. Dr. Lepper, in the package inserts, under "Respiratory Tract Infections," we have the following statement: Chioramphenicol may be employed for severe infections of the respiratory tract due to susceptible microorganisms and in the presence of contraindications or lack of response to other agents. PAGENO="0323" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2457 Does that tell you very much?. Dr. LEPPER. No. That is a typical ambiguous statement which tends to foster overuse. In the first place, the vast majority of the respira- tory infections are due to viruses and in contrast, I think, Dr. Best's statement chloramphenicol is not active against viruses. Early, it was thought to be useful for some viruses, because we misclassified certain organisms such as the psittacosis agent as a virus but is now recognized to be a very small intracellular bacteria. Also, a condition known as primary atypical pneumonia which was thought to be a virus infection at the time of the introduction of these agents turns out to be a small free-living bacteria, the mycoplasma. Thus, the initially reported antiviral activity has turned out to be a specific kind of antibacterial activity. We can say quite clearly now there are none of these antibacterials and antibiotics which are effec- tive against known virus, meaning things like polio, common cold virus, influenza virus, the mumps virus, and measles virus, and so forth. Now, the vast majority of respiratory infections are a virus. Among those which are bacterial, the vast majority, meaning over 95 percent, are bacteria such as the pneumococci and the streptococci. These re- spond better to penicillin than they do to chloramphenicol. Chioram- ptienicol is not as good a therapeutic agent in these and the one orga- nism that causes infections in which chloramphenicol is as good or better than penicillin is Hemophiis influenza, which is a bacteria that was once thought to cause the disease we now recognize as virus influenza. This was a mistake and the bacteria, therefore, got its name and has confused everybody since. Hemophilis influenza causes ear infections in children, makes up less than 10 percent of all bacterial mfections `which make up less than 5 percent of all respiratory infections. We are down to 0.5 percent or less that you are talking about. Except for the possibility, as we mention later, of Hemophilis influ- enza infections in the central nervous system being somewhat better treated by chloramphenicol, there is no evidence that the tetracyclines are not as good as chioramphenicol in the treatment of Hemophilis infections and they are less toxic. Therefore, again, there is no particular respiratory indication. In addition, Ampicillin, which is the newest of the penicillins, and Cepha- lothin, `~s4hich is ~ penicillin-like drug, both havt excellent anti-He- mophilis activity and also are less toxic. Hence, in the area of the respiratory infections of the primary type one sees in the community, there is no indication for chloramphenicol. In the hospital we have, because of the~ use of rather dirty aerosol equipment, engendered a fair number of infections of the lungs due to delivery of the gastrointestinal bacteria to the susceptible lungs. This is known as aerosol-induced pneumonia ~tnd is caused `by gram negative rods. These are very difficult to treat. They are often in the kmd of patients Dr. Best was talking about, severely ill patients, the patient who has otherwise fatal or very severely damaging underlying diseases. These pneumonias are difficult to treat and you have your choice, often, between a drug like Kanamvcin and a drug like chloramphen- icol, both of which have considerable toxicity. This choice usually is re- PAGENO="0324" 2458 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY solved at the laboratory level and somewhat by the age level because, when I mention gray sickness, you will see that in infants, where this was a problem because these infants had humidifiers on their incuba- tors, Kanamycin is a less toxic drug than chloramphenicol and re- placed chioramphenicol in the newborn nursery. In the older age group where renal function is naturally deteriorat- ing, chloramphenicol may be a better drug. So in this very restricted area of the gram negative rod pneurnonias acquired in the hospital, and which is usually preventable, chloramphenicol may be indicated. That, as far as I see, is the only respiratory tract use for the chloram- phenicol. In contrast to this potentially favorable effects are some serious side effects. First and foremost, the drug can produce a fatal aplastic anemia, the frequency of which appears to be dose dependent, although not in the sense that Dr. Dameshek used dose effect in the metabolic effect. In other words, there is a susceptible subgroup, but this sub- group can be disclosed to a larger and larger extent by increasing the dose, so it is dose dependent. It is the most frequent aplastic anemia, not associated with a malignancy of a known cause. This reaction probably is not in exaggeration of the dose related response which is the almost uniform interference by high doses, with blood cell formation due to blocking of protein synthesis, but is more of an idiosyncratic reaction probably of some metabolic origin and is not predictable. The most recent definitive study in California, which was done at the request of their Legislature, of all deaths from aplastic anemia in the State suggests that aplastic anemia occurs once in about half a million people other than those taking chloramphenicol. Among those taking chioramphenicol the rate for those taking a 5-gram total dose was about 1 in 40,000; a 71/2-gram total dose, 1 in 25,000. While these rates were low, it should be noted that the doses were also quite low. As a matter of fact, the package insert recommends 50 to 100 milligrams per kilogram per day. Most adults weigh 50 to 70 kilograms, so the recommended dose is from 3 to 6 grams. This obviously means that most of the patients in the California study were treated with ineffectual drug levels. There is no good evidence in the literature that bacterial diseases will respond to doses lower than those recommended, although the rickettsial diseases will respond to as low as 25 milligrams per kilo- gram in short courses. So they will respond to a total dose of something like 10 grams, 2 grams a day for 5 days, in a medium-sized adult. However, typhoid fever was shown not to respond to less than 50 milligrams per kilo per day, or a 3-to-4-gram-a-day dose. These are the only diseases in which they are a really good study on a dose effect curve for a disease. Mr. GORDON. I note in the publication from California, the report to the California State Assembly, dated January 1, 1967, in table 16 in the back, it says that the estimated mean grams of chioramphenicol received per patient is 9.55, 1965 to 1966. What is the significance of that particular dosage? Dr. LEPPER. This indicates that the vast majority of patients. re- ceiving chloramphenicol get an inadequate dose for the purposes for PAGENO="0325" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2459 which it is being prescribed, and the reason this happens is clearly that the vast majority is being used in such `things as the respiratory diseases, in which the condition it self-limited, or being used in the prophylactic situations which I have outlined, where the results can- not be evaluated. In our University Research Hospital I happened to have had the opportunity to study the use of antibiotics of all kinds, several years ago. At that time, well over 50 percent of all patients receiving chior- amphenicol, received 1 gram a day. One gram a day in adults should not be able to treat anything either by pharmacologic principles nor in any well substantiated study. Now, you say, why it is used in this dosage? It is used in this dosage, I believe, because-and I agree with Dr. Best-the message has gotten across in the university hospitals that it is a dangerous drug. For some reason the message hasn't gotten across that it doesn't do any good to give a dangerous drug in small doses if it doesn't do any good for the patient. Mr. GORDON. Dr. Dameshek, although I don't recall in what connec- tion, talked about 6 grams. Now, is that an average daily dosage? Dr. LEPPER. Six grams a day is the initial starting dose recommended for the treatment of typhoid fever. In other words, a concept of a load- ing dose followed by 3 to 4 grams a day, depending on the patient's size. The dose of 100 milligrams per kilo recommended in hemophilis meningitis translated to an adult is about 7 grams a day. The child is getting a standard dose equivalant to 7 grams a day, and because he is getting it intravenously, there is less wastage as oral drug has wastage. Consequently, he is getting a full 7 grams a day at the recommended dose and, as a matter of fact, if you use much less than this in hemo- philis meningitis, you begin to lose effectiveness. So I think it is clear from the California study, that the vast majority of the patients are getting a drug at a level you can't expect to work and in spite of that you are still getting aplastic anemia. Senator NELSON. Even at that low a level, it does expose the patient to the risk of aplastic anemia? Dr. LEPPER. Yes. At a rate of 1 in 20,000 to 1 in 40,000 as specified from the quote. In fact, the most definitive evidence from the treatment of typhoid fever and hemophilis meningitis is that the dose cannot be compro- mised. Yet it is. Now, there are several other blood dyscrasias that I have mentioned winch are less serious, but at times fatal, and many more reversible such as agranulocytosis, thrombocytopenia, and so forth, which also occur. Other reactions which are more related to prolonged use include iieuritides causing disability such as blindness, but fortunately usually reversible. Morbidity, such as gastrointestinal upset is more common than any of these, of course. One other serious, often fatal, reaction that is dose related is "gray sickness." This occurs only with an overdose in adults and children, but in young infants, particularly those born prematurely, in whom there is ~tn underdeveloped detoxifying mechanism, it can occur with a standard dose. Hence, the dose must be reduced in such instances. PAGENO="0326" 2460 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Other patients with diseases which damage these mechanisms, such as liver disease, also may be easily overdosed. The symptoms are those of abdominal distention, cyanosis collapse and often death in a few hours. This has an interesting history. Its use stemmed from the broad spectrum concept and in the midfifties because of the staphylococcal outbreaks in newborn nurseries and because of the frequency of the gram negative rod gastronintestinal organisms. Mother frequently infected the infant with such organisms in different ways, like prema- ture rupture of the membranes. Thus, many infants had infections caused by organisms which are susceptible to chloramphenicol as a general rule, and for this reason many nurseries began using chlor- amphenicol prophylactically in the newborn nurseries.. It was finally discovered in some controlled studies, one in Los Angeles County Hospital, that there were more deaths in the chloramphenicol group than there were in the control group, and out of this, gray sickness was discovered. Thus, in fact, we were poisoning the infants in the newborn nurseries all over the country at that time with an otherwise unrecognized syndrome. This use grew out of the concept of the broad spectrum and its prophylactic potential. For this reason chlora.mphenicol by and large is not used in the newborn. Almost all the recent papers on the treatment of newborn infections with gastrointestinal organisms transmitted from the mother to the child, emphasize Kanamycin as the choice. This is a direct out- growth of this unfavorable experience in the late fifties. This is a drug that has great therapeutic potential, but several seri- ous toxicities which can and continue to give much difficulty. Essen- tially it has an unfavorable clinical therapeutic index. On the toxicity side, the fact that the aplastic anemia can start even after the drug has been stopped and is almost completely nonpredicta- ble and irreversible, makes the therapeutic ratio based on death, one much less favorable than with several competitive agents, even in- cluding Kanamycin, which is a relatively toxic drug. For example, we have summarized for teaching purposes the 25 major diseases which antibiotics have helped control in the United States, and while chloramphenicol is potentially useful in at least half of these, we listed it as the drug of choice in only three-typhoid fever, other salmonelloses, certain gram negative rod infections in well- studied situations. This is best summarized, perhaps, by the 1966 edition of "New Drugs Evaluated by the Council on Drugs or the AMA" which says: This drug should be used only for the treatment of typhoid fever, other sainonelloses, and infections that do not respond to less potentially dangerous agents. That implies a trial of less potentially dangerous agents or a consid- erable knowledge of the ability to predict where a bacteria sensitive to chioramphenicol only is gomg to occur. The package insert itself has a strong similar warning, as has just been mentioned. I might point out one thing about typhoid fever. Interestingly enough, while chioramphenicol works very well in acute typhoid fever in shortening the duration and preventing gastrointestinal hemor- PAGENO="0327" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2461 rhage and perforation, which are the two complications besides toxic- ity that kill, it does nothing to prevent the carrier state. The chronic typhoid carrier, which is the public health menace, is not benefited by the use of chioramphenicol. One of the big errors in the use of chioramphenicol in typhoid fever is to begin to treat a patient because he is a carrier after he has recovered from the acute illness. This will not work. Ampicillin, probaldy does not work as well, as Dr. Dameshek pointed out, in acute typhoid fever works better for the carrier state, so that here we have a crossover of the drugs. So we are talking about a highly specific indication even in the typhoid area. Senator NELSON. Do I understand you to be saying that chiloram- phenicol is not indicated in the carrier? Dr. Lnppnu. That is correct. Senator NELSON. But is prescribed. Dr. LEPPER. It is often prescribed. Mr. GORDON. Wouldn't that qualification make Ampicillin really a drag of choice for typhoid fever? Dr. LEPPER. I think it is quite likely that Ampicillin will be the drug of choice for the milder cases of typhoid fever. I think there is the problem. We do not understand why chloramphenicol works as well in typhoid as it does because-and we make a clear differential here-the tetracyclines are equally active in the laboratory, but they do not work as well. This has been known, essentially, since 1949. We have never had a good explanation, as a matter of fact, still don't, because the mecha- nisms of action are similar and their body distributions are similar. Mr. GORDON. In typhoid. Dr. LEPPER. In typhoid fever. Streptomycin was very active against typhoid organisms in the laboratory. It never worked well at all. Even penicillin itself, in large doses, did not work as well as one would think from the laboratory data. There is some problem in ty- phoid about the intracellular parasitism of the organism that appar- ently chioramphenicol overcomes better than the other agents. In a highly toxic, severely ill typhoid, it is quite likely that one would still use chloramphenicol. Its use in the other Salmonelloses is not as well proven. It has been used as Dr. Best pointed out-when he said paratyphoid fever, he was talking about some of the other salmonelloses. In the other Salmonella, the actual documentation of chioramphenicol effectiveness is not clear because without drugs the diseases are so variable and infrequent. There are no good studies documenting the dose-effect curve similar to those that we have for typhoid fever. There is only one condition in which its activity seems sufficiently unrivaled to use without extensive prior laboratory study. That is typhoid fever. Here even the new and less toxic penicllin derivations do not seem as effective. Hemophilus influenza meningitis is another dis- ease for which some will make a case, and this is particularly true of the pediatricians, and stems from the fact that at the time chioram- phenicol was introduced it was studied mainly ~n pediatric clinics and tetracyclines were being studied concurrently in adult clinics. However, Ampicillin has come on the scene and this is as effective in the hands, at least, of the group working in the Los Angeles County PAGENO="0328" 2462 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Hospital, and it does seem to be an equal alternative. Therefore using the criteria of the package inserts would be the drug in chaice. I might say parenthetically, in our own study of about 800 of these patients over a period of about 10 years at the contagious diseases hos- pital in Chicago, tetracycline appropriately used was also equally good in an alternate case series, 400 chloramphenicol patients and 400 tet- racycline patients, with less than 2 percent death rate in each group. As a matter of fact, we went one period with 180 consecutive cases treated with tetracycline without a death. We feel tetracycline is a competitive drug in this area and also less toxic. The vast majority of the pediatric conimunity do not feel this way. Senator NELSON. The vast majority of the pediatricians do not feel that way? On what do they base their opinion? Dr. Li~prj~. Mainly, I `think, the historic-what happened was that hemophilus influenza meaningitis iii the late forties was being treated with a combination of antiserums, sulfanomides, `and streptomycin. The death rate with these procedures was `between 25 `and 50 per- cent. Both tetracycline and chloramphenicol lowered the death rate to less than 5 percent, practically overnight. This was so dramatic that, dependmg on which dru'g you used, you went on the stump for it. It so happens that the leading individual, a very fine person who worked with meningitis all her life, studied chloramphenicol and saturated the pedi'atric community that this was the drug of choice, and indeed this was very important because people were still using the streptomycin, the sulfanomides `and antiserum. This message had to get across. It has continued to plague us be- cause it has never been really challenged except by our tetracycline data `and the Ampicillin data available from the group in `Oalifornia. This is a problem of how do you get communication to change prior teaching. In many of the infections in which it is potentially effective, such as pneumococcic, streptococcic, and so forth, it h'a's never been shown to be as good as other less toxic `agents. This failure to demonstrate it in part is perhaps `because there has been a reluctance to use it by investigators because of the known tox- icity. Failure has been observed by us frequently enough to feel that it is `actually inferior. In rheumatic fever prophylaxis the tetracyclines are clearly inferior to penicillin and there is no reason to think that c'hloramphenico'l will not be equally inferior. One of the major reasons for treating respiratory infections in chil- dren is that they may have streptococcal infections and they may there- fore get rheumatic fever. Prevention of rheumatic fever is one of the major reasons for using antibiotics, going al'l the way back to the sul- fanomides which did not work well. It is quite likely from the tetracycline data, that chloramphenicol does not work well in this regard, so if there is any justification for giving antibiotics to children with respiratory diseases fairly indis- criminately, this one specific indication, most important reason for using them, doesn't hold for chioramphenicol. For an ad like the one Dr. Best referred to, "use certain respiratory infections," undoubtedly if you challenge the basis for this it is these PAGENO="0329" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2463 peculiar hospital infections we talked about caused by the gram nega- tivë rods. It implies perhaps certain very seriously ill people with pneumonia should get this. Most of these are caused by pneumococci. If you give chloramphenicol plus penicillin, which is a very common thing to do, it is quite likely that you may antagonize the activity of the pencillin, so you really get less effect in these patients than you would with penicillin alone. There is a very small group of Klebsiella infections which are en- teric organisms that occur particularly among the alcoholic patients as a primary pneumonia acquired outside the hospital. These we can usually pick out and they are picked out regularly by an initial smear examination of the sputum, on the basis of the staining characteristics of the organism. The relative merits of tetracycline and chloram- phenicol is not settled in these cases. Unfortunately, neither works very well. Thus, chloramphenicol rarely, if ever, is indicated in re- spiratory infections. In staphylococcal disease, during the late 1950's, there was a time when it was competitive drug. The major drugs, penicillin, tetra- cycline, and to a certain extent erythromycin, lost their effectiveness es- sential due to overuse and inbreeding of the resistant organisms. They were not chloramphenicol because its use had been somewhat restrained by aplastic anemia reports in the midfifties, had a marked resurgence in the late fifties because of the staphylococcal problem. I already indicated this led to its use in newborn nurseries, and the dis- covery of gray sickness. It also was used extensively in the 1957 influenza epidemic. Here, the real deficit of the drug as a competitive drug with really good antistaphylococcal antibiotics was shown by fairly high failure rates in postinfluenza staphyloccal pneumonia. It is just not as active a drug as the new penicillins. So, I think this is a historic use, that it is no longer a current indi- cation. There are many gram negative rod infections in which the drug probably is as good as others, but there are few in which there is not a better alternative, and this gets back to this statement that we should only use it when we know it is better than the others. And there are very few such situations. Because of its broad range of activity, it is often turned to in seri- ously ill persons before the organism is known. And Dr. Best did re- fer to this use. This, in my opinion, is a mistake since one can usually make a reasonable diagnosis and often another drug is clearly prefer- able when you make that reasonable diagnosis. For instance, it is difficult in the leukemia patient to differentiate between staphylococcal disease on the one hand and these gram nega- tive rods on the other. Usually one can get enough information from microscopic examinations of smears, medical history and examina- tion, and the nature of the portal of entry to get some idea of what is going on. If you can't do that, and this is particularly true in persons who seem to have "septic" shock, that is, shock associated with an infection, and these are often caused by gram negative rods, you have to pick empirically. Some very good people have studied this syndrome and PAGENO="0330" 2464 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY recommend this drug. It is, however, bacteriostatic or less rapidly active than Kanarnycin. The latter is also toxic, but is easier to control if careful attention is given to urine output and total dose. If one were clearly to enforce and follow the requirements of the package `insert, that it be shown to be the only active agent, it would not be possible to use it this way because it requires much more study of the patient than can be given in these shock situations. Now, this is one area in which I am sure one can find a good counter- argument about whether chlora.mphenicol should be used or whether Kanamycin should be used. I happen to belong to the school of thought that Kanamycin is the preferable drug because it is even a little broader than chloramphenicol in its activity, that only about 85 percent of the organisms in this kind of patient will respond to chloramphenicol, and 95 percent will respond to Kanamycin in the laboratory. At the clinical level, because they are critically ill patients, only a handful actually recover, regardless of what you use, but this is still a difference based on laboratory criteria that favors Kanamycin when one has to make an empiric choice. IJnfortimately, the advertising engendered aura about the broad spectrmn concept, and this has come about from a wide variety of these not `only for chloramphenicol but for the tetracyclines. All these ads esentially say is if a drug kills a wide enough variety of organisms you don't really have to worry about what you have. This is the broad spectrum concept, and it has led to a wholesale use of a wide variety of these drugs, including chloramphenicol, in a variety of minor re- spiratory infections, in which none of these should be used. The package insert clearly states that chloramphenicol should not be used this way, yet, because `of this miseducation of earlier years, this use is still extensive. In fact, since there are few, if any, indications for this drug outside of the hospital, if the AMA recommendations are followed, it might be wise to restrict it only to hospital use. * I might dilate a little. I would favor this method of control for several reasons. Granted, there is overuse in the hospital, and I have already documented, I be- lieve, a considerable amount of overuse in the hospital. On the other hand, the overuse in the hospital can be studied. It can be answered progressively as many of our other problems in the hospital because the physician group in the hospital by the nature of hospital accredita- tion is a self-disciplining organization and it has many of the char- acteristics, many of the learned professions have for internal self- discipline. Actually, we control, for instance, the frequency of cesarean sections this way, in which if a hospital upon accreditation examination is found to have twice the usual number, questions are really asked. What are the indications? What is the control in your hospital? If you don't have adequate control, you lose your accreditation. It is an intraprofessional discipline. Now, I am sure if we restricted the use of chloramphenicol to the hospital, while it will increase paper- work, and as a hospital adminstrator I have always felt that some day I will be crushed in a paper avalanche, I think the paperwork in this case is worth it. I believe the paperwork would lead the Joint Com- PAGENO="0331" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2465 mission teams to ask, "How much chioramphenicol is used in your hospital?" If it seems excessive, what kind of control is the staff exerting on the use of this? What is the average dose of chioramphenicol? Are the vast majority of the patients getting one gram a day, for instance? A totally inadequate level? So I think restricting to the hospital would, by taking out of the community, do away with a lot of the repeated use that Dr. Dameshek has emphasized, and which I agree is an important factor. It would also allow a sequential control of its overuse and a more precise definition of unagreed upon recommendations like septic shock and a better evaluation of where, precisely, this drug should be used. Senator NELSON. Are all the cases where chioramphenicol would be indicated cases of patients which ought to be hospitalized anyway? Dr. LEPPER. Yes. I know of no real indication-you might say, well, how about some of the urinary tract infections? Now, urinary tract infections come in two groups, those acquired in the hospital which are often due to `a multitude of organisms resistant to antibiotics because they are acquired in the hospital where the antibiotics are being used extensively, and chioramphenicol may be what looks like the best drug for some of these. A very small percentage, I might add, because there are more agents for treatment of urinary tract infections because in the nature of the concentrating mecthanism of the kidney, than there are for treatment in systemic infections. The second group, the vast; majority, are ac- quired in the community. Over 90 percent of the ones acquired in the community respond to a drug like the sulfanomides, as Dr. Kass has clearly shrown in his studies of urinary infections of the young preg- nant female. Of the remainder, almost all of them, will respond to nitrofuratoin- furadantine-so it is certainly less than 1 percent of the community- acquired infections which may need chloramphenicol. When it is used for a recurring bladder infection, it is just totally unacceptable by any standards. These infections are not serious enough to warrant it. So I know of no definite indication for out-of-hospital use. When you talk about serious pneumonias, such as those following surgical procedures and inhalation therapy, we have th'entioned, clearly they should be in the hospital. Bloodstream infections should, also. When you talk of typhoid fever, they should go into the hospital. So, certainly meningitis should be in the hospital. When you look at the cases that are mentioned by the AMA specif- ically, and which we teach the medical st;udents specificially, there are essentially no home indications for this durg. Finally, another `statement fostered by the `advert;isements of several years ago was that resistance was not a problem. We have concrete evi- dence that resistance in gram negative rods `and staphylococci appear almost immediately in patients receiving this drug and spread to others on the ward within 36 hours of giving the agent to as few as 15 percent of the patients on a ward. This, of course, is the big problem with prophylactic therapy. The recent description of extrachromasomal mechanisms of re- sistance, that is, the most recent mechanisms which explain how or- PAGENO="0332" 2466 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY gaaisrns get resistant-they have standard genes and extra parts of genetic material which are easily transmitted between organisms that allow the build-up of these populations of resistant organisms. These studies show that chloramphenicol resistance is commonly medicated by this mechanism. And this means, of course, chioramphen- icol resistance is potentially a serious problem, and indeed has been so documented recently. In short, it is likely that this is one of the most overused and poorly used drugs in the antibacterial armamentarium, in spite of the warnings by the AMA council and the package insert. My reaction, then, is that if you ask whether warnings have been adequate, I would say they, by all criteria, looking at what has hap- pened, have not been adequate. Senator NELSON. Both Dr. Best and Dr. Dameshek made what they said was a guess about the percentage of patients who receive chorarn- phenicol in cases in which it was clearly indicated out of the total number of patients who are given the drug? Do you have a guess of your own about that? Dr. LEPPER. Yes. My guess, of course, gets back to this idea of absolute indications and relative indications. I would think if we stuck to the absolute indications, if we take the AMA council's absolute indications, salmonella infections that are serious enough to treat, which is mainly typhoid fever, acute typhoid fever, even if we throw in hemo~hilis meningitis because this is so controversial and we can call it a definite area, and then we put in septic shock, which, for instance-there were perhaps 100 in a city like Chicago in the last 5 years-and we put in some of the urinary tract infections, perhaps 1 to 5 percent, you cannot come up with a figure that is much greater than 10,000 to 50,000 people. Senator NELSON. You come up with a figure of what? Dr. LEPPER. Between 10,000 and 50,000 people, and this is a rela- tively generous estimate in my opinion. I think if you `ask me if I were doing all of the ordering, how many would you use it in, I would probably use it in less than 10,000 people a year. Now, I will grant that statements such as using evidence of failure of other drugs, less toxic drugs, and you get into the problem of kanamy- cm toxicity versus chloramphenicol toxicity, you could increase this, but I don't believe you would get it over 100,000, no matter how you tried to increase it. Senator NELSON. Well, if the `figure is even rouglhly correct that the drug is being prescribed for somewhere around 3:1/2 million people, this is certainly a fantastic overprescription of chloromyoetin, isn't it? Dr. LETTER. I think-I certainly concur in this. This has been a great source of concern to some of us, at least. One must realize, however, that we may be talking about `two kinds of overuse. It is quite likely that the antibiotic overuse is greater than 50 percent for all antibiotics. In fact, because of the respiratory problem and the relatively few indications in the respiratory diseases, it is quite likely that we are talk- ing aibout a four- or five-fold overuse `for the entire antibiotic field, and then you talk about misuse within that remaining, you obviously have a very big overuse factor. PAGENO="0333" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2467 Senator NELSON. You heard the testimony of Dr. Dameshek in which he expressed his concern about the need to find some method to control the use of the drug, or at least of assuring that this drug wouldn't continue to be overprescribed. Is it your view that the situation is so serious that some method ought to be developed? Dr. LEPPER. Yes, I think it clearly is, as I made recommendation to restrict it to hospitals because when we have introduced some new drugs in recent years they have been originally restricted to hospitals. It has been fairly easy to prevent them, then, from becoming used for any more than some specific indications. We have never, to my know- ledge, gone the other direction to restrict an old drug back to the use in the hospital. However, this would certainly get around the massive overuse in respiratory infections in the community and the massive overuse in urinary tract infections in the c9mmunity, which happen to be the two most common infections in the community. It would also then allow us, as I say, to develop control mechanisms within the hospital as to what is a reasonable level of utilization such as we have for caesarian sections or therapeutic abortions, or other kinds of controversial procedures. In these the hospitals have very similar rates, and if some hopsital has excessive use, it becomes quite apparent to the accreditators that there is something different gomg on here. Senator NELSON. You mentioned that some drugs have been re- stricted to hospital use. Which drugs were you referring to? Dr. LEPPEE. Well, I think vancomycin was one such drug that was introduced for the staphylococcal problem, which was marketed only to the hospital pharmacists. It was not put on the general market. Senator NELSON. Was that a result of a regulation by FDA or was that a self-imposed restriction on the part of the manufacturer? Dr. LEPPER. I believe this was an era, sir-I am not awfully sure of the legal aspects_I believe there was an era in which new drugs were released sequentially by FDA for hospital use, followed by general community use, and some of the drug got as far as hospital use and were never released further for several reasons. Vancomycin specifically could only be given intravenously, and therefore was not a very competitive drug in the community, aild I don't believe it then got past being released for use outside the hospital. I believe, however, FDA did have that legal authority of approving drugs for use at one point along the way. I do know there has been a tremendous body of literature, talking about restricting drugs to hospitals on a voluntary basis, and this was done successfully in Aus- tralia with erythromycin when the staphylococccal problem was so bad and they wanted to try to keep an overuse of this drug from oc- curring. That is, try to limit it to staphylocoecal diseases so you wouldn't lose its effectiveness. This was somewhat successful in Australia for a period of about 2 years in the midfifties. In this country there was some talk about doing the same thing with erythromycin. It never happened on a voluntary basis. PAGENO="0334" 2468 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Thank you very much for your very valuable coii- tribution to the hearings, Doctor. We appreciate your taking th~ time to come here today. Dr. LEPPER. My pleasure. Senator NELSON. That will conclude the hearings until 10 o'clock on Thursday morning. I might ask, before you go, did either you, Dr. Dameshek, or you, Dr. Best, have any observations you wanted to add to anybody else's testimony? Dr. BEST. No, thank you. Dr. DAMESHEK. No. Senator NELSON. Thank you very much. (Whereupon, at 1:25 p.m., the subcommittee adjourned, to recon- vene at 10 a.m., on Thursday, February 8,1968.) PAGENO="0335" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THURSDAY, FEBRUARY 8, 1968 U.S. SENATE, MONOPOLY SUBCOMMITnE OF THE SELECT COMMIrIEE ON SMALL BuSINESS, Washington,D.C. The subcommittee met, pursuant to recess, at 10:10 a.m., in room 318, Old Senate Office Building, Senator Gaylord P. Nelson (chair- man of the subcommittee) presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; James H. Gross- man, minority counsel; Susan H. Hewman, research assistant; and William B. Cherkasky, legislative director, staff of Senator Nelson. Senator NELSON. Our first witness this morning is Dr. James Weston, Utah State medical examiner. Dr. Weston, the committee appreciates very much your taking the time to come here today. I have studied your testimony and know that it will be a very val- uable contribution to the record we are compiling with respect to a number of subjects involving the drug industry. You may proceed to present your statement in any way you wish. At such places in your statement where you would wish to elaborate in a way that would be helpful to understanding in the record, we would be glad to have you do so. I realize that if you wrote all the detail that you knew about any particular subject you would have a much longer statement than you might be willing to spend the time to prepare. But some elaboration would be helpful for the record in those cases where you would like to extemporize and explain in more detail any aspect of your statement. I assume you would have no objectioi~ if w~ should interrupt from time to time with a question? Dr. WESTON. No, sir. Senator NELSON. Thank you very much, Doctor. STATEMENT OP DR. NAMES T. WESTON, STATE MEDICAL EXAMINER, UTAH STATE DIVISION OP HEALTH, SALT LAKE CITY, UTAH Dr. WESTON. Do you desire that I read the entire statement into the record? Senator NELSON. That is probably the best way to proceed, unless you would prefer otherwise. Dr. WESTON. No; this is fine. 2469 PAGENO="0336" 2470 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Then when you arrive at some point in your state- ment where you would like to elaborate, feel perfectly free to do so. Did you submit a biography for the committee? Dr. WESTON. Yes; I believe it is attached. Senator NELSON. Your biographical data will be printed in full in the record preceding your statement, but if you wanted to make a brief summary of what your credentials are and what your present position is, go ahead. (The biographical sketch of Dr. Weston follows:) CURRICULUM VITAE-JAMES T. WESTON, M.D. Born: Newark, New Jersey, 1924. Family: Wife, Deon J~ames Weston, and 2 children, Debra Deon, nee 1956, and Christopher James, nee 1959. Education: Premedical Education: Cornell University 1942-44. Medical Education: Cornell University Medical Oollege, M.D., 1948. Postgraduate Training: Internship: Children's Hospital, Boston, Mass., 1948-49. Residency: U.S. Naval Hospital, San Diego, Oalif., 1951-52. Feliswship: Memorial Center for Cancer and Allied Diseases, New York City, New York, 1953-54. Military Experience: Lieutenant, Medical Corps, U.S. Naval Reserve, 1949-52~ Pathologist, U.S. Naval Hospital, Key West, Fla., 1949-50. Field Duty, Korean Theatre, 1950-51. Lieutenant Oommander, Medical Corps, U.S. Naval Reserve, currently. Professional Experience: Chief ~f Medical Division, San Diego, Calif., Coroner's Office, 1954-61. Associate Pathologist, San Diego County General Hospital, 1956-61. Associate Pathologist, Chula Vista Community Hospital, Chula Vista, California, 1959-61. Assistant Medical Examiner, City of Philadelphia, Pa., 1961 to 1967. Chief Medical Examiner, State of Utah, July 1967 to date. Oertification: American Board of Pathology-Anatomic Pathology, 1967. Licensure: Physician and Surgeon: California, September 3, 1952. Pennsylvania, December 14, 1961. Utah, September 1,1967. Membership: Fellow: American Academy of Forensic Sciences. Member: Utah Pathologists Association. Salt Lake Oounty, Utah State and American Medical Associations. Teaching Appointments: Visiting Lecturer in Legal Medicine, Jefferson Medical College, 1962 to 1967. Assistant Professor of Pathology, University of Utah Medical Coll~ge, 1 July 1967 to date. Current Research Interests: Child Abuse, with a sociopathologic correlation and analysis of the path- ologic ftndings. Currently preparing the pathology section of the compre- hensive volume on the subject to be published in early 1967 by University of Chicago Press. Single auto vehicular accidents, their cause. Special Interests: Data Retrieval Systems and their special application in Forensic Medicine. Community Activities: Youth Fellowship Advisor, Wasatch Presbyterian Church. Member-at-Large, National Council, Boy Scouts of America. PAGENO="0337" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2471 References: G. D. Cariyle Thompson, M.D., Director of Health, State of Utah, Dlvi- sion of Health, 44 Medical Drive, Salt Lake City, Utah. William H. Oarnes, M.D., Professor of Pathology, University of Utah Medical College, Methoal Drive, Salt Lake City, Utah. Joseph Edward Campbell, M.D., Assistant Medical Examiner, City of Philadelphia, 13th and Wood Sts., Philadelphia, Pennsylvania. PUBLICATIONS Author(s) Title Journal reference Britton, R. C., Weston, J. T., and Plastic Injection Techniques in Pedi- Am. J. Med. Museums: 31: 124-166. Landing, B. H. atric Pathology with particular ref- 1950. erence to Roentgenographic Study of Injected Specimens. Weston, J. T., and Gum, G. H Epithelial Atypias with Chemotherapy Cancer: 18: 179-186, 1955. in 100 Acute Childhood Leukemias. Weston, J. T_. Cardiac Arrest in Surgery Proceedings of National Coroner's Asso- ciation, 1959. Do Airway Foreign Body Fatalities in Annals of Otolaryngology, 74: 1144- Children. 1148, 1965. Do Forensic Pathology Slide Seminar Journal of Forensic Sciences (in prep- aration). Do The Pathology of Child Abuse Chapter in book edited by Kempe, C. H., and HeIfer, R. E., University of Chi- cago Press, 1967 (submitted for pub- lication). Dr. WESTON. Briefly, I am the chief medical examiner for the State of Utah, having served in the last 6 years as the assistant medical examiner in the city of Philadelphia. My education includes under- graduate and the doctor of medicine degree from Cornell University, following which I had my training in pathology at Children's Hospi- tal in Boston, in part in the naval service, and Memorial Hospital in New York City. My military experience includes V-12 training during the Second World War, and the Korean conflict shortly thereafter. I have served in California as the chief pathologist in the coroner's office in San Diego, and in Philadelphia, and finally where I am now in Utah. Hav- ing taught at Jefferson Medical College, and now assistant professor of pathology at the University of Utah Medical Center, I am certified by the American Medical Board of Pathology as a diplomate. Senator NELSON. What do your duties as Utah State medical examiner involve? Dr. WESTON. To direct the investigation and examination of all per- sons who are referred to us having died of suspectedly unnatural death in any form. This would include drug toxicity, which I haven't encoun- tered in Utah yet, but saw in Philadelphia prior to going to Utah. Senator NELSON. Thank you. Go ahead, Doctor. Dr. WESTON. Much of, or a good part of, my statement has already been covered by Dr. Dameshek and Dr. Best. I summarized much of what they have in the literature but I will read the entire statement. Senator NELSON. Go ahead. Dr. WESTON. In 1948 Chloromycetin-chlóramphenicol-was first put on the market by Parke, Davis & Co., as a broad-spectrum anti- biotic capable of controlling infections by a large number of organ- isms with a very low incident of immediate side effects, such as nausea 81-280 0-68--pt 6-22 PAGENO="0338" 2472 COMPETITIVE PROBLEMS IN THE DRUG INDVSTRY and vomiting, and yeast or other intercurrent infections. Ohloromy- cetin soon became a very popular, widely used drug. From 1948 to 1952 its sales rose markedly, and it has been stated by the company that over 8 million patients were treated with the drug during this period. However, reports began to come in which noted that blood dyscrasias were associated with its use. Of these blood dyscrasias, aplas- tic anemia was the most conunon. The Federal Food and Drug Admin- istration requested that the National Research Council make an investi- a~ation into the problem and submit a report of their findings. The council, recognizing the potential and serious toxicity of the drug recommended that the following warning be placed on the packages and in the circulars distributed with Chioromycetin. The Federal Food and Drug Administration concurred: Warn- ing to be placed at the top of the circular was as follows: Certain blood dyscrasias (aplastic anemia, thrombocytopenia purpura, granu- locytopenia and pancytope.uia have been associated with the administration of Chioromycetin. It is essential that adequate blood studies be made when prolonged or intermittent administration of this drug is required. Chioromy- cetin should not be used indiscriminately or for minor infectons. To appear on immediate container label: Warning: Blood dyscrasias may be associated with intermittent or prolonged use. It is essential that adequate blood studies be made. These warnings were subsequently placed by Parke, Davis on the appropriate packages and in the circulars enclosed with the parenteral forms of Chloromycetin, but no circulars were included in the pack- ages containing the oral preparations. Senator NELSON. You state that the circulars with the printed warnings were enclosed in the package forms; is that correct? Dr. WESTON. With the form for parenteral administration, that is injected. Senator NELSON. That is an injectible? Dr. WESTON. Yes, sir. It was not included in the material that was distributed for oral consumption initially. Senator NELSON. That meant that the injectibles that went di- rectly to the doctor did have the warnings; is that correct? Dr. WESTON. Yes, sir. Senator NELSON. And that the packages containing the tablet form of Chloromycetin which went to the pharmacist did not, is that correct? Dr. WESTON. That is correct. The injectibles, of course, may have been handled by the pharma- cists as an intermediary. Senator NELSON. But even the warnings that went to the pharma- cist weren't seen by the doctor anyway, is that correct? Dr. WESTON. Not necessarily. The ones that were packaged, some of them were put on the label proper. There are two types of warnings, one was put on the label proper, and one was put m the literature that the instructions in- cluded. Senator NELSON. If it were an injectible, of course, it ended up in the doctor's hands for his administration, is that correct? Dr. WESTON. Yes, sir. PAGENO="0339" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2473 Senator NELSON. If it were in tablet form, the usual procedure would be that the prescription would be written by the doctor and dispensed by the pharmacist, so the doctor does not see the package, is that not correct? Dr. WESTON. It could well happen. I don't know how many times- he could well have not seen the warning. I have seen or have heard the statement of several doctors who said they weren ot aware there was a warning put into the drug at this particular period in its chronology. Senator NELSON. But in the ordinary procedure of prescribing, the doctor writes the prescription and, unless it is in a hospital, the patient takes it `t)o the pharuuacist. The package containing tablets now con- tains `a warning but `the doctor ordinarily `does not see the drug or the package at all, unless it is'administered in `his office, does he? Dr. WESTON. That is correct, yes. immediately following this `announcement by the Federal Food and Drug Administration, Parke, Davis & Co. issued "President's Letter No. 4" on August 12, 1952. Despite the obvious limitations placed on the use of the `drug by the warning, the `statement was made in this letter, over the signature of the president of Parke, Davis & Co., that Ohloro- mycetin had `been "officially cleared by the Federal Food and Drug Administration and the National Research Oouncil with no restric- tions" on its use. In an open letter, published in the Journal of the American Medical Association, in August of 1952, Parke, Davis & Co. stated th'at `the above warning would be included in all their Ohloro- mycetin literature in the future. However, from 1952 to 1961, the ad- vertising for Ch'l'oromycetin contained' only the following words: I will comment on these `after I rea'd the warning: Chioromycetin is a potent therapeutic agent, and `because certain blood dys- crasias `have been associated with its administnation, it should not be used iadis- criminately or for minor thfections. ~uirtherniore- And `it is stated right in its warming- as with certain other drugs, adequate blood studies should be made when the patient requires prolonged ~ intermittent therapy. Senator NELSON. When it says adequate blood studies should be made if a patient requires prolonged or intermittent therapy, what is your judgment `as to what blood studies should' be made? That is, should they always be made when chloroamphenicol is administered or only under certain circumstances? D'r. WESTON. Well, let me `bring into text the chronology of this thing. At this particular time they were not aware of the fact that a single, as little `as 1 gram of ch'loromycetin would have caused the dyscarsias. This pretty much became apparent later on in the history. Of course, now we know that with 1 gram of Chloromycetin there may not be an alteration in the `bone marrow. `On the other hand, there m'ay well be an alteration `in the bone marrow and `actually, practically `speaking, there i's no w'ay of detecting this if you want to be strictly `honest `about it. However, with prolonged therapy you may see a morphological al- teration in the bone marrow. I `am sure Dr. Daineshek testified to this, PAGENO="0340" 2474 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and a certain percentage of the cases will go on to develop aplastic anemia or other dyscrasia. Senator NELSON. Regardless of the fact that you may not be `able to discover any bone marrow problem from blood studies, should `blood studies always be made when chloroamphenicol is administered? Dr. WESTON. Always be made. Senator NELSON. Always be made. Dr. WESTON. Yes, sir. Senator NELSON. Regardless of whether one dose or several doses are given? Dr. WESTON. That is correct. This warning did not begin with words of caution but with a glowing tribute to the efficacy of the drug. Also the types of bone marrow dyscrasias involved were not enumerated as they were by the Federal Food and Drug Administration. Further, the words "it is essential" were deleted, detracting from the emphasis on the require- ment for blood tests and the expression "as with certain other drugs" was added, thereby equilibrating the toxicity of Chloromycetin to that of other, unnamed medications. The Parke, Davis warning was not, at this time, placed at the top or beginning of this literature but was placed well down in the writing and often in small print. Witnesses in at least one malpractice action have testified that the Parke, Davis warning was no different from the warnings on many other drugs which led them to use Chloromycetin freely and without reservation.' This refers to the Incollingo v. Ewing, Parke, Davis and Cucinotta trial in which I appeared in the Philadelphia court, in which Dr. McGehee was present as a hematologist expert and he not only testi- fled to the fact that this had quite a contrary effect on the warning, it was equated with what one might anticipate with the sulfonimides, aspirin and a variety of common household medications which were used quite commonly, and to see it put in that same wastebasket was, in effect, saying that you are dealing with a drug which only very occasionally wifi give you an untoward reaction. I will cover more of Dr. McGehee's other testimony as we get on in the statement. Following the issuance of the FDA warning, the sales of Chloro- mycetin dropped precipitously. However, by 1960, sales of the drug reached a level even greater than that of its peak years in the early 1950's. This resurgence was due in large part to the promotional efforts put forth by Parke, Davis & Co. through its advertising and detail men. This vigorous overpromotion was made despite the well-docu- mented toxicity of the drug, by this time. Chloromycetin, it was urged, was still the most effective antibiotic in a wide variety of infections, with minimal side effects. The Parke, Davis campaign to bring Chloromycetin back into widespread use for a multiplicity of clinical conditions was evidenced very early. In November of 1952, just 4 months after the FDA warning requirement was issued, a letter was sent from the sales department of Parke, Davis to its professional sales staff. Included with the letter were "suggested details" and "ideas and suggestions" for promoting the use of Chloromycetin to physicians. `Incoflingo v. Ewing, Parke Davi8 and Cucinotta, Philadelphia Court of Common Pleas No. 6, December Term~ 196i, No. 3248. PAGENO="0341" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2475 The statements which follow were made under the heading "approaches to be used in detailing the drug." These are not taken as they might appear out of text. They are actually quotes of entire paragraphs within the text of these sug- gested details. Intensive investigation by the Food and Drug Administration, carried on with the assistance of a special committee of eminent specialists appointed by the National Research Oouncil, resulted in unqualified sanction of continued use oc~ C'hloromycetin for all conditions in which it had previously been used. Senator NELSON. That, of course, is not an accurate statement, is it? Dr. WESTON. Absolutely not. Senator NELSON. Because the sanction for continued use given by the Council was very qualified. Dr. WESTON. It was very qualified and the warning was elaborated on even more in the second warning. A sensible caution against indiscriminate use, which we have incorporated into our advertising and labeling, is a welcome addition to our literature and to the label on Ohioromycetin products, and in our opinion, would be `appropriate in those on any potent chemotherapeutic agent. Actually, such caution is an assurance that the full benefits of well-tolerated Ohloromycetin will be avail- able and free from misuse. Here again, it implies `that Parke-Davis themselves were responsible for putting this on, and again it equates `the toxicity of Chioromycetin with some of the other antibiotics. Quote No.3: Are the broad-spectrum antibiotics important factors in the incidence of blood dyscrasia's? Of course, it is logical to use Chloromycetin as an example, because it `has been the subject of intensive and thorough investigation. This is quite `a while after first reporbs of some blood dyscrasias with some of the other `antibiotics which had not been investigated `as inten- sively, but in which the incidence was of a much smaller magnitude than t'his drug. We ask for open-mindedness in approaching this subject (of drug induced blood dyscrasias). We assure you that Parke-Davis will take every means possible and exhaust every possibility in attempting to get at the solution of this baffling problem of modern therapeutics, involving, obviously, not only Ohioromycetin, but many other potent ehemotherapeutic agents as well. Again `an equation with other antibiotics. Before terminating this interview may I re-emphasize a fact which has not changed with `the developments of the past year? `Chloromycetin continues to be the outstanding wide-spectrum antibiotic because of its well-tolerated nature and its high degree of effectiveness. Your efforts (those of sales representatives) should all be `directed in a posi- tive direction designed to provide facts which will induce physicians to use Oh'lor*omycetin in the wide range of infections in which it it effective. Senator NELSON. As I understand it, it is effective in `a wide range of infections, is it fair to say that? Dr. WESTON. Yes; I think it is fair to say that Chloromycetin is probably as or more effective in `a wi'der spectrum of infectious dis- eases than any other antibiotic available `at this time. Senator NELSON. So `the apparent intent here is to persuade doctors to use it in a wide variety of infections including conditions for which, in fact, it should not be used `at all, or when there is `a substitute drug that may be as effective but less `toxic as t'his one? PAGENO="0342" 2476 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. WESTON. That is correct. The mechanics of this, I am sure, have probably been [pointed out by some of the other experts, but in testing a patient and an organism to determine its sensitivity, one has to take from the person a culture, which is really .a growth of the organism outside of the body, trans- plant this into an artificial media, and then attempt to grow this organism in this artificial media in the presence of the antibiotics that are available. There is an element of time entailed in this. You first have to take it out and grow it with the antibiotics and without the antibiotics, and if in its artificial media it is shown not to grow with the antibiotic, then, of course, this would be the ant~biotic choice. But this does require a matter of hours, days before you can determine this. By giving an agent which is effective in virtually every infection you pre- clude the necessity of doing this. Senator NELSON. Am I correct in my interpretation of the expert testimony that we have had thus far that although chloran~phenicol is effective in a wide range of infections, there are a number of those in- fections for which, in fact, it should not be used de~pite .the fact that it maybe effective, is that correct? Dr. WESTON. That, sir, this is true of most of them. I will come to that later on, in the vast majority of them. Senator NELSON. In the vast majority of areas where it. is effective it still should not he used, is that corr~t? Dr. WESTON. That is correct. This is quoted: A new full-color blotter, portraying all the product forms, will be supplied to you (sales representatives) very shortly, as will a desk~top pr~duet information card. A deluxe product booklet is being made ready for the press at this time. Other promotion material is in process of preparation and will be released as soon as possible. It should be kept in mind that the incidence of aplastic anemia is net known because statistics on this affection are incomplete and inadequate. In the survey, among those who received the estimated 8,000,000 courses of therapy of Chloro- mycetin, aplastic anemia is known to have appear~d in 193 patients. The ratio 193: 8,000,000 gives a rate of 1.74 per 100,000 which probably is not much greater incidence than would be expected in a population of sick persons who had not received any Ohloromycetin. Senator NELSON. Considering the present knowledge available about the risk, that is not a correct statement? Dr. WESTON. That is correct. The California study just completed establishes the most reliable statistics of what the anticipated inci- dence of fatal apiastic anemia would be, again taking into consider- ation not only registered cases hut a survey of death certificates which was occasionally followed up by follow-u~p investigation. Now, I should point out in all deferance to my colleagues that if I were prescribing Chloromycetin for a minor respiratory infection and a year from now it became apparent that this patient developed aplas- tic anemia, I would be somewhat reluctant to sign a death certificate on such a case as aplastic anemia having seen at least two malpractice cases that approached $200,000 awarded in the country in the last several years. Not only do you lose money in your insurance, but you lose patients this way. So, I think you have to view any reporting of the incidence of any untoward reaction to a drug with a rather jaun- diced eye, so to speak, and realize that it really touches only a small PAGENO="0343" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2477 segment of what may actually be happening. I would not want to sensationalize it. On the other hand, I do not think saying you can see one in a thousand or one in 10,000 is a true picture. I do not think anybody really knows, but I am sure we are seeing that there is a great deal more blood dyscrasia from Ohloromycetin than is reported in a voluntary register of any kind. Mr. GORDON. Dr. Weston, the figures given in the California report, if I am not mistaken, indicate that the risk of aplastic anemia is one in 524,600 per year in California for those who have not received chlor- amphemcol; is that correct? Dr. WESTON. Yes, sir. Mr. GORDON. But the Parke, Davis instructions to the detailed men said one in, 1.74 per 100,000? Dr. WESTON. Yes, sir. Mr. GORDON. You have no idea where they go that figure? Dr. WESTON. No; I do not. Mr. GORDON. Thank you very much. Dr. WESTON. The recent California survey reveals an incidence in 7'/2-gram doses of one fatal aplastic anemia in approximately 21,000. Mr. GORDON. That is for those who take Chloromycetin? Dr. WESTON. That is for those who take it; yes, sir. Thus Parke, Davis & Co. sought to convince the medical profession by its advertising and detailing that Ohioromycetin was the broad- spectrum antibiotic of choice, that its uses were in no way curtailed by the FDA announcement, and that the drug's toxicity was akin to that of many other drugs. The increase in sales speak for the wide- spread use of Ohloromycetin from the late 1950's to a total sales volume within the United States in 1962 of $37,499,733. Experts in malpractice trials have testified that the detail men of Parke, Davis were loath to discuss the bone-marrow toxicity of the drug and empha- sized its effectiveness in a wide variety of clinical conditions, this in- cludes again Dr. MeGehee in Ineollingo v. Parke, Davis and Assoc~- ates. Dr. McGehee at that time was a practicing clinician, practicing internal medicine as well as hematology and was aware by virtue of his hematology experience of the untoward effects as well as in constant contact with the detail men as is any practicing physician. Parke, Davis was highly successful in the period from 1952 to 1960 in setting the standard of care for the medical profession. However, in the late 1950's, reports of blood dyscarsias associated with Chioro- mycetin therapy began to multiply; and in 1961, the National Re- search Council was again asked to submit a report with recommenda- tions to the Federal Food and Drug Administration. The Council, at this time, recommended that the following warning, more forceful. and explicit be placed on the Chloromycetin packages and circulars: (Immediate container label): "WARNING: Blood dyscrasias may be asso- ciated with the use of chloramphenicoL It is essential that adequate blood studies be made (see enclosed warnings and precautions.)" And then the drug enclosure: WARNING: Serious and even fatal blood dyscrasias (aplastic anemia, hypo- plastic anemia, thrombocytopenia, granulocytopenia) are known to occur after the administration of chloramphenicol. Blood dyscrasias have occurred after short-term and with prolonged therapy with this drug. PAGENO="0344" 2478 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY This is the first instance of blood dyscrasias after short-term ad- ministration made reference to in the warning. Bearing in mind the possibility that such reactions may occur, chlorampheni- col should be used only for serious infections caused by organisms which are susceptible to its antibacterial effects. Chioramphenicol should not be used when other less potentially dangerous agents will be effective or in treatment of trivial infections. And I call your attention to colds "such as colds, influenza, viral infections of the throat, or as a prophylactic agent." Precautions: It is essential that adequate blood studies be made during treat- ment with the drug. While blood studies may detect early peripheral blool changes, snuch as leukopenia or granulocytopenia, before they become irreversi- ble, such studies cannot be relied upon to detect bone marrow depression prior to development of aplastic anemia. Senator NELSON. The warning says Chloromycetin should not be used for "viral infections of the throat." What about other viral upper respiratory tract infections? Dr. WESTON. I don't believe that it has ever been indicated in any viral upper respiratory infection. Senator NELSON. Why would this warning specify viral infections of the throat and neglect to mention all viral upper respiratory infec- tions? Dr. WESTo~. Because it was used quite widely almost from its incep- tion in preventing secondary infection which is a common complica- tion of any viral infections m the upper respiratory system. In other words, the common cold, as you are probably aware, starts out prob- ably as a virus infection. The virus attenuates the mucosa of the res- piratory tree, produces an excess secretion. This, in turn, opens it up to infections by bacteria which take over in the virulent stage when your discharge changes from water into a yellowish type of discharge. Then the antibiotic could be used to prevent the secondary stage of this infection, the bacterial stage. Senator NELSON. Has it been used prophylactically for rheumatic fever, for example? Dr. WESTON. Oh, I think it has; yes, sir. Not with recognition by any organized program of any kind, to my knowledge. Senator NELSON. That is why I was curious not as to why they sim- ply said viral infections of the throat rather than all upper respiratory infections. Mr. Goiwox. Dr. Weston, coining gack to the warnings about when it shouldn't be used, Dr. Best, who testified here on Tuesday, said that this caution is not observed by all members of the medical profession. Do you have any idea why thisisso? Dr. WnsT'oN. I cover that later on in my statement, but I can elabo- rate on it right here. There are probably-if I say it now it would just be recanting what I will say later on. Mr. GoRDON. All right, we will come to it. Dr. Wesa'oN. Since 196~, these warnings had been on the Chioro- mycetin packages, in the circulars placed in both the oral and paren- teral use Chloromycetin packages and in the Chioromycetin promo- tional literature put forth by Parke, Davis & Co. This warning has PAGENO="0345" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2479 also been boxed and placed at the head of the listing within the PDR, the Physicians' iDesk Reference, and I included a sample page for illustration.2 This has been consistent since this time. The type of warning which they have is exactly the same from year to year. It is placed at the head of the listing. Senator NELSON. What is the date of the warning on the Thermof ax page of the Physicians' Desk~Reference you have submitted? Dr. WEs~I~N. This is 1963. I checked with the latest edition and it is exactly the same. Senator NEr~soN. Thank you. Dr. WESTON. The causal relationship between Chlormycetin and blood dyscrasias, especially aplastic anemia, was clearly set out in the literature in the 1950's and 1960's. And here I make reference to Dr. Best's statement which I have included for evidence,3 which mcli- cates that between the period 1953 and 1964 there were 408 recorded cases who were known to have received chjQramphenicol during the year preceding a non-neoplastic depression of blood cell formation; of these 298 were U.S. reports, 25 were published in the literature and 273 were not, plus 110 foreign reports of which 70 were published and 40 were not. The registry also contains one United States and 65 foreign literature cases which were not covered in their review and notes that there have been additional published case reports which do not appear iii any review or in the registry. I already indicated, of course, that a voluntary registry of any kind cannot be statistically considered to be of very much significance. The accuracy of information in the registry is dependent upon the initiative of the physician in reporting such cases, evaluation of the validity of such cases and upon thorough search for such cases within the literature. This may be augmented by search within accurate statistical reporting, including review Of death certificates. This was done in the California statistical report. However, as was indicated by testimony in the California Senate proceedings published in January of 1963,~ (1) with the Senate of the California Legislature proposing the exclusion of Chloromycetin from the therapeutic regime of j~hysi- cians within their State initially, and subsequently proposing its use only in hospital admitted cases, a thorough followup of a relatively large number of cases by at least one physician has indicated that deaths subsequent to Chloromycetin therapy, which clinically and pathologically may have been due to blood dyscrasia, were masked within the statistics either intentionally or unintentionally as related blood conditions such as leukemia, spontaneous cerebral hemorrhage, or gastrointestinal hemorrhage, and, while this states unequivocally that chloramphenicol has been implicated in more reports to the reg- istry than has any other single drug, this cannot, therefore, be quanti- tated to represent the total incidence of untoward reaction. The estimated risk from exposure to Chloromycetin is statistically outlined in the following table taken from a comprehensive study of the drug by the California Department of Public Health requested 2 See attachment No. 1, P. 2496, infra. See attachment No. 2, p. 2497, infra. "Particularly Chloromycetin, a Study of Antibiotic Drugs." Report of California Senate Fact-Finding Committee on Public Health and Safety, January 1963. PAGENO="0346" 2480 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY after their Senate investigation that I referred to before,5 and here in the table you can see that with an assumed average dose of 41/2 grams the risk of death is one in 36,118, varying upwards to an assumed dose in grams at 71/2 with a risk of death of one in 21,671. Senator NELSON. These statistics don't indicate the length of the course of treatment; that is, how many times 4.5 grams was admin- istered to get these results? Dr. WF~si'oN. No, sir; it would be impossible in this report; it is all within the complete volume. It is the most accurate statistical tabula- tion that I have encountered. Senator NELSON. I see. So these dosages may have been for a course of treatment for 10 dosages or five or any variety of number of dosages; is that correct? Dr. WEs~roN. Yes, sir. (The table referred to follows:) ESTIMATED RISK OF DEATH FROM APLASTIC ANEMIA FOLLOWING EXPOSURE TO CHLORAMPHENICOL- CALIFORNIA, JAN. 1, 1963, TO JUNE 30, 1964 Risk of death Assumed average dose (in grams) Within 1 year from More than 1 year from Combined exposure exposure 4.5 1 per 40,769 1 per 316,634 1 per 36,118. 5.0 1 per 36,692 1 per 284,971 1 per 32,507. 5.5 1 per 33,356 1 per 259,065 1 per 29,551. 6.0 1 per 30,578 1 per 237,476 1 per 27,090. 6.5 1 per 28,224 1 per 219,208 1 per 25,004. 7.0 1 per 26,206 1 per 203,551 1 per 23,219. 7.5 1 per 24,461 1 per 189,981 1 per 21,671. Dt~. WESTON. In addition to the damaging effect upon the bone mar- row, Ch~~oromycetin has also been implicated in producing optic neu- ritis, an inflammation of the optic nerve in both children and adults with resulting extensive loss of vision.6 This untoward effect is appar- ently protected by use of high doses of other agents, namely pyridoxine and cyanocobalamin, in a small series of cases.8 The widespread use of Chioromycetin continued to grow from 1962, when its gross sales, as enumerated above, were approximately $39.5 million, to 1966, when the U.S. gross sales slightly exceeded $45.5 million and sales throughout the world during the same year were slightly in excess of $70.5 million. During this period, of which 3 years are subsequent to the widely publicized California State Senate in- vestigation, it is apparent that physicians are continuing to prescribe this agent in spite of the warnings to the contrary which are displayed quite prominently in Parke, Davis' literature. Some responsibility for such misuse may still rest with Parke, Davis as represented by the attached reproductions, and these are taken from JAMA advertise- ments ° within the last 3 months in which, in a double-page spread, as you can see, in large print for the physician who doesn't care to read ° "Fatal Aplastic Anemia and ChiorampheniCOl." Report to the California State Assembly and Senate by the California Medical Association and State Department of Public Health, with cooperation and assistance of the California Pharmaceutical Association, Jan. 1, 1967. o Cock-e, J.G.F.L.: Journal of Pediatrics, vol. 68, No. 1, pp. 27-31, January 1966. Huang, N.N.F.L.: Journal of Pediatrics, vol. 68, p. 27, January 1966. 8 Cocke, J. G. Amer. J. Dis. Child. 114 : 424-426, October 1967. 8 See attachment No. 3, p. 2506, infra. PAGENO="0347" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2481 the fine print, you see it indicated "When it counts Chloromycetin (chioramphenicol) can be useful in urinary tract infections." And then you have a whole page of fine print. The same thing is true, and these are incidentally in their original advertisements, partly in color "may he indicated in certain severe respiratory infections." They carried the same list of indications and warnings within the advertisement that is published elsewhere. Senator NELSON. In which type of severe respiratory infection is chlorampheniool indicated? Dr. WESTON. Well, categorically I would say chJoramphenicol is not indicated in any respiratory infection in which any other antibiotic which is less toxic is effective, and this is true of any infection in the body for that matter. Now, the only exception to that might be in a patient in which another antibiotic is effective, but the patient is so sensitive to the drug that you might endanger his life by administering it to him. Senator NELSON. Well, the headings says "May be indicated in cer- tain severe respiratory infections." There are, of course, a wide ran~'e of respiratory infections. Is there any respiratory infection itself, in addition to the one circumstance you just named, in which chloram- phenicol is the drug of choice? Dr. WESTON. Ye~s, sir. Senator NELSON. There is none in which it is the drug of choice? Dr. WESTON. No, not taking other antibiotics into consideration. They say this; I don't mean to imply that in the scope of the two-page advertisement they don't say exactly what I have said, because they do. It is in fine print, it says "Because of its wide antibacterial spec- trum and its ability to diffuse into effective forms Chloromycetin may be of value in the treatment of selected severe respiratory tract infect- tions due to susceptible microorganisms. However, as with any anti- bacterial agent, the administration of Chloromycetin must be adjunc- tive to the overall therapeutic approach to this family of diseases. Appropriately treated good results can be expected." Then they go on to say "The decision to choose Chloromycetin from a group of antibiotics suggested by in vitro studies to be potentially effective against specific and respiratory tract pathogen should be guided" by various, "by severity of infection, relative susceptibility pathogenically to the various antibacterial drugs, relative efficacy of the various drugs in this family of infections and the important additional con- cepts contained in the warning box." They say everything that I just said. If there is no other drug that is less toxic which can be used then use Chloromycetin, but they have put it, couched it in, quite different language than I think I expressed here. They have again equated it with the toxicity of other antibiotic drugs. Now, I have asked myself the question many times, why has this occurred? Referring back to the continuing widespread use. I believe the reason is twofold. Chloromycetin is a very effective antibiotic which may be used to control virtually the entire spectra of infections ranging from Rickettsial diseases, which include Scrub Typhus, Mur- me and Epidemic Typhus, Rickeettsiapox and Rocky Mountain Spot- ted Fever, and most of the gram negative and gram positive diseases in between. But as I indicated previously most of these infections, and PAGENO="0348" 2482 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY all of them at the present time, can be controlled by other antibiotics which do not have this toxic effect. It is also as effective in treating gram negative and gram positive organisms, including Hemophiis influenza, an organism responsible for an extremely dangerous, pre- viously quite uniformly fatal meningitis in the newborn and neonatal age group. Until quite recently, within the last two and a half, to 3 years there is no question but that if you suspected Hemophilis in- fluenza meningitis in the newborn age group, Chiloromycetin was the drug of choice and it was used quite commonly in a triple-shot type of treatment where it was combined with streptomycin and other anti- biotics to treat this disease. This was done in infants who were severely ill, quite often even without the benefit of cultures of any kind because you had little time to treat them in this state of their illness. Senator NELSON. Is there now another drug as effective? Dr. WESTON. Yes, I believe, Ampicillin which has been on market two and a half to three years, somewhat in that period of time, has now been demonstrated to be as effective, if not more effective, in treating Hemophilis influenza infections. Ampicillin is being combined usually in a triple medication form remembering there is not the opportunity for a culture, and consequently, you might be treating Hemophilis in- fluenza, you might be treating some other type of meningitis, you are not sure, but they don't wait ordinarily to determine what the orga- nism is. Senator NELsoN. Well, the fact that it is known to be effective in a wide spectrum of infections may account for its being very frequently prescribed. But it seems to me that some other factor accounts for the fact that it is used prophylactically for the trivial infections. Testi- mony before this committee has been that it should never be used prophylacticilly. The fact is that it has been used for treating acne, minor infections of the gum; it has been used for head colds. In fact, Doctor, one of the doctors testifying yesterday pointed out a case of a lady who was, given cholarmphenicol and was told that whenever she had a head cold to take some. She developed aplastic anemia. Well, the fact that it is effective against this wide range of conditions doesn't account for this kind of indiscriminate prescribing, it seems to me. Dr. WESTON. No, sir. Senator NELSON. It just has to be that the doctors who are prescrib- ing Chloromycetin in this way, it seems to me, can't be aware of what they are really doing. Dr. WESTON. No, sir. Let me give you a little personal experience. The day the telegram came in from the FDA recalling the 30-odd different products which had been shown to be absorbed and excreted at a slightly slower rate than the Parke-Davis preparation, I called attention to my secretary and said "Well, it looks like they might be starting to control the use of Chioromycetin; I sure hope they do." And she said "What do you mean?" And I said, "Well, I wouldn't want to give Chloromycetin to my child and I don't know any doctor who would give Chloromycetin to his child." She said, "Well, my son just got through taking it for 3 days," and I said, "Your son, for what?" "For flu," she said, and I said, "You mean your son just got through taking this?" And she said, "Yes, positively." And I went to the druggist that evening, unan- PAGENO="0349" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2483 nounced, without telling anybody who I was and said "Have you had an increase in the sales of antibiotics including Chloromycetin in the last 3 weeks," because in Utah we have had continued publicity about flu although we haven't documented it in any `of our laboratories ac- curately yet, and he said, "Yes, we have had a marked increase in all antibiotics and we have this usually, seasonally, including Chloromycetin." So there is no question; there never has been any question in my mind, but that it has been used indiscriminately, and this is an exam- ple of a lay person working in a medical center, who `had no idea of the degree of toxicity. I have read quite a bit in the California proceeding, I am sure you have already considered putting something on the prescription pack- age which actually ultimately wound up in the hands of the patient telling them that they were taking a drug which might cau'se serious reaction, and I feel perhaps, as most of the doctors do, that this is unwise because there may be a patient, possibly one in `a million, I don't know how many it would be, who may have to have this drug who is allergic to tetracycline, Ampicillin, or one of the other drugs and is in a life-threatening situation and if she were to receive this particular drug with a warning "This might kill you, it may depress your bone marrow, or it may do something else," I am sure I wouldn't want to take the drug and perhaps she wouldn't want to and yet it might, in that particular instance, be the agent of choice. So I am inclined to agree with the physicians, if there is going to be a warning, or if there is going to be restriction on its use, the restriction should lie with the person who prescribes it, not with the advertisement on the materia~l to the patient themselves, although this was considered at some length in the California hearings which you probably are aware of. Senator NELSON. Well, I am still puzzled about the explanation for the widespread prescribing of this drug for minor infections. It seems to me, since it is perfectly clear from the law suits that have already been tried, that the doctors are liable for prescribing it for a minor infection. The only logical conclusion, it would seem is that the doctor prescribing it really isn't aware of the caution that should be used with this drug. I can't come to any other conclusion. Dr. WESTON. Well, in my field I deal a great deal with human be- havior, working with things other than drugs, motivations, reason for automobile accidents and related accidents, aiid I would say that there is a widespread feeling, not only in physicians, but people in general that this won't happen to me, and this is really, in my estimation, the crux of the thing. I can't believe there are enough physicians uninformed about Chlo- romycetin today with what has been in the literature, including at least three editorial comments from the council on drugs in the JAMA, which have covered a full page. The Senate hearings in California were quite widely publicized and I can't believe that the doctor is that uninformed. He may well be, but I think that-I would have to con- clude that part of the responsibility at this point rests with the doctor. I can't blame it all on Parke-Davis, because he has to open the PDR, he has undoubtedly received samples from Parke-Davis, and warnings in the literature with the material. When a doctor gets up in a maiprac- PAGENO="0350" 2484 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY tice trial today and states he has never heard of a warning on Chioro- mycetm then I would `have to say I didn't believe him. You will find the same thing true with alcohol in motor vehicle ac- cidents. I am sure that you will find most experts will tell you that alcohol is present in 50 percent or greater of people who are killed in motor vehicle accidents if they are drivers, but this doesn't stop people from drinking and driving. This can't happen to me. This is a concept basically ingrained in human motivation. And I think it is one that has to be considered when we are talking about something which occurs 1 in 24,000 times. Mr. GORDON. But, Dr. Weston, a doctor can't say "This can't hap- pen to me." He is prescribing it for somebody else. Dr. WESTON. No, this is interesting. I went to 1~ doctors in the University of Utah before I left and I said "Do you prescribe Chioro- mycetin for your children?" And I didn't find one who said yes, they do. On the other hand, in that medical center complex I didn't find any that prescribed Chloromycetin for anybody. Senator NELSON. You didn't find any physician who prescribed it for anybody? Dr. WESTON. For anybody for anything at this point, no, sir. This is, of course, in a university setting which is different from what you find in a physician on the street corner, but I couldn't find anyone who thought it was indicated for any condition. Senator NELSON. Well, that is why it seems to me your explanation isn't really very satisfactory because here are doctors at a university teaching hospital who really know apparently what chlorampheni- col is all about, and they don't say "Well, it can't happen to me." So if the doctors who in that setting don't prescribe it, then how do you explain why doctors outside that setting will say "I know what it is all about, but it can't happen to me." Dr. WESToN. Well, I think you have to understand the spectrum of medical knowledge. At one extreme you have the university setting and at the opposite extreme you have the physician who hardly reads the Journal from one year to the next, practicing medicine, seeing 40 or 50 patients a day in his office and this physician is not going to read much more than the big print in this ad. This is the drug of choice, that is it. He hardly will get to the small print on the second page and I am sure he won't get very far in two paragraphs or a full page in small print like that in an advertisement. I think this is the crux of the thing. They don't understand what the toxic potentiality is. Senator NELSON. That is what I was getting at. It is more out of ignorance, then, that it is prescribed, at least in minor infections where it is clearly not indicated and in cases where there is clearly an effec- tive alternative. It must be ignorance rather than feeling, "Well, it only happens 1 in 24,000 times, and therefore, it is not much of a risk," don't you think? Dr. WESTON. Yes, but this type of ignorance is inexcusable. When I say the doctor can't be held blameless, I mean that I think this type of ignorance today in medical practice is inexcusable. I think a physi- cian has a certain obligation to overcome this degree of ignorance. If he is going to prescribe a drug he has an obligation to his patients PAGENO="0351" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2485 to insure himself that this drug does not have a risk beyond a certain potential. This is the drug of choice, so to speak. I don't think you can excuse him by saying he is ignorant today. *Senator NELSON. I don't say there is any excuse for that, but I say that ignorance on the part of the physician would appear to me to be the best explanation thus far. We had testimony recently, as you are aware, from three distinguished doctors on chioromycetin. I asked them to estimate what percentage of the patients who receive chloram- pherncol should actually receive it. All three said it would be a guess on their part, but they were in agreement that the drug was way over- prescribed, and their guess would be that around 90 percent of the people who received it should not have received it at all. Dr. WESTON. Yes, I think it is higher than th'at. I don't think that even 90 percent of the people should have received it. I think it is probably indicated today in less than 1 percent of the people that received it. Senator NELSON. In other words, in less than 1 percent of the cases in which chlorarnphenicol was prescribed it was in fact indicated? Dr. WESTON. Yes, sir. Now, you have got to take it almost year for year, remembering that during certain periods there is no question but that it was the drug of choice in certain conditions. Then other anti- biotics came onto the scene. That is why any legislation or any attempt to control it has to take into consideration what is going on with all the antibiotics at any one time. Senator NELSON. Obviously, then, there is a vast amount of over- prescription of this drug. Three recent witnesses thought that not more than 10 percent of those who receive the drug should receive it and you think not more than 1 percent. On balance, then, what is your judgment as to how much good this drug has done versus how much harm it has done? Dr. WESTON. Well, there are several ways of equating this. If you take as positive indications what was a positive indication, there are some things you will have to say you do not know, but if you take on the positive side of the ledger those things for which it was positively indicated until the advent of tetracycline and Ampicillin, you would be dealing pretty much with Salmonella infections, rickettsial infec- tions, and other infections in which the patient is either sensitive or in which the micro-organism is resistant to the antibiotic, this is the thing. You cannot throw in any type of formula because they did not run a culture to begin with, so you do not know whether the organism would have been sensitive to penicillin or streptomycin or sulfanamide or in the wider spectrum one of the other antibiotics at that time. On the other hand, if you want to take 300-some-odd cases of typhoid that occur in a year, between 100 and 200 cases of rickettsial diseases, and figure that every one of those would be fatal if it had not been treated, `then figured out on the basis of that, and take Parke, Davis' own figures in terms of grams and divide them up into five-gram doses, using California statistics which I firmly believe are the most accurate as far as the incidence of fatal blood dyscrasia, you would wind up with somewhere in the neighborhood of 2,250 people on a four and a half gram dosage who would have an untoward-~a fatal blood dyscrasia in a year from Chloromycetin as contrasted with 500 PAGENO="0352" 2486 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY or 600 who would die from rickettsial or Salmonella infection. So, I do not think there is any question but what they have done more harm than they have good with Chloromycetin just in this country, and, of course, you get outside of this country and you have an entirely dif- ferent situation. Senator NELSON. Thank you. So, if I understand you correctly, you feel that because of the overprescri~tion of this drug, on balance it has done more damage than it has good. Is that what you are saying? Dr. WESTON. Well, this is a hard question to answer for this reason. If you have a real bad meningitis and a choice of giving tetracycline or Chioromycetin and you give Chloromycetin, the Ohloromycetin will clear that meningitis but the tetracycline would have, too, the chances are. Now, for me to say categorically that Chloromycetin has done more harm than good would be to eliminate the fact that in the vast ma- j ority of cases where Ohioromycetin was used, it was used and it cleared up the infection, but another antibiotic could have cleared up the in- fection without this incidence of untoward effect, so you cannot really answer that question. Senator NELSON. You are counting the cases where Chioromycetin, chioramphenicol, was used and did effectively clear up the infection without any untoward result. Dr. WESTON. Yes, sir. Senator NELSON. But in the same case, tetracycline or Ampicillin could have done as effective a job without the risks. So in the case where you end up with a serious blood dyscrasia, aplastic anemia, that is a negative effect of the use of chloramphenicol, correct? Dr. WESTON. If you are going to answer that question affirmatively, yes, that would have to be considered a negative effect of chloram- phenicol. Mr. GORDON. So, on balance, considering the way it is being pre- scribed today, the conclusion, I think, was that it has done more harm than good; is that correct? Dr. WESTON. It has done more harm, taking into consideration the fact that another antibiotic may have been used other than chioram- phenicol and used as effectively, if not more effectively, than it has good. You cannot rule out the fact that Ohioromycetin has cured thousands of cases of meningitis and thousands of strep throats and done it effectively. But, so would have a dozen other drugs. The California legislation, in its attempt to curb the use of this drug, met with opposition from all segments of the medical com- munity, and this, I think, is important, including public health author- ities who indicated that sudh legislation was only seeking to control medical practice and that such a decision of judgment rested with the physician who could be controlled effectively through means al- ready at t;heir disposal if injudicious medical practice was established. Now, California has probably one of the most sophisticated systems for doing this. Such measures are resorted to only when willful gross negligence is evident, and in many States, the only means of doing this is the criminal court, I should say in most States. However, it would appear PAGENO="0353" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2487 from this taible from the previously referred to Council on Drugs report of July 1967, depicting the reasons the drug was given in 288 cases, that the physician has not assumed responsibility to inform himself of modern therapeutic practices or has chosen to disregard these warnings. And as Dr. Best testified to, the common cold is the disease treated in 12 percent of the cases. (The table referred to follows:) Some specific conditions for which chioramphenicol given ~-i.--~ ~ \ ~ - I I 0 5 10 15 Per cent of cases 2. Reasons why chioramphenicol given. Left, General nature of indica- tions. Right, Specific conditions; all those accounting for 3% or more of known indications plus selected conditions with lower percentages. Senator NELSON. Now, it is never indicated for the common cold, is it? Dr. WESTON. No, sir. In fact, if you look at that circular graph, you will see that most of them fit into the category of minor or unspecified infections in which it also is never indicated. Acne, of course, runs about 2½ percent, which is unbelievable, in university medical practice. My interest in chloramphenicol and its untoward effects is derived from experience in conducting postmortem examinations on two chil- dren who died at intervaJs of 12 to 36 months following exposure to chloromycetin, prescribed injudiciously for minor respiratory ail- ments. Numerous similar reports are in the literature. I would say cate- gorically, `that if you look at the reports of untoward reaction's to chloromycetin, in virtually every instance the drug is not indicated, whereas if you go back and look at your typhoid, and this has been done by several people, look at your typhoid that was treated during the period when it was indicated, you will find conversely no untoward reaction to chloromycetin. I am sure this varies-it is just a matter of chance. I do not see why there would be any reason for this particular person to be sensitive to it and this one not, but in most of the surveys that have to date been made, where it has been indicated there has not been an untoward reaction to it, this is very strange. Senator NELSON. Well, would one explanation obviously be that it is u'sed in typhoid cases 300 or 400 times a year, whereas it is given to over ~~/2 million individuals for other cases? Dr. WESTON. Yes. Reasons drug was given Lower G.U. infections Common cold Pneumonia, bronchopneumonia.. Pyelonephritis. Typhoid fever Septicemia Chronic bronchitis Ear and sinus infections Severe tonsillitis, phoryngitis.. Cellulitis, boils Subacute boct. endocarditis. . Acne Parotyphoid infections H. influenza meningitis 81-280 0-68-pt. 6-23 PAGENO="0354" 2488 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Would that statistically be the answer? Dr. WESTON. Statistically, I am sure it would, yes. I do not want to become sensational in this presentation but I would just like to tell you a little bit about the last ca.se that I examined. The father had a myocardial infarction shortly after the daughter died. The daughter had been sick for about 3 years. It is a case of a. youngster who had a bad cold and sore throat, tonsillitis. The mother was given a prescription by a physician, took it to the drugstore and got it filled. This particular prescription was for chloromycetin. In worked very effectively against the youngster's tonsillitis. The youngster got sick about 3 weeks later and the mother went down to the druggist and got the prescription refilled, took it home and gave it to her daughter again. The third time she went down to the druggist the druggist asked if she was sure she wanted this refilled? And the woman said, "Yes, 1 do." "Well," he said, "I can't do it without calling the doctor." So, he thereupon called the doctor and the doctor was not in. So she said, "Well, isn't there anything that you can do?" he said, "Yes, I have another physician that I can call." So, he called this other physician and said, "I have a little girl with real bad tonsillitis. She has had chloromycetin before. Can I give her a prescription?" He said, "Yes." So, therefore, upon telephone comnnrnication with the second doctor, never ever having seen the patient, he gave the little girl a third prescription. Well, all in all, she had some five different courses of chloromycetin. She came into the hospital and was treated for about 3½ years with hormones. The mother is now in a psychiatric institution because she has all the guilt reaction which goes with her having talked the druggist into prescribing this drug. The father is incapable of working any longer. This is not an unusual case. When chloromycetin is prescribed neither the druggist or doctors seem to realize the potential toxicity. On the other hand, if you talk to this doctor, after he had this type of drug reaction, and ask him whether he would give chloromycetin to this or any other patient for just about any condition, he would say: "No, I would not give it. I just will not give it, period." So, I have had the occasion to talk to three different doctors who have had this type of reaction. Dr. Wintrobe in our department, of course, has dealt with families going almost into the hundreds that have had this type of reaction since he is such a well-qualified hema- tologist. He tells you uncategorically, he would not give chloromycetin and he does not see how they give chloromycetin. It is an entirely different situation than if you have a youngster who is coming in with typhoid fever. You have got a kid with a cold, that is what it amounts to, a runny nose, and you are giving him something that could take his life away anywhere from 3 months to 3 years later. There just does not seem to be any way of equating the thing, as far as most university physicians are concerned at this time. It is really very sad; it is impossible. Now, to go on in the statement, Parke, Davis h'as, from its outset equated the untoward reaction to chlorornycetin to that with other drugs and, I am sure you will find in the literature if you look for it, PAGENO="0355" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2489 references to granuiocytopenia, treated with sulfonamides, and a sub- stantial array of medical literature now on `anaphylactic reactions, many of them due to penicillin, but you cannot equate the amount of penicillin which has been given tO the amount of chloromycetin given and quantitatively put it down on anaphylactic reactions even if they were `all uniformly fatal which they are not any longer. They are treated and suspected and watched for in quite a large percentage of the patients. So that you cannot equate them. Aspirin is another thing which in two malpractice trials I have seen introduced as something which causes untoward reactions. If you stop to think of `how many aspirin are administered or taken in this country in a year, this is a rather ridiculous argument. Certainly there are a smaller number of cases but my own personal search of the lit- erature reveals that more children die from taking aspirin `accidentally in `a home in 1 year than have been reported from untoward reactions to aspirin in 10 years'. So tha't again, you cannot equate aspirin. And if you are going to go into dicumarol, which is another thing I have seen in malpractice testimony, this is ridiculous, because here you have a man who is on the borderline of life and death. You are offering him the opportunity to keep his coronary arteries open at the cost of introducing an agent which has a very definite calculated risk and you cannot equate this any more than you could with a variety of anti-neoplastic agents that we are using which are known to be toxic, which are known to cause bone marrow damage. You are deal- ing with fatal conditions and potentially fatal conditions and we cannot put the two of them in the same sentence even in court tes- timony. Chloromycetin is indicated in any infectious disease in which an- other antibiotic with less toxic effect is not efficacious, or cannot he tolerated by the patient. Present indication, again depending on the method of administration, the sensitivity of the patient, could be con- strued to include at the very most typhoid fever, certain rickettsial infections such as epidemic, rnurine and scrub typhus, rickettsiapox and Rocky Mountain spot fever. It may be indicated in overwhelming infections where positive iden- tification in the organism and sensitivity to antibiotic would only serve to delay the value of effective chemotherapy and hasten death. Senator NELSON. May we back up a moment? Dr. WESTON. Yes, sir. Senator NELSON. Maybe I do not read this sentence correctly. You say: "Chioromycetin, (chloramphenicol) is indicated in any infectious disease in which another antibiotic with less toxic effect is not ef- ficacious." Dr. WESTON. Well, you have to take into consideration the method of administration. Tetracycline administered orally has frequently sufficient side effects to it that it causes the patient such gastrointesti- nal disturbance that he is incapable of keeping it within his system, and if you are going to talk about treating a patient with tetracycline, you have to consider that the patient will be capable of keeping the drug within his stomach and his intestine long enough for it to be absorbed, or you are going to have to administer it parenterally or by injection. Now, if you can do this, that is fine, but if you cannot do this, then you have got to use chloromycetin, is what I am saying. PAGENO="0356" 2490 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. I guess it is that sentence standing alone which bothers me. You are saying it is indicated in any infectious disease in which another antibiotic with less toxic effect is not efficacious, I assume you mean in any disease which is very serious and in wiuch no other antibiotic is effective. Is that what you are saying? Dr. WESTON. Yes. Any infectious disease which is capable of caus- ing death in which no other antibiotic as-I really would assume we are talking about serious infectious diseases. Senator NELSON. I knew you were, but standing alone, I thought that the sentence required clarification. Dr. WESTON. And here again, I think you have to be fair to Chloro- mycetin and say that some of the drugs that we are using today per- haps have not undergone the therapeutic trial that Chloromyetin has with respect to toxicity. Now, tests were made from 1948 to 1950 with Chloromycetin before we had enough to hold a hearing. Dr. Wintrobe and his associate really met with the council and discussed toxicity of Chioromycetin and some of these agents we are talking about using, especially for hemophilus influenza infections, have barely been on the market much longer than that. So while we are not aware of any toxicity, this does not mean that you can equate the drug at this time with something like Chloroinycetin and I would be the first to say that if Ampicillin 5 years from now was showing changes in the body which were toxic, it should be given the same sort of study that Chloro- mycetin has, but I do not think it has been on the market long enough yet to say beyond a doubt that it is nontoxic. The use of Chioromycetin should be accompanied by studies of pe- ripheral blood and if necessary the bone marrow at frequent intervals in order that toxicity may be detected as soon as possible. I do not think the physician should be misled into the concept-I questiou this-into the concept that this is going to detect every fatal bone marrow reaction. Conversely, the use of Chloromycetin, is positively contraindicated, in minor infections in any location in the body. In practice, there is no question but that limiting the use of Chloro- mycetin to hospital practice would result in danger in certain severe fulminating infections and consequently any measure designed to con- `trol the use of Chlorornycetin should make provision for the emergency dispensing of the drug by physician in such conditions. This may change. In fact, it already appears to be changing as practically the only infection which you can put into that category are these near fatal, early childhood infections of which the most serious is hemo- philius influenza and if this `triple medication including Ampicillin instea.d of Chloromycetin proves to be nontoxic over the next couple of months, I would say categorically that you could limit the use of Chloromycetin to hospital practice without endangering any person's life because you can get a patient into a hospital to treat typhoid fever and Salamonella infections or you can treat these with another anti- biotic on an outpatient basis. If the risk that is involved in this cannot be sufficiently transferred to the physician by way of communication I certainly would think that admission to the hospital is indicated. However, the evidence presented indicates that the misuse of the drug continues in spite of numerous warnings to the contrary and PAGENO="0357" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2491 previous attempts at legislation controlling its use in at least one State. With the numerous agencies available for reporting use of the drug in outpatient and hospital practice, it would appear at this time that a legislative attempt should, be made to limit the use of this toxic antibiotic to those conditions in which it is indicated. However dis- tasteful such measures may be to physicians, my personal experience in dealing with physicians who have been associated with severe un- toward reactions to the drug has revealed considerably more displeas- ure on their part at this time. Senator NELSON. You mean more displeasure about what? Dr. WESTON. About their untoward reactions, about their aplastic anemias. Whenever anyone has a reaction, they stop using Chloromy- cetin, has been my experience. Of course, it is too late. Senator NELSON. In the cases you have recited, are you talking about doctors who prescribed it for a case in which it was not indicated? Dr. WESTON. Yes, sir. Senator NELSON. They should not have prescribed it. Dr. WESTON. That is correct. Senator NELSON. And, in all of those cases the doctor would have been happier if there had been some restriction on his freedom of prescription, is that right? Dr. WESTON. Yes, sir. Senator NELSON. We had testimony to that effect on Tuesday. Dr. Lepper testified that there ought to be ssme limitation upon prescrip- tion of this drug. He was not prepared to say what kind of formula or what kind of a method should be used. One of the witnesses sug- gested that we follow the same procedure used in the prescription of morphine: That chloramphenicol be identified in a certain way and a record filed, and so forth. Bht, in any event, I understand your testi- mony to be that there should be some attempt, legislative or otherwise, to control the use of this drug. Dr. WESTON. Yes, sir. I would not limit it to this drug. I think that there are now and there will be, perhaps not nearly as toxic as Chloro- mycetin, but I am sure that experimentally the time will come when there may be another drug which may have untoward effects and any machinery which is set in motion~ to control these drugs, I think should take into consideration the fact that we are using drugs in different ranges of effectiveness and in different ranges of risk. Dicuma- rol certainly has a well accepted risk. We know a certain number of people are going to take Dicumarol to the point where they will bleed internally and subsequently die from- this. On the other hand, to ecjuate this with the effect it has in preventing perhaps thrombosis within a coronary artery, this is not a bad risk. The same is true of agents which are used for prevention of cancer or treatment of cancer. We have watched the antileukemic agents for a number of years and have seen the bone marrow of these patients sometimes go down to nothing, and then tried to build them up. We knew this was an ac- cepted risk. These were experimental drugs and I think any doctor that gives an experimental drug to a patient has an obligation to the patient or to the family to explain that this is an experimental drug. So, I think the legislation-and I am sure, as Dr. Lepper testified, that the PAGENO="0358" 2492 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY machinery is there. We have public health laws that require reporting of certain diseases and we have very definite controls on narcotics which have been very effective over a long span of years now, so that there is machinery there that we can utilize, but I think a study like this should not be directed at just one drug. I think we ought to look at the whole spectrum of drugs and separate the experimental drugs from the drugs which are proven therapeutically and have no toxic effects and then put ones like Chloromycetin in the center and control its use this way. I would not want to discriminate against chloro- mycetin. Senator NELSON. I was not suggesting that. I take it that you would suggest that some kind of a mechanism be established to control the drug. For example, a distinguished panel of experts from the medical profession would be formed to study the problem, and would make a recommendation to the FDA or some other appropriate place, that this drug should be in a special category to limit its achuinistration in one fashion or another. Is that the kind of thing you are talking about? Dr. WESTON. Yes, sir. Positively. Senator Nm~soN. Thank you. Dr. WESTON. It is recognized that considerable pressure may be brought to bear by numerous economics groups, including not oily the manufacturer, but the dispenser, when a commodity with gross national sales of the ma~rnitude of this agent is curbed to this degree. It should also be recognized in any legislation that extensive research is currently being conducted within the facilities of the manufacturer, Parke, Davis, to develop an agent capable of protecting the body against deleterious effects of this drug such as has been shown to occur in protecting the eye from untoward effects in a limited number of cases. With virtually every `State in the Nation requiring reporting of certain diseases and conditions to public health or other authorities and such stringent control carefully exercised on the use of addicting and now dangerous drugs, it would appear that the machinery is available `for effective control of other toxic drugs such as `Ohloro- mycetin. It remains to devise the legislation necessary and the method of implementation within `these agencies. Senator NELSON. The day before yesterday, in the testimony of some of the witnesses, the question was raised as to the reporting of side effects from this or any other drug. Would you think it would be valuable to the profession and to the public if hospitals, for example, were required to report to some central place-the FDA might be one or the AMA might be another-the information they accumulate each year about si'de effects of drugs used in that hospital? I am not saying that you would report all side effects, but side effects that were of significance and information about which would contribute to the body of medical knowledge. Would you consider that a useful, valuable thing to do? Dr. WESTON. No, sir. Senator NELSON. You would not? Dr. WESTON. No, sir. It is much the same as the battered-child legislation. We went to a great deal of trouble to get battered-child PAGENO="0359" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2493 legislation passed in-I believe it is present in all but two, maybe it is in all the States now. Senator NELSON. Which legislation is that? Dr. WESTON. This requires the reporting by a physician when he suspects that a child has been abused by its parents, and it just has not proven to be of the value that it was anticipated to be because even with an immunity clause in it, in that particular instance, pro- viding immunity to the physician in case he did make a false accusa- tion, you have other factors to consider. You have the factor that this family is treated by the doctor in this particular instance and the doctor reports this family, so he loses all the patients in the block as soon as word gets around. Senator NELSON. Maybe you did not understand my question. Maybe I did not make it clear. Dr. WESTON. Well, you have exactly--- Senator NELSON. I am saying hospitals, only hospitals, would re- port the medically significant statistical information on drug side effects. They have the patient there. The patient's records are there. They have qualified physicians in the hospital. For example, say that you have found a blood dyscrasia as a consequence of chioramphenicol. At the end of the year the significant statistics which you have ac- cumulated would be reported to a central place. That is my question. I was not referring to known side effects of a drug like penicillin that has been used over a period of many, many years. Dr. WESTON. Well, you have two cases now, one in excess of $200,000 and one approaching $200,000 in which awards have been made to families on the basis of Oiloromycetin. Do you suppose a doctor is going to be naive enough if he treats a patient with an upper respira- tory infection with Chloromycetin to admit this patient into the hos- pital and write down at the end of the hospital chart, if there is aaiy way to mask it, the fact that he has used this drug and that thIs patient has ultimately died from the untoward reaction? I do no1~ believe so. You cannot get the information either by voluntary or- - the accurate information either by voluntary or compulsory reportni r systems. Senator NELSON. I am not talking about getting information for purposes of prosecuting doctors, but we have heard you and somA other distinguished doctors testify and nobody can give us any idea really of how many cases of serious blood dyscrasias occur from thj~ drug or apparently from any other drug. All I am saying, for the benefit of educating the medical profession about the drugs, if you have x number of cases of a certain side effect from a particular drug, would not it be valuable to the researchers in the profession to know that the drug is causing it? This is what the medical profession hopes to learn as fast as it can about every drug and I am suggesting that they might learn it faster if the information accumulated in the hos- pitals around the country was furnished to FDA and the American Medical Association. That is my question. Dr. WESTON. Oh, I agree with your point. Do not get me wrong. I agree wholeheartedly with your point, but somewhere along the line, PAGENO="0360" 2494 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY in order for that to get reported by the hospital to the FDA, it has to appear in the hospital chart. Senator NELSON. Yes. Dr. WESTON. Well, have you ever seen lawyers go through hospital charts? I mean, what you are doing in effect is you are asking the doctor to invite upon himself a malpractice case. And they just do not do it. They are getting more and more cautious about malpractice and to put down anything that is equivocal in any way on a hos- pital chart is to invite its inspection by an attorney, and that is why I say in theory it sounds wonderful but it just-I have worked so much with malpractice cases, not only drug reactions but where doctors have had surgical misadventures, and as a matter of fact, in Philadelphia we had a very elaborate system whereby every patient that died in surgery, everyone who died after surgery, or everyone who died as a course of treatment, either immediately or delayed, as this would ordi- narily be, had to be reported to the medical examiner. They were referred down to the medical examiner's office for examination. In the course of that examination the hospital chart was subpenaed, a privi- lege allowed the medical examiner in that city. It is in many. The chart was brought in and summarized. Now, if in the course of the entire workup, including the hospital chart summary, post mortem examination, chemical studies, and every- thing else, it could be shown that the doctor was negligent, derelict in his duty, this case was anonymously presented to a committee of the medical society. It was quite effective in bringing the hospital, the physician, and his peers together and pointing out that they are doing something which is not being done by most of the physicians or, as a matter of fact, in some cases you are committing a gross error bor- dering on criminal neglect. That is in my experience the most sophis- ticated type of system we have in the United States today. This is similar to California which has set up their board of examiners and they can at will call for a hearing but if you were to go into most communities today, there actually is no agency that functions in this way; the result is that the physician is not protected to the degree that he should be and he protects himself. And that is why they are so conscious of malpractice today that it really has started to be felt in the way they practice medicine. Senator NELSON. I realize there are tiny 25-bed, 10-bed hospitals that may follow a different procedure, but is it not correct that you could go into any major hospital and the patient's record will show the case history, the diagnosis, the treatment, and so forth, if the patient is in there as a consequence of some dramatic reaction to a drug that has been administered, the record will show that, will it not? Dr. WEsToN. If the diagnosis is established. Senator NELSON. Yes. You do not mean to tell me that in major hos- pitals in this country if a patient comes in who has a dramatic reaction to a drug, and it is known what the drug is, it is known that this is a side effect, and they are treating this patient, the hospital would fail to disclose in the record what the patient's condition is? Is that happen- ing? The hospitals are hiding from the record the patient's diagnosis? PAGENO="0361" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2495 Dr. WESTON. The record is made by the doctor. The record is not made by the hospital. Senator NELSON. Well, the patient goes into a hospital and is being treated there. Dr. WESTON. The hospital supplies the paper. The doctor makes the record. The nurse writes her notes. But the record is made by the doctor. Senator NELSON. Is it common in the medical profession for a doctor who has made a diagnosis but is afraid he has made a mistake, to keep his patient in the hospital and be treating him covertly and not putting in the record what it is all alt, out? Dr. WESTON. I would not say it is common, but I have encountered it more times than I can count on my fingers and toes in the course of my reasonably limited career, so it is not so completely uncoiumon,~ and you have in the California proceedings the statements of at least one other physician who says that he saw blood dyscrasia misdiagnosed as leuke- mia, spontaneous cerebral hemorrhage, spontaneous GI hemorrhage. Now, I do not think there is any question but what some of the doc- tors in our medical community would be prone to cover up this sort of reaction if they had used the drug injudiciously and it had caused a bone marrow dyscrasia. I do not think there is any question about it. And, I think any doctor who came in here and said otherwise would be naive. Senator NELSON. It would not be possible, would it, for a doctor to fail to disclose all the details of a case if he had some kind of a clinical practice in which more persons than one were seeing the patient? If a person came in with a serious blood dyscrasia, I would assume he would then call upon other specialists in the hospital to evaluate the patient. Dr. WESTON. Well, that is the assumption that I am not making. Senator NELSON. I see. You scare me. I had assumed that. Dr. WESTON. If you do not take a bone marrow biopsy on one of these patients, you really sometimes are not going to know exactly what is going on in their bone marrow. I do not mean to frighten you, but I just know that it does occur. It is not in a very large segment of our profession fortunately, but it does occur in. a small segment, small percentage. Mr. GORDON. I have just one question. In the cases in which you were the medical expert, what were the issues involved? Dr. WESTON. Well, in the cases that I was the medical expert in, the issues revolved around three things, the first of which was the dicta I have already enumerated, the watering down, so to speak, of the warn- ing which was initially directed to be put on the product by Parke, Davis, and in this one I have already stated that at least two other physicians besides myself, felt that the tenor of the warning had been altered significantly in the form that it was presented to the physicians, and the impact of it was altered considerably by the promotion that occurred in addition to this. Now, the other issues concerned indications and contraindications for the drug and whether in fact a condition had been diagnosed at all in this particular circumstance. PAGENO="0362" 2496 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GORDON. Thank you very much. Senator Nni~soN. Dr. Weston, we appreciate very much your very valuable and useful testimony and I appreciate your taking the time from your busy schedule to come here and appear before the com- mittee. Thank you very much. Dr. WESTON. Thank you, sir. (The supplemental information submitted by Dr. Weston follows:) ATrACHMENT No. 1 WARNING Serious and even fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) are known to occur after the adininistra- tion of chioramphenicol. Blood dyscrasias have occurred after both short-term and prolonged therapy with this drug. Bearing in mind the possibility that such reactions may occur, chloramphenicol should be used only for serious infections caused by organisms which are susceptible to its antibacterial effects. Chloram- phenicol should not be used when other less potentially dangerous agents will be effective, or in the treatment of trivial infections such as colds, influenza, or viral infections of the throat, or as a prophylactic agent. Precautions: It is essential that adequate blood studies be made during treat- ment with the drug. While blood studies may detect early peripheral blood changes such as leukopenia or granulocytopenia, before they become irreversible, such studies cannot be relied on to detect bone barrow depression prior to develop- ment of aplastic anemia. INDICATIONS Oral and Parenteral. Ohioromycetin (chloramphenicol) is a broad-spectrum antibiotic having specified therapeutic activity against a wide variety of organisms. Chioromycetin (chioramphenicol) is indicated in the treatment of patients with rickettsial infections, including epidemic and murine typhus fevers, scrub typhus fever, Rocky Mountain spotted fever, and rickettsialpox; typhoid fever and certain other salmonella infections; urinary tract infections due to suscep- tible organisms; surgical infections such as postoperative wound infections, cellu- litis, infected sinus tract, and peritonitis or intra-abdominal abscess from ruptured intestine, diverticula, or appendix, usually due to microorganisms sensi- tive to cbloramphenicol; severe respiratory tract infections due to susceptible organisms, in those instances when contraindications to other drugs exist or when there is lack of response to other agents; meningeal infections due to susceptible organisms; and certain other miscellaneous infections, wherein other therapeutic agents have been found ineffective. The antibiotic is supplied in a number of product forms, of which the palmitic ester and the sodium salt of the succinic acid ester of chloramphenicol require conversion to free chloramphenicol before exhibiting marked antimicrobial activity. Chloramphenicol diffuses rapidly, but its distribution is not uniform. Highest concentrations are found in the liver and kidney; lowest concentrations are found in the brain and cerebrospinal fluid. Parenteral. Parenteral therapy with Ohloromycetin (chloramphenicol) is rec- ommended for patients too severely ill to take therapy orally. After symptoms subside, treatment may be continued with the oral preparation of choice for the individual. Topical (dermal, ophthalmic, otic). Chloramphenicol ophthalmic preparations ~~t1~out steroids have given good therapeutic results in bacterial conjunctivitis caused by Esch. coil, H. influenzae, Staph. aureus (Micrococous pyogenes), Strep. liernolyticus, and Morax-axenfeld. Ohloramphenicol ophthalmic preparations with steroids have given good results in nonpurulent conjunctivitis. Hydrocortisone is intended to suppress inflam- matory reaction when desirable. Chioramphenicol when used topically may be supplemented by appropriate systemic medication when necessary. PAGENO="0363" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2497 ATTACHMENT No. 2 [From the Journal of the American Medical Association, vol. 201, No. 3, July 17, 1~67] OHLORAMPHENICOL-ASSOCIATED BLOOD DY50RA5IA5 A REVIEW OF CASES SUBMITTED TO THE AMERICAN MEDICAL ASSOCIATION REGISTRY (By William H. Best, M.D.) Chioramphenicol, an effective broad spectrum antibiotic, was introduced in 1948. Only after three years of extensive use did it become evident that this drug was capable of seriously depressing bone marrow activity in rare recipients. It was in response to the delay in recognizing the toxic potentialities of this drug that the American Medical Association established the Registry on Blood Dyscrasias, hoping, among other things, to recognize such effects early when they occurred for other new drugs. The Registry and its study group have since accumulated data on a large number of drugs have issued periodic tabulations and resumé of cases submitted, and have authored commentaries on various associated problems.'~ During this period, chioramphenicol has been implicated in more reports to the Registry than has any other single drug. It appeared that useful information could be obtained through a more thorough review of Registry reports. Included in this study were 408 cases, reported to the Registry from 1953 through 1964, who were known to have received chioramphenicol during the year preceding a non-neoplastic depression of blood cell formation. Generalizations from this experience would be most valuable if cases reported to the Registry represented an unbiased sample of the condition as it occurred throughout the world. However, there are unavoidable and, no doubt, unidenti- fiable biases in this collection of cases. For example, most cases have been volun- tarily reported from selected sources, and the composition and attitudes of these sources have changed from year to year. Some cases were abstracted from the medical literature. Nonetheless, this appears to be `the best data available for study. The Registry contains a total of 298 US reports. 25 known to be published, 273 not; plus 110 foreign reports, 70 known to be published, 40 not. Yunis and Bloomberg reviewed much of the literature on this disorder, sum- marizing data on 94 cases.6 Twenty-one US and eight foreign literature cases are common to their review and to the Registry; their other cases are not in the Registry. The Registry contains 1 US and 65 foreign literature cases which were not covered in their review. There have been additional published case reports which appear neither in the review by Yunis and Bloomberg nor in the Registry. METHODS OF ANALYSIS During the years of existence of the Registry, the report form has gone through several different versions, more recent ones tending `to call for more complete information. In general, no systematic attempt has been made to obtain more detailed clinical information or late föllow-up of cases. Reports were coded and punched on 80-column i~omputer programming cards, using from 4 to 36 cards per patient, under the direction of Norman Dc Nosaquo, MD, and Mrs. Helene Weston of the AMA staff. Data transformation, reduction, tabulation, and analysis were performed by the author using computers and over 30 special computer programs. GENERAL CHARACTERISTICS OF CASES Age and $e~r.-Females accounted for 62% of 407 cases. There was a wide dis- tribution of cases by age with a rate of 0.5% to 1.5% of total cases per year of age from the teens through the 70's, occasional cases in older age groups, and a striking peak occurrence of about 5% per year of age in the 3- to 7-year age group. There was some difference in sex distribution at different ages: females accounted for 69% of 113 patients 0 to 9 years of age, 69 (73%) of 94 patients 10 to 39 years of age, but only 47% of 150 patients 40 years of age or older. The percentage of females was essentially the same for cases reported from the United States as compared to reports from elsewhere; however, there is a much less striking peak of occurrence for the 3- to 7-year age group in the latter series (Fig.1). N0TE.-Numbered footnotes at end of article, p. 2506. PAGENO="0364" 2498 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 0 0~ 0 0 a- 1. Age distribution of cases of chloramphenicol-associ- ated blood dyscrasia as related to geographic origin. The smaller 3- to 7-year age peak in the non-U.S. cases might represent either different patterns by which this drug is prescribed for various age groups, dif- ferent biases in the reporting of cases, or different hereditary patterns of age susceptibility to this complication as related to ethnic origin. The last of these possibilities seems unlikely, for 84% of the non-U.S. cases are from Europe or European-colonized countries, and a similar background is claimed for most white patients from the United States. In addition, 14% of US patients are nonwhite whereas only 9% of foreign cases are nonwhite, and nonwhites had a lower peak of occurrence at ages 3 to 7 than did whites. The Table presents data on some of the more common indications for use of the drug in relation to age and sex. Upper respiratory tract or ear infection were the indications in 29 (almost 40%) of 77 patients, in the under 10-year age group but in only 7 (about 10%) of 68 patients in the older age groups; lower respiratory tract infections and urogenital infections, on the other hand, each ac- counted for almost a third of indications in the elderly, but only about a tenth of childhood indications. A comparison of US with other reports in this regard reveals similar patterns of indications for most age groups except that there appears to be a slightly lower percentage of childhood cases corresponding to each of the three specific listed indications in the non-U.S. group. AGE, SEX, AND REASON FOR RECEIVING CHLORAMPHENICOL Age group 0-9 years 20-39 years 60-plus years Indication for chloramphenicol - Number of Number of Number of Number of Number of Number of patients females patients females patients females Upper respiratory tract or ear in- fections 29 19 4 2 7 4 Lower respiratory tract infections Urogenital infections Other indications 7 10 31 6 10 20 6 11 32 5 9 22 21 21 19 7 5 9 Total 77 55 53 38 68 25 Age distribution and geographic origin - USA. (249 cases) o---o Elsewhere (109 cases) 0 10 20 30 40 50 60 70 80 Age in years Race and Etlcivic Oi-igiiv.-Of the 346 patients whose race is known, 28 (8%) were Negro, 10 (3%) were Oriental, 3 were American Indian, and 2 were East PAGENO="0365" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2499 Indian. Negroes accounted for 11% of the U.S. group but were not present in the non-U.S. group. Only 18 (43%) of 43 nonwhite patients were female, whereas 191 ({3%) of 303 white patients were female. Ethnic origin was indicated for 144 white patients. Of these, 79% were north European, 6% Jewish, 6% east Europeans, 5% Spanish-American, and 4% south European. Other Gen~etio Information.-In a written communciation to the Registry (March 1, 1960), D. J. Fernbach, MD, called attention to a set of identical twins, both of whom developed blood dyscrasias related to chioramphenicol; a published report of these cases appeared subsequently.7 These identical twins, who were white males 3 years of age, had `been given seven- to ten-day courses of ehloramphenicol on several occasions during the pre- `ceding two years for severe upper respiratory tract infections. Twin A had six to ten such courses, the most recent being about a month before diagnosis, at which time trisulfapyrimidines was also given. Purpura developed characterized by thrombocytopeni'a and a hypoplastic marrow, which, over the course of about two month's, developed into pancytopenia. Three marrow trans- plants were attempted from twin B during the next two years, but without apparent improvement. Hemoglobin returned to normal after 11/2 years of corticosteriod and androgen therapy. The bone marrow became less hypocellular, but thrombocytopenia and moderate `leukopenia still persisted `six years after onset. Twin B had received only four courses of chloramphenieol, the most recent course (this drug only) being given tw'o weeks prior `to diagnosis, at about the same time that purpura appeared in twin A. Isolated thrombocytopenia asso- ciated with a hyperplastic marrow, including normal numbers of megokaryocytes, became evident when he was being worked up in preparation for the first marrow transplantation. He received no therapy and completely recovered within two weeks after chioramphenicol was discontinued. BLOOD AND BONE MARROW The reporting physician in each ease indicated `his diagnosis of the type of dyscra'sia utilizing his usual criteria plus the admonition on `the report form `th'at leukopenia would consist of leukocyte counts `of 3,000/cu mm or less. Further documentation was `usually not present, and only rarely did members of the hematology panel find it necessary `to change a diagnosis on the basis `of such documentation when present. All three major types of peripheral blood cells, eryt'hrocytes, leukocytes, and platelets, were jointly depressed in 75% of 358 cases; two cell types were de- pressed in 6%; and a single cell type was depressed in 19% (leukocytes in 9%, erythrocytes in 6%, and platelets in 4%). Isolated erythroid cell depression was more common at ages 20 to 59 years (15% of 134 cases) than in younger (2% of 144 cases) or older (two [3%] of 80 cases) age groups, but no other age trends were apparent. Depression of granulocytes was the most striking component of leukopen'ia in most instances, `but because the report forms did not always call for specific details in this regard, a more complete `statistical breakdown is not given. Bone marrow findings were available in 129 cases. In 3% of these, the marrow showed increased cellularity and in 7%, normal cellularity, often with other changes such as maturation arrest of the granulocytic series of vacuolation of eryth'rocytic precursors. Depression in number was noted for precursors of one of the major types of blood cell in 12% of cases; of two types in 5%; and of all three types (e.g., hypopl'astic or aplastic anemia) in 74%. Two marrows in the last category showed increased numbers of marrow lymphocytes, but on follow-up this apparently did not represent leukemia or lymphoma. Of 24 patients with only one or two cell types depressed in the blood 2 (8%) showed a normal to byper- plastic marrow, 15 (62%) had one or two cell types depressed in the marrow, and 7 (29%) `showed general marrow hypoplasia. of ios patients with `all three cell types depressed in the `blood, 10% showed a normal to hyperplastic marrow, 6% showed depression of one or two cell types in the marrow, and 84% showed general marrow hypoplasia. Clinical manifestations were not reported in detail for most cases, but those which were given conformed with what one might expect: manifestations of anemia, propen'sity to hemorrhage, and increased susceptibility to infection. PAGENO="0366" 2500 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DETAILS OF DRUG ADMINISTRATION General.-The reason that chioramphenicol had been given (for the most part infection or prophyl'axis against infection) was cited in 71% of the 408 cases (Fig 2). Reasons drug was given Some specific conditions for which chloramphenicol give Lower G U infections ~ Common cold ___________________ Pneumonia, bronctropneumofliO. ~ Pyelonephritis ___________ Typhoid fever ________ Sept icemia _________ Chronic bronchitis Ear and sinus infections Severe tonsillitis, pharyngitli.... Cellulitis, boils Subacute bad. endocarditis. Acne Paratyphoid infections H. influenza meningitis 0 5 10 Per cent of cases 2. Reasons why chioramphenicol given. Left, General nature of indica- tions. Right, Specific conditions; all those accounting for 3% or more of known indications plus selected conditions with lower percentages. Chioramphenicol was the only known drug administered during the prior six months to 40% of patients. One other drug was mentioned for 19%, two for 13%, and three or more for 28%. In one case, 17 other drugs were listed. In 9% of all cases, the only other drugs mentioned were members of what the study group considers to be generally "innocent" drugs-aspirin, the barbiturates, cliloral hydrate, digitalis glycosides, the penicillins, and the tetracyclines; in 37% of all cases, drugs other than "innocent" ones were administered, but no "toxic" drugs were given; in 9%, another toxic drug was administered, but suspicion was cast most strongly on chloramphenicol; and 4% suspicion was cast most .strongly on another toxic drug. Thus, in 96% of cases, there is strong suspicion that chlor- amphenieol was the causative agent, and in the remaining cases, this possibility cannot be ruled out. Since elimination of those patients receiving another toxic drug had virtually no effect on outcome of the dyscrasia, all cases were included in the analysis. Duration. and Dosage of Cli.ioramphenieoL-It is known that 9% of patients received this drug `at least once prior to the course in question. The dashed line of Fig 3 presents `a cumulative plot of average daily dose in milligrams per kilogram per day on a type of graph paper having logarithmic and probability scales. If the log-dose were distributed in gaussian fashion, such a plot should approximate a `straight line. Central portions of such curves are generally more accurate than the extremes. In this case there is some deviation from a single straight line, but the fit is not bad. At any rate, interpolation will provide estimates of dosage levels defining `selected percentiles. It is seen that 10% of patients received less than 8 mg/kg/day, 50% received less than 23 mg/kg/day, and 10% received greater `than 60 mg/kg/day. This is to be con- trasted with a manufacturer's recommendation for a starting dose of 50 mg/kg/day in adults and 50 to 100 mg per kilogram per day in children beyond infancy. Either smaller doses tend to be given to susceptible patients, or else the general trend in use of this drug is to administer smaller average amounts than recommended for initial therapy. The l'atter possibility seems more likely. There appears to be slight differences in patterns of daily dose administration for different age groups. Thus, the median doses were: 33 mg/kg/day for patients 0 to 9 years of age, 24mg/kg/day for those 10 to 39 years of age; and 18 mg/kg/day for `those 40 years of age and older. PAGENO="0367" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2501 ("u's) Daily dose,milligrams per kilogram per day (244 cases) 2 5 0 20 50 100 200 I I I `I I Ihlhhhhhll 99 0 0 0 95 `V ~ 90 o U) o o w 80 g~4c~ ~ .E 60 ~40 8 ~ 20 a) 4- go I 20 50 100 200 500 1,000 2,000 * 5,000 (c~'~D) Total dose, milligrams per kilogram body weight (280 cases) 3. Daily dose of chloramphenicol in milligrams per kilogram per day and total dose in milligrams per kilogram. Distribution of values for each curve is indicated cumulatively on log-normal coordinates. The number of days of therapy is similarly plotted as one of the curves in Fig 4. There is a concavity to the cumulative plot line. Although various interpreta- tions are possible, a tendency of physicians to use either short courses or pro- longed courses of therapy depending on the nature of the infection seems to be the most reasonable explanation for this nonlinearity. In 10% of cases, development of a blood dyscrasia was related to four days or less of therapy with chloramphenicol; in 50% it was related to 13 days or less; and in 10% to 150 days or more. In a few instances the drug was administered on only one occasion. Median duration of therapy by age group was: 11 days for patients o to 9 years, 13 days for those 10 to 39 years, and 15 days for those 40 years and over. Time from first to last dose is similarly shown in Fig 4. This time amounted to four days or less in 10% of the cases, 38 days or less in 50%, and 200 days or more in 10%. The main difference between these two curves, seen at their middle, is due to instances in which the drug was taken intermittently. Of the 329 patients on whom such information was available, 39% received the drug intermittently. The small crossover of these two curves at their extremes reflects the fact that slightly different subsamples were suitable for each and that each curve is only an estimate rather than a precise indication of the curves which would be obtained from a much larger population of similar cases. The total dose of chloramphenicol received by various patients is plotted cumulatively in Fig. 3. The cumulative plot closely approaches a straight line using these coordinates. In 10% of cases the total dose amounted to 60 mg/kg or less, in 50% to 280 mg/kg or less, and in 10% to 1,300 mg/kg or more. One would expect the 50% intercept to agree fairly well with the product of 50% intercepts for average daily dose and number of days of therapy, and indeed the figure of 21J9 mg/kg obtained in this fashion is not far from the value of the other curve of Fig 3, 280 mg/kg. There appears to be essentially no difference in total doses in milligrams per kilogram as related to age. Dosages of Chioramphenicol received I litl , lii II I il_I PAGENO="0368" 2502 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Time of ReactioR as Related to Therapy.-One tends to think of adverse reac- tions as occurring during drug administration or shortly after discontinuation. Such a relationship proves to be the exception for chioramphenicol-associated blood dyscrasias. Among the 284 patients for which such information was avail- able, only 22% showed manifestations of the dyscrasia while the drug was still being given as shown by the appropriate curve of Fig. 4. The median time from discontinuation of the drug until clinical evidence of the dyscrasia appeared was 38 days, and in 10% of cases this time was 130 days or longer. There is a definite downward bending of this curve, and one wonders whether time from first dose to reaction might not more nearly approach a log-normal distribution. This curve has also been charted to Fig. 4, and it shows an incomplete tendency to straightening. The reaction developed 10 days or less following initial dose in 10% of cases, in 95 days or less in 50%, and in 260 days or more in 10%. None of the patients in this series are known to have been continued on or re- challenged with the drug after the dyscrasia was diagnosed, and we would not recommend that this be done. IiiiiI I 1 ~t,i,I iiiil I .iii~~__l*, 0 5 10 20 50 100 200 500 Number of days 4. Number of days chioramphenicol received; elapsed time of chloramphenicol course; time from first dose to reaction; time from last dose to reaction; and survival time. Distribution of values for each curve is indi- cated cumulatively on log-normal coordinates. The survival curve is based on life-table analysis. SURVIVAL AND COURSE Life Table 8urvival Ci~rve.-Construction of a survival curve for a fatal disease on the basis of a series of patients, all of whom have not yet died at time of analysis, is best performed through the life table method.8 The present situation differs from that of a uniformly fatal disease in that, in addition to a tread towards mortality, there is also a trend towards recovery. Patients who have recovered are not known to have relapses unless the drug is admInistered further. In this instance, a satisfactory method of accounting for recoveries in life table analysis is to Consider all patients who have recovered to be still alive at a relatively long period following onset of the dyscrasia, regardess of the actual length of follow-up. The top curve of Fig. 4 shows the results of this analysis. Because of recoveries, the curve approaches an asymptote rather th:an describing a straight line on a log-probability plot. The overall mortality ap- proached is approximately 50%; 10% of the patients in the entire series have died within two weeks of onset of the dyscrasia. The 75% intercept (i.e., median survival for those with fatal outcome) is about 50 days. Rare cases may have a fatal outcome a year or more after diagnosis. Course-It was specifically reported in several instances that recovery fol- lowed withdrawal of the drug, and it Is presumed that this occured within a Delay, lost dose to reaction, 284 cases O~y. 99 95. 90 80- 60 0 0 0~ 5, (I) C 0 `-5) .~ CC C 5) C) 0) a- Various time trends Survival curve, life table method No. of cases Known dead I 08 Recovered 96 alive with sequelae. .75 Total...279 elapsed from first dose to reaction, 235 cases 40- 20- I0~ 5- Number of days drug actually. received, 204 cases Al PAGENO="0369" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2503 few weeks. Most of these instances were associated with depression of a single blood cell type. On the other hand, of the 75 patients known to be alive with persistent evidence of the dyscrasia despite cessation of the drug, 20 (27%) were alive 100 to 299 days after onset, and 11 (14%) were alive 300 or more days after onset. Recoveries have sometimes been noted after relatively long periods of disease. Death is known to have occurred in 186 cases, 95% from complications of the dyscrasia. Performane of an autopsy was noted for 24% of these cases; however, details of this examination were not usually reported. Therapeutic measures directed against the marrow depression were `usually not reported,, and no attempt was made to evaluate these. PROGNO5IS Detailed studies on prognosis have been `submitted for publication elsewhere (W. R. Best). The most important clinical findings are that improved survival is associated with fewer cell-types depressed, shorter delays in onset, larger daily doses, and occurrence in Negroes. COMMENT Yunis and B'loomberg° have reviewed various types of evidence hearing on the pathogonesis of those hematologiic reactions to chlo'ramphenicol which occur in rare eases at commonly employed dosage levels. They found no convincing evidence to support an autoimniune process, and the current data cannot be construed as adding such. Abnormal susceptibility due to some biochemical abnormality seems more likely, but the exact nature of such a disorder remains to be determined. Yu'nis and Bloomiberg suggest that a defect in localization, metabolism, or excretion of chloramphenicol, or an enzymatic or other bio- chemical deficiency involving a metabolic pathway that becomes essential in the presence of this drug, could account for these reactions. One suspects that there is an underlying hereditary difference between individuals who do and those who do not develop this reaction to cliloramphenicol. The occurrence of dyscrasias *in both members of a set of identical twins is one of the most interesting findings in the Registry relative to the genetic question. It is reasonable to suppose that many close relatives of Registry patients have reeeived courses of cMoramrthenicol comparable to those of corresponding affected family members, and that a high percentage, if not all instances of multiple cases in a single family would have, been called to the attention of the Registry. Yet, so far as we have been able to determine, the only instance in the Registry or the medical literature in which more than one member of a family has developed such a dyscrasia is this particular one involving the relatively rare sth combination of identical twins. One could reasonably expect several nontwin sibling `pairs in the total experience to date if this susceptibility to dhlorainphenicol required a homozygous `state relative to a single recessive gene. Simultaneous exposure t:o some `unusual environmental factor or the fact that the only known sibling pair developing this defect share an' identical genetic constitution strongly suggests that an unusual combination of genetic factors must `be present in *a homozygous form before this abnormal susceptibt'lity becomes manifest. Unusual racial or ethnic patterns of occurrence or course would be consistent with genetic disorders, but would not provide conclusive evidence thereof. Con- sidering the racial composition and patterns of medical curb of populations about `whom the Registry is most likely to receive reports, one `has no compelling reason to suspect that members of one race are more likely to develop this re- action, given a similar drug exposure, than are those of another. However, a striking difference in clinical course seems to be related to race in this `series. Nonwhite patients tend to have a much more benign course than whites, a trend not previously noted. Unusual patterns of occurrence relative to age or sex, if not otherwise ex- plained, would tend to `implicate developmental, degenerative, or hormonal fac- tors as `being of at least secondary importance. Females accounted for 54% `of cases `surveyed `by Yunis and Bloomberg° and 62% in the current report. `Some of the age-sex patterns noted can `reasonably be assumed to reflect dif- ferences in occurrence rates for various diseases for which chloramphenicol is 81-280 0-68-pt. 6-24 PAGENO="0370" 2504 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY often given (Table), but in addition, it seems likely from case data that there is an increased susceptibility to this complication in females prior tQ the mneno- pause. A peak occurrence rate was noted at 6 to 10 years of age by Yunis and Bloomnberg° and at 3 to 7 years of age in the present series, the differences being in part due to different tabulation intervals. The marked difference be- tween US and non-US reports in this regard suggests that thei~e may be different national medical trends in the approach to use of chioramphenicol. Upper res- piratory tract infections are frequent in this age group and account for a high proportion of uses. Thus, one ean neither confirm nor refute at this time the poc- sibility that children at this age may be more susceptible to chloramphenicol- induced marrow depression. Clinical Cltaracterization.-Yunis and Bloomberg6 interpret the data of their review as indicating that chioramphesilcol produces two `types of marrow toxicity. They state that the first of these usually occurs during therapy, is associated with a larger total dose, demonstrates a riormocellular marrow, shows anemia with or without leukopenia or thrombocytopenia, and is reversible on withdrawal of the drug. The `second type shows a delayed onset, is not necesarily dose-related, demonstrates an aplastic marrow with associated pancytopenia, and usually has a fatal outcome. A majority of cases in the current report conform in most re- spects to the second class, and there is another cluster which fits fairly well into the first class. However, a number of cases fall between or overlap these two groups. For example, nine of 60 patients in the present series who had at least two weeks delay between the last dose and development of the reaction showed a normocellular marrow or one with only isolated cellular depression, whereas Yunis and Bloomberg `found no such cases. All combinations of blood cell de- pression were seen in association with nonaplastic marrows, and half of the current series showing pancytopenia in contrast to a more limited spectrum seen in the series reviewed by Yunis and Blooiuberg. Patients with hypoplastic marrows tend to have received a smaller dose of drug, but there is an appre- ciable overlap. Thus, the 10%, 50%, and 00% intercepts of a cumulative dosage curve for 48 current cases with marrow hypoplasia were 5, 20, and 54 mg per kilo- gram per day, respectively; whereas for 28 cases with lesser degrees of marrow involvement the coresponding figures were 16, 31, and 88 mg per kilogram per day. These doses are well within usual recommendations. Curves for the dura- tion of therapy were very similar for the two degrees of marrow involvement with a median of 11 to 12 days. The cases reviewed by Yunis and Bloomberg on the other hand, show a median duration of therapy of about 35 days for patients with hypoplastic marrows, and about 20 days for those with nonhypo- plastic marrows. Unidentified biases in the report3ing of cases may account for `this difference between the two seribs. The implication of these authors in dividing chioramphenicol-associated blood dyscrasias into two groups is that there may two separate mechanisms involved. The current study would indicate that the cases as they occur are not always so sharply divisible, and that the possibility of a single pathogenetic mechanism is by no means ruled out. Findings in the identical twins reported here would speak for a single mechanism, for the patient with the greater number of prior courses developed typical aplasia, whereas his twin showed a readily reversible, isolated cytopenia. Preventive Aspeets.-The best educated guess as frequency of this complica- tion, probably an underestimate of true occurrence, is that of Leikin et al in which it would appear that less than one case of serious marrow toxicity occurs for every 100,000 courses of therapy. The data presently available are not appro- priate for further speculation in this regard. This study does, however, present a good deal of quantitative information rela- tive to the types of drug course which have been associated with this complica- tion. Marrow toxicity has been seen after low doses and high doses, chioram- phenicol alone and in combination with other drugs, short courses and long courses, continuous therapy and intermittent therapy, and single courses and repeated courses. Most patients have received chloramphenicol in dosage and duration commensurate with best clinical practice. Unfortunately, however, it cannot be stated that indications for use always conformed to optimal standards. Most experts w-ould consider chioramphenicol the treatment of choice in ty- phoid and paratyphoid infections, and some would include Hacino pit tins inflncnzae meningitis. These three conditions accounted for 6.6% of indications in the current series, most of these being from non-U.S. sources. Chioramphenicol is PAGENO="0371" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2505 also indicated in certain other serious acute and chronic infections depending on in vitro sensitivities and particular features of a patient's course. The report forms did not request sufficient data for further evaluation in the regard. The drug is inactive against common viral and upper respiratory tract infec- tions, but these conditions accounted for a significant percentage of stated indi- cations in this series. Thus, the most powerful preventive tool available is the use of this agent only for serious infections in which the balance of risks of adverse reactions against the risks of inadequate therapy tend to favor use of this antibiotic over alternative methods of treatment. It should be recognized that the risk of occurrence in any case treated with chloramphenicol is quite slight, but the risk of a fatality in that patient who develops this reaction is great. Some physicians have belittled this complication because they have seen no hint of a blood dyscrasia in the many courses of chloramphenicol therapy which they have directed. One should not be surprised at such an experience, for it is a rare complication; however, this is little consolation to the future patient under such a physician's care who dies of aplasia because chloramphenicol was given when it need not have been. Most patients develop manifestation of marrow depression after the drug has been stopped, often weeks or months later. It thus appears that monitoring blood counts during therapy would be of little or no value in preventing mobidity and mortality in the majority of cases. However, there is a minority of rections usually isolated cytopenias, which may, become apparent during therapy and repond to withdrawal of the drug. It is for the recognition of such cases that we recommend the occasional performance of blood counts during chloramphenicol therapy. Under the assumption that an isolated cytopenia represents a basically different and less dangerous type of toxicity, Yunis and Bloomber'g 6 do not feel that therapy need be stopped in such cases. We do not agree. No cases in which chioramphenicol was continued after the development of a cytopenia have come to our attention, and one would seem ill advised to continue therapy on the basis of this unproven theory. SUMMARY AND CONCLUSIONS This review involves 408 cases of chloramphenicol~associated non-neoplastic depression of one or more blood cell types that were reported directly to the AMA Registry on Blood Dyscrasias or abstracted from the medical literature. Various quantitative features of the occurrence of this dyscrasia and relation- ship to drug administration have been delineated. The dyscrasias noted range from readily reversible, isolated cytopenias oc- curring during therapy to delayed, progressive aplastic anemia. This range is not considered as necessarily indicative of more than one fundamental type of drug reaction. It is apparent that blood dyscrasias may occur in relation to con- ventional and even brief courses of therapy, and that signs of such reaction may not be seen until long after the course has been completed. The best approach to prevention thus lies in a sound appraisal of possible benefits and dangers whenever use of this drug is contemplated. The occasional monitoring of blood counts may prove worthwhile in rare cases, but its expected value in the usual case is sufficiently small that one cannot substitute such a practice for good judgment in deciding when the drug should or should not be used. A more complete bibliography indicating where previously published cases appear, together with other supplemental information, including rules and trans- formations used to estimate desired parameters from partial data, may be ob- tained by ordering Document No. 9515 from American Documentation Institute, Library of Congress, Washington, DC 20540, remitting $2.50 for photoprints or $1.75 for 35-mm microfilm. GENERIC AND TRADE NAMES OF DRUG Ohloramphenicol-Uhloromycetin, Cyiphenicol, Tega-Getin. N0TE.-From the Research Resources Laboratory, University of Illinois, Col- lege of Medicine, Chicago, and Biostatistics Research Support Center, Veterans Administration Hospital, Hines, Illinois. This report has been prepared at the request of the Panel on Hematology of the Section on Adverse Reactions of the AMA Department of Drugs. Reprint requests to Secretary, Council on Drugs, American Medical Association, 535 N Dearborn St, Chicago 60610. PAGENO="0372" 2506 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY REFERENCES 1Motulsky, A. G.: Drug Reactions, Enzymes, and Biochemical Genetics, JAMA 165: 835-837 (Oct. 19), 1957. 21Je Nosaquo, N.: Development arid Purpose of the Registry on Blood Dyscrasias, JAMA 170: 1925-1926 (Aug. 15), k959. 8Huguley, C. M., Jr. ; Erslev, A. J.; and Bergsagel, D. E.: Drug-Related Blood Dyscraslas, JAMA 177: 23-26 (July 8), 1901. 4Erslev, A. J., and Wintrobe, M.M.: Detection and Prevention of Drug-Induced Blood Dyscraslas, JAMA 181: 114-119 (July 14), 10132. ~ Best, W. R.: Drug-Associated Blood Dyscrasias: Recent Additions to the Registry, JAMA 185: 286-290 (July 27), 1963. 6 Yunls, A. A., and Bloomberg, G. R.: Chloramphenlcol Toxicity: Clinical Features and Pathogenesis, Frog Hemat 4: 138-150, 1964. 7Fernbach, D. J., and Trentin, J. J.: "Isologous Bone Marrow Transplantation In an Identical Twin With Aplastic Anemia" in Proceedings of the Eighth International Con- gress on Hemitology, Tokyo: Pan-Pacific Press, 1962, vol. 1, pp. 150-155. 8 Merrell, M., and Schulman, L. E.: Determination of Prognosis in Chronic Disease, Illustrated by Systemic Lupus Erythematosus, J Chronic Dis 1: 12-32 (Jan.) 1955. Leikin, S. L.; Welch, H.; and Gum, G. H.: Aplastic Anemia Dueto Chloramphenicol, Clin Proc Chil Ho8p Wash 17: 171-181 (July) 1961. ATTACHMENT No. 3 [From the Journal of the American Medical Association] WHEN IT COUNTS . . . CHLOROMYCETIN (CHLORAMPHENICOL) MAY BE INDICATED IN CERTAIN SEVERE RESPIRATORY INFECTIONS Because of its wide antibacterial spectrum and its ability to diffuse into infective foci, Chloromycetin may be of value in the treatment of selected severe respiratory tract infections due to susceptible microorganisms. However, as with any antibacterial agent, the administration of Chloromycetin must be adjunctive to the overall therapeutic approach to this family of diseases. Appropriately treated, good results can be expected in bacterial pneumonia and empyema; in bacterial complications of bronchiectasis and bronchitis; all of which are severe disorders often chronic and difficult to eradicate. The decision to choose Chloromycetin from among a group of antibiotics sug- gested by in vitro studies to be potentially effective against a specific respiratory tract pathogen(s) should be guided by severity of infection, relative susceptibility of the pathogen(s) to the various antibacterial drugs, relative efficacy of the various drugs in this family of infections, and the important additional concepts contained in the "warning box." Patients with respiratory tract infections usually become afebrile in 18 to 72 hours on recommended doses; roentgenograpbic clearing may be slower. Neoplastic, fungal, and mycobacterial disease as a cause of persisting respira- tory disease should be ruled out by appropriate means. CHLOROMYOETIN Detailed information, including indications and dosage, appears in the package inserts of Chloromycetin products for systemic use. Consult the appropriate pack- age insert. "Warning: Serious and even fatal blood dyscrasias (asplastic anemia, hypo- plastic anemia, thrombocytopenia, granulocytopenia) are known to occur after the administration of chioramphenicol. Blood dyscrasias have occurred after both short-term and prolonged therapy with this drug. Bearing in mind the possi- bility that such reactions may occur, ehloramphenicol should be used only for serious infections ca~ised by organisms which are susceptible to its antibacterial effects. Ohloramphenicol should not be used when other less potentially danger- ous agents will be effective. It Inust not be used in the treatment of trivial in- fections such as colds, influenza, or 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 le~ikopenia or granulocytopenia, before they become irreversible, such studies cannot be relied on to detect bone marrow depression prior to development of aplastic anemia." PAGENO="0373" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2507 Chioromycetin, an antibiotic having therapeutic activity against a wide variety of organisms, must, in accordance with the concepts in the "warning box" above, be used only in certain severe infections. Contraindications: Chioramphenicol is contraindicated in individuals with a history of previous sensitivity reaction to it. It must not be used in the treatment of trivial infections such as colds, influ- enza, or infections of the throat; or as a prophylactic agent to prevent bacterial infections. Precautions and Side Effects: Untoward reactions in man are infreq~ient; however, they have been reported with both short-term and prolonged adminis- trationof the drug. Among the reactions reported are blood dyscrasias as men- tioned in the warning. When, during the course of therapy, blood counts show unusual deviations which may be attributable to the drug such as reticulocyto- penia, leukopenia, or thrombocytopenia, therapy with chioramphenicol should be discontinued. Also reported are certain gastrointestinal reactions resniting in glossitis and stomatitis, which are indications to stop the drug. On rare oc- casions, superimposed infection by Candida albicans may produce widespread oral lesions of the thrush type. Diarrhea and irritation of perianal tissues have been reported. Pseudomembranous enterocolitis has been reported in a few patients. Hypersensitivity reactions manifested by angioneurotic edema and vesicular and maculopapular types of dermatitis have been reported in chioramphenicol-sensi- tive patients. Urticaria and vesicular lesions have been observed. They are usually mild in character and ordinarily subside promptly upon cessation of treatment. Febrile reactions have been reported. A reaction of the Jarisch-Herxheimer type has been reported following therapy in syphilis, brucellosis, and typhoid fever. Typhoid fever patients have exhibited a "shock-type reaction" characterized by circulatory collapse attributed to sudden release of endotoxin. Neurotoxic reactions, including optic and peripheral neuri- tides, headache, mild depression, "dazed feelings," internal ophthalmoplegia, mental confusion, and delirium have been reported. Symptoms of peripheral neu- ritis or decreased visual acuity call for prompt withdrawal of the antibiotic and the possible use of large doses of oral or parenteral vitamin B complex. When pro- longed high dosage is necessary, toxic side effects ~nay occur which call for dosage reduction or discontinuance of chloramphenicol therapy. Adults and chil- dren with impaired liver or kidney function, or hoth, may retain excessive amounts of the drug. In such instances, dosages should be adjusted accordingly. Toxic reactions, the signs and symptoms of which have been referred to as the "gray syndrome," with some fatalities, have resulted from high concentrations of the drug in the premature and newborn age groups. One case of "gray syn- drom" has been reported in an infant born to a mother having received chloram- phenicol during labor. The following summarizes the clinical and laboratory studies that have been made on these patients: (1) In most cases therapy with chloramphenicol had been instituted within the first 48 hours of life. (2) Symp- toms first appeared after 3 to 4 days of continued treatment with high doses of chloramphenicol. (3) The symptoms appeared in the following order: (a) ab- dominal distention with or without emesis; (b) progressive pallid cyanosis; (c) vasomotor collapse, frequently accompanied by irregular respiration; and (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 concentrations of chloramphenicol after repeated doses. (6) Termination of therapy upon early evidence of the associated symptomatology frequently reversed the process with complete recovery. Precautions: See "warning box" for precautions. The use of this antibiotic, as with other antibiotics, may result in an over- growth of nonsusceptible organisms, including fungi. Oonstant observation of the patient is essential. If new infections caused by nonsusceptible organisms appear during therapy, the drug should be discontinued and appropriate measures should be taken. Monitoring of liver and kidney function should be accomplished during therapy in patients with existing liver or kidney disease. Supplied: Ohloromycetin is available in a variety of forms including Kap- seals of 250 mg. PAGENO="0374" 2508 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WHEN IT COUNTS . . . CHLOROMYCETIN (CHLORAPHENICOL) CAN BE USEFUL IN URINARY TRACT INFECTIONS Urinary tract infections, often recurrent and resistant to treatment, are among the most frequent and most troublesome types of infections seen in clinical prac- tice. Successful therapy is largely dependent on identification and susceptibility testing of invading organisms, administration of appropriate antibacterial agents, and correction of obstruction or other underlying pathology. Ohioromycetin has proved to have a wide and effective range of activity against pathogenic invaders of the urinary tract, including the coliform group, certain proteus and aerogenes species, micrococci and enterococci. Clinical re- sponse usually parallels im vitro susceptibility. Relief of symptoms and repeated bacteriologic studies should be depended upon to indicate duration of treatment. Chloromycetin continues to be a most valuable drug in the management of urinary tract infections. The decision to choose Chloromycetin from among a group of antibiotics sug- gested by in vitro studies to be potentially effective against a specific pathogen should be guided by the severity of infection, the relative susceptibility of the pathogen to the various drugs, the efficacy of the various drugs in urinary tract infections, and the important additional concepts contained in the "warning box." OHLOROMYCETIN Detailed information including indications and dosage, appears in the package inserts of Chloromycetin products for systemic use. Consult the appropriate package insert. "Warning: Serious and even fatal blood dyscrasias (aplastic anemia, hype- plastic anemia, thrombocytopenia, granulocytopenia) are known to occur after the administration of chloramphenicol. Blood dyscrasias have occurred after both short-term and prolonged therapy with this drug. Bearing in mind the possibility that such reactions may occur, chioramphenicol should be used only for serious infections caused by organisms which are susceptible to its antibac- terial effects. Chloramphenicol should not be used when other less potentially dangerous agents will be effective. It must not be used in the treatment of trivial infections such as colds, influenza, or infections of the throat; or as a prophylactic agent to prevent bacterial infections. "Precautions: It is essential that adequate blood studies be made during treat- ment with the drug. While blood studies may detect early peripheral blood changes such as leukopenia or granulocytopenia, before they become irreversible, such studies cannot be relied on to detect bone marrow depression prior to de- velopment of aplastic anemia." Chloromycetin, an antibiotic having therapeutic activity against a wide variety of organisms, must, in accordance with the concepts in the "warning box" above, be used only in certain severe infections. Oontraindications: Chloramphenicol is contraindicated in individuals with a history of previous sensitivity reaction to it. It must not be used in the treatment of trivial infections such as colds, in- fluenza, or infections of the throat; or as a prophylactic agent to prevent bacterial infection& Precautions and Side Effects: Untoward reactions in man are infrequent; how- ever, they have been reported with both short-term and prolonged administration of the drug. Among 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 the drug such as reticuloeytopenia, leukopenia, or throinbocytopenia, therapy with chioramphenicol should be dis- continued. Also reported are certain gastrointestinal reactions resulting in glossitis and stomatitis, which are indications to stop the drug. On rare occa- sions, superimposed infection by Candida albicans may produce widespread oral lesions of the thrush type. Diarrhea and irritation of perianal tissues have been reported. Pseudomembraneous enterocolitis has been reported in a few patients. Hypersensitivity reactions manifested by angioneurotic edema and vesicular and maculopapular types of dermatitis have been reported in chloramphenicol- sensitive patients. Urticaria and vesicular lesions have been observed. They are usually mild in character and ordinarily subside promptly upon cessation of treatment PAGENO="0375" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2509 Febrile reactions have been reported. A reaction of the Jarisch-Herxheimer type has been reported following therapy in syphilis, brucellosis, and typhoid fever. Typhoid fever patients have exhibited a "shock-type reaction" characterized by circulatory collapse attributed to sudden release of endotoxin, neurotoxic reactions, including optic and peripheral neuri- tides, headache, mild depression, "dazed feelings," internal ophthaimoplegia, mental confusion, and delirium have been reported. Symptoms of peripheral neuritis or decreased visual acuity call for prompt withdrawal of the antibotic and possible use of large doses of oral or 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. In such instances, dosages should be adjusted accordingly. Toxic reactions, the signs and symptoms of which have been referred to as the "gray syndrome," with some fatalities, 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 having received chloramphenicol during labor. The following summarizes the clinical and laboratory studies that have been made on these patients: (1) in most cases therapy with chlorampheni- col 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 chloram- phenicol. (3) The symptoms appeared in the following order: (a) abdominal distention with or without emesis; (b) progressive palad cyanosis; (c) vasomotor collapse, frequently accompanied by irregular respiration; and (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 concentrations of chioramphenicol after repeated doses. (6) Termination of therapy upon early evidence of the as- sociated symptomatology frequently reversed the process with complete recovery. Precautions: See "warning box" for precautions. The use of this antibiotic, as with other antibiotics, may result in an over- growth of nonsusceptible organisms, including fungi. Constant observation of the patient is essential. If new infections caused by nonsusceptible organisms appear during therapy, the drug should be discontinued and appropriate measures should be taken. Monitoring of liver and kidney function should be accomplished during therapy in patients with existing liver or kidney disease. Supplied: Chloromycetin is available in a variety of forms including Kapseals® of 250 mg. Senator NELSON. Our next witness is Dr. Paul D. Hoeprich. Doctor, we appreciate very much your patience in waiting to appear. We ap- preciate your taking the time to come here today. STATEMENT OP DR. PAUL D. HOEPRICH, DIRECTOR, SECTION OF CLINICAL MICROBIOLOC+Y AND IMMUNOLOGY, DEPARTMENT OP INTERNAL MEDICINE, SCHOOL OF MEDICINE, UNIVERSITY OF CALIFORNIA, DAVIS, CALIF. Senator NELSON. Have you submitted a biography? Dr. HOEPRICH. No; I did not. Senator NELSON. Would you, then, for the record, summarize your professional background? Dr. HOEPRICH. Surely. At present, I am professor of medicine in the School of Medicine at the University of California at Davis. I have been in this positiQn since September 1, 1967. Prior to that time I was on the faculty of the Department of Medicine, University of Utah College of Medicine, where I was for 101/2 years, coming there from the medical faculty of Johns Hopkins. I got my degree in medicine at Harvard Medical School and had postgraduate training in bac- PAGENO="0376" 2510 COMPETITIVE PROBLEMS IN THE DRtTG INDUSTRY teriology and inimunology at Harvard and in teaching hospitals in Boston, New Haven, and in Cleveland. I am certified by the American Board of Internal Medicine and by the American Board of Microbiology. My particular interest is in- fectious diseases. In my academic ca~pacities I have headed, and do now head, sections within the department of medicine that are concerned with infectious diseases. Senator NELSON. Thank you very much. You may proceed to pre- sent your statement and at any time you may elaborate on any part of your statement if you think it will be helpful for the record. Dr. HOEPRICH. Thank you, Senator Nelson. Discovered in 1947, chioramphenicol is an antibiotic substance that is elaborated by the fungus streptomyces venezuelae. In concentrations that are readily attained in the blood and body fluids of humans given ordinary doses, chloramphenicol halts the growth of many kinds of micro-organisms that cause infectious diseases in man. These include: 1. Bacteria-~both Gram positive, for example, pneumococcus, and Gram negative, for example, typhoid bacilli. 2. Rickettsiae-minute micro-~organisms, smaller than bacteria, that cause diseases such as Rocky Mountain spotted fever. 3. Bedsoniae-sma.ller, even, than rickettsiae but larger in size than the true viruses, these micro-organisms cause infections such as psit- tacosis. 4. Mycoplasma-remarkably pleomorphic micro-organisms that fre- quently cause respiratory tract infections in man. INDICATIONS There are two primary indications for use of chioramphenicol. Note that this is in the context of what is presently available in the field of antimicrobial agents: 1. Typhoid fever. 2. Some infections caused by the so-called paratyphoid bacilli, that is, bacteria of the genus salmonella other than Salmonella typhi, the cause of typhoid fever. The nontyphoidal sahnonelloses should be treated with chloram- phenicol in all patients when there is: (a) Bloodstream invasion. (b) Spread of infections outside the gastrointestinal tract, for ex- ample, to involve the joints or the bones. (c) Severe, protracted, actual dysentery. In addition, all clinical forms of salmonella infection, regardless of severity, are indication for treatment with chloramphenicol in par- ticularly vulnerable persons. Senator NELSON. On the previous page, part c., severe protracted actual dys~nthry refers to that dysentery caused by salmonella; is that correct? Dr. HOEPRICH. That is correct; yes. However, it must be understood that true dysentery of this severity is quite unusual as a consequence of salmonella infection. Gastroenteritis with nausea, vomiting, diar- rhea, is the commonest clinical form of salmonellosis. This is best PAGENO="0377" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2511 treated symptomatically, without any antibacterial agent, specifically, without chloramphenicol. Senator NEL,soN. Thank you. Dr. HOEPRICH. On the other hand, all clinical forms of salmonella infection, regardless of severity, are indication for treatment with chioramphenicol in particularly vulnerable persons. These include: (a) The very young. (14 The aged. (c) Those with serious, underlying diseases that in some way com- promise body defenses-neoplastic diseases, metabolic diseases, col- lagenvascular diseases. There are other examples in this particular category. Mr. GORDON. Dr. Hoeprich, when you say there are two primary indications, does this mean when chloramphenicol is the drug of first choice? Dr. HOEPRICH. Chioramphenicol is the drug of choice; yes. Mr. GORDON. Does that mean first choice, when you say drug of choice? Dr. HOEPRICH. Yes. Mr. GORDON. It would be the drug of first choice for salmonella? Dr. HOEPRICH. In treating the infections, typhoid fever, and those nontyphoidal salmonella infections previously described. Mr. GORDON. I see. Typhoid fever is a type of salmonella infection? Dr. HOEPRICH. Yes. Itis caused by salmonella typhi. Mr. GORDON. I see. Dr. HOEPRICH. Now, there are secondary indications for use of chloramphenicol and these take the form of unusual circumstances: 1. Hypersensitivity that is so severe as to preclude use of another, otherwise preferable agent. For example, the agent of ~1irst choice for the treatment of Q fever is tetracycline; if use of tetracycline has provoked a life-threatening hypersensitivity reaction in the patient, chloramphenicol should be substituted. Hypersensitivity to tetracycline is quite unusual, but does occur. 2. Infection caused by a micro-organism proved to be resistant to the action of other antimicrobial agents but susceptible to chioram- phenicol. Gram negative enteric bacilli with such characteristics are sometimes cause for infection in humans. * 3. Augmented toxic hazards that mitigate against use of other, ordinarily preferable, antimicrobial agents. For example, severe infec- tion in the newly delivered mother may be caused by bacteria that are susceptible to tetracycline. However, tetracycline is peculiarly liable to cause acute liver injury of lethal proportions in such circumstances. Ohloramphenicol does not bear this risk and could be used, but only if the micro-organisms involved are not susceptible to other antimicrobics. Mr. GoRDON. In these two primary indications for chlorainp'henicol, would you be able to give an estimate, just off the top of your head, a rough estimate, as to the number of cases in the United States, say last year, of this type of infection? Dr. HOEPRICH. Well, of typhoid fever, there is an epidemic sur- veillance of this sort of thing in this country, so there are accurate figures. My guess is it is a few hundred cases, 200 or 300, perhaps, PAGENO="0378" 2512 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY in the course of a year. Of the nontyphoidal salmonella infections, there are considerably greater numbers and I suspect that these will be increasing in number as years go on and our society prefers more and more to eat food that is prepackaged, that has been handled and prepared by somebody else. So, I have a more difficult time arriving at some figure for nontyphoidal salmonelloses. These do occur in epidemic proportions. For example, we had in the Salt Lake City area in 1963- 64 an epidemic which resulted in the clinical occurrence of at least 1,000 cases. Mr. GORDON. How many cases? Dr. H0EPRIOH. At least 1,000, which were of such severity that a physician was consulted. Now, if you add to this the number of in- fections that were of lesser severity, you probably would have to multi- ply by a figure of around 10. All I am saying is that the nontyphoidal salmonelloses are much more common, much more frequent in occurrence and it is hard to arrive at an annual figure since there are, too, epidemic situations. By and large they are much less severe infections. Mr. GORDON. Do they occur frequently? Dr. HOEPRICH. They are occurring, I think, with more frequency- at least we notice them more now than we did in times past. Senator NELSON. For my information, I notice in the primary in- dications you do not include the rickettsial infections. Dr. HOEPRICH. No, I do not, Senator Nelson. As we see them in this country, and this is the basis on which I excluded them, the agent of choice is one of the tetracycline group of drugs. The occurrence of gastro-intestinal side effects of such severity that one cannot give tetracycline to a patient who has a rickettsial infection does occur. But in our society, in this country, it is very simple. You then put a needle in the vein and run in the drug and you handle it in that fashion. Now, if you are treating a rickettsial infection in Southeast Asia and you cannot conveniently or practicaly administer tetracycline by injection, and you have the choice of no therapy, which is the result if you give it by mouth and the patient vomits the material back up, or going to chloramphenicol. But that is not our situation here. I think the context is very important. CONTRAINDICATIONS Infections caused by micro-organisms that are not susceptihie to chloramphenicol should never be treated with this agent. These in- clude: 1. All parasitic infections-multicellular, for example, worms, and unicellular, for example, malaria. 2. All mycotic infections, for example, hist.oplasmosis. 3. Some bacterial infections, for example, those caused by Pseudo- monas species. My point is that there are some bacteria that are always resistant to chioramphenicol a.nd these should never be occasion for use of this drug. 4. All viral infections, for example, influenza, the common cold. Infections caused by micro-organisms that are susceptible to chior- amphenicol but are equally, or more, susceptible to other agents, should PAGENO="0379" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2513 never be treated with chioramphenicol. Excepting only the situations noted under indications, above, this interdiction includes all infections caused by bacteria, rickettsia, bedsonia, and mycoplasma. Undefined illnesses that mightbe infectious in cause should never be treated with chloramphenicol. Similarly, chloramphenicol should never be used as a prophylactic agent. Senator NELSON. Is it commonly used as a prophylactic agent? Dr. HOEPRICH. I do not think it is. Again, this is a function of time. There was a period in the history of the development of antimicrobiaJ therapy when this drug was used. At least as I observe it, as other agents have become available, and as the toxic hazards of chlor- amphenicol have been recognized, this kind of usage is quite uncom- mon. Senator NELSON. In the study that Dr. Best compiled, of the 408 aplastic anemia cases submitted, 5.5 percent were `ones in which the drug had been given for prophylaxis. Now, that was from 1953 to 1964. Has that statistic changed since then? Dr. HOEPRIOH. Well, I think so. There was, for example, a period of time when urologists would use this drug as prophylaxis against in- fection complicating prDstatic surgery. I think that this use has largely disappeared. I may be mistaken about this. I see just a limited segment of practice, and use may vary from area to area, I am sure. SIDE EFFECTS In order of increasing seriousness, there are four major side effects to administration of chloramphellicol. These are: (1) ecologic disrup- tions; (2) irritative phenomena; (3) direct toxicity; and (4) hyper- sensitivity. All except hypersensitivity are dose related-the higher the dose and the longer the period of administration, `the more likely become the adverse reactions (1), (2), and (3). Withdrawal of chlor- amphenicol, quite reasonthly, is the first step toward reversing such adverse effects. On the other hand, hypersensitivity reactions are not clearly dose related and do not predictably abate on withdrawal of the drug. 1. Ecologie `disruption is consequent to the selective elimination or suppression of those micro-organisms normally resident on and in persons that are susceptible to the antimicrobial action of chloram- phenicol. Elements of this resident nii~robiota that are resistant to chloramphethcol are freed of competition and can attain to abnormally high population densities. Also, micro-organisms resistant to chlorarn- phenicol may be acquired from the environment external to the per- son-drawn in, as it were, by the shelter' of chioramphenicol suppres- sion of microbial competition. Termed superinfections when the over- growing or invading micro-organisms cause disease, this side effect is not unique to chioramphenicol but is, to a greater or lesser extent, a liahility of any antirnicrobic used in therapy. 2. Irritation is most common in the gastro-intestinal tract, taking the form of nausea, vomiting, diarrhea that is often associated with a brassy, unpleasant taste in the mouth. There may be irritation in the crotch region. PAGENO="0380" 2514 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3. Direct toxicity varies with age. In the adult, anemia is the most common manifestation. Prolonged, high dosage use of chioram- phenicol can halt maturation of red blood cells in the bone marrow; anemia results. Rarely, there may be inflammation of the optic nerve, causing blurring of vision or perverted sensation-of a tingling, crawling feeling-in the skin. Premature and newborn infants are espeoially vulnerable to direct toxicity because the capacity to eliminate chioramphethcol in the urine, and to inactivate this antibiotic by chemical change in the liver, is not fully developed until the human is more than a month old. 4. Hypersensitivity to chioramphenicol is quite uncommon. Skin rashes, fever, inflammation of the tongue are annoying when they occur but are not life-threatening. Pancytopenia, a marked reduction in the numbers of all of the formed elements of the blood-the red and white blood cells, blood platelets-results when hypersensitivity to chioramphenicol brings about failure of production of these elements in the bone marrow. When such failure is complete, termed aplasia of the marrow, death is usually the outcome. Reactions of this severity are rare occurrences. Precise determination of incidence is not possible since: (a) The size of the population at risk is not known. (b) All cases of drug-associated marrow aplasia are not reported. (c) The incidence of bone-marrow failure without exposure to any cause is not known.' As a footnote to this statement (c), I put in the reference to the report from the California report which ha,s been cited previously, wherein a figure is given of one in 524,600 persons not exposed to chloramphenicol will develop fatal aplastic anemia, fatal bone-marrow aplasia. In the portion of the report which I had access to, I did not find any basis for this particular calculation and this is why I say I have no feeling for how reliable it is or how it was arrived at. It is one of the few figure~s that are put down on paper, however, as the natural, normal incidence, if you will, of bone-marrow aplasia. There is a certain risk, apparently, in just being alive to having bone marrow fail, and that is the problem of (c) ; I do not know what that risk is. However, several estimates of the risk of induction of pancytopenia from use of chloramphenicol have been made, and these are tabulated. I must apologize here, Senator Nelson. The first reference is in error, so I discovered after the copies of this statement were made. The first figure should actually be one in 80,000 and the reference is the Scottish Medical Journal, volume 7, page 96, 1962', and the refer- ence as given, the first one, one in 800,000, that is incorrect and should not be in the table. The second one is one in 10,000 to one in 100,000, which appeared in the British Medical Bulletin in 1960. The third one, one in 156,000 to one in 227,000, reference as given, and finally, the reference in the California State report. `According to the report to the California State Assembly and senate, made by the Cali- fornia Medical Association and State department of public health, dated Jan. 1, 1967, one In 524,600 persons In California, not exposed to chloramphenicol, will develop fatal aplastic anemia. PAGENO="0381" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2515 (The table referred to follows:) Source Incidence Am. J. Med. 19 :274, 1955 1 in 800, 000 Brit. Med. Bull. 16:67, 1960 1 in 10, 000 to 100, 000 Olin. Proc. Children's Hosp. Wash. D.C. 17: 171, 1961_~ 1 in 156,000 to 227,000 Report to California State Assembly and Senate, Cali- fornia Medical Assoc. and the State Dept. of Pub. Health, 1 Jan., 1967 1 in 24,200 to 40,500 Dr. HOEPRICET. I would like to say with reference to this last esti- mate, one in 24,200 to one in 40,500, that the variation here was cor- related with the assumed dose of chl'oramphenicol given to the patient. I think in the circumstance of bone-marrow aphasia where, so far as we understand it at present, hypersensitivity is the important mechanism, that the dose given to a particular individual probably is not the essential and entirely the critical factor. I would prefer, myself, in calculating this incidence, to regard any exposure to chior- amphenicol as being significant; if this is done, then the `inc~dence in the California report becomes one in 73,333 exposures to the drug, an incidence more nearly in keeping with other estimates. You may or may not agree that this is a justified interpretation, but it is mine. Mr. GoiwoN. Doctor, what is the importance of blood levels in treatment and in the production of side effects? Dr. HOEPRI0H. In treatment, I would say the importance of blood levels lies in the need to get enough anitimicrobic to the site of in- fection to inhibit the growth of bacteria. Ideally, we would like to measure, then, the concentration of the drug where the infection is. But suppose the infection is in the cover- ing membranes of the brain, in a meningitis. It is very difficult to get a piece of this to make analysis for the content of the drug. Therefore, we do the next best thing, we get at the thing which we can get at, namely, the blood, and by correlating clinical experience and the sus- ceptibility of micro-organisms to a particular antimicrobial, which can be determined very accurately in the test tube, we can arrive at some estimation of how much a person has to have aboard in his blood for there to be enough in the site of infection, where we cannot measure the drug, to bring about cure of an infection. Mr. GORDON. Has it ever been determined how high a blood level you would need? Dr. HOEPRICH. In a particular infection? Mr. GORDON. Yes. Dr. HOEPRICH. If you are treating, as an example, an infection caused by a pneumoccus-pneumococci are exquisitely susceptible to chloramphenicol, as well as to other agents. You would not need very much. I would say something like one or two micrograms per milliliter of blood. On the other hand, if your problem was an infection caused by Kiebsiella, a gram negative bacillus which is notably resistant to anti- microbic agents, you might well have to have 15, 20, 30 micrograms per milliliter of blood, and again if your infection is in an enclosed space, where we know penetration may be problem, or where there may be pus formation, or the infectior1 may be walled off by an actual mechanical membranous structure that is not very well supplied with PAGENO="0382" 2516 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY blood vessels, then we would have to insist that there be more in the blood to soak into the site of infection. Mr. GoiwoN. How about the relationship between aplastic anemia and blood levels? Dr. HOEPRIOH. I do not know that that has been demonstrated. In terms of a direct toxic effect., suppression of maturation, particularly of red cells in the bone marrow, this is definitely correlated with the quantity of chloramphenicol present in the individual. With bone marrow aplasia which is generally regarded as a form of hypersensi- tivity, I do not think the blood level is critical. A little bit has been enough to trigger bone marrow aplasia. Mr. GORDON. But, the higher the blood levels, the greater chance. you have of halting the maturation of the cell? Dr. HOEPRICH. Yes. With the direct toxic effects, there is no question that the more you have the more successful you are going to be in blocking maturation, or injuring the retina., the optic nerve, or any of the direct, irritative effects of nausea, vomiting, diarrhea. Rather than total failure of bone-marrow function, there may be selective depression yielding, by itself, anemia, or deficiency of white blood cells, or marked lack of blood platelets. Reactions of this kind are also not dependent on the dose of chioramphenicol but do occur most oft,en in persons who have taken the drug on more than one oc- casion. There is some indication that complete aplasia will not result if chloramphenicol is discontinued as soon as adverse effect on the bone marrow is detected; for example, increase in serum iron concentra- tion, fall in the number of white blood cells in the circulating blood. I mention these things because people do feel that there is a correla- tion here, that if you stop the drug, then nothing further ill will hap- pen in terms of bone marrow aplasia. You have to add to that, of course, that you do not know that an aplasia would have resulted had you kept on with the drag. So, it is one of those situations in which the physician's judgment plays a very major part. IMPACT OF ADVERTISING ON USE This is most difficult to judge. Perhaps some indication could be gleaned from comparing dollar volume of sales of chlora.mphenicol with advertising outlay for identical periods of time. Such data are not readily available. However, advertisements for chioramphenicol, as they a.ppear in medical journals, quite clearly suggest wider use than the limited indications previously described in this statement. Always this is done with written, covering insertions such as, "~ * * may be indicated * * ~ CC* * * in certain severe infections * * ~," along with refer- ence, in recent advertisements, to a, ~C* * * warning box." In the lat- ter, the hazard of aplastic anemia is fairly and adequately described. The device of display-an instrument, a patient, a physician-is freely used in this effort at subtle, implied, indirect recommenda- tion to prescribe chloramphenicol. For example, the display of a bronchoscope in an ad for chioramphenicol vaguely, indirectly, sub- liminally suggests that in serious, occult bronchopulmonary disease- it must be serious, why else the instrument; it must be occult, why else PAGENO="0383" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2517 the difficult procedure of bronchoscopy-chioramphenicol is a useful agent. Positive statement of the limited indications for use of chioram- phenicol would be far preferable. Senator NELSON. Are there certain bronchial conditions in which chloramphenicol is indicated? Dr. HOEPRICH. One can conceive that there might be. For example, infections caused by the gram negative bacilli such as the Salmonellae sometimes involve the tracheobronchial tract and, indeed, I have seen what one would have to call pneumonia caused by Salmonella typhi murium, one of this kind of micro-organisms; this was an indication for use of chlor:amphenicol. The circumstances that I referred to, Q fever, occurring in a patient who had a severe, life-threatening hyper- sensitivity reaction to tetracycline, this would be another instance; Q fever is present as a pneumonia when it occurs in humans. So these situations can occur. I do not think they are utterly impossible, but they are uncommon, I am sure. OTHER ASPECTS Chloramphenicol is a remarkably effective antimicrobial agent. In- deed, chloramphenicol would be a nearly ideal antimicrobic were it not for the adverse reaction of bone marrow aplasia. Although quite infre- quently in occurrence, fully developed aplasia is usually lethal. Be- cause, at present, there is no way to predict who will have this kind of adverse reaction, and because there are now available many alterna- tive antimicrobics, the use of chloramphenicol should be severely restricted to the few indications previously described. In those few situations when chlorampherncal must be used, its use must be circumscribed in these ways: 1. The blood must be monitored every 48 hours by measurement of the volume of packed red cells, number of white blood cells, along with differentiation of the kinds of white blood cells and examination for adequacy in numbers of blood platelets. I might add, here, that it is not generally available, but some would regard measurement of the iron concentration in the blood serum as a much superior monitoring device to any of the ones I have indicated. This is technically a difficult procedure and is certainly not generally available. Treatment must be stopped when any of these measurements falls below the accepted, minimal values. Senator NELSON. Do you consider when chioramphenicol is admin- istered to any patient that blood studies must always be made or some- times be made? Dr. HOEPRICH. I think they must always be made. 2. Dosage with chloranxphenicol must- (a) Never be excessive, that is, 15 to 80 milligrams per kilogram body weight per day in the adult; no more than 25 milligrams per kilogram body weight per day by injection in the premature or newborn infant; no more than 50 milligrams per kilogram body weight per day by injection in infants over 1 month in age. (74 Never be unduly prolonged. 3. Repeated use in the same person must be avoided. PAGENO="0384" 2518 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator Nr~soN. Today you heard Dr. Weston's testimony sug- gesting that some limitation, by legislation or otherwise, be imposed upon the use of this drug. We had similar testimony Tuesday from Dr. Lepper, and both Dr. Dameshek and Dr. Best, I believe, thought some kind of a limitation ought to be imposed. Do you agree or dis- agree with that? Dr. HOEPRICH. I think something should be done. The question is whether it should be at the level of limitation by direct decree of use of the drug itself. I am not sure that this ought to be the only mechanism. I know the suggestion has been made that its use be limited to hospitalized patients. I think this might be an undue restric- tion in that people with severe sahnonelloses are not always treated in hospitals. I, myself, think they should be. That does not mean that this always happens. So that I am concerned about that. I would wonder if it would not be possible to approach the matter, at the same time, from the other ~nd. As is obvious in my statement, I really think that this indirect suggestion for prescription in the advertisements is a point of attack that might be very useful. Senator NELSON. What is that? Dr. HOEPRICH. Well, this business of displaying a bronchoscope and saying it may be useful in bronchopulmonary infections. Indeed, it may be useful, but the approach should not be that it may be useful. Rather, say it is useful in salmonelloses, typhoid fever. In other words, I think a positive statement of indications and the complete prohibi- tion of quasi, occasional, possible, indirect suggestions, would be of great impact in terms of misuse of the drug. Senator NELSON. That would mean, I assume, that somebody with the authority, FDA, for example, would have to say with regard to drugs that create serious problems, "This is precisely the kind of adver- tising that you are allowed." Dr. HOEPRICH. Yes. I am encouraged in this thought because of the abolition of the man in the white coat on television with reference to aspirin ads, for example. I am encouraged to think this kind of approach can be used. That the display business can be taken out of ads. It has been in some circumstances. Senator NELSON. Tuesday the three doctors who testified made what they considered to be a guess, that only 10 percent of the patients who received chioramphenicol should, in their judgment, have received it. Today, it was Dr. Weston's judgment that 1 percent or less of all the patients that received it should have received it. Do you have any esti- mate of your own? Dr. HOEPRICH. Yes. I would occupy a middle ground. I would say probably around 5 percent of those who received it should receive it. Mr. GORDoN. Let us come back to the advertising problem for a moment. Even if the written advertising was controlled to some extent, and I think the FDA does have jurisdiction over that, court cases have certainly shown that the detail man, the salesman who visits a doctor, through his blandishments, I was going to say, through his promotional activities, vigorous promotional activities, seems to water down or to cancel out the written warnings, and I understand that the FDA does not have any control over that type of promotional activity. Do you have any ideas along this line? PAGENO="0385" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2519 Dr. HOEPRICH. Oh, I am sure that this can happen. I have to add, immediately, that I have never seen it happen. I suppose that does not mean anything, for any detail man whom I have talked with who rep- resents Parke, Davis would know better than to tell me that chloram- phenicol does not have anything to do with bone-marrow aplasia. I just find it difficult to evaluate that statement. It may be true, and if it is true, I cannot conceive of any mechanism for getting at it. You really cannot eavesdrop on a conversation between two people in a room. That is what it amounts to. Mr. GORDON. But something should be done about it, if possible? Dr. HOEPRICH. Yes, I think so; and the sales of this drug certainly far e~xceed the indications for its use. You can say that about a lot of other agents but the fact is we are talking about this drug. Senator NELSON. Thank you very much, Doctor. Your testimony has been very useful, very constructive. We appreciate your taking time from your busy schedule to come here and testify. Thank you. (Whereupon, at 12:40 p.m., the hearing was adjourned, subject to the call of the Chair.) 81-280 O-68-pt. 6-25 PAGENO="0386" PAGENO="0387" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TUESDAY, FEBRUARY 27, 1968 U.S. SENATE, MONOPOLY SUBCOMMIrPEE OF THE SELECT COMMITTEE ON SMALL BusIN1~ss, Was/thigton,D.C. The subcommittee met, pursuant to recess, at 10 a.m., in room 318, Old Senate Office Building, Senator Gaylord P. Nelson (chairman of the subcommittee) presiding. Present: Senator Nelson. - Also present: Benjamin Gordon, staff economist; James H. Gross- man, minority counsel; Susan H. Hewman, research assistant; and William B. Cherkasky, legislative director, staff of Senator Nelson. Senator NELSON. We will open the hearing of the Monopoly Sub- committee of the Small Business Committee. On the 6th and 8th of February five distinguished medical experts testified on the widespread and indiscriminate usage of chlorampheni- col for the treatment of cases for which it specifically was not indi- cated. The result has been numerous eases of unnecessary illness, permanent injury, or death. The tragedy is that these were cases which would have recovered without any drug at all or cases in which another drug was available and indicated as the drug of choice. *The most shocking aspect of the whole matter is that the drug is much more frequently prescribed for cases where it specifically should not be used than where it should, thus exposing tens of thousands of patients to wholly unnecessary lethal risks. The best estimate appears to be `that from 3i/2 to 4 million people per year are given this drug. The estimate of the medical experts is that ~0 percent of the people for whom it is prescribed should not receive it at all because it simply is not indicated for their case-and one witness put the figure at 99 percent. According to the medical experts, chioramphenicol is a very useful and effective antibiotic but it is the drug Of choice in a very limited number of cases where no other drug is effective and the disease is serious. Yet, the drug has been widely prescribed for minor condi- tions such as head colds, sore throat, acne, and other minor infections, 2521 PAGENO="0388" 2522 COMPETITIVE PROBLEMS IN THE DRTJG~ INDUSTRY as well as serious conditions where other equally effective drugs were available. The testimony before this committee and the accumulated evidence of the past few years raise important public policy questions: Who is responsible for the widespread overprescribing of this drug? What accounts for the dramatic coimmmications gap between the medical specialists who for 15 years have known and written about this drug and those who have continued to prescribe it for cases where it should not be used? WTl~at responsibility has the AMA assumed in notifying the medical profession about the proper use of this drug? And how effective have they been? Has the FDA effectively warned the profession and controlled the advertising of this drug? If not-as seems to be the case-why not? Is this not a dramatic example of the compelling effectiveness of advertising even on a. sophisticated audience in its own area of expertise? These, certainly, are questions which deserve careful attention and will get it from this committee. Since the hearings, the subcommittee staff and I have received letters and calls describing tragic cases of serious illness and death re- sulting from the unnecessary use of chloramphenicol. These letters speak for themselves. They will be printed in the record. Ironically and sadly one of our telephone calls was from an employee in the De- partment of Health, Education, and Welfare who lost `his son because he was given Ohioromycetin for an infected toe. I shall have printed in the record at the conclusion of my statement the letters and communications that the committee, subcommittee or I have received. We `have as carefully as possible deleted the identifi- cation of any of `the parties as well as the cities, unless they happen to be a particularly large city, simply `because it is not the purpose of the committee to single out any particular case that comes to its at- tention since these only represent a small sampling of the total num- ber of cases across the country. These letters will be printed and included as part of the record. (The letters referred to follow:) COLORADO, February 20, 1968. Hon. GAYLORD NELSON, U.S. Senator, Washington, D.C. Dr~R SIR: In the February 16 issue of Time magazine, I learned of your chairmanship of the Senate Monopoly Subcommthtee. With reference to the article regarding Chloromycetin, our family would like to state our interest in this antibiotic. In June, 1966, our then 19-year-old daughter went to Michigan, to work at a summer camp. She had just completed her sophomore year at Colorado State University. Upon arrival in she had a sore throat and was referred PAGENO="0389" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2523 to a local doctor. Upon examination, he gave (no prescription) her a number of pills or capsules (which we later learned were Chioromycetin). To make a long story short, she continued on until Labor Day, 1966, when she returned home very ill. Within a week she was in the hospital and her condition was diagnosed as aplastic anemia caused by the taking of Chloromycetin. She spent 8'/2 weeks in the hospital during which time she received about 60-70 pints of blood by transfusion. Since her discharge from the hospital in November, 1966, she has had to return to the hospital every four weeks to receive 4 pints of blood by transfu- sion at a cost of $100. to $200. a month-this in addition to the original transfusions. She was able to return to college in January, 1907, and by going to summer school last summer, is now into her last few months of college. We have a living example in our home of a physician's negligence in the use of a powerful drug. We do not know what the future holds for Lois as she is soon going to be ready to apply for teaching positions, and we do not know if she will be hired with an incurable `affliction-or how she will be able to manage "blood bills" on a normal salary. If another family can be spared the heart- ache we have felt and the expenses we have been faced with, we feel we must speak up in attempting to have this drug controlled. The history of case may be checked at the University of Colorado Medical Center, Denver, Colorado. Thank you for your courtesy in hearing us through to the end of this letter and we hope to learn of progress in the very near future in the control of the use of this potentially dangerous antibiotic. Respectfully, NAME WITHHELD. COUNSELLORS AT LAW, Phi lc4elphia, Pa~, February 19, 1968. Re of the Estate of ,deceased, Civil Action No. ,Our File: Senator GAYLORD NELSON, Chairman, Senate Small Business, Monopolies Subcommittee, Washington, D.C. DnAa SENATOR: Our office represents who died on June 25, 1967 at the young age of 25 as a result of two prescriptions for chloromycetin. I enclose here- with a certificate of death from the Commonwealth of Pennsylvania as proof of - demise and cause of death. I have read with great interest the latest newspaper commentary regarding the investigation of your committee into the infamous history of the drug chloro- mycetin. As a consumer I wish to add my thanks for your courageous stand against the giants of the drug industry and wish you all the success in the future. The main purpose in writing, Senator, is to inquire if any records of testimony by officers or executives of Parke Davis are available to the public in limited cases such as the one which confronts our office. We would readily make available any and all information that we have com- piled in pursuing the claim - Thanking you in advance for your co- operation, I remain Very truly yours, NAME WITHHELD. PAGENO="0390" 2524 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Date No. T:i~ i~ t~ c *tify that this a true cozy of the record which is ca filr in the Per.r.svlvan:a Dcpartn-,cr,~ of Health, in accordance with Act fi., P. 30~1, a'proved by the General Astiecably, June 29, 1933. (2 ~ (Fee for hit; certificate, $1. 00) t.. ` 7/ - C. L. Waibar, ~`r. 6iM.D. Secratar', o Harrosbar;, Pennaylvar.ia c ~-~-. CEITIFCATE OF DEATr( tsiiii~ Cu"~ OCCUuiD ci.') fl.n.~',i;;f o. CO bosnj. ~ * ;(;L5O)Lj',.;A s. 5e~; .~;;.,t. C-, I, ,a:.~..G - C- .. b.P;oCC-o,Zi..,,u..t,u cn. Wi'._ C-. C-;. ~ )5d,.~iC~y if cfh h,~ZtC. ..u) 4. i&w OF ~. (C,.,) b. t'-'JCC') .. e-. ~ a . -C-; a~..- ~ 5 CEC(AS)D ~ ! ... ._ ,,~ - . . - - - - ~ C-: / / ,,., - 5 OF `~ `FF3) .- )AFF~ \ 6. FeC-c. 05 ,. 6, ~s.e..,-J C-, ;. CZC)A))O .. 5C-~IiF6L0 Q u., .,.,.J .-~.e aCTUALLY . - cc tiw? b. c~ ..nC-- 0 fe. .,e..,d C-,d `,C-, ~.:~t-C-;C-'- C, -- / 7. FEY F. RiO fAC~C-5 CLOtS ifAtOFti', C- C~ ~ n -~ -~ a: `~I `r : ~C C -Y ~ ~ I I cc.- -. ~`EaZ.-3,TIf ~ "C-) Mi3~CAL CEROF,CATE li,~, 53 ~ 0 c-..? ..,,kO~ C-1 ph-~.i.; iC-1) ,`C-;..T..; - 03. tAO) OF STAFF-F E-o~ ,`-.)~. .c. ~ p.,- r~. ,)f 4. CI 6 ii. . C-C-)) AC-S ia-n~ ~ lAST 1. L~,:h ..., o,.-,,d ,y. ~i~' -, . / ECOLOATE CAtS) I.) ..L1_~iri...F3C-tr5..t~~....~,F3ii.fJF Ccd::,.f.cyih,4. ~.. ~ ~ ~ ~c4c/_.~. - (I - P/CT IL OTtO SONIC-CANT CONDOONS .-.a,Ee,c~ 4..:), b? .0 .4.,d 6FF. ~ ...e, le. C-; .-.T. -, a - -C- C- I T:~. .c... nC.) I - ...*;` .;..,A C-5' - ;.-.,,,-.,:.:.,`..,,,c/:-;;.,;'".' .C-C-.,?-....-a-/d :e:i.;.' ..,.,..,,i.c,;,.;,;.. - ,`.,.-~ - - - -. ` ~ .~: - ---- ~ ~ -- -. BROOKLYN, N.Y., February 19, 1968. Dr. WILLIAM R. BEST, University of Illinois, Chicago, Ill. DEAlt DR. BEST: I am enclosing copies of correspondence re the drug Chloro- mycetin. After I wrote to Senator Dirksen, I came upon the attached article in Time Magazine, February 16th issue. How can you oppose the restriction of this drug when -the evidence is such that it is not only administered in serious cases, but for minor colds, sore throat, etc. As you will note from the correspondence, my niece was the unfortunate statisrn tical "1" out of 100,000. When it comes so close to home, even that "1" is too much. I am shocked, that as a respected member of the medical profession, you feel that "infringing on a doctor's prerogative to administer whatever drug he s~es fit" supersedes safeguarding that "1" out of 100,000. PAGENO="0391" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2525 I am naturally upset and bitter about your stand on the unlimited dispensing of this lethal drug, and am, therefore, writing to ask you to please help someone else avoid the horrible tragedy of losing a young child because of lack of infor- mation, disregard of warnings on labels and indiscriminate prescribing. It seems so ridiculous to have to plead with a doctor to help save lives. Very truly yours, * NAME WITHHELD. ATTORNEY AT LAW, New Mecoico, February 16, 1968. Hon. GAYLORD NELSON, Senate Office Building, Washington, D.C. DEAR Sm: Publicity on your excellent work in exposing the laxity of the drug industry in protecting the public from the Latent dangers of antibiotius have 111- tered even out into my corner of New Mexico. You have conducted hearings within the past two weeks in which Chioromy- cetin a Parke Davis product was the focal point. I would appreciate very much your a~sistance in helping me obtain copies of the testimony before your com- mittee concerning Ohioromycetin. I am representing a rancher's family whose 16 year old daughter was prescribed a strong dosage for tonsillitis and then a refill after she had apparently recovered. The child died an excruciatingly pain- ful death from aplastic anemia which developed as a result of her susceptibility to the drug. My investigation in the matter has left me with the opinion that there must be many such cases which have never been accurately diagnosed. My concern, how- ever, is for my client and in order to `have optimum understanding of this problem I would like to have a record of your recent investigation and will appreciate your office's help in obtaining it. Needless to say I shall pay the customary charges for such publication as it come from the Superintendent of Documents. Yours very `truly, NAME WITHHELD. ORSXrnN, February 16,1968. Hon. GAYLORD NELSON, Senate Office Bui Wing, WasMngton, D.C. DEAR SENATOR NELSON: I have read with interest in the Drew Pearson column and Time Magazine of your efforts to control the drug `chloromycetin. I want to personally thank you and encourage you in your efforts. The reports indicate that only a few hundred people have died as a result of this drug. Something is wrong with the reporting. I lost a little boy at the age of seven, sixteen years ago, because a doctor gave him chloromycetin for a mild cold. There was no warning to the doctor and I could not blame Mm because he had accepted some of `the information in the Parke Davis advertising whleh was, to say the least, misleading. At the same time my son was in the hospital dying, three more children died in that same hospital within a two-month period. I have personally known several `adults who, as a result of chl'oromycetin given `by doc- tors for colds, influenza and the like, developed aplastic anemia and died. I didn't sue Parke Davis because no amount, of money would have repaid me for the loss of my son. However, I `think I made a mistake, and if all of us who have been affected by this drug' would have sued Parke Davis and pursued the matter further, perhaps it would have been corrected by `this time. I encourage you to continue your efforts and investigate the use and controls of this d'rug. I am fully aware `that in some instances it can be life~saving, but its indiscriminate and wide use for minor ills has resulted in the loss of the lives of many people. Every few years some congressmen complain about the loose way in which Parke Davis is handling the drug and a few newspaper articles appear. The death rate goes down, and soon afterwards the whole thing starts over again and the death rate increases. Again let me congratulate you on your efforts to correct the misuse of this drug. I hope you will be successful in bringing it under control. Sincerely, NAME WITHHELD. PAGENO="0392" 2526 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY PENNSYLVANIA, February 16,1968. Senator GAYLORD NilsoN, Washington, D.C. DEAi~ SENATOR N1~LsoN: I have just read in the Time magazine of February 16, 1968, the article on the hearings before the Senate Monopoly Subcommittee, of which you are the chairman, about the drug Chioromycetin. I had an adverse reaction from the patent drug Chioromycetin. June 1965 I had four abscessed teeth. I was running a temperature of 101°- 104°. I went to a local physician, was given a prescription for Chloromyce!tin 250 mg. of 4 hrs. On June 14, 1965, I had all of my lower teeth extracted by Dr. I was taken from Dr. office to Binghamton, N.Y. and was admitted to their I.O.U. I was under the care of Drs. . Lab work, sternal punc- tures was done, white count was 604) diagnosis, complete blood dyscrasia caused by the drug Chioromycetin. I received 42 transfusions-whole blood, packed cells, extra refined plasma with extra platelets. I have been ill since June 1965 and continue under the physician's care. I reported this adverse reaction to the drug Chioromycetin to Dr. James L. God- dard, Comm. of N.F.D.A. They sent an investigator from their regional office, Pa., to my home. I gave Mr. Chine (investigator) my statement, also signed depositions for him to have access to all of my hospital records, name and addresses of the attending physicians. Mr. Chin told me that he would send the report of his findings to the N.F.D.A., Washington, D.C., that I would hear from them. I never heard from them. After six months, I wrote to the N.F.D.A. I received a reply from Lau- rence H. Stern, also two pamphlets about (Jhloromycetin. I hope that this letter is not ignored by you. Suggestions-(1) Physicians should warn patients of adverse reaction from this drug; (2) Druggist should be compelled to put the name of the drug on the label when prescriptions are filled, also to give patient the leaflet issued by Parke-Davis Drug Co. with each prescription for Chloromycetin; (3) News media to be used to bring to the attention of the public the adverse reaction of this drug. Respectfully, NAME WITHHELD. NEW YORK, N.Y., February 10, 1968. Sen. GAYLORD NELSON, Chairman, Senate Subcommittee on Drugs, Washington, D.C. DEAR SENATOR NELSON: I am vitally interested in the current investigation carried on by the Senate Subcommittee on Drugs with particular reference to the drug Chloromycetin manufactured solely by Parke, Davis and Company. As Chairman of this Committee, you may interested in some of the background leading to the death of my sister, , at age 44 years. Marion took the drug, chloromycciin, in connection with a minor ailment while in Europe (Spain) during a vacation in October, 1966. I enclose copies of correspondence from my file on the matter. Your investigation indicates grave concern that doctors are not aware of the possible consequences after a drug such as chioromycetin is administered to a patient. This too, has been the concern of `s family. The sole purpose of our contact with Parke Davis after her death was to attempt to prevent the same tragedy to another family. We are advised by those physicians attending my sister before her death, that aplastic anemia which ultimately caused her death was most probably brought on by the drug chioromycetin. Can you imagine our frustration as we read the Parke Davis pronouncement Anacin could have been the cause of death? Then, the frustration compounded by the last paragraph of their correspondence of September 19, 1967 stating posi- tively that physicians are universally aware of the possible fatal results of the drug chloromycetin; finally, that Parke Davis would not contact the doctor in Spain about the administration of the drug for fear he would think them critical of him. Needless to say, we are not convinced doctors are universally aware of the po- tential fatal effects of chloromycetin. Furthermore, my sister was able Ito pur- PAGENO="0393" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2527 chase a second dose of 12 capsules while in Spain without further written pre- scription. This surely indicates either a lack of knowledge regarding the drug, or a complete lack of professional responsibility concerning it. Senator Nelson, if my sister's death could save the life of another, our loss would be easier borne. We would like to make any further information we have regarding this case available to you if it would help your investigation. In the meantime, we wish the work of your Committee every success and hope this case may assist you in someway as you investigate the failure of drug companies to adequately warn the medical profession here and overseas, of dangerous drugs. Sincerely yours, NAME WITHHELD. TEXAS, February 13, 1968. Hon. GAYLORD NELSON, Democrat of Wisconsin, Washington, D.C. DEAR SiR: I have just read an article by Drew Pearson in the Wall Street Journal on the subject of the danger of the drug Ohioromycetin, and of your in- terest in protecting people from the drug. I am sorry to say that I too am a victim of the drug, in the fact that my husband was given sixty (60) capsules of Chioromycetin in Sept. for a kidney infection, (which later was diagnosed as hepatitus) and is in a most critical condition, which has been diagnosed as "thrombocytopenia purpura" caused by the bone marrow's being destroyed from taking the drug. I called the Doctor attending my husband, who had said that a medication had destroyed the bone marrow and asked him "what drug had destroyed the bone marrow, that I didn't want any given to me." He said "we think Chioromycetin did it. It is a good drug used for some things, but in some people it destroys the bone marrow the same way it has done in your husband." He did not say may have done but has done. He has been in hospital since the 11th of November, living on blood transfu- sions. Some days as many as 4 pints of blood a day. I have no hopes of him ever getting well, but we have to keep giving him blood. One just can't say "let him die, its just one more death caused from taking Chloromycetin." I called the Doctor that gave him the drug and told him what the Doctors in Houston had told me. He said "we are well aware of the fact that it causes bone marrow depression. I had a patient to die from the same thing your husband has." I asked him if it were a child that I had heard of an 8 year old girl dying here from taking the drug and he said "no it was a young adult lady." And then he gave it to my husband! I have heard of others dying from the drug, but the one the Doctor told me died I would take as a fact, not hear say. If you could see my husband, he is bleeding under the skin so he is spots all over his body and black & blue since he has no blood platelets to make blood coagulate. Of course he bleeds inside too, you would uderstand my concern about the drug and do all you could to keep others from dying or going through what we have been. My husband is 59 which in these days isn't old. So I think the drug is killing him. I wrote Parke-Davis & Company, and Doctor Goddard in Washington the same thing I have written you. These are copies of the letters they wrote me. You can see that others will continue to die from ChlorOmycetin from what they wrote me. has 45,000 people here, so for two to die from one Doctor giving it is two too many. There are 50 or so Doctors here so no one knows how many others have died from the drug. Can you advise me what procedures we should take to help right a wrong and be sure that others don't die or suffer the way we have suffered? Thank you for any consideration you may give me. Yours Truly, NAME WITHHELD. NEW JERSEY, February 12, 1968. Hon. GAYLORD NELSON, U.s. Senate, Washington, D.C. Sin: I am writing to urge you to take the nee~sary steps to control chioromy- cetin beoause as Dr. Dameshek has said, according to the enclosed clipping, it is being used without the proper precautions. PAGENO="0394" 2528 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I have enclosed ~ picture of our small son, . We lost him five years ago at age six because our Doctor, one of the finest in , prescribed chlor- omycetin every time he had a cold and never over a three year period took a blood test. I won't go into detail about the last terrible six months of our child's life but if you have the power to save one child the suffering that he endured, and parents the terrible loss that we have had, you should move swiftly to do so. `~\Te place our faith in Doctors and when they prescribe medicine for our loved ones we take their advice. If some Doctors wifl not heed the warning about the dangers involved with a drug, it would be far better to remove it from the market. I was told (too late) that this had been done with chloromycetin for a few years because of its danger but was made available again. With that knowledge, a very fine Doctor prescribed it and made no effort to follow up on the results. Since this is a subject I feel so strongly about, I wifi be waiting to see what your committee can do to see that things like this do not continue to occur. I feel that this is not as uncommon as you may think since the hematologist that was called in to diagnose asked immediately if my child had been given any antibiotics. We also sent a case history to Johns Hopkins in Baltimore and received a call to bring him down and they would do what they could- on the day that he died. Sincerely yours, NAME WITHHELD. WISCONSIN, February 12, 1968. Hon. GAYLORD NELSON, U.S. Senate, Washington, D.C. MY Di~&i~ SENATOR NELSON: Earlier today, we heard a news broadcast in which you were quoted citing the potential danger of a drug called Ohloromycetin. Both my wife and .1 were shocked beyond words. Allow me to explain. Several weeks ago, our youngest daughter (age 10 years) was conftned to the hospital with a suspected virus attack. It appeared to be- come localized in the upper right abdomen. After numerous tests, the doctor prescribed the use of Ohloromyeetin. Instead of improving, she became much worse-becoming very weak and pale. On two occasions, she fainted-some- thing that never occurred before. After several days of this, we transferred her to a more specialized hospital . She underwent countless tests there with- out the doctors arriving at a diagnosis. After eight days, we brought her home. What worries us is the fact she never completely recovered after being admin- istered this drug. As I write this now, ~he is home in bed-having suffered another weak, fainting spell this morning. We need your help. Specifically, please verify the symptoms your committee attributed as serious side effects. In addition, please advise if there is a known remedy to counteract the side effects. Very truly yours, NAME WITHHELD. BROOKLYN, N.Y., February 8, 1968. Hon. EvnnErr DIRKSEN, Senate Oyflce Building, Washington, D.C. DEAR Sm: Although I am not a member of your immediate constituency in Illinois, I feel you are a concerned and learned representative of the greater con- stituency, the citizens of the United States. I, therefore, again seek your help. I must bring this to someone's attention. This, to me, is unbelievable com- placency and neglect on the part of either the F.D.A., the A.M.A., the doctors, drug manufacturers or who knows. This past Christmas, our ten-year-old niece died from aplastic anemia (a blood disease related to leukemia). Her six-month-old long-illness was definitely attri- buted to the administering by a physician of chloromycetin for a previous cold or flu. After going through the months of suffering with these parents, I could hardly believe my eyes when reading this small article attached, tucked away in the back pages of the Daily News (N.Y.)-especially the sentence stating that PAGENO="0395" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2529 the Senate committee investigating this might impose restrictions on the prescrip- tion of it. After seeing the horrible results of the administration of this drug, this should be screamed from the housetops to every doctor and parent in the land. How can a condition of this sort exist? Are we not protected from these lethal drugs by our supposedly thorough F.D.A.? Are not doctors definitely warned about the possible death-dealing effects of this drug? After witnessing this terrible tragedy happen to a laughing, healthy youngster because she was given a supposed cure for a cold bug, which in turn caused her death, I cannot remain silent. Her parents have been urged to see the doctor, etc. This will not bring the child back. But definite action in preventing recurrences of this to other children (or adults) is, without a doubt, mandatory. Without your knowledge of our seemingly ponderous government machinery, what can be done? I am sending copies of this letter and article to the several parties noted below, with the hope that public exposure of this situation might generate posi- tive action and perhaps some poor, unsuspecting patient will be given a more concrete safeguard than the chance reading of an article "tucked away on the back page of a newspaper." Thank you. Sincerely, NAME WITHHELD. WISCONSIN, February 8, 1968. Hon. Senator GAYLORD NELSON, U.S. Senate, Washington, D.C. DEAR SENATOR NELSON: May I commend you on your interest in and work on the use of the drug chloromycetin (chloramphenicol). As a father, who lost a lovely seven year old daughter in a dreadful death due to a doctor's repeated prescription of chloromycetin for trivial infections without observing the precautions spelled out by Parke, Davis & Co., I do appreciate your concern. A matter which still troubles as greatly is that this dotcor who was aware of the precautions advised me after Ann's death that he wouldn't adopt them in the future because the "odds" were such that he wouldn't see another case in his lifetime. As you point out it is inconscionable that physicians in some foreign lands don't know of these dangers. How much worse to know and ignore them! Again, I hope your efforts are successful in correcting a terrible situation. Sincerely, NAME WITHHELD. ATTORNEY AT LAW, Washington, February 8, 1968. Hon. GAYLORD NELSON, U.S. Senate, Senate Office Building, Washington, D.C. DEAR SENATOR NELSON: I read with great interest reference to your subcom- mittee on drugs in Drew Pearson's article of February 6, 1968. I represent the parents of a deceased three year old child whose action for the loss of the child is pending in the Superior Court of the State of Washington in and for the county of Adams, at -~-, Washington. The child, , repeatedly received prescriptions from a doctor for Chioromycetin in treatment of upper respiratory infections. On two occasions the prescriptions were refilled by the local drug- gist without so much as a telephone call to the doctor-at least according to the doctor. Even after showed petechiae and widespread, Strange eccymotic areas on her body, her doctor continued to prescribe Chloromycetin. He made no blood test to determine whether she was sustaining any diminishment in any of the components of the blood. died a painful death in June, 1966. The hematologist who tried to save her gave the opinion that her aplastic anemia from which she died was induced by the use of Chloromycetin. The doctor's insurance company has taken the position that the rate of deaths from aplastic anemia is no greater now than it was before the advent of Chloro- PAGENO="0396" 2530 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY mycetin, They claim that Benzine and certain cancer medications are a more probable cause. I would like very much to obtain copies of any reports by your committee in order to be as well prepared as I can be in this forthcoming trial. I would greatly appreciate it if you would inform me as to how I might obtain reports from your committee which have to do with Chloromycetin. Yours very truly, NAME WITHHELD. ATTORNEYS AT LAW, February 7, 1968. Hon. GAYLORD NELSON, U.S. Senator, Chairman, Senate Small Business Committee's Monopoly Subcom~- committee, Senate Office Building, Washington, D.C. DEAn SENATOR NELSON: I noticed from an account in the newspaper that your Committee has held hearings on the side effects of the proprietary drug Chloromycetin. At the present time we are interested in a man who was killed by the use of this drug when aplastic anemia developed after use of the drug. I am writing to inquire if it would be possible to get a transcript of the testi- mony before your Committee as it may concern the harmful side effects of the drug Ohioromycetin which is manufactured and marketed by Parke-Davis Company. Yours very truly, NAME WITHHELD. ATTORNEYS AND COUNSELORS AT LAW, New York, N.Y., February 7, 1968. Hon. GAYLORD NELSON, U.S. Senator, New Senate Office Building, Washington, D.C. HONORABLE Sin: I read a column written by Drew Pearson which `appeared in the New York Post on February 6th, 1968 concerning your Hearings involving Parke, Davis & Co. who are the manufacturers of a drug called cliloromycetin. At present, we are suing this company on behalf of a client whose `daughter died from aplastic anemia, after having taken chloromycetin for a minor throat infection. We would greatly appreciate receiving from you a copy of the testimony given by Parke, Davis & C~. concerning cthloromycetin. If there is any charge for this transcript, please advise us and we shall pay same. Thanking you in advance for any and all courtesies extended herein. Very truly yours, NAME WITHHELD. IoWA, February 7, 1968. DEAR SENATOR NELSON: I read Drew Pearson's article on your rift with Parke, Davis on chioromycetin. This restores my faith in people such as you. Our daughter passed away at Methodist Hospital in Rochester November 3, 1967, due to aplastic anemia, at the age of 15 years, 10 months. We were fairly sure she had had chloromycetin-but it was not until we arrived home Nov. 3 when I asked our d'octor-~he told me she had 12 capsules in June and that that amount would not cause aplastic anemia and that he was going to continue to use it. My wife and I were in shock and I got to thinking about his statements. Three weeks later I turned my grievanees over to the Iowa Medical Society and I have more grievances than just the drug. They are meeting this Sunday in Des Moines. My daughter went to the Dr. with her mother in June for a throat infection and was given 18 capsules of chloromycetin-w/o a throat culture-she later was given dosages of 18 and 16 without `any blood tests taken while on the drug- this adds up `to 52 rather than the 12. Her first symptoms were hemorrhages under the skin, and we were sent to and then back home-back to Iowa City to back home-in the local hospital 2 or 3 times and then back to Rochester where she lived for 2 weeks- so from Aug. 28 to Nov. 3 she failed rather fast. My wife and I, like many other citizens, `had never heard of chioromycetin- or its possible dangers. PAGENO="0397" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2531 We had so much faith in the F.D.A.-Drug Mfgr. and Doctors-that we cannot yet comprehend this terrible thing. Dr. hematologist termed her death "a monumental disaster and a great tragedy." If Parke-Davis and the Doctors could realize how it takes lives needlessly, and. ruins families. I cannot believe they would allow it to be used so freely. This is a personal plea for more action to safeguard others. Money could never replace my daughter-but a lawsuit either against the Doctor who administered the drug or Parke-Davis might impress upon them that the victims will not tolerate the present methods. I would appreciate an answer from you at your convenience-do we have any chance in a lawsuit? I telephoned your Administrative Assistant last might and he requested I write you this letter. I wish to thank you in advance for any consideration you give us. The count is now 61 rather than 60 needless deaths. Respectfully, NAME WITHHELD. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, FOOD AND DRUG ADMINISTRATION, Washington, D.C., February 2,1968. TEXAS. DEAR NAME WITHHELD: This responds to your letter urging that the drug Chloromycetin be taken off the market because of the serious side effects it can have. We can understand your personal concern and know you will be interested in details on the re-evaluation of this drug as long ago as 1952, when the harm~ ful side effects became recognized as a serious problem, and again in 1961. We accumulated all available data on the drug and presented the facts to a special committee of outstanding medical experts appointed by the National Research Council. After careful deliberation, that committee concluded that Ohloromycetin is a life-saving drug in certain illnesses where other safer drugs are not effective, and recommended that it be permitted to remain on the market for such pur- pose. They recommended that its labeling plainly warn physicians that the drug may cause serious blood disturbances and that it should not be used indiscrimi- nately or for minor infections. Sincerely yours, JEANNE M. MANGEL5, Consumer Inquiries Staff, Office of Education and Information. WiscoNsiN, December 28, 1967. DEAR SENATOR NELSON: I have been informed you are presently investigating, some drugs. I would like to know if one of them is Ohloromycetin. I was lYre- scribed this drug for a minor infection in 1965 and the result was my getting aplastic anemia. Which is the destruction or depression of the bone marrow. After many times in the hospital and much doctoring, I am hopeful of making a complete recovery. Due to my own experience, I am interested in the drug, Chioromycetin. Due to the serious complications this drug can cause, I would like to see it taken off the markOt, so what I have experienced wouldn't happen to anyone else. I am enclosing a copy of a article in Good Housekeeping magazine November 1966 about Ohioromycetin. Yours truly, NAME WITHHELD. PARKE, DAVIS & Co., Detroit, Mink., December 28, 1967. -, TEXAS. DEAR MRS. NAME WITHHELD: I have your letter of December 17 with respect to the illness and hospitalization of your husband and can appreciate your concern. Unfortunately, there are probably no effective drugs which may not on oc- caSion give rise to serious adverse reactions in some patients. This is a continuing PAGENO="0398" 2532 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY concern not only of manufacturers and physicians but of the public represented through the Federal Food and Drug Administration. In the case of Ohioromycetin, the matter of whether its marketing should be continued has been the subject of special reviews by Committees of the Division of Medical Sciences and of the National Research Council appointed at the re- quest of the Food and Drug Administration. These Committees have decided that its benefits outweigh its possible risks and that its marketing should be continued. You should know, perhaps, that bone marrow depression may occur without any known exposure and is also attributed .to many agents other than Chloro- mycetin. It is realized, of course, that this does not alleviate your personal situation or afford you any comfort. I do sincerely hope, however, that your husband ex- periences a recovery. In the meantime, perhaps you might be willing to let us know the name of your physician since we may wish to correspond with him. Cordially yours, JOSEPH F. SADUSK, Jr., M.D. PARKE, DAVIS & Co., Detroit, Mich., Septeimber 10, 1967. Nnw YORK. DEAR Ma. NAME WITHHELD: Please accept my apologies for not replying sooner to your letter of August 21. Review of the material so kindly sent on to us at your request by Drs. does not enable us to make a positive determination that Chloromycetin was necessarily the cause of the terminal illness of your sister. In this connection, may I point out that there does not seem to be any clear agreement among the physicians involved of the nature of the illness for which it was prescribed, the dosage directions or the duration of treatment. The situa- tion is further obscured by the fact that acetophenetidin, an ingredient of Anacin (which your sister also received), has also on occasion been associated with the development of blood dyscrasias. As indicated in my first letter to you, physicians are universally aware of the possible association between Chloromycetin and the development of blood dys- crasias. Under the circumstances, I do not see how any approach by us to Dr. Diez could be helpful or considered by him in any light other than as being critical of him. There is, of course, no reason why you should not write him directly if you so choose. Cordially yours, JOSEPH F. SADUSK, Jr., MP DEPARTMENT OF Hu~urH, EDUCATION, AND WELFARE, FOOD AND DRUG ADMINISTRATION, Washini/ton, D.C., July 10, 1967. NEW YORK. Daaa NAME WITHHELD: This refers to the copy of your letter to the manufac- turer of Chloromycetin which you sent to us, describing your sister's illness and death after use of the drug. We can certainly understand your personal concern and believe you will be interested in details on the re-evaluation of this drug as long ago as 1952, when the possible side effects became recognized as a serious problem, and again in 1961. We accumulated all available data on the drug and presented the facts to a special committee of outstanding medical experts appointed by the National Research Council. After careful deliberation, that committee concluded that Chloromycetin is a life-saving drug in certain illnesses where other safer drugs are not effective, and recommended that it be permitted to remain on the market for such purpose. They recommended that its labeling plainly warn physicians that the drug may cause serious blood disturbances and that it should not be used indiscriminately or for minor infections. We are enclosing a photocopy of the news release and copy of the committee recommendations that issued at that time.~ Sincerely yours, EDNA M. LOVERING, Consumer Inquiries Staff, Office of Education and Information. *These copies are not enclosed, since I am sure all of this material is available to the committee. PAGENO="0399" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2533 NEW YORK, July 10, 1967. JOSEPH F. SADUSK, Jr., M.D., Vice President, Medical Affairs, Parke-Davis ~ Co., Detroit, Mich. DEAR DR. SADUSK: Relative to our correspondence concerning the death of my sister, I have recently learned the name of the doctor in Spain who ex- amined and prescribed the drug Chioromycetin while she was in that country: Dr. , Seville, Spain. I know this a very common name in Spain, but I understand from Marion's companion on the trip, - serves as the hotel physician and hopefully, may be contacted at the above address. As previously stated, it is our sincere wish that everything possible may be done to prevent a similar tragedy. We hope Parke-Davis & Co. will be able to con- tact the doctor involved so that he may be completely aware of the potential consequences when administrating the drug Chloromycetin. We are convinced Marion's illness did not warrant the use of this powerful antibiotic. I will appreciate your continued advice as you proceed with inquiries concern- ing Marion's illness and death. Very truly yours, NAME WITHHELD. PARKE, DAVIS & Co., Detroit, Mich., July 20, 1967. NEW YonK. DEAn NAME WITHHELD: This is just a~ short note to tell, you that I have re- cently returned to the office after an extended `trip to find your letter of June 30. I have written to both Dr. and Dr. requesting the details of your sister's illness. Cordially yours, JOSEPH F. SADUSK, Jr~ M.D. NEW YORK, June 30, 1967. JOSEPH F. SADUSK, Jr., M.D., Vice President, Medical Affairs, Parke, Davis ~ Co., Detroit, Mich. DEAR Dn. SADUSK: Thank you for your prompt response to my letter of May 19, 1967 written shortly after the death of my sister, I very much appreciated your comments, and we are all particularly pleased that you will contact and discuss Marion's illness and death with the doctors who were directly involved with the case. As I stated before, the tragic consequence of taking the drug Chloromycetin appears tO be `the untimely death of a beloved daughter and sister. It is our sincere hope that a review and study of these cir- cumstances may help, in some measure and in some way, to prevent a similar tragedy to another. was doctor in . During her illness she was referred to Dr. who examined and did blood studies. These men may be contacted as follows: ,New York; ,New York. Thank you again for your interest in Marion's case. We will be most happy to hear from you again after you have had the opportunity to discus's to matter with the doctors involved. Very truly yours, NAME WITHHELD. PARKE, DAvIS & Co., Detroit, Mich., June 8,1967. SENECA FALLS, N.Y. DEAR (name withheld): I am hastening to respond to your letter of May 19 which has just been received in an envelope postmarked June 1, from Seneca Falls. We at Park-Davis deeply sympathize with you in the loss of your beloved sister and, needless to say, we should like to discuss the matter of your sister's illness with your physicians if you will send us their names and addresses. The matter of the possible association of bloOd diseases with Chloromycetin treatment has been the subject of review by many authorities and, indeed, I believe the National Research Council of the National Academy of Science in PAGENO="0400" 2534 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Washington, D.C., carefully reviewed the matter in late 1960 and early 1961. While it appears that Chloromycetin may be one of the causes of such blood disorders, it is likewise recognized that other drugs, as well as exposure to certain other toxic agents, may produce a similar effect. And, indeed, these disorders may occur without definable cause. Consequently, it is important to review each patient's record thoroughly in order to arrive at a decision. Even after a thorough review, it may not be possible to completely clarify the issue. In your sister's case, it would be important to review the history from the standpoint of all the other drugs she may have received. For instance, aminopy- rine and dipyrone are commonly prescribed in Europe for symptomatic reilef of infection, and since these agents are known to have a deleterious effect upon the blood, they must be taken into consideration along with other agents. I believe that physicians are universally well educated on the possibility of association of Chloromycetin with aplastic anemia so that this point generally is taken into consideration when Chloromycetin is prescribed. With every drug a physician prescribes he must balance off the benefit to be obtained against the risk involved since there is no drug which is free of the potential of toxic reaction. The questions asked and suggestions made in the next to the last paragraph of your letter are all good, but would be difficult to implement since these points would have to be applied against practically all drugs. As you may know, there are a number of drugs regularly used by physicians which are considerably more toxic than Chloromycetin. Even the other antibiotics carry certain risks which under appropriate circumstances may lead a physician to decide to use Chloromy- cetin as a lesser risk. I hope you will consider my reply responsive to your inquiry and, as I noted above, we should be most pleased to correspond with the physicians involved. Cordially yours, JOSEPH F. SADUSK, Jr., M.D. NEW YORK, May 1~9, 1967. PARKE DAVIS & Co., Detroit, Mielv. Gnr~mEMu~: My sister, , died May 3, 1967 after taking, by prescription, the antibiotic chloromycetin produced by Parke Davis and Company. Marion was 44 years old. To the best of my knowledge, after discussion with the attending doctors, the medication was responsible for the complete destruction of blood platlettes at the beginning. General infection at the end because of the absence of white corpuscles in her blood was the immediate cause of her death. A. post-mortem has been authorized, the results of which are not completed. took the antibiotic while on a trip to Europe. The prescription was filled in Spain, after a doctor's examination. She refilled the prescription once, twelve capsules. The total intake was 22 capsules. Two capsules were not taken. The first administration of the drug occurred in October, 1906. The first indi- cation of the nature of her illness was discovered state-side in February, 1967. We hope your interest in the case will prompt you to discuss the illness in detail with the doctors involved whose names I will gladly furnish on request. I am sure you will understand that I have made attempts to become familiar with this drug since my sister's tragic illness and death. I understand that serious and fatal blood dyscrasias have been known to occur in the past. I understand that the serious consequences of the administration of the drug are published for the benefit of the medical profession. I understand precautions are urged stating blood studies are essential during treatment with the drug. Perhaps it is not practical to advise the patient in the same manner, but I assure you Marion would have weighed the advice carefully before accepting the treatment pre- scribed had she been given the opportunity to do so. The illness for which chloromycetin was prescribed was not of a serious nature. Furthermore, the writing on the bottle containing the two remaining capsules is in Spanish, a language not understood by Marion. We know that the drug is beneficial to countless more people than it is fatal to others. It is difficult to find comfort in this fact. - was a vital, well re- garded, loved person who held a responsible, well paying job and supported her mother. I cannot be bitter or vindictive, because this fine woman has suffered a greater loss than I, and she is neither bitter or vindictive. I can, however, write to tell you of the tragic consequence of the drug taken by my sister. I can write to complain that her death seems needless to those left behind and that this drug, manufactured to cure, has taken a life. PAGENO="0401" COMPETITIVE PROBLEMS IN THE DRUG~ ~~DUSTRY 2535 Mother-none of us-seek liability from your Company. It is our sin- cere hope that something can be done to prevent the recurrence of the tragedy to another. We feel strongly the utter lack of professional responsibility on the part of the doctor. Is it possible the man did not understand the potential effects or had insufficient advice concerning the drug from the company? Is it im- practical to suggest that those to whom chloromycetin is available for adminis- tration should indicate, in writing, that they understand all of the undesirable effects the drug may produce in the human body during therapy, and after? If blood studies which are recommended during treatment could prevent a fatality, shouldn't they be mandated instead of merely recommended? Should the drug be withdrawn from a foreign market where the people entrusted with its adminis- tration may not be as professionally responsible as American doctors? It is difficult to be objective and not allow emotions to be a part of this letter, since experiencing the tragedy of `s death. Her Mother, her sister and I, however, feel a compelling responsibility to write to you, the drug manufacturer to express our concern that other deaths may occur needlessly if a more respon- sible attitude is not taken by the maker of the drug, and the medical profession entrusted with its administration. I will be pleased to receive a reply. Very truly yours, NAME WITHHELD. Senator NELSON. This morning our witness is Dr. William C. Hew- son, who is both a physician and a lawyer from Philadelphia. Dr. Hewson, the committee appreciates your taking the time to come here and give your testimony today. I have read it and it is a very valuable contribution to the hearing record. STATEMENT OP DR. WILLIAM C. HEWSON, PHYSICIAN AND LAWYER, PHILADELPHIA, PA. Dr. HEWSON. Thank you, Senator. Senator NELSON. You may proceed to present your testimony in any way you see fit. You may read it, and at any place in your statement where you feel it will be valuable for the record to extemporize and elaborate on any statement you make, the Committee will appreciate having your extended remarks. I assume you have no objection in the event that some questions occur to us during the course of your presentation. Dr. HEWSON. Thank you, sir. My name is William C. Hewson and I am a physician and a lawyer from Philadelphia. I attended undergraduate school at Temple Uni- versity in Philadelphia and graduated from the Temple University School of Medicine in 1954. Following a year of internship at the U.S. Naval Hospital, Bethesda, Md., I served for 2 years in the Navy, following which I took a 1-year residency in the general practice of medicine. From 1958 to 1964, I was a general practitioner of medicine in West Chester, Pa., a borough of about 25,000 inhabit- ants, located about 25 miles west of Philadelphia and 20 miles north of Wilmington, Del. In 1964 I left the private practice of medicine to attend the law school of the University of Pennsylvania, from which I graduated in 1967. I am now associated with the Philadelphia law firm of Beasley, Albert, Hewson & Casey. That is the end of the cre- dentials, sir. Senator NELSON. Go ahead. Dr. HEWSON. The marked overuse and misuse of the antibiotic drug, chloramphenicol (Chloromycetin), is now too well documented to be 81-280 0-68-pt. 6-26 PAGENO="0402" 2536 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY gainsaid. This fact was more than sufficiently brought out by the distinguished experts who have testified previously before this sub- committee. The reasons behind this overuse and misuse pose a com- plex problem. I believe the blame falls on both the physicians and the pharmaceutical company involved-namely, Parke, Davis & Oo., the holder of a patent on this dru~ until recently. This allegation of dual responsibility does not constitute a contradiction in terms, for the attribution of fault to one party need not exculpate the other. Th~it may be a little inartistically put, but I think all I am basically saying is the fact that it is a prescription drug and that the physician makes the final decision as to whether to dispense it, does not create a mantle to protect the drug company completely. I think the rest of the statement elucidates that concept to some degree. Even though a drug is available only on a physician's prescription, a drug house may be guilty of overprornotion of the product to the point of misleading the members of the medical profession as to both the indications for, and the restrictions on, its use. At the same time the ordering physicians may be aware to some degree of the potential untoward effects of the drug and yet prescribe it inappro- priately, in disregard of that knowledge. In the Oalifornia case of Love v. Wolfe and in our recent Philadelphia cose of Incollingo v. Ewing, both the prescribing physicians and Parke, Davis & Oo. were found liable for the negligent administration of Ohioro- mycetin to patients who subsequently died of aplastic anemia. That is from the effect of the blood on the bone marrow of these patients. Senator NELSON. These were cases in which the prescription of the drug was not indicated. Dr. HEWSON. That is correct. In both cases its use was for quite minor conditions. Senator NELSON. What were the dates of the prescription of the drug-not the trial of the case-but when was the drug prescribed for the patient? In what years? Dr. HEWSON. In Philadelphia it was prescribed in October of 1958, in July of 1959, and in January of 1960 for a little girl who was 4 years old in January of 1960. Then, there were additional prescrip- tions by phone, upon which I elaborate more later, during the months of February, March, and April of 1960. Then she came down with full-blown aplastic anemia in May 1960. Senator NELSON. And in the Love case? Dr. HEwsoN. I believe that goes back to 1958, Senator. Senator NELSON. Both of these cases were several years after knowl- edge was available as to the serious side effects of this drug. Dr. HEWSON. Yes, sir. They both came well after the 1952 publicity and subsequent warning and they both came before the 1961 warning was placed on the literature accompanying the drug. In the Love case the physician ordered courses of Chloromycetin for the plaintiff, Carney Love, for two conditions, first for infected gums and then for bronchitis. Senator NELSON. Was there anything definite in the case to demon- strate that the drug was indicated for these cases because of the seri- ousness of the infection? Dr. HEWSON. Senator, I do not have all the trial testimony of this PAGENO="0403" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2537 case. I have the appellate opinion oniy. They are not readily available to us. But, I do not believe so. Senator NELSON. But they were found liable in any event. Dr. IIEWS0N. There were no cultures taken to establish that it was a resistant infection. In the Incollingo case a pediatrician prescribed Chloromycetm for Mary Ann Incollingo on three occasions for infected throat and ton- sils; a second physician renewed Mary Ann's prescription by tele- phone on at least two occasions, without seeing the patient, for minor respiratory complaints. The two cases differed in that the prescribing physician in the Love case testified that he had been misled by the Parke, Davis advertising and detailing, while the initial prescribing physician in the Incollingo case stated that he was fully aware of the dangers inherent in the use of Chloromycetin and was not misled by the Parke, Davis promotional methods. Mr. GORDON. If I am not mistaken, in the Love case the court held that the vigorous promotional campaign by Parke, Davis Co. canceled out any written warning that the firm may have given. Is that correct? Dr. HEWSON. That is correct. That case was remanded once, has been up on appeal again and Parke, Davis' promotional methods have held that company in for something, I think, in the neighborhood of a $185,000 verdict. But it had been remanded for the second time to try the physician again. The two positions were not held to be mutually exclusive, and the doctor can be held negligent, also, despite the fact that Parke, Davis has already been deemed negligent for its promo- tional methods. In other words, he cannot hide behind the Parke, Davis promotional methods. Mr. GoRDoN. Is it correct that the court held that proof of the sales of Chioromycetin expressed either in grams or dollars was relevant to show a motive or reason for the alleged promotion of the drug which is a definite issue in the case? Dr. HEWSON. That is correct. That is an evidentiary problem-how relevant is the fact that they sold so much of the drug and so much of it was prescribed. It was held to be relevant in the sense that it might show a motivation or an intent to push the drug on the medical profession, to augment its sales. Mr. GORDON. Thank you. Dr. HEWSON. The renewing physician in Incollingo did testify that the drug company's promotional methods had misinformed him as to the proper use. of the drug. In both cases the pharmacist who filled the prescription was exculpated. The rationale of those decisions, holding the prescribing physicians and the promoting drug company reprehensible, is not only acceptable but correct, in my opinion. In IncoUingo the alleged negligence of Parke, Davis & Co. was bot- tomed on the theory that the company had in effect, by its overpromo- tion of Chloromycetin, set the standard for the medical profession for the use of that drug during the period from its first introduction on the market in 1948 until its prescription for the plaintiffs decedent in 1958, 1959, and 1960. Because of Parke, Davis advertising and detailing methods, it was argued, physicians had been misled into using the drug indiscriminately, in disregard of the potential toxic effects of the antibiotic, for conditions where drugs of lesser toxicity PAGENO="0404" 2538 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY should have been used. Thus, the widespread, irresponsible prescrip- tion of Chloromycetin, although apparently accepted by a majority of the medical profession, was not reasonably prudent, or legally con- donable, use of the drug. In other words, the general use of the drug was deemed not to be accepted legal use. The usual legal standard of the act of the reasonably prudent man under the circumstances was not met. These were not reasonably prudent physicians, nor was this reasonably prudent use of the drug. At least the jury so found. Historically, Chioromycetin was first introduced in 1948 as a broad- spectrum antibiotic of great efficacy and minimal side effects. Senator NELSON. It is still so advertised; is it not? Dr. HIEWSON. It is still very much so advertised, and I think every one has testified that it is a very effective drug, but that does not mean it should be used widely. There are other effective drugs, probably al- most nearly so effective, and without the serious side effect of toxicity to the bone marrow. Unlike the tetracyclines-Terrarnycin, Aureomycin, et cetera, which were also broad-spectrum antibiotics, Chloromycetin caused little gas- trointestinal upset. Also, it was more effective in the treatment of certain diseases, such as typhoid fever. Sales of the drug increased markedly from 1949 to 1952. However, reports of aplastic anemia resulting from the use of the drug appeared during that time, and the Federal Food and Drug Administration asked the National Research Council to submit a report on the toxic aspects of this antibiotic. The National Research Council, which was composed mainly of eminent physicians, I believe, recommended that a warning be placed on Chioromycetin containers and the circular within. Parke, Davis & Co. followed the recommendation of the Food and Drug Adininistra- tion; but the warning was required only on the circulars accompany- ing the injectable preparations, which are actually seldom seen by the prescribing physician. The injectable form of Chioromycetin is used in hospital practice for the most part; so that only the pharmacists were exposed to the FDA warning. The modified warning which Parke, Davis placed in most, but not all, of its promotional literature for Chioromycetin was weakened or diluted in at least five aspects from the recommended statement. Senator NELSON. Are you saying that the injectable preparations are not used very often in physicians offices? Dr. HEWSON. That is correct.. The injectable preparation at that time had to be used every 4 to 6 hours and, even as a starting dose, it was not feasible to use it in office practice. A later preparation was to be used every 12 hours or even 24. Senator NELSON. Is it still more commonly administered orally in office practice than it is by injection? Dr. HEWSON. Oh, yes; very much more. Senator NELSON. It is a tablet; is it not? Dr. HEWSON. It is a capsule or a liquid pediatric preparation. Senator NELSON. The package insert which contains the warning goes directly to the pharmacist at the drugstore; does it not? Dr. HEWSON. Senator, from 1952 to 1961 there was no circular with the oral preparation. After 1962 it was required with the oral prepara- tion, also; but that still goes to the pharmacist and he dispenses it without the circular enclosed, of course. PAGENO="0405" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2539 Senator NELSON. Well, are yOu saying after the drug was taken off the market in 1952 and then went back on to the market that the pack- age did not include a package insert to the pharmacist between that period and 1962? Dr. HEWSON. That is correct. First, I do not believe the drug ever was actually taken off the market and then the warning that was required by the FDA, and this was a Parke, Davis defense, too, stated that the warning was not required in the oral preparation and so was never put in until it was required by the FDA in 1961. The inference I get was that the FDA did not have the power or the authority to require it to be in the oral preparation until 1961. Senator NELSON. There must have been some form of package insert that described the use of the capsule in the package to the pharmacist; was there not ? Dr. HEWSON. My understanding is that no package insert was re- quired in the oral preparations. At least the warning was not required in that type, if there was one. Senator NELSON. That puzzles me a little bit. It would seem to me that some insert would have to be in there to explain what the drug was used for even if it did not contain `a warning. Dr. HEWSON. Of course, this is a prescription drug, Senator, and a physician has to prescribe the use for it. The pharmacist, of course, should be aware of correct dosage, but in general it is on the prescrip- tion as the physician writes it. Senator NELSoN. So now, there is a package insert required and the package insert contains the warning; does it not? Dr. IHEWS'ON. Since 1961. Also the boxes, the small individual pack- ages, had a one-sentence warning on it even as far back as 1952. Senator NELSON. Now, if the doctor is not dispensing it himself out of his own office, how does he get the warning as to the side effects of this drug? Dr. HEWSON. Well, first, most physicians do not dispense oral prep- arations of the drug in the office and they do not use the injectable form. I believe Parke, Davis did send out letters to 200,000 physicians in 1952 about the FDA investigation. Another source of information can be the advertising. Also, it can come from detail men. It can be from the Physicians' Desk Reference, which is sort of a bible to the practicing physician, although it really contains the literature on a drug as the drug company itself presents that information. It is really an advertising mechanism essentially. The wording does not come from an objective source. It comes from the drug companies. PrObably the best and most reliable source is the objective medical literature, case reports, et cetera. Senator NEI~SON. So the doctor who prescribes the drug does not regularly see the warning on a package insert because he does not see the package? Dr. HEWSON. That is correct. Senator NELSON. So, his source of information is medical literature and/or the advertising by the company `and the detailing by the detail man; is that correct? Dr. HEWSON. Correct. Yes, sir. Mr. GORDON. Dr. Hewson, do you know of any cases where Parke, PAGENO="0406" 2540 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Davis, either in letters to doctors or in advertising, adopted warn- ings on its own? Dr. HEwsoN. Oh, yes. After 1952, when the FDA warning was re- quired on the package inserts and in the cautionary statements on the boxes, Parke, Davis did include a warning on most of its promotional literature, but not on `all. This was not the same type-not the same warning, in effect, and certainly not in the same words that the FDA recomended. Mr. GORDON. It was required by the FDA; was it not? Dr. HEWSON. I do not believe so. Mr. GORDON. Adopted on their own? Dr. HEwsoN. That is right. They did adopt it on their own but they did not adopt the FDA warning. Their warning, and that was one of our arguments in the Inco77ingo case, was considerably diluted or watered down, weakened. In at least five aspects we felt it was changed and our experts so testified. Senator Nm~sON. Was the FDA warning just a suggestion to the company? Dr. HIEWSON. That is the way I read it, a recommendation, and they could only recommend it for the package inserts with the parenteral forms and for the enclosing boxes. Parke, Davis, itself, had to ~ut it, of its own volition into its advertising, but they chose to present it in a changed form. Senator NFLs0N. Did the law not authorize FDA to require warn- ings approved by them? Dr. HEWSON. The warning which they put in their literature? `Senator NELSON. Yes. Dr. E[EWSON. No. Senator NELSON. In their advertising, either? Dr. }I1EW5ON. I am sorry. That is what I meant by their litera- ture, too. Yes; did not require them to put~- Senator NELSON. Are you saying the FDA- Dr. HEWSON. We are talking about the period 1952 to 1961? Senator NELSON. Yes. Dr. HEWSON. Correct. Senator NELsON. The FDA during that period did not have the legal authority to veto any specific advertising, so to speak, or to re- quire any specific language in the advertising between 1952 and the Kefauver-Harris amendment in 1962; is that it? Dr. HEWSON. I understand they had a recommendatory authority only. They did not have the legal power to require it. Senator NELSON. Have you studied the law as to what authority they now have? Dr. HEWSON. No. I know only of what it is from 1962 from read- ing the cases and listening to the Parke, Davis defenses. Mr. GORDON. Can you tell us the five aspects in which Parke, Davis watered down, diluted the FDA warning? Dr. HEWSON. Oh, yes. The FDA warning began with the state- ment certain blood dyscrasias have been associated with the use of Chloromycetin. Senator NELSON. Now, this is the suggestion that FDA made? Dr. HEWSON. That is correct. This is what was put on the boxes and in the circulars with the parenteral forms of Chloromycetin. The first PAGENO="0407" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2541 change that was made was that Parke, Davis started their warning with "Chloromycetin is a potent therapeutic drug" which, we argued, is a self-serving statement which tends to dilute what follows. Also, in their warning they did not delineate the specific blood dyscrasias which were parenthetically enclosed in the FDA warning. In the part of the warning that referred to the taking of blood studies to determine bone-marrow changes, they added the phrase "as with certain other drugs," tending to equilibrate the toxicity of Chloromy- cetin with certain other unspecified drugs. The FDA warning contained the words, relative to the required blood studies, "It is essential." The Chioromycetin warning deleted "It is essential." The FDA warning was required to be placed at the top of the litera- ture in the injectable circular. The Parke, Davis warning was usually placed well down in its advertising in relatively small print. Following the 1952 investigation by the National Research Council and the ensuing warning, sales of Chloromycetin dropped precipi- tously. However, recovery was successful to the degree that the sales in 1960 were greater than the peak of any previous year. In 1960 enough Chioromycetin was sold to provide courses of therapy for nearly 4 million persons. Senator NELSON. What is your estimate of the number based upon? Dr. HEWSON. That, I believe, came from the Kefauver investigation. Senator NELSON. I see. Dr. HEWSON. There is literature on this. There are graphs which show these sales. These sales were made despite the statements in leading journals from knowledgeable physicians and from American Medical AssocIa- tion councils that the drug should be used only for typhoid fever and other salmonella diseases or for diseases caused by organisms proven to be resistant to other, less potentially harmful, anti-infective agents. The increased incidence of staphylococcal infections in the middle and late 1950's account for but a small part of the resurgence in the use of Chloromycetin; for staphylocci had been shown to develop resist- ance to it, and other, more effective, and less seriously toxic antibiotics were developed to combat these bacteria. The enthusiastic promotion of Ohloromycetin by Parke, Davis & Co. apparently played a signifi- cant role in the increased use of the drug. The advertisements for Chloromycetin emphasize its great versatil- ity and effectiveness, along with its ready tolerance and minimal side effects. And that `applies to the advertising today. This approach by Parke, Davis became evident soon after the FDA recommended the addition of the 1952 warning to the Chioromycetin literature. In Parke, Davis' "President's Letters," "Director's Letters," and "Ideas and Suggestions" to its promotional staff, as well as in its advertising, Parke, Davis asserted that `the indications for the use of Chloromycetin were unchanged-this is after 1952-that it was still the most effective and versatile antibiotic, and that it was well- tolerated,~ with rare side effects. The statements inferred that the toxicity of Chloromycetin was akin to that of other drugs. Appeal was made to `the doctor to base his evaluation of the drug on his past experiences with it. Detail men were to use `a positive approach in PAGENO="0408" 2542 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY dealing with physicians and to discuss the untoward affects only if the physician raised the question. The fact that a causal relationship between the use of Chioromycetin and the development of aplastic anemia had not been scientifically proven was emphasized. This latter argument was set forth despite the summary of the FDA report of 1952 which stated that- From the data available from ease records secured in this survey, it appears beyond a reasonable doubt that chioramphenicol, in certain susceptible indi- viduals, causes blood dyscrasias, including aplastic anemia, thrombocytopenic purpura, granulocytopenia, and pancytopenia; All of which are conditions of severe bone-marrow depression. Similarly, in April of 1960 a report by the Subcommittee on Blood Dyscrasias of the Committee on Research of the American Medical Association published a cautionary reminder to the medical profes- sions in the AMA Journal on the potential ill-effects of Chioromycetin on the blood-forming system. The report decried any possibility of a mere "chance association" in the case reports of aplastic anemia al- legedily caused by Chloromycetin and concluded that there was no longer even a reasonable doubt that the drug could cause aplastic anemia. Making note of the widespread, indiscriminate use of Oliloromycetin, the report called for judicious use of the antibiotic and stated that it should not be used prophylactically, in trivial infections, or in infections in which other, less dangerous antibiotics might be used effectively. This was the same year that Dr. Dameshek pleaded similarly to the profession in an AMA Journal editorial in which he reported four new cases of aplastic anemia (which he saw in 1 month, incidentally), as a result of Chioromycetin therapy for minor respira- tory infections. It was also the same year, 1966, that enough Chloromy- cetin was sold and prescribed to treat nearly 4 million patients. Such case reports and the inevitable conclusions therefrom must have, or should have, been known to Parke, Davis & Co. and to the medical profession in general. Yet, the Chloromycetin advertising was not altered until the second FDA warning became required in 1961. This warning was more specific, more forceful, and more detailed in its wording; and it was to be boxed and placed in a prominent position in the advertising. However, the tenor of the advertising and detailing did not change; emphasis was still placed on the broad-spectrum-type effectiveness of the drug, although its toxicity was documented in more detail. Obviously, as the huge sales of Chioromycetin since 1961 indi- cate, this change in the written advertising has not been an adequate deterrent to the indiscriminate use of this antibiotic. The small number of cases where Chloromycetin is specifically indicated can justify only a fraction of the doses prescribed. Undoubtedly, the fact that this un- fortunate pattern for the clinical use of Chloromycetin has already be- come established plays a role in its continued administration (which serves to emphasize the importance of proper education of physicians in the initial period of a drug's availability); but more important, I believe, are the factors of drug detailing and Dhysicians' inertia. Mr. GORDON. When you talk about educating a doctor in the initial period of a drug's availability, have you any idea how this should be done and who should do it? Dr. HEwsoN. Well, certainly it is a crucial period because many of the side effects such as bone marrow aplasia do not show up for several PAGENO="0409" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 2543 years or do not get well documented enough for everybody to become aware of it. Certainly, the most ëommon source of information to the physician is the drug company through its advertising, through its detailing, and through the Physicians' Desk Reference. Most desirable, of course, would be a more objective source of in- formation, a less enthusiastic source, not so ifiled with accolades to its effectiveness but giving a more thorough discussion of its potential toxicity or its side effects and their incidence. I do not know whether the FDA could undertake this or whether some local type of educa- tional system could be set up, but certainly the detailing and other ad- vertising and promotion should be on a more objective basis. Senator NELSON. Given the natural inclination of any company to increase its sales, is it really practical to rely upon a salesman of a product to accurately and scientifically inform the physician? It has not worked in this case. Dr. HEWSON. No, I do not believe~ it is. Certainly, there is a large pecuniary interest involved. The detailing is done by nonprofessiona] men who are still basically salesmen. Even though maybe they may not realize it, they are dealing with life and death rather than with just sales of a product which is innocuous. These drugs are all potentially toxic and Chloromycetin more so. Senator NELSON. When you consider that even as late as 1961, when the FDA quite belatedly, given all the information they had since 1952, insisted upon, under the law, a more specific warning; and given the fact that very distinguished hematologists such as Dr. Dameshek now of Mount Sinai Hospital were giving warnings to physicians, is it not clear that there is some rather dramatic breakdown in com- munications between the people who are informed about the drug and those who are prescribing it? Dr. HEWSON. Yes. I think there is no doubt about that. I think the advertising, if we can use the term "overpromotion," may get the drug started on its misuse and then I think your communications, your chances to get through, probably are eliminated and I think the detailing can maintain the misuse and abuse. Despite the 1962 warn- ings, sales have stayed very high for chloromycetin and I think that speaks to what you have said and affirms it. But, from here on I go to the detailing and to the physician's role, which is more important than what the drug company puts down in black and white because the detailing is on a very personal, usually two-man level, in a closed room; and it is much more difficult to control. Then, of course, we must consider the role of the physicians who do make the final deci- sion of whether the drug should be used; I think we have to look at them carefully-the role they have played and what they have done in this unrestrained use of the drug. Senator NELSON. But, given the circumstance that the whole medical profession, that is, at least those informed about the drug, and AMA, and FDA, were well aware for years that the drug was being over- prescribed-whatever fault there may be with the busy physician who is reading the clever advertising, and certainly there is some-is there not a grave responsibility that rests upon the medical profession itself, the American Medical Association, and the Government, the Federal Food and Drug Administration to remedy the situation. PAGENO="0410" 2544 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. HEWSON. Yes. I agree with you wholeheartedly, but I think the phrase you used, those who are informed, is the key to it. I thrnk that certainly Dr. Dameshek and Dr. Weston, hematologists, good intern- ists, stay well informed. They are academically oriented, but I do not think that speaks to the average physician. I think there is a communi- cations breakdown. I do not think the AMA could communicate that well with the average physician, and certainly I do not think the drug companies would or could. Senator NELSON. Is it not true that every major teaching hospital, at least, and every major first-rate hospital in every State of America for years has been very careful about the prescription of this drug and the prescription of it in such hospitals is at a much lower rate than it is outside of that hospital? Dr. HiEwsoN. That is correct, and I think that goes along with my position-that the physicians out in practice, the ones performing the great amount, rendering the grea.t bulk of medical care in the country, do not stay well informed, that your teaching hospital physicians are the vast minority of the physicians involved in giving medical care in this country. Senator NELSON. But if that is the case, to remedy it then, do you not have to give to the FDA and the major medical societies some kind of a responsibility here for noting so if that is not done? Are you not going to have to have some change in their practices or legislation respecting this kind of a problem drug? Dr. HIEWSON. Yes. No doubt you would have to mitigate or obviate the influence of the over-promoting drug company and still you have to control on the other hand, the prescribing physician, the everyday average prescribing physician. My own thought would be that the most workable solution would be to limit it to hospital practice where you could have a committee, even a one-man committee, determine when the drug should be used. As for control by a governmental agency or though legislation, I am sure that could be tried. I do not quite know how they could exert a complete control and still leave the drug in the hands of everyday physicians. And this does not speak just of Chloromycetin. Certainly, I think your investigations will probably put Chloromycetin in its rightful medical place, at least I hope so; but this is 20 years since the drug came on the market and certainly we have to worry about the next Chioromycetin. And other drugs are certainly misued and abused, but the side effects are not so dramatic. When you get aplastic anemia your chances are 50 to 75 percent that you will die. The side effects of other drugs, such as anaphylactic reactions to penicillin, have a much higher survival rate. Or the side effects of a potent drug like cortisone; they are usually reversible on stopping the drug. Senator Nni~soN. I note in reading Drs. Goodman and Gilman on chiloramphenicol, they are quite specific in stating that it should be administered only in a hospital except in very special cases where there is an agreement between the patient and the doctor that the blood studies will be made, as I recall, once every 48 hours. Dr. HEWSON. I am sure you have heard testimony to the effect, Sen- ator, that these blood studies probably are not reliable, that the im- mediate depression of the bone marrow does not reflect that long-term PAGENO="0411" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2545 depression, that there are two actual effects, and the long-term one is just unpredictable. It shows up months later, ususally. And by then the damage that is there is probably irreversible, and whether or not you are going to survive depends on how much your marrow has been affected. Certainly, if you see early changes you are going to discontinue use of the drug, but no one has proven that is an adequate preventative measure. Senator NELSON. But all the experts do recommend regular blood studies during the administration of the drug, do they not? Dr. HIEWSON. I think so. But as a prophylactic measure this has not been proven. Certainly one would give the patient the benefit of the doubt; but, if you will notice, even the second FDA warning states that blood studies may not be adequate to prevent damage from the drug. Senator NELSON. Go ahead. Dr. HFJWSON. In considering the physicians w'ho have ordered Chlo- romycetin in patently excessive and unrestrained fashion, one must initially recognize that most of the medical care is rendered in the United States by physicians who do not limit their practice to one field of medicine. And, we might add, who are not in the academic- oriented environment of the teaching hospital or medical school. They are busy practitioners with limited time for reading and keeping abreast of the multiple fields of medicine which their practices encoin- pass. They do not, and possibly cannot, take time to read the current medical literature or attend medical meetings and lectures. If medical journals are read, the advertising is often skipped over in order to peruse any articles of interest. A short talk from a detail man-Dr. Dameshek in his 1960 editorial refers to them as our medical pro- fession's ubiquitous mentors. A short talk from a detail man is much more pleasant and feasible than a search of the literature to gather information about a particular drug. These sales representatives of the pharmaceutical houses are usually pleasant, personable individuals. They generally offer samples of drugs as. an inducement to gain en- trance to the physician's office. Although not professional men, they do come with the approbation of a large, respected company and with apparent firsthand knowledge of tue drugs they detail. They offer an easily accessible source of information on new drugs. Most physicians are undoubtedly aware of the positive, salesman- ship approach of these representatives of the drug company. Their enthusiastic accolades to the drug being promoted are not accepted at face value by the physician, who undoubtedly takes this promotional technique into consideration when making the crucial decision of whether, on balance, the therapeutic effectiveness of the drug out- weighs its potential deleterious effects in a given clinical situation. This difficult balancing decision is obviously impaired if the physician is not made adequately aware of the drug's side effects. The great dis- service of the detail men is not in their exaggeration of a drug's bene- ficial uses but in their approach to its toxic effects. Commonly, the toxicity is not discussed thoroughly, is played down, or is not even broached. The otherwise uninformed physician is thereby grossly misled. Although he may recognize and allow for the affirmative ap- PAGENO="0412" 2546 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY proach of the detail man, the doctor may yet be instilled with unwar- ranted reliance if the toxic potential of the drug is not made known to him. The withholding of facts which may make the difference between life and death cannot be justified by the label of "sales promotion"; nor can the failure of the physician to seek complete data on a drug be accepted. Mr. Goi~ooN. What can you do about this? Dr. HEWSON. Shall we go into that now? I think the remedy is the last part of the discussion. And it is the most difficult part, I agree. Mr. GonnoN. All right. Dr. HEWSON. In my own experience as `a general practitioner, I do not recall the Parke, Davis `detail men ever discussing the relation- ship `between administration of the drug and the development of blood dyscrasias, other than on one occasion when I asked about the present incidence. I was told that it was still quite rare. One of our experts in the Incollingo case stated that these detail men we're so uninformed about the toxicity of Chioromycetin that he took it upon himself to give them a lecture on the subject. Another expert in the IncoUimgo case testified that he `had been lecturing-he was a `hematologist-4he had `been tecturing on ap'iastic anemia and the fact that `he had four cases of it which `he attributed to Chioromycetin. `Several men, I be- lieve three, from the administrative end of Parke, Davis came to visit him personally to ask what `his data were and `how well documented they were with the inference being that the relationship had never been proven. Two of the physicians to whom I have talked stated that Parke, Davis detail men `became at least annoyed when they were interrogated on the sithject of blood dyscrasias from Ohloromycetin. I `have talked to one fo~rmer Parke, Davis detail man who told me that he was in- structed to discuss the effectiveness of the drug affirmatively and to approach the subjects of its side effects only if asked; then he was to relate only the `incidence as given to `him by the company and to refer any `further questions to someone in Detroit. Of the `many physicians that I `have talked to with regard to these detailing methods not one has stated that the Parke, Davis man voluntarily `brought the toxicity to the physician's attention. In my `own practice I did treat the family of a Parke, Davis detail man, `and on one occasion he told, me that he was giving his child Ohloromycet'in, on `his own, for a painful ear. Apparently he, too, was misinformed about the drug's potential toxicity. The physician may be misled, then, by overpromotion in the detail- ing and the advertising of a drug (including the information in that old standby, the Physicians' Desk Reference, which contains the phar- maceutical house's promotional literature on its drugs) if he does not attempt to remain knowledgeable by referring to other more objective sources. Even if he becomes cognizant of the dangers of a drug, he may continue to prescribe it on the basis of his own safe experience with its use-a criterion which Parke, Davis has recommended. Physicians who do not practice a limited specialty and who are away from the stimulating intellectual atmosphere of a teaching hospital are prone to become lulled into mechanical, unchanging treatment by the absence of unhappy results from its use. PAGENO="0413" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2547 Unfortunately, a drug is often in great popularity before an ade- quate test of clinical use and subsequent case reports clarify the clan- gers attendant to its administration. If the side effects are acknowl- edged, emphasis on the statistical relationship-1 case of aplastic anemia for every 400,000 courses of the drug, which was the 1952 estimate; and, then at the Kefauver hearings, it was 1 in 225,000; and now, I believe, the next reference is to that, of even 1 case for every 22,000 courses-may make that untoward reaction seem too remote to be of concern in a given case. In addition, the pressure by patients for one of the antibiotic "wonder drugs" is not without its influence on many practitioners; for the lay mind has become imbued with the belief that these antibiotics are a panacea for all types of infections, major or minor~ bacterial or viral. Many patients even know the name of the drug which helped them, or helped someone known to them, in the past. The average physician, then, intelligent and well-trained, but still subject to human frailties, is not unaffected in his decisionmaking by such influences as the promotional activities of drug companies, the cajoling of his patients, and the apparent safety of statistics top weighted in his favor. Any effective remedy to the problem of misuse and overuse of drugs must not only assure proper education of the prescribing physician but must also provide for prescription by physicians who will not be mis- led into improper use of the product. The method most likely to over- come the indiscriminate use resulting from overpromotion by the phar- maceutical house and from physician error is to confine its administra- tion to the hospital environment, where it could be ordered only with the approval of a select physician, or a committee of select physicians, who would be most likely to be well aware of its indications, contra- indications, and potential toxicity. Since the only valid indications for the use of chloramphenical are limited to typhoid fever and other salmonelloses, and in other infec- tions where drugs of lesser toxicity are shown to be ineffective, the relatively few patients with these conditions could easily be required to undergo hospitalization for treatment with the drug. The chronic state of typhoid fever, which requires prolonged treatment and would, therefore, be impractical for hospitalization throughout therapy, no longer requires treatment by chloramphenicol. I think this is akin to what we do now for cases where we think someone should undergo a therapeutic abortion or sterilization. Such a procedure requires the approval of a select committee, and I think it is more workable pos- sibly than some administrative control. Senator NELSON. Who would decide which of the drugs on the market should be placed in this special class and should be adminis- tered only in hospitals and/or with the approval of a committee of physicians? Dr. HEwsoN. Oh, I think that would well fall within the area covered by the FDA. I think they do the most studies on toxicity and use of drugs and indications and contraindications. It would not be a long list of drugs, I am sure. Senator NELSON. Are you suggesting that the FDA, then, in con- sultation with experts in the medical profession, should be authorized PAGENO="0414" 2548 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to agree upon what class of drugs should be placed in this special category? Dr. HiEwsoN. Yes. I think the threshold decision of which drugs are to be placed in that category should come from the FDA, and I am sure they would make use of expert consultants from the profession. Senator NELSON. They do not have that authority now. Dr. HEWSON. I believe not. To require a report on all cases of aplastic anemia or even of dis- eases treated by chloramphenicol from the individual physician would not be conscientiously followed, as our experience with venereal- disease reporting has shown. The procurement of more accurate evaluation of the incidence of blood dyscrasias following the use of chioramphenicol, as from hospital reporting, would be academically helpful but doubtfully help curtail use of the drug by the average practitioner, and probably would not be conscientiously followed. Placing the drug in the hands of the academically oriented, knowl- edgeable specialists, some of whom are available to virtually all hos- pitals, should be an effective, workable resolution of the problem. That is the end of my statement, Senator. Senator NELSON. If you are correct-and I assume you are-that the FDA presently does not have the authority to consult the profes- sion and designate such a special category of drugs that should be admnnstered only in hospitals or under specific circumstances, would you recommend that legislation be passed to authorize the FDA to do this? Dr. }{EWSON. I have never researched it, but I do not know of a drug being placed in such a category; so I just assume-it has never come up legally in my experience-that they do not have the power. Yes; I think it would be a most worthy addition to our control of th'ugs to authorize that power. Senator NELSON. I do not know whether or not you read Dr. Dame- shek's testimony. Dr. HEWSON. Yes; I did. Senator NELSON. Two weeks ago he made a similar type of recom- mendation. And so did Dr. Lepper. Both suggested that some kind of limitation of supervision over its administration be required. Dr. HEWSON. Definitely. As Isay, I feel it has to be controlled from both sides. I think the physicians have to be controlled as well as the drug company and its promotional methods. Mr. GORDON. Dr. Hewson, on page 5 you referred to Parke, Davis' "President's Letter," "Director's Letters," "Ideas and Suggestions" to its promotional staff, et cetera. I wonder if you could give these to us for insertion into the record at this point. Dr. HEWSON. Certainly. I have them with me. (The documents referred to follow:) MA~ncnI 12,1952. Newspapers recently carried a story of two children's deaths allegedly as a re- sult of antibiotic therapy. One of two products mentioned was Chioromycetin. Within 24 hours retraction was made based upon more thorough investigation. Rich, et al., [Ann. flit. Med. 33:1459 (Dec.) 1950] described clinical, labora- tory, and autopsy findings in a patient who developed aplastic anemia while on Chloromy~etin therapy; Herrell of Mayo Clinic [Amer. Journ. Surg. 82:688 (Dec.) 1951] cites the Rich report, and not any experience of his own, as basis for his generalizations against the use of Cthloromycetin; and Loyd [Antibiot, PAGENO="0415" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2549 and Ohemother. 2:1 (Jan.) 152] states in the title that his patient's aplastic anemia is "due to chlorainphenicol" but in his conclusion is less positive, stating only the obvious, that it "appears that the blood dyserasia followed prolonged administration of chioramphenicol". We are aware of some additional cases, some of which may be the subject of a rbport. In an exchange of letters on these, one of the authors who plans to publish stated "Admittedly proof that Chioromy- cetin caused the aplasia is lacking. The evidence is only circunistanial". We will not criticize these reports and others which may appear from any viewpoint except to point out that they are `based on the premise that as one event precedes another in `time, there is a cause and effect relationship. One must realize that this is only the first step in such reasoning. The fact that a drug was administered prior to development of aplasia is by no means proof that the drug is the offender. At this time, there are ~bsolutely no cases known to use in which such proof is existent. We have had similar experiences with both Mapharsen and Dilantin when they were first introduced commerically and the same prOblems have been en- countered with streptomycin, the sulfonamides, thiouracil and others; therefore, the present situation is not entirely unexpected. We are increasingly convinced of the clinical superiority of our product as demonstrated by the many millions of doses given `throughout the world during the past several years. Clinical investigation of the effects of Chloromycetin on body cells and functions is continuing and several additional studies were recently initiated, but, to repeat, up to this date we cannot find any facts that will indicate that Chioromycetin causes apl'astic anemia or agranulocytosis. It is recognized that `the publications referred to frequently give rise to in- quires from your customers and that this problem is further complicated by the unethical tactics being employed .by representatives of certain competitors. With respect to the former, it is recommended that you reply to such inquires in harmony with the comments contained in this letter. With respect to the latter, you may be assured that we will not stoop to combat this type of competition but will continue to detail Ohloromycetin on its demonstrated merits. The primary concern of Parke, Davis & Company has always been and always will be to develop and sell only drugs which will protect or promote health and to advance `the cause of medicine. We are continuing to adhere rigidly to those precepts. Sincerely, H. J. LOYND, President. PRESIDENT'S Lm"rmi No. 1-JUNE 6, 1952 The New York Times of May 23, 1952, carried a story under a Boston date line to the effect that Dr. Louis Weinstein, chief of the Infectious Disease Service, Massachusetts Memorial Hospitals, told more tlan 2,000 physicians attending the 171st annual meeting of the Massachusetts Medical Society *that he knew of forty cases in the country in which chloromycetiu had produced "very severe depression in `the bone marrow". That same clay, at my suggestion, Dr. Gray wrote Dr. Weinstein asking him to produce whatever evidence he might have in support of the statement at- tributed to him. Dr. Weinstein's reply is reproduced verbatim herewith: MASSACHUSETTS MEMORIAL HOSPITALS, JOHN 0. HAYNES MEMORIAL, DEPARTMENT OF INFECTIOUS DISEASES, Brookline, May 26, 1952. J. P. GRAY, M.D., Parke, Davis ct Co., Detroit, Mich. DEAR DR. GRAY: I have your letter of May 23rd inquiring with respect to the statement in the New York Times concerning my remarks on bone marrow de- pression produced by chloromycetin. In the first place, I have no manuscript of my talk since it was given mainly from notes. I did not make the statement that I knew of 40 cases. The statement I made was, "It has been said that there are somewhere around 40 cases of severe depression of bone marrow which have PAGENO="0416" 2550 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY come to the attention of various doctors in the country." I am fully aware of the reports in the references which you write me about. Most of the information that I based the few remarks that I made about chioromycetin at the Massachusetts Medical Society on was obtained from a discussion with Dr. Joseph F. Ross, the hematologist to the Massachusetts Memorial Hospitals. Some of the information which he gave me with respect to the instances of bone marrow depression is strictly confidential, and ncnw of this was cited specifically in the talk that I gave. Dr. Ross himself has one patient who developed pancytopenia which was apparently related to chloromycetin. Dr. Ross tells me that he has knowledge of instances in which bone depression appeared to be produced by chloromycetin other than the case with which he had personal experience. I might point out to you that I am rather surprised by the attention which my remarks on chloromycetin drew because this part of my talk occupied no more than about two minutes out of the total of twenty which I spent discussing the untoward effects of all the antibiotics. As a matter of fact, in discussing chloromycetin I pointed out that the few cases which have been reported should not keep physicians from using this drug in any instances where it was indi- cated but that in patients receiving chronic chloromycetin treatment, it would be wise to examine the blood once or twice a week. This is in agreement with the statement made in the article in the J.A.M.A. of last week in which were re- ported two instances of bone marrow depression which were thought to be related to chloromycetin administration. I pointed out at the meeting, also, that we have not and do not intend to give up using chloromycetin on my service at the Haynes Memorial Hospital in any instances where this agent was indicated. I hope this gives you the information you would like. Sincerely yours, Louis WEINSTEIN, M.D. (Dr. Gray has written Dr. Joseph F. Ross, mentioned in the above letter, but a complete report has not been received from him to date.) * * * * * * If you are asked about the attitude and position of the Food and Drug Ad- ministration, I know you will be interested in this statement taken from the Washington Report on the Medical Sciences, Number 259, May 26, 1952: "Dr. Henry Welch, chief of antibiotic division, pointed out that evidence clearly fixing culpability on chioramphenicol is still lacking, many of the two score affected patients having been on other drugs as well. He observed further that followup studies conducted at Gallinger and Ohildrens Hospitals in this city `have disclosed no resultant anemias, also that the 40 cases reported nation- ally represent a statistically insignificant ratio of 1/400,000." * * * * * * * We are interested in facts, not rumors, and this letter is written with one pur- pose in mind, namely to give you factual information to present to any phy- sician, pharmacist or hospital official who might bring up the question. In such cases, please show them this letter and make sure that it is read in its entirety. Yours very truly, W. J. LOYND, President. [From the Journal of the American Medical AssocIation, June 28, 1952, pp. 15839-15840] BLOOD DYsCRASIA FOLLOWING THE USE OF CHLORAMPHENICOL Chloramphenicol (chloromycetin®) has been accepted by the Council on Pharmacy and Chemistry for inclusion in New and Nonofficial Remedies. Its antibiotic properties are well known, and when the council accepted this product there was much evidence to demonstrate its therapeutic value. At the same time there then was little reason to belleve that serious or fatal side-reactions would be demonstrated. Nevertheless, following a study of the chemical structure of the drug, the Council issued a warning at the time of acceptance even though there was meager evidence to prove that such a warning was necessary. Thus, on page 116 of New and Nonofficial Remedies, 1951, there appears the following statement: "Changes in the peripheral blood or the blood-forming organs have been re- ported only during the use of choramphenicol. Mild hemolytic anemias, PAGENO="0417" COMPETITIVE PROBLEMS IN. THE DRUG INDUSTRY 2551 granulocytopenia (no cases of agranulocytosis as far) and an arrest in the sat- uration of the forced elements in the marrow have been described." Recently there have, been additional reports of the effects of chioramphenicol on the blood and bone marrow. At least two types of reactions have been encoun- tered. In one there is a transient depression of the formed elements in the blood, involving red cells, white cells, and platelets during therapy with the drug. This type of reaction has been very uncommon, and in the experience of one group well versed in the field of antibiotic ther'apy it has seemed to occur in patients who were receiving very large doses or the drug or in patients who had renal insuffi- ciency. The blood of these patients returned to normal, or at least above pre- treatment values, as soon as therapy with the drug was stopped, and no per- manent deleterious effect was observed. A second `and more serious type of reaction that has been encountered is pro- duction of a true aplastic anemia. In the experience of one group, this anemia has occurred in patients who have previously received one or more courses of amphenical without untoward effect. When the drug was subsequently adminis- `tered, even in small doses, a severe blood abnormality has `appeared. Even deaths have been reported. Whether chloramphenicol continues to remain as one of the more useful antibiotics or whether it will be relegated to a place where its use will be confined to the treatment of patients with typhoid or serious infections for which no other therapy is available, remains to be seen. Further observations are in order. In the meantime, physicians should be on the alert for reactions fol- lowing therapy with this and any other antibiotic, or in fact any of the newer drugs. Few therapeutic agents, which are being introduced with ever increasing rapidity, are characterized not infrequently by their beneficial of life-saving qualities but also by their ability to cause injury or serious side-effects'. A calculated risk is involved whenever one prescribes any medication. The physi- cian is confronted constantly with the difficult task of determining whether the use of a given drug is likely to do more good for a particular patient than any possible harm. In spite of the vast amount of laboratory and clinical study that a new drug usually undergoes before it is placed on the market, subtle or insidious toxic effects, often of a serious nature, frequently are not recognized and brought to the attention of the medical prefession in general until after the drug has been on the market for some time and has enjoyed widespread clinical use. A propensity to cause injury to the bematopoietic system is particularly likely not to be generally appreciated until a new drug has undergone extensive use for a considerable period of time. Physicians wh.o observe hitherto unreported toxic effects or injuries attributable to a recently introduced therapeutic agent have the obligation or duty of bringing this information to the attention of the entire profession. If a physican does not have the time or inclination to prepare case reports of drug injuries for publication in a medical journal, he can perform a useful service by advising the office of the Ooundll on Pharmacy and Chemistry of the pertinent facts in such instances. By this means the Council will be pro- vided with necessary information that may serve as the basis for an early authoritative report or warning statement. SUGGESTED DETAIlS CULOROMYCETIN Doctor, I am glad you asked me about `the Ohioromycetin "situation." Needless to say, we of Parke-Davis are also concerned. We are pai4ticularly concerned about the increasing tendancy for newspapers and magazines to "practice" medicine~ For, despite many fine bits of reporting by competent medical writers, too often articles are characterized by: careless or illogical deductions, lack of scientific understanding, use of material out ocf context, and lack of proper perspective. (1-PP1O) Here is what Mr. John L. Bach, Director of Press Relations of the American Medical Association, recently had to say about this pertinent subject (Repeat Bach statement). 81-280 0-68-pt. 6-27 PAGENO="0418" 2552 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Ohioromycetin is among the important products that have run the gauntlet of newspaper evaluation. Perhaps the dramatic qualities of the antibiotic, itself, have contributed to this condition. A relatively few articles, however, have accused Ohioromycethi of being associated with certain blood dyscrasias. On the other hand, intensive investigation by the Food and Drug Administration, carried on with the assistance of a special committee of eminent specialists appointed by the National Research Council, resulted in unqualified sanction of continued use of Ohioroniycetin for all conditions in which it had previously been used. A sensible caution against indiscriminate use, which we have incorporated into our advertising and labeling, is a welcome addition to our literature and to the label on Chioromycetin products, and in our opinion, would be appropriate in those on any potent chemotherapeutic agent. Actually, such caution is an assur- ance that the full benefits of well-tolerated Ohioromycetin will be available and free from misuse. (2-PP1O) Here is the breakdown of the recent survey made by the Food and Drug Ad- ministration covering 539 patients. It should be borne in mind that this survey was specifically made for the purpose of ascertaining, if possible, the degree of involvement of (Jhloromycetin in the development of blood dyscrasia~. You will notice that there are three categories, "A", "B", and "C". These three categories relate to: "A" those cases in which Ohioromycetin was the only drug given; "B" those in which Chioromycetin was given in combination with other drugs; and "C" those cases in which Ohioromycetin was not involved. (3-PP10) On this page, Doctor, we have reduced to percentage the ualient points which we noted from the tabulation I have just shown you. Several interesting factors\are obvious from these data. The number of cases of blood dyscrasias found in this survey apparently associated with (3hloromy- cetin alone is only about 10 per cent of the total cases surveyed. In this survey specifically intended to find the facts on Chloromycetin, 3~1 patients out of a total of 539, more than 60 per cent of the total were of cases in which tMs antibiotic was not involved. (4-PP10) Are the broad-spectrum antibiotics important factors in the incidence of blood dyscrasias? Of course, it is logical to use Chioroinycetin as an example, because it has been the subject of intensive and thorough investigation. An investigation, incidentally, in which Parke-Davis wholeheartedly cooperatecL Here is a chart showing the increased use of Ohioromycetin from the time of its introduction Notice the steady, continued and rapid rise which now amounts to many millions of doses, comprising several millions of courses of therapy. (5-PP1O) Here, Doctor, we have plotted the mortality from aplastic anemia as reported by thirty States for the years of 1949, 1950, 1951. These figures, compiled `by Parke-Davis from data dbtained from the thirty States in which these figures were available for the three year period, revealed a specific mortality per 100,000 of 0.41 in 1949; 0.42 in 1950; and 0.43 in 1951. ((}-PP1O) Now, on this page we have plotted the two curves superimposed on the same set of coordinates: A. (Jhloromycetin curve; B. Mortality from aplastic anemia. The lack of parallelism leads to the impression that there is little relation `be- tween the two factors that, were Chloromycetin an important cause, would be expected to show parallelism at least. (7-~PP10) Up through October, 1952, 59 published papers, reporting on experience involv- ing more than 1700 patients, have presented data in which thorough blood studies had been made on each patient before, during, `and following therapeutic courses of Chloromycetin. Doctor, is it not significant, that in not one of these 1700 pa- tients was there any evidence of blood dyscrasia following administration of the antibiotic? PAGENO="0419" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2553 You may wonder about the resultS of laboratory animal studies. This type of investigation was started long before the commercial release of Chiorornycetin. Only by the use of the antibiotic in exceedingly high dosages given parenterally was it po~sible to produce even mild reversible anemia in dogs. As you know, it is difficult to depress bone marrow function in animals. In studies aimed at detection of possible bone marrow toxicity, many procedures have been followed but with little success. Attempts were even made to depress further the function of bone marrow in animals previously subjected to repeated injections of known depressants. However, recovery ocurred upon transfer to Chloromycetin therapy. These and related studies, both laboratory and clinical, as well as of manufac- ture control, have continued uninterrupted throughout to the present time. We ask for open-mindedness in approaching this subject. We assure you that Parke-Davis will take every means possible and exhaust every possibility in attempting to get at the solution of this baffling problem of modern therapeutics, involving, obviously, not only Chioromycetin, but many other potent chemo- therapeutic agents as well. And we assure you also that the profession will be kept fully informed, `as to the progress~ of this fundamental pharmacologic de- velopment insofar as Chloromycetin is concerned. Before terminating this interview may I re-emphasize a fact which has not changed with the developments of the past year? (Jhloromycetin continues to be the outstanding wide-spectrum antibiotic because of its well-tolerated nature and its high degree of effectiveness. (8-PP1O) (Jhloromycetin is definitely well-tolerated! Its relative freedom from unde- sirable side reactions, such as nausea, vomiting, headache, skin eruption, and enteritic symptoms frequently encountered in broad-spectrum antibiotic therapy, enhances its usefulness in clinical practice. (9-PP1O) And, as you know, Chloromycetin is highly effective as a specific therapeutic agent. You know, of course, of its singular effectiveness in typhoid fever; it is recognized as the outstanding specific therapeutic agent in that entity, not being equaled by any other known medicinal agent. Uhloromycetin is highly effective in man'y other conditions: in infiuenzal meningitis, in surgical infections, and isv many other conditions in which the etiologic agents fall within the extremely broad spectrum of Chloromycetin. Doctor, give Chloronvycetin the trial that the evidence before you justifies; we encourage you to use the antibiotic `in the most difficult clinical problems that you can find assuming that Chloromycetin is indicated. Your carrying out ade- quate blood studies will asure your patient that every safeguard is being taken, and you will have the opportunity thereby to prove to your own satisfaction, on the basis of your own experience, the truth about Ohloromycetin. We are con- fident that, again, on the basis of your own experience, you will continue to in- clude Ohloromycetin `as `an integral part of your `armamentarium, because it is the effective, potent, therapeutic agent that it has been found to be by physicians in all parts of the world. IDEAS AND SUGGESTIONS OHLOBOMYCITPIN In using this detail (FF10) you should carefully follow the instructions con- tained in Mr. Walker's accompanying letter. Start your interview with the Ohloromycetin Cream Detail (PP9). The special detail (PP1O) should not be introduced unless the physician brings up the subject or unless you know that he has ceased prescribing Ohioromycetin. Your efforts should all be directed in a positive direction designed to provide facts which will induce physicans to use Ohloromycetin in the wide range of infections in which it is effective. These fundamental points should be stressed: (1) Chlorouiycetin has been proved clinically effective against many of the infections due to gram-positive and to gram negative bacteria, to rickettsia, and to certain of the viruses. (2) Ohloro- mycetin is especially noted for its relative lack of irritation to the gastro- intestinal tract and of other side effects often associated with `broad-spectrum antibiotic therapy. (3) High blood serum levels, in general proportionate to size of dose, are readily attainable, and since the antibiotic is able to penetrate the blood-brain and other barriers, it provides broader clinical coverage. PAGENO="0420" 2554 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY It is suggested that you use a copy of the spectrum folder U 89-2 in lieu of literature for distribution when the occasion arises to give detail PP1O. A. new full-color blotter, portraying all of the product forms, will be supplied to you very shortly, as will a desk-top product information card. A deluxe product booklet is being made ready for the press at this time. Other promotion material is in process of preparation and will be released as soon as possible. The current literature on Chloromycetin Cream, T-68, is still applicable in detailing the physicians on that product form. SPECIAL CULOROMYCETIN DETAIL This detail approach has evolved from a talk given by Mr. Walker at a meeting of New York State pharmacists at the Hotel Statler in New York City. Vincent Oioffl, of the New York Branch, first used the newspaper comments in detailing and he was able to report very substantial territorial gains by incorporating this feature in his presentation. It should be kept in mind that the incidence of aplastic anemia is not known because statistics on this affliction are incomplete and inadequate. In the survey, among those who received the estimated 8,000,000 courses of therapy of Chloro- mycetin, aplastic anemia is known to have appeared in 139 patients. The ratio of 139: 8,000,000 gives a rate of 1.74 per 100,000 which probably is not much greater incidence than would be expected in a population of sick persons who had not received any Chloromycetin. In the survey also there were an additional 157 case records on patients who had aplastic anemia classified as group C (Cliloro- mycetin not involved). (And it is to be remembered that these do not constitute all the cases of aplastic anemia that had occurred; these were collected in a survey directed primarily at Chloromycetin.) In other words there were a few more patients (157 as compared with 139) found in the survey who had aplastic anemia unrelated to Ohioromycetin than there were those whose aplastic anemia was observed to have followed Chioromycetin therapy. Further, the incidence of this disorder is apparently on greater today than it was before Ohloromycetin was introduced and came into widespread use on the basis of recorded deaths by States' Registrars of Vital Statistics for recent years. Mr. Cioffi also stressed the possible importance of infection provoding a trigger mechanism for the production of aplasia. According to this theory, Chioromycetin, by eliminating the infection, allowed the patient to go on to such a development for which he was destined even before or without therapy. This approach was based on a talk given at a local medical group meeting by Frank Schley, New York District Coordinator for the Department of Clinical Investigation. Mr. Schley commented as follows: "A point of interest under investigation by certain hematologists at the present time is the significance of a lack of resistance to infection as a sypxntom of an impending blood dyscrasia. This very symptom may be the cause for which an antibacterial agent is ingested. In the past it has been said that infection is usually the cause of death in aplastic anemia. It is also recognized by hema- tologic authorities that bacterial and virus toxins have been incriminated as a trigger mechanism to initiate a blood disorder. Toxins produced by infectious themselves are blamed by eminent hematologic authorities. Lawrence, while at the University of Rochester, produced severe neutropenia and leukopenia in cats by a viral agent." Planned Presentation sheet 5-PP1O contains a curve plotted from reports of all recorded aplastic anemia deaths compiled by Parke-Davis personnel from data supplied by States' Bureaus of Vital Statistics. You will be interested in the complete totals: rates given represent specific mortality rates (aplastic anemia deaths per 100,000 total population, both sick and well), for the years cited: 1948 1949 1950 1951 Average, 16 States reporting all years 0. 3575 0. 4057 Average, 30 States reportingl949, 1950, 1951 only . 4113 Average, 35 States 1950 and 1951 only Average, 36 States reporting 1951 only 0. 4534 . 4222 .4237 0. 4667 . 4336 .4141 .3768 PAGENO="0421" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2555 BIBLIOGRAPHY We are also supplying to you for your background information a bibliography compilation entitled "Hematologic Aspects of Chloromycetin" which provides references and brief abstract of the contents of virtually all publications which have appeared beginning in 1948, in which there are references to hematologic aspects of Chioromycetin therapy. This compilation was prepared by the Depart- ment of Clinical Investigation by a staff under the direction of Miss Margaret Hanser. We expect to provide additional detailed bibliographic material of this sort as rapidly as it can be prepared. PAGENO="0422" PAGENO="0423" * . it does not help the physician who prepared his paper with only a medical audienc,e in mind. The doctor maybe discussing a subject based on only a handful of cases; yet his experimental research may be irnportant.enough to present to the medical meeting even though he knows it is `premature' in every sense of the word. in such a case, the physician is presenting his facts to his colleagues only and not to the public. For any organization to follow a general practice of mimeographing such a paper and passing it' on to writers, without first weighing its~impact on lay readers, is to do a dis- service not only to the doctor .who was invite~. to deliver the paper, bt~.t to the medical profession and the public as well." Bach, J. I..: Doctor. Meet the Press, J. A. M. A., 149:1137 (July 19) 1952. 1-PP~O PRINTED IN U.S.A. 2557 PAGENO="0424" 2558 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY U) Cl) a) 4.) W CI) CC~ (1) A Chloromycetin .tt alone 55 23 42% B Chlorornycetin and. other drugs 143 82 57% Chloromycetin not C involved in develop- 341 155 46% ment o±~ dyscrasia 539 2-PP1O PRINTED IN U.A.S. PAGENO="0425" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2559 Chioromycetin alone 55 x 100 1 539 - Chloromycetin not involved 341x 100 539 63.3% (these figures from survey by the PDA directed primarily at Chloromycetin) 3-PP1O PRINTED IN U.S.A. PAGENO="0426" 2560 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~ ~ ~* : ~ : ~ ~ ~ : ~ : 9x ~ ~ ~ ~ ~ ~ ~r-r~ ~ : : ~ ~ j J ~ Lf j ~ ~ ~ j 1-f ~ ~ ~ 7- 8x , - :+ 1' ~ j ±1 , ~ ~ ±1 : tj 7x r ~ ::;:::::::~ ~ . ~ ~ ~ ~ ~ ~ ~. ~I~i~1 ~ ~ `~I~ ~ ~ ~ ~ , ~! ~ ~ ~ Gx ~ I ~ ~ ~ ~ ~ ~ I~ ~ ~ ~ ~ --~-~ ~ , ~ ~ ~ , ~ ~ ~ . ~ ___i ~ ~_i__~~~ ~ ~ , ~ ~ ~ . i ~ ~ ~ ~ ~ ~ ~ . ~ ~ ~ ~ ~ ~ ~ ~ ~ ?,~It~,iIi CI) ~. ~ ~ t ~ ~ ~ ~ ~ ~ ~ ~ E-~ ~ ~ ~ ~ ~ ~ ~ ~ ~ , ~ ~ ~ ~ ~ I ~ I ~ j~j~~J_j~ ~ ~ ~ ~ ~ ~_ ~ ~t, ~ ~~I--~--' ~ t ~ -~jI ~ .1 ~ ~ ~ ~ , ~ ~ I ~ ~ ,~ ~) ~ ~ ~ ~ _f~ iIJ_~ ~ ~ ~ ~ ~ ~ I I ~ ~ . ~ -~~-- ~i ~ ~ ~ ~ ~ [-~--- II_Iii1 ~ ~ ~ I?~~p~I~ ~ ~ ~ ~ ~ ~ ~ I ~.--~- - - -- 1:1111 3x 2x ~ - ~ ~ 1 ~ . . ~ ~ ~ t ~~_~~i__ i~1~i ~ H-~__ t ~ ~-: ~ ~ ~ `tH~~~ ~, :, ~ ~ ~ Iii~iii~ lx ~ ~ II!'!!! !*~~~.!I!H ~ I ~ ~ ~ ~ ~ ~ ~ j ~ ~ I ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ I -~ : ~ ~ ~ ~ ~ ~ ~-~-----~- ~ IJ1~ ~ ~ ~ I ~ ~ ~ ~ ~ ~ ~ t~ ~ I J 1 ~ ~ ~Li I D-Lru~ ~ ~ ~ I ~ ~ . - ~ - .. 1949 1950 1951 PAGENO="0427" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2561 I~ ~ ~L 1.~ ~ ~ ]~ :PI(*m~I ~&!.I LE~fl~F ~ ~ ~ L ~ I- I- F ~ - liii FFr ltL 1L L I IiiLiIi~FJ [-lim__ j_i_ ~ I F~ L_ L~ 0 LY I [ . 0 1_ ~ LIII Lii U) L~F~ [L LThLLLLLLL L - ~ - ii- -TLEcLI-:~ ~ 1 - - - ~- ELLL~LF1 ~ - ~ ~1 ~ L -~-~--~ LIIELIELI ~ _1 ~- - ~---- ~ - LLLL[11 L -~ ~ ~ - LL!~1LLI E I_~~ - -- -- ~ - - -~- -~ - ~ -LLL1~LLLL[LLI k [L ~ ~ ------ -~ ~ -- -~ I E~~IL~1_ I -_ ~_ ~ _ -- -- L ~ ~ ---- ~ - -~-- ~ ~ ~- --- 11 LLFTLI _____________ __________________________ ELI -------- ~---- I ~ ~ 1949 1950 1951 5-PPIO PnI~flED IN U. $. A. PAGENO="0428" .Y.s.n ?~, ~ OIdd-9 1g61 O~6t 6~6t ft _______ ~ `~ 1 ~ r ~ ~ ~ ~ ~ ~ ~ ~ ~ I HFH~~i ~ 1m~* ` ~ ~ ~7 ~ , xt ~ ~i7 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ iT~ ~ ~ ~ ~ ~ ~! ~ H ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~- - ~ ~ IF-I H i R~T r ___________________ ~J -~ ~ _______ ~~---~--~,;t ~ x~ : -~ ~ , l4R~~: ~1~ft~R ~ ~L ~ ~ ~:i: `Eft *Hi~-~ ~- -H±FH±H- ±w-H-~-±-H-++++-H -H-H ~ H H-H-H-H-H XJ~ ~ ~ ~E~T ~I-~+~ H~-~-~ ~ ~ ~ ~ ~ l-~ -- ±:P~--' ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ H ~ ~ ~ ~ ~ ~ `II ~ ~ ~ ~ - ~ ~ ~ I:D: r r- nTr-~-r-r-1-~ n-mTr-m-m-t-?-n-n-r ~ ~ - ~1~ -1 ~ ~ -j ~ ~-T-'-!-rn--n--r-* I ~ ~ ~ ~ ~ n~rrr~-r-i-, 1~1-1~ -1 ~- -m-r--~-i-1-~-r-r-r--r-T-i--D-fl-D-fl-1- -~ ~ ---~-~ I~t-t-- ± *r-i-1 :~i~i~t-r-1--m- -i-; ~ ~ ~ ~ ~ i-~-- ~ ~ ~-i ~ t ~- IF ~ P :1- Q:~~~RT : `T~~T ::rr~: ~n ~ ~ __ ~ ~: ~ ~ ~ En- ~ ~ ~ ;-;~-m- rtrm ~ ~ ~ ~ ! ~ ~ ~ ~ ~ ~ i ~ ~ ! m-r-r-r A~LL~I1UNI ~rnici ~HI NI ~I&Tt~FIaOllcI ~ALLLL~dP~OD g~~g PAGENO="0429" COMPRTITIV E IN PIlE DR tTG ~JSPfty 2563 59 th~s12ed 1~TØ 1~rj ~flSto~ies ely~700 0~Oug~ blood ~c12 ~e1~o~ed on ~ 2. i ~ Not one of these seventeen hundred cases revealed any evidence whatever of blood dyscrasia following administration of the antibiotic. 7~ppj0 PRIN~Ø IN PAGENO="0430" 2564 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CHLOROMYCEk~J~L broad-spectrum antibiotic 8-PM 0 PRINTED IN U.S.A. PAGENO="0431" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2565 CHLOROMYCE~I~ e `~`broad- spe ctrurn antibiotic N 9-PP1O PRINTED IN U.S.A. PAGENO="0432" 2566 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PAa~, DAVIS & Co., DIRECTOR'S LETTER, UNITED STATES AND CANADIAN SALES DEPARTMENT, DECEMBER 22, 1952, LETTER No. 3 To members of the professional service staff. Gentleman: The summary of last summer's special survey by the Food and Drug Administration of the relationship of Chloromycetin to reported blood dyserasias has been published in the December issue of "Antibiotics & Chemotherapy." We are sending to you a quantity of reprints of this article for distribution to physicians. Attached to this letter is a specimen reprint marked to call your at- tention to significant facts which s1w~ul4 be kept in mind when evaluating the contents.' Here are some questions which you may be asked relative to this report to- gether with factual answers which are vital to a full understanding of the points developed in the survey. Question. What did the recent investigations show? Answer. Several hundreds of case records, collected from hospitals and physi- cians throughout the country by members of .the FDA field staff, were reviewed. Of 539 in which classification was possible, in only 198 (37 per cent) was there evidence that the development of blood dyscrasia was associated with the use of Chioromycetin either alone or in conjunction with other drugs. Question. Was Chioromycetin the only drug administered in these 198 cases? Answer. No. Chloromycetin was the only drug administered in 55 of the 198 patients. Other drugs had been given in the remaining 143 cases. Question. What "other drugs" were involved? Answer. These were numerous; in some instances they were mentioned speci- fically, but in most they were mentioned only by categories. Included were: analygesics, anticonvulsants, antihistaminics, antipyretics, antibiotics (other than Chloromycetin, of course), antimalarials, antibacterials, and other chemo- therapeutic agents. Question. What safeguards protect patients against blood distorders? Answer. Judicious use of potent therapeutic agents in the hands of the physi- cian; careful observation of the patient; avoidance, when possible, of prolonged or intermittent use; and adequate blood studies, especially during prolonged or intermittent therapy when required. There is no known method permitting de- termination in advance of those in whom blood dyscrasias are likely to develop. Question. What were the conclusions of the official agency (FDA) regarding further availability and use of Chloromycetin as a result of the survey? Answer. The F.D.A. concluded that serious blood dyscrasias following the use of Chloromycetin are uncommon. The report specifically stated that Chloro- mycetin is a valuable drug which, however, should not be used indiscriminately or for minor infections. When prolonged or intermittent administration is re- quired, adequate blood studies should be carried out. Attention of the physician is invited to these points through a warning on the label and through a statement in the literature on Chioromycetin. Question. What are the present indications for Ohjoromycetin? Answer. These are not changed. Chloromycetin is effective and is indicated in a wide range of bacterial, viral, and rickettsial infections, including: urinary tract infections; brucellosis; bacterial and primary atypical pneumonias; pertus- sis; enteric fevers (salmonelloses, including typhoid fever); dysenteries (shigel- loses); rickettsial infections (Rocky Mountain spotted fever, typhus fever, scrub typhus fever); acute gonorrhea; granuloma inguinale; and lyniphogranuloma venereum. Very truly yours, GRAYDON L. WALKER. PARKE, DAVIS & Co., June 16, 1954. Letter No. S To all sales representatives: An important highlight in the development of up-to-date information on the antibiotics was presented in a symposium on antibiotics held in Washington this winter. A number of papers dwelt on the matter of safety and efficacy of Chloro- `Retained in committee files. PAGENO="0433" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2567 mycetin. We are sending a limited quantity of each of the pertinent reprints to you and marked specimens are attached to this letter.1 We have bracketed in red certain salient points that you should especially look fer. We would add that a complete reading ocf each of these papers would be very helpful to you in getting a more complete picture of the situation. We would especially recommend, for example, a careful reading of Dr. Ethan Allan Brown's discussion of Dr. Perrin Long's article. Dr. Brown has put his finger on a number of points pertinent in modern-day antibiotic therapy. We believe that you will agree with us that these papers indicate an increas- ingly broader acceptance and interpretation of the role of Chioromycetin in the treatment of infectious diseases. These reprints constitute additional verifica- tion of our continuing belief that Chlocômycetin is truly one of the world's out- standing therapeutic agents. Very truly yours, GRAYDON L. WALKER. FJD3RUABY 18, 1960. To: U.S. Branch Managers. CHLOROMYCETIN We still receive an occasional report indicating that one of our sales repre- sentatives has not followed instructions which have been issued on several occasions in the past. Any discussion with a physician regarding Ohioromycetin must, without ex- ception, be in accord with good sound medical information which has been pro- vided by the Promotion Department, or in our regular literature. it is your personal responsibility to see to it that no salesman under your direction makes statements relative to Chloromycetin which cannot be substan- tiated in the literature or other officially approved promotion material. This is not a situation you can correct and then forget because you have the continuing problem of new sales representatives as well as regular sales representatives who may become a little careless because of the increase in specification and preference for Ohloromycetin by physicians. Please see to it that every man on your sales staff is advised again at this time and that the question receives appropriate emphasis at concentration meet- ings outlining again the importance of adhering strictly to sound medical in- formation as covered in our literature or in other approved promotion materiaL We usually do not give much credence to anonymous reports and the most recent accusations did not provide specific names and places, but we do want you to make it clear to every man on your staff that we will not retain in our employ any sales representative who makes statements which cannot be backed up in approved medical literature or other promotion material. We fully appreciate the situation in the field such as competition occasionally stimulating a re-hash of some of the old publicity about Oliloromycetin often by individuals who have had little actual experience with the drug as contrasted with the many physicians who have prescribed thousands of doses with no un- toward effects. However, the problem is in an area where it is difficult to prove anything and therefore, please establish a procedure to convey the above in- structions to your staff at regular intervals since we wish to adhere to our usual conservative policy of presenting only medical, facts that can be demonstrated beyond doubt. Very truly yours, GRAYDON L. WALKm. [From the Journal of the American Medical Association, vol. 172, No. 18, Apr. 30, 1960] CouNcu~ ox Disuas REPORT TO THE COUNCIL The Council has authorized publication of the following report. H. D. KAUTZ, M.D., Secretary. The Registry on Blood Dyscrasias sponsored by the Subcommittee on Blood Dyscrasias of the Committee on Research has received a number of case reports concerning the possible association of a blood dyscrasia with the use of chlor- 1Retained In committee files. 81-280 0-68-pt. 6-28 PAGENO="0434" 2568 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY amphenicol. The subcommittee has concluded that it might be proper to caution the professicm by publishing a reminder concerning the potential ill-effect of this drug on the hematopoietic system. It is hoped that publication of this in- formation will render a service to the medical profession. NORMAN DR NosAQuo, M.D., Secretary, Committee on Research. BLOOD DYSCRASIAS ASSOCIATED WITH CHLORAMPHENICOL-(CHLOROMYCETIN) THERAPY With an increase in the receipt of reports by the Registry on Blood Dyscrasias in which chloramphenicol is associated with the development of a blood dyscrasia, it becomes important once more to review briefly the toxic effect of this drug on the blood-forming organs of sensitive persons. The paucity of recent publica- tions in the American literature should not be construed to mean that the reports of chloraniphenicol-induced aplastic anemia some years ago were merely a chance association. There have been numerous reports in more recent years of chioramphenicol-induced aplastic anemia in the foreign literature.1 Between January, 1953, and January, 1~O, the Registry on Blood Dyscrasias has received a total of 223 reports of pancytopenia; of these, 91 were cases in which chior- amphenicol had been administered. Of the 91 cases, there were 34 instances in which cliloramphenicol was reported as being the only drug given. Severe reactions to antibiotics occurring in patients between late 1955 and early 1957 have recently been studied in a nationwide survey by Welch and colleagues2 of the Food and Drug Administration, Department of Health, Education, and Welfare. This study reported on 31 patients with aplastic anemia associated with chloramphenicol administration, of whom 23 died. Of these 31 cases, only 8 had been reported to the registry. Although some of these patients may have received chloramphenicol in the presence of a developing aplastic anemia, this explana- tion seems improbable. It is important to note that, in the survey of the FDA, few cases of aplastic anemia were associated with the administration of penicil- lin, streptomycin, the tetracyclines, or a sulfonamide. The Subcommittee on Blood Dyscrasias recognizes that chioramphenicol is a valuable and important addition to a physician's armamentarium. This is par- ticularly true since it has been shown that certain strains of staphylococci re- sistant to penicillin and the tetracyclines are sensitive to chloramphenicol. The manufacturer has repeatedly directed the attention of the medical profession to the need for judicious use of the drug by a warning statement in the labeling and advertising of the product. Although the warning statement specifically cautions against the indiscriminate use of the drug or against its use for minor infections, an examination of the reports received by the registery reveals that the drug has been used in such conditions as upper respiratory infections, includ- ing the common cold, bronchial infections, asthma, sore throat, and tonsillitis, miscellaneous urinary tract and ear infections, undiagnosed low-grade fever, and even disseminated lupus erythematosus, gout, eczema, malaise, and iron deficiency anemia. It is incumbent upon a physician when he prescribes chioram- phenicol that he carefully weigh the need for the drug in relation to the risk of possible serious toxic effects. Although the subcommittee recognizes that chioramphenicol is a valuable anti- biotic, it is also the opinion of the subcommittee that there is no longer a reason- able doubt that chloramphenicol may cause aplastic anemia. Periodic blood cell counts may be of some help; however, they cannot be relied on to detect signs of marrow toxicity sufficiently early so that chloramphenicol administration can be discontinued before an irreversible aplastic anemia develops. Therefore, judicious use of the drug must be the rule, and it should not be used prophylac- tically, in trivial infections, or in infections in which other, less dangerous anti- biotics may be used effectively. ~ (a) Visconti, P.: Sulla mielosi aplastica globale da cloramfenicolo: Contributo clinico, Riforma med. 70 :1043-1046 (Sept. 15) 1956. (b) Cable,, J. V., and Reid, J. D.: Jaundice and Aplastie Anaemia Following Chioramphenicol Therapy, New Zealand M. J. 56:532-535 (Oct.) (c) Shaw, R. G., and McLean, J. A.: Chioramphenicol and Aplastic Anaemia, M. J. Australia 1 :352-359 (March 16) 1957. (d) Louwette, R., and Lambreehts, A.: La toxicite sanguine du chloramphenicol, Rev. med. Liege 12 :10-16 (Jan. 1) 1957. (e) Madsen, N. 0.: Anaemia aplastica fremkaldt of chloramphenicol, Ugesk, laeger 119 :489-491 (April 18) 1957. (.1) Slamone, L.: Sull'emopatia da CAF, Riforma med. 71 :494-498 (March 4) 1957. 2 Welch, H.; Lewis, C. N.; Weinstein, M. I.; and Boeckman, B. B.: Severe. Reactions to Antibiotics: Nationwide Survey, Antibiotic Med. 4 :800-813 (Dec.) 1957. PAGENO="0435" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2569 [From the Journal of the American Medical Association, vol. 174, No. 14, Dec. 3, 1960] CHLOEAMPHENICOL-A NEW WARNING In one month recently, I saw 4 new cases of aplastic amenia. Although they ranged in age from 3 to 63, and came from different sections of the country, they had one common denominator; chloramphenicol had been used in the recent past for minor respiratory infections. There was no history of the use of other anti- biotics or potentially toxic drugs and since the anemia and the other manifesta- tions appeared a few months after the last administration of chloramphenicol, it seemed clear that this drug was responsible for the marrow aplasia. In our recently studied series of aplastic anemia (seen within the past 3 years) 8 of 30 had received significant amounts of chioromycetin, almost invariably for minor infections. Of the most recent 10 cases of aplastic anemia, 5 had followed therapy with chloramphenicol. The tragin thing about all these seriously ill cases, most of whom died, is that the drug need never have been given. It is becoming increasingly clear that chioramphenicol, an excellent broad- spectrum antibiotic, has antimetabolic effects, as well-that is, it may injure the intrinsic "machinery" of certain rapidly proliferating cells, notably of the bone marrow. Thus, Rubin and associates, using radioactive techniques, demon- strated a depressant effect of chloramphenicol on erythropoiesis; this occurred in 5 of 15 subjects receiving ordinary doses and in all of 4 cases with cancer who were given unusually large doses of the drug.' In another study by Saidi and Wallerstein2 10 of 22 cases treated with chloramphenicol for various infections developed striking vacuoliza.tion of nucleated red cells in the bone marrow, asso- ciated with a maturation arrest phenomenon and marked reduction in blood reti- culocytes. The possibility is present that these temporary changes could go on to complete or partially complete destruction of the bone marrow providing (a) that sufficient drug was used or (b) the patient became sensitized in some manner and was given a second course of drug therapy at another time. It is thus con- ceivable that both an immediate or direct effect as well as an indirect or hyper- sensitivity mechanism maybe responsible for the marrow reactions seen. Following the introduction of chloramphenicol in 1948 and the reports of the first cases of aplastic anemia between 1950 and 1952, many editorials and reports of special ad hoc meetings appeared. Evidently the medical profession was pro- foundly influenced; in any event, the sales of chioromycetin declined sharply, reaching their lowest level in 1954. This lull was short-lived. By 1958, there was a five-fold increase in the sales of the drug and by 1960, enough chlorainphenicol was being distributed, and presumably used, in the United States to supply 3,732,416 persons with 10 Gm. ëourses of drug! (These data were supplied through the kind cooperation of Dr. Harry (James, Parke Davis & (Jo., Detroit, Mich.) To those of us who see cases of aplastic anemia following the use of various possible etiologic agents, chloramphenicol stands out as the most important single historical factor. To be sure, evaluation of histories and even of statistics relat- ing to both the incidence of aplasic anemia and of chloramphenlcol as an etiologic agent is difficult. Nevertheless the importance of the chioramphenicol-aplastic anemia relationship persists, and one must naturally be concerned with the pos- sibility that an increased incidence in aplastic anemia may result as use of the drug increases so rapidly. Is the pharmaceutical house which introduced and popularized the use of chloramphenicol to be taken to task? This seems unfair for there can be no question that this respected company has gone to every effort for ferret out statistics of case reports to carry out experimental work in various animals and even to note the effects of marrow transplantation in chemically in- duced aplastic anemia of monkeys. Is it the physician, then, who is largely responsible? In a way he is, for without his prescription, the drug would not be administered. Certainly, if he regards ehioramphenicol lightly, to be dispensed like aspirin, for every minor esid and respiratory infection, he is not without blame. But are there certain mitigating factors? Some say that a person ill is a person to be treated! The urge to make a person comfortable and to cure his illness as quickly as possible in an urge each of us has. It follows then that a good antibioth~ of the broad `spectrum `Rubin, D.; Weisberger, A. S.; Botti, R. B.; and Storaasli, J. P.: Changes in Iron Metabolism in Early Chioramphenicol Toxicity, J. Gun. Invest. 37: 1286-4292 (Sept.) 1958. 2 Said!, P., and Wallerstein, R. 0.: Effect of Chloramphenicol on Erythropojesig. To be published. PAGENO="0436" 2570 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY variety and which can be readily administered is something to be used at every opportunity. This is part of the mores in this affluent society of ours. We have potent medicines; the patient is ill; we must treat! The days of simple herb medicines and of simple galenicals have long since passed. More often than not, the newer synthetics, most of them composed of molecules with benzene rings and nitrogen, NH, NH2, or NO2 groupings-are used, and all of them, it shoukl be said, are potentially harmful. What then can be done? A few suggestions may be offered: (1) Physicians must be warned, and in no uncertain terms by means of articles, edlitorials, meetings, announcements; not once, but repeatedly that chlorainrphenicol is not only a potent antibiotic but apparently an antimetabolite as well, having effects not only on bacteria but on the bone marrow. (2) By some means, whether by regulation or by self-discipline, promiscuous use of the drug should be avoided and its use restricted to impelling circumstances, i.e., for conditions in which no other antibiotic is currently effective. One realizes that this is more easily said than done, knowing the physician's individualistic nature. (3) The patient and the patient's family must be warned, either by the physician or by the druggist that this is a powerful drug; that It should be used only once; that its repeated use may result in serious blood reactions; that it should not be kept in the bathroom cabinet and used again if an apparently similar disorder supervenes. (4) The manufacturing drug house should instruct its detail men, our ubiquitous mentors, not to minimize the dangers of the drug, and to emphasize its value for certain specific conditions, and not for the whole gamut of infectious diseases. The journal advertising could be made more forceful regarding the necessity for guarding against use of the drug indiscriminately, and especially in minor infections, or in repeated courses; or off the bathroom closet shelf. Itt might be wise for the patient or his family to have some knowledge of what antibiotic is being used in a given case. Perhaps we physicians might also consider, at least for many of the acute, self-limited infections, the more conservative course (radical by present-day standards) of giving no potent medications at all, but rather such symptomatic care as asptrin, fluids, and the like. After all, the body defenses are usually capable of handling most acute upper respiratory infections. In any event, something must be done to reduce the incidence of grave insult to the bone marrow produced by some of the antibiotics. The practicing physician would do~ well to think twice before prescribing a potent antibiotic and to ask himself "Is this drug really necessary?" WILLIAM DAMESHEK, M.D., Boston, Mass. [From the Journal of the American Medical Association, Mar. 17, 19&2] COUNCIL ON DRUGS-REGISTRY ON BLOOD DYSCRASIAS REPORT TO THE COUNCIL In 1952, the Council on Drugs became concerned with the problem of hemato- toxicosis from the ever-increasing number of therapeutic agents. The Council's former Committee on Research recommended that a Registry on Blood Dyscrasias be formed; and after a 2-year pilot study, the Registry was permanently estab- lished. Reports are tabulated for each 6-month period, and the summary tabula- tion is distributed to medical schools, hospitals, medical societies, and collaborat- ing physicians. With expansion, the need for a résumé of the tabulated information has be- come apparent. The reports received by the Registry for the period January 1 to June 30, 1961, were used for this purpose. The information must be con- sidered raw data, since reports are received from many sources and no follow-up is possible. The résumé is intended to provide concise information regarding common associations between drugs and blood dyscrasias, to acquaint physicians with the existence of the Registry, and to encourage them to report cases of blood dys- crasia in which drugs or other chemicals may be the suspected cause. Résumé of Reports Received by Registry on Blood Dyscrasias January 1 to June 80, 1961 In the period from January 1 to June 30, 1961, 138 new cases of blood diseases suspected of having been caused by drugs or chemicals were reported to the PAGENO="0437" N COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2571 N. Study Group on Blood Dyscrasias of the American Medical Association. These included cases which were published in the American medical journals during the same period. Forty-eight cases noted in foreign medical journals are reviewed separately. These findings increase the total number of cases reported since 1955 to 1,504 and the total number of drugs and chemicals reported to be associated with the development of blood dyscrasias to 411. Because of the large number of drugs involved, it has become increasingly difficult to evaluate the data and establish firm etiological relationships between specific drugs and specific blood disorders. However, certain previously unsuspected hematological side effects of drugs may be recognized much earlier if data are gathered from all over the country. There- fore, the Study Group on Blood Dyscrasias feels that it is important to continue to act as a clearinghouse for all suspected instances of heinatological side effects which may arise from the use of drugs. In order to transform the accumulated data into useful information, the Study Group has recommended that a brief analysis of the reported material be pre- pared. A copy of the complete tabulation is available upon r&juest from the Council on Drugs. An anlysis of the new cases added to the tabulation during the first 6 months of 1961 does not justify any sweeping conclusions or condemnations. The drugs appearing in the tabulation are those which are known to have produced toxic reactions and which continue to cause trouble when used, or are those drugs which are widely used. A total of 163 different drugs and chemicals were associated with the 138 cases reported to the Registry during the period in review. A.-Ninety-eight drags were associated with one case each. Of these, only imi- pramine hydrochloride (TofrSnil) requires special mention. This drug was intro- duced, in 1959, for the treatment of depression. Since that time, it has been re- ported as a possible causative agent in 9 cases of leukopenia, 2 of which were fatal. However, only one additional case has been reported in the first 6 months of 1961. B.-Thirty-one drugs were associated with 2 cases each. The potentially toxic effect of quinidine (Asarum, Conchinine, Conquinine, Pitayine, Quindate) on platelets is emphasized by the fact that 2 patients developed thrombocytopenia after the administration of quinidine, the only drug used. 0.-Twelve drags were associated with 3 cases each. Dexamethasone (Deca- dron, Deronil, Gammacorten), a synthetic analogue of hydrocortisone, was re- ported to be associated with 2 cases of pancytopenia and 1 case of leukopenia. This drug is mentioned because it had not previously been associated with the develop- ment of blood dyscrasias. However, th all 3 cases, other drugs known to be po- tentially toxic were administered concurrently; thus, it seems dubious that dexa- methasone was the offending agent. D.-Eight drags were associated with 4 cases each. A definite cause-effect rela- tionship could not be established in any of these cases because of the variety of blood disorders induced and the many other drugs used concomitantly. E.-Fourteen drugs were associated with 5 or more cases each: Acetophenetidin (Phenacetin)-8 cases Acetylsalicylic Acid (Aspirin)-15 cases Chloramphenicol (Chloromycetin)-56 eases Chlorothiazide (Diuril)-7 cases Chlorpromazine (Thorazine) -11 cases Diphenhydramine (Benadryl)-6 cases Diphenyihydantoin Sodium (Dilantin Sodium)-5 cases Meprobamate (Equanil, Meprospan, Meprotabs, Miltown)-7 cases Novobiocin (Albamycin, Oathomycin)-5 cases Penicillins-17 cases Phenobarbital (Luminal)-1O cases Promazine (Sparine) -5 cases Sulfisoxazole (Gantrisin ) -6 cases Tetracycline (Achromycin, Panmycin, Polycycline, Tetracyn ) -18 cases As in previous tabulations, the drug associated with the highest number of blood dyserasias in this period is chloramphenicol. It was the only drug admin- istered in 23 of the 56 new cases reported to be associated with the use of chloramphenicol; in 28 of the remaining 33 cases, it had been employed in con- junction with drugs not known to cause blood dyscrasias. These results support PAGENO="0438" 2572 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the contention that chioramphenicol has a definitely toxic action on the bone marrow; therefore, it is mandatory for the physician to be aware of the potential toxicity of this otherwise valuable antibiotic. Senator NELSON. Doctor, we appreciate very much your taking the time to come here today. Your testimony has been very valuwble to the record. I want to thank you very much. Dr. HEWSON. It is a privilege to be asked, Senator. Senator NELSON. That wifi conclude the hearings until tomorrow morning at 10 a.m. (Whereupon, at 11:05 a.m., the hearing was recessed, to reconvene at 10 a.m., Wednesday, February 28, 1968.) PAGENO="0439" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WEDNESDAY, FEBRUARY 28, 1968 TJ.S. SENATE, MONOPOLY SUBCOMMITTEE OF THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to recess, at 10:15 a.m., in room 318, Old Senate Office Building, Senator Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senators Nelson, and Long of Louisiana. Also present: Benjamin Gordon, staff economist; James H. Gross- man, minority counsel; Susan H. Hewman, research assistant; and William B. Cherkasky, legislative director, staff of Senator Nelson. Senator NELSON. We will now open the subcommittee hearings. We have as a witness Mr. Edgar F. Elfstrom, publisher of the Daily News Tribune in Fullerton, Calif. We will also hear testimony from Dr. Watkins, of California, and Dr. Franklin Farman, of Lakewood, Calif. I have asked the gentlemen to join each other at the witness table, and if you have any comments or additions to make to the testimony of any one of the other witnesses that you think would be helpful for the record, just feel perfectly free to interject the remarks. I will ask Mr. Elfstrom to proceed with his statement. I assume that you have no objection to an interruption for a question if something occurs to us in the course of your testimony. Mr. ELFSTROM. Not at all. Senator NELSON. Will you proceed with your statement? STATEMENT OF EDGtAR F. ELPSTROM,, PUBLISHER, DAILY NEWS TRIBUNE, Y(TLLERTON, CALIF. Mr. ELFSTROM. At the outset, I want to say that I consider it a privilege to appear before you. And I assure you that I am grateful for having been asked. Senator NELSON. I want to say on behalf of the committee that we realize that you gentlemen have come all the way from California to testify, and we know that it imposes a considerable sacrifice and burden in time upon each of you. And we are appreciative that you are will- ing to take the time to come here and testify for the record in this hearing. We appreciate it very much. Mr. ELFSTROM. Thank you. Our family is one of the legion of victims of a Chloromycetin trag- edy. Our youngest daughter, a 19-year-old healthy, happy college 2573 PAGENO="0440" 2574 COMPETITIVE PROBLEMS IN THE DRuG INDTJSTRY student, was given this potent antibiotic, first for a sore throat by a general practitioner, and subsequently some months later for a minor urinary infection by a urologist which, expert medical advice has in- formed us, would have cleared up without medication if left alone. She was given more than 100 capsules of the drug intermittently over a period of some 6 or 7 months, and was hospitalized with aplastic anemia some months after the medication was discontinued. She passed away after 3 weeks of such intense suffering that it is beyond description, a nightmare Mrs. Elfstrom and I shall never forget as long as we live. We did not know the name of the antibiotic that had been prescribed for her, or anything about it, until just before her death when we set out to learn what had caused a youngster who had been the picture of health all her life to succmnb so quickly. Among other things, we learned she had never been given a blood study by any of the physicians who had treated her despite the fact the warning in effect then specifically called for such studies. In a meeting held with the grievance committee of our Orange County medical society, we heard these men say they did not know the meaning of "intermittent therapy" which the Food and Drug Administration said was especially dangerous. We also heard t:he president of our medical society say local doctors knew so little about the drug that they had asked an official of Parke, Davis who was attending a meeting in San Francisco at the time, to come down to Orange County to tell a group of physicians about the drug. Incidentally, this official did not appear. He said he had to return to his office unexpectedly; the consensus here was that when Detroit found out about the proposed meeting they ordered him to return immediately. After several such frustrations Mrs. Elfstrom and I decided we would dedicate ourselves to doing something about warning the public, the innocent public I hasten to add, of the hazards of this drug and about the way its mdiscriminate use was being promoted. If our memory serves us correctly, one of the well-known men of medicine who testified during the hearing conducted by the late Estes Kefauver in this very room, said "its sale was being pushed like soap." Our research has developed a mountain of material, so much in fact that it has more than filled a four-drawer legal-size file case. Included among the many medical articles and reprints that warn of the drug's potential danger are countless letters from distraught parents and relatives who have lost loved ones following Chioromycetin therapy for such minor infections as the common cold, sore throats and other upper respiratory aihnents for which antibiotics are not effective, mosquito bite, acne, infected gums, sore fingers, mumps, earache, and so forth. Here are excerpts from just a few- Senator NELSON. These are letters that you have received? Mr. ELrsmoM. Yes, sir. Senator NELSON. And you have copies of the letters? Mr. Eu~'smoM. Yes; they are in our files. Please add our daughter's name, Susan Alma Staggs, age two and a half, to the statistics you are gathering. She received Chloromycetin in August, aplastic anemia was diagnosed in October, and she passed away in Children's Orthopedic Hospital on December 8. God speed you on to the success of this mission- from a Washington family. PAGENO="0441" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2575 Senator LONG. May I ask if that is Washington, D.C., or the State of Washington? Mr. ELFSTROM. The State of Washington. My grandson, a boy of sixteen, was ill and we called in a man who was said to be one of the leading specialists in the country. This doctor prescribed Chioro- mycetin for the boy and it killed him-from the associate publisher of a group of prominent daily newspapers. My daughter, Pamela, passed away due to the 4jhloromycetin she was given. Only people like you and I know what we have all gone through. We all ap- preciate what you are doing. Maybe all of us in some small way can contribute to the ban of this terrible drug-from a Colorado mother. Barbara was a beautiful, chubby little girl with a head of blonde curls and blue eyes. She was the picture of health. We know nothing but that this awful drug took her life-from a New York mother. My two and a half year old daughter, Elizabeth, died August 17 of aplastic anemia. The previous September she had been administered Chloromycetin by a pediatrician who had attended the child since birth, for a sore thumb, two months later for a cold, and two times more for a sty, never taking a blood count. I have lost all interest in everything. I can not speak about what my baby went through, all in vain, but I want you to know there is someone who knows how you feel about your loss and understands-from a Long Island mother. My daughter Isabel died on August 14 of aplastic anemia, caused by Chloromy- cetin prescribed for an ordinary cold on two occasions within a year-from a New Jersey father. I have wanted so often to write and thank you but my daughter's death (a 35-year-old government scientist) incidentally, she was from WashingtOn here, although she died in California-came as such a shock that my health has not been good-from a California mother. Other letters tell of the death of a 21~year-old college football player who was given Chloromycetin for acne, of a Navy Wave who was given the drug in a naval hospital, of a Massachusetts father who was given more than 50 blood transfusions in the veteran's hospital following the onset of aplastic anemia caused by the drug. We have heard from physicians, too, who have had tragedies in their immediate families, such as this one from a doctor in Texas: In February my seven and a half year old son died from aplastic anemia due in the opinion of five specialists, including the State's outstanding hematologist, who attended him, to the routine administration and dosage of Parke, Davis' Chioromycetin by me for an ear-throat infection on the advice of representatives of Parke, Davis who repeatedly assured me of its safety, and urged its use, routinely, in general practice. Almost simultaneously there were two other deaths in this area, a child and an adult which appear to be attributable to the same cause. `Senator NELSON. May I interrupt a moment? This is a letter from a physician in Texas who administered the drug himself? Mr. ELFSThOM. Yes. Incidentally, I have a copy of his letter to me. Senator NELSON. What is the date of his letter? Mr. ELFSTROM. 1961. Senator Nnr~soN. 1961. This is some 9 years or thereabouts after the serious side effects of this drug were known to the company and to the medical profession; is that correct? Mr. Er~rsmoM. That is right. Dr. Watkins can tell you about that. I will find the letter in my file and give it to you. Also, let me interject here that it seems that the younger the per- son the quicker the reaction follows. An older person usually hangs on for quite a while with the anemia. I have records of a case in Detroit where more than 200 blood transfusions were given to this man before he passed away, and of a woman down in Miami, Fla., who was given more than 180 blood ti~ansfusions before she passed away. But the younger the person, the quicker the reaction. PAGENO="0442" 2576 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We could go on for hours telling about like countless tragedies that have come to our attention since we started to devote limitless tune to the problem. We are saddened by all of them because we know the suffering such tragedies bring. Some date back to the time of our disaster but many are recent as is this one from a father in Iowa who writes, in part: We lost our almost 16-year-old daughter November 3, 1967, at Rochester, due to aplastie anemia caused by Chioromycetin, and my wife and I do not seem to know how to live with it I will not go into detail but our daughter was given 52 capsules for a sore throat in June. Senator Nm~soN. Was she sent to Rochester for this treatment? Mr. EI~smoM. Let me go on, and I will explain it. Senator NELSON. What I want to get at was whether it was adniin- istered at Mayo. Mr. Eu?smoM. No. For instance, just last week we received a tele- phone call from this father, who said his wife, who had been teaching schrol, `had to resigo her position and he was afraid she was going out of her mind. Just before I left Oa'lifornia, I received a letter from this man that I would like to read into the record. It is dated February 21: DEAx Ma. ELFSTBOM: Thank you very kindly for your reply to my letter. Your information is deeply appreciated. "I am not a fluent writer, but I would like to furnish you with a résumé of our horrid experience with Ohloromycetin, hoping perhaps it might prove to be of some value to you in Washington, D.C. I would also like to assure you that if we can personally help in any way, we would be most happy to do so. We will even come to Washington on February 28 if there is anything we can do to help. Our 15-year-old daughter, Chris, was given 52 capsules of this drug in June and July of 1967 for a sore throat. Blood tests were not taken prior to or while she was taking this drug. A throat culture was not taken. My wife, daughter, or myself were not familiar with this drug. Ohris was allergic to sulfa, but I do know there are many other antibiotics of a less toxic nature that could have been prescribed. The first visible symptom was discovered by us the iatter pert of August, blood spots under the skin. We took her immediately to the same doctor who pre- scribed the drug and who had been our family doctor for 5 years-and he took the first blood tests. Her platelets were destroyed. That is the congealing factor of the blood. If you don't have platelets, you will just bleed to death. So he sent us to the Iowa City Hospital. Ohris was checked very thoroughly, bone marrow, etc. They diagnosed "Thronibo cyto penic purpura" and commenced with high dosages of cortisone. She was there a couple of weeks and was allowed to come home. She kept failing so we entered the local hospital and in a few days were on our way back to Iowa City, where she had another bone marrow test and more blood tests. This time they thought she had leukemia; we decided to take her to Mayo Clinic. Three clays of intensive testing and they diagnosed aplastic anemia; we had not even heard of this disease and felt a great relief. This was the first time we were alarmed about Ohioromycetin. We flew back hone and in a few weeks she was again admitted to the local hospital for hlood transfusions. Our local doctor was beginning to treat us dif- ferent and even sarcastic, and in a subtle way wanted out from under the case. One night at 12:30 a.m. she started bleeding profusely from her kidneys. I immediately called the doctor and he told me a little blood looked like a lot. I told him I knew better-he did not come to our home. The next morning about 7 a.m. I took a urine specimen to the hospital and in a few minutes he telephoned and alarmingly stated it was raw blood. The internist at Iowa City was gone for the week, so I chartered a plane to Rochester where she was admitted to the Methodist Hospital, with Dr. Bayrd, a hemotologist, in charge. PAGENO="0443" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2577 Chris was given four or five platelet transfusions and four or five pints of blood. She died exactly 2 weeks to the day we entered Rochester, from an over- whelming infection on November 3, 1967. In other words, when your antibodies are gone-these are the dis- ease-fighting particles of your blood-and when they are gone, any infection can take over. We allowed an autopsy hoping it might help some other victim. In a letter from Dr. Bayrd he termed her death "a monumental disaster and a great tragedy," and stated the drug should be used very sparingly. We flew back home that evening; the doctor telephoned me; I asked him how many capsules of Ohloromycetin he gave her. He reported 12 capsules and said "I'm sure that it didn't cause aplastic anemia," and that he was going to continue to use it. I have documented evidence that he prescribed 52 capsules. Incidentally, there is a case in California of a six and a half year old girl that died from aplastic anemia at the City of Hope Hospital which you have all heard of. And when the father began to check into the reason for it, he asked the doctor what he had given here. He had changed on his record the name of the antibiotic to TAO. But the father had been smart enough to get to the pharmacy first, and he found out that she had had two prescriptions of Chloroinycetin. I will go on with the letter: I would like to ask the president of Parke, Davis several questions: (a) If he or his wife watched one of their children die a little bit each day for 11 weeks with a disease that struck our daughter like rat poison, if he could still take pride in his promotional prowess? (b) How would he or his wife answer this question from a 15-year-old daughter "Mommy what is happening to me," and "why is God doing this to me," on the day that she passed away? (c) Could he go back to his office and watch the sales soar after watching his wife collapse on the hospital corridor floor? (d) How would he go home and tell an 11-year-old son he no longer has a sister who never did one thing wrong in her life but trust doctors? (e) Could he watch his wife turn from a happy, beautiful woman of 123 pounds deteriorate to 87 pounds and go back and step up the production of Ohloromycetin? (f) Could he spend 24 hours a day for 2 weeks with his daughter at Rochester, and return to the factory to see how sales are coming along? My wife had to resign from teaching school this year. I taught school and was a superintendent of schools for 12 years. My point is that we are fairly well educated and yet allowed our daughter to die needlessly. I did not intend for this to be so lengthy. Again thank you for your information and please give me the privilege of helping you, if you think I could. I am enclosing a picture of my daughter; perhaps the Parke, Davis president would like to study it for a while. I want to show it to you. (The photograph was displayed.) Mr. ELPsm0M. I want to keep the photograph, but she is the pic- ture of perfect health. I will proceed with my statement. Since 1961, there have been a number of bills introduced in the Cali- -fornia Legislature designed to control the indiscriminate use of Ohio- romycetin. Several called for a warning on the label going to the patient, with different wording, and one restricted use of the drug to hospital administration. None of them passed, even though doctors and dedicated men of medicine testified in their favor, due to the vigorous opposition of Parke, Davis, the Association of Pharmacists, and the California Medical Association. Following failure of the bills, resolutions were passed calling for hearings by committees from both the senate and the assembly, and PAGENO="0444" 2578 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY requesting the State department of public health to make continuing studies of the relationship of Chioromycetin to the development of aplastic anemia. These studies by the department of public health, the only ones so far made anywhere in the world to our knowledge have revealed that instead of the incidence of aplastic anemia following Chloromy- cetin from one in 800,000 as was introduced in evidence in a lawsuit here in Washington, to one in 36,118 with an average dose of 4.5 grams, or one in 21,671 with an average dose of 7.5 grams per person. When we first started working on the problem we tried to seek some cooperation from the Food and Drug AdministratiOn. But we just wasted our time. In fact, in one of his many communications to us, the then Conmiissioner, George P. Larrick, brushed us off with the statement: I am convinced, based on the views of FDA's medical staff and eminent medical authorities who are experts in the field of antibiotic use, that Chloromycetin is a valuable drug which saves more lives than it destroys. Senator NELSON. When was that statement made by Mr. Larrick? Mr. ELF5m0M. In a letter to me, sir. Senator NELSON. What year? Mr. Er~'smoM. 1962 or 1963, I have forgotten which, but I have a copy of the letter. Can you imagine this coining from the head of the FDA? Knowing what we did about the many tragedies that followed the indiscriminate use of this drug, this statement we considered an insult to our intelligence. We did not fare any better with the Medical Director of the FDA, Dr. Joseph F. Sadusk, Jr., who, we observe, subsequently has been ap- pointed a vice president of Parke, Davis. Strange bedfellows. We understand this man tabled a suggestion made by his deputy to reopen the question of Chioromycetin labeling in 1966. Senator LONG. Let me see if I get this straight. Do I understand that Dr. Joseph F. Sadusk, Jr., was `a Medical Director of the Food and Drug Administration, and supported Parke, Davis in their con- duct2 and that he subsequently became the vice president of Parke, Davis? Mr. ELFSTROM. That is right, sir. Senator LONG~ So he helped them with this activity and then took a job from them? Mr. Er4rsmoM. Draw your own conclusions. Senator LONG. I would say that this was very effective public rela- tions work on their part. Mr. ELFSTROM. Dr. Watkins `has some other information that you will find helpful. We are happy to acknowledge, `however, that the present Commis- sioner, Dr. James L. Goddard, and the current Director of the Bureau of Medicine of the FDA, Dr. Hethert L. Ley, have been cooperative and seem to be trying to find a solution to the problem. We know organized medicine will vigorously oppose any change, insisting that its prerogative to prescribe for its patients-a captive audience in every sense of the word-should not be interfered with. But how it can stubbornly insist on no `restrictions in the face of evi- dence that has been piling up `for years nOw of the continued indiscimi- nate use of this antibiotic is beyond compr~hension. We don't know how many times we have heard the statement made PAGENO="0445" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2579 by the profession that the problem can be solved by education. We submit, this process of educating physicians in the proper use of Ohioromycetin has been going on now foT nigh on to 20 years and still abuses continue. The other day a man who has devoted the past 10 years to seeking adequate legislation in California which would censor and/or repri- mand physicians who carelessly and repeatedily violate the code of good medical practice, dropped by to see us as he also has been inter- ested in the Chloromycetin problem. He said one of the physicians in his city had the audacity to tell him that doctors would have no worry about prescribing Chloromycetin if they carried plenty of mal- practice insurance. This is unbelievable. A physician here in our city who evidently was full of misinfor- * mation about the drug and the work we had been doing, said to a friend of ours that we should be behind bars. In January of last year the CMA News of our California Medical Association, stated: No reasonable basis exists for enactment of a special legislative category to restrict the use of the drug chioramphenicol by licensed physicians in California. And this was after release of the latest study of the department of public health which revealed an increase in the incidence of aplastic anemia following use of the `drug as mentioned above. We wrote the association, in part, as follows: If a layman can accummulate continuing and mounting evidence that this potent antibiotic is being prescribed for minor infections (in most instances without blood studies) contrary to the specific warning issued by the Food and Drug Administration, you must know it, too. Unless you can guarantee that members of the profession will pay heed to the FDA warning literally, you are going against the public interest by opposing legislation which would make such adherence mandatory. In reply the executive director of the CMA concluded his letter with: Your concern is understood and appreciated, but your conclusions and sug- gestions do not agree with those of this association. The medical profession has had a long and honored history of striving to protect `the public interest, and will continue to do so in the future. We were pleased to note that the several eminent men of medicine who appeared before this committee 2 weeks ago agree that some restriction-legislation or directive-is necessary and advisable. During the hearing on Chloromycetin conducted by the California Senate Factfinding Committee on Public Health and Safety, held in the State Building in San Francisco, Kenneth McGregor, the then vice president of Parke, Davis-who presented a prepared statement- was asked by one of the senators whether he would consider it bad medicine for~ a physician to prescribe Chloromycetin for a common cold or sore throat. Mr. McGregor hesitated for quite a while before he answered and then said it was a loaded question which he did not feel he should answer. Despite the opposition that developed, our crusade, if one could call it that, has been endorsed by a number of well-known men of medi- cine who have encouraged us in a task they knew would meet strong opposition but which they felt needed exposure by someone outside the medical profession. To name a few: From Dr. Walter C. Alvarez: PAGENO="0446" 2580 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I am so glad you are carrying on this fight. I think my old friend Dr. Meyer's suggestion of using certain drugs only on hospital patients is a good one. I plan to have another column on the subject which is stimulated by your good work. I have received many sad letters from people who have told me of the death of a child or relative-due to the unwise use of Chloromycetin-often for a mild iUness. From Dr. Daniel Liebowitz, prominent bay area internist who was asked to testify at the San Francisco hearing: You will have been of service to medicine if you can continue to spur legislation that will guarantee an adequate warning to patient, pharmacist and physician. From the deputy director of our California Department of Public Health: We do appreciate your deep interest in this matter and the highly effective manner in which you are exerting leadership in an effect to bring about an ade- quate solution. From Dr. Karl F. Meyer, of the University of California Medical Center, San Francisco, whose reputation is worldwide: We (referring to Dr. Maxwell Finland of Harvard University) both sincerely hope that you continue your efforts along the lines you have so auspiciously initiated. Others included Dr. Ohaucey Leake, professor of pharmacology of the University of California, San Francisco, who came to Sacramento in behaJf of legislation to control use of the drug. Another man of medicine whom we admire is Dr. Philip Condit, head of the division of infectious diseases for the California State De- partment of Public Health. He headed the Ohioromycetin study for the department and he and his staff deserve much commendation for their painstaking devotion to seeking the truth. In the California Senate hearing in Los Angeles he said: Chloroanycetin, an antibiotic recommended for use only in very serious infec- tions, is killing people to whom it need never have been given. In the current-February 1968-issue of the Reader's Digest, the Pharmaceutical Manufacturers Association has inserted an eight-page advertisement headed: "Medicines and Your Family's Health" which extols U.S. Patent 2,483,885, Chioromycetin. It states, in part: "The new drug, which was to prove effective against dozens of diseases, also caused occasional, and sometimes serious, side effects in some patients," minimizing its potential danger and saying nothing about the deaths that have resulted from its indiscriminate use. It has been our understanding that since the passage of the Kefauver- Harris amendment to the Food and Drug Act, advertisements for prescription drugs must carry at least a summary of any warning required by FDA regulations. Here is a case in point where such a requirement obviously has been ignored. It is a full-page advertise- ment in the February 1968 issue of the Bulletin, a publication of our Orange County Medical Association, which states above a picture of a physician sitting at a hospital desk, simply "A Name You Can Count On When It Counts-Chioromycetin (chloroamphenicol)-Parke Davis"-and in small print "Complete information for usage available to physicians upon request." Earlier this month Mrs. Elfstrom received a letter from a graduate student in biochemistry at one of our midwestern universities. Being PAGENO="0447" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2581 a member of the same church organization we are members of, she had just recently learned of our tragedy, and she wrote to tell us what she had been doing about Chloromycetin. We were very much interested in what she had to say and we believe you will be also. In part, she wrote: During my undergraduate studies at the University of Colorado, I worked in a hospital laboratory. At this time, 1 witnessed the very needless deaths of several people-especially young people-because of this unreliable drug. Realiz- ing the dangers of Chioromycetin, I decided to thoroughly research the drug and its actions for my thesis when I entered graduate school. During the past 12 months, I have worked with organ cultures of all types of blood marrow, including human marrow obtained from pathologists. I have used many different dosages of Ohloromycetin on the cultures-have worked with rats, monkeys, and humans (in vitro-to the extent of using human blood mar- row). Countless numbers of blood slides have been made and much work has been done with electron microscopy to determine changes within the various sys- tems of the body. We feel at this time .that we are on the verge of understanding the mechanisms of chloramphenicol that causes the blood marrow to cease its function. We are quite certain that it is caused by the extra radical compound that chioramphenicol has that other antibiotics do not. * * * Our next step is to prove that Chloromycetin is much more harmful than helpful and is grossly overused. The Congressional Record appendix of January 30, 1961, page A583, contains this statement by Dr. John M. Adams, chairman of the De- partment of Pediatrics at UCLA: Contrary to the belief of many doctors, Chloromycetin has an effect which is harmful in varying degrees to the bone marrow of all persons who take it. This effect, which can become manifest as a lethal disease called aplastic anemia, is not limited to certain susceptible individuals but is a universal effect. The time is long past due when the medical profession should be stopped from playing "Russian roulette" with this ~othnt drug. And it is dedicated men like you, Senator, who can bring this about. May God bless you, richly. Senator NELSON. Thank you very much for your testimony, Mr. Elfstrom. Mr. Gordon? Mr. GORDON. I have just one question to ask you. How do they handle the use of chloramphenicol in tile Los Angeles Hospital? Mr. ELFSTROM. I understand in the General Hospital that each pre- scription for Chloromycetin that is written by the doctor in the hos- pital has to be countersigned and OK'd by the head of the services. Mr. GORDON. They do have restrictions? Mr. ELFSTROM. Even in the hospital. Mr. GORDON. Even in the hospital. Senator NELSON. Are either of you doctors personally familiar with the practice in the Los Angeles Hospital on the use of chloram- phenicol? Dr. FARMAN. I used to be on the staff, but I am not at the moment. Senator NELSON. Our next witness will be Dr. Albe Watkins, of La Canada, Calif. Mr. ELFSTROM. Excuse me; for the record, I would like to submit the original of that advertisement. And this is a photocopy of that doctor's letter. Senator Nnr~soN. They will be included in the record. (The material referred to follows:) PAGENO="0448" 2582 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 102 ORANGE COUNTY MEDICAL ASSOCIATION PAGENO="0449" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2583 KODIrTZE, Tax., April 3, 1961. EDGAR F. ErrsTitoM, Daily News Tribune, Fullerton, Calif. DEAR MR. ELFSTROM: Senator Estes Kefauver has suggested I write you con- cerning the following matter, with which I gather from his letter, you are already tragically familiar. In Feb. 19431, my 7% year old son died from aplastic anemia due in the opinion of the 5 specialists, including the State's outstanding hematologist, who attended him, to the routine administration and dosage of Parke Davis' Chioromycetin (Chioramphenicol) by me for an ear-throat infection on the advk~e of repre- sentatives of Parke-Davis who repeatedly assured me of its safety, and urged its use, routinely, in general practice. Almost simultaneously, there were 2 other deaths in this area, a child and an adult which appear to be attributable to the same cause. I am contemplating legal action against Parke Davis Co.; please advise me o1~ your experience in this matter and how we who have had this terrible result in common may cooperate to the best interests of medicine and humanity. Respectfully, H. A. HooKs, M.D. Senator Nai~soN. Dr. Watkins. STATEMENT OF DIt. ALBE M. WATKINS, LA CANADA MEDICAL CENTER, LA CANADA, CALIF. Dr. WATKINS. As Mr. Elf strom has already stated, I, too, am greatly honored that you have accorded me, a California country doctor, this privilege of speaking before this august body. Practicing physicians are directly influenced by representatives of pharmaceutical companies or by journal advertisements to the extent I would estimate of 75 to 80 percent of their prescriptions. The re- maining 20 to 25 percent may be influenced by medical school or medi- cal association lectures-many representatives of the former may be working on grants from these large pharmaceutical companies. With reference to Chloromycetin (chloramphenicol), Parke, Davis in the early years completely omitted any report of toxicity for at least 16 to 18 months. This complete disregard of basic morality was directly responsible for my son's death. Later when forced to mention possible reactions they played down any such reports or insisted, as they did at conventions of AMA, that thare was not any proof of the drug Chloromycetin causing death. They insisted other medications had been taken concurrently as iron, aspirin, etc., for a long time. This drug was given me by a representative of Parke, Davis. And I have made it a habit when they come in to extol the virtue of the drug to ask them about the reactions first. And this man told me there were no reactions, this was a perfectly safe antibiotic. So I took the drug home and placed it in my medicine cabinet. A few days later my son suffered a urinary tract infection, and I went to the cabinet and I looked at the drugs I had. I picked up a bottle of sulfa, and I said, I don't want to give him this, because this might depress his blood-making system, his hemopoietic system. Imagine that. And I looked at Auromycin and Terramycin, and I said, sometimes this upsets the stomach, and I don't want him to get sick with the drug. And then I spotted the Chloromycetin. And I gave him the Chloro- mycetin, which caused his death several months later. 81-280 0-68-pt. 6-29 PAGENO="0450" 2584 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY A druggist, about 2 blocks from my office asked me "How did you happen to give him Chloromycetin?" This was in 1952. And I said, "This was the one drug that I thought was harmless." The pharmacist told me, "I told that representative 3 days before that that the drug was harmful, that a lady had died in Pasadena"- which was about 3 miles away from my office. So the representative of Parke, Davis knew at the time he gave me that drug, he delib- erately lied to me that the drug was harmless. And as I said, I went home and some days later gave it to my son, and that was the cause. This representative of Parke, Davis was given a 3 months' leave of absence. He later sold his home and moved out of the area. I under- stand his health was not too good after that. Parke, Davis has been one of the leading grant pharmaceutical com- panies, but by strange coincidence these grants always seemed to go where the criticism of their product, Chloromycetin, was the hottest, as to Dr. Doa.n, of the Ohio State University; University of Michigan; and many, many others. Mysteriously very little criticism of Chioro- mycetin continued from these schools after a Parke, Davis grant. A Dr. T. E. Woodward, University of Maryland, and many others receiv- ing substantial funds were always very vociferous in their praise of the drug in the face of evidence of its toxicity. It is my opinion that Parke, Davis was not nearly as interested in finding out why the drug was toxic as it was in stifling criticism. A Dr. Smith, formerly of AMA Council of Drugs, which at that time was critical of Parke, Davis promotional tactics, was given an executive position with Parke, Davis, as was more recently a former FDA official. I think he is today president of Parke, Davis. There was a rumor Dr. Welch, former head of the Antibiotics Division of the FDA, had some financial interest in Parke, Davis. While my own lawsuit was pending, a well-known ethical writer, David 0. Woodbury, Scottsdale, Ariz., came into my office to inform me Parke, Davis' chief attorney from New York had contacted Mr. Woodbury in his New England home, flew up, and had breakfast with the only purpose in mind to find out about my character. Mr. Wood- bury said he found it difficult to understand the gutter tactics of such a large, so-called ethical corporation. There has never been adequate control of this drug or its advertis- ing. The company was guilty of withholding all reports of reactions of the drug from the time of introduction until made to do so by AMA and FDA some 11/2 to 2 years after its introduction. They en- gaged in a series of correspondence with the families of the victims, denying any reactions and trying to blame any such reports on other products like aspirin taken at the same time. They were always very polite in expressing their sorrow at the loss of the child or the adult and were always glad, they said, to hear from the relatives of the victims at any future date. In my case, they were not so polite, but accused me of vilifying their innocent officials. They immediately, however, notified AMA and FDA of some re- ported reactions, reports which they had been withholding, for the first time after hearing from me because I told them I was writing to AMA and FDA concerning these reactions-reactions which they PAGENO="0451" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2585 had been sitting on for at least a year or a year and a half before receiving my letter. Their advertising during that period of time carried not one word of warning until they were forced to include this by both AMA and FDA. This is the letter I wrote to Parke, Davis when I heard my son- they first thought he had leukemia, they had gone through the usual routine, many doctors diagnosed it as granulocytopenia-purpura or leukemia. And hematologists in those days were able to decide it was aplastic anemia. This was the letter I wrote to Parke, Davis on May 5, 1952: DuAn Sras: This story is of the tragedy in one man's family due to his faith in a "reputable concern, and the representatives thereof" concerning a product of theirs, a "harmless antibiotic." We know the drug is harmless because every few days we get a bulletin from the company which has plastered all over the outside envelope "No evidence of intolerance," "No untoward effects with these children." "No evidence of toxicity," "No clinical manifestations of toxic symptoms," etc. ad infinitum. We felt doubly sure that this drug was safe be- cause we asked the salesman point blank about the gossip concerning its toxicity particularly from one prominent hospital-the Children's Hospital-I had heard two days before that there was some drug over there, and he wasn't quite sure, the man who told me, but he thought it might be Chioromycetin. But the salesman said no, it was not their drug, he~ didn't know anything about that. And he denied that any criticism of his product existed. We now know that he was duly informed, as this drug house will knOw later. We have-or had-by the time you receive this letter, four sons. Our third son unfortunately was born with a single kidney, and underwent plastic surgery 1 year ago on the ~ireter. He was getting along very well, watched his health like an adult, and participated in all usual activities of a ten year old. We were out of town for two days around the middle of February and unfortunately he developed a little Cystito-pyelo-nephritis, with a fever of 102 the day we returned. Being duly cautious of his health, I started to give him some penicillin, but thinking it was probably a gram negative infection decided sulpha or an antibiotic would be better. We decided not to give sblpha as it might depress his hemopoletie sys- tem (imagine) and we considered Terramyacin or Aureomycin might cause gastroenteritis-but then the thought recurred that we had another antibiotic which was entirely harmless and very effective. I might have done better had I taken a gun and shot him-at least he wouldn't have suffered. We, as parents are an M.D. of some 16 years practice. My wife, a graduate nurse of approximately 18 years, and our children being our only possessions of value, are well cared for. We noticed approximately 10 days after his 3-4 days of this harmless antibiotic, our son was very pale and a blood count revealed a depression of all components of 50 per cent. A repeat two days later was further depressed and petechial hemorrhages started. Our life from here on has been as near a hell on earth as you can imagine. Here, a very intelligent, hand- some little ten year old, who is so conscientious about his health he can't rest night or day, wondering why he is suddenly so ill, and bleeding, necessitating eight transfussions in as many days. He has had over 150 shots of penicillin, streptom AOTH. Vitamins, etc. Imagine, I didn't want to give him one shot of penicillin for his 102 fever. I would like to see the directors of this reputable company sit by this little fellow's bedside, see his worried expression and try to explain to him what happened. I would like for the learned scientist who developed this "harmless drug" give him every one of his 150 shots, as I've had to do-lay awake night after night, watching his every movement, wondering why it had to happen and praying asleep and awake finding it was a bad dream, and James is as healthy and fine as ever. This reputable old established company now knows this drug isn't harrnles&- as they have known for some~ time-we appreciate the company's asking for, and being granted the permission to notify all doctors of toxicity-only about two years too late, and the climate is getting littie too hot, the truth is finally out. Think of all the money that has been made by this product between the first reports of the toxicity and now. Can such a leading pharmaceutical house be PAGENO="0452" 2586 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY ignorant of the undercurrent that has been gathered over the country from Mayo to Harvard, to Boston, to Johns Hopkins, to Salt Lake City, to Texas and California. While James was sick, I wrote all over the country. I tried to find out about this, and I had letters from all these places I mentioned. We naturally reported it to the AMA. This company can give me credit for not being afraid to speak. I have nothing to lose from here on out, to the gov- ernment, or Pure Food and Drug, and we assure anyone interested, we are not finished. All of this is small recompense for the life of my beautiful, talented son-in convincing this company-(but not from warning them, that was done months ago) that the laws of Christianity apply as much to a corporation re- gardiless of their wealth and influence as to the lowly man on the street. If nothing more comes of it, we have lost our son, this company has lost more- for a dollar it has sold its honor and each individual in this concern, who is con- nected in this travesty of justice will remember it as long as they live and be judged accordingly thereafter. After he died, I put the family and three little children in the car and took off. We didn't know exactly where we were going, but we thought we would end up at the FDA. I would drive 400 or 500 miles a day and stop at a town. And when we stopped in the evening, I would go through the classified phone book and call just any doctor and ask, "Have you heard of anyone having reactions to this drug?" Coming across the United States, I picked up 15 cases from Cali- fornia to the FDA. When I finally arrived here in Washington on a Friday afternoon, Mr. Welch's secretary didn't want to let me in. I guess I didn't appear like a professional man. But I had driven all the way across the country, and I said, "I have come from Cali- fornia. I will sit here until he does let me in." And `he was very cordial to me. And he said I was the best agent he had. As a result of my coming across and acquainting him with the ones I had picked up across the country, they did the first survey. I left Washington and went to Philadelphia and Boston. When I arrived in Boston some 3 or 4 days later, they had picked up 188 cases that they knew nothing about before I made this trip across' here. And then I made a similar trip. We drove 11,000 miles the first year, and 9,500 the second year. I tried to go to all the universities, I tried to see ~vhat was going on. I went to Johns Hopkins-I have a letter from Johns Hopkins, by the way. In 1952 there was a directive from Johns Hopkins that for this drug to be allowed two or three doctors had to sign the order. And they were very careful in Johns Hopkins in 1952, they knew it was a dangerous drug. Senator NELsoN. May I interrupt for a moment? You mean before the drug could be administered in Johns Hopkins as early as 1952, that hospital's practice was to require the countersignature of `another doctor on the prescription? Dr. WA1~IuNs. Yes, sir. Senator NEr,soN. And the head of the service? Dr. WAmiNs. Dr. Conley was head of hematology. He was very kind to me. And he told me he had correspondence with Parke, Davis. I have other letters here- Senator NELsoN. I want to finish the point on the use of the drug in Johns Hopkins as early as 1952. Before it was administered, it was PAGENO="0453" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2587 required that more than one doctor sign the prescription or the order for the drug; is `that what you were saying ~ Dr. WATKINS. Yes, sir. They put out `a bulletin. I have it here, at Johns Hopkins for all interns and residents to read. Senator NELSON. Do you have `a copy of it? Dr. WATKINS. Yes, sir. Senator NELSON. What did it say ~ Dr. WATKINS. This letter was written to me on September 1, 1952. Memorandum: Subject: ChioramphenicoL At the request of Dr. A. McGehee Harvey, the following is submitted for the information of the entire medical staff of the Hospital: Cases of aplastic anemia attributable to the administration of chloramphenicol are occurring throughout the United States with alarming frequency. Observations to date suggest that two types of reaction may occur. Occasion- ally patients receiving this drug develop evidences of bone marrow depression during therapy. This may be manifested by leucopenia, granulocytopenia, throni- bocytopenia and anemia. In our experience in this Hospital there is suggestive evidence that this type of bone marrow depression may be treated to the plasma concentration of the drug since most of our patients either had received large doses, or had evidence of renal insufficiency. In these cases the blood has returned to normal after the drug was discontinued. A much more serious type of reaction concern the production of a real aplastic anemia. In cases of this type the occurrence of a blood disorder has apparently most often been associated with repeated administration of the drug, suggesting that a prior sensitization has occurred. In many of these patients relatively small doses 0g chioramphenicol have been used, and the blood disorder seems definitely not to be related to plasma concentration. An outstanding feature of the aplastic anemia associated with the use of chloramphenicol has `been the development of profound thrombocytopenia. In all of the fatal cases which have come to my aittention, death has resulted from hemorrhage. Leucopenia and neutropenia occur, but present a less serious prol- 1cm. Anemia in most of the cases apparently has been mild, except for that which can be attributed to hemorrhage. In a number of patients, death has not occurred for many months after the initial bone marrow depression. Efforts to `bring about bone marrow regeneration through the use of AOTH, cortisone, and numerous other agents have been extremely disappointing. Observations to the present time suggest that unless recovery occurs soon after the drug has been discon- tinued, it is naiL likely to occur. It seems not unlikely that as more individuals are sensitized `by the use of this drug, the incidence of aplastic anemia may increase. For this reason, and because of the serious nature of aplastic anemia, I believe that the drug should be used with very great caution. I recommend that cliloramphenicol be used only for the treatment of seriously ill patients suffering from infections not amenable to treatment with other antibiotic or chemotherapeutic agents. When chloram- phenicol is used, blood counts should be performed. However, I doubt that the precautions of frequent blood examinations will eliminate the danger of the use of this drug. That is very important, because they always said that you should get a blood count. But many people didn't show anything wrong with their blood count when they were taking it. This blood disease order came on months later, and a blood count did not help you at all. "It seems not unlikely that by the time blood changes have occurred, the disorder may be irreversible." This is by Dr. Edwin L. Crosby. I am sorry. I do not have that one. But Dr. Conley had to OK every bit of Chloromycetrn that was used. And I personally talked to Dr. Conley, who was head of the depart- ment at that time. I am sorry, I thought I had that letter with me. My recollection is, I was in his study, and he told me he had to OK it every time it was ordered, that he had to pass on it. And they watch those cases very carefully. PAGENO="0454" 2588 COMPETITIVE PROBLEMS IN THE DRUQ INDUSTRY Senator NELSON. Before it could be administered to any patient in that hospital? Dr. WATKINS. Yes; they did daily blood counts on it. On my two trips across the United States, stopping at nearly every university and inquiring in every good sized town, concerning reac- tions to Chioromycetin, I was convinced of many things. No. 1, that every case investigated, the victim would in all prob- ability have survived the original illness had they not been given any Chloromycetin. No. 2, that I would not gain much information from my own pro- fession. A doctor in Charleston, W. Va., Dr. William Thornhill, who had lost a 16-year-old son with five capsules was very helpful, but an internist in Colorado would have no part in helping me, saying "My daughter is gone. It was God's will." A psychiatrist in Oregon would not even see me. In all, we had rec- ords of around 30 physicians who either died or lost a member of their family. I feel convinced that many victims have been signed out as leukemia, and any doctor who had lost a case through his ignorance and malpractice would not leave a stone unturned in an attempt to cover up his malfeasance. This was way back in 1952. Doctors were particularly hard hit in those days, as I was, because we had great faith in Parke, Davis, we thought they could do no wrong, we thought if a Parke, Davis man came in our office and told us something was good, it was good. And that is the reason that this list we have here of doctors who have lost their life or their wife or one of their children were hard hit. And all of these, I think, have notified Parke, Davis. And this was previous to 1952. Some doctors are always comparing the calculated risks of using this drug with anticancer drugs and other dangerous drugs seldom used, usually used in hospitals, and only used in almost hopeless cases. They do not try to understand this drug is used on relatively healthy innocent little children with mild pharyngitis or some similar disease. In my records of many deaths, most of these victims had sore throats or urinary infections, although quite a few were treated for acne. You take a culture of someone with an infection in the hospital or throat or otherwise, and then you culture this on an agar medium. And Chioromycetin always comes back, it is always the drug, it is always the drug of choice, it is always No. 1. It is the one that the organism is sensitive to. Doctors were very much impressed with that until they became better informed. Doctors are impressed with in vitro studies in which Chioromycetin is always shown to be the really effective antibiotic-they do not stop to think that carbolic acid in the agar plate culture would give a simi- lar inhibiting, growth reading because it, too, is poisonous. I think Chioromycetin is so toxic that it kills the germs in the agar plate. As I say, many other poisons would, too. But the thing we have to understand is that doctors are human. We are in a competitive pro- fession, believe it or not. Every doctor is competing in the healing art, and he wants to make and perpetuate a good image of himself as a healer. So naturally he wants to use the drug that is going to give results, because that is the way he gets his patients to come back to him. PAGENO="0455" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2589 The Government and the pharmaceutical industry must take steps to protect the public, which my profession has failed to do. Long be- fore the reactions were common knowledge, all reputable drug corn- panies knew Chloromycetin was a dangerous drug. Before I knew it in 1952, other men came in and told me, repre- sentatives of other companies told me this. They so informed their salesmen but warned them not to make the profession or public aware, not to talk against a competitive product. After all, they, in turn, might be detailing something dangerous. I told one or two companies in those early days, especially Eli Lilly in Indianapolis, that there should be a central policy-governing body to reprimand and inhibit the unprofessional conduct and unethical practices of a few-otherwise they would all fall victim to severe Government supervision of their entire industry. The day is here, and many restrictions are already in evidence at this time. If, as Parke, Davis advises, this drug should be used for typhoid fever-where I am told it converts many acute cases into chronic carriers-and for rickettsial fever and salmonella, what do you think the gross sales would be since there are so few cases of these diseases in our country? Do you know anyone that has typhoid fever or any of these diseases? As a professional, I haven't seen one case of typhoid fever in 10 years. Compare this gross figure of, say, approximately $100,OQO- Senator NELSON. I believe you are talking about the cumulative sales over a period of time. I believe the sales were $70 million worldwide in 1966, and $45 million in the United States. Dr. WATKINS. I am not sure. It seems to me like I have a recollection of the sales being close to $200 million. Dr. FARMAN. $40 to $50 million. Mr. ELFSTROM. In 1960 it was $60 million. Dr. WATKINS. I thought it was very high in the fifties. I knew it was the most commonly used. Senator NELSON. I am talking about the testimony as to current sales. I don't know what it was in previous years. Dr. WATKINS. Compare this gross figure of, say approximately $100,000, if it were sold and used for diseases in which it might be of benefit, with a known calculated risk, to the millions grossed from the misdirected and criminal use of Chloroinycetin. I have a large, general practice averaging approximately 40 patients daily in the office, and numbering six to 12 patients in the hospital all the time. Although I have not ordered Chloromycetin for any patient in the last 16 years, and have not lost one patient with infection, I have had consultants on my cases use it. And never once, so help me God, have I seen a patient saved or benefited by the use of this drug. You say, what h:appened to it? For instance, we had a case this year that had a subacute bacterial endocarditis. The man was supposed to be allergic to penicillin. We tried various things, and nothing worked. And my consultant had permission to use chloramphenicol. I was interested in saving his life. It was a calculated risk, he would have died anyway. We had him on it for a week. It did nothing for him. And then we had to take a chance. He was supposedly allergic to peni- cillin, but we tried penicillin. And the man got well. PAGENO="0456" 2590 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I have talked to my colleagues and some believe they have on occa- sions seen good results, but I would feel in many of these oases another antibiotic would have done just as well. They resorted to Chloromy- cetin before I would have used it. The statistics offered by Parke, Davis for many years of one death to 400,000 users were challenged time and time again by reputable men. We challenged them away back in 1952. In my little area of 15,000 people north of Glendale, north of Pasadena, and north of Los Angeles, when this happened to my son, we had four cases within a radius of 4 miles, four cases. Now, you can magnify that over the whole United States. And they say one case in 400,000. But the company aware of the discrepancy continued to advertise this ratio, because no one or no organization had the power to force them to be truthful and accurate. Now these odds have been reduced to what we estimated 12 years ago, and if the truth were known and these little victims were not signed out as leukemia or other similar blood diseases, then this ratio percentage of odds would be much further reduced. This drug poisons in some degree every person who uses it. There is absolutely no way to prevent or to foretell where and when it will kill. The UCLA scientist said that. Everyone who uses this drug is poisoned in some way. Most of them recover. There is absolutely no way to pre- vent or to foretell when and where it will hit you. I mean this idea of a blood count every day does not mean very much. It might pick up some cases. But most of these cases have been recorded after they had the blood count, after they were ~ut of the hospital when they first showed evidence, like my son did, weeks later. Since most aplastic anemia cases die of brain hemorrhage can we not believe that many of the young and middle-age people who suddenly have a brain hemorrhage may. have at one time been treated with Cliloromycetin. It is unbelievable that this drug has been allowed outside of hospital use for the past 15 to 16 years. Personally, I have little or no faith in its value over penicillin, tetracyclines, and erythromycins. The abuses of this drug dates back to the time doctors were errone- ously told as was I, that Chloromycetin was the only absolutely safe antibiotic. Parke, Davis deliberately lied to me at the time I was given the drug. Now all these years later, although doctors have been warned by advertising in medical journals, by lectures, by newspapers, by magazine articles, even by radio and television-still my profession continues to use Chloromycetin indiscriminately. In my own small community of approximately 16,000 people, the drug is being prescribed. A few years ago, some really good friends and former patients called me in sheer desperation because their daugh- ter whom I had cared for as a small child had been, without her par- ents' knowledge, given Chloromycetin for acne while attending the University of California at Santa Barbara. She was dying of aplastic anemia at the UCLA Medical Center and the family thought I might know, because of my interest in this drug, of some successful treatment. They could not believe that 10 years after our own tragic loss that they so well remembered that practicing doctors were still prescribing the PAGENO="0457" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2591 drug. This tragedy has been repeated time and time again, and will continue as long as the drug is not restricted in its use. Would any of you gentlemen take the drug? Is there any doubt that if your doctor examined you in his office and said you needed an anti- biotic, do you think you might just look at the prescription and ask your doctor friend what antibiotic he is giving you? The public cle- serves the same consideration and protection you, knowingly now, can afford yourself. Senator NELSON. Thank you, Doctor. Dr. WATKINS. I have one other letter here. This is from Dr. Wmt- robe, who is, I think, head of hematology; he is a very well-known pro- fessor at Salt Lake City. This letter was written-I think it is the month of my tragedy; I wrote my letter on May 5. Senator N]~LsoN. What year? Dr. WATKINS. 1952. And he had had correspondence at this time with Parke, Davis. He told them of the toxicity of this drug. I have an- other letter from a doctor-we were trying to inquire from someone that we had heard had died in Michigan. And here the doctor writes me and says he could not find out any information. He says the reason is the family is in a bad mental state, and he thinks if he inquires into this that it might upset them more. That is what I heard all the way across the country. It was either God's will or he didn't want to upset the family any more. Here is a letter written in 1953 from a M. D. Levin, Baltimore, Md. He says he thinks it is a dangerous drug. And he says, "My personal experience not only supports your statements"-he is writing this to a doctor who had written about it being harmful-"but I would confront them with the statement that I personally warned the manu- facturer relative to this synthetic product quite a while ago." This was in 1953, in September. They had adequate information. And again I want to tell you how I nppreciate the opportunity to come before you. And I feel that if something can be accomplished by this, that my son, Dr. Farman's daughter, Mr. Elfstrom's daughter, and probably hundreds of thousands of others probably will not have died in vain. Senator NELSON. Counsel advises me that the figure I gave of $45 million in sales in 1966 were wholesale figures, so that it would be a higher amount on the retail level. Dr. WATKINS. There is a little profit on it. Senator I4~NG. I would like to question you about what you are saying here; that is, that assuming that this drug will kill, the number of deaths are far greater than anyone in this room knows. We lawyers used to joke about it. You take out title insurance. You think someone has good title to a piece of property he is selling, but we insure our- selves against our error, so that the insurance company will make good the loss in the event we make an error. Lawyers always joke about it, saying that doctors have an advan- tage over lawyers; doctors can bury their mistakes-and they fre- quently do. Now, in this particular case, just from my own practical experience, I know that doctors are very reluctant to admit they made a mistake. Dr. WATKINS. Yes, very. PAGENO="0458" 2592 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator LONG. Even if it were because someone lied to them or mis- informed them, they are very reluctant to admit that they made a mistake. I argued with my brother-in-law, who is a doctor, about whether I should pay a bill when a doctor improperly diagnosed the disease of a relative. And he advised me to go ahead and pay it, understanding what the problems are in medical practice. Being a doctor himself and the son of a doctor, he felt that I should by all means pay it. I recall another case where a friend was suffering some malady, and a very reputable doctor advised him that this was a disease that was bothersome, but by no means serious, and advised him of what the treatment should be. Subsequently, he went to one of the outstand- ing clinics of the country, where his disease was diagnosed as cancer. The doctor who made the original diagnosis insisted, and stuck by his original conclusion right up to the point where they took out part of the body, and there was a great big piece of cancer. So, if he had stayed by the original diagnosis, the man would have been dead. But there is no doubt about it, if your statement is correct-that these people die of this drug, that these figures-i in 400,000-might be off by 2 decimal points. And I assume that you believe that that is quite possible? Dr. WATKINS. Very definitely so; much higher than any estimate that has been made so far. For that victim the statistics are 100 percent. Senator NELsoN. Is there any place in FDA or anywhere else in the country where there is a record kept of all the known cases? Or is there any known procedure by which they are reported to any central place in the country? Dr. WATKINS. Not that I know of, but there again you are going back to the physician. And I am loyal to my profession. I think it is the most wonderful profession on the face of the earth. But doctors are human beings, and they have the same weaknesses that anyone else has. And the average doctor is not going to admit a mistake if he can help it; I say the average. And for something as serious as this, if there is any way he can get out from under it, I think he will. I think it is proven. Senator LONG. If he admits a mistake-and let's face it, doctors do make mistakes like anyone else-he is subject to the patients or at least the patients' relatives, going all over town an'd telling everyone they know that that doctor just killed that victim by preseribin~ the wrong drug. And that is a very grave injury to a doctor, I take it, to have that happen, when people go over the streets of his hometown saying that he killed somebody by prescribing the wrong drug. Dr. WATKINS. That is true. I made a habit for years after this of going around to Parke, Davis at the AMA conventions and asking the reactions to this drug. They say, it has never been proven. I think they will tell you today that it has never been proven, they took aspirin or other things at the same time. Senator LONG. The as~pirin might have killed him. Mr. ELFSTROM. That is what they told me. Dr. WATKINS. It has never been proven. I have a letter from a doc- tor in St. Joseph, Mo., a very good friend of mine. And this was after the thing broke. And the salesmen were coming in and telling him PAGENO="0459" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2593 this. He said, "It might be of interest to know that Parke, Davis is now detailing this drug in this area. One was here in the past month, and I told him of your experience with the drug, and he denied that anything such as that was happening in the country." Senator NELSON. What year was that? Dr. WATKINS. This was in 1952. But this was long after all this broke, all this news broke, because my trouble happened in May, and they were forced to admit this trouble in June, I think, or July of that year. This was in December. Senator NELSON. I take it from your testimony on page 5 that you believe that this drug should only be administered in a hospital. Do I understand you correctly? Dr. WATKINS. It is my opinion anyone sick enough to take Chloro- mycetin is certainly sick enough to be in the hospital. Senator NELSON. We have had testimony by previous medical ex- perts here suggesting that it should be administered only in hospitals, and Dr. Gilman makes the same contention in his book on therapeutics, Goodman `and Gilman, "The Pharmacological Basis of Therapeutics." Would you suggest, then, that the FDA or somebody be authorized to require that this drug be confined to hospital use? Dr. WATKINS. Absolutely, without any qualifications. Senator NELSON. It has been suggested by some that this would be in- convenient, because some people are out in rural areas away from hospitals, and so forth. How do you eyaluate that? Dr. WATKINS. I would say that if, as they recommend, they have a blood count, if it is that rural, if it is that behind the times, they prob- ably don't even have a means of taking a blood count of a patient. So I would feel today-this is America, and I think there are enough hospitals, I don't think there is any place where it would be impossible to get them into a hospital. I think it should be confined to them. Senator NELSON. I notice that Goodman and Gilman say on page 1246, among other things, that chloramphenicol should not be used on an outpatient basis unless the physician and patient arrange and ad- here to a definite followup schedule with visits at least every other day. Dr. WATKINS. I agree with that. But there again, what is he going to do when he sees them, if he takes ablood count? Here is a letter from the Mayo Clinic I would like to submit for the record but will read the last paragraph: "The point that seems most important to me is the matter of sensi- tivity that develops to the drug and consequently the inability of fol- lowing blood counts in order to avoid disaster in case the patient hap- pens to be one of the sensitive individuals." (The letter referred to follows:) MAYO CLINIC, Roclze8ter, Minn., June 7, 19~W. ALBE M. WATKINS, M.D., La Canada Medical Center, La Canada, Calif. Mv DEA.a Dn. WA~rKINs: Your recent letter to me has been held until I returned from a short vacation, consequently the delay in answering. I can certainly sym- pathize with you and know that any words we might offer are of little solace in view of the loss of your son. I am quite sure that steps are being taken to both recognize and publicize the effect of Ohioromycetin on the bone marrow and that in due time it will take its PAGENO="0460" 2594 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY proper place among our therapeutic agents, strictly in the field where it is re- quired and where the risk of its use wifi have to be balanced against the need of its therapeutic ability. I have already presented at our Staff Meeting a report of ten cases of aplastic anemia secondary to Ohioromycetin therapy. Six of these cases are already dead. This report will be published in the Proceedings of the Staff Meetings of the Mayo Clinic and I am sure that you receive these Proceed- ings regularly. If not, we should be very happy to send you a copy of this report. The cases, I believe, will be published in their entirety and there may be fur- ther follow-ups on the cases that are occurrent at the moment, by the time publication is complete. I could not, of course, supply you with the names and addresses of these patients for obvious reasons but the material in the Proceed- tags are, of course, open to all of the professions once they are published. Other hematologists, I am sure, are going to follow suit and publish their cases, in which Ohioromycetin is the etiologic agent or at least the common denominator in these cases of aplastic anemia and I would think that within a period of six months many reports will be available and that Chloromycetin will have been put in its proper therapeutic niche. The point that seems most important to me is the mat- ter of sensitivity that develops to the drug and consequently the inability of following blood counts in order to avoid disaster in case the patient happens to be one of the sensitive individuals. I do appreciate your confidence in writing to me in this hour of trouble and while time will never erase your sorrow I do hope that it will soon lessen it. Sincerely yours, M. M. HARGRAVES, M.D. Dr. WATKINS. The inability of the blood count, that is what he says, Dr. Hargraves, of the Mayo Clinic. This was back in 1952. Senator LONG. Let me understand this, because apparently this com- pany would contend that you are prejudiced, and there is no proof that this drug is what actually caused it, that these things might have happened anyway. Now, do I understand it that reputable institutions like Johns Hop- kins share your feeling that this drug may very well be causing these deaths, and that therefore, they would wish to use extreme care when this drug is administered? You say Johns Hopkins said that it should only be used when you have two doctors, is that right? Dr. WATKINS. Yes. That is what Dr. Conley told me at Johns Hop- kins in 1952. Senator LONG. Are there other well known hospitals or organiza- tions of doctors which have taken the same attitude toward this drug? Dr. WATKINS. The Los Angeles County General does. That order has to be countersigned. Senator LONG. So in Los Angeles County General they would insist that the order be countersigned? Dr. WATKINS. Many hospitals have this requirement. Mr. ELFsm0M. I think if you made a survey of all the hospitals in the country, you would find quite a few that have that requirement. Senator LONG. So there are quite a few hospitals that have con- cluded that you are right about this matter; this is what has caused these deaths. Mr. ELFsm0M. It is my understanding, Senator, that the Food and Drug Administration has this authority now to restrict the drug's use, to restrict the drug to the hospitals. In fact, they have the au- thority to take it off the market if they choose to. But we have never asked for that. Senator NELSON. I am not sure as to what legal authority we have. Dr. Goddard will be testifying tomorrow. And this among other questions will be raised with him at that time. PAGENO="0461" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2595 I think~I should say for Senator Long's benefit that the company does concede that in a certain number of cases, say, rarely, various blood dyscrasias do occur, including aplastic anemia. And they in- clude that information, as they have been required to do since 1962, on the package insert, in their precautionary statement. I think one of the problems is that despite the precautionary state- ment, a substantial number of the medical profession still continue to prescribe Chloromycetin for minor infections such as head colds and acne, and so forth and so on, whereas it should only be pre- scribed, according to the medical testimony we have heard, for typhoid fever and other groups of infections in which the disease is very serious, and for which there is no other antibiotic that will effectively do the job. The tragedy is that it is being prescribed for all kinds of cases in which it is not indicated. But the company does not deny that. Senator LONG. They have a patent, and they want to make a big profit every time it is used. And they get about 50 times what it costs them to manufacture it. Dr. WATKINS. Here is a brochure that came out, I think, in 1959, from the company, and right down here at the bottom it says "This is using it on dogs"-"Anemia developed in various degrees in these animals." And this is 1959. Senator NELSON. What is the pamphlet? Dr. WATKINS. It is Ohioromycetin from Parke, Davis. They knew about it in. dogs in 1959. Our tragedy was in 1952. His tragedy was in 1960. Mr. ELFSTROM. I think in the testimony before Senator Kefauver's committee, which I followed very closely, there was evidence in- troduced that a Dr. Radomski, who was with the Food and. Drug Administration at the time, had made a study of the drug on dogs, and had found some fatal effects from anemia. I think Dr. Radomski is now down at the University of Miami. Senator NELSON. I think that is conceded scientifically. One of the facts that we do not know is the precise incidence of blood dyscrasias, aplastic anemia, and so forth, because there has not been any really accurate statistical compilation. The statistics have always been guesses. As Dr. Watkins testified, it was once claimed that aplastic anemia would occur only once in 400,000 cases, and once in 200,000 cases, but there has not been a very scientific com- pilation of the statistics. So I think it is conceded by the experts at least that these are all sin~ply guesses. Is that not correct, Dr. Watkins? Dr. WATKINS. Yes, sir. Mr. ELFSTROM. In California, the department there states they can conservatively estimate the incidence as 1 in 21,000. Senator NELSON. Of .a~piastic anemia? Are either of you doctors aware of evidence of other serious blood d~scrasias which aren't in- cluded in the statistics on a~piastic anemia? In other words, are there other problems, other illnesses that occur as a consequence of this drug that do not result in a~plastic anemia? Dr. WATKINS. This has all evolved very slowly. You would not be- lieve the difficulty we had in the early days of trying to prove it, PAGENO="0462" 2596 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY against the con~any's wishes, of course, and all that they were trying to say, that aspirin and other things would cause it. But as this man from Mayo says, this is a common denominator in all these cases thait they got in the Mayo Clinic, and they `had a lot of them in 195~, the common denominator that these patients had taken was Chloromyce- tin. Not all had taken aspirin or phenobarbiital, but all of them had taken ChJoromycetin. So you had to do it the hard way. It has been a hard, uphill battle. And we said from the beginning that we thought many cases of leu- kemia `were caused by the drug-either was actually leukemia or they were signed out as leukemia. As I told you at the beginning, it takes an awfully good hematologist to tell the difference between leukemia and aplastic anemia in the early beginning. But there is a thought the Chloromycetin also causes leukemia, and I think there have been some published articles on that. Mr. GoIu~oN. In a recent iesue of the New England Journal of Medi- cine there is an article by Dr. William Dameshek on this subject. Dr. WATKINS. And I thmk once you prove that causing some forms of leukemia you are going to prove your statisti~s down to what it should be, that is all we want: honesty. If we had had an honest opinion in the beginning, the drug would have either been off the market or limited to hospitals. I honestly believe that the public would not have stood for this. But they had to really fight against a lot of opposition and money, because they really put the money around to the universities. Senator LONG. Doctor, I am going to have to leave to go over to the Senate Chamber. And `before I leave, I want to thank you for the testi- mony you have given here, and also to express my gratitude to Sena- tor Gaylord Nelson for his efforts to investigate this matter, and the related matters involved. I was once chairm'an of this subcommittee. When I became chairman of the Committee on Finance, Senator Nelson indicated to me `that he thought he had the time and would like to devote his effort to investigate the whole subject matter, and where abuses existed, to try to do something about it. I told him that at the time when he ran for reelection, he was not likely to get `a single campaign contribution, and it would probably assure him of a well-financed opponent on behalf of this $4 billion industry. But he has persevered, and I believe he is rendering a good service to the country as, for example, this matter and other disclosures th'at have been made in regard to abuses in the drug area. After some disclosures I and others made in earlier years, we in- sisted that there be prosecution for conspiracy with regard to the tetracycline use by certain companies; that is, a price-fixing deal. And the Justice Department finally mustered the initiative to go ahead and prosecuted the oases. And they were found guilty. And in this particular `area, I am most impressed by what you said about this. And I hope that we can obtain effective action on this. And perhaps one way or another they can do something aobut it. And it may be to require that they put `a label on that bottle and say in the opinion of many doctors, that this drug has been known to cause death. That is what you are saying, as I understand it. PAGENO="0463" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2597 Senator NELSON. We will now hear from Dr. Franklin Farman, from Lakewood, Calif. Doctor, we appreciate your being here today. STATEMLNT OP DR. FRANKLIN PAR~AR, LAKEWOOD, CALIF. Dr. FARMAN. I wish to thank you, Senator Nelson, and Mr. Ben- jamin Gordon, for inviting me to the hearing. It is a very great privilege and we hope we will be of some aid to the committee. I have a statement here that might fill in the background of this problem, as an introduction. I am a specialist in urology, and I belong to the American Medical and the California Medical Associations, and the American Urological Association, and the American Collsge of Surgeons. I wish to relate our experience with the Department of Health, Education, and Welfare, the American Medical Association, and Parke, Davis & Co., and to point out some of the reasons why chioramphen- icol should be restricted in its manufacture and use. In June 1952, we lost our daughter-S years old- through the ad- ministration of Ohioromycetin-trade name-manufactured by Parke, Davis & Co. Her death was one of many similar cases of blood dyscra- sias induced by the use of Chioromycetin which have continued to occur in the United States up to the present day. I quote from Dr. Walter 0. Alvarez, former Mayo Clinic clinician. Mr. Elfstrom also quoted from Dr. Alvarez. I wish to quote Dr. Alvarez, formerly of the Mayo Clinic, again. He stated in the Lincoln, Nebr. Evening Journal of November 24, 1952: The journal of the American Medical Association has had three articles tell- ing of nine such deaths, due apparently to the taking of chlorampheuicol. For these nine cases which are reported, there may well be hundreds more that were not reported. Senator NiasoN. In the case of your child, had you received any warning? Dr. FARMAN. Not personally. She was treated by our pediatrician. Senator NELSON. What was the nature of her problem? Dr. FARMAN. She had an upper respiratory infection. Senator NiiI1soN. Am I correct that the drug is not indicated as a drug of choice for respiratory ailments? Dr. FARMAN. It is not now, but in 1952 it was highly advertised for that. I will go into that later. Senator NELSON. Go ahead. Dr. FARMAN. This is true, even today-many cases of anemia and severe blood dyscrasia following the administration of Ohioromycetin are not recognized or reported. In June 1952 Mrs. Farman and I called personally upon the presi- dent of Parke, Davis & Co.-Mr. Harry Loynd-and asked him to re- move Chloromycetin from the market. Senator NELSON. You asked him to remove the drug from the mar- ket? Dr. FARMAN. Yes. We were right in his office, and we asked him to remove it from the market, and stated the reasons why. This he re- fused to do although it had been proven that Parke, Davis & Co. had been warned by various physicians that Chloromycetin was a toxic dangerous drug. PAGENO="0464" 2598 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY At that time, 1951, Chloromycetin accounted for about one-third of their gross sales, $40 to $50 million, out of a total of $138 million gross. This figure jumped to $86 million in 1960-mostly domestic market. Following our talk with Mr. Loynd, I went to Chicago and stated the facts to Dr. Austin Smith, then editor of the American Medical Association Journal. On June 28, 1952, Dr. Smith on the editorial page of the AMA Journal warned the medical profession of the Unit- ed States in regard to the dangers of the use of Chioromycetin. In ad- dition, several scientific articles appeared in medical literature in re- gard to blood dyscrasias resulting from the administration of Chloro- mycetin. And they have continued to appear in the past 15 to 18 years. In June 1953 Dr. Albe Watkins, of LaCanada, Calif., Dr. Patrick Corcoran, of Evansville, md., and I appeared before a committee of the American Medical Association in New York City. Through our efforts a resolution was passed by the house of delegates to the ef- fect that greater control in advertising of dangerous drugs should be undertaken. I might say that the passage of such resolution has very little effect, because it failed to curb hardly any advertising of the type that Parke, Davis particularly resorts to. Mr. GORDON. May I interrupt here for just a moment? A little further up on the page you say that on June 28, 1952, Dr. Smith, on the editorial page of the AMA Journal, warned the medical profession of the United States about the dangers associated with the use of Chioromycetin. Am I correct that this same Dr. Smith is now president of Parke, Davis & (Jo.? Dr. FARMAN. Yes, he is. I think he took over the first of the year, or last; year, which I hope is going to be a change in policy. Now, maybe this problem will be solved voluntarily. We may not need the legislation. Mr. GORDON. Thank you. Dr. F~uu~iL~N. Following the AMA convention in New York, Dr. Watkins, Dr. Corcoran, and I called upon the Department of Health, Education, and Welfare in Washington. We had a confere~nce with Commissioner George P. Larrick, then Deputy Commissioner, and Dr. Henry Welch, head of the Antibiotics Division of the FDA. Dr. Welch appeared to us to be quite evasive as to his department's responsibility. He seemed to feel they tested only for the purity of the product and not for the inherent danger of the drug itself or the claims of the manufacturer as to its safety and nontoxicity. It is a matter of public record that Dr. Welch was forced to resign his posi- tion in 1960, after having been exposed for cause by the Kefauver committee. In March 1953 we entered suit against Parke, Davis & Co. through our attorney, Mr. Thomas Bewley, of Whittier, Calif., for the wrongful sale-including advertising-and manufacture of Chloromycetin. A great many other suits were brought against this company throughout the United States for similar reasons. All of these suits were settled by Parke, Davis & Co. without court trial, including our own. In many cases the settlement was the highest amount allowable by the courts PAGENO="0465" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2599 for the death of a child. In our own case the money is being used as a memorial for the benefit of children. Since the Kefauver hearings Parke, Davis & `Co. have added warn- ings by package inserts of the potential dangers with the admini- stration of Chioromycetin. It was some time before these warnings were printed in fairly bold type which is easily readable to the medical profession. I call to your attention the Food and Drug Administration direôtive for adequate blood tests `during the entire administration of chioram- phenicol which, incidentally, can be carried out properly only in hos- pitals. Chloromycetin is still produced, as far as I know, from di- chioracetic acid, a known poison containing the nitrobenezene ring. You will find on inquiry that Chioromycetin is not produced in the same manner as other antibiotics. The manufacturer has stated "in its chemical nature, chloromycetin is unrelated to any other antibiotic"- this is `so; it is a synthetic drug produced from a toxic chemical. In my own mind, I don't classify it as an antibiotic, it is a synthetic toxic chemical. I think most of you `are familiar with the antibiotics, and how they are produced. They are really produced from mold or other `bacteria. And they have the `ability to inhibit the growth of other micro-organ- isms that cause infection. Dr. Watkins compared Chloromycetin to ca'rbolic acid. Well, this is `a synthetic `drug. And it'is produced from dichloracetic acid, which is `a known poison. I submit here an excerpt from my brief on Chioromycetin which was prepared for our `attorneys in 1953. (The material referred to follows:) A long list of diseases are given by Parke, Davis & Co. tin which (3hloromycetin is indicated clinically. Among these are: Bacterial Pneumonia Boutonneuse Fever Enteric Fever and Dysentery Epididymitis Gonococcus Infection Granuloma Inguinale Hemophilus Inthienzae Infection Herpes Zoster Infectious Mononucleosis Laryngotracheobronchitis Lymphogranuloma Venereum Measles Mumps Pertussis Primary Atypical Pneumonia Prostatitis Psittacosis Rocky Mountain Spotted Fever Scrub Typhus Surgical Infectious Syphilis Trachoma Tularemia Typhoid Fever Ulcerative Colitis Undulant Fever Urinary Tract Infections Typhus Fever 81-280 0-68-pt. 6-30 PAGENO="0466" 2600 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. FARMAN. They advocated in the early fifties some 28 diseases for which the drug could be used safely. This list has been reduced by pressure from the AMA and the FDA to about three, I mean typhoid fever and certain types of dysentery and meningitis. But very subtly Parke, Davis & Co. advertised its use for respiratory in- fection. Now, to my mind, this accounts for the great sale in the United States, because there are a lot of colds and other respiratory infections. Well-known authors state that the administration of chiorampheni- col always produces change in the bonemarrow, some degree of anemia or blood dyscrasia such as aplastic anemia. There are still being reported unfavorable reactions and deaths following the administration of Chloromycetin. One questions why this should be. It would seem the answer lies in the effect of advertis- ing-to which not only the lay public but also the medical public is susceptible. I know of no more tortuous death-as Mr. Elfstrom has brought out, and also Dr. Watkins-especially in children, than that of blood dyscrasias following the administration of this drug, `Chioromycetin. It would seem this company should long ago have removed from the market voluntarily the manufacturing of this synthetic chemical agent. If a physician desires to give Chloromycetin, it should be done under the most controlled condition of hospital administration and then only if the patient or his guardian is in full understanding and agreement. This is not taking the practice of medicine away from the doctor, it is only laying down the ground rules for good medical practice, protecting both the doctor, the patient, and the drug manufacturer. I have another little statement. I could enter it now or later. It is a suggestion from a doctor as to the matter of control. Senator NELSON. Go ahead right now. You are making a suggestion as to how the administration of this drug should be controlled? Dr. FARMAN. Well, it deals with the cost of drugs, and brings it out; it is very short. Senator NELSON. Sure. Go ahead. Dr. FARMAN. The cost of prescription drugs sold over the counter could be reduced by limiting the profit-now, I know this is very diffi- cult-of the manufacturer to a reasonable rate of return. It is my understanding that these manufacturers make a thousand percent, frequently, in the manufacture of drugs sold. The manufacturer could lower overhead and pass the benefit on to the consumer of prescription `drugs, and in the treatment of sick people. Three, promotional activities and extravagant advertising should be eliminated as a means of the distribution of prescription drugs. Four, in a sense, the large pharmaceutical firms have usurped the teaching of therapeutics after the doctor graduates from medical school. Five, new products should be introduced through the State univer- sities, or possibly State medical societies. The Council on Drugs of the American Medical Association has been helpful to the doctor. Six, the so-called detail man should be restricted in his activities, or eliminated from the doctor's office. There is a better way to obtain reliable drug information. PAGENO="0467" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2601 Senator NELSON. Thank you, doctor. You also suggest, as other doctors testified here have, that the drug should be administered only in a hospital; do I understand you correctly? Dr. FARMAN. Yes. A drug of this type-it is a toxic chemical, but there might be a few cases in hospitals where under proper supervision it could be administered safely. The trouble is, it is prescribed-the average general practitioner in the United States is too busy to be properly informed. They listen to the detail men, and they also read the `drug ads. And so so they prescribe anything that is advertised to them. But I feel that we are here-that is one purpose of our trip here, to get the FDA, or possibly Congress, to begin to pass legislation which is going to help the country. Senator NELSON. It has been suggested in previous testimony here that there are various methods which could be used. One of the sug- gestions that was proposed is that perhaps the FDA could be author- ized in consultation with the medical profession to designate certain very toxic drugs such as Chloromycetin as a special category of drugs, and determine the procedures under which they could be administered; that is, they may list whatever drugs are considered to be very dang- erous such as Chloromycetin, and simply require that they be admin- istered only in a hospital-or, as other testimony has been given, that you require that some of these drugs be handled in the same way that morphine is, for example. Would you think that some general procedure such as this would be workable? Dr. FARMAN. Yes, I do. I think we `are coming to a point in the United States where we should do something helpful. I think the laws don't quite cover yet the food and drug industry properly. I am very mudh in favor of eliminating Ohloromycetin from the market-if Dr. Austin Smith were `here today, we could ask him just to remove the `drug from t'he market and it would be very simple for you and the rest of us, `and I think maybe he would do it. And then we don't have to pass legislation. it is not a drug that you need. There are many other safe drugs that you can use. Of course, they won't claim that, and if you own stock in Parke, Davis, why you are interested in sales. But `here we are dealing with a human element. And we think the time has come when concerted action should be undertaken-I mean `both by the doctors and Mr. Elfstrom, the editor of the newspaper. It is hardly conceivable that this thing has `been going for 18 years, since 1950. Senator NELSON. `M'r. El'fstrom. Mr. ELPSTROM. I have a comment or two to make. I have qui'te a few `articles in my newspaper about various disasters t'hat have resulted from the indiscriminate use of this drug. And I am sure it `has been read by most of the physicians in the community, many of whom are familiar wit'h what I have been doing. But a short `while `ago I got a telephone call f mm a druggist in a neighborhood town `where `we circulate quite heavily. And he said, "The doctors here are prescribing Chl'oromycetin like `mad for the flu." Senator NELSON. For the flu? Mr. ELFSTROM. For `the flu. And here, `after not only t'he warning PAGENO="0468" 2602 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY that goes with the package, but all that has been in my newspaper, it is still being ignored. Another thing, we have spoken of the torture of a Ohloromycetm death. I `hate to describe it, because it brings back memories that I try to forget. But the body `gradually disintegrates. It gets ulcerated all over, and then bleeds to death. And to see a beautiful, healthy body deteriorate like that is just beyond description. Senator NELSON. Dr. Watkins. Dr. WATKINS. I would say a third of my son's body was gangrenous before he thed, a third of it, `black, smelly terrible. We could hardly stay in the room. A third of it. A friend of mine came in and said, "How can you put up with this?" And I said, "What can you do?" And `he said, "Why don't you put him to sleep?" I said, "He may never wake up." And `he said, "How can you stand it?" And so I put him to sleep, and `he never woke up. A third of him was gangrenous. Pursuant to what Dr. F'arman said, here is a letter from a man in Baltimore-you see, this drug originally came from the soil of Venezuela. It was rather expensive to bring this soil in and extract this Chloromycetin, or the name of this particular antibiotic from it. So Parke, Davis developed `this way of making it from this dangerous chemical that Dr. Farman brings up. He says: I personally warned the manufacturer relative to this synthetic product quite a while before any of the unfavorable results from its use came to our attention. This was in 1953. So here is a man, a scientist, that warned them that this synthetic drug, which costs `about 8 cents a capsule and sells for 60 cents-that is `a pretty good profit-it costs a lot more to bring it in from the soil than to do it naturally. Mr. ELFSTROM. Now, there is a peculiar circumstance in connection with my daughter's death. A few days before her death there was a woman in the hospital laboratory who came to us `and said that `they had a prayer circle in their churth, which was down at Newport Beach, and t'hey met the following day, and they would be glad to include our daughter in `their prayers-which we were grateful for. And she also said that her husband, who was the minister of the church there, `the Episcopal church, would he very glad to come up and offer what comfort he could, and would we like it. And we said, under the circumstances, we were in shock, we would like it, yes. And he was `a very dedicated man of God. He came up and he spent 2 days with us, and the last hours with our daughter. He witnessed her death, and how terrible it was. His name was Rev. John Parke, and I didn't know it at the time. A few weeks after her death, we went down to see the Reverend and brought a donation for his church in our daughter's memory for the help `that he had been. And we asked `him if he could suggest any way that we could help others. And he said, "I happen to be the grandson `of Parke of Parke, Davis, who has long since been out of the company," but, he said, "I will be glad to write to the president of the company `and explain to him wha't I have witnessed `and urge that something be done about it." PAGENO="0469" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2603 He got a very diplomatic reply from President Lloyd that was noncommittal. Mr. GORDON. Mr. Chairman, I want to make sure that all letters, articles, and other documents that have been referred to will be supplied for the record. Mr. Elfstrom, would you please make sure that we get them? Senator NELSON. The committee appreciates very much your coming all the way here from California. Your testimony is a very valuable addition to the record. And I am hopeful something coiistructive will result from it. We realize how much time each of you has put into trying to educate the public and the profession about the problem. You have made an invaluable contribution even prior to your being here before the committee, and we thank you very much. Mr. ELrsmoM. Thai~k you, sir. Senator NELSON. We will adjourn until 10 o'clock tomorrow morn- ing. Our witness will be Dr. James .L. Goddard, Commissioner of the Food and Drug Administration. (Whereupon, at 12:10 p.m., the subcommittee adjourned until Thurs- clay, February 29, 19&8, at 10 a.m.) PAGENO="0470" PAGENO="0471" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THURSDAY, FEBRUARY 29, 1968 U.S. SENATE, MONOPOLY SUBCOMMITTEE OF THE SELECT C0MMITrIE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to recess, at 10 a.m. in room 318, Old Senate Office Building, Senator Gaylord P. Nelson (chairman of the subcommittee) presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist; James H. Gross- man, minority counsel; Susan H. Hewman, research assistant; and William B. Cherkasky, legislative director, staff of Senator Nelson. Senator NELSON. The hearings of the Subcommittee on Monopoly will come to order. *This morning we have as our witness Dr. James L. Goddard, Com- missioner of the Food and Drug Administration, U.S. Department of Health, Education, and Welfare. * Dr. Goddard, we are very pleased to have you back again to testify before the committee. You may proceed as you see fit. I trust you would have no objection to interruptions for questions. STATEMENT OF DR. J~AMES L. GODDARD, COMMISSIONER OP THE FOOD A1Th DRUG ADMINISTRATION, U.S. DEPARTMENT OP HEALTH, EDUCATION, AND WELFARE; ACCOMPANIED BY WIL. LIAM W. `GOODRICH, GENERAL COUNSEL, AND DR. HERBERT L. LEY, DIRECTOR, BUREAU OP MEDICINE Dr. GODDARD. Thank you, Senator Nelson. I would like to introduce my colleagues, Mr. William Goodrich, the general counsel for the Food `and Drug Administration, on my left, and on my right, Dr.. Herbert Ley, Director of the Bureau of Medicine. Mr. Chairman, I appreciate `the opportunity of appearing before your committee today to discuss the Food and Drug Administration's action and intentions in regulating the interstate distribution on the antibiotic drug, chloramphenicol. The Nation has watched with great interest the testimony unfolding before this committee in the past weeks. The committee's hearings have brought renewed attention to important questions that concern us all: Is this a drug too dangerous to `remain on the market? Should its use be restricted in some way? Are the FDA, the medical profession, and 2605 PAGENO="0472" 2606 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the manufacturer of the drug taking all necessary steps to assure the safest possible use of the drug? Before discussing these questions and alternatives, however, it may be useful to outline what has been done in the past. Chlorampheniool was first isolated in 1947 from a soil sample collected in Venezuela. It was found that liquid cultures of the organism, Streptomyces venezuelae, possessed marked effectiveness a~a.inst several Gram nega- tive bacteria and also exhibited a.ntirickettsial and antiviral activity. Shortly thereafter the chemical structural formula was deternuned and the antibiotic was prepared synthetically. And, as you know, it was later patented by Parke, Davis & Co. In 1948, chioramphenicol was produced in amounts sufficient for clinical trials and general clinical use. It was found to be of value in the therapy of a variety of infections, including epidemic typhus in Bolivia and scrub typhus and typhoid fever in the Malay Peninsula. Mr. GoRDoN. How about the United States? Dr. GODDARD. I am talking now about the early uses of it, where it was used against epidemics particularly. On January 12, 1949, the Parke, Davis New Drug Application for Chloromycetin, that company's brand of chioramphenicol, was al- lowed by FDA to become effective. This followed clinical trials in the United States on appropriate types of infections, Mr. Gordon. In the summer of 1949, as the result of new legislation, chloromy- cetin was classified as a "certifiable antibiotic," subject to the batch certification provisions of the Food, Drug, and Cosmetic Act. Senator NELSON. In the New Drug Apjilication, did any of the experimental data submitted to FDA indicate the development of blood dyscrasias or other adverse side effects? Dr. Lrx. None, sir. Senator NELSON. How long did they experiment with it? Dr. GODDARD. Clinical trials, Dr. Ley, went forth over about 18 months? Dr. LEY. From early 1~48 until 1949, as I recollect, was the period that the clinical trials were in progress, both overseas and in this country. Senator NELSON. These were first on animals, I take it? Dr. GODDARD. It would have been animal work on toxicity, "LD 50's" and things of this nature would have been carried out. But the clinical trials were directed toward the patients with specific in- fectious diseases. Senator NELSON. I notice in reading the literature, and some of the testimony, that the experts always strongly urged or state that it is necessary that continuous blood tests be made, and that as soon as any changes are indicated in the blood, therapy be stopped immedi- ately. You mean that in all these trials they saw no blood changes at all? Dr. LET. Senator Nelson, in some of the early work in the Malay Peninsula, I was involved myself personally. We studied at that time the early report in 1948, covering about 50 patients with scrub typhus, and two patients with typhus fever. We occasionally noted drops in white blood cell count in these patients, who frequently, by PAGENO="0473" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2607 the very nature of their disease, had low white blood counts. At no time in the early studies did these drops become of significant im- portance, so that we elected to terminate therapy. Official recognition of the serious problems in terms of blood anom- alies resulting from the drug was not made until about 1950 or 1951. Senator NELSON. Do you mean. to say that in the testing on animals, where the range of experimentation would be much more flexible, they did not try dosages of such a nature that demonstrated dramatic blood changes? Dr. LEY. Yes, Senator Nelson. In some of the animal studies which were conducted about 1950 or 1951, in dogs specifically, there were `changes observed in the nature of temporary depression of bone marrow, anemias, which `are quickly returned to normal after the `drug was, discontinued. At no time, however, in dogs, as I',, understand the evidence, has an aplastic `anemia been ~bserved or described. Now, our expert committee pointed out that `any hinnain being will respond with a temporary decrease in hemo~lobin when given this drug. This normally disappears promptly `after the therapy is terminated. The estimate is that two grams `a day. will produce detectable tem- porary drops in `hemoglobins in about 50 percent of the individuals receiving the `drug. Senator N1n~soN. You are `saying, as I understood it, that these blood dyscrasias were noticed in 1950 and 1951. But I am saying what about the experimental data on `animals submitted with the New Diii Application in 1949? Did the company indicate `anything on bloo dyscrasias at all? Dr. GODDARD. No, sir. Senator NELSON. They did not? Dr. GODDARD. No, sir. In fact, it was not until 1953 that FDA itself carried out `animal studies, dog studies, `as a result of some of the problems being demonstrated in humans. The early studies on this drug, of course, suffer all the problems that we have to live with in drug `studies-as greater experience is gained `in wiiait we call phase 4, these adverse reactions then `begin to become `apparent. But to my recollection and to Dr. Ley's recollection, there was nothing in the New Drug Application that indicated that the `animal studies displayed `any problem's in the early stages. Senator NELSON. Did I understand from the testimony that there were `animal studies made prior to the application for marketing of the drug, and' that those studies were submitted to the FDA at the time? Dr. GODDARD. That is my recollection. We can dig that up `again. But we have looked at it, and I recall that there were animal studies. I will have to look again. Senator NELSON. Given a certain amount of this drug, a certain number of grams, the testimony has been that you get a blood dys- crasia, almost always, apparently. And I am just wondering why in the experimentation with animals, when they, could use larger dosages PAGENO="0474" 2608 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY than in human experimentation, that they did not discover anything that would warrant the attention of the FDA at that time concerning the side effects of this drug. Dr. GODDARD. Senator, let us reexamine the original NDA and see what that discloses. But I will also point out that the studies required at that time were not to the degree and depth that they have been since the 1962 amendments. They were not as sophisticated-the animal studies, I am speaking of-as they now are. So therefore it is quite possible that this was missed at that time. (The subsequent supplemental information follows:) STATEMENT OF THE FOOD AND DRUG ADMINISTRATION CONCERNING ANIMAL SrunrEs CONTAINED IN THE ORIGINAL CHLOROMYCETIN NDA Clinical use of Chieromycetin was originally proposed in NDA 6655. Sometime after the INDA was made effective, the drug was made certifiable. A reprint of an article by R. H. Smith et al. (Chioromycetin: biological studies, J. Bact. 55: 425, 1948) was filed as part of the NDA. Although the bulk of the article deals with microbiological studies, the following animal experiments are reported: 1. Acute toxicity studies in mice (I.V., S.C. and P.O.) and dogs (I.V. and I.M.). 2. Subacute toxicity studies in mice (S.C. and P.O.), rabbits (S.C.) and dogs (I.M. and P.O.). 3. Absorption and excretion studies in dogs. Senator NELSON. Go ahead. Dr. GODDARD. When citloraanphenicol was first introduced in 1949, it was widely heralded as a broad-spectrum antibiotic, effective against an impressive range of micro-organisms. It was also considered to be largely nontoxic. There was no indication at that time that the drug had any serious side effects. Early in 1950, however, a few published reports drew attention to the possibility that chioramphenicol might cause serious and fatal blood dyscrasias. The 1951 edition of New and Non-Official Remedies warned that "changes in the peripheral blood or blood forming or- ganisms have been reported during the use of chloramphenicol." An editorial in the Journal of American Medical Association, June 28, 1952, referred to additional reports of blood disorders. It went on to say- A second and mere serious type of reaction that has been encountered is production of a true aplastic anemia. In the experience of one group this anemia has occurred in patients who have previously received one or more courses of chioramphenicol without untoward effect. When the drug was subsequently administered, even in small doses, a severe blood abnormality has appeared. Even deaths have been reported. In response to these reports, FDA conducted a nationwide survey of case records in hospitals and clinics in an attempt to evaluate the magnitude of the problem and to determine whether a cause and effect relationship existed between the drug and the disease. This survey produced records of 410 cases of serious blood disorders, of which 177 were definitely known to have been associated with chioramphenicol. In 61 cases choramphenicol was the only drug administered. In half of these 177 cases the blood disorders were fatal. They include aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia. In June 1952, tue FDA referred the case histories obtained in the survey to the National Research Council (NRC). PAGENO="0475" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2609 Senator NELSON. When you say FDA discontinued the certification, did that remove it temporarily frOm the market? Dr. GODDARD. No further batches of the product could be introduced into the market. It was not recalled at that time. What was in place, and was being used, was permitted to remain on the market. Senator NELSON. Whatever was already in the marketplace could continue to be used? Dr. GODDARD. At that time. Senator NELSON. All the experts who have testified here on the ad- ministration of this drug, and have discussed the statistics of serious side effects, including death, were really unable to. come up with any- thing approaching an `accurate estimate .of the number of deaths or serious permanent injuries which have left people ill for the rest of their lives. Does FDA have any reasonably valid statistical information on how many people are being seriously and permanently affected adversely by the administration of this drug? Dr. GODDARD. Senator, this is a problem, as you well know, not only with this drug, but with many other drugs. We do not have the kind of data base that would give us, with a high degree of assurance, reliable data on which to draw such conclusions. Let me point out that the best study, in our opinion, is the one car- ried out by the California Medical Association. As a result of that survey, and study that they carried out, now somc- Dr. LEY. The survey was published in January 1967. Dr. GODDARD. It was published in January 1967. We note that they find a fatality incidence of 1 in approximately 24,000 persons receiv- ing this particular drug. Senator NRD50N. Fatal? Dr. GODDARD. Yes, sir. Senator NELSON. Now, how many had serious permanent side ef- fects-what percentage? Dr. GODDARD. I do not know that. Dr. Ley, do you? Dr. LEY. The chief figures in the report are aimed at fatalities. There are a number of other conditions which they mention, most of which I believe are reversible. Senator Ni~LsoN. Well, what about instances where the drug sup- presses the capacity of the bone marrow to produce blood by 20 per-* cent, or 10 percent, which leaves the person ill the rest of his life, al- though he lives. Are there any statistics on that kind of result? Dr. GODDARD. Senator, I would `be happy to have our people go through the OMA report again, and provide that `for the record, if I m'ay. I do not recall it. (The subsequent supplemental information follows:) STATEMENT OF THE FOOD AND DRUG ADMINISTRATION REGARDING NONFATAL COMPLICATIONS REFLECTED IN OALIF0RNIA MEnICAL AssoCIATIoN S~rrmx Our review cxf the California Medical Association Report does not disclose any non-fatal, drug related experiences with Chloramphenicol. The Oaiifornia study was based on a review of death certificates; therefore non-fatal complications of Chioramphenicol administration would not be reflected in the study. PAGENO="0476" 2610 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. LET. I have rough figures here, of a total of 79, in addition to the fatalities, who experienced a leukopenia, and 79 who had a bone marrow depression. Senator NELSON. From. what? Dr. LET. From the chlorainphenicol. Senator NELSON. What statistics? Dr. Lr~. This is a summary from the California report. Senator NELSON. One of the doctors who testified yesterday related that in his relatively small town of 16,000 people, he became aware of four cases of aplastic anemia at one time. And we have heard of similar situations through the mail that is coming into. our office from little towns of 800, 900 people. I have five or six from my own State. These letters are from people who just notice something in the paper about these hearings and write. It seems to me that the California study tends to give the physician a whole lot more security in prescribing this drug than the facts, as we know them, would justify. You have a risk of one death in 24,000. How many cases are there of permanent injury? Dr. GODDARD. As I said, Senator, I do not believe anyone has realistic figures on this. The incidence of nonfatal side effects which may be of long duration is probably higher than the incidence of fatalities, if the usual course of events is held to follow in this instance. However, the British study, which we think has certain deficiencies, points out that fatalities occur as often as 1 in 10,000 patients receiv- nig the drug. One has to be very careful in carrying out studies of this type, because aplastic anemia, as you well know, occurs from other causes-they may be idiopathic. And to simply relate all cases of aplas- tic anemia to chloramphenicol is not proper nor supportable. But none- theless, I have to go back to my original statement and say that the CMA study is the best one we have seen so far. Now, that does not mean that the incidence may not be higher. It simply reflects a lack of good data, Senator. Senator NELSON. But why is our data so poor? Dr. GODDARD. Senator, this is true in almost this entire field. We do not have good reporting. Hospital record systems vary throughout the United States. There is no requirement for reporting these kinds of episodes. It is done upon the initiative of a few physicians. We have had great difficulty in getting good reporting in our ad- verse reaction reporting system, even in those instances where we paid the resident physician $5 for submitting a report. It is extremely dif- ficult. Now, as we progress with the usage of computers in hospitals to store patient data, the kinds of activities that are being carried out in Michigan by Dr. Virgil Sloe's organization, and at a number of large hospital centers, it is going to be possible to extract much more signifi- cant information from existing hospital records. But in the present situation, where we are totally dependent upon the physician assuming-upon his own initiative-the burden of send- ing a report to a firm, the FDA, or the AMA, we do not get good reports. The AMA in fact has discontinued its adverse reaction report- ing system simply because of the lack of interest of participating PAGENO="0477" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2611 physicians. This in spite of reminder cards, tear-out cards in their weekly publication, the JAMA. And it is an extremely difficult subject to get at. I am convinced that small increments are being made. We are mak- ing some progress. But the problem is not unique to chloramphenicol. We are constantly up against the lack of good data, whether you are talking about chloramphenicol, the sulfa drugs, whatever you will. Senator NaI~soN. Well, I can appreciate that. But it seems to me that you have to start some place. And chloram- phenicol is not just another drug. As you know better than I, it is very, very limited in its recommended use. And, I guess, every hematologist in America is shocked at the indiscriminate prescription of the drug, and the unnecessary killing of innocent people. I understand you to say you would have to have drug reporting on all the drugs in the market from all the hospitals every smgle year if you want to follow such a procedure with chloramphenicol, and that it is probably un- necessary. But the medical profession has had long experience with the sulfas and penicillins and I guess has a pretty good idea about the problems there. At least the problems are not as serious as they are m the case of chloramphenicol, are they? Dr. GODDARD. I would have to say that the fatal reactions to some of the drugs you have mentioned, although not as frequent, also con- stitute a serious problem. Senator NELSON. Well, are you telling me, doctor, that the best clinicians in our great medical profession, who have the expertise, and the FDA could not sit down and select a dozen drugs that are not in a gray area at all, or a half dozen, on which we must have hospital reports and decide that reporting be required. Why can't we do that? Why go on needlessly injuring and killing people. Almost all the cases we hear about deal with persons who should never have had the drug in the first place. And, Dr. Weston, Utah State Medical Examiner, said he had never seen a case of a person who died from aplastic anemia when the drug was really indicated. Every single one of them were cases in which the patient should not have received the drug, as I recall. Dr. GODDARD. I would not q~uestion his testimony, Senator. But let me point out that in the California study, 7 out of 10 deaths that occurred, occurred in patients who received the drug for appropriate indications. Senator NELSON. Yes. But how are the cases selected? If it were prescribed for an inappropriate case-acne, or a head cold-there is a strong inclination on the part of the physician, when he finds out what he has done, not to report it. Any time it were given for a proper indication in a hospital, no doctor would hesitate for a moment to report that this was the result he got. So that is a loaded statistic, I think. Dr. GODDARD. I would tend to `agree with you, Senator. I am simply pointing out that it does occur in those patients who receive it for pmper indications as ~well. Senator NELSON. Well, I am assuming it does. A's you are aware, Dr. William Dameshek is a distinguished hematologist who has seen many, many cases and has written on the matter in the AMA Journal. He PAGENO="0478" 2612 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY testified here the other day. Let me read from something ~he wrote in 1960 for the AMA Journal. Now it is almost 8 years later. He states: By some means, whether by regulation or self-discipline, prcxmiiseuous use of the drug should be avoided and its use restricted to impelling circumstances, that for conditions for which no other antibiotic is currently efi~ectivn. Among 30 cases of aplastic anemia he had seen within the previous 3 years, he said 8 had received Ohioromycetiin. Almost invariably for minor infections. Of the 10 most `recent cases, five had followed therapy with Chioromycetin. The tragic thing about all of these seri- ously ill cases, most of whom died, is that the drug need never have been given at all. He does not come up with the sbathi~bics that the California study does, and my guess is that this is true because the California study included all the cases that were reported because they concerned oases in which the drug was indicated, orait least a lot of `them did. Dr. GODDARD. Senator, let me make it perfectly clear-I am not try- ing to whitewash this drug, or the excessive use of this drug by the medical profession, or be in a defensive posture with respect to the Food and Drug Administration's certification of the drug. I am simply trying to point out there are instances where it is properly prescribed, and it wifi stifi cause problems. The agency has, since 1952, made `attempts to curb the excessive usage of this drug, and we will continue to try to reduce this to its proper level of usage. I do not want you `to get the impression that I am defending un- proper prescribing habits. Senator NELSON. I did not intend to leave that impression. As a matter of fact, if you do not already know it, I have very high admira- tion for you. I do not think any previous Commissioner approaches you in the vigor with which you prot~ot the public interest, ~n'd in your concern `about it. I mean bh'wt in `all sincerity. But the cold, hard facts are that this issue is almost 20 years old, an'd not `a damned thing has happened, except that we prescribe more, more, more. And we heard five witnesses last week `who made guesses that 90 percent of the prescriptions are being given to people who should never `have it-down to Dr. Mark Lepper's estimate `that only one-third of 1 percent of `all `the cases who get it should get it. He is saying, then, that between 10,000 `to 50,000 people out of 4 million who receive it should get it. Well, this is `a disaster, `a catastrophe. And I do not see how we can go on for 18 years saying we are doing everything we can. We would be better eff, actually, in view of what has happened, if we never gave the drug at all. It is doing more harm than good. But the least we can do is get good and tough about how it is used, and under what circumstances. Four million people take this drug each year-it is just preposterous. And I do not understand why we just do not get tougher than nails about it. These warnings in the package insert, and in the journal advertise- ments, mean absolutely nothing. A representative of that company sat right here before me and acknowledged that they ran an ad in the British Medical Journal, February 1967, without a word of warn- ing, while they ran one 7 days later in this country with the warning. PAGENO="0479" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2613 They said they did not have to run it in England because the law did not require it. I asked what about the underdeveloped countries? They said that England has a sophisticated system for medical protection. I presume we have a sophisticated one here. But 4 million people are getting Chloromycetin who should not be getting it. Then you get to the underdeveloped countries where there is no protection at all, and you can see what is happening. All I am saying is that it is one, thing if a warning has not worked for a couple of years, but we are talking about 2 decades. I think we have to do something dramatic about this now. That is my whole point. Mr. GORDON. Dr. Goddard, you referred to the California study. Now, as I understand it, this study for the first time indicated that the risks were higher than were known at the time that the drug was put on the market; is that correct? Dr. GODDARD. That is correct. Mr. GORDON. The California study came out in January of 1967? Dr. GODDARD. That is correct. Mr. GORDON. Did the Food and Drug Administration notify all the doctors in the United States about these new risk estimates? Dr. GODDARD. No, we did not. Mr. GORDON. Why not? Dr. GODDARD. The California report itself, which was known to us at that time said, and I quote: No reasonable basis exists for the enactment of special legislative category to restrict the use of the drug chioromycetin by a licensed physician in Cali- fornia. Our data indicate that this antibiotic is being administered in accord- ance with good medical practice, and the risk use factor does not provide a sufficient basis to single out this drug for spe~ial legislation. They did not-and there are a number of other statements here- they did not recommend any additional steps be taken at that time. Senator NELSON. Who is "they" in this case? Dr. GODDARD. CMA, California Medjcal Association-joint study group. As you know, Senator, we have had a number of groups of qualified physicians meet on the subject of this drug over `the years. The latest one met last week to advise us on what steps could be taken and should be taken. And the question of restricting the drug to hospital usage has come up in almost every one of `these meetings. Also the question as to whether or not the drug should be withdrawn from the market. Both of these suggestions have been rejected by advisers who included peo- ple such as Dr. Dameshek, eminent physicians in their own fields of specialization who have detailed knowledge of the risks involved in the use of the drug. Senator NELSON. I believe Dr. Dameshek is prepared to say that some very tough regulations should be made-possibly treating it as you do morphine, or confining it to hospital use.~ His posture on what we should do about this now is much stronger than anything the FDA is recommending. Let me read what Dr. Dameshek said in testimony before us: The numerous warnings regarding indiscriminate use of chioromycetin have been practically without effect. It is now about time to consider more radical measures such as complete restriction of the drug for a few specific indications. PAGENO="0480" 2614 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Should one stop its use altogether-this would surely be a wrong thing to do-because the drug is a potent antibiotic and has a well-defined usage. Should one simply continue with a warning statement in the advertising and in the package? These seem to have little if any value. And then further in his testimony, he was willing to set up some procedure to strongly control its use. Dr. GODDARD. Our ad hoc committee, which met Monday, also basi- cally was in agreement with Dr. Dameshek. and Dr. Ley and myself certainly are. We have a revision of the indications to be used, the package insert, which I have before me. We are going to discuss this with the corn- pany in the next few days. These indications markedly limit the indi- cations for the usage of this drug. Senator NELSON. For the package insert? Dr. GODDARD. Yes, sir. But we are also going to take other steps which I mention in my testimony, which will not restrict this kind of information to dissemination through the package insert. As you well know, I think the package insert is an ineffectual way of getting at the transmission of information to physicians. This new informa- tion will also be required in PDR.. It will be required in so-called reminder ads. These reminder ads now operate under an exemption from the Secretary which permits Parke, Davis to advertise this drug without any warning whatsoever. And so we do have steps that we propose to describe today that we think will have some impact. They may fall short of what you wish, but there are certain problems we feel need discussion. Mr. GORDON. Dr. Goddard, I am not satisfied with the answer that I got to my question. Dr. GODDARD. .1 wondered if you would be. Mr. GoirnoN. Why didn't the FDA notify all the physicians in the United States about the new and additional risks which were revealed by the California study in January of 1967? Dr. LEY. Mr. Gordon, in response to this, I have to draw upon the memory and recollection of other people who were there, because I was not there at the time. The California study identified a level of risk between roughly 1 in 24,000 and 1 in 46,000 per death. This study was in essence within the broad limits already established for the drug by other studies. I am specifically referring to the study published in Britain in 1960, which identified a risk figure of somewhere between 1 in 10,000, and 1 in 100,000. As nearly as I can reconstruct the events that occurred at that time, the California study was weighed, evaluated, and con- sidered not sufficiently different from existing information to require a special type of action at that time. We are certainly- Mr. GORDON. We are not talking about action here. It is a question of relaying the information to the physicians in this country. The California study came up with a risk ratio of 1 in about 20,000. Before then the risk ratio was considered to be much lower. Now, would it be your opinion that the doctors in the United States should know of these new and higher risks? Dr. Lny. We certainly plan to include this, the study's estimate of risks, as a portion of the new labeling. PAGENO="0481" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2615 Mr. GORDON. This is new labeling, and you are planning to do it now. But it was January of 1967 when this report came out, almost a year and a half ago. Dr. GODDARD. The answer is that it would have been better to have done it then. That is the only answer I can give you. I have no reason for it not being done, other than the judgment that was made at that time, that there was a general knowledge that the risk was between 1 in 10,000 and 1 in 100,000. Mr. GROssMAN. Doctor, that is a pretty wide gap, isn't it? $ Dr. GODDARD. Yes, sir, and I think it reflects again the problem we have in not having available good data. Mr. GROSSMAN. That is what I wanted to ask you. How do you feel about some kind of a coordinated national-nationally enforced re- porting system. Is it possible to do something like this? In other words, it does not seem we are getting anywhere. On the point you raised be- fore-some doctors report if you pay them $5, some others do not. This does not seem to be a very effective way of effectively finding information. I would like to find out how many people who got the drug and should have gotten it ended up with some problems, as well as those who should not have gotten it. Dr. GODDARD. We would like to know that, too. But the development of an effective national reporting system is an extremely complicated problem, one that we have worked on. Dr. Ley may wish to speak to this. We have made some changes recently to try to get better drug data from a variety of sources. I know of no way to enforce-from the national level-a reporting system. Mr. GROSSMAN. What about regionally enforced, State enforced? In other words, isn't it time we tried something else-because the present systems just are not working. Dr. LEY. I think two facts should be pointed out. As far as the present legislation is concerned, the manufacturer is required to report to us all reactions reported to him. There is no re- quirement for any physician to report reactions to the manufacturer. But those that are reported, which are not any more than the top of an iceberg, must be reported to us. Senator NELSON. How many have been reported to you by Parke, Davis? Dr. LEY. Over the period from July of 1963 to the end of 1967, which is the end of our tabulation, a total of 93 hematologic reactions have been reported from Parke, Davis to us, of which 59 are reported as aplastic anemia. - Senator NELSON. That is really just a ridiculously useless figure. Everybody knows it is more than that. Dr. GODDARD. Senator, in answer to the previous question, let me say I have also had some experience with the reporting of other dis- eases which is required by law. Reporting, of syphilis is required by law-by the States. It is completely ineffeëtive. You get about 1 case out of 11 reported by the practicing physicians. Even though it is a legal requirement. Now, I do not know how we can do anything to get physicians to report adverse reactions to drugs when we cannot get them to report 81-280 0-68-pt. 6-3i PAGENO="0482" 2616 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY something as important as syphilis, in terms of breaking the chain of transmission. We can eradicate this disease in this Nation very quickly, if we had good reporting. Mr. GROSSMAN. Do you think it is because the individual doctor is afraid? Dr. GODDARD. No. Well, there are all sorts of reasons. One is that the demand for physician services has greatly increased. No question about it-most of the physicians are working 70 hours a week, and seeing, in the opinion of. many experts, far too many patients-because of the demand for services. This is increased by the kinds of programs we are now engaged in. I do not visualize it getting better, beca.ii~e our supply of physicians is not increasing rapidly in this Nation. The complexity of medical practice itself is increasing, so that the physician not only has to see more patients, but the kinds of things he has to do are more complicated. He has less and less time available for these kinds of activities which, frankly, he views as not being directly related to patient care, and therefore of a lower priority. And that is an understandable point of view. It is not perhaps commendable, but understandable. And so I am not optimistic about this kind of reporting until we can institute the kinds of automated data systems. This will take ~ years at a minimum, and then and only then will we begin to get this kind of information-not just on this drug, bu.t on many other drugs and many other conditions which would be valuable to us in our health efforts in this Nation. Mr. GROSSMAN. Do I imply from your later testimony that you do not favor a drug review committee type of program, on a local level, where- Dr. GODDARD. I think this would be absolutely wonderful. I have been preaching for a year and a half now to try to stimulate physicians and hospitals to have therapeutics committees in the hospitals which do more than consider the drugs to be included in the hospital formularies. Some hospitals do this. But they should begin to review the usage of drugs within the hospitals. Are they being properly used, what kinds of adverse reactions occur? Studies have been carried out by Cluff and others which show that a significant portion of hospital beds are being unnecesssarily occupied by people who have adverse reactions to drugs, and that proper attention here, as has occurred in the field of review of surgery within the hospitals, could markedly reduce the bed oc- cupancy, and thus in effect obviate the need for new construction in some instances. So I am very much in favor of therapeutics committees which review the use of chloramphenicol and other drugs in the hospital. Mr. GROSSMAN. It might be easier as a rep9rting system, too, if you had four or five doctors-they would be more likely to report the re- sults, because the responsibility is more diffuse. Dr. GODDARD. It would have many beneficial effects if such opera- tions were to be instituted in each of the majority of the 8,000 hos- pitals throughout the United States. I feel very strongly that this would be a desirable step forward. And I would hope that the committee would consider requesting the Joint Commission on Accreditation to appear and to give their views PAGENO="0483" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2617 as to how feasible it would be to incorporate within the provisions the requirements for accreditation one which spoke to the question of the existence of a therapeutic conimittee within the hospital. Mr. GROSSMAN. Thank you, doctor. Senator NELSON. What is the authority of the Joint Committee on Accreditation? What is the source of their authority? Dr. GODDARD. Senator, I think they have more leverage than author- ity. By denying certification, approval, to a hospital., they in effect shut off their supply of interns and residents, and this isa very crucial matter for those hospitals that use interns and residents to handle much of their caseload, much of the work that goes on. And so there is an authority related to certification of the individual institution rather than an authority that comes from a State or Fed- eral body. It is a voluntary program with participation by the hos- pitals in the United States. Not all of them participate-I do not recall the numbers, frankly, but it is a significant proportion of all hospitals that do. Senator NELSON. Do we have any statistics on how many hospitals in America have therapeutics committees? Dr. GODDARD. I will attempt to get them and supply them for the record, but it is a very small percentage at the present time. Senator NELSON. Small? Dr. GODDARD. I believe it is, in terms of the context we are talking about. (The subsequent supplemental information follows:) STATEMENT OF THE FOOD AND DRUG ADMINISTRATION REGARDING HOSPITALS WITH THERAPEUTICS COMMITTEES Information obtained from the American Hospital Association, Ohicago, Illi- nois, indicates that in September of 1967 there were 7,253 regisJtered hospitals in this country. Of these, approximately 1,700, were accredited. To become ac- credited, a hospital must have a "Pharmacy and Therapeutics Committee," unless the hospital staff is less than 10. Even a smaller staff must have this activity, if not a committee. Therefore, about 23 percent of registered hospitals in this country have Pharmacy and Therapeutics Committees. Dr. GODDARD. Now, many hospitals have committees which you might better call formulary committees, yes-these exist. But we are talking about a broader range of functions-the review of adverse reactions, the review of drug usage to see whether or not appropriate drug utilization is being carried out. This type of activity is not a common one. Senator NELSON. Do most of our major teaching hospitals have a therapeutics committee in the sense you are talking about? Dr. GODDARD. Most of the major teaching hospitals, Dr. Ley and I agree, would have such an activity. Senator NELSON. Well, I think that is a good suggestion. The com- mittee will consider inviting the Joint Committee on Accreditation to appear. Continue. Dr. GODDARD. The National Research Council established a commit- tee of outstanding hematologists and internists under the chairman- ship of Dr. John Holmes Dingle, professor of preventive medicine, Western Reserve University, to review and evaluate the chlorampheni- col problem. On August 7, 1952, the conimittee reported as follows: PAGENO="0484" 2618 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY An ad hoc Conference was held on 6 August and reviewed all available data presented by the Food and Drug Administration and by Parke, Davis and Company. The consensus of the Conference was as follows: 1. Certain cases of serious blood dyscrasias (aplastic anemia, thrombocyto- peale purpura, granulocytopenia, and pancytopenia) have been as.sociatecl with the administration of chioramphenicol. 2. Although this complication has thus far been uncommon, it is sufficiently important to warrant a warning on the label of packages of the drug and in advertisements of the drug and the recommendation that chioramphenicol not be used indiscriminately or for minor infections. 3. When prolonged or intermittent administration is required, adequate blood studies should be carried out. 4. In view of the paucity of information at the present time the Conference hopes that further study of serious reactions to chioramphenicol and other drugs will be promoted. The records of the Veterans Administration and military forces could be of great value in providing some of the desired information. Senator NELSON. This was 1952? Dr. GODDARD. That was 1952. Senator NELSON. Has any formalized procedure been instituted to accumulate the statistics and records from the Veterans' Administra- tion and the military forces respecting this drug? Dr. GODDARD. There is no formal system; no, sir. Senator NELSON. Well, here is a reconimendation made in 1952. Dr. GODDARD. We do know that the Veterans' Administration and the military forces have procedures within their own organizations con- trolling the use of chioramphenicol. But in terms of a formal system of transfer of information, no. Mr. GOODRICH. The recording system that we have originated with this type suggestion for all drugs, and the contracting and reporting system was set up on that basis, utilizing primarily the veterans and other military hospitals as reporting sources. Dr. LEY. And civilian hospitals as well. Mr. GOODRICH. In the beginning they were essentially these two re- source groups. *S~enator NELSON. What kind of statistics do we now have from the military and from the Veterans' Administration on the use of this drug and on its side effects? Dr. LEY. This effort ~has been implemented with considerable delay. Within the past year, we have pressed strongly for participation of the teaching hospitals in both the veterans hospital system and the military system in our hospital reporting program. We are at this point in time in a position in which the majority of these teaching hopsitals are participating. This is a very slow proce- dure to stimulate when we cannot actually force participation of this sort. Senator NELSON. Are you talking about military teaching hospitals? Dr. LEY. There are certain military hospitals which are accred- ited for teaching purposes, and Veterans' Administration hospitals similarly. Senator NELSON. How many are there in tile United States? Dr. LEY. Let me provide this information for the record, if I may. We can give you a complete statement on this reporting system. (The subsequent supplemental information follows:) PAGENO="0485" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2619 STATEMENT OF, THE FOOD AND DRUG ADMINISTRATION REGARDING FEDERAL HosPn~ALs ENROLLED IN FDA ADVERSE REACTION REPORTING PROGRAM (45 Hospitals-All Approved For Residences Except 3 USPHS Hospitals and 2 USAF Hospitals (approved for Internship Only)-As Marked With *) (7) Army Brooke General Hospital, Fort Sam Houston, Texas. Fitzsimons General Hospital, Denver, Colorado. Letterman General Hospital, San Francisco, California. Madigan General Hospital, Tacoma, Washington. Tripler General Hospital, Honolulu, HawaiL Walter Reed General Hospital, Washington, D.C. William Beaumont General Hospital, El Paso, Texas. (7) Navy The U.S. Naval Hospital, St. Albans, New York. The U.S. Naval Hospital, Philadelphia, Pennsylvania. The U.S. Naval Hospital, National Naval Medical Center, Bethesda, Maryland. The U.S. Naval Hospital, Portsmouth, Virginia. The U.S. Naval Hospital, Great Lakes, Illinois. The U.S. Naval Hospital, San Diego, California. The U.S. Naval Hospital, Oakland, California. (7) Air Force Willford Hall Hospital, Lackland AFB, Texas. Andrews AF Hospital, Andrews AFB, Washington, D.C. Travis AF Hospital, Travis AFB, California. Keesler AF Hospital, Keesler AFB, Mississippi. *Scott AF Hospital, Scott AFB, Illinois. Wright Patterson AF Hospital, Wright Patterson AFB, Ohio. *Oar~ell AF Hospital, Carswell AFB, Texas. V.A. (13) Veterans Administration Hospital, Birmingham, Alabama. Veterans Administration Hospital, Long Beach, California. Veterans Administration Hospital, Wadsworth GM & S Hospital, Los Angeles, California. Veterans Administration Hospital, Sepulveda, California. Veterans Administration Hosiptal, Ohicago West Side Hospital, Olitcago, Illinois. Veterans Administration Hospital, Dallas, Texas. Veterans Administration Hospital, Boston, Massachusetts. Veterans Administration Hospital, Bronx, New York. Veterans Administration Hospital, Oklahoma City, Oklahoma. Veterans Administration Hospital, University Drive Hospital, Pittsburgh, Pennsylvania.' Veterans Administration Hospital, Memphis, Tennessee. Veterans Administration Hospital, Richmond, Virginia. Veterans Administration Hospital, Wood, Wisconsin. U~PH~ (11) Baltimore, Maryland. Boston, Massachusetts. *(JEPvffle, Louisiana. Detroit, Michigan. *Galveston, Texas. New Orleans, Louisiana. Norfolk, Virginia. San Francisco, Oalifornia. *Savannah, Georgia. Seattle, Washington. Staten Island, New York. PAGENO="0486" 2620 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY Senator NEI1s0N. Dr. Goddard thinks it may be impractical to re- quire hospital reporting. Maybe you cannot enforce reporting in the civilian hospitals, so we do not get very good statistics. But 16 years ago the ad hoc committee made a recommendation, and over that period we could have accumulated all kinds of statistics. Yet, we cannot seem to do anything about that. The President of the United States and the Secretary of Defense could settle that in just about 5 minutes. Have you ever asked the Secretary of Defense? Dr. GODDARD. Not to my knowledge. Senator NELSON. Here is one arm of the Government worrying about the problems, and ad hoc committees making recommendations, and 16 years later these recommendations have not been implemented. Now, it does not surprise me-I have seen lots of bureaucracies in my lifetime. But 16 years seems like a long time on an important matter. Dr. GODDARD. I would agree. Senator NELSON. Go ahead, Doctor. Dr. GODDARD. Senator, just a followup point. Dr. Ley tells me they have been pushing this with the medical heads of the various military services, and VA, and it has been very slow. Dr. Ley feels somewhat more optimistic that they will give us this kind of information to a greater degree than they have in the past. So we have made the effort to get this kind of data from them. Now, the chloramphenicol was to be marked following this meeting with the label warnings as follows: Senator NELSON. Can you clarify for me the present legal authority that FDA has over prescription drug advertising? Dr. GODDARD. In 1962 the Kefauver-Harris amendments gave us authority to regulate drug advertising. Then in 1963 we promulgated regulations which require drug companies to provide information to physicians through the various media that they use to advertise their products. They must present the information in fair balance, with the bad along with the good, and the information on advertised effects- important information required for prescribing. And that is the basic authority we operate under. I do not know the section. Mr. GOODRICH. Section 502 (n) as amended by the Kefauver-Harris drug amendments required that in the case of prescription drugs, the manufacturer, packer, or distributor must include in all advertise- ments which he disseminated or caused to be disseminated, the estab- lished name of the drug, the formula, such information about effective- ness, side effects, and contraindications as should be specified in regu- lations. The regulations have been promulgated, put into effect in 1963. They are in the process of being revised, elaborated, and improved at the present time. Dr. GODDARD. We think improved. There is some disagreement on that, I might say. Senator NELSON. You have stated the general basis of the law. The law then authorizes the FDA specifically to go how far? Does the FDA have the authority to say that, "You shall put exactly this language in this way in your package insert, in the advertising in medical journals and elsewhere?" Do you have that power? PAGENO="0487" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2621 Mr. GOODRICH. Yes, we do. We have had this authority on the pack- age insert since the beginning of the new drug provisions. We have not had control over the claims of effectiveness. But all warnings essen- tial for safe use has been wtihin our authority, under the new drug provisions since 1938-in the case of new drugs-and since 1945 for antibiotics, when the first antibiotic was brought under certification. We have indeed specified in our antibiotic regulations, in the case of chloramphenicol, the precise box warning which now appears in PDR and in the labeling and in all the promotional material for this drug, except reminder advertising. It is the very warning that Dr. Dameshek recommended, and that our committee recommended in 1960. And we are, we think, improv- ing on it now with the benefit of another committee. Dr. GODDARD. But, Senator, we do not control the text of every advertisement that is produced. Mr. GOODRICH. But in the sense that he was asking, as I understood, if this became necessary, did we havethe authority to do that. And the law says that the ad shall include such information about side effects, counterindications, and effectiveness as we shall specify in the adver- tising. Now, we started off with a system which required that the ad- vertising limit its promotion within the claims authorized by new drug clearar~ce or by antibiotic clearance. We could become more ~pecific if that is necessary,. and we have become more specific in the case of Ohioromycetin. Senator NELSON. So you do have the authority to specify exactly the language as to safety and effectiveness. Mr. GOODRICH. Right.. Senator NELSON. So that if there is an exaggerated claim, you can simply direct the con~pany to change the language; is that correct? Mr. GOODRICH. The con~any has hearing rights and other protec- tions that go with this. But we have the ultimate authority to resolve the question. Senator NELSON. And before whom is the hearing conducted? Mr. GOODRICH. Before a hearing examiner in our department, with judicial review in the courts of appeal. Senator NELSON. Has there ever been a case where the drug company disagreed with what the FDA directed, and asked for a hearing? And, then, have there been cases where they asked for a hearing and later appealed the decision of the hearing to the courts? Mr. GOODRICH. There have been cases in which there was a request for a hearing. There have been-in other settings, but not that par- ticular one-appeals to the courts. But in general, the companies have not exercised their hearing rights in developing labeling and promotion for drugs. They have become convinced, I believe, that no drug can gain a place in medical practice or retain a place except on its scientific merit. And therefore the- Senator NELSON. Who is this? Mr. GOODRICH. The drug industry. They could not really press a drug onto the market over the objections of the Bureau of Medicine where there were scientific reservations. And so the way the procedure works is that the differences are resolved through the new drug procedures, or through the antibiotic procedures. PAGENO="0488" 2622 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Now, we, as you know, have required warnings to he sent out in "Dear Doctor" letters and other ways. We have not had a controversy over any of that activity so far. It is possible we will have sometime. Senator NELSON. But of course .they have successfully promoted chJoraiuphenicol over and against the best expertise of the medical profession for 18 years. Mr. GOODRICH. They have been required since 1952 to put on the warning which Dr. Goddard was just about to read you; in 1960 to strengthen that warning. And any promotion contrary to that warn- ing would be a violation. The company was allowed to use reminder advertising, and we are in the process of revising those regulations to discontinue that. Now, as you know yourself, I am sure, from the Kefauver hear- ings, there was evidence that Parke, Davis used detailmg pieces out- side the labeling. We did contact the company about that. They as- sured us that that was unauthorized and contrary to company policy, and that they would instruct their staff accordmgly. Now, detailing is a difficult practice to deal with. But if we have evidence that a product is being offered orally, or in any other way, in excess of the authorized claims or without the required warnings or in derogation of the required warnings, we have the procedures to take action. Senator NELSON. We will get to that a little later, because I want to ask you what you are doing about the most recent PMA ad in the Reader's Digest. But what puzzles me about this is that we have required them to include this warning in their ads. Dr. Dameshek approved it, he ad- vised me-apparently he was on the ad hoe committee. Dr. GODDARD. Not on this one. He was on the one in 1960, 1961. Senator NELSON. Yes. And so that warning was put on. And Dr. Dameshek's testimony is that it has been a total failure. So the fact is that everything that has been done has not worked. Would you not agree that if Dr. Dameshek and the experts who testified here are correct, that somewhere around 90 to 99 percent of the cases receiving chioramphenicol should not, and that our methods of controlling advertising and cautioning physicians have been a colossal failure? Dr. GODDARD. Yes-I think we would agree that the methods of in- forming the physicians and getting them to act on that information have been a failure. Senator NELSON. We will get to your recommendations later. Go ahead. Dr. GODDARD. The warning that was then required was: Warning-Blood dyscrasias may be associated with intermittent or prolonged use. It is essential that adequate blood studies be made. The following warning was to appear at the top of the package insert: Certain blood dyscrasiag (apiastic anemia, thrombocytopenic purpura, granu- locytopenia and pancytopenia) have been associated with the administration of Ohioromycetin. It is essential that adequate blood studies be made when pro- longed or intermittent administration of this drug is required. Chioromycetin should not be used indiscriminately or for minor infections. PAGENO="0489" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2623 In announcing the reinstitution of certification for chioramphenicol, FDA said: The ac1min~istration has weighed the value of the drug against the capabilities for causing harm and has decided that it should continue to be available for careful use by the medical profession in those serious and sometimes fatal dis- eases in which its use is necessary. Senator NELSON. In what year was that done? Dr. GODDARu 1952. The FDA characterized its experience as "an impressive reminder that highly potent drugs must be treated with extreme care and should not be employed unless there is a clearcut indication that they are needed." The Kefauver Subcommittee on Antitrust and Monopoly subse- quently reported that these warning measures were diluted by Parke, Davis instructions to its detail force, which the subcommittee said presented the report of the National Research Council as a blanket clearance of the drug. Nonetheless, the use of the drug dropped off markedly after the new warning issued. This was a short-term reaction; however, and use of the antibiotic increased during the years that followed. Senator NELSON. I realize you were not the Commissioner at that time. But I have read the Kefauver testimony, and I presume you have read it. It is a very impressive example of clever advertising language being used by the company to circumvent the statement of caution that was suggested by the FDA at that time, was it not? Dr. GODDARD. Yes. Senator NELSON. And as I recall the testimony before the Kefauver committee the company claimed that the drug had been completely cleared by the committee of the National Research Council or words to that effect. Mr. GOODRICH. This was in terms of instructions to the detail force. Now, you will recall, Senator, that prior~ to the enactment of the Ke- fauver-Harris amendments in 1962, we had no right to obtain that in- formation by inspection. We had no right to records of these drug companies. And we learned about this detailing through the mate- rial subpenaed by Senator Kefauver's committee. Now, we did have one of our own physicians detailed improperly in 1959, and we, on the basis of our own experience, contacted the com- pany immediately, calling attention to this misuse of a piece out of the literature to dilute the aplastic anemia warning. The company, from their president on down, gave assurance that that type detail- ing was not authorized. Under the existing law, we do have the right to inspection to ob- tain records of this sort. And we have asked, within the last few days, what detailing pieces there were, and we are told that there are none- no specific detailing pieces. Mr. GonnoN. Yesterday one of our witnesses who is a physician, Dr. Watkins, testified that a detail man misinformed him about the dangers of Chloromycetin. Two days ago IDr. Hewson, from Phila- delphia, testified that in his own experience as a general practitioner, he could not recall a Parke, Davis detail man ever discussing the re- lationship between administration of the drug and the development PAGENO="0490" 2624 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of blood dyscrasias. Several doctors testified in the Love v. Wolf case, in California, that Parke, Davis' detail men told of the virtues of Chioromycetin and minimized its dangers. Do you really accept the firm's assurance that the statement was both unauthorized and contrary to company policy? Mr. GOODRICH. They supplied us with instructions that they had sent to their force, and they are a part of the record in the Kefauver hearings, as you know. All that correspondence is included in the Kefauver records. I would not mean to imply in any way that the detail men were not making these presentations. Indeed, the detailing of our own physicians showed they were. But we took steps to call it to the company's attention. Now, the point of monitoring detailing is a very, very delicate point with us. We have no way, really, to monitor what goes on be- tween the detail men and the physician in his private office. We do have control over the printed and promotional material, so that the message will come through loud, clear, and repeatedly in the promotion about what the drug is for and what warnings should be observed. Senator NELSON. It has not in the case of this drug come through very loudly or very clearly, obviously. Mr. GOODRICH. Since 1960, there has been this warning, and the current PDR, if you look at it, has a black box warning right at the top of the column, which has Dr. Dameshek's warning. This discus- sion of Chloromycetin has been before the profession some time. Now, it is not effective, I know that, and I know that there is room for improvement. We are planning to do that. Dr. GODDARD. It is probably the strongest drug warning that exists, Senator. And in spite of that it is still being misused. The warning does not work. Senator N1~i~sON. So where do we go from there? I wanted to ask you a question. The FDA has the authority to require and does require the package insert. Am I correct in that? Dr. GODDARD. That is correct. Mr. GOODRICH. And it has done so for Chloromycetin since the 1960 ad hoc committee. Up until 1961, I believe it was, we allowed package inserts to be made available on request. But in response to the 1960 ad hoc committee recommendations, one of the conditions was that pack- age insert be included in all packages. Now, there has been on the bottle, on the carton, on the bottle con- taining the capsules, a warning since 1962 about blood dyscrasias. This is the one Dr. Goodard just read: Warning, blood dyscrasias may be associated with intermittent or prolonged use. It is essential that adequate blood studies be made. That has been on the bottle since 1952. Senator NELSON. For capsules, not injectables. Mr. GOODRICH. For all containers, yes sir. Senator N1~I~soN. But, the package insert in almost all cases goes to the gentleman who does not prescribe, that is, the pharmacist-so that does not help to warn the physician at all. Dr. GODDARD. Except this. All the detailing material that the detail PAGENO="0491" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2625 man leaves with the physician is also considered labeling, and it must also contain that same warning promptly displayed. Senator NELsoN. Is he required to leave the material containing this warning with the doctor? Dr. GODDARD. No, he is not. Senator NELSON. If you require the package insert, why wouldn't it be helpful at least to require him to leave it with the physician? Dr. GODDARD. If he leaves anything, the warning must be included. But he is not required to leave the drug or the warning upon the occasion of detailing. He may simply discuss the drug with the physician. Mr. GORDON. It is the oral presentation, however, which is the most potent presentation, is it not? Senator NELSON. Doctor, I have to go over to the Labor Committee to help them make a quorum for an executive session. We will recess for 10 minutes. (At this point in the hearing a short recess was taken.) Senator NELSON. We will now resume the hearings. Go ahead, Doctor. Dr. GODDARD. In 1955 Parke, Davis requested a deletion of part of the warning statement. The firm's letter pointed out that some patients with blood disorders attributable to Chloromycetin had received only a few capsules. The company regarded the warning, which referred to prolonged or intermittent therapy, as a legal liability in litigation. We rejected this proposal, and while strengthening the warning was suggested, the decision was made, to continue the warning as recommended by the scientific committee. In December 1959, one of our physicians, who was also in private practice, was visited by Parke, Davis' detail men who claimed that there was no more danger of blood dyscrasias with Chloromycetin than with any other antibiotic. The company was informed of this impropriety, and gave assurance that the statement was both un- authorized and contrary to company policy. In April of 1960 the Council on Drugs of the American Medical Association made another report on blood dyscrasias associated with chloramphenicol. The report said that although the warning had been in use for a long time, physicians continued to use the drug in- discriminately for minor infections, including those associated with the common cold. FDA asked the National Research Council in November 1960 to again consider the chloramphenicol problem in light of a new evidence accumulated since 1952. FDA wished to obtain the council's opinion as to whether chloramphenicol should be allowed to remain on the market, whether its use should be restricted to hospitals if it were to remain on the market, and what label changes the council would rec- ommend if the drug was allowed to remain on the market. The recommendations of the council were received by FDA in Jan- uary 1961. The council concluded that, due to its therapeutic value, chioramphenicol should remain on the market; due to some of its prop- er indications for use, home treatment, as opposed to hospital treat- ment exclusively, was reasonable; due to its serious effects, further warnings and increased education of the medical profession were necessary. PAGENO="0492" 2626 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In accordance with these recommendations, the labeling of chior- amphenicol was revised in February of 1961 to include a prominent "warning box" conta.ming the following information: Warning-~erious and even fatal blood dyscrasias (aplastic anemia, hypoplas- tic anemia, thrombocyto~nia, granulocytopenia) are known to occur after the administration of chloramphenicol. Blood dyscrasias have occurred after both short-term and prolonged therapy with this drug. Bearing in mind the possibility that such reaction may occur, chloramphenicol should be used only for serious infections caused by organisms which are susceptible to its antibacterial effects. Chioramphenicol should not be used when other less potentially dangerous agents will be effective. It must not be used in the treatment of trivial infections such as colds, influenza, or diifections 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 or granulocytopenia, before they become irreversible, such studies cannot be relied on to detect bone marrow depression prior to development of aplastic anemia. Mr. GORDON. Dr. Goddard, what is meant by "adequate"? Is this a scientifically fixed and precise term, or does it lend itself to individual interpretation? Dr. GODDARD. In the phraseology used in 1961, adequate blood studies to be made during treatment, was subject to judgment on the part of the physician. We subsequently have changed this phrase- ology. Mr. Goodrich points out that this is why we pointed out spe- cifically early peripheral blood changes, in that same context. Senator NELSON. Is the warning used in 1961 still the warning that isused? Dr. GODDARD. No, sir. It was subsequently revised, I believe-minor revisions were made in 1966, as I recall. Dr. LEY. Change from "should" to "must" not be used. Senator NELSON. One word. Dr. LEY. Yes, sir. Dr. GODDARD. "Chioramphenicol must not be used when other less potentially dangerous agents would be effective." That was the change. Senator NELSON. I would like to read to you a section of the warning statement: Bearing in mind the possibility that such reactions may occur, chloram- phenicol should be used only for serious infections caused by organisms which are susceptible to its antibacterial effect. I suppose if you read that sentence to even alayman, he would say, "Of course it should be used only against organisms which are sus- ceptible"; the sentence means nothing. And then the advertising con- tinues to talk about its value as a broad-spectrum antibiotic. The PMA ad in Reader's Digest says it is useful against dozens of diseases. It seems to me that the sentence is at best useless, and may be harmful. Dr. GODDARD. Of course, Senator, this refers to the use of sensitive testing-using the organisms obtained from the patient, cultured by disk, and then the antibiotics that are under consideration being used. That is what this particular sentence refers to. Senator NELSON. You mean the sentence is saying that a culture should always be taken, and then a test of its effect on the organism made prior to administration? Dr. GODDARD. That is what lies behind that sentence, Senator. Dr. Ley, do you wish to comment on this? Dr. LEY. Yes. This is a point which we discussed at great length with our advisory committee this past Monday. PAGENO="0493" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2627 For certain very serious `and acute infections, the physician should have the freedom to prescribe this drug where, if `he has not given it, the patient would be much more `seriously ill. We feel that the physician `also has the responsibility to initiate such sensitivity testing at this time as well. The example which weighed most heavily in our committee con- sideration was that of a youngster with a serious meningeal infection. If you delayed therapy until the sensitivity tests are available, such a child might suffer serious brain damage. The new labeling draft which we have considered with the conimittee makes provision both for the initiation of therapy, and requires the sensitivity test to be done con- currently. So `that I believe this one looseness in the wording of the old indications `and warning section is now corrected. Senator NELSON. The next sentence is, "Chloramphenicol should not be used' when other less potentially dangerous agents will be effective." Dr. GODDARD. That was changed in 1966 to say "must not be used when other less potentially dangerous agents will be effective." Senator NELSON. That is the one change made between 1961 and 1966? Dr. GODDARD. That was the one change. That is the one change as far as the box is concerned. Senator NELSON. Go ahead. Dr. GODDARD. Parke, Davis was required to mail the new prescrib- ing information to all medical doctors and osteopaths in February 1961 with a statement that the prescribing information would ac- company all oral and parenteral Chloromycetin products. Between 1963, when our prescription drug advertising regulations were first adopted, and 1966, Parke, Davis advertised Chloromy- cetin by reminder ads, which carried nO indications and no warnings. The regulations permitted this. Mr. GOIWON. Can you give us the reason why this type of ad should be exempted from carrying the warning? Dr. GODDARD. There is a history of this which Mr. Goodrich is more familiar with, and may comment on. But in general, it was felt that reminder ads, which are permitted under an exemption by the Secretary, serve a useful purpose. Mr. GoRDON. Why should it have been permitted? Mr. GooDRICH. There is a type of advertising and promotion that is used in the drug industry which features only the name of the drug and the name of the company. It does not purport to offer to the physician any indications for use, nor to indicate in any way what the drug is for. It simply is a reminder of the name of the drug and of the company that makes it. This type of advertising was defended by the drug industry at the public proceedings which preceded the establishment of the regula- tions. We concluded it was reasonable to allow reminder advertising, so long as no indications for use were made, or implied directly or indirectly, and so long as nothing was said about the drug other than its name and the name of the company. Now, we are reexamining that policy in evaluating the new regula- tions. And as the statement indicates, we propose to change the regu- lations so that Chloromycetin could not be advertised by reminder ads. PAGENO="0494" 2628 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GORDON. These reminder ads are designed to sell the drug, are they not? Mr. GOODRICH. Of course, all advertising is intended fOr selling, and I do not accept the idea that they are not. But the argument is that these are institutional type reminders, and as long as they do not carry any information to the physician about how to use the drug, it is not necessary to have the warnings on them. Mr. GORDON. Whose argument is that? Mr. GOODRICH. This is the argument advanced by the PMA at the hearing in 1962, when the regulation was adopted. Mr. GORDON. And you accepted the argument? Mr. GOODRICH. Yes. Mr. GORDON. Do you agree with it? Mr. GOODRICH. I do not. Mr. GoRDoN. Why hasn't something been done about it since 1952? Mr. GooDRICH. Because I did not have the power of decision. Mr. GORDON. I am not asking why you personally did not do any- thing. Why didn't the Food and Drug Administration do something about it since 1962? Mr. GOODRICH. The Commissioner in 1962 ~ind his advisers were persuaded that this was a practice that would not be abused and could be allowed. We reinstituted consideration of it last fall when the regulations were up again. The same arguments were advanced, and tentatively accepted this time. But we did point out that the reminder ads were being abused by being used for drugs having more serious side effects, and this issue brings it to a head with Chloromycetin. Dr. GODDARD. i[~t me also say, Mr. Gordon, that in my opinion we have had far more serious problems with drug advertising to contend with since I have been Commissioner t1ian the reminder ads. And I have directed most of my attention to the extent I can be directly in- volved in this to t.he other problems of drug advertising, along with Dr. Ley and Dr. McCleary, who have done such an outstanding job trying to clean up medical advertising. There have been serious prob- lems, in my estimation, some far more pervasive than the reminder ads as such. Senator NELSON. Just for clarification of the record, what is per- initted in the reminder ad? Dr. GODDARD. Only the name of the company, Senator, and the drug that they are reminding the physician of. "Don't forget Chloromyce- tin, doctor, Parke, Davis." Senator NELSON. They may not say in the reminder ad. "broad spec- trum antibiotic," any descriptive language like that? Dr. GODDARD. No, sir. Senator NELSON. So this is a reminder ad that complies with FDA regulations. It has a picture of a doctor and so forth, and says "A name you can count on when it counts. Chioromycetin, chlorampheni- col, Parke, Davis, complete information on usage available to physi- cian upon request," and so forth. That is a reminder ad? Mr. GOODRICH. Yes, sir. Senator NELSON. And they may not say more than that under the present regulations? Dr. GODDARD. That is correct. PAGENO="0495" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2629 Senator NELSON. And I understand you are reviewing that now? Dr. GODDARD. I would propose if the exemption is to be permitted to continue for Chioromycetin that the warning box be incorporated in the reminder ad itself, or the exemption be dropped completely. Senator NELSON. Thank you. Dr. GODDARD. Now, that of course has to go through the procedures that we described earlier. Senator NELSON. Which? Dr. GODDARD. Opportunity for public hearing, and review by the courts. Senator NELSON. Yes. But have you made that decision as to the re- minder ad? Dr. GODDARD. On this drug, basically, it has been made. Mr. GROSSMAN. Doctor, would that hold up for other drugs? Dr. GODDARD. It could, if there was an indicated need. We are reexamining the entire issue of reminder ads-not just this one. In 1964 the company decided to advertise the drug promotionally. That means the more routine type of advertising. They met with our medical advertising group to consider how this should be done. Our physicians noted that the package insert had no "Indications" section, but instead described the broad range of antimicrobial activity of the drug. To correct this, an indications section was devised and other changes made to emphasize that the drug was only indicated for, and should be prescribed in accordance with, the important information in the "warning box." In 1966, the company made the requested changes and discontinued the reminder ad campaigns. And I would add as a postscript that for a large part there may be still some reminder ads. Dr. LEY. Few only. Dr. GODDARD. The labeling was reviewed again in 1966 by the Acting Deputy Director of the Bureau of Medicine and the "box warning" was changed to say that the drug must (instead of should) not be used to treat trivial infections or in any other conditions except as described in the box. Despite these label revisions, editorials in the Journal of the Ameri- can Medical Association, and warnings in other publications such as the Medical Letter, the use of chloramphenicol has increased and con- tinues to increase. Most of this use, we believe, is for medical conditions for which the drug is not indicated or for which it is expressly pro- hibited such as acne, the common cold, simple infections, and the like. We are disappointed by a current advertisement in the Reader's Digest by the Pharmaceutical Manufacturers Association, which describes chloramphenicol as a prime member of a "class of drugs that fights 100 diseases" and characterizes it as a "broad spectrum" antibiotic effective against dozens of diseases, causing only occasional and some- times serious side effects in some patients. Senator NELSON. Doctor, you state that the use of the drug con- tinues to increase? Dr. GODDARD. Yes, sir. As measured by sales, the amount that is being certified by the Food and Drug Administrtaion through batch- by-batch certification. PAGENO="0496" 2630 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Do you, under your batch-by-batch certification, keep track, then, of total numbers of grams manufactured per year? Dr. GODDARD. Yes. Total number of grams. Those figures are on the way. I have asked that they be sent up here, and I am told they should arrive here within 15 minutes. Senator NELSON. You anticipated my question. Dr. GODDARD. Yes. And also I can tell you that those figures will be delivered monthly to my desk from now on. That is another procedural change we have made-so I can more closely keep track, along with Dr. Ley, who has not had these figures in the past either, of the amount being certified. Senator NELSON. And what period of time do the figures that you have requested from your office cover? Dr. GODDARD. One year. 1967. Senator NELSON. Do you have the statistics on prior years? Dr. GODDARD. We could go back, I believe, and dig those out of the files, sir, and we will do so if you wish to have them. Senator NELSON. I think it might be helpful to at least have a rep- resentative sampling every 2 years or so, since 1952, so we could see how many grams are marketed. Is it in grams that you keep the record? Dr. GODDARD. Yes. Senator NELSON. If you could supply that, along with the 1967 data so we can print it in the record at this point, I think it would be useful information. Dr. GODDARD. Be happy to do so. (The subsequent supplemental information follows:) STATEMENT OF THE FOOD AND DRUG ADMINISTRATION REGARDING GRAMS OF CHLORAMPHENICOL CERTIFIED IN PHARMACEUTICAL PREPARATIONS Year Parke, Davis Other firms (oral products only) For use orally or by injection: 1952 33 436,597 0 1953 5,943,165 0 19541 1955 18,638,518 0 1956 27,320,359 0 1957 28,872,529 0 1958 40,593,884 0 1959 50,070,646 0 1960 54, 606,330 0 1961 27,126,744 0 1962 34,934,914 582,650 1963 37,988,417 0 1964 32,619,478 250,000 1965 36,282,949 0 1966 43, 542,769 3,673,908 1967 37,641,898 9,838,274 Intended for topical use: 1952 68,496 1953 87,777 19541 1955 96,978 1956 100,756 1957 88,968 1958 92,232 1959 104,332 1960 119,993 1961 62,955 1962 99,614 1963 88,120 1964 98,563 1965 99,835 1966 95,435 1967 155,006 I Hot available. PAGENO="0497" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2631 CHLORAMPHENICOL CAPSULES AND TABLETS CERTIFIED TO OTHER FIRMS 1962' 1964 1966 1967 Firm Capsules Grams Capsules Grams Capsules Grams Capsules Grams Arco-Abello 273,600 68, 400 Labs. Atral 2, 000, 000 500, 000 Castillon Labs 42, 000 10, 500 Continental Labs 920, 000 230,000 9, 400, 000 2,350,000 Davis-Edwards 600,000 150,000 Instituto Luso Farmaco 2926,500 231,625 Lepetit 14,000 3,750 Mckesson Labs 9,857,942 2,464, 486 15, 190,253 3,797, 563 PharmUSA 2,989,465 747,366 14,062,842 3,515,711 Rachelle 100,000 250,000 Zambon 1,000,000 ?50,000 1 None certified in 1963 and 1965. 2 Tablets. Senator NELSON. Now, on the Reader's Digest ad-I read it through very carefully two or three times. I note that you are disappointed in it. Dr. GODDARD. Yes, sir; I am disappointed in this because for the past year and a half we have been watching with some concern the incur- sion, if I can use that word of the pharmaceutical manufaclurers indi- vidually and collectively in the lay media, in terms of an indirect form of advertising. And it gives us concern. We have noted and alerted them to this, and expressed our concern in meetings with them, because it seems to us that this is a logical step that they might consider taking. In fact we have had some past cases that have given us so much concern that we have called the company to task in an individual case. - This simply is another example of moving beyond the ethical ad- vertising in medical journals, and bringing the message directly to the public. And we view this as something rather serious. Senator NELSON. It had always been my understanding-you may correct me if I am wrong-that in prescription drug advertising, the sole constituency of the company is the medical and paramedical, if that is the case, people in the profession. The companies have never gone to the lay media, so to speak, to advertise a prescription drug, because the person there does not make the decision, presumably, about what he should get. Is that correct? Dr. GODDARD. That is correct. That is the assumption that our regula- tions first formulated in 1963, were based on. Senator NELSON. I do not know whether you have noted it, but I have received letters, and have, on a half a dozen occasions, picked up institutional-type pharmaceutical on the radio. You can hear it every morning here, if you turn your radio on at the right time, and every evening going home. Is that a new development in this field? Dr. GODDARD. Mr. Goodrich has followed this over the years. To my knowledge it is a fairly recent one. The whole field-for example, we picked up some ads on oral contraceptives that we were concerned about, because they represented to us at least a first step into the field of advertising directly to the user. Now, one of the things physicians do not like, and understandably so,is to have the patient come in and say, "Doctor, I want such and such 8i-280 0-68-pt. 6-32 PAGENO="0498" 2632 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY a drug." Now, there is enough of this occurring already. In my own private practice of medicine years ago I had patients come in and say, "I need a shot of penicillin." And some of them flatly told me if I would not give it to them, there was another doctor down the road that would, and he did. So Ilethimdoit. But the promotion of drugs to the public I find very distasteful and an unfortunate step forward. I am saying we are seeing signs of this occurring. Now, it is quite proper that the public have early information, be- cause they are keenly interested, on new developments in medicine. The press does an outstanding job on this. And it is indeed a fine bal- ance between what represents promotion of the specific product, whether it is for a new treatment for arthritis, which involves so many millions of people, or this type of publication, which is an ad by, not a company, but by an organization made up of companies. Senator NELSON. I suppose there is some kind of qualitative distinc- tion between an institutional-type ad which promotes the industry as a corporate citizen in a public ad vis-a-vis an ad that picks a specific drug and promotes it in the public media. Is that correct? Dr. GODDARD. Yes, sir; that would be true. Senator NELSON. Now, this is a case here, in the Reader's Digest, where the PMA selects chloramphenicol, and on page M-3 they print a special section, as they did on a previous occasion, as you are aware. Dr. GODDARD. Yes, sir. Senator NELSON. And this ad does have "advertisement" printed on each page now. The line at the top is, "There was nothing anyone could do to stop them from dying until the American doctor came down from the sky with a new drug." Then it goes on to say the things you mentioned in your prepared remarks. We have a copy of a letter here, signed by Mr. Stetler, from the Pharmaceutical Manufacturers Association, addressed to "Dear NARD Members"-National Association of Retail Druggists. Dr. GODDARD. I know the association, Senator. Senator NELsoN. I knew you were familiar with it. Dr. GODDARD. Yes, sir; I am familiar with that group. Senator NELSON. But I thought some of the rest of the audience and the record may not be. But this reads-and I will submit it for the record-"Dear Member, as you may know, the Pharmaceutical Manufacturers Association recently launched a major advertising pro- gram with the Reader's Digest." They mention that the response from the general public was indeed gratifying, "and over I million reprints of the ad were distributed to the public through various sources, among them the community pharmacy." Then it goes on to suggest that the PMA has more copies available. They say: A copy of the February insert is enclosed, along with a prepaid postcard requesting 50 copies of the reprint. Present inventory precludes us from offering more. However, if you would like more than 50 copies of the June reprint at no cost, please indicate and we will forward them in the latter part of May. Quite obviously this is part of a program of reaching the public by giving 50 to a pharmacist, for distribution to whomever he pleases- and I suppose particularly the general public. (The letter referred to follows:) PAGENO="0499" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2633 PHABMACETJTICYAL MANUFA0TURERS ASSOCIATION, Washington, D.cT., January 26, 1968. Dii~n NARD MEMBER: As you may know, the Pharmaceutical Manufacturers Association recently launched a major advertising program with the Reader's Digest. Our first supplement of "Medicines and Your Family's Health", which appeared in the November issue, was widely distributed to Congressmen, government administrators and related health groups. The response from the general public was indeed gratifying, and over one million reprints of the ad were distributed to the public through various sources, among them the community pharmacy. Because pharmacists are directly and we hope favorably affected by this program, Willard Simmons, the Secretary of NARD has suggested that members of your association might be interested in having an opportunity to play a greater role in disseminating this health information to the public. We hope that you will agree with us that this successful public information effort can be a useful public relations medium between you and your customers. A copy of the February insert' is enclosed along with a pre-paid post card requesting 50 copies of the reprint. Present inventory precludes us from offering more; however, if you would like more than 50 copies of the June reprint at no cost, please indicate and we will forward them in the latter part of May. We certainly hope that this joint venture will continue to strengthen relation- ships between your profession and our industry. Any comments you have will be appreciated. Sincerely, 0. JOSEPH STETLER. Senator NELSON. Now you have commented that YOU were distressed by this type of advertising. Is there anything FDA intends to do about it? Dr. GODDARD. There is nothing underour present regulations we can do about this type of advertising. Is that correct, Mr. Goodrich? Mr. GOODRICH. So lon~g as it is used by PMA. Now, if this ad were used by Parke, Davis, in accordance with the law it would be the responsibility of the manufacturer to include in all advertisements issued or caused to be issued, adequate information on side effects, con- traindications, and effectiveness. As long as this is a PMA. ad, and not a Parke, Davis ad, the law would not apply to it. There would still `be an issue whether or not P;arke, Davis caused this advertisement to he disseminated. We have no evidence that they did. In the area of the oral contrac~ptives, where the message went to the public2 we issued a statement of policy saying that where such drugs, prescri~tion drugs, were advertised to the patient directly, that the promotional material would have to have adequate information for the patient on side effects, contraindications, at least, in terms that the laity could understand. When we put our regulations out, we proceeded on the assun~ption that you hold, that the audience was the profession, and the regula- tions were oriented to get before the profession the knowledgeable understanding of this drug in terms professionals can understand, but which would not `be particularly useful to the laity. We have no regulations so far on advertising cqpy for prescription drugs that goes directly to the public. You will recall that we did write to you in answer to your inquiry in connection with the first PMA Reader's Digest advertisement, stating where we were in this program, and what we could do and planned to do. `Retained in committee files. PAGENO="0500" 2634 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator N1u~soN. Do I understand you to be saying that under the law the FDA has the authority to slwerv'ise or control the advertising done `by an individual company, hut no authority over an association of which individual companies are members? Mr. GOODRICH. The law says "manufacturer, packer, or distributor," and refers to an advertisement either issued `by him or caused to be issued. I left open the issue, or the question, whether or not this could be proven to he an advertisement caused to be issued by Parke, Davis. I have no idea that it could or could not. I just have no ~pithon on that based in the facts I now have. But I would not rule out the possibility of taking some action if it could be proved that the company caused this advertisement to be issued by an association. Senator NELSON. Well, now, as a lawyer, we are looking at a situa- tion in which we have a nonprofit association with which the mem- bers voluntarily associate themselves. The association is controlled by the membership, and supported by the membership. Under any reasonable concept of law, it seems to me that you can constructively impute to the members the actions of the voluntary association. Mr. GOODRICH. I think you do. But do you go from there to the next step, that the manufacturer caused this advertisement to be disseini- nated? Now, that is i'c~hat we would have to prove, in any event, sir. Senator NELSON. The reason I used the legal language, "construc- tively impute," is that you may not be able to prove that in a specific instance a company actually said to its association, "Will you run this ad on our drug?" Mr. GOODRICH. That kind of case would be easy for us. Senator NELSON. Yes. But it seems to me it should be just as easy the other way, when in fact this is a member, and these members do directly control the association, And if they cannot throw a cloak around themselves and separate themselves from the creature they control, you simply could proceed on the grounds that you construc- tively impute it to them. Now, if they were not a member of the asso- ciation, and were controlling the association, and ran a story on a drug made by a nonmember company, I would think then you would have to go to the specific case and prove the specific company had a specific agreement. But it does seem to me it is just autoinatic-cer- tainily you control this company, we impute this to you, and you are in violation of FDA regulations. At least that is part of the law that ought to be explored very carefully. Mr. GOODRICH. It is entirely possible that we could prove that this was caused to be disseminated by Parke, Davis. Senator Nm2soN. I am not talking about that. Just the very fact that they are members, you impute it to them. That is the legal ques- tion that I think is important here. Mr. GOODRICH. I am sure I would have great difficulties with the Department of Justice in doing that, bu~ we will explore that. Senator NELSON. I do not think you ought to have any trouble with a real lawyer. Dr. GODDARD. You are not suggesting the Department of Justice does not have real lawyers. Senator Nm~soN. I am suggesting that you probably would not have any trouble because they do have real lawyers. PAGENO="0501" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2635 Dr. GODDARD. Or that Mr. Goodrich is not a real lawyer. Most com- panies wish Mr. Goodrich were nOt. Seriously, Senator, we will explore this. We are aware of the grad- ual creeping encroachment into public media of paid advertisement on prescription drugs in a variety of forms. And I think it is bad. Senator NELSON. If the lawyers, with their great tendency to legal- isms and legal conservatism, said you could not impute this to the Parke, Davis Co., which I think the court ought to take judicial notice of-but if they did, would you not be prepared to recommend that the law be amended so that the same authority applies to adver- tising of this kind as it does to advertising in medical journals, by individual companies? Dr. GODDARD. If that is what it takes to stop this kind of practice; yes, sir. Senator NELSON. Now, there is another part of this ad that troubles me-you quoted from it, and I will quote from it again: "The new drug was to prove effective against dozens of diseases." The first implication is that it is just a drug indicated for wide use. But, all the scientific evidence we have is that it is a drug indicated for a very limited use-in typhoid fever and in diseases against which there is no other effective drug, and when the condition is very serious. But are there dozens of diseases in which this drug is indi- cated, really? Dr. GODDARD. Dr. Ley-I would have to say that it is probable that there are dozens of conditions in whiàh one could say this drug is in- dicated. Now, the wording here is very carefully done, as you recognize. It says, "was proved." Now, that, in a historical sense, is true. It does not speak to the issue of what the indications are today, or that there has been a charged curtailment of the indications, and that even more curtailments are being considered, or that there are serious problems viewed with respect to the usage and overusage of this drug. So the wording here is actually, in my opinion, factually correct. I think that if Dr. Ley and I sat down for a few minutes he and I could come up with a dozen indications for the use of this drug. Don't lose sight of the fact that one of the indications that is appropriate is for use in those conditions for which the organism has resisted other anti- biotics, and these are serious conditions. And so there are literally dozens of those. Certain kidney infections, to give you one example. It is that kind of clever wording that is in my opinion very mislead- ing in this kind of advertisement. It leaves the impression this is still the case today. And technically that is correct. But it certainly does minimize the side effects part. We would not approve this kind of thing in an ad to a physician who knows what lies behind each word. Senator NELSON. This does not say dozen. It says dozens-which means many dozens. Dr. GODDARD. More than 1 dozen would be dozens, would it not, Senator-to quibble about grammar? Senator NELSON. Well, if it is 2 dozen, they ought to say 2 dozen. I get the impression, when they say dozens that the- Dr. GODDARD. I think it is misleading. Senator NELSON. If I may say decades, I usually mean more than PAGENO="0502" 2636 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY two decades. I think `the implication here is that there are a whole lot of diseases for which it is indicated. Dr. GODDARD. That is the implication I draw from it, too, sir. And I think it is misleading, without question. Senator NELsoN. I understand your legal division is going to pursue this question further? Dr. GODDARD. Yes, sir. Mr. GORDON. I have one question `about this. The ad says, "Second in a series published `as a public service by the Pharmaceutical Manufacturers Association." Would you consider this a public service? Or would you say it is a public disservice to mislead? Dr. GODDARD. To answer your second question, yes, I am a poor lawyer, and I have to rely on Mr. Goodrich here, as to what we would properly define as a public service. Now, let me say, I just think this wthole campaign in Reader's Digest-the first series of `articles was full of errors. I think we detailed some of these `to the committee. I think they were misleading, too. Now, the drug industry has done things that it properly should receive credit for. I just do not think this is the way to get credit for them. Personal opinion. Mr. GORDON. They misled in two out of two cases. Why do they have to resort to this type of activity? Dr. GODDARD. This was `apparently their decision, to help their image. Th'a't is the only conclusion I can draw. Senator Npl,soN. I think in at least one respect, Doctor, the eight- page article on three drugs is a public service, because after all of the hearings we have held here, PMA uses only generic names in discus- sing the drugs. Dr. GODDARD. Yes, sir. We noted that, too. Senator NELSON. Which I was told is `a very bad thing. But at least the PMA. now is using just generic names in the three drugs they are mentioning. Dr. GODDARD. Hopefully we can get that done in a compendium, Senator. Senator NELSON. I hope so, too. Go ahead, Doctor. Dr. GODDARD. The exact number of patients who have suffered a serious or fatal blood disease as `a result of the indiscriminate us~ of chioramphenicol is not known. Various estimates place the incidence rate of blood dyscarsias from chioramphenicol at 1 person in 10,000 to 1 person in 100,000 who receive the drug, general reactions. Despite the risks associated with the use of chloramphenicol, if one may judge from the sales figures, use of the drug continues to be excessive. Where have the FDA, `the manufacturers, and the medical profession failed? Is the general medical community unaware of, or unconcerned `about, the risks associated with this drug? What must be done now? These are most difficult questions, and the answers do not come easily. The "box warning" in the labeling i's strongly worded and tells the physician quite bluntly the dangers of the drug, yet it has not accom- plished its intended purpose. PAGENO="0503" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2637 What other steps might be taken? We have considered restricting the use of chloramphenicol to hospitals. However, aside from the legal problems mvolved, we have learned that more than half the chior- amphenicol distributed in this country is purchased by, and presum- ably used in, hospitals. Senator NELSON. How do you get a record of that kind? Dr. GODDARD. The Goslin survey is one source of that information. Also we received from the company earlier this week detailed records showing that 59 percent of their drug was shipped to hospitals for their use. Now, that might be somewhat misleading. Fifty-nine per- cent would represent a maximum, Senator, because it includes hos- pitals which would dispense it on an outpatient basis. A substantial amount is used. I do have the Chioromycetin figures `handed to me. These are from the firm. The estimated distribution of Chloromycetin to U.S. hos- pitals in 1967-this is by Parke, Davis-amounted to 18,700 kilo- grams, or 59 percent of the total kilograms `distributed in the United States. Senator NELSON. Some of that is,, as you say, dispensed on an out- patient basis. Dr. `GODDARD. Primarily in the military and veterans' hospitals. Although it may include some of the university `hospitals, too. Senator NELSON. I's there any information or have any studies been made as to the differences among the hospitals in this respect. That is, we had testimony yesterday fram one of the doctors that Johns Hopkins, many years ago, initiated the policy of requiring that the chief hematologist, I believe, countersign any prescription for chlor- amphenicol. Well, obviously in a hospital doing that, I suppose the usage would be generally quite specifically confined to indicated uses, though it m%ht not be where you do not have a therapeutics commit- tee or something. Is there any information on the differences `between hospitals? Dr. GODDARD. Dr. Ley, do you have any comment on this? Dr. LEY. We have no overall information which would answer your question, Senator. We have locally explored with four hospitals the proportion of hospital usage which is inpatient, and the portion which is outpatient. This will vary considerably, and this is a very small `sample, so I would be reluctant to predict any generalization which could be ap- plied across the country. It would appear `somewhere in the order of a fifth to a sixth of the usage may be in the outpatient clinic of the hospital itself. We have no means, of course, of determining the amount of the drug which is used in the private physicians' offices of this country. That is the most difficult figure, and one that is almost impossible to cthtain. Senator NELSON. What I was getting at was-is there anything to demonstrate whether, say, teaching hospitals, large hospitals, use less of it for patients than smaller hospitals? Dr. LEY. I have no information ,sir. Senator NELSON. Please continue. Dr. GODDARD. In addition, restriction of the drug to hospital use PAGENO="0504" 2638 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY alone would pose an undue hardship on some patients for whom the drug is properly prescribed. There are fewer than 1,000 cases of typhoid fever in this country each year, but the maj or proportion occurs in rural areas which may not be served by hospitals and a few patients may re- quire continued use of the drug after their hospital discharge. Some persons, therefore, would be deprived of appropriate treatment unless they undergo the inconvenience and expense of a hospital confinement. Senator NELSON. Again, if the testimony of the experts before this committee is correct, that about 4 million people get the drug, and that 90 to 99 percent of that number should not get it, is the inconvenience to a relatively small number of people for whom it might be indicated outside the hospital, anywhere near as important as the exposure of over 31/2 million people to a drug that may have lethal effects when prescribed for a condition that does not warrant it at all In other words, if you are weighing the equities, so to speak, isn't the inconvenience of a few people, however many that may be, much less important than the tragedies that we are haying across `the country? If you require that hospital admission be a prerequisite for administra- tion of chloramphenicol 31/2 million people are not going to go to the hospital. I doubt whether a doctor is going to send them there for acne, sore throats, head colds. And, then, the physician would see that this is `a serious matter and therefore take another look `at the literature, wouldn't he? Dr. QOODARD. Senator, you are drawing an assumption here. First of all, let me point out and remind you that we believe at least 50 per- cent of it is administered in the hospital today. Now2 that would indicate 2 million people receive the drug when hospitalized which is still excessive by any estimate-2 million people. You would admittedly get at part of the problem. Now of course you are well aware of the fact that we can only restrict through labeling changes, and we do propose, in our labeling change, `a sentence in the warning saying, "Because of the necessity of repeated blood studies during therapy, it is desirable that patients be hospitalized if possible." Now, this is not what you are asking for, and I recognize that. But we have put the matter to our advisory group, and the problem has been before other advisory groups. Every time it answers this way. Just because eminent physicians suggest it does not mean restriction solely to hospitals would solve the problem. They recognize much of the misuse in hospitals. So I go back to what I said earlier and suggest that you also con- comitantly examine the question of whether therapeutics committees can be brought into being in all the hospitals as a means of getting at the misuse in hospitals. Now, beyond that, if you go more broadly, it certainly would re- quire legislation. And I think it would raise a serious question, one that you and your colleagues would want to explore in some depth, in order to control the misuse of drug. I could suggest a system, yes. I could suggest one, that would, for example, limit the amount of the drug manufactured, and preposition it in warehouses at various points of the United States, so it will be quickly available to those who need it. Then it could only be obtained after filling out the proper PAGENO="0505" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2639 form. I could suggest that. But that, to me, raises for serious discussion -What is the proper role of a Federal agency? This would represent a marked change in the philosophy behind FDA in terms of its role with respect to the practice of medicine. And it is not one that I would suggest to you. It is one that you may wish to explore. But I am loath to suggest it at this point in time. Senator NELSON. Well, I must say it is most frustrating. Dr. GODDARD. It is. Senator NELsoN. I have not come up with an answer. I have just been asking questions. Every expert that I have heard, and the material I have read, all say basically the same thing: it should only be used in a hospital, because if you are sick enough to have it, you ought to be in the hos- pital. Then Dr. Gilman goes on to say that it should be used in the hospital, and if there is an exception, that there should be a specific agreement between the doctor and the patient that he would see that patient, every 48 hours, and that continuous blood studies should be made. Now, this is the opinion of experts as I gather it from all over the country. Yet, their recommendations, are being violated wholesale. Are we supposed to sit here as toothless souls-our Government or anybody else-who cannot protest the country? This is incredible to me. Dr. GODDARD. I agree it is incredible, Senator. But how are you going to stop this practice from occurring? I am as baffled by it as you are, as to what steps can be taken. I know of no other drug that has been given the prominence in terms of warnings to the medical profession that this drug has over the past 18 years. And yet the sales indicate it is being more widely used today than ever before. I do not know how you caii control', it, other than taking steps through legislation, which I raised with you as one of the possibilities. Because after w-e are through talking about all the things we are going to do, there still will remain in your mind, I am sure, as it must in mine, a serious question as to whether `these new steps will be any more effective, other than temporarily, in reducing the amount used. And `then you ultimately have to come back and say "What is it that can be done that can control the misuse of this drug?" And I submit to you, sir, that it would require a legislative change, the na- ture of which has not been made in our society before with respect to this profession. And I am loath-it would have to be explored, I think, in greater depth with the physicians, with the hospital asso- ciation, with the pharmaceutical manufacturers themselves, because it has rather profound implications. Senator NELSON. You have no present `authority to say that it should be confined to hospital use? Dr. GODDARD. We could in the labeling, ,and that is as far as we could go. And we cannot enforce that. Senator NELSON. This is a fine state of affairs, where tragedies are occurring `all over this country, and we do not have any creative ideas for doing something about it. We are not attempting to interfere with anybody's rights. There is PAGENO="0506" 2640 COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY no right on the part of anybody in any profession to act contrary to all authority. Now, how it has come about I suppose is a very complicated busi- ness-history, advertising, busy physicians, all kinds of things. But the fact is that innocent people are dying from chioromycetin, and a whole lot more I suspect than is indicated in any statistics I have ever seen-to say nothing about those hidden thousands of cases who are just ill the rest of their lives, but do not die. Now, I think that if a profession fails in its responsibility, some- body has to do something about it. Dr. GODDARD. Sir, I believe we have some creative ideas that we are going to implement. Now, I have already said that I am sure you will, after hearing these ideas, have reservations about how effective they can be. I have also suggested something to you this morning which has never been looked at before-that is `the question of getting the Joint Commission on Accreditation into this. And they are a. very powerful organization. Now, perhaps through the combination of the things I am going to suggest to you, the suggestions I have already made, and the careful attention to this on a continuing basis, we can reverse a trend that is not only unfortunate, but unprecedented in t.he practice of medicine- and take the steps that will be needed to reduce the usage of this drug to a proper level. Now, that is all I can suggest short of a significant legislative change. Senator NELSON. I think after all these years there ought to be a significant change whether it is legislative or otherwise. Now, you are going to receive a monthly report, I understand, of how many grams are being marketed. Suppose 1 year from now there are still 4 million people getting it who should not. What do you say then? Do you say we still go on kill- ing people, but we do not want to interfere with anybody's right to prescribe this drug? Do we require the inconvenience of a few people having to go to the hospital annually who otherwise would not go? What `do we do a year from now? That will make 19 years. Dr. GODDARD. Well, I would hope, Senator, that we would continue exploring these ideas with other segments of the medical community that are involved, and then reach a decision as to whether or not change was needed beyond what I can suggest based on our present legislative authorities. I cannot presume to speak for the medical pro- fession of this country. I can only reflect the authorities that. Congress has provided us, and take steps that we as an agency feel are enforce- able-ones that will contribute hopefully to the solution of the prob- lem. Beyond that, I have only suggested to you some additional steps that you might take. And I have viewed these hearings as a very healthy start at tackling this problem, Senator. And I share with you your concern that. in spite of these steps I have mentioned we might very well not solve this problem in the next year. Senator NELSON. One of the ideas that has been suggested here, which is worth exploring, it seems to me-I have no intention of in- terfering with the discretion of the medical profession. It is a great profession. But it would not be an interference, it seems to me, if we PAGENO="0507" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2641 had some legislation that authorized the FDA and the appropriate authorities in the field of medicine to come to specific agreements on a drug like this, or two or three or whatever number it may be, and be equipped with the authority to be really tough-just really tough. Dr. GODDARD. Senator, you cannot do that without interfering with the practice of medicine. I will lay it on the table in front of you and say it cannot be done unless you are willing to interfere with the prac- tice of medicine. When you say exercise discretion, you are then saying you have to control discretion-the selection of the drug to be pre- scribed. You have got to limit it. Senator NELSON. Is it, in your judgment, an interference with the legitimate practice of medicine in a good teaching hospital to say to the doctor, "You cannot prescribe chloramphenicol for your patient without having the approval of representatives of the therapeutics committee, or having the order countersigned by the chief hematol- ogist?" Of course that is an interference. You are saying to that fellow, that doctor, that you cannot do it without consultation because this is so serious a matter that you have to have it countersigned. Is that an interference with the practice of medicine? Dr. GODDARD. Sir, that is a decision of that teaching hospital-the staff in its staff meeting agreed to it.. That was self-regulation. It is quite a different thing than a Federal agency imposing its will upon the practitioners of medicine in their own offices. This is what would have to be done to get at this problem the way you suggest. Senator NELSON. If you followed what Dr. Dameshek and some of the other experts said, all you are saying is that you are taking a very serious risk unless the drug is administered in the hospital. The next step after that ought to be that the Accreditation Uommittee move along the lines you suggest, and say that a hospital must have a therapeutic committee to be accredited. And the next step would be to persuade the therapeutics committee to follow this procedure, the countersigning, using their hematologist. This would not interfere with the valid .practice of medicine, would it? Dr. GODDARD. By your own description it is interference with the practice of medicine, and it is by mine. I am not saying what you suggest is wrong. I am simply pointing out that if you have the FDA do it, it is a basic philosophical change in what a Federal regulatory agency does vis-a-vis the practitioners. Senator NELSON. Well, supposing the FDA and the medical pro- fession and the Committee on Hospital Accreditation got together and said, "We will work out an agreement on a drug like this one and set up some rules, and ask the committee and the profession to enforce it themselves." I am not asking the Federal Government to do it. You would not be here, and these experts would not have ap- peared if the medical profession were policing itself. This is a ridic- ulous place to have to take up a professional matter. But it gets so bad that somebody has to do something. And if they do not do it, somebody else has to do it for them. That is the way it seems to me. You cannot read what is happening to the victims of chlorampheni- col around the country without being upset about that. Dr. GODDARD. I agree. Mr. GROSSMAN. Doctor-can we imply from what you say that the PAGENO="0508" 2642 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Administration will not propose any legislation to go beyond what you have said this year? Dr. GODDARD. That is correct. Mr. GROSSMAN. Can I ask you one other thing. What portion, do you feel, of the number of patients who get this drug should be in the hospital? You have talked here about typhoid fever, as well as people living in rural areas who might not be able to get into hospitals. Now, wouldn't it be a fairly hi~h proportion of these people who would be in hospitals, if we are talking about a very serious indication? Dr. GODDARD. Yes, sir. But let us just take an example. Take a clinic, which characteristically sees patients on an out patient basis. They have good laboratory diagnostic facilities. They do sensitivity testing. They culture the urine, let us say, and re~cover an organism. They find a particular infection that the patient has is due to an organism that is sensitive to chlorarnphenicol and not sensitive to other broad spec- trum antibiotics. Now, a kidney infection is a very serious thing, and yet it is not necessarily one which requires the patient to be hospitalized. The urinary tract infection in general must be viewed as a serious infec- tion, and yet in many instances these are treated on an outpatient basis. Now, having said that, let me say that I would guess-and it is only a guess, based on what I have read, other experts' testimony, and my own limited knowledge of this-that perhaps 80 percent of the patients who require Chioromycetin would in fact be hospitalized during the acute phase of this illness. Now, that does not include follow up treat- ment that is often required. Mr. GROSSMAN. But-this is another area where there are no statistics. Dr. GODDARD. No statistics at all; no, sir. Mr. GORDON. Dr. Goddard, do you have authority to take a drug off the market? Dr. GODDARD. Yes, sir. Mr. GORDON. You have done so in the past? Dr. GODDARD. Yes, sir. Mr. GoRDON. Have you found that it has interfered wit.h medical practice? Dr. GODDARD. Of course. And I have said on a number of occasions that Congress gave us certain authorities which in and of themselves must be viewed as, in part., interfering with the practice of medicine. We make decisions on which drugs will enter the marketplace, and which drugs are to be taken out of the marketplace. And that was what Congress said we should do. Mr. GORDON. All right. How about taking this drug off the market? Do you have t.he authority to do that? Dr. GODDARD. Yes, sir. And we have discussed that on every occasion that this drug has been reviewed by eminent groups of scientists, who have advised us-either through the National Academy of Science or directly-and in every instance there is unanimous agreement, as far as I know, that the drug should not be taken out of the market. Mr. GORDON. These people do not represent the public. The FDA represents the public. PAGENO="0509" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2643 Dr. GODDARD. Yes, sir. Mr. GoIuoN. These are merely advisory committees. Dr. GODDARI. Yes, sir. Mr. GoinjoN. You have the authority to make the ultimate decision. Dr. GODDARD. Yes, sir. Mr. GORDON. Now, considering all these things we have been talking about, for weeks, and for years as a matter of fact, have you reached a decision that, on balance, it would do more harm than good if the drug were taken off the market completely? Dr. GODDARD. Yes, sir. It is a preferred drug in Hemophilus influ- enzae meningitis-principally typhoid fever, and these other infec- tions which are often life-threatening. The number of these cases in my opinion far exceeds the number of fatalities that occur because of the drug being misused. Now, I am not minimizing the risk involved in misuse. I am simply saying that on balance, we have asked this question-this is the first question we have asked every advisory group, and they, every time, say that it should be left on the market. Mr. GORDON. But they do not know the statistics, do they? Dr. GODDARD. They have the same information we have, sir-the same that you have. Mr. GROSSMAN. Which is not very good, is it? Dr. GODDARD. No; not very good. Mr. GORDON. If you have the authority to go all the way, to take a drug off the market, are you saying that you do not have the authority to go part way, to confine it to hospital use? Dr. GODDARD. We could only try to confine it to hospital use by a change of labeling. I have read the new labeling we are going to dis- cuss with the company, that portion of it which recommends the drug be used in the hospital. We have no way of enforcing this. Senator NELSON. Is that going to appear on the new label? Dr. GODDARD. Yes, sir. Senator NELSON. How will that be worded? Dr. GODDARD. I will read the warning in toto. Warning, serious and fatal blood dyscraias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia and leukemia) are known to occur after the administration of chloramphenicol. BlOod dyscrasias have occurred after both short-term and prolonged therapy with this drug. Bearing in mind the possibility that such reactions occur, chioramphenicol should be used only for serious infections caused by organisms which are susceptible to its antimicrobial effects. Chloramphenicol must not be used when other less potentially dangerous agents will be effective. It must not be used in the treatment of trivial infections or where it is not indicated, as in colds, influenza and infections of the throat, or as a prophylactic agent to prevent bacterial infections. (Last sentence under- lined. Precautions. It is essential that adequate blood studies be made during treat- ment with the drug. While blood studies may detect early peripheral blood changes, such as leukopenia or granulocytopenia, before they become irreversible. such studies cannot be relied on to detect bone marrow depression prior to development of aplastic anemia. Because of the necessity of repeated blood studies during therapy, it is desirable that patients be hospitalized if possible. Senator NELSON. Read that last sentence again, please. Dr. GODDARD. "Because of the necessity of repeated blood studies during therapy, it is desirable that patients be hospitalized if pos- sible." PAGENO="0510" 2644 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GROSSMAN. You would like to increase that 80 percent figure to 100 percent if possible? Dr. GODDARD. Yes, sir. But we have to also say unless the other steps are taken, in terms of proper review of its usage in the hospitals, this is not going to necessarily change it. Senator NELSON. I take it, then, because of that recommendation on the label, that it is your judgment and that of your consultants, that it is desirable to use chloromycetin only in the hospital, when possible. And that means using "possible" the way I understand it should be used in outpatient treatment only in exceptional cases. Dr. GODDARD. Correct. Now, it was my judgment, and Dr. I~y's judgment, after a discus- sion with our consultants, and after looking at the past history, and discussing it with our staff, that this was one additional step that we would take, plus the others I have yet to describe to you. But I had to make that decision. I participated in the meeting of the advisory committee. I will tell you, sir, that our advisers did not vote unanimously on that point. Two of them said they felt, in spite of the very proper indications for outpatient use, that it should be labeled "for hospital use only." Four of them said, no, they felt such labeling was not proper. And so as is always the case, we had to make a decision, and ultimately I had to make one, and this represents our decision. Now, we think that this, plus the other steps we are recommending will be helpful. Certainly we hope to exploit these steps along with the information developed from this public hearing. We hope to ex- ploit these additional steps I am going to mention in such a way that it will help make a significant inroad into the excessive uses. I can only say that that is where we are today. Senator NELSON. Then, if I understood you correctly, two of the six advisers were of the opinion it should be confined to hospital use only? Dr. GODDARD. Yes. They also recognized the problem one has in de- fining a hospital. Does that include a nursing home? These kinds of things all get into it. Now, here again, the decision has to be made on the basis of what would be effective. We cannot enforce either one of these, Senator. It comes down to how can you enforce this-not what rwe say on the label-because that is clearly not helping. You know, this drug has the toughest warning I think of any drug I am familiar with. Senator NELSON. And `it does no good. Dr. GODDARD. It does no good. I cannot tell you that this new warn- ing is going to do any good. I can tell you the new warning, plus the "Dear Doctor" letter we intend to send to every doctor and hospital administrator, plus the material we are going to provide the publishers of medical magazines and new~p.apers, ~plus the constant review on the monthly production data, and the rewarning of the profession when it indicates any upswing, plus the change in the reminder ad- these r~present what we in our opinion feel we can do now within our present authority. Mr. GORDON. Do you have the authority `to prohibit all advertising and promotional activities with respect to this drug? PAGENO="0511" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2645 Dr. GODDARD. No, sir. Mr. GORDON. You have no such authority? Dr. GODDARD. No, sir. Senator NELSON. The ~position I have been suggesting about re~uir- ing that `administration `be limited to ho~pita1s oniy and the position you ultimately end i~p with are really very close together. Your posi- tion is that such ~a procedure is what ought to be followed `but not re- quired by law. The position of some of the e~perbs who have testified is that this is w.h~at ought to be done, even if it does require enforce- inent by law. Is that the difference between the two? Dr. GODDARD. Basically I would say the difference is-let me recast that in my words and see if we are in agreement. Your experts have said even if the law has ito be changed, it should be restricted to hospitals. Senator NELSON. Some say that, yes. Dr. GODDARD. Now, I submit to you that restriction to `hospitals `alone will not do the job. it has not so far. A~~~proximately 2 million of the pe~ple a year receiving the drug are getting it in hospitals. Obviously additional steps have to he taken. Senator NELSON. But you think it would be an improvement, or you do not think it should be recommended? Dr. GODDARD. Labeling represents~~ an improvement, by strongly suggesting only hospitalized patients should get it. Now what I am trying to say is that in itself will not do the job. There are additional steps that have to be taken. I suggested you get the Joint Commission on Accreditation to testify as to the possibility of adding to their standards. I do not know what their reaction will be. I have not talked to Dr. Porterfield about this. I have talked to the Surgeon General of the Public Health Service as to what addi- tional steps they might suggest, because they are dealing with problems of medical care. They have no suggestions. Senator, believe me, we will consider carefully suggestions that would help diminish the excessive use of this drug. But, as you well know, we have authorities under which we operate quite properly. These authorities do not permit the policing of this situation in a way that would make effective reduction occur within a short period of time. Senator NELSON. I am one of those that would be happy to give you more authority. Go ahead, please. Dr. GODDARD. I think, Senator, I have in effect summarized the rest of my statement-if I can just submit it for the record. Senator NELSON. There have been so many interruptions during your presentation-we will print your statement in full at the con- c]n~1ien of your testimony. Mr. GORDON. Dr. Goddard, it seems incredible to me that. the pub- lic, to such a large extent, is unprotected. What you really have told us here today, so far as I can see, is that the public has very little protection. Dr. GODDARD. I do not believe that is so. 1 think the public in this country has a greater measure of protection than the public in most nations. PAGENO="0512" 2646 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GORDON. That is not saying very much, however. Dr. GODDARD. Well, I would like to ask you, Mr. Gordon, what it is you propose be done. I am at my wits' end as to what can be done within the authorities and the philosophy of what FDA is supposed to be doing. Mr. GORDON. Well, for example, we discussed the possibility of re- restricting it to hospitals. We talked about the possibility of curtailing to a large extent, or abolishing, the promotional activities. Dr. GODDARD. I have told you that in both instances we do not have the means to enforce those suggestions. Mr. GoRDoN. I know, now that you do not have the authority. But given this, it seems to me that we are not in very good shape. Dr. GODDARD. What you are talking about basically is what pro- tection do you have from your doctor-to put it in its baldest terms. Let us call a spade a spade. That is what you are talking about. Now, I do not think you can legislate that. You are talking about one drug. You have to rely on the physician's judgment for every drug that he prescribes. And the physicians need good information. This committee is aware of the problem in that area. There needs to, be greater self-regulation in the form of therapeutics committees, and a lot of these steps need to be taken. But in the long run, I do not think you can regulate good practice of medicine. Senator NELSON. I do not think a.nybody is suggesting that, really. Dr. GODDARD. That is what it comes down to. Senator NELSON. I think we are talking about an extra special case here in which-as you know-in a 15-year period, 35 to 40 million people in America have been givin a drug and have thus been exposed to a possibly lethah dose for a condition in which it is just not needed. And there is no disagreement at all about that. We should not be help- less in the face of that situation. And, certainly nobody could say it was an improper interference to say that there is a category of drugs which must be used only under certain circumstances. I think that label ought to be a whole lot tougher. I think it ought to say "dangerous drug" at the top. I think it ought to say that medical evidence indicates that 90 to 99 percent of the people getting it should not be getting it, and great tragedies are occurring as a result. It should warn the `doctor not to use it without making some careful investiga- tions and studies. You ought to hit them in the teeth with it-hard. I do not see how we can expect to accomplish our goal with this new label. It contains a stronger warning, but physicians were not reading the last one. Dr. GODDARD. Well, Senator, I am willing to consider your sugges~ tions on rewording this. This is not the final copy yet. I do not think you have much faith in this either, even though it has been the strongest warning. These thoughts that you bring out are not unknown to the medical profession. There has never been a drug that has received the attention that chloramphenicol has in the form of editorials, news ar- ticles, tight language in the package circular, what is allowed in the ads and everything else. Now, I do not see the difference between "dangerous drug," and say- ing "serious and fatal blood dyscrasia.." The latter translates imme- diately to a physician that here is a drug to be reckoned with, or should. PAGENO="0513" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2647 But it apparently does not help. And I do not think it will change if you say "dangerous drug," I am sorry to say. But I am willing to consider that. Senator, you yourself said 18 years have gone by with this kind of information. Senator NELSON. And that sure shocks me. Dr. GODDARD. Yes, sir. And I say when you cut aside all the verbiage, it comes down to the fact that somebody has to make a decision. Are you going to have in this country a system that provides control, very tight control, on a drug or all drugs in a different fashion than we have ever had before. I am sorry-I am not trying to be obstreperous. I am simply trying to point out it gets down to that kind of funda- mental issue. Senator NELSON. I think it does. Thank you very much. You have been a very gracious and pleasant witness. (The complete prepared statement of Dr. Goddard follows:) STATEMENT OF DR. JAMES L. GODDARD, COMMISSIONER OF THE FOOD AND DRUG ADMINISTRATION, U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Mr. Chairman, I appreciate the opportunity of appearing before your Com- mittee today to discuss the Food and Drug Administration's action and intentions in regulating the interstate distribution On the antibiotic drug, chioramphenicol. The Nation has watched with great interest the testimony unfolding before this Committee in the past weeks. The Committee's hearings have brought renewed attention to important questions that concern us all: Is this a drug too dangerous to remain on the market? Should its use be restricted in some way? Are the FDA, the medical profession, and the manufacturer of the drug taking all necessary steps to assure the safest possible use of the drug? Before discussing these questions `and alternatives, however, it may b~ useful to outline what has been done in the past. Chioramphenicol was first isolated in 1947 from a soil sample collected in Venezuela. It was found that liquid cultures of the organism, Bterptomyces venezuelae, possessed marked effectiveness against severai Gram negative bacteria and also exhibited antirickettsial and antiviral activity. Shortly there after the chemicai structural formula was determined and the antibiotic was prepared synthetically. And, `as you know, it was later patented by Parke-Davis and Company. In 1948, chloramphenicol was produced in amounts sufficient for clinical trials and general clinical use. It was found to be of value in the therapy of a variety of infections, including epidemic typhus in Bolivia and scrub typhus and typhoid fever in the Malay Peninsula. On January 12, 1949, the Parke-Davis New Drug Application for Chloromycetin, that cempany's brand of chioramphenicol, was allowed by FDA to become effective. In the summer of 1949, as the result of new legislation, Chioromycetin was classified as a "certifiable antibiotic," subject to the bacth certification provisions of the Food, Drug, `and Cosmetic Act. When chloramphenicol was first introduced in 1949, it was widely heralded as a "broad spectrum antibiotic" effective against an impressive range of micro- organisms. It was also considered to be largely nontoxic. There was no indication at that time th'at the drug had any serious side effects. Early in 1950, however, a few published reports drew attention to the possibility that chloramphenicol might cause serious and fatal blood dyscrasias. The 1951 edition of New and Non-official Remedies warned that "changes in the peripherial blood or blood forming organisms have been reported during the use of chloramphenico~." An editorial in The Journal of American Medical As- sociation, June 28, 1952, referred to additional reports of blood disorders. It went on to say: "A second and more serious type of reaction that has been encountered is pro- duction of a true aplastic anemia. In the experience of one group this anemia has occurred in patients who have previously received one or more courses of chloramphenicol without untoward effect. When the drug was subsequently administered, even in small doses, a severe blood abnormality has appeared. Even deaths have been reported." 81-280 0-68-pt. 6-33 PAGENO="0514" 2648 COMPETITIvE PROBLEMS IN THE DRUG INDUSTRY In response to these reports, FDA conducted a nation-wide survey of case records in hospitals and clinics in an attempt to evaluate the magnitude of the problem and to determine whether a cause and effect relationship existed between the drug and the disease. This survey produced records of 410 cases of serious blood disorders, of which 177 were definitely known to have been associated with chioramphenicol. In 61 cases, chioramphenicol was the only drug admin- istered. In half of these 171 cases, the blood disorders were fatal. They included aplastic anemia; hypoplastic anemia; thrombocytopenia; and granulocytopenja. In June 1952, the FDA discontinued certification of chioramphenicol, and in July 1952, the FDA referred the case histories obtained in the survey to the Na- tional Research Council (NRC). The NRC established a committee of outstand- ing hemotologists and internists, under the chairmanship of Dr. John Holmes Dingle, Professor of Preventive Medicine, Western Reserve University, to review and evaluate the chloramphenicol problem. On August 7, 1952, the Committee reported as follows: "An ad hoc Conference was held on 6 August and reviewed all available data presented by the Food and Drug Administration and by Parke, Davis and Com- pany. "The consensus of the Conference was as follows: "1. Certain cases of serious blood dyscrasias (aplastic anemia, thrombe- cytopenic purpura, granulocytopenia, and pancytopenia) have been asso- ciated with the administration of chloramphenicol. "2. Although this complication has thus far been uncommon, it is sufficient- ly important to warrant a warning on the label of packages of the drug and in advertisements of the drug and the recommendation that chloramphenicol not be used indiscriminately or for minor infections. "3. When prolonged or intermittent administration is required, adequate blood studies should be carried out. "4. In view of the paucity of information at the present time the Confer- ence hopes that further study of serious reactions to chloramphenicol and other drugs will be promoted. The records of the Veterans Administration and military forces could be of great value in providing some of the de- sired information." The recommendations of the Committee were implemented and resumption of certification of the drug follow-ed. All chloramphenicol was to be marketed with the following label warning: "Warning-Blood dyscrasias may be as- sociated with intermittent or prolonged use. It is essential that adequate blood studies be made". The following warning was to appear at the top of the package insert: "Certain blood dyserasias (aplastic anemia, thrombocytopewie purpose, graimiocytopenja and pancytopenie) have been associated with the administration of Chloromy- cetin. It is essential that adequate blood studies be made when prolonged or intermittent administration of this drug is required. Chioromycetin should not be used indiscriminately or for minor infection>". In announcing the reinstitution of certification for chloramphenicol, FDA said: "The administration has weighed the value of the drug against its capabili- ties for causing harm and has decided that it should continue to be available for careful use by the medical profession in those serious and sometimes fatal diseases in which its use is necessary". FDA characterized its experience as "an impressive reminder that highly po- tent drugs must be treated with extreme care and should not be employed unless there is a clear-cut indication that they are needed". The Kefauver Subcommittee on Anti-Trust and Monopoly subsequently re- ported that these warning measures were diluted by Parke-Davis instructions to its detail force, which the Subcommittee said presented the report of the Na- tional Research Council as a blanket clearance of the drug. Nonetheless, the use of the drug dropped off markedly after the new warning issued. This was a short-term reaction, however, and use of the antibiotic increased during the years that followed. In 1955 Parke-Davis requested a deletion of part of the warning statement. The firm's letter pointed out that some patients with blood disorders attributable to Chloromycetin had received only a few capsules. The company regarded the warning, which referred to prolonged or intermittent therapy, as a legal liability in litigation. PAGENO="0515" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2649 We rejected* this proposal, and while strengthening the warning was sug- gested, the decision was made to continue the warning as recommended by the scientific committee. In December 1959, one of our physicians, who was also in private practice, was visited by Parke-Davis detail men who claimed that there was no more dan- ger of blood dyscrasias with Ohloromycetin than with any other antibiotic. The company was informed of this impropriety, and gave assurance that the state- ment was both unauthorized and contrary to company policy. In April of 1960 the Council on Drugs of the American Medical Association made another report on blood dyscrasias associated with chioramphenicol. The report said that although the warning had been in use for a long time, physicians continued to use the drug indiscriminately for minor infections, including those associated with the common cold. FDA asked the National Research Council in November 1960 to again con- sider the chioramphenicol problem in light of the new evidence accumulated since 1952. Specifically, FDA wished to obtain the Council's opinion as to whether chioramphenicol should be allowed to remain on the market; whether its use should be restricted to hospitals if it were to remain on the market and, what label changes the Council would recommend if the drug was allowed to remain on the market. The recommendations of the Council were received by FDA in January 1961. The Council concluded that, due to its therapeutic value, chioramphenicol should remain on the market; due to some of its proper indications for use, home treat- ment, as opposed to hospital treatment exclusively, was reasonable; due to its serious effects, further warnings and increased education of the medical profession were necessary. In accordance with these recommendations the labeling of chloramphenicol was revised in February of 1961 to include a prominent "warning box" con- taining the following information: "Warning-Serious and even fatal blood dyscrasias (aplastic anemia, hypo- plastic anemia, thrombocytopenia, granulocytopenia) are known to occur after the administration of chioramphenicol. Blood dyscrasias have occurred after both short-term and prolonged therapy with this drug. Bearing in mind the possibility that such reactions may occur, chioramphenicol should be used only for serious infections caused by organisms which are susceptible to i'ts antibacterial effects. Chloramphenicol should not be used when other less potentially dangerous agents will be effective. It must not be used in the treatment of trivia'l infections such as colds, influenza, or 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 or granulocytopeni'a, before they become irreversible, such studies cannot be relied on to detect bone marrow depression prior to development of `aplastic anemia." Parke-Davis was required to mail the new prescribing information to all medi- cal `doctors and osteopaths in February 161 with a statement that the prescribing information would accompany all oral and parenteral Ohioromycetin products. Between 1963, when our prescription drug advertising regulations were first adopted, and 1966, Parke-Davi's advertised Chloromycetin by reminder ads, which carried no indications and no warnings. The regulations permitted this. In 1964, the Company decided to advertise `the drug promotionally and met with our medi- cal advertising group to `consider how this should be done. Our physician's noted that the package insert `had no "Indications" section, but instead described the broad range of `antimicrobial activity of the drug. To correct this, an indications section was devis'ed and other changes made to emphasize that the drug was only indicated for, and should be prescribed in accordance with, the important infor- mation in the "warning box." In 1966, the Company made the requested ch'anges and discontinued the reminder ad campaign. The labeling was reviewed again in 1966 by the A'cting Deputy Director of the Bureau of Medicine and the "box warning" was' changed to say that the drug must (instead of should) not be used in trivi'al infection's or in any other condi- tions except as `described in the box. Despite these label revisions, editorials in the Journal of the A~neriean Medical Association, and warnings in other publications such as The Medical Letter, the use of ehioramphenicol has increased and continues to increase. Most of this use, PAGENO="0516" 2650 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY we believe, is for medical conditions for which the drug is not indicated or for which it is expressly prohibited, such as acne, the common cold, simple infections and the like. We are disappointed by a current advertisement in the Readers Dige$t by the Pharmaceutical Manufacturers Association, which describes chlor- amphenicol as a prime member of a "class of drugs that fights 100 diseases" and characterizes it as a "broad spectrum" antibiotic effective against dozens of dis- eases, causing only occasional and sometimes serious side effects in some patients. The exact number of patients who have suffered a serious or fatal blood disease as a result of the indiscriminate use of chloramphenicol is not known. Various estimates place the incidence rate of blood dyscrasias from chior- amphenicol at one (1) person in ten thousand (10,000) to one (1) person in one hundred thousand (100,000) who receive the drug. Despite the risks associated with the use of chioramphenicol, if one may judge from the sales figures, use of the drug continues to be excessive. Where have the FDA, the manufacturer, and the medical profession failed? Is the general medical community unaware of, or unconcerned about, the risks associ- ated with this drug? What must be done now? These are most difficult questions, and the answers do not come easily. The "box warning" in the labeling is strongly worded and tells the physician quite bluntly the dangers of the drug, yet it has not accomplished its intended purpose. What other steps might be taken? We have considered restricting the use of chloramphenicol to hospitals. However, aside from the legal problems involved, we have learned that more than half the chloramphenicol distributed in this country is purchased by, and presumably used in, hospitals. In addition, restriction of the drug to hospital use alone would pose an undue hardship on some patients for whom the drug is properly prescribed. There are fewer than 1,000 cases of Typhoid Fever in this country each year, but the majority occur in rural areas which may not be served by hospitals and a few patients may require continual use of the drug after their hospital discharge. Some persons, therefore, would be deprived of appropriate treatment unless they undergo the inconvenience and expense of a hospital confinement. Other measures have been suggested, such as requiring that every prescription for chloramphenicol be countersigned by a second physician or requiring per- mission by a board of physicians before the drug could be used. Such measures are not possible under current law, nor does it seem to me that such systems would be practical, desirable, or possible to enforce. It has also been suggested that this drug, along with other "dangerous drugs," be restricted to use by physicians registered with the Government in much the same way that narcotics are handled. This is not possible under the present law, nor is it particularly desirable. Most drugs are potentially dangerous, even when properly used and certainly when misused. Where should the line be drawn? Establishing this group of drugs would, it seems to me, create more problems than it would solve. It has also been suggested that detailed records, other than those kept by the pharmacist, be maintained for every patient in a hospital who receives this drug. The doctor would write his diagnosis and it would be kept in the hospital record. A copy of this record would be sent to the AMA, the PHS, or the FDA for review. Again, this is not possible under current law, nor is it practical for any such group to monitor prescribing practices to preclude misuse. What then is the best way to approach this problem? How do we reach the physician with this most important prescribing information? These hearings, I believe, have created an atmosphere of interest throughout the country, and have made many physicians take notice of the grave risks involved in misuse of chioramphenleol. We know additional action is necessary; we will not delay in taking this action. We plan to move with every means at our disposal to curb the misuse of chlor- amphenicol. We are taking, or soon will take, the following steps: 1. We are revising the chloramphenicol labeling so the indications for use are more restrictive and more clearly stated. We are revising the warnings to include the incidence of risk estimates of aplastic anemia developed by the California Medical Society. We are adding warnings against use of the drug in late pregnancy or in lactation. Leukemia also is to be listed as a possible side effect. PAGENO="0517" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2651 2. The FDA plans to send a "Dear Doctor" letter to every physician and hospital administrator throughout the country warning of the hazards of this drug and stating, in a positive manner, its indications for use. We will seek support at all levels of the medical profession, down to the county socie- ties, to be sure the message gets through to all prescribers. 3. All "reminder ads" for the drug will be required to carry a brief ~uni- mary of the dangers of the side effects associated with chloramphenicol; that is, every ad will be required to carry at least the "hox warning." In addition to these considerations, we have consulated with a special Ad Hoc Committee which met Monday, February 26, 1968 at the FDA Headquarters. This Committee was convened specifically to consider the chloramphenicol pr~b- lem, and to advise the FDA on the action we proposed to take to improve the prescribing information for this drug and to disseminate this information throughout the medical community. The Committee's opinion was that we should communicate directly with doctors and hospital administrators on new labeling for chioramphenicol. In addition, the Committee suggested contacting various professional publica- tions-Medical Tribune, Medical World News, AMA News, and the journals of every State medical society-to ask their cooperation in publicizing the proper use of the drug and the hazards associated with its use. This will be done. The Committee will shortly give us further results of its considerations concerning pediatric dosages for the drug. Mr. Chairman, we are most anxious to implement immediately all appropriate recommendations in order to take full advantage of the wide interest created by this Committee's hearings. I thank you for your time and attention this morning. If there are questions, I would be happy to answer them. (Whereupon, at 1 p.m. the subcommittee was adjourned, to recon- vene stthject to the cali of the Chair.) PAGENO="0518" PAGENO="0519" APPENDIX APPENDIX I. ARTICLES FROM VARIOUS SOURCEs iu~ DRUG CHLOROMYCETIN (CHLORAMPHENICOL) [From the New England Journal of Medicine, vol. 277, No. 19, Nov. 9, 1967, pp. 1035-1036] OHLORAMPHENICOL-INDUCED BONE-MARROW APLASIA ALTHOUGH chioramphenicol continues to be the leading single cause of drug- induced aplastic anemia, little progress has been made in elucidating the mccli- anism of its toxic effect. The reversible erythroid depression occurring concur- rently with chioramphenicol therapy is a pharmacologic effect.1 Although there is clearly a relation between this type of toxicity and dosage, there is none between dosage and reversibility. The occurrence of bone-marrow aplasia is only an occasional subject receiving chioramphenicol, coupled with the lack of a dose- effect relation, almost certainly indicates an individual susceptibility. In sensitive bacteria chioramphenicol in small concentrations causes complete inhibition of protein synthesis. There is good evidence that this action is exerted through stereospecific binding of the drug to the 50-S ribosoinal subunit, thereby inhibiting, in an as yet undefined manner, the formation of the peptide bond.2 The drug does not seem to interfere with the function of messenger RNA (mRNA) 2 In mammalian cells in vitro on the other hand, concentrations many times the usual therapeutic levels are needed to inhibit protein synthesis signi- ficantly. Recently, Weisberger et al.8 reported profound inhibition of mRNA- induced protein synthesis in a cell-free system from rabbit reticulocytes by small concentrations of chioramphenicol, reversed by increasing the concentration of messenger. They concluded that chioramphenicol inhibits protein synthesis in mammalian cells by interfereing with the binding of mRNA. to ribosomes. How- ever, other investigators are unable to corroborate these findings.4 In similar systems about 20 per cent inhibition of amino acid incorporation into ribosomes can be demonstrated at therapeutic drug concentrations. This slight inhibition is unrelated to the concentration of messenger in the system. Furthermore, chlo- ram~henicol does not bind to reticulocyte ribosomes, nor does it interfere with the ribosomal binding of mRNA.4 The problem of whether hematologic toxicity from chioramphenicol is related to its effect on protein synthesis cannot be re- solved at present. It is entirely possible that the reversible erythroid depression from the drug is related to its small inhibitory effect on protein synthesis as ob- served in vitro. The. length of exposure may render this small effect significant in the overall metabolism of the erythroid cell. Bone-marrow aplasia from chloramphenicol is more difficult to explain. Here some specific biochemical susceptibility is the most likely underlying factor. The demonstration that chioramphenicol inhibits the uptake of `~O formate into nucleic acids of bone-marrow cells from patients who have recovered from chioramphenicol-induced aplastic anemia supports this hypothesis.1 However, further studies in similar cases are needed to determine the significance of these findings. Several observations in patients with chloramphenicol-induced aplastic anemia suggest that this drug exerts its action at the, stem-cell level. Thus, the latent period between drug administration and the onset of anemia, the char- acteristic pancytopenia and the long duration of the aplasia after the drug has been discontinued are all compatible with an injury to a precursor pool common to all 3 cell lines. The persistence of aplasia long after discontinuation of the drug indicates either that chloramphenicol has a lethal effect on these cells or that, by affedting the genetic pattern of the stem cell, it causes the NoTE-Numbered footnotes at end of article, p. 2654. 2653 PAGENO="0520" 2654 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY propagation of a defective short-lived cell line. Recovery from aplasia however, suggests the emergence of precursor cells with "new" mitotic competence. This may result from biochemical "recovery" of the injured cells through the develop- ment of alternate metabolic pathways or the emergenc of a genetically different line of stem cells. This genetically different line of stem cells may be "normal" or may differentiate into an autonomous leukemic cell population. In the issue of the Jovrnal Brauer and Dameshek record 3 examples of acute myeloblastic leukemia developing in patients who had aplastic anemia that followed chioramphenicol therapy.5 As pointed out by the authors, aplastic anemia without known cause may be premonitory of acute leukemia; accord- ingly, any postulated relation between chioramphenicol and the leukemia in the 3 cases recorded must be regarded as conjectural. On the other hand, it is possible that acute leukemia would be seen much more frequently in patints with chloramphenicol-induced bone-marrow aplasia if they survived longer; most of these patients succumb to their disease within seven months from its onset. At present it is reasonable to consider any agent that is potentially myelotoxic as being also potentially leukemogenic. However, little can be said in this re- gard until more is known about the basic mechanisms by which chloramphenicol and other drugs injure the bone marrow. REFERENCES 1Yunls, A. A., and Bloomberg, G. R. Chloramphenicol toxicity: clinical features and pathogenesis. Progr. in Hematology 4: 138-159, 1964. 2Das, H. K., Goldstein, A., and Kanner, L. C. Inhibition by chloramphenicol of growth of nascent protein chains In E8cherichia coli. Molecular Pharmacol. 2: 158-170, 1966. Weisberger, A. S., Wolfe, S., and Armentrout, S. Inhibition of protein synthesis In mammalian cell-free system by chloramphenicol. J. Eo.,per. Med. 120: 161-181, 1964. 4Zelkowltz, L., Tchou, H., Arimura, G. K., and Yunis, A. A. Chloramphenlcol and pro- tein syntheis in mammalian cell-free system. GUn. Research 15: 67, 1967. See article, "Hypoplastic Anemia and Myeloblastic Leukemia Following Chlorampheni- col Therapy," by Dr. Brauer and Dr. Dameshek, p. 2402, supra. [From the American Journal of Disabled Children, vol. 114, October 1967, pp. 424-426] OHLORAMPHENICOL OPTIC NEURITIS APPARENT PROTECTIVE EFFECTS OF VERY HIGH DAILY DOSES OF PYRIDOXINE AND CYANOCOBALAMIN (By Maj. Joseph G. Cocke, Jr., MO, USA, Fort Sam Houston, San Antonio, Tex.) Over the last several years, there has been increasing recognition of an appar- ent deleterious effect of chlorainphenicol on vision in the form of an optic neuri- tis. Recognition of this entity has not produced any uniform Suggestion for treat- ment or prevention of the neuritis other than minimal total dosage or withdrawal of chioramphenicol once toxic eye signs are noted. Experience with a previously reported1 12-year-old girl with cystic fibrosis who developed an episode of chloramphenicol optic neuritis (CON) following pro- longed use of the drug has led to the suggestion that pyridoxine (B6) or cyano- cobalamin or both in very high daily doses may be of Significant value in preven- tion of optic neuritis while the patient is receiving sustained chloramphenicol treatment. REPORT OF A CASE A 12-year-old girl with proved moderately severe cystic fibrosis (OF), developed an optic neuritis in January 1964 following total dosage of 135 gm chloram- phenicol. From near total blindness associated with contricted visual fields, large central scotomata, papilledema, and retinal hemorrhages, her visual acuity im- proved to 20/50 for both eyes while receiving treatment. Also, visual fields widened except for small central scotomata, and fundus changes resolved save for minimal residual disc pallor. Therapy consisted of stopping chloramphenicol administration and administering large doses ascorbic acid, thiamine, pyridoxine, N0TE.-Numbered footnotes at end of article, p. 2656. PAGENO="0521" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2655 and cyanocobalamin for six months. Following cessation of treatment, vitamin intake was limited to three daily multivitamin capsules which had been given regularly for years. One multivitamin capsule contains 5,000~o vitamin A, 4OOj~ vitamin D, 75 mg vitamin C, 2~og B12, 2 mg B0, 2 mg B2, 3 mg riboflavin, 20 mg nicotinamide, and 5 mg calcium pantothenate. Measures for control of pulmonary infection, includ- ing antimcrobial agents other than chloramphenicol, were continued essentially as before the optic neuritis. In April 1965, it was felt imperative to reutilize chloramphenicol (40 mg/kg/24 hr). Three daily multivitamins were continued but no additional vitamins were prescribed. Visual signs and symptoms were carefully monitored. After a total dose of 47 gm chloramphenicol, visual acuity deteriorated to 20/70 in each eye, temporal disc margins elevated, and visual fields contracted. With the exception of accentuated temporal disc pallor, visual examination results returned to pre- chloramphenicol treatment levels when administration of this drug was stopped, and vitamins B0 (150 mg/24 hr) and B12 (150~og/24 hr) were added and continued regularly. In September 1966, chioramphenicol therapy was restarted (80 mg/kg/24 hr dose reduced in mid-November 1966 to 40 mg/kg/24 hr), and dosage of vitamins B6 and B~ was simultaneously increased to 200 mg/24 hr and 200~og/24 hr, respectively. The three daily multivitaminus and other treatment modalities were unchanged. Attempts to discontinue this drug therapy led only to decompensa- tion unresponsive to any measure other than restarting of chioramphenicol. As of July 14, 1967 the child has received a total dose of chioramphenicol in excess of 265 gm. Careful monitoring of visual acuity, fundus appearance, and visual fields have shown no deterioration. Interestingly, visual acuity has im- proved to 20/30 in each eye. Daily administration of chloramphenicol will con- tinue until circumstances require its withdrawal. COMMENT Earliest description2'3 of CON have implied an uncertain relationship between group B vitamins and chloramphenicol. In theory, the latter may either inter- fere directly with end effects of group B vitamins or cause vitamin B deficiency through destruetion of intestinal bacteria necessary for synthesis or utilization of group B members. More recently, Wilson4 has noted similarities between CON and visual disturbances reported in postwar studies of nutritionally deprived in- dividuals. The notion of nutritional deficiency, perhaps of group B vitamins, has been prevalent over the years. Consequently, vitamins have been used in treatment of CON in varying doses and under a wide range of therapeutic programs. Fifteen case reports `° have involved use of vitamins, dosage largely unspecified, in treat- inent of CON. Twelve patients given vitamins showed a return to normal visual acuity or functional return of vision; three w-ere left with significant residuals. Eighteen case reports 1015 detail no treatment with vitamins. In these patients, ten improved or cleared spontaneously, and eight were left with significant visual impairments. A cause and effect relationship with improvement while receiving vitamins has not been established, but the method which most consistently has yielded the best results has combined both immediate withdrawal of chioram- phenicol and the administration of vitamins. Methods of prevention of CON have received relatively little attention to the present. Reliance has been placed on early detection of visual abnormalities. The utilization of group B vitamins in large doses as prophylaxis against CON has not previously been recorded. Observations that many patients bad onset of CON while receiving multivitamin preparations have been interpreted by some16 to minimize the value of vitamins in prevention of CON. Upon inquiry, how- ever, the vitamin content of these preparations might best be categorized as small, randomly constituted, or unrecorded. As early as 1950, Woolington et al17 described routine administration of "mas- sive" doses of vitamins B and C during therapy with chloramphenicol. In a five- year study of 632 patients so treated, no episode of apparent visual derange- ment was recorded, although visual changes were not specifically monitored. PAGENO="0522" 2656 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY That large amounts of group B vitamins could serve to protect against CON is largely inference derived from this study of Woolington and from the seem- ingly salutory effect of group B vitamins noted in treatment of this condition. Further support may be added from the observations of Huang et al° in four patients with CON in whom the administration of chloramphemcol was con- tinued and treatment with vitamins alone instituted. Three patients so handled recovered excellent vision. A fourth child exhibited spontaneous improvement of CON while continuing chloramphenicol therapy. On relapse, vitamin ad- ministration was associated with partial improvement. With these considerations, it was decided that the third course of chloram- phenicol in this child would be arbitrarily accompanied by continuation of large does of vitamins B6 and B1~. The conduct of this patient's three courses of chloramphenicol delineates somewhat of an experimental pattern, the main variable having been the use of vitamin B6 and B2~ on the third course with all other factors, such as the use of chloramphenicol, multivitamins, and auxili- ary methods of treating CF, being basically unchanged. The conclusion in this one instance would indicate that vitamin B6 or B12 or both have in some unknown way permitted the safe administration of a total dose of chioramphenicol approximately 51/2 times that which resulted in an optic neuritis on last previous administration. A broader conclusion than this from a single case report is tenuous at best. However, it would appear reason- able to administer very large doses of group B complex vitamins to any patient in whom a large total dose of chloramphenicol may be anticipated. SUMMARY A 12-year-old girl with cystic fibrosis (OF) experienced two consecutive epi- sodes of chloramphenicol optic neuritis (CON) following total doses of 135 and 47 gm chloramphenicol, respectively. She has been spared a third occurrence, while continuing doses in excess of 200 gm chloramphenicol were given simul- taneously with very large doses of vitamins B6 and B12. The suggestion is made that large doses of group B vitamins given concomitantly with large total doses of chioramphenicol may serve as a preventive measure against CON. REFERENCES 1 Cocke, J. G.; Brown, H. E.; and Geppert, L. J.: Optic Neuritis With Prolonged Use of Chioramphenicol, J Pediat 68 : 27-31, 1966. 2Gewin, H. M., and Friou, G. J.: Manifestations of Vitamin Deficiency During Aureomycin and Chloramphenicoi Therapy of Endocarditis Due to Staplzylococeus aureus: Report of a Case, Yale J Biol Med 23: 332-338, 1951. 2Walienstein, L., and Snyder, J.: Neurotoxic Reaction to Chloromycetin, Ann list Med 36: 1526-1528, 1952. Wilson, W.: Toxic Ambylopia Due to Chloramphenicol, Scot Med J 7: 90-95, 1962. Cole, J. G.; Cole, H.; and Janoff, L.: A Toxic Ocular Manifestation of Chloramphenicol Therapy, Amer J Ophthal 44: 18-20, 1957. 6 Joy, R. J. T.; Scalettar, R.; and Sodee, D. B.: Optic and Peripheral Neuritis: Probable Effect of Prolonged Chioramphenicol Therapy, JAMA 173: 1731-1734, 1960. Walker, G. F.: Blindness During Streptomycin and Chioramphenicol Therapy Brit J Ophthal 45: 555-559, 1961. 8 Keith, C. G.: Optic Atrophy Induced by Chioramphenicol, Brit J Ophthal 48: 567, 1964. Huang, N. N., et al.: Visual Disturbances in Cystic Fibrosis Following Chloramphenicol Administration, J Pediat 68: 32, 1966. 10 Lasky. M.; Pincus. M.; and Kotlan, N.; Bilateral Optic Neuritis Following Chloram- phenicol Therapy, JAMA 151: 1403-1404, 1953. 11Prevatt, A. L., and Hunt, J. S.: Chronic Systemic Meliodiosis: Review of Literature and Report of a Case With Note on Visual Disturbance Due to Chloramphenicol, Amer J Med 23: 810-823, 1957. ~ Denning, C. R.: Bruce, G. M.: and Spalter, H. ).: Optic Neuritis in Chioramphenicol Treated Patients With Cystic Fibrosis, Seventy-Third Annual Meeting of the American Pediatric Society, Swampscott, Mass., May 3-4, 1963, abstract No. 93, p. 103. 12 Lietman, P. S.; Di Sant'Agnese, P. A.; and Wong, V.: Optic Neuritis in Cystic Fibrosis of the Pancreas, JAMA 189: 924-927, 1964. 14 Staid!, E. M.; Ndurite optique bilat6rale causSe par l'emploi thSrapeutique !)rolongd du chloramphSnicol, Un Med Canada 94: 1061-1062, 1965. 15 Chang, N.; Conrad, L. G.; and Gregg, R. H.: Optic Neuritis and Chloramphenicol, editorial, Amer J Dis Child 112: 46-48, 1966. 16 Chioramphenicol Blindness, Brit Med J 5449: 1511, 1965. 17 Woolington, S.S.; Adler, S.J.; and Bower, AG.; "Five Year's Experience With Chlo- ramphenicol," in Antibiotics Annual 1956-57, New York: Medical Encyclopedia, Inc., 1956, pp 365-375. PAGENO="0523" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2657 [From the Journal of the American Medical Association, Sept. 11, 1967, Vol. 201, No. 11, pp. 828-834] BONE MARROW DEPRESSION INDUCED BY CHLORAMPHENICOL OR PHENYLBUTAZONE LEUKEMIA AND OTHER SEQUELAE (By Joseph F. Fraumeni, Jr., MD) With two registries for adverse drug reactions, a follow-up survey was made of 151 cases reported of bone marrow depression follow- ing use of chloramphenicol (124 patients), phenylbutazone (24), or both drugs (3). Leukemia subsequently developed in three patients with bone marrow depression attributed to use of chloramphenicol, but only one had characteristics suggesting a cause-and-effect rela- tionship between drug exposure and leukemia. A review of clinical and epidemiologic information provides inadequate evidence that either drug is leukemogenic. Among other sequelae in the survey were four cases of hemolytic anemia; these four cases included two with paroxysmal nocturnal hemoglobinuria. Several problems arise in evaluating a causal association between drug exposure and dis- eases such as leukemia. The etiology of human leukemia is generally considered to be obscure. Epi- demiologic studies, however, have demonstrated that sufficient doses of ionizing radiation can induce chronic myeloctic leukemia or acute leukemia.1-4 Further- more, clinical observlation suggest strongly that these forms of leukemia are causally related to prolonged exposure to benzene.5 Since ionizing radiation and benzene are bone marrow depressants, one may suspect leukemogenic potential in other agents that cause marrow hypoplasia. The possibility os consistent with observations that aplastic anemia o~ccassionally precedes the diagnosis of chronic inyclocytic leukemia and acute leukemia.° This "preleukemic" period, which may last many years, has been noted following exposure to radiation or benezene.7 A numher of drugs with the capacity to depress bone marrow function have been suspected in the etiology of certain cases of leukemia, usually on the basis of case studies or uncontrolled surveys of leukemia patients. Among these drugs have been chloramphenicol,8-'° sulfonamides,11 aminopyrine,12 and amphetamine sulfate.13 Recently, interest has focused on phenylbutazone, for since 1960 a total of 29 cases of leukemia have been reported following its use.1427 Since there has been no information on the populations treated with this drug, it is unknown whether or not the leukemia cases were chance occurrences. This paper presents the findings of a follow-up survey of cases previously reported to two drug-reaction registries because of bone marrow' depression at- tributed to chloramphenicol or phenylbutazone, the drugs most commonly re- ported to cause aplastic anemia.28 The study. was undertaken to determine the frequency of leukemia following marrow depression and to evaluate evidence that either of the drugs may be leukemogenic. MATERIALS AND METHODS The patients with drug-induced bone marrow depression were ascertained from the Registry on Adverse Reactions of the American Medical Association (AMA) and the Adverse Reactions Branch of the Food and Drug Administration (FDA). Officials at each registry prepared a roster of physicians (total, 180) who had reported one or more cases (total, 234) of marrow depression attributed to phenylbutazone or chioramphenicol between 1954 and 1965. The marrow de- pression consisted of erythroid hypoplasia, leukopenia, thrombocytopenia, or pancytopenia, and was presumed to be exclusive or recognized leukemia, or other diseases or agents that might induce blood dyscrasias. Each physician was notified of the intended survey by a letter from registry officials, and was asked if we might contact him for follow-up information. The AMA and FDA then sent us a listing of 126 physicians who replied to the letter and were willing to partici- pate in the survey, along with the number of cases reported by each physician. Because of confidentiality of the data, neither registry divulged any information on individual patients prior to the survey. NoTE-Numbered footnotes at end of article, p. 2666. PAGENO="0524" 2658 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 1.-OUTCOME OF BLOOD DYSCRASIA ATTRIBUTED TO TOXIC EFFECTS OF CHLORAMPHENICOL OR PHENYL- BUTAZONE; RESULTS OF FOLLOWUP SURVEY OF 154 PATIENTS Chloramphenicol Phenylbutazone Interval' Interval' Chlor- .- ---~ ~am- pheni- col and Total phenyl- Number Number buta- Outcome cases 2 Ranges Median cases 2 Range 3 Median zone Recovery 47 (37) 1 week-7 13'~ month_ - 18 (72) 2 weeks-4 1 month_ - 2 67 year. years. Still undercare 19 (15) 6 months-S 4years 4(16)1-5 years...~ 43/2years 23 years. Death 50 (40) 1 day-33-~ 13.~ month... - 3 (12) 2 weeks-2 10 months_ 1 54 Unknown 10 (8)~f~ years. 10 Total 126 (100) 9 months 25 (100) 1 year 3 154 lnterval=period between diagnosis of blood dyscrasia and outcome. 2 Figures in parentheses are percentages. 3 Range=shortest to longest interval. Questionnaires for each reported ease were then mailed to the 126 physicians. These forms were designed to elicit information on the outcome of the blood dyserasia and on disorders which occurred subsequent to the onset of the dyscrasi'a. When leukemia was reported as one of these disorders, further data on the drug reaction and its course were requested from records of the registry and the reporting physician. During the course of this study four of the responding physicians called our attention to a total of six patients who had not `previously been registered at the AMA or FDA, but in whom leukemia developed following use of chloramphenicol or phenylbutazone. These patients were not included in the survey, but pertinent data submitted on these patients are summarized in a separate section below. RESULTS OF THE SURVEY Of 126 physicians sent questionnaires, 39 did not reply; ten returned forms which were not completed; and 77 sent completed questionnaires. Five physicians who did not complete the questionnaires said they were unable to recall eases previously reported; four had departed from the area or the original hospital; and one physician had died. In a few instances, a reply was received from an associate of the physician who originally reported the ease to the registry. The 77 physicians who returned completed questionnaires (43% of the original roster of reporting physicians) provided followup data on 154 patients with bone marrow depression (66% of the total cases originally reported). Of these cases, 126 were `attributed to chloramphenicol, 25 to phenyibutazone, and three to both drugs combined. The patients with toxic reactions to ehloramphenicol consisted of 46 males, 77 females, `and three with sex unrecorded; the median age at diagnosis was 38 years for males, and 19 years for females. The phenylbutazone reactions occurred in eight males and 17 females, with median ages of 51 and 48 years, respectively. Sixteen of the 77 physicians who returned questionnaires were from countries other than the United States. Outcome of Blood. Dyscrasia.-Pable 1 summarizes the results of the marrow depression among the 154 cases in the survey. The median period of observation was nine months for the chloramphenicol group, and one year for the phenyl- butazone series. For each outcome category there were no significant differences between the two drugs in the distribution of time intervals since diagnosis of the blood dyscarsia. Furthermore, there was a similar proportion of patients who were still being treated for toxic effects from each drug, at median intervals of 4 and 41/2 years, respectively, following diagnosis. The chloramphenicol series, however, h'ad a much higher proportion of deaths, while `the phenylbutazone group had a greater frequency of recovery. These differences persist even if the patients with toxic reactions to chloramphenieol who were lost `to follow-up (8%) are assumed to have recovered. Table 2 specifies the type of blood dyscrasia under treatment at the time of survey. Tables 3 `and 4 show the reported causes of death. PAGENO="0525" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2659 TABLE 2.-NUMBER OF PATIENTS UNDER TREATMENT AT TIME OF SURVEY, ACCORDING TO SPECIFIC BLOOD DYSCRASIA Blood Dyscrasia Chloramphenicol Phenylbutazone Erythroid hypoplasia (E) 2 Leukopenia(L) 4 Thrombocytopenia (T) 7 Pancytopenia 3 EandT 1 1 1 1 Landl Paroxysmal nocturnal hemoglobinuria (following pancytopenia) 2 1 Total 19 4 TABLE 3.-NUMBER OF PATIENTS DYING WITH DRUG-ATTRIBUTED BLOOD DYSCRASIA, ACCORDING TO REPORTED CAUSE OF DEATH Chloramphenicol Cause of death Chloramphenicol Phenylbutazone and phenylbutazone Hemorrhage 16 1 Infection 13 Hemorrhage and infection 4 Leukemia 5 11 "Aplastic anemia" 2 2 Other 2 2 Unknown 8 Total 50 3 1 1 Myelofibrosis with myeloid metaplasia. 2 One case had myocardial infarction; the other had pulmonary edema. TABLE 4.-SITE OF HEMORRHAGE AND TYPE OF INFECTION AMONG PATIENTS DYING FROM CHLORAMPHENICOL-ATTRIBUTED BLOOD DYSCRASIA Number Anatomic site of hemorrhage: of cases Cerebral 7 Gastrointestinal 7 Generalized Unspecified Total - 20 Type of infection: Septicemia 11 Peritonitis 2 Pneumonia 1 Osteomyelitis with sepsis 1 Unspecified 2 Total 117 1 In 11 patients who died the following organisms were found: E coIl (4 cases), Pseudomonas (3), unspecified gram- negative organisms (2), Proteus (1), and Staphylococcus (1). Leukcmia.-Six cases of leukemia were reported in the follow-up of 154 cases and are summarized in Table 5. Myelofibrosis (case 6) was considered here as "leukemia" since it is usually grouped with chronic myelogenous leukemia as a myeloproliferative disorder. The blood dycrasia preceding the diagnosis of leu- kemia was attributed to chloramphenicol in five patients, and to phenylbutazone in one. None of the patients had a prior history of radiation therapy. Four of the six patients were females, and the ages ranged from 2 to 71 years. Two of the cases were reported from outside the United States (cases 4 and 5). Study of the records available on the individual cases revealed that in three of the six patients (cases 4 through 6), leukemia had been diagnosed prior to the date on which the original drug reaction was reported to the registry. Since submission of the report might have been influenced by the development of leukemia, these cases must be excluded from the series for any calculation of PAGENO="0526" 2660 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY outcome rates. Thus, among the remaining 151 patients who had drug-attributed marrow depression, three received a diagnosis of leukemia a~fter submission of the initial registry report (eases 1 through 3). Among these three cases (all from the chloramphenicol series), only one had characteristics which would suggest a causal relationship between drug intake and leukemia. In case 1, a complete hemogram performed five months after the start of intermittent chloramphenicol therapy was entirely normal. Eight months after therapy began, the diagnosis of aplastic anemia was made from bone marrow examination; serial blood counts showed persistence of this condition until ~ years following the start of therapy when an abrupt conversion took place to acute myelogenous leukemia. Patient 2 did not have a clearly defined sequence of drug ingestion-marrow hypoplasia-leukemia. The diagnosis of "aregenerative anemia" was made three months after therapy with chloramphenicol; however, granulocytic hyperplasia of the marrow was present throughout the course of the pancytopenia. The diagnosis of chronic myelogenous leukemia was not made until death, 3~ years after drug ingestion, but it seems possible that this patient was in an early phase of leukemia at the onset of the drug-attributed blood dyscrasia. In case 3, the "latent period" between start of chloramphenicol therapy and diag- nosis of leukemia was relatively short (five months), and the reporting physician could not exclude the possibility that leukemia was actually present at the time of the initial leukopenia. Other ~equeZae.-The following diseases subsequently developed in nine patients who had recovered from hematotoxic effects of chioramphenicol: hepatitis in two; renal failure in two; and cirrhosis, systemic lupus erythematosus, lung cancer, hypernephronaa, and Gaucher's disease in one each. In addition, two patients who were still under care for cliloramphenicol-attributed marrow depression had a history of hemolytic anemia during treatment of the hypoplastic marrow with predxiisone and testosterone. In one case the hemolysis was asso- ciated with a positive Coomb's test reaction and subsided without additional therapy; in the other case, the hemolysis was successfully treated by splenectomy. (These cases are distinct from the two patients with toxic effects from chloram- phenicol, noted in Table 2, who were still receiving care for paroxysmal nocturnal hemoglobinuria.) Of four patients who recovered from toxic reactions to phenylbutazone, cir- rhosis, lupus erythematosus, aseptic necrosis of the femoral head, and gout developed in one each. Sequelae were also described in the two patients who recovered from hematotoxicity associated with the administration of both drugs; one patient had a transient granulocytic leukemoid reaction, and a disorder resembling Weber-Christian disease developed in the other. As with leukemia, it is possible that some of these diseases, although diagnosed subsequent to the blood dycrasia, were actually present at the time of drug administration. PAGENO="0527" TABLE 5.-LEUKEMIA REPORTED IN FOLLOW-UP SURVEY OF PATIENTS PREVIOUSLY REGISTERED FOR ADVERSE REACTION TO CHLORAMPHENICOL OR PHENYLBUTAZONE- SUMMARY OF CASES Leukemia Drug ingestion Initial reaction Sex Age, years Type' Latent period~ Drug3 Indication Duration Estimated Type Latent period 4 dose, grams Case: 1 F 67 AML 23-~ years C Bladder and lung Intermittently-8 months 14 Pancytopenia (marrow-"aplastic 8 months. infection, anemia"). 2 M 57 CML 3~years C (?) 5days 8 Pancytopenia(marrow- 3months. "aregenerative anemia"). 3 F 2 ALL 5 months C Septicemia 3 days 5 Leukopenia (rem tted after 3 weeks. androgen therapy). 45 M 14 ASCL 1 month C Tonsilitis 10 days 10 LeukOpenia thrombocytopenia...... 1 week. 5 5 F 17 ASCL 2 months C do 10 days 10 Leukopenia thrombocytopema 1 week 6 5 F 71 MF+MM Several years P Arthritis Intermittently-several years 0 0 4-0 6 Pancytopenia (marrow Several years fibrosis 1 CML=chronic myelogenous leukemia, AML=acute myelogenous leukemia, ALL=acute lym- 4 Latent period=interval between start of drug therapy and diagnosis of initial blood dyscrasia. phocytic leukemia, ASCL=acute stem-cell leukemia, and MF+MM=myelofibrosis and myeloid 5 Leukemia in cases 4 through 6 was mentioned on original report of adverse reaction to the registry metaplasia. and was excluded from survey for any calculation of leukemia frequencies. 2 Latent period=interval between start of drug therapy and diagnosis of leukemia. n Daily. 3 C=chloramphenicol, P=phenylbutazone. ci fyi I. PAGENO="0528" 2662 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CASE REPORTS OF LEUKEMIA FOLLOWING USE OF CHLORAMPHENICOL OR PHENYL- BUTAZONE During the course of this study reports were received of six additional cases of leukemia in the United States following bone marrow depression attributed to chloramphenicol or phenylbutazone. Toxic reaction to the drug, however, had not previously been registered at the AMA. or FDA, so these cases are summarized separately in Table 6. Although lacking a reference population, the characteris- tics of these cases were generally more suggestive of a causal relation between drug intake and leukemia than the leukemia cases detected by the follow-up sur- vey. All patients had myelocytic leukemia; in three it occurred subsequent to the use of chioramphenicol and in three others, following phenylbutazone therapy. All had evidence of bone marrow deficiency preceding the diagnosis of leukemia, which was termed "aleukemic" leukemia in four instances. There was no history of exposure to radiation thereapy. All patients were females, from 43 to 77 years of age. In the three patients treated with chioramphenicol, the infection antedated by many years the manifestation of hematological disorder. The estimated chloramphencol dose varied between 7 and 200 gm, with leukemia developing from 2 to 12 years after start of treatment. In three patients with leukemia following phenylbutazone treatment, the underlying rheumatic con- ditions were chronic and unlikely to be early manifestations of leukemia. The estimated doses of phenylbutazone exceeded 15 gm. and leukemia was diag- nosed from 1 to 12 years after the start of treatment. It is noteworthy that all previously reported cases of leukemia following the use of chioramphenicol or phenylbutazone occurred in countries other than the United States. Ohioramphenicol has been implicated much less frequently than phenylbutazone in the etiology of leukemia. Mukherji8 described a 63-year- old man in whom aplastic anemia developed following administration of 12 gm of chioramphenicol; the aplastic process persisted until seven months after drug exposure when a diagnosis was made of acute myelogenous leukemia. Lebon and Messerschmitt9 reported the case of a 5-year-old boy who died of acute myelo- genous leukemia following a one-year history of aplastic anemia, which may have been due to chioramphenicol therapy. In an epidemiologic study of leu- kemia in Israel, Davies and associates1° noted that 20 of 150 leukemia patients received drugs a "short time" before the iliagnosis of leukemia and in 11 cases the drug was chloramphenicol. PAGENO="0529" ~3 I ~ I ~ ~ c~ c~ i~ TABLE 6-REPORTS RECEIVED OF LEUKEMIA FOLLOWING CHIORAMPHENICOL OR PHENYLBUTAZONE THERAPY-SUMMARY OF CASES NOT PREVIOUSLY REGISTERED FOR ADVERSE REACTION 1 O ~ ~ ~- Leukemia Drug ingestion Initial reaction Sex Age years Type Latent period Drug Indication Duration Estimated Type Latent period dose, grams Case: 1 F 60 AML 2 2 years C Frequent common colds~ Intermittently-14 months___ 15 Leukopenia 23 months. 2 F 56 AML 2 12-15 years (10 C Cystitis lntermittently-12-15 years -- 200 Erythroid hypoplasia, leukopenia 12-15 years. months after initial (marrow-maturation arrest of reaction) WBC) 3 F 64 CML 9~ years C Sinusitis 1 week 7 Pancytopenia 1 month. 4 F 61 SML 12 years (7 months P Rheumatoid arthritis lntermittently-11-12 years -- 21 Leukopenia 11-12 years. after initial reaction) 5 F 43 AML2 1 year P Bursitis lntermittently-9 months >15 Leukopenia (marrow-maturation 9 months. arrest of WBC) 6 F 77 AML 2 3~ years P Rheumatoid arthritis lntermittently-3 years >50 Leukopenia 3 years 1 See table 5 footnote for explanation of symbols In addition SML=subacute myelogenous lea Termed aleukemic leukemia at diagnosis keinia.~ 0 t~j L~j PAGENO="0530" TAB LE 7.-RE VIEW OF LI TERATURE: LEUKEMIA FO LLOWING PHENY LBUTAZONE THERAPY Author and year Sex Age, years Leukemia --~-______________________ ~- Phenylbutazone ingestion Typo 1 Latent period 2 Indication Duration Bean 1960 M M M M M M Cast, 1961 F Garrett, 1961 F Cadman and Limont, 1962 M Chalmers and McCarthy, 1964 F . Thorpe 1964 F Hart, 1~64 M Woodliff and Dougan, 1964 M M M F F Sen and Siddique, 1964 M Chatterjea, 1964 M Dougan and Woodliff, 1965 F M M Stewart, 1964 - M Perers and Sjtlberg, 1965 M M Golding et al, 1965 F Jensen and Roll M M F 69 67 70 80 66 63 59 64 71 52 56 58 78 52 80 80 58 29 46 58 60 59 40 40 47 57 78 67 31 CML ALL ?LL (subacute) CML LL or LSA CML CML ?ALL ASCL Mono-ML (subacute) ASCL AML AML ALL AML AML AML AML AML ALL CLL ALL AL AML ALL A Mono L CML AML ALL 16 months Degenerative spondylitis (30 years) 3 weeks 4 years Spondylitis (many years) Intermittently-4 years 2 months Sciatica (45 years) 5 months 1 year Osteoarthritis and spondylitis (many years) ? 4 years Arthritis of hips (9 years) 4 years 18 months Osteoarthritis of knee (many years) 1 month 19 months Rheumatoid arthritis (10 years) 17 months 2 to 3 months Arthritis of knees 1 to 2 months 11 weeks Lumbago 6 days 3-~j years Rheumatoid arthritis (8 years) Intermittently-3~ years_ - - - 1 month Arthritis of ankle (acute) 17 days 17 months Back injury (35 years) 2 weeks 4 years Arthritis (30 years) Intermittently-4 years 63-i years Arthritis (6 years) Intermittently-6 years 4 years Arthritis (5 years) 4 years 23/~ years Arthritis (5 years) 17 months 5 years Arthritis (5 years) Intermittently-S years 4 months Arthritis of knee 4 months Significant period - ? Intermittently-significant period". 11 days Arthritis 8 days 3 years Arthritis (3 years) Intermittently-3 years 8 years Rheumatoid arthritis Intermittently-8 years 4 weeks Phlebitis 1 week 2 months Phlebitis S days 13 months Cervical spondylosis 2 weeks S years Rheumatoid arthritis (10 years) 5 years 15 months Arthritis (4 years) 4 months 27 months Rheumatoid arthritis (8 years) Several months 12 months Rheumatoid (?) arthritis (19 months) lntermittently-6 months ? 150 5 210 12-18 4 240 5. 1 5. 6 40.3 10 >276 33 8 9 ? 3.2 ? 50-100 2-6 1. 0 3 1.9 430 72 27 (?) 1 See Table 5 for abbreviations. In addition, LSA=lymphosarcoma, A Mono L=acute monocytic Oxyphenbutazone. leukimia, CLL=chronic lymphocytic leukemia. 4 Daily. Latent period=interval between start of drug therapy and diagnosis of leukemia. Estimated dose, ~ grams t!1 10 >100 ~ 24 j~j 0 w r17 LTj 0 `-l PAGENO="0531" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2665 Leukemia following phenylbutazone therapy has previously been reported in 29 cases as summarized in Table 7. Patients known to have received radiotherapy were not tabulated. As observed by Jensen and Roll27 the diagnosis of leukemia was not well established in at least three patients (cases 3 and 5 of Bean 14 and that of Garrett 18), and in certain other cases the brief "latent period" (time interval between phenylbutazone exposure and the diagnosis of leukemia) casts doubt on a causal relationship. Of the 26 patients with an apparently estab- lished diagnoisis of leukemia, 13 had time intervals of at least 18 months, the minimum latent period estimated for radiation-induced leukemia.1 These patients consisted of seven men and six women, who ranged in age from 52 to 80 years, suffered from some form of chronic arthritis, and recived phenylbutazone from one month to eight years. One patient had chronic lymphocytic leukemia, but the remaining 12 had either chronic myelogenous leukemia or acute leukemia. Only one patient in this group (patient 1 of Woodliff and Dougan 21) was noted to have bone marrow hypoplasia prior to the diagnosis of leukemia. It is of inter- est that two reports included retrospective leukemia surveys, in a search for prior exposure to phenylbutazone. At the leukemia registry of Western Australia, Dou- gan and Woodliff24 found that five of 55 adult patients with acute leukemia had a history of phenylbutazone therapy, while only five of 417 patients with "chronic leukemia and allied disorders" had a similar history. Although no comparison group was given, Jensen and Roll 27 reported that among 50 patients admitted to a Danish hospital with actute leukemia, three were known to have received phenylbutazone at intervals of 12, 15, and 27 months prior to the diagnosis of leukemia. c0MMuNT This follow-up survey of patients registered with bone marrow depression showed that those with hematotoxic effects from chloramphenicol had a sub- stantially less favorable outcome, with a greater mortality and lower recovery rate than those with phenydbutazone reactions. Deaths from chloramphenicol- induced marrow depression were attributed mainly to hemorrhage and infection. The hemorrhages were predominantly cerebral or gastrointestinal, and the infections were caused mostly by a variety of gram-negative organisms. Of ad- ditional interest in the chloramphenicol group was the occurrence of hemolytic anemia in four cases following the onset of bone marrow depression. Two of the patients were diagnosed as having paroxysmal nocturnal hemoglobinuria, re- cently recognized as a complication of aplastic anemia induced by drugs.~° It is likely that some nonhematologic sequelae were actually present prior to onset of the blood dyscrasia, and may have contributed to the development of toxicity. Such disorders would include liver and kidney ~ and systemic lupus cry- thematosus.3' - Wintrobe12 has commented on certain features of registries on adverse drug reactions which would limit epidemiologic application of the data. Reports of adverse reactions come from different sources of varying reliabifity, represent only a small proportion of patients affected, provide no information on incidence of the reactions, and may not necessarily signify a causal relation to the drug which is implicated.~ Use of these data for our follow-up survey of leukemia was further complicated' by (1) the problem of clearly separating the drug exposure and adverse reaction from the outcome (leukemia) ; (2) the relative sparseness of the data (cases and person-years at risk), so that only very large increases in leukemia incidence could be detected; and (3) the possibility that physicians who did not respond observed different outcomes than those who did (the direction of this potential bias could not be assessed). Despite these limitations, recognized at the outset of the survey, we felt that some value should come from observations which could be made prospectively from the ex- ceptional study group derived from the two registries. It is of interest that, whereas published case reports of leukemia following drug use have implicated phenylbutazone far more often than chloramphenicol, the latter drug was im- plicated in five of the six registered patients (Table 5), and three of the six unregistered patients (Table 6) in whom leukemia developed. After excluding three cases in which the development of leukemia may have influenced reporting to the registry, in a total of 151 patients there were three cases of leukemia (2%). These cases were from the 124 patients in the chlor- amphenicol group, while leukemia did not occur among 24 patients in the phenylburtazone series or three patients registered with toxic effects following PAGENO="0532" 2666 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY use of both drugs. Although the frequency of leukemia among persons with chloramphenicol-attributed marrow depression appeared to exceed expectation- 3/124 in our series as compared with the US age-adjusted leukemia mortality of 6/100,000/yr-an association observed between drug exposure and leukemia may have one or more of the following interpretations: (1) A causal relation- ship exists between drug exposure and the development of leukemia. (2) Patients undergoing drug therapy for disorders such as immunologic deficiency and eel- lagen disease may be at high risk of leukemia. (3) The ailment being treated is a manifestation or a complication of leukemia in its early phase (eg, rheumatic complaint, fever, infection). (4) Another therapeutic modality is leukemogenic (eg, radiotherapy). (5) The sequence of drug intake and leukemia is a chance occurrence. The possibility of a causal relationship between drug use and leukemia would be supported by the following case characteristics: relatively high dose of the administered drug; no evidence of leukemia at the time of drug use; and absence of diseases or other agents know or suspected to be leukemogenic. Furthermore, if the relationship is comparable to radiation-induced leukemia (1), the cytologic type should be chronic myelogenous or acute leukemia, and the interval between start of drug exposure and development of leukemia should exceed approximately 18 months. Among the three leukemia patients observed in the survey, only one had all the characteristics which would suggest a causal relationship between chloramphenicol exposure and leukemia. The significance of one case is, of course, unclear. Because of the small study group and relatively brief period of follow-up, the risk of leukemia would have to be very high for additional cases to have occurred. If exposure to marrow-depressing drugs does confer a later increased risk of leukemia, one might anticipate the risk to be greatest among persons in whom signs of marrow depression actually develop, as those in the present study. From a single case of leukemia following toxic effects from cbloramphenicol, however, it is not possible to conclude that chioramphenicol is, or that phenyl- butazone is not, leukemogenic. Since radiation-induced leukemia has a peak oc- currence three to eight years after exposure, a more realistic opportunity for evaluating leukemia risk awaits a larger sample size and longer period of ob- servation following the drug reaction. Finally, an evaluation between drug exposure or toxic effects and leukemia should benefit from cytogenetic studies of individuals treated with drugs that affect bone marrow function. Chromosomal abnormalities of blood cells have been described in the following situations where marrow depression may predispose to leukemia: (1) persons exposed to marrow depressants which are definitely or probably leukemogenic-radiation ~ and benzene34; (2) children born with Fan- coni's familial aplastic anemia, who appear to carry an excess risk of leukemia ~; and (3) certain forms of refractory anemia which later progress to leukemia.36' Indeed, cytogentic aberrations have been observed in virtually all groups of individuals who are, or seem to be, at high risk of leukemia.~ Demonstration of a consistent chromosomal abnormality in patients who receive a particular drug or in whom toxic effects develop would enhance the possibility that an observed sequence of drug exposure and leukemia may have a cause-and-effect relationship. GENERIC AND TRADE NAMES OF DRUGS Chloramphenicol-Uhloroniycetin. Phenylbutazone-Bntazolidin, Butadion, Artrizin, Pyrabuto!. Amphetamine sulfate-Benzedrine, Linampheta, Amitrene, Amphedrine, Am- phoid-& Prednisone-Deltasonc, Deltra, Ziletieorten, Paracort, Coton e, Lisacort, Al etasone. Aminopyrine-Pyramidon, Kalmine. Oxyphenbutazone-Tandeari~. REFERENCES `Brill A.B.; Tomonaga, M.; and Heyssel, R.M.; Leukemia in Man Following Exposure to Ionizing Radiation, Ann Intern Med 56: 590-609 (April) 1962. 2 Miller. R.W.: Radiation, Chromosomes and Viruses In the Etiology of Leukemia: Evidence From Epidemiologic Research, New Eng J Med 271: 30-36 (July 2) 1964. 3Court-Brown, W.M.. and Doll. R.: Mortality From Cancer and Other Causes After Radiotherapy for Ankylosing Spondylitis, Brit Med J 2: 1327-1332 (Dec 4) 1965. 4Bizzozero, O.J., Jr.; Johnson, K.G.; and Ciocco, A.; Radiation-Related Leukemia in Hiroshima and Nagasaki, 1946-1964; I. Distribution, Incidence and Appearance Time, New Eng J Med 274: 1095-1101 (May 19) 1966. 5Vigliani, E.C., and Saita, G.; Benzene and Leukemia, New Eng J Med 271: 872-876 (Oct22) 1964. PAGENO="0533" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2667 O DeGowin, ILL.: Preluekemic Phase of Acute and Chronic Myelocytic Leukemia, Clin Med 72: 1135-1143 (July) 1965. 7DeGowin, R.L.: Benzene Exposure and Aplastic Anemia Followed by Leukemia 15 Years Later, JAMA 185: 748-751 (Sept 7) 1963. 8 Mukherji, P.S.: Acute Myeloblastic Leukemia Following Chioramphenicol Treatment, Brit Med J 1: 1286-1287 (June 1) 1957. ° Lebon, J., and Messerschmitt, J.: Mydlose Aplasique d'Origine Médicamenteuse Mydloblastose aigue Terminal Rdflexions Pathogéniques, Le S'ang 26: 799-804 (No. 8) 1955. ~° Davies, AM., et al: Epidemiological Observations on Leukemia in Israel, Arch Intern Med 108: 86-90 (July) 1961. ~` Leonard, B.J., and Wilkinson, J.F.: "The Acute Leukaemias," in Wilkinson, J.F. (ed.) : Modern Trends in Blood Diseases, London: Butterworth & Co., 1955, pp 248-251. ~ Scheuer-Karpin, II.: Myeloblastic Leuaemia After Analgesic Drugs (A Common Aeti- ology for Acute Leukaemia and Granulocytopenia), Haematologica Polonica 3: 33-45 (Fasc 1-2) 1959. 13 Berry, J.N.: Acute Myeloblastjc Leukemia in a Benzedrine Addict ~S'outhern Med J 59: 1169-1170 (Oct) 1966. 14 Bean, R.H.D.: Phenylbutazone and Leukaemia: A Possible Association, Brit Med J 2: 1552-1555 (Nov) 1960. ~ Cast, I.P.: Phenylbutazone and Leukaemia, Brit Med J 2: 1569-1570 (Dec 9) 1961. ~ Garrett, J.V.: Phenylbutazone and Leukaemia. Brit Med J 1: 53 (Jan 7) 1961. ~ Cadman, E.F.B., and Limont, W.: Phenylbutazone and Leukaemia, Brit Med J 1: 798 (March 17) 1962. 18 Chalmers, TM., and 1~1cCarthy, D.D.: Phenylbutazone Therapy Associated With Leu- kaemia, Brit MedJ 1: 747 (March 21) 1964. ~° Thorpe, G.J.: Leukaemia and Phenylbutazone, Brit Med J 1: 1707 (June 27) 1964. 20 Hart, G.D.: Acute Leukemia Following Phenylbutazone Therapy, Caned Med Assoc J 91: 449-450 (Aug. 29) 1964. ~ Woodliff, H.J., and Dougan, L.: Acute Leukemia Associated With Phenylbutazone Treatment, Brit Med J 1: 744-746 (March 21) 1964. 02 Sen, S., and Siddique, K.K.H.: Phenylbutazone and Leukaemia, Bull Inst Postgrad Med Educ Res 6: 23-24 (Jan) 1964. ~ Chatterjea, J.B.: Leukaemia and Phenylbutazone, Brit Med J 2: 875 (Oct 3) 1964. 24Dougan, L., and Woodliff, H.J.: Acute Leukemia Associated With Phenylbutazone Treatment: A Review of the Literature and Report of a Further Case, Med J Aust 1: 217-219 (Feb 13) 1965. 25Perers, D., and Sjoberg, S.-G.: Akut Leukemia, Leukemoid Reaktion och Leukocytos after Behandling med Oxifenylbutazon, ~v Ldkartidn 63: 53-56 (Jan 5) 1966. ~° Golding, JR.; Hamilton, MG.; and Moody, H.E.: Monocytic Leukaemia and Phenylbu- tazone, Brit Med J 1: 1673 (June 26) 1965. 27Jensen, M.K., and Roll, K.: Phenylbutazone and Leukaemia, Acta Med Scand 178: 505-513 (Oct) 1965. 28 Huguley, CM., Jr.: Hematological Reactions, JAMA 196: 408-410 (May 2) 1966. ~° Quagliana, J. M.; Cartwright, G. E.; and Wintrobe, M. M.; Paroxysmal Nocturnal Hemoglobinuria Following Drug-Induced Aplastic Anemia, Ann Intern Med 61: 1045- 1052 (Dee) 1964. 20 Suhrland, L. G., and Weisberger, A. S.; Chioramphenicol Toxicity in Liver and Renal Diseases, Arch Intern M1d 112: 747-754 (Nov) 1963. 31 MeDuffie, F. C.: Bone Marrow Depression After Drug Therapy in Patients With Sys temie Lupus Erythematosus, Ann Rheum Dis 24: 289-291 (May) 1965. 32 Wintrobe, MM.: The Problems of Drug Toxicity in Man-A View From the Hema- topoietic System, Ann NY Aced Sci 123: 316-325 (March 12) 1965. °~ Bloom, A.D., et al: Cytogenetic Investigation of Survivors of the Atomic Bombings of Hiroshima and Nagasaki, Lancet 2: 672-674 (Sept 24) 1966. 3~ Tough, I.M., and Court-Brown, W.M.: Chromosome Aberrations and Exposure to Am- bient Benzene, Lancet 1: 684 (March 27) 1965. ~ Bloom, G.E., et al: Chromosome Abnormalities in Constitutional Aplastic Anemia, New Eng J Med 274: 8-14 (Jan 6) 1966. ~° Freireich, E.J., at al: Refractory Anemia, Granulocytic Hyperplasia of Bone Marrow, and a Missing Chromosome in 1~Iarrow Cells: A New Clinical Syndrome? abstracted, Clsn Res 12: 284 (April) 1964. ~ Dameshek, W.: Sideroblastic Anemia: Is This a Malignancy? Brit J Hacmat 11 :52- 58 (Jan) 1965. °°Fraumeni, J.F., Jr., and Miller, R.W.: Epidemiology of Human Leukemia: Recent Observations, J Nat Cancer Inst 38: 593-605 (April) 1967. [From Blood, August 1967, Vol. 30, No. 2, pp. 251-254] Editorial RIDDLE: WHAT Do APLASTIC ANEMIA, PAROXYSMAL NOcTURNAL HEMOGLOBINURIA (PNH) AND "HYPOPLASTIO" LEUKEMIA HAVE IN COMMON? (By William Dameshek `~) In 19l1, we reported 20 cases of severe aplastic anemia in which infusions of allogenic (homologous) hone marrow had been used as one of the therapeu:tic methods.' Seven of these patients made apparently complete reeoveries; whether *WILLIAiI DAI~1ESHEK, M.D.: Attending Hematologist, The Mt. Sinai Hospital, and Professor of Medicine, The Mt. Sinai School of Medicine, New York, N.Y. `McFarland, W., Granville, N., Schwartz, R., Oliner, H., Misra, D. K., and Dameshek, W.: Therapy of hypoplastic anemia with bone marrow transplantation. Arch. Intern. Med. 108: 23, 1961. PAGENO="0534" 2668 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY coincidentally or in relationship to the marrow infusions is not clear. Since then, the use of allogeneic bone marrow infusions has been well-nigh discarded for the induction of transplantation, chiefly because of the difficulties involved with sup- pression of the rejection phenomenon, as well as for the possibility of develop- ment of the graft-vs-host reaction. Of the recovered cases referred to above, three patients have subsequently (as of June 1067) developed the characeristics tea- tures of PNH. Originally it occurred to us that this unusually high incidence of PNH might have some ~bscure relationship to t.he infused allogenic marrow, but since PNH may follow aplastic anemia without the mediation of introduced marrow, this idea did not appear very likely. During a recent trip to the Far East where aplastic anemia appears to be unduly prevalent (perhaps because the use of cliloramphenicol is relatively un- inhibited), it was evident that the incidence of PNH was also unduly high. Thus, in Manila, the Philippines, Dr. Allen Caviles of the Philippines G~eneral Hospital informed me that he had observed 71 cases of aplastic anemia in three years, 53 of which had been subject to follow-up; one of these had developed PNH. In the same period, nine cases of PNH had also been observed, five of them having been previously diagnosed as aplastic anemia. Dr. Tien-tse Hwang in Taipei, Taiwan, reported that he had observed 10-44 new cases of aplastic anemia an- nually, as well as seven cases of PNH at the two hospitals where he worked, one of them the large National Defense Hospital. Among the first 10 cases of hypoplastic anemia he had seen in 1966, one of them subsequently developed PNH. From these several observations, the factor of coincidence for the two apparently disparate conditions of aplastic anemia and PNH seems unlikely. Dacie and Gilpin2 were the first to broach the possiblity that PNH and aplastic anemia might be related. This was subsequently further emphasized by Da'cie3' and particularly in Lewis and Dacie's recent paper. Of 46 cases of aplastic anemia, seven had a positive Ham test for PNH and two actually developed clinical evi- dence of the disease. Conversely, of 60 patients with PNH, 15 showed aplastic anemia sometime during their course. In two such cases of PNH we observed, the acid hemolysis tests became negative when aplastic anemia developed. In the cases presenting first as pancytopenia-hypoplasia, then later developing hemo- globinuria, it has been customary to stress PNH as the real or fundamental con- dition and the previously apparent hypoplasia as simply a pre-PNH manifestation. Names are important chiefly from the symbolic standpoint; they project images! They might be described as "bullets" profoundly affecting our response to a given set of circumstances. Thus, the term "PNH" invokes the concept of a peculiar form of hemolytic anemia in which hemoglobinemia (and hemoglobinuria) develop nocturnally. This puts the disease into the category of the various hemo- lytic anemias and the hemogiobinurias, which are characterized (among other fea- tures) by shortening of the red cell survival time, an active bone marrow with blood reticulocytosis, hemoglobinemia, and bilirubinemia. It has been shown that the shortened red cell survival in PNH is due to an intrinsic defect of the red cell.5' 6 Such defects are almost always of genetic origin. However, in PNH there is every indication that the disorder is an acquired one. How then can aplastic anemia and PNH be related? Pancytopenia in PNH has been noted since the early writings on this disease. Thus Crosby,~ pointing to the usual leukopenia and thrombocytopenia-i.e., pancy- topenia-suggested that all the bone marrow cells were involved in the disease. It is the red cell defect, however, that gives this condition its distinctive quality. Surely, the various factors in plasma which could `be implicated in the actual hemolysis of the red cells (complement, "properdin," etc.) are of little importance as compared with the red cell defect. Actually, PNH may be thought of as an acquired defect of the erythron occurring in a previously healthy individual. Once having developed, this defect is apparently self-perpetuating and ecologically 2Dacie, J. V., and Gilpin, A.: Refractory anemia: its incidence in three members of one family, with in one case a relationship to chronic haemolytic anemia with nocturnal haemo- globinuria. Arch. Dis. Child. 19 : 155, 1944. ~ Dacie, J. V.: Paroxysmal nocturnal hemoglobinuria. Proc. Roy. Soc. Med. 56: 587. 1963. Lewis, S. M., and Dacie. J. V.: The aplastic anemia-paroxysmal nocturnal haemo~ globinuria syndrom. Brit. 3. Haemat. 13 : 236, 1967. 5Heliem, A. 3., and Skaug, 0. E.: Paroxysmal nocturnal hemoglobinuria. II. Permeability and phosphate turnover in the red blood cells. Scand. 3. Clin. Lab. Invest. 7: 121. 1955. 6 De Sandre, G., Ghiotto, G., and Mastella, G.: L'acetilcolinesterasi eritrocitaria. II. Rap' porti con le malattie emolitiche. Acta Med. Patav. 16: 310, 1956. ~ Crosby, W. H.: Paroxysmal nocturnal hemoglobinuria: Relation of clinical manifesta- tions to underlying pathogenic mechanisms. Blood 8: 769, 1953. PAGENO="0535" COMPETITI\TE PROBLEMS IN THE DRUG INDUSTRY 2669 advantageous. Indications of the defect are present, not only in the undue hemol- ysis in the presence of dilute acid,8 but by a great reduction in red cell cholinesterase,6 a striking sensitivity to complement and immune antibodies,°' 10 a morphologic abnormality as seen by electron microscopy,11 and by the presence of a shortened red `cell survival time when the red cells of the patient are injected into a normal individual.12 Thus, a certain proportion of the nucleated red cells of `the bone marrow may be said to have developed an acquired, self-perpetuating abnormality which is sufficient to result in hemoglobinemia and/or hemogiobi- nuria. Stated in this way, PNH may be considered as a growth disturbance of the erythroblastic component of the marrow. Conceivably, it could be called "neo- plastic," a new kind of growth. Why should a previously healthy individual develop this defect involving at least a portion of his red cell series? Why should leukopenia and thrombo- cytopenia be so commonly present? This brings us squarely to the heart of the matter. The more than coincidental relationship of PNH to aplastic anemia and the fact that the latter disease has been commonly associated with expo- sure to various chemicals or ionizing radiation suggest the possibility that the same agent which results in total marrow destruction may result in injury but not total destruction of one or another component of the marrow. Thus, one may speculate that certain chemicals, which in large dosage may destroy all the elements of the marrow, may in smaller amounts result in "selective" destruction of one of the marrow components or perhaps only in the loss of a key enzyme of some cells. Such injured cells might retain the capacity to re- produce themselves despite this deletion, and in this manner the formation of a self-replicating clone of abnormal cells niight be induced. PNH could thus' be a form of neopiasia-of the red cell series-developing, at least in some cases, as the result of an insult to the marrow. Similar reasoning has been applied to the development of leukemia. As cases of aplastic anemia are followed, whether these are chemically or radiologically induced, or in association with congenital defects (Fanconi syn- drome, the Werner syndromee), it becomes evident that a number of them eventually develop increasing groups of primitive leukocytes in the marrow- i.e., "acute" or primitive cell leukemia. It is conceivable that this type of leu- kemia is based upon the initial development of a small clone of primitive leukocytes with defective maturation; eventually such a clone may gam eco- logic dominance. Thus it is evident that marrow hypoplasia may be followed in some cases by "hypoplastic" primitive cell leukemia. in others by the devel- opment of a new type of (defective) red cell growth-i.e., PNH. From this, one may infer that a sufficiently severe "insult" to the marrow-whether chem- ical, ionizing radiation, or viral-may result `in a variable degree of injury with a variable degree of hypoplasia (hypoplastic anemia). In some cases, abnormal clones of either leukocytes or red cells could conceivably arise during the process of repair. If the preponderance of bizzarre cells were of the white cell type, "leukemia" would be diagnosed; if, on the other hand, the red cell injury were sufficiently marked as to result in hemoglobinuria, then the diagnosis of PNH would necessarily be made. Thus, at least some examples of the apparently different conditions of PNH, aplastic anemia, and "hypo- plastic" leukemia might have a common denominator in the form of an "in- suit" to the marrow. As a correlative statement, what looks like "aplastic anemia" today might be either "acute leukemia" or PNH two years from now. 8 Van den Bergh, A. A. H. : Ictere hemolytique avec crises hdmoglobinuriques fragilit~ globulaire. Rev. Med. (Paris) 31: 63, 1911. 0 Ham, T. H., and Dingle, J. H.: Studies on destruction of red blood cells. IL Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria; certain immunological aspects of the hemolytic mechanism with special reference to serum complement. J. Clin. Invest. 18: 657. 1939. 10Rosse, W. F., and Dacie, J. V.: Immune lysis of normal human and PNH red blood cells. I. The sensitivity of PNH red blood cells to lysis by complement and specific antibody. J. Clin. Invest. 45: 736, 1966. . ii Cecchi, E., and Conestabile, E.: Paroxysmal nocturnal hemoglobinuria. Electron-micro- scopic study of red blood cells. Lancet 2: 466, 1957. . ~ Dacie, J. V. : Diagnosis and mechanism of hemolysis in chronic hemolytic anemia with nocturnal hemoglobinuria. Blood 4: 1183, 1949. 8With Dr. E. Perez-Santiago and Dr. Norman Maldonado, I have recently observed, at the Centro Medico of the University of Puerto Rico, a fascinating case of pancytopenia- hypoplastic anemia occurring in a young woman with the Werner syndrome (progeria). Subsequently, she developed increasing numbers of plasma cells in the bone marrow, and the previously diffuse hypergammaglobulinemia had begun a "monoclonal" spike. It was evident that she was now developing multiple myeloma. PAGENO="0536" 2670 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY It is conceivable that such a time lag might be essential to establish a sufficient mass of abnormal cells to result in clinical evidence of one or the other disease. This attempt to put together in one pathogenetic package such apparently diverse abnormalities as aplastic anemia, PNH, and a form of leukemia is not meant to tear asunder the neat cornpartmentalization by which we, as physi- cians, tend to classify disease. Certainly, these "pigeonholes" have merit. On the other hand, in some circumstances they may impede at least conceptual progress. The usual tendency is to refer to the sequence of aplastic anemia- PNH as coincidental disorders, or perhaps as one condition "masquerading" for a time as another. It is conceivable that "lumping," as opposed to "splitting," might be better here. Thus, as in the myeloproliferative disorders and now perhaps in the field of aplastic anemia, PNH, and "hypoplastic" leukemia, a "vague" approach, as opposed to strict categorization, may have much in its favor. That a single "insult" to the marrow may be responsible for bringing about different kinds of abnormalities, sometimes occurring together, some- times sequentially, deserves considerations, not only from the conceptual standpoint but from the experimental approach as well. [From Clin-Alert, May 10, 1967] CHLORAMPHENICOL TOXICITY For fifteen years the profession has been divided into those who fear the toxicity of chloramphenicol and rarely use the drug, and a large number who ignore the possibility of marrow aplasia and prescribe chloramphenicol freely. Ohloramphenicol is prescribed much less frequently in Great Britain than in the United States. The British Committee on Safety of Drugs recommends that chloramphenicol not be used except for treating typhoid fever or H. influenza meningities, or, in the case of other infections, when no other antibiotic will suffice. If these recommendations are followed, the occasions for prescribing chloramphenicol would be few and far between. Leading Articles, British M.J. 1:649 (Mar. 18), 1967; Meade (London, Eng.), Ibid. 671. [From New Drugs, 1967, ch. I, pp. 1-3] ANTIBACTERIAL AGENTS CHLORAMPHENICOL AND DERIVATIVES Chloramphenicol (chioromycetin) is a broad spectrum antibiotic originally derived from Streptornyces venczuelae, but now produced synthetically. The drug is also available as the esters, chioramphenicol palmitate and chlroam- phenicol sodium succinate. It was effective antimicrobial activity against many strains of gram-positive and gram-negative bacteria Rickettsia, and "viruses" of the psittacosis-lymphogranuloma group. However, because serious blood dyscrasias have occurred after therapy with chloramphenicol (see under Adverse Reactions), this drug should be used only for the treatment of typhoid fever, other salmonelloses, and infections that do not respond to less potentially dan- gerous agents. Chloramphenicol is highly effective in the treatment of typhoid fever, but is not so uniformly effective in other Salmonella infections. It also may be used in the treatment of infections of the meninges and of the urinary and respiratory tracts when the causative organism is susceptible to its action and other therapeutic agents are ineffective or are contraindicated. However, the physician should bear in mind the precautions to be exercised and the adverse reactions that may occur with chioramphenicol. As with other antibiotics that are effective systemically, there are few indications for its topical use. ADVERSE REACTIONS The most serious toxic effect associated with the use of chloramphenicol (chioromycetin) is aplastic anemis w~tlt pancytopenia~ Data in the AMA Reg~ istry on Adverse Reactions indicate a disproportionately higher number of re- ports of aplastic anemia occurring in patients receiving chloramphenicol than in those receiving any other drug. About 75% of the blood dyscrasias associated PAGENO="0537" COMPETITIVE PROBLEMS IN THE DRUG INDU$TRY 2671 with chioramphenicol were report as cases of aplastic anemia with pancyto- penia; other forms noted include erythroid hypoplasia without pnacytopenia, thrombocytopenia with no change in red or white blood cells, leukopenia, and agranulocytosis. Aplastic anemia has occured after the administration of small doses for short periods, as well as after prolonged therapy; the other forms of blood dyscrasias appear more likely to be associated with large doses or pro- longed therapy and also are more likely to be reversible if the administration of chloramphenicol is discontinued. Skin rash and gastrointestinal and neurologic reactions, including optic and peripheral neuritides, also have been reported. Sensitization may occur when the drug is applied topically. As with other antibiotics, an overgrowth of nonsuscep- tible organisms may occur when chloramphenicol is used. In premature and newborn full-term infants, chioramphenicol has produced toxic reactions referred to as the "gray syndrome," which is characterized by abdominal distension, progressive pallid cyanosis, and peripheral vascular col- lapse; in a number of cases, death has resulted. PRECAUTIONS It is essential that adequate blood studies be made during treatment with this drug. However, although blood studies may reveal early peripheral blood changes such as leukopenia or granulocytopeni'a before they become irreversible, the studies cannot be relied upon to detect bone marrow depression prior to the development of aplastic anemia. Because of the possibility that serious and even fatal blood dyscrasias (aplastic anemia, hypopiastic anemia, thromboey'topenia, granulocytopenia) may occur after both short~term and prolonged therapy with chloramphenicol [chloromy- cetin], the drug should be used only for serious infections caused by organisms that are susceptible to its antibacterial effect. Chloramphenicol should not be used when other less potentially dangerous agents will be effective; or in the treatment of trivial infections such as colds, influenza, or infections of the throat; or as a prophylactic agent to prevent bacterial infections of the respiratory tract. The dosage `recommendations for premature and newborn infants should not be exceeded: moreover, the levels of the drug in the blood should be carefully followed, since the concentration in premature infants `and in those under two weeks of age differs from that in older infants. This difference is due to th'e immaturity of metabolic mechanisms for the disposition of chloramphenicol, as well as `of many other drugs; thus, `high blood concentrations result and tend to increase wi'th succeeding doses. Since patients with impaired hepatic or renal function may retain an excessive amount of chloramphenicol because of decreased metabolism and excretion, the dosage should be adjusted accordingly or, preferably, the blood concentration should `be determined `at appropriate intervals. PHARMACOLOGY Chioramphenicol [chloromycetin] is absorbed rapidly from the gastroin- testinal tract and, after a single oral dose, the maximal blood concentration is reached within two hours. It appears to be well distributed, although not uni- formly, in the body tissues. The drug passes readily into the cerebrospinal and pleural fluids, and appreciable quantities are found in the bile. It passes into the aqueous and vitreous humor of the eye and crosses the placental barrier. Chloramphenicol is rapidly conjugated by the liver to a monoglucuronide which has no antibacterial activity. It is excreted mainly in the urine. The rate of excretion is proportional to the blood `level, `and 5% to 10% of the total a'mount excreted is in the active form. Chioramphenicol Sodium Succinate, U.S.P. [Chioromycetin sodium succinate] 0 H NH~CHC1, 0 02N )-~----CH2OCCH2CII2~ONO ~IIl~[ ~ D_(-)_threo~2,2~dichloro_N[~i_hythoxy..a(hydroxymethyl)..p_fljtrophenethyl} acet- amide, a-sodium succinate PAGENO="0538" 2672 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ACTIONS AND USES Chloramphenicol sodium suecinate is similar to the parent compound in ac- tion, uses, and adverse reactions, and thus it has the same indications for use (see the Introductory Statement). However, because of its high aqueous solu- bility, it may be preferred for parenteral administration when oral therapy is not feasible, when it is important to achieve a high blood level quickly, or when higher blood concentrations are required than can be conveniently attained by oral administration. This ester is the preferred parenteral dosage form for pediatric use. The sodium succinate derivative has no antibacterial activity in vitro; its effectiveness in vivo depends upon the liberation of the parent compound. Concentrations of the drug in the cerebrospinal fluid average about one half of those in the serum; inflammation of the meninges does not appear to increase the rate of diffusion. After administration of chioramphenicol sodium succinate, the unchanged ester, free chloramphenicol, and metabolites of the latter appear in the urine. ADVER5E REACTIONS Chloramphenicol sodium succinate may produce the same adverse reactions as the parent compound (see the introductory statement on chioramphenicol). In particular, it should be borne in mind that the latter may cause aplastic anemia, thrombocytopenic purpura, and agranulocytosis, and that it has produced hypersensitivity and neurotoxic reactions. A bitter taste, which occurs 15 to 20 seconds after injection and persists for 2 to 3 minutes, is experienced by patients receiving chloramphenicol sodium succinate intravenously. Intramuscular injection of the sodium succinate ester is apparently less ir- ritating than is injection of the base, although moderate local pain at the site of injection occurs in a substantial proportion of patients; a significant inflamma- tory reaction seems to occur only after repeated injections. Intravenous admin- istration is also well tolerated. PRECAUTIONS Ohioramphenicol sodium succinate should be used with the same precautions applicable to the parent compound. All patients receiving this form of the drug should have periodic hematologic studies and should be carefully observed for clinical manifestations of the blood dyscrasias that have been associated with the administration of chloramphenicol. Dosage recommendations in premature or newborn infants should not be ex- ceeded, and assay of blood concentration is advisable. Chioramphenicol sodium succinate should not be used in trivial infections or in infections in which the causative organism has not been demonstrated to be susceptible to its effect. DOSAGE AND PREPARATIONS Routes of Administration .-Intramuscular, intravenous, subcutaneous. Dosage.-Ohloramphenicol sodium succinate is prepared for use by dissolving the powder in water for injection or other suitable aqueous diluents. A 10% solution is prepared for intravenous administration and the total dose is in- jected over a period of one minute or is added to a larger volume of fluid and infused slowly. A 25% to 40% solution is used for deep intramuscular injection, and a 10% solution is injected subcutaneously or added to fluids for subcuta- neous clysis. The dosage of chioramphenicol sodium succina'te should be adjusted on the basis of the severity of the infection, response, and tolerance. If doses higher than the following are used for severe infections, they should be reduced after clinical improvement is noted. The usual dose for adults and children is 50 mg. per kilogram (23 mg/lb.) of body weight given in divided doses every six or eight hours. Premature infants are given 25 mg./kg. (12 mg./lb.) daily in divided doses, usually at 12-hour inter- vals, either intramuscularly or intravenously. Full-term newborit infants up to two weeks of age are given 2,5 mg./kg. daily in divided doses every four to six hours by the intramuscular or intravenous route. Generally, in infants over two weeks of age, ~i daily dose of 50 mg./kg. is required to produce effective blood levels. However, even when using these general guides to infant dosage, chloram- PAGENO="0539" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2673 phenicot blood levels should be determined frequently for every premature and newborn infant, and an attempt should be made to maintain a blood level as near 10 to 20 ~g./10O ml. of serum as possible. It is also advisable to make blood level determinations for any infant if the drug is given for more than four days. Preparations.-I~jectjon: Powder 250 mg., 1 gm. Supplied by.-Parke, Davis & Company [Chioromycetin Sodium Succinate]. Year of introduction: 1959. Evaluated for N.N.D. 1962. Revised: 1965. [From Clin-Alert, Aug. 18, 1966] CHLORAMPHENICOL OPTIC TOXICITY Blindness occurring in children with cystic fibrosis has been reported by several investigators, and it has been suggested that the ocular complications are due to severity of the disease or to its treatment (Olin-Alert No. 11, 1966). The authors studied 42 children with cystic fibrosis of whom 19 were found to have some degree of engorgement of the retinal vessels, and this was related to the severity of their lung disease and not to antibiotic therapy. Ocular damage was not observed in patients receiving very large amounts of tetracydines, sulfona- inides, erythromycin, and novobiocin. However, of 19 children who had been given chloramphenicol, one developed optic neuritis after receiving the drug for 69 weeks, and this caused permanent blindness. Ohlorainphenicol should probably not be given to children with cystic fibrosis for periods longer than one month be- cause optic neuritis has occurred after only 31/2 months of such treatment.- Keith et al. (London, Eng.), Arch. Dis. Child. 41 : 262 (June), 1966. [From the American Journal of Disabled Children, July 1966, vol. 112. pp. 46-48] OPTIC NEURITIS AND CHLORAMPHENICOL (By Nora Chang, M.D., Conrad L. Giles, M.D., and Robert H. Gregg, M.D.,* Detroit) Optic neuritis has been associated with chloramphenicol therapy in both adults and children.1° It is our purpose to report two additional cases occurring in children with cystic fibrosis, who were treated with large doses of chloram- phenicol over a prolonged period of time. REPORT OF CASES Case 1.-This 5-year-old white girl is one of apparently identical twins with moderately advanced cystic fibrosis. The diagnosis was established elsewhere on the basis of symptoms which began at the age of 2 months. The diagnosis was confirmed here at the age of 3 years on the basis of the clinical picture, the chest x-ray, and a sweat test (chloride greater than 100 mEq/liter). Treatment included postural drainage, nighttime mist tent, pancreatic extract, vitamins, and sodium oxacillin at various times. At the age of 4~/2 years (July 1964), because of progression of her respiratory disease, she was given chloram- phenicol in a dose of 750 mg/day (57 mg/kg). This dose was continued for a period of 6'/2 months, and the oxacillin was continued simultaneously. At this time the mother reported evidence of visual impairment and the chloramphenicol was discontinued and oxacillin continued. Ocular examinations at that time revealed a vision of counting fingers only at two feet. Ophthalmoscopically she demonstrated dilated and tortuous veins with mild edema of the disc in each eye. The diagnosis of retinopathy of cystic fibrosis in association with optic neuritis, probably due to chloramphenicol, was made. *Recejved for publication March 3, 1966. From the departments of pediatrics and ophthalmology, Wayne State University, and Children's Hospital of Michigan Detroit. Reprint requests to 5224 St. Antoine St, DetroIt 48202 (Dr. Gregg). NOTE-Numbered1 footnotes at end of article, p. 2676. PAGENO="0540" 2674 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY One month later, the vision .had improved slightly to counting fingers at ten feet, and the retinopathy was less apparent, although definite pallor of each disc was noted. Examination two months after discontinuing the drug showed no change in vision, but less retinopathy and less pallor of the optic nerve head. Four months later the vision rose to 20/200 in the left eye, but remained un- changed in the right eye. After five months, the disc still showed residual pallor although the vision had risen to 20/50 right eye, and 20/40 left eye. Nearly six months after the initial evaluation, the vision was 20/40+ bilater- ally, minimal optic nerve pallor was present, and no evidence of retinopathy was seen. No change was seen on subsequent examinations. The respiratory symptoms have continued to progress in severity. Case 2.-This 17-year-old white girl was said to be free of symptoms until the age of 9 years. A diagnosis of cystic fibrosis was made at the age of 13 in another hospital, was confirmed here (same basis as in case 1), and she has been fol- lowed here for most of the last four years. She has had advanced changes of cystic fibrosis with severe diffuse lung changes, marked clubbing, and exercise limitation throughout that time. In the past two years she has been intermit- tently febrile and cyanotic. Initially, treatment consisted of pancreatic extract, vitamins, postural drain- age, a nighttime mist tent and tetracycline. There was some improvement on this regimen. She then moved from the city and when next seen in July 1963 at the age of 15, she was worse. Sodium oxacillin was begun (750 mg/day), but she did not improve, and after two months, chlor- amphenicol in a dose of 1.5 gm/day (49 mg/kg) was added. `Some improvement followed and these medications were continued for the next 16 months. At this time she complained of photophobia, and chioramphenicol was discontinued and oxacillin continued. Her glasses had been changed by a local optometrist midway in this 16-month period. She was referred to the ophthalmologist following the inability of her optom- etrist to improve vision above the level of 20/60. The patient had noted a slow decrease in central vision over the three months preceding her ophthalmologic evaluation. Examination showed a marked reduction in vision to counting fingers at ten feet with a myopic correction in each eye. The remainder of her examination, except for a 12° central scotoma (to a 2 mm white test object at 1,000 mm), was normal. The condition of the retinal vessels and optic nerve head was physiologic. When the patient was reexamined on March 1, 1965, the vision was 20/50- in the right eye and 20/40- in the left eye. Ophthalmoscopy was again normal. PAGENO="0541" C C C 02 CHLORAMPHENICOL OPTIC NEURITIS-CHANG ET AL. Summary of reported cases Case Age, Sex Basic year disease Dose, Duration of Rx Symptoms Ocular findings Outcome Author mg/kg. 1 22 M Bacterial endocarditis 2 months Yellow; blurred vision Decreased visual acuity; papillitis Vision normal Gewin et al. 2 24 F Ulcerative colitis and abscess 53-~ months Blurring vision Decreased visual acuity; bilateral scotomata; Vision normal Wallenstein. edema of nerve fibers; appearance of new et al. vessel on nerve head. 3 ? M Bacterial endocarditis 13~ months Cloudy vision; progressed to Discs pale, blurred, edematous; numerous Poor vision re- Lasky. blindness, hemorrhages in various parts of fundi. covery. 4 32 M Chronic melioiodosis 21 months 2 episodes of visual complaints; Decreased visual acuity; visual fields and Vision normal Prevatt et al. blurred foggy vision; unable fundi normal. to read. 5 44 M Bacterial endocarditis 63-~ months Blurred vision, a feeling of Decreased vision; pericentral scotomata, con- Vision normal Cole et al. "looking through a film." striction of visual fields bilaterally; edema of discs; dilated retinal veins. 6 20 M Melioidosis Approximately 4 Blurred vision; inability to Papilledema: constricted visual fields Vision normal Joy et al. months, focus. 7 37 F Pyelonephritis Approximately 12 Film in front of eyes. Decreased visual acuity; scotomata bilaterally Vision normal Wilson. months intermit- optic discs swollen, marked edema over tently. maculae. 8 31 F Polycystic kidney pyuria Approximately 10 Failing vision Decreased visual acuity central scotomata Vision slightly Wilson months bilaterally myopic changes in retina and improved slight pallor of discs. 9 4 F Cystic fibrosis Approximately 15 Peering at objects Decreased vision exotropia optic atrophy Poor vision re Keith months. bilaterally. covery. 10 2 M Cystic fibrosis 27-53 24 months Sat close to TV; had trouble Vision normal Leitman et al. feeding himself. 11 4 M Cystic fibrosis.. 59 43~ months Fell over toys; had trouble Counts fingers at Lietman et al. feeding himself 2-3 feet 12 5 M Cystic fibrosis 40 8 months Sat close to TV held objects Decreased visual acuity bilateral central Vision normal Leitnam et al close; had difficulty finding scotomata; blurred disc margins, and tor- toys. tuous vessels. 13 6 M Cystic fibrosis 41 9 months Sat close to TV; could not rec- Decreased visual acuity; bilateral central Vision normal Leitnam et al. ognize brother at 10 feet. scotomata; edema of discs, engorged and tortuous veins. 14 6 F Cystic fibrosis 54 8 months Held objects close Decreased visual acuity; blurred and elevated Remained on Leitman et al. disc margins; tortuous veins, clumping of chlorampheni- macular pigment. col; counts fingers at 6-7 ft. 15 6 M Cystic fibrosis 45-60 33~ months Held objects close, had diffi- Disc blurred, hyperemic, and elevated; yes- Vision normal Leitman et al. culty seeing blackboard in sels tortuous; peripapillary capillary dila- school. tation with hemorrhage. . 16 5 F Cystic fibrosis 57 63/i months Did not read or watch TV Decreased vision; retinopathy of cystic fibro- Vision improvecL... Present report. sis and optic neuritis. 17 17 F Cystic fibrosis 49 16 months Light spot in front of eyes Marked reduction in vision central scoto Vision normal Present report difficulty in seeing. mata. PAGENO="0542" 2676 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In spite of repeated attempts to reexarrdne the patient, further follow~up was delayed until Aug. 23, 1965, when a vision of 20/20 was recorded in each eye and the disc and retina were normal. COMMENT It is presumed that the causative agent in these cases was chioramphenicol. All. other therapeutic agents were continued after chloramphenicol was stopped. In the previously reported cases (now totaling 15), chioramphenicol was the only common drug.'° The retinopathy of cystic fibrosis of the pancreas, characterized ]jy retinal hy- pervascularity or papilledema or both.1° is not at all similar to the changes de- scribed here, and usually does not affect vision. These changes are thought to be related to the pulmonary status. A summary of the clinical findings in our cases and those from the ilterature are given in the Tahle. The mechanism of optic neuritis in this condition (or in any other) is not known. SUMMARY Two cases of optic neuritis associated long-term chloramphenicol therapy are reported. GENERIC AND TRADE NAMES OF DRUGs Chloramphenicol-GhloromyCetifl. Sodium oxacillin-Prostaphlin, Resistopen. Tetracycllne-AchrOmyCin~, Panmycin, Polycycline, Steclin, Tetracyn. REFERENCES 1 Gewin, H.M., and Friou, G.J.: Manifestations of Vitamin Deficiency During Aureomycin and Chioramphenicol Therapy of Endocarditis Due to Staphylococcus Aureus, Yale J Biol Med 23: 332-338, 1951. Wallenstein, L., and Snyder, J.: Neurotoxic Reaction to Chioromycetin, Ann Intern Med 36: 1526-1528, 1952. Lasky, M.A.; Pincus, M.H.; and Katlan, N.R.: Bilateral Optic Neuritis Following Chloramphenicol Therapy, JAMA 151: 1403-1404, 1953. ~ Prevatt, A.L., and Hunt, J.S.: Chronic Systemic Meliodosis: Review of Literature and Report of a Case, With Note on Visual Disturbance Due to Chioramphenicol, Amer J Med 23: 810-823, 1957. ~ Cole, J.G.; Cole, H.G.; and Janoff, L.A.: A Toxic Ocular Manifestation of Chlorampheni- col Therapy, Amer J Ophthai 44: 18-20, 1957. 6 Joy, R.J.T.; Scalettar, H.; and Sodee, D.B.: Optic and Peripheral Neuritis: Probable E~ect of Prolonged Chioramphenicol Therapy, JAMA 173: 1731-1734, 1960. ~ Wilson, W.: Toxic Amblyopia Due to Chloramphenicol, Scot Med J 7: 90-95, 1962. 8 KeIth, C.G.: Optic Atrophy Induced by Chloramphenicol, Brit J Ophtlzal 48: 567-570, 1964. 8 Lietman, P.S.; di Sant `Agnese, P.A.; and Wong, V.: Optic Neuritis in Cystic Fibrosis of the Pancreas: Role of Chioramphenicol Therapy. JAMA 189: 924-927, 1964. 10Bruce, G. M.; Denning, C. R.; and Spalter, H. F.: Ocular Findings in Cystic Fibrosis of the Pancreas, Arch Ophthal 63: 391-401, 1960. [From the Medical Journal of Australia, 1: 681-2, Apr. 16, 1966] CHLORAMPHENICOL AND EYE DAMAGE The more notorious side-effects of chioramphenicol, such as aplastic antemia, are w-ell enough known to need no comment, but it may not be generally recog- nized that prolonged administration of the drug can also seriously affect the sight. Two recent papers from the U.S.A. dealing with children whose serious degree of fibi~ocystic disease had necessitated their taking a prolonged course of the antibiotic, serve to highlight the problem, although there have `been occa- sional reports of visual troubles assocated with chloram~henicol therapy since 1903. The first report, by J. C. Cocke, R. E. Brown and L. J. Geppert, is from San Antonio, Texas,1 and tells of a girl, aged nine years, who was given a total of 135 grammes of chioramphenicol over a four and a half month period for a resistant Pseudonzonas infection. Three attempts were made to withdraw the drug, but on each occasion the child `became febri'le within 24 hours, and it had to be started again. Frequent physical, hiematological and chemical tests revealed no signs of any adverse reaction to the drug until over a period of about three weeks she suddenl~' developed a marked loss of vision. On questioning, it `appeared that the child had first noticed a gradual haziness of objects, then had difficulty with read- 1 J~ Pediat., 1966, 68 :27 (January). PAGENO="0543" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2677 ing fine print, until finally even large print became obscure. One week before her admission to hospital she could distinguish the largest objects only as vague shadows. Apart from her defective vision, no abnormalities were detected on physical examination, and her chest symptoms were minimal. Her visual fields were found to be markedly constricted, and on both sides there were dense cen- tral `scotomas. Her visual acuity ~vas down to 5/400. On fundoscopic examination, the veins were seen to be moderately engorged and tortuous, land there were flame h~emorrhages radiating from the discs, which were slightly elevated. Her chloramphenieol therapy was stopped at once, and she was treated with intramuscular injections of vitamin B12, and oral doses of ascorbic acid, thiamine and multiviltamin capsules (of six different types!) on a presumptive diagnosis of optic neuritis. Her vision slowly improved, although she needed streptomycin and colistin to control her chest symptoms, and after five months her vision had nearly returned to normal. Some residual signs of damage still remained, however. In the other `series, N. N. Huang, R. D. Harley, V. Prom'adhattavedi and A. Sproul from Phil!adei~hla 2 tell of nine ~h'ildren with `severe symptoms of fibro- cystic `chest inviolvement, whose `ages Tanged from `six and a half to 14 years, and whose general condition varied from fair to poor (their condition required treat- ment with various other antibiotics and aerosol therapy, as well as the chloram- phenicol), who were given courses that ranged from 81 to 252 days. The total doses given at the time the ocular symptoms became noticeable were from 81 to 283 grammes, and, as in the first case mentioned, frequent blood examinations had failed to demonstrate any abnormality. The first complaint of the children was of impairment of vision. On being tested for visual ability they were all found to have a marked decrease in acuity, and bilateral central scotomas. Fundoscopic examination revealed disc blurring in six of the nine children, and three had retinal hiemorrhages. In addition, two of the children complained of numbness and cramps in their feet which caused them more discomfort than their visual disturbances. Subsequent developments varied, apparently quite haphazardly, and the confusion is such that no very definite conclusion can be derived from them. Two children died from the effects of their disease shortly after the eye signs were discovered, on having stopped taking chloramphenicol, the other having continued the therapy. No ocular im- provement was noted in either of them before their deaths. Two others were given no vitamin or other treatment aimed specifically at the eye symptoms, which cleared up spontaneously in both cases, although one continued to take chloramphenicol. In the one who stopped treatment, vision improved in a matter of hours from the time of stopping the drug. Of the remaining five children, all of whom were given vitamins in varying combinations and quantities, one showed a quick improvement on stopping chloramphenicol, two showed improve- ment despite continuing with the drug, and two showed only slight improvement after first continuing with chlorarnphenicol, and then stopping it and taking corticosteroids instead. The authors consider that the conditions they report represent forms of optic neuritis and retrobulbar neuritis, although they are at a loss to explain the mechanism of their causation by chloramphenicol. They do suggest, and this would seem very sensible, that those patients who for one reason or another require long-term courses of chloramphenicol therapy should, in addition to their usual h~ematological check-ups at regular intervals, have a frequent assessment of visual acuity, and that parents of patients should be advised to test their children's sight regularly with a small visual chart. In some instances, too, the development of numbness and cramps in tIre feet may be a forerunner of visual disturbance, and should also be watched for. However, in explanation of some of the conflicting data mentioned above, there is evidence to suggest that some of the toxic effects of chloramphenicol may be related to a deficiency of vitamins of the B group, particularly riboflavine, and in a paper read at the recent annual meeting of the Australian Pacdiatric Association in Canberra on April 3, G. Morgan, G. Wise and P. O'Gorman Hughes, from the University of New South Wales, tell of four patients with chloramphenicol toxicity of differing varieties, one of whom developed amblyopia which was alleviated by the administration of B-group vitamins, despite his continuing with chloramphenicol. None of which is to suggest that chloramphenicol is not a thoroughly efficient and often life-saving drug. But, as with such things as nuclear fission and motor- cars, the greater the potential advantages, the greater the parallel dangers, not all of which can always be forecast. 2 J~ Pediat., 1966, 68: 32 (3anuary). PAGENO="0544" 2678 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Clin-Alert, Jan. 20, 19661 GHLOBAMPHENICOL OPTIC TOXICITY A. Report From Te~z'a.s: Attention has been previously directed to apparent deleterious effects of chioramphenicol (Chioromycetin) on the eye (Clin-Alert No. 63, 1962; Olin-Alert No. 188, 1905). Nine cases of blindness due to optic atrophy presumably induced by the antibiotic are on record. The present authors report a case of probable chloramphenicol-induced optic neuritis in a 9-year-old child with cystic fibrosis of the pancreas. Treatment with a total of 135 Gm. chloramphenicol over an 18-week period resulted in loss of visual acuity second- ary to bilateral optic neuritis. Vision gradually returned to near normal upon withdrawal of the antibiotic and the administration of high doses of vitamin B complex.-Cocke et al. (San Antonio, Texas), J. Pediat. 08: 27 (Jan.), 1966. B. Report From Pennsylvania: Visual disturbances were observed in 9 of 33 children with cystic fibrosis who received long-term (81 to 252 days) treatment with chloramphenicol. Daily doses ranged from 30 to GO mg/Kg. The major clinical feature at onset of symptoms was marked bilateral reduction of visual acuity. Two patients had severe visual impairment and permanent residual effects with partial optic atrophy. Six children had varying degrees of blurring of optic discs, retinal hemorrhages or venous engorgement. Two other children had minimal fundoscopic changes. Visual field examination revealed bilateral central scotomas in all patients tested. Vitamin B complex therapy seemed to be of some benefit in overcoming the visual disturbances. The authors believe that the chloramphenicol-induced optic reaction probably represents a neurotoxic effect of the antibiotic rather than a complication of cystic fibrosis. "Frequent test of visual acuity in children receiving chloramphenicol must be carried out by the parents and/or physician in order to detect early signs of visual impairment."- Huang et al. (Philadelphia, Pa.), J. Pediat. 68: 32 (Jan.), 1966. [From the Journal of PediatrIcs, January l9~6, pp. 27-31] OPTIC NEURITIS WITH PROLONGED USE OF CHLORAMPHENICOL CASE REPORT AND RELATI0NSH~ TO FUNDUS CHANGES IN CYSTIC FThROSIS Treatment over 41/~ mont/b period wit/b 135 Gm. of chioramphenicol resulted in loss of visual acuity to 5/400 secondary to optic neuritis in a 9-year-old girl wit/b cystic fibrosis of the pancreas. Partial return of vision occurred after cessation of therapy and administration of large doses of B-coinplecc vitamins. The suggestion is made that visual and fundal changes in cystic fibrosis may be directly and all but entirely related to prolonged IbSC of chloramphenicol in the control of pulmonary complications in cystic fibrosis. (By Joseph G. Cocke, Jr., Captain, MC, USA.* Richard E. Brown, Captain, USAF (MC), and Leo J. Geppert, Colonel, MC, USA, San Antonio, Texas) (From the Pediatric Service, Department of Medicine, and the Ophthalmology Service, Department of Surgery, Brooke General Hosptial, Brooke Army Medical Center, Fort Sam Houston, Texas) The hematopoietic toxicity of ehloramphenicol is well known. Certain less fre- quent manifestations of toxicity have aJso been noted, such as anaphylaxis, psychiatric, disturbances,1' 2 and skin and mucous membrane involvement.8 Most particularly, there has been increasing recognition to the apparent deleterious effects of chloramphenicol on the optic nerve and fundus in the form of an optic neuritis.~4 Concurrently, visual and fundal changes in cystic fibrosis15 of the pancreas, not unlike optic neuritis, have been described. Originally these changes were *Address, Pediatric Service, U.S. Army Hospital, Fort Ord; Calif. NoTE-Numbered footnotes at end of article, p. 2681. PAGENO="0545" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2679 related to the severity of the pulmonary disease. More recently, vision altera- tions have been reported related to prolonged use of chloramphenicol. Recent experience with optic neuritis in a child with cystic fibrosis has led to this case report, and subsequent suggestion for refinement of concepts relating to visual and fundal changes in cystic fibrosis. CASE REPORT C. L. was a 9-year~o1d Caucasian girl with proved cystic fibrosis and moderately extensive pulmonary disease. With no previous experience with extensive anti- biotic therapy, she `began a course of treatment with chloramphenicol in late August, 1963, which continued until the middle of January, 1964. The total close given over the 41/2 month period was 135 Gm.; the daily dose was 1 Gm. The organism, Pseudomonas aeruginosa, was sensitive to chioramphenicol. Three attempts were made to withdraw the drug. On each occasion the child became fubrile within 24 hours. Treatment with `alternate drugs was unsuccessful, and symptoms cleared oniy after restarting *chloi~amphenieol. Physical, hematologic, and chemical examinations at weekly or biweekly intervals showed no sign of adverse change. In October, 1963, her vision was 20/40 in both eyes. Her basic disease remained stable under treatment. Other than chloramphenicol, the patient was taking 400 mg. of glyceryl guaiacolate, pancreatic supplement tablets with each meal, and one standard multivitamin capsule daily, In addition, positive pressure inhalation therapy followed by postural drainage was done on a regular basis. On Jan. 17, 1964, the child was admitted to the hospital following discovery of a severe loss of vision that had `been concealed for 3 or 4 weeks. On retrospec- tive questioning, the onset wa's noted to have been gradual, starting with haziness of objects. Within a week or so, fine, then large, print became blurred. One week prior to admission she could see no more than shadowy outlines of even the largest objects. Her teacher could date a deterioration of handwriting `and read- ing ability to the approximate time of onset of visual symptom's. Physical examination on admission showed `a normal temperature, pulse, and respiration rate. She was 127 centimeters (50 inches) tall and weighed 23 kilo- grams (50.5 pounds). Pulmonary findings were minimal with no evidence of superimposed acute infecti'on. There was no cyanosis or clubbing of the fingers.' Positive neurologic finding were limited entirely to the optic nerve with no eVi- dence of clouded sensorium nor other cranial or peripheral nerve involvement. Fundoscopic examination revealed choked nerve heads bilaterally with elevation of one to two diopters of the disc. Veins were moderately engorged and tortuous. There were flame hemorrhages radiating from the disc. Visual fields showed peripheral constriction with dense central scotomas (Fig. 1). Visual acuity was 5/400. I 100 LEFT EYE RIGHT EYE 90 Fig. 1. Visual fields Jan. 22, 1964. Vision 5/400 in both eyes. 81-280 0-68-pt. 6-35 PAGENO="0546" 2680 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Laboratory vlata Admission urinalysis was normal, hematocrit was 40 percent and the heino- globin level was 12 Gm. per 100 ml.; total white count was 12, 100 e.mm. with 82 percent neutrophils, 16 per cent lymphocytes, and 12 percent eosinophils. None of these values `changed notably throughout hospitalization. A lumbar puncture showed a pressure of 180 mm. at rest. No cells were present in the spinal fluid; protein was 11 mg. per 100 ml.; sugar, 62 mg. per 100 ml.; there was no increase in globulin. Serum total protein was 7.3 Gm. per 100 mL with 5.0 Gm. per cent albumin and 0.80 Gm. gamma globulin. Determinations of serum sodium, potassium, chloride, 002, calcium, and phosphorus were normal on two separate occasions. Throat and sputum cultures repeatedly grew Pseudomonas aeruginosa. With a working diagnosis of optic neuritis from chloramphenicol, therapy consisted primarily in stopping the drug and administering 1,000 P~g of B12 intramuscularly and 150 mg. of both thiamine and ascorbic acid orally daily, coupled with 6 standard naultivitamin capsules a day. The pulmonary problem was handled with a continuation of the intermitten positive pressure inhalation and postural drainage program. In addition, streptomycin and colistin were required toward the end of the hospital course to combat recrudescence of pneumonitis. Visual acuity was noted to improve slowly. By the seventeenth hospital day, vision was 20/400 in both eyes. On the twenty-seventh hospital day it was 20/100 bilaterally, and remained thus until discharge. Very little improvement in visual fields was noted during hospitalization. The fundus showed slow resolution of the swelling of the nerve head with a decrease in the extent of the hemorrhages and exudates and an improvement in the retinal edema. On the thirty-ninth hospital day, the patient was discharged with treatment of three multivitamin capsules and 50 /~g of B12 orally daily. She was followed through July, 1964; visual acuity improved to 20/50 in the right eye and 20/60 in the left eye. The fundus showed resolution of all acute changes and minimal postneuritic optic atrophy. Visual fields (Fig. 2) demonstrated small `bilateral central scotomas and no change in the peripheral constriction. RIGHT EYE 180 There are 15 fairly detailed case reports and two abstracts 4-14 ~f visual changes related to prolonged use of chloramphenicol in the English literature. Initial visual symptoms have been, primarily, haziness and blurring of vision and halos about objects. After a variable length of time, loss of visual acuity occurs. Acute fundus changes have been described as papilledema, venous engorgement with occasional flame hemorrhages, and exudates. Visual fields show moderate LEFT EYE Fig. 2. Visual fields June 25, 1964. Vision 20/50 left eye; 20/60 right eye. DISCUSSION PAGENO="0547" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2681 peripheral constriction with central scotomas of varying sizes. Related peripheral nerve symptoms of burning, tingling, or numbness of extremities have been reported in several cases.5'" °` `~ Pathologic changes have recently been reported in 2 children with cystic fibrosis.14 Both cases showed loss of the ganglion cell layer of the retina and a degree of demyelinization of the .optic nerve fibers centrally to the chiasm. A definite cause and effect relationship has not `been established between prolonged use of chloramphenicol and deleterious effects on vision. However, circumstantial evidence leads to this conclusion in the individual cases. The prognosis for the eventual return of visual acuity in any given case would appear to be good. Peripheral field changes usually show slight to moderate im- provement. The rationale for treatment of these visual disturbances with high doses of B-complex vitamins after cessation of chioramphenicol therapy lies in the sug- gestions previously made that the neurotôxicity is related to an interference with the B-complex group either directly~ at the cellular level,5 or indirectly through sterilization of the gut.1' Bruce and associates 15 attribute visual changes to cystic fibrosis per se, speculating' as to the relationship with severe pulmonary changes. Lietman and colleagues14 propose two separate ocular lesions in cystic fibrosis: One, as de- scribed by Bruce, presumably with no effect on visual acuity; and the other, an optic neuritis with visual impairment, but without specific objective signs on funduscopic examination. A more unified concept as to the etiology of the visual and ocular pathology may be derived by reinterpretation of the results of these observers. On close comparison all cases, ours included, have a~ strikingly similar funduscopic pic- ture, consisting in almost every instance of the one lesion that best explains acute loss of acuity and relates to chloramphenicol as the underlying common denominator, namely, papilledema as a manifestation of optic neuritis. Macular changes are not necessary to explain the visual loss associated with optic neuritis. Previously the relative absence of macular abnormalities had been responsible for the division of ocular lesions in cystic fibrosis into the two categories noted above. The visual changes in cystic fibrosis may perhaps be considered as directly, and all but entirely, related to the prolonged use of chioramphenicol. By elimination of the consideration that fundus changes may be due to cystic fibrosis per Se, and by assuming that optic neuritis does occur with recognizable fundus changes, as this unified concept suggests, sight-conserving measures may be made more practical. Any child receiving long-term chioramphenicol therapy, who is found to have papilledenia, venous engorgement, hemorrhages, exudates, and/or visual impairment, might reasonably and prudently be considered for drug elimination or dosage reduction. Further, the potential protective role of B-complex vitamins in long-term therapy with chloramphenicol seems deserving of study. Chioramphenicol remains one of the most useful drugs for the treatment of pulmonary complications of cystic fibrosis. Recognition of yet another flaw in the two-edged sword that is chloramphenicol is essential lest we be guilty of adding more weight to the burden of those already heavily taxed. SUMMARY A case of probable chloramphenicol optic neuritis in a 9-year-old female with cystic fibrosis of the pancreas is presented. Treatment with 135 Gm. of chioram- phenicol over a 41/2 month period resulted in a loss of visual acuity secondary to bilateral optic neuritis. Gradual i~eturn of vision to near normal occurred after withdrawal of chioramphenicol and treatment with high doses of B-complex vitamins. It is suggested that in cystic fibrosis, visual changes may be directly, and all but entirely, related to the prolonged use of chloramphenicol. REFERENCES `Hill, C. F. L., Armstrong, ~f. V., McDonald, C. K., and Anott, E. N. : Treatment of typhoid fever with chioramphenicol, Lancet 2: 802, 1950. Phadke. M. V., Joshi, V. S., and Naik, S. G.: Toxicity of chioramphenicol in children, J. Indian M. A. 87: 26, 1961. PAGENO="0548" 2682 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Tomaszewski, T.: Side-effects of chloramphenicol and aureomycin, with special refer- ence to old lesions, Brit. M. 3. 1: 388, 1951. Gewin, H. M., and Friou, G. 3.: Manifestations of vitamin deficiency during aureo- mycin and chloramphenicol therapy of endocarditis due to ~S'tap1i.ylococcus aureus: Report of a case, Yale 3. Blol. & Med. 23: 332, 1951. 5Wallenstein, L., and Snyder, 3.: Neurotoxic reaction to chloromycetin, Ann. mt. Med. 36: 1526, 1952. 6 Laskey, M., Pincus, M., and Kotlan, N.: Bilateral optic neuritis following chlorampheni- col therapy, 3.A.M.A. 151: 1403, 1953. Cole, J. G., Cole, H., and Janoff, L.: A toxic ocular manifestation of chloramphenicol therapy, Am. 3. Ophtb. 44: 18, 1957. 8 Prevott, A. L., and Hunt, 3. S.: Chronic systemic melioidosis: Review of literature and report of a case, with note on visual disturbance due to chioramphenicol, Am. 3. Med. 23: 810, 1957. °Joy, R. 3. T., Scalettar, R., and Sodee, D. B.: Optic and peripheral neuritis: Probable effect of prolonged chloramphenicol therapy, J.A.M.A. 173: 1731, 1960. 10Walker, G. F.: Blindness during streptomycin and chioramphenicol therapy, Brit. 3. Ophth. 45: 555, 1961. U Wilson, W. : Toxic ambylopia due to chloramphenicol, Scot, M. 3. 7: 90, 1962. 12Denning, C. R., Bruce, G. M., and Spalter, H. F.: Optic neuritis in chloramphenicol treated patients with cystic fibrosis, Abst. No. 93, p. 103, Amer. Pediat. Soc., Seventy-third Ann. Meet., Swampscott, Mass., May 3-4, 1963. ~3Huang, N. N., Promadhat, 3., and Sproul, A.: Longterm therapy with chloramphenicol and optic neuritis in patients with cystic fibrosis, Abst. No. 162, p. 79, Third Interscience Conference on Antimocrobial Agents and Chemotherapy, 1963. 14Lietman, P. 5., di Sant'Agnese, P. A., and Wong, V.: Optic neuritis in cystic fibrosis of the pancreas, 3.A.M.A. 189: 924, 1964. ~ Bruce, G. M., Denning, C. R., and Spalter, H. F.: Ocular findings in cystic fibrosis of the pancreas, Arch. Ophth. 63: 391, 1960. [From 3. Chron. Dis. 1964, vol. 17, pp. 899-914] FATAL APLASTIO ANEMIA AN EPIDEMIOLOGICAL STUDY OF ITS RELATIONSHIP TO THE DRUG CHLORAMPHENICOL (By KATHRYN M. SMIcK, M.D.,° PHILIP K. CONDIT, 1V[.D.,f REBECCA L. PROCTOR, M.D.,1 and VERNON SUTCHER, M.A.~) (The Division of Preventive Medical Services, California State Department of Public Health) (Received 20 November 1963) The purpose of this study was: (1) to determine the frequency of exposure to chloramphenicol, and also of exposure to other drugs and agents, in persons who died from aplastic anemia in the period Januai-y 1957 through June 1961 in California; (2) to determine the manner in which chloramphenicol was used both before and after the onset of aplastic anemia; and (3) to estimate the risk of fatal aplastic anemia in Oalifornia among persons receiving chloramphenicol. CAUSATIVE FACTORS IN APLASTIC ANEMIA A number of specific agents have long been known to cause aplastic anemia. Prominent among them are benzene from occupational exposure and gold and organic arsenical compounds used in medical treatment. Although exposure to benzene, gold and arsenical compounds has decreased, aplastic anemia has con- tinued to occur. Consequently attention has focused on the role of other poten- tially toxic agents. These include ionizing radiation, non-medicinal chemicals, and drugs used in the practice of medicine. The antibiotic chioramphenicol is the drug most commonly suspected in recent years of an etiological role in aplastic anemia. Incrimination of the drug as a toxic bone marrow depressant has been well documented since chioramphenicol ~ Public Health Medical Officer, Bureau of Communicable Diseases, California State Department of Public Health. Now at the Contra Costa County Health Department, Martinez, California. tBureau Chief, California State Department of Public Health. tPublic Health Medical Officer, California State Department of Public Health. §Associate Public Health Statistician, Bureau of Communicable Diseases, California State Department of Public Health. PAGENO="0549" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2683 became commercially available in 1949.15 In addition, since 1953, the Study Group on Blood Dyscrasias of the Council on Drugs of the American Medical Association has maintained a Blood Dyscrasia Registry and has published semi-annual com- pilations of voluntarily reported blood dyscrasias associated with drugs and chemical agents. During this period, chloramphenicol was the drug most often associated with pancytopenia. The three nation-wide surveys of the United States Food and Drug Administration between 1952 and 1957 also indicated that chlor- amphenicol had been used with greater frequency than any ether drug in persons who subsequently developed aplastic anemia.68 In the early years of chloramphenicol use, the evidence of its toxicity was de- rived entirely from clinical case reports and from the frequency of its association with blood dyscrasias. In recent years, laboratory and clinical studies have con- tributed a variety of findings supporting the earlier indications of chloramphenicol toxicity for bone marrow.~'4 Animal experimentation to detect chloramphenicol toxicity has not been par- ticularly rewarding. However, recent work suggests that chronic bone marrow toxicity can be produced in monkeys by feeding them with chloramphenico1.'~ The physiological and biochemical mechanisms involved in toxic bone marrow suppression are not known. Also unknown is the relationship of mid reversible changes to the severe changes of aplastic anemia. In vitro studies with human bone marrow cultures hold promise of elucidating the nature of chloramphenicol's effect on bone marrow function. Already such studies have shown, by measuring ~ uptake and incorporation, that chloramphenicol causes a marked decrease in iron uptake by red blood cells thus directly interfering with heme synthesis.1° VITAL STATISTICS Available morbidity data on aplastic anemia are derived from a variety of sources and are not necessarily representative of the occurrence of this disease in the general population. Representative statistical data concerning the occur- rence and distribution of aplastic anemia are available only for fatal cases in which the cause of death was recorded as aplastic anemia on the death certificate. Table 1 indicates the numbers and rates of deaths from aplastic anemia in the United States, California and Canada. Approximately 60-80 persons die each year in California from aplastic anemia while about ten times as many die in the United States-that is, about five deaths from aplastic anemia per million popu- lation. Table 2 shows that in 1960 the risk of dying from aplastic anemia in California varied from about one person per million at ages 25-34 years to 27 persons per million at ages 65 years and over, with the years of childhood and youth involving greater risk than the years between ages 25-54 year. 1 Development and purpose of registry on blood dyscrasias, J. Amer. med. Ass. 170, 1925, 1959. 2 Dameshek, W.: Chloramphenicol-a new warning (Editorial), J. Amer. med. As8. 174, 1853, 1960. ~ Blood dyscrasias associated with chloramphenicol (chloromycetin) therapy, J. Amer. med. Ass. 172, 2044, 1960. ~ Registry on Blood Dyscrasias: Report to Council, J. Amdr. med. Ass. 179, 888, 1962. 2Ersley, A. J. and Winthrobe, M. M.: Detection and prevention of drug-induced blood dyscrasias, J. Amer. med. Ass. 181, 114, 1962. 0 Lewis, C. N., Putnam, L. B., Henricks, F. D., Kerland. I. and Welch, H.: Chioram- phenicol (chloromycetin) In relation to blood dyscraslas with observations on other drugs, Antibiot. 4 Chemot her. 2. 601, 1952. ~ Welch, H., Lewis, C. N. and Kerland, I.: Blood clyscrasias, a nationwide survey, Antibiot. 6 Chemot her. 4, 609, 1954. 8 Welch, H., Lewis, C. N., Weinstein, H. I. and Boeckman, B. B.: Severe reactions to antibiotics, Antibiot. Med. din. Ther. 4, 800, 1957. Krakoff, I. H., Karnofsky, D. A. and Burchenal, J. H.: Effects of large doses of chloramphenicol on human subjects, New Engl. J. Med. 253, 7, 1955. ~° Rubin, D., Weisberger, A. S. and Clar, D. R.: Early detection of drug-induced erythro- poietic depression ; J. lab. din. Med. 56, 453, 1960. 11 Rosenbach, L. M., Caviles, A. P. and Mitus, W. J.: Chloramphenicol toxicity: reversible vacuolization of erythroid cell, New Engl. J. Med. 263, 724, 1960. 12 McCurdy, P. R.: Chloramphenicol bone marrow toxicity, J. Amer. med. Ass. 176, 588, 1961. ~ Saidi, P., Wallerstein, R. 0. and Aggeler, P. M.: Effects of chloramphenicol on erythropoiesis, J. lab. din. Med. 57, 247, 1961. ~ Gussoff, B. D., Lee, S. L., and Lichtman, H. C.: Erythropoietic changes during therapy with chloramphenicol, Arch. intern. Med. 109, 104, 1962. i~ Hrenoff, A. K. and Anderson, H. H.: Chronic toxicity of chloramphenicol to bone marrow of macaques, Med. Eo,p. 4, 183, 1961. 26Vas, R., Bain, B. and Lowenstein, L.: Effect of chloramphenicol in human bone-marrow cultures, Blood 20, 424, 1962. PAGENO="0550" 2684 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 1.-DEATHS FROM APLASTIC ANEMIA, CALIFORNIA, 1949-61, UNITED STATES, 1949-60 AND CANADA, 1950-60 Year California Uni ted States Canada Number Rate Number Rate Number Rate 1949 1950 63 64 5. 9 6. 0 638 610 4. 3 4. 0 (i) 73 (1) 1951 61 5.5 671 4.4 73 5.3 1952 54 4. 6 828 5.3 73 1953 70 5.8 774 4.9 66 5. 1 5 1954 50 4.0 681 4.2 64 1955 53 4. 1 633 3. 9 55 1956 53 3.9 656 3.9 69 1957 59 4.2 669 3.9 64 4. 3 1958 59 4. 0 843 4.9 87 3. 9 5. 1959 61 4.0 2921 5.2 91 1960 81 5.2 ~971 5.4 75 1961 86 5.2 (1) (1) (1) (1) 1 Not available. 2 Includes Alaska. Includes Alaska and Hawaii. Note: Rates are per 1,000,000 population. Sources: National Office of Vital Statistics; Dominion of Canada, Bureau of Statistics; and State of California, Department of Public Health. TABLE 2.-APLASTIC ANEMIA DEATH RATES BY AGE AND SEX, CALIFORNIA, 1960 Age groups Total <15 15-24 25-34 35-44 45-54 55-64 >64 California popula- tion 15, 717, 000 4, 764, 000 2, 080, 000 2, 130, 000 2,278, 000 1, 793, 000 1, 296, 000 1, 376, 000 All deaths 1 135,334 11,201 2,221 2,932 6,383 12,965 20,949 78,643 Aplastic anemia deaths 81 14 9 3 6 3 9 37 Male 36 4 5 1 2 0 4 20 Female 45 10 4 2 4 3 5 17 Death rates per 1,000,000 population All deaths 8, 610. 7 2, 351. 2 1, 067. 8 1, 376. 5 2, 802. 0 7, 230. 8 16, 164. 4 57, 153. 3 Aplastic anemia deaths 5. 2 2. 9 4. 3 1. 4 2. 6 1. 7 6. 9 26. 9 I Includes 40 cases age not stated. Source: State of California, Department of Public Health. CORRELATION BETWEEN DEATHS AND SALES If chloraanphenicol is responsible for a substantial proportion of aplastic anemia deaths and the pattern of prescriptions is more or less constant over time then fluctuations in the number of deaths might be expected to correlate with fluctuations in the volume of sales of chloramphenicol. In connection with the present study, an effort was made to determine if there was a statistical association in time between the volume of chloramphenicol sales and the num- ber of deaths from aplastic anemia. The mortality and sales data for California, the United States and Canada were charted on a population ratio basis as shown in Figs. l-3.~ Sales reached a peak in 1951, dropped off precipitously during the early 1950's and then increased again during the late 1950's. A time lag occurs between sales by the manufacturer and deaths from aplastic anemia because of the normal lapse of time until the drug is actually taken and aplastic anemia develops. To test the hypothesis that sales of chioramphenicol and deaths from aplastic anemia are associated, Kendall partial rank correlation coefficients (tau) were computed with the effect of population held constant. `~Manufacturer's sales data provided by Parke, Davis & Co. PAGENO="0551" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2685 I 1 1 I 1950 `51 `52 `53 154 55 `56 `57 `58 YEAR So~u.~o; 1o.r0o, 3,&~vio o.~d Coi~t~iy. L1te of (J,.lifon.io, Do1 ~x~t of Iublio boilS, 0 0 0 -1 U in F' 13 --3.0 °` F' ci Deaths were compared with sales in the same year, sales in the previous year and sales two years previously. Since precise significance levels for partial tan are not available, approximate significance values were obtained by using the tables for first-order tan. For California and the United States, all correlation coefficients were significant at <0.05. The relationship is strongest between deaths and sales of chloramphenicol two years previously for California and between deaths and sales in the previous year for the United States. The Cana- dian data show no relationship between sales and deaths. (It has been sug- gested that some of the drug sold in Canada may be re-sold to other countries. If true, this would mitigate any relationship to aplastic anemia deaths in the Canadian population). These partial correlations for the United States and California are consistent with the hypothesis that there is a casual relationship between chloramphenicol and aplastic anemia. The death certificate study here reported represents a further investigation of this hypothesis. 250,000 I - ~- ci ~200000 `9~ 150,00(9- c - \\ . I ~ ~ *50,000~~ . ~ -/-------- - I It / DEATHS f~ . `_~% - - 70 6.0 -.5.0 ~, `59 `60 `61 .0 Fio. 1. Death rates for aplastic anemia and sales rates for chloramphenicol, C'slifornia, 1950-1961. PAGENO="0552" I- z 0 0 p. 0 0 0 0 0 0 C' p. 2686 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SALES z Source: P~.r~;e, Ocvio cod ~ Ik.t~cn'1 OCti:o o~ V~to1 St~tiuticu, FIG. 2. Death rates for aplastic anemia and sales rates for chioramphenicol. United States, 1950-1960. -1.0 0 I .0 1950 `51 `52 `53 `54 `55 `56 `57 `58 `59 `60 YEAR PAGENO="0553" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2687 *1-' A. 0 0 ,1, AC 3.0 ~ IA AC LA 250,000 SALES 150, IA C IA 0 0 0 0 .4 AC I I I~ I I____~_~I _1~~ 1)50 `5) `52 `53 `54 `55 `56 `57 `58 `59 `60 lEAR -1.0 .0 1:11 ~Ai C. 1LthIou vi AC~.)A~ .11 (.4 .1 ,ctivtiC~. FIG. 3. Death rates for aplastic anemia and sales rates for chioraniphenicol, Canada, 195C)-1960. PAGENO="0554" 2688 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY METHODS OF STUDY The study population consisted essentially of all reported deaths with aplastic anemia or pancytopenia recorded as the underlying cause (International Statis- tical Classification No. 292.4) in the study period January 1957-June 1961. Before drawing the study sample, the study population was adjusted by excluding 34 deaths which did not occur in hospitals; by excluding 6 deaths in which pancy- topenia was obviously secondary to a condition other than primary aplastic anemia; and by adding 17 deaths actually due to aplastic anemia but incorrectly coded to some other classification. Deaths which did not occur in hospitals were excluded from the study primarily because laboratory evidence would not be available to confirm the diagnosis of aplastic anemia. Hence, the number in the study population (283) differs from the number of officially reported aplastic anemia deaths (306) for the 4'/2-year period. The study sample was randomly selected and consisted of one-third of all hospital aplastic anemia deaths in the 3~/2 years. January 1957 through June 1960, and all of the hospital aplastic anemia deaths in the second half of 1960 and the first half of 1961. Initially 149 deaths were included. Eleven deaths (nine leukemias and two myleomas) were then excluded leaving a final study sample of 138 deaths. Hospital records were the sole source of study information in analyzing deaths from aplastic anemia. The following information was extracted from the hospital records: (1) date of clinical onset of blood dyscrasia defined as appearance of persistent or progressive symptoms of bleeding, w-eakness or infection or of labora- tory findings suggestive of aplastic anemia; (2) laboratory findings with emphasis on blood and bone marrow; (3) autopsy findings; (4) other diseases past and present; (5) family history; (6) exposures to drugs, chemical agents, and ionizing radiation; and (7) various characteristics of the usage of cbloramphenicol. The medical information recorded on death certificates is subject to inaccura- cies. The significance of the results in a study like the present one depends on accuracy of diagnosis in the study sample from the viewpoint of hematological disease. The medical record data were reviewed by the study staff to evaluate the diagnosis, particularly to separate those cases with medical record evidence sup- porting a diagnosis of aplastic anemia, from those cases w-ith satisfactory evi- dence of a diagnosis of another blood. dyscrasia, and from those cases lacking sufficient evidence for any definitive hematological diagnosis. These categories were designated as `aplastic anemia,' `other blood dyscrasias' and `undiagnosed,' respectively. The criteria for designating a study death as aplastic anemia were: (1) bone marrow findings consistent with aplastic anemia; (2) pancytopenia of peripheral blood; and (3) absence of conditions of which aplastic anemia (pancy- topenia) might be only symptomatic. RESULTS The criteria used resulted in dividing the 138 deaths into three categories: (i) 86 of these met the study criteria for `aplastic anemia'; (ii) 25 had `other blood dyscrasias'; and (iii) 27 were `undiagnosed'. In all study deaths in all three categories there was evidence of a severe blood disorder. The 86 cases classified as `aplastic anemia' showed pancytopenia and bone marrow findings consistent with aplastic anemia. In the second category-'other blood dyscrasias'-there was pancytopenia in only 9 cases while bone marrow findings supported a diag- nosis other than aplastic anemia in more than half. Myeloproliferative and myalo- fibrotic disorders predominated. The quantity and quality of the diagnostic medical evidence in the first two categories were good. However, in the second category-'other blood dyscrasias'-the medical evidence did not lead the phy- sician who certified the cause of death to the diagnosis which the study team considered a logical consequence of available data. Age-sea ratio The age-sex composition of the study sample varied remarkably with the three diagnostic categories. The `aplastic anemia' category had an equal number of males and females and a high proportion (30 per cent) of dE~aths in persons under PAGENO="0555" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2689 15 years of age. The `other blood dyserasias' category was two-thirds male with no persons under 35 years. The `undiagnosed' category was characterized chiefly by persons of advanced age. Family history Occurrence of a family history of blood dyscrasias in the study sample was of interest because of recent knowledge of drug-induced blood disorders related to a genetic deficiency of an enzyme in the red blood cells. Most hospital records con- tained no reference to blood dyscrasias in the family. Only nine indicated familial occurrence of such a blood disorder. Because of the few recorded familial cases and the variety and vagueness of the disorders described in other members of the families, it is impossible to relate family history findings to the study sample. Related diseases Certain disease conditions may have been related to the development of blood dyscrasias in the study sample. Viral diseases are thought to be capable of pre- cipitating aplastic anemia in the weeks immediately following the acute episode. Collagen diseases may involve bone marrow as part of a systematic process. Impairment of liver or kidney function may interfere with detoxification and exce- tion of drugs or chemicals. These conditions occurred in the study sample, their frequencies varying with the diagnostic category. Prior to onset of symptoms of blood dyscrasias, viral infections as well as other infections occurred predomin- antly in the `aplastic anemia' category. Nineteen out of a total of 24 persons with viral infections and 21 out of a total of 28 with other infections were in the `aplastic anemia' category. Five of a total of six persons with collagen disease were in the `aplastic anemia' category. Thirteen persons with renal disorders and a large number of persons with miscellaneous medical conditions were distributed throughout the three categories. Viral infections less than one month before the onset of the blood dyscrasias were recorded for 10 persons, all in the `aplastic anemia' category. All were chil- dren under 15 years of age except one person aged 21 years. Four had had rubeola, two of whom also had had frequent upper respiratory infections; the other six had had respiratory infections. Four, including the two with rubeola, had been treated with chloramphenicol, three with other antimicrobials but no record of chloramphenicol, and one with another drug not known to be toxic to blood. Blood counts before the onset of blood dyscrasias were available for only two of the ten persons. In one the blood was described as normal 5 days before the onset of bleeding. In the other there were peripheral blood changes con- sistent with viral infection. The above observations permit no conclusions as to the influence of viral disease on the subsequent development of aplastic anemia since - many of these cases might have received chloramphenicol for the viral infection. Expossre to toxic agents Exposure was defined as contact with a drug or chemical agent by ingestion, injection, inhalation, or skin or mucous membrane contact in the 6 months preceding clinical onset of blood dyscrasia. It also included therapeutic applica- tion of ionizing radiation and, in the case of radioactive isotopes, diagnostic or therapeutic application at any time during the person's life. Data on diagnostic X-rays were omitted, not because they were considered insignificant but because the medical records did not provide this information. The exposure data for the study sample of 138 deaths are summarized in Table 3. Eighty-eight persons were reported to have had exposure to a total of 118 different drugs plus a number of incompletely identified drugs, other chemi- cal agents and radiation. Forty-six persons-one-third of the study sample- were exposed to agents known to be toxic to blood. Ohioramphenicol accounted for the exposures of 30 persons, while 11 other agents accounted for exposures of the remaining 16. These 12 agents (listed on p. 908) are commonly or poten- tially toxic for blood cells and are designated as agents known to be toxic for blood in the remainder of this paper. PAGENO="0556" 2690 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 3-NUMBERS AND PERCENTAGES OFSTUDYSAMPLE BY DIAGNOSTIC CATEGORY AND EXPOSURE TO DRUGS AND OTHER AGENTS Exposure Total Aplastic anemia Diagnostic category Other blood Undiagnoscd dyscrasias Total 138 (100.0) 86(100.0) 25 (100.0) 27 (100.0) Agents toxic to blood 46 (33. 3) 32 (37. 2) 5 (20. 0) 9 (33. 3) 30 (65.2) 25 (29.1) 1 (4.0) 4 (14.8) 16 (34.8) 7 (8.1) 4 (16.0) 5 (18.5) 25 (18.1) 17 (19.8) 4 (16.0) 4 (14.8) 17 (12.3) 13 (15.1) 2 (8.0) 2 (7.4) 14 (10.1) 11 (12.8) 2 (8.0) 1 (3.7) 36 (26. 1) 13 (15. 1) 12 (48. 0) 11 (40. 7) Note: If a death is classified in more than one type of exposure, it is assigned to the one above. Figures in parentheses are percentages. 4-Amino-pteroylglutamic Gold preparations Sulfonamides acid Phenylbutazone Thiotepa Chiorpromazine Ohioramphenicol Ionizing radiation Oolchicine Prochiorperazine Diphenythydantoin Quinacrine Most cases had been exposed to more than one agent. However, seven drugs, at least three chemical agents and ionizing radiation constituted the single recorded exposure in a total of 18 study deaths. Death The exposure to digitoxin occurred in an elderly man who had anemia with renal disease and uremia, not aplastic anemia. It was not certain that the penicillin exposure actually antedated the onset of aplastic anemia. The toluene exposure was considered a likely but not certain event. The hospital records of many of the cases with a single recorded exposure offered no assurances that careful exposure histories had been taken. Although the bone marrow depressant effects of ionizing radiation are well- known, most hospital records of study deaths contained no reference to radiation exposure. Seven persons were stated to have had such exposure, of whom six were women past middle age. Three of these had received pelvic X-ray therapy for non- malignant menopausal conditions 12-20 years before the onset of aplastic anemia. One. had received 90 ~tO of radioactive iodine for diagnostic study 5-8 months before the onset of aplastic anemia and had also received chioramphenicol, mepro- bamate and other drugs. One had had 6000 ~C of radioactive phosphorus for polycythemia vera 5 years before anemia. The sixth person had X-ray treatment for carcinoma 5 years before the onset of a myeloproliferative disorder. The record of the remaining person, an elderly man, indicated only that extensive diagnostic X-ray and isotope studies had been done. It is difficult `to assess the significance of these exposures to radiation. They were not of such magnitude nor did the time relationship to the blood dyscrasias suggest that they were causal. On the other hand, knowledge of the long-term effects of such exposures is meagre and the pos- sibility of causal relationship cannot be disregarded. About 15 percent of the study sample (20 cases) had reported exposure `to chem- ical agents other `than drugs. Half of these exposures were to insecticides and Chloramphenicol Other Agents not known to be toxic to blood Drugs not specified and chemical agents No exposure No information Agents Chloramphenicol Ionizing radiation Meprobamate Phenylbutazone Digitoxin Protamin zinc insulin Agents Death 3 "Reducing pills" 1 3 Penicillin 1 2 Toluene 1 1 Toxaphen insecticide spray 1 1 Insecticide sprays with unknown 1 ingredients 3 PAGENO="0557" half `to a variety of other chemical agents. Medical record information was often inadequate to identify the chemicals in the products to which exposure occurred. In four eases, the only recorded exposure was to insecticides. The drugs associated with three or more deaths each are described graphically in Fig. 4 according to whether they were given alone, with other agents known to be toxic, or with other agents not known to be toxic to blood. I I [~~S ~Q~L*'J t~~i EE~ EI~ f~::~ t~:~' L:~ I I o 5 15 29. 25 DRIflS ASSOCIATED WITH "OTHER BLOOD DYSCRASIAS" ~HD "UIIDIAOiJOSED" CATECO~L~S Ill THECI Cal HORS DEATHS Chloraznphenicol [1~Th.2'.j Barbiturates Sulfonamides [H] Penicillin AcetyIaali~ylic acid *I I 0 5 11) Ntt~~h~r of Only drug admininiercd L~1 Drug not known to be toxic to blood also administered Drug known to be toxic to blood also administered Fia. 4. Drugs associated with `aplastic anemia' category in three or more deaths. Exposure to chioramphenicol Antimicrobial drugs were given to 42 persons most of who were in the `aplastic anemia' study category. More persons (30) received chioramphenicol than received all other antimicrobial drugs combined (28). Half the persons who received chioramphenical had `also received another antimicrobial drug, for the most part not known to be toxic to bone marrow. Of the 30 chloramphenicol exposures, 25 occurred category. Their age distribution is shown in Table 4. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2691 Chloramphenicol Penicillin Barbiturates )leprobnmatc Tetracycline Acetylsalicylic acid Sulfonamides Chlortetracycl inc Ephedrinc Minophyllin Prednisone 10 Nuiher of Deaths in the `aplastic anemia' PAGENO="0558" 2692 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 4.-NUMBER AND PERCENTAGE OF STUDY DEATHS IN "APLASTIC ANEMIA" CATEGORY EXPOSED TO CHLORAMPHENIcOL,1 BY AGE GROUP Exposure to chloramphenicol Age group, years Aplastic anemia deaths Number Percent of total Percent of deaths exposure All ages 86 25 29.1 100.0 <15 26 10 38.5 40.0 15-44 25 8 32. ~ 32. ~ 45-64 16 25. o 16. o >64 19 3 15.8 12.0 1 Within 6 months of clinical onset of aplastic anemia. The following is a résumé of case history information for the 30 persons in the study sample reported to have received chloramphenicol. "Ten individuals under age 15 years, two boys and eight girls, and all in the category `aplastic anemia', received chloramphenicol. Nine had taken the drug for upper respiratory conditions (including the complications of otitis media, allergies, rubeola, and tonsillitis) and one for furuncles. Most of the children had taken the drug of three or more episodes of illness, and also received other antibiotics. The total dosage for all courses of treatment was estimated to be 1-15 g. The time interval between the last ingestion of chloramphenicol and the clinical onset of aplastic anemia was as follows: not stated in two; 2_31/2 months in four, and in four others, previously treated with chloramphenicol, the symptoms of aplastic anemia occurred while taking the drug. "Six individuals, aged 15-34 years, three males and three females, all in the `aplastic anemia' category, received chioramphenicol. They were treated for ure- thritis (two), pharyngitis, a cold, pneumonia, and acne. Four had a single course of the drug with estimated dosage of 1-lOg; aplastic anemia followed in 1 week, 2 months, 3 months and 4 months. One had two courses with a total dosage of approximately 45 g, followed in one month by aplastic anemia. The remaining person had more than 50 g in small daily doses over a 5-month period terminat- ing with onset of aplastic anemia. "Three women, aged 35-54 years, had chloramphenicol. One, treated with sev- eral short courses of the drug for furuncles, had a diagnosis of anemia 6 months before treatment. The relationship of this anemia to the furuncles and to the manifestations of aplastic anemia 6 months after the furuncles is not clear. Two had chloramphenicol in the hospital following minor surgery 1 month and 6 months before onset of aplastic anemia. "Six individuals, aged 55-74, two men and four women, were treated with chloramphenicol. Three had only one course of the drug in a period of 5-10 days followed in 11/2, 2 and 3 months by aplastie anemia. The conditions treated were upper respiratory infection, virus pneumonia, and chest cold. Three persons had intermittent treatment over periods of 6-9 months with dosages estimated at 25-100 g. The conditions treated were chronic purulent bronchitis unresponsive to other drugs, chronic urinary tract infection in a person who had reacted adversely to other drugs, and chronic finger nail infection. "Five individuals, aged 75 years and over, four men and one woman, received chloramphenicol for chronic respiratory symptoms, pneumonia, and urinary tract infections. In three cases dosage and dates were not stated. One man re- ceived a total of about 28 g over a 21-month period and had evidence of aplastic anemia 2 months after last treatment. Another received 22 g in two courses with- in a 2-week period and developed symptoms of aplastic anemia 2 months later." The 30 study deaths with chioramphenicol exposure differed epidemiologically from the 108 study deaths without record of chloramphenicol. 1. The chloramphenicol-exposed group was younger than the remainder of the study sample. The average age for the 30 chioramphenicol-exposed deaths was 35.6 years and for the 108 not so exposed, 52.2 years. 2. The average time between clinical onset of blood dyscrasia and death was shorter among those exposed to chloramphenicol than among those not so exposed-an average of 3.1 months for those with chloramphenicol compared to 7.3 months for those without chloramphenicol. 3. There was a concentration of cases with clinical onset in the months of April and May among persons exposed to chloramphenicol (Fig. 5). This peak af- PAGENO="0559" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2693 Total Study Somple With Chioratuphenicol * Without Chlorwnphcnicol 11A1'I.ASTIC ANEMIA CATEGORY 241 *24 221. 22 1 ~o . 10 Z 8 8 6. / \ 6 / 4 / 4 2 / 2 0 L_._.J_..__L_~___________ ~. 0 >~ ~ ~. `7 ~ ~ `7 ,0 ~ tO Fia. 5. Study sample and `aplastic anemia' category with and without chioram- phenicol by month of onset. fected all ages but was more pronounced in the young. There was no such con- centration by month of onset at any particular time of year among persons not exposed to chioramphenicol. The above three findings suggest that cases of aplastic anemia associated with chloramphenicol constitute a rather distinct entity. Characteristics of use of chlorarnphenicol Before onset of blood dyscrasia.-The salient features of chioramphenicol usage among the group studied can be summarized as follows: The drug had been used for a variety of conditions ranging from acne to life-threatening staphylococcal pneumonia. It was most commonly employed for non-hospitalized patients, with- out prior bacteriological studies or drug sensitivity tests, and without blood studies. Phe only two persons reported to have had bacteriological identification of the causative organisms (staphylococcus) also had sensitivity tests indicating sensitivity to other antimicrobial drugs as well as to chloramphenicol. As far as could be ascertained from hospital records only two of the 30 persons who received chioramphenicol had blood counts during treatment with the drug. Of the 30 persons who received chloramphenicol during the six months before the onset of the blood dyscrasia, 12 received two or more courses. Another 12 received only one course of 10 days or less. The remaining six received chioram- phenicol as follows: one continuously for 5-6 months, one intermittently for 6 months, one intermittently for 7-9 months, one intermittently for 8 months, one a "long course" and one an unknown amount of unknown duration. STUDY 5A~1?LE ...~..\ 11,1' C ~-, `.~` ~. > ~ " .0 ~t o tO tC PAGENO="0560" 2694 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY After onset of blood dyscrasia.-The manner in which chioramphenicol was used in the study sample after onset of blood dyscrasia was also observed. In view of widespread medical information on the toxicity of chioramphenicol for bone marrow, it is of interest that 24 of the 138 study cases received treatñient with chioramphenicol after the onset and diagnosis of blood dyscrasia. Twenty of these cases were in the "aplastic anemia" category, two in the "other blood dys- crasias" category, and two in the "undiagnosed" category. Recurrent life-threaten- ing infections are a major problem in the treatment of aplastic anemia. The severity of the chioramphenicol-treated infections in the study sample is sug- gested by the fact that eight persons were infected by Stapl~ylococous and seven by Pseudonionas. It is clear that the medical basis for treatment of in- fections following onset of blood dyscrasias differed strikingly from that of in- fections preceding blood dyscrasias. Eighteen of the 24 persons had bacteriological identification of the causative microorganism, and also had antibiotic sensitivity tests. In 10 the organism was sensitive to chloramphenicol and to one or more of the other commonly used anti- biotics; in three the test results were not in the medical records. In no case was it stated that chioramphenicol was the only drug to which the organism was sen- sitive. Half of the 24 patients treated with chloramphenicol during the course of their blood dyscraisia did not receive the drug until the last two weeks of life, several not until the last day of life. In some cases the risk of chloramphenicol to already severely depressed bone marrow was recognized by the physician and was considered to be less hazardous than treatment of the infection with a pos- sibly less effective antibiotic. In those 12 cases treated with the drug only in the last two weeks of life, the prognoisis was grave in all cases. Those persons re- ceived it for only one day in 8 cases, for 2-3 days in 3 cases, and for 7 days in one case. Among the persons who received chloramphenicol earlier than 2 weeks before death two persons received three courses, in one case totalling 7 days and in the other 25 days. The person treated most extensively with chlorampheni- col after onset of blood dyscrasia received four courses, two of 10 days each, one of 20 days and one of 4 weeks, beginning 22 months before his death. Since all of the study cases terminated fatally regardless of the nature of treatment, it is im- possible to assess the effect of chloramphenicol on the course of the blood dys- crasia. Only 3 of the 24 persons who received chloramphenicol after onset of a blood dyscrasia had also received it in the 6 months preceding onset of the blood clys- crasia. On additional two persons received it about 8 and 12 months before onset of blood dyscrasias. Estimate of risk of chloranipheaicol-assocjated fatal aplastic anemia The number of deaths from aplastic anemia associated with chloramphenicol between 1957 and 1960 was estimated in the following way. The number of study cases in the first 3~ years was multiplied by three since a 1-in-3 random sample of all reported deaths were reviewed. Estimated aplastic anemia deaths for this period were 40, corrected for rounding in the sample. Since a 100 per cent sample of deaths was studied in the last half of 1960, the estimated n~imber 4, is actually the sample value for that period. Thus, it is estimated that a total of at least 44 aplastic anemia deaths with recorded exposure to chlorainphenicol oc- curred in the 4-year period 1957-1960. On the basis of sales data provided by the manufacturer and on the assumption that 4 g. of chloramphenicol was an average course of treatment, the number of persons in California receiving chloram- phenicol in the study years was also estimated. The ratio of the estimated number of persons with aplastic anemia who had received chloramphencol to the number of persons receiving the drug in California indicates the risk of fatal aplastic anemia among persons treated with chloramphenicol to be 1:60,000. This estimate of risk is believed to be conservative for two reasons. (1) The number of deaths from aplastie anemia associated with chloram- phenicol is probably underestimated due to (a) exclusion of out of hospital deaths from the study; and (b) incompleteness of hospital records on prior drug administration. (2) The number of persons in the general population receiving the di~ug is probably overestimated since (a) available sales figures are not restricted to chloramphenicol prescribed by physicians but also include drug use by veterinarians; and (b) the 4 g dosage used in these calculations is lower than the 10 g estimate generally believed to be the actual dosage administered. PAGENO="0561" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2695 COMMENTS This study was carried out at the request of the California State Legislature be- cause of concern with potential hazards to the p~iblic health from chloram- phenicol and other antibiotic drugs. Prior to this study the evidence of an associa- tion between chioramphenicol and aplastic anemia consisted of clinical case re- ports, the Food and Drug Administration surveys, the American Medical Asso- ciation's Blood Dyscrasia Registry, and pathological findings of suppression of bone marrow function by chioramphenicol. Concomitant with this study a statisti- cal investigation was carried out; a significant statistical correlation was found between the volume of chioramphenicol sales and the number of reported aplastic anemia deaths. This study, based on a random sample of reported aplastic anemia deaths, showed a more frequent association with chloramphenicol than with any other drug or agent with a risk of aplastic anemia of at least 1:60,000 persons treated. No single piece of evidence establishes a definitive link between chloram- phenicol and aplastic anemia. However, all findings point in the same direction and, combined, strongly s~iggest that cliloramphenicol is causally related to aplas- tic anemia. The study data reveal that during the time period covered by the study, in many instances chloramphenicol was used injudiciously for conditions in which another medication would have been equally effective. Chioramphenicol was rarely used according to the criteria recommended by the American Medical Association's Council on Drugs, the American Academy of Pediatrics, the Food and Drug Administration and many eminent medical authorities. Since periodic blood counts can not be relied on to detect signs of bone marrow toxicity before irreversible aplastic anemia develops, then judicious use of the drug must be depended on to minimize the toxie effects. Judicious use prohibits it for prophylaxis, for trivial conditions, and for infections in which a less dangerous drug may be equally effective. SUMMARY A study of reported aplastic anemia deaths in California indicates that there were at least 30 cases with exposure to chioramphenicol among 138 deaths com- prising a random sample of deaths attributed to aplastic anemia during 1957- 1961. Exposure to chloramphenicol occurred with greater frequency than expo- sure to any other single agent. It is conservatively estimated that the risk of fatal aplastic anemia in persons receiving chloramphenicol is 1: 60,000; prob- ably the risk is much greater. Examination of the indications for use of chloram- phenicol and the controls on its use, as reported in the hospital records of the persons who subsequently died of aplastic anemia, suggests that chioramphenicol was used often for minor conditions where its potential advantage over other means of treatment was dubious. Acknowledgnvents.-Valuable assistance was provided by Lester Breslow, M.D., and William H. Clark, M.D., as consultants in epidemiology; William R. Ga~ey, Ph.D., and Florence Morrison, MA., as statistical consultants; and Ruth C. Steinkamp, M.D., as consultant in hematology. [From Prescribers' Journal, 4 : 2, 1964, pp. 2-5] CHLORAMPHENICOL (By Maxwell M. Wintrobe, M.D., College of Medicine, University of Utah, Salt Lake City) The Registry on Blood Dyscrasias of the American Medical Association began to collect reports of blood dyscrasias associated with consumption of drugs and exposure to various other potentially toxic agents in 1955. By June, 1963, a total of 1,484 reports had been received, chiefly from physicians in the United States. In addition, 550 reports had been gleaned from medical journals published out- side the United States, thus providing a total of 2,034 reports. The total number of drugs and chemical substances mentioned in these reports was 463. In considering the above data it must be recognized that (1) they probably represent only a small fraction of the blood dyscrasias which have occurred in association with exposure to various drugs and chemical substances. Reporting has been voluntary and has not depended even on a systemic or organized cam- 81-280 0-68-pt. 6-36 PAGENO="0562" 2696 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY paign to encourage physicians to report to the Registry; and (2) not all in- stances of blood dyscrasia associated with the taking of some drug or other chemical agent necessarily represent true cause and effect relationships. In some instances the association may have been purely coincidental. It is noteworthy, nevertheless, that of the above-mentioned 2,034 reports, 407 were associated with consumption of chioramphenicol. In 171 instances this was said to be the only drug to which the patient had been exposed. In an addi- tional 33 cases, another drug had been taken which was not considered to be potentially harmful and in 133 cases the potential toxicity of the drugs taken in addition to chioramphenicol was uncertain. Only in 70 instances was the asso- ciated drug thought to be potentially toxic. It can hardly be denied that data such as these make chioramphenicol suspect as a possible cause of blood dyscrasia. It is especially significant that of the 171 instances in which only chioramphenicol had been taken, the blood dyscrasia observed was aplastic anaemia, with~ pancytopenia, in 128; in an additional 18 cases there was erythroid hypoplasia without pancytopenia. Only in 7 cases was thrombocytopenia, without change in red or white cells noted, and only in 16 instances was leucopenia or agranulocytosis observed. This disproportionate incidence of aplastic anaemia is probably very significant. Were these occurrences only a matter of coincidence, one would have expected that the number of cases in the various categories of reported dyscrasias asso- ciated with exposure to a single agent would have been similar to the incidence of * various dyscrasias in the whole series. The data for the whole series of more than 2,000 reports are- Percent Aplastic anaemia with pancytopenia 31.4 Thrombocytopenia 15.5 Leucopenia or agranulocytosis 38. 1 Erythroid hypoplasia without pancytopenia 4.1 Haemolytic anaemia 5.8 Megaloblastic anaemia 2. 5 Miscellaneous 2. 6 Total 100.0 In contrast to these figures, it is to be noted that of the blood dyscrasias asso- ciated with chloramphenicol 74.9 per cent were reported as cases of aplastic anaemia with pancytopenia. Aplastic anaemia is the most serious of the blood dyscrasias associated with drug therapy: the mortality rate is in excess of 50 per cent and, even when recovery does take place, it is only after months or years of serious illness. Unfortunately, there are no adequate data by which one could estimate the likelihood of development of aplastic anaemia in association with exposure to chioramphenicol. However, even if the reports received represent only a very small fraction of the cases of aplastic anaemia which occur, in view of the wide use of this antibiotic the incidence must be assumed to be low. The mode of action of the drug in producing irreversible bone marrow injury also is unknown. A number of studies indicate that the administration of chioramphenicol in such doses that serum concentrations reach high levels is associated with (1) evi- dence of reduced utilization of iron for haemoglobin synthesis, as indicated by increase in serum iron and increased saturation of the iron-binding globulin; and (2) interference with the production or maturation of thhe erythroid cells, as indicated by vacuolation of erythroblasts, a progressive increase in the mye- bid: erythroid ratio in the bone marrow, and reticubocytopenia. There is also some evidence that (3) modest reduction in the number of platelets; and (4) vacuo- lization of marrow granulocyte precursors and leucopenia may take place. These changes, observed in human subjects, have been reversible. It remains to be determined whether the same or a different mechanism, perhaps one depending on a subtle congenital abnormality in the metabolic handling of chloramphenicol, is involved in the development of severe and irreversible aplastic anaemia. It is interesting that in a number of reported cases, bone narrow damage w-as observed after the second or third exposure to chioramphenicol, rather than following the first. No clear association with the amount of drug consumed has been observed. Paradoxically, in many instances of aplastic anae- mia, the use of the drug could not have been justified on the basis of the recog- nized primary indications for the administration of chboramphenicol. PAGENO="0563" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2697 The lessons to be learned The observations concerning chioramphenicol described above do not justify prohibition of the use of this valuable antibiotic. However, certain limitations are indicated. Similar limitations apply to therapeutics in general. 1. Many modern therapeutic agents are potentially very valuable-but they are also potentially harmful. 2. The indiscriminate use of a potentially toxic therapeutic agent in the absence of a clearcut indication is not justified. 3. A shotgun should not be used when a rifle would be better. An exact diagnosis permits the use of a specific agent instead of a "wide spectrum" therapeutic agent which the physician hopes will bring down the target he cannot see. 4. A cannon should not be used to kill a mouse. The risks involved in the use of a therapeutic agent should be weighed against the seriousness of the disease to be treated and the possibility of treating the condition with another agent which is less potentially toxic should be considered. 5. The physician must at all times be alert to the possible occurrence of an adverse reaction. 0. Specifically, with reference to chloramphenicol, it would seem wise to restrict the daily oral dose to approximately 30 rng. per kg. body weight and to limit the course of therapy to 14 days. It has been suggested, hut not proved that, when higher doses must be used, or therapy must be prolonged or repeated, serum iron and iron-binding capacity and reticulocyte counts may be found to give warning of impending trouble. [From the Journal of the American Medical Association, May 11, 1964, vol. 188, No. 6, pp. 531-532] DRUG-INDUCED BLOOD DYCRA5IA5 I. APLASTIC ANEMIA (By Allan J. Erslev, M.D. Philadelphia*) Aplastic anemia is a frequent manifestation of drug toxicity, and is charac- terized by pancytopenia and a fatty hypoplastic bone marrow.1-3 It seems be~t to restrict the term aplastic anemia to conditions in which the red marrow has been largely replaced by fatty tissue, although normal or even hypercellular foci occasionally may be present. A drug or chemical is believed to play an etiological role in about one half the cases reported. Chloramphenicol appears to be by far the most important of- fender,4 but publish'ed case reports and those sent to the Registry on Blood Dyscra- sias of the American Medical Association attest to the potential bone marrow toxicity of mephenytoin (Mesantoin), sulfonamides, phenylbutazone (Buta- zolidin), some insecticides and solvents, and many other compounds (Table). However, it is difficult to separate drug-induced from idiopathic cases, and un- fortunately there is no test which provides proof of an etiological relationship. Therefore, conclusions must be drawn on the basis of personal judgment and statistics, particularly since everyone in our industrialized society is exposed to potentially toxic chemicals. The characteristic signs and symptoms of severe pancytopenia are weakness and pallor, hemorrhage and ecchymoses, and a decreased resistance to infections. The demonstration of a pancytopenia in the absence of adenopathy, splenome- galy, bone tenderness., or evidence of an underlying disease strongly indicates a diagnosis of aplastic anemia. The crucial piece of evidence is the demonstration of a hypocellular fatty bone marrow. Bone marrow aspira~tions should be made *Dr. Erslev is Cardeza Research Professor of Medicine, Jefferson Medical College. 1 Huguley, C. M., Jr.: "Drug-Induced Blood Dyscraclas," In DM Disease-a-Month, Chicago: Yearbook Medical Publishers, Inc., October, 1963. 3 Scott, J. L.; Cartwright, G. B.; and Wintrobe, M. 1~L: Acquired Aplastic Anemia: Analysis of Thirty-Nine Cases and Review of Pertinent Literature, Medicine (Bait) 38: 119 (May) 1959. Harris, J. W.: Red Cell: Production, Metabolism, Destruction, Normal and Abnormal, Cambridge, Mass. : Harvard University Press, 1963. McCurdy, P. B.: Chloramphenlcol Bone Marrow Toxicity, JAMA 176: 588 (May 20) 1961. PAGENO="0564" 2698 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY from several sites and these examinations should preferably be supplemented by a bone marrow biopsy. The most important therapeutic measure is to suspect all drugs or chemicals in the patient's environment and, if possible, discontinue the exposure. Since recovery, whether spontaneous or in response to the removal of an etiological agent, is very slow, the goal of therapy is to prevent death from complications during the period of waiting. Transfusion should be given sparingly to maintain a hemoglobin level that is sufficient for reasonable activity. The prophylactic use of antibiotics is inadvisable, but the patient should be instructed to report promptly any symptoms or signs of infection. If infection develops, it should be treated quickly, vigorously, and persistently. Transfusion of fresh blood from donors with high leukocyte counts (chronic myeloid leukemia or myelofibrosis) has been claimed to be beneficial in severe infections.5 Likewise, fresh blood from donors with high platelet counts (polycythemia vera) may be helpful in counter- acting severe hemorrhagic episodes.° Testosterone7 in pharmacological doses, prednisone, and splenectomy occasionally have appeared to induce permanent remissions. DRUGS ASSOCIATED WITH APLASTIC ANEMIA All reports Sole agentl Total reports of aplastic anemia in Registry (through December 1963): 674. Chloramphenicol (Chloromycetin) 299 157 Sulfonamides (antibacterial): 2 Sulfamethoxypyridazine (Kynex Midicel) 12 3 Sulfisoxazole (Gantrisin) 28 3 Other 118 18 Sulfonamide derivatives (nonantibacterial): 2 Acetazolamide (Diamox) 10 3 Chlorothiazide (Diuril) 12 1 Chlorpropamide (Diabinese) 4 2 Tolbutamide (Orinase) 11 6 Analgesics: Phenylbutazone (Butazolidin) 34 16 Anticonvulsants: Mephenytoin (Mesantoin) 22 7 Trimethadione (Tridione) 5 2 Benzene 10 8 Other organic solvents 48 18 Insecticides: Benzene hexacholoride (Lindane) 13 7 Chlorophenothane (DDT) 19 3 Chlordane 12 4 Gold 10 8 1 Reports in which patient received listed drug either alone or with other presumably innocent drugs. 2 Risk of aplastic anemia from most sulfonamide derivatives is slight, but as a group they are frequently associated with development of aplastic anemia. Since the mortality rate, even in well-treated cases of aplastic anemia, is about 50%, the most appropriate approach is prevention. Aplastic anemia is obvi- ously a rare complication and in a serious illness the usefulness of a potentially toxic drug may far outweigh its possible harm. However, the mere awareness that certain drugs are prone to produce aplastic anemia should lead to caution in their use and to the institution of hematological safeguards; although the pathogenesis is still unknown, it appears that in some cases the reaction is reversible before the self-perpetuating, almost irreversible aplastic phase sets in. Therefore, patients who require treatment with these drugs should have a white blood cell count and differential, an estimation of platelets, a reticulocyte count, and a hemogloblin determination at the onset of treatment and at reasonable intervals thereafter. The results of these tetsts should give warning of early bone marrow injury and, if heeded, may result in a decrease in the incidence of fatal drug-induced aplastic anemia. ° Freireich, B. 3., et al.: Transfusion of Granulocytes From Donors With Chronic Mye- locytic Leukemia to Leukopenic Recipients, abstracted, J Olin Invest 41: 1359 (June) 1962. o Freireich, B. J., et a).: Response to Repeated Platelet Transfusion From Same Donor, Ann Intern Mcd 59: 277 (Sept.) 1963. Shahidi, N. T., and Diamond, L, K.: Testosterone-Induced Remission in Aplastic Anemia of Both Acquired and Congenital Types. Further Observations in 24 Cases, New Bag J Med 264: 953 (May 11) 1961. PAGENO="0565" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2699 GENERIC AND TRADE NAMES OF DRUGS Chloramphenlcol-Uhloromycetin. Phenylbutazone-Butazolidin. Testosterone-4ndroUn, Andronaq, Andrusol, Malestrone, Mertestate, Neo-Hombreol F, Oreton, Testrandrone, Testosteroid, Testrone, Testryl. Prednisone-Paracortol, St crane, Sterolone. Sulfamethoxyridazine-Kynex, Midicel. Sulfisoxazole-Gantrisin. Acetazolamide-Diamo~v. Chlorothlazld-Diuril. Chlorpropamide-Diabinese. Tolbutamide-Orinase. Trimethadlone-Tridione. {From Archives of Internal Medicine, November 1963, vol. 112, pp. 747-754] CHLORAMPHENICOL TOXICITY IN LIVER AND RENAL DISEASE (By Leif G. Suhrland, M.D., and Austin S. Weisberger, M.D., Cleveland*) Erythropoietic depression can be detected in patients receiving chlorampheni- col before any noticeable decrease occurs in peripheral blood values. Previous studies,12 have shown that an increase in serum iron content and an increased saturation of iron-binding globulin precedes the fall in hematocrit by an ap- pi~eciable interval in patients exhibiting toxic effects. These changes have been correlated with prolonged plasma clearance (T/2) of radioactive iron (Fe59), delayed appearance of Fe5° in circulating erythrocytes, and decreased marrow uptake of Fe59 as detected by external scanning. Utilizing these techniques it has been shown that erythropoietic depression due to chloramphenicol is more frequent than in general realized. Early detection permits dllscontinuatio~n of the drug before irreversible damage to the hematopoietic system occurs. The mechanism by which chloramphenicol produces erythropoietic depres- sion is unknown. There is evidence that the nitrobenzene moiety may be im- portant since replacement of the nitro group by a methylmercapto, a methyl- sulfonyl, or a sulfamoyl group results in increased erythropoietic toxicity.2-4 Other factors such as the amount and duration of therapy may be factors in producing toaxicity. Kunin, Glazko, and Finland5 have shown that the half life of chioramphenicol metabolites is increased in severe renal disease and in some patients with hepatic cirrhosis. The possible relationship of these observations to hematologic toxicity was not, however, investigated. The present study was undertaken to determine whether decreased excretion or impaired conjugation might be factors in producing erythropoietic depression. Accordingly, the incidence of erythropoietic depression was determined in patie~ts with either renal or hepatic insufficiently and correlated with alterations in serum concentration of chlorarnphenicol metabolites. It was found that there was a marked increase in the incidence of erythropoietic depression in both liver and renal insufficiency and that there was a significant increase in serum con- centration of free or active chioramphenicol in all patients developing hematologic toxicity. MATERIALS AND METHODS Sixteen patients with hepatic insufficiency due to Laennec's cirrhosis of the liver were studied. The diagnosis was established by clinical findings and con- firmed by laboratory evidence of impaired liver function. The ages ranged from 30 to 64 years with a mean age of 42 years. There were six white males, one Negro male, six Negro females, and three white females. Of these 16 patients, two had ascites, three had jaundice, four had both ascites and jaundice, and seven patients had neither ascites nor jaundice. Nineteen patients with chronic renal insufficiency were also chosen for study. All had hyposthenuria and blood urea nitrogen values of over 22 mg% but less than 70 mg%. All of the patients had chronic pyelonephritis associated with other *Received for publication April 12, 1963; accepted May 10. Presented in part at 44th annual session of the American College of Physicians, April, 1963. Assistant Professor of Medicine (Dr. Suhrland) ; Professor of Medicine (Dr. Weisberger). From the departments of medicine of Highland View Hospital and the University Hospitals of Cleveland, and from the School of Medicine, Western Reserve University. Supported by USPHS grant He 03952-05. NoTE-Numbered footnotes at end of article, p. 2706. PAGENO="0566" 2700 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY diseases such as diabetes, hypertensive cardiovascular disease, obpstructive urop- athy, or renal calculi, but none had any detectable liver disease. There were six white males, seven Negro males, four white females, and two Negro females in the group with ages ranging from 36 to 88 and a mean age of 56. Sixteen patients without renal or hepatic insufficiency were selected to match as nearly as possible the two previous groups insofar as age and sex distribution and degree of anemia. Four patients had hemiplegia, two patients had amputa- tion of the lower extremity secondary to arteriosclerosis obliterans, two patients had .osteomyelitis, four had paraplegia due to trauma, two had quadriplegia secondary to compression fracture of cervical vertbra, two patients had brain tumors. Chloramphenicol was administered orally in divided doses of 0.5 gm four times daily for a period of one month unless evidence of erythropoietic toxicity as previously defined was detected.2 Before administering the drug, two initial blood samples were obtained on separate days for peripheral blood and iron studies. Thereafter, samples were drawn once weekly during the study period with patients in a fasting state between hours of 8 AM and 9 AM. Routine blood cell counts were performed at weekly intervals. Serum iron, iron-binding globulin (IBG) saturation, and plasma clearance of ~ (T/2) and its appear- ance in the erythrocyte were determined by methods previously described.2'3 External scintillation counting was performed over the liver, spleen, and sacrum after Fe ~ administration. Bone marrow examinations were performed on all patients exhibiting toxic effects as determined by ferrokinetic data and on the majority of the patients included in the nontoxie group. Assa'y for elvioramphenicol and its metabolic products.-Free chioramphenicol and its chief metabolites were measured in the serifln and urine of 45 of the 51 patients included in this report by the following modifications of the methods of Glazko et al° and Levine and Fischbach.7 Arylamine Was determined by diazotization of 1.0 ml of an acid filtrate of serum (prepared by addition of three volumes of 4% trieliloroa'eeti'c acid to one volume of serum) with 2.0 ml of 0.5% N HC1 and 0.5 ml of 0.1% sodium nitrite. After five minutes, 0.5 ml of 0.5% ammonium sulfamate was `added and allowed to stand for three minutes and coupled with 0.5 ml of 0.1% naphthylethylene- dllamine hydrochloride. After incubation at 37 C for three hours, the purple color change was read at 555 m,u and compared with standards (100 mg/liter chlor- amphenicol, treated as for serum) after correction for undiazotized blanks prepared by substituting water for `sodium nitrite. Total nitro compounds were determined by the above procedure `after reduction of 1 ml acid filtrate with 1 ml titanous chloride (0.25% in 0.5 N HC1) for two minutes, followed by precipitation of the titanium by 0.5 ml of 1.4 N NaOH. Cor- rection was made for the preformed arylamine measured above. This fraction consists chiefly of free chloramphenicol plus that conjugated as the glucuronide. Extractable cliloramphenicol, hereafter referred to *as the "free" form and representing the microbiologically active form of the drug, waS m~asured by applying the above procedure for total nitro compounds to an extract ~n'ade by diluting 1 ml serum with 2 nil phosphate buffer (0.2 MpH 6.0), treating twice with 10 ml chloroform-ethyl acetate (3:1), `backwashing the extracts with 10 ml of the same buffer, evaporation of the extracts on a water bath, and resolution in 1 ml 1% tricliloroacetic acid. Urine was assayed in the Same manner as serum after a 20-fold dilution. Criteria for erythropoietic depression.-Patients were `classified as exhibiting either definite erythropoietic depresSion (toxic) or no signifl~ant depression (nontoxic) on the basis of ferrokinetic studies as well as on the basis of changes in the peripheral blood. A significant rise in serffin iron, increase in iron-building globulin (IBG) saturation, prolongation of plasma clearance of Fe59, delayed appearance of F&° in erythrocytes, and decreased marrow uptake of F&9 were considered evidence of erythropoietic depression. The criteria for considering the changes in these parameters significant of toxicity were essentially the same as those described in a previous publication.2 The ferrokinetic changes were cor- related with a decrease in reticu'locyte count and a subsequent fall in `hemo- globin and hematocrit values. The appearance of vaculoated erythroblasts in the marrow was considered further evidence for toxicity but was not relied upon as the sole criterion. PAGENO="0567" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2701 RESULTS Employing the criteria previously outlined, erythropoietic depression was demonstrated in eight of 16 patients (50%) with hepatic insufficiency and six of 19 patients (32%). with renal insufficiency (Table 1). No erythropoietic depres- sion or toxicity was demonstrable in 16 patients without hepatic or ren'al in- sufficiency. In the patients with liver disease erythropoietic depression occurred in seven of nine patients (18%) with either ascites or jaundice and in all four patients with both ascites and jaundice (Table 2). TABLE l.-INCIDENCE OF ERYTHROPOI ETIC DEPRESSION Condition Number Number toxic Percent toxic No liver or renal disease 16 0 0 Renal disease 19 6 32 Liver disease 16 8 50 TABLE 2.-ERYTUROPOIETIC DEPRESSION IN LIVER DISEASE Signs Number Number toxic Ascites 2 1 Jaundice.~.T.. 3 2 Ascites and jaundice 4 4 No ascites or jaundice 7 1 Total 16 8 The duration of treatment of the patients showing toxic effects varied from 10 lays to 28 days. In the majority of the patients chloi~amphenicol was discon- tinued after the second week of therapy with a mean time of 18 days for all patients showing toxic effects. Only one patient in this group received chioraphen- icol for the full 28 days. The changes in serum iron and per cent `saturation of IBG are summarized in Table 3. The initial value represents the average of two determinations obtained on separate `days. In both toxic groups there Was `a significant rise in serum iron accomg~anied by a marked increase in per cent saturation of IBG. This in- crease in per cent saturation of IBG in the toxic groups represented an `absolute change of 64% over initial values. In the nontoxic groups with liver or renal dis- ease slight increases in serum iron and per cent saturation of IBG were observed, but the mean changes in per cent saturation of IBG were less than 15% over initial values. Ferrokinetic `studies with Fe°~ demonstrated a prolonged p1~sma clearance time (P/2) and a delay in the appearance of the Fe5° in RBC in both toxic groups (Fig 1 `and 2). After six days maximum `amounts of radioactivity LIVER son.Toxlc / RENAL NON.TOXIC / -, r~ ~ -/ /s' ~ I I I 1 I 1 1 75 100% 7$ so 25 10 HOURS Fig 1.-The mean plasma clearance time, T/2. T/2 for nontoxic patients was 65 minutes; for renal disease with toxicity, 140 minutes, and for liver dis- ease with toxicity over 240 minutes. as 25 5 4 6 g 5~ 15 14 56 1* 25 DAYS Fig 2.-The mean appearance time of radioiron in circulating RBC. Both the liver and renal non- toxic groups have normal appearance times with maximal amounts of Fe°° present after six-seven days. The delayed appearance of radioiron in the toxic groups is shown with maximal amounts of Fe59 not reached for 16-18 days. PAGENO="0568" 2702 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY appeared `in the red cells in the nontoxic groups, but in the toxic groups maximum radioactivity did not appear until after 16 days. TABLE 3.-SERUM IRON AND PERCENT SATURATION OF IBG I Number Mean serum Fe (jig percent) Mean IBG saturation, percent Initial Maximum Initial Maximum Liver disease: Toxic group Nontoxic group Renal disease: Toxic group Nontoxic group No liver or renal disease: Nontoxic 8 8 6 13 16 78±45~ 286±74 77±43 127±32 47±26 240±68 51±21 89±35 97±45 131±54 27±13 91± 8 25±11 i~9±10 20±14 84±16 18± 9 30±11 30±13 39±19 I Iron-binding globulin. Changes in perijiheral blood values of the toxic and nontoxiic groups are shown in Table 4. The toxic group in patients tsviith liver disease had ti mean fall in hema~tocrit of 8%, and the toxic group with renal disea~e showed a mean decrease of 5%. The hematocrit values of patients comprising the i~ontox*ic groups did not change significantly. The reticulocyte counts of all groups decreased under treat- ment, but the n~agnitude of the fall in `both toxic groups iv~as greater than in the patients without erythropoietic depression. It should be nOted that the mean control reticulocyte ooun*ts of patients with liver and ren~il disease were more than twice the value in patients without liver or :renal disease. TABLE 4.-PERIPHERAL BLOOD CHANGES IN CHLORAMPHENICOL TOXICITY Hematocrits Reticuloc yte counts Control value Lowest on drug Control value Lowest on drug Liver disease: Toxic Nontoxic Renal disease: 35±5.8 41±3.3 27±5.7 40±5.4 1.7±0.4 1.7±0.4 0.4±0.2 0.9±0.3 Toxic Nontoxic No liver or renal disease 38±6. 8 33±4.7 43±4. 0 33±8.6 31±5.2 41±3. 8 2. 1±0.3 1.6±0.3 0. 8±0. 3 0.6±0.2 1. 0±0.2 0.9±0. 3 The blood levels of "free" chloramphenicol, total nitro compounds, and arylamines were measured Lu all but one patient in each of the hepatic and renal insufilciency groups and in 12 of the 16 patients without renal or liver disease. The serum levels of "free" chloramphenicol are summarized in Table 5. In the groups of patients without renal or liver disease and showing no erythropoietic depression, serum "free" chloramphenicol ranged from 0 to 3.4~cg/ml with a mean of 1.2~g/ml. In the patients with liver or renal disease but no erythropoietic depression, serum "free" chloramphenicol ranged from 2.0~cg to 12.0~cg/ml with a mean of 3.9~g/ml. In five patients with renal disease and erythropoietic de- pression, serum "free" chloramphenicol ranged from 15.O~sg to 25.0~g/ml with a mean of 20.3~cgJml. Serum "free" chloramphenicol concentration in the eight patients with liver disease and toxicity were 8.0~cg to 3O.0~cgjml with a mean of 19.Ojsg/ml. Standard deviations are shown, and the differences in serum "free" chioramphenicol values between the groups without erythropoietic depression and the liver and renal disease groups showing erythropoietic toxicity are statis- tically significant with a P value of less `than 0.005. No correlation could be drawn between hematologic toxicity and serum levels of total nitro compounds or arylamine (Fig 3, a and b). PAGENO="0569" - . . . . : . . * . *.~ . - . *. . S . . . S *S* ..&.P. S.. SsS .S~. me~ TOXIC $014 TOXiC LIVER AND RENAL DISEASE - . S I $ *~. S mean . S. ~ S S S. * . m*m~ S I. I I. ~___ TOXIC NON TOXIC LIVER AND RENAL DISEASE TABLE 5.-SERUM LEVELS OF "FREE' CHLORAMPHENICOL Fig 3.-A, Maximum serum levels of free chloramphenicol. Distri.. bution of serum free chioramphenicol levels in liver and renal disease. Only one patient in the nontoxic group has a se- rum level of over S~ug/ ml. B, Maximum serum levels of total nitro com- pounds. Lack of correla- tion between total nitro compounds and toxicity. The slightly higher mean value in the toxic group is due to elevated levels of free chloramphenicol. Patients Range, serum level pg/MI Mean, p/MI SD No liver or renal disease: Nontoxic 0-3. 4 1.2 ±0. 7 Renal and liver disease: Nontoxic 2. 0-12. 0 3. 9 ±2. 4 Renal disease: Toxic Liver disease: Toxic 15. 0-25. 0 8. 0-30. 0 20. 3 19. 0 ±4. 8 ±7. 7 Between nontoxic and toxic groups P<0.005. The correlation between the rise in serum level of "free" chlorasnpenicol and the rise in serum iron in one patient with liver disease is shown in Fig. 4. Chior- amphenicol in a daily dose of 2.0 gm was administered for 14 days and produced a continual rise in serum "free' chioramphenicol to 30.4ug/ml. Paralleling this increase in "free" chlorainphenicol the serum iron rose from 38~cg% to a high of 332JLg%. During this period the hematocrit did not change appreciably and fell to significnnt levels only after the drug had been discontinued. Also after cessation of chloramphenicol administration, the serum iron propmptly returned to pretreatment levels. The reticulocyte count, not shown, fell to a low of 0.2% on day 15 but rose `to 7.0% six days after chioramphenleol was discontinued. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2703 A ~ 20 .cg./.l. 15 l0 5 0 B6° so 20 10 0 PAGENO="0570" 2704 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Fig 4.-In a patient with liver disease and tox- icity, the relationship be- tween increase in serum iron and free chloram- phenicol is demonstrated. The hematocrit did not change signifitantly until one week after the drug had been discontinued. The data demonstrate that an increased incidence of erythropoietic depression due to chioramphenicol occurs in patients with hepatic or renal insufficiency. In patients with liver disease the toxicity appears to be correlated with the degree of hepatic damage. Thus, a much higher frequency of toxicity was observed in patients with either jaundice or ascites than in those without these complications. Furthermore, erythropoietic depression occurred in all patients with both jaun- dice and ascites. No direct correlation was observed between the degree of nitro- gen retention and incidence of erytliropoietic depression. It should be noted that administration of chloramphenicol was discontinued as soon as a significant rise in serum iron level was observed and before any evidence of erythropoietic depression could be detected in the peripheral blood. Accordingly, one might an- ticipate a greater degree of toxicity in these patients if administration of chlor- amphenicol had been continued for a longer period of time. In addition, the amount of drug administered per patient represents a comparatively low dos- age schedule. If larger amounts of chloramphenicol had been used, a much higher incidence of toxicity could have been anticipated. Drug hypersensitivity did not seem to be a factor since previous exposure to the drug had no relationship to the development of toxicity. Furthermore, three patients who had recovered from erythropoietic depression were `treated with small daily doses of 250 mg for 28 days. There was no evidence of `toxicity in this group. It is apparent that the toxicity of the free drug and its metabolic products differ. Thus, there was a lack of correlation between arylamine, the monoglu- curonide metabolites, and erythropoietic depression. In every instance erythro- poietic depression was correlated with a high free chloramphenicol serum level. This suggests that those who developed toxic effects were either unable to con- jugate at a normal rate or unable to excrete the free form of the drug. MeCurdy has obtained similar results on the correlation between bone marrow depression and elevated levels of free chloramphenicol in serum or plasma.8 In this report toxicity was defined by reticulocytopenia and abnormal vacuol'ated blast cells in the bone marrow. The elevated mean plasma level of free choram- phenicol found six-eight hours after a dose of the drug was quite similar to our mean values in spite of different dosage schedules and routes of administration. The meta'bolites were not measured. It should be emphasized that the blood samples in the present report were drawn 10-12 hours following the last dose of LETEU OF FREE' CILORARPRIRICOL, I IRON AIR IEIATOCRIT II TOXICITY a I * 0 a 2 DAYS cHLORAMPHEHICOL 500 450 400 350 250 200 150 100 50 2 4 6 8 10 12 14 16 .18 20 22 I COMMENT PAGENO="0571" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2705 the drug with the patients in a fasting state. This tended to minimize fluctuation in serum iron due to diurnal variation and changes in chloramphenicol blood levels due to difference in rate of absorption from the gastrointestinal tract. The reason for the correlation of erythropoietic depression with high free chlorapiphenicol levels is not known. Studies on the mechanism of chioramphenicol toxicity in vitro have, in general, revealed no effect on immature erythrocytes or bone marrow function unless levels far exceed those found in the blood when therapeutic doses of the drug are employed.9'10 The amount of chloramphenicol re- quired to produce in vitro depression far exceeds the levels observed in this study. Although protein synthesis by bacterial ribosomes in cell-free systems is readily inhibited by chioramphenicol, mammalian ribosomes are not affected by remark- ably high concentrations of chloramphenicoL~'12 This biological difference makes it possible to use chloramphenicol advantageously in the treatment of bacterial infections. However, chloramphenicol probably does have some effect on hemo- globin synthesis since the drug blocks the reticulocyte response in patients with pernicious anemia receiving cyanocobalamin (vitamin B12) and also prevents the reticulocyte response to iron in patients with iron deficiency anemia.13 Since patients with liver disease and renal disease are known to have a shortened erythrocyte life-span and an inadequate marrow compensatory activity, chlor- amphenicol might be expected to induce anemia with greater frequency in these patients. However, bone marrow function as reflected by peripheral blood values did not appear to be a factor in the development of toxic effects. The manner in which chioramphenicol affects hemoglobin synthesis in im- mature celisis not known. Preliminary experiments indicate that chloramphenicol may interfere with the deposition of messenger ribonucleoprotein on the ribosomes of mammalian reticulocytes.'~ Whether these observations are related to the pro- found changes that occur in iron metabolism is still speculative. Nevertheless, the serum iron is a sensitive index of early toxic effects and often begins to rise three- four days after beginning treatment. Similarly when the drug is stopped, the serum iron promptly returns to pretreatment levels. These changes in serum iron and per cent saturation of IBG are consistent and may represent a specific bio- chemical lesion produced by the drug. The majority of the patients who did not develop toxic effects did show slight elevation in serum iron during treatment, but these were not sufficient to be interpreted as being significant of toxicity. In addition, other bone marrow depressants such as radiation, alkylating agents, and antimetabolites do not produce a consistent elevation of serum iron and per cent saturation of IBG. The relationship of erythropoietic depression to aplastic or hypoplastic states associated with chloramphenicol remains unknown. However, it is reasonable to assume that the erythropoietic depression observed in this study represents a reversible stage in the development of aplastic anemia that is usually irreversible. Therefore, in severe renal or liver disease chloramphenicol should be used with caution and followed carefully with frequent, serum iron and reticulocyte counts. If possible, determination of free chloramphenicol in the serum would be an additional safeguard. In liver disease the presence of both ascites and jaundice or other evidence of severe parenchymal damage constitutes a contraindication to the use of this drug. SIJMMARY In 16 patients with liver disease treated with chioramphenicol eight developed erythropoletic depression. In this group with liver disease, the frequency of toxic effects was markedly increased in the presence of both ascites and jaundice. In 19 patients with moderately severe renal disease six showed signs of toxic effects. A group of 16 patients without renal or liver disease showed no evidence of bone marrow toxic effects. An elevated level of serum free chloramphenicol was found in all instances of erythropoietic depression. There was no correlation between the metaoblic prod- ucts of chloramphenicol and toxicity. Drug hypersensitivity did not appear to a factor in the development of erythropoietic depression. Mrs. Janet Bullinger provided technical assistance, and Dr. Robert Greenway aided in serum iron and chioramphenicol determination. Leif G. Suhrland, M.D., Highland View Hospital, 3901 Ireland Dr., Cleveland 22, Ohio. PAGENO="0572" 2706 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY REFERENCES 1Rubin, D.; Weisberger, A. S.; Botti, R. E.; and Storaasli, J. P.: Changes in Iron Me- tabolism in Early Chioramphenicol Toxicity, J Clin Invest 37: 1286, 1958. 2Rubin, D.; Weisberger, A. S.; and Clark, D. R.: Early Detection of Drug Induced Erythropoietic Denression, J Lab Clin Med 56: 453, 1960. Suhrland, L. el., and Weisberger, A. S.: Hematologic Toxicity of a Chloramphenicol Analogue, Amer J Med Sd 244: 54, 1962. `Jiji, H. M.; Gangarosa, E. J.; and de la Macorra, F.: Chioramphenicol and Its Sul- famoyl Analogue, Arch Intern Med 111: 70, 1963. 5Kunin, C.; Glazko, A. J.; and Finland, M.: Persistence of Antibiotics in Blood of Patients With Acute Renal Failure: II. Chloramphenicol and Its Metabolic Products in the Blood of Patients With Severe Renal Disease or Hepatic Cirrhosis, 3 Clin Invest 38: 1498, 1959. Glazko, A. 3.; Wolf, L. M.; and Dill, W. A.: Biochemical Studies on Chloramphenicol: I. Colorimetric Methods for the Determination of Chloramphenicol and Related Nitro Com- pounds, Arch Biochem 23: 411, 1949. 7Levine, J., and Fischbach, H.: The Chemical Determination of Chloramphenicol in Biological Materials, Antibiot Chemother (NY) 1: 59, 1951. 8McCurdy, P.: Plasma Concentration of Chloramphenicol and Bone Marrow Suppres- sion, Blood 21: 363, 1963. 9Yunis, A. A., and Harrington, W. J.: Patterns of Inhibition by Chloramphenicol of Nucleic Acid Synthesis in Human Bone Marrow and Leukemic Cells, 3 Lab Clin Med 56: 831, 1960. `°Borsook, H.; Fischer, E. H.; and Keighley, G.: Factors Affecting Protein Synthesis in Vitro in Rabbit Reticulocytes, J Biol Chem 229: 1059, 1957. U Allen, E. H., and Schweet, R. S.: Synthesis of Hemoglobin in a Cell-Free System: I. Properties of the Complete System, J Biol Chem 237: 760, 1962. `~ Von Ehrenstein, G., and Lipmann, F.: Experiments on Hemoglobin Biosynthesis, Proc Nat Acad Sc! 47: 941, 1961. `~ Said!, P.; Wallerstein, R. 0.; and Aggeler, P. M.: Effect of Chloramphenicol on Erythro- poiesis, J Lab Clin Med 57: 247, 1961. "Weisberger, A. S., and Wolf, S.: Unpublished observations. [From the Journal of the American Medical Association, July 27, 1963, vol. 185, No. 4, pp. 273-279] THE USE AND ABUSE OF THE BROAD SPECTRUM ANTIBIOTIC (By Edwin M. Ory, M.D., and Ellard M. Yow, M.D., Houston) (From the Department of Medicine, Baylor University College of Medicine, and the Ben Taub Infectious Disease Research Laboratory, Jefferson Hospital) The term "broad spectrum antibiotics" was originally used to designate anti- biotics that were effective against both gram-positive and gram-negative bacteria, in contrast to penicillin, which is effective chiefly against gram-positive orga- nisms, and streptomycin, which is active primarily against gram-negative bac- teria. The broad spectrum antibiotics have an antimicrobial spectrum which includes some gram-positive and some gram-negative organisms. as well as certain rickettsiae, larger viruses, protozoa, and pleuropneumonia-like organisms. Al- though the antimicrobial spectra of other antibiotics vary in their breadth of coverage, this article will be limited to a discussion of the tetracyclines and chioramphenicol. Tli e Tetracyclines There are four basic tetracyline homologues. The first two were prepared entirely by fermentation methods. Chlortetracycline hydrochloride was isolated from Streptornyces aureofaciens by Duggar' in 1948 and oxytetracycline, produced by S rimOsas, was introduced in 1950. Tetracycline was prepared by catalytic hydrogenation of the chlorine radical and introduced for clinical use in 1953. Demethylchlortetracycline, produced by a mutant of Duggar's original strain, was described in 1957 2 and was introduced for clinical use in 1959.36 Many other homologues of the tetracyclines have been produced and some are under investi- gation.' However, none of these is available yet for clincial use. Various additives and combinations have been developed and marketed. It is claimed that they increase absorption, reduce gastrointestinal irritation, prevent overgrowth of Candida (Monilia) and other fungi, and are synergistically active against bacteria. In general, such effects are either minor or negligible and have been exaggerated in the promotion of the various preparations.8 Fixed combina- tions of tetracyclines with other antibiotics rarely offer a therapeutic advan- tage, for the second antibiotic in such combinations is usually present in smaller N0TE.-Numbered footnotes at end of article, p 2714. PAGENO="0573" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2707 than therapeutically effective quantities and there are no known specific indica- tions for fixed combinations of antibiotics. In addition, the incidence of side effects and the expense to the patient is sOmetimes increased when mixtures are used. In general, all of the tetracyclines have the same antibacterial spectrum when each tetracycline is tested against individual strains of organisms. In most in- stances, when an organism is resistant to one tetracycline it will be resistant to the other homologues.° Pharmacology The tetracyclines are incompletely absorbed from the gastrointestinal tract 8 and large amounts can be recovered from the stools after oral administration.10 This property may contribute to the changes in fecal flora and anal irritation. Absorption is probably increased and higher blood levels are attained if the antibiotic is taken during the fasting state. On the other hand, some patients have less gastric irritation if the drug is taken after a meal. The tetracyclines are inactivated by the formation of chelates when they combine with metallic ions, chiefly calcium and magnesium, in the gastrointes- tinal tract. Because of this property, various preparations, including combina- tions with citric acid, a phosphate complex, sodium hexaphosphate, and gluco- saminic hydrochloride, have been developed. However, flO significant therapeutic superiority has been demonstrated by the use of these combinations. Aluminum hydroxide markedly reduces absorption.8' 11-13 The tetracyclines are absorbed by the stomach, duodenum, and ileum, but very little is absorbed by the colon. The distribution of the tetracyclines in body tis- sues and fluids varies slightly with each homologue.11' 12 The drugs are present in the milk of lactating women and pass through the placenta into the fetus; they also appear in the salvia, cornea, sciera, iris, and vitreous humor. Levels are lower in spinal fluid than in blood. The highest spinal fluid levels are obtained with tetracycline, the lowest with chiortetracycline, and inttermediate levels occur with oxytetracycline. The concentrations of chlortetracydine in the bile are 8 to 16 times higher than those in the blood. Demethylchlortetracycline is also con- centr~ited in the liver and bile.33 The drugs have an affinity for fast-growing tis- sues, liver, tumors, and areas of new bone formation. This property has recently been utilized in the development ofi a test for gastric carcinoma.34 Prolon1ged ad- ministration of the tetracyclines may produce a yellowish discoloration of the teeth.~ Tetracycline has been found to diffuse into ischeniic tissues in measurable amounts.4 10 17 The tetracyclines are bound to plasma protein in varying amounts. How- ever, the binding is reversible and may be one of the most important factors responsible for the differences in renal clearance rate among `the various tetra- cyclines. The principal mechanism of excretion is by the kidneys, probably by simple glomerular filtration. Kunin and associates18 have studied the excretion rates of the various homologues under various conditions of pH, urine flow, and renal function. They have shown that the half-life of tetracycline plasma levels is pro- longed and is increased in the presence of oliguria and renal failure. The half-life may increase from a normal value of 8 hours up to 108 hours in patients with renal failure. Ohlortetracycline is an exception; since it is rapidly inactivated in alkaline solutions at body temperature, its halMife is not significantly in- creased in the presence od renal failure.4 Adequate blood levels are obtained when tetracycline, oxytetracycline, and chlortetracycline are administered in doses of 250 to 500 mg four times daily. Demethylehiortetracydilne produces somewhat higher and more prolonged blood levels because of its slower renal excretion and greater stability. Therefore, ade- quate blood levels are obtained when 150 mg is given 4 times daily.3 ANTIMICROBIAL SPECTRUM The tetracyclines inhibit a broad range of microbial agents, including both gram-positive and gram-negative bacteria. Mycobacterinrn tabcrculosig, rickett- sial the psittacosis-lymphogranuloma venereum group of large viruses, and the agent of primary atypical pneumonia (Eaton agent) ~ The latter is now known to be a pleuropneumonia-like organism. The most sensitive organisms in the gram-positive group include the pneumococcus, Strep~tococcus ~rida~im~, some strains of staphylococci, and most strains of group A beta hemolytic streptococci.2° PAGENO="0574" 2708 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Sensitive gram-negative organisms include most strains of Esoher 1z~ia~ coli, the meningococcus, gonococcus, Hemophilus inflnenza,e, and Pasteurella, BruceUa, and Shigella strains, Aerobacter and Proteus species vary considerably in their sensitivity to the tetracyclines. Some strains of Pseudoimonas aerugi~mo&~ and Bacteroides have been found to be sensitive to the tetracyclines. The tetracyclines are generally considered to be bacteriostatic agents; they suppress the multiplication of organisms and depend on the host defense mecha- nisms to eradicate the remaining organisms. When the host defenses are good, excellent therapeutic results will be obtained in certain infections, such as uncom- plicated pneumococcal pneumonia, tularemia,2' and certain gram-negative bacil- lary urinary tract infections. On the other hand, superior results are obtained when a bactericidal agent such as penicillin is used in eradicating group A beta hemolytic streptococci from the pharynx; penicillin is also more effective in pneumococcal meningitis in which phagocytosis may be less efficient than in the lung and in which the cerebrospinal fluid concentrations are obtained more con- sistently with penecillin than with the tetracyclines. Certain organisms develop resistance to tetracyclines more readily than others. Some gram-negative bacilli, such as E coli and Aerobacter and Proteus organisms. readily become resistant. Staphylococci also develops resistance to this group of drugs.~ Pneumococci have not been observed to develop resistance. In one study, in which 218 strains of group A beta hemolytic staphylococci were tested, 42 strains (or 20%) were found to be resistant to tetracycline and demethylchlor- tetracycline.~ It is difficult to tell whether resistance develops by means of mutation and selection in those organisms that were previously sensitive, or whether superimposed infections with organisms of established resistance occur after t1~e strains have been eradicated. Probably both mechanisms occur under certain circumstances. Adverse effects and tooioity The tetracyclines are relatively sale antibiotics when given in moderate dosage and when the course of therapy is not prolonged. Even when therapy has been given over a long period of time, such as in chronic bronchitis, the adverse effects have been few if the patient was otherwise in good general health. The most frequent untoward effects have been nausea, vomiting, and diarrhea. These effects can be minimized if the lowest effective dose is given after meals. The symptoms usually subside when the drug is discontinued. Superimposed infection with other resistant organisms, particularly with Staph aurcus and strains of Pseiulonwnas, Proteus, and other gram-negative organisms, has been the most serious hazard to patients receiving prolonged or large doses of the tetracyclines. This is particularly true in patients who are hospitalized with chronic debilitating illnesses, such as chronic pulmonary disease and neo- plastic disease, in patients who are being treated with corticosteroids, or in those who are receiving radiation or antitumor therapy. This complication, however, is not limited to tetracycline therapy. These patients may develop superimposed infections regardless of therapy, and it is difficult to assess the role of tetra- cycline drugs in producing such effects. Drug fever and rashes have been observed infrequently. Local application is more likely to be associated with dermatitis, but this form of therapy is rarely indicated. Photosensitivity, manifested by marked sunburn after exposure to direct sunlight, has developed during therapy with demethyichiotetracycline. This reaction apparently occurs more frequently and is more severe in southern areas where the sunlight is more intense. Blood dyscrasias have been observed in patients who have received tetracycline therapy, but causal relationship has not yet been definitely established. Patients who develop agranulocytosis and pancytopenia while receiving tetracyclines have recovered without discontinuation of the therapy. Other less well-known adverse effects have been described and are of interest. although they are rarely of clinical importance. Each of the earlier homologues has produced morphologic and functional changes in the liver during prolonged intravenous therapy, a negative nitrogen balance, and increased riboflavin excre- tion into the urine?2 THERAPETJTIC INDICATIONS AND CLINICAL USE The effectiveness of the tetracyclines in the treatment of a large group of infec- tions has been weli established. The tetracyclines have been in use longer than PAGENO="0575" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2709 any other antibiotics except penicillin and streptomycin, and they have proved to be unusually safe, well-tolerated, and effective, as ~vell as convenient to use orally. Reactions are usually not serious and are very rarely fatal. As newer antibiotics have been introduced they have supplemented the tetracy- dines and have filled in the therapeutic gaps when used against organisms usual- ly resistant to them, eg. Proteus Pseudo~rn~onas, and other resistant strains of coil- form organisms. The chief disadvantage of tetracycline therapy is the expense as compared to that of penicillin and sulfonamides. In, addition, certain organisms either de- velop resistance or are replaced by resistant strains after prolonged or repeated courses of tetracycline therapy. In the following clinical situations, the tetracycline drugs are considered as first or equal choices: Respiratory infeotions.-(a) Pneumonitis due to Eaton Agent (primary atypi- cal pneumonia), psittacosis, II influenzae, or pneumocci (in patients allergic to penicillin or when oral therapy is necessary) ; (b) chronic bronchitis due to mixed organisms, especially II influenzae and pneumococci; ~ (c) infections due to some strains of Kiebsiella (combined with streptomycin or kanamycin); and (d) acute bronchitis of undetermined etiology. Urinary tract infections.-Infections due to sensitive coliform organisms, espe- cially when they are acute and not acquired in the hospital (often combined with streptomycin, kanamycin or the colistine [colistin sulfate and colistimethate sodium]). Other grant-negative infeotions.-(a) Infections due to sensitive strains of E coli, Aerobacter, Proteus, and coliform organisms (frequently combined with streptomycin, kanamycin, or the colistins if bacteremia is present) ; (b) brucel- losis (either alone or combined with streptomycin); (~) tularemia (either alone or combined with streptomycin) ; (d) Bacteroides (usually alone or combined with another antibiotic if sensitivity studies indicate that another antibiotic would be effective) ; and (e) Shigella. Rickettsial diseases.-(a) Rocky mountain spotted fever and (b) typhus fever. Vitca diseases and nvisceflaneous.-(a) Psittacosis, (b) lymphopathia venerum, (c) tracthoma, and (d) granuloma inguinale. Uzostridica infections.-(a) Tetanus and (b) CTostridium~ perfringens (gas gangrene). Protozoal diseases.-Amebiasis. In general documented eviden~ce reveals little difference `in therapeutic effec- tiveness between the four main, tetracycline homologues. There may be an oc- casional strain that exhibits a differential sensitivity pattern favoring one homo- logue over another, but these differences are quantitative rather than qualitative. If a given patient falls to respond to one tetracycline homologue, there is rarely any advantage in changing to another homologue. PREPARATIONS The four homologues are marketed under a variety of brand names, each containing a specific salt or additive, with the claim that there, is optimal ab- sorption. It has been emphasized that there is little, if any, advantage of one salt or additive over the other. On the other hand, those homologues that contain calcium and dicalcium salts actually depress absorption.8' ~ Therefore, calcium compounds are no longer incorporated in commercial preparations of the tetra- cyclines. When prolonged treatment is to be given, their combination with anti- fungal agents such as nystatin and amphotericin B may delay or decrease the overgrowth of Canclicla organisms about the anus and in the vagina. Oral preparations of tetracycline, oxytetracycline, and chiortetracycline are available in capsule and tablet form in 50, 100, and 250 mg sizes. They also are supplied in liquid form for administration as drops and by the teaspoonful. Capsules of demethylchlortetracyeline contain 150 mg. Liquid preparations of this homologue also are available. The tetracyclines are prepared for topical ap- plication as ophthalmic and otic solutions and ointments and as troches and surgical powders. If a patient is unable to take tetracycline orally, intravenous administration by continuous drip should be initiated. The usual dose for adults is 500 mg every 8 to 12 hours, occasionally, larger doses are indicated. There are several prepara- tions `available for intramuscular injection. However, intramuscular administra- PAGENO="0576" 2710 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tion is extremely painful and is seldom tolerated by the patient for very long periods.3°' 3° Oombining such preparations with a local anesthetic lessens the immediate pain, but persistent tenderness prevents prolonged administration by this route. If individual doses do not exceed 1(X) mg the drug is tolerated much better, but the levels achieved are lower than those that can be obtained when the drug is given orally or intravenously. Preparations containing vitamins, acetylsalicylic acid (aspirin), acetophenet- idin (phenacetin), caffeine, or antihistamines contain only 12~S mg of tetra- cycline and have no advantage over the antibiotic alone. C1z,loran~phcnicol Ohioramphenicol was isolated in 1947 from culture filtrates of Streptoniyces venezt~elae. The chemical formula was soon identified and the antibiotic was successfully synthesized. The formula is presented below: KI> 0. / \ II 02N " `~ CH-CH-NHCCHCI2 I I OH CH2OH The aromatic ring structure appears to be essential for biologic activity. The isomers of chioramphenicol are inactive. A. wide variety of alterations in the molecule have been made, but most of these changes have resulted in loss of antibiotic potency, and none of the resulting formulations have been superior to the parent drug. Chloraniphenicol is generally considered to be a bacteriostatic agent, although, by varying the concentration, a bactericidal effect can be demonstrated against some strains of microorganisms. Cliloramphenicol acts on sensitive bacteria by inhibiting protein synthesis. Considerable information is `ivailable as to the precise enzyme systems involved. These vary with different organisms.28 In the light of the known toxicity of chloraniphenicol, it is interesting that its effect on the host cells differs from its effect on bacterial cells. Chioramphenicol has a broad antimicrobial spectrum and is active against many strains of gram-positive and gram-negative bacteria, the rickettsiae, and a few strains of viruses. There is, however, considerable variation in the sen- sitivity of different strains of organisms within the same species. Ths variability is most frequently encountered among the gram-negative bacilli. AlthOugh Fi2° and Hodgnian3° stated that staphylococci maintain their in vitro sen- sitivity to chioramphenicol despite its extensive use in hospitals, other investi- gators have noted chloramphenicol-resistant strains of staphylococci in in- creasing numbers.3° Antibiotic synergism and antagonism have been extensively studied in vitro and in experimental animals; however, these phenomena are difficult to assess clinically and there is little documentation of such a clinical phenomenon. Pharmacology Crystalline chioramphenicol is absorbed unchanged as the metabolically active form of the drug. It is almost completely absorbed from the gastro- intestinal tract. Therapeutic levels appear in the blood within 34) mm after ingestion, reach their peak in 2 hours, and disappear within 12 to 22 hours.3°'3° The height and duration of the blood levels are generally proportional to the dose. Circulating chloramphenicol is rapidly conjugated by the liver to a mono- glucuronide which has no biological activity and is highly water soluble. A small amount of chloramphenicol is converted, probably also in the liver, to a biologically inactive aminodial hydrolysis product.3° 3°' 3° Assays for chloramphenicol are carried out by two methods: (a) the microbial assay method, which uses a turbimetric procedure against Sli-igella sonnei and measures active chloramphenicol only and (b) the chemical assay method which determines total aromatic nitro compounds, including both active chloramphen- icol and the inactive metabolites. Comparative determinations by the two methods indicate that most of the chioramphenicol in the blood is in the active form. Sixty per cent of the active chioramphenicol in the blood is reversibly bound to the plasma albumin. PAGENO="0577" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2711 Seventy to ninety per cent of an administered dose is recovered in the urine within 24 hous. The rate of excretion is proportional to the blood leveL30'32'~ Five to ten per cent of the total urinary excretion is active chioramphenicol. The remainder consists of inactive aromatic nitro compounds, the glucuronide comprising the major portion. The active chioramphenicol is excreted by glomerular filtration. The filtration rates are low, indicating that the protein- bound portion does not pass the glomerular membrane. The glucuronide is excreted by the renal tubules. The clearance rate of the inactive fraction is 3 to S times that of creatinine. Less than 3% of the total does is excreted in the bile, primarily as the monoglucuronide, and less than 1% of the total does appears in the stool. Kunin, Glazko, and Finland7~ studied serum levels in anuric patients. They reported that the serum half-life of active chloramphenicol was not significantly prolonged in anuric patients; however, the half-life of the metabolic products of chloramphenicol was markedly extended in patients with severe renal disease but no toxic effects were observed. The same investigators found that the serum half-life of active chloramphenicol was prolonged in patients with cirrhosis of the liver. This appears to be due to a slower rate of glucuronide conjugation in these patients.37 Distribution After chloramphenicol has been absorbed, it rapidly diffuses throughout most of the body fluids. The chief factor which limits diffusion throughout the various body fluids appears to be due to protein binding. Thus, the spinal fluid concen- tration is only 30% to 50% of that in the blood stream. Chloramphenicol appears to diffuse into joint and pleural spaces in somewhat higher concentrations. It penetrates the aqueous and vitreous humor of the eye and crosses the placental barrier. The concentration in the newborn infant's blood is 30% to 80% of that in the maternal blood.38 THERAPEUTIC INDICATIONS AND CLINICAL USE Although chloramphenicol is a broad spectrum antibiotic whose effectiveness has been established in a variety of infections due to gram-positive and gram- negative organisms, its toxic effects may be extremely serious and it should not be used when penicillin, the tetracyclines, or erytbromycin are effective. This fact reduces the specific indications for the use of this drug to severe salmonella infections, especially typhoid fever. Formerly, chioramphenicol was considered the drug of choice in the treatment of H i~vf1uenza~ meningitis. A recent compara- tive study of a large group of patients indicated a mortality rate of 24.5% with oxytetracycline, 8.4% with tetracycline, and 12.5% with chloramphenicol therapy.38 Chloramphenicol is highly effective and specific in the treatment of typhoid fever. Bacteremia ceases within a few hours after the first dose. During the next 2 days the patient begins to feel better, although the temperature remains elevated. During the third and fourth day there is dramatic improvement with fall in temperature and disappearance of symptoms. The dose for adults is 2 to 3 gm of chloraniphenicol per day administered at 6- or 8-hour intervals. If treat- ment is discontinued as soon as the patient becomes afebrile, relapse will often occur. This can be prevented in the majority of cases by continuing chlorampheni- col for `at least 12 days after the afebrile state has been reached. The effectiveness of chloramphenical is less dramatic in other salmonella in- fections and is usually ineffective in eradicating the carrier state. The development of the newer semisynthetic penicillins may reduce the need for chloramphenicol in the treatment of staphylococcic infections. Probably there are some urinary tract infections in which chloramphenicol is the drug of choice when the organism is resistant to the tetracyclines, erythromycin, and other anti- biotics, or to some of the newer antibiotics, such as the colistins, but such in- stances are uncommon. There is no justification for employing chloramphenicol prophylactically in surgical patients or in those with salmonella infections or respiratory infections due to virsuses. Chloramphenicol (as well as most antibiotics) has been used far more exten- sively than the `above indications justify, despite repeated warnings in the litera- ture. Several authors have emphasized that fatal reactions have occurred in 81-280 0-68-pt. 6-37 PAGENO="0578" 2712 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY patients who received chioramphenicol for minor respiratory infections or some other infection for which the indication for chloramphenicol was questionable or absent. To~r4 city The most common and serious toxic effect associated with chioramphenicol therapy is the development of aplastic anemia. This may occur after the ad- ministration of small doses for short periods or may appear only after prolonged therapy. Aplastic anemia is the most important complication of chloramphenicol therapy; it occurs more commonly in association with this antibiotic than with any other drug.40~ If the aplastic anemia is detected early, and the antibiotic is discontinued, the bone marrow may recover, but often the disease ends fatally. Other forms of bone marrow depression may occur with chloramphenicol therapy, such as leukopenia, granulocytopenia, and thrombocytopenia. These are more likely to be associated with large doses or prolonged therapy and are more likely to be reversible if the drug is discontinued. Consequently, all patients re- quiring chlorainphenicol therapy should have frequent blood counts, at least twice weekly in the early weeks of therapy and once weekly later. However, it should be emphasized that, although frequent blood counts can be relied upon to detect early changes in the peripheral blood, pancytopenia of the bone marrow may occur without warning. Recent reports suggest that many patients receiving chioramphenicol therapy have demonstrated hematopoietic changes which may be unrecognized but re- versible. Some patients exhibited a marked delay in uptake of radioactive iron by the red blood cells and others have developed anemia. The earliest demonstra- ble toxic effects on the hematopoietic system are an increase in plasma iron and in the saturation of iron-binding globulin, reflecting a decrease in the iron uptake of the erythroid tissue.43~ Morphologic changes resulting from chloramphenicol therapy have been de- scribed by several investigators.'8' ~° ~ A depression in the reticulocyte count below 0.5% occurs in the peripheral blood of most patients during the toxic phase, and bone marrow aspirations reveal striking vacuolation in young erythroid cells.41 These changes are usually reversible and disappear within a few days after the drug is discontinued. In fact, rapid bone marrow recovery is usually accompaiiied by evidence of hyperplasia (reticulocytosis and sometimes throm- bocytosis and leukocytosis). Such a rebound phenomenon is not observed in those patients in whom the bone marrow depression is not reversible. Chloramphenicol seems to act at the proerythroblast level, at which maximum vacuolation is seen, rather than at the stem-cell level. Patients with anemia in whom the marrow is active appear to be particularly sensitive to the marrow-depressing effect of chloramphenicol. Increasing the dosage of chloramphenicol above 40 mg/kg of body weight appears to induce hematopoietic depression. When chloramphenicol is administered in higher concentrations than those ordinarily used, it depresses leukocyte respiration and inhibits the synthesis of nucleic acid by normal and leukemic bone marrow cells. The exact mechanism of bone marrow suppression remains unexplained. There has been one case of acute myeloblastic leukemia reported after chloramphenicol therapy.18 Premature and newborn infants are particularly susceptible to the toxic ef- fects of chioramphenicol and there have been several reports of deaths of new- born infants due to chloramphenicol therapy.50' 49-51 In most cases, the drug was given within 48 hours after birth and the majority of infants affected were pre- mature by birth weight. They developed a symptom complex called the "gray syndrome." Almost all of them received doses larger than 100 mg/kg of body weight daily. The symptoms appeared after 3 or 4 days of treatment. The first evidence of toxicity was vomiting or regurgitation of feedings, followed by re- fusal to suck and abdominal distention. Respiratory distress, flaccidity, and an ashen gray color then developed. Deaths occurred in the seriously affected babies 24 to 48 hours after the onset of the first symptoms. In the others the symptoms usually disappeared within 24 to 36 hours alter the drug was dis- continued. Blood concentrations, which were reported in a few infants, showed progressive accumulation of total nitro compounds to unusually high levels. However, autopsy studies did not reveal the cause of death and no characteristics changes were found. tFurther studies, including the reproduction of the "gray syndrome" in ani- mals, have elucidated the pathogenesis of this entity. In the newborn infant the PAGENO="0579" COMPETITIVE PROBLEMS IN THE DRUt~ INDUSTRY 2713 immature liver is deficient in conjugation mechanisms and there is a decrease in the renal tubular secretion of the chloramphenicol glucuronid. This results in abnormally progressive accumulations of chloramphenicol and some of its degra- dation metabolites. The toxic effect in the newborn infant has been directly related to the high level of active chloramphenicol that accumulates in the blood stream after repeated doses. Thus, the "gray syndrome" in newborn infants may be prevented by reducing the size of the dose to no more than 25 mg/kg per day in premature infants or infants under 2 weeks of age.525' Other toxic reactions resulting from chioramphenicol therapy include nausea and, occasionally, diarrhea. The gastrointestinal symptoms are mild and the drug is usually well tolerated. Secondary, infections, due to the presence of yeasts, may also occur. Allergic reactions are rare. Angioneurotic edema, vesicular and maculo- papular eruptions, and fever have been observed. In addition, acute necrosis of the liver has occurred after cliloramphenicol therapy and peripheral neuritis as- sociated with optic neuritis has been reported during the prolonged adminis- tration of relatively large doses.80 PREPARATIONS AND DOSAGE Ohloramphenicol can be given orafly, intramuscularly, subcutaneously, intra- venousty, and rectally. It is available in 50,, 100,' and' 250 aug capsules for oral administration. This preparation contains crystalline chioramphenicol; effective blood `levels are usually obtained within one-half `hour after ingestion. However, in patients who are severely ill, particularly in those with signs of peripheral circulatory collapse, absorption is often delayed and intravenous therapy should be utilized. A liquid preparation of cliloramphenicol, available as the palinitate ester, is designed for use in young children.80' 56 This preparation is palatable in contrast to the extremely bitter taste of the crystalline form. Therapeutic levels are not attained until 2 or 3 hours after administration because the ester must be hydrolyzed before absorption occurs. Since as much as sO% of the dose is `lost in the stool, the amount given must be higher than when the drug is administered in the crystalline form.80 Each 4 cc contains 125 mg of chiorampherlicol and the recommended dose is 100 to 200 mg/kg of body weight per day, given sit 6- or 8~bour intervals. A preparation containing chloranxphenicol and dthyd.rostreptomyci'n is mar- keted. There are no specific indications for this preparation. Two preparations are available for intramuscular administration, a micro- crystalline powder and a suspension. The latter i's prepared by adding physiologic saline or sterile water. Effective blood levels may not be obtained for 2 to 3 hours after intramuscular administration. Peak blood levels will be lower `but will last longer than with the same dose of an oral preparation. Ohloramphenicol sodium succin'ate is a highly water-soluble ester and hence is more readily absorbed than the microcrystalline form. It is available in sterile vials containing crystalline powder equivalent to 1 gm of chlorainpheniool which may be dissolved in sterile water, normal saline, or glucose solutions. This preparation is suitable for initramuscular~ subëutaneous, or intravenous use. Therapeutic blood levels are obtained within one-half hour after intramuscular administration. Peak blood levels occur in 11/2 to 2 hours and therapeutic levels persist for 6 to 8 hours. This is the preferable preparation for parenteral use. Several preparations are available for topical administration, including a cream, an ointment, drops for ophthalmic use, and drops for otic use. However, there is little `indication for the use of these formulations. The dose of chioramphenicol in adults is 2 to 3 gm daily. Baylor University College of Medicine, Texas Medical Center, Houston (Dr. Yow). GENERIC AND TRADE' NAMES OF DRUGS Chloramphenicol-ChloromyCetifl. Chiortetracycline hydrochloride-Aureontycin Hydrochloride. Oxytetracydline-Terramycifl. DemethylchlortetracyCline hydrochloride-DeclOmycifl Hydrochloride. Tetracycline-Achromycifl, Panmycin, Polycycline, Tetracyn. Kanamycin sulfate-Kantrea'. Nystatin-Myco8tatin. Ampliotericin B-Fungizone. Erythromycin-ErythrOnsycin, Ilotycin. Dilsydrostreptomycin sulfate-DlhydrostreptOmyCin Sulfate. PAGENO="0580" 2714 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY BEFERENCES `Duggar, B. M., et al: Aureomycin: Product of Continuing Search for New Antibiotic, Ann NY Acad Sd 51: 177-181 (Nov) 1948. 2 McCormick, J. R. D., et al: New Family of Antibiotics: Demethyltetracyclines, J Amer Ohem Soc 79 : 4561-4563 (Aug. 20) 1957. Kunin, C. M., and Finland, M.: Demethylchlortetracycline: New Tetracycline Antibiotic that Yields Greater and More Sustained Antibacterial Activity, New Eng J Med 259 : 999- 1005 (Nov20) 1958. Kunin, C. M.; Dornbush, A. C.; and Finland, M.: Distribution and Excretion of Four Tetracycline Analogues In Normal Young Men, J Olin Invest 38: 1950-1963 (Nov) 1959. Shapiro, J. L., and Phillips, F. M.: Demethylchloretetracycline in Clinical Practice, JAMA 176: 596-602 (May 20) 1961. 6 Sweeney, W. M.; Dornbush, A. C.; and Hardy, S. M.: Demethylchlortetracycline and Tetracycline Compared, Amer J Med Sd 243 : 296-308 (March) 1962. 7Dimmling. T.: Experimental and Clinical Investigation with Pyrrolidinomethyl Tet- racycline, Antibiot Ann 7: 350-357, 1959-1960. 8 Sweeney, W. M., et al: Absorption of Tetracycline in Human Beings as Affected by Certain Excipients, Antibiot Med 4: 642-656 (Sept. 10) 1957. Wood, W. S., et al: Tetracycline Therapy; Clinical and Laboratory Observations on 184 Patients with Tetracycline, Arch Intern Med 59: 351-363 (Sept.) 1954. 10 Sweeney, W. M.; Dornbush. A. C.; and Hardy. S. M.: Antibiotic Activity in Urine and Feces After Oral and Intravenous Administration of Demethylchlortetracycline, New EngJMed263:620-624 (Sept.20) 1960. 11 Kunin, C. M., and Finland, M.: Clinical Pharmacology of Tetracycline Antibiotics, Olin Pharmacol Ther 2: 51-69 (Jan.-Feb.) 1961. `~ Kunin, C. M. : The Tetracyclines, Pediot Olin Amer 8: 1001-1012 (Nov.) 1961. `3Kunin, C. M.; Jones, W. F.; and Finland, M.: Enhancement of Tetracycline Blood Levels New Eng J Med 259: 147-156 (July 24) 1958. `~ Berk, J. E., and Kantor, S. M.: Demethylchlortetracycline-Induced Fluorescence of Giastric Sediment. JAMA 179 : 997-1000 (March 31) 19&2. `5Annotations. Tissue Localization of Tetracycline. Brit Med J, 1: 1401 (May 19) 1962. 16 Du Buy, H. G., and Showacic, J. L.: Selective Localization of Tetracycline in Mito- chondria of Living Cells, Science 133: 196-197 (Jan.) 1961. "Finland. M.: Medical Progress; Emergence of Antibiotic-Resistant Bacteria, New Eng JMed253:909-922 (Nov.24) 1955. 18 Kunin, C. M., et al: Persistence of Antibiotics in Blood of Patients with Acute Renal Failure. I. Tetracycline and Chlortetracycline, J Olin Invest 38: 1487-1497 (Sept.) 1959. 10 Kingston, J. H., et al : Eaton Agent Pneumonia, JAMA 176: 118-123 (April 15) 1961. 20 Houser, H. B.. et al: Effect of Aureomycin Treatment of Streptococcal Sore Throat on Streptococcal Carrier State, Immunologic Response of Host, and Incidence of Acute Rheumatic Fever, Pediatrics 12: 593-606 (Dec.) 1953. 21 Overholt, E. L., et al: Analysis of Forty-Two Cases of Laboratory-Acquired Tularemia: Treatment with Broad Spectrum Antibiotics, Amer J Med 30: 785-806 (May) 1961. 5° Knight, V., et al: Studies on Staphylococci from Hospital Patients. II. Effect of Anti- microbial Therapy and Hospitalization on Carrier Rates, Ann NY Acad Sci 65 : 206-221 (Aug. 31) 1956. 5°Kuharlc, H. A.; Roberts, C. E., Jr.; and Kirby, W. M. M.: Tetracycline Resistance of Group A Beta Hemolytic Streptococci, JAMA 174: 1779-1782 (Dec. 3) 1960. 5° Normal, P. 5., et al: Long-Term Tetracycline Treatment of Chronic Bronchitis, JAMA 179 : 833-840 (March 17j 1962. 5°Boger, W. P., and Gavin, J. J.: Evaluation of Tetracycline Preparation, New Eng J Med261:827-832 (Oct.22) 1959. 26 B.; Yow, E. M.; and Townsend, E.: Concentration of Tetracycline in Serum Following Parenteral Administration, J Lab Olin Med 47: 203-209 (Feb.) 1956. 3'McKechnie, J., and Yow, E. M.: Comparison of Patient Tolerance of Procaine Penicillin, Tetracycline, and Oxytetracycline when Administered Instramuscularly, Antibiot Med 7: 765-770 (Dec.) 1960. 5°Wissman, C. L., et al: Mode of Action of Chioramphenicol. I. Action of Chioramphenicol on Assimilation of Ammonia and on Synthesis of Proteins and Nucleic Acids in Escherichia Ooli,JBact67:662-673 (June) 1954. 5°Fisher, M. W.: Susceptibility of Staphylococci to Chloramphenicol: Survey of Experi- mental and Clinical Experiences, Arch Intern Med 105 : 413-423 (March) 1960. ~° Hodgman, J. E.: Chioramphenicol, Pediat Olin 8: 1027-1042 (Nov.) 1961. 31 Koch, M. L.: Increased Incidence in Pathogenic Chloramphenicol-Resistant Staphy- lococci Accompanying Increased Use of Drug in Hospital Practice, Antibiot Med 3 : 458- 460 (Dec.) 1956. 5° Glasko, A. J., et al: Biochemical Studies on Cliloramphenicol (Chloromycetin). II. Tissue Distribution and Excretion Studies. J Pliarmacol Exp Ther 96: 445-459 (Aug.) 1949. 5°Kelly, H. S.; Hunt, A. D.; and Tashman, S. G.: Studies on Absorption and Distribution of Chioramphenicol, Pediatrics 8: 362-367 (Sept.) 1951. 5°Krakoff, I. H.; Karnofsky, D. A.; and Burchenal, J. H.: Effects of Large Doses of Chloramphenicol on Human Subjects, New Eng J Med 253: 7-10 (July 7) 1955. NOTE-Additional references available froni the author on request. {From the Journal of the American Medical Association, July 27, 1963] USE AND MISUSE OF ANrrslovrcs Effective chemotherapy for combathig infectious diseases has become ,a possibility only during the past 15 years, and the list of complex, liighiy portent drugs is continually changing and increasing. The dramatic consecpiences of this PAGENO="0581" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2715 breakthrough in phaninacologlical, microbiological, and clinical science are re- flected in sharply declining death rates the world over. Unfortunately, however, the plethora of new drugs and combinations of drugs may be a mixed blessing to physicians who attempt to thread their way through a maze of colLificting claims concerning such complex matters as sensitivity spectra, blood levels, potency, and safety. Many of the new antimicrobials are clearly outstanding contributions to the art of chemotherapy and are, as such, real triumphs of pharmacological research. Others are molecular modifications of established compounds and are introduced with claims that some desired feature-such as greater potency, more rapid ab- sorption, more sustained blood levels, reduced bacterial resistance, or fewer side effects-has been added to the more familiar properties. Since all such claims need to be viewed skeptically until they have been ccsvfirmed by impartial in- vestigators and extended experience, compounds of this type often make only a numerical rather than a qualitative contribution to the list of available drugs, and thus add only confuslon. Other formulatIons offered by the pharmaceutical industry tend to make care- ful clinicians definitely uneasy. These include the fixed-ratio mixtures of two or more antimicrobial agents, which are `said to be designed to reduce the chances of superinfeetion, patient sensitization, or bacterial resistance, and the formula- tions containing additives that are claimed to enhance absorption, delay excre- tion, or otherwise affect blood levels or potency. Clearly violating the princi- ples of rational therapy are the complex combinations of amtipyretics, anti- histaminics, or vitamins, with minimal amounts of the antibiotic. Since the host of ingenious topical preparations-lozenges, aerosols, and oinjtments-iappear to sensitize as often as they relieve, their value also is open to serious question. Obviously, the opportunities for misuse or even frank abuse of antimicrobial chemotherapy are rife for the unwary, and unquestionably some physicians hare been guilty of misusing these agents. With this Therapeutic Number the Council begins its ~ponsorship of a series of authoritative communications which should help to bring the physician up to date on individual aspects of antibiotic therapy and increase his sense of security in prescribing these agents. Ory and Yow (p 273) write about the tetracyclines and chioramphenicol, and Hewitt (p 264) differentiate's the burgeoning group of penicillins from one another. Ory and Yow stress the fact that the tetracyclines are similar in their anti- bacterial spectra and should always be administered singly rather than as mix- tures which increase both the cost and hazard for the patient. These authons also discredit many promotional myths, such as claims for additives designed to in- crease absorption, reduce gastrointestinal irritation, prevent overgrowth of Can- dMa, and so on, and wisely point out once again the frequently forgotten distinc- tion between the primarily bacteriostatic and the primarily bacterioeidial drugs. Referring to the grim record of chloramphenicol `as a cause of serious and fatal blood dyscarsias, they remind us that it should not be used -sviien other antibiotics are effective, a fact which limits its specific indications to the treatment of severe salmone'lloses, particularly typhoid fever. The choice and administration of one of the many available penicillins is an art in itself, and Hewitt's refresher course is timely indeed. Although the newer ones may help to mitigate the problems of penidillinase resistance, they do not supplant the older penicillins which, as Hewitt reminds us, continue to the drugs of choice in many clinical situations. At the same time he athiocates oral ad- ministration whenever possible, and suggests doing away with the needlessly sen- sitizing topical and aerosol preparations altogether. Subsequent contributions to this series will present definitive information and considered opinion on other aspects of antibiotic therapy. Perhaps it will become possible in the future to match organism, patient, and antimicr~bial drug pre- cisely; if so, all patients may one 4ay reap the benefits of `a fairly exact and predictable `science. But, then and now, before prescribing any drug the physi- clan may well reflect on Hewitt's wise admonition: "With further contributions now `being made by the molecular manipulation of all agents, the physician must more than ever make a clear decision on whether antibiotic therapy for an individual patient Is necessary at all." PAGENO="0582" 2716 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Clin-Alert, Apr. 30, 1963, No. 108] (3HLOEOMYCETIN The Hematology Committee of the British Association of Clinical Pathologists reviewed 40 cases of Chloromycetin (chloramphenicol) -induced blood dyscrasias, 35 of which were hitherto unreported. Thirty-one patients died. Onset of toxic symptoms varied widely (immediately after the drug was given `to one year after cessation of therapy). Dosage analysis revealed that while a high dose and repeated courses seem more likely to cause trouble, single courses of less than 10 Gm. Chioromycetin can cause fatal aplasia. Use of Chioromycetin is justified only in treatment of life-endangering infections when no other effective antibiotic is available * * * example, typhoid fever. There is every indication, however, that Chloromycetin has been used indiscriminately in a wide variety of mild infections and that extravagant doses have been given-Sharp (Secre- tary), British M.J. 1: 735,1963. [From the British Medical Journal, No. 5332, pp. 735-737, Mar. 16, 1963] OHLORAMPHENICOL-INDUCED BLOOD DY5CRA5IA5: ANALYSIS OF 40 CAsEs (By A. A. Sharp, M.D.) Preseifted on behalf of the Haematology Conlmittee* of the Association of Clinical Pathologists Ten years have elapsed since the first reports were published to inform the medical profession that clilorainphenicol could act as a bone-marrow poison and that the resulting aplasia could be irreversible and lead to the death of the patient (British Medical Journal, 1952). Since then reports of the toxic effects of chloramphenicol have continued to appear, but the drug has remained in use as a popular and useful antibiotic. The British Medical Josrnal (1901) was again provoked to give warning of the dangers of this drug, but deaths attributable to chioramphenicol have con- tinued to be reported. The latest report of the Study Group of Blood Dyscrasias of the American Medical Association (January, 1962) recorded 73 cases of pancytopenia, 4 with thrombocytopenia, 4 with leucopenia, and 17 with anaemia which were caused by this drug. The Haematology Committee of the Association of Clinical Pathologists de- cided to ask members of its association how many cases of chioramphenicol- induced blood dyscrasias they had encountered and to report such cases to the secretary of this Committee. To date, reports of 35 hitherto unpublished and five published cases of suspected chloramphenicol blood dyscrasias have been received. This is admittedly a random sample of such cases, and while there are obviously still an unspecified number of unpublished cases it was thought worth while to report an analysis of the clinical and laboratory data supplied with these case reports. ANALYSIS OF CLINICAL DATA Time.-These 40 cases occurred in the period 1953-62. Severity.-Thirty-one of the 40 patients have died. In 27 death was attributed directly to chioraniphenicol therapy. Age and sea~.-There is no obvious specific age or sex incidence. Interval between therapy and diagnosis of marrow damage-The commonest interval was 1-3 months after the cessation of therapy; in two cases the blood dyscrasias developed immediately after the drug had been given, in two cases at approximately 9 months, and in one case 1 year after cessation of therapy. Dose.-In 18 patients the total dose of chloramphenicol was 10 g. or more, and in four it exceeded 50 g., one receiving 250 g. In eight patients, however, the total dose was less than 10 g., and in one infant the amount given did not exceed 2 g. Six received intermittent or continuous courses or unspecified amounts over one year, and 12 had more than one course of the drug. In 14 cases details of therapy were insufficient to assess the total dosage of the drug the patient had received. *Dr. E. K. Blackburn (chairman), Dr. M. G. Nelson, Dr. F. G. J. Hayhoe, Dr. J. Humble, Dr. D. Robertson-Smith, Dr. G. H. Tovey, and Dr. A. A. Sharp (secretary). PAGENO="0583" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2717 Blood pioture.-In 21 cases the periph'eral blood showed a severe pancytopenia (anaemia, leucopenia, and thirombocytopenia). Twelve cases showed selective aplasia with either leucopenia or thrombocytopenia. No case showed selective red-cell aplasia. In seven cases specific data relating to the peripheral blood picture were not given. Clinical prescntation.-The commonest presenting symptom was spontaneous bleeding-for example, epistaxis, purpura, menorrhagia. In one case jaundice was the earliest sign of complication. Prognosis.-The details of the marrow changes were available in only 25 reports. All 12 patients with aplastic marrows died. In eight the marrow was classified as hypoplastic, but they too died. The marrow derived from five of the nine patients who recovered was hypoplastic. Therefore recovery may take place if the marrow is not completely aplastic. Complete marrow aplasia would appear to carry a hopeless prognosis. DISCUSSION Ohloramphenicol is an efficient antibiotic, but its use is justified only in the treatment of life-endangering infections when no other effective antibiotic is available-for example, typhoid fever. Yet this series has shown that fatalities apparently due to chloramphenicol therapy have occurred in numbers sufficient to cause concern. Further, it would seem that this drug has been used indiscriminately in the treatment of a wide variety of mild infections and that extravagant doses of the drug have been administered. Hutchison and Pinkerton (1902) have suggested that the incidence of blood dyscrasias due to chloramphenicol might be 1 in 80,000 patients treated, in which case it might be argued that this risk justifies the use of this antibiotic in even trivial infections. However, these authors based their imputation on the num- ber of deaths reported to the Registrar-General, and incidence based on the Registrar-General's report can be misleading; it is likely that more cases do exist than are officially recorded. Dameshek (1900) has stated that in the majority of fatal cases the patient w-ould not have died if he had not received this drug. There would appear to be no justification for using ebloramphenicol to treat nonspecific pyrexial ill- nesses or nasopharyngeal infections in childhood, or recurrent bronchitis, asthma, chronic or post-prostaJtectomy urinary infection, recurrent boils, or superficial skin infections unless it has been shown by careful bacteriological sensitivity tests that the offending organism is sensitive to no other antibiotic. This present series shows that, while a high dose and repeated courses ap- pear to be more likely to cause trouble, single courses of less than 10 g. can cause fatal aplasia. The wide distribution of the time of onset df symptoms attributable to the toxic effect of the drug suggests that two possible mechanisms exist: (1) a hypersensitivity reaction-immediately dangerous but probably reversible; this is often accompanied by immediate systemic symptoms; (2) a slow direct poison- ing of marrow "stem" cells due to the accumulation and retention of the drug or its breakdown products in the blood or tissues and so to the delayed effect. The variation of the toxic dose suggests that an individual idiosyncrasy to this drug may exist. A retrospective survey such as that presented here can never be satisfactory, as significant data are not collected and not all cases are reported. Thus no statistical analysis of dose, time reliutionships, or incidence rates can be cal- culated. Only by insisting that chloramphenicol and other drug-induced dyscrasias are notified to some responsible authority as they occur can the case be made whether the popularity or efficiency of this drug as an antibiotic outweighs its established toxic effect. - The purpose of this paper has been to stress once more the dangers of using this antibiotic and to appeal for the compulsory notification of this and other drug- induced blood dyscrasias to a responsible central body in order that a true as- sessment of the relative risks can be made. This appeal is especially pertinent to the present concern of the medical profession and lay public regarding the dangers of modern drug therapy. In the meantime this Committee w-ould be grateful if any doctor encountering a case where it is suspected that chioramphenicol might have produced damage to the bone-marrow would send the relevant data to the secretary of this Corn- inittee. PAGENO="0584" 2718 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The Committee expresses its thanks to the Council of the Association of Clinical Pathologists for their encouragement and permission to publish these data; to the Chairman of Council, Professor D. F. Cappell, for his criticism and advice; and to all those members of the Association who took the trouble to supply the Committee with case reports. It also wishes to thank Dr. M. M. Wintrobe, Chairman of the Study Group of Blood Dyscrasias of the American Medical Association, for his advice and encouragement. [From the Journal of the American Medical Association, July 14, 1962, vol. 181, No. 2, pp. 114-119] DETECTION AND PREVENTION OF DRUG-INDUCED BLOOD DYSCRASIAS (By Allan J. Erslev, M.D., Philadelphia, and Maxwell M. Wintrobe, M.D., Salt Lake City*) The reluctance of most physicians to report cases of suspected drug-induced blood dyscrasias is due to the difficulty in establishing a definite casual relation- ship between drug and disease; the evidence for this in most cases is inadequate. Unfortunately, this reluctance may lead to a delay in the recognition of toxic effects of new drugs. For example, cases of suspected chloramphenicol-induced aplastic anemia were observed sporadically soon after the drug was released in 1949, but so few case reports appeared that its potential toxicity was not apparent until 3 years later. By that time 12 individual groups had accumulated 37 cases of chloramphenicol-induced aplastic anemia, enough to warrant publication of a firm, but belated, warning. In order to prevent similar delays, the Council on Drugs of the American Medical Association established a Study Group on Blood Dyscrasias to act as a clearinghouse for all suspected cases caused by drugs and chemicals.1 Report forms were distributed, and physicians were urged to report immediately all cases of blood disease in which a drug or chemical might have been of etiological significance. Cooperation has been excellent. Since the institution of this program in 1955, a total of 1,195 cases of blood dyscrasia have been reported in this country alone. The reported cases are tabulated, and a summary is distributed semiannually to all cooperating physicians, to heads of various departments of medical schools, and to medical libraries, medical societies, hospitals, and drug companies.2 Because of the great number of cases and the variety of drugs involved and because of the fact that, in such a summary, well-founded as well as less plausible suspicions may be tabulated together, it is obviously difficult to accept these case reports as scientific proof of the toxicity of a drug. However, when used in conjunction with published reports on the effects of drugs on blood cells and with knowledge of the approximate annual consumption of specific drugs, these tabulations have provided much useful information. They have kept the medical profession aware of the potential toxicity of new as well as of older drugs in common use and have led to specific warnings of the toxicity of the phenothia- zines and chloramphenicol.5 In addition, it is contemplated that the Study Group w-ill from time to time publish an analysis of all the cases in the Registry in the hope that this will result in a better understanding of the heterogeneous group which has been designated as drug-induced blood dyacrasias.6 Only through Brit. med. J., 1952. 2, 136. (1961). 1, 1019. Dameshek, W. (1960). J. Amer. med. Ass., 174, 1853. Hutchinson, H. E., and Pinkerton, P. H. (1962), Scot. med. J., 7, 96. *Assocjate Professor in Medicine, Cardeza Foundation, Jefferson Medical College (Dr. Erslev) ; and Professor of Medicine, University of Utah, College of Medicine (Dr. Wintrobe). ~ Development and Purpose of Registry of Blood Dyscrasias, JAMA 170: 1925-1926 (Aug. 15) 1959. 2 Registry on Blood Dyscrasias: Report to Council, JAIIA 179: 888-890 (March 17) 196° 3Blood Dyscrasias Associated with Chlorpromazine Therapy, JAMA 160: 287 (Jan. 28) 4Blood Dyscrasias Associated with Promazine Hydrochloride Therapy, JAMA 165: 685- 682~~ D~scrasias Associated with Chloramphenicol (Chloromycetin) Therapy, JAMA 172: 2044-2045 (April 30) 1960. Huguley, C. M.; Erslev, A. J.; and Bergsagel, D. E.: Drug-Related Blood Dyscrasias, JAMA. 177: 23-26 (July 8) 1961. PAGENO="0585" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2719. a better understanding of the pathophysiology of these iatrogenic disorders will it be possible to detect them earlier and, perhaps, to prevent them altogether. PATHOGENESIS The drug-induced blood dyscrasias may appear as leukopenias, thrombocy- topenias, anemias, or pancytopenias or, in some cases, as defects in clotting factors. As a corollary, the Study Group urges that all cases in which drugs cause adverse effects on the clotting mechanism be reported; however, these disorders are outside the scope of the present discussion. The pathogenesis of drug-induced cytopenias often is believed to involve an im- mune mechanism. It is envisioned that certain drugs in a few hypersensitive indi- viduals will render the blood cells antigenic and that these antigens will elicit a destruQtive antibody response. Such a sequence of events has been dem~nstrated convincingly in cases of thrombocytopenia caused by allylisopropylurea (Sedormid)7 or quinidine8 and in eases of hemolytk~ anemia caused by stibophen (Fua*din)° or quinidline.'° If strict immunologic criteria are used, these appear to~e be the only cases in which we can be certain of a pathogenetic antigen-antibody mechanism. Moeschlin and \Vagnerl have described leukocyte agglutinins in aminopyrine-induced agranulocytosis, and leukocyte agglutinins or platelet agglu- tinins have been found in many other cases of cytopenias suspected of hating been caused ~y drugs."3 These agglutinins, however, ate active against normal cells; thus, their action is not, as in the first eases mentioned, only against cells "coated" with the particular drug in question. It is important to realize that the presence of an agglutinating substance does not necessarily indicate that an immune mech- anisin is operating, since many unrelated chemicals and proteins are capable of coating and clumping blood cells.14 In those cates in which an immunologic pathogenesis has been established or strongly suspected, the blood dyserasia has always been characterized by peri- pheral ~elluiar destruction and a bone marrow which shows compensatory hyper- plasia. In blood dyscrasias characterized by bone marrow suppression or bone marrow hypoplasia, the evidence that they are caused ~y an immune mechanism with circulating antibodies has not been convináing. In short, although some cases of drug-induced blood dyscrasias have been indu~ed by an antigen-antibody mecha- nism, the great majority cannot ~e explained adequately in this manner. The pathogenesis in these cases is obscure, but it may be related to a deficiency in the metabolic handling of certain drugs. This deficiency maybe qualitative and depend on the genetic deletion of ~ertain enzymes, or it may represent merely a quantita- tive individual difference in susceptibility to specific drug actions. A genetic deficiency of the enzyme glucose-6-phosphate dehydrogenase has explained the sporadic occurrence of hemolytic anemia after the ingestion of pri- niaquin~ and other oxidant drugs.'5 It ha!s ~een shown that glucose-6-phosphate dehydrogenase is necessary for the generation of reduced triphosphopyridine nueleotid~ (TPN) which, in turn, replenishes the red blood cell stores of reduced glutathione which is vital for prevention of the hemolysis by oxidizing compounds. A deficiency may result in the oxidation of the sulfhydryl groups of the globin chains and cell membranes, in turn, producing denatured hemoglobin, Heinz bodies, and red ~lood cell lysis.'° A deficiency in the red blood cell content of gin- ~iose-6-phosphate dehydrogenase and in the regeneration of reduced glutathione can be recognized easily with appropriate laboratory tests and should be looked `Ackroyd, J. F.: Role of Sedormid in Immunologic Reactions that Results in Platelet Lysis in Sedormid Purpura, Olin ~5ci 13 : 409-423 (Aug.) 1954. 8 Schen, R. J., and Rabinovitz, M.: Thrombocytopenic Purpura Due to Quinidine, Brit Med J 2: 1502-1505 (Dec. 20) 1958. 0 Harris, J. W.: Studies of Mechanism of Drug-Induced Hemolytic Anemia, J Lab Olin Med 47: 760-775 (May) 1956. 10Freedman, A. L.; Barr, P. 5.; and Brody, E. A.: Hemolytic Anemia Due to Quinidine: Observations on Its Mechanism, Amer J Med 20: 806-816 (May) 1956. 11 Moeschlin, S., and Wagner, K.: Agranulocytosis Due to Occurrence of Leukocyte- Agglutinins, Acta Hacmat 8: 29-41 (July-Aug.) 1952. Tullis, J. L.: Role of Leukocyte and Platelet Antibody Tests in Management of Diverse Clinical Disorders, Ann Intern Med 54: 1165-1180 (June) 1961. "Zuker, M. B., et al.: Thrombocytopenia with Circulating Platelet Agglutinin, Platelet Lysin and Clot Retraction Inhibitor, Blood 14: 148-161 (Feb.) 1959. `~ Jandi, J. H.: Agglutination and Sequestration of Immature Red Cells, J Lab Olin Med 55: 663-681 (May) 1960. "Beutler, E.: Drug-Induced Hemolytic Anemia, in Metabolic Basi8 of Inherited Disease, edited by J. B. Stanbury; J. B. Wyngaarden; and D. S. Fredrickson, New York City: McGraw-Hill Book Company, 1960, pp. 1031-1067. 1~ Jacob, H. S., and Jandl, J. H.: Effects of Sulfhydryl Inhibition on Red Blood Cells. I. Mechanism of Hemolysis, J Olin Invest 41: 770-792 (April) 1962. II. Role of Thiols in Oxidant Drug Action, J Olin Invest 40: 445-475 (March) 1961. PAGENO="0586" 2720 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY for carefully in all cases of hemolytic anemia, whether exposure to drugs has occurred or not. A hypersensitive person may respond to minimal concentrations of a chemical; for example, children have developed hemolytic anemia `after exposure to aniline laundry marks" or to naphthalene in moth-protected cloth- ing.'8 Drugs marked by an asterisk in the table have been associated with the production of oxidative hemolytic anemia." Other biochemical abnormalities of blood cells, which render them hypersensi- tive to specific drugs and chemicals, will undoubtedly ~e found. Since these abnor- malities would be primarily genetic, it is important to obtain a complete family history and to inquire about consanguinity, which often may be the first clue to a genetic mechanism." Because of this interest, the report form distributed ~y the Study Group on Blood Dyscrasias contains a space for checking the presence or absence of consanguinity. A quantitative difference in the response to a drug may also be of pathogenetic importance in the development of many blood dyscrasias. In a number of drugs, the difference between therapeutic and toxic levels is quite small, and severe cellular suppression or destruction may ~ecaused by a minor metabolic deviation from the normaL In order to relate the development of a blood dyserasia to this mechanism, excessive doses of a drug given to normal individuals should cause the same type of toxic reaction which is observed when regular doses are given to hypersensitive individuals. Results of recent studies strongly suggest that chloramphenicol-induced bone marrow suppression represents an accentuated normal response to the drug. Toxicity studies in animals, with the possible exception of monkeys,'° have failed to reveal that chioramphenicol has marrow-suppressive properties. How- ever, studies in man have shown that large doses given for prolonged periods of time will cause bone marrow suppression and maturation arrest. Krakoff and co-workers" and Ozer and co-workers" gave large doses of chloramphenicol to 5 people, and all 5 developed pancytopenia and bone marrow suppression. In addition~ studies by Saidi and co-workers" and by Rubin and co-workers'4 have shown that mild reversible bone marrow suppression is a common com- plication of chioramphenicol therapy. Results of in vitro studies of normal bone marrow have shown also that chloramphenicol in high concentrations inhibits desoxyribose nucleic acid (DNA)" and heme `° in a manner which could explain the lack of cellular proliferation and the impariment of iron utilization observed in vivo. The metabolic handling of chloramphenicol has been studied in a few patients after they had recovered from chioramphenicol- induced paneytopenia, and, in these patients, the drug was found to be detoxi- fied and excreted in a perfectly normal manner." Consequently, it appears that the pancytopenia which occassionally is found in patients treated with chloram- phenicol may represent an exaggerated response to the suppressive action of chloramphenicol on bone marrow. A few cases have been reported in which the action of chloramphenicol on the blood cells has been suggestive of an antigen-antibody reaction,6 but, in the great majority of cases, there is no evi- dence that this is caused by an immunologic mechanism or by a genetic abnor- ma1ity in the handling of or in the response of this drug. "Graubarth, J., et al.: Dye Poisoning in Nursery: Review of 17 Cases, JIMA. [28: 1155-1157 (Aug. 18) 1945. "Dawson, J. P.; Thayer, W. W.; and Desforges, J. F.: Acute Hemolytic Anemia in Newborn Infant due to Naphthalene Poisoning: Report of 2 Cases, with Investigations into Mechanism of Disease, Blood 13: 1113-1125 (Dec.) 1958. "Motuisky, A. G.: Drug Reactions, Enzymes and Biochemical Genetics, JAMA 105: 835-837 (Oct. 19) 1957. 20 Hrenoff, A. K., and Anderson, H. H.: Chronic Toxicity of Chioramphenicol to Bone Marrow of Macaques, Med Erp 4: 183-190, 1961. "Krakoff, I. H.; Karnofsk-y, D. A.; and Burchenal, J. H.: Effects of Large Doses of Chioramphenicol on Human Subjects, New Engl J Med 253: 7-10 (July 7) 1955. "Ozer, F. L.; Truax, W. B.; and Levine, W. C.: Erythroid Hypoplasia Associated with Chioramphenicol Therapy, Blood 10: 997-1001 (July) 1960. "Saidi, P.; Wallerstein, R. 0.; and Aggeler, P. M.: Effects of Chloramphenicol on Erythropoiesis, J Lab tJl'in Med 57: 247-256 (Feb.) 1961. 24 Rubin, D., et al.: Changes in Iron Metabolism in Early Chioramphenicol Toxicity, J Gun Invest 37: 1286-1292 (Sept.) 1958. "Yunis, A. A., and Harrington, W. J.: Patterns of Inhibition by Chloramphenicol of Nucleic Acid Synthesis in Human Bone Marrow and Leukemic Cells, J Lab GUn Med 56: 831-838 (Dec.) 1960. 20Erslev, A. J., and Lossifides, I. A.: In Vitro Action of Chloramphenicol and Chloram- phenicol-Analogues on Metabolism of Human Immature Red Blood Cells, to be published. "Glazk-o, A. J. : Personal communication. PAGENO="0587" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2721 ETIOLOGY A total of 411 drugs have been mentioned as possible etiological agents in the 1,195 cases of blood dyscrasia reported in this country since 1955. Of these cases, 488 have been associated with the administration of a single drug and 707 with the administration of combinatiOns of drugs. It is particularly difficult to pinpoint the responsible agent when a number of drugs have been admin- istered, and it is hard to prove a specific cause-effect relationship even when a single drug has been given. Studies of the cases of agranulocytosis28 and hypo- plastic anemia have suggested that about 40% are of idiopathic origin; that is, they could not be associated with a specific cause. Furthermore, civilized man is exposed to so many chemicals at work and at home (food additives, deter- gents, solvents, and "smog") that it is impossible to assert that the single drug he received was the only significant chemical exposure. Consequently, not all of the 109 drugs listed as having been given alone were necessarily of etiological importance. After a thorough analysis of these cases, as well as a critical review of the pertinent literature, the Study Group has compiled a list of 54 drugs believed to be potentially toxic to the blood cells (see table). This list does not state the degree of toxicity of the individual drugs but merely states that these drugs have been associated with the development of blood dyscrasias under circum- stances which have convinced the members of the Study Group that a cause-effect relationship exists. In addition to being a useful compilation of potentially toxic drugs, this list may be used to evaluate cases in which multiple drugs have been administered. These cases can be divided into 2 categories: In the first category are those cases in which one of the drugs administered is known to be potentially toxic and, presumably, is responsible for the detrimental effects. In the second category are those cases in which 2 or more drugs were administered, none of which are known to be toxic. In these latter cases, a greater degree of suspicion of the potential toxicity of `the unknown drugs is justifiable. DRUGS on CHEMICALS SHOWN BY DIRECT OR CIRCUMSTANTIAL EVIDENCE TO BE ASSOCIATED WITH BLOOD DYSCRASIAS Acetanilid3° Pamaquin8° Acetazolamide Phenindione Acctophenetidin3° Phenylbutazone Allylisopropylacetylurea Phenylhydrazine~° Aminopyrine Primnaquine3° Aminosalicylic ~ Primidone Arsphenamine Probenecid3° Benzene ` Promazine Carbutamide Pyrimethamine Chloramphenicol Quinacrine Chlordane Quinidine Chlorothiazide Quinine Chlorpromazine Ristocetin Chlorpropamide Stibophen Oolchicine Streptornycin Diphenyihydantoin Sodium Sulfacetamide3° Dipyrone Sulfadiazine Gamma Benzene Hexachloride Sulfamethoxypyridazine 3° Gold Salts Sulfanilamide°° Imipramine Sulfisoxazole Lead ` Sulfoxone°° Mepazine Thiazolsulfone°° Meprobamate Thiobarbital Methimazole Thiouracils Methyiphenylethyl Hydantoin Toibutamide Naphthalene3° Primethadione Nitrofurantoin°° ` Trinitrotoluene °~ McGovern, F. H.': Granulocytopenia Following Ingestion of Causalin JAMA 115: 1359 (Oct. 19) 1940. 20 Scott, J. L.; Cartwright, G. E.; and Wintrobe, M. M.: Acquired Aplastic Anemia: Analysis of 39 Cases and Review of Pertinent Literature, Medicine 38: 119-172 (May) 1959. 00These drugs have been associated with the induction of hemolytic anemia principally in patients with glucose-S-phosphate dehydrogenase-deficient cells. PAGENO="0588" 2722 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY An analysis of the 411 drugs mentioned as possible etiological agents revealed that a relatively small number of chemicals were associated with the great ma- jority of cases. The 14 most important agents are tabulated in Figures 1, 2, and 3 and are divided into 3 groups; i.e., those drugs or chemicals used alone, those used in association with other drugs or chemicals not known to be toxic, or those used in association with drugs or chemicals known to be potentially toxic. Pancytopenia L ~i~i 0 20 40 60 80 100 120 140 160 180 200 Fig. 1.-Drugs commonly associated with development of pancytopenfa. Figure 1 emphasizes the dominant role of chloramphenicol in the etiology of drug-induced pancytopenias. Not only had chloramphenicol been administered to 200 patients who subsequently developed pancytopenia, but, in one-third of these, it was the only drug given. The tetracyclines and penicillin were associated also with a large number of cases but in only 3 instances were they administered alone. Other commonly used drugs, such as, acetylsalicylic acid (Aspirin), aceto- phenetidin (Phenacetin), and barbiturates, were found to be associated with a considerable number of cases of pancytopenia but very rarely were they the only drug given. These findings suggest a chance association rather than an etiological relationship; this is supported by the fact that the relative frequency with which these commonly used drugs were associated with pancytopenia, leu- kopenia, and thrombocytopenia is about the same as the relative frequency with which these diseases occur. The following drugs all have been associated with a significant number of cases of pancytopenia: sulfonamide such as sulfisoxazole (Gantrisin), diuretics such as acetazolamide (Diamox), hypoglycemic agents such as chlorpropamide (Dia- binese), phenothiazines such as chlorpromazine (Thorazine) and promazine (Sparine), hydantoins such as diphenylhydantoin (Dilantin) and methylphenyl- ethyl hyclantoin (Mesantoin), and pyrazolones such as aminopyrine (Amido- pyrine), dipyrone, and phenylbutazone (Butazolidin). However, in order to gain a valid impression of the potential toxicity of these drugs, it is necessary to know the extent of their annual consumption by humans. Unfortunately, such data are not readily available, and one must rely on estimates. Chioramphenicol ___________.i Tetracyclinen (. PenicI~n Sulfonanudes ~ Phenotinazines ] ~ Hydantoins Insecticides (Chiordane. Lindane, DDT) j ~ Pyrano!ones :iin Only drug administered Adnrinisteeed in combination ocith another Thouracils drug or drugs not noon to be oem Quinidine u Admnisteeed in combination with another -- drug or drugs non to be potentally tocic I.! et h inn a to! Ogitalis Glycosides IEI ~arbiturates Acetophenetidin Acetytsaticylic Acid (Aspirin) ~ 1T1 PAGENO="0589" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2723 Itrronnhocytoprn;a 0 2~O 4b 60 80 i6o Fig. 2.-Drugs commonly associated with development of thrombocytopenia. Figure 2 shows that the sulfonamides and quinidine, when given alone or with other drugs not known to be toxic, are associated with the development of a num- ber of cases of thrombocytopenia, thus establishing a convincing cause-effect relationship. Leukopenia Fig. 3.-Drugs 0 20 40 6'O ~0 1~0 1~ 1~0 1~0 1~0 2~0 220 240 260 commonly associated with development of icukopenia. Solton.,midns Qoiiolim Tetraryi l;n's P `IOn Clilorancyl c',iiiol PI.eootl;i.eF:1iiS Pyrznlnsec ttyd.tn;n'i tnsn'nt;c;,I,s (C inrd,ine, L;nit:1ril. TOT) TI _~J ____u ~IIJ Tn 1111 ~I11 `Ct 10 (l;.iy AiJni';;'tennl ennh;r,;;t 5.1 `1.1CC in'." `C CI'(IO' riot t";s*, tn hi to, ~ on) in Otis C)y'n:;des 0:1 rh iuriCs Acel Cphe `C it ii Anety(s.nlcyi;c Acid (Aspirin) I I I 1 I ~ 1 H ED Phenoth;azines Tetracycines Penicillin Scilonamides Pyrazoiones Chioramphenicol Ilydantoins Methimarote Thiouracits Insecticides (Chlord:1nr, lindane. DOT) Quinidine Digitalis Gtycosides Barbiturates Acetophenetidin Acetytsaticylic Acid (Aspirin) TD I S N 0 Only drug admin;stered Administered in combinat;on with another J drug or drugs not known In be tonic Administered in combination with another j drug or drugs known to be potentially tonic :1 PAGENO="0590" 2724 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Figure 3 shows that the phenothiazines such as chlorproniazine, promazine, trifluoperazine (Stelazine), prochiorperazine (lJompazine), and perphenazine (Trilafon) are quantitatively the most important offenders in the production of leukopenia and agranulocytosis. It is probable that the pyrazolones such as ami- nopyrine, dipyrone, and phenylbutazone or the antithyroid agents such as propyl- thiouracil or methimazole (Tapazole) are more toxic since they still are asso- ciated with a significant number of cases of leukopenia, despite their relatively infrequent use. The etiological role of the tetracyclines, penicillin, sulfonamides, and chloramphenicol is difficult to assess, since these drugs are used frequently in treating infections associated with unrecognized leukopenia. DEITuOTION AND PREVENTION When treating patients with cytopenias, it is always important to consider the possibility that a drug or a chemical may have played an etiological role in their development. A thorough occupational and personal history will reveal a signifi- cant degree of exposure to a toxic agent in about 50% of patients with throm- bocytopenia, leukopenia, and pancytopenia. This information will lead to the only rational therapy known-discontinuing further exposure to the suspected agent. It is gratifying to see this simple remedy result in rapid improvement. However, the absence of a prompt response does not rule out cause-effect relationship, since the blood dyscrasia may have reached a slowly reversible or a completely irreversible stage. In an attempt to establish a definite etiological relationship, appropriate in vitro tests for agglutimins, heniolysins, clot retraction inhibitors, or cellular enzymes (glucose-6-phosphate dehydrogenase) should be carried out. Unfortu- nately, a useful in vitro test for drug action on bone marrow has not yet been developed. In vivo tests based upon the readministration of a small amount of the suspected drug should be reserved only for those cases in which the suspected agent is considered to be of extraordinary value in the future management of the patient. When this valuable, but somewhat dangerous, test is used, it is important to realize that a negative response to a small test dose will only rule out an antigen-antibody mechanism and not the possibility of the more common bio- chemical hypersensitivity. In order to test biochemical sensitivity, the suspected drug has to be readministered for a prolonged period of time. However, such a therapeutic trial is rarely justified unless conditions for thorough hematological supervision are available. It has been shown that early detection of some blood dyscrasias will lead to prevention of serious hematological complications. Peripheral cellular destruction can be stopped promptly if the offending drug is discontinued, and bone marrow suppression may be reversed completely if it is detected early enough. The most important requisite for early detection is the realization that the administration of drugs always entails a risk and that for some drugs this risk may be quite sub- stantial. Administration of these drugs should always be preceded by appropriate blood counts; i.e., white blood cell count, determination of hematocrit levels and hemoglobin concentration, platelet count, and reticulocyte count. Because of the short "lifespan" of the reticulocytes, this count is the most sensitive index to a change in the rate of red blood cell production. Recently, it has been shown that serum iron will increase if suppression of the erythroid marrow prevents normal iron utilization, and this increase may be an early and sensitive index of bone marrow suppression.n Thus, these hematological values should be determined at reasonable intervals; i.e., weekly for drugs like chloramphenicol and the pyra- zolones which involve greater risk and less frequently for drugs like the anti- thyroid compounds, quinidine, the hydantoins, and the phenothiazines, which often are administered for prolonged periods. A change in any one of these values should immediately lead to further hematological study and to temporary or permament discontinuation of the suspected drug. SUMMARY Since 1955, the Study Group on Blood Dyscrasias of the AMA Council on Drugs has received reports on 1,1~5 cases of blood diseases suspected of having been caused by drugs. A review of these reports reveals that such commonly used drugs ~` Rubin, D.; Weisberger. A. S.; and Clar, D. R.: Early Defection of Drug Induced Erythropoletlc Depression, J Lab Olin Med 56 : 453-462 (Sept.) 1960. PAGENO="0591" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2725 as acetylsalicylic acid and penicillin are associated with all varieties of blood diseases but that this association is coincidental and is rarely present if the drugs are given alone. On the other hand, some~ drugs are predominantly associated with specific blood diseases and often have been found to be the only drugs given to patients who subsequently develop a blood disease. Chioramphenicol is the drug most often associated with pancytopenia; the sulfonamides are most often associated with thrombocytopenia; and the phenothiazines are most often associated with leukopenia. A simple awareness of the potential toxicity of drugs will lead to appropriate examinations and to the establishment of safeguards for the detection and possible prevention of drug-induced Mood dyscrasias. 1025 Walnut St., Philadelphia (Dr. Erslev). [From the Journal of the American Medical Association, Mar. 17, 1962, vol. 179, No. 11, pp. 888-890) REGISTRY ON BLOOD DY5CRA5IA5 REPORT TO THE COUNCIL* In 1952, the Council on Drugs became concerned with the probelm of hemato- toxicosis from the ever-increasing number of therapeutic agents. The Council's former Committee on Research recommended that a Registry on Blood Dyscrasias be formed; and after a 2-year pilot study, the, Registry was permanently estab- lished. Reports are tabulated for each 6-month period, and the summary tabuia- tion is distributed to medical schools, hospitals, medical societies, and collab- orating physicians. With expansion, the need for a résumé of the tabulated information has become apparent. The reports received by the Registry for the period January 1 to June 30, 1961, were used for this purpose. The information must be considered raw data, since reports are received from many sources and no follow-up is possible. The résumé is intended to provide concise information regarding common asso- ciations between drugs and blood dyscrasias, to acquaint physicians with the existence of the Registry, and to encourage them to report cases of blood dyscrasla in which drugs or other chemicals may be the suspected cause. RÉSUMÉ OF REPORTS RECEIVED BY REGISTRY ON BLOOD DYSCRASIAS JANUARY 1 TO JUNE 30, 1961 hf the period from January 1 to June 30, 1961, 138 new cases of blood diseases suspected of having been caused by drugs or chemicals were reported to the Study Group on Blood Dyscrasias of the American Medical Association. These included cases which were published in the American medical journals during the same period. Forty-eight cases noted in foreign medical journals are reviewed separately. These findings increase the total number of cases reported since 1955 to 1,504 and the total number of drugs and chemicals reported to be associated with the development of blood dyscrasias to 411. Because of the large number of drugs invOlved, it has become increasingly difficult to evaluate the data and establish firm etiological relationships between specific drugs and specific blood disorders. However, certain previously unsuspected hernatological side effects of drugs may be recognized much earlier if data are gathered from all over the country. There- fore, the Study Group on Blood Dyscrasia feels that it is important to con- tinue to act as a clearinghouse for all suspected instances of hematological side effects which may arise from the use of drugs. In order to transform the accumulated data into useful information, the Study Group has recommended that a brief analysis of the reported material be pre- pared. A copy of the complete tabulation is available upon request from the Council on Drugs. An analysis of the new cases added to the tabulation during the first 6 months of 1961 does not justify any sweeping conclusions or condemnations. The drugs appearing in the tabulation are those which are known to have produced toxic *The Council has authorized publication of the above report. PAGENO="0592" 2726 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY reactions and which continue to cause trouble when used or are those drugs which are widely used. A total of 163 different drugs and chemicals were associated with the 138 cases reported to the Registry during the period in review. A.-Ninety-eight drugs were associated with one case each. Of these, only imipramine hydrochloride (Tofrãnil) requires special mention. This drug was introduced, in 1959, for the treatment of depression. Since that time, it has been reported as a possible causative agent in 9 cases of leukopenia, 2 of which were fatal. However, only one additional case has been reported in the first 6 months of 1061. B.-Thirty-one drugs were associated with 2 cases each. The potentially toxic effect of quinidine (Asarum, Conchinine, Oonquinine, Pitayine, Quindate) on platelets is empahisized by the fact that 2 patients developed thrombocytopenia after the administration of quinidine, the only drug used. 0.-Twelve drugs were associatetd with 3 cases each. Dexamethasone (Deca- dron, Deronil, Gammacorten), a synthetic analagoue of hydrocortisone, was re- ported to be associated with 2 cases of pacytopenia and 1 case of leukopenia. This drug is mentioned because it had not previously been associated with the development of blood dyscrasias. However, in all 3 cases, other drugs known to be potentially toxic were administered concurrently; thus, it seems dubious that dexamethasone was the offending agent. D.-Eig1~t drugs were associated with 4 cases each. A definite cause-effect relationship could not be established in any of these cases because of the variety of blood disorders induced and the many other drugs used concomitantly. E. Fourteen drugs were associated with 5 or more cases each: Acetophenetidin (Phena'cetin)-8 cases Acetylsallcylic Acid (Aspirin)-15 cases Chloramphenicol (Ohloromycetin)-56 cases Ohlorothiazide (Diuril)-7 cases Ohlorproniazine (Thorazine)-iil cases Diphenhydraniine (Benadryl)-6 cases Diphenyihydantoin Sodium (Dilariitin Sodiuan)-5 cases Meprc~bamate (Equanil, Meprospan, Meprotabs, Miltown)-7 cases Novobiocin (Aibamycin, Cathomyein)-5 cases Penidlllins-17 cases Phen~barbital (Luminal)-1() cases Promazine (`Sparine)-5 cases Suifisoxazole (Gantrisin)-6 cases Tetracycline (Acbromycin, Panmycin, Polycycline, Tetracyn) -18 cases As in previous tabulations, the drug associated with the highest number of blood dyscrasias in this period is chloramphenicol. It was the only drug administered in 23 of tue 56 new cases reported to be associated with the use of chioramphenicol; in 28 of the remaining 33 cases, it had been employed in conjunction with drugs not known to cause blood dyscrasias. These results support the contention that chloramphenicol has a definitely toxic action on the bone marrow; therefore, it is mandatory for the physician to be aware of the potential toxicity of this otherwise valuable antibiotic. The drugs associated with the next highest number of blood dyscrasies are the tetracyclines and penicillins. In none of the reported cases was one of these anti- biotics used as the only drug; in most of the cases they were used in conjunction with drugs known to have toxic potentialities. It is qiiite possible that the peni- cillins and tetracyclines have been listed frequently because they have been used in the treatment of early symptoms of illnesses which were later recognized as blood diseases. Acetylsailcylic acid was reported to have been given to 15 patients who devel- oped blood dyscrasias. This is probably a gross underestimate, since acetylsali- cylic acid in some form is used so extensively that it is fair to assume that the great majority of all patients with blood dyscrasias have been exposed to this drug. However, it has been used so long and with such impunity that it seems un- likely that this drug has hidden hematoxic properties. The same may be true in the case of phenobarbital, a widely used sedative. The remaining drugs, with the possible exception of novobiocin, are all recog- nized as having potentially hematotoxic side effects; they should be used only with full awareness of this potential danger. As a guide, the members of the Study Group have listed a number of drugs which, in their opinion, have been PAGENO="0593" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2727 shown to have definite hematotoxic side effects. The list does not state the degree of toxicity of the individual drugs; but it indicates that certain drugs have been associated with the development of blood dyscrasias in a manner which has con- vinced the Study Group that a specific cause-effect relationship exists (Table). DRUGS OR CHEMICALS SHOWN BY DIRECT OR CIRCUMSTANTIAL EVIDENCE TO BE ASSOCIATED WITH BLOOD DYSCRASIAS (1) (2) (3) (4) (5) Hemo~ Pancyto- Throm- Leuko- Drug lytic penia bocy- penia Anemia atiemia topenia Acetanilid X Acetazolamide x Acetophenetidin X Allylisopropylacetylurea X Aminopyrine X x Arsphenamine X X X X Benzene X X X X Carbutamide X X X X Chioramphenicol X X X X Chlordane X X X X Chlorothiazide X X Chlorpromazine X Chlorpropamide X X X X Coichicine X X X X Diphenylhydantoin sndium x Dipyrone X Gamma benzene hexachloride X X X X Gold salts X X X X Imipramine X Lead X Mepazine X Meprobamate X X X X Methimazole X Methyl-phenyl-ethyl-hydantoin X X X X Naphthalene X Nitrofurantoin X Pamaquin X Para-aminosalicylic acid X Phenindione X Phenylbutazone X X X X Phenyihydrazine X Primiaquine X Primidone X Probenecid X Promazina X Pyrimethamine X X X Quinacrine X X X X Quinidine X X Quinine X Ristccetin X Stibophen X Streptomycin X X X X Sulfacetamide X Sulfadiazine X Sulfamethoxypyridazine X X X X X Sulfanilamide X X Sulfisoxazole X X Sulfoxone X Thiazolsulfone X Thinbarbital X Thiouracils X Tolbutamide X X X X Trimethadione X X X X Trinitrotoluene X X X X In the foreign medical journals, 48 cases incriminating 34 different drugs were reported during the first 6 months of 1961: Twenty drugs were associated with 1 case each. Seven drugs were associated with 2 cases each. Two drugs were associated with 3 cases each. Two drugs were associated with 4 cases each. With the exception of benzene (Benzol, Cyclohèxatriene), no definite cause- effect relationship could be established between these 31 drugs and chemicals and the associated blood dyscrasias. The fact that benzene was reported to be the only 81-280 0-68-pt. 6-38 PAGENO="0594" 2728 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY possible offending agent in 3 cases of pancytopenia reemphasizes this drug's known marrow-suppressive properties.1 Three drugs were associated with 5 or more cases: Acetophenetidin (Phenacetin)-5 cases. Aminopyrine-8 cases. Sulfonyldianiline (Dapsone, Avlosulfon)-8 cases. Sulfonyldianiline was reported to have been the only drug given to 8 patients who subsequently developed anemia.2 This drug has previously been associated with the development of one case of pancytopenia and 2 cases of anemia. Its chemical name is 4,4-diaminodiphenylsulfone, and it is used for the treatment of leprosy and dermatitis herpetiformis. Since it is so rarely used, the large num- ber of cases in the tabulation must be viewed with some concern. Sulfonyl- dianiline should be used only with full awareness of its potentially toxic effect. Aminopyrine, an old drug of well-known toxicity, continues to be responsible for many cases of granulocytopenia. Acetophenetidin was found to be associated with a number of cases, both here and abroad; this is not surprising in view of its wide employment as an analgesic. This analysis did not unearth any new, commonly used toxic drugs. However, it did reemphasize the fact that many drugs are potentially toxic, and that there is always a calculated risk in administering drugs to patients. In order that the medical profession may be served in the most efficient manner, the Study Group urges every physician to report to the AMA Council on Drugs immediately if he should suspect that a blood disease may have been caused by a drug or chemical. A smoothly functioning reporting system will aid the Study Group in the early detection of any hematotoxic properties in new drugs and will enable it to alert the medical profession to such potential dangers. Report forms may be obtained from the Council on Drugs, American Medical Association, 535 N. Dearborn St., Chicago 10. [From the Journal of the American Medical Association, July 8, 1961, vol. 177, No. 1, pp. 23-26] DRUG-RELATED BLOOD DYSORASIAS (By Charles M. Hugulay, Jr., M.D., Atlanta, Ga.; Allan J. Erslev, M.D., Phila- delphia, Pa.; and Daniel E. Bergsagel, M.D., Houston, Tex.C) Side effects of drugs constitute a continuing problem which has 2 aspects: (1) the known risk of occasional idiosyncrasy from an established drug and (2) the as yet undetermined potentiality of a newly introduced drug to produce serious side effects in an occasional patient. Among the most serious side effects of drugs is the development of a blood dyscrasia: agranulocytosis, aplastic anemia, hemo- lytic anemia or thrombocytopenia. The Study Group on Blood Dyscrasias of the Ai\IA Council on Drugs is charged with the task of investigating possible relationships of drugs to blood dyscrasias. Although the medical profession is aware of the possibility that blood dyscrasias may be produced by newly introduced drugs, the lack of a means for reporting such instances has sometimes led to long delays in the accumulation of a sufficient number of cases to arouse a suspicion concerning the drug. To provide a more rapid means of collecting information, a Registry of Blood Dyscrasias has been established, and physicians are encouraged to report to this Registry all cases of drug-induced blood dyscrasias. A simple report form has been devised and all drugs known to have been administered during the past 6 months preceding the onset of the blood dyscrasia are listed. In addition to the reports submitted, a search of the world literature is now made so that cases gathered from this source are also incorporated in a semi-annual tabulation. This tabulation is available upon request. 1 McLean, J. A.: Blood Dyscrasia After Contact with Petrol Containing Benzol, Med J Aust (no. 2) 47: 845 (Nov. 26) 1960. 2 Gentele, H.; Lagerhoim, B.; and Lodin, A.: Macrocytic Anemia Associated with Der- matitis Herpetiformis and 4,4-Diaminodiphenylsulfone Treatment, Acta Dernvatovener (~tockh) 40: 334, 1960. *Associate Professor of Medicine, Emory University School of Medicine (Dr. Huguley) Associate Professor of Medicine, Jefferson Medical College (Dr. Erslev) ; Associate Hema- tologist, Department of Medicine; University of Texas, M. D. Anderson Hospital and Tumor Institute (Dr. Bergsagel). PAGENO="0595" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2729 A registry, established to stthly blood dyscrasias that might be related to drugs, received 448 reports of such cases during the year 1960. There were 97 cases of pancytopenia.. Among the 31 cases in which a single drug was implicated, 5 drugs were associated with more than 1 case: chloramphenicol, methyl-phenyl-ethyl-hydantoin, phenylbutazone, and the 2 insecticides, gamma benzene hexachlo- ride and chlordane. There were 44 cases of thrombocytopenia, and among the 16 cases in which a single drug was implicated the one most frequently involved was quinidine (5 cases). Among 93 cases of leukopenia there were 8 in which chlorpromazine was the only drug implicated. It is evident that certain drugs must be used only if the physician is alert, and alerts his patient, to the fever, sore throat, weakness, pallor, or bleeding that may be the first sign of developing blood dyscrasia. Such a system has many inadequacies, but it does make available more cases for study than the review of the literature alone. Thus, the Registry has served to emphasize the continued high association of chlorarnphenicol admin- istration in patients who develop aplastic anemia, the potentiality of chlor- promazine and promazine to produce agranulocytosis, and the production of thrombocytopenia by ristocetin (Spontin). Attention has been called to such findings by a series of statements published in the Journal.'-4 A total of 1,318 cases of blood dyscrasiâs possibly related to drugs were reported to the Registry as of Dec. 31, 1960. In many instances, multiple drugs had been given. However, even when only one drug had been administered prior to diagnosis, a causal relationship might not have existed. This is particularly true of drugs which are used very commonly. Nevertheless, when reports indicate a frequent association of a particular drug with blood dyscrasias, caution is warranted. REPORTS TO THE REGISTRY or BLOOD DYSCRASIAS During the year 1960, the Registry received 448 reports of blood dyscrasias. There were 97 cases of pancytopenia. Of the 31 cases in which exposure to only one agent was reported, five drugs were associated with more than one case: chloramphenicol (Ohioromycetin), methyl-phenyl-ethyl-hydantoin (Mesan- tom), phenylbutazone (Butazolidin), and the insecticides, gamma benzene hexachlorido and chlordane (see Table 1). Chloramphenicol was reported as the only drug given to 19 patients and had been given in association with other drugs in 34 other patients, a total of 53 of the entire 97 cases of pancytopenia. Drug Only drug With other Total drugs TABLE 1.-REPORTED INCIDENCE OF PANCYTOPENIA ASSOCIATED WITH DRUG ADMINISTRATION (1960) Drug Only drug With other drugs Total Totalcases Chloramphenicol(Chloromycetin) 19 34 Methyl-phenyl-ethyl-hydantoin (Mesantoin) 2 3 PhenyIbutazon~(Butazolidin) 3 3 Gamma BenzenehexachIoride(inse~ticide) 2 1 Chlordane(insecticide) 2 3 53 5 6 3 5 Thrombocytopenia was reported in 44 cases. Here again only five drugs were reported in more than one case as the only drug administered. The drugs are listed in Table 2. - `Blood Dyscrasias Associated with Chiorpromazine Therapy, JAMA 160 : 287 (~Tan. 28) 1956. 2Blood Dyscrasias Associated with Promazine Hydrochloride Therapy, JAM& 165: 685- 686 (Oct. 12) 1957. ~ and Purpose of Registry of Blood Dyscrasias, JAMA 170: 1925-1926 (Aug. 15) 1959. Bloed Dyscrasias Associated with Chioramplienicol (Chloromycetin) Therapy, JAMA 172: 2044-2045 (April 30) 1960. PAGENO="0596" 2730 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 2.-REPORTED INCIDENCE OF THROMBOCYTOPENIA ASSOCI ATED WITH D RUG ADMINISTRATION (1 960) Drug Only drug With other drugs Total Total cases 44 Chloramphenicol (Ctilorqmycetin) Quinidine Sulfamethoxypyridazine (Kynex, Midicel) Chlorothiazide (Diuril) Hydrochlorothiazide (HydroDiuril) 3 5 3 3 2 3 3 0 1 0 6 8 3 4 2 Leukopenia was reported 93 times. Only 4 drugs appeared more than once as the only drug administered prior to onset. These drugs are listed in Table 3. TABLE 3.-REPORTED INCIDENCE OF LEUKOPENIA ASSOCIATED WITH DRUG ADMINISTRATION (1960) Drug Only drug With other drugs Total Total cases 93 Chlorpromazine (Thorazine) 8 13 lmipramine (Tetranil) 2 6 Methimazole (Tapazole) 2 1 Phenylbutazone (Butazolidin) 4 3 21 8 3 7 Of the entire 448 cases, chioramphenicol had been given alone to 24 patients and together with other drugs to 46 patients, a total of 70 patients. Phenylbuta- zone was the only drug administered to 8 patients and was received by a total of 17 patients. Both of these drugs were associated with cases of each type of blood dyscrasia under discussion here. As a rule, other drugs tended to be related to only one type of dyscrasia; for example, of the 22 patients who devel- oped a dyscrasia after receiving chlorpromazine, 21 had leukopenia, and all 8 cases associated with quinidine administration were thrombocytopenia. Members of the Study Group have compiled a list of cases with hypoplastic anemia and agranulocytosis seen in their respective institutions during 1959 and 1960. In each case an opinion was rendered as to whether the dyscrasia probably was or probably was not caused by a specific drug. In this 2-year period, 74 cases of hypoplastic anemia were seen at these 8 institutions and, of these, 33 were thought to be unrelated to drugs. Thirty-three were associated with the administration of chloramphenicol and 8 with other drugs. The idiopathic cases were about equally divided by age and sex, whereas among the cases associated with chloramphenicol administration there were 28 females and only 5 males. Twenty-seven of these 33 patients were in the 1 to 10-year-old age group. This predilection of hypoplastic anemia associated with chioramphenicol for young girls has been noted previously.6 Thirty-three of the total 74 patients were al- ready dead, and only 9 had recovered during the short period of follow-up. The production of a blood dyscrasia by a drug is not usually the result of the pharmacological properties of the drug but more often is the consequence of an idiosyncrasy in the patient which produces a sensitivity to the drug. In some types of drug-related blood dyscrasias, the pathogenetic mechanism is under- stood and can be demonstrated by laboratory methods. In other types, the media nism is wholly unknown. Drug-induced hemolytic anemia is a classic example of the type of blood dyscrasia in which the pathogenetic mechanism has been demonstrated. In the red blood cells of the susceptible person there is a deficiency of an enzyme, glucose-6-phosphate dehydrogenase (G-6-PD), which is important in the me- tabolism of glucose. A side effect of the action of the enzyme is the maintenance of a supply of reduced glutathione (GSH). Deficiency of this enzyme in erythro- cytes is a newly recognized heritable disorder and can be demonstrated by incuba- °Welch, H.; Lewis, C. N.; and Kerlan, L. : Blood Dyscrasias: Nationwide Survey, Antibiot Chemot her 4: 607-623 (June) 1954. PAGENO="0597" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2731 tion with acetyiphenyihydrazine, which results in a fall in the erythrocyte con- tent of GSH. The depletion of GSH is somehow related to the susceptibility of the erythrocyte to destruction. It is possible by testing for G-6-P dehydrogenase activity or for glutathione instability in the erythrocytes to determine the suscep- tibility of a given person to drug-induced hemolytic anemia. Among the drugs which can produce acute hemolytic anemia in susceptible persons are the 8-amino- quinoline antimalarials, such as primaquine, certain sulfonamides, acetanilid, acetophenetidin, nitrofurantoin (Furadantin), and many others. Favism is as- sociated with the same or a closely related heritable deficiency. The subject has been reviewed by Beutler.3 Hemolytic anemia can also be produced through an immune mechanism in which antibodies are formed against a combination of the drug and the erythro- cyte and may lead to agglutination of and damage to the erythrocyte only in the presence of the drug. Such a mechanism has been demonstrated in hemolytic anemias produced by stibophen (Fuadin)7 and quinidine.8 This is very rare. Thrombocytopenia has been produced through a similar immune mechanism by drugs such as allylisopropylacetylurea (Sedormid) ,~ quinidine, and quinine. This mechanism, however, has not been demonstrable in all cases of thrombo- cytopenia attributed to drugs. In some cases of agranulocytosis due to drugs, an immunologic mechanism has been demonstrated, for example, in agranulocytosis produced by amino- pyrine.1° In other cases such a mechanism could not be shown. Aminopyrine and dinitrophenol, the drugs first shown to produce agranulocytosis, are now seldom the cause of granuiocytopenia because they are seldom used. The antithyroid drugs, propyithiouracil, methyithiouracil, and methimazole (Tapazole) and the phenothiozine derivatives, notably promazine (Sparine) and chlorpromazine (Thorazine) are the more common causes of agranulocytosis today. Aplastic anemia remains the most difficult problem among drug-induced blood dyscrasias because it has such a serious prognosis and because it takes so long to recognize the casual relationship* to a drug. The mechanism of production is unknown. Only a very small proportion of the patients who receive a drug capa- ble of producing aplastic anemia will be sensitive to it. Pancytopenia may appear only after prolonged administration or repeated courses of the drug. Most patients with aplastic anemia have received several drugs. Furthermore, aplastic anemia may occur in patients who have had no known exposure to drugs or toxic chem- icals. These factors n~ay be responsible for the late recognition of the relation- ship of a drug to aplastic anemia. Nevertheless, some drugs have been so often associated with aplastic anemia as to leave no doubt that they can produce it. In recent years the most common agent associated with aplastic anemia has been chioramphenicol (chlornmycetin). Because chlorainphenicol is associated with such a large proportion of the cases of pancytopenia reported in recent years, it is appropriate to consider in more detail the henuopoletic effects of this drug. Chloramphenicol has been observed to cause a general inhibition of protein synthesis by bacteria11 and has been shown to block the synthesis of many enzymes.12 Two types of hematological toxi- city have been observed: (1) a temporary erythroid hypoplasia, associated with anemia and occasionally with thrombocytopenia and leukopenia, and (2) a se- vere, often fatal, pencytopenia. 0 Beutler, E.: Drug-Induced Hemolytic Anemia, in Metabolic Basis of Inherited Disease, edited by J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson, New York: McGraw- Hill Book Company, 1960, pp. 1031-1067. Harris, J. W.: Studies on Mechanism of Drug-Induced Hemolytic Anemia, J Lab Gun Med 47: 760-775 (May) 1956. 8Freedman, A. L.; Barr, P. S.; and Brody, B. A.: Hemolytic Anemia Due to Qulnidine: Observations on Its Mechanism, Amer J Med 20: 806-816 (May) 1956. ~ Ackroyd, J. F. : Role of Sedormid in Immunologic Reaction that Results in Platelet Lysis in Sedormid Purpura, Gun ~ci 13: 409-423 (Aug.) 1954. 10 Moeschlin, S., and Wagner, K.: Agranulocytosis Due to Occurrence of Leukocyte- Agglutinins, Acta Hacmat 8 :29-41 (July-Aug.) 1952. 11 Gale, B. F., and Folkes, J. P.: Assimilation of Amino Acids by Bacteria: 15. Actions of Antibiotics on Nucleic Acid and Protein Synthesis in Staphylococcus Aureus, Bioclzem J 53: 493-498 (Feb.) 1953. ~ Brock, T. D.: Chloramphenlcol, Bact Rev 25: 32-48 (March) 1961. PAGENO="0598" 2732 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The temporary erythroid hypoplasia has been observed mainly in patients given large doses of chioramphenical, 4 to 12 gm. daily for 10 to 35 days.'~16 A retricu- locytopenia,13' ~ a rise in serum iron, a reduced rate of clearance of plasma Fe-59, and blockade of the uptake of Fe-59 by erythrocyrtes14 have been the first changes noted. These changes are followed by anemia. Some patients have developed thrombocytopenia13' 15 and some have had leukopenia.15' 16 Marrow stud- ies have revealed erythroid hypoplasia 15 with abnormal vacuolization of the cyto- plasm of erytbroblasts 16, and sometimes of cells of the inyeloid series.13 When chloramphenicol is discontinued, all of these abnormalities are reversed. Reticulo- cytosis develops within 5 to 7 days, w-ith peaks as high as 17.6%,b6 and the hemo- globin level returns to normal. Following recovery from erythroid hypoplasia, one of the above patients was given 2 gm. of chloramphenicol per day for 7 days without recurrence of toxicity, but when the dose was raised to 12 gm. per day the anemia reappeared~'3 Patients with infection or anemia seem to be more sus- ceptible to this effect of chioramphenicol than are normal people.17 The adminis- tration of chloraniphenicol to patients with pernicious anemia blocks the reticu- locyte response to vitamin Bu and, in patients with iron deficiency anemia, it blocks the response to intramuscular administration of iron.17 Reticulocytosis occurs in these patients several days after chioramphenicol is discontinued. The other hematologic response to chloramphenicol is a severe pancytopenia. All of the marrow cell types are affected, and the marrow is hypoplastic. The process is progressive over a long period of time, and recovery, if it occurs, is slow. This complication has been observed in patients treated with conventional doses, and appears to be more c~mimon in children, especially young girls.5 Test doses of chioramphenicol have seldom been given to patients who have recovered from pancytopenia. One unpublished case has been reported; the patient received a second course of chloramphenicol following recovery from marrow toxicity thought to be due to previous chloramphenicol administration.18 This patient, a 15-month-old male infant, received 125 mg. of chloramphenicol every 6 hours for 8 doses before the initial dyscrasia was reported. The total leukocyte count fell from 9,800 per cubic millimeter on the day therapy w~as started to 3,800 on the second day, 1,900 on the fourth day and then gradually returned to normal. This dose of chioramphenicol is tolerated without demonstrable blood changes by the vast majority ~f patients who receive it and, thus, this reaction is suggestive of a drug idiosyncrasy. The mechanism by which chloramphenicol produces aplastic anemia appears to be different from that which leads to the acute changes in erythropoiesis. The difference may be only quantitative, however. SUMMARY It is incumbent upon the physician to maintain a lively awarness of the risk of blood dyscrasia associated with the use of certain drugs and to use such drugs only when the potential benefits of administration considerably outweigh the relatively small risk of developing a blood dyscrasia. When it is necessary to use such drugs, it is important that appropriate hematological studies be made at intervals and that the j~atient be warned to re~oft immediately the development of fever, sore throat, weakness and pallor, or a bleeding tendency. Conversely, it is also important that the physician be aware that in the event of develop- ment of infection or easy bruising in a patient who has been taking such drugs, blood cell counts must be made immediately. If agranulocytosis, thrombocyto- penia, or pancytopenia is present, further administration of the drug must be stopped. Needless to say, this is the most important therapeutic measure. 12Krakoff, I. H.; Karnofsky, D. A.; and Burchenal, J. H.: Effects of Large Doses of Chioramphenicol on Human Subjects, New Engi J Med 253: 7-10 (July 7) 1955. 14Rubin, D.; Weisberger, A. S.; Botti, R. E.; and Storaasli, J. P.: Changes in Iron Metabolism in Early Chioramphenicol Toxicity, J Gun Inve8t 37: 1286-1292 (Sept.) 1958. ~ Ozer, F. L.; Truax, W. E.; and Levin, W. C.: Erythrold Hypoplasla Associated with Chioramphenicol Therapy, Blood 16: 997-1001 (July) 1960. 16Rosenbach, L. M.; Caviles, A. P.; and Mitus, W. J.: Chioramphenicol Toxicity: Reversible Vacuolization of Erythroid Cells, New Engi J Med 263: 724-728 (Oct. 13) 1960. 17 Saldi, P.; WaUerstein, R. 0.; and Aggeler, P. M.: Effect of Chioramphenicol on Erythropoiesis, J Lab Gun Med 57 : 247-256 (Feb.) 1961. ~ Unpublished Report. PAGENO="0599" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2733 [From the Journal of the American Medical Association, May 20, 1961, vol. 176, No. 7, pp. 588-593] CHLORAMPHENICOL BpNE MARROW TOXICITY (By Paul R. MeCurdy, M.D., Washington, D.C.*) The capacity of chiorarnpheiiicol to suppress bone marrow activity has recently been reemphasized.1 Although the incidence of irreversible or slowly reversible blood dyscrasia caused by chioramphenicol is not great, the serious nature of these effects is sufficient reason to restrict its use to situations in which an equally effective and less toxic antibiotic is not available. The purpose of this report is to present studies in 15 patients in whom early toxicity was recognized by morphologic stuthes available to the clinician, and the drug was discontinued before irreversible damage occurred. Recent studies 2, 3 Ia have suggested that the occurrence of marrow toxicity due to chloramphenicol is more frequent than is indicated by sporadic reports of apiastic anemia which continue to appear in the literature. Using sensitive radioiron techniques, Rubin et al. found evidence for suppression of red blood cell production in 5 of 15 patients tested.2 Saudi `and associates reported morpho- logic changes in the primitive red cells of the marrow in each of 10 patients who received 40-85 mg/kg. of chioramphenicol per day, whereas 12 subjects who received 11-45 mg/kg. per day had no such changes.8' Ia When Krakoff et al. gave 6 or more grams of chloramphenftcol daily to 4 patients with carcinoma, toxic depression of the hemoglobin and reticulocyte count was found in each.4 The latter 2 reports suggest that the occurrence of toxicity is partially dose- dependent, an effect which previously has not been emphasized. Eleven patients were seen in consultation because of anemia or bleeding during chioramphenicol therapy. Four others were being treated with chloramphenicol without the physician in charge being aware of the subtle hematologic changes that were under way. Depression of erythropoiesis, manifested in a drop in reticulocyte count, was the first and most frequent warning of trouble; it was followed in order by suppression of thrornbopoiesis and leukopoiesis. The reversible stage is unpredictable and sometimes quite short. In each of these cases the bone marrow recovered after chioram- phenicol administration was stopped. Ohloramphenicol should not be given for trivial infections. When it must be used, serial reticulocyte counts should be done, and a sudden or severe drop calls for study of the bone marrow. MATERIAL AND METHODS Intensive hematologic investigations 011 15 instances of bone marrow depres- sion believed `to have been produced by chioramphenicol form the clinical material for this report. Eleven patients (cases 1-9, 14, and 15) were seen in consultation because of an anemia or because of bleeding and thrombocytopenia. Four patients (cases 10-13) were being treated with chloramphenicol, but the physicians in charge were not aware of the subtle hematologic changes which were under way. In 12 of the 15 patients bone marrow punctures and cell studies were done during the period of toxicity. The slides of all these were available for retrospective interpretation of morphologic changes. In two instances the marrow was examined early during recovery, and in the final case the marrow was not examined. In 4 patients, serial bone marrow aspirates were examined before, during, and after recovery from the suppressive effects of chloramphenicol. REPORT OF CASES Case 1.-A 64-year-old Negro male was admitted to the hospital because of mental deterioration and heart disease and was treated for pneumonia with 2 gm. (28 mg/kg.) chloramphenicol daily for 24 days. The hematocrit reading fell from 40 vol.% prior to therapy to 21 vol.%. Reticulocyte count was 0.4%, platelet *From the Department of Medicine, Georgetown University School of Medicine and Georgetown Medical Division, D.C. General Hospital. Assistant Professor of Medicine, Georgetown University School of Medicine and Medical Officer, D.C. General Hospital. NoTE-Numbered footnotes at end of article, p. 2742. PAGENO="0600" 2734 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY count was 27,000, and white blood cell count was 5,200. Bone marrow w-as nor- mally cellular, but red blood cell elements were reduced and early forms contained vacuoles (Fig. la). White blood cells were normal on the peripheral blood smear. The patient had also received meprobamate, choline theophyllinate, tetracycline, and bis-hydroxycoumarin, but all had been discontinued 2 or 3 weeks prior to the discovery of marrow toxicity. He was given 600 ml. of sedimented red blood cells, and chioramphenicol was discontinued, but he died of heart disease prior to complete marrow recovery. At postmortem examination, 5 days after admin- istration of the last drug, there was still a definite reduction of erythroid cells in the marrow. Other marrow elements were normal. There was minimal early liver cirrhosis. Case 2.-A 50-year-old Negro female was admitted because of pneumonitis. She received 2 gm. (42 mg/kg.) of chioramphenical daily for 17 days and again for 27 days after a 6-day rest. At the end of the second course, the hematocrit was 23 vol.%, reticulocyte count 0.0% and white blood cell count 10,375. Platelets were adequate on the peripheral blood smear. The bone marrow was cellular, but there was a reduction in the red blood cell elements. The rubriblasts and prorubricytes were vacuolated. The drug w-as stopped and 600 ml. of sedimented red cells were administered. The hematocrit reading rose to 31 vol.%, where it stabilized. Twelve days later, the reticulocyte count was 2.3%. Although she had received promethazine hydrochloride in addition to streptomycin during the first course of chloramphenicol, no medicaments except milk of magnesia and cascara were given during the second course, when marrow suppression became evident. One month later, after apparently complete recovery from marrow hypoplasia, she died of her pulmonary infection. At postmortem examination, the liver w-as found to contain minimal fatty infiltration. The bone marrow w-as hyperplastic in all hematopoietic elements. Case. 3.-A 55-year-old Negro male was admitted because of coma and con- vulsions. He had a short, acute psychosis, compatible with dilirium tremens. He was given 2 gm. (37 mg/kg.) of chloramphenicol prophylactically for 22 days. At the end of this time he had hematemesis. The hematocrit level had fallen from 45 to 26 vol. % and the platelet count was 30,000. Reticulosytes were 0.1% and the white blood cell count, 3,600. The marrow was hypocelluar and the primitive rubriblasts contained vacuoles. He was given 2,000 ml. of whole blood and chioramphenicol therapy was discontinued. Four days later the hematocrit reading was 35 vol.%, reticulocytes 1.8%, white blood cells, 7,375, and platelets were 47,000. After 2 weeks the hematocrit was 44 vol.%, reticulocytes 1.5%, white Fig. 1..-Vacuolization of primitive red cell precursors of marrow in chloramphenicol toxicity. a, Case li 1,, Case 7; c, Case 9; d, Case 13. PAGENO="0601" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2735 cells 5,100, and platelets 134,000. No more transfusions had been given. There was no renal disease, but liver function was impaired. The BSP (bromsulpha- lein) was 35% and the prothrombin time remained elevated 2 to 5 seconds over the control, despite parenteral vitamin K therapy. Other medicaments during the period included procaine penicillin, tetracycline, and propantheline bromide. His blood was essentially normal when he was transferred one month later to a psychiatric institution for custodial care. Case 4.-A 48-year-old mildly diabetic Negro male was admitted for therapy of aseptic necrosis of the right femoral head resulting from a traumatic posterior dislocation 20 years before. He had cirrhosis of the liver (BSP 33%). Follow- ing an arthrodesis, he developed wound abscesses and chronic osteomyelitis. He was treated with procaine penicillin, streptomycin, and novobiocin with only temporary benefit. Chloramphenicol was given, 2 gm. (29mg/kg.) daily in 3 courses for 36, 69 and 7 days. Ten days later he was placed on 3 gm. (44 mg/kg.) daily for a total of 76 more days. At the end of this last period he complained of blurred vision, and the hematocrit reading was found to be 16.5 vol.'%. No reticu- locytes were found in the peripheral blood. White blood cell count was 7,800 and platelets 192,000. The bone marrow was cellular, but there was a decrease in red cell precursors, and the primitive rubriblasts contained vacuoles. The drug therapy was stopped and he was given 300 ml. of packed red cells. The reticulocyte count reached a peak of 8.7% 9 days after the drug was stopped. The hematocrit gradually returned to 40 four weeks later. The patient's visual disturbance disappeared. He had received iproniazid for 6 months prior to the episode of marrow depression but no other drugs for 5 months. Six weeks later he was again given 2 gm. of chloramphenicol daily for 18 days, and his hema- tocrit reading fell from 42 to 32 vol.%. However, during this period he had further surgery and a depressant effect of this trauma on erythropoiesis must be considered. Case 5.-A 24-year-old paraplegic Negro male was admitted by transfer from another hospital 2 months after an auto accident in which he had suffered a fracture-dislocation of his neck. During the next 8 months he received 3 courses of chloramphenicol orally for a troublesome bladder infection. Two grams (39/kg.) were given daily for 72 days; 2 gm. daily for 16 days; and 4 gm. (77 mg/kg.) daily for 10 days. He also received sulfasoxazole and tetracycline for the same purpose. Other drugs included meprobamate, zoxazolamine, diph- enylhydantoin, phenobarbital, nitrofurantoin, and tripelennamine for varying periods of time. Ten months after admission, 2 gm. of chloramphenicol were administered intramuscularly daily. After 21 days the dose was increased to 4 gm. daily orally and this was continued for an additional 19 days. At the end of this period the hematocrit reading was 21 vol.%, reticulocytes were 0.0% and the platelet count was 18,000. The white blood cells appeared normal on a peripheral smear, although the laboratory reported a count of 4,150. The bone marrow aspirate was cellular, but there were very few red blood cell precursors, and the primitive rubriblasts contained vacuoles. Megakaryocytes appeared adequate despite the thrombopenia. He was given 1,500 ml. of whole blood, and chloramphenicol therapy was stopped. Five days later reticulosytes were 0.1%, but 11 days after administration of the last chloramphenicol they had risen to 0.5%, and to 1.3% after 7 more days. The urinary tract infection was controlled with streptomycin, sulfasoxazole, and later vancomycin and tetracycline. Nitro- furantoin and methenamine mandelate (Mandelamine) were also given. Fourteen months after the acute episode of marrow suppression, chloramphenicol was again administered in several 6-10 day courses of 2 gm. daily. For this period very little laboratory data are available. However, during the last such course, the hematocrit reading fell from 35.5 to 27 vol.%, then spontaneously rose to 41.5 two months after the last dose of the drug. Despite the frequent urinary tract infections, his blood-urea-nitrogen level remained normal. Liver function as measured by the BSP, prothrombin time, and serum albumin and globulin was also normal. Case 6.-A 38-year-old chronic alcoholic Negro female was admitted because of abdominal pain, nausea, and vomiting. She had tuberculosis, and had had a thoracoplasty in 1950. She had received no chemotherapy for 5 months, and there was no evidence for activity of the tuberculosis at this time. Chloramphenicol was given prophylactically for presumtive pancreatitis, 3 gm. (90 mg/kg.) daily PAGENO="0602" 2736 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY for 5 days intramuscularly and then 2 gm. (60 mg/kg.) daily for 6 more days. The hematocrit reading had been 36 vol.% shortly after admission but was found to be 14.5 vol.% after the course of chloramphenicol. The platelet count was 22,000. Reticulocytes were not determined then, but 6 days later they were 0.8%. Bone marrow aspiration was cellular, but there was almost complete lack of red blood cell elements. The number of megakaryocytes was reduced. Granulocytes appeared normal in the peripheral blood smear and in the bone marrow. Primi- tive rubriblasts contained numerous vacuoles. She was given 600 ml. of sedi- mented red blood cells and 500 ml. of whole blood. Nine days after the chloram- phenicol was discontinued, reticulocytes were 4.1%. Three weeks after cessation of therapy, the marrow contained adequate red cell precursors but maturation was atypical. Two weeks later it was frankly megaloblastic. After 6 days of treatment with approximately 1.25 mg. of folic acid daily (~4 of a 5 mg. tablet), the number of reticulocytes had risen from 0.6% to 6.6%. The hematocrit read- ing rose from 30 to 39 vol.% in 3 weeks. Later, a Schffling test was normal. Caste 7.-A 17-year-old Negro female with presumptive sickle cell anemia (com- plete genetic data are not available), was treated with chloramphenicol for osteomyelitis of the proximal tibia, receiving 1.5 gm. (29 mg/kg.) daily intra- muscularly for one day, 2 gm. (38 mg/kg.) daily orally for one day and 3 gm. (58 mg/kg.) daily orally for 17 days. At the end of this time, the hematocrit read- ing had dropped from 31 to 16.5 vol.% and reticulocytes from 3.8% to 0.5%. The bone marrow aspirate contained decreased numbers of erythroid cells and a few of the primitive rubriblasts contained vacuoles (Fig. lb). Recovery from the aplastic crisis was prompt after cessation of chloramphenicol therapy. Whereas aplastzic crises unrelated to this drug are seen in patients with sickle cell anemia, both the time relationship and the presence of abnormal primitive red blood cells strongly suggest that the drug was responsible. Case 8.-A 3-year-old, 42 lb. (19.1 kg.) Negro female was admitted because of a fever of unknown origin. Eight days later she was given chloramphenicol, 0.8 gm. (42 mg/kg.) daily for 2 days, followed by 2 gm. (105 mg/kg.) daily for 13 days because of an initial but later untenable diagnosis of typhoid fever. The hematocrit reading fell from 32 to 25 vol.%. Five days after the drug was stopped, the reticulocytes were 0.0%. On the next day, the marrow contained increased erythroid activity and there were no vacuoles in the rubriblasts. Nineteen days after therapy was stopped, the hematocrit value had spontaneously risen to 36 vol.% and reticulocytes were 2.2%. Other than a few days of tetracycline soon after admission, she received no other drugs. Case 9.-A 50-year-old Negro female was found to have apathetic thyrotox- icosis and was treated with methimazole. She also received 2 gm. (43 mg/kg.) daily of chioramphenicol for 11 days. The hematocrit reading fell from 34 to 27 vol.% during this therapy and the reticulocyte count from 4.8% to 1.0%. White cells and platelets were normal. The marrow aspirate contained some reduction in red cell precursors and the rubriblasts were vacuolated (Fig. lc). Methimazole therapy was not discontinued. Four days after the last chloram- phenicol, the marrow was slightly more cellular and there were more erythroid elements. No vacuoles were seen. The reticulocyte count had risen to 3.2%. Seven days later the hematocrit value had returned to the prechloramphenicol level of 34 vol.%. Case 10.-A 25-year-old Negro male was admitted following a 2-week debilitat- ing illness due to typhoid fever. The bone marrow was cellular; granulocytes were increased but red cell precursors were normal. The patient was treated with 3 gm. (44 mg/kg.) of chioramphenicol daily for 3 days followed by 4 gm. (60 mg/kg.) daily for 10 days, and then 2 gm. (29 mg/kg.) daily for two days. On the day following reduction in dosage from 4 to 2 gm. daily, the reticulocytes were 0.1% and the bone marrow contained reduced numbers of erythroid cells. The rubriblasts contained vacuoles. Three days after cessation of therapy, the reticulocytes were 0.2%. The next day they were 1.0%, and 6 days after ad- ministration of chloramphenicol was stopped they were 5.2%. The hematocrit PAGENO="0603" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2737 reading, low on admission, rose to 32 vol.%, first with transfusion and then as thepatient's typhoid improved. It fell again to 27 vol.% as marrow suppression intervened. Twenty-three days after* chioramphenicol therapy was stopped, it had spontaneously climbed to 41 vol.%. He received no other drugs. There was no evidence for functional impairment of kidneys but his BSP was 14%. 30 20 l0 R.L.K. SEVERE CiRRHOSIS 20 25 30 DAYS Fig. 3.-Course of marrow depression with chiorampheni. col and recovery in 35-year.old Negress with severe alcoholic cirrhosis (Case 11). Fig. 2.-Serial marrow studies in chioramphenicol toxicity -Case 11 severe liver cirrhosis: a, prior to therapy; b, day after cessation of therapy; c, (1 days after last dose of drug. Case 12 severe liver cirrhosis: d, before chioramphenicol; e, after 9 days of therapy; f, 4 days after last administration of chioramphenicol. CHLORAMPHENICOL gms. E Hct. Ret~c. 0 5 0 15 PAGENO="0604" 2738 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Ja~se 11.-A 35-year-old chronic alcoholic Negro female (R.L.K.) was admitted with severe decompensated cirrhosis. She had aseites and a mental picture resem- bling "pre-coma." Five days after admission she was given chiorairaphenicol 2 gm. (44 mg/kg.) daily by mouth. Photonilerographa of the serial bone marrow aspirates are shown in figures 2a-c. She received no other med~icaments during this period. Her course is depicted in Figure 3. There was no evidence for depres- sion of white blood cells or platelets. When her previous record was reviewed, it was found that 3 years previously she had received 1.5 gm. (33 mg/kg.) of chioramphenicol daily for 6 days and the hematocrit reading had dropped frosn 38 to 30 vol.%. Again, 2 years later, she was admitted with severe cirrhosis and was given 2 gm. chioramphenicol daily for 17 days. The number of reticulocytes dropped from 3.4 to 0.1% three days prior to the cessation of therapy because of diarrhea. They were 5.2% 18 (lays after the last dose of the drug. The fall in hematocrit value from 33 to 25 vol.% with a need for blood transfusion was iiii- mistakably associated with chioramphenicol, although it was not so recognized at the time. No change in white blood cell count was noted. Platelet counts and bone marrow studies were not done. G.H. SEVERE CIRRHOSIS CHLORAMPNEP4ICOL Hct. Retic. E ~WM4~ 40 Hot. 0 5 10 15 20 25 30 35 DAYS Fig. 4.-Course of marrow depression with chiorampheni. col and recovery in :38-year.old Negro male with severe alcoholic cirrhosis (Case 12). PAGENO="0605" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2739 Case 12.-A 38-year-old Negro male was admitted with decompensated cir- rhosis, asci.tes, and "pre-coma." He was given chlorainphenicol succinate in- tramuscularly, 2 gm. (34 mg/kg.) daily for 10 days. His course is shown in Fig- ure 4, and serial bone marrow aspirates are illustrated in figures 2d-f. He also received menadione, tetracycline, and methenamine mandelate during the period of study. Case 13.-A GO-year-old Negro male was admitted because of generalized arteriosclerosis. He had moderate liver disease, with a BSP of 16%. He was given 2 gm. (34 mg/kg.) of chioramphenicol daily for 10 days. After 4 days, a tracer dose of Fe59 was given intravenously and 14 days later, only 54% had appeared in the red blood cells. Serial bone marrow aspirations were performed and at the end of chloramphenicol therapy, there was a reduction in red cell prescursors and the primitive rubriblasts contained vacuoles (Fig. ld). Four days after therapy was stopped, there was slight erythroid hyperplasia and marrow morphology was normal. During therapy the hematocrit reading fell only 2 points but reticulocytes were 0.1% on the day chloramphenicol was stopped and* rose to 2.4% five days later. Case 14.-A 54-year-old Negro female was hospitalized for anemia and uremia due to chronic glomerulonephritis. She was given chloramphenicol 3 gm. (48 mg/kg.) daily for 28 days. Prior to therapy, the reticulocyte count was 3.6% and after 11 days of therapy it was 0.3%. There was no leukocyte depression and no clinical evidence of thromlocythpenia. Bone marrow aspirates prior to therapy showed moderate erythroid hyperplasia. None was obtained later. One day after chloramphenicol therapy was stopped, she died. No postmortem marrow specimens are available. Case 15.-A 45-year-old Negro female was admitted with pulmonary tubercu- losis. During her first 3 weeks in the hospital, she was treated with isoniazid, para-aminosalicylic acid, and prednisolone. The findings in a bone marrow aspi- rate were consistent with an acute and chronic infectious process. The hematocrit value remained at 25 vol.%. At the end of this period she was given a 2-week course of chioramphenicol 2 gm. (44 mg/kg.) daily because of a superimposed pneumonia. The hematocrit reading rose to 30, then fell to 28 vol.%. The day after this drug was discontinued reticulocytes, which had been about 1.0% on several occasions, dropped to 0.0%. Four days later they were but 0.1%. Six days after the last chloramphenicol administration they had risen to 1.2% and the bone marrow showed moderate erythropoietic activity. The next day reticulocytes were 4.0%. The hematocrit value had returned to pre-treatment levels by the 16th day. Isoniazid was not discontinued. No other drugs but procaine penicillin were given during the period of chioramphenicol therapy. RESULTS The clinical features of these patients are summarized in the table. There were 8 females and 7 males, ranging in age from 3 to 68 years. All were Negro, reflect- ing the preponderant patient population of the hospital. Results of hemoglobin electrophoresis were available in 13. Of these, 10 had normal hemoglobin; one had sickle cell trait; one had hemoglobin C trait; and one had sickle cell anemia. PAGENO="0606" 2740 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~ .~ .~ ~ ~ E ~ 0 I~C~ *~ ~ ~ ~ >- .3 ~ ~ E 3 ~ 0 ~ ~ z5z~ 0 © © + © © © © © © © © + -H +©++© +©©+ + +++©+ 1~. 0. +++++ + +©+ + +++I I +© I © + + © © © © © 0 © I© (I) 0 © +© © © © © © © 00 © I© 19 ©. 0 © © © 0 00- 0 U- 0 +++++ + +++ + +++++ *0 It) ~ ~.q ~ - .0 o Oo 0 ,_ *0 0 COC'4 ~ ~ ~ C~4~ c~r- c ~WC~J~ ~ I 0 0 = o 00000 5000000000020 E ~ C.) - ~ C~~4C~4C1)~4 0 II. C-) -~ 5 C.) - © 1© ++ © ©©© © +© ©©© SLI.525 U- ~ ~ u.5~u.u~ ~ d II -r PAGENO="0607" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2741 All patients had evidence for depression of erythropoiesis coincident with chloramphenicol therapy, in which depression was not judged to be the result of their underlying disease. In one patient (Case 6) a rapidly developing anemia (hem'atocrit reading 14.5 vol. %) heralded marrow depression. In all patients the reticulocyte counts during toxicity were low, usually below 0.5%. In all 12 available bone marrow aspirations obtained within 48 hours of the last dose of chloramphenicol, there was striking vacuolization of primitive rubriblasts (Fig. 1). Marrows obtained 4 days or longer after cessation of drug therapy did not show these changes. In one instance, vacuolization was observed as early as 6 days after the institution of chloramphenicól therapy: Four days later, another bone marrow smear from this patient showed progression of these changes. No similar abnormalities were observed in control studies of the marrow done after three or more weeks of chloramphenicol therapy in 2 patients who did not de- velop anemia. Serial marrow observ'ations that were made in 2 patients are illus- trated in Figure 2. The course of the erythropoietic depression in these 2 indi- viduals is shown in Figures 3 and 4. Throinbocytopenia was seen in 4 and leukopenia in one of the patients of this series. Reversal of marrow hypoplas;ia followed withdrawal of ch1oramphe~n&eol in the 14 patients who survived more than a few days after the drug was stopped. The rapid marrow recovery which followed cessation of chloramphenicol treat- ment was usually accompanied by evidence for marrow hyperplasia, such as reticulocytosis and sometimes thrombocytosis `and leuko~ytc~sis. One patient (Case 1) died of other causes before recovery was complete and another (Case 14) died of unrelated medical causes the day after chloramphenicol was discontinued. Ten of the patients had mild to severe preexisting liver disease. Three of the four patients selected for serial marrow aspiration had severe alcoholic cirrhosis with hepatomegaly. Although it is known that chloramphenicol is detoxified by conjugation with glucuronic acid in the liver,5 and that patients with seriously damaged livers may achieve quite high serum levels of free chloramphenicol when treated with 2 gm. a day,6 we could come to no conclusions regarding the role of these factors in this group of Isatients. Four patients in this group had received previous chloramphenicol therapy. Ten received the drug for longer than 2 weeks. In one patient, marrow depres- sion became evident after 71 days of treatment and in another after 40 days. In 8 the drug was given for 2 to 4 weeks. In 5 patients chloramphenicol was admin- istered for less than 2 weeks. Two adult patients received 4 gm. daily (60-77 mg/kg. per day) and four more were given 3 gm. daily (44-90 mg/kg. per day) for a part of the course of therapy which preceded the development of toxicity. The one child in this series received a rather high dose of 2 gm. daily (105 mgI kg. per day). Although 8 patients received no more than 2 gm. daily, every patient in this entire series either received more than 40' mg/kg. per day, or had liver disease. COMMENT From the above data, it appears that suppression of erythropoiesis is the most frequent toxic' effect of chloramphenicol on the bone marrow. In `this series measurable depression of thrombopoiesis and leukopoiesis coincident with treat~ ment with this antibiotic was less common. The frequency with which depression of `red cell production ~y chioramphenleol has `been found when sought2'2' Sa strongly suggests that some degree of marrow depression is a common conse- quence of treatment with this drug. Since the red cell life span is 120 days and the average course of chloramphenicol therapy is 5 to 10 days, brief mild erythropoietic depression easily may be overlooked. In this study the reticulo- cyte count was found to be the most readily available tool for measuring the effect of chloramphenicol on erythropoiesis. In 12 of the 15 patients that form the substance of this report, the reticulocyte count during drug toxicity was 0.5% or lower. In 2 others, the values represented a significant fall from previous levels. In the remaining case, r~ticulocyte counts were not done at the height of toxicity. The bone marrow morphologic changes of chioramphenicol toxicity including reduction in red cell precursors with vacuolization of primitive rubriblasts have been reported by others.3' ~` It is likely that vacuolization is a nonspecific change which may result from other causes as well. When these changes are found in a patient who is taking chloramphenicol, until proved otherwise they are indica- tive of marrow depression by this drug. PAGENO="0608" 2742 COMPETITIVE PROBLEMS IN THE DRIJG INDTJSTRY The present studies suggest the following modus operandi for chioramphenicol therapy: (1) for trivial infections avoid the use of the drug altogether; the risk of chloramphenicol treatment may be greater than that of the disease itself; (2) obtain serial reticulocyte counts on all i~atients receiving chloramphenicol; and (3) if the reticulocyte counte drops abruptly or falls below 0.5%, obtain a bone marrow aspirate for study. Stop therapy with the drug if vacuoles are seen in the primitive rubriblasts or if there is a marked reduction in the erythro- poietic activity of the marrow. Although in this series leukopenia and throm- bopenia were always accompanied by erythropoictic abnormalities, the possibility of selective depression of these elements can not yet be completely discarded. At the present time lack of knowledge regarding the mechanism of toxicity makes it difficult to predict which patients will develop irreversible marrow depression as a result of chloramphenicol treatment. 011 the one hand, the morphologic changes in the marrow and their frequency along with evidence of dose-dependency in some patients suggests a direct chemical effect.1' ~ On the other hand reports of bone marrow hypoplasia after token doses of ehloram- phenicol are compatible with a hypersensitivity phenomenon.8 Both direct toxic poisons and hypersensitivity ~ may cause vacuolization of cells. The fact that in vitro studies done outside the humoral environment within the host have failed to demonstrate metabolic abnormalities induced by therapeutic levels of the drug10' 11 is consistent with but does not prove a hypersensitivity mechanism for toxicity. The sensitivity of erythropoiesis to chloramphenicol noted in this Study may be a result of the more ready diffusion of free chloram- phenicol into red cell precursors than into the other cells of the marrow.n Despite common belief, the toxicity is probably not related to the nitrobenzenè ring of chloramphenicol, since an analogue without this structure proved to be considerably more toxic.13 This and other studies indicate that most patients developing chloramphenicol toxicity seem to pass through 2 phases of marrow depression, an initial reversible period of variable duration followed by an often serious period of damage which does not remit until the drug is stopped and may not remit, no matter what is done. Early in the reversible stage rapid recovery follows cessation of treat- ment. Later in the reversible stage, cessation of therapy is followed by a slower return of the marrow to normal. These same principles which apply to the erythropoietic system also `apply to depession of thrombopoiesis and leukopoiesis by chloraniphenicol. In a few patients, the reversible stage m:ay be quite short. This may be because of prior therapy, high doses, or of hypersensitivity. One or all of these factors may be enhanced by high drug levels caused by high doses or abnormalities in drug metabolism as in liver disease. Our present state of knowledge does not permit more than a speculative explanation for the under- lying mechanism for the toxic effects of chloramphenicol reported in this study. SUMMARY AND CONCLUSIONS Fifteen patients with bone marrow depression associated with chloramphenicol treatment are presented~ Erythropoiesis was most often affected, follow'ed ill order by suppression of thrombopoiesis and leukopoiesis. Monitoring erythro- poiesis by serial reticulocyte counts during chloramphenicol therapy has been found to be of value in detecting early evidence of drug toxicity. REFERENCES 1 Dameshek, W.: Chioramphenicol-New Warning: Editorial, JAM4. 174: 1853-1854 (Dec. 3) 1960. 2Rubin, D.; Weisberger, A. S.; Bott, R. E.; and Storaasli, J. P.: Changes in Iron Metabolism in Early Chioramphenicol Toxicity, J. Olin Invest 37: 1286-1292 (Sept.) 1958. Saidi, P., and Wallerstein, R. 0.: Effect of Chioramphenicol on Erythropoiesis, Olin Res 8: 131 (Jan.) 1960. 3a Saidi, P.; Wallerstein, R. 0.; and Aggeler, P. M.: Effect of Chloramphenicol on Erythropoiesis, J Lab Olin Med 57: 247-256 (Feb.) 1961. ~ Krakoff, L. H.; Karnofsky, D. A.; and Burchenal, J. H.: Effects of Large Doses of Chioramphenicol on Human Subjects, New Engl J Med 253: 7-10 (July 7) 1955. Kunin, C. 1~1.; Glazko, A. J.; and Finland, M.: Persistence of Antibiotics in Blood of Patients with Acute Renal Failure: II. Chioramphenicol and Its Metabolic Products in the Blood of Patients with Severe Renal Disease and Hepatic Cirrhosis, J Olin Invest 38: 1498-1508 (Sept.) 1959. PAGENO="0609" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2743 McCurdy, P. R.: Unpublished Observations. Rosenbach, L. M.; Caviles, A. P.; and Mitus, W. J.: Chloramphenicol Toxicity; Re- versible Vacuolization of Erythroid Cells, New Engi J Med 263: 724-728 (Oct. 13) 1960. 8 Core, T. E., Jr., and Akelson, S. M.: Aplastic Anemia Following Two Days of Chloram- phenicol Therapy; Case Report of Fatality in Six-Year-Old Girl, J Pediat 41: 340-342 (Sept.) 1952. ° Latta, H.: Some Cytologic Effects of Antibodies, in Mechaaisms of Hypersen8itivity. Edited by Shaffer, J. H., LoGrippo, G. A., and Chase, M. W., Boston: Little, Brown & Co., 1959, pp. 123-137. 10Follette, J. H., and others: Effect of Chloramphenicol and Other Antibiotics on Leukocyte Respiration, Blood 11: 234-242 (March) 1956. 11 Yunis, A. A., and Harrington, W. J.: Patterns of Inhibition by Chloramphenicol of Nucleic Acid Synthesis in Human Bone Marrow and Leukemic Cells, J Lab tJlin Med 56: 831-838 (Dec.) 1960. ~ Weiss, C. F.; Glazko, A. J.; and Weston, J. K.: Chloramphenicol in Newborn Infant: Physiologic Explanation of Its Toxicity When Given in Excessive Doses, New Engi J Med 262: 787-794 (April 21) 1960. ~ Rubin, D.; Weisberger, A. S.; Clar, D. R.: Early Detection of Drug Induced Erythro- poietic Depression, J Lab Clin Mcd 56: 453-462 (Sept.) 1960. 19th St. and Massachusetts Ave., S.E., Washington 3, D.C. The author is grateful to Dr. C. B. Favour for help with the manuscript and Miss Mona Gieschen, MT., ASCP for technical assistance. Supported in part by a grant from the Damon Runyon Memorial Fund for Cancer Research, Inc. [From the Journal of the American Medical AssocIation, Dec. 3, 1960, pp. 1853-1854] CIILORAMPHENICOL-A NEw WARNING In one month recently, I saw 4 new cases of aplastic anemia. Although they ranged in age from 3 to 63, and came from different sections of the coimtry, they had one common denominator: chioramphenicol had been used in the recent past for minor respiratory infections. There was no history of the use of other antibiotics or potentially toxic drugs and since the anemia and the other mani- festions appeared a few months after the last administration of chloramphenicol, it seemed clear that this drug was responsible for the marrow aplasia. In our recently studied series of aplastic anemia (seen within the past 3 years) 8 of 30 had received significant amounts of chloromycetin, almost invari- ably for minor infections. Of the most recent 10 cases of aplastic anemia, 5 had followed therapy with chloramphenicol. The tragic thing about all these seriously ill cases, most of whom died, is that the drug need never have been given. It is becoming increasingly clear that chloramphenicol, an excellent broad- spectrum antibiotic, has antimetabolic effects as well-that is, it may injure the intrinsic "machinery" of certain rapidly proliferating cells, notably of the bone marrow. Thus, Rubin and associates, using radioactive techniques, demonstrated a depressant effect of chloramphenicol on erythropoiesis; this occurred in 5 of 15 subjects receiving ordinary doses and in all of 4 cases with cancer who were given unusually large doses of the drug.1 In another study by Saidi and Wallerstein2 10 of 22 cases treated with chloramphenicol for various infections developed striking vacuolization of nucleated red cells in the bone marrow, associated with a maturation arrest phenomenon and marked reduction in blood reticulocytes. The possibility is present that these temporary changes could go on to complete or partially complete destruction of the bone marrow providing (a) that sufficient drug was used or (b) the patient became sensitized in some manner and was given a second course Of drug therapy at another time. It is thus conceivable that both an immediate or direct effect as well as an indirect or hypersensitivity mechanism may be responsible for the marrow reactions seen. Following the introduction of chloramphenicol in 1948 and the reports of the first cases of aplastic anemia between 1950 and 1952, many editorials and reports of special ad ltoc meetings appeared. Evidently the medical profession was profoundly influenced; in any event, the sales of chloromycetin declined sharply, reaching their lowest level in 1954. This lull was short-lived. By 1958, `Rubin, D.; Weisberger, A. S.; Botti, R. E.; and Storaasll, J. F.: Changes in Iron Metabolism in Early Chioramphenicol Toxicity, J GUn Invest 37: 1286-1292 (Sept.) 1958. ~ Saidi, P., and Wallerstein, H. 0.: Effect of Chloramphenicol on Erythropolesls. To Be Published. 81-280 0-68-pt. 6-39 PAGENO="0610" 2744 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY there was a five-fold increase in the sales of the drug and by 1960, enough cliloramphenicol was being distributed, and presumably used, in the United States to supply 3,732,416 persons with 10 Gm. courses of the drug! (These data were supplied through the kind cooperation of Dr. Harry Carnes, Parke Davis & Co., Detroit, Mich.) To those of us who see cases of aplastic anemia following the use of various possible etiologic agents, chloramphenicol stands out as the most important single historical factor. To be sure, evaluation of histories and even of statistics relating to both the incidence of aplastic anemia and of chioramphenicol as an etiologic agent is difficult. Nevertheless the importance of the chioramphenicol- aplastic anemia relationship persists, and one must naturally be concerned with the possibility that an increased incidence in aplastic anemia may result as use of the drug increases so rapidly. Is the pharmaceutical house which introduced and popularized the use of chloramphenicol to be taken to task? This seems unfair for there can be no question that this respected company has gone to every effort to ferret out statistics of case reports, to carry out experimental work in various animals and even to note the effects of marrow transplantation in chemically induced aplastic anemia of monkeys. Is it the physician, then, who is largely responsible? In a way he is, for without his prescription, the drug would not be administered. Certainly, if he regards chloramphenicol lightly, to be dispensed like aspirin, for every minor cold and respira'tory infection, he is not without blame. But are there certain mitigating factors? Some say that a person ill is a person to be treated! The urge to make a person comfortable and to cure his illness as quickly as possible is an urge each of us has. It follows then that a good antibiotic of the broad spectrum variety and which can be readily administered is something to be used at every opportunity. This is part of the mores in this affluent society of ours. We have potent medicines; the patient is ill; we must treat! The days of simple herb medicines and of simple galenicals have long since passed. More often than not, the newer synthetics, most of them composed of molecules with benzene rings and nitrogen, NH, NH2, or NO2 groupings-are used, and all of them, it should be said, are potentially harmful. What then can be done? A few suggestions may be offered: (1) Physicians must be warned, and in no uncertain terms by means of articles, editorials, meetings, announcements; not once, but repeatedly that chloramphenicol is not only a potent antibiotic but apparently an antimetabolite as well, having effects not only on bacteria but on the bone marrow. (2) By some means, whether by regulation or `by self-discipline, promiscuous use of the drug should be avoided and its use restricted' to impelling circumstances, i.e., for conditions in which no other antibiotic is currently effective. One realizes that this is more easily said than done, knowing the physician's individualistic nature. (3.) The patient and the patient's family must be warned, either by the physician or by the druggist that this is a powerful drug; that it should `be used only once; that its repeated use may result in serious blood reactions; that it should not be kept in the bathroom cabinet and used again if an apparently similar disorder supervenes. (4) The manufacturing drug house should instruct its detail men, our ubiquitous mentors, not to minimize the dangers of the drug, and to empha- size its value for certain specific conditions, and not for the whole gamut of infectious diseases. The journal advertising could be made more forceful regard- ing the necessity for guarding against use of the drug indiscriminately, and especially in minor infections, or in repeated courses; or off the bathroom closet shelf. It might be wise for the patient or his family to have some knowledge of what antibiotic is being used in a given case. Perhaps we physicians might also consider, at least for many of the acute, self-limited infections, the more con- servative course (radical by present-day standards) of giving no potent medica- tions at all, but rather such symptomatic care as aspirin, fluids, and the like. After all, the body defenses are usually capable of handling most acute upper respiratory infections. * In any even, something must `be done to reduce the incidence of grave insult to the bone marrow produced by some of the antibiotics. The practicing physician would do well to think twice before prescribing a potent anti'biotic and to ask himself "Is this drug really necessary?" WILLIAM DAMESHEK, M.D., Bosto~v, Mass. PAGENO="0611" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2745 [From'the Journal of the American Medical Association, June 28, 1952, p. 840] BLOOD DYSCRASIA FOLLOWING THE USE OF CHLORAMPHENICOL Chloramphenicol (chloromycetin®) has been accepted by the Council on Pharmacy and Chemistry for inclusion in New and Nonofficial Remedies. Its antibiotic properties are well known, and when the council accepted this prod- uct there was much evidence to demonstrate its therapeutic value. At the same time there then was little reason to believe that serious or fatal side-reac- tions would be demonstrated. Nevertheless, following a study of the chemical structure of the drug, the Council issued a warning at the time of acceptance even though there was meager evidence to prove that such a warning was necessary. Thus, on page 116 of New and Nonofficial Remedies, 1951, there appears the following statement: "Changes in the peripheral blood or the blood-forming organs have been re- ported only during the use of chioramphenicol. Mild hemolytic anemias, granu- locytopenia (no cases of agranulocytosis so far) and an arrest the maturation of the formed elements in the marrow have been described." Recently there have been additional reports of the effects of chloramphenicol on the blood and bone marrow. At least two types of reaction have been encountered. In one there is a transient depression of the formed elements of the blood, involv- ing red cells, white cells, and platelets during therapy with the drug. This type of reaction has been very uncommon, and in the experience of one group well versed in the field of antibiotic therapy it has seemed to occur in patients who were receiving very large doses of the drug or in patients who had renal in- sufficiency. The blood of these patients returned to normal, or at least showed pretreatment values, as soon as therapy with the drug was stopped, and no per- manent deleterious effect was observed. A second and more serious type of reaction that has been encountered is pro- duction of a true aplastic anemia. In the experience of one groi~p, this anemia has occured in patients who have previously received one or more courses of chlor- amphenicol without untoward effect. When the drug was subsequently adminis- tered, even in small doses, a severe blood abnormality has appeared. Even deaths have been reported. Whether chloramphenicol continues to remain as one of the more useful antibiotics or whether it will be relegated to a place where its use will be confined to the treatment of patients with typhoid or serious infections for which no other therapy is available, remains to be seen. Further observa- tions are in order. In the meantime, physicians should be on the alert for re- actions following therapy with this and any other antibiotic, or in fact any of the newer drugs. New therapeutic agents, which are being introduced with ever increasing rapid- ity, are characterized not infrequently by their beneficial or life-saving qualities but also by their ability to cause injury or serious side-effects. A calculated risk is involved whenever one prescribes any medication. The physician is confronted constantly with the difficult task of determining whether the use of a given drug is likely to do more good for a particular patient than any possible harm. In spite of the bast amount of laboratory and clinical study that a new drug usually undergoes before it is placed on the market, subtle or insidious toxic effects. often of a serious nature, frequently are not recognized and brought to the at- tention of the medical profession in general until after the drug has been on the market for some time and has enjoyed widespread clinical use. A propensity to cause injury to the hematopoietic system is particularly likely not to be generally appreciated until a new drug has undergone extensive use for a consid- erable period of time. Physicians who observe hitherto unreported toxic effects or injuries attributable to a recently introduced therapeutic agent have the obligation or duty of bringing this information to the attention of the entire profession. If a physician does not have the time or inclination to prepare case reports of drug injujries for publication in a medical journal, he can perform a useful service by advising the office of the Council on Pharmacy and Chemistry of the pertinent facts in such instances. By this means the Council will be provided with necessary information that may serve as the basis for an early authoritative report or warning statement. PAGENO="0612" PAGENO="0613" Appendix Il. Additional FDA Submissions (~\) DEPARTMENT OF HEALTH EDUCATION AND WELFARE FOOD AND DRUG ADMINISTRATION Hay 7, 1968 Dear Doctor: Serious and often fatal blood dyscrasias are know:i 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 th'e Journal of the American. Medical Association. Because the amount of chloramphenicol distributed exceeàs that to bd expected if the drug were prescribed only for its valid indications, the Food. and Drug Administration believes that chloramphenicoi is often ~-escribed for conditions for which it is not indicated, including trivial conditions sucn 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 st~bstance of which has been and will continue to bepart of thex~ec~ently revised labeling of this drug WARNING Serious and fatal blood dyscrasias . fions of the throat; or as a prophy. (aplostic anemia, hypoplastic one. lactic agent to prevent bacterial mia, thrombocytopenia. and gr000. infections. locytopenia) are known to occur after the administration of chlorom- phenicol. In addition, there have Precautions: It is essential that ade. been reports of aplastic anemia quate blood studies be made daring attributed to chloramphenicol which treatment with tile drug. While later terminated in leukemia. Blood . blood studies may detect early dyscrasias have occurred alter both peripheral blood changes, such as short term and prolonged therapy leukopenia, reticulacytopeaia. or with this drug. Chloramphenicol granulocytopenia, before they c- must not be used when less poten. come irreversi~lc, such studies con. tially dangerous agents will be not be relied on to detect bane effective, as described In the indi. marrow depression prior to develop. cationu' section. It must not be ment of aplastic anemia. To facili. used In the treatment of trivial . tate appropriate studies and obser. Infections or where It Is not mdl. vation during therapy, it Is desirable coted. as In colds, ln~uenua. lnf.c. that patients be hospitalized. 2747 PAGENO="0614" 2748 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY To clarify further the status of this drug in the therapy of infectious disease, *the indicationR for use have been state4 in the recently revised labeling as follows: The revised labeling suggests that patients being treated with chloramphenicol be hospitalized where indicated to facilitate observation during therapy. `It also includes cautionary information regarding use in prognancy 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 Agsociation and State Department of Publ-ic'Health, January 1, 1967. `I. ~~=~&Y BOX" AND THIS INDICATIONS SEC- ~IOVELL S TYPIII - - TION, CHLORAMPHENICOL MUST BE USED ONLY IN THOSE SERiOUS Chloramphenicol is a drttg of choice. INFECTIONS FOR WHICH LESS Itis not rCConltOtCilde(l for theroutinc POTENTIALLY DANGEROUS DRUGS treatment of the t)photd carrier ARE INEFFECTIVE OR CONTRA- state. INDICATED. HOWEVER CHLORAM- , PIIENICOL MAY BE CHOSEN TO -. SERIOUS INFECTIONS CAUSED INITIATE ANTIBIOTIC THERAPY 10 SUSCIsL TulLE S IRAINS IN ON THE CLINICAL IMPRESSION ACCORDANCE \\ITII 1 III~ CON- THAT ONE OF THE CONDITIONS CE1 TS EX1 BESSEl) AIlO\ Is: BELOW IS BELIEVED TO BE PRES- a. Salmonella species ENT; IN VITRO SENSITIVITY TESTS I). if. itiflvcvzoe, specilicalls' men- SIIOULD BE PERFORMED CONCUR- iageal infections RENTLY SO THAT THE DRUG MAY r. ItickctEia lIE DISCONTINUED AS SOON AS d. Lymphogranuloma-psittacosis POSSIBLE IF LESS POTENTIALLY group DANGEROUS AGENTS ARE `IN- e. Various gram-negative bacteria DIC/ITED BY SUCH TESTS. THE ,,. causing Itacleremia, meningitis~ DECISION TO CONTINUE USE " or other serious gram-negative OF CHLORAMPHENICOL BATHER infections THAN ANOTHER ANTIBIOTIC f. Other susceptible organioths WHEN BOTH ARE SUGGESTED BY which have Item demonstrated IN VITRO STUDIES TO BE EFFEC- to lie resislani to all oilier op- TIVE AGAINST A SPECIFIC PATHO. propriate anti-microbial agents. GEN SIIOULD BE BASED UPON SEVERITY OF THE INFECTION, SUSCEPTIBILITY OF THE PATHO- GEN TO THE VARIOUS ANTIMICRO- ). CS STIC FIBROSIS REGIMENS BIAL DRUGS, EFFICACY OF THE VARIOUS DRUGS IN THE INFEC- `is the Oroatmest ot typhoid lever some TION, AND THE IMPORTANT ADD!- authorities mcnmmoed that chiommphesi. TIO'SAL CONCEPTS CONTAINED IN f 810 1 th t t~t t~h b THE `WARNING BOX" ABOVE: atebrile to tosses the possibility at relapse. PAGENO="0615" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2749 The revision of the labeling dfchloramphenicol was approved by.a special.com~ mittec of experts in hematology infectious disea o~ and other m'~dical fields convened by the }ood and Drug Administration o~ }ebruorj 26 l'Gd It copy of the revi~eo ~libeling is enclosed for your attent on `lo o,i~t u~ in further evaluation of this prosieri tne Fooc aid Drug Adninis- tration requests that you report to us any adverse reactions a~sociated with the usc of cl~lordmphenicol A facsimile of our Diug L