PAGENO="0001" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~ HEARINGS BEFORE THE SELECT COMMITTEE ON SMALL BUSINESS UNITED STATES SENATE NINETY-SIXTH CONGRESS FIRST SESSION ON PRESENT STATUS OF: COMPETITION IN THE PHARMACEUTICAL INDUSTRY PART 34 JANUARY 31, FEBRUARY 1 AND 5, 1979 SAFETY, EFFICACY, AND USEFULNESS OF DARVON AND OTHER PREPARATIONS CONTAINING PROPOXYPHENE 0 Printed for the use of the Select Committee on Small Business U.S. GOVERNMENT PRINTING OFFICE 40-224 0 WASHINGTON : 1979 ó~-/~:~.2~ jf~/ For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 PAGENO="0002" SELECT COMMITTEE ON SMALL BUSINESS GAYLORD NELSON, Wisconsin, Chairman LOWELL P. WEICKER, Ja., Connecticut BOB PACKWOOD, Oregon ORRIN G. HATCH, Utah S. I. HAYAKAWA, California HARRISON H. SCHMITT, New Mexico RUDY BOSCHWITZ, Minnesota LARRY PRESSLER, South Dakota WILLIAM B. CHERKASKY, Thvecutive Director GERALD D. STURGES, Professional Staff Member ROBERT J. DOTCHIN, Minority Staff Director STANLEY A. TWARDY, Jr., Minority Counsel (II) SAM NUNN, Georgia JOHN C. CULVER, Iowa WALTER D. HUDDLESTON, Kentucky DALE BUMPERS, Arkansas ROBERT MORGAN, North Carolina JAMES R. SASSER, Tennessee DONALD W. STEWART, Alabama MAX BAUCUS, Montana CARL LEVIN, Michigan PAGENO="0003" CONTENTS Statement of- Adriani, John, M.D., Department of Health and Human Resources, Page office of Charity Hospital at New Orleans, La 16738 Beaver, William T., M.D., associate professor of pharmacology and anesthesia, Georgetown University Schools of Medicine and Dentistry, Washington, D.C 16738, 16746 Boynoff, Morris, pharmacist, Mendocino, Calif 16738, 16779 Durrin, Kenneth A., Director, Office of Compliance and Regulatory Affairs of the Drug Enforcement Administration, accompanied by Donald E. Miller, Chief Counsel 16689 Finkle, Dr. Bryan S., director, Center for Human Toxicology at the University of Utah Health Sciences Center, and assistant professor of pharmacology-toxicology and pathology 16964 Furman, Robert H., M.D., vice president, Corporate Medical Affairs, Eli Lilly & Co., accompanied by Edgar G. Davis, vice president, Corporate Affairs; and John M. Holt, Secretary and General Coun- sel, Pharmaceutical Division 16882 Hudson, Page, Ml)., chief medical examiner of the State of North Carolina 16656 Kennedy, Hon. Donald, Ph. D.,: Commissioner, Food and Drug Administration, accompanied by Richard Cooper, Chief Counsel, FDA; and J. Richard Crout, Director, Bureau of Drugs, FDA 16789 Lasagna, Louis, M.D., chairman of the department and professor of pharmacology and toxicology, University of Rochester School of Medicine and Dentistry 16959 Lewman, Larry V., M.D., forensic pathologist, Multnomah County, Oreg., medical examiner 16680 McBay, Arthur J., chief toxicologist, office of the chief medical examiner, Chapel Hill, N.C 16669 Moertel, Charles G., M.D., Mayo Clinic, Rochester, Minn 16628 Newman, Michael A., M.D., internist, Washington, D.C 16738, 16772 Wolfe, Sidney M., M.D., Public Citizen's Health Research Group__ 16562 EXHIBITS Letter dated January 31, 1979, to Senator Nelson, chairman, Senate Small Business Committee, from Senator Larry Pressler, Senate Small Business Committee 16561 Letter dated November 21, 1978, to Hon. Joseph Califano, Secretary, De- partment of Health, Education, and Welfare, from Sidney M. Wolfe, M.D., Health Research Group 16567 Letter dated January 31, 1979, to Senator Nelson, chairman, Senate Small Business Committee, from Edgar G. Davis, vice president, Corporate - Affairs, Eli Lilly & Co 16615 Advertisement, "Darvon-N 100 contains no aspirin or codeine," Eli Lilly & Co., dated February 1979 16620 Letter dated January 23, 1979, to Sidney M. Wolfe, M.D., Health Research Group, from Quentin D. Young, M.D., chairman, Department of Medi- cine, Cook County Hospital, Chicago, Ill 16622 Article, "Relief of Pain by Oral Medications-A Controlled Evaluation of Analgesic Combinations," by C. G. Moertel,M.D., D. L. Ahmann, M.D., W. F. Taylor, Ph. D., and N. Schwartau, from the JAMA, July 1, 1974, pp. 55-59 16651 Letter dated September 22, 1975, from Arthur J. McBay, Ph. D., and Page Hudson, M.D., office of the chief medical examiner, Chapel Hill, N.C., from the Journal of the American: Medical Association, vol. 233, No. 12, p. 1257 16658 (III) PAGENO="0004" Iv Article, "Fatal Poisoning With Pi opoxyphene: Report From 100 Consecu- tive Cases," by P. Hudson, M.D., M. Barringer, AB, and A. J. McBay, Page Ph. D., from Southern Medical Journal, vol. 70, No. 8, August 1977___ 16659 Letter dated November 30, 1976, to Administrator, Drug Enforcement Ad- ministration, Department of Justice, from Page Hudson, M.D., chief medical examiner, and Arthur J. McBay, Ph. D., chief toxicologist - 16676 Fact sheet, "Compliance and Regulatory Affairs," from the Drug Enforce- ment Administration, U.S. Department of Justice, December 1978 16722 Fact sheet, "The Diversion Investigation Unit Program," Drug Enforce- ment Administration, U.S. Department of Justice, December 1978 16726 Fact sheet, "DAWN (Drug Abuse Warning Network)," Drug Enforce- ment Administration, U.S. Department of Justice, December 1978 16730 Article, "The Controlled Substances Act-Schedules of Controlled Sub- stances," Drug Enforcement Administration, U.S. Department of Justice, December 1977 16733 Article, "Fatalities Due to Propoxyphene," from the FDA Drug Bulletin, vol. 9, No. 1, February-March 1979~. 16826 Article, "The Comprehensive Approach to Patient Care-Section 5-The Placebo Response," by L. A. Morris, Ph. D., and A. K. Shapiro, M.D., Practice of Medicine, vol. X, ch. 32, 1977 16832 Article, "The Placebo Effect in Medical and Psychological Therapies," by A. K. Shapiro, from Handbook of Psychotherapy and Behavior Change, 1978, pp. 369-410 16840 Letter dated February 16, 1979, to Senator Gaylord Nelson, chairman, Senate Small Business Committee, from Robert H. Furman, M.D., vice president, Corporate Medical Affairs, Eli Lilly & Co 16895 Letter dated January 18, 1979, to Sidney M. Wolfe, M.D., Health Re- search Group, from Vincent J. M. DiMaio, M.D., Institute of Forensic Sciences 17002 APPENDIX Statement of Hon. Joseph A. Califano, Jr., Secretary of Health, Education, Welfare, February 15, 1979 17004 Order of the Secretary denying petition, in re petition to suspend new drug applications for propoxyphene, U.S. Department of Health, Ed- ucation, and Welfare, February 15, 1979 17006 Article, "A Company at W'ar: How Lilly Defended Darvon-Marshaling Forces in `Red Flag Alert'," by Peter T. Kilborn, from the New York Times, February 18, 1979, sec. 3, p. 1 17012 Letter dated January 22, 1979, to Senator Gaylord Nelson, chairman, Senate Small Business Committee, from Vernon McKenzie, Principal Deputy Assistant Secretary, U.S. Department of Defense 17019 Letter dated January 24, 1979, to William Q. Sturner, M.D., chief medical examiner of Rhode Island, from Bryan S. Finkle, Ph. D., director, Center for Human Toxicology, University of Utah, plus summary of Darvon-related deaths in Rhode Island, 1974-78 (submitted at request of committee staff) 17021 Letter dated January 26, 1979, to Senator Gaylord Nelson, chairman, Senate Small Business Committee, from James G. Price, M.D., associ- ate professor, Department of Family Practice, Kansas University Medical Center 17041 Letter dated January 31, 1979, to Senator Lowell P. Weicker, Jr., Senate Small Business Committee, from Norman R. and Shirley I. Toffolon, Farmington, Conn 17043 Letters dated January 26 and 30, 1979, to Senator Gaylord Nelson, chair- man Senate Small Business Committee, from Edgar G. Davis, vice president corporate affairs, Eli Lilly & Co 17043, 17044 Notice of public hearing on "Propoxyphene," by the Food and Drug Ad- ministration from the Federal Register, vol. 44, No. 43, March 2, 1979, pp. 11837-11849 17082 HEARING DATES January 31, 1979: Morning session 16557 February 1, 1979: Morning session 16737 February 5, 1979: Morning session 16789 PAGENO="0005" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Competition in the Pharmaceutical Industry) WEDNESDAY, JANUARY 31, 1979 TJ.S. SENATE, SELECT COMMITTEE ON SMALL BusINEss, Washington,D.C. The committee met, pursuant to notice, at 10 a.m., in room 6226, Dirksen Senate Office Building, Hon. Gaylord Nelson, chairman, presiding. Present: Senators Nelson, Morgan Baucus, Weicker, Hatch, and Hayakawa. Also present: Gerald D. Sturges, professional staff member; Stanley A. Twardy, Jr., minority counsel; and Judith K. Hillegonds, staff assistant. Senator NELSON. The Senate Committee on Small Business will be in order. The Senate Small Business Committee today resumes its hearings on competitive problems in the drug industry, and during the next several days we shall be hearing testimony specifically on the safety, efficacy and usefulness of propoxyphene, an analgesic widely sold under the trade name Darvon. Testimony by medical experts in 1970 before this committee held that Darvon, on which Americans spent $140 million in 1977, is less effective than aspirin. Since that time, no independent, well-designed studies have offered any evidence to the contrary. Major Federal agency actions taken since the hearings 8 years ago that affect Darvon and preparations containing propoxyphene include: 1. The Drug Enforcement Administration ordered that dextro- propoxyphene be included in schedule IV of the Comprehensive Drug Abuse Prevention and Control Act of 1970, effective March 14, 1977. The principal effect of schedule IV classification is to limit a patient to one propoxyphene prescription and no more than five refills in any 6-month period. 2. The Food and Drug Administration amended the labeling for propoxyphene-containing preparations, effective August 7, 1978, "to include a warning against their use in pregnancy and a warning about their additive depressant effect when used with certain other products that ar.e central nervous system depressants." 16557 PAGENO="0006" 16558 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3. The Pharmaceutical Reimbursement Board of the Department of Health, Education, and Welfare set maximum allowable cost (MAC) limits for propoxyphene HCL capsules, 65 mg., and propoxy- phene HCL with APC (aspirin-phenacetin-caffeine) capsules, 65 lug., effective April 10, 1978. MAC's are established for multiple source drugs for which signifi- cant amounts of Federal funds are or may be expended under HEW programs and for which there are or may be significantly different prices. HEW estimated that setting MAC's for both forms of propoxy- phene would result in a combined savings of between $1.7 and $2.1 mil- lion per year in its outpatient programs alone. (For fiscal year 1976, HEW estimated that its medicaid outlays for these two propoxyphene products totaled $4.2 million.) Along with the agency actions that were taken, there was a promised one that was not. When he testified on February 3, 1971, Brig. Gen. George J. Hayes, Medical Corps, U.S. Army, Principal Deputy Assistant Secretary of Defense (Health and Environment), told the Monopoly Subcom- mittee of a memorandum from the Defense Medical Materiel Board concerning a list of 30 drug items proposed for reclassification to "limited standard" with eventual deletion from the Federal supply catalog. There were five analgesics on the list, including Darvon and Darvon Compound-65 (propoxyphene HCL with APC). Darvon Compound-65 was indeed deleted from the catalog later in 1971, but Darvon was not. In reply to my letter asking details in prep- aration for this hearing, Vernon McKenzie, Principal Deputy Assist- ant Secretary of Defense, explains it was not deleted "since two serv- ices re/commended retention." He continues: The item was retained since propoxyphene hydrochloride, 65 mg. was never declared ineffective in a 65 mg. dose and is considered by many physicians, both military and civilian, an effective analgesic and alternative to aspirin for patients unable to tolerate aspirin, such as patients with gastrointestinal dis- orders, that is, peptic ulcers. McKenzie's use of the phrase, "was never declared ineffective," puts him wide of the mark. The phrase is from the lexicon of the FDA's Drug Efficacy Study Implementation (DESI), and the report on pro- poxyphene HCL from the National Academy of Sciences-National Research Council, Drug Efficacy Study Group, and the FDA's con- clusion based on that report had been published in the Federal Reg- ister on April 8, 1969-22 months before General Hayes testified. The DESI study concluded that propoxyphene HCL was effective for the relief of mild to moderate pain when administered as described in its labeling guidelines. DESI was not the issue. The issue was set forth in the discussion portion of the Defense Med- jcal Materiel Board's memo: 1. Medical authorities state that propoxyphene is a weaker analgesic than codeine and no more effective than aspirin in equivalent doses. 2. There is a questionable advantage of propoxyphene over much less expensive and proven analgesics. PAGENO="0007" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16559 Clearly, the issue perceived by the Board then was the relative efficacy of propoxyphene. Because it clouded this perception, the Department of Defense spent $526,050 on preparations containing propoxyphene in fiscal year 1977, and $359,690 in fiscal 1978, through central purchasing. Local purchases by individual services may have added to those figures. Since the hearings 8 years ago, propoxyphene has been given a hard look by the experts who evaluate drugs for physicians and phar- macists. Here are three of these copyright evaluations: 1. A March 1972 monograph prepared for the formulary service of the American Society of Hospital Pharmacists declares: A limited number of controlled studies indicate that 65 mg. of propoxyphene hydrochloride is no more effective than 30 to 45 mg. of codeine or 650 mg. of aspirin and may be inferior to these drugs. In a discussion of side effects, the monograph advises: Side effects following administration of the recommended dosage of propox- yphene include dizziness, headache, sedation, somnolence, paradoxical excite- ment and insomnia, skin rashes and gastrointestinal disturbances (including nausea, vomiting, abdominal pain, and constipation). Euphoria may occasionally occur. 2. In 1976, the U.S. Pharmacopeial Convention, Inc. published the National Formulary and the USP Guide to Select Drugs-a first-of- its-kind list whose "major importance to the practitioner and student is in highlighting those drugs that should receive attention and be used as preferred drugs." Drug selection was accomplished by the Subcommittee on Scope through a system of expert advisory panels. Scope is a subcommittee of the USP Committee of Revision, whose members are elected by the members of the U.S. Pharmacopeial Convention. The Subcom- mittee on Scope comprised 18 physicians, 1 dentist, 1 toxicologist and 8 pharmacists. The explanation to the guide declares: In summary, there are two reasons for using the drugs listed in this book: (1) They have been judged best from the standpoint of medical merit; and (2) their standards of pharmaceutical quality are generally publicly known and more readily assured. Propoxyphene was not listed in the National Formulary and the USP 1976 Guide to Select Drugs. 3. In its chapter on mild analgesics, the American Medical Associa- tion Drug Evaluations (Third Edition, 1977), prepared by the AMA Department of Drugs in cooperation with the American Society for Clinical Pharmacology and Therapeutics, says of propoxyphene: On the basi.s of several controlled studies using single-dose assays to deter- mine analgesic efficacy, it is estimated that the milligram potency of propoxy- phene hydrochloride is about one-half to two-thirds that of codeine; 65 mg of propoxyphene hydrochloride is no more effective, and usually less so, than 650 mg. of aspirin. In addition to the lack of significant effectiveness over placebo. re- cent data have shown that Darvon has greater abuse liability than was originally, believed, and leads all other prescription drugs in the United States in drug-related deaths. Accordingly, Public Citizen's Health Research Group has peti- tioned HEW Secretary Califano to remove this drug from the market PAGENO="0008" 16560 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY as an imminent hazard. This petition, as well as a petition to the Attorney General of the United States seeking, alternatively, to place Darvon in schedule II, will be discussed at these hearings and will be made a part of the printed record. During 1977 there were 589 propoxyphene-related deaths reported to the Drug Enforcement Administration (DEA), which collects data from only one-third of the population of this country. For 1974-77 there have been 2,154 Darvon-relatecl deaths reported toDEA. In 14 of the 23 metropolitan areas for which data comparing deaths are available, this drug was associated in the first half of 1977 with more deaths than heroin and morphine combined. These figures do not tell the whole story, however. According to an official of the National Institute of Drug Abuse, "The most reliable studies indicate that heroin use is generally con- fined to those cities, whereas physicians throughout the country pre- scribe propoxyphene more than any other prescription painkiller, and based on the pieces of the puzzle we know about, it does appear Darvon is involved in more deaths than heroin, probably by a ratio of nearly 2tol." Given the lack of significant efficacy, the easy availability of pain- killers superior to Darvon, and the high abuse liability, it is puzzling that this drug is one of the most widely prescribed drugs in this country, for which the medical profession, as well as Eli Lilly & Co., must take the blame. Darvon is promoted more heavily to physicians than any other prescription painkiller. In addition, the National Academy of Sci- ences-National Research Council, in its review of this drug, found that: An obvious effort has been made to avoid pointing out that dextropropoxy- phene is structurally closely related to the narcotic analgesics methadone and isomethadone, that its general pharmacological properties are those of the narcotics as a group, that poisoning produced by dextropropoxyphene is essen- tially typical of narcotic overdose (complicated by convulsions) and should be treated as such, and that the distinction in dependence-producing properties and abuse liability between dextropropoxyphene and various other narcotics is es- sentially quantitative, rather than qualitative. That this effort, unfortunately, appears to have been successful is attested to by the fact that the majority of the house staff and attending physicians who make liberal use of Darvon as- sume that its pharmacology is basically similar to that of aspirin or phenacetin rather than to that of the narcotics. According to the highly respected Medical Letter, propoxyphene has been used as an alternative to aspirin. `While adverse reactions to aspirin are observed in about 5 percent of hospitalized patients, only a small fraction are serious-for ex- ample, severe gastrointestinal bleeding, interference with normal clot- ting processes. "Inasmuch as propoxyphene is largely prescribed as Darvon Com- pound-OS, which includes aspirin, the potential toxicity of aspirin is not avoided." (The Medical Letter, May 20, 1972.) With respect to another of the 10 Darvon formulations manufac- tured by the Lilly Co., the Medical Letter disclosed that Darvon is 1 Statement by Nicholas Kozel of the National Institute of Drug Abuse as reported In the Indianapolis News, Nov. 22, 1978. PAGENO="0009" COMPETITIVE PROBLEMS IN THE DRUG tNDUSTRY 16561 also combined with acetaminophen, Darvocet-N, which, in recom- mended dosage (two tablets), is probably no more effective than two tablets of acetarninophen or aspirin, and is much more costly. Propoxyphene preparations can be abused, and serious toxicity and death occur when they are taken in overdose. Since Darvocet-N contains acetarninophen, also highly toxic in large amounts, poisoning with this combination will be more difficult to treat than poisoning with either component above. (The Medical Letter, July 20, 1973.) The use of fixed combinations of Darvon with aspirin or acetamin- ophen, which accounts for the major proportion of IDarvon sales, then, is unjustified and constitutes poor medical practice. Since Darvon's analgesic attributes are inferior to aspirin, aceta- minophen, and codeine and presents greater risks to the individual- as well as to society-what is the medical justification for having it on the market? There appears to be none, and unleas compelling evidence from independent sources is presented that Darvon and its combinations are medically necessary for an identifiable group in our population, these drugs should be removed from the market. Referring to second-rate drugs, the renowned pharmacologist, Dr. Walter Modell, said: But they also do harm by their very existence in the drug market. I take the stand that, as a general principle, everything that adds to the difficulty in deal- ing with and understanding drugs also makes drugs more dangerous. Thus, the excessive number of needless drugs constitutes a present danger. We can make the useful drugs both less dangerous and more efficient by weeding out the useless, the ineffective and the duplicates, and by so doing, make it possible for the physician to learn in depth about the potent drugs he will prescribe for his patients. We must add only those new drugs that really add something more than their mere presence.1 Darvon is an excellent example of a relatively ineffective, hazard- ous, expensive, unnecessary, and second-rate drug. The committee has received a letter from Senator Pressler, of South Dakota, stating he cannot be present today, and this letter will be made a part of the record. [The document follows:] U.S. SENATE, Washington, D.C., January 31, 1979. Hon. GAYLORD NELSON, Chairman, Small Business Committee. DEAR SENATOR NELSON: This letter is to advise that I will be absent from all or at least portions of the Small Business Hearings this morning at 10a.m. due to my attendance and participation in the Budget Committee meeting scheduled at the same time. Please have the clerk of the committee enter this into the official record. Sincerely, LARRY PRESSLER, U.S. Senate. Senator NELSON. Is there any committee member who wishes to make a statement? Our first witness this morning is Dr. Sidney M. Wolfe, M.D., di- rector, Health Research Group, Washington, D.C. Your statement, Dr. Wotfé, will be printed in full in the record. You may proceed to present it however you desire. 1 Drug Industry Antitrust Act, hearings on S. 1552, pp. 320-321. TestImony of Dr. Walter Modell. PAGENO="0010" 16562 C0MPETIT~VE PROBLEMS IN THE DIWG INDUSTRY STATEMENT OF SIDNEY M. WOLFE, M.D., PUBLIC CITIZEN'S HEALTH RESEARCH GROUP Dr. Wor~T. Thank you for the invitation to discuss our petitions to ban or severely restrict the use of propoxyphene, most commonly known as Darvon. In the November petitions, we pointed out that Darvon led all other prescription drugs in the annual number of drug deaths, and, as was pointed out by N. Kozel of the National Institute for Drug Abuse, Darvon is probably related to even more deaths per year than heroin and morphine combined. Since the original petitions, we have obtained more information, particularly about the toxicity in animals and humans of propoxy- phene and especially its main metabolite, into which the body changes it, nor-propoxyphene. We have also learned tha.t a substantial portion of Darvon deaths are not due to suicide but are accidental and often occur in people chronically using the drug for pain or, in some cases, for its euphoric effects. When people use propoxyphene, the drug is metabolized by the liver to nor-propoxyphene. the metabolite nor-propoxyphene, because the person did not live long it takes to get ~to half the maximum concentration in the blood), is only 12 hours, the main metabolite, nor-propoxyphene, stays around much longer, having a half-life of 38 hours. Because of this long half-life, people using Darvon on a chronic basis accumulate large amounts of the metabolite nor-propoxyphene in their blood. Much of the early human toxicology on propoxyphene looked just at blood levels of the drug itself and unless the blood level was one or two micrograms per milliliter of blood, or more, the death was often not attributed to propoxyphene. In cases of suicide where death occurs shortly after ingestion of sometimes 10 or 20 pills, the blood propoxyphene level is, in fact, usu- ally above 1 or 2 micrograms per milliliter with much lower levels of the metabohte nor-propoxyphene. because the person did not live long enough to convert the drug into the metabolite. In chronic users, however, there is much more nor-propoxyphene than propoxyphene in the blood. Someone regularly taking as little as two pills-65 milligrams per pill-three times a day can get a blood propoxyphene level of 0.68 microgram per milliliter, but a nor-pro- poxyphene level of 1.2 micrograms per milliliter.' A cancer patient, chronically using two 65 mg. pills every 4 hours- recommended dose in 1 pill every 4 hours-just twice the recommended dose, had a propoxyphene blood level of 0.87 microgram per milliliter and a nor-propoxyphene level of 3.1.' The fact that people using Darvon at or slightly above the recom- mended dose can get nor-propoxyphene blood levels of 1 to 3 micro- grams per milliliter is particularly alarming in view of the following findings: `verb~1~3~ and Inturrisi, J. Chromatography 75 :195, 1973. PAGENO="0011" COMPETITWE PROBLEMS IN THE DRUG L~DUSTRY 16563 (a) In many cases of accidental death due to Darvon, the blood nor- propoxyphene levels are in this 1 to 3 micrograms per milliliter range with propoxyphene levels much lower, often less than one, as in the patients cited above.1 This is different than one would see in the suicide cases. (b) Comparable blood levels, 1 to 3 micrograms per milliliter, of nor-propoxyphene in animals can cause significant blocking of con- duction through the heart, a toxicity which can lead to arrhythmias and death. Although the medical literature, because of people who had takeit Darvon and developed toxicity, as long as 15 years ago, contained many cases of Darvon poisoning in which patients had abnormal elec- trocardigrams showing an inhibition of electrical conduction through the heart and although many Darvon deaths were said to be of cardiac origin, the first animal study on the cardiac toxicity of propoxyphene and nor-propoxyphene was not done until 1976 by the major manufac- turer, Eli Lilly~ From a source within Lilly, we have obtained an 11-page progress report of dog experiments, dated February 16 to August 15, 1976. On March 17, 1977, a short one-half page abstract of this study- omitting critical information-was sent by Lilly to FDA with a note t.hat "a complete presentation of this data will be submitted in a manuscript that is now being prepared." As of several weeks ago, when I forwarded this report to FDA and a]most 2 years after Lilly's promise to FDA, the "complete presenta- ~ion" had not been sent to FDA by Lilly nor has it ever been published. A stamp on the top of the report says it should "not be published or disclosed to unauthorized persons without the specific written permis- sion of Dr. I. H. Slater." The half-page abstract was published, but it does not contain im- portant information in the study provided to us from sources inside of the company Whereas, on a legal technicality, apparently consideration is being given to reprimanding the company for this. A stamp on top of the report, without specific permission of Dr. Slater, was put on it, and also it mentions it should be kept locked up. I think it is an interesting commentary that the company decides to keep to itself, for all practical purposes, critical information about a drug so widely used which the company sells, and makes a fortune from. The study showed that both propoxyphene and nor-propoxyphene could cause inhibition of cardiac electrical conduction in the 1 to 3 micrograms per milliliter range and that nor-propoxyphene was even more potent than propoxyphene in one important type of inhibition. There is a range level of nor-propoxyphene 1 to 3 microgram range, that people using the drug on a regular basis, at or even as little as twice above the recommended dose can get in their blood. Although the Lilly study says the blood concentrations of propoxy- phene and nor-propoxyphene were "substantially higher than required Personal communcatiOn, Dr. Boyd Stevens, coroner, San Francisco, and Dr. Larry Lewman, deputy coroner, State of Oregon. PAGENO="0012" 16564 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY for analgesia"-pain relief-the levels of nor-propoxyphene causing inhibition in these dogs were the same 1 to 3 micrograms per milliliter range which can be seen in people who are chronically using the drug. For the first time in the current labeling of Darvon there is mention, 2 years after the study was done, of the possibility of cardiac conduc- tion problems. There is no mention of nor-propoxyphene, the fact it accumulates, or that there is evidence of this. It just says problems can occur with the drug. A recently published Danish study' also shows that nor-propoxy- phene in the 1 to 3 micrograms per milliliter range in rabbits can cause significant delay or inhibition of cardiac conduction and cardiac arrhythmias also were seen. An earlier Danish study of 11 cases of Da.rvon poisoning 2 showed that four patients had cardiac conduction delays similar to those de- scribed above with blood nor-propoxyphene and propoxyphene levels of: NPX P1 0.78 0.47 .74 .79 .51 .35 .23 In other words, they had more of the metabolite than of the drug itself in their blood. One of the four patients also ingested a substantial amount of alcohol, but this in itself is not known to cause the cardiac delays. According to both Dr. Larry Lewman, deputy coroner of Oregon, and Dr. Boyd Stevens, coroner of San Francisco, most of the Darvon deaths are not suicides but accidents. One of the criteria for making this decision is a nor-propoxyphene blood level as high or higher than the propoxyphene level, often sug- gesting chronic use of propoxyphene. Blood nor-propoxyphene levels in such accidental deaths are often slightly less than 1 microgram, 1,2, 3, or 4 micrograms per milliliter of blood with propoxyphene levels often less than 1. The margin of safety or the therapeutic index of a drug is the ratio between the amount needed to achieve the therapeutic effect (in this case alleged relief of pain) and the amount causing toxicity. According to Danish toxicologist. Dr. J. Simonsen Darvon has a "narrow therapeutic index": He says that. "just foui times the ordi- nary therapeutic dose can produce highly serious poisoning." The experience concerning Darvon varies from one part of the country to the other. In North Carolina, they published studies suggesting most deaths are suicides, but even in a paper by Dr. McBay, who will testify later, one of his patients had a blood level of propoxyphene of 0.8, and a level of nor-propoxyphene of 2, suggesting in fact they had not in fact taken a huge suicidal dose, and several of their patients are also listed as accidents rather than suicide. 1 Luncl-3acobsen, Acta. pharmacol. et toxicol., 42, 171, 1978. 2 Gustafson and Gustafson. Acta. Med. Scand. 200, 241, 1976. `tlgeskr. Laeg. 137(44) 2605-2609, 1975. PAGENO="0013" COMPETITIVE PROBLEMS IN THE DRUG r~DIISTRY 16565 One of the criteria for making a decision it is an accident rather than a suicide, is that the metabolite level (nor-propoxyphene) is higher than the blood propoxyphene level. San Francisco chief coroner Dr. Boyd Stevens told me that "if you double the Darvon dosage and take just one to two bar drinks, you can get into the toxic or lethal range." These remarks have to do, I would imagine, with chronic use; but they may even refer .to acute ingestion. Dr. Stevens points out that partly because of its relative weakness as a painkiller, patients may well be inclined to take two pills or more instead of one, finding that one did not work as well as they thought it would. He says, therefore that many of the Darvon accidental deaths are not abuse-in the strict sense. This very low margin of safety ~ very likely related in many cases to the accumulation, as described above, of the toxic metabolite nor- propoxyphene in people regularly using the drug. In the above-mentioned study by Simonsen, the author himself discussed the fact that we may be, just seeing the tip of the iceberg as far as Darvon deaths. The study describes two elderly people found dead with no evidence of suicide whose deaths would otherwise have been attributed to natural causes but for a Danish law requiring autopsy on those dying alone. Subsequent toxicologic analysis showed both to be Darvon deaths. Since Darvon's effectiveness in relieving pain is somewhere between that of aspirin, or acetaminophen (as in Datril, Tylenol) and a placebo and substantially less than that of codeine (in schedule II and III), it is of interest to look at the number of deaths and the death rate of these preferable analgesics in comparison to Darvon. Deaths per million Drug Deaths, 1977 1 prescriptions a Damon Codeine Aspirin3 Acetaminophen ~ 590 255 150 77 19 5 <1 <1 I DAWN Quarterly Report January-March 1978. 2 1977 prescriptions filled from National Prescription Audit, l.M.s. 3 1977 retail sales of aspirin of $500,000,000 and acetaminophen, $150,000,000-assume average cost of $1 for aspirin, $1.50 for acetaminophen and use deaths per million bottles. When the possibility of controlling Darvon by putting it into the weak control of schedule IV was first raised in 1973, Lilly responded by saying that if the drug should wind up in schedule IV, despite its protests, "we believe it wouldn't have `any material effect on sales of the product."' In the year before Darvon was put `into schedule IV (March 1976 to February 1977), there we're 459 deaths related to its use. In the first year of schedule IV (March 1977 to February 1978), the number wa.s 510. Although there appears to be a decrease in deaths during the latter part of 1978, these data underestimate the eventual 1Wall Street Journal, Aug. 6, 1973. PAGENO="0014" 16566 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY number of reported deaths, since, all 1978 records are not completed and sent to DEA until well into 1979. Although there has been an apparent but slight decrease in emer- gency room visits involving Darvon, this is not accompanied by any evidence yet of a decrease in fatalities. Now, as far as codeine is concerned, the various studies or pharma- cology books described it as being half or two-thirds as effective as codeine. Senator N1~soN. Dr. Wolfe, when you make reference to Darvon in the first sentence, are you talking about just propoxyphene, or are you talking about Darvon combinations? Dr. WOLFE. I am talking about propoxyphene alone in comparison with aspirin or acetaminophen. Darvon compound `also has aspirin in it, `and I think the prepon- derance of studies failed to show that Darvon plus aspirin is more effective than aspirin alone, aspirin alone being a very effective pain- killer. Senator NELSON. What studies do you rely upon for this statement relative to the effectiveness of propoxyphene? Dr. WOLFE. I can provide a list of the studies. They are listed in our petition to the Justice Department which we submitted to you, on the effectiveness of the drug. [The list follows:] PAGENO="0015" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16567 ~OR RELEASE TUESDAY, NOVEMBER 21, Joseph Califano Secretary Department of Health, Education, and Welfare Humphrey Building, Room 615-F 200 Independence Avenue, S.W. Washington, D.C. 20201 Dear Secretary Califano: According to recent information we have obtained from the Drug Enforcement Agency (DEA), Department of Justice, the narcotic propoxyphene (as in Darvon)--closely related to methadone'--leads all other prescription drugs in the United States in drug-related deaths. In l~ U.S. cities (see page 3) there were more propoxyphene (DPX)-related deaths than morphine and heroin-related deaths in 1977. 1The above figure is from the Second Edition (1978) of Clinical Pharmacology by Melmon and Morrelli, MacMillan Publishing Co., Inc., New York. I-IEAI.1 I R IS6ARCI I (Ho UI' * 2000 I' S I sI~I!. NW., W,\.sIIINonr~, l).C. 20036 * (202) M72-I13 2(1 pubh~c cifizen November 21, 1978 %I,(I~'C S~s SIMILARITY BETWEEN PROPOXYPHENE (DPX) AND METHADONE I) / PAGENO="0016" 16568 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Because propoxyphene is of so little value as a pain- killer--although Americans spent about l~O million dollars in 1977 for the Lilly-manufactured Darvon drugs1--is so widely abused and is so lethal, I urge you to either: a) Ban immediately the marketing of propoxyphene as an imminent hazard under the Food, Drug and Cosmetic Act, 21 U.S.C. §355(e), and make it available only as an investigational drug for treating narcotics addicts2 or, in the alternative, b) Support our petition3 (see enclosure) to reschedule DPX as a Schedule II narcotic which would impose production quotas and prohibit refills of prescriptions. The following information is excerpted from our Drug Enforcement Agency petition: o During 1977 alone there were 589 propoxyphene (DPX)- related deaths reported to DEA from their Drug Abuse Warning Network (DAWN) which collects data from only 1/3 of the population of this country. GIn the past ~ years (l97~4-l977), there have been 2,l5~ DPX-related deaths reported to DEA. Most recently, as heroin has become somewhat better controlled, DPX-related deaths have even surpassed heroin and morphine-related deaths in many cities. In l~ of the 23 metropolitan areas for which data comparing DPX-related deaths with heroin/morphine deaths are available, propoxyphene (DPx) was associated with more deaths than heroin/morphine in the first half of 1977. The cities are Boston, Buffalo, Cleveland, Dallas, Denver, Indianapolis (home of Lilly, producer of Darvon and other propoxyphene drugs), Miami, Minneapolis, New York, Oklahoma City, Philadelphia, Phoenix, San Antonio and Seattle. 1 Propoxyphene is also available as a generic drug but most sales are for Lilly products including Darvon, Darvocet, Darvocet-N, Darvon-N, Darvon Compound 65, etc. 2 DPX is currently approved by FDA as an investigational drug for treating narcotic addiction. 3 Under the Controlled Substances Act, 21 U.S.C. §811(a), the Department of Justice is being petitioned by Health Research Group today to move propoxyphene to Schedule II. PAGENO="0017" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16569 0 DPX DEATH RATES IN U.S. CITiES In order to compare various U.S. metropolitan areas in terms of DPX-related deaths, the number of such deaths for each area between July 1973 and December 1977 was divided by population (in millions) of that area. These results can be seen in Table 2. TABLE 2 FROPOXYPHENE(DPX-AS I N DARVON) DEATh RATES FOR U.S. )~1ETR0POLITAN AREASa DPX-Rclated Deaths Popui:itiond Deaths/Million Rank Area (y/73_12/77)b (In Iililioii;) People 1 Phoenix 81 l.2]8 66.5 2 San Francisco 189 3.129 3 San Diego 95c : :1.588 59.8 ~ Dallas 80 1.690 117.3 5 Denver 61 1.387 6 Los Angeles 276 6.91)5 39.7 7 Cleveland 713 1.975 39.5 8 San Antonio 37 .9)19 39.0 9 Miami 52 l.~I39 36.1 10 Buffalo 146 1.327 311.7 11 Detroit 132 ~l.17~l 31.6 12 Oklahoma City 21 .683 30.7 13 Philadelphia 133 13.797 27.7 l~4 Boston 72 2.731 26.') 15 New York City 2714 11.316 2'l.2 16 Chicago 151 6.983 21.6 17 Atlanta 32 1.432 20.9 18 Washington, DC 60 2.936 20.~l 19 Indianapolis 15 l.i~I7 13.1 20 Minneapolis 20 1. 81)6 10.8 21 Seattle l~l 1.1311 9.9 22 Kansas City 11 1.268 6.7 23 New Orleans 9 1.091) 8.2 a. These are the 23 rnetropoli1;an areas which have eon under sur- veillance by the DAWN Network for at locaL 2 1/2 years. b . 1)PX-Re la Led Pea tha (except Han Diego) ale 1 I, Inia:, t.i O1) Hy Section of Drug Enforcement Ago ncy, Dopai Lie. 1 f Jur Lice. Included are all deaths where (Irug is a contr.lhul:lng factor or in which a toxic level is found (or suspected because of ingestion history). a. Deaths for San Diego are from San Diego coroner `a office since San Diego did not become part of the DAWN Syatem until mid-1975. (San Diego includes only 19714~1977.) d. Populations of metropolitan areas are from DAWN (Department of Justice) Quarterly Report (July-September 1977). 45-224 0 - 79 - 2 PAGENO="0018" 16570 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY For example, Phoenix, the leading U.S. metropolitan area-- as far as DPX-associated death rates--had 81 deaths during that interval. With an area population of 1.218 million the rate was found to be 81 divided by 1.218 or 66.5 deaths per million. At the other end of the list of metropolitan areas is New Orleans. Its DPX-death rate is 8.2 per million or less than 1/8 that of Phoenix. * Although DPX was placed in Schedule IV by DEA in Narch, 1977, this appears to have had little effect on its prescribing or abuse, as has been the case with other drugs placed in Schedule IV. (Schedule IV allows a prescription to be called in over the phone and as many as 5 refills each 6 months. Schedule II would place production quotas on the manufacture of DPX, disallowS oral prescriptions and not allow ~ refills.) In 1977, there were 33.5 million prescriptions filled for DPX drugs, down only 9.5% from 37 million in 1976. In 1977, during the last 9 months of which DPX was in Schedule IV, there were 589 DPX-related deaths, up from 14~5 in 1976, before Schedule IV "controls' were imposed. * According to a 1976 Department of Justice Report on the abuse of DPX, DPX-related fatalities outranked all prescription drugs in death-rate even when the number of prescriptions written were adjusted for. By dividing the number of drug-related deaths by the number of prescriptions, DPX (in this instance plain propoxyphene sold as Darvon by Lilly) was well ahead of all drugs including phenobarbital and valium. In addition to evidence that DPX (mostly Lilly's Darvon products) is doing more damage than the wares of dope-pushers in many U.S. cities, it is important to analyze why doctors have made DPX so popular. - DOCTORS MISLED ON DPX EFFECTIVENESS Originally introduced as a "non-narcotic" by Lilly in 1957, Darvon(DPX) was said by the company, to be "equal to codeine... milligram for milligram" in its pain-killing properties. At present the preponderance of properly-controlled studies fail to show that DPX is any more effective than aspirin and many show it to be less effective than aspirin, or, in some cases, no more effective than a placebo. It is clearly less effective than codeine. The other attractive feature of this "non- narcotic" was that doctors didn't need a narcotic prescription to use it. The American Medical Association book on Evaluation (1st Edition, 1971) stated, of DPX, that "its popu- larity is probably due to the fact that it does not require a PAGENO="0019" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16571 narcotic prescription, rather than to its effectiveness as an analgesic. ..." DOCTORS ALSO MISLED ON DPX DANGER Lilly also claimed DPX had fewer side effects than codeine" but by 1970, the respected source of drug information, The Medical Letter wrote "many physicians are not sufficiently aware that coma, circulatory and respiratory depression, convul- sion and death can result from overdose with propoxyphene, that the clinical picture is similar to that seen with narcotic drugs. . . A recent survey (1977) of U.S. physicians shows that most continue to think DPX is a much less dangerous drug than other drugs, which, in fact, are involved in far fewer drug deaths than DPX.1 A FINE LINE BETWEEN USE AND ABUSE In larger than recommended doses DPX produces a euphoria or "high" which makes it attractive as a drug of abuse. It is generally agreed that DPX can be addicting--albeit less so than morphine--and one study concluded that "addiction2can occur under the usual circu~sstances of medical prescribing." The 2nd Edition of ClinicalPharmacology (1978) by Melmon and Morelli stated that "the most prominent effects (of DPX) may be its addictive quality." The Department of Justice DAWN (Drug Abuse Warning Network) data show that among patients in emergency rooms whose source of drugs could be ascertained, over 90% obtained their DPX with legal prescriptions.3 NATURE OF DPX DEATHS In a May ~, 1978 letter to FDA, Oregon Deputy State Medical Examiner Dr. Larry Lawman wrote that "propoxyphene is by far the most common cause of fatal drug overdose in Oregon." 1 International Journal of Addiction 12, ~3, 1977. 2 International Journal of Addiction 9, 775, l97~. 3 DAWN Quarterly Report, July-September 1977. PAGENO="0020" 16572 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY He went on to say that although some DPX overdose deaths were, in fact, attempted suicides, "accidental overdoses of DPX" was the category "into which most of the DPX overdoses in Oregon appear to fall." In other words, the margin between the doses which achieve the desired euphoria and those which are harmful or even fatal is extremely narrow. Dr. Lewman did not believe that education of physicians ~ras adequate and suggested, in the same letter to FDA, that DPX be moved into Schedule II. (On November~7, 1978, Oregon Public Health Officer, Dr. Edward Press, redirected this request to reschedule DPX in Schedule II in a petition to the Department of Justice, Drug Enforcement Administration.) In summary, DPX is the deadliest prescription drug in the U.S., has been related to the deaths of thousands of people in the U.S. (and elsewhere) and is even outdoing morphine and heroin in l~4 U.S.cities in its relationship to drug deaths. In my view, there are two possible courses of action: 1. Invoke the Imminent Hazard Section of the Food, Drug and Cosmetic Act, 21 U.S.C. §355(e), and immediately suspend the New Drug Application (and marketing) of DPX. If you deter- mine that there is no legitimate use for DPX as a pain-killer or that the risks of DPX outweigh any benefits even as a pain- killer, and that the drug should therefore be eventually removed from the market, the magnitude of DPX deaths during the 2-3 years that would transpire before the "slow" banning procedures mandate use of the imminent hazard provision. The evidence of DPX-caused deaths is more than sufficient to prove that this drug is "posing a significant threat of danger to public health." In the British Me~ical Journal, an editorial on the "Dangers of Dextropropoxyphene"' queried, "How good is the case for using the drug at all?" After discussing the lack of "hard data on its therapeutic value.. .compared with other analgesics", the journal goes on to say that "any doctor prescribing the drug rather than a simple, less expensive and potentially leas toxic preparation should be aware of the hazards and able to justify his choice." 1 British Medical Journal 1, p. 668, 1977. PAGENO="0021" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16573 The one use, now under investigation, for which the benefits of DPX may outweigh its: risks is in the treatment of narcotic addiction. Because DPX is a narcotic, it has been used to withdraw addicts from other narcotics, such as methadone, its close relative. Since there~ is in existence an Investiga-. tional New Drug (IND) approval for DPX, this use would not be altered by declaring it an imminent hazard and stopping its marketing as an analgesic. 2. Reschedule DPX in Schedule II. If you believe there is a legitimate use for DPX as a pain-killer---despite its relative ineffectiveness for this indication--it could be placed in Schedule II for those people for whom both~ aspirin and acetaminophen and other less dangerous analgesics were not effective or not tolerated. I do not know-how large a group, if any, this might be but I would estimate that it is less than 1% of those currently using DPX. The enclosed petition to the Drug Enforcement Administration seeks this rescheduling under the Controlled Substances Act, 21 U.S.C. §811(a). This act requires that the Secretary of HEW submit an opinion to the Department of Justice concerning any proposed scheduling or re- scheduling of drugs. Although I favor the imminent hazard route and this letter constitutes our petition to ban DPX as an imminent hazard to the piblic health, you must decide how best to protect the American public from this deadly drug which--in addition--is wasting more than l~O million dollars a year of health care resources. I look forward to a prompt reply. Sincerely, Sidney M. Wolfe, M.D. Director Health Research Group SMW:prn (1 Enc los ure ~ NOTE: Legal and/or scientific research for the petition was contributed by Ellis Gordon, Michael Lipsett, an attorney now attending University of California, San Diego Medical School, and Deborah Schechter, staff associate of the Health Research Group. Staff researchers at the Department of Justice, Drug Enforcement Agency, were also helpful in providing data not otherwise available. PAGENO="0022" 16574 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY Sidney M. Wolfe, M.D. and Public Citizen Health Research Group Petitioners TO: Honorable Griffin Bell Attorney General of the United States; and Honorable Peter Bensinger, Administrator Drug Enforcement Administration, Department of Justice PETITION REQUESTING TRANSFER OF THE NARCOTIC DEXTROPROPOXYPHENE (IDARVON) AND ITS SALTS FROM CONTROLLED SUBSTANCES SCHEDULE IV TO SCHEDULE II. I. PETITIONERS Petitioner Sidney Wolfe is a medical doctor licensed to practice in Washington, DC. Petitioner Public Citizen Health Research Group is a Washington- based, non-profit organization engaged in public interest research on health issues, including drug abuse. II. AUTHORITY FOR PETITIONERS Petitioners' authority to submit this petition derives from the Controlled Substances Act, 21 U.S.C. § 811(a), and the Administrative Procedure Act, 5 U.S.C. § 553(e). III. THE CASE In 1977 the Administrator of the Drug Enforcement Administra- tion (DEA) found that the widespread abuse of dextropropoxyphene (Darvon) justified its inclusion in Schedule IV of the Controlled Substances Act. Despite the restrictions which Schedule IV places on the prescription of dextropropoxyphene, this drug continues to be widely prescribed and abused. Petitioners contend that in order to curb such abuse dextropropoxyphene must be subjected to the stringent controls of Schedule II. PAGENO="0023" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16575 Under the Controlled Substances Act, the Attorney General may by rule transfer a drug into Schedule II if he finds that: (1) the drug has a high potential for abuse; (2) the drug has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions, and (3) abuse of the drug may lead to severe psychological or physical dependence. 21 U.S.C. §~8ll, 812 (b)(2). There is substantial evidence that dextropropoxyphene (Darvon) fulfills these three cri- teria of Schedule II. In addition, there is reliable medical evidence that this drug is relatively ineffective as, an analgesic, the primary purpose for which it is prescribed. From a therapeutic standpoint, nothing would be lost by restricting the availability of this drug through the imposition of Schedule II controls. PAGENO="0024" 16576 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Sidney N. Wolfe, M.D. and Public Citizen Health Research Group Petitioners TO: Honorable GrIf fin Hell Attorney General of the.United States; and Honorable Peter Bensinger, Administrator Drug Enforcement Administration, Department of Justice PETITION REQUESTING TRANSFER OF THE NARCOTIC DEXTROPROPOXYPHENE (DARVON) AND ITS SALTS FROM CONTROLLED SUBSTANCES SCHEDULE IV TO SCHEDULE II. TABLE OP CONTENTS I. PETITIONERS 1 II. AUTHORITY FOR PETITIONERS 1 III. THE CASE 1 IV. INTRODUCTION V. CRITERION I - HIGH POTENTIAL FOR ABUSE 5 Older DPX Death Studies 7 Recent DPX Death Studies 9 DPX Related Deaths 11 DPX Death Rates in U.S. Cities 11 VI. CRITERION 2 - ACCEPTED MEDICAL USE 15 VII. CRITERION 3 - DEPENDENCE (ADDICTION) 16 VIII. ANALGESIC IMPOTENCE OF PROPOXYPHENE 20 IX. LEGAL ANALYSIS 23 PAGENO="0025" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16577 IV. INTRODUCTION Dextropropoxyphene (hereafter DPX) is structurally related to methadone, a synthetic narcotic; its effects are qualitatively similar to those of narcotics. In 1956, a year before DPX was first marketed as Darvon by Eli Lilly and Company, it was reported that this drug could produce narcotic-like effects of respiratory depression, pupil constriction, arid euphoria, and could reduce the severity of withdrawal from morphine.1 Nevertheless, this narcotic analogue was introduced to physicians as a non-narcotic analgesic, equal, milligram for milligram to codeine, but without the potential for addiction and abuse of the latter.2 As a result of DPX's being promoted as a potent non-narcotic analgesic, DPX gained such popularity that it has become one~ of the most commonly prescribed drugs in the United States.3 Despite promotional efforts of the Lilly Company to the contrary, DPX remains a narcotic, more harmful and less effective than originally believed. In larger than recommended doses it produces a euphoric "high", which makes it attractive as a drug of abuse. Side effects of DPX, such as dizziness, constipation, nausea and vomiting are typical of narcotics. High doses of DPX produce the characteristic quartet of narcotic overdose--respiratory depression, pinpoint pupils, coma, and circulatory collapse--as well as convulsions, cardiac arrhythmias and pulmonary edema.~ The respiratory depression produced by DPX overdose can be reversed by naloxone, which is used to treat narcotic overdose.5'6'~ Physical and psychological dependence on DPX can occur, although this depen- dence is not so severe as that daused by morphine.8 Like the narcotics heroin and morphine, DPX is deadly. From April 1975 to June 1977, (the most recent date for which reliable published comparative statistics are available), it was the second most frequently implicated drug (2nd only to heroin and morphine) in coroners' reports of drug-related deaths in large American metropolitan areas.9 PAGENO="0026" 16578 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Even the Eli Lilly Company has had to modify its public posture. By 1972, it had conceded that "propoxyphene's general pharmaco- logic properties are those of the narcotics as a group."1~ Placing DPX in Schedule IV has not significantly affected the sales or abuse of this dangerous narcotic. The value of Lilly's sales (revenue to manufacturer) of 7 DPX products increased from $82,001,000 in 1976 to $82,878,000 in 1977.11 Considering that the retail drug markup. is often close to 7Q%l2, Americans spent nearly $l~0,000,000 during 1977 on Lilly-produced Darvon and Darvon combinations, even though there was a slight decrease in the total number of prescriptions. This does not include the products of the other 32 companies licensed to produce DPX. While reported abuse of DPX has not significantly increased since March 1977, neither has it declined as will be seen in the next section. This is due in large part to the ready availability of DPX--the vast majority of DPX abusers obtain the drug with legal prescriptions. This petition will show that the more stringent controls of Schedule II should be imposed on DPX in order to restrict its availability. V. Criterion 1 - High Potential For Abuse In determining that a drug should be included in Schedule II, it must be established that the drug has a high potential for abuse* 21 U.S.C. §812 (b)(2)(A). A drug's potential for abuse can be estimated in clinical tests such as those for opiate narcotics. "Assessing Abuse Potential. . . .A drug is considered to be nonopioid with respect to abuse liability (1) if it does not suppress the opioid withdrawal syndrome when tested in subjects physically dependent on morphine, (2) if it does not produce morphine-like physical dependence when given chronically, and (3) if postaddicts neither consistently identify it as "dope'(morphine-like) nor repeatedly request it when offered the opportunity to do so. On the other hand, if a compound is found to share these key character- istics with morphine, it is considered. to have a high abuse liability `13 * As used herein, "abuse" refers to intentional non-thera- peutic use of a drug. This included taking a drug for any of the following reasons: (1) dependence (addiction); (2) psychic effects; (3) attempted or successful suicide. See section on Legal Analysis, below, for discussion of legis- lative interpretation of the term. PAGENO="0027" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16579 According to clinical trials using.these criteria, DPX's abuse liability is lower than that of morphine and codeine. However, ultimately the abuse liability of a drug must be evaluated in light of the prevalence of its abuse. Indeed, in determining the proper scheduling for a drug, the Attorney General is directed to con- sider a drug's "actual or relative potential for abuse." 21 U.s.c. § 811 (c)(l). Looking for evidence of DPX abuse, one discovers an embarrassment of riches. Prior to the inclusion of DPX in Schedule IV in 1977, there was extensive medical and statistical documentation that this drug, alone and in combination with alcohol and other drags, was subject to both oral and intravenous abuse which resulted in over a thousand deaths between 1969 and 1975 l975.l~26 Reviewing the medical literature and nation-wide drug abuse statistics, a study commissIoned by the Justice Department found in 1976 that: 1. Dextropropoxyphene is a centrally active narcotic analgesic (pain-killer) with a spectrum of activity qualitatively similar tO morphine, the prototype narcotic analgesic. 2. Dextropropoxyphene prodOces a mild to moderate physical dependence of the morphine type. Unlike morphine, development of dextropropoxyphene dependence requires the administration of doses in excess of the recommended therapeutic dose. 3. Intravenous administration of dextropropoxyphene to experienced addicts prOduces "pleasant" morphine-like effects which cannot always be distinguished from those of morphine. ~ Dextropropoxyphene has properties which lead individuals to self-administer either orally or intravenously excessive amounts of the drug. 5. Tolerance develops to the "pleasant" effects of dextro- propoxyphene as well as to other effects so that indi- viduals can ingest or inject doses of the drug which would be in the lethal range for nontolerant individuals. 6. Self-administration of dextropropoxyphene in increasingly higher doses for the reasons noted in No. 3, ~, and 5 has produced physical dependence. PAGENO="0028" 16580 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7. Intravenous self-administration of dextropropoxyphene in man utilized the pellet formulation of Darvon which is no longer available* but the new propoxyphene for- mulations are soluble in warm water and on a pharmacological basis can be utilized intravenously for the same effect. 8. Single doses of dextropropoxyphene in excess of 800 mg can he lethal if untreated and it is estimated that in excess of 200 individuals die yearly of dextropropoxyphene overdose in the United States. 9. Most abusers of dextropropoxyphene appear to obtain the drug by legal prescription but thefts of Darvon from pharmacies and practitioners are being reported and the drug is available on the street at $0.25-$l.50. per capsule.27 In summary, DPX's narcotic-like pharmacologic properties have made it a highly abuseable drug. OLDER DPX DEATH STUDIES In a huge Lilly-sponsored study involving medical examiners with a jurisdiction covering 52 million people, it was reported that DPX had been implicated in at least 1,022 deaths by the middle of 1975.28The authors found that, the number of deaths involving propoxyphene is increasing each year, and at a faster rate than total drug deaths. They also found that 65.9% of all the cases had the word propoxyphene in the tcause of death? statement on the death certificate." and that "in 3~.l% of the cases the cause of death was officially attributed to something other than propoxyphene alone. In Detroit, the number of drug deaths involving DPX tripled from 1973 to 1975.29 A similar pattern was observed in North Carolina, with 21 such deaths in 1973, 30 in l97~, and 16 during jy~j~ the first three months of l975.~° * Although the easily separable DPX pellet is no longer found in Lilly DPX capsules, at least a few other pharmaceutical companies still produce DPX in this highly abuseable preparation. See FDC Reports, December 12, 1977. PAGENO="0029" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 16581 The aforementioned study commissioned by the Justice Department provided an analysis of drug-associated fatalities reported in the DAWN system* from July 1973 to September 1975. This analysis showed that DPX was involved in 1,221 deaths, second only to heroin. Furthermore, DPX displayed the greatest relative toxicity of all the drugs reported in the DAWN system. One measure of toxicity utilized was deaths per 1000 emergency room mentions of the drug in the DAWN statistics as compiled in a Department of Justice study on DPX abuse.3' Reports from coroner's offices of drug-related deaths divided by the number of mentions for the same drug in the DAWN emergency room network showed that DPX was the highest of any drug with 113 coroner-reported deaths for every 1000 emergency room mentions. It ranked ahead of heroin/morphine(98) diazepam (valium)(l8) and phenobarbital (1014). Another index of its fatal toxicity as a function of how often it is prescribed can be found by dividing the number of deaths by the number of prescriptions for the; drug. Again, DPX outranked all prescription drugs(including diazipam) in the same study.32 Why is DPX so toxic? As with other narcotics, it can cause pulmonary edema (fluid accumulation in the lungs) and respiratory depression which can frequently result in fatal respiratory arrest.3~~6 In addition, DPX and its metabolites can depress electrical conduction in heart muscles which can result in arrhythmias and cardiac arrest.**37~8 Fatalities among those using the drug for its psychic effects are due to the small margin of safety between toxic doses and those required to achieve euphoria. 149,50 * Drug Abuse Warning Network, a Drug Enforcement Administration program then operating in 146 states. The statistics cover reports from hospital emergency rooms and from medical examiners (i.e. cor- oners), who had submitted reports at least 90% of possible reporting days during the life of the DAWN program. ** Specifically atrioventricular nodal conduction. The implici~tion of this important finding is that persons with underlying cardiac disease who take DPX even at prescribed doses may inadvertently trigger an arrythmia culminating in cardiac arrest. PAGENO="0030" 16582 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY RECENT DPX DEATH DATA From April 1975 to June 1977, DPX remained the second most commonly mentioned drug in DAWN coroners' reports after a combined category of heroin (Schedule I) and morphine (Schedule II).51 Most recently, as heroin has become somewhat better controlled-- at least as reflected by a rdduction in deaths from its use--DPX- related deaths have surpassed heroin(and morphine) related deaths in many cities. According to the latest DAWN report published by the Drug Enforcement Agency,52 in l~4 of the 23 cities (61%) for which data comparing DPX-associated deaths with heroin/morphine deaths were available, DPX was associated with more deaths than heroin/morphine in the first half of 1977. * These cities were: BOSTON, BUFFALO, CLEVELAND, DALLAS, DENVER, INDIANAPOLIS, MIAMI, MINNEAPOLIS, NEW YORK, OKLAHOMA CITY, PHILADELPHIA, PHOENIX, SAN ANTONIO, SEATTLE. The DAWN statistics also demonstrate that DPX has been abused much more frequently than several Schedule II drugs. The following table shows the number of mentions that DPX, methaqualone (Quaalude), amphetamines, and secobarbital received in the total DAWN system during the, last full year for which comparative data were available. TABLE I PROPOXYPHENE(DPX) RELATED DEATHS (JULY 1976 - JUNE 1977) CORONERS' REPORTS # CORONERS' REPORTS. Dextropropoxyphene (DPX) ~9l Diazepam( Valium) 388 Meprobarnate(Miltown) ` 316 SCHEDULE IV Chlordiazepoxide(Librium) 70 Flurazepam(Dalmane) . 66 Amphetamines 27 Methaqualone(Quaaludes) 57 SCHEDULE II Secobarbital(Seconal) 222 Similarly, as also shown in the table, the DAWN statistics show that DPX is more frequently abused than the reported Schedule IV drugs. * The most recent time period for which data are available. PAGENO="0031" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 16583 In relation to reported Schedule IV drugs, DPX is involved in more coroners' reports than the three others. Although these comparative data include just 3 months during which DPX had become subject to Schedule IV restrictions, more recent data* including all of 1977 reveal that the control require- ments of Schedule IV have failed to significantly alter the prevalence of DPX abuse. Figure 1A shows the time trend for the past four years for DPX-related deaths. FIGURE lA TIME TREND FOR DPX-RELATED DEATHS 600 589 570 0 500 ~NN~ Propoxyphene- ~4OO Related Deaths (Coroner's Reports) 300 200 SOURCE: Dept. of Justice, Drug 100 Enforcement Administration, 1978. 0 ____________________________________________________________ 19fl 1975 1976 19 7 CEach. point represents the total - at the end of the year.) DP~ Into Schedule IV It can be seen that deaths involving DPX declined somewhat between 1975 and 1976, due, perhaps in part, to the warnings then appearing in the medical and lay press.53'5~ * Obtained from the Section of Information Systems, Drug Enforce- ment Administration, Washington., DC. PAGENO="0032" 16584 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY However, by the time DPX was added to Schedule IV (March 1977), these drug-related deaths were once again on the increase. The total number of DPX-related deaths in the U.S. for the last ~ years is 2,l5~4 Recent reports of DPX-related deaths from abroad indicate that this crescendo of abuse is not limited to the United States.5559 DPX-HELAThD-DEATHS~ As mentioned previously, in about 2/3 of cases, DPX is *mentioned on the death certificates as `cause of death" whereas in 1/3 of cases the death is attributed to `something other than DPX alone." 60 In this Lilly-sponsored studyGl in 214%of the DPX-related deaths, DPX was the only drug involved and in an additional 18% DPX and alcohol were involved. In other cases, even though additional drugs were involved, DPX was mentioned on the death certificate in the"cause of death" statement. More recent data show an increase in the percentage of cases in which DPX was the only drug involved. By 1977 (See Figure lA) there were 589 DPX-related deaths of which 190 or 32% involved only DPX. (Up from 2~% in the Lilly study and 23.8% in 1976.) DPX DEATh RATES IN U.S. CITIES In order to compare various U.S. metropolitan areas in terms of DPX-related deaths, the number of such deaths for each area between July 1973 and December 1977 was divided by population (in millions) of that area. These results can be seen in Table 2. PAGENO="0033" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16585 Rank Area 1 Phoenix 2 San Francisco 3 San Diego 14 Dallas 5 Denver 6 Los Angeles 7 Cleveland 8 San Antonio 9 Miami 10 Buffalo 11 Detroit 12 Oklahoma City 13 Philadelphia 14 Boston 15 New York City 16 Chicago 17 Atlanta 18 Washington, DC 19 Indianapolis 20 Minneapolis 21 Seattle 22 Kansas City 23 New Orleans TABLE 2 PROPOXY?HENE(DpX_A5 IN DARVON)DEATJ-r RAThS FOR U.S. METROPOLITAN AREASa DPX-Related Deaths Populationd (?/73_l2/77)b (In Millions) 81 1.218 189 3.129 95c 1.588 80 1.690 61 : 1.387 276 6.945 78 1.975 37 .9119 52 1.1439 46 1.327 132 : 14.1714 21 .683 133 4.797 72 2.731 27~4 11.316 151 6.983 32 1.532 60 2.936 15 1.1147 20 1.846 14 1.411 11 1.268 9 1.0914 Deaths/Mi llion Peqple 66.5 60.4 59.8 147.3 44.0 39.7 39.5 39.0 36.1 314.7 31.6 30.7 27.7 26.4 24.2 21.6 20.9 20.4 13.1 10.8 9.9 8.7 8.2 a. These are the 23 metropolitan~areas which have been under sur- veillance by the DAWN Network for at least 2 1/2 years. b. DPX-Related Deaths(except San:Diego) are from Information Systems Section of Drug Enforcement Agency, Department of Justice. Included are all deaths where drug is a contrAbuting factor or in which a toxic level is found (or suspected because of ingestion history). c. Deaths for San Diego are from San Diego coroner's office since San Diego did not become part of the DAWN System until mid-1975. (San Diego includes only 19714-1977.) d. Populations of metropolitan areas are from DAWN (Department of Justice) Quarterly Report (July-September 1977). 40-224 0 - 79 - 3 PAGENO="0034" 16586 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY For example, Phoenix, the leading U.S. metropolitan area-- as far as DPX-assOCiated death rates--had 81 deaths during that interval. With an area population of 1.218 million the rate was found to be 81 divided by 1.218 or 66.5 deaths per million. At the other end of the list of metropolitan areas is New Orleans. Its DRY-death rate is 8.2 per million or less than 1/8 that of Phoenix. Inspection of the time-trend of DAWN emergency room reports, as seen in Figure 1B, reveals that there has also been no remark- 62 able decline since Schedule IV controls were imposed early in 1977. FIGURE lB TIME TREND FOR DPX-ASSOCIATED EMERGENCY ROOM VISITS 5000 )4 3~4O ~o 3909__ DARVON-RELATED EMERGENCY ROOM 3000 MENTIONS 2000 1000 a_________________________________________________ l97~4 1975 1976 977 DPX INTO SCHEDULE IV (Each point represents the total at the end of the year.) Clearly the controls of Schedule IV have not significantly diminished the reported abuse of this drug. Noreover, since the DAWN statistics only account for approximately 30% of U.S. population with 582 emergency rooms and 103 medical examiners (coroners) PAGENO="0035" CO~tPETITWE PROBLEMS IN THE DRUG INDUSTRY 16587 included in the system, the above data, represent only a partial picture of DPX abuse.6~ As can be seen in Table 3, within a year after amphetamines, methaqualone and secobarhital were placed in Schedule II, there were decreases of 50%, 52.14%, and 147.6% respectively, in the number of prescriptions. Within 14 years, all had decreased substantially more so that prescriptions for each were about 25% of what they had been before Schedule II was imposed.: Placing drugs in Schedule IV, however, has much less effect on the number of prescriptions. For diazepam (valium) Schedule IV caused only a 6.9% decrease in prescriptions the first year. TABLE 3 EFFECT ON ThE NUMBER OF PRESCRIPTIONS OF PLACING DRUGS IN SCHEDULE IV OR SCHEDULE II Annual Number of Prescriptions (Millions) Before % Change Scheduling 1 Year After In Prescriptions Schedule IV Diazepam 58 Million 514 Million -6.9% (Valium) Flurazepam 11.5 Million 12.75 Million +10.9% (Dalmane) Propoxyphene 37 Million 33.5 Million -9.5% (Darvon) Schedule II Amphetamines 16 Million 8 Million -50.0% * Methaqualone 142 Million 20 Million -52.~4% (Quaaludes) Secobarbital 8 Million 14.3 Million ~147.6% (Seconal Flurazepam, already on the rise when placed in Schedule IV, rose an additional 10.9% during the first year. Thus, placing DPX in Schedule IV has predictably had little effect on the number of prescriptions, availability or abuse(See Figure lA, p 7, as measured by annual DPX-deaths). Since there is continuing evidence even relative to the Schedule II drugs for its abuse (See Table 1, p 6),DEA should transfer DPX to Schedule II. PAGENO="0036" 16588 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY VI. Criterion 2 - Acceoted Nodical Use A second finding that must be made if a drug is to be included in Schedule II is that it have an "accepted" medical use or an accepted medical use with severe restrictions. 21 U.S.C. § 812(b).(2). Over thirty million prescriptions for DPX preparations were issued and refilled in l977,6~ providing evidence that DPX is still widely `accepted' in the medical community, despite considerable evidence that at best DPX is no more effective an analgesic than aspirin.6~ Physicians' misconceptions about the effectiveness and the abuse potential of this drug have led to overprescribing and abuse. Among patients whose source of drugs could be ascertained in DAWN emergency rooms, over 9O~ had obtained their DPX with legal prescriptions.66 In a recent survey of physicians' attitues towards various drugs, DPX was rated as one of the most innocuous, while other controlled substances which are less lethal than DPX (e.g. Librium, Seconal, Methadrine and Phenobarbital), were considered to he more dangerous.6~Thus the abundant prescribing of DPX could be more accurately characterized as an "accepted medical mis-use." However, DPX Napsylate (DPX-Nap) does have a medical use in the detoxification and maintenance of narcotic addicts,6870 although the use of DPX for the purpose is presently under the Investigational New Drug Provision of the Food, Drug and Cosmetic Act. In high doses DPX-Nap exerts significant morphine-like effects, and can suppress symptoms of withdrawal from other narcotics.7l The literature suggests that DPX-Nap may be most beneficial in assisting withdrawal from methadone.7273 DPX-Nap is physically less addictive than methadone, which has made it attractive as an agent to detoxify narcotics addicts. However, because such high doses are required to suppress symptoms of narcotic withdrawal and because DPX has such a high potential for abuse, detoxification must be carefully supervised and access to DPX-Nap strictly controlled. PAGENO="0037" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16589 Other than narcotic detoxification, not yet an approved" indication for use of the drug, its use as a pain-killer or analgesic is clearly an accepted medical use even though, as discussed above, it has led to widespread abuse and, as wil~l be seen, is much less effective than generally believed. We would agree with the statement in the January 3, 1970 Medical Letter that "65 mg dose of DPX has mild analgesic effect and can be tried in patients in whom the usual doses of analgesics such as aspirin or acetaminophen (as in Tylenol or Datril) are not effective or not tolerated." We would add, however, that the number of such people is extremely small and were the use of DPX limited to this population, the number of prescriptions would be more like 300,000 per year than 30 million (1/100 as much use as now). VII. Criterion 3 - Dependence (Addiction) The last finding that must be made regarding DPX is that its abuse may lead to severe psychological or physical dependence.* 21 U.S.C. § 8l2(b)(2)(c). This disjunctive language of the Controlled Substances Act indicates that a finding of either severe psycho- logical or physical dependence resulting from DPX abuse will justify its inclusion in Schedule II. There is substantial evidence that DPX can produce strong psychological dependence and, sometimes, significant physical dependence. Clinical trials have shown that DPX can produce physical addiction, as manifested by withdrawal symptoms. Although this apparently does not occur at recommended doses for relief of pain,~~ patients undergoing narcotic withdrawal using DPX-Nap have become physically addicted to the latter.75 In 1956, Fraser and Isbell * As used herein, phjrsical dependence refers to a condition of latent central nervous system hyperexcitability induced by fre- quent administration of a drug. Signs and symptoms of abstinence or withdrawal appear when drug administration suddenly ceases. (In the case of opiates, a withdrawal syndrome can be precipitated by administration of narcotic antagonists such as naloxone and nalorphine.) Psychological dependence on a drug can develop along with, or in the absence of, physical dependence. A salient characteristic of psychological dependence on a drug is the tendency for the latter toprovide positive reinforcement for repetLtive drug use by direct action on the central nervous system. PAGENO="0038" 16590 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY concluded that: "[D-propoxyphene] has addictive liability. This is indi- cated by, (a) the induction of opiate-like symptoms when administered in large oral doses to former opiate-addicts, (b) its ability to partially suppress signs of abstinence from morphine, (c) the production of consistent, although very mild, signs of abstinence when the drug was abruptly discontinu~ after 53 or 5~ days of addiction in five subjects."' Four years later these investigators undertook controlled ex- periments which suggested that the addictive potential of DPX was"substantially less than that of codeine."77 Case reports tend to substantiate the claim that the physical dependence produced by DPX is generally moderate; however, psychological dependence can be significant. Elson and Domino reported a case of DPX addiction `characterized by extreme psychic craving, euphoria, and tolerance to the dextropropoxyphene hydrochloride.. .The patient showed definite withdrawal ~ includin~g chills, profuse perspirati&n, cram~in~g, abdominal ~ headaches, nervousne~ and diarrhea."~8 (emphasis added) Reviewing the literature on DPX dependence in 1971 (six published reports), Salter stated: "It is evident from these reports that propoxyphene can produce both strong psychological dependence and some degree of physical dependence, although quantitatively, less than that of morphine or codeine. Significant tolerance does occur and mild to moderate withdrawal symptoms may sometimes be elicited in a depep~ent person by sudden discontinuance of the propoxyphene."'~ (emphasis added) Occasionally physical withdrawal symptoms may be severe. Mattson et al. described ~ patients chronically dependent on high doses of DPX: "Not only did the patients continue using the drug for its psychic effect, but 3 of them were unable to stop be cause dis continuation produced withdrawal symp toms characterized by perspiration, tremulousness, and nausea which were promptly relieved when more propoxyphene was taken. One patient developed a severe deliripm lasting four days after discontinuation of the drug.'TOO PAGENO="0039" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16591 Judging from the published literature, oral abuse usually appears to lead to dependence and psychic craving only in doses much higher than the so-called therapeutic dose for relief of pain symptoms.8l Yet Salguero et al. described a case of severe psychic (but minimal physical) dependence in an individual whose average intake was only 65 mg every 2 to ~ hours, or just 1.5 to 3 times the recommended therapeutic dose.82 The Justice Department study even noted cases of psychic dependence developing at the recommended therapeutic levels for pain.8~ Addiction to DPX may occur in individuals with no prior psychiatric history or drug abuse. Exemplifying DPX addiction in persons innocent of prior drug abuse are cases of newborn infants, addicted in utero, who have displayed signs and symptoms of withdrawal shortly after birth.~'8~'86 In l97~, in a review of the literature and presentation of seven new cases, Maletsky pro- vided convincing evidence that: 1. Addiction to propoxyphene can occur in individuals neither psychiatrically ill nor addiction prone; 2. Addiction can occur under the usual circumstances of medical prescribing; 3. Tolerance and withdrawal can be clearly demonstrated; ~. Addiction can occur without the initial euphoria.°7 (emphasis added) Considering the relative analgesic ineffectiveness of DPX at low doses, it is not difficult to understand why patients might in- crease their dosage in trying to achieve better pain relief, however, some patients may become inadvertently addicted. It is clear that oral administration is sufficient to maintain addiction; intravenous injection is not necessary.88 Indeed, dependence cannot be maintained for long by intravenous or subcu- taneous infusion because of DPX'S destructive effects on the veins and soft tissues.8~ Nevertheless, narcotic addicts shoot DPX intravenously when more potent narcotics are in short supply, e.g., when the addicts are incarcerated.90 PAGENO="0040" 16592 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In light of the foregoing evidence of psychic and physical dependence and tolerance, the Administrator of the DEA found that "Abuse of DPX may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule 111.91 If this is true, the dependence produced by drugs and other substances in Schedule III, and a fortiori by those in Schedule II, should be considerabiy more severe. Yet it is not clear that certain drugs in Schedule II produce any greater degree of physical or psychologic dependence than DPX. Of ampheta- mines, for example, a widely-used medical textbook states that, "Physical dependence manifested as withdrawal signs is difficult to establish.. . The development of tolerance is also not easy to prove."92 Goodman and Oilman, an authoritative pharmacology text states: For a long time it was believed that, except for drug craving, prolonged sleep, general fatigue, lassitude, and depression, there were no withdrawal symptoms from amphetamine-like drugs and, therefore, no physical dependence.. It is still considered true that abrupt discontinuation of sympathomimetic amines does not cause major, grossly observable, physiological disrup tions that would necessitate the gradual withdrawal of the drug. But the prolonged sleep, lassitude, fatigue, and depression, that follow discontinuation of these drugs are difficult to attribute merely to the preceding loss of sleep and weight.. .iiost observers now recognize the existence of a withdrawal syndrome following discontinuation of amphetamine- like drugs. Its role in perpetuating drug use or relapse is not clear.93T~mphasis added) The relation between this withdrawal syndrome, characterized by fatigue and hunger, and amphetamine use has not even been firmly established. Yet amphetamines have been included in Schedule II, despite the lack of evidence of severe physical dependence. DPX is far more widely abused than the amphetamines and, when abused it produces a comparable degree of psychological dependence and a greater degree of physical dependence. Thus DPX represents an even stronger case for inclusion in Schedule II. PAGENO="0041" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16593 VII. Analgesic Impotence of Propoxyphene WhAle DPX's potential for abuse has been understated, the claims for its analgesic potency have been grossly exaggerated. No significant analgesic effect has ever been shown for DPX pre- parations in properly conducted* clinical studies. In a review of the published literature undertaken in 1970, Miller et al., dis- covered that only 20 of 2~3 studies" on DPX had been conducted double_blind.**9~ Even among these 20 studies, several had design defects such that their results were of questionable validity. Gleaning what remained of the analgesic efficacy of DPX in relieving several kinds of pain,, the authors concluded: "Propoxyphene is no more effective than aspirin or codeine and may even be inferior to these analgesics.. .When aspirin does not pro- vide adequate analgesia, it is unlikely that propoxyphene will do so ." Sixteen of the studies reviewed by Miller had compared DPX with placebo. In nearly half of these(7/l6), there was no significant difference in analgesia between DPX and placebo. Four of these latter studies included tests using 65 milligram (mg) doses of DPX, which remains the manufacturers' suggested dose.95 Three more recent double-blind studies have suggested that, at the manufacturer's recommended dose, DPX is no more effective in j~q4~ relief than placebo~6,97,98 Moertal et al. concluded: "The therapeutic credentials of both propoxyphene(Darvon) $9.50 per 100 doses of 65 mg) and ethoheptazine(Zactome, $7.)40 per 100 doses of 75 mg) must be classified as very equivocal. In this study, neither showed a significant advantage over pq~, and both were significantly inferior to aspirin~79 * I.e., including,at a minimum, randomization and double-blind observation. ** A double-blind trial exists where neither patient nor observer knows which treatment the patient is receiving. This minimizes bias and preconceptions of patient and observer both, and is imperative in a study design in order to achieve meaningful results. PAGENO="0042" 16594 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Although Dr. C.M. Gruber, one of Eli Lilly's medical spokesman, took exception to this conclusion,~-°° his own published investi- gations have also shown that DPX is no more effective than placebo in single 65 mg doses.* 101 In 1977 Miller reviewed 13 double blind studies** of DPX's analgesic effectiveness, twelve of which had been published sub- sequent to his earler review.102 Five of these thirteen studies purported to evaluate the relative efficacy of DPX hydrochloride and DPX napsylate, which was introduced in 1971 by the Lilly Company just before its patent on DPX hydrochloride expired. Miller's conclusion: "The introduction of the napsylate salt PRX [i.e. dextropropoxyphene] has not provided a more effective preparation, and the napsylate has no other clinically significant advantages over the hydrochloride." Lacking proof of superior analgesic efficacy, the popularity of DPX Napsylate products (Darvon-N, Darvocet-N, Darvon-N with ASA, etc.) attests to the superior efficacy of the Lilly Company's promotional efforts. The other eight studies reviewed by Miller once again failed to demonstrate that DPX had any analgesic advantage over the other less expensive medications. Indeed, as noted above, three of these studies suggested that DPX was no more effective than placebo. Miller's review also discussed all the double-blind studies comparing DPX hydrochloride and DPX napsylate combination products with other analgesics. Considering the paucity of well-designed studies comparing combination drugs with single analgesics, the fact that most analgesic preparations prescribed are combinations is surprising. Miller found ~ one well-designed study comparing acetaminophen (the active ingredient in Tylenol, Datril, etc.), acetaminophen plus DPX (i.e. Darvocet), DPX alone, and placebo.103 * Dr. Gruber's conclusion in his 1977 study (note 90) that DPX in multiple doses does provide significantly greater relief than placebo is suspect because he neglected to * randomize the patients in his study. ** Including 2 of the 3 just discussed. PAGENO="0043" COMPETITIVE PROBLEMS IN THE DRuG INDuSTRY 16595 That study demonstrated that acetaminophen alone was as effective in pain relief as acetaminophen plus DPX. In other words, the analgesic property of this combination can be attributed to the acetaminophen by itself. Similarly, in his review Miller discovered ~j~j~y one good study comparing aspirin with aspirin plus DPX.1~ The authors of that study found that propoxyphene napsylate plus aspirin was `significantly inferior to aspirin plus either codeine or oxycodon; but not significantly different from aspirin alone." In other words, here once again, the DPX combination analgesic provided no significant benefit over plainaspirin. Finally, of only five double-blind studies on DPX and aspirin, phenacetin, and caffeine (APC)~ combinations, Miller found that two compared DPX and APC with APO alone. One of these two studies found that DPX Napsylate plus APC was superior to APC alone.105 This alleged superiority of DPX-APC over APC alone must be interpreted in light of the above-mentioned well-designed studies where no such difference in pain relief attributable to DPX could be detected. That is, the alleged advantage of DPX plus other anal- gesics must be quantitatively minute since none but this particular Lilly study could discover it. Thus Miller states: "There is little evidence that combinations of PRX{Li.e. DPX] with other analgesics are superior to one analgesic alone. Aspirin or acetaminophen appears to be just as effective when given alone as when given with PRX." In conclusion he declares: "It is now more doubtful than ever that PRX HC1[i.e. DPX] 65 ing provides an analgesic effect equal to that of aspirin 650 mg. . . There is no conclusive evidence that combinations of PRX with other analgesics are more effective than PRX or other analgesics alone. In view of these findings, the continued widespread use of PRX preparations is perplexing." It is clear that from a therapeutic standpoint, little if any- thing would be lost by restricting the availability of DPX. DPX is apparently no more effective in pain relief than aspirin or aceta- minophen. PAGENO="0044" 16596 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY IX. ~pgg~l Analysis The evidence of the actual abuse and acute toxicity of DPX summarized above demonstrates that the more stringent Schedule II controls are now warranted. DPX's abuse potential has been compared to that of other drugs which have been placed in Schedule I by DEA. As Dr. Theodore Cooper, then Assistant Secretary for Health admonished in a 1976 memorandum recommending that DPX be placed in Schedule IV:* `AS with most psychoactive drugs, abuse potential of a particular drug is usually described in terms of proto- type or `reference' drugs. In this respect, propoxyphene has been compared to codeine, morphine and heroin. Such comparisons have included both acute physiological and psychological effects of propoxyphene apd the chronic effects of high dose administration."lOO Dr. Cooper acknowledges DPX's potential for abuse and acute toxicity are well recognized, and the facts of widespread actual abuse confirms Dr. Cooper's reference to the similarities between DPX and heroin and morphine. Perhaps most compelling of the evidence thus far assembled concerning the extent of DPX's actual abuse is the DAWN statistics which demonstrate that deaths in- volving DPX abuse in l~ major metropolitan areas occur more frequently than deaths involving heroin and morphine combined.107 * Although Dr. Cooper recommended that DPX be placed in Schedule IV, it's difficult to reconcile this recommendation with his finding that DPX's potential for abuse is equiva- lent to substances like heroin and morphine, which have been placed in Schedule I. However, whatever reasons Dr. Cooper may have had in 1976 for not advocating more stringent controls on DPX, his recommendation was untenable in light of then existing statistics which established the unchecked actual abuse of DPX. PAGENO="0045" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16597 The effect of transferring DPX to Schedule II is that the drug will be subject to requirements that prescriptions be in writing and ~pgy~ not be refilled, 21 U.S.C. § 829(a), and that the drug will not be produced in excess of government-established quotas based on estimated medical and scientific need. 21 U.S.C. § 826(c). In contrast, ScheduleIV allows prescriptions for DPX to be transmitted orally and refilled five times in any six month period. 21 U.S.C. § 829(b). Moreover, the penalty for violating provisions of the Act where a Schedule II drug is involved is substantially more severe than for a Schedule IV drug.~8 As has been the case with amphetamines and other widely abused drugs which DEA has been forced to transfer into Schedule II to curb their abuse, DPX abuse will not subside unless the more strin- gent Schedule II controls are imposed. Because of the CSA's overriding emphasis on protecting the public from hazardous drugs, Congress, in the CSA Act, requires the Attorney General to determine the schedule in which to place a particular drug on the basis of three factors; its potential for abuse, its currently accepted medical use, and the degree to which it causes physical or psychological dependenceJ09 To provide guidance to the Attorney General, the statute further states that the Attorney Generals inquiry must include an evaluation of the following factors: 1. Its actual or relative potential for abuse. 2. Scientific evidence of its pharmacological effect, if known. 3. The state of current scientific knowledge regarding the drug or other substance. ~. Its history and current pattern of abuse. 5. The scope, duration and significance of abuse. 6. What, if any, risk there is to the public health. 7. Its psychic or physiological dependence liability. 8. Whether the substance is an immediate precursor of a substance already controlled under this subchapter. f21 U.S.C. § 811(c).] PAGENO="0046" 16598 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In addition to the factors listed in Section 811(c) of the Act, the Attorney General must request the recommendation of the Secretary of HEW, including the Secretary's consideration of the eight factors listed above. 21 U.S.C. § 811(b). It is apparent from the statute that the critical inquiry in considering whether to transfer a substance to a more stringent category is its potential for abuse. Indeed, the statute requires that this factor be considered before any further proceedings are initiated. 21 U.S.C. § 811(a)(1)(A). Furthermore, four of the cri- teria enumerated above specifically concern the substance's potential for abuse. 21 U.S.C. §~ 8ll(l),(1~),(5) and (6) The statutory emphasis on the substance's potential for abuse and the Congressional intent that abuse be the principal, if not the determinative part of the inquiry is confirmed by the House Report accompanying the passage of the Act, which describes the factors influencing the Attorney General's inquiry as follows: A key criterion for controlling a substance, and the one which will be used most often, is the substance's potential for abuse. If the Attorney General determines that the data gathered and the evaluations and recommendations of the Secretary constitute substantial evidence of potential for abuse, he may initiate control proceedings under this section. Final control by the Attorney General will also be based on his findings as to the substance's potential for abuse.110 The House Report continues with the definition of "potential for abuse", which includes factors relating to (1) the health of the drug user or the safety of the community; or (2) the extent that the drug is diverted from legitimate drug channels; or (3) the finding that individuals are taking the drugs on their own initiative rather than on the basis of medical advice.111 Unquestionably, the hundreds of deaths due to DPX overdose each year illustrate that DPX's potential for abuse exceeds the requirements of each of these criteria. In a similar vein, the House Report further provides that "misuse of a drug in suicides and attempted suicides, as well as injuries resulting from unsupervised use are regarded as indicative PAGENO="0047" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16599 of a drug's pbtential for abuse.11? In this context, it is signi- ficant that 55% of the emergency rteom mentions of DPX from July- September 1977 consisted of suicide attempts, according to the DAWN statistics.113 Another 18% were associated with addiction or psychic effects.?tl~ Furthermore, the courts which have construed the CSA have also relied almost exclusively on the substance's potential.for abuse in reviewing the propriety of decisions to place a drug in a particular schedule. Indeed, in The National OrganizatiOITL%p~ the Reform of Marijuana Laws (NORML) v. Drug Enforcement Adminis~r~- tion, 559 F.2d 735(D.C.Cir. 1977), the Court of Appeals rejected DEA's claim that the lack of established medical use for cannabis, standing alone, required that it be included in Schedule I. 559 F.2d at 7~7. Rather the Court held that under the CSA, DEA is bound to balance medical usefulness against the other factors enumerated in the Act, which the Court summarized as the potential for abuse and the danger of dependence. cf. United States v Maiden, 355 F.Supp. 7~3, 7148-7'49 ni~ (D.Conn. 1973) In addition to evidence of DFX's overwhelming abuse, two other factors further point to the need for tighter controls on DPX's availability. First, DPX's toxicity, discussed above.115 DPX is particularly dangerous because the margin between the doses necessary to achieve the euphoric state and those which. are harmful and often lethal is extremely narrow. As DEA recognizes, although the statute and the legislative history are silent on the weight to be given to acute toxicity in assessing the appropriate schedule for a substance, toxicity is an extremely important consideration to weigh.~6 In the case of DPX, toxicity weighs heavily towards the imposition of more stringent controls. PAGENO="0048" 16600 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Second, the minimal therapeutic value of DPX must also be balanced against the harm and death that this drug is causing to hundreds of individuals each year. As demonstrated above, aspirin or acetaminophen(Tylenol) appears to be at least as effective when given alone as when given with DPX.117 For those who can not take aspirin, and choose to take DPX over the other analgesics, Schedule II controls will hardly present a barrier to use of DPX, which will remain available on a prescription basis. In conclusion, the extent of DPX abuse as presented above, plainly demonstrates that the present controls are wholly in- adequate. DEA is required by law to curb the abuse of this minimally effective and extremely toxic drug by transferring DPX to Schedule II and should not retreat from its legislative mandate. PAGENO="0049" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16601 FOOTNOTES 1. Fraser, H.F., and H. Isbell, Report to Drug Addiction Committee 20 April 1956, Addendum to Minutes of the 17th Meeting of the Committee on Drug Addiction andNarcotics of the National Research Council," Washington, DC 30-31 January 1956. 2. See, e.g., Grubsr, C.M., Codeine Phosphate, Propoxyphene Hydrochloride and Placebo," JAMA 1614(9): 966, 1957. 3. Therapeutic Category Report in National Prescription Audit, Dedham, Massachussetts, R.A. Gosselin and Co., Inc. 1969, cited in Tennant, F., "Complications of Propoxyphene Abuse," Arch Intern Med 132: 191, 1973. 14. Ph3rsicians Desk Reference, Medical Economics Company, 1978, p. 999. 5. Kersh, E.S., "Treatment of Propoxyphene Overdosage with Naloxone," Chest 63(1): 112, 1973. 6. Tarala, H., and J.A.H. Forrest, "Treatment of Propoxyphene Poisoning," Brit Med J 1: 5514,; 1973. 7. Vlasses, P.H. and T. Fraker, "Naloxone For Propoxyphene Overdosage," JAMA 229: 1167, 19714. 8. See Criterion 3--Dependence,(Addictton), infra at 13. 9. DAWN Quarterly Report July-September 1977, Drug Enforcement Administration, p 9. 10. Physician's Desk Reference, Medical Economics Co., 1972, p.. 8145. 11. Therapeutic Category Report in National Prescription Audit, Dedham, Massachussets, R.A. Gosselin and Co., Inc., December 1977. 12. Burack, R. and F.J. Fox, The 1976 Handbook of Prescription Drugs, Random House, New York, 1976, p.329. 13. Goodman, L. and H. Oilman, e.ds., The Pharmacologic Basis of Therapeutics, 5th ed., MacMillan Publishing Co., Inc., New York, 1975, p.319. l~4. Sturner, W.Q., and J.C. Garriott, "Deaths Involving Propoxyphene-- A Study of ~4l Cases over a Two-Year Period," JAMA 223(10): 1125, 1973. 15. Tennant, F.S., "Complications of Propoxyphene Abuse," Arch Intern Med 132: 191, 1973. 16. Tennant, F.S., "Drug Abuse in the U.S. Army Europe," JAMA 221: 11146, 1972. 17. Gravey, R.H., et al., "Incidence of Propoxyphene Poisoning: A Report of Fatal Cases," J For Sci 19: 72, 19714. 18. Thompson, E., et al, "Spectrophotometric Determination of d-propoxyphene (Darvon) in Liver Tissue," J For Sci 15:605, 1970. 19. Qureshi, E., `Propoxyphene Hydrochloride Poisoning," JAMA 188: 1470, 19614. 20. Butz, W.C., "Pulmonary Arteriole Foreign Body Granulomata Associated with Angiomatoids Resulting From the Intravenous Injection of Oral Medications, e.g., Propoxyphene Hydrochloride (Darvon)," J For Sci 114: 317, 1969. 40-224 0 - 79 - 4 PAGENO="0050" 16602 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 21. Chambers, C.D., and W.J.R. Taylor, "Patterns of Propoxyphene Abuse," mt ~ Clin Pharm 14(2): 2140, 1971. 22. Vetter, C., and L. Fenner, "Drug Incidents Associated with Deliberate Nontherapeutic and Therapeutic Use: Calendar Year 1975," FDA Office of Planning and Evaluation, March 1976. 23. Finkle, B.S., et al., "A National Assessment of Propoxyphene in Postmortem Medicolegal Investigation, 1972-1975," 3 For Sci 21(14): 706, 1976. 2~1. Drug Control Division, Bureau of Narcotics and Dangerous Drugs, "A Study of the Abuse Potential of Dextropropoxyphene with Control Recommendations," May 1973, revised January 1976. [Hereinafter referred to as "Drug Control Division."] 25. McBay, A.J., and P. Hudson, "Propoxyphene Overdose Deaths," JAMA 233: 1257, 1975. 26. Monforte, J.R., and W.U. Spitz, "Drug Deaths Involving Propoxyphene--An Assessment of Metropolitan Detroit," Prey Med 5: 573, 1976. 27. Drug Control Division, ~ note 214, at 92-93. 28. Finkle, B.S., et al., suora note 23. 29. Monforte, J.R., and W.U. Spitz, ~ note 26. 30. McBay, A.J., and P. Hudson, ~ note 25. 31. Drug Control Division, ~ note 214, at 8la. 32. Id. at 8lb. 33. Swarts, C.L., "Propoxyphene(Darvon)Poisoning," Am J Dis Child 107: 113, l96~4. 314. Feinberg, A., "Propoxyphene Hydrochloride(Darvon)Poisoning," Clin Ped 12(7): 1402, 1973. 35. Fisch, H.P., "Pulmonary Edema and Disseminated Intravascular Coagulation After Intravenous Abuse of d-propoxyphene(Darvon)," South Med J 65(14): 1493, 1972. 3E. Bogartz, L.J., and B.C. Miller, "Pulmonary Edema Associated With Propoxyphene Intoxication," JAMA 215:259, 1971. 37. McCarthy, W.H., and R.L. Keenan, "Propoxyphene Hydrochloride Poisoning: Report of the First Fatality,: JAMA 187: 1460, 19614. 38. Gary, N.S., et al., "Acute Propoxyphene Hydrochloride Intoxi- cation," Arch Int Med 121: 1453, 1968. 39. Karliner, J.S., "Propoxyphene Hydrochloride Poisoning," JAMA 199: 152, 1967. 140. Singh, S., et al., "Acute Propoxyphene Intoxication: A Case Report and Review," Am J Ther Clin Rept 1: 83, 1975. 141. Qureshi, E.H., ~ note 19. PAGENO="0051" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16603 142. Warren, R.D., et al., Fatal Overdose of Propoxyphene Napsylate and Aspirin, JAMA 230: 259, 19714. 143. Sigurd, B.M., and 0. Jensen, Propoxyphene Poisoning,' Dan Med Bull 18(6): 166, 1971. 1)t4. Hyatt, H.W., "Near Fatal Poisoning Due to Accidental Ingestion of an Overdose of Dextropropoxyphene Hydrochloride by a Two- Year Old Child," N Eng J Med 267, 710, 1962. 145. Nickander, R., et al., "Propoxyphene and Norpropoxyphene Pharmacologic and Toxic Effects in Animals," J Pharm Exp Ther 200(11): 2145, 1977. 146. Cawood, R., and J.L. Thirkettle, "Poisoning by Propoxyphene Hydrochloride (Doloxene), " Br Med J 2: 132)4, 1966. 147. Baselt, R.C., and J.A. Wright,, "Propoxyphene and Norpropoxy- phene Tissue Concentrations in Fatalities Associated with Propoxyphene Hydrochloride and Propoxyphene Napsylate," Arch Toxicol 3)4: 1)45, 1975. 148. Physicians Desk Reference 1978, p 998. 149. Worm, K., "Determination of Dextropropoxyphene in Organs From Fatal Poisoning," Acta Pharmacol and Toxicol 30: 330, 1971. 50. Fraser, H.F., and H. Isbell, "Pharmacology and Addiction Liability of dl- and d-propoxyphene," Bull Narc 12: 9, 1960. 51. DAWN Quarterly Report, July-September 1977. 52. 7Jj~. 53. See e.g., "Apparent Rise in Darvon-Linked Deaths Spurs FDA to Reconsider Curbs on Drug," Wall Street Journal, September 22, 1975. 514. McBay, A.J., and P. Hudson, ~ note 25. 55. Carson, D.J.L., and E.D. Carson, "Fatal Dextropropoxyphene Poisoning in Northern Ireland," Lancet: 8914, 1977. 56. Simonsen, J., "Accidental Fatal Drug Poisoning with Particular Reference to Dextropropoxyphene," Foren Sci 10: 127, 1977. (Denmark) 57. "Dangers of Propoxyphene," Br Med J 1: 668, 1977.(U.K.) 58. "Distalgesic Caution in U.K. Journal," SCRIP, May 6, 1978 p 23. 59. Whittington, R.M., "Dextropropoxyphene Overdosage in the West Midlands," Br Med J 2: 172, 1977. 60. Finkle, B.S., et ml., ~ note 23. 61. Id. 62. Data obtained from the Information Resources Unit, Drug Enforcement Administrat~on, Washington, DC. 63. DAWN Quarterly Reports, July-September 1977, Drug Enforcement Administration at p 2. PAGENO="0052" 16604 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6)4. Therapeutic Category Report of National Prescription Audit, ~ note 11. 65. See Analgesic Impotence of Dextropropoxyphene, infra at 17. 66. DAWN Quarterly Report, ~ note 51, p 13. 67. Crowther, B., et al., Differences Among Medical Professionals in Their Attitutes Towards Drugs," mt ~ Addic 12(1): 1)3, 1977. 68. Tennant, F.S. "Propoxyphene Napsylate (Darvon-N) Treatment of Heroin Addicts,' J Nat Med Ass 66(l):23, 197)4. 69. Inaba, D.S., et al., "The Use of Propoxyphene Napsylate in the Treatment of Heroin and Methadone Addiction," West J Med 121: 106, 197)4. 70. Tennant, F.S., et al., "Comparative Evaluation of Propoxyphene Napsylate CDarvon-N) and Placebo in Heroin Detoxification," mt J Addic 12(1)): 565, 1977. 71. Jasinski, D.R., "Therapeutic Usefulness of Propoxyphene Napsylate in Narcotic Addiction," Arch Gen Psychiatry, 31): 227, 1977. 72. Tennant, F.S., et al., "Outpatient Withdrawal from Methadone Maintenance with Propoxyphene Napsylate (Darvon-N)," J Psychedelic Drugs 7: 269, 1975. 73. Tennant, F.S., et al., "Propoxyphene Napsylate Treatment of Heroin and lIethadone Dependence: One Year's Experience," J Psychedelic Drugs 6: 201, 1971). 71). Chernish, J.M., and C.ii. Gruber, Jr., "Demonstration of Absence of Physical Dependence to Therapeutic Doses of Dextropropoxyphene Hydrochloride (Darvon) Using the `Allyl Test'," Antibiot Med Clin Ther 7: 190, 1960. 75. See Tennant, F.S., et al., Bj~PTh notes 72 & 73. 76. Fraser, H.F., and H. Isbell, ~ note 1. 77. Fraser, H.F., and H. Isbell, ~ note 50. 78. Elson, A., and E.F. Domino, "Dextropropoxyphene Addiction," JAMA 183: 1)82, 1963. 79. Salter, F.J., "Propoxyphene: Dependence, Abuse and Treatment of Overdosage," Am J Hosp Pharm 28: 208, 1971. 80. Mattson, R.H., et al., "Dependence and Central Nervous System Toxicity Associated with the Use of Propoxyphene Hydrochloride," Trans Amer Neurol Ass 91): 299, 1969. 81. See, e.g., Tennant, F.S., ~P7.O notes 15, 72,73; Fier, M., "Addiction to a Massive Dose of Darvon," J Med Soc N Jers 70(5): 393, 1975. PAGENO="0053" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16605 82. Salguero, C.H., et al. ,"Propoxyphene Dependence," JA~ 210: 135, 1969. 83. Drug Control Division, ~ note 2~, pp 61-62. 8~. Klein, R.B., et al., "Probable Neonatal Propoxyphene With- drawal: A Case Report," Pediatrics 55(6):882, 1975. 85. Quillian,W.W., and C.A. Dunn, "Neonatal Drug Withdrawal from Propoxyphene, " JAMA 235: 2128., 1976. 86. Tyson, H.K., "Neonatal Withdrawal Symptoms Associated With Maternal Use of Propoxyphene Hydrochloride," J Pediatrics 85: 68'4, 197'4. 87. Maletsky, B.M., "Addiction to Propoxyphene (Darvon): A Second Look," mt J Addict 9(6): 775, l97~. 88. Maletsky, B.M., gj~~ note 87; Tennant, F.S., ~ notes 72 and 73. 89. Tennant, F.S., ~ note 15. 90. Chambers, C.D., et al., "Five Patterns of Darvon Abuse," mt J Addict 6(1): 173, 1971. 91. Federal Register ~42(29): 8636, February 11, 1977. 92. Meyers, F.H., E. Jawetz, and A. Golfien, Review of Medical Pharmacology, 5th ed., Lange Medical Publications, Los Altos, California, 197b, p 295. 93. Goodman, L., and A. Oilman, The Pharmacologic Basis of Therapeutics, 5th ed., MacMillan Publishing Co., Inc., New York, 1975, p.305. 9C. Miller, R.R., et al., "Propoxyphene Hydrochloride: A Critical Review," JAMA 213: 996, 1972. 95. Physicians' Desk Reference,, 32nd ed., 1978, p.998. 96. Moertel, C.G., et al., "A Comparative Evaluation of Marketed Analgesic Drugs," N Eng J Med 286: 813, 1972. 97. Hopkinson, J.H., III, et al., "Acetaminophen Versus Propoxy- phene Hydrochloride For Relief of Pain in Episiotomy Patients," J Clin Pharmacol 13:251, 1973. 98. Gruber, C.M., "Codeine and Propoxyphene in Postepisiotomy Pain," JAMA 237: 273~1, 1977. 99. Moertel, C.G., et al, 9~PF~ note 96. 100. Gruber, C.M., "Effectiveness of Propoxyphene,"(letter) N Eng J Med 286: 1158, 1972. 101. Gruber, C.M., et al., "Comparative Evaluation of Analgesic Agents in Postpartum Patients: Oral Dextropropoxyphene, Codeine and Meperidine," Aneath Analg LIl: 538, 1962; see also ~ note 93. PAGENO="0054" 16606 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 102. Miller, R.R., `Propoxyphene: A Review,' Am J Hosp Pharm 3)4: 413, 1977. 103. Hopkinson, J.H., III, et al., ~ note 97. 10~4. Moertel, C.G., et al., "Relief of Pain by Oral Medications, a Controlled Evaluation of Analgesic Combinations," JAMA 229: 55, 197)4. 105. Bauer, R.O., et al., "Evaluation of Propoxyphene Napsylate Compound in Postpartem Uterine Cramping," J Med 5: 317, 197)4. 106. Memorandum from Theodore Cooper, M.D. to Peter Bensinger, "Scheduling Re commendations for Prop oxyphene," August 12, 1976. 107. See infra at 6. 108. The penalty under the Act where a controlled substance under Schedule II is involved is up to 5 years imprisonment, a fine of up to $15,000 or both. In the case of a Schedule IV Substance, the penalty is up to 3 years imprisonment, a fine of up to $10,000 or both. 21 U.S.C. § 814l(b)(l)(B) and (b)(2). 109. 21 U.S.C. § 812. The findings required for Schedules II and IV are as follovs: (2) Schedule II (A) The drug or other substance has a high potential for abuse. (B) The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restric- tions. CC) Abuse of the drug or other substance may lead to severe psychological or physical dependence. ~4) Schedule IV (A) The drug or other substance has a low potential for abuse relative to the drugs or other substances in Schedule III. (B) The drug or other substance has a currently accepted medical use intreatment in the United States. (C) Abuse of this drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule III. 110. H.R. 91-1)4)4)4, 91st Congress, 2d Session pt. 7, at 3)4, cited in U.S. Code Cong and Admin New 1970, p )460l.[Herinafter referred to as H.R. 91-1)4)4)4] 111. The term "potential for abuse"is adopted from Section 20 1(v) of the Food, Drug and Cosmetic Act as defined in 21 C.F.R. 166.2(e), cited in U.S. Code Cong. and Admin. News 1970, p )460l. 112. H.R. 91~1)414)4, ~qpp~ note 110, at )4602. 113. DAWN Quarterly Report, ~ note 9,at 13. 11)4. Id. 115. Infra at 5. 116. Drug Enforcement, Vol 2, No 2, Spring 1975, at 39. 117. Infra at 17. PAGENO="0055" COMPETITIVE PROBLEMS IN THE DRUG LNDUSTRY 16607 Senator HAYAKAWA. Mr. Chairman, I am called to Foreign Relations to fill out a quorum, but I do want to ask a question. Senator NELSON. Go ahead. Senator HAYAKAWA. When you say, Dr. Wolfe, that Darvon is less effective than aspirin, is it not true that, depending on the individual, for some people Darvon is more effective and for some people it is not, that people go from one to the other as a painkiller, because of the unique differences in each of us, as individual physiological systems? Dr. WOLFE. `Well, that is an interesting question. Pain is a very difficult thing to measure, and in some studies, there are a number of studies showing that giving a sugar pill, just a placebo, because of the doctor-patient intervention, will and can have a substan- tial relief on pain in someone. Therefore, when one does studies on large numbers of people, this has to be taken into account, so that not only does one want to compare Darvon or propoxyphene with aspirin, but also with a placebo. Whereas in individual cases, there may be someone who says they get a better response, overall when one accounts for the placebo effect and other problems, by means of properly con- trolled studies where patients have been randomized, and where investigators do not know whether a placebo or the drug has been given out, these studies really fail to show that propoxyphene or Darvon is any better than aspirin, and in many of them they show it is not as good as aspirin. Senator HAYAKAWA. But these studies covering a large number of people still do not face the question of the individual. If I as an individual find that aspirin does not work for me for a particular kind of pain, recurrent pain, and I find that Darvon does, does it matter what research on it of a few thousand people displays? Dr. WOLFE. Yes and no. In one sense if aspirin does not work, and there are some people who have intolerance to aspirin, they have an ulcer, whatever, another alternative is acetaminophen. If that does not work, another alternative is codeine. All three of these, as I will discuss shortly, are considerably safer than Darvon, and whereas there may be someone such as yourself who cannot take aspirin, we are not able to locate a group of people at all who find that aspirin, or acetaminophen, or codeine do not work. There are three choices, not just one, other than Darvon. Senator HAYAKAWA. These questions bother me; that is, there are many, many painkillers besides the two mentioned Dr. WOLFE. And they are all safer, that is the main point. Senator HAYAKAWA. That is not the question. If people continue to take however more than the recommended dose, thereby endangering our health, as you say, is this the fault of the manufacturer, or is it the fault of the individual for failing to observe the recommendation. If the prescription says recommended dose, not more than one every 4 hours, and people continue to persist in taking two or three or four every 2 hours, whose problem is that, is it the Government's problem? I am asking you, does the Government have to be the universal babysitter, or is the Government to let people who are capable to decide for themselves whether or not to follow a recommendation given on a scientific basis. PAGENO="0056" 16608 COMPETJT~VE PROBLEMS IN THE DRUG INDUSTRY Dr. WOLFE. Well, that is certainly a problem, whether we are talking about smoking or saccharin or Darvon, but I think in this case, because the drug is often not. very effective, without being a drug abuser or a dope addict, whatever, many people may well understandably be inclined, having paid their money for the Darvon, to try two instead of one. The t.hing that distinguishes this case from a lot of other drugs, is that you can start getting into trouble at very little more than the recommended dose. There are other drugs, such as aspirin, where you have to take maybe 20 or 30 times above the recommended dose to start getting into serious trouble. The margin of error, or the safety margin, is extremely low with Darvon, and as the San Francisco coroner in your home State has said, if you double the Darvon doses, and you take one or two bar drinks, you can get int.o the toxicological range. The patient with cancer was under medical supervision, taking two instead of one every 4 hours. This can happen. I think if Darvon were much safer than it is and more effective than it is, we could tolerate it. There are a lot of drugs on the market where people can get into difficulty, taking 5, 10, 20 times the recommended dose, but you cannot put everyone in a glass house. In the case of Darvon, I think the drug needs to be put in a glass house, because it isso dangerous at low levels, probably, in many cases; because the metabolite is building up. Senator HAYAKAWA. Thank you, Dr. Wolfe. Excuse me, Mr. Chairman. I have to go to my other committee. Senator NELsoN. When you first responded to Senator Hayakaw&s question, I think you said you made reference to something being safer than aspirin, and I think you meant safer than Darvon. You better look at your testimony when you get the record back. One further followup question on the point raised by Senator Haya- kawa. The marketing of drugs is based upon a very specific statute, which says you must prove efficacy and safety by well-controlled sci- entific studies, and that does not permit subjective judgments by a phy- sician and patient about what helps them or does not help them, since it has to be based upon well-controlled studies, as everybody knows. Almost all problems people have are self-limiting. People all over this country-a substantial percentage of people-are getting from their doctor an antibiotic for a common cold, and there is not an anti- biotic that affects the cold, because there are some 200 cold viruses. Yet they will get well, because everybody gets well, so they attribute the act of getting well to having taken an antibiotic, as having an effect on the virus causing the cold. That is why the statute has to be well- defined. Dr. WOLFE. Another example that comes to mind, where both doctors and patients may have been inclined to say, I want to use this drug, because it seems to work, is where a properly controlled study was done to see whether the drug really worked is DES, also manufactured by the Eli Lilly Co. This drug was given to millions of women, and when a properly controlled study was done to see whether it really protected against miscarriages, it turned out it did not work at all. PAGENO="0057" COMPETITIVE PROBLEMS IN THE DRuG tNDIJSTRY 16609 In fact, in one study, it caused more miscarriages than the placebo, so that the fact an individual doctor might prescribe the drug does not mean it works. What the study showed is that a woman who had a miscarriage in a previous pregnancy and who got the drug might have had a mis- carriage anyway, even if she had not gotten the drug. That points out what you are saying; we need to have well-designed, well-controlled studies, whether it is on the effectiveness of DES to prevent miscarriages to see that when a drug is first marketed it is effective. Once the effectiveness law was: passed, Darvon was reviewed, and certainly there were some questions raised about its effectiveness, par- ticularly studies which showed that the drug was more effective than a placebo, but less effective than aspirin. That, in and of itself, would be grounds for marketing it, on the question of effectiveness alone. I think here we have a double problem, not only is it less effective, or no more effective than a number of other painkillers, it also is con- siderably more dangerous. Since we have been discussing the comparisons between Darvon and other painkillers, I have a chart on table IV, which examines the total number of deaths as measured by the drug abuse warning network system. [The information follows:] Deaths per million Drug ~: Deaths 1977 1 prescriptions 2 Darvon 590 19 Codeine 255 5 Aspirin 3 150 <1 Acetaminophen3 77 <1 1 DAWN Quarterly Report January-March 1978. 2 1977 prescriptions filled from National Prescription Audit, I.M.S. 3 1977 retail sales of aspirin of $500,000,000 and acetaminophen, $150,000,000-assume average cost of $1 for aspirin, $1.50 for acetaminophen and use deaths per million bottles. Dr. WOLFE. In 1977 for Darvon and codeine, if you divide the total deaths by the number of prescriptions for aspirin and acetaminophen, all we were able to obtain were marketing figures for aspirin, retail sales, so for these two, we were able to figure out how many deaths per bottle sold there were, one index of aspirin and acetaminophen toxicity. For Darvon, there were 590 deaths during that reported period as listed in the Drug Abuse Warning Network Quarterly Report, Janu- ary of 1978, and the rate of deaths per million prescriptions was 19. Codeine was 255 deaths, or 5 deaths per million prescriptions. Aspirin was 150 deaths, less than one per 1 million bottles, and for acetaminophen, it was 77 deaths, or also less than one death per million bottles sold-the same as for aspirin. I note in looking at the Justice Department's testimony, that they point out that barbiturates, at least several of them, have a higher rate of deaths per million prescriptions. An earlier report they put~ out in 1976, at least looked at one bar- biturate, and they looked at the death and in that case the death rate was lower than for propoxyphene. In today's testimony they show the death rate per million prescriptions of barbiturates such as PAGENO="0058" 16610 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Seconol. The importance of this is that recognizing the dangers of Seconol and most of the other barbiturates, the Justice Department has scheduled them in schedule II, and that has resulted in a substantial decrease in the prescribing of the drugs, in the emergency room visits occasioned by the use of the drug, and a lesser but important decrease in the deaths due to some of these drugs. In comparing something like Darvon to something such as Seconol in schedule II, it really points out that schedule II is able to have an important impact by decreasing prescribing of the drug. Senator NELSON. Did you have handy, or did you put in your peti- tion, I do not recall it, what happened in the prescription of ampheta mines, when they were put on schedule II? Dr. WOLFE. This is in the original petition. On page 14 of the PEA (Department of Justice) petition, we looked at amphetamines, Quaalude `and Seconol, and some others, to see what happened within 1 year of their being put into schedule II. They experienced a 50 percent, 52 percent, and 47.6 percent fall in prescriptions, respectively, and by the end of 3 years, there was a decrease of approximately 75 percent. In other words, only about a quarter or less of the prescriptions that had been written before scheduling, were written within several years afterward, so that at least as one of the alternative proposals that we have made to the Justice Department, or the HEW for con- trolling the drug, moving Darvon into schedule II would cause a major decrease in prescribing, and, therefore, in emergency room visits and deaths. All of `these `have gone down somewhat since they have been put on schedule II. Senator NELSON. Let me ask a question. On page 8 of your petition, you make reference to some 1,200 deaths reported by the Drug Abuse Warning Network from July 1973, to September 1975. Dr. WOLFE. That was a study commissioned by the Justice Depart- ment. It is page 8 of the testimony. Senator NELSON. I am puzzled about this 26-month period. Was that a selection of that period by you~ or was that the study period done by Justice? Dr. Wor1rE. You are talking about page 6 of the petition to the Justice Department? Senator NELSON. Yes. Dr. WOLFE. There was a study commissioned by the Justice Depart- ment looking at those drugs associated with fatalities in parts of the country, about `a third of the country, related to Darvon. This is their study, not ours. Senator NELSON. That is the 26-month period they select them- selves? Dr. WOLFE. Yes. Senator NELSON. Do not the statistics now indicate a reduction in the deaths from use of propoxyphene, if you take it by the quarter in 1978? Dr. WOLFE. Well, not really. On the bottom of page 4 of the testimony today, I go into that. Let me just read these two sentences, and then answer your ques- tion as to why it appears that there may have been a decrease. PAGENO="0059" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16611 In the year before Darvon was put in schedule IV, March 1976 to February 1977, there were 459 deaths related to its use. In the first year of schedule IV, March 1977 through February 1978, the number was 510. Although there appears to be a decrease in deaths during the latter part of 1978, these data underestimate the eventual numbers of re- ported deaths, since all 1978 reports are not completed and sent to DEA until well in 1979. In other words, if we look now,: early 1979 or late 1978, or a year ago, early in 1978, if we looked at the last part of 1977, we would see what appeared to be a fall-off in deaths, not only due to Darvon, but anything else, simply because in terms of getting all these coroners' reports, it takes well into 1979, before they are complete. So that each year, if you look in January, it looks like everything is getting better, not only for Darvon, but for everything else. If you look later in that year, there have been many more reports filed, so that at this time, all we can look at is the period up to the early part of 1978, where the data is complete, and that period of time, that 1 year after as opposed to the 1 year before, putting into schedule IV, really does not suggest any change. There has been a fall in the emergency room visits, which I see the Justice Department will discuss in their testimony, but this has not, at least as of yet, been accompanied by any evidence of decrease of fatalities. The prescribing has gone down from I think 33 million to 30 million over the last year or so. It still is very widely prescribed. Does that answer your question? Senator NELSON. Yes. Dr. WOLFE. As stated in the petition to HEW rescheduling Darvon in schedule II only makes sense if it is possible to identify a group of people for whom the substantial risks of the drug are outweighed by the questionable benefits, taking into account the availability of aspirin, codeine, and acetaminophen, all safer and more effective. I am still unable to identify such a group of people and therefore believe an imminent hazard ban is the preferable way of meeting this serious problem. Senator NELSON. Let me go back to that previous question. Are you saying that DEA releases the statistics from the last quar- ter of 1978, which are not complete, and subsequent to that when all of the records are in, some time during the following year, they update that last quarter? Dr. WOLFE. Yes; I think they have been very cautious about that. Senator NELSON. Is that what happens? Dr. WOLFE. That is what happens. They release on a fairly regular basis all of this data, but they point out, particularly for the last few months, that the data with respect to deaths is often understated, because they have not gotten all of the reports in yet. Senator NELSON. As you say, if you look at any year in the past several years, it is the same pattern? Dr. WOLFE. Yes. Senator NELSON. Because Lilly has a chart that indicates a rather dramatic lowering. PAGENO="0060" 16612 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. WOLFE. I would say the chart is misleading, because each year it takes well into the following year before all of the reports are in, and this is nothing new, the Justice Department is perfectly aware of that. Senator NELSON. Then what does DEA do in a succeeding year- with additional statistics as they come out? Do they update the last quarter of the previous year? Dr. WOLFE. That is correct. Senator NELSON. When they issue these statistics for the last quar- ter of the previous year, do they have a footnote saying these are incomplete? Dr. WOLFE. Yes; they do. Senator NELSON. So that shows in their footnote on the use of Darvon for the last quarter of 1978? Dr. WOLFE. Yes. Again, I just had a glance at it a few minutes ago, I think in their statement this morning, they point out the reports, not only for the last quarter, but perhaps for the last half of the year of 1978, are not complete yet, and, therefore, even though it appears the number of deaths are falling, that may not eventually turn out to be the case, so they do point that out in their testimony this morning. Senator NELSON. OK. Dr. WOLFE. One other thing, when the possibility of putting Dar- von in a different schedule (schedule IV) was raised in 1973, Lilly responded and I quote, "we believe it would not have any material effect on the sale of the product." I think they anticipated that schedule IV, which certainly is no- where near as strong as schedule II, often does not have a substantial effect on prescribing. In our petition to the Justice Department, we looked at two other drugs that had been placed in schedule IV, Valium and Dalmane, and in each case, there was very little effect in the first year, after placing them in schedule IV. Valium went down 4 percent, and Dalmane, which was on the rise, continued to rise, so schedule IV is not anywhere near as effective as schedule II, in terms of controlling use and the predictable conse- quences of people using a drug as dangerous as Darvon. As stated in the petition to HEW, rescheduling Darvon in schedule II only makes sense if it is possible to identify a group of people for whom the substantial risks of the drug are outweighed by the ques- tionable benefits, taking into account the availability of aspirin, co- cleine, and acetaminophen. all safer and more effective. I am still unable to identify such a~ group of people and therefore believe an imminent hazard ban is the preferable way of meeting this serious problem, This is the problem Senator Hayakawa raised, some- one who cannot take aspirin or codeine or acetaminophen. When you look at all three, I would like to see what people would not benefit from at least one of those. Senator NELSON. You are saying there is no target group for whom Darvon would be a better drug than either codeine, acetaminophen. or aspirin? Dr. WOLFE. That is correct, all of which are much less expensive and much less dangerous as I pointed out. PAGENO="0061" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16613 I have never seen any evidence of that at all, and I think that is a critical issue. In a letter to me from Dr. Quentin Young, chief of medicine at Cook County Hospital in Chicago, dated January 23, 1979, he states that Darvon was banned from the medical clinics there in 1974 and from the entire hospital in June 1977. This is the second largest medical clinic in the United States. Dr. Young said: The reasons for eliminating Darvon from the drug list included high cost and absence of any therapeutic superiority over aspirin and aspirin-related drugs for its legitimate indications. Another,: more serious concern was our obser- vation, in this large public hospital, that Darvon was increasingly utilized as an illicit drug by persons who had become dependent upon it. We concluded that an agent devoid of any significant, unique value which was the object of dangerous abuse by growing numbers of people, had no place on our hospital outpatient formulary. While I feel that we served our patients well by avoiding this potentially dangerous drug, we are also serving the public which supports us with tax dollars by avoiding an unnecessary, large expenditure. But most important, we have trained in these 5 years over 300 physicians to practice medicine without resort- ing to this much overused drug * * * Since there are over 500 doctors in training at Cook County Hospital one can assert that a significant number of physicians on the threshold of their training have a unique therapeutic advantage over their contemporaries. Thus, it is quite possible-even less dangerous and much less ex- pensive to practice medicine without the use of Darvon. Further comment on the prospect of an imminent hazard ban was received from chief coroner of San Francisco, Dr. Boyd Stevens, in a letter to me dated January 9, 1979. The experience of this office with propoxyphene preparations indicates that this is an abused drug with little analgesic quality and whose daughter com- pounds are of no significant analgesic property, but are potentially toxic. Because of its frequency of abuse and because of its propensity for toxic results in relatively low doses when mixed with other compounds such as alcohol, the position of this office is that propoxyphene should be withdrawn from the market. Barring the withdrawing of propoxyphene from the pharmaceutical market, we would support it being placed at a schedule II rating of the Control Substance Act. In summary, exploiting doctors' desires for a safe and effective painkiller Lilly pushed Darvon 21 years ago as equally effective as codeine, nonaddicting and safer than codeine. All three statements are false yet millions of Americans have used this expensive and weak painkiller, thousands have died as a result of its toxicity and Lilly has reaped well over one-half of a billion dollars from its sales. The information that chronic use of Darvon leads to high blood levels of the toxic metabolite nor-propoxyphene has never been publicly acknowledged by Lilly, lest it might frighten doctors and patients from using the drug. I hope these hearings provide any additional incentive still needed for the Government to act on Darvon as quickly as possible. Thank you. Senator NELSON. Thank yoU, Dr. Wolfe. Mr. Edgar G. Davis, vice president for corporate affairs, Eli Lilly & Co., sent a letter to my office shortly before the hearings, which he has asked to have read into the record. I shall do so, and you may wish to comment on it. PAGENO="0062" 16614 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The letter is dated January 31, 1979, and reads as follows: DEAR SENATOR NELSON: We were dismayed by the reckless and irresponsible suggestion made by Dr. Wolfe at page 2 of his prepared statement that Lilly had not submitted to the FDA "critical information" with respect to certain dog studies conducted in 1976. The facts are to the contrary. After the experiments were completed, in ac- cordance with accepted research procedure, the scientists involved prepared an abstract of the work which contained all the critical information. This was pub- lished in 1977 in Federation Proceedings, Vol. 36, page 586. The authors presented their findings at the Federation meetings in March 1977. The abstract was submitted By Lilly to the FDA in the same month. Following this, the scientists undertook the preparation of a manuscript for journal publication, expanding on the abstract. This manuscript was submitted in March 1978 to the Journal of Toxicology and Applied Pharmacology for con- sideration, was accepted for publication in May 1978, and will appear in the January 1979 issue of the Journal. While this time period may seem lengthy to a layman, it is consistent with the publication practices of scientific journals. The abstract and the forum presentation included all the essential informa- tion on the experiments. Lilly takes strong exception to Dr. Wolfe's characteriza- tion and unwarranted insinuations. Lilly, in more than a century of service to the medical profession and to the ill, has developed and maintained a merited reputation for integrity. The Company has always shared scientific information concerning its pharmaceutical products with the appropriate agencies of government. It does not withhold information bearing on the safety and efficacy of its products. We respectfully request that this letter be read into the record during Dr. Wolfe's appearance today. We resent this unfair attack on Lilly's scientific integrity and public responsibility. Dr. WOLFE. I would like to respond to that. The statement is misleading, to be generous with it. First of all, I have copies of the abstract that was sent in, the ab- stract they referred to, and that I referred to in the testimony. The abstract was sent to the FDA, as I said in the testimony, and it did not contain critical information as I also said in the testimony. The critical information I am referring to which is contained in the full report that was provided by a source in the company, is that the drug can cause second degree heart block. There is no mention in the abstract that the drug can cause second degree heart block. Even though, as the company states in its letter that you just read, they submitted a copy of the manuscript to the Journal of Toxicology and Applied Pharmacology, they in fact did not submit a copy of the manuscript at least as of a~ couple of weeks ago to the FDA. Whereas I can well understand it may take some time to get a paper published, I think it is indefensible they did not submit to the FDA as they promised to do 2 years ago, the full study, including the fact it caused second degree heart block, therefore, I think that their statement is extremely misleading. The information I referred to was omitted from the abstract, and FDA, as I mentioned, is considering reprimanding the company for this, even though technically they cannot bring criminal proceedings against the company. I would like to add one other thing which I left out. Senator NEI,soN. Wait a minute. I will ask the FDA to comment on that issue, as well, of course, as the Lilly Co., when they testify next Monday. Mr. TWARDY. I would like to submit for the record a copy of the let- ter which was sent by Eli Lilly & Co. to the FDA and the abstract which accompanied it. [Original copy of letter and abstract follow:] PAGENO="0063" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 16615 ELI LILLY AND COMPANY IN DIANAPOLIS, IN 0 lANA 46206 January 31, 1979 The Honorable Gaylord Nelson Chairman Select Committee on Small Business United States Senate Washington, D.C. 2O5lO~ Dear Senator Nelson: We were dismayed by the reckless and irresponsible suggestion made by Dr. Wolfe at page 2 of his pre- pared statement that Lilly had not submitted to the FDA `critical information" with respect to certain dog studies conducted in 1976. The facts are to the contrary. After the experiments were completed, in accordance with accepted research procedure, the scientists involved prepared an abstract of the work which contained all the critical information. This was published in 1977 in Federation Proceedings, Vol. 36, page 586. The authors presented their findings at the Federation meetings in March, 1977. The abstract was submitted by Lilly to the FDA in the same month. Following this, the scientists undertook the prepara- tion of a manuscript for journal publication, expanding on the abstract. This manuscript was submitted in March 1978 to the Journal of Toxicology and Applied Pharmacology for consideration, was accepted for publication in May 1978, and will appear in the January 1979 issue of the Journal. While this time period may seem lengthy to a layman, it is consistent with the publication practices of scientific journals. The abstract and the forum presentation included all the essential information on the- experiments. Lilly takes strong exception to Dr. Wolfe's characterization and unwarranted insinuations. PAGENO="0064" 16616 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Lilly, in more than a century of service to the medical profession and to the ill, has developed and maintained a merited reputation for integrity. The Company has always shared scientific information concerning its pharmaceutical products with the appropriate agencies of government. It does not withhold information bearing on the safety and efficacy of its products. We respectfully request that this letter be read into the record during Dr. Wolfe's appearance today. We resent this unfair attack on Lilly's scientific integrity and public responsibility. Respectfully yours, ( Ed,gar G. Davis Vice President Corporate Affairs Copies to members of the Subcommittee PAGENO="0065" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16617 Mr. A. Z. c~= ~r~z 17, 1977 7~ ~x~d flt ~ ~UZ**t3 c~ ~g*, ~`D 1~Q ~ I~~C4~t Contxol ~ 1Oa~4 56Q~ ~ ~ ~c~vjUa, ~a~yla~3 2O2~7 ~t1~ ~ ~ p xy~n z~a~yla~a, Lilly, with ~ with~t aapiri~ ~n~a1 ~t ~e ~zel~s.d a~traet c~rt~ittq a j~haxa~tcxjy ~ r~pr.wita t~ &fl4%1~1 art ~1er ia ~ o~ c1i~1~ i~f ~tic~n to ~ *IIth~.ttt~ at this tja*. v.~1 tr2ly y~ura~ ~ 3ax~tt, )I.,D. X'sdi~l Mvj~ar 1c~u1atory Affalts 40-224 0 - 79 - 5 PAGENO="0066" 16618 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THIS DOC~4ENT CONT~IN~ TR~iDE SECRETS, OR COi~IERCIAL OR F NANCX)4L INPOR~'1ATION, PRV.TILEGED OR CONFIDENT!itt, DELIVERED IN CONFIDENCE AND RELIjINCE TiiA~ SUCH INFOR~ ~ION WILL NOT 1~E MADE AV~IT2tBLE TO ~EE FU~LIC WX'rHOU'L' ~RE EXPRESS WRITTEN CONS~T OF ELI LILLY )~N~ a~iPAN~1~ IND - i65~5 - flARV'N~-N~, ~ropexypheae ~psylate~ Lilly Tw~1ve-Hooth ~cport D1t~SICIi O~' CARUIAC CJNDUCTICN 3Y PROPOX'~?EDTE AND ~R2RO?OXYPR~E The ~otlowins ~b~cract ia a preli=inary report of co~dtttricu depreiO~ pr~uced by propoxyphcne snd notproposyphe~e~ A cc~plect pro~otatiou ô~ t-hia ~ata ~iill be ±ubi~i.tted ~.n ~ a~ea~crLpC that is now bcie~ ~reparod. PHARMACOLC(~'i DEPR~ES1ON 0~ C.'SDL~C CC~WU~TICi UY R0~XYt~1T~E ANu r~OiU'~O- PoXbTHt2~R. ~ The Lilly Re~n.'rch Lab ;iteri.~~, dtenapuli3 lini. 4n206 The t~ntr~Lly a~tieg ~nit.~ic. ~j~-pr'exyphano (L), a~l ~-dcrnCtiV/l r~eCaboii ~e, d-rrropox~'phcuc (T), ar.~ potcn~ loc~t nne~thi.e. Since L~c~t ,~nc.~tthcticn d~rese e~rdiac entiduction. we ~tu4icd the cff~ct~ of theni~ .sg~nca o~ condiit~- tion in the c..~riine hee~t bcLn -1~ vtuo and in i~ro. ~en P ~as i.nfu~ed trenOutly ir.rn niOu.~ dogs ac d~a-t ~f ~`. I to 21 ~o1o/k~ (0i3 to S ~~Ikc), the ?-R interval ~a prelon~ ed in a ~once~,tratiOfl de~erder.~ nanner. A -30~ pro1on~ntLon of the interval ~ obse:~'ed sc 21 ~~Le/k~. Norpropoxypliene c71 ~~,ole/kg. 1v), prolon~nd the P-ft inC~rvit 177.. dia bundle CleeCtr.V~n were record.~d in pantobarbit~t e~thetized do~rz pret~e~tcd `wi.th ptopr~nOlal a~;d ~trO~inc to bloCk neuregenif. f~flucitco~~. Zptraver.oun adnini.str~tiun of e&ther P or NP pro loosed r~'rduetinn tt~a in the AV node and infra-Illa conduc- ay~crn. AV nodal cor4uct~.ort ~ prolon~efJ ~O7. by p an~1 NP at do~nn °f 3.3 ± 0.5 ~1e/Ic:; and 6.5 + 1.2 ~~,le/kg, r~- spetcivoly. Tnfra-Hia tonduoti~n ~e pru1on~d 107. by P sod NP at do~c~ of 17.1 ± 1.2 ~~o1e/kg and 7.5 ~ 2.8 ~fyr~le/k~, ro- apsetively. In inoloted canine Purkin.~e fibers euperfusd ~ vi3~g, both a~cnca d~pense..i the aiviteucs ate of nat of phm'e 0 of the action pocericiiL (~_.~) and thorteatd tction pat~nd.~i duration. The con cntrtttUi~n that prod~~~i ~ ~0Z d~cro.soe ~n were 2..5 IO~ N With and 1.2 t 10~ M ~aith ~U'. 1i,nn P and NP, like othcr locti anotchetics, dopross cardiac con- duction ia the caninc heart, in ~ ~nd in vitro, Donald a. Enijand, Ph.D. Associate Sr. ?h~reacologi5t 2/10/77 PAGENO="0067" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16619 Dr. WOLFE. I mentioned briefly that doctors treat symptoms of pain. It is one of the most common problems a person brings to the doctor, therefore a pain reliever that is very effective, that is safe, is something that physicians would reach for. The way the drug was originally pro- moted, I think, accounts for a lot of abuse, and I would like to refer to a current ad running in medical journals for Darvon, which I think is appalling. This describes how the drug industry in this country promotes phar- maceutical products. It is a three dimensional picture of the word pain in reds and purples, with a woman draped over the letters, just for those wanting to see it. This is how Lilly pushes Darvon, with obnoxious advertisements like this. Senator MORGAN. Could you point it this way so we could see it? Dr. WOLFE. I think I will just pass it around. The advertisement apparently works. It appears to me Darvon is much more advertised than any other painkilling drug. Senator NELSON. Is this a 2- or 3-page ad? Dr. WOLFE. It is a 2-page ad, and on the back are much smaller letters, some of them warning about the drug. [The advertisement follows:] PAGENO="0068" 16620 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY * * ~ I PAGENO="0069" Warnings: C. N S Additive Effects and Overdosag~ -- Propoxyphene in combination with alcohol, tran- quilizers, sedative hypnotics, and other central nervous system depressants has additive depressant effects, and the patient should be so advised Patients taking this drug should be warned not to exceed the dosage recommended by their physician loxic ef fects and fatalities have occurred following over doses of propoxyphene alone and in combination with other central nervous -system depressants 1 he magorit'y of these patients have had previous histories of emotional disturbances or suicidal ideation or at- tempts as well as histories of misuse of tranquilizers, alcohol, or other C N S active drugs Caution should be exercised in prescribing unnecessarily large amounts of propoxyphene for such patients _______ - Propoxyphene can produce drug dependence characterized by psychic depen- dence and, less frequently, physical dependence and tolerance Propoxyphene will only partially suppress the withdrawal synorome ri individuals physicaltyde- pendent on morphine or other narcotics The abu~e liability of propo~yphene is qualitatively similar to that of codeine although quantitatively less, and propoxy phene should be prescribed with the same degree of Caution appropriate to the use of codeine ~ in Ambulatory Patients - Propoxyphene may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery The patient should be cautioned accordingly. ~g~jj~g~y-Safe use in pregnancy has not been established relative to possible adverse effects Darvocet~P4a 100 proçx~xyphene napsylate with acetamincphen COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16621 (jv on fetal development. Instances of withdrawal symp toms in the neonate have been reported following usage during pregnancy Therefore, propoxyphene should not be used in pregnant women unless, in the Description: Each tablet cit Darvocet N 50 contains judgment cf the physician, the potential benefits out- 50 mg propoxyphene napsylate and 325 mg aceta weigh the possible hazard~ minophen Each tablet of Darvocet N 100 contains ~~ge in Children---Propoxyphene is not recom- 100 mg propoxyphene napsylate and 650 mg mended for use in children, because documented acetaminophen . . clinical experience has been insufficient to establish indication: These products are indicated for the safety and a suitable dosage regimen in the pediatric relief of mild to moderate pain, either when pain is : age group. present alone or when it is accompanied by lever Precautions: Confusion, anxiety, and tremors have Contraindkations: Hypersensitivity to propoxy-: been reported in a few patients receiving propoxy phene or to acetaminophen Øhene concomitantly with orphenadrine The central- ____________________________ nervous-system depressant effect of propoxyphene may be additive with that of other C.N S depres sants, including alcohol. Adverse leactions: The most frequent adverse re actions are dizziness, sedation, nausea, and vomiting These effects seem to De more prominent in ambula- tory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down Other adverse reactions include constipation, abdominal pain, skin rashes, lightheadedness, head~ ache, weakness, euphoria, dysphoria, and minor visual disturbances The chronic ingestion of propoxyphene in doses exceeding 800 mg per day has caused toxic psy- choses and convulsions _______ Cases of liver dysfunction have been reported Administration and Dosage: A narcotic prescription is not required These products are given orally The usual dose is 100 mg propoxypherie napsylate and 650 mg aceta- minophen every four hours as needed for pain Additional information available to the profession on request from Eli Lilly and Company, Indianapolis, lndana 46206 Eli Lilly and Company, 4nc I Carolina, Puerto Rico 00630 $OO)U PAGENO="0070" 16622 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. You have a letter with your testimony from Cook County Hospital, and that will be made part of the record. [The letter follows:] COOK COUNTY HOSPITAL, Chicago, Ill., January 23, 1979. SYDNEY WOLFE, M.D., Health Research G~roup, Washington, D.C. DEAR DOCTOR WOLFE: On July 1, 1974, Darvon in all its forms was banned from the prescription options for all physicians working in the outpatient setting of our hospital (the General Medical Clinic of Fantus Clinic). This is the largest clinic by far in the Cook County Hospital complex seeing on an average of 200 patients per day. The doctors are predominantly members of the house staff; each of our 160 Department of Medicine trainees attends that clinic one session per week. The same rules apply to other specialty clinics under the jurisdiction of the Department of Medicine which average another 200 patient encounters per day. The reasons for eliminating Darvon from the drug list included high cost and absence of any therapeutic superiority over aspirin and aspirin related drugs for its legitimate indications. Another, more serious concern was our observation, in this large public hospital, that Darvon was increasingly utilized as an illicit drug by persons who had become dependent upon it. We concluded that an agent devoid of any significant, unique value which was the object of dangerous abuse by growing numbers of people, had no place on our hospital outpatient formulary. While I feel that we served our patients well by avoiding this potentially dangerous drug, we've also served the public which supports us with tax dollars by avoiding an unnecessary, large expenditure. But most important, we have trained in these five years over 300 physicians to practice medicine without resorting to this much overused drug. Finally, it is most interesting and gratifying to note that following the excellent experience of the Department of Medicine outpatient clinics (elimina- tion of this drug without physician or patient difficulty), the Drug and Formu- lary Committee of the entire hospital decided ia June 1977 to delete the drug from the hospital formulary (see attached communication from Mr. E. H. Stine- baugh, Director of Pharmacy Services). The entire medical staff had so dimin- ished its "dependence" on Darvon that it took nearly 18 months for the exist- ing supplies to be exhausted Since there are over 500 doctors in training at Cook County Hospital, one can assert that a significant number of physicians on the threshold of their training have a unique therapeutic advantage over their contemporaries Sincerely yours, QUENTIN D. Youxo, M.D. Chairman, Department of Medicine. Attachment. COOK COUNTY HOSPITAL, Chicago, Ill., March 8, 1978. Memo to: Medical Staff. From: Ernest H. Stinebaugh, Director, Department of Pharmacy Services. Re: Propoxyphene HC1 (Darvon). At the Drug and Formulary Committee Meeting in June, 1977 propoxyphene HC1 was deleted from the formulary. Provisions were made at that time to con- tinue using existing stocks until depleted. The stocks of propoxyphene HC1 are now near depletion and the drug will no longer be available on prescription in Cook County Hospital or health centers. The committee made its decision based upon several review articles: 1. Drug Therapy Review: Propoxyphene, A Review. Miller RR et al, American Journal of Hospital Pharmacy, Volume 34, April, 1977, page 413ff 2. Propoxyphene HC1 A Critical Review, Miller RR, Journal of the American Medical Association, Volume 213, Number 6, August 10, 1977, page 996ff 3. Medical Letter, Volume 12, Number 2, January 23, 1970, page 5 as well as considerations that 4. Propoxyphene is a controlled substance and the burden of providing proof of use and distribution outweighs its usefulness, PAGENO="0071" COMPETITIVE PROBLEMS IN :THE DRUG INDUSTRY 16623 5. The potential encouragement of street abuse is great by having it generally available from Cook County Hospital and clinics. Published data suggests that alternate therapy is 600mg of aspirin or acet- aminophen. Potent analygesics also available are acetominophen with codeine and aspirin with codeine. I refer you to page 14 in the Drug List for a complete listing of analygesics on formulary. Senator NELSON. Any further questions? Senator MORGAN. Dr. Wolfe, I did not hear all of your testimony, and I apologize for that.. Wifl you tell me the extent of your research, how did you arrive at your conclusions? Dr. WOLFE. Which conclusions are you speaking of? Senator MORGAN. All of them, with regard to Darvon, and whether or not it was more effective, or less effective than aspirin and the other drugs, are these based upon publications, or are they based upon inde- pendent research by your group, or by public citizens health researdh groups? Dr. WOLFE. Well, all of the work, which is much more detailed in the petition to the Justice Department, is based upon a review of pub- lished studies on the safety and on the effectiveness, of the drug. In addition, we used information supplied by the Justice Depart- ment Drug Abuse Warning Network. Any statement that we make concerning its effectiveness with respect to aspirin and anything else, is based on a large number of published studies that we have reviewed. One of the witnesses this morning, in addition to reviewing the pub- lished literature has also done studies himself, comparing Darvon with other analgesics, and I think reaches the same conclusions as I do. Senator MORGAN. I am asking, what have you done? Have you done any research? Dr. WOLFE. I have reviewed the published literature and used infor- mation from the Justice Department to reach the conclusions that I have. Senator MORGAN. Do we have a copy of the petition, Mr. Chairman, that you have alluded to? Senator NELSON. The committee has a copy of the petition that has been filed, and it will be made a part of the record. Senator MORGAN. It would be of interest to me, Doctor, to know what your background is, so that I can determine how much weight to give your evaluation of other publications. Dr. WOLFE. Let me briefly go over it. My training is in internal medicine. I was on the staff of the National Institutes of Health for 5 years, doing medical research on both: clinical and laboratory problems. I have published a fair number of papers on various kinds of research that I have done. Senator MORGAN. That is all I have, Mr., Chairman. Senator NELSON. Any other questions? . Mr. TWARDY. Dr. Wolfe, you indicated there was no effectiveness requirement in 1957 when Darvon was first marketed. Dr. WOLFE. That is correct. Mr. TWAImY. However, pursuant to a law passed in 1962, was not the FDA required to study the effectiveness of drugs marketed prior to 1962? PAGENO="0072" 16624 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY iDr. WOLFE. That is right. In doing that, for Darvon, because it was a pre-1962 drug, the Na- tional Academy of Sciences, particularly for the 32-milligrams, the smaller size Darvon which was then widely used, found that it really was not much better than a placebo. Mr. TWARDY. But the FDA did allow Darvon to stay on the market, and gave a blanket approval to the effectiveness of the 65-milligram dose, did it not? Dr. WOLFE. That is correct, because, as I stated, as long as it could be shown that that form, the 65-milligrams, was better than a placebo, that would meet the test of effectiveness. Mr. TWARDY. So in short, the FDA did deem the 65-milligram dos- age of Darvon to be effective? Dr. WOLFE. Right, more effective than a placebo, and therefore meet- ing the law. Mr. TWARDY. I might have missed this, but to whom is the adver- tisement that Lilly has here for Darvon circulated? Is it to the public as a whole or just to doctors? Dr. `WOLFE. There is an ad that appears-I have seen that same ad in five or six medical journals in the last month or so. Mr. TWARDY. But it is circulated then to the medical profession? Dr. WOLFE. That is right. I think that if physicians saw this kind of ad, if patients saw that kind of ad, they would be much more inclined to use Darvon. Mr. TWARDY. That is all; thank you. Senator NELSON. Thank you, Dr. Wolfe. Dr. WOLFE. Thank you. [The prepared statement of Dr. Wolfe follows:] TESTIMONY OF SIDNEY M. WOLFE, M.D., PUBLIC CITIZEN'S HEALTH RESEARCH GROUP Senator Nelson and members of the subcommittee: Thank you for the invitation to discuss our petitions to ban or severely restrict the use of propoxyphene, most commonly known as Darvon. In the November petitions, we pointed out that Darvon led all other prescription drugs in the annual number of drug deaths and, as was pointed out by N. Kozel of the National Institute for Drug Abuse, Darvon is probably related to even more deaths per year than heroin and morphine combined. Since the original petitions we have obtained more information-particularly about the toxicity in animals and humans of propoxyphene and especially its main metabolite, norpropoxyphene. We have also learned that a substantial portion of Darvon deaths are not due to suicide but are accidental and often occur in people chronically using the drug for pain or, in some cases, for its euphoric effects. PROPOXYPHENE AND NOR-PROPROXYPIIENE BLOOD LEVELS IN CHRONIC DARVON USERS When people use propoxyphene (PX), the Lirug is metabolized by the liver to nor-propoxyphene (NPX). Whereas the 1/2 life of PX in the blood is only 12 hours (meaning the time it takes for the drug to fall to half of its highest level), the main metabolite, NPX, stays around much longer, having a half-life of 38 hours. Because of this long half-life, people using Darvon on a chronic basis accumulate large amounts to the metabolite NPX in their blood. Much of the early human toxicology on PX looked just at blood levels of the drug itself and unless the blood level was 1 or 2 micrograms per milliliter (ml.) of blood, or more, the death was often not attributed to PX. In cases of PAGENO="0073" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16625 suicide where death occurs shortly after ingestion of huge numbers of pills, the blood PX level is, in fact, usually above 1 or 2 micrograms and milliliter with much lower levels of NPX. In chronic users, however, there is much more NPX than PX in the blood. Someone regularly taking as little as 2 pills (65 milligrams per pill) 3 times a day can get a blood PX level of .68 micrograms per ml. but an NPX level of 1.2 micro- grams per ml.' A cancer patient, chronically using two :65 mg. pills every four hours (recom- mended dose is 1 pill every four years) had a PX blood level of .87 micrograms per ml. and a NPX level of 3.1 1 The fact that people using Darvon at or slightly above the recommended dose can get NPX blood levels of 1-3 micrograms per ml. is particularly alarming in view of the finding that: (a) in many cases of accidental death due to Darvon, the blood NPX levels are in this 1 to 3 range with PX levels much lower (often less than 1) as in the patients cited above,2 and (b) comparable blood levels (1 to 3 micrograms per ml.) of NPX in animals can cause significant blocking of conduction through the heart, a toxicity which can lead to arrhythmias and death. Although the medical literature, as long as 15 years ago, contained many cases of Darvon poisoning in which patients had abnormal electrocardiograms showing an inhibition of electrical condition thru the heart and although many Darvon deaths were said to be of cardiac origin, the first animal study on the cardiac toxicity of PX' and NPX was not done until 1976 by Lilly. LILLY STUDY NEVER PUBLISHED NOR SENT TO FDA From a source within Lilly, we have obtained an 11 page progress report of dog experiments, dated February 16, 1976 to August 15, 1976. On I~iarch 17, 1977, a short 1/2 page abstract of this study--omitting critical informatioa-was sent by Lilly to FDA with a note that "a complete presentation of this data will be submitted in a manuscript that is now being prepared." As of several weeks ago, when I forwarded this report to FDA and almost 2 years after Lilly's promise to FDA, the "complete presentation" had not been sent to FDA by Lilly nor has it ever been published. (A stamp on the top of the report says it should "not be published or disclosed to unauthorized persons with- out specific written permission of Dr. I. H. Slater.") The study showed that both PX. and NPX could cause inhibition of cardiac electrical conduction in the 1-3 micrograms per ml. range and that NPX was more potent than PX in one important type of inhibition. Although the study says the blood concentrations of PX and NPX were "sub- stantially higher than required for analgesia" (pain relief) the levels of NPX causing inhibition in these drugs were in the same 1-3 microgram per ml. range which can be seen in people who chronically use PX. (See p. 2 of testimony). DANISH STUDIES ON CARDIAC TOXICITY A recently published Danish study' also shows that NPX in the 1-3 microgram per ml. range in rabbits can cause significant delay or inhibition of cardiac con- duction and cardiac arrhythmias also were seen. An earlier Danish study of 11 cases of Darvon poisoning4 showed that 4 patients had cardiac conduction delays similar to those described above with blood NPX and PX levels of: NPX: 0.78 - 0.47 0. 39 . 74 0. 79 .51 0. 35 .23 (One of these patients also had ingested a substantial amount of ethyl alcohol but this is not known to cause the above-mentioned cardiac conduction delays.) 1 Verbeley and Inturrisi, J. Chromatography 75: 195, 1973. 2 Personal Communication, Dr. Boyd Stevens, Coroner, San Francisco and Dr. Larry Lewman, Deputy Coroner, State of Oregon. `Lund-Jacobsen, Acta. pharmacol, et toxicol., ~2, 171, 1978. ~ Gustafson and Gustafson, Acta. Med. Scand. 200, 241, 1976. PAGENO="0074" 16626 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY BLOOD NPX LEVELS IN ACCIDENTAL DEATHS According to both Dr. Larry Lewman, Deputy Coroner of Oregon, and Dr. Boyd Stevens, Coroner of San Francisco, most of the Darvon deaths are not suicides but accidents. One of the criteria for making this decision is an NPX blood level as high or higher than the PX level, often suggesting chronic use of PX. Blood NPX levels in such accidental deaths are often slightly less than 1, 1, 2, 3 or 4 micrograms per ml. of blood with PX levels often less than 1. DARVON MARGIN OF SAFETY IS TOO LOW The margin of safety or therapeutic index of a drug is the ratio between the amount needed to achieve the therapeutic effect (in this case alleged relief of pain) and the amount causing toxicity. According to Danish toxicologist Dr. J. Simonsen ~, Darvon has a "narrow therapuetic index": He says that "just four times the ordinary therapeutic dose can produce highly serious poisoning." San Francisco Chief Coroner Dr. Boyd Stevens told me that "if you double the Darvon dosage and take just 1 to 2 (bar) drinks, you can get into the toxic or lethal range." Dr. Stevens points out that partly because of its relative weakness as a painkiller, patients may well be inclined to take 2 pills (or more) instead of 1. He says, therefore, that many of the Darvon accidental deaths are not abuse-in the strict sense. This very low margin of safety is very likely related in many cases to the accu- mulation, as described above, of the toxic metabolite norpropoxyphene (NPX) in people regularly using the drug. In the above-mentioned study by Simonsen, he discusses the fact that we may be just seeing the tip of the iceberg as far as Darvon deaths. The study describes 2 elderly people found dead with no evidence of suicide whose deaths would otherwise have been attributed to natural causes but for a Danish law requiring autopsy on those dying alone. Subsequent toxico- logic analysis showed both to be Darvon deaths. DARVON VS. MORE EFFECTIVE PAIN-RELIEVERS Since Darvon's effectiveness in relieving pain is somewhere between that of aspirin (or acetaminophen as in Datril, Tylenol) and a placebo and substantially less than that of codein (in Schedule II and III), it is of interest to look at the number of deaths and the death rate of these preferable analegsics in comparison to Darvon. Deaths Per Million Drug and Deaths: 1977 6 Prescriptions ~ Darvon-590 19 Codeine-255 5 Aspirin s_150 <1 Acetaminophen 8_77 <1 PREDICTABLE INADEQUACY OF SCHEDULE IV When the possibility of controlling Darvon by putting it into the weak control of Schedulue IV, was first raised in 1973, Lilly responded by saying that if the drug should wind up in Schedule IV, despite its protests, "we believe it wouldn't have any material effect on sales of the product." In the year before Darvon was put into Schedule IV March 1976-February 1977, there were 459 deaths related to its use. In the first year of Schedule IV (March 1977-February 1978), the number was 510. Although there appears to be a decrease in deaths during the latter part of 1978, these data underestimate the eventual number of reported deaths since all 1978 reports are not completed and sent to D1~A until well into 1979. Although there has been an apparent but slight decrease in emergency room visits involving Darvon, this is not accompanied by any evidence yet of a decrease in fatalities. 5Ugeskr. Laeg. 137(44) 2605-2609. 1975. DAWN Quarterly Report January-March 1978. 1977 Prescriptions filled from National Prescription Audit, I.M.S. 8 1977 Retail sales of Aspirin of S500 million and acetaminophen, $t50 million-assume average cost of SI for asnirin. S1.S1) for acetaminophen and use death per million bottles. Wall Street Journal, Aug. 6, 1973. PAGENO="0075" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16627 IMMINENT HAZARD BAN As stated in the petition to HEW, rescheduling Darvon in Schedule II only makes sense if it is possible to identify a group of people for whom the substantial risks of the drug are outweighed by the questionable benefits, taking into account the availability of aspirin, codeine, and acétaminophen, all safer and more effec- tive. I am still unable to identify such a group of people and therefore believe an imminent hazard ban is the preferable way of meeting this serious problem. CONSEQUENCES OF A BAN In a letter to me from Dr. Quentin Young, Chief of Medicine at Cook County Hospital in Chicago, dated January 23, 1979 (see attachment 1), he states that Darvon was banned from the medical clinics there in 1974 and from the entire hospital in June 1977. Dr. Young said: "The reasons for eliminating Darvon from the drug list included high cost and absence of any therapeutic superiority over aspirin and aspirin related drugs for its legitimate indications. Another, more serious concern was our observation, in this large public hospital, that Darvon was increasingly utilized as an illicit drug by persons who had become dependent upon it. "We concluded that an agent devoid of any significant, unique value which was the object of dangerous abuse by growing numbers of people, had no place on our hospital outpatient formulary. "While I feel that we served our patients well by avoiding this potentially dan- gerous drug, we're also serving the public which supports us with tax dollars by avoiding an unnecessary, large expenditure. But most important, we have trained in these five years over 300 physicians to practice medicine without resorting to t1ii~ much overused drug. * * "Since there are over 500 doctors in training at Cook County Hospital, one can assert that a significant number of physicians on the threshold of their training have a unique therapeutic advantage over their contemporaries." Thus, it is quite possible-even less dangerous and much less expensive to prac- tice medicine without the use of Darvon. Further comment on the prospect Of an imminent hazard ban was received from Chief Coroner of San Francisco, Dr. Boyd Stevens, in a letter to me dated January 9, 1979. "The experience of this office with propoxyphene preparations indicates that this is an abused drug with little analgesic quality and whose daughter compounds are of no significant analgesic property, but are potentially toxic. "Because of its frequency of abuse and because of its propensity for toxic results in relatively low doses when mixed with other compounds such as alcohol, the position of this office is that Propoxyphene should be withdrawn from the market. "Barring thte withdrawing of Propoxyphene from the pharmaceutical mar- ket, we would support it being placed at a Schedule 2 rating of the Control Substance Act." SUMMARY Exploiting doctors' desires for a safe and effective painkiller Lilly pushed Darvon 21 years ago as equally effective as codeine, non-addicting and safer than codeine. All three statements are false yet millions of Americans have used this expensive and weak painkiller, thousands have died as a result of its toxicity and Lilly has reaped well over 1/2 billion dollars from its sales. The information that chronic use of Darvon leads to high blood levels of the toxic metabolite norpropoxyphene has never been publicly acknowledged by Lilly. lest it might frighten doctors and patients from using the drug. I hope these hearings provide any additional incentive still needed for the government to act on Darvon as quickly as possible. Thank You. Senator NELSON. Next we will have a panel of witnesses. We call Dr. C. G. Moertel, Mayo Clinic, Rochester, Minn. Dr. Page Hudson, chief medical examiner, Chapel Hill, N.C. Dr. Arthur J. MeBay, chief toxicologist, office of the chief medical exam1ner, Chapel Hill, N.C. PAGENO="0076" 16628 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY And Dr. Larry V. Lewman, pathologist and medical examiner of Multnomah County, Oreg., and deputy State medical examiner, State of Oregon. Would you mind all coming up and joining in a panel. First, I will ask Mr. Charles Moertel to present his testimony. Before we begin, I wonder, for the purposes of keeping an accurate record, starting at my far left, if each of you would identify yourselves for the reporter, so that whenever you speak, he will attribute the comments correctly in the printed record. Dr. MCBAY. IDr. McBa.y. Dr. MOERTEL. Dr. Moertel. Dr. LEw~L&x. Dr. Lewrnan. Dr. HuDsoN. Dr. Hudson. Senator NELSON. Dr. Moertel, you may proceed. Would you mind identifying your specialty in the field of medicine? STATEMENT OP CHARLES G. MOERTEL, M.D., MAYO CLINIC, ROCHESTER, MINN. Dr. MOERTEL. Yes. [R.ésumó follows:] PAGENO="0077" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16629 CURRICULUM VITAE Name: Charles G. Moertel, M. D. Date and Place of Birth: October 17, 1927, Milwaukee, Wisconsin Marital Status: The former Virginia Sheridan. Four children Present Position: Chairman, Department of Oncology, Mayo Clinic Director, Mayo Comprehensive Cancer Center Professor of Oncology, Mayo Medical School Education: 1945 - 1946 University of Illinois Chicago, Illinois 1948 - 1949 Northwestern University Evanston, Illinois 1949 - 1953 University of Illinois Chicago, Illinois B.S. ,, M.D. 1953 - 1957 University of Minnesota Minneapolis, Minnesota M. S. House Staff Training: 1953 - 1954 Los Angeles County General Hospital Los Angeles, California. Internship 1954 - 1957 Mayo Foundation Rochester, Minnesota Residency - Internal Medicine 1957 - 1958 Mayo Clinic Rochester, Minnesota Assistant to the Staff Certification and Licensure: 1962 Am. Board of Int. Med. Fellowship Training: Dates as above As above Military Service: 1946 - 1947 U. S. Army PAGENO="0078" 16630 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Professional Experiences: 1958 - present 1958 - present Mayo Clinic Rochester, Minnesota Consultant, Oncology Staff St. Mary's, Methodist Hospitals Rochester, Minnesota Staff, Oncology Associate Editor, Cancer Yearbook Chairnan, Gastrointestinal Cancer Committee Eastern Cooperative Oncology Group Cochairman, Gastrointestinal Tumor Study Group, DCT, NCI Phase I Study Group, DCT, NCI Consultant, Medical Letter Oncologic Drug Advisory Committee, FDA Committee on Cancer Immunotherapy, Immunology Branch, NCI Board of Directors, American Society for Clinical Oncology Editorial Board, Cancer Associate Editor, Cancer Medicine Special Advisory Committee, Sec'y Califano, DHEW President-elect, American Society of Clinical Oncology Chairman, Clinical Program Subcommittee, American Association for Cancer Research Council on Cancer, American Medical Association Board of Directors, Society for Clinical Trials 1971 - 1974 1972 - 1974 1973 - present 1973 1974 1974 1974 - present - present - present - 1977 1975 - 1978 1975 - 1976 - 1976 - present present present 1978 - present 1978 - present 1978 - present 1978 - present PAGENO="0079" American College of Physicians American Gastroenterologic Association AmericanAssociation for Cancer Research American Society of Clinical Oncology Sigmi XI Society of Surgical Oncology Society :for Clinical Trials Graduate School University of Minnesota Minneapolis, Minnesota Instructor in Medicine Assistant Professor of Medicine Associate Professor of Medicine Professor of Medicine Mayo Medical School Professor of Oncology Mayo Medical School COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16631 Professional Societies: Educational Experience: 1959 - 1963 1963 1969 1972 - 1968 - 1972 - 1976 1976 - present Research Interests: 1955 - 1956 1957 - 1958 1958 - present Pathologic Anatomy Clinical Pathology - Radioisotope Studies Clinical Research - Cancer Chemotherapy and Clinical Oncology Clinical Pharmacology PAGENO="0080" 16632 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Thank you. Dr. Moertel. You may present your statement. It will be printed in full in the record. and you may present it as you wish. Dr. MOERTEL. As you can see from curriculum vitae, I am a cancer doctor. I have been devoted to the care of cancer patients for a lot of years. We do cure many cancer patients, and there has been substantive progress in clinica.l research, but with all this, we must still admit that most patients afflicted with cancer will die of their disease. For these patients our primary concern must be they die in dignity and in com- fort. The single most overriding responsibility we have as physicians is the relief of the pain. Unfortunately, in this vital area, we, a~s physicians frequently per- form rather poorly. Our medical schools' instruction in the practical use of drugs is of- ten inadequate. In our judgment in prescribing drugs for pain, it is quite comparable to the public's jucl~uinent in purchasmg over-the-counter drugs for pain. Both are largely governed by advertising. We, as doctors, are no less vulnerable than the public-at-large to the persuasive influence of Mad- ison Avenue. For vivid evidence of our confusion in this regard, you only have to look at the Physicians Desk Reference. For those of you not familiar with this, the manual is distributed free of charge to all physicians each year by tTie Pharmaceutical Manufacturers Association, and it lists all prescription drugs promoted by Pharmaceutical companies. In the 1978 edition, there were 149 drugs advertised to be given by mouth for relief of pain. More than a decade ago, because we were disturbed by our ineptitude in the management of pain of the cancer patient, we initiated at the Mayo Clinic carefully controlled research studies to evaluate the rela- tive effectiveness of the many medications for pain that were available to us. Senator NELSON. Doctor, before you move to your next point, back to the 149 chugs advertised in the Physicians Desk Reference: Do you mean there are 149 that were identified as analgesics of one kind or another, each by a different name? Dr. MOERTEL. Many were by different names, many were different combinations of comparable ingredients. Sena.tor NELSON. But they had a different name? Dr. MOERTEL. They had different brand names. There were some with different consistency. and many times they were quite comparable in consistency. Senator NELSON. Of the 149, how many represented different com- pounds? I realize you have Darvon compound, which may be propoxyphene, and then von h~v~ asnirin and cecleine, and von have all of these, but how many different pain relieving combinations were there in these 149 named analgesics? Dr. MOERTEL. Yes: well, of course, there are so many combinations of individual drugs, but as far as individual drugs. I would estimate PAGENO="0081" COMPETIPTVE PROBLEMS IN T~E ~flUQ INDIYSTRY 16633 there are probably approximately 15 drugs of the analgesic category and probably about 12 drugs of the narcotic category, that go into the various mixtures that make up this 149. Senator NELSON. Some of the 149, I take it, were over-the-counter, and some were prescription drugs, is that correct? Dr. MOERTEL. That is right. Senator NELSON. Of those that were over-the-counter, how many in- volve drugs that we all hear of all of the time? Dr. MOERTEL. The over-the-counter drugs at the present time pri- marily involve aspirin or acetaminophen. These are the bases for most of the over-the-counter drugs. To these may be added a number of variations. Caffeine may be added to these, phenacetin is occasionally added, although not too frequently anymore. Occasionally the antihistamines are added for a sedative effect along with an analgesic agent, but almost all of them are based on either a primary aspirin base or primarily an academino- phen base. Senator NELSON. Thank you. Dr. MOERTEL. More than a decade ago, because we were disturbed by our ineptitude in the management of pain of the cancer patient, we initiated at the Mayo Clinic carefuly controlled research studies to evaluate the relative effectiveness of the many medications for pain that were available to us. Our only vested interest was our patients in pain. These studies were not paid for by any drug company. To insure that the results of these studies could not be in any way influenced by us or by preconceived ideas of our patients, we double- blinded the studies. By this, I mean that all of the pain medications we gave to the patients looked exactly alike and were identified only `by code number, so that neither we nor the patient could tell which was which until the study was over. The drugs were administered in randomized sequences and we only broke the code when the entire study was complete. Senator NELSON. So neither the patient nor the prescribing physi- cian knew the drug lie was giving? Dr. MOERTEL. That is correct. T'hey were entirely blinded both to us and to the patients. Now, in our first study, which is displayed on the chart on the easel, we looked at analgesic drugs in their pure form, and in this study we compared nine different analgesics as well as placebo or sugar pill. This study involved close to 600 drug evaluations, and our results with the four drugs that are pertinent to this hearing discussed in this graph. As you can see in the lower part, even with cancer pain, there will be a substantial number of patients who claim relief with sugar pills. Darvon use alone showed some advantage over sugar pills, but this was small and it was not statistically significant. That is the difference which could easily have occurred by accident. Acetaminophen or APAP, commonly marketed as Tylenol or Datril, showed a much more substantial degree of relief; and surprisingly, leading the pack, two simple aspirin tablets. 40-224 0 - 79 - PAGENO="0082" 16634 COMPETITIVE PROBLEMS IN THE DRUG INDIJSTRY The superiority of aspirin over Darvon was statistically significant, and by that I mean that the odds are 20 to 1 that this difference did not occur by chance alone. These results were quite startling to us because at that time Darvon led the market in PrescriPtion drug sales. - It can reasonably be argued that although interesting, these results really are not a fair evaluation of Darvon. Although Darvon is sold in pure form, it is usually marketed in combination with aspirin or APAP, or with APC as the so-called Darvon compound. In our second study we, therefore, looked at aspirin alone compared to aspirin plus a variety of other drugs that are commonly marketed in aspirin containing drug combinations. This study involved 100 patients in 1,000 separate drug evaluations. In this chart, table 2, you can see that again aspirin showed a sig- nificant advantage over placebo. The addition of a full dose of Darvon to aspirin, however, provided essentially no improvement in pain relief. You can also see that within this same study it was demon- strated that two prescription druas did provide better relief than aspirin alone, and these are the combinations of either Taiwin-penta- zocine-or codeine with aspirin. Senator NELSON. These are drugs containing aspirin? Dr. MOERTEL. This is a combination of Talwin plus aspirin, or a combination of codeine plus aspirin, and also a combination of Darvon plus aspirin. Senator MORGAN. Wliat is Taiwin? Dr. MOERTEL. Ta.lwin is a. trade name. It is a. narcotic antagonist, which has been found to have some analgesic activity as well. It was demonstrated that the standard and time-honored codeine- aspirin combination also showed a statistically significant advantage to the Darvon-aspirin combination, aga.in the odds better than 20 to 1 that this difference did not occur by accident. Based on our results we would have to conclude that if Darvon alone has any pain-relieving effect, this is trivial and simply does not match up to common, inexpensive over-the-counter drugs. We must also conclude that the combination of Darvon with aspirin holds no advantage to aspirin alone, and if a patient requires a stronger analgesic the physician should prescribe some other more effective drug regimen. These, however, are just the results from a single institution; and although we feel our studies were of sound design and conducted meticulously and analyzed without bias, it is possible that there could be some unrecognized distorting quirk in our methodology or that cancer pain is not representative of other types of pain. We only really feel comfortable with clinical experimental results when they are confirmed by others. Over the remainder of my testimony I would like to review all of the published medical literature of which I am aware that pertains to the clinica.l evaluation of Darvon as an analgesic agent. Here I am only going to refer to the controlled, randomized, double- blind studies. PAGENO="0083" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16635 When your end point of a study is as subjective as pain relief, these are the only kind of studies you can believe. In all, we found 34 such studies involving various types of pain, and these are listed in the bibliography which I have supplied. In table 3 I have displayed the, results of the 23 studies in which standard doses of Darvon alone were compared with placebo. You can see that none of the studies favored sugar pills. In four of the studies there was essentially no difference between Darvon and sugar pills. In seven the results favored Darvon but the difference was not statistically significant. Our first study is included in these. In 12 of the 20 studies Darvon was favored and the results were statistically significant. Based on these overall results it is reasonable to conclude that Darvon alone does have some analgesic activity although it is not very striking. If, for example, aspirin alone had been tested in the 23 study populations of patients with relatively mild pain, it could be reason- ably anticipated that aspirin wOuld have been strongly favored in all 23. In the next chart, table 4, I have displayed the results of 14 studies in which Darvon alone at standard doses was compared to common over-the-counter drugs-aspirin alone, acetaminophen or APAP alone, or APC. Among this group there were no studies favoring Darvon, in one study there was no difference, and in the remaining 13 of the 14 studies the over-the-counter drugs were favored over Darvon. In seven of these the differences were statistically significant. In table 5, I have shown the studies involving standard doses of Darvon in combination with aspirin, APAP, or APC compound. The results of these combinations are compared to the results of the over-the-counter drugs used alOne with the addition of Darvon. Three studies favored Darvon combinations, three favored the over- the-counter drugs used alone, and 6 of the 12 studies showed no difference. It is of interest that there are two other studies of this kind that have not appeared in the medical literature although they have been highly publicized in lay `media. It seems that some admen at a proprietary pharmaceutical company must have been looking at the overall Darvon literature and decided they could make a real good sales pitch by showing their over-the- counter analgesic was just as good as Darvon compound. So `they proceeded to contract out for two clinical research studies and that is exactly what they showed. Perhaps you remember the subsequent ads that appeared in the media displaying an Anacin tablet side by side with a Darvon com- pound capsule and accompanied by the advertising claim that Anacin had been shown in two mediëal studies to provide just as much relief as the high-priced prescription item. Senator NELSON. May I ask before you go to the next paragraph, if I recall you correctly, it was only after the addition of the acetamino- PAGENO="0084" 16636 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY phen or aspirin to the Darvon that you found some studies to show it more effective? Is that correct? Dr. MOERTEL. When acetarninophen or APC or aspirin were added to Darvon, most studies showed no difference to the over-the-counter drugs used alone. There were three that showed an advantage for Darvon with over- the-counter combination, there were three that showed the advantage for the over-the-counter preparation used alone. Senator NELSON. My question was, is it that Darvon with aspirin or acetaminoplien then showed a difference over Darvon alone? Is that not correct? Dr. MOERTEL. No; I did not display any studies of this kind. There are studies of this kind that have been reported in the litera- ture that do show that addition of aspirin or APC to Darvon does produce an improvement in pain effect over Darvon alone, but these were not displayed in my charts or in the material which I have pre- sented to you. Senator MORGAN. Dr. Moertel, if I follow you correctly, then your conclusions are that the ad compared Anacin, an over-the-counter drug, as being as good as Darvon, is that correct? Dr. MOERTEL. Yes. Senator NELSON. I did not hear that. Dr. MOERTEL. I think it was predicted ahead of time that this would be shown, as the research studies were contracted. Senator MORGAN. What I was saying, Mr. Chairman, that the wit- ness addressed those ads that say that Anacin or other aspirin, which are over-the-counter drugs, are just as good as Darvon. Senator NELSON. The evidence from your studies showed that they are better than Darvon, did they not-that aspirin alone or acetamino- phen alone is more effective? Mr. MOERTEL. Than Darvon alone, that is correct, but when Darvon is added to the aspirin, then it comes out about the same as aspirin. Senator MORGAN. I have seen in the literature Darvon-N or Darvon-T. What does it mean? Dr. MOERTEL. The original preparation of propoxyphene as it was marketed in 1957, was a hydrochloride compound. More recently, Darvon napsylate or l)arvon-N has been prepared. Darvon napsylate is just another tag that is chemically put on the end of the Darvon molecule. It does not in any way influence the analgesic effect of Darvon, and that has been proven repeatedly. It was put on the market, because it provides a more stable tablet formulation with aspirin. You could mix it up in the same compressed capsule with aspirin, better than you can the hydrochloride form. Senator MORGAN. So when you are referring to Darvon, it does not matter whether it has the T or the N to it? Dr. MOERTEL. Provided they were used therapeutically in equivalent doses. Senator MORGAN. 100 milligram napsylate is equivalent to 65 milli- grams of the other, in other words? Dr. MOERTEL. Yes. PAGENO="0085" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16637 In these studies I have shown the results of 10 studies in which com- binations of Darvon plus over-the-counter drugs were compared to combinations of codeine or Taiwin (pentazocine) plus over-the- counter drugs-8 of the 10 comparisons favored either the codeine or the Taiwin combinations. In short, the results of our Mayo Clinic studies are entirely con- sistent with preponderance of the studies done by other investigators. It can be concluded that Darvon does have some pain relieving activity, but this is very minor and does not match up to the safer and readily available over-the-counter drugs. Combinations of Darvon with aspirin, APAP or APC are not bet- ter than using the over-the-counter drugs alone. If the patient requires more pain relief than over-the-counter drugs can provide, the physician should not prescribe Darvon compound or Darvocet-N because he has other more effective drug combinations available to him. The only real difference between the Darvon compound and over- the-counter analgesics is the price. If you use 1978 Redbook average wholesale prices and add on a 30-percent markup for retail sales, the price for 100 tablets of Darvocet-N plus asprin is $11.50 and for 100 tablets of Darvon-N plus APAP is $13.50. If you are a careful shopper you can go to your corner drugstore or supermarket and get 100 two- tablet doses of APAP for about $2 or 100 two-tablet doses of aspirin for less than $1. The case against Darvon would seem obvious. In the face of all this evidence, what arguments can be made in favor of Darvon. There are three you will probably hear. The first is that the studies showing Darvon to have little: or no value are not pertinent because they involved single doses of Darvon given as needed for pain. This argument is not credible. First, because there is no clinical evidence from well controlled studies to support it. Also, the typical patient who may have a headache or a backache or pain after dental extraction doesn't want medication that he has to take regularly over a long period of time before it gives optimum relief. He wants to take a single dose that will give him pain relief quickly. Finally, the pharmaceutical manufacturer itself in its advertising to the physician and in its package insert, recommends that Darvon be taken as needed. Another argument is that :65 milligrams of Darvon hydrochloride is about equal in effectiveness to 65 milligrams of codeine when both are given by mouth. Basically, I feel that is pretty close to true, but that is really a bit of smokescreen. Sixty-five milligrams of cOdeine given alone by mouth is really not a very effective analgesic. Given by a hypo, this dose is very effective. By mouth, however, it has been shown repeatedly tO be no better than aspirin, and in our first study, although I did not display it on the graph, it was not quite as good. Now, you can get effective pain relief by using codeine alone, by mouth, but when you use it by mouth, you have to use a much larger dose. PAGENO="0086" 16638 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The important issue is whether these drugs add to the effectiveness of aspirin or APC, because that is the way they are both usually prescribed. Here, when codeine is added, as in Empirin compound with codeine, you do get a significant improvement in analgesia. When Darvon is added, you do not. Yet, another argument I am sure you will hear. For the past 20 years, Darvon has been prescribed by more doctors than any other prescrip- tion analgesic, and how could all these doctors be wrong. Well, this contention really has a very hollow ring in the face of medical history. Over the centuries, it has at one time or another been the consensus of the most learned doctors that miraculous cures of almost all diseases could be obtained through the use of such things as mummy dust, unicorn's horn, poltices, purges, blood-letting, or even into this century, leeching. I rather suspect this happened be,cause some enterprising corpora- tion cornered the market on leeches, and then proceeded to spend an enormous amount of money advertising them in the medical journals. Within just the past 40 years, I am sure many of us here still remem- ber the revered family physician with his black satchel filled with compartments containing innumerable bottles of medicines, and he would stake his reputation on each and every one of them. Since then I would estimate at least 95 percent of these drugs have been shown to be without any value, and are no longer used. It is only in very recent years that doctors have just begun to blend compassion for the sick with scientific method. I very much hope that you gentlemen will encourage this trend. So to summarize. I will answer specifically the four questions ad- dressed to me when I was invited to testify before this committee. The first question. from my knowledge and experience what is the relative efficacy of Darvon as comnared to other analgesics? In my judgment Darvon is inferior to the commonly marketed aspirin, acetaminoplien, or APC combinations. The second question. is it possible to treat patients for pain with analc~esics other than Darvon? Absolutely. For patients with mild pain you can do just as good a job, if not better, with aspirin or APAP alone, and you can do it. at about one tenth of the price. IVith rerrarcl to the use of f)arvon combine tions for the treatment of moderate pain, you can achieve significantly superior pain relief usin~r combinations of aspirin with codeine, aspirin with oxycodone, or aspirin with pentazocine or Talwin. For the treatment of severe pain, the use. of Darvon either alone or in comhbiation is grossly inadequate treatment and is really inhumane to the patient. The third qfleQtinn, is it. possible to maintain good medical practice without the use of Darvon? Yes. I would seriously question whether the use. of Darvon is rrood mcdi - cal practice at all. And the last (mesti(m. ~v1iat is the medical justifica~ tion for u~im~ Darvon? I know of none. Thank you. PAGENO="0087" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16639 Senator NELSON. Then I guess you answered the question I intended to ask. You say there is no justifiable reason for using Darvon. I was going to ask if there has been isolated any special target group that benefits more from Darvon than from another analgesic, keeping in mind the estimate that about 5 percent of all patients are allergic to aspirin. If that is the case, perhaps they should have acetammophen, or if there is something wrong with that, codeine. Have any scientific studies identified a target group of special beneficiaries for the use of Darvon? Dr. MOERTEL. I think the important part of that question, and in answer to Senator Hayakawa's question is the last statement you made, that is, is there a group that has been identified by scientific study to be a target area, and the answer is simply that no specific group has been identified as such a target group. Of course, there are people that claim I only get relief with Darvon. We had a number of these patients in our study, and when they did not know what they were taking, their strong beliefs were simply not so. Darvon has a great mystique about it, and when many of us take medications, this mystique is a very helpful therapeutic thing, but whether or not there is any pharmaceutical properties in Darvon that makes it particularly effective for a given group, there is no study to my knowledge that has ever demonstrated it. Senator NELSON. Thank you very much for your very helpful testimony. Any questions? Senator MORGAN. No questions. Mr. TWARDY. Just a simple question. I notice the others on the panel have indicated they are representing their own views and not those of the institutions where they practice. Are your views those of the Mayo Clinic or your own? Dr. MOERTEL. I would only purport to present my personal views in this testimony. I am not representing the Mayo Clinic or any statement other than my own. Mr. TWARDY. You seem to have indicated the idea of a multidose study. Was the cancer study which you conducted a single dose or a multi- dose study? Dr. MOERTEL. That was a single-dose study. Mr. Tw~uu~y. Might the results have been different if it had been a multidose study? Dr. MOERTEL. That is a very iffy question, and I would have to answer yes to any "might" question, but no, we did not demonstrate it. Mr. TWARDY. So it is possible that if a multidose study had been made the patients would have experienced a more satisfactory result? Dr. MOERTEL. I have never found it demonstrated that this is so, so as a physician and a scientist, I must question it, until somebody produces the information to prove it. Senator NELSON. Thank you very much, Dr. Moertel. Dr. MOERTEL. Thank you. Senator NELSON. We have a paper that was written for the Journal of American Medical Association, by you, Dr. Moertel. PAGENO="0088" 16640 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Do you wish to have that printed in the hearing record? Dr. MOERTEL. Senator Nelson, I did not submit that reprint to you. I would be very pleased to have it printed though, if this is the desire of the committee. Senator NELSON. It addresses itself to these studies. The title is "Relief of Pain by Oral Medications, a Controlled Eval- uation of Analgesic Combinations." Dr. MOERTEL. This is undoubtedly a reprint of the second study of which I referred, but as I said, I did not provide that reprint to the committee. Senator NELSON. We will review it, and if it adds to your testimony, we will simply print it in the record. [The prepared statement and supplemental information of Dr. Moertel follows:] TESTIMONY BEFORE THE SELECT COMMITTEE ON SMALL BUSINESS, U.S. SENATE, CHARLES G. MOERTEL, M.D., MAYO CLINIC, ROCHESTER, MINN. Studies involving Darvon and its combinations conducted at the Mayo Clinic have primarily involved treatment of the patient with advanced cancer. For these patients our single most overriding responsibility is relief of pain. Unfor- tunately in this vital area we as physicians frequently perform rather poorly. In our medical schoo's instruction in the practical use of drugs is often inadequate. Our judgment in prescribing drugs for pain is quite comparable to the public's judgment in purchasing over the counter drugs for pain. Both are largely governed by advertising. We as doctors are no less vulnerable than the public at large to the persuasive influence of Madison Avenue. For vivid evidence of this you only have to look at the Physicians Desk Reference. This is a manual distributed free of charge to all physicians each year by the Pharmaceutical Manufacturers Asseciation. It lists all prescription drugs promoted by pharmaceutical companies. In the 1978 edition there were 149 drugs advertised for relief of pain by oral route of administration. More than a decade ago, because we were disturbed by our ineptitude in the management of pain of the cancer patient, we initiated at the Mayo Clinic care- fully controlled research studies to evaluate the relative effectiveness of the many mdications for pain that were available to us. Our only vested interest was our patient in pain and these studies were not paid for by any drug company. To insure that the results of these studies could not be in any way influenced by us or by any preconceived ideas of our patients, we double blinded the studies. By this I mean that all of the pain medications we gave to the patients looked exactly alike and were identified only by code number. Neither we nor the patients could tell which was which. The drugs were administered in randomized sequences and we only broke the code when the entire study was completed. In our first study we looked at analgesic drugs in their pure form and thhi study compared nine different analgesics as well as placebo or sugar pill. It involved close to 600 drug evaluations. Our results with the four drugs that are pertinent to this hearing are displayed in Table 1. As in all studies, even with cancer pain, there will be a substantial number of patients who claim relief with sugar pills. Darvon showed some advantage over sugar pills, but this was small and not statistically significant-that is the difference could easily have occurred by accident. Acetaininophen or APAP-commonly marketed as Tylenol or Datril-showed a much more substantial degree of relief; and surprisingly, l~adin~ the pack, two simple aspirin tablets. The superiority of aspirin over Darvon was statistically significant-by that I mean that the odds are greater than 20 to 1 that this difference did not occur by chance alone. These results were quite startling to us because at that time Darvon led the market in prescription drug sales. It can reasonably be argued that although interesting these results really aren't a fair evaluation of Darvon. Although Darvon is sold in pure form, it is usually marketed in combination with aspirin or APAP or with APC as the so-called Darvon compound. In a second study w-e, therefore, looked at aspirin alone compared to aspirin plus a variety of other drugs that are commonly marketed in aspirin containing drug combinations. This study involved 100 patients in 1000 separate drug evaluations. In Table 2 you can see that again PAGENO="0089" COMPETITWE PROBLEMS IN THE DRUG INDUSTRY 16641 aspirin showed a significant advantage over placebo. The addition of a full dose of Darvon to aspirin, however, provided essentially no improvement in pain re- lief. You can also see that within this same study it was demonstrated that two prescription drugs did provide better relief than aspirin alone. These are the com- binations of either Talwin (Pentazocine) or coedeine with aspirin. The time honored codeine-aspirin combination also showed a statistically significant ad- vantage to the Darvon-aspirin combination-again the odds better than 20 to 1 that this difference did not occur by accident. Based on our results we would have to conclude that if Darvon alone has any pain relieving effect, this is trivial and simply doesn't match up to common, in- expensive over-the-counter drugs. We must also conclude that the combination of Darvon with aspirin holds no advantage to aspirin alone, and if a patient requires a stronger analgesic the physician shOuld prescribe some other more effective drug regimen. These, however, are just the results from a single institution; and although we feel our studies were of sound design and conducted meticulously and analyzed without bias, it is possible that there could be some unrecognized distorting quirk in our methodology or that cancer pain is not representative of other types of pain. We only really feel comfortable with clinical experimental results when they are confirmed by others. Over the remainder of my testimony I'd like to review all of the published medical literature of which I am aware that pertains to the clinical evaluation of Darvon as an analgesic agent. Here I'm only going to refer to the controlled, randomized, double~blind studies. When your endpoint of a study is as subjective as pain relief, these are the only kind of studies you can believe. In all, we found 34 such studies involving various types of pain and these are listed in the bibliography which I have supplied. In Table 3 I've displayed the results of the 23 studies in which standard doses of Darvon alone were compared with placebo. You can see that none Of the studies favored sugar pills. In four of the studies there was essentially no difference between Darvon and sugar pills. In seven the results favored Darvon but the difference was not statistically sig- nificant. Our first study is included in these. In 12 of the 20 studies Darvon was favored and the result were statistically significant. Based on these overall results it is reasonable to conclude that Darvon alone does have some analgesic activity although its not very striking. If, for example, aspirin alone had been tested in the 23 study populations of patients with relatively mild pain, it could be reasonably anticipated that aspirin would have been strongly favored in all 23. In Table 4 I've displayed the results of 14 studies in which Darvon alone at standard doses was compared to common over the counter drugs-~aspirin alone, acetaminophen or APAP alone, or APC. Among this group there were no studies favoring Darvon, in one study there was no difference, and in the remaining 13 of the 14 studies the over-the-counter drugs were favored over Darvon. In seven of these the differences were statistically significant. In Table 5, I've shown the studies involving standard doses of Darvon in com- bination with aspirin, APAP, or APO compound. The results of these combinations are compared to the results of the over-the-counter drugs used alone without the addition of Darvon. Three studies favored Darvon combinations, three favored the over-the-counter drugs used alone, and 6 of the 12 studies showed no difference. it's of interest that there are two other studies of this kind that have not appeared in the medical literature although they have been highly publicized in lay media. It seems that some ad men at a proprietary pharmaceutical company must have been looking at the overall Darvon literature and decided they could make a real good sales pitch by showing their over-the-counter analgesic was just as good as Darvon compound. So they proceeded to contract out for two clinical research studies and that is exactly whatthe studies showed. Perhaps you remember the subsequent ads that appeared on the media displaying an Anacin tablet side by side with a Darvon compound capsule and accompanied by the advertising claim that Anacin had been shown in two medical studies to provide just as much relief as the high priced prescription item. In Table 6 I've shown the results of ten studies in which combinations of Darvon plus over the counter drugs were compared to combinations of codeine or Taiwin (pentazocine) plus over-the- counter drugs. Eight of the 10 comparisons favored either the codeine or the Talwin combinations. In short, the results of our Mayo Clinic studies are entirely consistent with preponderance of the studies done by other investigators. It can be concluded that Darvon does have some pain relieving activity but this is very minor and PAGENO="0090" 16642 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY does not match up to the safer and readily available over the counter drugs. Com- binations of Darvon with aspirin, APAP or APC are not better then using the over- the-counter drugs alone. If the patient requires more pain relief than over-the- counter drugs can provide, the physician should not prescribe Darvon compound or Darvocet N because he has other more effective drug combinations available to' him. The only real difference between the Darvon combinations and over-the- counter analgesics is the price. If you use 1978 Redbook average wholesale prices and add on a 30% markup for retail sales, the price for 100 tablets of Darvocet N plus aspirin is $11.50 and for 100 tablets of Darvon N plus APAP is $13.50. If you are a careful shopper you can go to your corner drug store or supermarket and get 100 two tablet doses of APAP for about $2.00 or 100 two tablet doses of aspirin for less than $1.00. To summarize, I will answer specifically the four questions addressed to me when I was invited to testify before this committee. The first question, from my knowledge and experience what is the relative efficacy of Darvon as compared to other analgesics? In my judgment Darvon is inferior to the commonly marketed aspirin, acetarninophen, or APC combinations. The second question, is it possible to treat patients for pain with analgesics other than Darvon? Absolutely. For patients with mild pain you can do just as good a job, if not better, with aspirin or APAP alone, and you can do it at about one tenth of the price. With regard to the use of Darvon combinations for the treatment of moderate pain, you can achieve significantly superior pain relief using combinations of aspirin with codeine, aspirin with oxycodone, or aspirin with pentazocine or Talwin. For the treatment of severe pain, the use of Darvon either alone or in combination is grossly inadequate treatment and is really inhumane to the patient. The thir~l question, is it possible to maintain good medical practice without the use of Darvon? Yes. I would seriously question whether the use of Darvon is good medical practice at all. And the last question, what is the medical justification for using Darvon? I know of none. TABLE 1.-MAYO CLINIC EVALUATION OF ANALGESICS IN PURE FORM Percent Agent Patients pain relief Aspirin, 650 mg 57 Acetaminophen (APAP, 650 mg) 57 Darvon HCI, 65 mg 57 Placebo 57 62 50 43 32 Note: Aspirin superior to Darvon, p<0.05. Reference: 22. TABLE 2.-MAYO CLINIC EVALUATION OF ANALGESIC COMBINATIONS Regimen Patients Percen t pain relief Codeine, 65 mq plus ASA 100 Talwin, 25 mg plus ASA 100 Darvon N, 100 mg plus ASA 100 Aspirin alone, 650 mg (ASA) 100 Placebo 100 55 s~ 41 39 23 Note: Codeine plus ASA superior to aspirin alone and to Darvon plus ASA, p<0.05. Reference: 23. TABLE 3.-PUBLISHED COMPARISONS OF DARVON I WITH PLACEBO Study result Number of studies Strongly favoring Darvon Favoring Darvon No difference Favoring placebo Strongly favoring placebo 12 7 4 0 0 I Darvon at standard doses. Darvon HCI 32.5 to 65 mg; Oarvon N 100 mg. References: 1,4,5,6,7,9,1O,11,12,13,15,16,lg,23,26,28,31,32,33,34. PAGENO="0091" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16643 TABLE 4.-PUBLISHED COMPARISONS OF DARVON WITH OVER-THE-COIJNTER (OTC) ANALGESICS (ASPIRIN, ACETAMINOPHEN (APAP), OR APC) Number of Study result studies Strongly favoring Darvon 0 Favoring Darvon No difference 1 Favoring OTC drugs 6 Strongly favoring OTC drugs References: 5,12,13,15,16,19,20,21,23,26,29,33. TABLE 5.-PUBLISHED COMPARISONS OF DARVON PLUS OTC DRUGS (ASPIRIN, APAP, APC) VERSUS OTC DRUGS USED ALONE Number of Study result studies Strongly favoring Darvon plus OTC 2 Favoring Darvon plus OTC 1 No difference~ 6 Favoring OTC alone 2 Strongly favoring OTC alone 1 References: 2,3,10,11,12,17,18,19,22,24,26,28. TABLE 6.-PUBLISHED COMPARISONS OF DARVON PLUS OTC DRUGS VERSUS CODEINE OR TALWIN PLUS OTC DRUGS Number of Study result studies .. Strongly favoring Darvon plus OTC 0 Favoring Darvon plus OTC 0 No difference 2 Favoring codeine or Talwin plus OTC~ Strongly favoring codeine or Talwin plus OTC 4 References: 5,6,10,12,22,23,25,26,27. REFERENCES 1. Baptisti, A., Jr., Gruber, CM., Jr., and Santos, EL.: The effectiveness and side-effect liability of propoxyphene hydrochloride and propoxyphene napsylate in patients with postpartum uterine cramping. Toxicol. Appi. Pharacol. 19 :519- 527, 1971. 2. Bauer, R.O., Baptisti, A., Jr., and Gruber, CM., Jr.: Evaluation of pro- poxyphene napsylate compound in postpartum uterine cramping. J. Med. 5:317- 328, 1974. 3. Bedi, S.S.: Comparison of aspirin and dextroproPoXYPhene with aspirin as analgesics in rl1eumatOid arthritis. Br. J. Clin. Pract. 23 :413-417, 1969. 4. Berdon, J.K., Strahan, J.D. Mirza, K.B., et al: The effectiveness of dextro- propoxyphene hydrochloride in the control of pain after peridontal surgery. J. Peridont. 35 :106-111, 1964. 5. 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Jr., Steffens, A.O. et al: Acetaminophen versus propoxyphene hydrochloride for relief of pain in episiotomy patients. J. Clin Pharmacol. 13 :251-263, 1973. 17. Hopkinson, J.H., Blatt, G., Cooper M. et al: Effective pain relief: Com- parative results with acetaminophen in a new dose formulation propoxyphene napsylate-acetaminophen combination, and placebo. Current. Ther. Res. 19:622- 630. 18. Howard, G.M., Levy, J. Dougherty J.: Clinical evaluation of analgesic potency of dextro propoxyphene hydrochloride on orthopedic patients. New York J. Med. 61 :3285-3288 1961. 19. Kay, B.: A clinical comparison of orally administered aspirin, dextro- propoxyphene and pentazocine in the treatment of postoperative pain. J. Int. Med. Res. 2 :149-152, 1974. 20. Lipton, S., Conway, M., and Au Akbar F.: Current Med. Res. & Op. 3:175- 180 1975. 21. Marrs, J.W. Glas W.W. Silvani J.: Report of an investigation of d-pro- poxyphene hydrochloride. Amer. J. Pharm. 131 :271-276 1959. 22. Matts, S.G.F.: A double-blind comparison of pentazocine-paracetamol and dextropropoxyphene-paracetamol compound tablets. 23. Moertel, C. G., Ahmann, D.L., Taylor W.F. et al: A comparative evaluation of marketed analgesic drugs. N. Eng. J. Med. 286:813-815 197 24. 1\Ioertel, C. G., Ahmann, D.L., Taylor, W.F. et al: Relief of pain by oral medications a controlled evaluation of analgesic combinations. J. Am. Med. Assoc. 229-55-59 1974. 25. Ping, ItS., and Reclish, CIt.: Dextro propoxyphene, a new non-narcotic analgesic, J. Indiana State Dent. Assoc. 40:90-95, 1961. 26. Prockop L.D., Eckenhoff, J.E., McElroy, R.C.: Evaluation of dextropro- poxyphene, codeine and acetylsalicylic compound. Obstet. Gynec. 16:113-118, 1960. 27. Robbie, D.S., and Samarasinghe, J.: Comparison of aspirin-codeine and pharacetamol-dextropropoxyphene compound tablets with pentazocine in relief of cancer pain. J. Tnt. Med. Res. 1 :246-252 1973. 28. Sadove, M.S., Schiffrin, M.J.. Au, SM.: A controlled study of codeine, dextro propoxyphene and Ro 4-1778/1. Amer. J. Med. Se. 241 :103-108, 1961. 29. Smith, M.J., Levin, H.M., Bare, W.W. et al: Acetaminophen extra strength capsules versus Propoxyphene compound -65 versus placebo: a double blind study of effectiveness and safety. Current Ther. Res. 17:452-459, 1975. 30. Strumia E. and Babbini, M.: A comparative evalution of mefenamic acid, propoxyphene, flufenisal and placebo in osteoarticular pain. J. mt. Med .Res. 1 :258-260, 1973. 31. Sunshine, A., Laska, E., Slafra, J. et al: A comparative analgesic study of propoxyphene hydrochloride, propoxyphene napsylate, and placebo. Toxicol. Appl. Pharmacol. 19:512-518, 1971. 32. Wang, R.I.H.: A controlled clinical comparison of the analgesic efficacy of Ethoheptazine, Propoxyphene and placebo. Europ. J. Clin. Pharmacol. 7:183- 185, 1974. 33. Wang, R.I.H., Gruber, C.M.: A double-blind method for evaluating anal- gesics in men. Amer. J. Med. Sci. 235 :297-300, 1958. 34. Wang, R.I.H. and Sandoval. R.G.: The analgesic activity of propoxyphene napsylate with and without aspirin. J. Clin. Pharmacol. 11:310-317, 1971. PAGENO="0093" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16645 [V1o~o Chnic'Evaluation of Anu1~esics in Vure, Form ~ 3p1 rin, ~ 7 A ~ (APAP)1~5O~ ~ Darvon ~ ~ o 10 20 30 40 50 ~0 70 ~ PAGENO="0094" 16646 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~c~1-~r~5 CO~irv~o5n~ 4A51 l~Iw,n, a5~ AS!' D0rvonW,ioov~,4ASI LQ~ `Placebo Corn b~ ~iatioris ~5~5 l7wn reIieF M~,o C~r~c, ~ Iuat~Ion o~ lOCH PAGENO="0095" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16647 Ra~idom iZ~d :6 ompxri so n~ o~ Darvon with Pluccbo Str~nq(~ fovorirr ~vor~9 ~urvon~~ No difkrence, f~ivormn3 1~k~bo1 Q~: St~ronth `f~wor~j PIui~ebo 0 4 ___~__~_8 ~Q o'1~ ~thdIe5 PAGENO="0096" 16648 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~kandorn Led Corn pari~ons o~ JI)ürvon with ~ (OTC) lAna Iqe&ic~ (Aspirin, APAP, or IAPC) S~rongJ~i &orir~j D~wvoj ~ ~avorin~ Darvon (0 No difkrence ~WorinB OTC dru~ &~ron~jIy 1ovorrn~ C I Ci dru&s ~ Skaidte5 number o~ PAGENO="0097" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16649 ~ndom~zed C6m~or~ons ~ Darvon+ OTC dy~u~5(R~pinnJ1WAP, RPC) `~iersus OIC cku~ used alone~ S~ronal'~i `~a~onc~ OTC ~ovor~ n~Darvon OT([ ~ ~o d~er~nc~ ~ ~ ~avorirv~ 01 C Qlor~ Stron~ £~vor~ri~j (ilL uIorie~ 4I~ `M1Ad(es n nun*~r o~P 40-224 0 - 79 - 7 PAGENO="0098" 16650 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY RQndomiLed Compari~ori5 of Ikirvon ~ O~C ~. Cod~ne or~lWIfl pkuS OK ~ru~ Stror~Li ~UYOrin~ 0 ~t~orv/ri Combinctho ~vorin9 Darvori (,,om in `0n5 No di~re~r'c~ ______ f~vorir~ (ode,ir)e orT~/wi~' Comb inutiori5 ~ SLrun ly 4~vorin3 Co- d~tne,or Owirl ombi- (\&tions Number oF ~tud~5 PAGENO="0099" BY FAR the most common pharma- cologic challenge encountered by the physician today is relief of pain. The demand for oral analgesics dominates both the prescription and nonpre- scription drug markets. The 1978 Phy- sicians' Desk Reference lista 113 dif- ferent brand-name drugs promoted for pain relief by oral administration; to this list must be added perhaps an even larger number of nonpromoted, generic prescription drugs and heav- ily promoted over-the-counter prepa- rations. - Although several analgesics and narcotics have been demonstrated to produce significant relief of pain when given alone, the modern trend among pharmaceutical industry, phy- sician, and patient seems dearly to be in favor of analgesic combinations. Of oral analgesics listed in the Physi- cian.o' Desk Reference, 83% are csmbi- nations. The largest-selling pre- scription drug in this csuntry, Darvon Compound-65, and the two largest- selling brand name over-the-counter drugs, Anacin and Excedrin, are all combination analgesic drugs. Whether this great popularity of an- algesic drug csmbinations is the re- suit of true therapeutic superiority or superiority in promotional efforts be- comes a difficult point to resolve on the basis of scientific evidence. Al- though the need for well-designed programs of clinical evaluation of an- algesic drug combinations is great, investigators have seemed reluctant to enter this sensitive arena, and con- trolled trials of analgesic combina- tions have been recorded only in- frequently in the literature. In a previous double-blind eval- uation of single analgesics,' we found aspirin.at a dosage of 650 rug to be significantly superior to placebo and to be unexcelléd in analgesic effect by any of the other single-entity medica- tions we tested at manufacturers' recommended dosages. Aspirin also has proved to have con- sistent analgesic activity in con- trolled studies conducted by numer- ous other investigators,: and 650 mg probably approximates the ideal dos- age. The purpose of this study was to compare the analgesic effectiveness of 650 mg of aspirin used alone with the analgesic effectiveness of the same dose of aspirin in combination with other drugs of the type com- monly incorporated into marketed analgesic combinations. Materials and Methods One hundred patients were chosen for study, each of whom hod chronic or recurring pain problems resulting from unresectable cancer. All were ambulatory outpatients, and all could reliably tolerate oral medications. The patients did not have appreciable systemic symptoms related to their malignant disease, and they were not receiving any antitumor treatment (eg, chemotherapy or radiation ther- apy) that could confuse observation of analgesic side effects. The pain that the patients experienced was as- sumed to be related to intro-abdomi- nal, retroperitoneal, pelvic, or osseous malignant tumors. The degree of pain was classified as mild or moderate. Patients were excluded from study if they gave a history of an allergic re- action to any of the studied drugs. Patients also were not accepted for study if they had previously been on a schedule of narcotic drugs that was judged capable of producing any de- gree of physiologic dependence. Par- ticularly, patients were chosen who in our opinion were intelligent, depend- able observers. They were informed they were participating in a random- ized type of study. Patients were not allowed any other analgesics, narcot- ics, sedatives, stimulants, anti- COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16651 Relief of Pain by Oral Medications A Controlled Evaluation of Analgesic Combinations Charles G. Moertel, MD; David L. Ahmann, MD; William F. Taylor, PhD; Neal Schwartau * A double-blind study of analgesic drug combinations was conducted, involving 100 patients with pain due to cancer The combinations of 650 mg of aspirin plus either 65 mg of codeine, 9,76 mg of oxycodone, or 25 mg of pentazocine hydrochloride each produced significantly greater pain relief than aspirin alone. Side effects for a single dose of these effective combina- tions were essentially equal and clinically tolerable. The combinations of 650 mg of aspirin plus either 65 mg of caffeine, 32 mg of pentobarbftal so- dium, 25 mg of promazine hydrochloride, 75 mg of elhoheplazine citrate, or 100 mg of propoxyphene napsylate did not show significant advantage in an- algesic effect over aspirin alone, (JAMA 229:55-59, 1974) From the Mayo Clivic, Rochester, M,nn. Reprint requests to Mayo Cl,rric, Rochester. MN 559nt (Dr. Moertel). JAMA, July 1, 1974 * Vol 229, No 1 Analgesic Combinations-Moerlel et at 55 PAGENO="0100" 16652 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY cmstics. antilepres-anto. tranquil- lust-s. sr alcoholic beverages during the study. The fellow ing single agents and drug combinations ivere evaluated in each patient: placebo. 6.50 mg of aspi- rin. 65 mg ut catteine pius 650 mg of aspirin. :32 mg of pentebarbital so- dium plus 6-50 mg of aspirin. 2.5 mg of promazine hydrochloride plus 6.50 mg of aspirin. 75 mg of ethoheptazine cit- rate plus 650 mg of aspirin, 100 mg of propoxyphene napoylate plus 6.50 mg of aspirin, 75 mg of ethoheptazine cit- rate plus 650 mg of aspirin, 100 mg of propoxyphene napsylate plus 650 mg of aspirin. 25 mg of pentazocine hy- drochloride plus 650 mg of aspirin, 9.76 mg of oxydone plus 6-50 mg of as- pirin. and 6.5 mg of codeine sulfate plus 650 mg of aspirin. Oxycudone is not marketed and st-as not available to us in pure form. \Ve therefore em- ployed the marketed Nucodan svhich csntains oxycudone salts plus a mi- nute amount of homatropice tereph- thalate and a small dose of an aca- optic drug. pentylenetetrazol. put in separate envelopes. To prevent any degradation resulting ft-sm inter- action between drags during storage, aspirin and the other component of the combination svere alsvays deliv- ered in separate capsules. net mixed in the same capsules. Regular com- mercial forms of each study druig svere used. Lactose (liSP) svas em- ployed as a placebo and also as a filler for all study drags. Each patient st-as given a single dose of each of the study preparations and placebo in randomized sequences according to the latin-square method (10 such latin squares. each lOx 10 in size). One drag preparation was directly fol- lowed by another, and there svas no planned placebo or no-treatment in- terval hetsveen active drags. Each po- tient received only one test sequence of each of the study preparations. Patients svere instructed to take the planned single dose whenever they felt definite pain, hut no more often than every six hours. The inter- vals hetsveen doses svere variable, therefore, depending on the require- ment of the patient for analgesia, hot none st-em shorter than six hours. A corresponding variability occurred in the total period required for each pa- tient study (median time for comple- tion, five days: mean, nine days). In essence, this study svas designed to repraduce the conditions ttnder svhich a physician prescribes an analgesic svith the direction that it be used ev- ery six hours as needed for pain. \Vith each dose, patients svere asked to record the time of adminis- tration, the time st-hen the onset of definite pain relief was noted, and the time svhen pain returned. They svere also asked to record svhat percentage of their initial pain st-as gone at the time st-hen they obtained maximum relief from the medication. Specific inquiry st-as made regarding the fol- lousing side effecta: upset stomach, nausea, vomiting, sleepiness, dizzi- ness, impaired thinking, and excite- ment. Patients were also asked to mention any additional side effects they may have experienced. This in- formation was recorded on a separate form for each drug dose. It should he emphasized that these observations were recorded by the pa- tient himself immediately after each drug-dose experience. They were not recorded or interpreted by a medical observer. It should also he emphasized that this svas a study only of single- dose administration, nut of prolonged administration. Statistical analysis was done in stages. First, the possible effects of sequence of drag administration were evaluated. These proved to he negli- gible and, consequently, the data ss'ere reanalyzed ignoring sequence effect. Significance testing of differ- ences of pairs of drugs, after overall Table 1-Comparative Therapeutic Effect of Analgesic Preparations An Reported by 100 Patients Mean Percent Rank Analgesic Prnpanaticn Pain Retief*t Sum't Codeine sulfate. 65 mo~sspirie. 650 mu 631Sf 42015) Ooycodoee. 970 mc~ospirie. 600 mu 031Sf 430lS) Pestaznoiee hydrochloride. 20 mg-v aeoirie. 000 mu n9tSl 4ffOlB) Prooeoypher.e eepsylate. Ito m4± aspirie. OtO mu SSINSI 511 INS) Promaziee hydrochloride, 25 mu± aepinie. 050 mu 51 INS) 5561801 Pestobarbital sodium. 32 mg-i- aspirie. 600 mu 5OINS) 081 INSt Caffeine. 60 mg--aspirin. 600 mu 40(NS) 603(551 Ethoheptaaieec itrate. 75 mu± aspirie. 650 mu 481551 fftglNSl Aspirin. 600 mu 51 15Sf SO4lNSt Placebo 3311) 72 `Leners in parentheses indicate sigeificaeoe 5, siusifinant superiority to aspirin aloen IP<.tnl; B. borderline superiority to aspirin alcee 1Pm tO); NO, cc siqrifioaet difference from aspirie alone; I, siunifinart ieferiority to all other preparatioes fP<.tsf. fLeast sigeificant difference for superiority (Pu-.t5l is 6.2. en the basis of a one-sided test for superiority of a preparatios u-then compared to aspirie. OLeast siunifloast difference for sope riority 1P.tat is 61.8. or the basis of a one-sided test for superio6ty of a preparation when compared to aspirin. Table 2.-Sedative ElOect ol Analgesic Preparations Among 100 Patienls Analgesic Preparation Patients Promaziee hydrochloride. 25 mu±aspirin. 600 mu 40' Peetobarbital sodium. 32 mg±aspirie. 600 mu 27' Ooycodoee. 8.76 mg±aspirie. 600 mg 24 Pentozociee hydrochloride. 25 mu--aspirie. 650 mu 21 Codeine sulfate. 65 mg±aspinis. 650 mu 20 Propooyph eon rapsslate. too mg+aspirio. 650 mu 16 Ethoheptazire citrate, 75 mg±aspiris. 650 mu 16 Caffeine. 65 mg--aspieis, 050 mu 14 Aspirie. 650 mu r~Placnbo 13 `Sitoiflcaet increase in sedation oser placebo IP<.tSl. 56 JAMA, July 1. 1974 * Vcl 229. No 1 Analgesic Combioalioos-Moertef et a) PAGENO="0101" significance was confirmed, was done by the Fisher least-significant-differ- ence method. Results To avoid any-possible distortion and to make full use of data, analge- sic effects wore el'aluated in three First to be studied was the propor- tion of patients who claimed greater than fuR pain relief at any time dar- ing the six hours following drug ad- ministration. This approach seemed to be best in selection of patients who obtained a trulyniseful therapeutic effect. The results (Figure) indicated that aspirin alone had a significant advantage in. analgesic effect over placebo. The combinations of aspirin plus either caffeine, pentobarbital, promazine, `ethoheptazine, or prop- oxyphene were not significantly su- perior to aspirin.atone. The coml)ina- tions of aspirin plus either codeine, oxvcodone,. or pentazocine were es- sentially equal iniheir significant su- periority to aspirin alone as well as to each of the other aspirin combina- tions. The second cneans of analysis (Table 1) employed the mean percent- JAMA, July 1, 1974'. Vol 229, No 1 age of analgesia achieved l)y each of the ten drugs as described by each pa- tient. This method atlosn's a relative crediting of all the degrees of analge- sic effect varying from none to com- plete relief of pain. Again, aspirin is significantly superior to placebo; again, the combinations of aspirin plus either caffeine, pentobarbitat, proma- zine, ethoheptazine, or propoxyphene showed no significant superiority to aspirin; and again, aspirin plus either codeine, oxycodone, or pentazocine are significantly superior to aspirin alone. By this means of analysis, as- pirin plus propoxyphene assumes an equivocal position, ranking above as- pirin alone but not at statistically sig- nificant levels, and ranking signifi- cantly belonv aspirin plus codeine or oxycodone but not significantly below aspirin plus pentazocine. The third method of analysis (Table 1), perhaps the most important one from a comparative standpoint, em- ploys the relative ranking of analge- sic effect assigned by each patient to each -of the test drugs or combina- tions, ie, the drug to nvhich an individ- ual patient attril)uted the greatest percentage of relief of pain was given the rank of one, the lowesl percent- ~n~m ] age of pain relief a rank of ten. Ties were broken on the basis of duration of relief of pain. The figures recorded in Table I are the sums of ranks ac- corded each drug (or combination) by the 100 patients. All of the study preparations demonstrate a signifi- cant advantage over placebo. Still, as- pirin plus either codeine, oxvcodone, or pentazocine are the leaders with a significant advantage over aspirin atone. Again, aspirin plus propoxy- phene is in fourth position, signifi- cantly inferior to aspirin plus either codeine or oxycodone, but not signifi- cantly different from aspirin atone. Analgesic ranks of each of the other combinations are approximately that of aspirin. For none of the three methods of analysis did the order in which the drug preparations were given have a detectable influence on the grade of therapeutic effectiveness accorded any single drag. The latin-square de- sign of this study permitted a careful analysis which led to this finding. No practical advantage n-as found for any of the study drag prepara- tions with regard to the median time elapsed from ingestion to onset of definite pain relief. This ranged from Analgesic Combioutions-Moerlel et a! 57 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16653 Superior to Aspirin Alone P< .05 I Codeine Sulfate, 65 mg + Aspirin. 650 mar Pentazocine Hydrochloride, 25 mg + Aspirin, 650 mgj______________________________________ Ouycodone. 9 mg + Aspirin, 650 mgI___________________________ _________ Proposyphene Nupsylale, 100 my a Aspirin, 650 mg~____________________________ Ethoheptazine Citrate, 75 mg Aspirin, 650 mg[ I Promuzine Hydrochloride, 25 mg a Aspirin, 650 myl I Pentobarbital Sodium, 32 my Aspirin, 650 mg r I Caffeine, 65 mg a Aspirin, 650 mgi_______________________ Aspirin, 650 my Placebo I 0 20 40 hi of 100 Patients Achieoing >50% Relief Comparative Iherapeatic effect of placebo, aspirin alone, and aspirin combinations ac- cording to percentage at patients achieving significant lie, more than 50%) relief of pain 60 PAGENO="0102" 16654 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 45 to 60 minutes (50 minutes for aspi- rin alone). Also, no practical differ- ence was found in the median dura- tion of pain relief that ranged between four and six hours (five hours for aspirin alone). Except for sedation, all of the side effects for which we made specific in- quiry or which the patients volun- teered occurred at a frequency nearly equal for all len drags. The barbitu- rate sedative, pentobarbital, and the phenothiazine tranquilizer, proma- zine. produced a significant increase in sedation over the placebo (Table 2). The codeine, oxvcodone, pentazocine, and propoxyphene combinations also produced increases in sedative effect when compared to placebo or aspirin alone, but these were not at a statisti- cally significant level. Comment The problem of evaluating the ef- fectiveness of analgesic combinations is made very complex by the fact that essentially all marketed products of this kind contain one or more of the analgesic-antipyretic type drugs, ie, aspirin, acetaminsphen, or phenace- tin. Since each of these drugs has well-established analgesic activity. the question is not whether the com- binations will relieve pain; it is as- sumed that they will. The primary question is whether the addition of sedatives, stimulants, tranquilizers, or other analgesic agents of less well- established effectiveness really adds anything of value for the patient. Do these additives actually increase pain relief, or do they simply provide a ve- hicle for sales promotion and in the process subject the patient to in- creased cost, increased side effects, and increased risk of drug sensi- tization reactions? Analgesic Combinations of No Signif- icant Value-As in our previous study, aspirin again demonstrated a significant advantage in pain relief over placebo. The addition of the amount of caffeine equivalent to that in about one-half cup of coffee clearly added nothing to analgesic activity. A number of controlled evaluations of caffeine pius aspirin and phenacetin (APC) have also shosvn no superiority of this combination to aspirin alone for the relief of headache, postpartum pain, and acute and chronic pain problems of varying etiologies. Thirty-two milligrams of caffeine plus 400 mg of aspirin is the Anacin formula. Over-the-counter products such as Excedrin, Vanquish, Empirin compound, and APC compounds are mixtures of caffeine pius a lesser dose of aspirin (195 to 257 mg) with the deficit in aspirin made up by the addi-- tion of other analgesic-antipyretico such as phenacetin, acteminophen, or salicylamide. Although each of these preparations is several times as ex- pensive as generic aspirin, there is no acceptable evidence that any provides the patient with- more effective pain therapy. The widespread popularity of these preparations is clearly a trib- ute to the effective techniques of Madison Avenue. The appealing presumption that al- laying anxiety and apprehension will blunt pain perception has led to the marketing of a variety of combina- tion analgesic preparations contain- ing barbiturates or tranquilizers such as Darvo-tran, Equagesic, Fiorinal, Phenaphen, and Trancogesic. No es-i- dence, however, supports this concept, and the work of Dundee and Moore' has seriously challenged it. In our study, the barbiturate and the tran- quilizer produced the expected side effect of sedation, but they added nothing to analgesic effect. Certainly, if a patient presents a valid clinical indication for sedatives or tranquil- izers, they should be employed, but for their osvn sake, not svith the idea that they svill contribute to pain re- lief. In viesv of the many potential hazards associated svith indiscrimi- nate use of barbiturates and tranquil- izers, the marketing of such drags in combination products directed pri- marily tosvards analgesia must be se- riously questioned. In our earlier study, ethoheptazine was essentially identical to placebo in analgesic effect. In the present study, its combinalion svith aspirin produces an identical analgesic effect to aspirin alone. There seems to be no valid indication for prescribing this agent either alone as Zactane, in com- bination with aspirin as Zactirin, or in combination svith aspirin and meprobamate as Equagesic. Propoxyphene hydrochloride used alone in our initial study showed a slight hut insignificant advantage over placebo, and it *as significantly inferior to aspirin.' Propoxyphene napsylate (Dat-von-N) has been intro- duced as a drug that has the same an- algesic effect as the hydrochloride form but allows more stable tablet formulation svith aspirin. In this study, the propoxyphene napsylate combination was ranked higher than aspirin alone by all means of analysis, but in no instance was the difference statistically significant. It con- sistently ranked lower than codeine plus aspirin, and by all three methods of analysis, this difference seas statis- tically significant. Thus, the thera- peuticvalue of propoxyphene remains equivocal. The conflicting evidence in the literature regarding the effec- tiveness of prspoxyphene, both alone and in combination, has been exten- sively reviesved by Beaver and by Miller and associates. Unquestion- ably, prspoxyphene and its combina- tions are exceedingly popular pre- scription items, hot it remains to be clearly established that this popu- larity reflects true analgesic effec- tiveness. Effective Analgesic Combinutions.- Three combinations-aspirin pins 65 mg of codeine, aspirin plus 9.76 mg of oxycodone, and aspirin pins 25 mg of pentazocine hydrochloride-shosved a significant superiority in analgesic effect over simple aspirin and over all the other combinations tested. Co- deine and pentazocine hydrochloride when used alone had shown a signifi- cant superiority over placebo in our earlier study.' The side effects of these three combinations were equally tolerable in the present single-dose study. It should be em- phasized, however, that sve employed only a 25-mg dose of pentazocine hy- drochloride compared to the marketed form containing 50 mg. In oar earlier study, we had found the 50-mg dose of pentazocine hydrochloride to pro- duce sufficient gastrointestinal and central-nervous-system side effects to limit seriously its usefulness for the ambulatory outpatient. Oxycodone presents the vet",' distressing hazard of increased addiction potential when compared to other available oral agents used for relief of mild to mod- erate pain. The serious addiction problems that may be associated svith oxycodone- were stressed ten- years ago in the comprehensive review of Bloomquist.' He presented evidence that addiction liability was at least 58 JAMA. July 1, 1974 * Vol 229, No 1 Analgesic Combinations-Moertel et at PAGENO="0103" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16655 comparable to that of morphine, and patient went about hio uuual life ac- superior to placebo by all means of he concluded that increased misuse tis'ities during this study, and the pa- statistical analysis. In addition, both of oxycodone-containing drugs had tient himself selected the time when pentobarbital and promazine have a caused the addiction of numerous per- he felt an analgesic was required. By well-established sedative activity, sons not associated with the illicit this means, the therapeutic procedure and in this study both shosved a sta- drug trade. Since then the oxycsdone- was tested in the same setting in tistically significant increase in soda- containing drugs (eg, Percodan) have which it would be applied clinically. tive activity in comparison to placebo. been reclassified under the narcotic Also, the oubjective result was On the basis of this evidence, we feel control laws. In view of the essen- recorded directly by the patient with- justified in presuming that our studs' tially equal analgesic and single-dose out the possible distortion that could design is adequate to detect both an- side effects when compared to co- be introduced by a physician, nurse, algesic activity and side effects under demo, there would seem to be little or technician interviewer. Although conditions closely simulating the cir- reason for the physician to subject his this method has obvious advantages, cumstance when an oral analgesic patient to the increased addiction it also has some very definite limita- preparation is prescribed in clinical hazard of the oxvcodone analogue. tions. Accuracy of results is depen- practice. We must emphasize, how- Another major difference between dent on the reliability of the patient ever, that our results can be strictly these three effective analgesic combi- in following instructions and upon his applied only to the patient population nations is cost. On the basis of the ability to record observations clearly, and methods we employed. They can- average cast among a hospital phar- Innumerable uncontrolled variables not be interpreted as representative macy, a medical-center pharmacy, a may and frequently do influence the of the analgesic response that may be chain-store pharmacy, and a private- patient's response to each of the mdi- obtained for pain problems of differ- ly owned neighborhood pharmacy in vidual drugs studied. These include ent etiology, nor can they be assumed Rochester, Miss, on July 11, 1973, one changes in his emotional status, to have any direct application to hundred doses of oxycodone (9.76 mg) whether he is rested or fatigued, the long-term response to analgesic plus aspirin (200 Percsdan tablets) the many and varied environmental agents. will cost the patient $18.12. One hun- stresses to which he may be sub- dyed doses of codeine sulfate (65 mg) jected, whether the drug is taken in a plus aspinn will cost $10.61. Pentazo- fasting state or on a full stomach, Thu incoatigation van sapported by grant vine is not marketed in combination whether the patient is active or at CA-ii9ii fran, the National inatitstns of with aspirin, and to obtain the combi- rest after taking the medication, and nation tested in this study, the pa- others. If, however, the experimental tient must break a 50-mg pentazocine system is sensitive and of rational References (Talwin) hydrochloride tablet in half design, these uncontrolled variables ~ ~ I A and take aspirin separately. It would should distribute themselves with of markotod anaignnic ~ag~ N Engl J Mad seem worth the nuisance, however, reasonable uniformity throughout the 286:8i3-8i0, i972. since 100 doses of 25 mg of pentazo- population studied, so that statistical ~ A~ r~;i~v;f cine hydrschloride (50 Talwin hydro- analysis will recognize differences in 250:577.604, toss hloride tabi t ) cost nb $4 9 th apeut eff ct f the~ e st In this ~ 1k N 14 OS iI)A J 21! Studo Methodology: Strengths and study, there were built-in quality con- su 2sis7e~so5~, i960 Limitations-The methodology of this trols of sensitivity provided by known 4. Dundee JW Mason J: The myth of pheno. study was purposefully designed to differences between the drug prepa- thiasepsiotiationAoth:aias095,po i96i. approximate closely the conditions rations that should be detectable. As- phene hydeonkioride A critical ms-mv JAMA that exist when the physician pre- pirin has an analgesic activity estab- 2i3:000.ioO6, i075. be Ig s f a mb I I oh d b5 m ou t gators a d 6sdImms~P E~i ~h C M dos i27 130 tory patient with a pain problem. The in this study aspirin was significantly 1903 JAMA, July 1, 1974 * Vol 229, No 1 Analgesit Csmbinaiions-Monrtel ci al 59 PAGENO="0104" 16656 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Our next witness is Dr. Page Hudson, chief medical examiner of the State of North Carolina. STATEMENT OF PACE HUDSON, M.D., CHIEF MEDICAL EXAMINER OF THE STATE OF NORTH CAROLINA Dr. HUDSON. Thank you, Mr. Chairman. Senator MORGAN. Before Dr. Hudson begins, I might say that Dr. Hudson is a very noted, highly respected member of the medical pro- fession in North Carolina. He and I worked together many years ago when I was attorney general, and lie became chief medical examiner. Senator NELSON. Let me say the witnesses were invited today because of their national distinction, and we are delighted to have you here. Dr. HUDSoN. Senator Nelson, members of the committee, I am very grateful for the opportunity to speak. Unless requested specifically, I would prefer to not go into my entire statement. Senator NELSON. Your statement will be printed in full in the record. It is always helpful to the hearing process, after you get to about the third witness, if you can skip anything that might be particularly repe- titious. But you may present it however you desire. Dr. HUDSON. Thank you. My statement speaks to some material that has already been cov- ered, so I would tend to skip that. My particular area in medicine is what is called forensic pathology, which is that medical specialty that involves the detection, identifica- tion, and investigation and other studies of real or suspected unnatural deaths, and I practice and write and teach in this field of medicine and related sciences, and I have had the pleasure of serving as chief medi- cal examiner of the State of North Carolina. I will address myself to the experiences in that State. Several years ago it became apparent to my colleague, Dr. Arthur J. McBay, who is here, who is chief toxicologist with the office of chief medical examiner, and to me that propoxyphene was responsible for an increasing number of deaths in our State. We examined rather carefully our cases and our criteria, we have conferred with authorities in other States and with many physicians in our State, particularly physicians involved with daily patient care. We began to get the feeling that we were into something that was awesome, at least to us, and that is that a drug medication appeared to exist, did exist, that was at the top in prescription popularity, one that had but a trace of benefit and that was reaching the point of causing more deaths than any drug, licit or illicit. We saw the numbers of deaths from propoxyphene increase from just an occasional case in the late 1960's, or early 1970's, to 20 or so a year, a peak of 50 in 1975, and 40 or so the following year and 30 in subsequent years, and it was the drug causing the greatest number of deaths. For the past 2 or 3 years. the deaths due to propoxvphene have been approximately twice that of the barbituates collectively. PAGENO="0105" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16657 We believe that most of these in our State have been suicide, in the area of two-thirds or three-quarters of them. Some of course are very difficult tO distinguish `between suicide and accident. We published some of our data and concerns in a letter to the Journal of American Medical Association in September 1975, and after assess- ing our data, we published an article about propoxyphene in the South- ern Medical Journal in August 1975, and I think copies of these have been made available to you. [The information follows:] PAGENO="0106" 16658 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Letters Letter8, if cLearly marked "For P-ublicatinee," will be published as space pernu its and at the discretion of the editor. They should be typeu'ritten triple-spaced, with five orfeu'er references, should not ezceed two pages itt Length, and will be subject to editing. Letters are not acknowledged. * Propoxyphene Overdose Deaths To the Editor-We are observing an alarming increase in North Carolina in the number of deaths attributable to propoxyphene. We doubt that the phenomenon is peculiar to this state. Most physicians may not be aware of the problem, in spite of the article in THE ~oua~.a by Sturner and Garriott (223:1125, 1973). This state's Medical Examiner Sys- `em detected 21 deaths in 1972 and 21 .n 1973 attributable to propoxyphene. Thirteen such deaths were identified in the first half of 1974, and 17 more in the last half of that year. In the first three months of 1975, sixteen more deaths have been recorded. In comparison, there has been an aver- age of 39 barbiturate deaths annually from 1971 to 1974. There have been only three barbiturate deaths during the first quarter of this year, when there were 16 propoxyphene deaths. Most of the propoxyphene deaths have been suicidal overdoses; some- have been accidents. Propoxyphene is a prescription an- algesic second only to aspirin in r~pu- larity. The drug in the various forms of Darvon was the most commonly )rescrlhed drug in 1972. Although i)arvon is the most widely used pro- poxyphene, it is also available as Dolene, Pro-Gesic-~5, arid SK-G~. The relath'ely new napsylate salt of pro- poxyphene, Darvon-N, is reputed to be safer than hydrochloride salt be- cause of its poor solubility. We are unaware that one form of propoay- phene is demonstrably safer than an- other. We offer several possibilities to ac- count tor the increase in reC)gfliZCd propoxyphene deaths: (1) the resched- uling-induced decrease in avaiabll- ity of rapid-acting barbiturates. (2) stricter controls on the much 1055 le- thal analgesic codeine; (3) the ntis- oonceplln among many physicians that propoxyphvine- is essentially harmless; and (.4) the situation ~hat Medicare svili pay for propOXVL)lic-r.e Clifed ey Jann 0 Archc. MO. Sen ~ prescriptions but will not pay for aspirin. Communities that are not detect- ing propoxyphene deaths may not have adequate death investigative systems including competent tox- icology facilities. Recent improve- ment in techniques may account for discovery of cases that would other- wise have gone undetected.' It is our opinion that 15 to 20 of the 65-mg capsules (or of the 100-mg napsylate salt compressed tablets) may cause death, and that somewhat lesser amounts may do so with ethanol or other central nervous system depres- sants. In our experience, blood con- centrations of propoxyphene together with other depressants that exceed 0.1 mg/100 ml, and of propoxyphene alone that exceed 0.2 mg/100 ml, can cause death. ARTHUR J. McBur, PAD PAGE HuDson, MD Oflice of the Chief Med'cal Examner Chapel H~5, NC t.Mnfluy AJ, Turk P.F, Corbett OW. u, a!' Determina- tint `f propox~phene in bioluginel muteriulu. J Per,:nete &z 19.81-09, 1~4. J~MA S'pt 22. ~975-VoI 233. No 12 -~.- r; 1?~7 PAGENO="0107" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16659 Fatal Poisoning With Propoxyphene: Report From 100 Consecutive Cases PAGE HUDSON, MD, MICHAEL BARRINGER, AB, and ARTHUR J. McBAY, PhD,t Chapel Hill, NC investigations, autopsy, and toxicologic findings are reviewed individually by career medical examiners! forensic pathologists at the OCME. Additional investi- gation or death certificate modification is made when indicated. We sotigltt propoxyphene-related deaths from case records of the state's OCME. We did not include 12 propoxyphene deaths recorded before Jan 1, 1972, and five victims who had significant blood concentrations (0.2.0.6 mgldl) of propoxyphene but who also had apparently fatal natural disease (four victims of coro- nary thrombosis or myocardial infarction and one with bilateral pneumococcal lobar pneumonia). The reports included varying antounts of social and isychiatric history. immediate past history, and scene clescri1)tion for each of the 10(1 cases. Eighty-nine of the 100 had autopsy; toxicologic studies were done on each. Each case was reviewed independently by at least two experienced staff members for concurrence on cause and on manner of death, eg, accident versus suicide, undetermined versus suicide. We considered death due to propoxypltene alone pure if (1) tlte blood concentration was 0.2 mg/dl or higher, or an appropriate liver concentration existed in cases where the blood sample was exhausted from other studies or was not submitted; (2) there was not a significant concentration of other drugs or alcohol; (3) no more than minor injury or natural disease was found; and (4) appropriate history and autopsy findings were described. Our "mixed category criteria included the above except that there was also blood ethanol concentration of over 15(1 mg/dl (0.15%) or other drug with at least one half the minimum fatal concentration acce1)ted by recognized sources.35 We classified as accidental the deaths of those victims with relatively low propoxyphene levels who tad bight ethanol levels and si-hose behavior immediately pre- ceding death was not an apparent variation from their usual. Deaths of many of the victims with a strong his- tory of `drug abuse" were termed accidental. TIte suicide classification included those with previous suicide attempts, evidence of depression or disassocia- tion, and ingestion-by a conspetent adult-of so many tal)lets or capsules in a short time so that accident seemed precluded. The manner of death was ruled undetermined ss-lten the evidence for suicide ss'as approximately equal to that for accident. PRopoxvpitcxc, usually sold as Darvon or some variattt thereof, is a centrally ;tcciitg narcotic analgesic. It lt:ts immense clinical popularity, questionable effectiveness, and poorly recognized toxicity. Pro~toxy phette w:ts first marketed (as Darvon) its 1959. 1 lie first report of a death frotit overdose was published in I 9h4.t Subse- quent articles Ofl propoxypltette deaths and abuse were reviewed in the May 1973 report of lie Bureact of Narcotics and Dattgerous Drugs.2 The first known cases in North Carolina, tlte soctrce of tlte present report, were certified itt I 9h9 wlten (se were identified. More tlt:tn 17(1 have beett docittttented itt this state since then, titost in lie past live sears. Al- tlti)uglt the states Medical Exattitner Svstettt attd toxt- cology facilities beg:tn in I 9(i8, tttatty of cIte states 1 counties and 5.3 tttillion to1tcilattott have l)eett repre- sented only since Jan 1, 1972. We are reporting our first 100 propoxyphene deaths from tltat date. This is the first published study from a large state and is intended to provide insight ittto the problem of propoxyphene poisoning. MATERIALS AND METHODS Case records of lie states Office oh Ice Chief Medical Examiner (OCME) constitute the data base for this study. All "unusual, unnatural or stispicious" deaths are reported to physician county medical examiners. They investigate the deaths and authorize further examination if indicated (eg, autopsy, toxicology, or additional interviewing). Autopsies in these cases. are performed by hospital pathologists serving their communities as regional pathologists. The state's OCME is responsible for appointment of these officials, quality control, instruction, guidance, record main tenance, and many of the autopsies as well as all of the toxicologic analyses. ilte tttedic;tl exatttitiers tttcl regtctttal tatltttlogtsts report specific identifying, epidemiologic, demo- graphic, and descriptive data plus narrative and opinions. Appropriate samples are taken for toxicologic analyses when autopsy is done; blood samples only are submitted from all other cases. The reports from case 248v,~tupd~t,wNC275t4(D~ttsth) 5t~tssi E~vvw tO ~" 938 August 1977 * SOUTHERN MEDICAL JOURNAL * Vol 70, No.8 ABSTRACT: The first 100 deaths caused by propoxyphene and recorded by the Chief Medical Eoaminer of North Carolina were studied. Victims ranged evenly in age from the setond to the seventh decade. Over 65% were suicides with a female to mate ratio of 2:1. Blood propooyphene concentrations of 0.2 mg/dh were fatal, representing rapid ingestion of approoi. mutely ten capsules. In North Carolina, deaths due to propooy. phene have increased from five in 1969 to 49 in 1975. Raising physician-awareness of propooyphene's tooicity and placing the drug in Schedule It are two of the authors' recommenda- tions for reducing the number of propooyphene deaths. RESULTS Propoxyphene accounted for more deaths in North Carolina in 1975 than any other drug, excluding acute ethanol poisoning. With the 49 identified in 1975, the total rose to 136 in seven years. The detailed data are from the 100 consecutive cases from January 1972 to August 1975. A majority of propoxyphene deaths were clearly suicides, comprising 65 of the tOO (Table). Women PAGENO="0108" 16660 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY TABLE. Ow Hwdsid Cos,s satiw P,opuiyphiTi Diiths by M of OutS, Sw, usd Puuiusw of Sigsifiit Lwu!s of Othot bogs. i~y!adisg were overrepresented, 58 to 42 overall and 45 to 20 among certified suicides. Men dominated in the acci- dental group, commonly having high blood alcohol concentrations at the time of death and a history of drug and alcohol abuse. Propoxyphene deaths were relatively evenly dis- tributed among the age groups from the last half of the second decade through the sixth, although the fifth decade did account for 30 of the 100. There seas no marked age difference among the suicides, accidents, or undetermined groups or between men and ss'omen. A small number (eight) of propoxyphene victims whose deaths ss'ere judged accidental and who had no other significant detectable drugs, including alcohol, had a lower average age (26 years) than other groups. The average age for other groups seas about 40 years regard- less of sex, manner of death, or presence of drugs or alcohol. Thirteen of the 100 victims ss'ere black, the remainder white. There ss-ere no marked racial differences in manner of death, age, sex, or presence of other drugs. Blood propoxyphene concentrations were obtained in 51 of the 65 deaths that ins-olved no significant concentration of other drugs or alcohol. The average concentration seas 0.8 mg/dl, the range 0.2 mgldl to 2.7 mg/dl. In the same 65, the 47 liver propoxyphene concentrations averaged 9,8 mg/dl and ranged from 0,8 mgldl to 33.0 mg/dl. In 37 of the 65, propoxyphene analyses were done on both liver and blood. Twenty of the 35 "mixed" deaths had ethanol as the only other drug present having a possible significant concentra- tion, The mean blood ethanol concentration was 200 mg/dI among the 20, Blood propoxyphene concentra- tions ssere available in 19 of the 20, the mean of these seas 0.5 mg/dl; liver concentrations were as-ailable in 13 with a mean of 1,4 mg/dl. The remaining 15 of these "mixed" deaths with a fatal les-el of propoxyphene included as other possible significant drugs, salicylates (3), meprobamate (2), phenobarbital, secobarbital, amobarbital, butabarbital, ethchlors-ynol, diazepam, amitriptyline, methadone, a possible hydrocarbon, and a combination of isopropyl alcohol, thioridazine, and secobarbital. Usually the propoxyphene had been prescribed for the eventual victim, Prescription size, when knoss-n, ranged from 20 to 240, with 50 to 100 capsules the usual range. The specific commercial preparation of pro- poxyphene u-as known in one third of the cases, All but two of the formulations were Darvon or Dais-on based, eg, Dais-on Compound'65 and Darvon-Nl00. Death occurred rapidly in the majority of the vic- tims. Over 50% had been seen alive two hours or less before being found dead. Frequently, the acute collapse and death were witnessed. Approximately 30% were found dead in bed and close approximation of the timO betss'een ingestion and death seas not possible. The remaining 20% include primarily those living three hours or more and those with unknown time of inges- tion or death. History of depression, pres-ious suicide attempt, statement of suicidal intent, and suicide notes were common but not sufficient to present significant fre- quency data in a group of this size, Individual reports offered history of s-arious forms of drug abuse in 26 instances, 14 of these being primarily alcohol abuse, Chronic, partially disabling physical problems such as rheumatoid arthritis, pancreatitis, and persistent back and leg injury were noted in 14 victims. Autopsy served principally to eliminate other causes of death, The lungs svere typically congested and edematous, 80% of them seeighing 800gm or more. The average weight seas 1,000 gm. Abundant white froth was commonly observed in the respiratory tract. Pink- stained gastric content or other visually detectable evidence of medicinal material in the stomach seas noted in approximately 10%. Fatty vacuolization of hepatic cells beyond a trace or "plus-minus" degree was present in approximately 50% of the victims. DISCUSSION Recognition of a large atid increasing number of propox~ phene deaths in North Carolina lead us to exantine ses eral aspects of lie apparent problem. Tltese include: (I) diagnostic criteria; (2) increase in case freqtiencs: (3~ e-',perience in other parts of the nation; (1) characterisiks of population affected; (3) sources of the drug; and (6) popularity and efficacy. Diagno Cots-em. Ilie inchisidttal diagnoses were made deductis el~ front the case histories, from autopsies that yielded no anatomic explanation for death, and fronr toxicologic analsses iltat revealed propoxspliene blood levels at least tenfold greater than tlte iherapeutic lesels. Our experience indicates a propox~pltene 1)100(1 lesel of ((.2 mg/dl is adequate to cause death. This is consistent with tlte published work of others.67 We believe it possible that some of our subjects with that les el might base survived without he additive effect of alcolml or other drugs. (2) Inc own- in Can' Frcqnetuv. l'lie number of deatlts associated svitl poisoning dtie to drtigs or other chemicals is diflicult to measure in large population groups it the Unhed States and in ilte nation as a whole. I'he paudit\ (if adet1uate statewide systems for the investigation of suspicious or uniiatural deaths, tlte unavoidable provincialisnt of otlterwise competent count)-cits invessigatise ssstenss, and ilte relatise ininiaturity of forettsic oiedicine in the United States give little aiid late data on the hazards of many drugs, andl oth.'r chemicals. We have seen an increase from rare cases from 1969 to 1971 to over a score each year from 1972 to 1974. Hudson et a( * FATAL POISONING WITH PROPOXYPHENE 939 PAGENO="0109" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16661 Forty-nine propoxyphene victims were certified in 1975. This increase may be due largely to enhanced suspicion, search efforts, and new technics. The un- supervised lay coroners isIto preceded the development of our Medical Examiner System had little knowledge or stimulus to obtain tests for propoxyphene or other drugs. There was no system pr~s'iding a knoss-ledgeable person to counsel the investigations or laboratory sup- port when drugs were suspected. At present, the county medical examiners in North Carolina are guided to consider each death ins-estigated as possibly drug related. Furthermore, each case is reviess-ed at thte OCME by the Chief `loxicologist and a forensic pathologist is-Ito can order additional toxi- cologic studies. The technics for detection of propoxyphtene hase been refined during the past five years. An inade5uatc spectrophotometric method si-as improved in l972~ and further im1)ros-ed in h974.° Gas chromatography is non- our analytical method of preference because it allows detection of blood propoxypliene anti its active metabolite norpro1toxy1)henc)° The former method detects `propoxyphene but only part of the norpro- )oxypltene. Technics that are inlerior in sensitivity and specificity to both methods are still being tisecl in many laboratories. A recent national surs'ey~ of toxi- cologic laboratories reported 5(1 to 138 responding' toxicology laboratories tlicl not test for pro~)oxyphicne; nine indicated a negatis-e result on lie proficiency test samples; 24 reported detection butt no tjtiantitation. Of the 54 attempting tluantitation, ottis 16 were is-itltin 30% of the correct concentration; of tltese 10, only five, including ours, is-crc within 10%. We believe the improvements in the local itteclical examiner investigation and in tecitnics for detecting propoxyphene were primarily responsible for tite increase in propoxyphene deaths from four in 1971 to 22 in 1972. The jump from 28 cases in 1974 to 49 in 1975 is alarming since the system and teclunics did not change drastically. Our toxicologic dattt ittdic;ttc the rise is associated with a shift in popularity of drugs. Barbiturates itad been identified in store drug deatits titan any other agent until 1975. In that year deaths from barbittirates decreased while tropoxyphuene fatalities increaseth attd otiucr miscelitineouts atid fatal drug deatits showed no significant cluange. \Vc offer no adec1uate explanation for tiuc marketh shift. (3) Expeu-uence in 0/lieu' Pat/s oft/ic Nit/tout. In 1973 Sturner and Garriottt reported frotti Dallas 49 dciutlts invols-ing propo~~yputette atttong wlticit ten is-crc clue to propox)-pltcne alone, 12 to propoxypitente md ethanol, and two to propoxypltene is-itii oilier drugs. In 1973 the Drug Controj Dis-ision of the Bureau of Narcotics and Dangerous Drttgs (BNDD) reported propoxypltene data including death cases front 34 states during the years 1971 antI h972.~ Pro1uoxyphtene is-as judged solely responsible for 23(1 deaths and con- tributing in 27 otiters itt thue BNDD st/id)'. Our cotatacts witlu other titedical exatttincr svstcnts atid coroner offices indicate distinct imicreases. A rccettt national surveyt2 has uncos-cred os-cr 1,1(1(1/ )ro1toxyuhtcttc chetitius 940 August 1977 * SOUTHERN MEDICAL JOURNAL * Vol 70, No. 8 between 1972 and 1974 in selected medical examiner systems and coroner offices. Thuese data suggest pro~toxyphtene deaths are not a local or regional (4) Cluaracteu'istuc,u of tlte Population A_fjist ted. Pro- poxyphuene deathts occur at all ages. In our study uhue fifth decade accounted for 3(1% of the 1(1(1 deaths with the as-erage age of approximately 4(1 years for both is-omen and nien. There were feus- deathts antong ilte )-ottnger adults and adolescents, a group popularl)- associated us-ithi "drug abuse.' We did find that "pure" propoxypitene deaths which is-crc rulcch acctchctutztl cliii occuir at a younger as-crage age (20), ahuhtotighu tite nuitsi- her (eight) is-as stitall. This is consistent with thuc data from Stturner and Garriottt and with the BNDD re Titere is-as good evidence thuat (i5% of the pro1tox~-- phtenc s-ictims committed suicide. However, titany if not all of tue 12 certified as undetermined anti souse of the less titan thoroughly cons-incing accidents also `nay itavc been suicide. `This statement reflects our cons-icuion that rapidi ingestion of enough tills (ic, 10 to 20 65-mg propoxyphene capsules) to cause death occurs as a result oh a purposeful abuse by a knowictige- able terson, an accidental ingestion ity a ctmriouus chuthh, or a deliberate consutiupumon h)y a suicidal individual. Automatisni hiss been a uroposed ntechuantsttt mu drug deaths bttt we anti others disagree with the re;usttn- ing.tt 4 Aniong the theathus wit/cit the OCSIE anti local titechical exanuiners agreed to ciassift- as munuheucruiuumimh, ti/any s-icuittts wouhch hiss-c 1usd to ingest 2(1 ttr uuuorc (/5 tug c,'u1usules within a short period of ii mute. Somume of those ruled accidental dime to high blooth alcohol cotucenurtu- uions ins-ohsed the subject t1uuickiy consuming i(t mit Lu capsules. We esuimtuauc 8(1% to 85% of mite ucrsons uhyitig froutu propoxy~uiucnc consumiuption cousumumiuted sumiciuhe, leasing 15% to 2(1% for accidental and abutserelateth deau its, Women oumunuimberech men tutore titan i/to to omuc among uhuc clearly defined propoxyphuene suicides (45 of (iS). By comparison, the 1974 tOtal druug suicithe cases inchumded 5(i it-ut/ten and 27 n/tnt. Total suicides by all agents included 189 women, 507 men, There was no significant difference betus-cen the sex ramiuu its propox-1ultenc sumicides anti total chrug suicides. `Ihuc relatively larger uro1uoruion of muucn in the accident anti, tmndeucrmincd manner of death grotu~u appeturs tut be due to timeir greater fre9ucncy of alcohol con/situ//p uion withm thrug abuse. We huase not fouund that urejuuthice rcgaruhing gender anti drumg use wtus a significant fzucuor ins thcucruuuimuauion of muuanncr of cheauhu, eg, assumuuimmg ami Overdose cheauhu was accidental rathuer titan a suicithe primutarihy- becaumse time s-icmum was male. \\Te ui-crc not surprised to find uhuau at least omuc u,1utar- her of tue cases inus-olved persons us'iuiu a history uuf drug abuse and tiutut 14 u)f these were ahcoiuohmcs. Our atmuopsy data indicate that ap1uroxinuaueiy one half of tue 11(11 victims nuay have abused alcohuol; os-er 3(1% tad hauuy cluamuges in hue his-cr. `This finching thocs tot cutnurathmcu tue deauhu reports, for muuany- if uiuemi'u tire not thcuailech hucyotuth hue imummuucchiauc circummuusuanccs of theauhu. "lite 14 PAGENO="0110" 16662 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY histories of chronic illness and disabilits such as back pain might be anticipated. Botit the alcoltoi.drug and chronic disability groups are at higlt risk for drug. related deaths in our experience. (5) Sott rca of Drttgs. The source of the propoxypitene was tlte victims ossn prescription in tlte majority of tite cases. We were impressed ssitlt the frec1uency ssitlt wlticlt ilte fatal overdose closely followed a prescription refill. A relative or friend's prescription was tlte source for several deatlts. Instances of tlteft or otiter illicit sources ssere rare. Sturner and Garriottt reported tltat in at least 31 of their 41 propoxyphene-involved deaths the source was tlte victim's prescription. Prescription size seas reported to us in less titan one titird of tite cases. fite smallest ss-as twenty 15 ntg capsules, tite largest 240 (about 21) times tite letital dose). Tite majority were for 4() or more; l))() or greater was comnson. Several patients itad a refill or a second propoxypitene prescription in addition to part of the original prescription. Tite prescription of 12)) or more dose forms seas most frequent at \`eterans Administra. tion Hospitals. (6) Popttlartly and Efficacy. Propox~pltene has been number one among prescriptions dispensed in retail pitarmacies in tite US since tite late 1969s.tt As Darvon and Darvon-N individually, and wttlt tlteir various additives, propoxypitene itas even surpassed diazepam (Valium) in prescription popularity. Tite drug Itas been vigorously promoted as safe tltrouglt advertising and detailing. Its trade name seems pleasant and easy to remember; tlte capsules and compressed tablet forms are relatively attractive. Prescribing pltssiciatts and pltarmacists inform us titat public andprivate tltird. party compensation pays for propox~pltene but not for aspirin. Presently classified as an uncontrolled sub- stance, propoxypitene is obviously easier to prescribe titan controlled analgesics. Furtlter enltancing its usage is tite reaction of tite patient sslto titinks titat ite is getting more attention if Ite receives attractive capsules or colored compressed tablets ratiter titan soft, ssltite tablets Ite knows are aspirin purcitasable witltout prescription. One major review noted, "It appears that factors otiter titan intrinsic titerapeutic value are responsible for tite commercial success of propox)- In support of propoxypltene's usage, a manufacturer's representative wrote, "Dat-von products have won a remarkable acceptance by patients and plt~sicians since titeir introduction."tT Investigators of analgesic effectiveness rebutted: "The implication that gen~'al acceptance of a titerapeutic procedure by plt~sicians in a given era constitutes obligate proof for effectiseness is not tenable. If this were true, we wottid still be bound to the mummy dust, unicorn's torn, leeciting, purga. tives, blood letting, and mustard plasters universally endorsed by our forebears. We must constantly offer citahlenge to all our sacred cows, so titat our patients may be afforded tite Itigitest care at tite most reasonable Clinical reviews of the drug and evaluations of analgesics indicate inferiority to aspirin and other less toxic analgesics, and tjuestionable advantage over placebos.9 Tite 1973 BNDD report concluded, "Cur- rentl~ propox~pltene is being used clinically, (1) in place of codeine in tite belief titat it is equally effective and less toxic, anti (2) in place of aspirin in tlte belief tltat,it is tttore effective isitit no increased toxicity. In contrast, tlte Ituman pitarmacologic and toxicologic evidence clearly indicates titat titis rationale for clinical CONCLUSIONS AND RECOMMENDATIONS We Itave documented a rapidly rising rate and num- her of propoxy1tltene deatits and anticipate oser 1,00)) propo~ phene cleatlts tltis year in the United States. Most ss'ihl l)e suicides. Probably sotite of these sictims would take their own lives were tite propoxvpltene not available. Howeser, as a large proportion of suicide attempts are ititpulsive rather titan planned, ready availabilip (if an effectise agent enhances chances of successful cootpletion of tite self-chestructise act. .\lany factttrs that have little to do isitlt any intrinsic effective- ness of the drug cause it to be readily available in large quantits to a vast number of people. Propoxyphtene's titeager mlterapeutic effectiveness adds irony to tragedy. Our studies and interviesss have revealed repeatedly that tttany physicians regard thte drug to be relatively innocmtotts, to be prescril)edl witit impunity. Our recottinsenchations include lie following: (I) education through standard medical chtannels concern- ing propoxvpltenes analgesic and toxic effects; (2) phtssicians voluntary reduction in average prescription size; (3) estal)hishttnent of mite same thtird-parmy payment standards for analgesics such as aspirin and acetamino- phten as for propoxypltene; (4) enhtanced patient is-am- ing of the hazards of combining ahcohtol and "pain killers and other stood affecting drugs; and (5) place- ment of propox~pltene in Schedule II of mite "Controlled Substances Act of Public Law 91-513. More discritttinating prescription writing and reduced drug availability could diminish not oniy )ro~)oxy~hiene poisonings bitt also thte total suicides anti drug-related accidents. Relerences (I,, (i,! f.,(.,Iit'. f.4.((.l 187:4tiO-4(it. (`04 0,,,- C, ,,ti,. Di ~`i,~((. ~ \,0,,(,eS ,id Dtigi'i,~t~ So,,,,,, SVQ. (Oo, i'.(( JC: D,o:t~, io,,,t, jog ,j,oo,t,t,,oo: -, f 41 m."o-~ ,,,oi , ,,,,-,oo `oo,,t. f43t( `23: ( (Oil (30. (373 5. (V.,f(,,oo JE., iliggo JO. t(,(l (Vi: D0(00((j(( .(liOi( p(,'f,',\'(,l0O0 a ill. Not, i)JF. i(o,g,tl (F. it:,p~, RJ. St of: Q,,.,oti (Ojgg()f Hudnon at at * FATAL POISONING WITH PROPOXYPHENE 941 PAGENO="0111" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16663 kN~d ~~lg~.i 1~g,. N E~g1J M~d 2811:819-819, 972 7. ~ CM J~:EIf,6li~ ~ (IC! C h! N Elg(J .866 28:1: 158, 1972 (9. ~h(I OR. 866(9:11(1 2, I'.:oi :C( J: `9()p((9l) 942 August 1977 * SOUTHERN MEDICAL JOURNAL * Vol 70, No.8 12. B~ss~t IF: Mis,,s! of p,'opooyph~oo. (lou~o h! !diU~!). JAMA 235:1686. 1976 OfflO! 91 h! Chi(f. M(diOO( E(1l66!, COC:ooooC(I(: of 6(99(0(6, Vol 84, No, Ii, Joo 965 4. Do!p6l JL: D,og ooI:oooIio::, h69hiIo',66 ioiog (0(1 b2hO6jo9, 4,'oh G8o P.:y(hiooy3l:211;-229, 1(174 5. 1 hoo 9810 CoI9go': Rpo,Iio No6:oo( P9(00((1oo .6(1111. E6dhoo:, Mo~,, 14.6 Goo(Ii9 loot Co. oh, ((61:, p 8 PAGENO="0112" 16664 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. HuDsoN. With that, I would also say that we can look at some factors that have influenced the changing numbers in our State. Be- ginning in late 1968. we began putting in a statewide system for the evaluation and examination and investigation of sudden, unexpected and suspicious deaths. I believe that the onset of that system enhanced suspicion of specific designated deaths for investigation, but particularly a development of toxicology enabled us to begin to get these facts and to see the numbers go from a rare 1 or 2 or 3 up into the twenties. Then the system leveled off, as far as sophistication and techniques across the State but then the number of propoxyphene deaths continued to increase up to 50 in 1975. With that as background, I would like to speak to some of the ques- tions that you posed in your letter. What does the volume of prescriptions written for propoxyphene show? Propoxyphene has been at or very close to the top in total new pre- scription frequency for over 10 years. This is combining primarily the trade names of Darvon. Darvon-N 100, Darvon Comp, and others al- ready discussed. In view of prescription volume and prescription size, are doctors aware of the dangers of Darvon and other prescriptions containing propoxyphene? No; I believe they could hardly have been less aware. I do hope that that is changing now. I have seen some signs that perhaps it has in the past year. Repeatedly I have seen physicians frankly shocked to learn of the frequency of propoxyphene fatalities. Some stated they had heard of propoxyphene victims but assumed they were "young punks shooting drugs" as opposed to the kinds of folks their own patients represented. The reactions have varied from, "I think it is a good drug, my pa- tients ask for it." to "I don't know why I use it; it isn't worth a damn without aspirin in it." Is it sound practice to prescribe 120 or more dose forms of propoxy- phene, as you have found done most frequently at Veterans' Adminis- tration hospitals? In my opinion, no. I realize that there are severe logistical and other problems in man- aging chronically ill patients who live many miles from the medical centers and/or have physical or othe.r disabilities that handicap fre- quent visits. . However, propoxyphene is one of the pacifiers given these patients. Chronic use requires increasing doses for such analgesic effect as propoxyphene does have, but it has not been demonstrated that the patients develop any protection against overdose. Twenty dose units of propoxyphene is an ample amount for 5 to 7 days of pain relief. The pain that persists longer than that signifies a need for more than a mild and hazardous analgesic. I am familiar with Veterans' Administration hospitals. or at least several of them, and I lmow that a large proportion of the medica- tion is given out to patients or outpatients to take home is intended at least to be pacifiers or placebos to some extent the patient, and perhaps PAGENO="0113" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16665 even to some extent the physician. He-the physician-wants to do something for the patient butit is particularly dangerous to give large quantities of mood-affecting drugs to patients with psychiatric, alco- hol, or drug-addiction problems. But it is done commonly. In my experience this group of hospitals has been one that stood out in my mind. What is the medical justification for having propoxyphene on the market? As I see it, the only justification is habit, custom, acceptance by phy- sicians and patients. As has been discussed, propoxyphene offers no efficacy, no more than over-the-counter preparations, but except that the over-the-counter preparations lack the "psychic" authority of prescription drugs. Also, there is more magic in having a prescription than something which somebody obtained over-the-counter which seemingly would not be that effective or give that same effect. It-nonprescription medication such as aspirin-is not that im- pressive to the patient. I believe it is generally true the third party payees usually do not pay for aspirin, acetaminophen and the like, but they do for the pret- tier, more expensive, less effective propoxyphene. Do the benefits of the drug outweigh its risks? No. The benefits are minimal if indeed they exist. The risks are the demonstrated frequency of drug abuse, accidental combination with other central nervous system depressants, and availability to the po- tential suicide victim, among others. In your experience, what is the relative abuse liability of propoxy- phene and codeine? I do not know what the abuse frequency and addiction severity would be if the two drugs were used by equal numbers and types of people at equivalent dose levels. I believe no one knows. There is inexplicably an awareness within the medical profession of addiction potential of codeine but the proper awareness has not yet developed for propoxyphene. The margin of safety for codeine may be greater than that of pro- poxyphene. There have been hundreds of proven deaths from propoxyphene for every one documented for codeine. I see no logic in having codiene in schedule II with propoxyphene in schedule IV. We are aware of some 200 or so of propoxyphene deaths in North Carolina during the same period of time; we have been able to iden- tify three deaths that primarily used codeine. Your last question, please discuss the nature and extent of DA1~VN deaths involving propoxyphene, including the manner of classifica- tion of these deaths as suièidaL accidental, or undetermined, and the role of toxicologic analyses of blood, liver, and tissue in determining the presence of propoxyphene and its chief metabolite. If I may, I for one have not been impressed with the DAWN data, primarily because of its vagueness, more specifically to the term "drug related." The definitive identification, or what to me approaches the definitive identification of a drug is not only the history of the opportunity 40-224 0 - 79 - 8 PAGENO="0114" 16666 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to abuse that drug in statements by friends of the victims, but rea- sonable efforts to rule out other causes of death, and best yet, toxolog- ical determination, that particular form of chemistry that detects the drug and measures it and demonstrates it to be in sufficient quantity to cause death. Most of the cases referred to in the DAWN material seems to me from my readings not to reflect that quality of data, that quality of verification of drug-related data necessary as far as specific drugs are concerned. In our own State, as far as manner of death is concerned, we be- lieve that with rather careful review that approximately two-thirds or three-quarters of the deaths are suicide. I am chagrined that our American social and medical systems in a broad sense, have allowed this to come about, that this drug which has been available for 20 years, has been accounting for as many or more drug deaths than any other for so many years, and we have, such a lack of awareness generally within and without the medical profession. Thank you. Senator NELSON. Thank you very much, Doctor. Dr. HUDSON. Thank you. [The prepared statement of Dr. Hudson follows:] STATEMENT OF PAGE HUDSON, M.D., CHIEF MEDICAL EXAMINER (NORTH CAROLINA); PR3FESSOR AND ChAIRMAN O~' Divis:ox or FORENsIc PAThOLOGY. FNIVEIIsITY OF NORTH CAROLINA SCHOOL OF MEDICINE, CHAPEL HILL, N.C. I am a doctor of medicine specializing in forensic pathology and am certified by the American Board of Pathology iii anatomic pathology and in forensic pathol- ogy. Forensic pathology is that medical specialty that involves the detection. identification, investigation and other studies of real or suspected unnatural deaths. I practice, write and teach in this field of medicine and related sciences. My employment is as Chief Medical Examiner. My appearance here is with the permission of North Carolina's Division of Health Services, Department of Human Resources; however I choose to volunteer that my opinions are my own as a private citizen and do not represent an official stance or policy of North Carolina. It became apparent several years ago that propoxyphene was responsible for increasing numbers of deaths in North Carolina. Dr. Arthur J. McBay who is Chief Toxicologist to the Office of the Chief Medical Examiner and I examined our cases, methods, criteria and diagnoses. We conferred with authorities in other states and with many physicians involved daily with patient care. We got the strange feeling that we were among the first discoverers of a relatively ol)vious and moderately aw-esoine phenomenon : A drug inrdication exi'ted that was at the top in prescription popularity, one that had but a trace of benefit and that was reaching the point of causing more deaths than any drug, licit or illicit, in this country. We published data and our concerns in a letter in the Journal of the American Medical Association in September 1975. After further developing our data we pub- lished an article about propoxyphene hazards in the Southern Medical Journal in August 1977. Copies of this have been made available to you with copies of my statement. The article still expresses my sentiments, those of Dr. McBay I believe and those of Dr. Michael Barringer, a surgeon who was a medical student when he co-authored the article. Dr. McBay and colleagues have published on their improved techniques for detecting and measuring propoxyphene. Our concept of the more cogent elements of our article is as follows: Our data are from a statewide death investigation system covering a state of about 5.5 million people. We believe inferences can legitimately be draw-n from our data that can be extended to the national population. The number of deaths as- sociated with poisoning due to drugs or other chemicals is difficult to measure in large population groups in the United States and in the nation as a whole. PAGENO="0115" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16667 The paucity of adequate statewide systems for the investigation of suspicious or unnatural deaths, the unavoidable provincialism of otherwise competent county-city investigative systems, and the relative immaturity for forensic med- icine in the United States give little and late data on the hazards of many drugs, poisons and other chemicals. We have seen an increase in propoxyphene deaths from rare cases in 1969 through 1971 to over a score annually from 1972 through 1974. Forty-nine were certified in 1975. Subsequent years have yielded at least 30 each. Development of the new medical examiner system with enhanced suspicions, search efforfs, and new toxicology techniques may have accounted for the initial increase. There was another surge in propoxyphene deaths well after our medical examiner system was stabilized. Reports from other investigators including the BNDD (now DEA) indicate the North Carolina experience is not a regional phenomenon.. At least 65, per- haps 80 percent of the deaths are suicides. The drug the victims used bad been prescribed for them in most instances. Ten dose units appeared adequate to cause death but more were generally used. The prescription size ranged from 20 to 240 units. Females were predominant except among the "accidental over- doses". Alcohol and other drugs were~ commonly present, usually not in signifi- cant quantity (and not really more frequently or at greater concentrations than detected with gunshot suicides). The great popularity of propoxyphene (almost entirely Darvon, Darvon Comp 65, Darvon-N 100 and the like) appears to be due to factors other than its effec- tiveness. These appear to include: (a) Vigorous marketing and detailing efforts. (b) Fortunate name. (c) Attractive appearance. (d) Third party compensation for propoxyphene but not for aspirin or acetaminophen. (e) Public concept of the drug as a "real" medicine as opposed to plain aspirin. (f) Physicians' concept of the drug as essentially harmless. Independent evaluations of analgesics generally rank propoxyphene as equiv- alent to placebo and less efficient than aspirin. Our recommendations included: (1) Education through standard medical channels concerning propoxyphene's analgesic effects. (2) Pliysicia as' voluntary reduction in average 1)rescrll)tioll size. (3) Establishment of the same third party payment standards for analgesics ~;uch as aspirin and acetaminophen as for propoxyhene. (4) Enhanced patient warning of the hazards of combining alcohol and "pain killers" and other mood affe~ting drugs. (5) Placement of propoxyphene in Schedule II of the "Controlled Substances Act" of Public Law 91-513. We concluded with the opinion that "more discriminating prescription writing and reduced drug availability could diminish not only propoxyphene poisonings but also the total suicides and drug-related deaths". Some of the other issues discussed in the article are addressed in my responses to the following questions posed in Senator Nelson's invitation to appear here today. Q. What does the volume of prescriptions written for propoxyphene show? A. Propoxyphene has been at or very close to the top in total new prescription frequency for over 10 years. This is combining primarily the trade names of Darvon, Darvon N 100, Darvon Comp and others. Q. In view of prescription volume and prescription size, are doctors aware of the dangers of Darvon and other prescriptions containing propoxyphene? A. No. They could hardly have been less aware. Repeatedly I have seen physi- clans frankly shocked to learn of the frequency of propoxyphene fatalities. Some stated they had heard of propoxyphene victims but assumed they were "young punks shooting drugs" as opposed to the kinds of folks their own patients rep- resented. Reactions have varied from, "I think it's a good drug, my patients ask for it", to, "I don't know why I use it; it isn't worth a damn without aspirin in it." Q. Is it sound practice to prescribe 120 or more dose forms of propoxyphene, as you have found done most frequently at Veterans Administration hospitals? A. No. I realize that there are severe logistical and other problems in manag- ing chronically ill patients who live many miles from the medical centers and! PAGENO="0116" 16668 COMPETITIVE PROBLEMS 1N TfIE DRUG INDUSTRY or who have physical or other disabilities that handicap frequent visits. How- ever, propoxyphene does is one of the pacifiers given these patients, diazepam (\Talium) another. Chronic use requires increasing doses for such analgesic effect as propoxyphene does have but it has not been demonstrated that the patients develop any protection against overdose. Twenty dose units of propoxy~ phene is an ample amount for 5-7 days of pain relief. The pain that persists longer than that signifies a need for more than a mild (and hazardous) analgesic. I have worked with VA hospitals and know that a large proportion of the medication given outpatients or patients to take home are intended, at least in part, to be placebos or pacifiers to aid the patient in believing he is being helped and to keep him from bellyaching such as by writing his representative or sena- tor. It is particularly dangerous to give large quantities of mood-affecting drugs to patients with psychiatric, alcohol or drug-addiction problems. But it is done commonly. The VA hospitals stand out in my mind in this regard. Q. What is the medical justification for having propoxyphene on the market? A. The only justification is habit, custom, acceptance by physicians and pa- tients. There are cheaper, safer, more effective mild analgesics than propoxyphene readily available, even over-the-counter (OTC) preparations. But OTC's lack the psychic authority of prescription drugs. Also, third party payees usually do not pay for aspirin, acetaminophen and the like but they do for the prettier, more expensive, less effective propoxyphene. Q. Do the benefits of the drug outweigh its risks? A. No. The benefits are minimal if indeed they exist; the risks are the dem- onstrated frequency of drug abuse, accidental combination with other central nervous system depressants, and availability to the potential suicide victim, among others. Q. In your experience, what is the relative abuse liability of propoxyphene and codeine? A. I do not know what the abuse frequency and addiction severity would be if the tw-o drugs were used by equal numbers and types of people at equivalent dose levels. I believe no one knows. There is inexplicably an awareness within the medical profession of addiction potential of codeine but the proper aware- ness has not yet developed for propoxyphene. The margin of safety for codeine may be greater than that of propoxyphene. There have been hundreds of proven deaths from propoxyphene for every one documented for codeine. I see no logic in having codeine in Schedule II with propoxyphene in Schedule IV. Q. Also please discuss the nature and extent of DAWN deaths involving propoxyphene including the manner of classification of these deaths as suicidal, accidental or undetermined, and the role of toxicologic analyses of blood, `liver and tissue in determining the presence of propoxyphene and its chief metabolite. A. The North Carolina propoxyphene manner of death data are referred to in the Hudson, Barringer, McBay reprint, last paragraph of its front sheet, page 938; also the succeeding paragraph on the following page; particularly the three paragraphs on page 940 of the article. Relative to manner of death, I disagree with the recent published statement by the very able medical examiner/forensic pathologist from the excellent medical examiner system in Oregon. He, I believe, contends that the majority *of the *propoxyphene deaths are accidents due to the buildup in the body of propoxyphene's chief break-dow-n product or metabolite, norpropoxyphene. The explanation of our difference is somewhat long and technical and I shall not go into that now unless requested to. It does concern the understanding of propoxyphene metabolism and interpretation of toxicological testing results. I believe most toxicologists and forensic pathologists who have studied the matter agree with Dr. McBay and me that the majority of the deaths are suicide. An exception is an able group in a county in California. There I believe it is the custom to certify many drug overdoses as accident in the absence of a suicide threat or note in spite of chemical and other evidence that the deceased took 20-30 capsules a short time before death. The concentration of propoxyphene in blood, as revealed by appropriate toxico- logical analysis is the best indication of the number of dose units ingested. The norpropoxyphene disappears much more slow-ly from the blood than propoxyphene. Its presence reflects the size of the recent dose and the survival time following that dose. but also may represent buildup or accumulation from normal doses- or a combination of the two, e.g., normal dosage for a few days plus a very recent, PAGENO="0117" COMPETITWEI PROBLEMS IN THE DRUG INDUSTRY 16669 massive, fatal dose of propoxyphene. We now consider liver concentrations to rarely be of value. In conclusion, I as a physician am chagrined with the role that the medical "sciences" have had in the availability of the drug propoxyphene. If my concept of the current scope and function of the Food and Drug Administration (FDA) is correct, I do not believe it would license propoxyphene if that drug were being offered now as a new medication, on the grounds of inadequate efficiency alone. PAGE HUDSON, M.D. I~EFERENCES 1. McBay, A. J., Hudson, P.: Propoxyphene overdose deaths. JAMA 233 :1257, 1975. 2. Baselt, II. C., Wright, J. A., Turner, J. B., Cravey, R. H.: Propoxyphene and norpropoxypliene tissue concentrations in fatalities associated with propoxy- phene hydrochloride and propoxyphene napsylate. Arch. Toxicol. 34 :145-152, 1975. 3. McBay, A. J. Propoxyphene and: norpropoxyphene concentrations in blood tissues in cases of fatal overdose. Clii~. Chem. 22 :1319-1321, 1976. 4. Finkle, B. S., McCloskey, K. L., Kiplinger, G. F., Bennett, I. F. A national assessment of propoxyphene in postmortem medicolegal investigation, 1972-1975. J. Forensic Science 21 :700-742, 1976. 5. Moertel, C. G., Ahmann, D. L., Taylor, W. F., and Schwartau, N. A com- parative evaluation of marketed analgesic drugs, New Eng. J. of Medicine 280 :S13-815, 1972. 6. "Pain Underkill and Overkill." Emergency Medicine, Jan. 1975. 7. Owen, N. L. Abuse of propoxypliene, JAMA ~t6 :z0i(~, 1971. 8. Maletzky, B. M., Addiction tO propoxyphene (Darvon) : A second look, mt. J. of Addictions 9 :775-784, 1974. 9. Drug Control Division, Bureau of Narcotics and Dangerous Drugs: A study of the abuse potential of dextropropoxyphene with control recommendations. May 1973. 10. Hudson, P., Barringer, M., McBay, A. J., Fatal poisoning from propoxy- phene: report from 100 cases. Submitted for publication. 11. Moertel, C. G., Ahmann, D. L.: Effectiveness of propoxyphene (Darvon). Letter to the Editor, NEJM 280 :1158, 1972. Senator NELSON. I will now call on Dr. Arthur J. MeBay, chief toxicologist, office of the chief medical examiner, Chapel Hill, N.C. STATEMENT OF ARTHUR 3~. MOBAY, CHIEF TOXICOLOGIST, OFFICE OF THE CHIEF MEDICAL EXAMINER, CHAPEL HILL, N.C. Dr. MOBAY. Senator Nelson, Senator Morgan, and members of the committee. I do not know whether you want me to recite part of my back- ground or what. I have not got it in my statement. Senator NELSON. It is not in your statement? Dr. MCBAY. No. Senator NELSON. For the record it would be helpful to recite it. Dr. MOBAY. Fine. I have a bachelor degree and a master of science degree in pharmacy. I have been a registered pharmacist since 1940, although I am not actively practicing pharmacy. I have a Ph. D. degree from Purdue University, 1948, in medicinal chemistry. I was a member of the department of legal medicine at Harvard Medical School for about 10 years, and my principal job at that time was supervisor of the Massachusetts Department of Pub- lie Safety Laboratory. PAGENO="0118" 16670 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY This is a crime laboratory. My principal efforts were in either homicide or toxicology investigations. In 1969, I became chief toxicologist for the State of North Caro- lina, and for the office of the chief medical examiner, and I was made a member of the staff of the department of pathology and department of pharmacy of the University of North Carolina. At the time, I am a full professor in both departments. I am board certified in toxicology and forensic toxicology. I am a member of several toxicological societies, pharmaceutical society, National Safety Council on Alcoholic and Drugs. Senator MORGAN. Were you on the North Carolina Drug Authority? Dr. McB~~y. Yes, I was. We were together. Senator MORGAN. I thought you were. Dr. MCBAY. Propoxyphene lad been the most frequently prescribed analgesic until 1976, when Tylenol with codeine (CIII), and until 1977, when Empirin Compound with codeine (CIII), exceeded it in popularity. It was the second most frequent prescription in 1971 and 1972. It has been reported that 33.5-million prescriptions were dispensed in 1977 containing propoxyphene. In our opinion, the acute adult oral lethal dose is about 12-20, 65-mg. doses, or over 800 mg. In those deaths where the number of prescribed dose.s were reported. the smallest was for 20, 65-mg. capsules, the larg- est 240-more than 20 times the lethal dose. The majority were for 40 or more; 100 or greater was common. Several patients had a refill or a second propoxyphene prescription. The prescription of 120 or more doses was most frequent at Veterans' Administration Hospitals. There is obviously great danger in allowing a patient to have `access to large amounts of this drug. Although we are mainly concerned with deaths resulting from over- doses of this dnig, something should be said `about the value of this drug as an analgesic. If it were a unique and valuable analgesic which was useful where other `analgesics could not. or would not be efficient, then the benefits of this drug might outweigh the costs. Of the many reports on this substance as an analgesic, there are prac- tically no adequately controlled studies which demonstrate a signifi- cantly greater analgesic effect than other analgesics such as aspirin, actaminophen, and codeine; some studies report the drug as not sig- nificantly more efficient than a placebo. I am principally concerned with the toxicity of this drug and the ultimate toxicity that kills people. I would like to state when there is an overdose, and certainly if any- body takes the recommended dose of most drugs, they should not die as a result of taking them. I am sure that people have taken as much as 1~800 mg. or as much as 2,000 mg. of this drug and survived, going into withdrawal if the drug is discontinued abruptly. But I have very little faith in the reported data, but whenever it was reported, and whenever we could track it down. the smallest dose was for about 20, 65-mg. capsules, the largest was for 240, which is more than 20 times the lethal dose. PAGENO="0119" COMPETITIVE~ PROBLRMS IN~ THE DRUG INDUSTRY 16671 The majority with 40 or more, and 100 or greater, was common. In some of the data in the drug abuse warning prescription audits, somewhere around 35 to 40 doses seemed to be the average prescription size. I am not qualifying myself on the efficiency of this drug, but I do have to teach students about this drug, and I can give the relative toxicity without discussing benefits. If it is a very beneficial drug, the chance must be taken the individ- ual will not take an overdose. In the past 5 years in North Carolina, 183 deaths were attributed to propoxyphene, 26 were attributed to salicylates (aspirin), 3 to codeine, and none to acetaminophen. We believe these data are similar to those from the relatively few communities having adequate death investigation systems including toxicology. In our opinion, overdoses from these other drugs which are used more frequently than propoxypl~ene are much safer at least as far as fatalities are concerned. Tl~e most serious problem with dextropropoxyphene is that over~ doses often lead to death. With the advent of better analytical methods, it soon became apparent that deaths were being attributed to this drug. Obviously we do not try to detect it when nobody suspects the drug is causing deaths, so those deaths will not be attributed to the drug. In our laboratory the following numbers of cases were documented: 1970 3 1971 2 1972 21 1973 21 1974 30 1975 50 1976 1977 36 1978 31 Our data is complete for 1978, unless we discover some mistake, it is 31, so there is no question that the deaths are there. In the last 5 years 183 deaths have been reported in North Carolina which has a population of about 5.5 million. It is the 11th most populous State. If the death rate for the entire United States was the same there would be at least 1,200 deaths yearly of discovered deaths for the country in 1978. The reported deaths are those that are discovered. There is no way of ascertaining how many deaths are due to the drug that are not attributed to the drug. Propoxyphene is ranked as third in frequency of occurrence in deaths reported in DAWN VI, which is the Drug Abuse Warning Net- work publication. It is preceded by alcohol in combination and heroin/morphine. In North Carolina and in seven standard metropolitan areas it is a more frequent cause of death than heroin, as it probably is in most of this country. The majority of deaths are suicidal in North Carolina when the manner of death could be determined. Many of the deaths attributed to PAGENO="0120" 16672 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY overdoses of propoxyphene involve other drugs including alcohol and diazepam. In the deaths we have attributed to propoxyphene there was in our opinion, and I am sure Dr. Hudson has read this and agrees with me, there was a sufficient quantity of the drug to cause death in the absence of the other drugs but the other drugs may have been contributory factors in the deaths. Of the 183 deaths attributed to propoxyphene at least 145 or about 80 percent did not have enough alcohol or any other drug that we found to have caused death; in each sufficient propoxyphene to cause death was found, at least in our opinion. In seven cases greater than 20 rng/dl of sahcylate was found. This could come from a propoxyphene-aspirin containing product. Of course, ~e have no way of knowing if somebody takes propoxy- phene alone, or aspirin alone, or they take another product with it. Most of our cases involved deaths of middle-aged individuals and not the younger drug abusers. In fact, I do not recall any deaths in the young abusers, certainly not by injecting the drug. Although propoxyphene was introduced in 1957, it was not until around 1970 that analytical procedures for adequately detecting and measuring it in the relatively low concentrations present in the blood of those fatally poisoned began to be reported. Twelve articles of propoxyphene overdoses published from 1960-70 reported four fatalities. This is in the literature. Eighteen articles published from 1971-75 reported 117 fatalities. A survey published in 1976, reported 1,022 propoxyphene-associated cases in the years 1969 through July 1975. There were only 2 in 1969, 7 in 1970, and 11 in 1971 for a total of 20 cases. And, 1~002 cases were reported for the 31/2 years 1972-July 1975. This survey cove.red a 5-year period and covered `approximately one- fifth of the United States. It was the same areas each year. In the same 9 years, 1970-78 we have discovered 228 fatal overdoses in North Carolina. In spite of greatly improved analytical procedures which allow for the identification and quantification of not only the parent druq pro- poxyphene, but also its longer-lived pha.rmacolo rically active meta.bo- lite, nor-propoxyphene, many laboratories either do not detect the drug or are unable to quantitate it and its metaholite. In establishing that the drug is a cause of death it is essential that about one microgram of propoxyphene be found in a milliter of blood and not be confused with the usually greater concentration of nor- propoxyphene, the metabolite. A therapeutic close of 130 milligrams (two 65-mg doses) of propoxy- Pliene hydrochloride produces concentrations of the order of 0.1 mcg/ ml of blood. This is about one-tenth what we consider a lethal blood concentration. In a national proficiency testing program in 1978. and others are similar, which involved 273 laboratories. 120 laboratories reported that propoxyphene was identified and nor-propoxyphene was identified by 32. PAGENO="0121" COMPETITIVE PROBLEMS IN~ THE DRUG INDUSTRY 16673 Only 67 reported quantitative results for propoxyphene with a range of 0.7-13.0 meg/mi for a serum containing 5 meg/mi and 13 reported a range of 0.3-3.0 meg/mi of nor-pro'poxyphene for a serum containing 2 meg/mt The specimen which contained about five times the lethal concentra- ti'on was identified by about only 44 percent of the laboratories and quanti'taited by about 25 percent with a very wide range of results. This could serve as an evaluation of the state-of-the-art of analysis for the drug in 1978. We infer that many cases are missed because of generalized inade- quacy `of the laboratories. In 1971 when the patent on propoxyphene `hydrochloride expired, propoxyphene napsylate was intrpduced. It was hoped that its lower solubility would prevent poisoning by overdoses, unfortunately we have seen no evidence of this. In 1978 in North Carolina `where 31 deaths were attributed to pro- proxyphene, the trade names were given in the histories on 17 reports. Thirteen ha'd the trade names `of one manufacturer; eight were for a propoxyphene hydrochloride product and six were for `a propoxy- phene napsylate product; one case had both names. Hopefully propoxyphene napsylate would not be absorbed as rapidly and could prevent a large overdose from hitting the patient at one time. Unfortunately, we have seen no evidence of this, and it is hearsay, but it is all we have to go on when the patient is dead. We cannot talk to him. Here we are talking of not only a sole manufacturer or distributor for propoxyphene. There are quite a number, 17 or more, I do not know how many there are. Our attention was attracted' to the drug in 1972 when we applied a specific method of analysis developed in our laboratory to specimens submitted from a number of unexplained deaths. We were not the only ones to have specific methods of analysis at that time. If an adequate method of analysis for the drug had existed, it is interesting to speculate whether overdose deaths would have been detected and if they had, would the use of the drug have been dis- couraged. If propoxyphene were not, legally available, it is our opinion that there would be no incentive to prepare th'e compound or to traffic in this drug for the illicit market. We have been asked to comment on DAWN death data. I have been critical in the past, and I continue to be critical of the data as far as deaths are concerned, and I can comment only on the material made available to us. We do not buy the service. Occasionally I see the material prin'ted in the literature, and occasionally some has been supplied to me. My criticism centers around what appears to be a great deal of the data that is generated on "mentions" of drugs. In our experience drugs, mentioned by emergency room personnel or by medical examiners which we assume have been mentioned by the patient or others may be entirely different from those found by toxico- logical analysis. PAGENO="0122" 16674 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We value this information, but we are not a bit surprised to find some other drug present when the person has died, or indeed when they are in the hospital. We do some work on samples obtained from living patients. As for the medical examiner DAWN data, it is our opinion that it is hopelessly confused in the "drug induced" or "drug related" deaths by naming drugs which may be present but may not be enough to cause death or to be a contributory cause. This is further complicated by allowing a cause of death determi- nation to be supported by factors other than "Toxicological Labora- tory Report" (p. 8, DAWN VI). This goes all the way down to what somebody has said about the drug. The data would be meaningful if it was based on the cause of death as certified by the medical examiner where the determination was based on the finding of a toxicologically significant concentration of substance in the body of the deceased. There indeed, at least the cause of death is a public record and is readily available, even without the Public Information Act, it always has been available to my knowledge. Table 4.7, page 57 of DAWN VI indicates that there were 308 diazepam-induced deaths and 209 codeine-induced deaths. A national survey reported that two deaths of the 1,239 "diazepam- related deaths" surveyed "could be substantiated as deaths resulting from the actions of diazepam and diazepam alone." There were only two of these that could be substantiated. Thus of 1,239 diazepam-related deaths, only two could be substan- tiated to diazepam alone. One of these was in Canada, the other was in the United States. In North Carolina in the past 5 years we have two deaths certified as diazepam deaths and three deaths certified as codeine deaths. We are talking about in our State of a very small number of deaths. Yet a rather large number in the DAWN data is graphically illus- trated in an article where codeine was blamed for "16.6 drug-related deaths per million pills," and as a pharmacist, the last pill I have seen was a digitalis pill, so I use pills in quotes. Propoxyphene was blamed for 1,090 deaths or "1.6 drug-related deaths per million pills." We believe that there were far fewer than 420 codeine deaths, which is the fig~ire given. Using data generated by the same company there were two codeine- containing generic preparations which totaled 1,43L000 prescriptions. Tylenol with codeine was ranked 7th in prescription frequency and Empirin compound with codeine was ranked 14th with Dalmane being ranked 13th. What I am trying to get at, I had to use some published tables, I did not hav~ cli of the data. The DAWN data Projects 12,795~0o0 Dalmane prescriptions. Esti- mating at lea~t 13 million prescriptir~ns for Tylenol with codeine and 10 million for Empirin compound with codeine for a total of about 23 million codeine-containing prescriptinn~ being used in the United States for a year, usin! an estimate of 36 pills per prescription could give a total of 828 million pills or 0.5 deaths per million pills. PAGENO="0123" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16675 Our projections would mean that rather than "16.6 codeine-related deaths per million pills" there would be about 1/30th that number or 0.5. It is our opinion that more than 23 million codeine prescriptions are dispensed and that less than 100 deaths are attributable to codeine. The company that produced the statistics should be able to confirm or correct our estimates. It appears that the deaths related to codeine were attributed to codeine "pills." Most prescriptions for codeine are for tablets of codeine combined with aspirin 01 acetaminophen which were not included but represent about 98 percent of the codeine dispensed. Had this been done in the case of propoxyphene the 1.6 propoxy- phene related deaths per million "pills" would have been about 16. In summary, the DAWN data and interpretations of it make it appear that there are many codeine deaths and that the death rate per million doses is very high and that codeine is about 10 times more lethal than propoxyphene. We find in North Carolina that there are about 75 propoxyphene deaths to 1 codeine death. At least from the major side effect of a drug, it is far less toxic and it is prescribed in great quantities much greater than indeed propoxy- phene is. From the survey it has also been estimated that there are about 880 Valium-related deaths. In our opinion deaths due to Valium are very rare and in our opinion should be 10 or less. In the 1-year interval May 1976 to April 1977, 10 marihuana-related deaths have been estimated. We know of no documented death due to marihuana in the United States at anytime. What I am saying is that projected data gives some rather strange results, and since my colleagues know of no marihuana direct death in the United States at any time, I believe they will support me, yet there is a survey that says with marihuana, there were 10 deaths by projection. Opinions: There are at least 1,200 deaths a year in the United States due to propoxyphene. These are estimated from reported deaths, and in my opinion this is a rather low figure. The majority of these are suicidal overdoses from about 12 or more tablets or capsules obtained by a legal prescription. The average pre- scription is for about 30 dose units. Propoxyphene was present in the majority of our cases in sufficient concentrations to cause death even if the other drugs found were not present. Deaths would have been attributed to the drug earlier and even probably to a greater extent now, even now more frequently if ad- equate toxicological analyses were available. Determination that death is caused by a drug should only be made when sufficient concentration of the drug is found in appropriate speci- mens and no other adequate explanation for death is found. Propoxyphene is a narcotic, opiate, central nervous system depres- sant, analgesic of questionable value. PAGENO="0124" 16676 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Aspirin, acetaminophen, or codeine are much safer and appear to be sufficiently effective. Thank you, sir. Senator NELSON. Thank you very much, Dr. McBay, for your state- ment. Given your scientific judgment of marihuana. I trust that when you get back to Chapel Hill you will be very popular with the students. Anyone have any questions? Mr. STURGES. Mr. Chairman, just for the record, may we note that Dr. Hudson and Dr. McBay wrote to the Drug Enforcement Adminis- tration November 30, 1976. to state that, in their opinion, placing pro- poxyphene on schedule IV was inadequate, and recommending that the drug be placed on schedule II or, at least, schedule III. If possible. can we include this letter of theirs in the record? Senator NELSON. Is that still your position today? Dr. MCBAY. Yes. Dr. HUDSON. Yes. [The letter follows:] OFFIcE OF THE CHIEF MEDICAL EXAMINER, Chapel Hill, MU., November 30, 1976. ADMINISTRATOR, Drug Enforcement Administration, Department of Justice, Washington, D.C. Attention: DEA Federal Register Representative. GENTLEMEN: We object to and protest the placing of dextropropoxyphene in Schedule IV of the Controlled Substances Act. Our studies and others indicate that deXtropropoxyphene is directly responsible for more deaths in the United States than any other prescription item, even the barbiturates collectively. (1-4, 10) It probably takes more lives than any single chemical except alcohol. Our conservative estimate is 1000 propoxyphene deaths; 2000 annually may be much closer to the truth. This is exceptionally ironic since its efficiency as an analgesic has been reported as less than that of aspirin. (5, 11) We grant that most of these deaths are suicides but suggest that in the susceptible the likelihood of attempt increases with availability of means. Classical drug abuse with propoxyphene has long been described in the medical literature. We note also the close similarity in chemical structure that dextropropoxyphene bears to methadone, a habituating narcotic. Absurdity is heaped upon absurdity with Schedule IV placement of propoxy- phene when codeine is in Schedule II. There may be abuse potential for codeine but the evidence is scant. In our combined experience with living patients and with death cases and as consultants to law enforcement agencies, we recall en- countering no codeine abusers and no codeine deaths. This was true also before "scheduling" of drugs. In our opinion abuse of dextropropoxyphene may lead to greater physical and psychological dependence than does codeine. (6-8) It is difficult for us to believe that dextropropoxyphene has a lower potential for abuse than does phenobarbital in Schedule III. We could cite other incongruities. We have been in direct communication with officials of Eli Lilly & Company, principal marketers of dextropropoxyphene. Their public comments relative to dextropropoxyphene deaths being primarily alcohol and mixed drug problems and to being a "regional phenomenon" are to us specious and self-serving. Admittedly there has been only relatively recently d°velopment of good chemi- cal methods to detect dextropropoxyphene poisoning. This, added to the general lack of adequate death investigation systems in this country has contributed to a late recognition of deaths due to America's most popular analresic prescription drug. We wonder if reticence to admit a mistake contributes to scheduling the drug no higher than Schedule IV. (0) We also speculate that if this drug had just been created, it would not be licensed by the F.D.A. because of its lack of effec- tiveness. PAGENO="0125" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16677 Individually and collectively we sincerely believe, on the basis of our profes- sional experience, that dextropropoxyPhene should at least be placed in Schedule III to minimize its use and abuse, but preferably placed in Schedule II with the hope that its use would be greatly discouraged. Yours truly, PAGE HUDSON, M.D., Chief Medical Examiner. ARTHUR J. MCBAY, Pb. D., Chief Toxicologist. Senator NELSON. We thank you very much for your testimony, Dr. McBay. Dr. MCBAY. Thank you. [The prepared statement of Dr. McBay follows:] STATEMENT BY ARTHUR J. MCBAY, PH. D., CHIEF TOxIcOLOGIsT, OFFICE OF THE CHIr~s' MEDICAL EXAMINER, PROFESSOR OF PATHOLOGY AND PHARMACY, UNIVER- SITY OF NORTH CAROLINA, CHAPEL HILL, N.C. My appearance here is with the permission of the North Carolina Division of Health Services and the Chief Medical Examiner; however the opinions I volun- teer are my own as a private citizen :and do not represent an official stance or policy of the state of North Carolina. Propoxyphene had been the most frequently prescribed analgesic until 1976 when Tylenol with codeine (CIII), and until 1977 when Empirin Compound with Codeine (CIII), exceeded it in popularity (1). It was the second most frequent prescription in 1971 and 1972. It has been reported that 33.5 million prescriptions were dispensed in 1977 containing propoxyphene. In our opinion the acute adult oral lethal dose is about 12-20 65-mg doses or over 800 mg. In those deaths where the number of prescribed doses were reported, the smallest was for 20, 65-mg capsules, the largest 240 (more than 20 times the lethal dose). The majority were for 40 or more; 100 or greater was common. Several patients had a refill or a second propoxyphene prescription. The prescription of 120 or more doses was most frequent at Veteran Adminis- tration Hospital (2). There is obviously great danger in allowing a patient to have access to large amounts of this drug. Although we are mainly concerned with deaths resulting from overdoses of this drug, something should be saidabout the value of this drug as an analgesic. If it were a unique and valuable analgesic which was useful where other anal- gesics could not or would not be efficient, then the benefits of this drug might outweigh the costs. Of the many reports of this substance as an analgesic, there are practically no adequately controlled studies which demonstrate a significantly greater analgesic effect than other analgesics such as aspirin, actaminophen and codeine; some studies report the drug as not significantly more efficient than a placebo. In the past 5 years jn North Carolina 183 deaths were attributed to propoxy- phene, 26 were attributed to salicylates (aspirin), 3 to codeine and none to ace- taminophen. We believe these data are similar to those from the relatively few communities having adequate death investigation systems including toxicology. In our opinion overdoses from these other drugs which are used more frequently than propoxyphene are much safer at least as far as fatalities are concerned. The most serious problem with dextropropoxyphene is that overdoses often lead to death. With the advent of better analytical methods it soon became appar- ent that deaths were being attributed to this drug. In our laboratory the following numbers of cases were documented: 1070-3. 1971-2, 1972-21, 1973-21, 1974-30, 1975-.~0. 1971i-34. 1977-36. 1978-31. In the last .~ years 183 deaths have been re- ported in North Carolina which as a population of about 5.5 million. If the death rate for the entire United States was the same there would he at least 1200 deaths yearly. The reported deaths are those that are discovered. There is no way ascertaining how many deaths are due to the drug that are not attributed to the drug. Propoxvphene is ranked as third in frequency of occurrence in deaths reported in DAWN VI. It is ureceded by alcohol in combination and heorin/morphine. In North Carolina and in 7 standard metropolitan areas it is a more frequent cause of death than "heroin", as it probably is in most of this country. PAGENO="0126" 16678 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The majority of deaths are suicidal in North Carolina when the manner of death could be determined (2). Many of the deaths attributed to overdoses of pro- poxyphene involve other drugs including alcohol and diazepam. In the deaths we have attributed to propoxyphené there was in our opinion a sufficient quantity of the drug to cause death in the absence of the other drugs but the other drugs may have been contributory factors in the deaths. Of the 183 deaths attributed to propoxyphene at least 145 or about 80% did not have enough alcohol or other drug to have caused death: in each sufficient propoxyphene to cause death was found. In 7 cases greater than 20 mg/dl of salicylate was found. This could come from a propoxyphene-aspirin containing product. Most of our cases involved deaths of middle-aged individuals and not the younger drug abusers. Although propoxyphene was introduced in 1957. it wasn't until around 1970 that analytical procedures for adequately detecting and measuring it in the rela- tively low concentrations present in the blood of those fatally poisoned began to be reported. Twelve articles (3) on pror)oxyphene overdoses published from 1960-1970 reported 4 fatalities. Eighteen articles (3) published from 1971-1975 reported 117 fatalities. A survey published in 1976 (4), reported 1022 propoxy- phene-a.ssociated cases in the years 1969 through July 1975. There were only 2 in 1969, 7 in 1970, and 11 in 1971 for a total of 20 cases; 1002 cases were reported for the 3~/2 years 1972-July 1975. In the same nine years, 1970-1978 we have dis- covered 228 fatal overdoses in North Carolina. In spite of greatly improved analy- tical procedures which allow for the identification and quantitatión of not only the parent drug propoxyphene but also its longer-lived pharmacologically-active metabolite, norpropoxyphene, many laboratories either do not detect the drug or are unal)le to quantitate it and its metabolite. In establishing that the drug is a cause of death it is essential that about 1 microgram of propoxyphene he found in a milliliter of blood and not be confused with the usually greater concentration of norporpoxyphene. A therapeutic dose of 130 mg (2 65-mg doses) of propoxyphene hydrochloride produces concentrations of the order of 0.1 meg/mi of blood. This is about one-tenth what we consider a lethal blood concentration. In a national proficiency testing program in 1978 which involved 273 labora- tories. 120 laboratories reported that propoxyphene w-as identified and norpro- poxyphene was identified by 32. Only 67 reported quantitative results for pro- poxyphene with a rane of 0.7-13.0 meg/mi for a serum containing 5 meg/mi and 13 reported a range of 0.3-3.0 meg/mi of riorpropoxyphene for a serum containing 2 meg/mi. The specimen which contained about five times the lethal concentration was identified by about only 44% of the laboratories and quantitated by about 25% w-ith a very wide range of results. This could serve as an evaluation of the state of the art of analysis for the drug in 1978. We infer that many cases are missed because of generalized inadequacy of the laboratories. In 1971 when the patent on propoxyphene expired. propoxyphene napsylate was introduced. It was hoped that its lower soiubiiity would prevent poisoning of overdoses, unfortunately we have seen no evidence of this. Tn 1978 in North Caro- lina where 31 deaths were attributed to propoxynhene. the tradenames were iriven in the histories on 17 reports. Thirteen had the traclenames of one manu- facturer: 8 were for a propoxyphene hydrochloride product and 6 were for a propoxyphene napsylate product (one ease had both named). Our attention w-as attracted to the drug in 1972 when we applied a specific method of analysis developed in our laboratory to specimens submitted from a number of unexplained deaths. If an adequate method of analysis for the drug had existed in 1957. it is interesting to speculate whether overdose deaths would have been detected and if they had. would the use of the drug have been dis- couraged. If propoxyphene were not legally available, it is our oninion that there would he no incentive to prepare the compound or to traffic in this drug for the illicit market. REFERENCES (1) Pharmacy Times. April 1973. 4. 5. 6. 7. (2) Hudson, P.. l3arringer, M.. and McBay. A. J.. Fatal Poisoning with Pro- poxyphene: Report from 100 Consecutive rases.. S. Med. J.. 70: 938-942. 1977. (3) Miller, R. R.. Propoxvphene: A Review., Am. J. Hosp. Pharm., 34: 413-423, 1977. (~`) Finkle. B. S.. McClo~key. K. L.. Kiplinirer. G. F.. and Bennett. I. V. A National Assessment of Propoxvphene in Postmortem Medicolegal Investigation. 1972-1975.. J. Forensic Sci.. 21: 706-742. 1976. PAGENO="0127" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16679 (5) College of American Pathologists 1977 Special Toxicology Set T-C Labora- tory Survey Specimen T-14. DAWN DEATH DATA We have been asked to comment oii DAWN death data. (1) We can only coin- ment on material available to us. It appears that a great deal of the data is gen- erated on "mentions" of drugs. In our experience drugs mentioned by emergency room personnel or by medical examiners which we assume have been mentioned by the patient or others may be entirely different from those found by toxicolog- ical analysis. As for the medical examiner DAWN data, it is our opinion that it is hopelessly confused in the "Drug Induced" or "Drug-Related deaths by naming drugs which may be present but may not be enough to cause death or to be a contributory cause. This is further complicated by allowing a Cause of Death Determination to be supported by factors other than "Toxicological Lab. Report" (p. S DAWN VI). The data would be meaningful if it was based on the cause of death as certified by the medical examiner where the determination was based on the finding of a toxicologically significant concentration of substance in the body of the deceased. Table 4.7 page 57 of DAWN VI indicates that there were 308 diazepam-induced deaths and 209 codeine-induced deaths. A national survey reported that 2 deaths of the 1239 "diazepam-related deaths" surveyed "could be substantiated as deaths resulting from the actions of diazepam and diazepam mt'one.' (2) One of these was in Canada, time other was in the United States. In North Carolina in the past 5 years we have 2 deaths certified as diazepam deaths and 3 deaths certified as codeine deaths. Another problem with the DAWN data is graphically illustrated in an article where codeine was blamed for "16.6 Drug-Related Deaths per Million pills" and propoxyphene was blamed for 1090 deaths or "1.6 i)rug Related per Million pills." (3) We believe that there were far fewer than 420 codeine deaths. Using data generated by the same company there were 2 codeine-containing generic prepara- tions w-hich totaled 1,431,000 prescriptions. (4) Tylenol with codeine was ranked seventh in prescription frequency and Empirin compound with Codeine was ranked 14 with Dalmane being ranked 13. The DAWN data projects 12,795,000 Dalmane prescriptions. Estimating at least 13 million prescriptions for Tylenol with codeine and 10 million for Empirin Compound with Codeine for a total of 23 million codeine-containing prescriptions, using an estimate of 36 pills per prescription would give a total of 828 million pills or 0.5 deaths per million pills. Our projections would mean that rather than "16.6 codeine-related deaths per million pills" there would be about 1/30th that number or 0.5. It is our opinion that more than 23 million codeine prescriptions are dispensed and that less than 100 deaths are attributable to codeine. The company that produced the statistics should be able to confirm or correct our estimates. It appears that the deaths related to codeine were attributed to codeine "pills." Most prescriptions for codeine are for tablets of codeine combined with aspirin or acetaminophen which were not included but represent about 98 percent of the codeine dispensed. Had this: been done in the case of propoxyphene the 1.6 propoxyphene related deaths per million "pills" would have been about 16. In summary the DAWN data and interpretations of it make it appear that there are many codeine deaths and that the death rate per million doses is very high and that codeine is about 10 times more lethal than propoxyphene. We find in North Carolina that there are about 75 propoxyphene deaths to one codeine death. From the survey it has also been estimated that there are about 880 "Valium" related deaths. In our opinion deaths due to Valium are very rare and in our opinion should be 10 or less. In the one year interval May 1976 to April 1977, 10 marihuana related deaths have been estimated. We know of no documented death due to marihuana in the United States at anytime. REFERENCES (1) Project Dawn VI, May 1977-April 1978, I.M.S. American Ltd. Ambler PA. (2) Finkle, B. S. and i~IcCloskey, K. L., The Role of Diazepam in Postmortem Medico-Legal Investigation-Center for Human Toxicology-Salt Lake City, Utah. November 1977. (3) DAWN Data-Drug Related Deaths Tallied, U.S. Journal of Drug and Alcohol Dependence 2 :2, April 1978. (4) 1977 Top 200 Drugs. Pharmacy Times, p. 41-48, April 1978. PAGENO="0128" 16680 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY OPINIONS There are at least 1,200 deaths a year in the United States due to propoxyphene. The majority of these are suicidal overdoses from about 12 or more tablets or capsules obtained by a legal prescription. The average prescription is for about 30 dose units. Propoxyphene was present in the majority of our cases in sufficient concen- trations to cause death even if the other drugs found were not present. Deaths would have been attributed to the drug earlier and even now more frequently if adequate toxicological analyses were available. Determination that death is caused by a drug should only be made when suffi- cient concentration of the drug is found in appropriate specimens and no other adequate explanation for death is found. Propoxyphene is a narcotic, opiate, central nervous system depressant, anal- gesic of questionable value. Aspirin, acetaminophen or codeine are much safer and appear to be sufficiently effective. Senator NELSON. Our next witness is Dr. Larry V. Lewman, forensic pathologist, Multnornah County, Oreg., medical examiner. You are last on the panel. I am sorry you had to wait so long. STATEMENT OF LARRY V. LEWMAN, M.D., FORENSIC PATHOLOGIST, MULTNOMAH COUNTY, OREG., MEDICAL EXAMINER Dr. LEWMAN. My name is Larry V. Lewman; I am a physician; my specialty field of practice is forensic pathology. My current responsibility is to investigate unexplained deaths throughout the State of Oregon, under the Oregon State Medical Examiner's Law. I am Board certified in both anatomic and forensic pathology and my training, duties, and responsibilities similar to Dr. Hudson's. The State of Oregon has experience, since the mid-1970's, an increase in propoxyphene deaths that could best be characterized as alarming. It is now the No. 1 cause of drug overdose death in the State of Oregon and has been for the last 3 years. During the past 3 years, propoxyphene deaths have equaled or ex- ceeded the combined total of deaths from barbiturates and heroin. The largest number of deaths attributed to this drug was 39 from July 1977 to July 1978. There is a population of approximately 2 million in Oregon, and this represents an incidence rate of about 2 per 100,000 population. The figure by itself does not mean much, unless you compare it with something. I will compare it with the homicide rate as everybody un- derstands murder. Depending where you go in the State of Oregon; the rural com- munities or the city of Portland, the rate of death from propoxyphene varies from between one-third to a little less than one-half the homicide rate. Slightly less than half as many people die from propoxyphene as die from homicidal violence. Our statistics are, I think, as accurate as any in the country and far more accurate than most. WTe have a Statewide medical examiner system. These deaths are investigated by physicians, and are under the statewide control of two forensic pathologists. We have a toxicology setup that is as good as any on the west coast or in the country for that matter, to chemically analyze autopsy specimens. PAGENO="0129" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16681 Manner of death simply means accident, suicide, homicide, undeter- mined, that is, we do not know. The breakdown of these deaths in our State: About 60 percent I believe are accidental, the other 40 percent are about equally divided between suicides and undetermined. If I thought most of these deaths were suicides, I would not be here beating on the table. I do not think they are. Obviously, a person bent on destroying himself can take an overdose of almost anything. Barbiturates remain the most common drug overdose suicide in the State; about 20 percent of propoxyphene deaths are so ruled. This, I realize, conflicts with the large survey of propoxyphene deaths, done by the Finkle-McCloskey group in Utah. Finkle stated 45 percent of these are suicides. I think their data is inaccurate, and I think it is inaccurate because the toxicology is incom- plete. Dr. Wolfe stated in his testimony: that in only 22 of the 1,022 cases surveyed by Finkle were nor-propoxyphene levels determined. We find the propoxyphene/nor-propoxyphene ratio vitally impor- tant in making the distinction between suicide and accident. The majority of the propoxyphene overdoses in the State fall in the accidental category. I believe about 60 percent are accidental deaths. Certainly some of the 20 percent ruled undetermined would also fall into the accidental category. Of these, the majority (about 60 percent), involved propoxyphene and its metabolite as the only significant drug detected. The other 40 percent of accidental deaths are attributed to the com- bined effects of propoxyphene and another agent, usually alcohol or Valium (diazepam). The background history of these drug abusers runs the gamut of the socioeconomic spectrum. I think generally you can characterize them as low middle class to middle class. Most of them are middle age to young middle age, 20's to 30's, we find a slight male bias. Some of them have become addicted to the drug, while taking it for legitimate pain problems, such as on-the-job injury or a postsurgical complication of some sort. Others have become addicted while taking the drug for its euphoric effect or psychosomatic pain. Generally, these people do have an unstable mental history, alco- holism, multiple drug abuse, psychiat.ric hospitalization, and so forth. For the most part, these are not the illicit drug abusers; not the street users of heroin. The source of the medication in most of our deaths was legitimate physician prescription. Rarely did we find that the patient was run- ning around to different doctors, and different pharmacies to hide his abuse. Why? He does not need to. Propoxyphene is a s~hedule IV medication under the Comprehen- sive Drug Abuse Prevention and Control Act. The prescription can be refilled up to five times in a 6-month period without the physician being further consulted. 40-2240-79-9 PAGENO="0130" 16682 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. The prescription would include how many tablets? Dr. LEWMAN. It is not limited to my knowledge. Senator NELSON. So then you are saying the doctor may give a pre- scription which may be renewed five times, with the doctor deciding how many tablets would be included in each prescription? Dr. LEWMAN. That is right, and have no knowledge of when or if it is refilled. We have 30 to 34 million prescriptions a year for this drug that can potentially be refilled lip to five times. That I submit has a potential for a lot of abuse. Why do I think most of these deaths are accidental? First. I want to state I have not seen a case of anybody dying from this drug when it is taken as recommended. The real nitty-gritty of t.his problem, I think, is that these are accidental deaths, and this re- sults from the breakdown product of the drug. After propoxyphene is taken, it is broken by the liver, into a series of compounds, which we will refer to as metabolites, or breakdown products, and the most significant of these is nor-propoxvphene. Nor-propoxyphene is significant because of its long half-life. It has about a 40-hour half-life. The parent drug, propoxvphene. has a life of about 8. 10, 12 hours. If a patient has taken several of these pills every 4 to 6 hours, the. parent drug (propoxyphene' is being rapidly broken down. The nor-propoxvphene metabolite. however, is accumu- lating for almost 2 days and eventually can reach toxic or lethal levels. The metabolite problem is not addressed in the package insert data and there is a minimum amount of information in the literature. I am certain that prescribing physicians and the patients taking it are unaware of the significance of this toxic metabolite. I do not think the propoxyphene deaths, in fact, I am sure they are not unique to the State of Oregon. I will echo Dr. McBav's and Dr. Hudson's comments about Valium deaths and codeine deaths. I have seen a handful of codeine deaths. I have never seen an over- dose of Valium alone in years of investigating drug deaths. I am sure it could happen. but I ha.ve not seen one. I feel the data is wrong in that respect but I think the most signifi- cant thing about the DAWN data. is that it does not reflect the ma- joritv of the country. We have to remember that death investigation systems, in most States in this country, rema.in in an abysmal state. In many States of this country, you still have, an elected coroner system, which means you have funeral directors. gas jockeys, police officers, district attorneys, and so forth, anyone that can get 50 per- cent of the votes plus one, running around investigating deaths. These people are~ simply not trained, they do not have t.he investiga- tive background, they do not have the technical apparatus to . accur- ately diagnose and report these deaths. It is a complex investigational problem, and much of the country is simply not yet adequate to the task. All I can do is estimate. I think we probably have 3.000 to 4,000 propoxyphene deaths in the United States every year. I arrive at this figure by simple taking the statistics from the good sound death in- PAGENO="0131" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16683 vestigation systems such as North Carolina and Oregon statewide, and local systems such as San Francisco, Phoenix, and Dallas. Apply our incidence figures nationwide and you probably have 3,000 to 4,000 deaths annually. EDUCATION HAS DECREASED THESE DEAThS IN OREGON Last year during April we had eight propoxyphene deaths in a period of 2 weeks in the Portland area alone. This led to a media blitz. I appeared on television several times. So did my partner. Editorials were printed in the newspapers, locally and statewide. Information was disseminated to physicians through- out the State and the numbers have dropped drastically. From July 1977 to January 1978; we had 18 propoxyphene deaths. From January to July 1978 we had 21. After this media blitz, we had eight in the last half of the year. I think we have demonstrated that education of the physicians and the public can decrease these deaths, but I view this as a temporary reduction. I might add that I am frustrated on the Federal level. I am not here to cast stones at Eli Lilly. I have found they have shown more interest `and concern about the problem than the FDA. I wrote to the FDA, May of last year. I have not as yet received an acknowledgment of my letter. I do not think the mail is that slow. MY RECOMMENDATIONS I am not addressing myself to banning this medication. I think that there has to be a balance between the therapeutic benefit and the obvious danger. Depending on which study you read, it is less than, equal to, or better than aspirin. I do not intend to address myself to that problem, I think it has already been adequately covered. I do, however, firmly and unequivocably recommend propoxyphene be transferred to a schedule II drug under the Controlled Substances Act. The case for this to me is absolutely irrefutable. It is an uncon- trolled narcotic. It has the abuse potential of a narcotic, the with- drawal symptoms of a narcotic, and the addiction problem of a narcotic. In every sense of the wOrd, it is a narcotic. And yet if you look already at schedule II narcotic preparations such as codeine, demerol, dilaudid, deaths from propoxyphene outnumber deaths from these other narcotics by a factor of multiple times; no comparison. Transferring propoxyphene ~to schedule II would go a long way toward alerting physicians and patients alike to its dangers; it would at least somewhat prevent the indiscriminate refilling; it would re- quire written prescriptions and place strict controls over the manu- facture and distribution of this,' drug. SUMMARY I think this is probably the No. 1 cause of prescription drug over- dose in the United States today. It is unquestionably the No. 1 cause of prescription drug overdose in Oregon by a wide margin. PAGENO="0132" 16684 COMPETITWE PROBLEMS IN THE DRUG INDUSTRY By this time tomorrow, 10 more ilLS, citizens will have died from propoxyphene overdose and most of these will have been preventable accidents. I think the time has come to put a stop to it. Thank you. Senator NELSON. So it is your conclusion after looking at what you conclude to be the best statistical evaluations-in North Carolina, Sai~ Francisco, and Oregon-that in fact a substantial percentage, a major- ity of deaths, are accidental and not intentional? Dr. LEWMAX. I believe they are in my jurisdiction. Dr. Hudson apparently does not think so. We have not compared toxicological data. In my cases: First we look at the background history of the patient, is there an empty bottle of pills filled 2 hours ago or is there not. The toxicologic data is very significant. We find a high nor-propoxy- phene/propoxyphene ratio and low stomach (gastric) totals in ac- cidental cases. If we look at the suicide cases, we find a large amount of propoxyphene in the stomach. This indicates the individual has ingested a large amount of medication at once. In suicide cases, we find a higher ratio of propoxyphene to nor- propoxyphene. So I do not reach this conclusion just on toxicology, but on the entire spectrum of the investigation of the death. Senator NELSON. Do you see any inconsistency in having methadone listed on schedule II and propoxyphene not? Dr. LEWMAN. Oh, absolutely. I think I have had two cases of methadone deaths in the last year. You can say this about any of the narcotics in schedule II. Propoxy- phene is hands down by a multiple of several times more common as a cause of drug overdose death than any of them. Senator NELSON. And how is propcxyphene related to methadone? Dr. LEWMAN. It is chemically very similar. I could not draw the structure. Dr. McBay could probably ad- dress himself to that question better than I. They are chemically very similar. They are both narcotics. Senator NELSON. Thank you very much for your testimony. We appreciate the time that all of you have taken from your busy work to come here to testify on this important subject, and if you have any additional material you wish to submit, the record will be open for another 2 weeks. Senator LEVIN. Mr. Chairman, I wonder in that regard, if we could have comments, either now briefly or in writing, as to your duty and responsibility of your profession, I gather in future hear- ings we will be hearing from Lilly as to their defense, and so forth, but one of the most striking things in the hearings this morning is apparently the inadequacy of the professional defense that is per- ceived by the four obviously qualified people is a problem. I know this is not the purpose of the hearing, whether we could have some thought addressed to that, I think the first line of defe.nse probably is the profession against this kind of problem, the Govern- ment is slow to act, and I am just wondering if there are any brief thoughts, it is kind of late for this, but perhaps later in writing, you gentlemen could give us some brief thoughts. Senator NELSON. Fine. PAGENO="0133" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16685 Anybody wish to comment on it at : this moment? Senator LEVIN. To put it more sharply, are your views shared by your colleagues, in your various areas of expertise, who have had the kind of background that you have had and done this kind of re- search that you have done? Dr. LEWMAN. In the field of forensic pathology, yes. Dr. MOERTEL. I think in the field of clinical pharmacology, my views are shared by those knowledgeable in research studies of analgesics. I do feel that there. is a problem in education, and I wish I knew the answer to that, Senator. I think it is very important but the problem is that as we survey the physicians who prescribe drugs, we find that. most of their edu- cation is achieved through the drug companies themselves, the detail man being the most effective educator. When w~ get to the other education media, they really do not have as strong an impact on the physician as we would like them to have. I agree there is a problem here. How you address the problem I think is very difficult. I do not know the answer to that. Dr. HUDSON. To the same point, between the efficacy of drugs, and the frequency with which they are used, it is not very good. There are some drugs that are not so popular, and others that are, and we are talking about what has beeh referred to as part of ad- vertising, and partly of whatever it is that captures people's imagina- tion as far as things inducing them to purchase or to prescribe medication. Senator NELSON. Your observations in response to Senator Levin's question are the same as the responses we have gotten over a period of 11 years from distinguished pharmacologists who have been asked that kind of question, and the same as the findings of various studies that have been done respecting the prescribing practices of physicians. Thank you very much. I appreciate your taking the time to testify. Dr. LEWMAN. Thank you. [The prepared statement of Dr. Lewman follows:] STATEMENT OF LARRY V. LEWMAN, M.D., FORENSIC PATHOLOGIST, MULTNOMAH COUNTY, OREG., MEDICAL EXAMINER PROPOXYPHENE-RELATED DEATHS IN OREGON HISTORY OF PROPOXYPHENE-RELATED DEATHS IN OREGON There has been an alarming increase in the nnmber of propoxyphene-related deaths in the state of Oregoa since the mid-1970's. Propoxyphene was by far the number one cause of fatal drug overdose in the state during 1976, 1977 and 1978; and the numbers have been on the increase until the latter half of 1978. The statistical increase is best reflected by comparison with the other most com- mon agents causing drug overdose deaths, namely barbiturates and intravenous narcotics (heroin). During 1975, propoxyphene-related deaths approximately equalled deaths from the barbiturate group, and deaths from intravenous nar- cotics outdistanced both by a factor of about. 1.5 to 1. During 1976 and 1977, propoxyphene deaths approximately equalled the combined total of narcotics and barbiturate deaths during both years. The computer print-out for 1978 has not yet been completed, but it is my impression that propoxyphene-related deaths exceeded the combined totals of narcotics and barbiturate deaths by a wide margin this past year. PAGENO="0134" 16686 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THE NUMBERS IN PERSPECTIVE The largest number of propoxyphene-related deaths in any year in Oregon was thirty-nine (39), occurring during fiscal July 1977 to 1978. The population of the state is approximately 2,000,000 representing an incidence rate of 2 per 100,000 population. This is approximately one-third the homicide rate for the state. 1\Iultnomah Couuty includes the city of Portland and is the state's largest metro- politan area. The incidence of fatal propoxyphene abuse in Multnomah County is greater than the state at large. During tl1e July 19~7 to July 1978 year, almost one-half as many individuals died propoxyphene-related deaths as succumbed to homicidal violence. DEATH INVESTIGATION ~N OREGON Oregon has a state-wide Medical Examiner System responsible for the investi- gation of violent and unexplained deaths throughout the state. This is in contra- distinction to states retaining an elective coroner system in which frequently unqualified and untrained individuals are responsible for directing the death investigation program in an individual county. Each Oregon county has an appointed trained physician responsible for the investigation of violent and unexplained deaths in that county. The program is under the state-wide control of two Board Certified Forensic Pathalogists in Portland. All Medical Examiner cases are reviewed by one of the state pathologists. Suspected drug-related deaths fall under the State Medical Examiner's Law and must be investigated by the physician-medical examiner in charge. This is true whether the death occurs at home or in a hospital. The medical examiner or his trained deputy visits the death scene, obtains a history, seizes medication and backchecks prescription dates, number of pills, etc., with the prescribing physician and the pharmacy. A complete postmortem examination is conducted by a certified pathologist and body tissues and fluids obtained for toxicologic analysis. Drug analyses are done by the Department of Toxicology at the University of Oregon Medical School, under the direction of Dr. Jack Aitchison, a Forensic Toxicologist. The laboratory is equipped with the most advanced instrumenta- tion, including a gas chromatograph/mass spectrograph set-up. Only a handful of laboratories on the west coast possess this degree of sophisticated instrumentation. Following the completion of the background investigation, autopsy and toxi- cology studies, the medical examiner comes to a conclusion about the cause and manner of death and signs the death certificate. SUICIDE, ACCIDENT OR UNDETERMINED? Most fatal propoxyphene overdoses fall into three categories, and I will dis cuss each briefly in light of my experience as a Forensic Pathologist and Medical E~aminer in Oregon. S~icidcs.-Obviously, a person bent on destroying himself can take an over- dose of almost anything. The short-acting barbiturates remain the drugs of choice in most suicides in Oregon, and deliberate self-destruction by propoxyphene is not common. I realize this conflicts with the Journal of Forensic Sciences article, Volume 21, No. 4 by Finkle-McCloskey, et al., in which they surveyed Iropoxyphene deaths from several jurisdictions and concluded that approximately 45 percent of these overdoses were of suicidal manner. I believe this conclusion is inaccurate because of incomplete toxicologic data. Propoxyphene is broken down to norpropoxyphene by the liver. The authors surveyed one thousand twenty-two (1,022) propoxyphene-related deaths, and the concentration of nor- propoxyphene in the tissues was determined in only twenty-two. Experience in Oregon suggests that the relative concentrations of norpropoxyphene and propoxyphene in the tissues is of vital importance in distinguishing between suicidal and accidental manner of death. Between 20 and 25 percent of propoxy- phene-related deaths are considered suicides. An approximately equal percentage of propoxyphene-related deaths were signed as "manner undetermined." This simply means that following thorough investigation, autopsy and toxicologic examination, the medical examiner was unable to determine whether the death represented an intentional act or an accidental overdose. PAGENO="0135" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16687 Propoxyphene in combination with other compounds.-As in most studies, pro- poxyphene-related deaths in Oregon commonly involve other compounds, most commonly ethanol, diazepnm, and a wide variety of others. When it is felt that another chemical agent contributed along with propoxyphene to the death, the death is attributed to the combined effects of propoxyphene and the other agent or agents, and is so indicated on the death certificate. If propoxyphene is the only drug detected in significant quantities and other agents are either absent or felt to be insignificant in their concentrations, death is attributed to propoxy- phene alone. Of the propoxyphene-related deaths ruled either accidental or undetermined manner, approximately 60% represented deaths from propoxyphene alone. The remaining 40% resulted from the combined effects of propoxyphene and other agents, most commonly ethanol or diazepam (Valium). Accidental overdoses of propocvyphene.-~It is this category into which most of the propoxyphene overdoses in Oregon appear to fall. About two-thirds (2/3's) of propoxyphene-related deaths are determined to be accidental. Of these, the majority involve propoxyphene and its metabolite as the only significant com- pounds detected on thorough toxicologic screening. BACKGROUND HISTORY OF ABUSERS The cases in Oregon run the gamut of the sociologic and socioeconomic spec- trum. Most involve deaths of individuals, in their 20's or 30's with a slight male bias. A few were offspring or spouse of physicians and professionals; some be- come clearly addicted to the medication while using it for a legitimate variety of pain problems such as on-the-job injury or surgical complications. Others became addicted while using the drug for pain of psychosomatic origin or for its euphoric effect. In the majority of instances, exaaiination of the individuals' background elicited an unstable mental history and, in many cases, a pattern of multiple drug abuse, psychiatric hospitalization, alcoholism, and the like. A few has a history of in- travenous narcotism at some time during their life. For the most part, however, propoxyphene abusers are not the illicit drug abusers prone to use heroin or `street drugs." SOURCE OF MEDICATION In the large majority of cases, propoxyphene was obtained by legitimate phy- sician prescription. Eli Lilly's Darvon products were the medications most ofter~ obtained. In a few instances, deceased individuals obtained drugs from different physicians and frequented different pharmacies in an attempt to hide their abuse. More commonly, the drug was obtained from a single physician and a single pharmacy. We should remember that propoxyphene is a Schedule IV medication under the Comprehensive Drug Abuse: Prevention and Control Act of 1970. This enables the patient to refill an oral prescription up to five times during a six-month period without the knowledge of his physician. Illicitly-manufactured propoxyphene is not a significant problem in Oregon. It is rare that the source of the drug was an "on the street" purchase. Commercial bottles or propoxyphene were discovered in a handful of cases and were likely obtained in pharmacy burglaries. In each of these instances, the deceased in- dividual has a strong history of multiple drug abuse and usually a heroin habit. WHY THE ALARMING NUMBER OF ACCIDENTAL DEATHS FROM THIS DRUG? It should be noted that I have yet to see a case of accidental death from this drug when taken as recommended, i.e., 65-100 mg every 4-6 hours. In every in- stance, the deceased has taken more than the recommended amount of medica- tion, though the repetitive nature in: which it is taken prohibits me answering the question "How much is too much?" In my opinion, these accidental deaths result not from propoxyphene itself, but from its metabolic breakdown product. Propoxyphene is broken down tQa variety of compounds by the liver, the most significant of which is nor-propoxy- phene. The crux of the problem is the largely-unrecognized toxicity of the nor- propoxyphene metabolite and its prolonged retention in the body. Finkle's study alluded to the fact that nor-propoxyphene may be toxicologically more important in many cases than the parent drug. In Finkle's survey, the level of nor-propoxy- phene was determined in a miniscule percentage of cases, and the authors cited PAGENO="0136" 16688 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the lack of nor-propoxyphene toxicity data as a problem in analyzing the effects of this drug. Nor-propoxyphene is toxicologically significant because of its prolonged reten- tion. Nor-propoxyphene has a half-life in the body of about 38-40 hours. This is between three and four times the half-life of the parent drug, propoxyphene. As the patient takes the drug every few hours, the desired effect, whether it be euphoria or pain relief, is dissipated in the first several hours. The propoxy- phene is being rapidly metabolized while the toxic nor-propoxyphene metabolite is constantly building up because of its long half-life. Accidental propoxyphene overdoses in Oregon consistently reflect nor-propoxy- phene levels between 2-10 times propoxyphene levels. In accidental deaths, total gastric (stomach content) levels are generally low, indicating that a large amount of drug was probably not ingested at once. These results are in contra- distinction to the suicide case in which we find higher blood propoxyphene/nor- propoxyphene ratios and a large amount of propoxyphene in the stomach. REPORTED DEATHS ARE A SMALL PERCENTAGE Large numbers of propoxyphene deaths are not unique to the state of Oregon in 1978. There is no question in my mind that the 589 propoxyphene-related deaths reported through the DAWN network in 1971 represents but a small percentage of the deaths from this drug nationwide. It should be recognized that medical-legal death investigation systems in most states in this country remain in an abysmal state. Many states and communities still operate under an elected coroner system which results in a wide variety of untrained individuals attempting to investigate all types of unexplained death. For example: In one neighboring state, elected coroners include a newspaper editor, funeral directors, ambulance attendants and prosecuting attorneys. Each of these individuals is responsible for directing the death investigation program in his or her particular county, and that authority is autonomous. Not only are they inadequately trained to investigate such deaths, but they do not have access to the sophisticated instrumentation required to do drug analyses; and autop- sies are done on an infrequent and inconsistent basis, depending upon the coroner's budget, w-hims and training. I can guess at how many propoxyphene- related deaths occur in communities with such a set-up, and this constitutes much of the nation. Suffice to say, many are missed. I would estimate that there are about 3,000 to 4,000 propoxyphene-related deaths annually in the United States. I arrive at this estimate by taking incidence figures from sound and well-run state-wide medical examiner systems such as North Oarolina and Oregon and local jurisdictions such as Dallas, Phoenix, Miami and San Francisco. There are, of course, others. PUBLIC AND PHYSICIAN EDUCATION HAS DECREASED PROPOXYPHENE-RELATED DEATHS IN OREGON During the past few years, the Oregon State Medical Examiner's Office has attempted, on an episodic basis, to alert the public and physicians to the dangers of this medication through press coverage and publications to physicians. The dramatic increase in these deaths early last year, including eight in a two-week period in Portland. prompted a "media blitz." Several articles appeared in news- papers throughout the state, and some of this attained nationwide attention. I appeared on several local television news shows and talk showsand recorded radio interviews throughout Oregon and in some neighboring states. Information was disscminated to Oregon physicians through the State Medical Examiner's Newsletter and the Oregon State Health Division's Communicable Disease Sum- mary. The state recorded eight propoxyphene-related deaths during the six months following thi~ "blitz." This is in contrast to the two preceding six-month periods in which the state recorded 21 and 18 propoxyphene-related deaths respectively. I feel we have demonstrated that public and physician education can help decrease the numbers of these deaths. 1)ut this is not the answer to the problem. I expect the decrease to be temporary and the problem to recur as the publicity subsides. I view- widespread pul)licity as a short-term deterrent w-ith some long- range beneficial effect in educating tl1e physician-prescribing community. Oregon's attempts at bringing the attention of the federal government to this problem have met with frustration. My letters to two officials of the FDA written PAGENO="0137" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16689 in early May have yet to meet with any response whatsoever. Oregon State Health Officer, Dr. Ed Press, has similarly petitioned the FDA for reclassifica' tion of propoxyphene in November, 1978. IMMEDIATE RECOMMENDATION I do not intend to address in any detail the proposed ban of propoxyphene. A decision on banning any medication must be based both upon its potential hazard to the community and its therapeutic benefit to those not abusing it. My role is limited to the investigation of deaths involving propoxyphene. I don't prescribe it; I rarely have an opportunity to evaluate its therapeutic benefit. Though I am aware there are several studies indicating that propoxyphene is of limited value as an analgesic, testimony to that effect must come from others more directly involved with its clinical effects. If it is determined that this drug is of no therapeutic benefit as a pain reliever, it should be banned. I firmly and without reservation suggest that propoxyphene be reclassified as a Schedule II drug. There can be no question but that propoxyphene is a narcotic, acts like a narcotic and has the abuse and addiction potential of a narcotic. Propoxyphene-related deaths outnumber deaths from other narcotic compounds such as Demerol, Dilaudid, Codeine, Percodan, Methadone and others by a multiple of several times. Most of these other narcotics are already Schedule II preparations. Placing propoxyphene under Schedule II controls would help alert physicians and patients to its danger. prevent indiscriminate refilling, require a written prescription, and in general place much more strict controls on the manu- facture and prescribing of this medication. SUMMARY COMMENTS Propoxyphene is probably the number one cause of drug overdose in the United States today. The investigation and detection of these deaths is a complicated problem; and many, if not most, death investigation systems in this country are inadequate to this task from the standpoint of personnel, training and instru- mentation. Unquestionably, many propoxyphene-related deaths are not recorded. Propoxyphene is definitely the number one cause of drug overdose in the state of Oregon by a wide margin, surpassing the combined total of deaths from heroin and barbiturates. Data from the best death investigation systems in this country, for the most part give similar results. By this time tomorrow, about ten more U.S. citizens will have died from the effects `of propoxyphene, and most of these will have been preventable accidents. The time has long since come to put a stop to it. Senator NELSON. Our final w-itness this morning is Mr. Kenneth A. Durrin, Director, Office of Compliance and Regulatory Affairs of the Drug Enforcement Administration, and he is accompanied by Mr. Donald E. Miller, Chief Counsel. STATEMENT OF KENNETH A. DURRIN, DIRECTOR, OFFICE OF COM- PLIANCE AND REGULATORY AFFAIRS OF THE DRUG ENFORCE- MENT ADMINISTRATION, ACCOMPANIED BY DONALD E. MILLER, CHIEF COUNSEL Mr. DURRIX. Mr. Chairman, members of the committee, gentlemen, I am very pleased to be here representing the Drug Enforcement Administration. Accompanying me is Mr. Donald Miller, Chief Counsel of DEA. Mr. Bensinger asked me to convey to you, Mr. Chairman, his regret that he could not be here personally, and he also asked me to commend you and your committee for holding this kind of hearing on propoxy- phene. In oiii deliberations in response to the petitions we have received fiomn the Health Research Group, and from the State of Oregon, we PAGENO="0138" 16690 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY certainly will be taking full vantage of the results emanating from your hearings and from your deliberations. In 1978, of the 1.4 billion prescriptions dispensed in retail phar- macies, 31.2 million were for products which contained propoxyphene. In this country, 59 companies now market approximately 150 products which contain propoxyphene alone or on combination with other substances. Propoxyphene is an abused drug and its abuse can and does lead to physical dependence. and you have heard testimony that it is perhaps half as effective as codeine. DEA needs to identify and evaluate the scope and extent of drug abuse in the United State.s. DAWN, the Drug Abuse `Warning Network is one of the major indicators of drug abuse in this area. There have been a number of comments on the Drug Abuse Warning Network, and I would like to say that we are in our seventh year with this system, which when taken into proper contex.t as an in- dicator system, has proven to be very valuable in terms of showing what the current situation is in the 24 cities which are reporting. I will comment on that a little more later in my testimony in terms of the earlier comments here. Now, in the DAWN program, the emergency room mentions rela- tive to all drug mentions in DAWN has remained essentially constant over the past 3 years, ranging from 2.4 percent in 1975 to 2.2 percent of all drug mentions in 1978. In terms of frec~uency of being noted in emergency room reports, propoxyphene ranked seventh in 1975, 1976, and 1977. The next year, 1978, propoxyphene ranked eighth because phencycli- dine came into more prominence. Propoxyphene ranks third behind heroin and alcohol in combination with other drugs in terms of drugs associated with death in DAWN ME reports. This confirms comments here this morning, indicating that propoxy- phene was the highest cause of death among legitimate drugs. Based on information received since January 1975 from medical examiners who have consistently reported to DAWN, the number of propoxvphene-related deaths is as follows: 1975, 502; 1976, 429; and 1977. 5°~. It will be 6 to 9 months before we have comulete data from medical examiners regarding deaths in calendar yea.r 1978. This data incidently is updated monthly based upon reports in from the medical examiners; however, because of the lagtime, it does take a good 6 to 9 months. The data we have, as I have indicated, through the end of 1977. indi- cates the problem has remained at. a high constant level through that time, and the first 3 months of 1978 continues to remain at that high level. Senator NELSON. Did von hear Dr. Wolfe's testimony? Mr. DtTRRTN. I certainly did. Senator NELsON. Did you agree with that? Mr. DumnN. Yes: I do. Senator NELSON. Does it take. some months into the next year to get the statistics of the final quarter? Mr. DUERIN. Yes: we worked closely with Dr. Wolfe and his staff in terms of furnishing them with information. PAGENO="0139" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16691 According to DAWN ER reports, suicide is the motivation behind 56 percent of the incidents. Psychic effect accounts for 13 percent; dependence accounts for another 5 percent of the reasons for pro- poxyphene abuse. In the remaining 26 percent of the cases, DAWN does not record a specific motivation. According to DAWN ME mentions, the following were recorded as the manner of death: Percent Suicide 44 Accidental (unintentional overdose) motivation for taking drug unknown__ 22 Accidental (unintentional overdose) motivation for taking drug psychic effect or dependence 13 Undetermined 21 In looking at this data, it tends to confirm another comment made earlier that there are a large number of persons who are accidentally killing themselves, using propoxyphene alone, or in combination. How is propoxyphene obtained? Based upon the DAWN emergency room data, legitimate prescrip- tions are used at least 58 percent of the time. This contrasts sharply with 1 percent reported as obtained through a street buy, or the 4 percent obtained through other illegal activity such as theft and forged prescriptions. In other words, we have here a product which patients are obtaining through legal prescriptions, and then are having toxicity problems with it. Now, with regard to scheduling drugs, drugs are placed in schedule II, or a lower schedule according to their abuse potential and currently accepted medical use. For schedule II, the criteria are currently accepted medical use and high abuse potential with severe psychic or physical dependence lia- bility. Each succeeding schedule requires a lesser potential than is reflected for schedule II and a lesser degree of dependence liability. Now, with regard to propoxyphene despite the fact it is a highly toxic drug, as a matter of fact, the highest toxic drug in terms of contributing to deaths of legitimate drugs in the United States, it has not in the past indicated a high abuse potential, or a severe dependence liability. In other words, a drug can be highly toxic without possessing those factors. The issue of severity of abuse potential and the addiction liability of propoxyphene, compared to morphine-like drugs, has been discussed and reviewed by experts in the field, over a period of several years. The 1957 findings of Drs. Fraser and Isbell of the Public Health Service Center that, "(propoxyphene's) overall addiction liability is estimated to be no greater, and is probably less, than that of codeine" were repeatedly confirmed. In 1973, DEA first proposed to HEW that propoxyphene be placed under control. HEW did not feel control was warranted at that time, but that we should continue tomonitor the drug. In March 1976, DEA submitted updated information to HEW re- garding the abuse of propoxyphene. PAGENO="0140" 16692 COMPETITIVE PROBLRMS IN THE DRUG INDUSTRY The ensuing deliberations resulted in HEWT's recommendation to control propoxyphene in schedule IV, and DEA controlled the drug effective March 14, 1977. Senator NELSON. Let me back up. What did you say in comparing codeine with propoxyphene? Mr. DIIRRIN. Drs. Fraser and Isbell stated, and this is a quote "(propoxyphene's) overall addiction liability is estimated to be no greater, and is probably less, than thatof codeine." Senator NELSON. In your judgment, from your experience, would you agree with that statement? Mr. DURRIN. Yes, I would, sir. Again, I am not a medical expert, I am a regulator, but I would. Senator NELSON. If that is correct, would you believe that propoxy- phene ought to be on schedule II as is codeine? Mr. DURRIN. No; codeine was placed on schedule II as a result of the international convention, and when the Controlled Substances Act was passed, it was placed on that schedule to conform to the treaty; but I might point out that only about 3.5 percent of the codeine dispensed for medical purposes in the United States is in schedule II products. About 75 percent of the codeine is in combination products in sched- ule III and another 10 percent is in the codeine cough syrups in schedule V. The bulk of the legitimate codeine products in the United States are on a lesser schedule, which I feel is appropriate. The Public Citizens Health Research Group and the Oregon Depart- ment of Human Resources have petitioned to place propoxyphene in schedule II. In response to these petitions, DEA has undertaken a survey to up- date information on the abuse of propoxyphene. Data regarding the nature and extent of propoxyphene-related unlawful or unprofessional activities has been soli~ited from each State government. Data is being assembled from several othe.r sources: DAWN, DEA lab analysis of evidenciary exhibits. DEA enforcement case files, com- pliance investigations, theft reports and the scientific and medical literature. I anticipate that this information will be assembled and evaluated by early spring of this year. Shortly thereafter, these findings will be submitted to HEW for its evaluation of the medical and scientific issues associated with the peti- t'ion for rescheduling. Since criteria for scheduling is largely based on potentia.l for abuse and the severity of psychological or physiological dependence, I think that it ma.y be vaiuable to use the available abuse data to compare pro- poxyphene `with other drugs in schedules II and IV. In terms of the DAWN ME mentions per million prescriptions dis- pensed in retail pharmacies, propoxyphene falls in the same general class as codeine, meprobamate, diazepam, and amitriptyline. The schedule II drugs responsible for a substantial portion of the DAWN ME mentions, are implicated in deaths at least 10 times `more frequently than propoxyphene. For example: Pentobarbital-178 mentions per million Rx. AmobarbitaJ-416 mentions per million Rx. PAGENO="0141" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16693 These figures are contrasted with propoxyphene which is implicated in 15 deaths per million prescriptions dispensed. I want to emphasize that this does not show the complete picture. One of the biggest problems, and it has been alluded to here this morning is that with propoxyphene, unlike some of these other drugs, it is regarded by many of the medical profession in my judgment, and by patients as well, as a relatively innocuous drug in terms of relative possibility of harm, and it has proven to be, according to the data and according to the testimony you have heard here this morning, far from a harmless substance. A significant question, and one that has a bearing on the outcome 0± the pending petitions, is "Has placing propoxyphene in schedule IV as of March 1977 had an impact on its abuse?" `With respect to DAWN ER. mentions, I can point to a statistically significant decrease since that time. At this point there is insufficient data for DAWN ME reports to make a comparable claim for ME mentions. It will be another 6 to 9 months before that data is complete for 1978. For medical examiners mentions, from January 1975 to February 1977, they average about 40 a month, and from April 1977 through December of 1977, which is as far as we can go at this point, they average about 42 mentions a month, and as I indicated, during the first 3 months of 1978, they are running about the same level. `With regard to propoxyphene, the number of thefts are very slight compared with some of the other drugs that we have under control. It just does not appear to be a product that is preferred by thieves. This is in sharp contrast to the well-orchestrated attempts to divert such drugs as the amphetamines, phenmetrazine, the barbiturates, methaqualone, methadone, and hydromorphone, all schedule II sub- stances. Fraudulent prescriptions and illegal dispersing are not prob- lems with propoxyphene as they are with the drugs I just noted, although there are some problems with propoxyphene in that area. Regardless of what I have just said, the Drug Enforcement Adminis- tration is most concerned about the abuse of propoxyphene. The siz- able number of deaths alone is cause for constant monitoring and interest in this problem. The toxicity problem with propoxyphene is very real. The Drug Enforcement Administration feels consideration should be given to several possible options in order to determine the best means of addressing the toxicity problem. The petitions set forth two of these: Removal of propoxyphene from the market or placement in schedule II. The questions of medi- cal usefulness of propoxyphené and the need for its continued market- ing are determinations for HEW and the FDA, and DEA does not presume to venture into that area. As to rescheduling, under the provisions of the CSA, DEA has moved into schedule II substances that we believe had a high popu- larity among abusers and which are available on the streets in significant quantities. I just mentioned several of those. `We will be looking for data of a similar nature, to determine whether propoxyphene meets schedule II criteria. PAGENO="0142" 16694 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In addition, HEW's recommendation is required as part of the scheduling process. At this point in time. Mr. Chairman, I do not want to prejudice data yet to come in. but it is our preliminary conclusion, that it is questionable whether the data we are gathering will support the cri- teria required by law for the placement of propoxyphene in schedule II; that is, a high level of abuse as contrasted with other drugs, and a severe dependence liability. Even though propoxyphene is the lead- ing cause of deaths among legitimate drugs, it does not, according to our preliminary information, reflect such a high level of abuse or a severe dependence of liability. However, even though this is likely to be the case, the very signifi- cant toxicity problem cannot be ignored. If Congress wishes to move IDarvon to schedule II an amendment to the Controlled Substances Act, which of course would not require meeting the legal criteria, would probably be necessary. If Congress decides to explore this, they will be supported by the DEA. Now, schedule II would have an impact on the quantity of propoxy- phene dispensed and hence there would be less available to cause the toxicity problems. There would be no refills. Senator NELSON. Your responsibility is not to make a judgment as to whether it is an effective drug for the purpose it is used, or whether it has any significant medical therapeutic effect on the function? Mr. DURRTN. That is correct. Senator NELSON. So the testimony of Dr. Moertel, and all of the others, in particular about the studies done to show it is less effective than ordinary over-the-counter drugs, over-the-counter drugs having fewer side effects, is not a factor that you take into consideration? Mr. DURRIN. That is correct. We defer to the FDA, HEW for the medical and scientific judgment. Incidentally, on that score, as I indicated in connection with our response to go to the petitions. we have been canvassing State officials for information on propoxyphene in their States, and I had a response from one State where the official indicated that the problem, one of the major problems in regard to propoxyphene was because medicare pa- tients cannot receive a payment for aspirin, which would be the drug of choice in many instances, so they are getting prescriptions for propox- yphene, with whatever toxicity problems that ma.y result because pro- poxyphene is reimbursable under medicaid in that State and aspirin is not. I think that. is a sorry commentary. Schedule II, as I said, would have an impact on t.he quantity of propoxvphene dispensed. and no refills would significantly cut down on the dispersing of propoxyphene. There is also the. psychological inipact of schedule II as seen with substances we have placed there. Many prescribers prefer to write for a lesser scheduled drug, and, of course, there is also the practical factor that prescriptions must be in writing and no telephone prescriptions would he allowed. However, even thoueh there would be a lessening in terms of the prescribing of the l)roluct; the majority of the propoxyphene mentions center around legitimate prescriptions as already mentioned here this morning by others. PAGENO="0143" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16695 While schedule II prescriptions are not refillable, an average pro- poxyphene prescription is roughly 40 dosage units, and the experts tell us it takes approximately 20 dosage units to cause death, proba- bly less in combination with alcohol or with other drugs. So that even though we feel based upon our experience, there would definitely be a lessening in terms of the number of units of propoxyphene dispensed in the United States, toxicity would still continue to be a serious prob- lem with this drug, even though it~ were on schedule II. The main impact and thrust of schedule II, is to prevent diversion of drugs that are in high demand by abusers, and with this particular product, the problem is the patients who obtain the drug legitimately and end up having problems with it, eit.her intentionally or unintentionally. If the Food and Drug Administration and HEW determine that removal from the market is not appropriate, it seems to us that there are additional options within FDA's purview over drug usage which directly address the toxicity problem. These include: A labeling change, perhaps a boxed warning, which would strengthen the warning to physicians of the toxicity problem and of the use of the drug in suicides. A curtailment of the indications for use which would limit the drug's use to those conditions where it is clearly superior to other less toxic substances. Discouragement of use, again through a labeling change, for the chronic, long term conditions whiäh would necessitate that the patient continually have sizable quantities of the drug on hand. Finally, a patient package insert which would warn the patient of the drug's dangers. Only the Food and Drug Administration can pass upon the via- bility of these suggestions. Certainly, a review of propoxyphene's potency, efficacy, and risk-benefit~ ratio by FDA's medical experts is in order in light of the questions raised in the petition by Dr. `Wolfe and the Public Citizen Health Research Group. In support of this, the Drug Enforcement Administration will provide appropriate data to the FDA. Mr. Chairman, whatever the mechanism, it is imperative that every effort be made to substantially reduce the number of propoxyphene- related deaths. The Drug Enforcement Administration will work to this end. Senator NELSON. Any questions? Senator LEVIN. You indicated you would support a move in Con- gress to consider the movement to schedule II? Mr. DURRIN. Yes, sir. Senator LEvIN. Have you recommended such a bill be introduced? Mr. DURRIN. No; we have not, sir. Senator LEvIN. Why is that? Mr. DURRIN. Well, basically, it is an extraordinary procedure that would not normally be part of our process in terms of a drug. The type of problem with this drug is not essentially a drug abuse problem in the usual sense. It is a toxicology problem, and normally, that is addressed by HEW. `We have certainly monitored the deaths, and we of course furnished Dr. `Wolfe information on deaths, in connection with his petitions, but that is not primarily a DEA area of responsibility. PAGENO="0144" 16696 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. MILLER. Could I elaborate on this? `We still have to wade through a great deal of difficulty in deter- mining what constitutes a high potential for abuse, and what consti- tutes a severe dependence liability. We know that Darvon is killing people, it is unsafe, insofar as some users are concerned. Whether that constitutes high potential for abuse, we still have to receive evidence on this. We have our people on the streets trying to determine whether it really has a high abuse potential, or whether it is something lower, which would disqualify it from going into schedule II. Senator LEvIN. Is that something defined by the law or in the regulations? Mr. MILLER. We are held to this by the law. We have the criteria in order to put it into schedule II, it must have a high potential for abuse. Senator LEvIN. Is the definition of high potential for abuse in the regulation? Mr. MILLER. There is no definition. `We work it on a case-by-case basis, depending on the cling. `We have never been able to come up with satisfactory regulations on it. `We rely to a great extent on the legislative history, but basically, it comes down to the evidence itself, the extent the drug is used, and the witnesses themselves that appear at the administrative hearings. Mr. DURRIX. I might add that for all of the drugs placed on sched- ule II, we have developed clear and convincing evidence of the high Potential for abuse, and the severe dependence liability. Mr. STURGES. Mr. Durrin~ on page 5, you gave the number of pro- poxyphene-related deaths, reported by the consistently reporting of medical examiner panel, as 429 for 1976 and 528 for 1977, and you say these numbers come from a DAWN system computer tape. Yet these numbers are lower tha.n the most recent quarterly report numbers: The quarterly report for April-June 1978, which is hot off the press, shows 480 deaths for 1976 and 599 for 1977. `What is the difference between the tape and the quarterly report? Mr. DURRIN. Mr. Sturges, for the purpose of trending data, we go to our consistent panel of reports, which is 103, out of a total of 111 medical examiners in the systems from January 1975 through Novem- ber 1978. The reason for this is that we have had people drop in and out of the system, and, of course, this would skew the figures if we were to use that data for the purpose of trending the deaths. What we have used in 1975, 1976, and 1977 is the consistently re- ported data, which of course is less than the total number of DAWN deaths. The higher figures are correct and accurate figures in terms of total nmuber of deaths reported, but they are not comparable from year to year, because they would skew the data. Mr. STURGES. Well, I thought these were the total consistent DAWN system numbers, but you are saving the latest quarterly report includes more than that? Mr. DURRIN. They include the consistently reporting medical ex- aminers, but they include several other medical examiners as well. PAGENO="0145" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16697 Mr. STURGES. As for data lag, vfrtually all of the numbers for the quarters involved are higher in the April to June report than they were in the January to March report, which goes to the point that information continues to roll in for 6 months, and even up to 2 years, after the reporting period. Mr. DURRIN. That is correct, the numbers continue to increase, and we update as I said on a monthly basis. You can draw no conclusion whatsoever from the 1978 figures at this point. As I said, the first 3 months of 1978 are probably pretty much en- tirely in, indicating the deaths are continuing at about the same level as previously. Senator LEVIN. The clear and convincing evidence test you have referred to is that what the law provides, or is that by regulation? Mr. MILLER. Our regulations and the Administrative Procedures Act icquires only substantive evidence, as distinguished from beyond a reasonable doubt, or by preponderance. We only have to show there is substantial evidence, which is a w'hole lot less difficult to l)rove. However, when we go into an administrative hearing, in making a determination as to whether propoxyphene should be moved from schedule IV to schedule II, we are in a full-fledged rulemaking area, and the data that is going to be submitted will have to be weighed through with witnesses, and statistics, and whatever information we may have, and, finally, it comes down to is there a substantial amount of evidence that the drug has a high potential for abuse; and secondly, does it have a severe dependence-producing liability. That will be exceedingly difficult to do in an administrative area, because it will take a long time to do, and I can tell you that in case you do iiot know it, it took us nearly 7 years to control the tranquilizers. We were tied up in hearings that never ended; we went through the court procedures and the difficulty in doing this administratively. If you have a drug that is very difficult to fit within the criteria within the Controlled Substances Act, and Congress sees that there is a need to control it quickly, and not take months and years, then the Congress will have to act. I can assure you, it will not be a simple case of the Government acquiring sufficient data that will constitute a certainty or substantial evidence that propoxyphene has a high poteiitial for abuse~ as distinguished from one that has a low potential for abuse. Meeting the criteria for schedule III and schedule IV as to whether or not it has a severe dependence-producing liability is not clear because all those schedules say dependence-producing liability relative to the higher schedule. Then drop: down a schedule, and it says as less than that scheduled above, and you get down to another schedule, and you say dependence-producing liability relative to the other schedule, so the criteria are uncertain. All I am saying is that unless we get a great (Teal more information, that convinces us we can safely go into a hear- ing, it will take a long, long tim~ to control it. Senator NELSON. Thank you very much for taking the time to come to testify. The committee will recess until tomorrow morning at 10. IWhereupon, the committee was in recess until 10 a.m.] iThe 1)reflaled statement and supplemental information of Mr. Dur- rin follow :] 40-224 0 - 79 . 10 PAGENO="0146" PAGENO="0147" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16699 STATEMENT of ~1R. KENNETH A. :DUP~IN, DIRECTOR OFFICE OF COMPLIANCE AND REGULATORY AFFAIRS* DRUG ENFORCEMENT ADMINISTRATION U.S. DEPARTMENT OF JUSTICE before the Monopoly and Anticompetitive Activities Subcommittee Select Committee on Small Business United States Senate Gaylord Nelson, Chairman January 31, 1979 Dextropropoxyphene (Darvon) PAGENO="0148" 16700 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Chairman Nelson, Members of the Monopoly and Anticompetitive Activities Subcommittee: Gentlemen, I am very pleased to be here this morning representing the Drug Enforcement Administration at this hearing on the use and abuse of dextropropoxyphene. Dextropropoxyphene, more commonly called propoxyphene, is related chemically and pharmacologically to methadone. P~opoxyphene is used orally for the relief of mild to moderate pain. Propoxyphene was first marketed in the United States in 1957 by the Eli Lilly Company under the trade name, Darvon. Within a few years, it became the most prescribed drug in America; twenty-two years later, it continues to maintain a considerable share of the market. In 1978, of the 1.4 billion prescriptions dispensed in retail pharmacies, 31.2 million were for products which contained propoxyphene. In this country, 59 companies now market approximately 150 products which contain propoxyphene alone or in combination with other substances. Almost half of these drugs are trade-name products. Clearly then, Mr. Chairman, any decisions regarding propoxyphene will have considerable impact on the pharmaceutical industry. PAGENO="0149" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16701 Propoxyphene is an abused drug and its abuse can and does lead to physical dependence. Propoxyphene is most often ingested. Intraveneous abuse of propoxyphene is usually a self-limiting process because of the resulting vascular and tissue damage. Patients who have histories of chronic pain, psychiatric disturbance, or multiple drug ingestion and who escalate the dosage of propoxyphene over rather long periods of time, abuse and/or become dependent on this drug. Patterns of abuse range from a single episode of ingestion to chronic daily use of high doses over long periods of time. In 1976, when the Department of Health, Education and Welfare (HEW) concurred in the DEA proposal that propoxyphene be placed into Schedule IV of the Controlled Substances Act, the Secretary noted the following about the abuse potential and addiction liability of propoxyphene: The abuse liability ofpropoxyphene is qualitatively similar to that of codeine although quantitatively less. . . .Propoxyphene can produce a psychological and physical dependence which is qualitatively similar to that produced by `classical' opiates (e.g., morphine or codeine) but which is quantitatively less. Put another way, this means that propoxyphene affects most of the same systems of the body as morphine or codeine but the results are less intense. -2- PAGENO="0150" 16702 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Although it is seldom publicized, an important responsibility of the Drug Enforcement Administration is regulating the distribution of legitimate drugs and substances handled by legal drug inporters, manufacturers and pharmacies, and prescribed by doctors. In conjunction with this aspect of our mission, DEA needs to be able to identify and evaluate the scope and extent of drug abuse in the United States. The Drug Abuse Warning Network--DAWN--has proven to be one of the major indicators in this area. DAWN is a program that collects and analyzes data from hospital emergency rooms (DAWN ER's) and medical examiners (DAWN ME's) nationwide on a monthly basis in order to: 1. Identify drugs currently abused. 2. Determine existing patterns of abuse in a selected sample of Standard Metropolitan Statistical Areas (SMSA). 3. Monitor systenwide abuse trends including the detection of new abuse entities and new polydrug combinations. 4. Provide current data for the assessment of the relative hazards to health, both physiological and psychological for drug substances. 5. Provide data needed for rational control and scheduling of drugs of abuse. -3- PAGENO="0151" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16703 To provide a standard from which all DAWN data is interpreted, DAWN statistics are reported in terms of specific drug abuse `mentions' involved in a hospital emergency room or drug-related deaths. Since DAWN accepts from one to six substances per episode, the drug mentions are equal to or exceed the number of episodes. The ratio of propoxyphené emergem~cy room mentions relative to all drug mentions in DAWN has remained essentially constant over the past three years, ranging from 2.4 percent in 1975 to 2.2 percent of all drug mentions in 1978. In terms of frequency of being noted in emergency room reports, propoxyphene ranked seventh in 1975, 1976 and 1977. The next year, 1978, propoxyphene ranked eighth because phencyclidine came into more prominence. The substances mentioned more often than propoxyphene in DAWN emergency room reports are: diazepam (e.g., valium), alcohol (in combination with other drugs), heroin, aspirin, amitriptyline formulations (non-scheduled antidepressants), and flurazepam (a Schedule IV hypnotic related to diazepam). Propoxyphene ranks third behind heroin and alcohol (in combination with other drugs) in terms of drugs associated with deaths in DAWN ME reports. Based on information received since January 1975 from medical examiners who have consistently reported to DAWN, the number of propoxyphene- related deaths is as follows: -4- PAGENO="0152" 16704 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1975 502 1976 429 1977 528* Thus far, for 1978, 315 propoxyphene-related deaths have been reported by the above-mentioned panel of medical examiners. (Because there is considerable variation in the time which elapses between the date of death and the filing of the report, it will be six to nine months before statistically useful 1978 data is available.) Based on the 1975 through 1977 data, no consistent increase or decrease in the number o-f deaths is evident.** * All DAWN data was extracted from the DAWN system computer tapes identified as the "November 1978 System Tape". Comparisons across time are based on data received from the medical examiners who report to DAWN throughout the time period being studied. Collectively, these are referred to as a consistently reporting panel. Between January 1975 and November 1978, 1774 propoxyphene-related deaths were reported to DAWN from such a panel. Medical examiners who reported to DAWN but not throughout the entire period reported an additional 190 propoxyphene-related deaths. At various times, data from either panel has been released to the general public. As a result, there may be variations in the absolute numbers for the same time period. ** See pages 15 - 18 for the complete monthly data. -5- PAGENO="0153" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16705 Throughout almost four years of availabld data, certain facets of propoxyphene abuse remain relatively constant. According to DAWN ER mentions for propoxyphene, over half of the time, 56 percent, suicide is the motivation behind the incident. Psychic effect accounts for 13 percent; dependence accounts for another 5 percent of the reasons for propoxyphene abuse. In the remaining 26 percent of the cases, DAWN does not record a specific motivation. According to DAWN ME mentions, the following were recorded as the manner of death: suicide 44% accidental (unintentional overdose) - motivation for taking drug unknown 22% accidental (unintentional overdose) - motivation for taking drug psychic effect or dependence 13% undetermined 21% I cannot present to you a profile of a propoxyphene abuser, because there is no clear-cut demographic model. There are a greater number of propoxyphene-related mentions in the 20-29 age range, accounting for 40 percent of all ER mentions and 35 percent of: all ME mentions. Women tend to be involved in propoxyphene-related incidents more often than men, representing 59 percent of all ER mentions and 53 percent of all ME mentions. In proportion to their respective -6- PAGENO="0154" 16706 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY population size nationally, blacks are reported less frequently than are whites. It is noted that, for both ER episodes and ME mentions, white females over age 50 have a disproportionate number of mentions.* Where do these individuals obtain propoxyphene? Based on DAWN ER data, legitimate prescriptions are used at least 58 percent of the time. This contrasts sharply with the one (1) percent reported as obtained through a street buy or the four (U percent obtained via other illegal activity such as theft and forged prescriptions. No source is recorded for approximately a third, 37 percent, of all incidents. There is no known clandestine manufacture of propoxyphene. Prior to comparing the DAWN data regarding propoxyphene to other controlled substances, I believe it is important to digress for a moment to discuss scheduling -- that mechanism by which controlled substances are classified into one of five categories or schedules. Procedures for the control of dangerous drugs were established under the Controlled Substances Act of 1970 (CSA). It is very important to bear in mind that drug scheduling actions are not solely the responsibility of the DEA; we work very closely with HEW, and at the Staff level with the Food and Drug Administration (FDA) and the National Institute on Drug Abuse (NIDA). * See pages 19 and 20 for complete data. -7- PAGENO="0155" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16707 Simply stated, drugs are scheduled according to their abuse potential and currently accepted medical use, somewhat in the following manner: Schedule I : No accepted medical use in the United States; high abuse potential Schedule II : Currently accepted medical use; high abuse potential with severe psychic or physical dependence liability Schedule III: Abuse potential less than those in Schedules I and II Schedule IV : Abuse potential less than Schedule III Schedule V : Abuse potential less than Schedule IV The regulatory requirements are established based on these same schedules. Regulatory requirements include, but are not limited to, aspects of registration, recordkeeping, distribution restrictions, dispensing limits and manufacturing quotas. There was an ongoing debate between 1956, when the issue of control was first raised, and 1977, when propoxyphene was placed into Schedule IV of the CSA, regarding whether this drug posed a public health hazard, the kind and magnitude of which warranted greater controls on its manufacture and distribution. In these debates, the issue of severity of abuse potential and addiction liability of propoxyphene compared to morphine-like drugs was always paramount. The 1957 findings of Drs. Fraser and Isbell -8- PAGENO="0156" 16708 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY of the Public Eealth Service Addiction Research Center that, (propoxyphene's) overall addiction liability is estimated to be no greater, and is probably less, than that of codeine" were rep~atedly confirmed. In 1973, DEA first proposed to HEW that propoxyphene be placed under control. * HEW did not feel control was warranted at that time, but that we should continue to monitor the drug. In March 1976, DEA submitted updated information to HEW regarding the abuse of propoxyphene. The ensuing deliberations resulted in HEW's recommendation to control propoxyphene in Schedule IV, and DEA controlled the drug effective March 14, 1977. Thus, unauthorized manufacture, distribution and possession of propoxyphene became a criminal offense. Labeling carries a CIV symbol, annual inventories by manufacturers and distributors are required and prescriptions may be refilled no more than five times and are valid from date of issuance for only six months. The scheduling of propoxyphene is once again controversial. There are proponents who now maintain that propoxyphene more correctly belongs in Schedule II. The Public Citizens Health Research Group and the Oregon Department of Human Resources have petitioned to place propoxyphene in Schedule II. In response to these petitions, DEA has undertaken a survey to update information on the abuse of propoxyphene. Data regarding the nature and extent of propoxyphene-related unlawful or unprofessional activities has been solicited from each State government. Data is being assembled from several other sources: DAWN, DEA lab analysis of -9- PAGENO="0157" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16709 evidentiary exhibits, DEA enforcement case files, compliance investigations, theft reports and the scientific and medical literature. I anticipate that this information will be assembled and evaluated by early Spring of this year. Shortly thereafter, these findings will be submitted to HEW for its evaluation of the medical and scientific issues associated with the petition for rescheduling. Since criteria .for scheduling is largely based on potential for abuse and the severity of psychological or physiological dependence, I think that it may be valuable to use the available abuse data to compare propoxyphene with other drugs in Schedules II and IV. In terms of the DAWN ME mentions per million prescriptions dispensed in retail pharmacies, propoxyphene falls in the same general class as codeine (Schedule II, III), meprobamate (Schedule IV), diazepam (Schedule IV) and Arnitriptyline formulations (unscheduled). The Schedule II drugs responsible for a substantial portion of the DAWN ME mentions, are implicated in deaths at least ten times more frequently than propoxyphene. For example: pentobarbital 178 mentions per million Rx seco/amobarbital 234 1 It It It secobarbital 259 " Amobarbital 416 1 It tt It~ * See page 21 for the complete list. PAGENO="0158" 16710 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY These figures are contrasted with propoxyphene which is implicated in 15 deaths per million prescriptions dispensed. Propoxyphene mentions from DAWN hospital emergency rooms show that approximately 115 ER mentions occur per million prescriptions dispensed. By comparison, for diazepam, another Schedule IV drug and the drug most often involved in DAWN ER reports, there are 386 mentions per million prescriptions dispensed. A significant question, and one that has a great bearing on the outcome of the pending petitions, is "Has placing propoxyphene in Schedule IV as of March 977 had an impact on its abuse?" With respect to DAWN ER mentions, I can point to a statistically significant decrease since that time. * At the present time, there is insufficient data with respect to DAWN ME reports to allow one to make a comparable claim. It will be another six to nine months before the 1978 data is completed. Also worth noting is the diversion problem, or more precisely, the lack of one. While there has been some diversiOn of propoxyphene through thefts from registrants, it does not appear to be a preferred drug by thieves. This * See pages 17 and 18 for specific data. - 11 - PAGENO="0159" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16711 is in sharp contrast to the well-orchestrated attempts to divert such drugs as the amphetamines, phenmetrazine (pre1udin~, the barbiturates, methaqualone, methadone, and hydromorphone (Dilaudid) -- all Schedule II substances. Similarly, fraudulent prescriptions and illegal dispensing are not problems with propoxyphene as they are with the other drugsI just noted. Nevertheless, the DEA is most concerned about the abuse of propoxyphene; the sizable number of deaths alone is cause for constant monitoring and interest in this problem. The toxicity problem is very real. Consideration should be given to several possible options in order to determine the best means of addressing the toxicity problem. The petitions set forth two of these: removal of propoxyphene from the market or placement in Schedule II. The questions of medical usefulness of propoxyphene and the need for its continued marketing are determinations for HEW and the FDA, and DEA does not presume to venture into that area. As to rescheduling, under the provisions of the CSA, DEA has moved into Schedule II substances that we believe had a high popularity among abusers and which are available on the streets in significant quantities. For example, we rescheduled amphetamines, fast-acting barbiturates, - 12 - PAGENO="0160" 16712 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY phencyclidine and methaqualone. We will be looking for data of a similar nature in the study on propoxyphene now underway to determine whether it meets Schedule II criteria. In addition, HEW's recommendation is required as part of the scheduling process. The majority of DAWN ER propoxyphene mentions center around legitimate prescriptions. While Schedule II prescriptions are not refillable, an average propoxyphene prescription is 40 dosage units and the experts tell us it takes approximately 20 dosage units to cause death--probably less in combination with alcohol or other drugs. If HEW (FDA) determines that removal from the market is not appropriate, it seems to us that there are additional options within FDA's purview over drug usage which directly address the toxicity problem. These include: -- A labeling change, perhaps a boxed warning, which would strengthen the warning to physicians of the toxicity problem and of the use of the drug in suicides -- A curtailment of the indications for use which would limit the drug's use to those conditions where it is clearly superior to other less toxic substances. - 13 - PAGENO="0161" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16713 -- Discouragement of use, again through a labeling change, for the chrOnic, long-term conditions which would necessitate that the patient continually have sizeable quantities of the drug on hand. -- A patient package insert which would warn the patient of the drug's dangers. Only the Food and Drug Administration can pass upon the viability of these suggestions. Certainly, a review of propoxyphene's potency, efficacy and risk-benefit ratio by FDA's medical experts is in order in light of the questions raised in the petition by Dr. Wolfe and the Public Citizen Health Research Group. In support of this, the Drug Enforcement Administration will provide appropriate data to the FDA. Whatever the mechanism, it is imperative that every effort be made to substantially reduce the number of propoxyphene-related deaths. The Drug Enforáement Administration will work to this end. - 14 - 40-224 0 - 79 - 11 PAGENO="0162" Propoxyphene - Related Deaths Reported by a Consistent Panel of Medical Examiners Associated with the Drug Abuse Warning Network 6O~ Reporting hrEorr~)lete (I~) I rr~ ~hl ri ~ 20 1IlIlhhI,F1 ~ $1 ~ l~ 111 0- I I ~, ~i I . LJ1 ~ 1978 Source: DEA DAWN Computer Tape Throutjh November 30, 1978 Printout: January 16, 1979. pgs. 21--24 Captioned: D - Propoxyphene vs. All Other Drug/Substances 1975 1976 1977 PAGENO="0163" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16715 Propoxyphene Related Deaths Reported by a Consistent Panel of Medical Examiners Associated with the Drug Abuse Warning Network 1975 1976 1977 1978* January 41 38 50 37 February 50 31 49 44 March 55 35 50 44 April 47 33 42 29 May 43 30 49 31 June 33 42 31 37 July 40 32 45 27 August 37 44 55 20 September 47 34 40 21 October 40 31 39 15 November 38 32 36 10 December 31 47 42 * Deaths occurring within the last 6 to 9 months are under-reported due to the reporting procedures used by the Medical Examiners. Sources: DEA DAWN November 1978 System Tape Printout: January 16, 1979, pg. 21-24, captioned D-propoxyphene vs. all other drugs/substances. - 16 PAGENO="0164" I. Propoxypheae - Related Injuries Reported by a Consistent Panel of Emergency Rooms Associated with the Drug Abuse Warning Network 400- ~ 300- oW ~ 200- 100 1975 - 1976 1977 1978 Source: DEA DAWN Computer Tape Through November 30, 1978 Printout: January 16, 1979, pgs. 17-20 Captioned: D - Propoxyphene vs. AU Other Drug/Substances PAGENO="0165" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16717 Propoxyphene-Related Injuries Reported by a Consistent Panel of Emergency Rooms Associated with the Drug Abuse Warning Network 1975 1976 1977 1978 January 306 305 25,0 239 February 286 254 243 230 March 281 274 315 278 April 306 270 266 261 May 259 316 294 202 June 283 285 282 198 July 309 289 245 212 August 303 319 256 219 September 262 269 251 247 October 327 295 259 210 November 289 310 249 206 December 253 288 251 Source: DEA DAWN November 1978 System Tape Printout: January 16, 1979, pg. 17-20, captioned D-propoxyphene vs. all other drugs/substances. A standard nonparametric test procedure known as the Mann- Whitney U test was used to test the levels of propoxyphene mentions for significant differences between the time periods before and after CSA controls (March 14, 1977) were instituted, i.e., January 1975 - February 1977, and April 1977 - November 1978, respectively. This test was chosen for its generality and particularly for its freedom from the normality assumptions required for most comparable test procedures. According to the results of this test at the 95% confidence level, the number of propoxyphene mentions reported by consistently reporting DAWN emergency rooms was significantly lower during the time period following the institution of CSA * controls. Reference for Mann-Whitney U test: Nonparametric and Shortcut Statistics in Social, Biological, and Medical Sciences by Merle W. Tate and Richard C. Clelland, pages 89-91 and 137; published by Interstate Printers and Publishers, Inc., Danville, Illinois (1959). - 18 - PAGENO="0166" 1~ 0 0 LTj 0 w L~i 02 Age, Race and Sex of Propoxyphene Users Based on DAWN Emergency Room Mentions: January 1, 1975, to November 30, 1978 H . Age Race-Sex 1 - 9 10 - 19 20 - 29 30 - 39 40 - 49 50+ Unknown Total N % ~ White Male Black Male TOTAL MALE 5 2 7 633 143 776 1,389 389 1,778 596 156 752 292 49 341 227 32 259 19 8 27 3,161 779 3,940 (24.5) White Female Black Female TOTAL FEMALE 1 0 1 1,631 709 2,340 2,619 1,092 3,711 1,400 419 1,819 803 173 976 559 78 637 53 24 77 7,066 2,495 9,561 (59.3) Other Race - Both Sexes + Unknowns 2 692 1,005 511 227 139 36 2,612 (16.2) N TOTAL % 10 (0.1) 3,808 (23.6) 6,494 (40.3) 3,082 (19.1) 1,554 (9.6) 1,035 (6.4) 140 (0.9) 16,113 (100) January 9, 1979, pg. 1-14, Source: DEA DAWN November 1978 System Tape Printout: Captioned Race and Sex Groupings. PAGENO="0167" Race-Sex ~.. . 1 - 9 10 - 19 20 - 29 30 - 39 40 - 49 50+ . Unknown Total N % White Male Black hale TOTAL MALE 0 0 0 52 13 65 327 73 400 173 35 208 77 12 89 83 1 84 0 0 0 712 134 846 (43.1) White !emale Black Female TOTAL FEMALE 0 0 0 48 33 81 194 73 267 175 40 215 203 26 229 239 9 248 3 0 3 862 181 1,043 (53.1) Other Race - Both Sexes + Unknowns 0 9 28 23 8 7 0 75 ( 3.8) N Total % 0 (0.0) 155 (7.8) 695 (35.4) 446 (22.7) 326 (16.6) 339 (17.3) 3 (0.2) 1,964 (100) Source: DEA DAWN Captioned November Race and 1978 Sex System Tape Printout: January 9, 1979, Groupings. Age, Race and Sex of Propoxyphene Users Based on DAWN Medical Examiner Mentions:- January 1, 1975, to November 30, 1978 0 pg. 16-26, PAGENO="0168" 16720 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Drug-Related Deaths in Relation to Availability of Drugs* 1975-1977 Mentions/ DAWN ME ~1illion CSA Mentions Prescriptions** Schedule Heroin 4618 N.A. I Alcohol plus other drugs 4059 N.A. 0 Propoxyphene 1642 15 IV Diazeparn 1300 8 IV Methadone 1296 N.A. II Secobarbital 1229 259 ii Amitriptyline formulations 958 18 0 Pentobarbital 947 178 II Seco/Amobarbital 821 234 II Phenobarbital 815 31 IV Codeine 621 5 11,111 Aspirin 530 N.A. 0 Amobarbital 451 416 II Ethchlorvynol 441 75 IV Glutethimide 318 47 III Meprobamate 274 10 IV * Drugs which accounted for 74% of DAWN Medical Examiner mentions. ** Mentions were collected from Standard Metropolitan Statistical Areas which include approximately a third of the population. Prescription data was collected nationwide. The number of deaths per million prescriptions would be proportionately higher for each drug if nationwide death statistics were available. Source ME Mentions: DEA DAWN November 1978 System Tape Printout: January 9, 1979, pg. 6-10, captioned Totals For Grouped Years. - 21 - PAGENO="0169" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16721 KENNETH A. DURRIN Since October 1976, Mr. Durrin has been the Director of the Drug Enforcement Administration Office of Compliance and Regulatory Affairs. From 1969 to that time, he was in charge of the Compliance Programs for DEA and its predecessor agencies. Mr. Durrin has been a career Federal Investigator since his graduation from Albany Law School, Union University, in 1952. He is a member of both the American Society for Industrial Security and the International Association for Chiefs of Police. PAGENO="0170" 16722 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FACT Sheet Compliance and Regulatory Affairs United States Department of Justice Drug Enforcement Administration DEA's mission is not only to stop the flow of illicit drugs in this country, but also to regulate the distribution of legitimate drugs-- substances handled by the legal drug import- ers, manufacturers and pharmacies, and prescribed by doctors. Along these lines DEA has the responsibility for monitoring the importation of legitimate drugs into the United States and reviewing all import-export activities in line with existing treaty obligations. Abuse of these legitimate drugs is sub- stantial. According to a nationwide study of the National Institute on Drug Abuse (NIDA), - the non-medical use of psychothera- peutic drugs ranks second to marihuana among youth and all adults ...," with "one in ten young people and one in seven adults having some non-medical experience with an over-the-counter or prescription sedative, tranquilizer or stimulant." DEA's experience has bees that when as addict is unable to find his illicit drug of choice--for example heroin or cocaine--he will tend to substitute the legitimate drugs. During a heroin shortage, for instance, we are increasingly likely to uncover forged prescriptions, non-medical drug purchases, drug burglaries and employee drug theft--in other words, diversion of licit drugs for illicit purposes. DEA's regulatory program--established to minimize this diversion--pursues an essential, although seldom publicized, DEA mission. In October 1976, in recognition of the importance of DEA's regulatory mission and in order to consolidate regulatory functions, the Office of Compliance and Regulatory Affairs was formed. This is a principal office and reports directly to the Administrator and Deputy Administrator. The new Office brings together registration, regulatory control and investigative activities formerly the responsibility of the Compliance Investi- gations Division in DEA's Office of Enforce- ment, and the drug scheduling and drug information activities formerly the respon- sibility of the Special Programs Division of the Office of Science and Technology. Dialogue with the pharmaceutical industry and the Department of Health, Education and Welfare shows that this action should be a step forward in raising the level of importance of Compliance and Regulatory Affairs within our own agency and improving DEA'S effectiveness with other agencies and the pharmaceutical industry. The regulatory mechanism as created by the Controlled Substances Act (CSA) of 1970 centers upon a "closed distribution system," the cornerstone of which is the required annual registration of all handlers and prescribers of controlled substances. DEA now has more than 57D,ODO registrants and collect more than $2.7 million in annual registration fees. Controls begin with a pre-registration investigation of all wholesale handlers. This preliminary step is taken to ensure that registration is in the public interest (that is, that the firm has adequate security, no violative history, State approval, etc.(. It also ensures that those within the firms who are responsible are knowledgeable of - requirements under the Controlled Substances Act. Following registration, under this program DEA monitors and periodically investigates registrants to ensure they are accountable for the controlled substancm handled. When violations are uncovered, appropriate action is taken. Since the passage of the Controlled 12178 PAGENO="0171" `-Ill _..LJ ~ Thb co~vpssv~ ~ ~vk~~g veh~do~. Cov~ p~t~v~d sev~~~ty ~ v~tv5 It/&~~v systev. Th~ ~bo~v photvg~aph~ x'k~'~ w Eli Lilly ~,d Comp~vy, lvdiwapvlis. dv,ivg DEA Co,~pli~vvv~i~intivv. Substances Act which took effect in May 1971, DEA has accomplished a number of important actions, not the least of which relates to drug scheduling action. These actions, of course, are not our exclu- sive mandate; in making our recommendations we work very closely with the Food and Drug Admin- istration and the National Institute on Drug Abuse. Examples of these actions would be the moving of Phencyclidine (PCP) from Schedule Ill to Schedule II and the March 14, 1977 fisal order placing dex- tropropoxyphese (Darvon, et al.) under control in Schedule IV. Since May 1971, we have controlled 35 drugs, have moved eleven drugs to another schedule and have decontrolled six drugs. In add- ition, controls on several hundred commercial preparations which contain controlled substances have been lessened by classifying these products as exempted, excepted or excluded. Simultaneous to rescheduling certain drugs we also establish production quotas for those substances. Quotas create smaller inventories and a less zealous marketing atmosphere which, when coupled with stringent security and regulatory safeguards on pre- scribing and dispensing the drugs, substantially re- duce the potential for diversion. In setting quotas, DEA again relies heavily upon the FDA to furnish with estimates of legitimate medical need. For example, just prior to Schedule II control, in 1971, U.S. amphetamine production was approx- imately 66,000 pounds per year. The quota for 1977 is 7,700 pounds. Despite this cutback --- drastic though it may seem --- no one with a legitimate need for these drugs has been deprived. As with amphetamines, substantial production decreases have also been ef- fected on phenmetrazine (Preludin), methaqualone (Quaalude, et al.( and the three fast-acting barbi- turates, amobarbital, secobarbital, and pentobarbi- tal. While success has been obtained in reducing diver- sion at the manufacturer/distributor level, success at the retail level (e.g., physicians, pharmacies( is much less dramatic. Under the Controlled Substances Act, the primary responsibility at this level is left with the States. DEA is required to register every professional who possesses a valid State license, un- less he has a drug felony conviction or materially falsifies his registration application. However, the number of retail registrants totals more than 50,000, and State police are COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16723 ce ~ " ~- -I ,~; ~l PAGENO="0172" 16724 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~- --~ H limited in the resources they can devote to handling thin number. In keeping with DEA's legislative mandate, DEA is devoting all possible attention and resources to this problem. Memoranda of Understanding have been signed with 45 States and the District of Col- umbia delineating Federal/State roles. We have also developed a State criminal investigative operation targeted against willful retail registrant diversion. This operation, called the Diversion Investigative Unit (DIU) program is DEA supported, State run and State manned. Another example of DEA's Federal/State cooper- ative effort involves the assistance afforded by DEA in the development and implementation of indivi- dual State Mini-DAWN Networks. Additionally, a Voluntary Compliance Program has been established. This program has direct responsibility for coordinating DEA's efforts to ob- tain self-regulation from State regulatory agencies, health professionals and their respective associations. This program is aimed at increasing registrants' efforts to prevent diversion and to direct their in- terest in upgrading their level of self-regulation and self-enforcement. The Office of Compliance and Regulatory Affairs also maintains the following three unique computer- ized systems: 1. Drug Abuse Warning Network (DAWN) Project DAWN (Drug Abuse Warning Network) is a federal program initiated by the Drug Enforce- ment Administration to assist the government in identifying and evaluating the scope and extent of drug abuse in the United States. DAWN, jointly funded by the National Institute on Drug Abuse (NIDA) includes over 900 different-facilities which supply data to the program. The original design and development of the program was con- ceived by the scientific staff of the Office of Science and Technology in the Drug Enforcement Administration. The system is used as a means to assist the officials aIld others concerned with the problems of drug abuse to identify the parameters of the drug abuse phenomenon. DAWN repre- sents a continuing and dynamic effort that will be constantly revi~'wpd and modified to obtain more precise information upon which regulatory deci- sions can be based. PAGENO="0173" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 16725 2. Automated Reports and Consolidated Order System (ARCOS) ARCOS is a computerized system which provides for the monitoring of drug transactions of selected controlled substances. These transactions are re- ported by approximately 2,000 manufacturers, distributors, importers and exporters. The system provides a government capability to monitor the selected controlled substances from point of im- port or manufacture to point of export or distri- bution to the dispensing level. The system pro- cessed approximately 17.5 million transactions in FY77, an increase of 3.6 million over FY76. 3. Project Label This program represents a systematic and compu- terized activity of continuously updating and maintaining a listing of all products containing controlled substances currently marketed by trade and generic name, by manufacturer, by components and composition, by acquisition and NDC number and by appropriate CSA Schedule. Co~ptia~~ ~ ~ th~ Sch~dffl~ III, 1V V ~ H~~y PAGENO="0174" 16726 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FACT Sheet United States Department of Justice Drug Enforcement Administration The Diversion Investigation Unit Program The term "illicit drug traffic" is actually a generalization covering a number of types of drugs and their movement to various groups of abusers. For example, the traffic in heroin from Southeast Asia is distinct from the traffic in cocaine from Latin America. Similarly, the traffic in LSD from clandestine laboratories differs from the traffic in diverted legitimate drugs. In a broad sense, the illicit drug traffic can be viewed as consisting of three facets: (a) Traffic originating in foreign countries )b) Traffic originating in domestic clandestine laboratories (ci Traffic originating through diversion from legitimate commerce. Traditionally, Federal, State and local governments have given overwhelming priority to combating the traffic originating in foreign countries (e.g., heroin, cocaine, marihuana). To a lesser extent, efforts have been expended on combating the traffic originating in domestic clandestine labora- tories (e.g., LSD(. The lowest priority had been given to combating diversion from legitimate commerce (e.g., amphetamines, barbiturates, tranquilizers, etc.). There was a reason for this. In deploying the limited resources of law enforcement, heavy consideration must be given to the relative harm to society caused by these various drugs. If the harm caused by drug A is greater than that caused by drug B (whether due to the amount of abuse or the innate characteristics of the drug), then emphasis must be placed on combating the traffic in drug A. Traditionally, the illicit drugs originating from foreign sources have been viewed by law enforcement and the public as the most harmful. In recent years, however, we have witnessed Office of Comptance and Regulatory Affairs a shift in the market towards what has been termed "poly-drug" abuse. Without delving into a statistical or sociological analysis of this trend, suffice it to say that the legally produced drugs used in treating various illnesses in this country are becoming more prevalent in the illicit market. As the demand increases, so follows the supply. We do not believe this shift in the market is such as to require a dramatic shift of law enforcement priorities and resources. We do believe, however, that a limited shift is necessary. Furthermore, this shift will have to take place primarily at the State and local levels of law enforcement. The working legislation of DEA is the Controlled Substances Act of 1970. A study of this Act will show that DEA has been given considerable authority to monitor the comm~rce of controlled drugs at the manufacturing and wholesaling levels. Its authority at the retail level is markedly less. The rationale of Congress in limiting Federal authority at this level was threefold: (1) to conduct the same degree of scrutiny at this level as at the other levels would require a very large increase in Federal resources; (2) the responsibility for monitoring this level has traditionally been held by the States; and (3) the business sphere of the manufacturers and wholesalers is of an interstate nature, while the business sphere of the retail handlers is of intrastate nature. Due to resource and legal restraints then, there is a marked difference between the strong Federal presence at the upper levels of the drug industry and the inherently lesser Federal presence at the retail level. There is little commonality in the nature and extent of regulation of health professionals by State governments. The most prevalent mode is to assign this responsibility to various 12/78 PAGENO="0175" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16727 regulatory boards (i.e., Board of Pharmacy, Board of Medicine, etc.(. These boards are generally responsible for the full regulation of professional practice within the State which encompasses a broad range of issues, only one of which is the prevention of diversion. For example, a Board of Pharmacy may be responsible for monitoring continuing education requirements, coordinating reciprocity of licensure with other States, monitoring the professional ethics of pharmacists in the State, assuring that the pharmacies are properly equipped and staffed, and a number of other issues which, although vital to the practice of pharmacy, have little to do with combating the criminal diversion of drugs by pharmacists. Its staff, if there is one at all, may consist of one or two investi- gators for the entire State. This staff may even consist of practicing pharmacists who work for the Board on a part-time basis. This bleak picture of the Boards of Pharmacy becomes good by comparison with the boards of other professions. These other boards are so poorly equipped that in many States they rely upon the Board of Pharmacy's staff to conduct investigations of their professions. The pattern among all these boards is that they are not oriented, equipped, staffed, trained, or in some instances even empowered, to properly combat diversion by the health professionals they are charged with regulating. These shortcomings are not the fault of the boards. In our experience, they are fully aware of their deficiencies, but are unable to alleviate their situation. The causes for this are complex, but essentially derive from a lack of public awareness of this facet of the illicit drug problem. The State law enforcement agencies (State Police, State Bureau of Investigation, etc.( ,-~ DEA cv,,~plu~~ ~ ~ ~ do not oftenl pursue the diversion of drugs by health professionals in any real sense. The same can be said for local police departments within the State. This is primarily due to the traditional assignment of this responsibility to the regulatory boards. Other contributing factors include a lack of resources, and a lack of training and orientation in this area. The State and local prosecutors as a general rule have no experience in prosecuting criminal cases against health professionals. There is even a reluctance to accept such cases due to their oddity, sensitivity, or complex nature. In sum, there is little Federal, State, or municipal effort expended on curtailing diversion of drugs from the retail level. There are about 15 billion dosage units of controlled drugs manufactured in the United States each year. Based upon subjective and statistical indicators, the most conservative estimates on the extent of diversion of these ..H PAGENO="0176" 16728 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY drugs range between 200,000,000 and 250,000,000 dosage units per year. Some estimates greatly exceed this range. Based upon surveys of cases and conservative projection, about 90 percent of this diversion is occurring at the retail level. This would be expected, since there is relatively little energy being expended to stop it. Diversion at the retail level can occur in a number of ways; the most predominant of which are criminal diversion by a health professional (Or an employee thereof(, forged prescriptions, and theft. Among these, the most predominant is criminal diversion. Eliminating criminal diversion at this level requires the availability of a broad range of techniques, authorities, and mechanisms. These include the following; regulatory operations within the drug industry, down through the practice of pharmacy and medicine. This should be suffrcient to identify and act upon regulatory and criminal violations by a health professional. A thorough capability in law enforcement techniques, including surveillance, under~ cover techniques, rules of evidence, arrest and search procedures, court testimony, etc. A full set of available sanctions ranging from administrative through regulatory to criminal prosecution, depending upon the nature of the violations and the situation. The ability to use tanctions available at both the Federal and State levels. Resources and support to conduct such operations on a scale sufficient to have an impact on the problem. There is essentially no existing entity at the Federal, State, and local level with these capabilities. To summarize the foregoing, the diversion of drugs from legitimate industry has been a lesser are~a of public and governmental attention. Due to shifting trends with the drug traffic, however, this facet of the drug problem is becoming more important. Law enforcement and regulatory agencies at all levels must begin making some adjustments to it. The adjustment that a growing number of States are finding to be sufficient and meaningful is the Diversion Investigation Unit Program. Under this program, DEA serves as a catalyst to bring funding, manpower, expertise and scattered jurisdiction together into a unified effort. These units are manned and run by State authorities. They are trained by DEA; and a DEA Agent is assigned on a full. Cr~,t,rI ,,f ~ k~y m d~g A thorough ability to conduct enforcement! PAGENO="0177" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16729 Istig~to~s ~ i~~'~w,y ~ ,,~It f,~ It d~,gs, ,~th ,~pst~ti~ ~ th~ H~'y Oitp~ C",,,p~y, ~ D.C. time batit to tupply CDntinuing expertite and tupport. The DIUt ere detigned to dram ott the experience of a varied group of invettigatort; including thone from State regulatory boardn, State lam enforcement agencien, and DEA. Thene inventigatorn, mhen antigned to the DIU, are releaned from other dutien in their renpect- ive agencien to enable them to concentrate nolely on divernion canen. To ennure that no tingle agency han complete control over the unit, a Policy Board in entabli- nhed. Each concerned agency han one voting member on the Policy Board. The Policy Board providen overall direction and nupport for the unit. Training in an integral part of the DIU concept. The inventigatorn annigned to the unite receive a tpecialized training courne, normally of one-meek duration, in the proceduren involved in developing criminal canen againet violative regiutrantn. In order to obtain the necennary pronecutive follow-up, upecial neminarn are held by DEA for dintrict attorneyn and county pronecutorn to echool them in the fine pointn of pronecuting divernion canen. Judgen are alto invited to attend thene teminarn. The DIU wan conceived at a "teed" program. Itt objective mat to launch the participating State off to a tound ttart by meant of direct Federal funding and tupport, and ultimately to have a Seace-nuntained, permanent, D IU- type program. The program wan initiated on a pilot baum in Texan and Michigan in Septem- ber 1972 and uhortly thereafter in Alabama jDecember 1972j. All three pilot Staten have endorned the program and are ntill operating them under State funding. Upon nuccenn of thene pilot programn, plant were made to implement DIUn in neven add- itional Staten. Thene were: California, Illinoin, Mannachunettn, New Jerney, Pennnyl- vania, North Carolina and Florida. All but Plorida are etill in operation. New Unite are now operating in Georgia, New Hamp- uhire, Nevada, Wanhington, Hawaii, Main, and the Dintrict of Columbia. Three more ntaten will join the program in FY-79. The DIU Program han demonntrated how a concerted effort of highly trained pernonnel can curtail the divernion of drugn on a State- wide level. The project bringn together thone independent State agencien that have a role in regulatory drug enforcement into a tingle, cohenive unit. Each agency contributen epecialized ekille to the benefit of the other participantu in the unit. State police annigned to the unite have become expert in the area of regulatory inventigatione. Likewine, regulatory innpectorn have become expert in the techniquen of criminal inventigation. In effect, a crone-fertilization of experience, training, and knowledge han taken place. The DIU in an excellent example of what can be accomplinhed when concerted State agencien unite in a cooperative effort with Federal agencien to eupprenn the illicit divernion of controlled nubntancen. 4e-224 0 - le - PAGENO="0178" 16730 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FACTS Sheet United States Department of Justice Drug Enforcement Administration Project DAWN (Drug Abuse Warning Network( is a federal program initiated by the Drug En- forcement Administration (DEA( to identify and evaluate the scope and extent of drug abuse in the United States. DAWN, jointly funded with the National Institute on Drug Abuse (NIDA( includes over 900 different facilities which supply data to the program. The original design and development of the program was conceived by the scientific staff of the Office of Science and Technology in the Drug Enforce- ment Administration. Since its inception in June 1972, the Project DAWN contract has been negotiated on six separate occasions. Each separate negotiation usually involved some mod- ification in the areas of (1( SMSA coverage, (2( number and types of participating facilities, and (3( time collecting intervals associated with Project DAWN, I, II, Ill, IV, V, VI, andVIlI. (See chart, DAWN Systems Statistics, below( The Purposes of DAWN DAWN has been designed to: 1. Identify drugs currently abused. 2. Determine existing patterns of abuse in a selected sample of SMSA's (Standard Met- ropolitan Statistical Areas(. DAWN SYSTEM STATISTICS 3. Monitor systemwide abuse trends includ- ing the detection of new abuse entities and new polydrug combinations. 4. Provide current data for the assessment of the relative hazards to health, both physio- logical andipsychological, and relative abuse potential for drug substances. 5. Provide data needed for rational control and scheduling of drugs of abuse. Information Collected DAWN, which has been in existence since July 1972, and in essentially its current format since July 1973, derives its information from episode reports provided by selected hospital emergency rooms, medical examiners and crisis centers. A reporter in each participating facility completes a report for each drug abuse contact seen by the facility. The reasons for contact are medical or1psycho- logical in nature (hospital emergency rooms and crisis centers(, or deaths of the individual (medi- cal examiners(. The information provided by DAWN is limited to drug abuse cases which are treated, medically or psychologically, in a par- ticipating hospital or crisis center. Even in a standard Metropolitan Statistical Area (SMSA( in which all hospital emergency rooms partici- pate, the only abuse cases reported by DAWN are those in which the abuser or someone in contact with the abuser perceives a problem requiring assistance from a reporting modality. All drug abuse related deaths, however, which occur in a county with a participating medical examiner/coroner will be included in DAWN data. For the purpose of this study, the following definitions were adopted: 1. Drug Abuse was defined as the non-medi- cal use of a substance for any of the DAWN (Drug Abuse Warning Network) Correlation between designated DAWN-Phase citation and time interval of data collection period. Desionation Time Interval DAWN I September 1972 - Match 1973 DAWN II April 1973- March 1974 DAWN III April 1974- April 1975 DAWN IV May 1975 -April 1976 DAWN V May 1976-April 1977 DAWN VI May 1977 - April 1978 DAWN VII May 1978 - April 1979 12/78 PAGENO="0179" 200 A.M.F. = 822 Ixdxx 100=527 100 ~\\ `y__ Index - 1975 1976 30C FLURAZEPAM A.M.F.2~4 Index 100=173 Soxexe: DAWN Qxxx-te,-/y Repx,t, Ap,-iI -Jxee 1977 following reasons: psychic effect, physio- logical dependence, and attempted or successful self-destruction. For the pur- poses of this definition, non-medical use means: a. The use of prescription drugs in a manner inconsistent with accepted med- ical practice. b. the use of OTC (over-the-counter) drugs contrary to approved labeling. c. the use of any other substance (heroin, marihuana, peyote, glue, aerosols, etc.) considered non-medical, and which J~d~S\ ~L should be reported with the exceptions of alcohol, caustics, household poisons and other hazardous material, which should be reported only if used in con- - junction with another drug, e.g., barbi- turates/alcohol, clorox/Diazepam, etc. Psychic effects include: euphoria, high, kicks, mood alteration, alleviation of un- happiness, sexual enhancement, trips, drug experiences, including experimentation and use for pleasure and fulfillment, use for social or recreational purposes or because of peer pressure. 2. A drug involved death may be either: a. A drug induced death caused by a drug "overdose" where a toxic level is found or suspected, or a death caused by a drug reaction such as an immune reac- tion or, b. A drug related death in which a drug(s) is present and is a contributing factor, but not the sole cause of death. Any incident involving a drug abuse episode or a drug-related death is reportable. Source of Data The reporting facilities are concentrated in 24 SMSA's. Of the 24 SMSA's, 20 were "saturated" which indicates an effort was made to solicit participation of all emergency rooms and med- ical examiners in the DAWN system. In 3 SMSA's (New York, Chicago and Los Angeles), facilities were randomly selected, drawing a sample equal to about 50% of all ER visits occurring within the SMSA. DEA Use of DAWN Project DAWN data is currently being used within DEA for drug control and scheduling purposes; for following specific drug trends on a regional or local basis (see chart, above and left) for measuring she effectiveness of a drug control action and for allocating resources and staff relative to specific drug problems. Specific examples of the field application of DAWN in- clude the following: * DAWN data indicated Nccessive abuse of - Dilaudid in the Philadelphia SMSA. Follow- ing the arrest of several `script" doctors in the Philadelphia area, DAWN data reflected a noticeable decrease in Dilaudid mentions. Dil- audid ranked second in frequency of drug men- tions prior to the arrests and eighth afterwards. * DAWN data about PCP was one of the indica- tors that assisted Federal and local law en- forcers in the identification and elimination of a clandestine laboratory operation in Detroit, Michigan. *An increase in the DAWN mentions for meth- adone in Texas served to alert area law en- forcement agencies to the extent of metha- done trafficking there. Independent investiga- tors verified the DAWN findings. *DAWN provided some of the first indications that Mandrax, a foreign made methaqualone product, was appearing on the drug abuse scene in this country. Who Uses DAWN? Government agencies (DOD, NIDA, FDA) State and local law enforcement agencies, pharmaceutical firms, Single State Agencies, Drug Abuse Trends As Shown By DAWN Data January 1975 - June 1977 HE 80 IN/MO R PH INE* A.MF. = Axeeege Mxethly F~xqxeecy -3,whegxxxage --Ied,ee,mbee COCAINE* METHAOUALONE MARIHUANA ~ ~ A.M.F. 154 A.M.F. = 144 - Index 100=116 Index 100=111 0 -,-`-,-`-`. 5 ,- Index 1975 1976 1977 Ivdex 1975 1976 1977 A.M.F. = 72 Iedtx iOO = 54 c~ n~ex P1975 1976 1977 PcP. 500 - 400 A.M.F.80 Index 100=40 - - - - 300- ~.T. I ;~ Ivdex 1975 19/5 1911 Ix~ex 1975 1976 1977 0 LTd LTd 0 LTd 02 LTd ci ci 03 1' PAGENO="0180" 16732 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DAWN VI: SMSA's and Facilities State and local drug abuse authorities and private organizations have used DAWN data or have re- quested access to it. Generally it is used to assess the drug abuse problem and follow the trends of the changing abuse patterns. Even though DAWN Phase VI has been modi- fiedsomewhat in SMSA and facility coverage, the overall program, at the Federal level, still repre- sents one of the most comprehensive drug abuse data gathering indicator networks in size and scope. This system has assisted various government agencies and a number of state, local and private organizations to quantitatively and qualitatively evaluate a general or specific drug abuse problem. An example of DEAn emphasis on Federal/ State cooperation was recently demonstrated in New Hampshire. January 6, 1978, marked the be- ginning of a new era for DAWN when Governor Meldrim Thomson, Jr. of New Hampshire author- ized the implementation of a statewide drug abuse data gathering program patterned after the DAWN System. This action is significant as it represents the forerunner of a larger DEA program to en- courage other states to develop Mini-DAWN systems. The United States Air Force Drug and Alcohol Branch,Social Actions Division, Human Resources Development, Headquarters, Pentagon has incor- porated DAWN data into a drug abuse indicator evaluation system. This evaluation will be distrib- uted to all major commands so that base command- ers can initiate various types of countermeasures depending upon the level of drug abuse in their areas. DAWN data was used extensively in preparing the barbiturate study requested by the Office of Drug Abuse Planning and by the Food and Drug Administration in preparation for the ampheta- mine hearings conducted in December, 1977. Project DAWN can enable U.S. authorities to evaluate drug abuse problems as seen by medical, social and governmental indicators. It can pro- vide system-wide and regional profiles for types of drug abuse and the abusers themselves. It can enable planners to prepare for the future, as well as providing action agencies the means to detect and react to developing problems. Analyses of this sort can allow for evaluation of the impact of alternative strategies in specific communities. The availability of comparable information for more than one community will assist our efforts to understand causal relation- ships and thut permit more accurate programmatic emphasis and direction of resources. It in important to note that the DAWN data is interpretive and should not be used by itself. DEA and NIDA have attempted to use it in conjunction with the other information available from a variety of sources, including state and local labor- atory reports, other epidemiology studies and actual first-hand investigations. The system is used as a means to assist the officials and others concerned with the problems of drug abuse to iden- tify the parameters of the drug abuse phenomenon. DAWN represents a continuing and dynamic effort that will be constantly reviewed and modi- fied to obtain more precise inforñtation upon which regulatory decisions can be based. Additional Information on DAWN Requests for additional information or specific data should be directed to: Mr. Jsseph B. Murphy Chief, Information Systems Sectisn Office of Compliance & Regulatory Affairs DPag Enforcement Administration Washington, D.C. 20537 SMSA's Atlanta, GA - Minneapolis, MN ---- - - - Boston MA New Orleans, LA Buffalo, NY New York, NY Number of Facilities IDAWN VI) Chicago, IL Oklahoma City, OK Hospital Emergency Room IERI 778 Cleveland, OH Philadelphia. PA Medical Enaminer/Coroner IME) 111 Dallas, TX Phoenix, AZ Denver, CO Norfolk, VA Crisis Centers 23 Detroit, Ml San Antonio, TX T I -I-s 912 Houston, TX San Diego. CA Indianapolis, IN San Francisco, CA Kansas City, KA MO Seattle, WA Miami, PL Washington, D.C. PAGENO="0181" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16733 The Controlled Substances Act Schedules of Controlled Substances Schedule I substances. Drugs in this schedule are those that have no accepted medical use in the United States and have a high abuse potential. Some examples are heroin, marihuana, LSD, peyote, mescaline, psilocybin, the tetrahydrocan- nabinols, ketobemidone, levomoramide, racemoramide, benzylmorphine, dihy- dromorphine, morphine methylsulfonate, nicocodeine, and nicomorphine. Schedule II substances. The drugs in this schedule have a high abu~e potential with severe psychic or physical dependence liability. Schedule II controlled substances consist of certain narcotic drugs and drugs containing amphetamines or methamphetamines as the single active ingredient or in combination with each other. Examples of Schedule II controlled substances are: opium, morphine, co- deine, hydromorphone, methadone, pantopon, meperidine, cocaine, oxycodone, anileridine, oxymorphone; and straight amphetamines and methamphetamines. Also in Schedule II are phenmetrazine, methyiphenidate, amobarbital, pentobar- bital, secobarbital, and methaqualone. Schedule III substances. The drugs in this schedule have an abuse potential less than those in Schedules I and II and include compounds containing limited quanti- ties of certain narcotic drugs and nonnarcotic drugs, such as: derivatives of barbi- turic acid, except those that are listed in another schedule, glutethimide, methy- prylon, chlorhexadol, phencyclidine, sulfondiethylmethane, sulfonmethane, na- lorphine,benzphetamine, chlorphentermine, chiortermine, mazindol, and phendi- metrazine. Paregoric is in the schedule as well. Schedule IV substances. The drugs in this schedule have an abuse potential less than those listed in Schedule III and include such drugs as: barbital, phenobarbi- tal, methylphenobarbital, chloral betaine, chloral hydrate, ethchlorvynol, ethina- mate, meprobamate, paraldehyde, pentaerythritol chloral, methohexital, fenflur- amine, diethyipropion, and phentermine. Schedule V substances. The drugs in this schedule have an abuse potential less than those listed in Schedule IV and consist of preparations containing moderate, limited quantities of certain narcotic drugs, generally for antitussive and antidi- arrheal purposes, which may be distributed without a prescription order. Drug Enforcement * December 1977 21 PAGENO="0182" Common'y Encountered Contro~ed Substances H £ ~ ~ ~ ~ 0 ~ \\ ~ ~ ~ 4 ~ PAGENO="0183" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16735 I ~ ~ IL ~ L:~ :si~a ~ ~ &~~pR~a fl oo~ ~ c' oiccuc'c cc' thcccc,'tc'cccccctccc'cccctfccccccpccccflcc'c'ctCcfcfl ccc d,c'ccc'dof~cccc c'c~ cc "c'c"ccp ccc"'' ,c'ltc,OflOf ccc' cccVc Drug Fnforcccmrut * Drcrmtcrc 977 Regulatory Requirements: Federal Trafficking Penalties PAGENO="0184" PAGENO="0185" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY (Present Status of Competition in the Pharmaceutical Industry) THURSDAY, FEBRUARY 1, 1979 U.S. SENATE, SELECT COMMrrrEE ON SMALL BUSINESS, Washington, D.C. The committee met, pursuant to call, at 10:07 a.m. in room 5110, Dirksen Senate Office Building, Hon. Gaylord Nelson, chairman, presiding. Present: Senators Nelson, Bumpers, Stewart, Weicker, Hatch, Hayakawa, and Boschwitz. Also present: Gerald D. Sturges, professional staff member; Stan- ley A. Twardy, Jr., minority cOunsel; and Judith K. Hillegonds, staff assistant. Senator NELSON. We will resume the hearings this morning with a panel of witnesses consisting of Dr. John Adriani, Department of Health and Human Resources, office of Charity Hospital at New Or- leans; Mr. Morris Boynoff, pharmacist, Mendocino, Calif.; Dr. Wil- ham T. Beaver, associate professor of pharmacology and anesthesia, Georgetown University Schools of Medicine and Dentistry; and Dr. Michael Newman, internist, Washington, D.C. If you gentlemen would all join at the witness table, we would take your presentations one at a time and then each of you may comment on any other's testimony as you desire. Gentlemen, the committee is very pleased to have you here this morning and appreciates your taking the time from your very busy schedules to come and testify on this pending matter. I would ask Dr. Adriani to present his statement first unless you had some particular order in which you wanted to proceed. It is nice to see you a~a.in. Dr. Adriani, and you may proceed and present your statement. Let me say for purposes of the hearing record, we are happy to have you or any of the other witnesses comment on any of the statements made by previous witnesses. Yesterday, Dr. Moertel presented very strong testimqny based upon studies done at the Mayo Clinic and reached a very strong conclusion about Darvon, which is set forth on the last page of his statement. At some stage, when you have completed all your testimony, I would like to have your comment on his conclusions. Go ahead, Dr. Adriani. 16737 PAGENO="0186" 16738 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY STATEMENTS FROM A PANEL CONSISTING OF: FOHN ADRIANI, M.D., DEPARTMENT OF HEALTH AND HUMAN RESOURCES, OFFICE OF CHARITY HOSPITAL AT NEW ORLEANS, LA.; MORRIS BOYNOFF, PHARMACIST, MENDOCINO, CALIF.; WILLIAM T. BEAVER, M.D., ASSOCIATE PROFESSOR OF PHARMACOLOGY AND ANESTHESIA, GEORGETOWN UNIVERSITY SCHOOLS OF MEDICINE AND DENT- ISTRY, WASHINGTON, D.C.; AND MICHAEL A. NEWMAN, M.D., INTERNIST, WASHINGTON, D.C. Dr. ADRIANI. Good morning. It is a pleasure to be here once again. As you can see from my statement I was here November 24, 1970, to discuss the same subject we are discussing today, but from a little different point of view. Senator NELSON. For purposes of the record, Dr. Adriani, would you give a little bit of your background, so that those who read these hearings will know your background, including your service as chair- man of the American Medical Association Council on Drugs? Dr. ADRIANI. I am emeritus professor of surgery (anesthesiology) at Tulane University School of Medicine. I am still active in the de- partments of pharmacology and anesthesiology at the Louisiana State University School of Medicine and a consultant in anesthesiology and pharmacology in the Department of Health and Human Resources of Louisiana and consultant in various hospitals in New Orleans and still on the staff at the Charity Hospital. I have appeared before this committee in the past. On one occasion I appeared in my own behalf, while I was chairman of the council. of drugs of the AMA. At that time we discussed various things. One of the things we discussed at that time was the publication of a drug compendium. You were very much interested in the publication of such a book on drug information-you had the feeling that doctors did not get enough drug information; the scl100ls did not have enough input and doctors were using drugs empirically. I agree with you on that. We still have that problem. althoug~i it seems to be correcting itself. I am still active, not retired, but I have given up the chairmanships of the various departments I held at Tulane, LSU and Charity. I was the chairman of the anesthesia de- partment at Tulane. at LSU and chief of the anesthesiology service at Charity Hospital for 35 years. I am also on two advisory panels of the Food and Drug Administra- tion; one on the evaluation of topical analgesic drugs and the other on oral cavity preparations. As I said before, my statement starts off with the fact that I was here in 1970. At t!hat time, we were talking about analgesics, partic- ularly propoxyphene. As I recall it the question that was at issue was the matter of the Government, particularly the Armed Forces, spend- ing a premium amount of money for Darvon when other drugs that were more effective could have been used and were much less expen- sive. The issue of lack of effeetiveness was fairly well emphasized. Now, my experience with Darvon goes back when they first began to evaluate it, as an investigational drug. I could not see from the PAGENO="0187" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16739 study that we did that it had any marked advantage over anything else that we were using in the line of analgesics and I advised them of this. In any case, my advice was not accepted. My feeling on effectiveness is the same way today and has not changed. In addition, the Lilly laboratories also prepared an intra- venous solution to be used instead of Demerol for anesthesia in drip form. Since Demerol was a narcotic under restriction and Darvon was not, this would have solved a pi~oblem. We found that we had variable results. Sometimes we got marked response of respiration from the drug and had to reverse it with antinarcotics. This dosage form was abandoned. Our experience as far as efficacy is concerned is that Darvon is not an effective drug. It is pretty well established that it is far less effec- tive than aspirin. Aspirin is one of the best analgesics we have. Most of the analgesia. obtained from Darvon is from a placebo effect. Dar- von works when it is combined with other analgesics such as aspirin orAPC. At that time (1970) efficacywas at issue. Today, safety is at issue. The attitude that most of us adopted was that even if it does not do any good it does not do any harm. Then occasional cases began to ap- pear in the literature where patients had taken doses in excess of 100 milligrams and developed convulsions and died. In addition to that, the drug was thought to be nonhabit forming. It was shown prior to release of the drug (1957) that it did relieve some of the withdrawal symptoms of patients who were habituated to and dependent on narcotics. It does have narcotic qualities and today, individuals who are narcotic drug-dependent seem to like it and take it, For awhile there we had a problem with Darvon because the addicts were taking it intravenously. They dissolved the hydrochloride salt and were taking it intravenously. A less soluble form, the napsylate salt was made. That step has reduced problems arising from intra- venous use. We have now the problem. of patients taking it orally over long periods of time getting cumulative effects, and of drug-dependent subjects who need more than the usual doses. These doses are ap- parently toxic. There are fatalities among drug-dependent persons as a result of overdosage. Today it is not only a question of efficacy, Mr. Chairman. We also have the question of safety and dependency. The question is, is the risk involved in its .use worth the benefit that the drug has? There are other drugs that are safer, more effective, and less expensive. Actually there is really no need to have this drug. I do believe the popularity of the drug is due to the fact that it was widely promoted. It is much more expensive than aspirin and other analgesics and not as good. We have been able to control the use of it at Charity Hospital because we have it under restriction just as we do narcotics and the doctor has to write a prescription for Darvon in the same manner as he has to for other narcotics. Senator NEr~sox. Does Charity permit the use of Darvon? Dr. ADRIANI. In some cases but the number is small. Senator NELSON. What kind of a case is it that justifies the use of Darvon? PAGENO="0188" 16740 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Dr. ADRIANI. None. Some of the orthopedic surgeons use it. Senator NELSON. Pardon me? Dr. ADRIANI. Some of the orthopedic surgeons use it when they treat fractures. There are those who feel if you use aspirin, aspirin causes bleeding in the stomach and Darvon does not and, therefore, they pre- scribe it instead. Senator NELSON. But. Dr. Moertel iust said he could not think of any target group that should use Darvon; that if there is a problem with aspirin there is acetaminophen, and there is codeine. I take it there is no target population for the use of Darvon. Do you? Dr. ADRIANI. I agree with him, but the impression exists that Dar- von can be used in place of aspirin and then you do not have to worry about the bleeding problem which is not the problem they have made it out to be. Senator NELSON. How does that square with the situation in which- I do not have the figures present-I am told a very substantial per- centage of the propoxyphene seen in the marketplace is there in com- bination form, either with acetaminophen or with aspirin, so those who are turning to Darvon for that alleged reason and prescribing the com- bination product are giving the aspirin anyway. Dr. ADRIANI. That is right. I do not agree with those who prescribe it and their reasons for using it. As far as I am concerned, I have not prescribed the drug since I stopped investigating it before it was marketed. The last time I appeared before this committee in reference to Darvon I remarked t.hat my wife was with me and she had a frac- ture in the kneecap. She was in the hotel with a cast. Her doctor had given her Darvon for pain. I felt., as far as I was concerned, that what- ever effect she was getting was from a placebo effect and not from the Darvon. We have known all along that the efficacy of this drug has been in doubt. The main thing we are concerned with now is the matter of safety, and that is a very important issue. So. the question is to determine what we are going to do about a drug like this. When do we really need it? Actually, if it were taken off the face of the earth, medical pract.ice would not suffer. I do not know of any situation where a patient cannot be treated because we do not have Darvon. There are other drugs we must have. If we have a man with heart failure and do not have diLritalis, we are "stuck". We need digitalis, but Davron does not fall in that cate- gory. It is not a drug t.hat we really need. Since it is not as safe asoriginally believed, it is not innocuous and is falling into t.he hands of individuals who are getting it for illicit use. Mv feeling is that a stron~er restriction should be imposed on its availability to patients, either by having it in schedule II or by taking the drug off the market completely, one or the other. The problem seems to be greater in drug-dependent persons. There are some things that we know now that were not known before about the drug. Two ladies mentioned to me they had taken Darvon and had cocktails served to them afterward and they became acutely ill. This is a central nervous system depressant that has an additive effect with alcohol. That is not generally known and has not been told to patients. As far as I am concerned, I can see no need for the drug. PAGENO="0189" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16741 We have a welfare program in Louisiana and the most expensive item and most widely prescribed drug in the program, until recent- ly, has been Darvon. The Secretary of Health and Human Resources Administration of Louisiana spbke to me about this. I told him Dar- von could be dispensed with and is no longer a drug that' the State supplies free. A year ago they did the same thing with some drugs be- cause the bill was tremendous and the budget could not stand it. They took them off the market and we thought we would hear about it, particularly from the State Medical Society but nothing was said and apparently nothing will be~ said, so far as I know, about Darvon. This was implemented just several weeks ago. Senator NELSON. You took it out of the welfare program in the State of Louisiana? Dr. ADRIANI. Yes. Senator NELSON. That is to say you will not reimburse for it? Dr. ADRIANI. That is right. If a doctor wants to prescribe it, the patients pay for it. Senator NELSON. One of the problems cited yesterday by one of the witnesses, more than one as a matter of fact, was that prescription drugs are reimbursable and that nonprescription drugs are not. This witness felt that maybe inducing some doctors to prescribe Darvon, which is reimbursable even though it is not a good analgesic, simply saves the patient some money. Whether or not this is a fact, I do not know. Dr. ADRIANI No; I think it is the fact that doctors have been brain- washed that Darvon has some superior quality and are not familiar with the fact that it is a very feeble analgesic. When a drug is added to the hospital formulary, it is done by the Pharmacy and Thera- peutics Committee. We had to fight to keep Darvon off. Means nothing. Can't remember what I said but it is not important. Codeine has been used and is much more effective than Darvon and certainly aspirin is much more effective. Codeine and aspirin is a very useful combination. Senator BUMPERS. Mr. Chairman, one question. I was not here yes- terday and I am curious. The press has reported the dangers and how many people have died in a day or year from Darvon. What is there about Darvon that makes it more dangerous than aspirin? Dr. ADRIANI. Well, as I say, it is a central nervous system depressant. Senator BUMPERS. As I look at. the ingredients about the only thing it has that aspirin does not have is caffeine and propoxyphene. Dr. ADRIANI. Yes. Recent evidence shows that it is a breakdown product that is harmful. Every drug we take is either carried to the liver where it is transformed to another chemical that is less harmful or excreted by the kidney. Occasionally some of the byproducts of a drug are more harmful than' the parent compound. The transforma- tion is supposed to reduce the toxicity but with Darvon the toxicity increases. In the case of aspirin the detoxification occurs very quickly to harm- less products. They have found that Darvon is metabolized to a com- pound called nor-propoxyphene. This has greater toxic effects thar~ Darvon and certain aftereffects. It affects the central nervous system and causes convulsions. It accumulates in the body if you keep taking it. It is not eliminated right away. We refer to the time a drug stays PAGENO="0190" 16742 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY in the body as the half-life. Nor-propoxyphene has a long half-life- 70 hours. if you take three or four capsules a day a cumulative effect results until you reach a point where you have a lethal dose circulating and in the tissues. Senator BUMPERS. Thank you, very much. Dr. ADRIANI. My recommendations are summarized at the end of my statement. The drug could be under stricter controls and placed in schedule IT. It is possible to maintain standards of good medical practice with- out propoxyphene; therefore, manufacture could be discontinued. There is no medical justification for continuing its use as an anal- gesic because it has no therapeutic advantage over other drugs of similar potency that merit its being prescribed for relieving pain. There will probably be some "static" so to speak, from the medical profession because once doctors have a drug and you take it away from them they claim the Government is coming in and telling them how to practice medicine. When some regulatory agency says we are going to emove a drug from the market, it should do so with concurrence of the medical community. We did this with the amphetamines. The Com- missioner of Food and Drugs called in experts and we decided with him how amphetamines should be handled; that they should be resultated. The indications allowed were published in the Federal Reg- ister. For a regulatory agency, that is the Government, to come in and say we are going to make this drug no longer available, I am afraid there will be many complaints-maybe not justifiable, but there will be complaints. Senator NELSON. Well, I guess you answered the question. In general, from your statement, you agree with what Dr. Moertel from the Mayo Clinic said yesterday as to his conclusions. Dr. ADRIANI. Yes. Senator NELSON. Thank you, very much, Dr. Adriani. Any questions? Senator HAYAKAWA. Doctor, thank you for your testimony. Our staff has dug up a statement that you made in 1968 and may I quote: "The nonaddictive agents such as propoxyphene and other anal- gesics should be used in the postoperative period for pain relief." Now, can you reconcile this statement with your statement today that there h~s been doubt corcerning the effectiveness of this drug as a mild analgesic since its introduction? Dr. ADRT\XI. I am sorry. I did not get the last part of your question. Senator HAYAKAWA. Today you are saying there has been some doubt concerning the effectiveness of this drug as a mild analgesic since its introduction. Tn 1968, you apparently did not have these doubts that you are ex- pressing pretty much based on research conducted since 1968. Dr. ~A DETANT. Well, with the work that we did we did not find that the drug was any more effective than other analgesics and was less effec- tive. I do not know if I still have the correspondence in my file and it has been quite a number of years now-1956 or 19~7 when I (lid it, hut I said that T could not see an point in marketing this drug, that I did not think it had any particularly therapeutic value. PAGENO="0191" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16743 Senator HAYAKAWA. But what I am quoting is your statement that propoxyphene and other analgesics should be used in the postoperative period for pain relief. -These are~ your own words, Doctor, in 1968. Dr. ADRIANI. In 1968? Senator HAYAKAWA. Yes, in an article in Anesthesia and Analgesics, on drug dependence, an article you wrote with Dr. Morgan on drug considerations. Senator NELSON. May I refresh your memory? You may recall in the hearings in 1970 in which you testified- Dr. ADRIANI. Yes. Senator NELsON [continuing]. I would have to look back in the rec- ord, but the fact was discovered subsequently that propoxyphene is addictive and was not known in 1970. In 1970, one of the arguments for Darvon was that unlike codeine, which might have addictive proper- ties, Darvon did not, and therefore as to that particular problem Dar- von was preferable. Dr. ADRIANI. Yes. Senator NELSON. In the past 8 years it has been clearly demon- strated-what was not known then-that it is addictive. Dr. ADRIANT. Yes. Senator NELSON. The only issue in our hearings in 1970, as I recall it, was the issue of effectiveness, in which all of the expert witnesses testified as did you that it was less effective. Dr. ADRIANI. That is right. Senator NELsON. Less effective than aspirin or acetaminophen. Dr. ADRIANI. Now you are referring to an article that I wrote using analgesics in drug-dependent persons, is that right? Senator HAYAKAWA. Drug dependency is a consideration; yes. It was on drug dependency. Dr. ADRIANI. It was an article on drug dependency and I have al- ways advocated that if we know that a patient is drug-dependent we do not use a narcotic or any drug that we know that produces depend- ency. We do not want to get him back on drugs that cause dependency. At that time, the addiction liability of propoxyphene was minimal. There seemed to be some discussion that it was but not significantly so, and we did not consider it addicting like codeine. Generally, most addicts start with codeine and move over to Demerol and then something else stronger. I had a former pupil who became dependent on codeine. This man stayed with codeine all the time, which is unusual. In relieving pain in patients who we know were drug dependent and are no longer dependent; they have been cured, so to speak; we stay away from addicting drugs or we do not give them any- thing. A drug like propoxyphene at that time seemed to be indicated. Senator HAYAKAWA. I understand at that time the addictive quality that you say exists in propoxyphene had not been clearly established; is that what you are saying? Dr. ADRIANI. That is right. Senator HAYAKAWA. Thank you, very much. Senator NELSON. Any other questions? Thank you. Senator Bm~IPEP~S. How much caffeine, or how many milligrams of caffeine are in an ordinary cup of coffee? PAGENO="0192" 16744 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. ADRIANI. I think it is 30 milligrams, I am not sure. Senator BUMPERS. Thank you. Senator NELSON. Thank you, Dr. Adriani. Dr. ADRIANI. There is a typographical error in my statement. There are 32 milligrams of caffeine and in the Darvon compound I have 32 or something like that. Senator NELSON. The printed record will be corrected to show 32 milligrams in your prepared text, which will be printed in full in the record at this point. [The prepared statement of Dr. Adriani follows:] STATEMENT OF JOHN ADRIANI, M.D., PROFESSOR PHARMACOLOGY AND ANESTHESI- OLOGY, LOUISIANA STATE UNIVERSITY SCHOOL OF MEDICINE; CONSULTANT PHAR- MACOLOGY AND ANESTHESIOLOGY, DEPARTMENT OF HEALTH AND HUMAN RE- SOURCES OF LOUISIANA, NEw ORLEANS, LA. DEXTROPROPOXYPHENE (DARVON) Mr. Chairman: I appeared before this Committee on November 24, 1970, and testified on matters pertaining to the efficacy of certain internal analgesics, one of which was propoxyphene, the subject of today's hearings. Propoxyphene was introduced and marketed under the trademark name Darvon by the Lilly Labora- tories in 1955. There has been doubt concerning the effectiveness of this drug as a "mild" analgesic Since its introduction as a prescription item for oral use. Paren- teral dosage forms are not available. Propoxyphene is chemically allied to metha- done, a narcotic that is equipotent to morphine on milligram for milligram basis and with approximately the same degree of liability for causing physical depend- ence. Propoxyphene was described as a non-narcotic analgesic as far as thera- peutic efficacy and addiction liability was concerned. It did not appear to have the propensity for causing physical dependence in nondrug dependent persons. It was known that it provided some degree of relief from withdrawal symptoms in per- sons manifesting physicial dependence to narcotics. The National Academy of Sciences-National Research Council Review Panel on effectiveness of drugs for the relief of pain, found propoxyphene to be less effective than is implied by claims of the manufacturer. On a milligram for milligram basis, propoxyphene was alleged to be equal to codeine in intensity and duration of analgesic action. The Panel found, however, that 65 mg of propoxyphene was equivalent to approxi- mately 30-40 mg of codeine in analgesic potency. The Panel also concluded that 32 mg propoxyphene, in most instances, was no more effective than a placebo. Claims that propoxyphene has fewer side effects than codeine cannot be justified if effective doses of the two drugs are compared. Beaver, in reviewing the literature on mild analgesics (Beaver, A.P.: Ameri- can Journal of Medical Sciences 251, p. 576. 1906) noted that studies comparing dextropropoxyphene with aspirin or APC, propoxyphene 32.5 (65 mg) showed it to be consistently inferior to aspirin 325 mg or 650 mg or APC (Aspirin Phena- cetin Caffeine) mixture. No convincing evidence has been introduced since this review that any way establishes the superiority of 0~ rn~ doses of propoxyphene over 2 tablets of either aspirin or APC compound used alone. Propoxyphene is generally combined with other analre~b~s. Annarently. it is not able to "stand alone" as an analgesic and must be fortified with other drugs to be effective. The oric!inal Darvon compound preparation contained 32 mg of propoxyphene, 327 mg of aspirin and 165 mg of phenacetin and 32 mg of caffeine. Darvon compound (65) contained the same amount of aspirin, phenaeetin and caffeine and double the amount of propoxvphene. Darvon ASA contains 65 mg of propoxyphene and 325 mg of aspirin, the equivalent of 1 aspirin tablet. Other combinations are available also but none appear to have any superiority to the combination with aspirin. These added drugs w-ere included in the form of pellets in the propoxyphene (Darvon) capsule. Although there has been doubt about its effectiveness, little has been said about the safety of the drug. From time to time isniated case reports have ap- peared in the literature of fatalities from propoxyphene when doses in excess of 100 m~ w-ere ingested. Recently there has been a marked upswirug of the num- ber of adverse reports from the effects of the drug and reports of fatalities from PAGENO="0193" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16745 its use. Although propoxyphene is listed as a "non-narcotic analgesjc", it is capab'e of producing both psychic and physical dependence. Most of the mdi- viduals dependent upon the drug have a history of abuse of other drugs. Drug dependent users used to remove the aspirin pellet from the capsule of Darvon compound (propoxyphene hydrochloride with aspirin), dissolved the propoxy- phene and used it for intravenous injection to obtain a euphoric effect. Propoxy- phene hydrochloride is soluble in water. This practice was obviated by using an insoluble form of the salt of propoxyphene; namely the napsylate. The reported cases of dependence upon propoxyphene obviously does not pre- sent a true picture of the problem because it does not account for the total num- ber of addicts; yet, relatively speaking, the risk of dependence in non-drug de- pendent persons of propoxyphene appears to be low compared in non-depend- ent individuals to morphine and meperidine. The Committee on Problems for Drug Abuse of the Notional Academy of Sciences, National Research Council, and other groups have suggested that the term non-narcotic be deleted from advertising by manufacturers since its significance is misinterpreted. Tl~e desig- nation "non-narcotic" does not mean that a drug does not produce dependence. It is a term with a legal connotation that indicates neither special narcotic pre- scriptions are required nor other narcotic controls are imposed prescribing the drug. The fact that propoxyphene hydrochloride (Darvon) was not subjected to the Federal Narcotic Control, plus the fact that it was widely promoted and the impression created that it was innocuous, to a large extent, explains the voluminuos sales of this analgesic. Americans spent over $140,000,000 in 1977 for Lilly manufactured Darvon and Darvon combinations products. The napsyl- ate (Darvon-N Lilly) which was recently introduced is more stable than the hydrochloride. Because of differences in molecular weight, a close of 100 mg of napsylate is required to provide the amount of propoxyphene equivalent to 65 ing of the hydrochloride. The pharmacologic effects of both salts are similar. - Propoxyphene has been one of the most frequently prescribed drugs in the Lou- isiana State Medicaid and Welfare Programs. It is now no longer on the list of drugs the State furnishes without cost. At Charity Hospital (an 1800 bed gen- eral hospital), where the drug has been controlled since its admission to the Hos- pital Formulary List, only 7000 units w-ere prescribed in 1978. Reservations about the efficacy of propoxyphene continue to be expressed. In a recently published double-blind study of single doses of propoxyphene, aspirin and other oral anal- gesics in patients with cancer, Moertel and associates (Moretel, C.G. et al: New England Jour. Med. 280, 813, April 13, 1972) were unable to demonstrate that even 65 ing of propoxyphene was significantly superior to a placebo. In this study, aspirin w-as the most effective analgesic tested. Until recently, the attitude towards l)arvon has been one of complacency and indifference even though there has been doubt about efficacy all along because the drug was considered safe. The feeling has been "it may not do much good but it does not do any harm". Now-, the question of safety has come sharply into focus and there is considerable concern about its continued use. Propoxyphene is not without adverse effects. In non-dependent individuals, approximately 0.5% of the reactions that occur are minor consisting of nausea, vomiting, drowsiness, rash and vertigo. Hallucinations and disorientation are rare but have been observed. The drug niay also cause encephalopathy in patients with diminished liver function. The frequency of adverse effects varies with dosage. There is no evidence that truly analgesic doses of propoxyphene are less harmful than equal analgesic doses of other drugs. An increasing imumber of cases of ingestion of lethal and nearly lethal doses of I)ropoxyphene is being reported. In general, the symptoms of overdosage are similar to those resulting with other narcotic drugs. Various degrees of respira- tory, central nervous system and circulatory depression are usually present. On time other hand, convulsions, seldom seen w-itli narcotics, as well as coma, have been reported and deaths have resulted. Death usually results from hypoxia accompanied by pulmonary edema and cardiac failure. Propoxyphene toxicity can be treated w-ith narcotic antagonists, such as Naloxone. The dependence to propoxyphene in narcotic dependent peisons is now well documented. It is substantially less intense than that seen with morphine or heroin but nonetheless it does occur. Physical dependence has been observed r)ar- ticularly \vi tim high closes. Some physicians a 11(1 pham-muacologists have suggested that dependence would be mnore frequent if the drug w-ere administered iii high emiough closes to provide effective a mia lgesia. Orally administered propoxyphene 40-224 0 - 79 - 13 PAGENO="0194" 16746 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY is reported to be widely abused by adolescents since propoxypliene preparations have been reformulated to eliminate the pellets in the propoxypliene in capsules. Abuse by intravenous injection seems to be On the decline. The possibility of convulsions increases as the dose is increased. Dependent persons require large doses to obtain the desired effect and this dose may be the lethal one for certain individuals. The margin of safety is narrow when doses exceeding 100 mg are used. According to recent information released from the Drug Enforcement Agency, propoxypliene leads all other restricted prescription drugs in the United States in drug related deaths. Because propoxyphene is of so little value as an analgesic an(l becoming more widely abused and is not as safe as has been assumed, it is urged that the drug be controlled more strictly and placed in Schedule II or removed from the market. According to a report prepared by the Health Research Group (200P3 N.W., Washington, D.C.) during 1977 alone there were 589 pro- poxyphemie related deaths reported to this group which collects data from areas covering only 1/~ of the population of this country. This number is greater than the nunml)er resulting from the use of heroin. Since the question of safety is now before us and since there is so much doubt about its efficacy as an analgesic, the following conclusions, suggestions and recommendations can be made concerning propoxypliene: i. The drug could be under stricter controls and placed in Schedule II. 2. It is possible to maintain standards of good medical practice without pro- poxyphene; therefore, manufacture could be discontinued. 3. There is no medical justification for continuing its use as an analgesic because it has no therapeutic advantage over other drugs of similar potency that merit its being prescribed for relieving pain. Senator NELSON. Next, we will hear from Dr. William T. Beaver, associate professor of pharmacology and anesthesia at Georgetown University. it has been hard to hear Dr. Adriani from that microphone. Per- haps you can push it about 6 inches back. STATEMENT OP WILLIAM T. BEAVER, M.D.-Resumecl Di. BEAVER. I will do the best I can, Senator. I appreciate being in~rited back to talk after the almost 10 years since I was here last. I)uring the last 15 years, I have had repeated occasion to review the literature on propoxyphene. In 1965, I wrote a review of the clin- ical pharmacology of the mild analgesics. which included a substan- tial section on propoxyphene. In 1966 and 1967, I served as a member of the Panel on Drugs for Relief of Pain, Drug Efficacy Study of the National Academy of Sciences-National Research Council and was the primary reviewer on propoxyphene and its combinations for the Panel. On November 24, 1970, I appeared before this subcommittee to discuss the relative merits of various mild analgesics in the relief of pain, and a portion of this testimony was devoted to a critique of PiO1)oxYPhefle, or Darvon. Fioni 1969 to 1976, I served as a consultant for the Food and Drug Administration, primarily on matters related to analgesic drugs and the design and interpretation of controlled clinical trials for drug efficacy. While serving as a consultant for the FDA, I prepared a special critique of the efficacy of propoxyphene based on my review of the published literature and the New Drug Applications for various propoxv~hene products. This critique, submitted to Henry E. Sim- mons, M.D., Director, Bureau of Drugs, plus recommendations for revision of the propoxyphene labeling served as the basis for the re- PAGENO="0195" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16747 labeling of propoxyphene products which occurred in 1972. In 1976, I assisted the FDA in revising the propoxyphene labeling to reflect increased medical awareness (Finkel et al., 1976; McBay and Hudson, 1975) of the incidence of fatal overdose with propoxyphene alone and in combination with other ceiitral nervous system depressants. I subsequently served as a FDA consultant to their Controlled. Substances Advisory Committee in the matter of the advisability of scheduling Darvon under the Controlled Substances Act. The com- mittee recommended placing propoxyphene products in schedule IV. The Department of Health, Education, and Welf are concurred in this recommendation, and, in February 1977, the Drug Enforcement Administration issued a.n order to that effect. Since 1976, I have con- tinned to follow the literature on propoxyphene, in part because I am chairman, Advisory Panel on Analgesics, Sedatives and Anti-inflam- matory Agents for the 1975-80 revision of the United States Phar- macopeia. Now, concerning the general pharmacologic properties of pro-* poxyphene, propoxyphene or dextropropoxyphene (Darvon) is struc- turally related to the potent narcotic methadone and is itself a harcotic in all pharmacologic and toxicologic respects. It produces the full spectrum of pharmacologic effects in animals and man characteristic of the narcotics, and these effects are selec- tively reversed by the specific narcotic antagonist naloxone. Quanti- tatively, however, propoxyphene is substantially less potent on a milligram basis thaii narcotics . such as morphine, hydromorphine (Dilaudid) and methadone. In addition, high doses of propoxyphene have certain excitatory properties not noted with most other narcotics which, while they tend to discourage deliberate abuse of propoxyphene, make convulsions a common feature of propoxyphene overdose in addition to the usual narcotic overdose manifestations of respiratory depression and coma. In relation to propoxyphene's analgesic efficacy, which seems to be one of the major subjects that has been talked about thus far in these hearings, on reviewing those studies which have appeared in the in- terim, I find little necessity to modify my evaluation of the efficacy of dextropropoxyphene which appeared in 1966 which I presented in my testimony on November 24, 1970. Propoxyphene compared to placebo: In addition to the studies cited in my 1966 review, eight additipnal controlled analgesic studies have confirmed that a 65 milligram dose of propoxyphene hydrochloride or the equivalent 100 milligram dose of propoxyphene napsylate is sta- t.istically significantly superior to placebo in relieving postoperative and trauma pain, postpartum uterine cramping, postpartum episiot- omy pain, pain subsequent to oral surgery in outpatients and chronic pain of mixed etiology. A couple of studies have also. succeeded in demonstrating a statis- tically significant difference between placebo and either 32 milligrams of propoxyphene hydrocholoride or the equivalent 50 milligram dose of propoxyphene napsylate; but these obviously represent threshhold or marginally effective doses of ipropoxyphene, the analgesic effect of which doses can only very rarely be measured in even the most sensi- tive analgesic assays. PAGENO="0196" 16748 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Five additional studies since my original testimony have also con- firmed the existence of a significant positive slope for the dose-response curve of propoxyphene using various graded doses of the hydrochlor- ide salt from 32 to 200 milligrams and/or the equivalent doses of the napsylate salt of 50 to 300 milligrams. In my opinion, the above cited studies alone and in conjunction with those I have previously reviewed, prove beyond any doubt that pro- poxyphene hydrochloride in doses of 65 milligrams and higher or pro- poxyphene napsylate in closes of 100 milligrams and higher have some analgesic activity in patients with pain of a wide variety of etiologies. Indeed, since propoxyphene produces narcotic-like responses in all pharmacologic tests with which I am familiar, can produce drug de- pendence of the classic narcotic type and produces an overdose syn- drome characteristic of narcotics, I would find it impossible to explain how the drug could possibly not be an effective analgesic at some dose level. Now, several double-blind studies which ostensibly meet the mini- mum criteria for a controlled clinical trial of analgesic efficacy have not demonstrated a statistically significant difference between the anal- gesic effect of 65 milligrams of propoxyphene hydrochloride and a placebo treatment. There are a number of possible explanations for this state of affairs, and most of them hinge on an understanding of the concept of assay sensitivity as it applies to clinical trials of analgesics. Because of the multiplicity of known and unknown variables which affect the course of a patient's pain and its response to analgesics, and because there is no satisfactory measure of a patient's pain other than the patient's own subjective reports of this experience, analgesic clin- ical trials vary greatly in their ability to demonstrate the efficacy of even known effective analgesics. That is, they vary widely in their assay sensitivity. Therefore, unless an analgesic clinical trial contains an internal measure of assay sensitivity that demonstrates that the trial is capable of measuring an analgesic effect of the magnitude an- ticipated to result from administration of the test drug, for example propoxyphene, a negative finding concerning the efficacy of the test drug has no meaning. Most of the clinical trials which did not distinguish propox~rphene from placebo either did not contain a measure of assay sensitivity or were clearly insensitive in that they also could not distinguish known analgesics. for example. codeine or aspirin from placebo. Furthermore. since single closes of propoxyphene 65 milligrams are almost certainly less effective than the usually used doses of the mild analgesic standards. codeine 65 milligrams, aspirin 650 milli- grams. acetaminophen 050 milligrams or two APC tablets, an oral mild analgesic study may have adequate assay sensitivity to demon- strate a statistically significant difference between one or more of these standards and the placebo. while still not being able to identify the less substantial analgesic effect of propoxyphene 65 milligrams as statistically significant. That is my interpretation of the results of Dr. Moertel's study which was Presented in the New England Journal of Medicine and which he discussed yesterday at these hearings. PAGENO="0197" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16749 Now, concerning the comparisions of propoxyphene with other mild analgesics, first propoxyphene compared to codeine. Since propoxyphene is a "weak" narcotic, oral codeine is the most appro- priate standard of comparison. My review of the literature in 1966 led n'ie to the conclusion that ~ hyclrocholoride was definitely less: potent on a milli- gram basis than codeine, my best estimate of the relative potency of the two drugs being that propoxyphene is one-half to two-thirds as potent as codeine. In the interval, no definitive relative poteiic~~ assay comparing graded closes of the two drugs has appeared, but, the results of a few more recent clinical studies are generally consistent with the above estimate. Two other studies designed to evaluate the analgesic effect of two consecutive doses of each of the study medications, suggest that pro- poxyphene napsylate 100 milligrams is approximately equianalgesic to codeine 60 milligrams, but deficiencies in data presentation make it impossible for me to judge the yalidity of this interpretation. Mr. Chairman, I am leaving out the reference citations which back up all of these statements that I have been making because I assume they will appear in the printed jecorci of my statement. Senator NELSON. Yes; they will appear in the record. Dr. BEAVER. Now, propoxyphene compared to aspirin, acetamino- phen or APC: The results of studies I reviewed in 1966 and a few more recent studies comparing propoxyphene hydrochloride 65 milli- grams or propoxyphene napsylate 100 milligrams with aspirin 650 milligrams, acetaminophen 650 milligrams or 1,000 milligrams, or APC 2 tablets are consistent with the evaluation which I presented to this subcommittee in 1970; namely, that propoxyphene at recom- mended doses is certainly no more, and probably less, effective than usually used doses of aspirin, acetaminophen or APC. Concerning the efficacy of prôpoxyphene as a constituent of drug combinations. Relatively little propoxyphene is used as a single-entity analgesic. Well over 80 percent of the prescriptions for propoxy- phene products are for combinations of propoxyphene with acetamino- phen, APC, or aspirin. The rationale for these combinations is the same as that which under- lies combinations of codeine and other yet more potent narcotics with these same antipyretic-analgesics; namely, production of more intense analgesia than can be provided by using a single agent and reduction of side effects by ieducing the dOse of any one analgesic. Although experimental evidence to substantiate these theoretical rationales is far from ideal or complete, there is a substantial body of evidence from well-controlled clinical analgesic trials to indicate that combinations of appropriately chosen doses of antipyretic- analgesics with narcotics do, in fact, achieve these objectives. The slopes of the log dose-response curves of analgesic drugs are relatively fiat, with the result that even successive doubling of the dose produces only modest increments of analgesic effect. Narcotics and antipyretic-analgesics such as aspirin are known to produce analgesia by different mechanisms, and the simple additive PAGENO="0198" 16750 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY effect of a narcotic and an antipyretic-analgesic given together is often significantly greater than the analgesia achieved by doubling the close of either ding administered alone. Furthermore, antipyretic-analgesics probably exhibit a ceiling of analgesic effect at about the usually used doses-650 to 1,000 milli- grams-and the usefulness of higher doses may also be limited by increased incidence of adverse effects and serious cumulative toxicity. Increasing doses of codeine, j~ropoxyph1ene and other narcotics are associated with a progressively increasing incidence and severity of gastrointestinal and central nervous system side effects and increased risk of drug dependence. The problem of providing adequate pain relief in the face of the above noted limitations of currently available analgesics may some- times be circumvented by combining an optimal dose of an antipyretic- analgesic with an orally effective narcotic in a modest dose which is reasonably safe and well-tolerated. Older relevant studies for both codeine and propoxyphene combina- tions are cited in my 1966 review. There are a few more recent studies whicli appear to demonstrate a significant increase in analgesic effect produced by the addition of prO~)Oxyphene to acetaminophen. J)i. Moertel and his associates showed a small increase in the effect of aspirin 650 milligrams produced by the addition of propoxyphene napsylate 100 milligrams, but the difference was not statistically significant.. Now I would like to briefly touch on the adverse effects of propoxy- pliene. There are. really three types and it is important to think clearly about this issue, to keep these types of adverse effects separate in one's mind, because they have different implications in relation to drug abuse. TI three types are adverse effects seen at recommended thera- l)eut.ic (loses; adverse effects seen in overdose and the issue of drug dependence on P ropoxvphene. In relation to adverse effects of propoxyphene at therapeutic dose levels or recomnlende(l dose levels, which is propoxyphene hydro- chloride 65 milligrams or propoxyphene napsylate 100 milligrams, propoxyphene produces an extremely low level of adverse effects. As a matter of fact, most studies are unable to demonstrate a signifi- cantly higher incidence of adverse effects with these doses of pro- poxyphene than with a placebo. When large enough groups of ambulatory patients are studied to demonstrate any difference in terms of adverse effects between ther- apeutic doses of propoxyphene and placebo, the adverse effects con- sist of a very low incidence of tiaiisea and drowsiness. Considering the extraordinarily large use of propoxyphene prod- ucts, there is extremely little in the entire literature which indicates that the drug in recommended therapeutic doses can produce any serious adverse effects, and even minor adverse effects seem to occur only infrequently. Now, concerning the toxicity of propoxyphene in overdose: As noted above and as is amply attested to by numerous individual case reports and several epidemiologic studies; propoxyphene, like any PAGENO="0199" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16751 other narcotic, can be lethal in ovedose; although the full extent of this problem was not appreciated until relatively recent. Back in the late 1960's we were aware of only occasional cases of overdose. I can recall that, when I reviewed the New Drug Applica- tion in 1971 for the FDA, I really could only scratch up a handful of lethal cases of propoxypliene overdose froiii its introduction until that time. My guess is that the very substantial increase which has ap- peared over the course of the last several years does not necessarily reflect a true, very substantial increase in the number of propoxy- phene related deaths, but rather that dependable analytical methodol- ogies to demonstrate propoxyphene in the bloodstream was only really developed and became available in the late 1960's and the early 1970's. When you start looking for something with a useful tool, you begin to find it, and that may account for the discrepancies. In regard to the dependence liability of propoxyphene, since pro- poxyphene is pharmacologically a narcotic, it has some ability to produce drug dependence of the narcotic type, and this has been recognized siiice before the drug was marketed. Propoxyphene can produce the classic triad of psychic dependence, physical dependence and tolerance, and, in those patients who are able to tolerate high enough doses to result in substantial physical dependence, a narcotic-type abstinence syndrome has been observed on withdrawal. "Street abuse" of the drug clearly occurs, as does dependence sec- ondary to therapeutic use. However, in my opinion, relative to the extremely wide use of propoxyphene, the demonstrated incidence of serious deliberate abuse of the drug to experience its mood effects is not great and is certainly less than is the case with potent narcotics. Senator NELSON. May I ask a question. Dr. Beaver? Yesterday, the witnesses who testified from North Carolina and Oregon were divided on the question of whether or not intentional overdose was a serious question. * One of the witnesses felt very strongly that a good many, over half of the deaths that occuiied. were not drug abusers or those who intentionally overdosed themselves, based on the study of the stomach contents and so forth. So his argument was not because it was being abused-any drug can be abused-but because people were getting overdoses unintentionally. Dr. BEAVER. Let me clarify the point. T believe what the mHe(liCaheX- aminer from Oregon was pointing out was that he felt that many of these deaths were associated with accidental overdose as O1)pOsed to deliberate suicidal overdose. rlhat is the (listinction I think lie was making. Neither of those things is the same as what I am talking about~ which is the deliberate use of the drug to experience the mimood effect that is to say, drug abuse consi(lerations. Senator NELSON. I was only saving, if it was time Oregon witness. that it is his feeling that most of the deaths were not intentional overdosages. Dr. B1i~~vER. Weie not suicidal, hut neither suicides nor accidents are specifically related to the use of the drug for mood effect. Senator NELSON. I understand. PAGENO="0200" 16752 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. BEAVER. What I am talking about here is the degree to which people seek this drug out and take it to get "high" and that sort 0± thing, the same way heroin is abused. I am pointing out that that type of abuse of the drug, from what I can tell, is relatively low, and it was predicted to be low on the basis of the work that was done back in the 1950's for very particular reasons. I digress from my testimony because it is important to explain this. Physicians are very sensitive about this. They are almost paranoid about the issue of inducing drug dependence in their patients with the narcotics they give them. So there has been a tremendous effort over the years to develop narcotics which would not have that effect, good analgesics which do not have a narcotic-type abuse liability. Darvon was, in pai~t, a result of this line of work. When it was tested at Lexington, it turned out it did have the narcotic-type abuse liability, but only to a very limited degree. If you gave small doses to the post- addicts they would report it as being narcotic, but they said, "It is very weak, give me more." You give a higher dose and they say, "Yes, that feels better, but give me some more." So you give a higher dose and some subjects would have convulsions. Propoxyphene has a toxicity which discourages deliberate abuse in the sense of people taking it to get "high" and, of course, the whole focus at that time was to avoid such problems. You see, the problem that this brings along with it is that you have a drug which may be inherently more toxic when somebody takes it in overdose than conventional narcotics. So you have the two-edged sword. You are trying to make a drug that people do not like to abuse, and you do it by making the drug more toxic, but this creates certain other kinds of problems. I am trying to bring out the history of why we are in the situation we are in at the moment. Senator BUMPERS. Dr. Beaver. you heard Dr. Adriani's response to my question about what the dangers are and he saidi it is the part of piopoxyphiene that goes to the liver and l)ecomes nor-propoxyphene and builds up in the liver and stays in the body and cumulatively, the danger is greater than normal analgesics. Dr. BEAVER. This is a interesting hypothesis andi I will mention this further in my testimony. I would point out we know very little about nor-propox'vphene There are only a couple of studies in the literature on the metabolite when it is given alone to animals. We know essential- ly nothing about what this material does when giveii alone to man. Most of the Darvon overdose deaths which I have read about in re- viewing the literature can very adequately be explained simply on the basis that this drug is a. narcotic and P1Oduces narcotic depression and coma; produces convulsions which makes it hardier to treat the overdose audi the patient then dues. The nor-propoxyphene matter is something that has recently come up and represents an interesting pharmacological lead that may, in fact., account for some of the aspects of the poisoning that we have not been able to account for. But one must make the distinction between something w-hich is well established scientifically, in fact. andi some- thing that is just. an interesting pharmacological leadi. Senator HATCH. Doctor. it is my understanding people are not dying from piopoxyphene per se, but from ingesting overdoses of the drug PAGENO="0201" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16753 and the testimony has been that from 10 to 20 times the normal dose is the amount causing these deaths. Yesterday, Dr. Moertel of the Mayo Clinic and Sidney Wolfe, a physician, indicated, if I am correct, that two capsules of Darvon were lethal. Dr. BEAVER. That is categorically not the case. Senator HATCI-i. In other words, you are totally refuting what they say. Dr. BEAVER. I do not believe they actually said that, but it is not the case. Senator HATCH. Assuming they did, why would they say something like that? Dr. BEAVER. Did you say that? Dr. WOLFE. I was quoting the coroner in San Francisco who said people using it on a regular basis, twice the normal dosage, not two capsules we are talking about but two capsules every 4 hours instead of one. Senator HATCH. I am glad you were here to correct that. With regard to those who take propoxyphene regularly in recom- mended dosage over many years; some people have indicated t~hey may be dying from a drug buildup. What does the record show with regard to that, is there a buildup potential here? Dr. BEAVER. There is a buildup when the drug is taken repeatedly at 4-hour intervals at the recommended dose of 65 milligrams. Senator HATCH. I see. Dr. BEAVER. At the recommended dose of 65 milligrams there is an accumulation of both propoxyphene and nor-propoxyphene. Both of these flatten out at some level because the more there is, the more rap- idly both of these things are eliminated. You get to the point here where the amount coming in equals the amount going out, at which time you get a plateau. For the usual recommended therapeutic dose of propoxyphene there is no evidence that when you take 65 milligrams every 4 hours indefi- nitely you can build up a blood level of either or both of these mate- rials which is fatal. Senator HATCH. As a matter, of fact, at the University of Utah, Dr. Finkel indicated that the record shows millions of patients who use it in the normally prescribed manner do not suffer any serious or fatal effects at all, is that correct? Dr. BEAVER. That is correct. Senator HATCH. And Dr. Finkel's findings affirmed that. Dr. BEAVER. That is correct. Senator HATCH. Do you knOw of any deaths which occurred from normal, prescribed use? Dr. BEAVER. I have not been able to identify any, but you see, often with the literature on this subject even the medical examiner is not certain of what dose was taken. When you have somebody who is dead, it is sometimes not possible to determine how much of what they took, ~Darticularly until very recently when you had methods for measuring blood levels. I found no evidence that the usual therapeutic dose of propoxyphene can result in death, and, as I pointed out, it does not PAGENO="0202" 16754 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY even tend to result in much in the way of subjective side effects or even serious adverse effects. Senator HATCH. Or even a buildup which could cause death? Dr. BEAVER. Yes. Now, the matter which I think is a reasonable question here is what happens if someone crowds the dose a bit be- cause they are not getting enough pain relief in taking 65 milligrams every 4 hours, so they decide to take twice that-130 milligrams every 4 hours. This will accumulate to a higher plateau level and there will also be more propoxyphene in the blood. A lot of people in fact, take double the dose and they seem to get away with it, though you get more side effects. Then the question is, if on top of that situation somebody then takes a modest overdose, but not a massive overdose, whether you now have the stage set for a lethal occurrence, and I think some of these cases that were described by the coroner in Oregon may represent that kind of a situation. That, sir, is my educated gu~s~ froui looking at the data in the litera- ture. Somebody has'~1~ë~idy~ö1ten up to a blood level such that even a small overdose on top of that-in other words, it no longer takes 15 to 20 capsules to kill you,jyj~ichis-what.McBay and Hudson would say is a single lethal dose, but now a l6wer single overdose will kill if the person has already been taking it for a long period of time. Senator B05CHwITz. If the person, is taking it as prescribed, it is not a problem. Is that your conclusion? Dr. BEAVER. Yes; that is my conclusion, and I do not know if any of the people who testified here have argued that if it is taken as pre- scribed it constitutes a problem. I think the problem, as I envision it, is that propoxyphene is a drug which is very commonly available and, in overdose, quite clearly can kill. Senator HATCH. What you seem to be saying is that overdose is drug abuse and that overuse coupled with other drugs or alcohol can kill. Dr. BEAVER. Yes. Senator HATCH. But you do not think anybody would refute your statement that normal, prescribed use would not kill and would not be dangerous to the normal human being? Dr. BEAVER. That is right, but you have to consider the issue as to the margin of safety and how far these two doses are away from each other in any given case. If they are close enough you can have a fairly risky situation. It is obvious that if you have a drug which used in its appropriate way at a certain dose produces no serious side effects and it ta.kes a liundred~ times that to kill you, that drug is safer than a drug which, if you only take ten times the usual therapeutic close can kill you, because the likelihood of people dying from overdose is going to be inversely related to the size of the lethal overdose relative to the thera- peutic close they usually take. WTith aspirin, it is hard to commit suicide because most adults can- not stomach enough aspirin to poison themselves. Senator HATCH. With regard to Darvon-in the prescribed dose it is not a serious drug problem? Dr. BEAVER. I would say that. I would like, to continue my dis- cussion briefly with the adverse effects of alternative mild analgesics PAGENO="0203" COMPETITIVE PROBLEMS, IN THE DRUG INDUSTRY 16755 because any &ttempt to assess the benefit/risk ratio for propoxyphene must necessarily take into account the known adverse effects of alter- native mild analgesics. I am concerned that there is expressed or implicit in certain recent discussions of the usefulness of propoxyphene the assumption that alternative mild analgesics are more or less devoid of adverse effects and are in some general sense "safe." This is clearly not the case, and I can speak to this on the basis of having worked extensively in this field since about 1963. Aspirin can be lethal, not only in overdose, but also at usual thera- peutic dose levels in individuals who ale hypersensitive to the drug or who experience massive gastrointestinal bleeding or other bleeding associated with aspirin's effects on blood coagulation. Until recently, acetamninophen has been felt to be singularly free of adverse effects, and this is probably still true at conservative thera- peutic doses. However, it is becoming increasingly apparent that over- dose with acetaminophen can produce massive hepatic injury resulting in death, and in Great Britain, where the use of acetaminophen is even more widespread than in the United States, it has been esti- mated that acetamin'ophen poisOning is now a leading cause of acute hepatic failure. Chronic use of phenacetin-containing analgesic mixtures has been associated with potentially fatal renal damage, and the Food and Drug Administration's Over-the-Counter Analgesic Review Panel has recommended removing phenacetin from the over-the-counter market for that reason. The relative contribution of phenacetin as opposed to other mild analgesics in the development of this syndrome is a subject of debate, and it is unclear whether acetaminophen may not also produce serious renal injury when abused in combination products for prolonged periods of time. The incidence of adverse reactions to codeine in usual therapeutic doses is low. The drug can produce a typical narcotic overdose syn- drome and death, but the reported incidence of this appears low rela- tive to codeine's extremely wide ëlinical use. Codeine may be safer in this iespect than equi-analgesic amounts of propoxyphene, although further study would have to he done to estab- lish this. Codeine has narcotic-type dependence liability, although, like propoxyphene, the incidence of this problem is very low con- sidering the wide therapeutic use of codeine-containing combinations. Oral pentazocine is an effective mild analygesic more or less com- parable to codeine in potency. Because the drug is a mixed agornst/ antagonist rather than a classic narcotic, there is reason to believe that lethal overdose would be even less of a problem than with either propoxyphene or codeine. However~ pentazocine seems to produce a somewhat higher incidence of unpleasant adverse effects at usual therapeutic doses than equi-effective doses of codeine, and pentazocine occasionally produces frank psychotomimetic reactions which may be very disturbing to the patient. . . . While pei~tazocii~e has less abuse liability than regular narcotics, deliberate self-administration of the ding for its mood effects un- doubtedly occurs, and the Food and Drug Administration's Controlled PAGENO="0204" 16756 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Substance Advisory Committee has recently recommended scheduling pentazocine in schedule IV. The purpose of the above comments on alternative mild analgesics was not to denigrate the value of these drugs for the patient with pain, but rather to put the adverse effect liability of propoxyphene in some reasonable perspective. Now, concerning the adverse effects of schedule II narcotics. The only currently available alternative oral analgesics to the mild analgesics discussed above are the schedule II narcotics. These include such drugs as morphine, hyciromorphone, hycirocodone, oxycodone, levorphanol, anileridine, mepericline, and methadone. While in substantial oral doses, these drugs are all capable of pro- ducing significantly greater pain relief than the mild analgesics noted above, they are all quite capable of producing lethal narcotic overdose, and all have a clearly higher dependence and abuse liability than pro- poxyphene, codeine or pentazocine. In addition, doses of these schedule II narcotics which produce pain relief greater than the mild analgesics are also associated with a significantly higher incidence of disturbing gastrointestinal and cen- tral nervous system adverse effects. Therefore, their use would only seem to be indicated for those patients for whom conventional mild analgesics or combinations prove ineffective or not tolerated. I will list, not necessarily in order of importance the number of fac- tors which seem to me responsible for the popularity of propoxyphene products. First, it has been claimed that the popularity of propoxyphene in the face of its less than impressive performance in controlled clinical trials is primarily due to the extensive and effective promotional efforts for Darvon by Eli Lilly & Co. Indeed, the best ballpoint pen that I ever owned was given to me by a Lilly detail man and is emblazoned with the words "Darvocet N-l00." However, many drug companies utilize the services of inventive adver- tismg agencies and have dedicated swarms of detail men at their dis- posal and yet, much to their chagrin, these companies are unable to stir up the sustained high demand for their analgesic product which has been accorded the Darvon family. I think one must look further than promotional efforts alone to explain the success of propoxyphene over the past 20 years. which leads me to reason number two. Physicians seem to need a mild analgesic which is as effective as aspirin, acetaminophen or APC but which is not available over-the- counter. Many patients feel that these antipyretic-analgesics cannot be ter- ribly effective because they are available over-the-counter and have a psychological need to receive an analgesic which is only available on prescription. Physicians recognize awl respond to this need. Propoxy- phene products are available in a variety of impressive colors, shapes and sizes and are only available through prescription. Furthermore, as noted above, over 80 percent of prescriptions for propoxyphene prod- ucts are for combinations containing aspirin, acetaminophen or APO and these. combinations are at the very least as effective as the anti- pyretic-analgesics which they contain. This must be coupled with the fact that at recommended doses propoxyphene produces an extremely PAGENO="0205" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16757 low incidence of any sort of adverse effects and a virtually zero inci- dence of serious adverse effects. One must also consider the alternatives which the physician has available. When Darvon came on the market in 1957, the significant mild analgesics available as single entites and in combination included aspirin and other salicylates, acetaminophen, phenacetin, and codeine. Today, over 20 years later, the only addition to this group has been oral pentazocine. When the patient with persistent pain tells his doctor that his current medication is either ineffective or poorly tolerated-a repetitive occurrence for many patients with chronic pain problems- the physician needs alternatives available. Useful alternative medica- tions have simply not been forthcoming. Number three, physicians in general are very sensitive to the issue of the dependence liability of narcotic drugs. In many situations, this con- cern has been far in excess of what was warranted by any realistic evaluation of the likelihood of producing iatrogenic narcotic dependence. This anxiety extended to codeine, which in fact has extremely low abuse liability when used in any medically responsible way. Propoxyphene was probably originally perceived by physicians as a non-narcotic substitute for codeine and propoxyphene-containing combinations were marketed which corresponded to all of the existing codeine-containing combinations. Until the beginning of 1977, propoxyphene was an unscheduled drug, which implied that it was safer than codeine and its combina- tions in terms of dependence liability and also made for more con- venient prescribing and dispensing. Number four, although the most appropriate and, in fact, most popu- lar use of both propoxyphene and codeine is in combination with the antipyretic-analgesics, there are occasional pain problems in which the physician can quite legitimately want to prescribe either propoxy- phene or codeine alone. These include situations where there is an allergy or contraindication to the use of aspirin and acetaminophen. It would also include situations in which the practitioner wished to use a mild analgesic with no associated antipyretic effect. Number five, there is, in fact, good evidence that combinations of narcotics with antipyretic analgesics produce more analgesic than the antipyretic-analgesic given alone, and this increment of analgesic effect may often make the difference between unsatisfactory and satis- factory pain relief for particular patients. This increment of analgesic is often associated with very little increase in adverse effects and therefore, constitutes a very real benefit for the patient. To my way of thinking, this constitutes the major acceptable ra- tionale for the use of propoxyphene. It should be noted that this ra- tionale does not apply if the prescribed dose of a combination con- tains substantially less than the usual full therapeutic dose of the antipyretic-analgesic constituent. Senator NELSON. With regard to your fourth point, if the patient were allergic to aspirin, of course I assume the doctor then would not want to prescribe the compound of aspirin and propoxyphene. PAGENO="0206" 16758 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. BEAVER. Would not? Senator NELSON. Would not. Dr. BEAVER. That is correct. `What I am saying here is that. there are a few situations where you would want to give either codeine or propoxyphene alone. To my view, the major use of either of these drugs is in combination with drugs such as aspirin or acetaminophen and actually the drugs aspirin and acetaminophen are the first line drugs among the mild analgesics, and then one can add narcotics to them. Now, getting back to my sixth point, controlled clinical trials of analgesics invariably compare the average responses of groups of patients to the various treatments. While the average relative performance of various analgesics is the best predicator of how the generality of patients with pain will respond, individual pat.ients may. for reasons which we simply do not currently understand, derive a better analgesic effect from a drug which on the average is less effective than another. Controlled clinical trials of analgesics are not currently designed to explore this phenomenon, and the determination of the optimal analgesic regimen for any given patient must ultimately be based on the empirical observation of the effect of various analgesics in that patient. It is, therefore, in the patient's interest to have as wide a variety of effective analgesics available as possible, even though some of these may on the average be less efficacious than others. Item No. 7'-virtually all controlled clinical trials of analgesics, including propoxyphene, have involved comparison of single adminis- trations of various analgesics; however, in the practice of medicine, most patients receive not a single dose but repetitive doses of analgesic drugs for the control of their pain. While up to this time the results of single administration studies have seemed to constitute reasonably accurate predicators of the rela- tive performance of analgesics when administered repetitively-if one keeps in mind the impact of the development of tolerance to nar- cotics-it is conceivable that repeated administration of some analge- sics results in a higher level of efficacy than would be predicted on the basis of single-dose administration. Propoxyphene has a substantially longer half-life in the blood than other mild analgesics such as codeine, acetaminophen or aspirin. When administered every 4 to 6 hours, as mild analgesics. usually are, there will be a significantly greater cumulation of propoxyphene levels than with alternative mild analgesics. We do not currently understand the relationship between the blood level of an analgesic and the analgesic effect experienced by the patient, but a plausible argument~ can be made on the basis of blood level data that one might expect greater analgesia after a few repeated doses of propoxyphene relative to alternative mild analgesics than is, in fact, seen in single administration studies. Unfortunately, few analgesic studies of repeated dosing have been done to examine this hypothesis, and those that have been done are difficult to interpret. It is, therefore, possible that practitioners empiri- cally find that propoxyphene products are more effective in regular PAGENO="0207" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16759 clinical use-that is, when administered in repeated doses-than would be predicted on the basis of the cOntrolled clinical trials which involve single administrations of test medication. Senator NELSON. When you say repeated doses, what do you mean by that, over a period of days or weeks? Dr. BEAVER. Even three or four doses in the course of, say, 12 to 20 hours. The cumulation reaches about 90 percent at its maximum if propoxyphene is given, say, every 6 hours for about 6 doses or so. Beyond that it does not go up any further. Senator NELSON. In your testimony, my impression is you are care- fully addressing the question of a patient who may not respond to aspirin or acetaminophen and therefore; if I understand your testi- mony, there may be circumstances in which the doctor then would pre- scribe something that had a narcotic in it, whether codeme or propoxyphene. Let me ask you this: As a matter of good medical practice for a pa- tient who the doctor had not evaluated as one whose pain problem was not controlled by the ordinary mild nonprescription analgesics, for that patient what is the drug of choice? Dr. BEAVER. Oh, my feeling in this matter is very much the same as Dr. Moertel's. I do not know whether he said so yesterday, but he has written about this in a recent paper. I feel the basic mild analgesics of choice are aspirin and acetaminophen. That is where you start and then you start moving on, start adding certain other things to these drugs if they alone are not effective. Now, the situation you have, though, with a practitioner is that very often the patient, when he arrives at the doctor's office, has already tried out aspirin or APC because they can be purchased over-the- counter. In other words, the patient says, "I have this problem with headache and I have tried aspirin and it does not help" or "I twisted my ankle and it hurts. I have taken some aspirin and it gives me some relief but not enough relief." For the doctor to turn around and say, "take two aspirin every 4 hours" is perceived by the patient and the doctor as perhaps inappropriate. You see, all of these reasons I am giving you are not equally defensi- ble reasons for using propoxyphene. What I am trying to do is to get to the issue that repeatedly comes up and is never really grappled with: Why doctors are prescribing $80 million worth of this stuff a year when controlled clinical studies seem to indicate propoxyphene is sort of a mediocre drug. What I am pointing out here is that there are a lot of considerations that go into the use of analgesics in the actual practice of medicine as it is practiced. They have not been stated and I am trying to define them. We can argue with some of these reasons, and I am not necessarily for all of those different reasons concluding they are good reasons for doing something. I am merely trying to get them on the table so we can consider them. Suppose propoxyphene were to vanish from the market tomorrow. Puff, and its just gone. I can guarantee one thing that would not hap- pen. The physicians who are now prescribing propoxyphene and, its combinations would not tell their patients to go home and take two PAGENO="0208" 16760 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY aspirin or two acetarninophens. They are going to go to some other combination or product which is only available by prescription, be- cause that is one of the reasons they are using propoxyphene now, so they will go to another prescription analgesic. This brings up the issue of what other ones there are and what are the dangers of these materials. Senator NELSON. Are you suggest.ing if you made all of these pre- scription drugs, which would increase the price, that that might be better? Dr. BEAVER. Well, people need to have the ability to go to the drug- store and get something effective for pain relief for situations that they do not consider important enough to go to a physician. I have said many times that if there were a green aspirin that no- body knew was an aspirin except the. doctors, and you could prescribe it and it came in long green tablets or capsules or blue and green cap- sules and so on, this would be a very useful medication from the stand- point of the physician because it would allow the tangible therapeutic symbol of writing the prescription for the patient. The patient comes into the doctor with a self-limiting illness. The doctor does a history and physical and comes to the conclusion that if he can prevent the l)atient from doing something foolish within the next few days the patient will get better. Now, the patient has some pain so the physician wants to do some- thing about this, and it may very well be that an appropriate thing to do is to say, "go home and ta.ke two aspirin every 4 hours and stay in bed or get lots of fluid or take two Tylenol," but the patient may feel, "look, I have spent $25 and I have lost a half-day of my time and this boob tells me to go home and take two aspirin." The doctor is sensitive to this possibility, so what happens is that the doctor wants to prescribe something that may be a little bit more effective than two aspirin and that can only be gotten by prescription so the patient will feel that lie has been treated. \\Tell, the doctor writes a prescription for, say, a. Darvon combina- tion with aspirin, APC. or acetaminophen, or a small amount of co- deine with aspirin or APC. These are slightly more effective than the aspirin and they fulfill this perceived need to give a prescription. The reason I am bringing this out is that you are unlikely to change this aspect of medical practice. this need to give something by pre- scription, so if one were to ban l)roPoxyphene~ just flatly ban it., doc- tors would not just tell people to take over-the-counter drugs; they will use other combinations and other drugs available only by pre- scription. Therefore, part of the implication of banning propoxyphene has to be a consideration of what are the risks of other kinds of preparations, prescription drugs that the patients might get instead. Senator NELSON. That. sounds as if you are really saying that if it were banned. many doctors for whatever reason would not. engage in what would be the best. medical practice in terms of treating a head- ache or something like that but., in fact., would look for something else. You look at. the studies and you know there is a. rather frighten- ing situation in the use of antibiotics, where on find for the com- mon cold, 95 percent of the doctors give something. maybe aspirin. PAGENO="0209" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16761 and about half of that 95 percent give an antibiotic and there is no *virus controlled by it. Dr. BEAVER. And hopefully, they no longer give chloramphenicol~ After your hearings it went down a long way. I think that was a very extremely valuable result of our hearings. It is true that from an objective standpoint, doctors often practice less than optimal medicine, but as I said, there are a lot of patients who come into the doctor's office and say they have already tried aspirin or acetamino- phen and it has not helped, so the option the doctor has is to give this or something else. Senator NELSON. Well, a. little while back you said something about agreeing with Dr. Moertel, but let me read to you his last paragraph of his statement yesterday. Dr. BEAVER. Well, this was not his statement yesterday. I was talking about a paper published in the Anstralian-New Zealand Medical Journal where he gave a hierarchy of how he would treat pain starting with aspirin and acetammophen, and if that did not work, he would add codeine at certain close levels, and if that did not work, he would go to larger doses of orally effective narcotics and if that did not work, he would go to injections. There is that hier- archy and we would not be that much at variance. Can I just finish this statement? Senator NELSON. Sure. Go ahead. Dr. BEAVER. There are a larger number of unresolved issues here concerning the benefit/risk ratio of Darvon and its place as an anal- gesic, and these deserve further study. Since a majority of fatal piopoxyphene overdoses seem to result from mixed intoxication with propox~Tphene and other central nerv~ ous system depressants, some effort should be directed at determining whether propoxyphene is simply adding to the depressant effects of other drugs or is producing a supra-additive interaction which is paiticimlaily hazardous. Second, although the descriptions of fatal poisoning with propoxy- phene which I have studied suggest that this drug is producing death in the same way as any classical narcotic overdose-albeit, the overdose syndrome is usually complicated by the presence of convul- sions-studies should be clone to determine whether propoxyphene has a direct cardiovascular toxicity in excess of other narcotics, and further studies should be done to elucidate the role of nor-propoxy- phene in the toxicity produced by propoxyphene. Three, since codeine-containing combinations are the logical alter- native to existing Darvon coiñbinations and are prescribed to an even greater extent than Darvon combinations it would appear logical to make a conceited effort to determine whether the apparent lower in- ciclence of codeine-related deaths is a real phenomenon and, if so, why? Four, controlled analgesic studies involving repeated dose adminis- tration of propoxyphene compared to other mild analgesics should be done to determine whether the predicted increase of efficacy of pro- poxyphene on repeated-dose administration really occurs. Dr. McBay feels that codeine is very rarely related to overdose death. The DAWN data would indicate it is lower than propoxyphene. This needs to be clarified, because if codeine is trimly extremely seldom 40-224 0 - 70 - 14 PAGENO="0210" 16762 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY related to overdose death, then one has a very clear and perhaps pref- erable alternative that you can generally recommend. On the other hand, if codeine is onl a little less likely to produce overdose death than Darvon. you get into an "out of the frying pan into the fire" situation if you just flatly ban one drug and then every- body rushes to the other. That matter needs to be settled. Another point in my statement is alternatives to the use of propoxy- phene and other narcotics. The number of oral analgesics which might be predicted to have advantages over propoxyphene and other currently available mild analgesics in terms of increased analgesic efficacy and/or decreased adverse effect liability are currently in various stages of clinical testing. These include the nonsteroidal anti-inflammatory drugs such as ~ndoprofen, suprofen, zomepirac. cliflunisal and many others; narcotic antagonist analgesics such as butorphanol, nalbuphine, buprenorphine, propiram and others; and compounds of uncertain mechanism of action such as nefopam. There are controlled clinical studies indicating that all of these compounds are effective oral analgesics and other studies indicating they may have certain real advantages over existing drugs. The public interest would be served by seeing that these drugs get on the market without undue delay. I would point out that the average physician will very quickly start prescribing a drug which has real advantages for his patient if such a drug becomes available. Since Darvon came on the market in the late 1950's, if there were a number of other drugs out there and studies showing they had some- thing to offer, my suspicion is you would not have to push clinicians into moving away from Darvon, because they would perceive these other drugs had real advantages for their patients with less 1)Otential hazard. Senator NELSON. Thank you, very much, Dr. Beaver. We may have some additional questions. Dr. BEAVER. Senator, there are a number of references in my state- ment that I did not give orally and I would ask that the full text of the statement be printed in the record. Senator NELSON. Without objection, your full statement will appear in the record at this point.. [The prepared statement of Dr. Beaver follows:] STATEMENT ON THE EFFICACY AND SAFETY OF PROPOXYPHENE (DARvON) n~ WILLIAM T. BEAVER, M.D., ASSOCIATE PROFESSOR OF PHARMACOLOGY AND ANESTHESIA, GEORGETOWN UNIVERSITY SCHOOLS OF MEDICINE AND DENTISTRY, WASHINGTON, D.C. This statement is in response to the request of the Monopoly Subcommittee of the Senate Small Business Committee that I discuss what I consider to be the relative efficacy of Darvon as compared to other analgesics, the medical justifica- tion for its use and any other aspects of Darvon which I consider relevant to a critique of its safety and efficacy. During the last 15 years, I have had repeated occasion to review the literature on propoxyphene. In 1965. I wrote a review of the clinical pharmacology of the mild analgesics, which included a substantial section on propoxyphene [Beaver, 1965 and 19661. In 1966 and 1967, I served as a member of the Panel on Drugs for Relief of Pain, Drug Efficacy Study of the National Academy of Sciences- National Research Council and was the primary reviewer on propoxyphene and PAGENO="0211" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16763 its combinations for the Panel. On November 24, 1970, I appeared before this Subcommittee to discuss the relative merits of various mild analgesics in the relief of pain, and a portion of this testimony was devoted to a critique of propoxyphene (Darvon®). From 1969 to 1976, I served as a consultant for the Food and Drug Administration, primarily on matters related to analgesic drugs and the design and interpretation of controlled clinical trials for drug efficacy. While serving as a consultant for the FDA, I prepared a special critique of the efficacy of propoxyphene based on my review of the published literature and the New Drug Applications for various propoxyphene products. This critique, sub- mitted to Henry E. Simmons, M.D., Director, Bureau of Drugs, plus recommenda- tions for revision of the propoxyphene labeling served as the basis for the re- labeling of propoxyphene products which occurred in 1972. In 1976, I assisted the FDA in revising the propoxyphene labeling to reflect increased medical awareness [Finkel et a!., 197U ; McBay and Hudson, 19751 of the incidence of fatal overdose with propoxyphene alone and in combination with other central nervous system depressants. I subsequently served as a FDA consultant to their Controlled Substances Advisory COmmittee in the matter of the advisability of scheduling Darvon under the Controlled Substances Act. The Committee recom- mended placing propoxyphene products in Schedule IV. The Department on Health, Education, and WTelfare concurred in this recommendation, and, in February 1977, the Drug Enforcement Administration issued an order to that effect. Since 1976, I have continued to follow the literature on propoxyphene~ in part because I am Chairman, Advisory Panel on Analgesics, Sedative~ amid Anti-inflammatory Agents for the 1975-1980 revision of the United Stateu Pharmacopeia. In addition, for the purpose of this testimony, I have studied a letter dated November 21, 1978 from Dr. Sidney Wolfe of the Health Research Group to Joseph Califano, Secretary of the Department of Health, Education, and Welfare urging an immediate ban on the marketing of propoxyphene as an imminent hazard under the Food, Drug and Cosmetic Act, and a petition by the same group to the Attorney General of the United States and the Drug Enforcement Adminis- tration resquesting the transfer of propoxyphene from schedule 1V to Schedule II under the Controlled Substances Act. I have read those literature references cited in that petition with which I was not already familiar and have reviewed the response to the letter to Secretary Califano prepared by the Eli Lilly Com- pany and submitted to the Food and Drug Administration on December 28, 1978. I have also reviewed those clinical trials relevant to the analgesic efficacy of pro- poxyphene products appearing in the archival literature since my review of this subject for the Food and Drug Administration dated May 18, 1971. The critique which follows represents my opinions derived from examination of the above cited data base, my general knowledge and experience as a clinical pharmacol- ogist primarily concerm1ed with the clinical evaluation of analgesic drugs and my experience as a clinician and consultant responsible for the use of analgesics in the management of patients with various acute and chronic painful states. GENERAL PHARMACOLOGIC PROPERTIES OF PROPOXYPHENE Propoxyhene or dextropoxyhéne (Darvon®) is structurally related to the potent narcotic methadone and is itself a narcotic in all pharmacologic and toxicologic respects. It produces the full spectrum of pharmacologic effects in animals and man characteristic of the narcotics, and these effects are selectively reversed by the specific narcotic antagonist naloxone. Quantitatively, however, propoxyphene is substantially less potent on a milligram basis than narcotics such as morphine, hydromorphone, (Dilaudid®) and methadone. In addition, high doses of propoxyphene have certain excitatory properties not noted with most other narcotics which, while they tend to discourage deliberate abuse of pro- poxyphene, make convulsions a common feature of propoxyphene overdose in addition to the usual narcotic overdose manifestations of respiratory depression and coma. ANALGESIC EFFICACY On reviewing reports of studies which have appeared in the interim, I find little necessity to modify my evaluation of the efficacy of dextropropoxyphene which appeared in 1966 [Beaver, 1966] and which I presented in my testimony before this Subcommittee on 24 November 1970. PAGENO="0212" 16764 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Propoceyphenc vs. placebo: In addition to tl1e studies cited in my 1966 review, several additional controlled analgesic studies have confirmed that that 65 mg dose of propoxyphene hydrochloride or the equivalent 100 mg dose of propoxy- phene napsylate is statistically significantly superior to placebo in relieving post- operative and trauma pain [Sunshine et ci., 1970; Sunshine et ci., 1971; Young, 1978], postpartum uterine cramping [Baptisti et ci., 1971; Gruber et ci., 1971], l)Ostpartum episiotomy pain [Berry et ci., 1975], pain subsequent to oral surgery in outpatients [Winter et ci., 1973] and chronic pain of mixed etiology [Wang, 1974]. A couple of studies have also succeeded in demonstrating a statistically sig- nificant difference between placebo and either 32 mg propoxyphene hydrochloride [Sunshine and Kantor, 1966] or the equivalent 50 mg dose of propoxyphene napsylate [Sunshine et ci., 1971] but these obviously represent threshold or marginally effective doses of propoxyphene, the analgesic effect of which doses can only very rarely be measured in even the most sensitive analgesic assays. Propoceypliene dose-response curve: Several additional studies have also con- firmed the existent of a significant positive slope for the dose-response curve of propoxyphene using various graded doses of the hydrochloride salt from 32 to 200 mg and/or the equivalent doses of the napsylate salt of 50 to 300 mg [Sun- shine et ci., 1970; Sunshine et ci., 1971; Sunshine et ci., 1978; Baptisti et ci., 1971; Gruber et ci., 1971]. In my opinion, the above cited studies, alone and in conjunction with those I have previously reviewed [Beaver, 1966], prove beyond any doubt that propoxy- phene hydrochloride in doses of 65 mg and higher or propoxyphene napsylate in doses of 100 mg and higher have some analgesic activity in patients with pain of a wide variety of etiologies. Indeed, since propoxyphene produces narcotic-like responses in all pharmacologic tests with which I am familiar, can produce drug dependence of the classic narcotic type and produces an overdose syndrome characteristic of narcotics, I would find it impossible to explain how the drug could possiblye not be an effective analgesic at some dose level. Yet, several double-blind studies which ostensibly meet the minimum criteria for a controlled clinical trial of analgesic efficacy have not demonstrated a statistically significant difference betw-een the analgesic effect of 65 mg of propoxyphene hydrochloride and a placebo treatment. There are a number of possible explanations for this state of affairs, and most of them hinge on an understanding of the concept of assay sensitivity as it applies to clinical trials of analgesics. Because of the multiplicity of known and unknown variables which affect the course of a patients pain and its response to analgesics, and because there is no satisfactory measure of a patient's pain other than the patient's own subjective reports of this experience, analgesic clinical trials vary greatly in their ability to demonstrate the efficacy of even known effective analgesics: i.e., they vary widely in their assay sensitivity. Therefore, unless an analgesic clinical trial contains an internal measure of assay sensitivity that demonstrates that the trial is capable of measuring an analgesic effect of the magnitude anticipated to result from administration of the test drug (e.g., propoxyphene), a negative finding concerning the efficacy of the test drug has no meaning [Modell and Houde, 1958; Houde et al. 1965, 1966]. Most of the clinical trials w-hich did not distinguish propoxyphene from placebo either did not contain a measure of assay sensitivity or were clearly insensitive in that they also could not distinguish known analgesics (e.g., codeine or aspirin) from placebo. Furthermore, since single doses of propoxyphene 65 mg are almost cer- tainly less effective than the usually used doses of the mild analgesic standards, codeine 65 mg, aspirin 650 mg. acetaminophen 650 mg or 2 APCtablets, an oral mild analgesic study may have adequate assay sensitivity to demonstrate a statistically significant difference between one or more of these standards and the placebo, while still not being able to identify the less substantial analgesic effect of propoxyphene 68 mg as statistically significant [Moertle et al., 1972]. Other confounding factors in the interpretation of mild analgesic clinical trials include the fact that some types of pain may respond much more dramatic- ally to peripherally-acting analgesics (e.g., aspirin and acetaminophen) than to centrally-acting narcotics (e.g., coreine and propoxyphene) [Cooper and Beaver, 1976; Bloomfield et al, 1976] and the fact that patients who have received narcotics develop tolerance to these drugs and w-ill subsequently experi- ence more pain relief from aspirin or acetaminophen relative to codeine or pro- poxyphene than narcotic-naive subjects [Houde et al., 1965, 1966]. PAGENO="0213" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16765 Propo~yphene vs. codeine: Since propoxyphene is a "weak" narcotic, oral codeine is the most appropriate staiidiird of comparison. My review of the literature in 1966 [Beaver, 1966] led me to the conclusion that propoxyphene hydrochloride was definitely less potent on a iiiilligram basis than codeine, my best estimate of the relative potency of the two drugs being that propoxyphene is 1/~ to 2A as potent as codeine. In the interval, no definitive relative potency assay comparing graded doses of the two drugs has appeared, but the results of a few more recent clinical studies are generally consistent with the above estimate [Moertel et al., 1972; Sunshine and Kantor, 1960; Forrest, 1970]. Two other studies [Gruber, 1977; Young, 1978], designed to evaluate the analgesic effect of two consecutive doses of each of the study medications, suggest that propoxyphene napsylate 100 mg is approximately equianalgesic to codeine 60 mg but deficiencies in data presentation make it impossible for me to judge the validity of this interpretation. Propowyplienc vs. asp~ren, acctannnophcn or APU: The results of studies I reviewed in 1966 and a few more recent studies comparing propoxyphene hydro- chloride 65 mg or propoxyphene napsylate 100 mg with aspirin 650 mg [Moertel et al., 1972], acetaminophen 650 mg or 1000 mg [Moertel et al., 1972; Hopkins et al., 1973; Berry et al., 1975] or APC 2 tablets are consistent with the evalua- tion which I presented to this Subcommittee in 1970; namely, that propoxyphene at recommended doses is certainly no more, and probably less, effective than usually used doses of aspirin, acetaminophen or APC. Efficacy of propoxyphene as a constitvcnt of drug combinations: Relatively little propoxyphene is used as a single-entity analgesic. Well over 80 percent of the prescriptions for propoxyphene products are for combinations of propoxy- phene with acetaminophen, APC or aspirin. The rationale for these combinations is the same as that which underlies combinations of codeine and other yet more potent narcotics with these same antipyretic-analgesics; namely, production of more intense analgesia than cnn be provided by using a single agent and reduc- tion of side effects by reducing the dose of any one analgesic. Although experi- mental evidence to substantiate these theoretical rationales is far from ideal or complete, there is a substantial body of evidence from well-controlled clinical analgesic trials to indicate that combinations of appropriately chosen doses of antipyretic-analgesics with narcotiCs do, in fact, achieve these objectives [Beaver, 1966; Beaver, 1975]. The slopes of the log dose-response curves of analgesic drugs are relatively flat, with the result that even successive doubling of the dose produces only modest increments of analgesic effect. Narcotics and antipyretic-analgesics such as aspirin are known to produce analgesia by different mechanisms, and the simple additive effect of a narcotic and an antipyretic-analgesic given together is often significantly greater than the analgesia achieved by doubling the dose of either drug administered alone. Furthermore, antipyretic-analgesics probably exhibit a ceiling of analgesic effect at about the usually used doses (650-1000 mg) and the usefulness of higher doses may also be limited by increased incidence of adverse effects and serious cumulative toxicity. Increasing doses of codeine, propoxyphene and other narcotics are associated with progressively increasing incidence and severity of gastrointestinal and central nervous system side effects and increased risk of drug dependence. The problem of providing adequate pain relief in the face of the above noted limitations of currently available analgesics may sometimes be circumvented by combining an optimal dose of an antipyretic- analgesic with an orally effective narcotic in a modest dose which is reasonably safe and well-tolerated. Older relevant studies for both codeine and propoxyphene combinations are cited in my 1966 review. There are a few more recent studies which appear to demonstrate a significant increase in analgesic effect produced by the addition of propoxyphene to acetaminophen [Hopkinson et al., 1973], APC [Bauer et al., 1974] and aspirin [Wang and Sandoval, 1971]. Moertel and his associates showed a small increase in the effect of aspirin 050 mg produced by the addition of propoxyphene napsylate 100 mg, but the difference was not statistically significant. ADVERSE EFFECTS OF PROPOXYPHENE Adverse effects of propoxyphcnc at therapeutic dosc lcvei: At recommended dose levels (propoxyphene hydrochloride 65 mg or propoxyphene napsylate 100 mg Q4H, PRN for pain), propoxyphene produces an extremely low level of adverse effects. In fact, most studies are unable to demonstrate a significantly higher PAGENO="0214" 16766 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY incidence of adverse effects with these doses of propoxyphene than with a placebo [Baptisti et al.. 1971; Gruber et al.. 1971: Gruber. 1977: Moertel et al., 1972; Moertel et al., 1974; Sunshine et al., 1971. Wang, 1974]. When large enough groups of ambulatory patients are studied to demonstrate any difference in terms of adverse effects between therapeutic doses of propoxyphene and placebo, the adverse effects consist of a very low incidence of nausea and drowsiness [Winter et al., 1973]. Considering the extraordinarily large use of propoxyphene products, there is extremely little in the entire literature which indicates that the drug in recommended therapeutic doses can produce any serious adverse effects, and even minor adverse effects seem to occur only infrequently. Toaieity of Pro po;;yphene in Overdose: As noted above and as is amply attested to by numerous individual case reports and several epidemiologic studies [McBay and Hudson, 1975; Finkle et al., 1976; Sturner and Garriott, 1973] propoxyphene, like any other narcotic, can be lethal in overdose. Unlike most other narcotics, the propoxyphene overdose syndrome is complicated by a high incidence of con- vulsions, which complicates its treatment. Dependence Liability of Propos-ypliene: Since propoxyphene is pharmaco- logically a narcotic, it has some ability to produce drug dependence of the nar- cotic type, and this has been recognized since before the drug w-as marketed [Fraser, 1960]. Propoxyphene can produce the classic triad of psychic de- pendence, physical dependence and tolerance, and, in those patients who are able to tolerate high enough doses to result in substantial physical dependence, a narcotic-type abstinence syndrome has been observed on withdrawal. "Street abuse" of the drug clearly occurs, as does dependence secondary to therapeutic use [Chambers et al., 1971; Maletzky, 1974]. However, in my opinion, relative to the extremely wide use of propoxyphene. the demonstrated incidence of seri- ous deliberate abuse of the drug to experience its mood effects is not great and is certainly substantially less than is the case with potent narcotics. ADVERSE EFFECTS OF ALTERNATIVE MILD ANALGESICS Any attempt to assess the benefit/risk ratio for propoxyphene must neces- sarily take into account the known adverse effects of alternative mild analgesics. I am concerned that there is expressed or implicit in certain recent discussions of the usefulness of propoxyphene the assumption that alternative mild anal- gesics are more or less devoid of adverse effects and are in some general sense "safe". This is clearly not the case. Aspirin can be lethal, not only in overdose, l)ut also at usual therapeutic dose levels in individuals who are hypersensitive to the drug or who experience mas- sive gastrointestin~d bleeding or other bleeding associated with aspirin's effects on blood coagulation. TTntil recently, acetaminophen has been felt to be singu- larly free of adverse effects, and this is probably still true at conservative thera- peutic doses. however, it is 1)ecoming increasingly apparent that overdose with acetaininophen can produce massive hepatic injury resulting in death, and in Great Britain, where the use of acetaminophen is even more widespread than in the United States, it has been estimated that acetaminophen poisoning is now a leading cause of acne hepatic failure. Chronic use of phenacetin containing analgesic mixtures has been associated with potentially fatal renal damage, and the Food and Drug Administration's Over-the-Counter Analgesic Review Panel has recommended removing phena- cetin from the over-the-counter market for that reason. The relative contribu- tion of plienacetiii as opposed to other mild analgesics in the development of this syndrome is a suh~ect of debate, and it is unclear whether acetaminophen may not also produce serious renal injury when abused in combination products for prolonged periods of time. The incidence of adverse reactions to codeine in usual therapeutic doses is low. Time drug can produce a typical narcotic overdose syndrome and death, but the reported incidence of this appears low relative to codeine's extremely wide clinical use. Codeine may be safer in this respect than equi-analgesic amounts of propoxyphene, although further study w-ould have to be done to establish this. C'oedine has narcotic-type dependence liability, although, like propoxyphene, the mcidence of this problem is very low considering the wide therapeutic use of codeine-containing combinations. Oral pentazocimie is aim effective mild analgesic more or less comparable to Codeine iii potency. Because the drug is a mixed agonist/antagonist rather than a classic narcotic, there is reason to believe that lethal overdose would be PAGENO="0215" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16767 even less of a problem than with either propoxyphene or codeine. However, pentazocine seems to produce a somewhat higher incidence of unpleasant ad- verse effects at usual therapeutic doses than equi-effective doses of codeine, and pentazocine occasionally produces frank psychotomimetic reactions which may be very disturbing to the patient. While pentazocine has less abuse liability than regular narcotics, deliberate self-administration of the drug for its mood effects undoubtedly occurs, and the Food and Drug Administration's Controlled Substance Advisory Committee has recently recommended scheduling penta- zocine in Schedule IV. The purpose of the above comments on alternative mild analgesics was not to denigrate the value of these drugs for the patient with pain, but rather to put the adverse effect liability of propoxyphéne in some reasonable perspective. ADVERSE EFFECT5 OF SCHEDULE II NARCOTIC5 The only currently available alternative oral analgesics to the mild analgesics discussed above are the Schedule II narcotics. These include such drugs as morphine, hydromorphone (Dilaudid®), hydrocodone (Diocodid®); oxycodone (constituent of Percodan®), levophanol (Levodromoran®), anileridine, meper- idine (Demoral®) and methadone. While in substantial oral does, these drugs are all capable of producing significantly greater pain relief than the mild anal- gesics noted above [Moertel, 1976], they are all quite capable of producing lethal narcotic overdose, and all have a clearly higher dependence and abuse liability than propoxyphene, codeine or pentazocine. 1n addition, doses of these Schedule II narcotics which produce pain relief greater than time mild analgesics are also associated with a significantly higher incidence of disturbing gastrointestinal and central nervous system adverse effects. rrherefore, their use would only seem to be indicated for those patients for whom conventional mild analgesics or combina- tions prove ineffective or not tolerated. WHY DO DOCTORS PRESCRIBE PROPOXYPHENE? I have listed below, not necessarily in order of importance, a number of fac- tors which seem to me responsible for the popularity of propoxyphene products. 1. It has been claimed that the popularity of propoxyphiene in time face of its less than impressive performance in controlled clinical trials is primarily due to the extensive and effective promotional efforts for Darvon® by Eli Lilly & Com- pany. Indeed, the best ball I)oimlt pen that I ever owiied was given to me by a Lilly detail man and is emblazoned with the words, "Darvocet N-100". However, many drug companies utilize the services of inventive advertising agencies amid have dedicated swarms of detail men at theii' disposal, and yet, much to their chagrin, these companies are unable to stir up the sustained high demand for their analgesic product which has been accorded the Darvon® family. I think one must look further than promotional efforts alone to explain time success of pro- poxyphene over the past 20 years. 2. Physicians seem to need a mild analgesic which is as effective as aspirin, acetaminophen or APC which is not available over-the-counter. Many patients feel that these antipyretic analgesics cannot be terribly effective because they are available over-the-counter and have a psychological need to receive an anal- gesic which is only available on prescription. Physicians recognize and respond to this need. Propoxyphene products are available in a variety of impressive colors, shapes and sizes and are only available through prescription. Furthermore, as noted above over 80% of prescriptions for propoxyphene products are for combi- nations containing aspirin, acetaminophen or APC and these combinations are at the very least as effective as the antipyretic-apalgesics which they contain. This must he coupled with time fact at recommended doses propoxyphene produces an extremely low incidence of any sort of adverse effects and a virtually zero inci- dence of serious adverse effects. One must also consider the alternatives which the physician has available. When Darvon® came on the market in 10.57, the significant mild analgesics avail- able as single entities and in combination included aspirin and other snlicyhates, acetaminophen, phenacetin and codeine. Today, over 20 years later, the only addition to this group has been oral pentazocmne (Talwin®). When the patient with persistent paul tells his doctor that this current medication is either ineffec- tive or poorly tolerated (a repetitive occurrence for many patients with chronic pain problems), the physician needs alternatives available. Useful alternative medications have simply not been fortimcomin~. PAGENO="0216" 16768 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3. Physicians in general are very sensitive to the issue of the dependence lia- bility of narcotic drugs* In mai~y situations, this concern has been far in excess of what was warranted by any realistic evaluation of the likelihood of producing iatrogenic narcotic dependence. This anxiety extended to codeine, which in fact has extremely low abuse liability when used in any medically responsible way. Propoxypliene was probably originally perceived by physicians as a non-narcotic substitute for codeine and propoxyphene-containing combinations w-ere mar- keted whicli correspond to all of the existing codeine-containing combinations. Tntil the beginning of 1977, propoxyphene was an unscheduled drug, which mm- plied that it was safer than codeine and its combinations in terms of dependence liability and also made for more convenient prescribing and dispensing. 4. Although the most appropriate and, in fact, most popular use of both pro- poxyphene and codeine is in combination with the antipyretic-analgesics, there are occasional pain problems in which the physician can quite legitimately want to prescribe either poropxyphene or codeine alone. These include situations where there is an allergy or contraindication to the use of aspirin and acetaminophen. It w-ould also include situations in which the practitioner wished to use a mild analgesic with no associated antipyretic effect. 5. There is, in fact, good evidence that combinations of narcotics with anti- pyretic-analgesics produce more analgesia than the antipyretic-analgesic given alone, and this increment of analgesic effect may often make the difference be- tween unsatisfactory and satisfactory pain relief for particular patients. This increment of analgesia is often associated with very little increase in adverse effects and therefore constitutes a very real benefit for the patient. To my way of thinking, this constitutes the major acceptable rationale for the use of propoxyphene. It shoud be noted that this rationale does not apply if the pre- scribed dose of a combination contains substantially less than the usual full therapeutic dose of the antipyretic-analgesic constituent. 6. Controlled clinical trials of analgesics invariably compare the average re- sponses of groups of patients to the various treatments. While the average rela- tive performance of various analgesics is the best predictor of how the generality of patients with pain will respond, individual patients may, for reasons which w-e simply do not currently understand, derive a better analgesic effect from a drug which on the average is less effective than another. Controlled clinical trials of analgesics are not currently designed to explore this phenomenon, and the de- termination of the optimal analgesic regimen for any given patient must ulti- mately be l)ased on the empirical observation of the effect of various analgesics in that patient. It is therefore in the patient's interest to have as w-ide a variety of effective analgesics available as possible, even though some of these may on the average be less efficacious than others. 7. Virtually all controlled clinical trials of analgesics, including propoxyphene, have involved comparison of single administrations of various analgesics; how- ever, in the practice of medicine, most patients receive not a single dose but repetitive doses of analgesic drugs for the control of their pain. While up to this time, the results of single administration studies have seemed to constitute rea- sonably accurate predictors of the relative performance of analgesics when ad- ministered repetitively (if one keeps in mind the impact of the development of tolerance to narcotics). it is conceivable that repeated administration of some analgesics results in a higher level of efficacy than w-ould be predicted on the l)asis of single-dose administration. Propoxyphene has a substantially longer half- life in the blood than other mild analgesics such as codeine, acetaminophen or aspirin. When administered every four to six hours, as mild analgesics usually are, there will be a significantly greater cumulation of propoxphene levels than with alternative mild analgesics [Waife et al. 1975]. We do not currently under- stand the relationship between the blood level of an analgesic and the analgesic effect experienced by the patient, but a plausible argument can be made on the basis of blood level data that one might expect greater analgesia after a few re- peated doses of propoxyphene relative to alternative mild analgesics than is, in fact, seen in single administration studies. Umifortunately. few- analgesic studies of repeated dosing have been done to examine this hypothesis. and those that have been done are difficult to interpret [Gruber. 1977: Young, 1978]. It is. therefore possible that practitioners empirically find that proproxyphene products are more effective in regular clinical use (i.e.. w-hen administered in repeated doses) than would l)e predicted on time basis of the controlled clinical trials which involve single administrations of test medication. PAGENO="0217" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1G769 SOME UNRESOLVED ISSUES In my mind, there are a number of unresolved issues relevant to the benefit! risk ratio of Darvon and its place as an analgesic which deserve further study. 1. Since a majority of fatal propoxyphene overdoses seem to result from mixed intoxication with propoxyphene and other central nervous system depressants [Finkle et al., 1976], some effort should be directed at determining whether pro- poxyphene is simply adding to the depressant effects of other drugs or is produc- ing a supra-additive interaction which is particularly hazardous. 2. Although the descriptions of fatal poisoning w-ith propoxyphene which I have studied suggest that this drug~ is producing death in the same way as any classical narcotic overdose (albeit, time overdose syndrome is usually complicated by the presence of convulsions), studies should be done to determine whether propoxyphene has a direct cardiovascular toxicity in excess of other narcotics, and further studies should be done to elucidate the role of norpropoxyphene in the toxicity produced by propoxyphene [Nickander et al., 1977]. 3. Since codeine-containing combinations are the logical alternative to existing Darvon combinations and are prescribed to an ever greater extent than Darvon combinations, it would appear logical to make a concerted effort to determine whether the apparent lower incidence of codeine-related deaths is a real phe- nomenon and, if so, why? 4. Controlled analgesic studies involving repeated-dose administration of pro- poxyphene compared to other mild analgesics should be done to determine whether the predicted increase of efficacy of propoxyphene on repeated-dose administration really occurs. ALTERNATIVES TO THE USE OF PROPOXYPHENE AND OTHER NARCOTICS A number of oral analgesics which might be predicted to have advantages over propoxyphene and other currently available mild analgesics in terms of increased analgesic efficacy and/or decreased adverse effect liability are currently in va- rious stages of clinical testing. These include the non-steroidal anti-inflammatory drugs such as indoprofen, suprofen, zornepirac, difiunisal and many others; narcotic antagonist analgesics such as butorphanol, nalbuphine, buprenorphine, propirarn and others; and compounds of uncertain mechanism of action such as nefopam. There are controlled clinical studies indicating that all of these com- pounds are effective oral analgesics and other studies indicating they may have certain real advam1tages over existing drugs. The public interest would be served by seeing that these drugs get on the market without undue delay. I would point out that the average physician will very quickly start prescribing a drug which has real advantages for his patient if such a drug becomes available. BIBLIOGmiAPIIY Baptisti, A., Jr., Gruber, CM., Jr., and Santos, E. IL.: The effectiveness and side-effect liability of propoxyphene hydrochloride and propoxyphene napsylate in patients w-ith postpartum uterine craniping. Toxicol. Appl. Pharmacol. 19: 519-527, 1971. Bauer, R.O., Baptisti, A., Jr. and Gruber, C., Jr.: Evaluation of propoxyphene iiapsylate compound in post partum uterine cramping. J. Med. 5: 317-328, 1974. Beaver, W. T.: Mild analgesics: a review of their clinical pharmacology. Amer. J. Med. Sci. 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L. and Smith, 1~I.: Acetaminophen versus propoxyphene hydrochloride for re- lief of pain in episiotomy patients. J. Clin. Pharmacol. 13: 251-263, 1973. Houde, R. `W., Wallenstein, S. L. and Beaver, W. T.: Clinical measurement of pain. In: G. deStevens: Analgctics. New York: Academic Press, 1965, pp. ~5-122. Houde, R. W., Wallenstein. S. L. and Beaver, W. T.: Evaluation of analgesics in patients with cancer pain. In: L. Lasagna: Clinical Pharmacology-Section 6 of the International Encyclopedia of Pharmacology and Therapeutcis. New York: Pergamon Press, Ltd. 1966, p. 59-97. Maletzky, B. M.: Addiction to propoxypliene (Darvon) ; a second look. Int. J. Addictions 9: 775-784, 1974. McBay, A. J. and Hudson, P.: Propoxyphene overdose deaths. J.A.M.A. 233: 1257, 1975. Modell, W. and Houde, R. W.: Factors influencing clinical evaluation of drugs with special reference to the double blind technique. J.A.M.A. 167: 2190-2198, 1958. Moertel, C. G., Ahmann, D. L., Taylor, W. F. and Schwartau, N.: A com- parative evaluation of marketed analgesic drugs. N. Eng. J. Med. 286: 813-815, 1972. Moertel, C. G., Ahinann, D. L., Taylor, W. F. and Schwartau, N.: Relief of pain by oral medications: a controlled evaluation of analgesic combinations. J.A.M.A. 229:55-59,1974. Moertel, C. G.: Relief of pain with oral medications. Aust. N. Z. J. Med. 6: 1-8, 1976. Nickander, R., Smits, S. E. and Steinberg, M. I.: Propoxyphene and norpro- poxyphene: pharmacologic and toxic effects in animals. J. Pharmacol. Exp. Ther. 200: 245-253, 1977. Sunshine, A. and Kantor, T. G.: Oral analgesic compounds in postsurgical pain: A study of Bandol (SQ 10,269) at Bellevue Hospital. Minutes of the 28th meeting of the Committee on Problems of Drug Dependence, Appendix 30, 4764- 4768, 1966. Sunshine, A., Laska, E. and Slafta, J.: A comparison of the analgesic effects of Tramadol (Upjohn U-26. 225A) and propoxyphene HC1. Minutes of the 32nd meeting of the Committee on Problems of Drug Dependence, 6902-6904, 1970. Sunshine, A., Laska, E., Slafat. J. and Fleischman, E.: A comparative analgesia study of propoxyphene hydrochloride. propoxyphene napsylate, and placebo. Toxicol. Appl. Pharniacol. 19: 512-518, 1971. Sunshine, A., Slafta, J. and Gruber, C., Jr.: A comparative analgesic study of propoxyphene, fenoprofen, the combination of propoxyphene and fenoprofen, aspirin, and placebo. J. Clin. Pharmacol. 18: 556-563, 1978. Sturner, W. Q. and Garriott, J. C.: Deaths involving propoxyphene. J.A.M.A. 223: 1125-1130, 1973. Waife, 5. 0., Gruber, C. M., Jr., Rodda, B. E. and Nash, J. F.: Problems and solutions to single-dose testing of analgesics: Comparison of propoxyphene, codeine, and fenoprofen. Int. J. Clin. Pharmacol. 12: 301-304, 1975. Wang, R. I. H.: A controlled clinical comparison of the analgesic efficacy of ethoheptazine, propoxyphene and placebo. Europ. J. Gun. Pharmacol. 7: 183- 185, 1974. Wang. R. I. H. and Sandoval, R. G.: The analgesic activity of propoxyphene napsylate with and w-ithout aspirin. J. Cliii. Pharmacol. 11: 310-317, 1971. Winter, L., Jr., Calman. H. I.. Caruso. W. A. and Post, A.: A double-blind comparison of ethoheptazine citrate, propoxyphene hydrochloride, and placebo. Curr. Ther. Rei. 15: 338-390, 1973. Young, R. E. S.: A two-dose evaluation of propoxyphene napsylate and codeine in postoperative pain. Curr. Ther. Res. 2~: 495-502, 1978. PAGENO="0219" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16771 Senator NELSON. I believe Dr. Newman wants to get out of here before noon and we will hear from him next. Senator BosdnwITz. What do you, therefore, conclude? Do you con- clude that the drug Darvon should be kept in schedule IV or put into schedule II? Dr. BEAVER. I did not conclude this. This was not really the question that was addressed to me by Senator Nelson in the letter. It went to the place of Darvon in medical practice, and I said yes, it seems to have some place. If I could answer those questions which I did not specifically speak to. I did compare propoxyphene to other drugs. I feel you can certainly practice good medicine without Darvon. It was practiced without Darvon before 1957. We have other drugs. On the other hand, losing Darvon means one less alternative in various situations. Now, what should you do? There is the issue of just banning the drug as an imminent hazard. I am not terribly fond of that idea for a couple of reasons. One is, quite aside from the legal implications of this, there is nothing about Darvon that has come out recently which is fundamentally different than what we knew back in 1976 and 1977. It is not that there is some clear-cut, well-demonstrated new hazard that has anpeared. It just seems to' be more of the same, I do not think there has been an increase in Darvon deaths since the drug was put on schedule IV. Now, it is debatable whether or not there has bee.n a de- crease, but the problem about banning the thing as a hazard is, as I pointed out, doctors will use something else and the other things they may use may include combinations with sedatives and barbiturates which have higher abuse liability than Darvon. Senator BosornvlTz. I thought you said they are reluctant to do that. What about codeine? Dr. BEAVER. They may go tO codeine. Some will go to codeine and I think that would be a perfectly appropriate movement. Senator BosdllwlTz. That does not have abuse liability? Dr. BEAVER. It does have some; and it may in the sense of drug dependence be somewhat more than Darvon. It is more effective and you can take higher doses for mood effect without getting sick. They may also go to potent schedule II narcotics, things such as, Percodan, and these have a higher abuse liability than either codeine or Darvon. Then the question is, "`What about rescheduling?" There might be something said to this. One could, for example, treat the drug as codeine is currently treated. This would involve putting the entity itself on schedule TI and the combinations on schedule III. Now, seeing that the major perceived problem here is not the de- liberate abuse of the drug for its mood effects, but rather suicidal or possibly accidental poisoning, I am not sure how much effect that would have, but what it would, do is clearly alert physicians to a change in status of the drug and get them to thinking about it more seriously. My feeling is that one of the problems with this drug is that ph~r- sicians have taken it altogether too casually. Senator BosoHwrrz. When was it put under schedule IV? Dr. BEAVER. 1977. Senator BOSCHWITZ. Any changes in the prescription levels? PAGENO="0220" 16772 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. BEAvEn. The prescriptions have gone down a little since then. If something like this were done and combined with a big black box up at the front end of the label and slapped into all the advertising pinpointing what the real risk of this drug was in terms of over- dose and death, it might get physicians to use the drug in a bit more conservative way in terms of the amount prescribed, the kind of people they would prescribe it for and so on and it would generally alert them and this would be a useful option. Senator BoscHwiTz. Is the medical profession pretty much aware of the problems that have been discussed here? Dr. BEAVER. I think perhaps the single, most important function a hearing such as this serves is to create a public awareness of this kind of problem; so it is all over television and things like that and people, including physicians, will be asking questions and trying to find out more about it. Senator BoscHwrrz. Senator, I do not want to hold up the doctor who wants to leave at noon. I would also like to leave at noon but I might ask Dr. Adriani one question. Would you address yourself briefly to Dr. Beaver's point that when the patient goes to a doctor and that patient has already been taking aspirin-to identify with this, my doctor normally does not charge me $25, but then the only thing the doctor does is confirm that I should go home and take two aspirin; famous last words of medical advice- is what the doctor does important psychologically or should that not be a consideration? Dr. ADRIANI. I do not t.hink so. Here you have a drug inferior to aspirin. In prescribing, you want to prescribe the ideal medicine to a patient, and the best drug available for him irrespective of how he busy it, whether he buys it by prescription or over-the-counter. Aspirin is bought over-the-counter. It is the best drug we have for arthritis. There are certain drugs like nitroglycerine and adrenalin which should be prescription for asthma and angina. The asthmatic can get adrenalin over-the-counter since he may need it in a hurry and not have time to get a prescription. The public is becoming more and more aware of what we do in the practice of medicine and the mistakes we make in medicine. They know aspirin is a good drug and do not object to buying it over-the-counter when told t.o do so by a doctor. Patients know what they are getting on prescription. The days are disappearing when a patient did not know what was being prescribed but now we have more and more full disclosure of everything. Senator BOSCHWITZ. Sorry to hold up, Dr. Newman. I see your testi- mony is a little shorter. Senator NELSON. Dr. Newman, you may go ahead. Your statement will be printed in full in the record and you may present it however you like. STATEMENT OF MICHAEL A. NEWMAN, M.D.-Resumed Dr. NEWMAN. Thank you. My name is Michael A. Newman and I appreciate t.his opportunity to testify about the safety, efficacy, and usefulness of propoxyphene, or Darvon. PAGENO="0221" QOMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16773 I am a doctor of medicine certified by the American Board of Internal Medicine. Testimony has been and will be presented by ex- perts familiar with the pharmacology and epidemiology of propoxy- phene. I testify as a physician engaged in the full-time practice of internal medicine in the District of Columbia. who daily sees and cares for patients. My opinion of propoxyphene is that it is a mild analgesic with pharmacological properties similar to narcotics although it is much less potent. It has not been shown to be of greater efficacy than either aspirin or codeine in relief of pain. We are a heavily medicated sOciety taking prescription, proprietary, licit, illicit, begged, borrowed,~ and stolen drugs. Why? Is it because physicians prescribe drugs too readily or inappropriately? Perhaps, but there are other factors involved. Drugs may be prescribed for rea- sons unrelated to disease or efficacy. Propoxyphene illustrates the problem of prescribing drugs. Some drugs develop a public following-they become "pharmacological cele- brities," their glamor and mystique unrelated to their efficacy, safety, or cost. Propoxyphene is such a drug. Today, physicians seem to have a few misconceptions about the efficacy of propoxyphene. But many physicians are uninformed about the toxicity and abuse of the drug. Consequently, unaware of its dangers, physicians too often prescribe it in an effort to provide comfort and relief or in response to a patient's expectations or request. These hearings will help inform physicians and patients about the toxicity and abuse of propoxyphene. Classifica- tion of propoxyphene under schedule II would further alert physicians and patients to its dangers and reduce its use. Pain is perhaps the most frequent reason why patients come to see a physician. But pain is a symptom, not a diagnosis. Ideally, proper treatment of a patient depends on the correct diagnosis. But patients are not always interested in or appreciative of the thought, time, test- ing and expense entailed in establishing a diagnosis. Patients want relief as soon as possible. They often specify what medication they believe is necessary. Their belief being based on prior experience, hearsay, recommendations of relatives or friends, and articles in news- papers or magazines. Physicians, like public servants, are influenced by their "constitu- ents"-in this case, their patients. The public may be surprised, but many physicians want to act not only in the `best interests of their patients, but to please them as well. On occasion, sound clinical practice and good medical judgment may not satisfy patients seeking a specific treatment or drug. I and many other physicians have experienced such instances of dissatisfaction in response to sound medical recommendations, particularly when a drug is not prescribed. I would disagree with Dr. Beaver's point that this means you need to go ahead and prescribe a drug. I have had experience both in a prepaid and in fee-for-service practice. Certainly, one of the things you are aware of is that patient satisfaction is important, but I still feel that physicians do not need to prescribe drugs on that basis. I do not pre- scribe drugs on that basis. I know patients may be disappointed and PAGENO="0222" 16774 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I anticipate it by saying, "I can see you are a bit unhappy that you have not gotten a prescription." They acknowledge that `and seem to leave satisfied. I think that is very simple. I do not think it is necessary to provide the prescription just to satisfy a patient. Additionally, consider the fact that efficacy is elusive and subtle especially when we attempt to distinguish between biologic and non- biologic or placebo effects. Often patients conclude, ipso facto, that because they felt better the drug was effective. This operant condi- tioning is a powerful factor and it is difficult to dissuade a patient of such persuasion or belief. A physician in the midst of a busy day and unaware of the dangers of propoxyphene may find it easier to prescribe the drug rather than explain that aspirin is more effective and much safer. This is deplor- able, but it happens. I think it is happening to a lesser extent because physicians are more cautious in what they prescribe and patients are asking tough questions when they get prescriptions, at least that is my view of practical practice here in Washington. For many patients, a prescription for a drug like propoxyphene seems tangible proof that their illness was seriously considered and t.heir visit to the physician worthwhile. A prescription for aspirin has no such connotations and even sug- gests the opposite. Despite much merit in the recommendation, the jokes and cartoons a.re about the physician saying, "take two aspirin and call me in the morning." There are no similar jokes about Darvon. Drugs like propoxyphene give pseudolegitimacy to the complaint or illness for the patient, his family. friends and coworkers in a way that aspirin does not. Also, patients seem happier pa.ying the doctor when a presciption is written rather than paying for a visit after being told to take two aspirin or to follow a regimen of heat, rest, and exercise. Thus, drugs a.re prescribed for many reasons not all of them valid. Clearly, the physician has the final responsibility in recommending how to proceed and what drug, if any is to be prescribed based on valid medical medications and knowledge of efficacy and safety. But unfortunately, this is not always what occurs. What I am saying is it is possible to practice good medicine without prescribing propoxyphene and many other drugs and the indications for propoxyphene are very limited. I would in no way feel constrained in my practice of medicine by having propoxyphene available only on an investigational basis or by having it scheduled as a class II narcotic. Unfortunately, despite efforts by this committee and others to inform physicians and the public about the lack of superiority, the toxicity and the potential for abuse of propoxyphene~ it probably will remain a widely prescribed and used drug unless it is rescheduled as a. class I narcotic. I strongly urge that this be done. I thank you for this opportunity to present. my views as a practicing physician before this committee. I would `be glad to answer any questions. I want to take a. few moments for some additional comments. First of all, I support Dr. Charles Moertel's testimony 100 percent. I can see no reason why propoxyphene needs to be available. PAGENO="0223" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16775 I believe Senator Hatch was concerned if someone taking Darvon at the prescribed or recommended dose could conceivably experience a fatal or lethal overdose. I am not a clinical pharmacologist, but I see the situations where people are taking medicine at the prescribed dose and then combine it with something else such as alcohol or tranquilizers or some other medication. The combination or interaction has the potential for being lethal even if both are within the prescribed recommended doses. That is a point that does concern me. Another point in terms of prescribing drugs is that we have already had experience with DES with radiation to the head and neck and an increased incidence of cancer, with respect to the use of estrogens and increased instances of endometrial cancer and what we are go- ing to find out about birth control pills in the future is unknown. The same point pertains to Darvon. Just now as you heard it's been on t.he market for 20 years and only now are we learning more about its metabohites and potentially, serious cardiotoxic effects that it has. Who knows what we may find out in the future? I think it would be unfortunate to continue to have a drug such as Darvon widely and readily available without being aware of what its potential side effects are. The most important point I want to make as a practicing physician is that I can practice medicine day in and day out and not be con- cerned about patients being disappointed, or be concerned about pa- tients leaving me because I do not use it. I would not hesitate at all to say that I think it need never be prescribed. Senator NELSON. Thank you very much, Dr. Newman. We will now hear from Morris Boynoff, a pharmacist from Men- docino, Calif. Senator BosclIwITz. Dr. Newman, how convincing did you find your explanations that aspirin is more effective and safer? Do your patients accept that? Dr. Newman. My experience is that patients do accept it. Some- times patients respond that they cannot take aspirin but they can take one of the buffered aspirin preparations. That is quite common. There are some people who are legitimately allergic to aspirin. In those instances, acetaminophen is equally acceptable. If you talk to patients and explain why you are doing something or not doing something, they accept it. Senator BoscJIwITz. Therefore you do not prescribe Darvon? Dr. NEWMAN. I use a type of prescription where I keep a carbon copy of all the prescriptions that I write. I went back and looked at the pre- scriptions for the past 6 months and found I had not prescribed Darvon in the past 6 months and I cannot really recall having pre- scribed it. Senator Boscl-IwITz. What do you prescribe instead? Dr. NEWMAN. As an alternative to aspirin or acetaminophen, I pre- scribed codeine. But, many times I do not prescribe anything. Some- times people are going to hurt. I am a big prescriber of "time." Senator Boscnwrrz. And your patients accept that? Dr. NEWMAN. The patients accept that; yes. Senator BosclIwITz. Dr. Beaver, are you a practicing physician, or have you practiced? PAGENO="0224" 16776 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. BEAVER. I do not have a private practice of medicine. My practice or work is involved mainly in consulting on pain problems at the University Hospital. I am the analgesic consultant at the Washington Home Hospice where we are taking care of terminal cancer patients. I have done a little private practice. Senator BoscHwrrz. Do you consult with the patients or the doctors? Dr. BEAVER. Both. WTe do not disagree at all on what is appropriate. I was trying to describe my insights into why physicians do the things they do, which I think is what you have also said, Dr. Newman. I am not saying one should, therefore, prescribe whatever the patients ask for. Dr. NEWMAN. As a physician, I would say there are types of pain, such as pain related to a specific acute episode. The issue of chronic pain is a problem where I am not persuaded that drugs are the only modality. There are a variety of modalities of managing patients with chronic pain, and drugs are not the only modality to be used there. I am sure Dr. Beaver would agree with that. In many instances peo- ple who have taken a large number of drugs for severe pain have been able to stop using those drugs entirely by using other modalities such as biofeedback, electrical stimulation, better control of the underlying process, hypnosis~ and so forth. Very often we think if the 1)roblem is pain, a pill is necessary. That simply is not the best approach. Senator NEIsox. Yesterday~ Dr. Moertel from Mayo Clinic stated the following in his last paragraph; and I would ask you if you want to comment on it: To summarize, I will answer specifically the four questions addressed to me when I was invited to testify before this committee. The first question, from. my knowledge and experience what is the relative efficacy of Darvon as compared to other analgesics? In my judgment Darvon is inferior to the commonly marketed aspirin, aceta- minophen, or APC combinations. The second question, is it possible to treat patients for pain with analgesics other than Darvon? Absolutely. For patients with mild pain you can do just as good a job, if not better, with aspirin or APAP alone, and you can do it for about one-tenth of the price. With regard to the use of Darvon combinations for the treatment of moderate pain, you can achieve significantly superior pain relief using combinations of aspirin with codeine, aspirin with oxycodone, or aspirin with pentazocine or Talwin. For the treatment of severe pain, the use of Darvon either alone or in combination is grossly inadequate treatment and is really inhumane to the patient. The third question, is it possible to maintain good medical practice without the use of Darvon? Yes. I would seriously Question whether the use of Darvon is good medical practice at all. And the last question, what is the medical justifi- cation for using Darvon? I know of none. Dr. NEw~r~~x. I agree with Dr. Moertel's last paragraph entirely. Senator NELSON. Dr. Adriani. would you agree or disagree? Dr. ADRIANI. I agree with that. That summarizes my statement. Senator ~ELSOX. Dr. Beaver. Dr. BEAVER. In terms of the. comparative efficacy aspect of the thing, we are in reasonable agreement as I went. to considerable pains to document in my prepared testimony which is part of the record. WTith regard to the aspect of combinations. I agree that those of codeine and certainly oxycodeine are likely to be more effective. In the PAGENO="0225" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16777 treatment of severe pain, Darvon is certainly seldom going to be ade~ quate even in combination with optimal doses of aspirin. Is it possible to maintain good medical practice without the use or Darvon and what is the medical justification for using Darvon? I have gone into a number of possible ones in my testimony exploring to some degree both sides of the issue. Senato,r BosduwlTz. Please excuse my ignorance, but Dr. Newman, could you just de~cribe the side effects or `other effects of codeine? Dr. NEWMAN. The side effects of codeine? Senator BosdnwiTz. Is it addictive? Dr. NEWMAN. Codeine is a narcotic. Codeine has addictive qualities. Senator BosdllwiTz. More addictive than Darvon? Dr. NEWMAN. There are no studies I am aware of that comment on the addictive quality of codeine versus Darvon. Darvon is the most closely related to methadone and there is no question about its addictive properties. I am not a clinical pharma- cologist, but I have not seen any~ studies comparing whether propoxy- phene or codeine are equivalent or not in terms of their addictive qualities. We are talking about narcotics, and a property of narcotics is that they are addictive. The most common side effect I see as a physician prescribing codeine is gastrointestinal problems. Codeine gives people anything from an upset storriach to severe cramps, nausea, and vomiting. In terms of side effects of any of these compounds, I have not seen the data to compare the incidence or side effects. Senator BosdnwiTz. Dr. Beaver, would you comment briefly on the side effects of codeine? Dr. BEAVER. Mainly what you see is some nausea, rarely vomiting, also drowsiness and dizziness. These are when the side effects occur, and these minor types of side effects are qualitatively very similar to the ones you see with Darvon. Senator Bosc.HwITz. Thank you. [The prepared statement of Dr. Newman follows:] STATEMENT OF MICHAEL A. NEWMAN, M.D. Mr. Chairman and members of the Senate Small Business Committee, my name is Michael A. Newman and I appreciate this opportunity to testify about the safety, efficacy and usefulness of propoxyphene (Darvon). I am a Doctor of Methcme certified l)y the American Board of Internal Medicine. Testimony has beeii and will be presented by experts familiar with the pharmacology and epidemiology of propoxypliene. I testify as a physician engaged in the full time practice of internal medicine in the District of Columbia who daily sees and cares for patients. My opinion of propoxyphene is that it is a mild analgesic with pharmacological properties similar to narcotics although it is much less potent. It has not been shown to be of greater efficacy than either aspirin or codeine in relief of pain. We are a heavily medicated society taking prescription, proprietary. hicit, illicit, begged, borrowed, and stolen drugs. Why? Is it because physicians prescribe drugs too readily or inappropriately? Perhaps, but there are other factors involved. Drugs may be prescribed for reasons unrelated to disease or to efficacy. Propoxyphene illustrates the problem of prescribing drugs. Some drugs develop a public following-they become "pharmacological celebrities", their glamor and mystique unrelated to their efficacy, safety, or cost. Propoxyphene is such a (Irug. Today. physicians seem to have few misconceptions about the efficacy of pro- poxyphiene. But many physicians are uninformed about the toxicity and abuse of this drug. Consequently, unaware of its dangers, physicians too often prescribe 40-224 0 - 79 - 15 PAGENO="0226" 16778 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY it in an effort to provide comfort and relief or in response to a patient's expecta- tions or request. These hearings will help inform physicians and patients about the toxicity and abuse of propoxyphene. Classification of propoxyphene under Schedule II would further alert physicians and patients to its dangers and reduce its use. Pain is perhaps the most frequent reason why patients come to see a physician. But pain is a symptom, not a diagnosis. Ideally, proper treatment of a patient depends on the correct diagnosis. But patients are not always interested in or appreciative of the thought, time, testing and expense entailed in establishing a diagnosis. Patients want relief as soon as possible. They often specify what medi- cation they believe is necessary. Their belief being based on prior experience, hearsay, recommendations of relatives or friends, and articles in newspapers or magazines. Physicians, like public servants, are influenced by their "constituents"-in this case their patients. The public may be surprised, but many physicians want to act not only in the best interests of their patients, but to please them as well. On occasion, sound clinical practice and good medical judgment may not satisfy patients seeking a specific treatment or drug. I and many other physicians have experienced such instances of dissatisfaction in response to sound medical recom- mendations; particularly, when a drug is not prescribed. Additionally, consider the fact that efficacy is elusive and subtle especially when we attempt to distinguish between biologic and non-biologic or placebo effects. Often patients conclude, ipso facto, that because they felt better the drug was effective. This operant conditioning is a powerful factor and it is diffi- cult to dissuade a patient of such persuasion or belief. A physician in the midst of a busy day and unaware of the dangers of propoxyphene may find it easier to prescribe the drug rather than explain that aspirin is more effective and much safer. This is deplorable, but it happens. For many patients, a prescription for a drug like propoxyphene seems tangible proof that their illness was seriously considered and their visit to the physician worthwhile. A prescription for aspirin has no such connotations and even sug- gests the opposite. Despite much merit in the recommendation, the jokes and car- toons are al)out the physician saying, "take two aspirin and call me in the morning". There are no similar jokes about Darvon. Drugs like propoxyphene give pseudo-legitimacy to the complaint or illness for the patient, his family, friends and co-workers in a w-ay that aspirin does not. Also, patients seem happier paying the doctor when a prescription is written rather than paying for a visit after being told to take tw-o aspirin or to follow a regimen of heat, rest and exercise. Thus, drugs are prescribed for many reasons not all of them valid. Clearly, the physician has the final responsibility in recommending how to proceed and what drugs, if any, are to be prescribed based on valid medical medications and knowledge of efficacy and safety. But unfortunately, this is not always what occurs. It is possible to practice good medicine without prescribing propoxyphene and the indications for its use are very limited. I would in no way feel constrained in my practice of medicine by having propoxyphene available only on an in- vestigational basis or by having it scheduled as a Class II narcotic. TJnfortu- nately, despite efforts by this Committee and others to inform physicians and the public about the lack of superiority, the toxicity and the potential for abuse of propoxyphene, it probably will remain a widely prescribed and used drug unless it is rescheduled as a Class II narcotic. I strongly urge that this he done. Thank you for this opportunity to present my views as a practicing physician before this Committee. I would be glad to answer any questions. CURRICULUM VITAE Michael Arthur Newman, M.D., Practice of Internal Medicine, 916 19th St., N.W. Suite 300, Washington, D.C. 20006. Married: Marian Gitlin. Children: Sarah. Birth: September 30, 1941-Los Angeles, California. $ocial ~S'ecvrity: 561-50-5641. Education: 1959-Diploma, Los Angeles, High School; 1963-Bachelor of Arts, Stanford University; 1964-Training Course in Marine Biology, University of Singapore; 1969-Doctor of Medicine, University of Rochester School of Me~i- PAGENO="0227" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16779 cine; 1970-Internship (Medicine and Pediatrics) University of North Carolina; 1971-Residency (Medicine) University of North Carolina; 1973-Residency (Medicine) Johns Hopkins University. Certification: American Board of Internal Medicine, Julle 18, 1975. No. 047780; National Board of Medical Examiners, July 1, 1970. No. 103449. Medical Licensure: Maryland D 13352, issued 1971; District of Columbia 5496, issued 1971. Military Obligation: U.S. Public Health Service, Surgeon (R) (T) PHS-33359, July 1, 1971 through June 30, 1973. Professional Ecrperience: Assistant Clinical Professor of Medicine, Georgetown University School of Medicine, current. Assistant Clinical Professor of Medicine, George Washington University School of Medicine, current. Assistant Professor of Health Care Science and Medicine, George Washington University School of Medicine. Associate Medical Director, George Washington University Health Plan, Feb- ruary, 1975-July, 1976. Chief, Professional Resources Branch, Health Services Division, I-Iealth Main- tenance Organization Service, I-Tealth Services amid Mental Health Administra- tion, Department of I-Iealth, Education and Welfare, December, 1971-July, 1973. Special Assistant to the Director, Health Maintenance Organization Service, Health Services and Mental Health Administration, Department of Health, Edu- cation and Welfare, July, 1971-December, 1971. Peace Corps Volunteer-Malaysia, 1963-65. Fellowships: 1960-Summer Fellow in Epidemñiology, California Department of Public Health, A Study in Epidemniological Status and of Health Beliefs and Practices in Two Communities in Bolivia. 1968-Health, Education and Welfare Fellowship (P.L. 480), A Study of Infant Diarrheal Diseases: Mohd. All Jinnah Post Graduate Institute, Karachi, Pakistaii Seato Cholera Research Center, Dacca, Pakistan. honors: Outstanding Intern of the Year Award, 1970-71--University of North Carolina. Publications: Newman, Michael A. (Ed) The Medical Director in Prepaid Group Practice, American Group Practice Association, Alexandria, Virginia, 1973. Raft, D., Newman, M., Spencer, R.: Suicide on L-Dopa, Southern Medical Journal, 65: 312. Travel: Mexico, Japan, Hong Kong. Cambodia, Thailand, Malaysia, Singapore, Indonesia, Ceylon, India, Pakistan, Bangladesh, Kenya, Uganda, Liberia, Britain, Netherlands, France. Senator NELSON. Mr. Boynoff, YOU may proceed. I am sorry to get to you so late. STATEMENT OP MORRIS BOYNOPP-Resumed Mr. BOYNOFF. In the interest of time, I will not read my prepared statement.. I will subimt it for the record and review a couple of com- ments that have come to mind. Senator NELSON. Your statement will be printed in full in the record. Mr. BOYNOFF. Thank you, Mr. Chairman. One of the questions that has been central to what I have heard is what would happen if propoxyphene were not available to physicians? We have that situation in California, in a practical sense, not legal, and we have had the situation under our medicaid program whichop- erates on a closed formula basis. Now, physicians as people involved in meeting human needs, as all of us are engaged in one health activity or anotl~ier are also concerned with the costs that are inflicted by their decisions upon their patients PAGENO="0228" 16780 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and since medicaid was devi'sed to bring poor people into the main stream of medical care, that out-of-pocket cost to those specific pa- tients is also important to the prescribing physician. In 1967 when medicaid programs started in California we had a closed formulary and physicians then could not or would not pre- scribe propoxyphene for their medicaid patients. Senator NELSON. What year was that? Mr. BOYNOFF. 1967. Senator NELSON. And the formulary did not list propoxyphene? Mr. BOYNOFF. And does not as of this moment. So we have approxi- mately 11 plus years of experience, of large numbers of patients presenting pain symptoms, treated without propoxyphene. Now, the Medi-Cal formula does include narcotic pain relievers. It does not include the nonprescription pain relievers, although non- prescription drugs are included in the formulary and contraceptive devices and medical supplies. Senator NELSON. But not nonprescription analgesics? Mr. B0YN0FF. As a matter of fact. I believe our enabling act in California aspirin is specifically prohibited from being included so that the consultants that we call for authorization to supply non- formulary medications to patients and still be assured reimbursement and I have been told in the instance of a youngster with a clissemi- nated juvenile arthritis who survives currently on aspirin, that even though it was clearly indicated as the drug of choice, the consultant was prohibited by regulations for payment of aspirin so that young- ster's parents purchased the aspirin over-the-counter. My point is that sometimes we are entrapped into dealing with images and codeine being an opiate has a poor reputation but it is unusual to receive a prescription, from a. physician stipulating co- deine alone. Codeine alone is a schedule II narcotic complicated by the fact that in California., schedule II narcotics require the physician to write his prescription order on a State-supplied triplicate form and we have used that in California since 1938 or 1939 so that the kind of separate and unequal documentation required for schedule II narcotics almost assuredly guarantees that the prescriber will seek something more moderate in activity. For these 11 years physicians have ordered codeine but alw-ays with aspirin and caffeine or with acetaminophen because that drops it down to schedule III and permits it to be a verbal telephone order. Senator BoscHwlTz. Schedule II is allowed under the verbal tele- phone order? Mr. BOYNOFF. No; anything lower than schedule II. Senator BoscHwlTz. So codeine when mixed with aspirin is what? Mr. BOYNOFF. When combined with a non-narcotic is schedule III. Senator BoscIIwITz. I thought you said it was a schedule II. Mr. BOYNOFF. No; I have attained that age where I am now coin- petent to look at some phenomenon from sort of a. historic and retro- spective standpoint and I think that the entire controversy regarding propoxyphene really relates first. of all to the pharmacological question which is most difficult, if not. impossible at this state-of-the-art to quan- tify. Is it a pain reliever? PAGENO="0229" COMPETITIVE PROBLEMS IN THE 1~RUG INDUSTRY 16781 Well, you pay your money and you take your answer. An item that was handed to me by a patient when I could not resist the ego satis- faction of saying I was going toWashington who brought me this ad and it is an ad stipulating that two 500 milligram tablets of acetamino- phen are more effective than Darvon and in the area of attempting to measure pain relief, we are handicapped by the fact that we have not as yet devised a way of measuring pain. We measure it descriptively. We say "moderate," or "severe" or "intolerable." These are all adjec- tives. They are not measures, and even with a well-defined double-blind crossover study when push comes to shove, somebody has to ask the patient how do you feel. I can think of no more totally subjective nonobjective measure so let us get back into historical perspective. Eli Lilly & Co. had the great good fortune to come along at the legally opportune moment. It was during that era before the Kefauver-Harris amendments to the Food, Drug, and Cosmetics Act which meant a company proposing to market a product did not have to prove efficacy. They did not have to prove it was useful or it would, in fact, relieve pain. They merely had to demonstrate that if used as prescribed, it was safe. But there was an even more important coincidental factor and that is that the Comprehensive Drug Abuse Prevention and Control Act had not yet been enacted so the second factor was that under the older Harrison Narcotic Act, even Empirin compound with codeine could not be telephoned. The Department of the Treasury administering the Bureau of Narcotics had not yet, as yet, accepted the invention of the telephone. It had to be in writing and as a young pharmacist attempting to establish his own self- employed practice in an urban area-this was in the Berkeley, Calif. area-I spent a great deal of time nudging physicians to followup in writing their telephone prescriptions. I hope that the statute of limitations has run out admittedly to an illegal activity but that is common practice and the patient presents himself to the pharmacy in pain. It is a continuing pain and the previous supply has been used up so I never felt that morally or in any way other than the literal interpretation of the law that I was doing wrong but just the need to assemble all these documents to justify my inventory in the event of an audit meant that physicians themselves, you see, were easily impressed and I am talking about multimillion dollar slick advertising. I am talking about facts taken out of context which remain faCt so that Eli Lilly introduced Darvon and Darvon compound prior to the current laws relative to the intro- duction of new drugs and behold, Doctor, it can be telephoned. We are saving you time. Well, over the years there have been millions upon millions of what the advertising people call imprints or ex- posures but it is impossible to pick up a professional or scientific jour- nal without a 50-50 chance of seeing an ad for Darvon in one form or another. Now, the reason I am belaboring this is to show that all of us: Physi- cians, scientists, pharmacists, nurses, all kinds of people are human and the accumulative impact of the repetitive statement has its effect. I would also like to point out that in the area of giant corporations, decisions are made on market possibilities rather than on human needs. PAGENO="0230" 16782 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY There is nothing intrinsically or inherently wrong with that. That is how our system works and we see in 1962 or 1963 collectively through the Congress of the TTnited States who decided that it was, in fact, time for a change in the system and so the Kefauver-Harris laws were amended to the Food and Drug Act and we learn through misadventure and learn through our mistakes. The point I am really trying to make is that there is this area in medical practice that requires some kind of response; that even though a physician can educate the patient to the fact that I am doing what is best for you, that even though you are disgruntled there is no document in your hand and I want you to go home and take two aspirin, put the ice pack on, give the injury a rest and it has greater merit. In our cultural milieu we are so drug oriented that patient expec- tations become a very important factor in the pharmacy, in the medical office, in the radiology where. the X-rays are taken because patients are more and more informed and ask more and more questions. Now, I leave it to the clinical pharmacologist and the academic world to determine the exact degree of efficacy of propoxyphene but let me point out some of the economics of propoxyphene, that even though rescheduling it as a schedule IV product might have at corporate headquarters a discernible impact on sales. Senator NELsoN. You said even if you reschedule it. Mr. BOYNOFF. I beg your pardon, even if it is taken out of the area of an unscheduled drug and put in schedule IV I have not in my practice seen any diminution of its use. Part of that reason is I would find it very difficult to determine whether or not less propoxyphene were used because it has been so lit~ le. I have the great good fortune. of being in a geographically iso- lated community. I have close and daily contact with the 12 physicians, the two nurse practitioners and the two dentists and we share educa- tional conferences at our local hospital and there is good rapport and good continuing day-to-day contact.. None of the prescribers feel diminished, offended, attacked if a pharmacist calls and says these two really should be given together or this drug should not be given every 4 hours. Its biological half-life recommends that it should only be given every 6 or 8 hours and I get thanked for this, that we all share a common concern for helping meet the needs of other people who have come in for help, so I could not see a diminution in the use of propoxyphene because the practitioners in my community sense very strongly and regard it as a kind of placebo that is indicated in those cases where they do not want to use opiates or do not want to send the patient out saying take two aspirin and call me in the morning. And because of the close geographic isolation the people who are chronic drug users are easily identified and with the kind of patient records I maintain for every patient for whom I dis- pense medication, by pulling a 5 by 8 card out of the drawer I can im- mediately scan that particular patient's drug profile, the frequency of use and if, for example, as was stated earlier a patient is doubling up on the dose, I pick up on that before the physician; frequently the physician w~ho is authorizing the legal five number of refills and even under California law even though refills have been authorized, the pharmacy may not supply them except at chronological intervals PAGENO="0231" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16783 agreeing with the prescribed dosage and I say medically, if someone wants more before the appropriate term has elapsed, he does not get it. In any event, even though it iS a schedule IV drug from a practical standpoint as a community pharmacist it has increased the number of times I have to call the physicians to generate a new prescription. The other impact I really cannot make a conjecture as to its cause outside of the fact that we are all trapped in the inflationary spiral, but the January 5 issue of Drug Topics, this happens to be a companion publication to Medical Economics, and it gets widely read, the two bits of literature are widely read,but the patent date has expired. I was a member of the Pharmaceutical Reimbursement Committee to HEW's program of establishing maximum allowable costs for drug reimbursement under federally financed health care programs. Well, propoxyphene was one of the drugs we discussed. It is a vari- able starting at the low end at a cost of under $15 per thousand all the way up to the January 5 price announcement from Lilly, the Darvon Compound 65 would now cost the pharmacies $80.52 per thousand. In between there are other firms just as equally prostigeous as Eli Lilly, Parke, Davis, and Smith, Kline & French. Their products are supplied in the $24 to $25 range, not $80 and so as I perceive the prob- lem we are talking about a drug that is not very useful and in the main since Darvon is much easier to remember I am talking about the national picture for all and Darvon is a much easier name to re- member than propoxyphene-much easier. In California legally for the past 18 months or so we have had what is euphemistically called a product selection law, even though the physician using the trade name on the prescription the pharmacist may substitute a different brand and we get into a nebulous area of the law as I understand it. There are two messages implicit in the use of the trade name rather than the assigned name. When a physician writes Darvon, he is telling the pharmacist-or she as I do not mean to be sexist-the pharmacist is being told that the patient is to receive propoxyphene. The second nonverbal message is that I should buy the propoxy- phene from Eli Lilly & Co. That is the virtue of the trade name, but it has lost that virtue under the enactment of the product selection law. We have another very interesting proviso in the California law since for medicaid patients, pharmacies receive reimbursement on the basis of the actual cost of the drug, plus a fee for their services. You see, there is no threat to the pharmacies. Senator NELSON. It is a flat fee, not a percentage? Mr. BOYNOFF. Indeed. Most of us use the same approach for the private patients and insurance patients, so there is no personal income involved in selecting a less expensive product. The cheaper drugs are not a threat to the pharmacists' income. Historically, when it was illegal it did, and manufacturers generated a lot of antisubstitution support from pharmacists just on the basis of that, but the proviso of our law in California is that the difference in cost between the prescribed brand name drug and the nonbranded generics if selected, must be passed through. The difference in wholesale costs are the patients' money and I strongly feel is reasonable. So I must say those few patients receiving PAGENO="0232" 16784 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY propoxyphene in my pharmacy receive it at much less than Lilly's wholesale cost, let alone the addition of my fee. I would like to conclude by stating that I do not really feel that toxicity, that suicides, that misuses are really that important to the entire argument surrounding propoxyphene. I just think it is no darn good. Senator NELSON. Thank you very much for your very thoughtful testimony. I appreciate it. I do not need to ask you to comment on Dr. Moertel's statement because you just did. Mr. BOYNOFF. I think I just agreed. Senator NFJ~sox. I want to thank you all very much for taking the time to come here and present your very useful t.estimony on the issue on which we are conducting the hearings. We will continue these hearings on Monday, February 5 at 10 a.m., in this room, 5110 Dirksen Office Building. Thank you very much. [Whereupon at 12:30 p.m., the committee recessed, to reconvene at 10 a.m. Monday, February 5, 1979.] [The prepared statement of Mr. Boynoff follows:] Mr. Chairman, members of the committee; I am Morris Boynoff, a community pharmacist practicing in Mendocino, California. I shall attempt to convey to you observations on propoxyphene as seen from a pharmacist's frame of reference. My practice is located in a small, isolated coastal village 175 miles north of San Francisco. The health care community consists of twelve physicians, three dentists and two nurse practitioners. I am the only pharmacist, and because I am unwilling to diffuse my time and energy into activities not related to health matters, my pharmacy is modeled in the pattern of an office, rather than a retail store. In the nine years I have been in Mendocino, I have been repeatedly impressed by the time spent by all practitioners attending conferences, seminars and other educational meetings in their constant efforts to remain abreast of new develop- ments. My day to day contacts with them, the information they seek from me concerning drug actions and interactions, and their obvious concerns involved inselecting safe, effective medications for their patients allows me to exercise more decision-making judgments than most community pharmacists. On one point we are all agreed: Propoxyphene is not a significantly useful drug. Recalling the enthusiasm w-ith which it was greeted when introduced as "a non-narcotic effective analgesic," it received wide use. With more and more experience, however, its limitations were perceived by many prescribers, and I find that I dispense very few propoxyphene-containing products. It seems to to be viewed as a "probably ineffectual" drug, prescribed only when discom- for seems mild and use of opiates unwarranted. Its infrequent use suggests to me that it is chosen to fulfill patient expectations in conditions judged to be self-limiting. The fact that it is almost always ordered as a mixture containing other analgesics also conveys the silent message that little trust is put in the inherent capacity of propoxyphene alone. Another clue to a commonly held view relative to the usefulness of the drug is the fact that it has never been admitted to our Medi-Cal (Medicaid) formulary. At first it seemed to be barred because of high cost. But even with propoxyphene products now available from multiple sources at greatly reduced prices, the Medi-Cal drug advisory committee has still not added it to the formulary. As patents on drug molecules expire, my search for reliable sources of supply at competitive costs begins. The continuing allegations made by major manufactur- ers that less expensive brands are not therapeutically equivalent have encouraged FDA to require bioavailability studies for many products. When results of such studies are presented, the pharmacist can make reasonable choices. Published data, combined with experience in my practice have resulted in my exclusive use of non-branded propoxyphene products. PAGENO="0233" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16785 Basic to the entire controversy surrounding this drug is our inability to measure pain. In articles attempting to quantify results, descriptive terms, not measure- ments, are the norm. Even in double-blind crossover studies on pain relief, results must still be based on subjective observations such as asking patients how they feel. In the face of such a totally personal phenomenon as pain, the elements of imprecision are built into all studies. Complicating the problem is the matter of confusing advertisements and promotional materials. A prime example of such a tactic was a letter sent to physicians and pharma- cists by Lilly following publication of a review article on analgesics in the New England Journal of Medicine. In their letter the drug firm objecting to the author of the article placing propoxyphene in the category of minor pain relievers along with aspirin and acetaminophen. This letter then cited other literature in which propoxyphene was described as an effective agent. A month or so later another letter was sent, stating that with the knowledge of FDA they were writing to call our attention to the fact that the articles cited in their previous letter really referred to propoxyphene compound rather than to plain propoxyphene! Even though the drug was placed in Schedule IV of the Comprehensive Drug Abuse Prevention and Control Act of 1970, little effect has been noted on its frè- quency of use. To the pharmacist it has merely meant that after five authorized refills or after a six month period, a new prescription order must be generated. The net result has been an increase in the number of times a physician's office must be contacted and no visible diminution in the amount of propoxyphene used. I cannot conceive of this controversy continuing for so prolonged a period were it not for the economics involved. Prices range from a low of under $15 per 1,000 capsules of propoxyphene compound 65mg. from Rugby Laboratories to a high of $80 for Darvon Compourid-65, just ihcreased from $76 this month. Between these two extremes, other prestigious firms such as Parke-Davis, Lederle and Smith- Kline price their offerings in the $24 to $30 range. To a large degree. I feel strongly that we are once again viewing the unwillingness of drug manufacturers to simply allow the merit of a product to determine its use. I would like to conclude with a report of a "survey" I conducted among all the practitioners in my community. When informed of the petition asking the Food and Drug Administration to withdraw propoxyphene's certification as an anal- gesic, each respondent made the same observation: I can certainly get along with- out it. PAGENO="0234" 16786 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY JANUARY© 1979 the twice monthly news magazine c,~ i~1~ F iYLF} PFC( C; PAGENO="0235" Nu. 44461 ~r. Gohr~ Kellogg 1 every 4 hnU~ :~ec~ec~ for palfl' COMPOUt'~~' `Li COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16787 I.. More effeaiw0 The extra~strength non-aspirin in DatrilS5OO~ worked better than two leading prescription pain relievers. Datril 500 is a non-aspirin pain reliever from Bristol-Myers for the relief of headaches, minor aches and pains. You can buy it without a prescription. Yet, in tests against two leading prescription pain relievers, here's what two major medical studies reported: 9The extra-strength amount of non-aspirin in Datril 500 was significantly more effective in relieving pain. More effective than both Darvän~ Compound-65 and Darvocet-N~ 100. These prescription products are effective. But the 1000 milligrams of pain reliever Datril 500 puts into two tablets were even more effective. Use only as directed. H~pkk~t iA Eff,i# Pth~ R .LC,,,~7 ~R~thw;th ~ ~ A ~ Fi'~&iHui. ~ N yi~&.Œ&~A~iph..' C~b'~Ai'~, A.'~d P ~AA ~ 7h~p. P.,. l9~622A3i, 1976, 9'ith,M.t& `Ai,s~ph..~ 1,'. 1t~'h Cp ~ C'~~pii~d45 ~ PA9~AN A DbAbii~d1Ndy.f ~ Nt 1tøy" C,.~ Th~.p 9..,. 17;492'419,1975,ih,kit Nt ~ ..tg..i: .lN...pt..J ...pty.dtth..Nm.,',It,i~....,th,sd.thkNtD,tl1O7. Try DotS 500 From Bns~oI~Myers PAGENO="0236" PAGENO="0237" COMPETITIVE PROBLE~MS IN THE DRUG INDUSTRY (Present Status of Competition in the Pharlllaceutical Industry) MONDAY, FEBRUARY 5, 1978 U.S. SENATE, SELECT COMMITTEE ON SMALL BUSINESS, Wa.shington, D.C. The committee met, pursuant to call, at 10 :05 a.in., in room 5110, Dirksen Senate Office Building, Hon. Gaylord, Nelson, chairman, presiding. Present: Senators Nelson, Baucus, Levin, WTeicker, Hatch, Haya- kawa, and Boschwitz. Also present: Gerald D. Sturges, professional staff member; Stan- ley A. Twardy, Jr., minority counsel; and Judith K. Hillegonds, staff assistant. Senator NELSON. Our first! witness this morning will be Donald Kennedy, Commissioner of Food and Drugs accompanied by J. Rich- ard Ciout, Director, Bureau of Drugs and Richard Cooper, Chief Counsel, Food and Drug Administration. Commissioner, we have your statement. You may proceed to present it as you desire. STATEMENT OF HON. DONALD KENNEDY, PH. B., COMMISSIONER, FOOD AND DRUG ADMINISTRATION, ACCOMPANIED BY RICHARD COOPER, CHIEF COUNSEL, FDA; AND ~F. RICHARD CROUT, DIREC- TOR, BUREAU OF DRUGS, FDA Commissioner KENNEDY. Thank you very much, Mr. Chairman. I am glad to have the opportunity to discuss our activity with respect to propoxyphene. Although previous actions by both FDA and the Drug Enforce- inent Administration have had an important impact on the labeling and use of these drugs, the abuse and misuse of propoxyphene is none- theless a genuine problem. Senator NELSON. May I ask a question at this point? I have a copy marked "draft" and then you have another one. Are they significantly changed in any respect? I have marked up the copy marked "draft." Commissioner KENNEDY. I would say that the changes are not ex- tensive, Mr. Chairman~ although I do not regard them as insignificant either. I think you will be able to follow just fine on your draft copy except for one or two places, but I would rather be held to the final version if that is all right. 16789 PAGENO="0238" 16790 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. I assume the changes were significant or you would not have bothered to make them. Commissioner KENNEDY. Correct, sir. Thank you. Darvon, generi- cally propoxyphene hydrochloride and combinations with aspirin, phenacetin, and caffeine, known as Darvon Compound, Darvon Com- pound 65, were first marketed in 1957 by the Eli Lilly & Co. after approval on the basis of safety alone. After passage of the Drug Amendments of 1962, a panel of experts established by the National Academy of Sciences National Research Council reviewed propoxyphene products and concluded they were effective for the relief of pain. This group of drugs was then approved for effectiveness by FDA in 1969. Senator NELSON. May I ask a question? You say "reviewed propoxy- phene products." You are referring in that case to the combinations with acetaminophen and APC, as well as propoxyphene alone? Commissioner KENNEDY. Only Da.rvon at that time and Darvon Compound and Darvon Compound 65. The new propoxyphene prod- ucts containing the ha.psylate salt of propoxyphene rather than the hydrochloride either alone or in combination with acetaminophen (Darvocet-N), (Darvon-N) or aspirin (Darvon-N with ASA) were approved and marketed in 1972. The term propoxyphene products, plural, refers to just. propoxyphene in various dosages and terms. Senator NELSON. Were these conclusions of the NRC based upon double-blind studies or review of the literature? Commissioner KENNEDY. They were based entirely on review of the literature at the time. The NRC committees did no new studies of their own. Senator NELSON. But they did review a good many of the drugs required to produce controlled studies to prove efficacy. You are say- ing they did not in this case? Commissioner KENNEDY. That is right, they did not. Senator NEI~soN. But in many drugs you have required that. Commissioner KENNEDY. Yes; that is correct. For many years, propoxyphene-containing products have been among the most fre- quently prescribed prescription drugs in the tTnited States. I am putting up a chart for people who cannot see the chart in my statement so they can look at appendix A. Both the chart and the. appendix show the number of outpatient prescriptions totaling over 39 million annually in those years, since 1964. Products containing propoxyphene peaked in popularity from 1973 to 1975 with retail prescriptions totaling over 39 million an- nua.lly in those years. While the total number of prescriptions has dropped to some 31 million for 197$. based on the projection of 9 months data, propoxyphene products are still very popular. You will see that Darvocet-N, the napsylate compound ranked 12 and Darvon itself 93 and there is a point to be made about that just in passin~. Something like 80 percent of the propoxyphene used out. there is used in its various combination forms with aspirin. acetaminophen and whatever and when we are talking about use in the real world, we are talking primarily about combination use. Senator NELSON. This is what I wanted to clarify for the record. Your chart shows the ranking of these four; three of them in combi- PAGENO="0239" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16791 nation and one of them propoxy~hene alone, so they are ranked among the first 200 most widely prescribed drugs. Is that correct? Commissioner KENNEDY. That is correct. Senator NELSON. And the fiiston your chart, Darvocet-N 50 and Dar- vocet-N 100, are combinations of propoxyphene and acetaminophen. Is that correct? Commissioner KENNEDY. Darvocet-N occurs in a couple of combi- uations. That is one of the places in which your draft testimony has to be adjusted. The first two entries for Darvocet-N were confusing because neither one alone-they should have been combined in establishing a ranking for napsylate compound and so `if you would consult the chart on page 2 of the final version of our testimony I think that will clarify your question. That chart has three entries instead of four. It combines the entries for the Darvocet-N product and shows that together they ranked 12th and that rank is established primarily by the company product. Senator NELSON. The Darvocet-N 50 and Darvocet-N 100 are simply combinations of propoxyphene and acetaminophen in different amounts, is that correct? In other words, the Darvocet-N 100 must be a different combination of acetaminophen and propoxyphene than Darvocet-N 50, is that not so? Commissioner KENNEDY. Well, it certainly is a different amount of Darvon, but let us just straighten this out, Mr. Chairman, because it is confusing working from two sets of testimony. Senator NELSON. But just so the record is clear, you combine them in your chart, subsequent chart, as just Darvocet-N, and that, I take it7 is simply a combination product in which the only two active ingredi- ents are propoxyphene and acetaminophen. Commissioner KENNEDY. It is different amounts of propoxyphene but it is a combination product. Senator NELSON. Then yourother one, Darvon compound-65 is pro- poxyphene with APC-~aspiriñ, plenacetin, and caffeine? Commissioner KENNEDY. Yes. Senator NELSON. Just one more thing for clarification because I did not see it in your original written statement, but I think you did testify to it. Do you say that 80 percent of all Darvon, or all propoxy- phene sold, is in combination with either codeine, acetaminophen, or aspirin? Commissioner KENNEDY. Not codeine. Senator N1~J~soN. No codeine combination at all? Some of the double- blind tests include it. Commissioner KENNEDY. I do not believe there is any codeine com- bination at all. Senator NEr~soN. Some of the double-blind tests had them in combi- nation, I think. Commissioner KENNEDY. That is correct, for the purpose of con- ducting studies there may have been combinations given but I do not know of a marketed combination. Senator NELSON. In `the marketplace, 80 percent of the propoxy- phene sold is in combination with either aspirin or acetaminophen? PAGENO="0240" 16792 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Commissioner KENNEDY. Yes; that is approximately correct with one reservation. Recall that we are talking here about patient prescrip- tions. The index we are reporting here is an index based on retail phar- macy sales. There obviously is au additional amount of use in hospitals. That use might tilt the statistics a little bit but I think not very much. Now, as I mentioned NAS-NRC reviewed propoxyphene products for efficacy in the late 1960's. The chairman of the NAS-NRC Drug Efficacy Study Group Panel on Drugs for Relief of Pain was Louis Lasagna, an expert in the field of clinical pharmacology and analgesia. A 1966 article review by William T. Beaver, another expert in the field of analgesia, concluded the following: In summary dextropropoxyphene is a mild oral analgesic which has proven superior to placebo in doses of 65 milligrams but which is of questionable efficacy in doses less than 65 milligrams. The drug is definitely less poteat than codeine, the best availalbe estimates of the relative potency of the two drugs indicating that dextropropoxyphene is approximately one-half to two-thirds as potent as the latter drug. Likewise, dextropropoxyphene in 32-milligram to 65- milligram doses is certainly no more, and possibly less effective than the usually used doses of aspirin or APO. FDA announced the results of the DESI review- in 1969. The an- nouncement described the indications for which the drugs were deemed effective-for the relief of mild to moderate pain. Reservations about the efficacy of propoxyphene continued to be ex- pressed during the 1970's. For example. R.. R. Miller and associates in 1970 reviewed all available double-blind studies of propoxyphene and concluded that ~ * * It is no more effective than aspirin or codeine and may even be inferior to these analgesics." C. G. Moertel and associates in a 1972 double-blind study of single doses of propoxyphene. aspirin, and other oral analgesics in patients with cancer, were unable to show that even 65 milligrams of propoxy- phene was significantly superior to placebo. In this study, aspirin was the most effective analgesic tested. R. R. Miller in a second review in 1977 concluded that propoxyphene was no more effective than I)lacebo in three studies, whereas in five others propoxyphene was not more effective than other analgesics. On the other hand. Sunshine and others. in a 1978 study. found propoxyphene napsylate at 200 milligrams, twice the recommended dose, to be significantly better than placebo. The. lowest dose used- 50 milligrams-w-as only slightly better than placebo but the usual dose of 100 milligrams w-as not tested. Mr. Chairman, in your letter of invitation you asked me to comment on the reasons for the sustained popularity of piopoxyphene as an analgesic in view of its limited effectiveness. The answer to this ques- tion is complex and involves a number of factors. First, I think it is important to point out a significant number of people-typically 30 to 35 percent-in clinical trials on analgesics ob- tain pain relief from placebo. Recent research suggests that this placebo response is due to ac- tivation within the brain of the same neural receptors that are affected by narcotics. The pain relief obtained is just as real. and may be just as great in many instances, as that provided by drugs. The placebo response may be enhanced by encouragement. from the prescribing physician. Thus, any prescription analgesic is likely to offer pain PAGENO="0241" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16793 relief to the many people who tend to be placebo responders-even if its inherent effectiveness is minimal. I think Dr. Beaver in his testimony before you last week, at least as it was reported to us, gave a very thoughtful account of this part of the problem. Senator BosdllwlTz. Dr. Beaver in his testimony last week gave us a great deal of what you are. giving us now. Perhaps, in the interest of time, you could summarize his cOnclusions and go on to new material. Many of us have other meetings to go to and time is of the essence. Commissioner KENNEDY. Well, I understand that, Senator, and I will be glad to move through as quickly as I can. Perhaps then I will delete my attention to the questions that I was asked by your chair- man about propoxyphene's po~ularity by saying that there were a number of reasons why physicians particularly at the time of its in- troduction chose to precribe it. It is of relatively short term effect; its utility in patients who for reasons of gastric problems, liability to liver damage, cannot take large amounts of aspirin or acetammophen, and so forth. During the past 4 years, a number of prescriptions were written annually for the propoxyphene product has declined. Senator NELSON. Where are you now? Commissioner KENNEDY. I am sorry, I am at the bottom of page 6, Mr. Chairman. Senator NELSON. I wish you would go back to your item 4 on page 6 starting, "propoxyphene ~ * Commissioner KENNEDY. Yes; I was pointing out as Dr. Beaver had and did not want to bore you with it, that propoxyphene has been mar- keted in an array of dosage forms, combinations, and salts that offer physicians a wide variety of options for managing patients with pain- fiil disorders; combinations that do not work on one patient may be switched to another. One supposes that this is useful to the physician and to the patient, not only because the exploration may yield a com- pound that is more physiologically active, but also prospectively the patient feels more attended to and it is possible that placebo response is maybe mobilized by the switch. Senator NELSON. Well, these comments, and your sentence on page 7 under "Safety of Propoxyphene," state that as compared with other prescription analgesics, the adverse reactions, the side effects, as- sociated with propoxyphene are mild and infrequent. Dr. Moertel did studies that you are familiar with and T would like to make some reference to his testimony, so that you may want to comment. Dr. Moertel states in his testimony of the double-blind studies that he did at the Mayo Clinic: Darvon showed some advaut~ge over sugar pills lint this was small nuid not statistically significant-that is, the difference could easily have occurred by ac- cident. Acetaminopluen or APAP-commorily marketed as Tylenol or Datril- showed a much more substantial degree of relief: and surprisingly, leading the pack. two simple aspirin tablets. The superiority of aspirin over Darvon was statistically significant * * * Now. in his double-blind studies lie has the sentence on page 3 of his testimony: The addition of a full dose of Darvon to aspirin, however, provided essentially to improvement in pain relief. 40-224 0 - 79 - 16 PAGENO="0242" 16794 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY So Darvon standing alone was, at best, a weak analgesic with some advantage over sugar pills. Aspirin with a full dose of Darvon in his double-blind studies provided essentially no improvement in pain re- lief. Now. if the argiinient of those who advocate the use of Darvon or prescribe it is that they are prescribing it because their patient is al- lergic to aspirin or acetaminophen. I suppose it might be a justifiable reason. But about 80 percent of what they are prescribing is propoxy- phene with aspirin anyway, so for all of those prescriptions the argu- ment about allergy or gastrointestinal bleeding certainly makes no sense. Commissioner KENNEDY. That is correct. Senator NELSON. Now-, if these studies by Dr. Moertel are correct that Darvon added to aspirin has no additional significant effect why does not the FDA prohibit the combination? Moertel's studies indicate that adding Darvon to aspirin does not increase effectiveness. Why then permit the patient to be exposed to an additional drug with the side effects it has if, in fact, it is not additive or synergistic in combination? Commissioner KENNEDY. Let me say two things in response to that, Mr. Chairman. First, the Moertel st.udy was the only one available, or if all studies on this point agreed, we would not be in difficulty but as I tried to indica.te in my testimony the results of controlled clinical trial on the effect of analgesics are plagued with inconsistency between trial and it is a very difficult matter to decide. Senator NELSON. There may very well be studies I have never heard of, but in the testimony and in the literature and in the references I have looked at from the hearings we had 8 years ago, and in the testimony thus far. I do not see any double-blind studies that show that Darvon added to aspirin is more effective than aspirin alone. Have I missed any? Commissioner KENNEDY. Well, we will review those studies. I do not know of any specifically. Senator Nelson. The point I was trying to make rather is that studies on Darvon compound alone and on Darvon in various combinations it comes out differently in terms of~ its relative efficacy in different people's hands. Moertel's studies only covered cancer patients. For example, one might expect differences betw-een that type of study done on patients with other sorts of pain. My point is not that there is evidence that this particular compound is more effective than either ingredient alone., but that there is a lot of ambiguity in clinicaT trials in this whole area and I was going to go on and say that FDA is going to review- the evidence on these products over the next year. It may very well be that we will find that some of the combinations are not effective, but it w-ill be a difficult business to sort out. Senator NELSON. But the FDA has taken a very correct and strong stand on the 1962 amendments, which require proof of efficacy based on well-controlled scientific studies. Everybody who has testified and who is an expert in this field, of course, has said there is a great deal of subjectivity in judging pain relief. PAGENO="0243" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16795 Both you and Dr. Beaver have addressed the question of the placebo effect, which may be based on a physiological response because of encouragement from the doctor and the fact the patient got a pill. However, in order to allow this drug to be on the market or remain on the market, does not the law require you to come up with well- controlled studies that would show that, in combination, propoxyphene and aspirin are more effective than either one alone? The law is fairly clear. It requires the posit.ive~ proof of well-con- trolled studies to support the introduction of a drug in the market- place. You have been very strong in that position on the combination antibiotics, requiring proof or ordering them off the market. Are they all off now? Commissioner KENNEDY. Ahnost. Senator NELsoN. So my query is: How do you justify under the statute-which requires well-controlled studies-the presence in the marketplace of a combination of active ingredients for which there appears no scientifically controlled studies that prove it is more effective? I may be wrong. Maybe there aie studies out there. But in all the literature I have looked at. I have not noticed one well-controlled study that would prove that it is more effective in combination than standing alone. Commissioner KENNEDY. WelL clearly at the time that the com- bination products were~ introduced and at the time that we did our review, the NAS-NR.C Committee and our reviewers found the evi- dence at that time persuasive enough to allow the marketing of these compounds. It often happens, Mr. Chairmarn that as time goes on and evidence from clinical trials on already marketed drugs accumulate, that we have to change our minds and that is why I am telling von that there is going to be a careful review of the effectiveness as well as the safety of these products and that it might very well result both in large changes or in consideration of withdrawal of those of the combination product. You are quite right in youi~ assertions what our policy was. Senator NELsoN. I am sure you iniderstand very well that once a drug is in the marketplace and being used by hundreds of thousands or millions of people, all kinds of reactions that were not anticipated, due to limited, controlled studies, are disclosed almost inevitably over a period of time. And I recognize this drug was in the market- place in combination before the efficacy amendments of 1962, is that not correct? Commissioner KENNEDY. Some of its combinations were. Senator NELSON. However, if a new drug application (NDA) were before you now, would you require well-controlled studies demon- strating that in combination the drug was more effective than it was as a medicine administered alone before you would permit it to go into the marketplace? Commissioner KENNEDY. Yes, sir. Senator NELSON. Are you aware of any well-controlled studies as of this date that would support it going into the marketplace as a combination product if the application were currently pending? PAGENO="0244" 16796 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Commissioner KENNEDY. Let me give you a very specific answer. I know of no studies that could be used for the justification of 65 milli- grams of IDarvon. plus 200 of aspirin; that is studies adequate to demonstrate controlled clinical trials, that that combination of in- gredients is superior to either ingredient at that dosage level and that is what we would consider necessary to demonstrate, to allow the marketing of a combination. Senator NELSON. Have there been any studies that identify a specific target population for propoxyphene alone? Commissioner KENNEDY. That is a specific target population that cannot be benefited by other combinations of analgesics, or a single analgesic but needs propoxyphene alone? Senator NELSON. Yes Commissioner KENNEDY. No, there is no such study. Senator NELSON. It is interesting to note the widespread use of Darvon, either as a single entity or in combination form, and then read the literature tha.t argues in support of the idea of using it be- cause some people have a reaction to aspirin or acetaminophen or codeine. Yet it would appear from talking with physicians and listen- ing to people comment that it is very common to prescribe Darvon in combination as the dnig of choice for mild analgesia without first identifying a patient for whom it would be preferred. Is propoxyphene so far as you know the drug of first choice as a mild analgesic without previously identifying a specific indication for it? Commissioner KENNEDY. Well Senator, that is a question about actual prescribing practice that I just do not feel equipped to answer. I will say this. if you just look at the prescribing behavior out there and note tha.t 80 percent of it is for the drug in combination with one of those other two on the analgesic ingredient list you cannot make much of a case that it is being restricted to patients who cannot take aspirin or acetaminophen because most of the Darvon being prescribed is being prescribed in combination with those drugs. As to the 20 percent of the Darvon being prescribed by itself, I have no idea in what proportion of those cases physicians seek first to ascertain whether the patient has a gastric ulcer, history of liver disease, or whatever would make that patient ineligible for receiving that medication. I just do not know. Senator NELSON. Go ahead. Commissioner KENNEDY. I had several points to make, Mr. Chair- man, about. safety and if it is satisfactory to you I will move through the material on pages 7 and 8. but not cover every paragraph. Senator NELSON. Your statement submitted today will be printed in full in the record and you may present it in any way you desire. Commissioner KENNEDY. Yes. We had some dialog a. moment ago about the statement that compared with other prescriptions, the side effects of propoxyphene is mild and infrequent and that is quite in- dependent from the problems we are going to be mentioning in a little while. The drug abuse potential of propoxyphene was recognized as early as the late 1950's but was not a major public concern until the late 1960's and early 1970's. PAGENO="0245" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16797 Chronic propoxyphene use sometimes results in~physical and psy- chological dependence of a type similar in nature but not degree, to that produced by morphine. Intravenous "street" use by drug addicts was popular in the late 1960's but waned, particularly because of its ability to cause vascular and other tissue destruction, and because of formulation changes in the product. This pattern of abuse resulted in overdose deaths that resembled those seen with heroin and methadone, for example, respiratory de- pression and pulmonary edema. As a result of these problems, DEA placed it under schedule IV of the Controlled Substances Act (CSA) in 1977. Our analysis of the available data on propoxyphene fatalities shows that the majority of associated deaths occurred because of deliberate overuse or abuse, as shown in the two tables in appendix B. Propoxy- phene is one of the most frequently used drugs in suicides and suicide gestures; in absolute incidents it follows only the barbiturates and nonbarbiturate sedative-hypnotics in associations with drug-induced suicide. However, when viewed in relation to the number of prescrip- tions issued, the relative number of deaths from propoxyphene is lower than that for a number of other drugs. We know of no cases at present in which death was caused by pro- poxyphene products alone when taken in customary doses and in which neither alcohol nor tranquilizers were also involved. There are, however, a number of "accidental" deaths which have ap- parently occurred as a result of the consumption of propoxyphene in quantities smaller than those used in suicide, yet still in excess of recom- mended therapeutic dosage and usually combined with alcohol and/or tranquilizers. Mr. Chairman, let me emphasize that mentioned in this chart, com- binations of agents are often involved in these deaths. There is no implication because propoxyphene is mentioned in a coroner's report or in an emergency room report that it is, in fact, the cause of death. It may be a particinant in a combination death or might, indeed, have little or nothing to do with it. Senator NELSON. In the testimony last week, one of the witnesses made the point that many laboratories across the country lack the ability to detect and measure the presence of propoxyphene in the blood with accuracy at either low or lethal concentrations. The wit- ness said that means many cases of propoxyphene overdose are prob- ably missed. Wkiere the drug is established as a cause of death, there is the question of classifying the death as accidental or suicidal or, fail- ing such judgments, as undetermined. However, the forensic pathologist from Oregon took a view that was opposite from yours and several other witnesses who had said it was the intentional overdose that was causing deaths; people intending to commit suicide. He took an opposite view, that that was not the case. He thought well over 50 percent were accidental. Are you familiar with his testimony on that point? Commissioner KENNEDY. Yes; in a general way I am, Senator Nelson. At the risk of responding at, tedious length, let me begin by saying it is not an easy problem. First of all, the measurement of blood pro- PAGENO="0246" 16798 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY poxyphene is not one that everybody knows how to do very well and you find a good deal of laboratory inconsistency in that measure- ment. Second, I recall all the data we have on associations with death come~s from something called the Drug Abuse Warning Network (DAWN) which gets a coroner's re.port from 23 or 24 cities in the United States. It covers a significant portion of the United States population between one-third and one-half or I think it is 40 percent., but not all of it and you have to ask two different questions-first, are the DAWN reported deaths correct due to accident suicide and so on and do they reflect, albeit, what. the pattern of national deaths really is, and that is not easy to tell either. The testimony you have heard from Oregon and to a degree from San Francisco essentially proposes that there. are deaths that go un- recorded in most places, hence a.re not a significant part of the DAWN data which result primarily from nonoverdose deaths, although they may be combination abuse deaths in some sense; a. moderate number of Darvon pills combined with alcohol or perhaps with ordinary dos- ages of tranquilizers but not a.busers in the sense that a grossly exces- sive dose was taken and so forth. That is a hypothesis that is difficult to evaluate. It has to be taken seriously. You heard from Dr. Wolfe about nor-propoxyphene and its lifetime compared with propoxyphene. and you heard him propose from some animal data he has shared with us that there is progressive heart block associated with the accumulated nor-propoxyphene that can be gen- crated in the system as a consequence of ordinary repeated use, clay-by- day, coupled perhaps with a slight, overdose and with a few drinks, or whatever else. That is a possibility, Senator, that is very difficult to evaluate at this time. I think the fairest thing we can say at the moment is that the DAWN deaths, the ones that are reported in generating these numbers are in overwhelming majority suicides or massive large acci- dental overdoses, but that there is still an unevaluated possibility that there is a large set of deaths out there in the world that we are not measuring that is much more accidental in character and that re- lat.es to this different action of propoxyphene on which the animal data are just beginning to give us an indication. That is something we are going to be. looking a.t. We take it. very seriously, but I think it is still difficult, to evaluate at this time. Senator NELsoN. I raise. it because it is a viewpoint not uncommonly expressed. As a forensic pathologist, he was looking at the end result and made the point that in many of these cases, if it were a suicide, you would expect to find a whole lot of propoxyphene in the stomach and it was not there. I would not want to go on further to say what he said. since the record speaks better for itself tha.n I can, but I think it is worth looking at his conclusions. Having looked at people who died and have found propoxyphene involved one way or the other, he checked cities that. had a good toxicology system and pathologist available, to do appropriate stu(lies and he did an extrapolation from that to reach his conclusion. I have no qualification to judge his methodology or conclusions or anything else, but it did seem to me-since he was t.aking a position PAGENO="0247" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16799 different from the other witnesses and from most of what else I have read-that it would be worthwhile taking a look at his testimony and the methodology he used in reaching his conclusion. Commissioner KENNEDY We certainly will examine that testimony when we obtain the transcript if only for the purpose of correcting the record on the point of his correspondence with the Food and Drug Administration Mr. Chairman, which hurt me a little because we were not really casual with his mail as he said we were. Senator NELSON. Maybe the Post Office was at fault. Commissioner KENNEDY No, no, he forgets the answers. I would like to make one more point about the pattern of deaths, but first one thing that you said in your comments, Mr. Chairman. There is something else about west coast data and that is although it pains me a hit to say so, suicide is more frequent on the west coast than it is on the east coast. If you look at the large cities that report out DAWN data, the big leaders in suicides are all out there-San Francisco, Seattle, Port- land, Los Angeles are all cities in which the suicide rates are higher than they are in eastern cities and the differences are significant-GO percent. Anybody extrapolating accidental or intentional death data from there is going through an entire population, may be extrapolating from figures that are different from the ones that somebody on this coast would use. Senator NELSON. But on that point, I do not know that he listed the cities he samples, but if in fact he was using west coast cities then that would support his testimony, since he concluded the largest per- centage was accidental and not suicides. Commissioner KENNEDY. Not arguing with his testimony~ Mr. Chair- man, just making a point that if one tries to go from DAWN data to estimates of death for the entire Nation which I took it he was doing, that is when he gave you the 3,000 or 4,000 figure, there is a reason quite independent o.f accidental deaths why somebody from the Pacific coast would give you 3,000 and somebody from the Atlantic coast would give you 1,600 or 2,000, that is all. It has to be factored in. Senator NELSON. I do not know what cities he used, and I do not want to try to judge from his testimony anyway. He was, however, not coming up with statistics t.h~t supported the proposition that most of the deaths were intentional. He was coming up with statistics that argued otherwise. Commissioner KENNEDY. T understand. There is another point about the distribution of deaths from the. DAWN data and again, let me emphasize they are from the DAWN data and that has to do with an analysis by age groups and 1 think, Mr. Chairman, since we have covered most of the material before here in our colloquy I will move to the middle of page 9 and make two points about physicians and deaths. Here, you have been given an age distribution both of which men- tion are note quite the same as prescriptions written but almost the same; that is, there are mentions by physicians of having arranged that a patient get a drug, whether they are actual prescriptions written or by the patient being told to refill or to take more, but they would be approximately proportional to the prescriptions. PAGENO="0248" 16800 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY As you can see from the chart, there are a large number of these product.s supplied to people over 60. Indeed, 33 percent of all the pre- scriptions written for Darvon and IDarvon-containing products are written for the portion of our population over 60 years old. Another third are written, you see there, that other high point is for another third or so of those prescriptions that are written for people in the age group 20 to 40. Now, it is in the younger fraction of this age group that most of the deaths occur at a mean age of 25. Actually. that point represents the age intervals between 20 and 30 and there is another 22 percent or so of those deaths in that next point which represents the age range 30 to 40. Now, you add those together so that you cover that 33œ percent of the prescriptions that are written for the entire age range 20 to 40 and you discover that over 52 percent of the deaths fall into that age group and yet, the people over 60 who account for an equal fraction of the prescriptions are only accounting for 8 percent of the deaths. In other words, if I may be permitted a little liberty for the sake of description the young adults and people over 60 are equally likely to take a Darvon, but the people over 60 are only one-fifth as likely to do themselves damage as a consequence of that. I would think that ultimately the public policy solution that we apply to this problem has to take account of the fact that the risks and benefits associated with the use of these products at least as we judge the risks (from the DAWN data) which are distributed very unevenly through our population. Let me just summarize if I may, Mr. Chairman, th~ actions that FDA has taken over the past several years in response to problems associated with these issues regarding the efficacy and safety of pro- poxyphene products. In 1972, because of misleading statements on the effectiveness of Darvon made to physicians in a letter from Eli Lilly & Co., we required the manufacturer to issue a "dear doctor" letter stating: There is no substantial evidence to demonstrate that 65 milligrams of Darvon is more effective than 650 milligrams of aspirin-two 5-grain tablets-and the preponderance of evidence indicates that it may be somewhat less effective. In April 1976, FDA's Controlled Substances Advisory Committee recommended that propoxyphene and its salts and preparations be controlled in schedule IV of the CSA and as pointed out earlier, the DEA adopted that recommendation a year later. Labeling for propoxyphene was further revised in 1978 to add a warning against the additive depressant effect of the products when used in conjunction with alcohoL tranquilizers, sedative hypnotics, and other central nervous system depressants. and to require additional information on adverse reactions, drug interactions, and management of overdosage. A warning against use of the products during preg- nancy was also added because of the danger of causing addiction in the fetus and producing a. neonatal withdrawal syndrome. That is a problem with any member of the narcotic family of drugs. Now finally, I will just point out what you know very well that on November 22. 1978, the Secretary of the Department of Health, Edu- cation, and Welfare was petitioned by the Health Research Group to PAGENO="0249" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16801 suspend approval of the NDA's for propoxyphene-containing prod- ucts under section 505 (e) of the. Federal Food, Drug, and Cosmetic Act on the grounds that the continued marketing of these drugs repre- sents an imminent hazard to the public health. HRG requested alternatively that if the Secretary did not suspends he support HRG's petition to DEA that propoxyphene be rescheduled as a schedule II narcotic under the Controlled Substances Act. FDA's Bureau of Drugs is conducting a new review of all data bear- ing on the safety and effectiveness of propoxyphene including those studies referenced in the HRG petition. In summary, Mr. Chairman, the current status of propoxyphene presents us with an important and complex regulatory problem. The problems associated with its misuse are indeed troubling; but they must be weighed against significant benefits from the drug. Propoxyphene is widely used; it provides pain relief for many people. Although it is not a powerful analgesic, it has advantages for persons who cannot tolerate aspirin or acetaminophen. It is prescribed and administered or dispensed in a special medical setting that pro- vides significant psychological amplification of its effects. I am sorry that we cannot offer you a more definitive conclusion at this time. But we are still developing our analysis, Mr. Chairman. These hearings have helped materially in that regard, as well as drawing public atten- tion to a disturbing abuse problem. We will continue to give the matter close scrutiny. Senator NELSON. When you are saying propoxyphene, are you talk- ing about propoxyphene alone? Commissioner KENNEDY. Propoxyphene in the totality of its dosage forms and its pattern of distribution. Senator NELSON. So that I do not forget it. I want to ask again-and you maybe are already reviewing the NRC studies of 1969, covered in your statement here: Is it your policy to continue to evaluate drugs, both prescription and over-the-counter, under the 1962 act? If so, will it be part of this review that you are now making to survey the litera- ture to determine whether or not there is adequate proof of the ef- ficacy-pursuant to the requirements of the statute-of combinations of propoxyphene and acetaminophen, propoxyphene and aspirin? If not, will you pursue the same course the FDA I1as pursued in the past of requiring companies to come up with controlled studies if, in fact, there is not adequate proof that the drug is effective? Will you require additional evidence to show that, in fact, it meets the statute? Is that part of the procedure you are now going through? Commissioner KENNEDY. Yes. We absolutely will review effective- ness information as well as safety information. The procedure for changing the marketing status of the drug is a. little, different for some of these combination products which are, in fact, post-1962 drugs and are not so-called chugs reviewed under the transitional provisions of the 1962 amendments, but that is a technical difference. WTe can and will review the, efficacy of the combination products as well as the single dosage. Senator NELSON. But just a further question. If there are not ade- quate controlled studies to prove its efficacy in combination, are you or are you not required under the law to request. that. the studies be made ? PAGENO="0250" 16802 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Commissioner KENNEDY. Oh. yes, we could require studies. Senator NELSON. I mean are. you required or not? Some combinations of this drug were on the market before 1962 and I have forgotten the grandfather clause provisions if, in fact, there are some as to efficacy. There were some as to safety. As I recall it, when we had hearings maybe 3 years ago reviewing the progress of tl1e FDA. and the N1~C under the requirements of the 1962 act, drugs were classified as effective, probably effective, and in- effective. Is that correct? Commissioner KENNEDY. That is correct. Senator NELSON. And if they were not identified as effective, the FDA was requiring evidence of effectiveness under the provisions of the statute. Is that correct? Commissioner KENNEDY. Yes. Maybe I can help, Senator. I was not trying to put up any challenge to the requirement for adequate and well-controlled policy demonstrating effectiveness. It applies retro- actively under the terms you describe under the efficacy statute and it applies to products afterwai'd. The only difference I was trying to call attention to was a tcehnical difference-effective, probably effective, and not effective apply to those pre-1962 drugs that are treated under the transitional provisions of the law and drugs introduced post-1962, all have to meet that standard. Some of the Darvon combination products are present and some are post-1962 but the central point is that they have to meet that standard on a continuing basis and if we approve a drug on a limited set of trials that appear to demonstrate effectiveness and then a much larger body of research comes in that challenges that initial conclusion and appears to put the weight of the evidence on the other side, we are obliged to take up the matter again and reevaluate that new- drug application and begin withdrawal proceedings if the burden of the evidence shows t.hey are not effective. Senator NELSON. I guess that is what is confusing me and I apologize for not having relooked at the statute. It has been 2 or 3 years since we have had hearings on this. What I am really saying is t.he literature that T have looked at, and it may not be all of it, of course, but, in Dr. Moertel's studies and others I can recall none that found propoxyphene in combination with aspirin was more effective than aspirin alone-that is, noade- quate controlled studies to refute Moertel's studies or, more positively to demonstrate adequately that in combination they are more effective. If that is the case, then is it not under the law the requirement of the FDA-based upon the simple evidence there is to the contrary-to say: It is not clear from adequately controlled studies that they are more effective in combination and therefore, we now request the company to produce the study to prove it and if they cannot, the combination should not be in the marketplace. Am I stating that correctly? Commissioner KENNEDY. You are absolutely correct. Senator NELSON. And that is a Procedure we will be following? Commissioner KENNEDY. That is why we are doing the review. This review is being done to evaluate safety questions because that kind of PAGENO="0251" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16803 challenge to continued marketing could come either because we come to understand the risks are higher or because we come to understand that the benefits are lower and these questions have been raised on both sides with respect to these drugs and that is why we are examining them. I only want to point out, Mr. Chairman, that an examination as far as efficacy is concerned is more difficult with these drug products than it is for most because of the confounding effect of the high rate of placebo response. Everyone who has dealt with this kind of clinical trial knows it is a tough experiment to do and to interpret. That really makes our con- clusion for us, Mr. Chairman. I think there is little more that I can say except that these hearings have helped materially, obviously, in bringing some of these problems, to our attention. We plan to use the record of the hearing as well as, of course, the reviews that we had underway in considering what to do next. Senator NELSON. I have no more questions at the moment. I may have after reviewing the testimony, and if so, I will submit them and you can answer in writing for the record. Commissioner KENNEDY. We will be delighted to do so. Senator NELSON. Any questions? Senator LEVIN. Thank you, Mr. Chairman. I wonder if you could comment first of all on the several dozen effects of Darvon? Apparently, one of the offenses of its efficacy and now I am quoting the testimony is yet to come, but we had a similar bit of testimony last year about its great pain-relieving effects that come after several doses have been administered. Can you comment on that, p'ease? Commissioner KENNEDY. I aiii not sure because I have not seen the testimony you are referring to, whether that means accumulative effect of several doses of a particular formulation or whether instead what is being referred to as its avai~abiiity in a number of different dosage forms. Senator LEVIN. Have you seen any studies involving either one of those two approaches where they are comparing several doses of Darvon and several closes of aspirin 01 codeine? Commissioner KENNEDY. Not formally, although I believe that a number of physicians believe if they are able to use a number of dosage forms with a given patient that they have a higher probability of getting that patient on something that will work for him or her. Senator LEvIN. Have you seen any studies comparing that? Commissioner KENNEDY. No:; no standardized studies. Senator LEVIN. Pursuing the chairman's question for a minute, what. were the efficacy standards in 1972 when the Darvon combination was marketed, the proof of efficacy when you added Darvon to aspirin and vice versa? Commissioner KENNEDY. Adequate and well-controlled studies showing effectiveness. Senator LEVIN. Of the combination over the single ingredient? Commissioner KENNEDY. WelL I will have to take a moment for con- sultation. You see, the advanthges over a single ingredient is not part of the law but its part of regulation as I understand it and I will have PAGENO="0252" 16804 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to ask the Bureau whether at that time in history that standard was being applied to all combinations. Senator LEvIN. I would like to pursue that line of questioning, Mr. Chairman, if I could. Was that in the regulation? Commissioner KENNEDY. Now, having refreshed my knowledge of history or rather gotten for the first time the information I can tell you. In 1972 what happened, Senator, was that a new salt of Darvon, the napsylate was marketed. The Bureau's policy at the time was that a new salt, but with the same active ingredient all they needed to show is bio-availability. That is the same amount gets into the bloodstream in the same period of time so that as much active ingredient is mobil- ized and available to do what it is going to do. So the napsylate salt was approved in 1972 but without any new clinical trials. The combinations~ of the napsylate salt with aspirin and acetamin- ophen were not new combinations; they were combinations of a new salt but they did not have to meet those. clinical trials. In fact, the effi- ciency studies that supported the introduction of that new salt in 1972 were the same ones that had actually supported the efficacy review that had permitted the continued marketing of those combination products in 1969. Senator LEVIN. In 1977 I understand that the propoxyphene was placed on schedule IV. - Commissioner KENNEDY. That is correct. Senator LEVIN. Did the manufacturers in general, or the specific manufacturer of Da.rvon agree to that or opposed to the schedule? Commissioner KENNEDY. They did not oppose it. Senator LEvIN. Do you have the power to require the manufacturer of Darvon to put on the label the same thing that he was required to do in 1972 and that is to state in a letter to physicians at that time that there was no evidence to demonstrate that 65 milligrams is more effec- tive than 650 milligrams of aspirin? Commissioner KENNEDY. We probably could. Senator LEVIN. Do you think it is appropriate to have that on the label? Commissioner KENNEDY. We would have to support it convincingly and quite possibly convince a judge. Senator LEvIN. Is that you' standard proof. "convincingly"? Commissioner KENNEDY. It is not our standard but quite frequently or not infrequently when we propose labeling changes that a drug's sponsor does not agree with us, or finds it unreasonable, we find our- selves litigating the matter. Senator LEVIN. Is that the standard used by the courts have you found? Commissioner KENNEDY. Well, I would think, in general, I think it has been our experience if we can show- a court that the scientific evi- dence with regard to efficacy or safety is on the side of the statement that we are asking the manufacturer to make, that we win. Senator LEvIx. In your opinion is that statement true that you re- quire the manufacturer of Darvon to make? Commissioner KENNEDY. The "Dear Doctor" letter, yes. Senator LEVIN. You think you could carry that burden of proof in court? PAGENO="0253" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16805 Commissioner KENNEDY. I would suspect we could. Senator LEVIN. Why do you not require it to be placed on the label in that event? Commissioner KENNEDY. I would think that is something that would be considered as a part of the review that we are undertaking. The labeling for doctors and its impact on what actually happens in the prescribing world is something else. It is not always clear that you have very much of an impact that way. I think that is sometimes why labeling changes are something that comes to mind is when effec- tiveness is at stake as opposed ~o safety. We find that box warnings with regard to safety labeling have some impact, although not as much as we would like. Effectiveness, I think there is some doubt on our part there. Senator LEVIN. Will you let us know the results of your consideration on that question? Commissioner KENNEDY. We certainly will.' Senator LEVIN. The last question I have has to do with your com- ments about significant benefits of the drug. We have not heard yet from the manufacturer, but based on your own testimony and based on the testimony of others, the reasoiis that you give for that conclu- sion is one that it was widely used. I do not presume that leads to a conclusion that it has a significant benefit necessarily and the second part is that it provides pain relief for many people. Do I understand you to say it has no greater pain relief than aspirin? Do you accept those studies or not? Commissioner KENNEDY. Yes; I accept those studies but I think at the same time one has to be realistic. I think that a person who re- ceives pain relief is experiencing the end point of a very complicated physiological process and I think the perception that a drug is helping is very often significant. Senator LEVIN. That goes to your psychological implications, point four, but in terms of pain relief for many people you do accept the studies that say it is no greater, perhaps less than aspirin? Commissioner KENNEDY. Yes. Senator LEVIN. That does nOt lead to your conclusion does it, that it has a significant benefit? Commissioner KENNEDY. Let me back off a minute and say that I think there might be a real difference in the real world situation there. Remember, that what is really happening in the world is that Dar- von and its combinations are being prescribed by a physician to some- body who is experiencing pain whereas the OTC analgesics are being pursued at the corner drug store or the physician is saying take two aspirin and call me in the morning. There is a real difference between those two things and one cannot forget that this drug is not just a molecule; it is part of a therapeutic approach that is going on out there. Senator LEVIN. That goes back to your physiological point again. That is point 4. Point 2 in terms it provides pain relief. You have stated you agree with the studies relative to aspirin. 1 See FDA drug bulletIn of February-March 1979 following Commissioner Kennedy's prepared statement, page 16826. PAGENO="0254" 16806 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Point 3, its advantages to people who cannot tolerate aspirin. There I presume at least 80 percent is used by people who cannot take aspirin. Commissioner KENNEDY. That is correct. Senator LEVIN. And you do not know whether the other 20 percent who take it alone can tolerate aspirin. Certainly, 20 percent take it for that purpose alone. Conimissioner KENNEDY. Very much less. Senator LEVIN. Can you estimate what percent of the people who take Darvon get relief or can get relief from aspirin and can take aspirin? Commissioner KENNEDY. You have moved us to the real world again and it is people who are taking Darvon in a particular therapy setting and asking them to change not only their drug but their behavior and I think that is a very difficult question to answer. Senator LEVIN. From the studies, though, the objective studies put- ting aside the psychological implication questions, would you state it is over 80 percent putting aside the psychological aspects of having the prescribed drug instead of buying it at the supermarket counter? Commissioner KENNEDY. Yes; if one were able to eliminate those entirely, perhaps over 90 percent~ Senator LEVIN. What it really comes down to is the biggest ad- vantage of Darvon is that it is prescribed. Commissioner KENNEDY. Well, there are some others. I mean com- pared with other things it really does, if used alone, have lower side effects and so forth, but I think if you take into account that 80 per- cent is prescribed in combination and so forth, then I would think a major advantage of it is that it is prescribed. Senator LEVIN. Thank you. Senator BAucus. No. 1, in listening to your testimony here the question arises in my mind is the degree to which you consider psy- chological amplification, I guess my point is-a drug which obviously does not safely test for some reasons has tremendous psychological implications. Do you weigh that or do you not weigh that? Commissioner KENNEDY. I would be very unhappy to be in that position, Senator, but I fortunately think I never will be because the absolute essential property that the drug must have if it is to yield that kind of physiological amplification is if it is generally thought that the amplification is psychological instead of physiological. It is to be thought of as something else and I guess at the front end of an approval process, it would not occur to me I think to consider the psychological effect of a drug as an important part of the efficiency criteria given, however, that 35 million prescriptions a year are writ- ten for it and it is out there it seems to me that I would have to take that very much into account. Senator BAUCUS. How do you measure psychological applications? Commissioner KENNEDY. Well, you would experimentally get people to report their pain and to report their pain after having been given a physiological active analgesic and having been given something known not to contain any physiological active principal and then ask the question under circumstances where a certain percentage of people show placebo response, experience pain relief in response to placebo without some other kind of intervention and you then ask PAGENO="0255" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16807 the question, does a higher percentage of them show placebo re- sponses when, for example, placebo is prescribed by a doctor, dis- pensed by a pharmacist, and so fOrth. Specific studies to test that have not been done in this universe, but there is other evidence to suggest that the act of prescribing and the involvement of health professionals in the therapeutic setting do increase the probability that that response will occur. We could supply the committee with studies to that effect. Senator BATJGUS. If you would, please.1 My second general question has to do with the timing of your study. Will you give me some indication of your timetable, when you plan to complete the studies and make the studies known ~ Commissioner KENNEDY. Well, this review will be completed within a few months I would say. There is a scheduled meeting of the Con- trolled Substances Advisory Committee on February 12 and 13 at which we will share with that advisory committee a number of the safety considerations and we will respond to the need to advise DEA on the petition to reschedule. We will be continuing our review of the efficacy studies and should discuss those with another advisory committee later on in the spring. I would estimate that 3 or 4 months would be required to complete what we have undertaken now. Senator BAUCUS. Thank you. Senator NELSON. Thank you, very much. We appreciate your tak- ing the time to come and testify. Commissioner KENNEDY. Thank you, Mr. Chairman. Senator NELSON. Commissioner Kennedy's full statement will ap- pe.a.r in the record.at this point. [The prepared statement and supplemental information of Com- missioner Kennedy follows:] 1 See studies submitted by the Food and Drug Administration following Commissioner Kennedy's prepared statement, page 1082G. PAGENO="0256" 16808 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY STATEMENT BY DONALD KENNEDY COMMISSIONER FOOD AND DRUG ADMINISTRATION PUBLIC HEALTH SERVICE DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE BEFORE THE SELECT COMMITTEE ON SMALL BUSINESS UNITED STATES SENATE FEBRUARY 5, 1979 PAGENO="0257" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16809 Mr. Chairman and Members of the Committee: I appreciate the opportunity to discuss the activities of the Food and Drug Administration (FDA) with respect to propoxyphene. Although previous actions by both FDA and the Drug Enforcement Administration (DEA) have had an important impact on the labeling and use of these drugs, the abuse, and misuse of propoxyphene is nonetheless a genuine problem. USE PATTERNS OF PROPOXYPHENE Darvon (propoxyphene hydrochloride) and combinations with aspirin, phenacetin, and caffeine (Darvon Compound, Darvon Compound-65) were first marketed in 1957 by the Eli Lilly Company after approval on the basis of safety alone. After passage of the' Drug Amendments of 1962, a panel of experts established by the National Academy of Sciences-National Research Council (NAS-NRC) reviewed propoxyphene products and concluded they were effective for the relief of pain. This group of drugs was then approved for effectiveness by FDA in 1969. New propoxyphene products containincT the napsylate salt of propoxyphene rather than the hydrochloride, either alone (Darvon-N) or in combination with acetaminophen (Darvocet-N) or aspirin (Darvon-N with ASA), were approved and marketed in 1972. 40-224 0 - 79 - 17 PAGENO="0258" 16810 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY For many years propoxyphene-containing products have been among the most frequently prescribed prescription drugs in the United States. Appendix A (attached) shows the number of outpatient prescriptions written by year since 1964. Products containing propoxyphene peaked in popularity from 1973 to 1975 with retail prescriptions totaling over 39 million annually in those years. While the total number of prescriptions has dropped to some 31 million for 1978 (based on the projection of 9 months data), propoxyphene products are still very popular. The following table shows the rank of each ariona the 200 most prescribed druqs for the years 1972 throucjh 1977: Rank Among the Top 200 Most Prescribed ~ 1972 1973 1974 1975 1976 1977 Darvocet-M - 87 24 20 18 12* Darvon 32 mg & 65 mg 35 47 68 71 78 93 Darvon Compound-65 APC 2 3 3 6 15 20 *Darvocet_M was divided into two groups (50 and 100) for the year 1977 only. The 1977 rank for Darvocet-N 100 was 18; for Darvocet-M 50 was 169. -2- PAGENO="0259" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16811 EFFICACY OF PROPOXYPHENE As I have said, ~!AS-1iRC reviewed propoxyr~hene products for efficacy in the late 60's. The chairman of the NAS.-NRC Drug Efficacy Study Group Panel on Drugs for Relief of Pain was Louis Lasagna, M.D., an expert in the field of clinical pharmacology and analgesia. A 1966 article review by William 1. Beaver, M.D., another expert in the field of analgesia, concluded as follows: "In sumary, dextropropoxyphéne is a mild oral analgesic which has proven superior to placebo in doses of 65 mg or more ~ut which is of questionable efficacy in doses lower than 65 mg. The drug is definitely less potent than codeine, the best available estimates of the relative potency of the two drugs indicating that dextropropoxyphene is approximately 1/2 to 2/3 as potent as the latter drug. Likewise dextropropoxyphene in 32 mg to 65 mg doses is certainly no more, and possibly less effective than the usually used doses of aspirin or A. P.C." FDA announced the results of theDESI review in 1969. The announcement described the indications for which the drugs were deemed effective-- for the relief of mild to moderate pain. -3- PAGENO="0260" 16812 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Reservations about the efficacy of propoxyphene continued to be expressed during the 70's: -- R. R. Miller etal. in 1970 reviewed all available double-blind studies of propoxyphene and concluded that it `. . . is no more effective than aspirin or codeine and may even be inferior to these analgesics." -- C. G. Moertel etal. in a 1972 double-blind study of single doses of propoxyphene, aspirin, and other oral analgesics in patients with cancer, were unable to show that even 65 mg of propoxyphene was significantly superior to placebo. In this study, aspirin was the most effective analgesic tested. -- R. R. Miller in a second review in 1977 concluded that propoxyphene was no more effective than placebo in three studies, whereas in five others propoxyphene was no more effective than other analgesics. On the other hand, Sunshine etal., in a 1978 study, found propoxyphene napsylate at 200 mg (twice the recommended dose) to be significantly better than placebo. The lowest dose used (50 mg) was only slightly better than placebo but the usual dose (100 mg) was not tested. -4- PAGENO="0261" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16813 POPULARITY OF PROPOXYPHENE Mr. Chairman, in your letter of invitation you asked me to comment on the reasons for the sustained popularity of propoxyphene as an analgesic in view of its limited effectiveness. The answer to this question is complex and involves a number of factors. First, I would point out that a significant number of people--tyr)ically 30-35 percent--in clinical trials on analciesics obtain pain relief from a placebo. Recent research suggests that this placebo response is due to activation within the brain of the same neural receptors that are affected by narcotics. The pain relief obtained is just as real, and may be just as great in many instances, as that provided by drugs. The placebo response may be enhanced by encouragement from the prescribing physician. Thus, any prescription analgesic is likely to offer pain relief to the many people who tend to be placebo responders--even if its inherent effectiveness is minimal. Second, by far the most popular propoxyphene-containing products are those combinations containing aspirin, phenacetin or acetaminophen in addition to propoxyphene. They are thus clearly effective products even thoucih the contribution of their propoxyphene component may be relatively small. Third, until recently propoxyphene has been viewed by the medical profession as a relatively safe analgesic. It does not carry the risks of serious gastro-intestinal bleeding associated with aspirin, the liver damage associated with overdoses of acetaminophen, or the kidney damage assoc4ated with phenacetin. -5- PAGENO="0262" 16814 - COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Neither does propoxyphene cause drowsiness or constipation to the same extent as codeine. Addiction liability from propoxyphene is relatively low, compared to that from morphine and other Schedule II narcotics. This factor is the major reason it was placed in Schedule IV rather than Schedule II of the Controlled Substances Act (CSA) in 1977. The most prominent safety problem associated with propoxyphene is the risk of death due to overdosage--a problem whose extent has become apparent only in recent years. Fourth, propoxyphene has been skillfully marketed in an array of dosage forms, combinations, and salts that offer physicians a wide variety of options for managing patients with painful disorders. And finally, no other prescription analgesic possesses a combination of properties so attractive to the general physician for the management of patients with mild to moderate pain. Propoxyphene-containing products have been prescribed for nearly two decades on the assumption that they were safe, relatively low in addiction potential, and more effective than over-the-counter drugs. Codeine, which has been classified in Schedule II for some time because of its well-known dependence liability, is the only other prescription analgesic with similar usage. In the past four years the number of prescriptions written annually for propoxyphene products has declined by about 15 pei~cent. This drop-off parallels a similar but more moderate decrease in the rate of prescriptions for all drugs. We attribute this decline to a -6- PAGENO="0263" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16815 combination of factors: an increasing awareness by physicians of abuse potential and the problem of deaths associated with propoxyphene, the placinç' of propoxyphene in Schedule IV of the Controlled Substances Act in 1977, and qrowinq competition from certain newer drucis such as the non-steroid anti-inflammatory agents used for arthritis. SAFETY OF PROPOXYPHENE Propoxyphene is structurally related to the narcotic analgesic methadone. Although its general pharmacologic properties are those of the narcotics as a group, it dOes not compare with them in analgesic potency. Compared with other prescription analgesics, the adverse reactions (side effects) associated with propoxyphene are mild and infrequent. The drug abuse potential of propoxyphene was recognized as early as the late 1950's but was not a major public concern until the late 1960's and early 1970's. Chronic propoxyphene use sometimes results in physical and psychological dependence of a type similar in nature but not degree to that produced by morphine. Intravenous street' use by drug addicts was popular in the late 1960's but waned, particularly because of its ability to cause vascular and other tissue destruction, and because of formulation changes in the product. This pattern of abuse resulted in overdose deaths that resembled those seen with heroin and methadone (for example, respiratory depression and pulmonary edema). As a -7- PAGENO="0264" 16816 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY result of these problems DEA placed it under Schedule IV of the CSA in 1977. Our analysis of the available data on propoxyphene fatalities shows that the majority of associated deaths occurred because of deliberate overuse or abuse, as shown in the two tables in Appendix B. Propoxyphene is one of the most frequently used drugs in suicides and suicide gestures; in absolute incidents it follows only the barbiturates and non-barbiturate sedative-hypnotics in associations with drug-induced suicide. However, when viewed in relation to the number of prescriptions issued, the relative number of deaths from propoxyphene is lower than that for a number of other drugs. We know of no cases at present in which death was caused by propoxyphene products alone when taken in customary doses and in which neither alcohol nor tranquilizers were also involved. There are, however, a number of `accidental deaths which have apparentlyoccurredas a result of the consumption of propoxyphene in quantities smaller than those used in suicide, yet still in excess of recommended therapeutic dosage and usually combined with alcohol and/or tranquilizers. The mechanism of death in those cases is commonly attributed to respiratory depression, a typical action of narcotics, although cardiac toxicity must be considered with seriousness. ifl testimony -8- PAGENO="0265" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16817 before the Subcomittee last week Dr. Sidney Wolfe stressed the cardiotoxicity of propoxyphene and its longer-lived metabolite norpropoxyphene in animals. We have examined the references cited by Dr. Wolfe and they do give cause for concern. The demonstration of dose-related progressive conduction block is clear in experimental animals and in some patients with acutely toxic doses there are similar electrocardiographic changes. What is still hypothetical is Dr. Wolfe's proposal that there may be significant numbers of deaths unrecorded by the DAWN system that are truly accidental (that is, not involving overdoses) and for which the cardiotoxic phenomenon is responsible. When analyzed according to age groups, the various data sources reveal significant differences in levels of use, misuse and abuse, as shown in the two tables in Appendix C. Most notable is the marked discrepancy between the average age of suicide, death or emergency room visits and the actual population for which propoxyphene is prescribed. For example, whereas over 33 percent of propoxyphene prescriptions are written for the over 60 population (the group most subject to cardio-vascular, respiratory and central nervous system problems) only 8 percent of deaths occur in this group. Although the same percentage of prescriptions was written for the age 20-39 group, 57 percent of the deaths occurs in these groups. -9- PAGENO="0266" 16818 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY REGULATORY ACTIONS Over the years, in response to problems associated with efficacy and safety of propoxyphene products, FDA has taken a number of actions: -- In 1972, because of misleading statements on the effectiveness of Darvon made to physicians in a letter from Eli Lilly and Company, we required the manufacturer to issue a `Dear Doctor" letter stating: "There is no substantial evidence to demonstrate that 65 mg of Darvon is more effective than 650 mg of aspirin (two 5-grain tablets), and the preponderance of evidence indicates that it may be somewhat less effective." -- In April 1976, FDA's Controlled Substances Advisory Comittee (CSAC) recommended that propoxyphene (and its salts and preparations) be controlled in Schedule IV of the CSA. -- DEA, in March 1977, placed propoxyphene, its salts and preparations, in Schedule IV of the Controlled Substances Act. -- Labeling for propoxyphene was further revised in 1978 to add a warning against the additive depressant effect of the products when used in conjunction with alcohol tranquilizers, sedative hypnotics, and other central nervous system depressants, and to require additional - 10 - PAGENO="0267" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16819 information on adverse reactions, drua interactions, and management of overdosage. A warning against use of the products during pregnancy was also added because of the danger of causing addiction in the fetus and producing a neonatal withdrawal syndrome. - RECENT DEVELOPMENTS AND ACTIONS On November 22, 1978, the Secretary of the Department of Health, Education, and Welfare was petitioned by the Health Research Group (HRG) to suspend approval of the NDAs for propoxyphene-containing products under section 505(e) of the Federal Food, Drug, and Cosmetic Act on the grounds that the continued marketing of these drugs represent an imminenthazard to the public health. HRG requested alternatively that if the Secretary did not suspend, he support HRG's petition to DEA that prOpoxyphene be rescheduled as a Schedule II narcotic under the Controlled Substances Act. FDA's Bureau of Drugs is conducting a new review of all data bearing on the safety and effectiveness of propoxyphene including those studies referenced in the HRG petition. - 11 - PAGENO="0268" 16820 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CONCLUSION In summary, Mr. Chairman, the current status of propoxyphene presents us with an important and complex regulatory problem. The problems associated with its misuse are indeed troubling; but they must be weighed against significant benefits from the drug. Propoxyphene is widely used; it provides pain relief for many people. Although it is not a powerful analgesic, it has advantages for persons who cannot tolerate aspirin or acetaminophen. It is prescribed and administered or dispensed in a special medical setting that provides significant psychological amplification of its affects. I am sorry that we cannot offer you a more definitive conclusion at this time, but we are still developing our analysis. These hearings have helped materially in that regard, as well as drawing public attention to a disturbing abuse problem. We will continue to give the matter close scrutiny. Mr. Chairman, my staff and I will attempt to answer any questions you may have. - 12 - PAGENO="0269" Rx's DISPENSED (IN MILLIONS) C~) ~ © Cl © Cl © Cl ~ I- F I C ______ 0 ________________ 0 F, ____________________________________________ .~ 2 ~ ~ - C 2 .~ :*:*:*:*:*:*:*:9'//////////7/f/7'/f/' /7//f,, ~ ~ _______________ I ~I x w a z 40 EXHIBIT 0 TRENDS IN DAWN MEDICAL EXAMINER MENTIONS; CONSISTENT REPORTERS, TOTAL SELECTED DRUGS; 1976 Q1 THROUGH 1978 Q1 160 150 140 130 120 110 50 30 20 HEROIN/MORPHINE METHADONE SOURCE: DAWN QUARTERLY (April-June, 1978) PAGENO="0397" EXHIBIT E t~j I, 11 TRENDS IN DAWN EMERGENCY ROOM MENTIONS; CONSISTENT REPORTERS, TOTAL DEA-SELECTED DRUGS; 1976 a1 THROUGH 1978 Q2 0 0 0 Co 0) LU -J > x LU 0 z Q2 Q3 0 Co 90- 85 \ O~ ,~ ~ -#*~ -\.--4-,'-------I~---\ -4- \, Qi \ ~2 1978 ---~ \ ~ TOTAL SELECTED DRUGS NONNARCOTIC ANALGESICS PROPOXYPHENE SOURCE: ~ QUARTERLY (April-June, 1978) PAGENO="0398" EXHIBIT F ADDITIONAL CASE DETAIL ON OREGON MEDICAL EXAMINER CASES ATTRIBUTED TO PROPOXYPHENE; JANUARY 1, 1978, THROUGH MAY 31, 1978. SOURCE: OFFICE OF OREGON STATE MEDICAL EXAMINER. 0 Multiple of maximum Concentration Multiplex of thera- Case and Propoxyphene level therapeutic concentra- Norpropoxyphene Other agents (mg%)/estimated peutic concentrations ~ej date measured mg% tions in normal subjects** level measured mg% measured total in normal subjects -~j 1, 1/4/78 1.8 36-90 3.6 Alcohol .06% -i 2, 1/13/78 0.63 13-32 3.2 3, 1/23/78 0.65 13-33 9.1 4, 1/30/78 0.22 4-11 0.53 Meprobamate l.7/1.5g' 4X 400mg 0 w 5, 2/4/78 3.2 64-160 2.6 Alcohol .24% 1.6X Driving limit t~ tel 6, 2/7178 0.37 7-19 1.4 Alcohol .15% lOX Driving limit 7, 3/1/78 0.4 8-20 1.6 1~12 8, 3/21/78 0.3 6-15 none Diazepam 0.4/270mg' 27X 10mg 9, 4/8/78 0.1 2-5 0.36 Methaqualone Trace 10, 4/9178 0.25 513 1.0 Diazepam O.3/200mg' 20X 10mg Alcohol 0.14% 0.9X Driving limit Acetaminophen 1B.0/23.3g' 40X 650mg 11, 4/9/78 3.3 66-165 12.6 AmolSecobarbital 0.3/141mg' /265mg' Diazepam 0.5/330mg' 33X 10mg Alcohol 0.16% 1.1X Driving limit ~ 12, 4/1 1178 0.9 18-45 1.0 Phenobarbital 0.7/48mg' Alcohol 0.02% 13, 4/16/78 0.9 18-45 3.9 Dilantin l.B/l200mg' 12X 100mg 14, 4/16/78 0.25 5-13 0.75 Diazepam 0.6/400mg' 40X 10mg 15, 4/19/78 0.05 1-3 0.4 Methadone O.04/75mg' (gastric methadone 47mg) 16, 4/23/78 0.1 2-5 06 Diazepam Trace continued PAGENO="0399" EXHIBIT F (CONTINUED) ADDITIONAL CASE DETAIL ON OREGON MEDICAL EXAMINER CASES ATTRIBUTED TO PROPOXYPHENE; C) JANUARY 1, 1978, THROUGH MAY 31, 1978. SOURCE: OFFICE OF OREGON STATE MEDICAL EXAMINER. Multiple of maximum Concentration Multiples of thera- Case and Propoxyphene level therapeutic concentra- Norpropoxyphene Other agents (mg%)/estimated peutic concentrations date measured mg% tions in normal subject~" * level measured mg% measured total in normal subjects ______ __________ L'J 17, 4/28178 0.1 2-5 0.2 Stelazine (not measured) 18, 4/30178 0.05 1-3 0.1 Alcohol 0.26% l.7X Driving limit ~ Acetaminophen 5.O/6.48g lox 650mg 19, 5/15/78 0.2 4-10 1.0 20 5/28/78 0 2 4 10 09 Alcohol 0 08% 21. 5/29/78 0.55 11-28 0.9 Glucose 17 mg% 22. 5/31/78 0.01 .2.5 1.5 Diazepam 0.2/133mg' l3X 10mg Z Amitriptyline 0.09/1360mg' 54)( 25mg `Baselt,R.C..et al.; "Therapeutic and Toxic Concen~ations of More Than 100 ToxicologicallY Significant Drugs in Blood, Plasma, or Serum'; Clin. Chem., 21(1): 44-62, 1975 d **Achieved in normal subjects with the ingestion of three capsules of either 65mg propoxyphene ~ hydrochloride or 100mg propoxyphene napsylate. One dose every four hours is the recommended regimen. The first number shown on each line is the estimated multiple for the chronic propoxyphene sutject and the second number is the estimated multiple for a one-time ingestion. C~i PAGENO="0400" 16952 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY Senator NELSON. Senator Weicker? Senator WEICKER. A great deal of attention has been given to the effectiveness of propoxyphene compared to other analgesics. Commis- sioner Kennedy noted the most popular propoxyphene containing products are those products containing other analgesics such as aspirin. Does the combination of propoxyphene with aspirin produce a syner- gistic result that a double dose of aspirin would not? Dr. FURMAN. When you say "synergistic" that implies that 2 plus 2 equals 7 or 8.1 think the feeling is that the combination of the two pro- duces a greater analgesic effect than either one alone, and that is not a synergistic effect. There is a very sound pharmacologic reason for combining propoxy- phene, which is a centrally acting analgesic agent in the sense that codeine is, with something like aspirin or acetaminophen, which has a peripheral site of action. There is evidence that the reason aspirin is effective is that it blocks the synthesis at the site of pain, injury, or wound, of agents such as prostaglandins. By combining centrally acting agent such as propoxy- phene with a peripherally acting agent such as aspirin, you have the best of two worlds, so to speak. You can get effective analgesic in most instances with doses that do not elicit unwanted side effects, and it is quite understandable and quite reasonable that the combination prod- *uct would be the more popular one because it makes the most sense. Senator WEICKER. Can all those persons who now use propoxyphene safely use other analgesics, such as aspirin, or codeine, to obtain the pain relief they ~et from propoxyphene? Dr. FURMAN. The key word in your question is "safely." There are individuals who, because of disease states or idiosyncracies, can take one analgesic and not another. I do not think one would be wise to make a blanket statement that those who receive analgesia from propoxyphene can safely switch to codeine or aspirin and expect to get the same analgesia. Senator WEICKER. Dr. Finkle's study showed that most of the deaths associated with propoxyphene involved use of the drug in combina- tion with alcohol or other drugs such as tranquilizers. This raises what seems to me to be an entirely different problem than the one that has been layed at your doorstep during the course of these hearings. What is your view insofar as what the pharmaceutical industry, or the FDA itself, can do in regard to educating the public in this area? Dr. FURMAN. Well, we have educated, and will continue to educate, physicians in respect of the proper use of propoxyphene products. We are in the process of modifying our package literature to provide the physician with more adequate information on the management of overdose; but I think what you are touching upon, Senator Weicker, is the overall problem of a pill-popping, drug-abusing society. If one takes a look at the suicide rate per 100,000 in the United States over the last few years, one gets really quite depressed at the realization that thousands of people are killing themselves one way or another. Some of these individuals are using drugs; but, I submit, is the situa- tion improved if they sit in a car with the motor running and the garage door shut, or blow their brains out with a gun, rather than use a drug to do this? We still have a societal problem of considerable dimensions. PAGENO="0401" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16953 Now, we had some preliminary discussions with Dr. Finkle hoping that, perhaps in concert with interested members of industry and Gov- ernment, a more precise evaluation of the dimensions of the problem could be undertaken in the next few years. I must emphasize these are very preliminary discussions, and there is no guarantee that they will provide answers to these questions, but they are questions which desperately need addressing. Senator WEICKER. Thank you. Senator NELSON. Senator Levin? Senator LEVIN. In 1972 you wrote a letter apparently at the request of FDA at least according to their testimony, "There is no substantial evidence to demonstrate that 65 milligrams of Darvon is more effective than 650 milligrams of aspirin." I guess that is comparing one Darvon. Dr. FURMAN. One Darvon to two aspirin. Senator LEVIN. And the preponderance of evidence indicates it may be somewhat less benefit. Was that true then in your opinion? If so, is it still true? Dr. FURMAN. By "preponderance of evidence" they meant well- controlled, double-blind, placebo studies, and I think literally that was correct at that time. Senator LEVIN. And now? Dr. FURMAN. I think there are studies which compare propoxyphene hydrochloride, 65 milligrams, or napsylate, 100 miligrams, favorably with aspirin but do not demonstrate greater efficacy. I want to make it abundantly clear that aspirin is a truly remarkable drug-it lowers temperature and it is being used and evaluated for people with coronary heart disease and stroke. We are not embarrassed that propoxyphene and two aspirin tablets are equal. Senator LEVIN. Are there many people would you estimate now that are using propoxyphene that could get equal results from aspirin? Dr. FURMAN. That is a very difficult question to answer, Senator, because people who are now relying on propoxyphene for relief and control of pain, by and large, are people who have had access pre- viously to acetaminophen and aspirin. Somehow or other, sooner or later, they got a prescription from their doctor for propoxyphene and have found that propoxyphene or propoxyphene-combined products effectively do the job. Senator LEVIN. Have you authorized studies, your company that is, comparing the efficacy of aspirin and propoxyphene? Dr. FURMAN. Yes, sir, we have. Senator LEVIN. Could you estimate how many of those studies have taken place? Are those double-blind studies? Dr. FURMAN. Some were. Some of the early studies of propoxyphene compared with aspirin and codeine were double-blind studies. I could not tell you how many, offhand. Senator LEVIN. Would there be many? Dr. FUR~L&N. Several. Senator LEvIN. Could you furnish us all of the studies you have au- thorized, all the double-blind studies you have authorized comparing propoxyphene with aspirin and codeine? Dr. FURMAN. We would be glad to do that. Senator LEVIN. Thank you. 40-224 0- 79 - 26 PAGENO="0402" 16954 coMr't~rIT±vE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Any other questions? Senator WEICICER. I would like to point out one thing that might be helpful to describe the relationship between the pharmaceutical manu- facturer and the medical profession itself. I am afraid it comes across, at least it did to me in these hearings, that the relationship under con- sideration is one between a very sophisticated institution such as the pharmaceutical manufacturer and the public as a whole, which might n4~t be in the possession of the knowledge needed to evaluate the prod- uct. Yet, in fact, it seems to me that there is a pretty extensive filtering system or jury on the product itself, in terms of the medical profes- sion which must prescribe the drug. Now certainly there can be no lack of degree or sophistication at- tributed to that body of society. At the same time, what is the proce- dure for the use of a drug? Is there a considerable comment made by the physicians themselves-do they ask questions of the manufacturer? Can you describe that process to us? It is entirely left out of the im- pression given at these hearings. The general question of safety and efficacy of a drug is an important one. But one must realize that the drug goes out into a marketplace that is comprised of very knowl- edgeable and sophisticated persons, that is, doctors, who are able to make the types of judgments on the product commensurate with their knowledge. Can you comment on that? Dr. FURMAN. In every piece of package literature and every ad- vertisement and every communication where these products are men- tioned, we-almost without exception-provide the product labeling which carries the recommended dosage, the indications, the contrain- dications, and information on treatment of overdosage. These are continually reviewed. As I indicated, we are now in the process of strengthening the part of the package that deals with the management of overdosage. We bring this to the attention of the physician. Instances of over- dose, fatal or not, and overdose information also appear in medical literature. This literature is scanned by our in-house physicians. We have com- mercial survey companies that keep their eye on newspapers and other news media for any example of a misuse of propoxyphene. We make every effort to followup each one and get information. As new evidence of pharmacologic action-good, bad, or indifferent- is received by our scientists and other research laboratories, it is evaluated and shared with the FDA, reported at open scientific meet- ings, and, when judged appropriate and necessary, is put in the package piece. Reference was made in one of the hearing days last week that the Physicians' Desk Reference is distributed free of charge by the Pharmaceutical Manufacturers Association. That is not correct. It is distributed by the publisher. The information in the Physicians' Desk Reference is information on products that are approved by the FDA and is in full conformity with FDA requirements as to labeling. We feel that there is a continual flow of information and resource material available to the physician for the adequate, proper, and safe use of these agents. PAGENO="0403" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16955 Senator WEICKER. In other words, the point I am making here I think there is a local grocery store in Washington that makes the point that the best customer is an educated consumer. We are not talking about the public at large. The real consumer is the physician himself. Dr. FURMAN. Yes, sir. Senator WEIcKi~1n. Certainly, nobody can ascribe a lack of educa- tion to that particular individual as far as this product is concerned. If the product does not work, it seems to me that it would not be prescribed. We are not talking about a drug that might have just burst on the market in a fit of temporary popularity. We are talking about some- thing on the marketplace for 21 years. Now, if it is no good, why do doctors go ahead and recommend it? I do not understand this, unless there is some sort of a tie-in between the industry and the doctor's prescriptions, and that is illegal. If there is, I want to hear about that. Dr. FURMAN. I think you put your finger on the answer regarding efficacy. Propoxyphene is out there and it works, and it has enjoyed great usefulness and popularity for more than two decades. The FDA did not have to ban blood-letting. Somebody last week testified that propoxyphene was essentially a nostrum like ground ram's horn and this sort of nonsense. These nostrums are not per- ceived as effective by the physician indefinitely. Their patients are sick; and I think, Senator Weicker, you are correct, that this is a useful drug; that the physician is not prescribing it willy-nilly. He is using it. He gets the report from his patient that it works, and he is content it is safe and effective; and that is the reason the drug has been successful for more than two decades. Senator WEICKER. I would imagine that probably Darvon's days are numbered, not in the sense of what Government can or cannot do to it, but in the sense that people are seeking to discover a better product in the sense of what it can do. Dr. FURMAN. We, olirselves, will, I hope, come out with a better product; but over the last two decades, as I think Dr. Beaver pointed out, nobody has come up with a better type of centrally acting analgesic. Senator WEICKER. I gather, to emphasize what you are saying, that you are not claiming that propoxyphene is better than aspirin in all cases. Dr. FURMAN. No. Senator WEICKER. I just wanted to make that point. I am very much for consumers as my voting record indicates. However, I think it is very important that the picture be made clear as to what is involved and who is involved in this particular instance, so we do not perceive this to be another case of the corporate world ripping off the man on the street. There are other factors involved here and a filtering process that makes this situation considerably different than just the normal situation of the consumer and the corporate product. Dr. FURMAN. I appreciate your comments. Senator HATCH. On page 3 of Dr. Wolfe's testimony there is a reference to a Danish study concluding Darvon has a small margin PAGENO="0404" 16956 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of safety. I believe he referenced that as few as four doses could be a severe problem. Can you comment on that? Dr. FURMAN. I believe that you have reference to a study by a Danish investigator. Senator HATCH. That is right. Dr. FURMAN. Simonsen. Senator HATCH. It is on page 3. Dr. FURMAN. Oh, yes. This is interesting because Simonsen has reported a series of 30 patients; 30 deaths from drug abuse and, of these 30, some 15 were related to the use of propoxyphene. What Dr. Wolfe did not tell us is that, of these 15 propoxyphene-related deaths, 8 occurred in individuals who used a formulization which is peculiar to Scandinavia, a so-called slow-release or delayed-release propoxy- phene product that contains twice the standard recommended dose of propoxyphene. So, if one were to take four of this sustained-release product, one would be, in effect, dosing oneself with eight 65-milligram capsules of propoxyphene hydrochloride. And, if the individual took a drink or two along with these and helped elute the propoxyphene from the sustained-release preparation, he would be in serious trou- ble, as were many of these patients. One of these individuals killed himself with 8 of these sustained- release tablets, which means he took the equivalent of 16 doses of propoxyphene hydrochloride. Senator HATCH. Is that the 65-milligram level? Dr. Ftm3i~N. Yes, sir. I should point out that we do not have such a formula. We have never had a formula of this sort anywhere in the world. The 15 patients in this publication included seven that were classified as drug addicts. In addi4 ion, four had taken alcohol and three had taken barbiturates along with the propoxyphene. Senator HATCH. Well now, Dr. WOLFE stated, "The information that chronic use of Darvon leads to high blood levels of the toxic metabolite nor-propoxyphene has never been publicly acknowledged by Lilly." Could you please comment on this? Dr. FURMAN. Nor-propoxyphene occurs in the liver within minutes of propoxyphene's reaching the bloodstream. In a constant-dose situation, the level of nor-propoxyphene rises to a plateau at which it remains, the amount excreted equaling the amount that is formed. Since it has a slightly longer half-life-that is, it is excreted n~ore slowly-the concentrations of nor-propoxyphene attained in a chronic dose situation exceed, in many instances, those of propoxyphene. Information on the metabolism of propoxyphene and the pharma- ceutical activity of nor-propoxyphene has been developed mainly in the Lilly laboratories but has been confirmed, and this information has been published by both European and [J.S. investigators. The concern about nor-propoxyphene is based on its local anesthet- ic property, which might interfere with normal heart conduction. In an experiment on anesthetized animals with electrodes inserted in proper portions of the heart, evidence of delayed conduction can be elicited. In two abstracts submitted to the meetings of the Federated Socie- ties, these studies were described. One of these abstracts, which w~s sent to FDA, indicated that propoxyphene and its principal metab- PAGENO="0405" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16957 olite nor-propoxyphene, when infused into an anesthetized dog, produced delay in conduction-that is to say, heart block-in a dose- related manner; namely, as the dose was increased, the degree of conduction delay was increased. This conduction delay is referred to by cardiologists as heart block. I submit that anyone with a reasonable knowledge of cardiac physiology would have regarded the abstract sent to the FDA describ- ing this work as containing the essence of the information, the neces- sary information on which to make a judgment regarding this experimental cardiac effect. I can assure you that the cardiac abnor- malities that have been described in the medical literature and individ- uals taking a fatal overdose indicate that the cardiac problems arise when respiration is depressed Or ceases. These people accumulate car- bon dioxide in the bloodstream, and become depleted of oxygen. This is a bad situation for the heart, and it makes the patient vulnerable to abnormal heart action. When respiratory movements are restored by a mechanical ventilator and the carbon dioxide is washed out of the body and normal oxygenation occurs, the heart abnormality-with rare exception-disappears. This occurs over a timespan of minutes to hours, which precludes any significant change having occurred in the concentration of nor-propoxyphene. Furthermore, studies by Dr. Tennet in California, in which he administered at least twice the routine dosage of propoxyphene to indi- viduals in a heroin-maintenance program, have shown in such indi- viduals, for a period of more than 2 years, that electrocardiograms taken at 3-month intervals showed no effect whatsoever of the long term use of large doses of propoxyphene. Our own studies on volunteers equipped with a Holter monitor, which makes a continuous tape recording of the EKG, show that the recommended dose of propoxyphene for periods as long as a week produces no discernible effect on the EKG. Senator HATCH. Thank you. Senator NELSON. Anything else? Senator BAUCUS. I have one question concerning cost. What would be the changes in cost to Lilly if Darvon is rescheduled to schedule II. Dr. FURMAN. The cost changes? Senator BAUCUS. Manufacturing costs on a per unit basis. Dr. FURMAN. Senator, I have no idea. I am sure it would increase manufacturing costs, but this is beyond my area of knowledge and capability. Sorry. Senator BAUCUS. You have any estimate, any guess? Dr. FURMAN. It would be the wildest guess, sir. I would not hazard a guess. Senator BAUCUS. But you do think the cost would increase? Dr. FURMAN. Oh, yes, I believe so. Senator BAUCUS. Just a rough guess. Is it a 1-percent increase, 5 percent? Your guess. Dr. FURMAN. Your guess is as good as mine, Senator. Senator BAUCUS. Yours is a lot better than mine. Dr. FURMAN. I am not sure. Senator BAUCUS. The same line of questioning with respect to con- sumer costs. Would you expect the market price to increase if Darvon is rescheduled as schedule II? PAGENO="0406" 16958 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. FuRi~t~&N. Again, I would hesitate to comment on that. It would depend on the manufacturing costs. Senator BAUCUS. Since manufacturing costs would increase in your judgment although you are not sure to what degree, do you therefore expect the market price of the product to increase? Dr. FURMAN. I would expect so. Senator BAUCUS. It would be list price? Dr. FURMAN. The actual retail price is not determined by us but determined by the retail pharmacist; and that, in turn, is determined by at least what he has to pay the distributor. Senator BAUCUS. But you would expect the retail price to be higher? Dr. FURMAN. Well, I cannot conceive of it going down. I guess it would go up. Senator BAUCUS. Thank you, Mr. Chairman. Senator NELSON. I certainly do not wish to prolong this, and when you testified and went through page 5 I did not raise the question, but later in a dialog with you Senator Weicker did, so I do not want it to go by without some comment for the record. In reference to the sentence in your prepared testimony in which you state, "In the final analysis, the true measure of the therapeutic usefulness of a drug is determined in the field of clinical practice," I gather from the dialog between you and Senator Weicker that it was agreed between you that if a drug is widely used in the marketplace, that demonstrates its therapeutic value. I only want to point out that we have had 12 years of hearings with testimony by distinguished national and internationally known clin- icians who would strongly refute that proposition. I would simply call your attention to the testimony on antibiotics. Even the Journal of the American Medical Association, which has been very careful over the years never to criticize the drug industry, which supports the publication of the magazine, did in 1957 and in subsequent editorials strongly urge doctors to quit prescribing combi- nation antibiotics on the grounds it was a very bad clinical practice. The fact that use of combination antibiotics was widespread did not make it good medical practice. To argue as so many do that if it is widely used in the marketplace, it must be a good drug is overwhelmingly refuted by the evidence. Dr. FURMAN. May I respond, Mr. Chairman? Senator NELSON. Certainly. Dr. FURMAN. I think your concern and your distrust are under- standable, in part justified; but let me point out there are notable exceptions in the antibiotic field. For example, in the treatment of strep fecalis infection and septicemia, combinations of penicillin and streptomycin are extremely effective. One of the cost-effective anti-infective agents recently approved by the FDA, Bactrim and Septra, is a combination product. The combi- nation of propoxyphene and salicylate makes a very justifiabk )iiarmacologic union in view of t.he peripheral and centrally acting ~odalities of these compounds. The analgesia demonstrated in animal experiments-I know of no placebo responders among animals-plus clinical trials tend to make me feel that most physicians using propoxy- phene really know what they are doing. PAGENO="0407" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16959 Senator NELSON. I would not want to mention when and where, but I was on a trip to a convention and everybody on the trip got Darvon. Nobody got an aspirin or anything else. He was given Darvoti. On the question of placebo on animals, that may be so, but it is very difficult to explain the false pregnancies that dogs sometimes get. Dr. FURMAN. Makes it a very interesting business. Senator NELSON. Thank you very much. I appreciate your taking the time to come. If you have anything you wish to add to the testimony we would be happy to receive it for the record. Dr. FURMAN. Thank you. Senator NELSON. Our next witness is Dr. Louis Lasagna, chairman of the Department and Professor of Pharmacology and Toxicology, University of Rochester School of Medicine and Dentistry. The committee is pleased to have you come today. Your statement will be printed in full in the record and you may proceed any way you desire. We are already at 12:30, but we need to complete our testi- mony, so we will proceed. STATEMENT OP LOUIS LASAGNA, M.D., CHAIRMAN OP THE DEPART- MENT AND PROFESSOR OP PHARMACOLOGY AND TOXICOLOGY, UNIVERSITY OP ROCHESTER SCHOOL OP MEDICINE AND DENTISTRY Dr. LASAGNA. My name is Louis Lasagna. I am professor of pharma- cology and toxicology and professor of medicine at the University of Rochester School of Medicine and Dentistry. For over a quarter of a century I have engaged in research on analgesic drugs, and have writ- ten extensively in this area. I appreciate this opportunity to share my thoughts with you in regard to the suggestion that propoxyphene constitutes a major drug abuse problem and an imminent hazard to the health of the U.S. public. Propoxyphene is unquestionably an effective analgesic drug, either when given alone or in combination with such drugs as aspirin or acetaminophen. This judgment was reached by the Analgesic Drugs Panel which I chaired in the late 1960's for the National Academy of Sciences-National Research Council at the request of the FDA Com- missioner, and is an opinion still supported by a, review today of the world literature on pain-relieving drugs. It is unfortunate that some who are concerned about the euphorigenicity or toxicity of propoxy- phene feel constrained to deny the ability of propoxyphene to relieve pain. Millions of patients have taken, and continue to take, propoxy- phene for its analgesic properties. No placebo effect can explain its popularity. It has been known for years that while propoxyphene, like any drug which affects the central nervous system, can be abused by some in- dividuals, the risks of such abuse are minuscule. National and inter- national expert advisory committees have repeatedly taken up this issue since the original marketing of the drug, and have never seen a need to reclassify propoxyphene as a drug with high addiction liability. More recently, drug-associated fatalities have been observed in in- dividuals taking excessive doses of propoxyphene, especially in combi- PAGENO="0408" 16960 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY nation with alcohol and other CNS depressants. After an investigation of this new concern, the Eli Lilly Co. revised labeling for propoxy- phene and undertook a campaign aimed at acquainting U.S. physicians with this important new information. When HEW recommended to the Justice Department that propoxyphene products should be placed in schedule IV, so far as I know the manufacturer did not oppose the listing. I believe that both the FDA and the several manufacturers of pro- poxyphene are cognizant of these new developments concerning this drug and have not shown any reluctance to take appropriate steps to inform the prescribing physician. The data from the Government-financed drug abuse warning net- work-.-DAWN-while far from a perfect representation of national drug abuse problems, nevertheless provides information which contra- dicts the allegation that propoxyphene abuse is increasing and con- stitutes an imminent hazard. I have followed the DAWN data for some years because of my interest in drug reporting systems. The most recent reports available to me-Project DAWN VI and the January-March 1978 DAWN Quarterly Report-show, for exam- ple, that there are more yearly mentions of aspirin in emergency room reports-7,212-than of propoxyphene-4,111. The crisis centers in the DAWN system reported a yearly total of 488 propoxyphene mentions, as opposed to 7,243 for heroin/morphine, despite the much smaller number of people exposed to the latter narcotics. Propoxy- phene is also mentioned less often than heroin/morphine in medical examiner reports in the DAWN system, with only 486 mentions of all sorts for the entire year. More important, I believe, is the pattern of decreasing reports for propoxvphene when one looks at the data base recommended by DAWN itself for the best assessment of time trends, that is the so-called consistent reporters. The number of emergency room drug mentions for propoxyphene peaked in Octeber-DecenTher 197& at 892 and has decreased to 753 for the January-March 1978-the most recently analyzed period. Similarly, the propoxyphene mentions for consistently reporting medical examiners peaked in January-March 1977 at 16~ and de- clined to 125 for the most recently analyzed period, October-December 1977. I believe that the available data in general support the image that the profession has had of propoxyphene-an analgesic which can be useful in treating people with mild to moderate pain with a minimum of side effects and no significant toxicity unless taken in doses much larger than those recommended for medical use. Some drug abuse will occur with any analgesic drug. It is of inter- est, for example, that DAWN reports twice as many mentions in its emergency rooms for aspirin and two-thirds as many for acetamino- phen, as for propoxyphene. These two OTO drugs, available to any- one without a prescription, can also, in large doses, produce organ damage and death, even without the ingestion of other drugs. Brand- ing these OTO analgesics as an "imminent hazard," nevertheless, would be as foolish as recommendations to do so for propoxyphene. The concept that propoxyphene is an excessively expensive and ex- PAGENO="0409" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16961 cessively prescribed analgesic has its supporters, but the proposed remedies for these putative prc~blems would represent a dangerous and ill-advised precedent. Our medical care system should not be politi- cized `by unscientific pressures to abolish a drug, or to impose manu- facturing quotas on it whenever a group of inthviduals ob)ect to the extent of use and the cost of a given drug. The implications of yielding to such demands `are ominous for medical care. If propoxyphene is banned today, which drug will be doomed for extinction tomorrow? Aspirin? Acetaminophen? Nareotic substitutes for propoxyphene? Valium? it is appropriate to debate these issues, but I do not believe that a thoughtful and dispassionate analysis of propoxyphene will find it necessary to accuse the FDA or the manufacturer of either apathy or irresponsibility. I would urge, Senator, that you exert your considerable influence to help convene meetings involving the FDA, the DEA, the relevant scientific advisory groups for these agencies, and representatives of responsible and prestigious professional and patient groups to assess what we know about propoxyphene, to plan studies for obtaining better data on the motivations and circumstances leading to abuse from: propoxyphene and other drugs, to consider the implications of en- couraging the substitution of other non-narcotic and narcotic anal~ gesics for propoxyphene, and to study the level of information among physicians and patients as to the benefits and risks of propoxyphene and of competing analgesics, and the treatment of accidental or pur- poseful overdose. Such meetings could identify what educational ef- forts might be needed to optimize medical care for patients in pain. Thank you for the opportunity to express these personal opinions. Senator NELSON. Thank you, Dr. Lasagna. You did not identify for the record the fact that you were as I recall it, Chairman of the NRC Panel on Propoxyphene. Dr. LASAGNA. On Analgesic Drugs. Senator NELSON. What year was that? Dr. LASAGNA. That was in the 1960's. Senator NELSON. 1969, was it? That was before the evaluation under the 1962 act. Dr. LASAGNA. Yes, sir. Senator NELSON. Have there~ been any further evaluations? I forgot to ask Mr. Kennedy under the provisions of the 1962 act as to the effectiveness of Darvon in combination, but are you aware? Dr. LASAGNA. Well, certainly nothing like the NRC review. If I may comment, Senator, on that deliberation, if you look at our report for analgesic combinations most of the time we were forced to say that such and such a combination contained an analgesic of known efficacy in standard dosage and we did not know whether the other ingredients present added to or subtracted from that analgesic, but for Darvon compound we were able to say, because there were some studies available, that, in fact, the data supported the notion that propoxyphene added for example to aspirin did give something over and above what aspirin gave of itself. There were several studies available at the time of our review and there are several I am sure that have been printed since that time and I would be glad to submit those references to you. PAGENO="0410" 16962 co~nETn~iv~ PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. I would be happy to have the references. The testimony of Dr. Moert8l on his double-blind studies at Mayo Clinic was the addition of a full dose of propoxyphene to aspirin did not in those studies indicate any additional effectiveness. Now, I do not know how many of these studies there are on that, but I would like to have the number. Dr. LASAGNA. I might say, Senator, in addition to this `being a mucky field-oral analgesic evaluation-imprecise I should say, aspirin is such a good drug that it is not easy to top it, but while there are cer- tainly studies that have been done that failed to show the superiority of the combination and there are others that do show it. It is a field that is less precise than we would like to have. Senator NELSON. Any questions? Senator HAYAKAWA. Is it not true that that which is effective on others, that is some patients, is not effective on others so that there are people for whom let us say aspirin does no good but propoxyphene does and there are people for whom propoxyphene does no good and aspirin does. Are there not these individual differences? Dr. LASAGNA. Yes; there are. Senator HAYAKAWA. I am interested in your statement that while it can be abused, propoxyphene in other words, risks are minuscule; that is the risks occur when people take far more than the recom- mended dosage. Is that correct? Dr. LASAGNA. Yes, sir. I had references to two kinds of risk. One is the risk of abusing the drug in the sense we usually mean, taking the drug for kicks. There are some people who use the drug for that purpose; there is another risk in regard to individuals taking more of the drug than is recommended or taking it in combination with other drugs or alcohol. Senator HAYAKAWA. What concerns me is the attempt to ban one drug after another or to make them more difficult of access. Aspirin has been shown to be dangerous when abused and aceta- minophen is dangerous when abused and valium obviously so. So if propoxyphene is banned today, where do we go next? This passion for banning seems to indicate a kind of passion that some regulators have of creating an ultimately totally risk-free society which is, of course, beyond human possibility. Nevertheless, what you are saying is that propoxyphene abuse is decreasing rather than increasing in cases where it does occur; is that correct? Dr. LASAGNA. At least that is the conclusion I come to on the basis of the data available to me. Senator HAYAKAWA. I see. Well, I am grateful to you for a not too technical exhibition of this problem and I agree with you that FDA~ DEA and the science community should obtain better data. on the motivation leading to abuse of the substance. But so far as I am concerned I think like aspirin and many other things like Empirin and Bufferin and everything else, it is a useful substance to have available as one of the many, many substances we might take for relief of pain. There is no one analgesic that is good for everybody, is there? Dr. LASAGNA. That is right. PAGENO="0411" COMPETIPIVE PROBLEMS IN THE DRUG INDUSTRY 16963 Senator HAYAKAWA. Thank you, very much. Senator NELSON. Any other questions? Thank you very much, Dr. Lasagna, for taking the time to come here and present your testimony today. We appreciate it very much. [The prepared statement of Dr. Lasagna follows:] STATEMENT BY LoUIS LASAGNA, M.D., PROFESSOR OF PHARMACOLOGY AND ToxI. COLOGY AND PROFESSOR OF MEDICINE AT THE UNIVERSITY or ROCHESTER SCHOOL OF MEDICINE AND DENTISTRY. ROCHESTER, N.Y. My name is Louis Lasagna. I am ProfeSsor of Pharmacology and Toxicology and Professor of Medicine at the University of Rochester School of Medicine and Dentistry. For over a quarter of a century I have engaged in research on anal- gesic drugs. and have written extensively in this area. I appreciate this opportunity to share my thoughts with you in regard to the suggestion that propoxyphene constitutes a major drug abuse problem and an imminent hazard to the health of the U.S. public. Propoxyphene is unquestionably an effective analgesic drug, either when given alone or in combination with such drugs as aspirin or acetaminophen. This judg- ment was reached by the Analgesic Drugs Panel which I chaired in the late 1960's for the National Academy of Sciences/National Research Council at `the request of the FDA Commissioner, and is an opinion still supported by a review today o~. the world literature on pain-relieving drugs. It is unfortunate that some who are concerned about the euphorigenicity or toxicity of propoxyphene fegi constrained to deny the ability of propoxyphene to relieve pain. Millions of patients have taken, and continue to take, propoxyphene for its analgesic properties. No placebo effect can explain its popularity. It has been known for years that while propoxyphene, like any drug which af- fects the central nervous system (CNS), can be abused by some individuals, the risks of such abuse are minuscule. National and international expert advisory committees have repeatedly taken up this issue since the original marketing of propoxyphene, and have never seen `a need to reclassify propoxyphene as a drug with high addiction liability. More recently, drug-associated fatalities have been observed In Individualt taking excessive doses of propoxyphene, especially in combination with alcohol and other CNS depressants. After an investigation of this new concern, the Eli Lilly Co. revised labeling for propoxyphene and undertook a campaign aimed at acquainting U.S. physicians with this important new information. When HEW recommended to the Justice Department that propoxyphene products should be placed in Schedule IV, so far as I know the manufacturer did not oppose the listing. I believe that both the FDA and the several manufacturers of propoxyphene are cognizant of these new developments concerning this drug and have not shown any reluctance to take appropriate steps to inform the prescribing physician. The data from the government-financed Drug Abuse Warning Network (DAWN), while far from a perfect representation of national drug abuse prob- lems, nevertheless provides information which contradicts the allegation that propoxyphene abuse is increasing and constitutes an imminent hazard. I have followed the DAWN data for some years because of my interest in drug report- ing systems. The most recent reports available to me (Project DAWN VI and the January' March 1978 DAWN Quarterly Report) show, e.g., that there are more yearly mentions of aspirin in emergency room reports (7212) than of propoxyphene (4111). The crisis centers in the DAWN system reported a yearly total of 488 propoxyphene mentions, as opposed to 7243 for heroin/morphine, despite the much smaller number of people exposed to the latter narcotics. Propoxyphene is also mentioned less often than heroin/morphine in medical examiner reports in the DAWN system, with only 486 mentions of all sorts for the entire year. More important, I believe, is the pattern of decreasing reports for propoxyphene when one looks at the data base recommended by DAWN itself for the best assessment of time trends, i.e., the so-called "consistent reporters." The number of emergency room drug mentions for propoxyphene peaked in October-December 1976 at 892 and has decreased to 753 for the January-March 1978 (the most re- cently analyzed) period. PAGENO="0412" 16964 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Similarly, the propoxyphene mentions for consistently reportiiig medical ex- aminers peaked in January-March 1977 at 169 and declined to 125 for the most recently analyzed period (October-December 1977). I believe that the available data in general support the image that the profes- sion has had of propoxyphene-an analgesic which can be useful in treating peo- ple with mild to moderate pain with a minimum of side effects and no signIficant toxicity unless taken in doses much larger than those recommended for medical use. Some drug abuse will occur with any analgesic drug. It is of interest, e.g., that DAWN reports twice as many mentions in its emergency rooms for aspirin and two-thirds as many for acetaminophen, as for propoxyphene. These two OTC drugs, available to anyone without a prescription, can also, in large doses, produce organ damage and death, even without the ingestion of other drugs. Branding these OTC analgesics as an "imminent hazard", nevertheless, would be as foolish as the recommendation to do so for propoxyphene. The concept that propoxyphene is an excessively expensive and excessively prescribed analgesic has its supporters but the proposed remedies for these putative problems would represent a dangerous and ill-advised precedent. Our medical care system should not be politicized by unscientific pressures to abolish a drug, or to impose manufacturing quotas on it whenever a group of individuals object to the extent of use and the cost of a given drug. The implications of yielding to such demands are ominous for medical care. If propoxyphene is banned today, which drug will be doomed for extinction tomorrow? Aspirin? Acetaminophen? Narcotic substitutes for propoxyphene? Valium? It is appropriate to debate these issues, but I do not believe that a thoughtful and dispassionate analysis of propoxyphene will find it necessary to accuse the FDA or the manufacturer of either apathy or irresponsibility. I would urge, Senator, that you exert your considerable influence to help convene meetings invoviing the FDA, the DEA, the relevant scientific advisory groups for these agencies, and representatives of responsible and prestigious professional and patient groups to assess what we know about propOxyphene, to plan studies for obtaining better data on the motivations and circumstances leading to abuse from propoxyphene and other drugs, to consider the implications of encouraging the substitution of other nonnarcotic and narcotic analgesics for propoxyphene, and to study the level of information among physicians and pa- tience as to the benefits and risks of propoxyphene and of competing analygesics, and the treatment of accidental or purposeful overdose. Such meetings could identify what educational efforts might be needed to optimize medical care for p~tienth in pain. Thank you for the opportunity to express these personal opinions. Senator NELSON. Our final witness. is Dr. Bryan S. Finkle, director of the center for human toxicology at the University of Utah Health Sciences Center, and assistant professor of pharmacology-toxicology and pathology. Your statement will be presented in full in the record, together with your memo which is attached to your statement. STATEMENT OF DR. BRYAN S. FINKLE, DIRECTOR, CENTER FOR HUMAN TOXICOLO~+Y AT THE UNIVERSITY OP UTAH HEALTH SCIENCES CENTER AND ASSISTANT PROFESSOR OP PHARMACOL- OGY-TOXICOLOGY AND PATHOLOGY Dr. FINKr~E. I would like to point out I have brought copies of my statement, not available earlier and I see the clerk has attended to that. As you have said, I am Dr. Bryan S. Finkle, director of the Center for Human Toxicology at the University of Utah Health Sciences Center and assistant professor of pharmacology4oxicology and pathology. I have been continually engaged in forensic toxicology, medico-legal investigation and clinical toxicology for some 22 years. I welcome the PAGENO="0413" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16965 opportunity to present to you a short-I hope no more than about 10 minutes-statement on the toxicology of propoxyphene, and I thank you for this opportunity. The role of propoxyphene and its major metabolites in medico-legal investigation has been of interest to toxicologists for the past decade. As the availability of the drug and its subsequent prescription by physicians increased so, inevitably, its frequency of occurrence in cases of sudden, unexplained death presented analytical and pharmacolog- ical problems for forensic and clinical scientists. As a direct result of several reports in the early 1970's which indi- cated an apparent growing involvement of propoxyphene in forensic toxicology cases the Center for Human Toxicology, University of Utah-supported by Eli Lilly & Co. and FDA-under my direction undertook an independent natiOnal collaborative study in 1975-76 to assess the role of propoxyphene in post mortem cases and place the drug in perspective against demographic and epidemiological infor- mation about the deceased individuals. The study was also designed to evaluate the current laboratory techniques used to detect, identify, and quantitate the drug and its metabolites in biological specimens. The results of the study, which involved 18 forensic toxicologists~ medical examiners, and coroners, was published in the Journal of Forensic Sciences in 1976. Senator NELSON. Let me ask a question for clarification. On the first page you say the Center for Human Toxicology is supported by Lilly and the FDA. Are you saying the Center for Human Toxicology is supported by Eli Lilly & Co. and the FDA, or did they support this particular study? Dr. FINKLE. The latter is correct. Would be that it was the former. I have attached to my statement a reprint of that study for your information and perusal. Senator NELSON. Is that the one we have here called "Memorandum forthe record"? Dr. FINKLE. No, it is not, Senator. It is a separate document. Senator NELSON. Very well. Dr. FINKLE. The principal findings indicated that during the period 1970-75, the number of deaths involving propoxyphene increased each year and at a faster rate than total drug deaths. About half of the 1,022 cases studies were suicides. The deceased were not part of the illegal drug abuse population and had no particular propensity for the use of heroin or narcotics, but were a particular medical population with a marked tendency to hypochondria, chronic minor illnesses, and emo- tional problems, and misuse of a variety of prescription drugs and alcohol. It was confirmed that propoxyphene can be a dangerous drug when misused, deliberately or accidentally, but most especially in combina- tion with alcohol and/or other central nervous system depressant drugs. I am not speaking here of the fixed drug combinations in Darvon such as aspirin, but the many other drugs such as barbiturates and tran- quilizers and so on which are listed in the table appended as part of this statement. From a toxicology perspective propoxyphene appeared to be no more dangerous than many other potent drugs available, and that typical of PAGENO="0414" 16966 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the modern forensic toxicology scene. it presented as `a, mix~d drug, con~bination phenomenon. The report; also described the potential importance of propoxyphene- metabolite toxicity and noted the need for improved laboratory meth- ods to detect and quatititate the drug. Since this report other papers have been published which corrobo- rate the findings, and corollary data have been developed through medical examiner reports to the Drug Abuse Warning Network sys- tem-DAWN. An uncritical analysis of DAWN data would indicate that the oc- currence of propoxyphene in sudden, unexplained death cases has con- tinued unabated in the last 2 years. In order to inspect the validity of this assumption I undertook `a short; followup study, with particular reference to those sites which matched DAWN reporting areas and those at which particular case reports were announced. The appended table shows some of the results and clearly indicates that since 1975 there has been a small but consistent decrease in the number of propoxyphene-associated drug death cases each year. This is an important trend. Further, it is clear that suicides continue to predominate in this pop- ulation and that propoxyphene occurs most often in multiple drug deaths in which the particular toxicological significance of propoxy- phene and its metabolites is not usually defined. If the human toxicology of propoxyphene is to be truly described then it is imperative that its role in each case be evaluated, and only reported for statistical purposes in those cases in which it is toxi- cologically significant. Any other practice will inevitably lead to erroneously inflated case reports and provide a misleading basis for possible public health regulation and drug control. A summary of the findings of this most recent study are attached for your information. [The summary referred to follows:] PAGENO="0415" 0 - DCF - D - INCIDENCE OF DPX-ASSOCIATED CASES, BY SITE, BY YEAR Finkle Alameda County Oakland, CA Dade City, FL Dallas City/County Site Code 1969 1970 1971 1972 1973 1974 1975 1976 __________ __________ 6 3 3 3 9 ii ~- - - 7-10/yr." ------------~ 0 - - 2 13 10 ii - - - - - 14 10 16 12t Of lit lit 1977 1978 WCD - - 8 12 24t 32t l7~ i4~ lOf Georgia G - 1 2 5 6 6 4 1 1 1 6 - - - Hennepin County, MI HC - - ) - - - 2 3 9 10 - - - o Illinois - - Las Vegas City/County LV - - - - 2 1 2 - - LosAngelesCity/County LA -- - 37 33 63 32 - - - St. Paul, MN SP - - - 1 2 3 3 8 ii - - - New MexIco North Carolina NM - - NC 2 3 Orange County, CA OC - - Oregon OR - - Philadelphia City/County PH - - San Diego City/County SD - - Utah UT - - Toronto + Ontario TOR - - - 44 39 46 42 - - Maryland MD - - - - - 19' 45" 32" 43" Phoenix, Maricopa County MC - - - - 8+ 18t 28t lOf lOf Sources (unless otherwise noted): Finkle et al, 1975 survey `McBay/N.C. memo dated December 19, 1978 "Finkle update memo dated December 21, 1978 fFlnkle update January 29, 1979 "Correspondence and Iorma 1639, State Medical Examiner, Oregon - - 4 2 23 23 32 25 (21') (21') (30') (50') 34' 36' 31' - 8 12 15 ~--------- 1 5-20/yr." ---- - 1 0 0 5 - 40" 21/Omo" - 25 22 28 38" 25" 25" (20" - 20 ` 24 23 i9j- 26f 24f 17t ci - - 7 ii 2 ~---- (5/yr. ------------` ist `~1 revised 1-30-79 PAGENO="0416" 16968 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. FINKLE. It has been asserted that the number of deaths caused by propoxyphene is now greater than those from heroin. This ques- tion was addressed at each of the study sites. At most sites this is sim- ply not true; and in those areas where propoxyphene is detected in unexplained death cases with greater frequency than heroin/morphine this is clearly a function of the dramatic reduction in heroin fatalities in almost all areas of the United States since 1976 and not related to a supposed increase in propoxyphene cases. Again, this points to a need for careful examination of individual cases before general, epidemiological inferences are drawn. The report-and this statement-certainly do not exonerate pro- poxyphene as a safe drug; it is of major concern to all toxicologists. There is no absolutely safe drug, and it is irresponsible to condemn a valuable pharmacological agent before accurate data are available to place its adverse effects in perspective with those of other similar drugs, and current forensic and clinical toxicology experience. If I might digress; the memorandum to which you referred, Sena- tor, is a report to myself of that study and the principal findings of the followup study. I would now like to add one,thing. You will ~iotice that in my view a very important study site is at Dallas City and county, and the Institute for Forensic Sciences at Dallas was included in the followup study and was also in the original study. An important letter was sent to me by Dr. Vincent DiMaio who is the deputy chief medical examiner at that office. The letter came to me `too late for in- clusion in my prepared statement and I would now like to read it into the record and include it as part of my testimony. Senator NELsoN. Go ahead. Dr. FINKLE. The letter was originally addressed to Dr. Wolfe in response to a letter Dr. Wolfe sent to Dr. DiMaio. It reads: I am in receipt of your letter dated December 18, 1978, concerning the Health Research Group's petition to the DEA requesting transfer of propoxyphine to schedule II of the Controlled Substances Act. It is my opinion that the danger of propoxyphene is overinfiated. Propoxyphene like any other drug can kill if misused. Accidental deaths from the use of pro- poxyphene are rare. Most alleged accidental deaths are drug abuse deaths. Any drug abused is dangerous. More common than drug abuse deaths with propoxy- phene are suicides. I do not think that by making propoxyphene difficult to ob- tain, one will decrease the rate of suicides. One will just change the drug or its use. All one has to do is compare the method of suicides in different areas of the country to realize that access to drugs would make little difference in the suicide rate. In the latest data from our office propoxyphene accounts for nine deaths; six of these were determined to be suicidal gestures. Along with your letter was a copy of a letter to Joseph Califano, Secretary of Health, Education, and We'fare. This was apparently a public letter released on Tuesday, November 21, 1978. I think your cause might be taken more seriously if in this letter you had not included data that was incorrect. On page 3, table 2, you list the propoxyphene-related deaths from July 1973 to December 1977. I am afraid that I cannot believe any of the figures in that table. The reason I do not is that for Dallas you indicate that there were 80 such deaths in that period of time. I would like to inform you that from January 1973 to December 1977 in Dallas there was a total of only 30 deaths due to pro- poxyphene. An additional 25 individuals died of a combination of multiple drugs and also had propoxyphene detected in their blood. If you include both, then the maximum number of cases would be 65 rather than 80. PAGENO="0417" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16969 Senator NELSON. Let me interrupt you. I thought the first figure was 30 and the combination deaths were 25. That ought to be 55, not 65. Dr. FINKLE. That is correct, Senator. In fact, in a number of the mixed drug deaths the propoxyphene was present only in small, therapeutic amounts and was only incidental. Part of the epidemic of propoxyphene deaths being reported is that until fairly recently many toxicology laboratories were deficient in their ability to detect propoxyphene. Therefore, such deaths were being missed for many years. Some of the cases in which the propoxyphene was taken intravenously were considered as morphine deaths. To go on: I am afraid that I also doubt your contention on page 2 of your letter that propoxyphene was associated with more deaths than heroin/morphine in the first half of 1977. While methods of deaths from propoxyphene are readily available and used by toxicology laboratories, many of these laboratories are unable to detect mor~ phine in the blood. Thus, they will miss rapid deaths from morphine or heroin injections and if so, and some propoxyphene is found they may attribute such deaths to propoxyphene rather than morphine. I want to include this letter because Dallas was part of the followup study that I conducted. Essentially, the facts that are in this letter are supported by my findings when I went to Dallas and examined their cases file by file, and I wOuld like to further state that in my opinion the medical/legal investigation system in~ Dallas City and County is one of the best in the country and that their toxicologists and their toxicology laboratory certainly ranks in the top three or four in the country. I ended my statement by saying that the current trend indicates a decrease in propoxyphene cases and that this is important. Further, it is clear that suicides continue to dominate in these cases. Several questions must be addressed. Most victims are suicides; can legislation prevent suicidal ingestion of multiple drugs? What needs to be done to better understand the toxicology of mul- tiple drug usage? Research is desperately needed in this area. What is the role of alcohol-the drug of abuse and death-in combination with propoxyphene? If this analgesic is removed from medical use, what will take its place? Are there safe, toxicologically benign alternatives? This is a critical question to be answered before any precipitant action is taken. Few medical-science problems are solved by negative action; there is need to maximize the medical assets of propoxyphene and minimize its liabilities through decisions based on clinical and pharmacological understanding, and with a refined, focused system designed to care- fully monitor its performance prospectively. The Center for Human Toxicology staff have carried out retrospec- tive studies at great labor and cost on four or five different agents to date. If only there were established a refined system of monitoring these drugs and some other like-drugs prospectively as they were used in the medical context by physicians and patients, then this kind of retrospective panic data gathering with all its loose ends would not be necessary, and we would be in a much better position to provide your committee. FT)A, and other agencies with the kind of informa- tion you truly need. 40-224 0- 79 - 27 PAGENO="0418" 16970 CO~ETITh7E PROBLEMS IN `L'IIE DRUG INDUSTRY I am not an advocate for propoxyphene or any other particular drug, but a biomedical scientist who recognizes a critical need for a method of effective evaluation of human toxicology. DAWN is a valuable but blunt tool, not designed for this purpose but so often misused because it is the only instrument available. It is not good enough alone for toxicologists' purposes. A cool, continuous examination of toxico- logical facts as they become available through a prospective monitor- ing system is required, together with improved laboratory practice and applied research. The overriding purpose should be better medicine and improved public health through the dispassionate work of medi- cal examiners, coroners, and toxicologists. They are the ombudsmen of public health, and their professional efforts deserve better than ill- considered interpretation resulting in hasty, self -~Ief eating legal regu- lation. Thank you. Senator NELSON. Thank you very much, Dr. Finkle. We appreciate your taking the time to come and present your testimony today. It will be included in full in the record, of course, along with the memo- randum you have submitted and along with the other documents. I want to thank all of the witnesses very much for appearing here today. As I said earlier, the record will be kept open for 2 weeks for submission of any additional testimony or documents. Again, thank you very much. That will conclude the hearings. [Whereupon, at 1:05 p.m., hearings in the above-entitled matter were concluded.] [The prepared statement of Dr. Bryan S. Finkle, together with a memorandum for the record, biographical data, and letter to Dr. Sidney M. Wolfe, foilow:] PAGENO="0419" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16971 Statement To The U.S. Senate Select Committee On Small Business Chairman: Senator Gaylord Nelson THE MEDICO-LEGAL TOXICOLOGY OF PROPOXYPHENE I am Dr. Bryan S. Finkle, Director of the Center for Human Toxicology at the University of Utah Health Sciences Center; and Assistant Professor of Pharmacology-Toxicology and Pathology. Gentlemen: I welcome the opportunity to present to you .a short (10 mInute) statement on the current toxicology of propoxyphene and I thank you for this privilege. The role of propoxyphene and its major metabolites in medico-legal investigation has been of interest to toxicologists for the past decade. As the availability of the drug and its subsequent prescription by physicians increased so, inevitably, its frequency of occurrence In cases of sudden, unexplained death presented analytical and pharmacological problems for forensic and clinical scientists. As a direct result of s~veral reports in the early 1970's indicating an apparent growing Involvement of propoxyphene In forensic toxicology cases the Center for Human Toxicology, University of Utah, (supported by Eli Lilly and Company and F.D.A.) under my direction undertook an independent national collaborative study in 1975-76 to assess the role of propoxyphene in postmortem cases and place the drug in perspective against demographic and epidemiological Infor- mation about the deceased Individuals. The study was also designed to PAGENO="0420" 16972 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY evaluate the current laboratory techniques used to detect, Identify and quantitate the drug and Its metaboiltes in biological specimens. The results of the study, which Involved eighteen forensic toxicologists, medical examiners and coroners, was published in the Journal of Forensic Sciences in 1976. The principal findings indicated that during the period 1970-75, the number of deaths involving propoxyphene increased each year and at a faster rate than total drug deaths. About half of the 1,022 cases studied were suicides. The deceased were not part of the Illegal drug abuse population and had no particular propensity for the use of heroin or narcotics, but were a particular medical population with a marked tendency to hypochondria, chronic minor Illnesses and emotional problems ,and misuse of a variety of prescription drugs and alcohol. It was confirmed that propoxyphene can be a dangerous drug when misused, deliberately or accidentally, but most especially in combination with alcohol and/or other central nervous system depressant drugs. From a toxicology perspective propoxyphene appeared to be no more dangerous than many other potent drugs available, and that typical of the modern forensic toxicology scene it presented as a mixed drug, combination phenomenon. The report also described the potential Importance of propoxyphene- metabolite toxicity and noted the need for improved laboratory methods to detect and quantitate the drug. Since this report other papers have been published which corraborate the findings, and corollary data have been developed through Medical -2- PAGENO="0421" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16973 Examiner reports to the Drug Abuse Warning Network system (DAWN). An uncritical analysis of DAWN data would indicate that the occurrence of propoxyphene in sudden, unexplained death cases has continued unabated in the last two years * In order to inspect the validity of this assumption I undertook a short follow-up study in the past three months, at some of the 1975 sites in my prior study, with particular reference to those which matched DAWN reporting areas and those at which particular case reports were announced. The appended table shows some of the results and clearly indicates that since 1975 there has been a small but consistent decrease in the number of propoxyphene- associated drug death cases each year. This is an Important trend. Further, it is clear that suicides continue to predominate in this population and that propoxyphene occurs most often in multiple drug deaths in which the particular toxicological significance of propoxyphene and its metabolites is not usually defined. If the human toxicology of propoxyphene is to be truly described then it is imperative that its role in each case be evaluated, and only reported for statistical purposes in those cases in which it is toxicologically significant. Any other practice will inevitably lead to erroneously inflated case reports and provide a misleading basis for possible public health regulation and drug control. A summary of the findings of this most recent study are attached for your information. * -3- PAGENO="0422" INCIDENCE OF DPX*ASSOCIATED CASES, BY SITE, BY YEAR Alameda County Oakland, CA Dade City, FL Dallas City/County Wayne County Detroit, MI Georgia Hennepin County, MI Illinois Las Vegas City/County LV Los Angeles City/County LA St. Paul, MN SP North Carolina Orange County, CA Oregon OR Philadelphia City/County PH San Diego City/County SD 3 3 9 11 ~--------- 7.10/yr." ~> C - 2 13 10 11 - - - - 14 10 16 12t 6t lit lit - 8 12 24t 32t l7~ 141 16j 2 5 6. 6 4 - - 0 - .4 1 1 1 6 - - - - 2 3 9 10 - - - - 2 1 2 5 - - - - 37 33 63 32 - - - - 1 2 3 3 - - - 02 - - 4 8 11 - - - 2 .3 2 23. 23 *32 25 . (21') (21') (30') (60') 34' 36' 31' - - - 8 12 15 ~-------- 15-20/yr." ---- - 1 0 0 5 - 40" 21/Omo" - 25 22 28 38" 25" 25" (20" - 20 24 23 19t 26f 24t l7~ 2 ~--- (5/yr. ------------~ "40" 15t 02 Finkle Site Coda 1969 1970 1971 1972 1973 1974 1975 1976 0 - 3 DCF - - D - - WCD - - G - 1 HG - - IL - - I. r~c 1977 1978 Now Mexico NM - - NC OC Utah UT - - - - 7 11 Toronto + Ontario TOR - - - 44 39 46 42 - . - Maryland MD - - - - - 19" 45" 32" 43" Phoenix, Maricopa County MC - - - - . 8+ 18t 28t 10) 16) Sources'(uniess otherwise noted): Finklo et al. 1975 survey `McBay/N.C. memo dated December 19, 1978 "Finkle updato memo dated December 21. 1978 fFlnkle update January 29, 1979 "Correspondence and I~orms 1639, State Medical Examiner, Oregon revised 1-3O~79 PAGENO="0423" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16975 It has been asserted that the number of deaths caused by propoxyphene is now greater than those from heroin. This question was addressed at each of the study sites * At most sites this is simply not true; and in those areas where propoxyphene is detected in unexplained death cases with greater frequency than heroin (morphine) this is clearly a function of the dramatic reduction in heroiC fatalities in almost all areas of the United States since 1976 and not related to a supposed increase in propoxyphene cases. Again, this points to a need for careful exami- nation of individual cases before general, epidemiological inferences are drawn. The report (and this statement) certainly do not exonerate propoxyphene as a safe drug; it is of major concern to all toxicologists. There is no absolutely safe drug, and it is irresponsible to condemn a valuable pharmacological agent before accurate data are available to place its adverse effects In perspective with those of other similar drugs, and current forensic and clinical toxicology experience. Several questions must be addressed: Most victims are suicides; can legislation prevent suicidal ingestion of multiple drugs? What needs to be done to better understand the toxicology of multiple drug usage? Research is desperately needed in this area. What is the role of alcohol (THE drug of abuse and death) in combination with propoxyphene? If this analgesic Is removed from medical use what will take its place? Are -4-- PAGENO="0424" 16976 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY there safe, toxicologically benign alternatives? This is a critical question to be answered before any precipitant action is taken. Few medical-science problems are solved by negative action, there Is a need to maximize the medical assets of propoxyphene and minimize its liabilities through decisions based on clinical and pharmacological understanding; and with a refined, focussed system designed to carefully monitor its performance prospectively. I am not an advocate for propoxyphene or any other particular drug, but a biomedical scientist who recognizes a critical need for a method of effective evaluation of human toxicology. DAWN is a valuable but blunt tool, not designed for this purpose but so often misused because It is the only instrument available. It is not good enough alone for toxicologists' purposes. A cool, continuous examination of toxicological facts as they become available through a prospective monitoring system is required; together with improved laboratory practice and applied research. The overriding purpose should be better medicine and improved public e health through the dispassionate work of medical examiners, coroners and toxicologists. They are the ombudsmen of public health and their professional efforts deserve better than ill-considered Interpretation resulting in hasty, self-defeating legal regulation. -5- PAGENO="0425" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16977 MEMORANDUMFOR THE RECORD January 29, 1979 Subject: PROPOXYPHENE: TOXICITY STUDY 1978-79 Further to current reports concerning the Incidence of propoxyphene in postmortem medico-legal investigation, a study has been under- taken during the past several weeks by Drs. Bryan S. Finkle, James C. Garriott, Institute of Forensic Sciences, Dallas, Richard F. Shaw, San Diego County Coroner's Office and Yale Caplan, State of Maryland Medical Examiner's Office, Baltimore. The study included seven site visits and a telephone survey of six additional Medical Examiner-coroner offices covering some major metropolitan areas and states across the United States. The general purpose of these activities was to assess propoxyphene in the forensic toxicology of drug fatalities but specifically to: 1. Evaluate the accuracy of the data on DPX deaths In Dr. Sidney Wolfe's letter to HEW Secretary Califano dated Nov. 21, 1978. 2. Critique the method and cases which are reported to the DAWN data collection system. 3. Consider how (2) differs from the Finkle-McCloskey system of case evaluation. 4. Determine if Heroin is responsible for more deaths than propoxyphene. 5. What other drugs, particularly analgesics, outweigh Heroin in this context. The following summarizes the findings: A. Telephone Survey U) PHILADELPHIA (City and County) In 1974 thIs site had 14.0/106 population DPX associated cases, i.e. 28 cases. Cases peaked to a maximum in 1975 and have since decreased steadily: 1975-38,1976-25, 1977-25, l978~2O. Propoxyphene - DPX Tricyclic Antidepressants - TADS PAGENO="0426" 16978 COMPETITIVE PROBLEMS IN THE DRUG INDTJSTRY MEMORANDUM FOR THE RECORD - 2 - January 2~, 1979 DPX ranks sixth in frequency of occurrence in toxicology cases, behind alcohol, carbon monoxide, narcotics, tricyclic antidepressants and barbiturates. The greatest current increase Is in TAD's, flurazepam and cocaine. DPX continues to occur principally, in multiple drug intoxications. (ii) OAKLAND - ALAMEDA. County In 1974 there were 11 DPX associated cases, at 10. 0/106 population. There has been little change in the past 4 years with 7-10 cases per year. Opiate narcotic deaths have decreased; and greatest increase in TAD cases. * (iii) ORANGE COUNTY - California In 1974 experienced 15 DPX associated cases at 10.0/106 population. Since then cases have remained relatively constant each year at about 15-2 0 per year. The drug still ranks in the top five In frequency of occurrence, usually in multiple drug deaths. No information available on narcotics deaths, but TAD, flurazepam, diazepam increasing and a surprising reappearance of chioral hydrate. (lv) N. CAROLINA STATE There were 32 DPX cases in 1974 at 6.4/106 population. The cases reached a peak in 1975 at 50 cases and have since decreased steadily, 1976-34, 1977-36, 1978-32. This experience is best summarized in a report to the Southern Medical Journal, V. .~Q, No. 8:938, Aug. 1977 by Page Hudson, et al. - There is evidence of an "Improving situation" re DPX. Opiate narcotics have never been a major fatality problem in this state at less than 15 cases/year during the past eight years. There has been a major increase in amitriptyline cases. The character of the DPX cases, i.e., multiple drugs, accidental and suicide cases remains unchanged since 1975. PAGENO="0427" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16979 MEMORANDUM FOR THE RECORD - 3 - January 29, 1979 (v) STATE OF MARYLAND This site was not Included in the 1975 Finkle study. However, cases reached a maximum in 1975 as the following table shows: 1974 1975 1976 1977 1978 PROPOXYPHENE 19 45 32 43 ç4O OPIATE NARCOTICS - 54 44 17 BARBITURATES - 42 39 43 TOTAL DRUG DEATHS - 118 103 140 - There has been a significant decrease in Heroin deaths, whereas propoxyphene associated cases have decreased only slightly. DPX's role remains essentially in multiple drug fatalities. B. SAN DIEGO SITE VISIT U) The geographical area and population base used for the DAWN reporting system and the 1975 Finkle study are the same at this site. (ii) The population has Increased; 1975 - 1.4, 1977 - 1.6, 1978 - 1.7 x 106. Wolfe's population base is accurate but it is important to note that the DPX cases per million population on P. 12 of his letter Is for a 3 year period which obviously inflates the DPX case frequency. The rate per year matches closely the Finkle study (BF: 92 cases 1974-77 = 57.8/106/3 YR= 19.3/YR. SW: 95 cases 1974-77 = 59.8/106/3 YR = 19.9/YR) (iii) At this site the DPX involved cases which are reported to DAWN and those included In a Finkle type study are the same because no "Drug Related" cases are reported to DAWN on the 1977 0MB 43-R-0545 form. This is because there is considerable danger of misinterpretation of these cases. (Drug Related cases have been reported since November 1978). A "Drug Related" case does not necessarily mean that the drug was in any way contributory to the death; e.g., in deaths from Gun Shot Wounds, Motor Vehicle Accidents, a paraplegic who might die from non-drug related causes. The case merely indicates that DPX or its metabolites were present in the blood or tissu~at~~y concentration. The Finkle case criteria and DAWN "Drug Induced" cases match much more closely, but eyen here there is a problem for DAWN because most of the DPX cases involve multiple drugs and the PAGENO="0428" 16980 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MEMORANDUM FOR THE RECORD - 4 - January 29, 1979 separate agents are not reported In a way that permits discrimination of their potency or relative toxicological significance in a given case. In consequence, cases in which, for example, a combination of alcohol and barbiturates was the cause of death, but in which also toxicologically insignificant concentrations of DPX were detected, would be reported as "Drug Induced" and recorded by DAWN and Wolfe as a "DPX case. It was not possible In the time available to inspect and evaluate each of these actual cases but it certainly should be done If a true picture of DPX toxicology is to be clearly established. It should be noted that the Finkle study was a SURVEY and that local pathologists' opinion relative to the role of DPX as expressed on the case death certificates was not questioned. There Is obviously room for a more critical evaluation of these "Drug Induced" and "Drug Related" cases which probably reflect unrealistically high numbers. (iv) At San Diego, DPX continues to occur principally in multiple drug deaths. Section B of the DAWN report form does NOT indicate a rank ordering of potency. (July-Dec.) - 1973 1974 1975 1976 1977 1978 DPX Total 17 23 19 26 24 17 DPXOnly 8 6 3 6 3 2 DPX & Alcohol Only 2 0 6 1 6 2 DPX in Multiple Drug 7 17 10 19 15 13 Cases (v) Deaths from Heroin are decreasing rapidly; this probably reflects the current strength of the street drug which is 3-5% Heroin in contrast to 20-25% in the early 1970's. The ratio for DPX-to-Heroln associated deaths is extremely variable for any particular period of time and is, therefore, an unreliable indicator of increased DPX fatalities. e.g. FIRST 6 MONTHS 1977 FIRST 6 MONTHS 1978 HEROIN DPX 12 DPX CASES ACCIDENT 17 7 28 HEROIN CASES SUICIDE 0 1 RATIO 1: 1.2 UNDETERMINED 0 2 17 10 RATIO 1: 1.7 PAGENO="0429" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16981 MEMORANDUM FOR THE RECORD - 5 - January 29, 1979 DPX Is almost constant since 1975 whereas Heroin has decreased - the ratio then quite erroneously Indicates an apparent increase in DPX cases. There are NOT more DPX deaths in San Diego (even currently) than Heroin fatalities. By selection of site and time, anc~ use of the DPX/ Heroin ratio, it is possible to show that, DPX is a major problem compared to Heroin, but it is quite / misleading and a futile exercise in assessing the toxicity of propoxyphene (cf DALLAS) (vi) DPX does rank as a drug frequently encountered in forensic toxicology. For 1977 the ranking (detected in blood and tissues by analysis) is: 1. Alcohol 490 5. Propoxyphene 31 2. Barbiturates 86 6. Diazepam 31 3. Morphine (Heroin) 83 7. Codeine 17 4. Trlcyclic Antidepressants 46 8. Doxepin 13 (~mitriptyline 36, Imipramine 4, Desipramine 6) The TADS, codeine, Doxepin,PCP, and Chloral Hydrate are all increasing significantly each year. DPX is not. Comparing two analgesics: Codeine occurs at about half the frequency of DPX, but Is increasing. This does raise the question, if DPX were to be removed, what would fill the void. Today codeine and acetaminophen are the likely toxicological candidates. DALLAS CITY AND COUNTY SITE VISIT The geographical area and population served by this site is not the same as the DAWN reporting area, but it does represent the major portion of the DAWN area and the Medical Examiners office does make DAWN reports. [M. Examiner 1.3, DAWN 1. 7 x 10,6]. All of the criticisms of the DAWN reporting system especially the lack of discrimination between cases, and in toxic significance, noted at the San Diego site were also found in Dallas. This site does report "Drug Related" cases which undoubtedly explains the larger case numbers seen in the Wolfe letter versus those in the 1975 Firikle survey. PAGENO="0430" 16982 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MEMORANDUM FOR THE RECORD - 6 - January 29, 1979 Propoxyphene associated cases peaked in 1975 and are now stable, or even decreasing slightly, as follows: 1972 1973 1974 1975 1976 1977 1978 DPXOnly . 2 5 5 4 7 9 3 MULTIPLE DRUGS 11 5 11 22 6 11 13 TOTAL 13 10 16 26 13 20 16 The Suicide, Accident Manner of Death has not changed since the Finkle study. There are more DPX associated deaths than Heroin at this site, since 1975. In the first half of 1977: 8 DPX (4 DPX only and 4 Multi-drug) against 1 Heroin death. In 1978: 11 Intravenous narcotism cases (9 morphine and 2 Dilaudid) 16 DPX. Drug Frequency Pattern Is as follows: TOTAL DPX HEROIN BARBS ALCOHOL ALONE MIXED ALONE MIXED ACUTE 1972 13 28 3 - 10 32 - 1973 10 11 4 1 8 9 6 1974 16 9 3 I 9 13 11 1975 26 5 - 5 8 28 5 1976 13 14 4 6 4 11 16 1977 20 4 7 9 7 10 10 1978 16 9 .2 20 2 13 - The mixed drug cases are the most critical toxicologically. e.g. 1974 22 of 125 cases 1975 50 of 128 cases 1976 21 of 117 cases 1977 22 of 115 cases All of the other observations and comments from this site match San Diego very closely. Particularly, DPX is a multi-drug case problem which Is NOT revealed in DAWN, or the significance of DPX in multi-drug cases. PAGENO="0431" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16983 MEMORANDUM FOR THE RECORD - 7 - January :29, 1979 PHOENIX-MARICOPA COUNTY SITE VISIT The jurisdictional population of the Medical Examiner's office is 1.2 million. This site reports to the DAWN system, but only "Drug Induced" cases; not those classified as "Drug Related". The current experience with DPX cases is as follows: From July ma i~.a i~2~ i~i~ TOTAL DPX 8 18 28 10 16 15 DPXONLY 3 2 6 4 5 5 DPX & Alcohol Only 1 8 10 3 3 2 DPX IN MULTIPLE I 8 12 3 8 8 DRUG CASES Propoxyphene is the most frequently detected drug in postmortem cases, followed by morphine, barbiturates and TAD' s. The frequency of other analgesics such as acetaminophen and codeine Is of a very low order. DPX has only outranked morphine (Heroin) for the past two years because, although DPX has itself decreased, Heroin deaths have dramatically dropped to negligible numbers: 1973 1974 1975 1976 1977 1978 (HeroinYMorphine 13 31 41 33 5 6 Cases MIAMI - DADE COUNTY SITEYI~U The forensic toxicology experience with propoxyphene and Heroin Is as follows: Propoxvphen~ Total Toxiojt~i Year Cases Heroin(Morphine) Total Multipi~ Suicides Acciden 1973 174 11 11 5 11 0 1974 228 14 10 3 7 3 1975 261 30 12 9 7 5 1976 245 24 6 5 5 1977 252 9 11 ~ 11 0 1978 249 22 11 8 9 2 PAGENO="0432" 16984 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MEMORANDUM FOR THE RECORD - 8 - January 29, 1979 It should be noted that at this site Heroin fatalities still out number propoxyphene associated cases. There has been no significant decrease in narcotic deaths which is contrary to the general U . S. experience since 1976. DPX is principally a multiple drug case problem in a population dominated by suicides. DETROIT - WAYNE COUNTY SITE VISIT The jurisdictional population at this site is 2.7 million, and matches the DAWN reporting area. All sections of the DAWN, Medical Examiner report form are completed routinely. DAWN case numbers are greater than those in the Finkle study because only cases in which DPX was significant were included in the latter whereas DAWN records all cases in which the drug was detected. The following table gives the relevant case data: 1974 1975 1976 1977 1978 Total Toxic Cases 3539 3289 3371 2747 3116 Total Drug Cases -- 423 287 151 123 Total DPX Cases 24 32 17 14' 16 DPXAlone 6 8 7 6 6 DPX & Alcohol Only 4 6 3 2 0 DPX in Multiple Drug 14 19 7 6 10 Cases The DPX case numbers are decreasing and the main involvement is in multiple drug deaths. Suicides are predominant. This office is ~y conservative in designating a death as suicide, preferring Not determinable' if there is any doubt at all. 1974 1975 1976 1977 1978 Total DPX Cases 24 32 17 14 16 Suicides 8 13 4 7 10 Accidents 1 2 1 0 1 Undeterminable 15 18 11 7 5 Until 1975 Detroit has a national lead for the annual number of Heroin deaths. Those deaths have dropped largely since 1976 but still outnumber DPX involved cases by a wide margin. PAGENO="0433" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16985 MEMORANDUM FOR THE RECORD - 9 - January 29, 1979 HEROIN (MORPHINE) 1971 - 1973 1974 1975 1976 1977 1978 100 -~ 250 -~ 300 341 208 66 55 Here, the toxicologist believes that federal law enforcement and control over Mexican heroin has severely, restricted availability, and this is the main reason for the case decrease, rather than the weaker strength of the current street heroin. In frequency of occurrence DPX is fourth behind alcohol, diazepam and morphine, and is followed immediately by the barbiturates. Other analgesics, codeine, acetaminophen and meperidine are of a very low frequency. 40-224 0 - 79 - 28 PAGENO="0434" 16986 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY BRYAN S. FINKLE, PH.D. DIRECTOR, CENTER FOR HUMAN TOXICOLOGY Dr. Bryan S. Finkle is Director of the Center For Human Toxicology at the University of Utah Health Sciences Center, and holds Assistant Professorships in Pharmacology-toxicology and Pathology. He was born and educated in England, and spent ten years in forensic science at the Scotland Yard laboratory, specializing in toxicology. An 18-month leaveof absence was spent in the U.S. in 1963-65, first as a research associate in toxicology at Cuyahoga County Coroner's Office and Western Reserve University School of Medicine, and then as a criminalist specializing in toxicology in the Santa Clara County Laboratory, California. He joined the latter permanently in 1966, and lectured in forensic toxicology at the University of California School of Criminology at Berkeley in 1971. Dr. Finkle is consultant to several government and private agencies involved with the toxicology of drug abuse. He is Past President of the International Association of Forensic Toxicolo9ists, Past President of the Forensic Sciences Foundation, Past Vice-President of the American Academy of Forensic Sciences, and a member of several state, national,, and international organizations of forensic scientists and toxicologists. For the past 20 years he has been closely associated with research into the problems of alcohol and drugs. His maTh professional interests are in the study of operations management in toxicology; instrumental, automated analytical methods; GC-MS as a tool in toxicology; and studies and experiments to provide a data base for interpretation of analytical toxicology data. He has made many contributions to the scientific literature and books concerned with forensic and clinical toxicology. PAGENO="0435" CO~IPETITWE PROBLEMS IN THE DRUG INDUSTRY 16987 CURRICULUM VITAE BRYAN S. FINKLE BIRTH: Sunderland, England, March 5, 1936. ADDRESS: Center For Human Toxicology,~ University of Utah, Salt Lake City, Utah 84112, Telephone (801) 581-5117. EDUCATION: National Certificate: Chemistry, Physics, Pure Mathematics, Rutherford College of Advanced Technology, Durham University, England, 1956. Higher National Certificate: Chemistry, Physics,, Pure Mathematics, Northampton College of Advanced Technology, London University, England, 1957. Forensic Science Training Program, specializing in Toxicology, Metropolitan Police Forensic Science Laboratory, New Scotland Yard, London, England. Directed by L.C. Nickolls, 1956-60. Ph.D., Department of Pharmacology, University of Utah College of Medicine, 1977. PROFESSIONAL CERTIFICATIONS: American Board of Forensic Toxicology. Forensic Alcohol Supervisor, Certified by California State Department of Public Health. Forensic Blood Alcohol Analyst, Certified by the California Association of Criminalists. EMPLOYMENT: Primary Academic Appointment. Assistant Professor of Biochemical Pharma- cology and Toxicology, College of Pharmacy, University of Utah, 1977 - Assistant Professor of Pathology, College of Medicine, University of Utah, 1978 - Director, Center For Human Toxicology, University of Utah, Salt Lake City, Utah, January 1976 - Head, Divisions of Analytical, Clinical and Forensic Toxicology. Center For Human Toxicology, University of Utah, Salt Lake City, Utah 1973-75. Chief Forensic Toxicologist. Laboratory of Criminalistics, Department of District Attorney, Santa Clara County, California, 1966-73. Research Associate and Demonstrator in Toxicology. Western Reserve University, Cleveland, Ohio, 1963-64. Research Associate, Toxicology. Cuyahoga County Coroner's Office, Cleveland, Ohio, 1963-64. PAGENO="0436" 16988 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY EMPLOYMENT CONTINUED: Forensic Scientist (Toxicology). Metropolitan Police Forensic Science Laboratory, New Scotland Yard, England, 1956-63, 1965. Analytical Chemist. Swan-Hunter, Newcastle-on-Tyne, England, 1953-56. UNIVERSITY OF UTAH COMMITTEE APPOINTMENTS: College of Pharmacy Space Committee 1977 - University Instrumentation Committee 1978 - TEACHING EXPERIENCE: Lectures and Demonstrations in Toxicology, Western Reserve University School of Medicine, Department of Pathology, Cleveland, Ohio, 1963-64. Orientation and In-Service Training in Toxicology, Laboratory of Criminalistics Professional Staff, Department of District Attorney, Santa Clara County, California, 1966-74. Lecturer in Alcohol, Drugs and Driving, Attorney Staff, Department of District Attorney, Santa Clara County, San Jose, California, 1966-73. Lecturer in Analytical Toxicology, Resident Pathologists, Valley Medical Center, Santa Clara County, California, 1964-65. Lecturer in Alcohol, Drugs and Driving Problems, Santa Clara County School Districts, California, 1969-71. Lecturer in Toxicology, School of Criminology, University of California at Berkeley, 1971. Leader, Seminar Workshop in Clinical Toxicology, American Society of Medical Technologists, Las Vegas, Nevada, 1971. Lecturer, Drug Education Course for Teachers and Counselors, "Dialogue on Drugs", University of California, Santa Cruz Extension, 1971. Lecturer, Advanced Analytical Toxicology, University of Sao Paulo, Brazil, Department of Toxicology and Biopharmaceutical Sciences, Sao, Paulo, Brazil ,1973- Lecturer, Advanced Clinical Toxicology, American Society of Clinical Pathologists, Chicago, Illinois, 1974 - Leader, Seminar Workshop, Analytical Techniques in Clinical Toxicology, Intermountain States American Society of Medical Technologists, Wyoming, 1976. University of Utah: Principles of Pharmacology, College of Medicine. Graduate Course in Analytical Toxicology, Col. of Pharmacy. Clinical Toxicology, School of Medical Technology and College of Nursing. Drug Abuse, College of Pharmacy Analytical Techniques in Pharmacology, Col. of Medicine Clinical and Forensic Toxicology, Col. of Medicine. PAGENO="0437" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16989 DOCTORAL GRADUATE STUDENT TRAINING: Postdoctoral Fellows: Kevin L. McCloskey 1976-78 Michael Morgan 1979-80 Preliminary Examinations Committee 1978. James Melby Thesis Committee, Toxicology of~Cocaine, 1977-79, Ronald Jordon. Prethesis Research Rotations 1978-79: Leslie Bornheim, Donna Webber. RESEARCH GRANTS AND CONTRACTS AWARDED: A National Assessment of Drug Involvement in Postmortem Cases. #271-76-3327. Awarded July 1, 1976-77. National Institute on Drug Abuse. The Forensic Toxicology of Propoxyphene, 1975 - Eli Lilly Pharmaceutical Company. Pharmacokinetic Service Laboratory for the Quantification of LAAM and Other Drugs by Gas Chromatography-Mass Spectrometry. ~#27l-76-3323. Awarded May 1, 1976 - National Institute on Drug Abuse. Toxicological Analysis in Cases of Suspected Sudden Infant Death Syndrome. #240-76-0052. Awarded June 30, 1976-78 Health Services Administration: Office for Maternal and Child Health. Forensic Toxicology and Pharmacokinetics of Drugs in Drivers. #271-76- 3323. Awarded Sept. 29, 1977 - National Institute on Drug Abuse. The Forensic Toxicology of Diazepam, 1976-78 Hoffmann-La Roche, Inc. Toxicology of Glutethimide and Other Nonbarbiturate Sedative Hypnotic Drugs. U.S.V. Laboratories 1977 - Incidence of Drugs Among Fatally Injured Drivers, (Subcontractor) DOT-NHTSA. Awarded Oct. 1, 1978 - Cannabinoids: Survey of Drug Related Casualties. #271-78-3532. NIDA Awarded Sept. 1978 - PROFESSIONAL SOCIETIES: American Academy of Forensic Sciences American Association for the Advancement of Science American Association of Clinical Chemists California Association of Criminalists (1965-76) California Association of Toxicologists Forensic Science Society of Great Britain International Association of Forensic Toxicologists Sigma Xi Western Pharmacology Society Society of Toxicology PAGENO="0438" 16990 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY HONORS: Distinguished Service Award, Santa Clara County District Attorney's Office, Califorqia, 1965. American Academy of Forensic Sciences Award of Merit, 1974, for Outstanding Service to Forensic Science. (Fellow and Past Vice-President) President. International Association of Forensic Toxicologists, 1975-78. President. Forensic Science Foundation 1976-78. Certificate of Honor, Awarded for Research in Toxicology by University of Ghent, Belgium, 1976. Visiting Professor of Toxicology, University of Sao Paulo, Dept. of Toxicology and Biopharmaceutical Sciences, Sao Paulo, Brazil, 1973, 1978. Honorary Member. Gesellschaft Fur Gerichtliche Medizin. German Democratic Republic 1978. PROFESSIONAL AREAS OF SPECIAL INTEREST: Staff and Laboratory Operations Management in Toxicology. Instrumental, Automated Methods in Analytical Toxicology. Gas Chromatography-Mass Spectrometry as an Analytical Technique in Toxicology, Pharmacology and Clinical Medicine. Studies and Experiments to Provide Data Base for Interpretation of Analytical Toxicology Results. Biodisposition of Drugs and Metabolites in Man. PROFESSIONAL CONSULTATION ACTIVITIES: Fluoride Toxicity Studies, Union Carbide, Cleveland, Ohio 1964. GC/MS Applications in Forensic Science, Hewlett-Packard, 1969-70. Development of Analytical Systems and Forensic Science Education Program, NASA Space Technology Applications, Jet Propulsion Laboratory, Pasadena, California, 1969-75. GC/MS Applications Development in Forensic Sciences and Siomedicine, Finnigan Corporation, Sunnyvale, California, 1971-77. Toxicology Methods for Drugs of Abuse, Veterans Administration Hospitals, Palo Alto, California, 1971-73. Salt Lake City, Utah, 1973 - Quality Control and Proficiency Testing in Analytical Toxicology; Toxicology Resource Coninittee, College of American Pathologists, 1974 - Toxicology Research and Evaluation, National Institute on Drug AbuseReview Com. Washington, DC, 1974 - Gas Chromatography-Mass Spectrometry. National Institute on Drug Abuse 1974 - PAGENO="0439" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16991 PROFESSIONAL CONSULTATION ACTIVITIES CONTINUED: Determination of Marijuana in Drivers, Midwest Research Institute and Department of Transportation, Kansas City, Missouri, 1974-75. Forensic Toxicology and Medico-legal Investigation, State of Montana, 1974- Bioavailability Studies, CIBA Pharmaceutical Company, Summit, New Jersey, 1974-75. Medico-legal Aspects of Propoxyphene, Eli Lilly Pharmaceutical Company, 1975- Medico-legal Aspects of Diazepam. Hoffmann-La Roche Pharmaceutical Company, 1976 Toxicology of Glutethimide and Other Nonbarbiturate Sedative Hypnotic Drugs, U.S.V. Laboratories 1977- Forensic Toxicology and Medico-legal Investigation, State of Wyoming 1977- Quality Control and Proficiency in Analytical Toxicology, Center For Disease Control, Atlanta, Georgia 1977- State of California, Dept. of Justice, Forensic Science Laboratory Drugs and Driving Program 1977-78. National Institute of Law Enforcement and Criminal Justice, Forensic Toxicology 1977- State of Utah, Forensic Science Systems Development 1978- Province of Alberta, Canada. Forensic Toxicology Laboratory, Design and Operations Management, 1979. PROFESSIONAL ORGANIZATION APPOINTMENTS: Co-chairman and Secretary, California Association of Toxicologists, 1968-73. Toxicology Editor, `What's New", American Academy of Forensic Sciences, 1968-70. Toxicology Consultant, Forensic Science Foundation--Study of an Early Warning System of Drug Toxicity and Developing Patterns of Drug Abuse, 1971. Toxicologist, Technical Advisory Committee, Santa Clara County Task Force, Drug Abuse Coordination Program, 1971. Program Chairman, Toxicology Section, American Academy of Forensic Sciences, 1971-72. Member, Santa Clara County Medical Society, Committee on Drug Abuse, 1971-73. Vice-President, Santa Clara County Drug Abuse Coordinating Council, Pathway, 1972. Secretary, Toxicology Section, American Academy of Forensic Sciences, 1973. Program Chairman for American Academy of Forensic Sciences, 1973. PAGENO="0440" 16992 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY PROFESSIONAL ORGANIZATION APPOINTMENTS CONTINUED: Chairman of the Council, American Academy of Forensic Sciences, 1973-74. Chairman of the Toxicology Section, American Academy of Forensic Sciences, 1973-75. National Safety Council, Executive Board, Committee on Alcohol and Other Drugs, 1973 - Vice-President, American Academy of Forensic Sciences, 1973-74. President, Executive Board, California Association of Toxicologists, 1973. Member, Forensic Science Foundation, 1973-76. Trustee, Board of Trustees, Forensic Science Foundation, 1975-76. President, Forensic Sciences Foundation, 1976-78. Member, Education Committee, American Academy of Forensic Sciences, 1974-75. Representative for the American Academy of Forensic Sciences to the American Association for the Advancement of Sciences, Pharmaceutical Sciences Section, 1975-77. Chairman, Ad hoc Committee on Toxicology Methods, American Academy of Forensic Sciences, 1974-76. President, International Association of Forensic Toxicologists, 1975-78. Regional Secretary General and Chairman, Toxicology Section; The International Association of Forensic Sciences, 1975-78. PUBLICATIONS BOARDS - APPOINTMENTS: Editorial Board, Journal of Forensic Sciences, 1975- Editorial Board, Journal of Analytical Toxicology 1976- Advisory Board Member, Handbook of Analytical Toxicology, Chemical Rubber Company. 1975-78. Die Toxikologisch-Chemische Analyse, Editorial Advisory Board. Pub. Verlag Theodor Steinkopff. Evaluation of Analytical Methods in Biological Systems. Editorial Advisory Board. Pub. Elsevier. Editorial Consultant to Mosby Publishing Company. Reviewer For: Clinical Chemistry - Analytical Chemistry Science PAGENO="0441" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16993 * INVITED PRESENTATIONS AND ABSTRACTS AT SCIENTIFIC AND PROFESSIONAL MEETINGS: * Gas Chromatography in Clinical Chemistry. Ohio Association of Clinical Chemists, Annual Meeting, Columbus, Ohio, 1964. * Gas Chromatographic Identification of Central Nervous Depressants. National Association of Clinical Chemists, Boston, Massachusetts, 1964. Applications of Gas Chromatography in Clinical and Forensic Toxicology. Northern California Association of Clinical Chemists, San Francisco, California, 1964. * Quantitative Determination and Distribution of Meprobamate and Glutethimide in Biological Material. American Academy of Forensic Sciences, Toxicology Section, Honolulu, Hawaii, 1966. * Drug Involvement in Drinking Driver Cases. California Association of Criminalists Seminar, 1967. Leader/Chairman~ Toxicology Workshop: Interpretation of Barbiturate Metabolite Methodology. California Association of Criminalists Seminar, 1967. Leader/Chairman, Toxicology Workshop: Toxicology of Phenothiazine Drugs, California Association of Toxicologists, 1971. * Computerization of Toxicological Data. California Association of Criminalists Semi-Annual Seminar, Tahoe, California, 1968. M.D.A.: A Fatal Case. California Association of Criminalists, Semi-Annual Seminar, Los Angeles, California, 1969. * "Now is the Winter of Our Discontent... .": A Toxicologist's Introspective View of Pathology and His Role in Postmortem Investigation. American Academy of Forensic Science, Joint Session, Pathology, Biology and Toxicology, Chicago, Illinois, 1970. * Examination of Marihuana Smoke for Cánnabinoid Compounds. California Association of Criminalists Seminar, 1967. Panelist, The Characteristics of a Center For Criminalistics Information California Association of Criminalists, Fall Seminar, Concord, California,l970. * GC/MS: Determination of Commonly Encountered Drugs in Body Fluid Extracts, The Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, Cleveland, Ohio, 1971. * GLC/MS As A Tool in Analytical Toxicology. American Association of Clinical Chemists, Northridge, 1971. Seminar Leader, Modern Analytical Toxicology Problems. Southern Association of Forensic Scientists, Savannah, Georgia, 1971. GLC/M5: State of the Art. American Association of Clinical Chemists, Buffalo, New York, 1971. PAGENO="0442" 16994 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY INVITED PRESENTATIONS AND ABSTRACTS* AT SCIENTIFIC AND PROFESSIONAL MTGS. CONT'D: * Secobarbital AbuSe and Traffic Accidcnts. Forcnsic Science Institute Seminar, Oaklond, California, 1971. Seminar Leader, Analytical Toxicolocy Problems Related to Drurs of Abuse. Unviersity of Indiuna Medical Schcol, ~epartment of Phamacology, Indianapolis, 1971. * Laboratory Resources. Drums of Abuse Analysis. Palo Alto Wedical Clinic, Symposiu~i on Practical t~anagement of Drug Abuse Problems, Palo Alto, California, 1972. * Applications of Computerized GC/WS in Forensic Toxicolooy. The Pittsburgh Conference on Analytical Chemistry and Applied S~ectroscopy. Cleveland, Ohio, 1972. * GC/MS: A Solution to Some Analytical Toxicological Problems. DuPont Symposium on GC/MS Applications. Wilmington, Delaware, 1972. * Drugs of Abuse: Laboratory Resources. Western Conference on Criminal and Civil Problems. Wichita, Kansas, 1972. Workshop Leader, Toxicology and Gas Chromatography. Denver, Colorado, 1972. * Identification of Drug Metabolites by GC/MS and Comouter Library Search Tehc'~iques. Society of Applied Spectroscopy, San Francisco, California, 1972. Forensic Toxicology: Drugs and Their Effects. California Tr~l Lawyers Association, 1972. Toxicology Workshop. California Society of Pathologists, 1972. Analytical Problems Posed by Drug Abuse. Bay Area Seminar for Analytical Development, 1973. Physiological and Toxicology Asoects of Smoke Produced During Combustion of Polymeric Materials. Fl~ability Research Center, Univ. of Utah, 1973. * New Observations on Narcotics Metabolism: Heroin and Cocaine in Blood and Urine. Brain Research Institute, University of Tennesee, 1973. * New Analytical Methods in Forensic and Clinical Toxicolooy (Session President). American Academ~ of Forensic Sciences, Dallas, Texas, 1974. * The Toxicology ofOrug Abuse in California. Forum Brasileiro de Toxicologia. InstitLto Oscar Freire, Sao Paulo, Brazil , 1973. * Applications of flass-Spectrometry in Forensic Toxicology. Second Latin American Congress ~n Toxicoloyy, Santa Fe, Argentina, 1973. PAGENO="0443" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16995 * INVITED PRESENTATIONS AND ABSTRACTS AT SCIENTIFIC AND PROFESSIONAL MTGS. CONT'D. Forensic Toxicology for Pathologists. College of American Pathology, Albuquerque, hew Mexico, 1973. * * Indistinguishable from Magic--The Threat and the Pronise of Laboratory Utopia. American Academy of Forensic Sciences, Dallas, Texas, 1974. * Mass Spectrometry. Department of: Pharmacology, University of Texas Medical School, San Antinio, Texas, 1974. Education in Forensic Toxicology. Western Conference on Civil and Criminal Problems, Wichita, Kansas, 1974. * Analytical Methods in Drug Metabolism. Department of Pharmacology, University of Indiana Medical School, Indianapolis, Indiana, 1974. * Analytical Methods in Clinical and Forensic Toxicology. Eli Lilly Seminar Series. Indianapolis, Indiana, 1974. * Instrumentation in Clinical Toxicology. American Chemical Society and American Association of Clinical Chemists. University of New Mexico, Albuquerque, Mew Mexico, 1974. * ~ GC/tIS Computer Techniques. American Society of Clinical Pathologists, Chicago, Illinois, 1974. * Interpretation of Clinical and Forensic Toxicology Data. American Chemical Society Seminar. Pharr~acology Department, University of Vermont Medical School, Burlington, Vermont, 1974. Forensic Science in State Law Enforcement. Attorney General `s Conference Montana, 1976. * Analytical Techniques Necessary to Detect the Drugged Driver. 6th Inter- national Conference on Alcohol, Drugs, and Traffic Safety, Toronto, Canada, 1974. * The Use of a GC-lIS-COM System of Analysis to Control Illegal Drug Use in Sport. 10th International Symposium on Chromatography, Advancement of Spectroscopic and Physico-Chemical Analytical Techniques. Barcelona, Spain, 1974. Application of Isolated Perfused Liver to Toxicology Problems. California Association of Toxicologists, San Jose, California, 1974. * GC/MS: Married Bliss or Breach of Promise? Seventh International Meeting of Forensic Sciences. Zurich, Switzerland, 1975. * Traffic Safety as it Relates to Drug Abuse. The Citizen's Conference on State Legislatures, Snowmass, Colorado, 1975. * ~GC-MS-Computer Techniques For The Identification of Poisons. Institute For Legal Medicine. Karl llarx University, Leipzig, G.D.R. 1975. * Forensic Science in the United States. Medical-Legal Institute, Brno, Czechoslovakia, 1975. PAGENO="0444" 16996 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY INVITED PRESENTATIONS AND ABSTRACTS*AT SCIENTIFIC AND PROFESSIONAL N1TGS. CON'D: * Drug Detection in Drivers and Sportsmen. Institute for Forensic Toxicology. Charles University, Prague, Czech. 1975. * The Use of Gas Chromatography-Mass Spectrometry in Clinical Toxicology. Indiana Clinical Biochemistry Forum, Indianapolis, Indiana, 1975. The Center for Human Toxicology, Concept and Scientific Program. State of Illinois, Public Health-Toxicology Seminars. Chicago, Illinois, 1975. * Forensic Toxicology Associated with Sudden Infant Death Syndrome. HEW Conference on SIDS. Santa Fe, New Mexico, 1975. The Metabolism of 1-alpha Acetyl Methadol. Department of Pharmacology, University of Indiana, School of Medicine, Indianapolis, Indiana, 1975. * Isolated Perfused Liver Techniques Applied to Drug Metabolism and Toxicology Problems. American Academy of Forensic Sciences, Washington, D.C., 1976. * The Forensic Toxicology of Propoxyphene. University of California at Davis, Dept. of Environmental Toxicology, 1976. * GC-MS Development in Forensic Science. American Society of Mass Spectro- metry, San Diego, California, 1976. * GC-CI-MS Multiple Ion Monitoring Quantitative Analysis of l-'~<-Acetyl Methadol (LAAM) in Biological Samples. American Society of Mass Spectrometry, San Diego, California, 1976. New Concepts and Developments in Toxicology Education and Research. The International Association of Forensic Toxicologists European Centennial Meeting. Ghent, Belgium, 1976. Clinical Toxicology in Smaller Hospitals: Intermountain States Regional Medical Technology Seminar-Workshop. Wyoming, 1976. * GC-MS in Biochemical Toxicology. University of Wisconsin at Madison, Dept. of Toxicology - Seminar Series. 1976. * The Toxicology of Sudden Infant Death Syndrome. Second Annual SIDS Seminar. Providence, Rhode Island, May 1977. * The Pharmacokinetics of LAAM. ICI-USA, Inc., Wilmington, Delaware, April 1977. * Review of GC-MS in Forensic Toxicology. lid-Atlantic and Northeastern Associations of Forensic Scientists. Mount Laurel, New Jersey, April 1977. PAGENO="0445" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16997 * INVITED PRESENTATIONS AND ABSTRACTS AT SCIENTIFIC AND PROFESSIONAL MTGS. CONT'D. * New Analytical Techniques in Neuroscience. University of Utah College of Medicine, March 1977. Toxicology in Homicide Investigation. Rocky Mountain States Police Acadamy. Cheyenne, Wyoming, May 1977. * The Human Metabolism of l-ct-Acetyl Methadol (LAAM). University of Illinois (Chicago), Dept. of Pharmacology, Col. of Medicine, Nov. 1977. * International Conference on Hepatotoxicity Due to Drugs and Chemicals. Fogarty Intl. Center. N.I.H. Bethesda, Maryland, Nov. 1977. * An Assessment of the Significance of Diazepam in Postmortem Toxicology. American Academy of Forensic Sciences, San Diego,. California, 1977. Toxicology in the Hospital Emergency Room. Seminars on Emergency Medicine. University of Utah Medical Center, Nov. 1978. * Determination of Methaqualone and its Metabolites in Plasma, Saliva and Urine After a Single Oral Dose. American Academy of Forensic Sciences, Atlanta, February 1979. * New Techniques for the Analysis of Basic Drugs in Blood for Medico-legal and Clinical Purposes. American Chemical Society, Hunt Valley, Maryland, April, 1978. * Drugs and Driving - Analytical Toxicology. Belmont, Maryland. University of Michigan, Highway Safety Research Institute, April, 1978. * Forensic Science in the Administration of Justice. LEAA Executive Training Program in Advanced Criminal Justice Practices. Kenner, Louisiana, March 1978. * Any Sufficiently Advanced Technology is Indistinguishable From Magic. International Symposium on Instrumental Applications in Forensic Drug Chemistry. Washington, D.C. May 1978. * The Toxicology of Current Street Drugs. American Association of Clinical Chemists, San Francisco, July 1978. Toxicology in the 1980's. California Association of Toxicologists, San Francisco, August 1978. Drugs, Alcohol and Driving, Utah Bar Association. Salt Lake City, Utah, Oct. 1978. * The Quantitative and Qualitative Analysis of LAAM, Nor-LAAM and Dinor-LAAM by GC-CIMS. (and) * The Biodisposition of LAAM and its Primary Metabolites in Man. Review Meeting on the Pharmacology, Metabolism and Pharmacokinetics of LAAM, Washington, DC, Oct. 1978. PAGENO="0446" 16998 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PUBLICATTOi~S: Jackson, J.V., and Finkle, 3.S.: Occurrence of pseudo-barbiturates in post-mortem material. Hature 199:1061-1063, 1963. Sunshine, I.., and Finkle, B.S.: The necessity for tissue studies in fatal cyanide poisonings. mt. Archiv fur Gewerbepathologie urd Gewerbehygine 20:558-561, 1966. Finkle, B.S.: The identification, `quantitative determination, and distri- bution of meprobanate and glutethimide in biological rneterial. J. Forensic Sci. 12:509-528, 1967. Finkle, B.S., Biasotti, A.A., and Bradford.L.W.: The occurrence of some drugs and toxic agents encountered in drinking driver investigations. J. Forensic Sci. 13:236-245, 1968. Sunshine, I., Maes, R., and Finkle, B.S.~ An evaluation of methods for the determination of barbiturates in biological materials. Clin. Toxicol. 1:281-296, 1968. Smith, W.C., Harding, 0.14., Biasotti, A.A., Finkle, B.S., and Bradford, L.W.: Breathalizer experiences under the operational conditions recocmended by the California Association of Criminalists. J. Forensic Sci. 9:58-64, 1969. Maes, R., Hodnett, U., Lundesman, H., Kananen, 6.. Finkle, B.S., and Sunshine, I.: The gas chromatoaraphic determination of selected sedatives (Ethchlorvynol, Paraldehyde, ~eprobar-ate, and Carisprodol) in biological material. J. Forensic Sci. 14:235-254, 1969. Finkle, B.S.: Drugs in drinking drivers: A study of 2,500 cases. J. Safety Res. 1:179-183, 1969. Finkle, B.S.: A progress report on a statewide comouter program for analytical and case toxicology eata. Fifth International t~eeting of Forensic Sciences, Toronto, Ontario, Canada, 1969. Lebish, P., Finkle, B.S., and Brackett, J.W., Jr.: Determination of amphetamine, methamphetamine, and related amines in blood and urine by gas chromatography with hydrogen-flane ionization detector. Clin. Chem. 16: 195-200, 1970. Finkle, B.S., Contributor: Investiaation of the problems and opinions of aged drivers. liational Safety Council Research Report ~5/68, 1968. Finkle, 8.S., Cherry, E.J., and Taylor, D.H.: A GLC based system for the detection of poicons, druas, and hu~an retabolites encountered in forensic toxicology. J. Chromatoarac~ic Sci. 9:393-419, 1971. Finkle, 8S.: Ubiquitous reds: A local perspective on secobarbital abuse. Clin. Toxicol. 4:253-264, 1971. Bradford, L.W., t3iasotti, A.A., Finkle, B.S., Harding, D.M., and Smith, W.C,: Inquiry into standards of practice of blood alcohol analysis. J. Forensic Sd. 11:127-130,. 1971. PAGENO="0447" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 16999 PUULlLATlO1~S COIIT'D: FInkle, B.S., Contributor: flannual of Toxicolnriy Met.hod~. (Sunshine, 1., Ed. in Chief). Chemical Rubber Lumpany, Cleveldnd, Urno, 1971 and 1975. Forrest, F.M., Forrest, r.s., and Finkle, 3.S.: Alcohol-ch1orpror~azine interaction in psychiatric patients. Aqressolojie 13:67-74, 1972. Finkle, B.S., and Taylor, D.M.: A CC/MS reference data system for the identification of drugs of abuse. J. Chromatographic Sci. 10:312-333, 1972. Finkle, B.S., and Taylor, 0.11.: A CC/MS reference data system for the identification of drugs of abuse. Finnigan Spectra 2, 1972. "Statement--Secobarbital Abuse'. U.S. Senate Judiciary Cornittee Proceedings. Senator Birch Bayh, Committee on Juvenile Delinquency. 1972. A GC/MS system for the identification of drugs, narcotics, and poisons. Proceedings: Sixth International t~eeting of International Association of Forensic Science, Edinburgh, U.K. ~972. Secobarbital Abuse--A major factor in escalating traffic accidents in California. Proceedings: Fourth International Congress of Traffic Medicine. Paris, France, 1972. Finkle, B.S., Co-author: Techniques of Combined Gas Chrcnatography-- Mass Spectrometry. Aeplications in Orcanic Chemistry and Biochemistjy. (McFadden, W.) Wiley & Sons, 19/2. Finkle, B.S.: Forensic Toxicologyof Drug Abuse: A status report. Analytical Chem. 44:18-26, 1972. Finkle, B.S.: A comprehensive CC/MS reference data system for toxicological and biomedical purposes. J. Chronatogra~hic Sd. i2-3C~~-32E, 1975. Finkle, B.S.: Forensic Toxicology - Relationship to analytical chemistry. Forensic Science- American Chemical Society Symposium Series, 1974. Finkle, B.S.: A descriptive aDprëciation of modern laboratory instrumentation, with special emphasis on gas chromatography and mass soectrcnetry. Lenal Medicine Annual - 7th Ed. 1975. Ed. Cyril 11. Wecht, Pub. Appleton-Century-Crofts. Finkle, B.S.: "Will the real drugged driver please stand up" - An analytical toxicology assessment of drugs and driving. Proceedings of the Sixth International Conference on Alcohol, Drugs and Traffic Safety, 1974. Finkle, B.S.: GC-1IS: Married Bliss or Breach of Promise. Microfilm. Journal of Legal Medicine, 1976. Finkle, B.S., and Franklin, M.R.: The Formation of cytochrome P-450-455 nm complexes in vivo and isolated perfused rat liver. American Society for Pharmacology and Experimental Therapeutics. 1975. Finkle, B.S.: Contributor. Methodology for analytical toxicology. (Sunshine, Ed. in chief) CRC. 1975. PAGENO="0448" 17000 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PUBLICATIONS COHT'D: Publications of Case Reports in the Bulletin of the International Associa tion of Forensic Toxicologists: Two Placidyl (Ethchlorvynol) Deaths. 2(1), 1965 Driving Under the Influence of Meprobamate and Glutethinide. 2(1), 1965 Librium and Valium Detection in Urine. 2(2), 1965 Fatal Darvon (Propoxyphene) Ingestion. 4(3), 1967 Brevital (Methohexital) Death. 4(3), 1967 Fatal Ingestion of Viodex (Amphetamine). 4(4), 1967 Two Arsenic Deaths. 5(1), 1968 Fatal M.U.A. Case. 5(2), 1968 Detection of Tybamate in Urine. 6(3), 1969 Barbiturate and Chloral Hydrate Death. 8(1), 1971 Amphetamine-Tuinal Involvement in a Fatal Single Vehicle Accident. 8(1), 1971 Fatal Multiple Drug (7) Ingestion. 8(1), 1971 Low-Level Alcohol-Barbiturates Fatality. 8(1), 1971. Three Cocaine Fatalities. 8(3-4), 1972 Drugs and Driving. Four Cases. 10(16), 1974 Pentazocine Fatality. 10(16), 1974 Flurazeparn and Alcohol Fatality. 10(16), 1974 Formaldehyde-Methanol Suicide. 11(2), 1975 Amitriptyline and Chlordiazepoxide Death. 11(2), 1975 Fatal Ethchlorvynol. 11(2), 1975 Finkle, B.S., McCloskey, K.L., Kiplinger, G.F., Bennet, I.F.: A National Assessment of Propoxyphene in Post-Mortem Medico-Legal Investigation. 1972 - 1975. J. For. Sci. V2l#4, October 1976. Finkle, B.S.: BC-MS Development in Forensic Science. American Society of Mass Spectrometry, San Diego, California, 1976. (Abstract) Jennison, T.A., and Finkle, B.S.: BC-Cl-MS Multiple Ion Monitoring Quantitative Analysis of l-~K-Acetyl Methadol (LA/UI) in Biological Samples. American Society of Mass Spectrometry, San Diego, California, 1976. (Abstract) PAGENO="0449" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17001 PUBLICATIONS CONT' D. Finkle, B.S., Contributor. Die Toxikologisch-Chemische Analyse (R.K. Mueller, Ed. in Chief) Verlag Theodor Steinkopff. 1976. Finkle, B.S., Jennison, T.A., and Chinn, D.M.: The Analytical Toxicology and Human Metabolism of 1- ct-Acetyl Methadol (LAAM). American Academy of Forensic Sciences, San Diego, CA, 1977. In Press, J. For. Sci. Finkle, B.S., Kopjak, L., McCloskey, K.L.: Forensic Toxicology Applications of High Pressure Liquid Chromatography. American Academy of Forensic Sciences San Diego, CA, 1977. In Press, J. For Sci. Finkle, B.S., and McCloskey, K. L.: Proficiency Testing in Toxicology. Letter to the Editor. J. For Sci. 22#4, 1977. Finkle, B.S., and McCloskey, K.L.: The Forensic Toxicology of Cocaine. Chapter 8, NIDA Research Monograph #13:153. Cocaine 1977. Finkle, B.5., and McCloskey, K.L.: The Forensic Toxicology of Cocaine. J. For Sci. 23#l, 1978. Pierce, W.O., Lamoreau, T.C., Urry, F.M., Kopjak, L., and Finkle, B.S.: A New, Rapid Gas Chromatography Method for the Detection of Basic Drugs in Postmortem Blood, Using a Nitrogen Phosphorus Detector. Part 1, Qualitative Analysis. J. Anal. Tox. 2#l:26, 1978. Finkle, B.5. Book Review: A Bibliography of Drug Abuse, Including Alcohol and Tobacco. The Am. J. Pharm. Educ. March 1978. Jennison, T.A., Finkle, B.S., Chinn, D.M., and Crouch, D.J.: The Quantitative Analysis of 1-ct-Acetylmethadol and its Principal Metabolites in Biological Specimens by Gas-Chromatography-Chemical Ionization- Multiple Ion Monitoring Mass Spectrbmetry. J. Chrom. Sci. 17: (Feb. 1979) Finkle, B.S., Jennison, T.A., Chinn, D.M., Ling, W., and Holmes, E.D.: The Plasma and Urine Disposition of l-ct-Acetylmethadol and its Principal Metabolites in Man. Submitted to Clin. Pharmacol. Ther. 1978. (1979) Shaw, R.F., Finkle, B.S.: The History and Development of the California Association of Toxicologists. Clinical Toxicology. In Press. Published Spring, 1979. Chinn, D.M., Finkle, B.S., Crouch, D.J., and Jennison, T.A.: The Postmortem Biodisposition of l-o-Acetylmethadol and its Principal Metabolites in Some Cases of Sudden Death. J. Analy. Tox. In Press 1979. Peat, M.A., Finkle, B.S., and Deyman, M.E.: High Pressure Liquid Chromatographic Determination of Chlordiazepoxide and its Major Metabolites in Biological Fluids. J. Pharm. Sci. Submitted. Finkle, B.S., McCloskey, K.L., and Goodman, L.S.: Diazepam and Drug Associated Deaths - A United States and Canadian Survey. J. Am. Med. Assoc. Submitted. 40-224 0 - 79 - 29 PAGENO="0450" 17002 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SOUTHWESTERN 1TELzPHONE E38-1131 INSTITUTE OF FORENSIC SCIENCES AREA CODE 214 REPLY TO: AT DALLAS P.O. ROX 35728 5230 M,&c,! Ce~tm Da!ae. Tmas 75235 518 Office ~f the Medic~t E:~siser January 18, 1979 Sidney M. Wolfe, M.D. Health Research Group 2000 P Street, N.W. Washington, D.C. 20036 Dear Dr. Wolfe: I am in receipt of your letter of December 18, 1978, concerning the Health Research Group's petition to the DEA, requesting transfer of propoxyphene to Schedule II of the Controlled Substances Act. it is my opinion that the danger of propoxyphene is overinflated. Propoxyphene, like any other drug, can kill if misused. Accidental deaths from the use of propoxyphene are rare. Most alleged accidental deaths are drug abuse deaths. Any drug abused is dangerous. More common than drug abuse deaths With propoxyphene are suicides. I do not think that by making propoxyphene difficult to obtain, one will decrease the rate of suicide. One will just change the drug or means used. All one has to do is to compare the method of suicide in different areas of the country to realize that access to drugs would make little difference in the suicide rate. In the latest data from our office, propoxyphene accounts for nine deaths; six of these were determined to be due to suicidal ingestion. Along with your letter was a copy of a letter to Joseph Califano, Secretary of HEW. This was apparently a public letter, released on Tuesday, November 21, 1978. I think your cause might be taken more seriously if in this letter you had not included date which is incorrect. On Page 3, Table 2, you list the "DPX-related deaths" from 7/73 to 12/77. I am afraid that I cannot believe any of the figures in that Table. The reason I don't is that for Dallas you indicate that there were eighty such deaths in that time period. I would like to inform you that from January 1, 1973 to December 1977, in Dallas, there was a total of only thirty deaths due to propoxyphene. An additional twenty-five individuals, dying of a combination of multiple drugs, also had propoxyphene detected in their blood. If you inclpde both, then the maximum number of cases would be sixty-five, rather than eighty. In fact, in a number of the C~jX~~ drug deaths", the propoxyphene was present only in small therapeutic amounts and was only incidental. PAGENO="0451" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17003 Part of the `epidemic" of propoxyphene deaths being reported is that until fairly recently, many toxicology labs were deficient in their ability to detect propoxyphene. Therefore, such deaths were being missed for many years. Some of such cases, in which the propoxyphene was taken intravenously, were considered morphine deaths. I am afraid that I also doubt your contention in Page 2 of your letter to Mr. Califano that propoxyphenewas associated with more deaths than heroin-morphine in the first half of 1977. While methods of detection of propoxyphene are now readily available and used by toxicology labs, many of these labs are unable to detect morphine in the blood, thus they will miss rapid deaths from either morphine or heroin injections. If so, and some propoxyphene is found, it is possible that they may attribute such deaths to propoxyphene, rather than to morphine. Thank you. Sincerely yours Vincen J.M. DiMaio, M.D. VJMD/aw cc/Joseph Califano PAGENO="0452" 17004 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY APPENDIX STATEMENT OF HON. JOSEPH A. CALIFANO, JR., SECRETARY OF HEALTH, EDUCATION, AND WELFARE I am announcing today Several actions to alert the public to the risks associ- ated with Darvon, and to consider what further steps HEW should take to pro- tect the public. Darvon-a pain reliever which is also sold under other trade names such as Darvon Compound and Darvocet-N, and under its scientific name, propoxy- phene-is the third most frequently described brand name drug in this na- tion. Last year, 31 million outpatient prescriptions were written for propoxy- phene products. Propoxyphene is generally not dangerous when taken as di- rected; yet it is known to be a dangerous drug in a number of circumstances. Propoxyphene is now second to barbiturates as the prescription drug most often associated with suicides. Propoxyphene has also been a cause of accidental deaths, usually when used along with alcohol or tranquilizers. Propoxyphene is also an addictive drug, though less so than heroin or mor- phine, and it is often abused. For all these reasons-suicides, accidental deaths, and potential for addic- tion-propoxyphene is a drug which has raised serious concerns. In November 21, 1978, the Health Research Group petitioned me to declare propoxyphene an imminent hazard to health under the Food, Drug, and Cosmetic Act, and to remove the drug immediately from the market. Alternatively, they asked me to recommend to the Attorney General that propoxyphene be shifted from Schedule IV to Schedule II of the Controlled Substances Act, an action which would restrict production and sale of the drug in various ways. On the basis of the limited evidence now available, I do not believe that there is sufficient justification for the extraordinary step of declaring propoxyphene an imminent hazard and immediately removing it from the market without the opportunity for a hearing. Accordingly, I am denying the Health Research Group's petition at this time. However, the current evidence is sufficient to conclude that propoxyphene should be prescribed and taken only with extreme care: (a) Doctors and dentists should not prescribe Darvon or other forms of pro- poxyphene to people who may be suicidal or addiction prone. (b) Doctors and dentists should warn patients that Darvon and other forms of propoxyphene can be lethal if taken to excess, or if taken along with alcohol of tranquilizers. (c) Pharmacists should be cautious in filling prescriptions for Darvon and other forms of propoxyphene where there is reason to suspect abuse, or where the patient is taking other drugs which may present risks when combined with this drug. Pharmacists should also warn people orally and on prescription labels not to take the drug with alcohol or tranquilizers. (d) People who do choose to take propoxyphene should be careful not to take it with alcohol or tranquilizers. These are precautions which health professionals and the public can take on their own to limit the risks from propoxyphene. Although I believe the current evidence does not warrant a finding of imminent hazard at this time, I also believe that this evidence compels us to inform the public promptly of the risks involved. and to evaluate further the dangers of propoxyphene. Therefore, based on the recommendations of FDA Commissioner Donald Ken- nedy and of the Surgeon General, Dr. Julius Richmond, I am today directing the Commissioner of the Food and Drug Administration (FDA) and the Surgeon General to take the following actions: First, within 30 days, to distribute to one million doctors, dentists. pharmacists and other health professionals throughout the country a special Drug Bulletin which will warn of the risks of taking propoxyphene, and urge them to talk with patients about these risks. FDA will also disseminate information on propoxy- phene to the public, by means of an article in the FDA Consumer magazine, and through public service announcements in the media. Second, on April 6, to hold a hearing to allow the public an opportunity to comment on the need for additional FDA regulatory action on propoxyphene, including withdrawing it from the market. The hearing will consider the ways PAGENO="0453" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17005 in which propoxyphene is used, its effectiveness, and its risks. In addition, the FDA will conduct a comprehensive study of the scientific data of propoxyphene, including the evidence and testimony taken recently by Senator Gaylord Nelson's Senate subcommittee. While I am denying the imminent hazard petition at this time, I have directed Commissioner Kennedy to notify me immediately if, at any time during the course of the public hearings and study of the data, evidence develops which may warrant the declaration of an imminent hazard. Third, by June 1, to complete the administrative process, including delibera- tions by an advisory committee, and prepare a recommendation to the Justice Department on whether propoxyphene should be placed under more stringent controls as provided in the Controlled Substances Act. Propoxyptiene is cur- rently subject to Schedule IV, which places no limits on production, allows prescriptions to be filled merely by a telephone call by the doctor to the druggist, and permits up to five refills every six months. The Health Research Group has proposed that propoxyphene be transferred to Schedule II, which would place limits on the manufacture of the drug, prohibit dispensing it without a written prescription, and ban refills. Rather than summarily suspen'ding~ propoxyphene from the market, I have directed that steps be taken both to protect the public immediately from the health risks, and to conduct a more deliberate, comprehensive review of the facts concerning the drug. In the course of this review, I have asked the FDA actively to solicit the participation in the hearing of doctors, coroners, researchers, and others who have information on propoxyphene. In the case of propxyphene, these are still unresolved questions which prevent us from saying at this time that it constitutes an imminent hazard to health. But as we take the steps I have announced today, we will develop better answers to these questions, and we will consider whether propoxyphene should be removed from the market as an imminent hazard, whether its removal should be con- sidered in the ordinary administrative process, whether more stringent controls should be placed on its production and sale, and whether the warnings on the labels should be strengthened. One unresolved question is how extensive is the harm associated with Darvon and other forms of propoxyphene. In 1977, there were 607 propoxyphene-related deaths reported to the Drug Enforcement Administration's Drug Abuse Warning Network (DAWN), which covers about one-third of the United States. This was more deaths than for any other prescription drug, and that fact alone is obviously a cause for concern. However, under the DAWN reporting system, mentions of propoxyphene as related to death can mean merely that the deceased person had the drug in his or her blood, not necessarily that it was in fact the cause of death. Another unresolved question is the extent to which deaths that are asso- ciated with propoxyphene are accidental, result from abuse, or are sucides. Yet another unresolved question concerning propoxyphene is whether or not it is effective-whether it has any benefits which justify its use despite the risks which exist. Propoxyphene has been a very widely used pain reliever. Propoxyphene is occasionally sold alone, and it may have some therapeutic advantages for people who react adversely to other pain relievers. But it is far more often sold as a compound with pain relievers such as aspirin or acetaminophen. Several studies indicate that most or all of the effectiveness of these combinations is due to the elements other than propoxyphene. Neverthe- less, since pain is such a subjective symptom, some people m~ty experience. psychologically or physically, more relief from propoxyphene which is pre- scribed by a doctor than they would from over-the-counter pain relievers such as aspirin. Overall, the best evidence thus far is that propoxyphene is no more effective-and may be less effective-than aspirin, codeine, and other pain relievers. Because of these unresolved questions concerning propoxyphene and the un- certainties in the data, I have asked the Commissioner of the FDA to focus on these questions as well as others: 1. What amount of propoxyphene alone is required to produce fatalities? What is the relationship of this amount to the proper dosage? Does propoxyphene build up in the body? 2. Do deaths result when propoxyphene is taken at recommended doses, either alone or in combination with other drugs? How many of the deaths associated with propoxyphene are suicides; how many are accidents resulting from abuse; and how many are accidents resulting from normal use? PAGENO="0454" 17006 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3. How does propoxyphene cause death? Is it primarily by depressing rerpira- tion, or is there a previously unrecognized toxic effect on the heart? 4. Is there scientific evidence that propoxyphene adds significantly to the ef- fectiveness of aspirin or other pain relievers in combination products? The public hearing and FDA study will seek the best answers we can develop to these questions. Meanwhile, as the result of the actions I have announced today, the doctors and people of this country will be warned that propoxyphene should be taken only with care. U.S. DEPARTMENT OF HEALTH, EDUCATION. AND WELFARE In re Petition to Suspend Xew- Drug Applications for Propoxyphene OFFICE OF THE SECRETARY I. Issue The issue presented to me is whether, as currently labeled and distributed, propoxyphene, a drug for use in the relief of pain, should be declared an "Im- minent hazard" under section 505 (e) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 355(e), and approval of the new drug applications for the drug summarily suspended prior to the initiation of the ordinary procedures for withdrawal of approval of those applications. Thus, I must decide whether there is now sufficient evidence available showing that the continued use of propoxyphene constitutes so serious a threat to public health as to warrant an interim suspension of general distribution of the drug pending initiation and completion of the procedures to determine whether propoxyphene should be re- moved permanently from the general market. This proceeding was initiated by a petition filed by the Health Research Group (HRG), a consumer advocacy group concerned with health matters. HRG also petitioned the Department of Justice to impose new restrictions on the production and dispensing of propoxyphene under the Controlled Sub- stances Act, 21 U.S.C. 801. In its petition to me, HRG requests that, in the event I do not suspend marketing of the drug, I support the HRG petition at the Department of Justice. II. Background Propoxyphene hydrochloride, alone or in combination with aspirin, phen- acetin, and caffeine, was first approved and marketed in 1957. The most widely sold brand names of propoxyphene products are Darvon, Darvon Compound. and Darvon Compound-65, all manufactured by Eli Lilly and Company. The original approval of propoxyphene was on the basis of safety only. After the enactment of the Dirng Amendments of 1962, the efficacy of propoxyphene products was reviewed by the National Academy of Sciences/National Research Council, which concluded that the products are effective for the relief of pain. In the early 1970's, the Food and Drug Administration approved as safe and effective additional products manufactured by Eli Lilly and Company contain- ing propoxyphene: the napsylate salt of propoxyphene either alone (Darvon-N) or in combination with acetaminophen (Darvocet-N) or aspirin (Darvon-N with ASA). All propoxyphene products are "new drugs" and are subject to new drug application (NDA) requirements. In 1977, through joint activity by the Department of Health, Education, and Welfare and the Department of Justice, all products containing propoxyphen'~ were controlled under `Schedule IV of the Controlled Substances Act for the first time, because of their potential for abuse. This action limited refills on propoxyphene prescriptions, and imposed certain labeling and recordkeeping requirements on manufacturers. In 1978, FDA revised the labeling of these products to contain additional warnings on adverse reactions, particularly ad- verse interactions of propoxyphene with alcohol, tranquilizers, sedative-hyp- notics, and other central nervous system depressants; and to advise on man- agement of propoxyphene overdoses. III. History of this Petition On November 21, 1978, Sidney XI. Wolfe, M.D.. Director of HRG, petitioned me to take one of two actions: (a) "Ban immecliate~y the marketing of propoxyphene as an imminent hazard under the Food, Drug, and Cosmetic Act, 21 U.S.C. § 355(e), and make it avail- PAGENO="0455" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17007 able only as an investigational drug for treating narcotics addicts or, in the alternative, (b) "Support [the Health Research Group's] petition . . . [to the Attorney General and the Administrator of the Drug Enforcement Administration] to reschedule [propoxyphene] as a Schedule II narcotic which would impose production quotas and prohibit refills of prescriptions." Dr. Wolfe argues that propoxyphene is relatively ineffective: "[a]t present the preponderance of properly-controlled studies fail[s] to show that DPX [propoxyphene] is any more effective than aspirin and many show it to be less effective than aspirin, or, in some cases, no more effective than a placebo. It is clearly less effective than codeine." HRG also contends that propoxyphene is unsafe because its limited effectiveness is outweighed by the several hundred deaths per year that are associated with its use. These deaths are reported in the Drug Enforcement Administration's Drug Abuse Warning Network (DAWN). HRG suggests that many of~ these deaths are the result of accidents rather than suicide. Upon receiving the HRG petition, I requested FDA Commissioner Donald Ken- nedy and his scientific colleagues in the Bureau of Drugs to evaluate it and ad- vise me on the proper response. On January 17, 1979, Commissioner Kennedy forwarded to me the Bureau's detailed analysis of the use and risks of propoxy- phene, accompanied by a discussion of the options available to me and copies of the materials cited in the analysis. Additional materials were compiled by the Bureau and submitted to me on February 10,1979. On January 30, February 1, and February 5, 1979, the Senate Select Committee on Small Business held hearings on the safety and effectiveness of propoxyphene. The testimony presented at those hearings has been included in the materials submitted to me. In addition to the materials referred to herein, I have relied on an examination of the full record created with FDA's assistance. TV. Procedures and criteria for suspension of a new drug application A. The Statutory Framework The Secretary of Health, Education, and Welfare, and his delegate, the Com- missioner of Food and Drugs, are responsible for the administration of the Food, Drug, and Cosmetic Act (the "Act"). 21 U.S.C. 301; 21 CFR 5.1. The provisions of the Act require that all "new drugs" be subject to a new drug application "ap- proved" by the Secretary before they may be shipped in interstate commerce. 21 U.S.C. 505(a). To obtain approval for an NDA, a manufacturer must prove, inter alia, that such a drug is safe and effective. The burden of establishing safety and efficacy of a new drug under the condi- tions prescribed, recommended, or suggested in the proposed labeling of the drug remains at all times on the manufacturer. Whenever new evidence warrants the conclusion that an approved new drug is unsafe or ineffective, the Food and Drug Administration is required to remove the drug from the market. Section 505(e) of the Act establishes two procedures for removing an approved drug from the market: "withdrawal" and "suspension." 1. Procedures for withdrawal of approval of an NDA.-The Act requires the Commissioner to withdraw an NDA if, new evidence shows either that a drug is "unsafe for use" under the conditions for which it was approved, or that the manufacturer can no longer sustain its burden of demonstrating that the drug is safe and effective. The administrative procedure for withdrawing approval of an NDA ordinarily includes notice to the manufacturer of an opportunity for a hearing, the conduct of a full evidentiary hearing before a hearing officer, and a decision by the Commissioner based on the hearing record. This procedure usually requires at least six months, and sometimes much longer. A drug may remain on the market for years while withdrawal proceedings are underway. 2. Procedures for suspension of approval of an NDA.-The elaborate pro- cedural protections against improvident withdrawals emphasize the impor- tance of the immediate suspension provision available under section 505(e) of the Act.1 Established in 1982, this summary procedure permits the Secretary 1 Section 5O5(e~ provid'~c. in pertinent part, as follows: If the Secretary (or in his absence the officer actinc as Secretary~ finds that there is an Imminent hazard to the public health. hemay suspend the approval of such [new drug] application Immediately and give the applicant the opportunity for an expedited hearing under this subsection. * * * PAGENO="0456" 17008 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to act promptly to suspend approval of an NDA temporarily, and thereby re- move the drug from the market, if it represents an "imminent hazard" to the public health. Once having suspended approval, the Secretary must provide the manufacturer with an expedited hearing on whether the drug should be permanently removed from the market. This special authority is vested solely in the Secretary, and may not be delegated. The summary suspension procedure provides a critical procedural tool to carry out the obligation of this Department and of FDA to protect the public health and safety. Rapid action may be necessary if scientific data raise seri- ous new questions concerning the safety of the drug. If new evidence or further and more careful analysis of existing evidence indicates that a life-threatening or other serious risk is present, the summary suspension procedure allows the Secretary to end promptly, this serious risk. The summary procedure does not eliminate the need to conduct a full administrative proceeding to arrive at a final and conclusive judgment as to whether the drug should be permanently removed from the market. B. Criteria for S~uspension In my 1977 order suspending the NDA's for phenformin under the "imminent hazard" provisions of the Act, I examined at length the text of section 505 (e), the legislative history of the suspension provision, and pertinent court deci- sions. In re New Drug Applications for Phenformin, Order of the Secretary Suspending Approval, pp. 24-35 (DHEW July 15, 1977). I there concluded that the following factors should be weighed in determining whether approval of a new drug application should be suspended on the' ground that continued use of the drug will constitute an imminent hazard to the public health: 1. The severity of the harm that could be caused by the drug during the com- pletion of customary administrative proceedings to withdraw the drug from the general market. 2. The likelihood that the drug will cause such harm to users while the administrative process is being completed. 3. The risk to patients currently taking the drug that might be occasioned by the immediate removal of the drug from the market, taking into account the availability of other therapies and the steps necessary for patients to adjust to these other therapies. 4. The likelihood that, after the customary administrative process is com- pleted, the drug will be withdrawn from the general market. 5. The availability of other approaches to protect the public health. These criteria were reviewed and upheld in Forsham v. Calif ano, 442 F. Supp. 203 (D.D.C. 1977). V. Evaluation of propoa~yphene vnder the criteria for suspension In analyzing the record in this matter, I have been guided by the expert advice and opinions provided by FDA. In assessing and weighing the evidence, I have recognized that the record of a full evidentiary hearing is not before me. Under the criteria set forth in part IV above, I am not persuaded that suspen- sion of the propoxyphene NDA's should be ordered at this time. Although I am trouble by the evidence that propoxyphene carries life-threatening risks and is of limited efficacy, I believe that the standards for summary removal of a drug from the market have not been met by the evidence now before me. Therefore, I am denying for the present the ERG petition to declare propoxyphene an imminent hazard. Nevertheless, because of my concerns about propoxyphene-associated deaths, I have ordered that several steps be taken to minimize as rapidly as possible avoidable harm from the drug and to gather further information on its risks and benefits. I have directed the Commissioner to have FDA complete expeditiously a com- prehensive review of all available information concerning propoxyphene to deter- mine whether the various products containing the drug meet the safety and efficacy requirements of the Act and, thus, whether proceedings should be begun to withdraw the new drug applications for any or all of those products. In the course of this review, FDA will hold a public hearing to receive information and views on the continued marketing of propoxyphene. This hearing is scheduled for April 6, 1979. If at any time during this review evidence appears suggesting that PAGENO="0457" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17009 propoxyphene meets the criteria for suspension, FDA will immediately submit it to me. I will then consider, in light of that evidence, whether to suspend any or all of the NDA's for propoxyphene products. Three other steps, described below, will provide information to physicians, dentists, pharmacists, and the general public, in order to increase awar~ness of the risks of propoxyphene, and may result in the imposition of additional restrli- tions on the production and distribution of the drug under the Controlled Sub- stances Act. A. Severity and Likelihooclof Harm to the Public Health The principal harm from propoxyphene is death. As HRG points out, propoxy- phene is associated with a significant number of deaths. In 1077, the DAWN sys- tem reported 607 propoxyphene related deaths, more than those associated with any other prescription drug. The DAWN data provide, however, only a very rough basis for estimating the true number of deaths that may be caused by use of propoxyphene. The DAWN reports include all deaths in which prOpoxyphene is found in the bloodstream of the deceased. In some of these cases, propoxyphene, particularly in conjunction with alcohol or a tranquilizer, may have caused the death. On the other hand, if propoxyphene happened to be found in the blood of a person who died in an unrelated car accident, that case would be reported in the DAWN statistics as a propoxyphene-associated death. The DAWN statistics also do not reflect all of the deaths in the country, but include only deaths in 24 major cities, covering slightly over 30% of the total U.S. population. Thus, it is likely that additional deaths associated with propoxyphene are occurring in areas which are outside the DAWN reporting system. The absolute number of deaths must he viewed in perspective with the actual consumption of the drug. Propoxyphene is very widely used; last year, about 31 million out-patient prescriptions were filled, and additional quantities of pro- poxyphene were used in hospitals, clinics, and physicians' offices. The ratio of propoxyphene-associated deaths (i.e., the number of times the drug is mentioned in coroners' reports included within the DAWN system) to dispensed out-patient prescriptions is lower than that for the barbiturates, the non-barbiturate seda- tive-hypnotics, amitriptyline, doxepin, and pentazocine. In fact, propoxyphene now ranks 12th out of 27 drugs in ratio of drug~associated deaths to dispensed prescriptions. The reason for these deaths has long been thought to be suicide. Undoubtedly this motivation accounts for a significant proportion of the deaths. In its peti- tion, HRG contends, however, that many of the deaths are the unintended result of drug abuse. The petition appears to suggest that in a search for euphoria, or because of a dependence on the drug, a user may take an excessive dose of propoxyphene or combine the drug w-ith alcohol, narcotics, tranquilizers, seda- tive-hypnotics, or other substances that depress the central nervous system. The result can be an accidental death. It is true that most identified propoxyphene-associated deaths appear to be the result `of misuse of the drug, either in attempting suicide or in a drug abuse accident. In the report by Baselt et. al. (ref. 1), some of the cases classed as "accidental" involved such large quantities of propoxyphene that it is very likely that the drug was not being used for therapeutic purposes at the recommended dosage level. Since filing the HRG petition, Dr. Wolfe has raised the question whether many of the deaths attributed to propoxyphene are due to a cariotoxic effect of its major metabolite, norpropoxyphene~ This hypothesis, which would imply the existence of previously unidentified cases of propoxyphene-caused deaths pos- sibly occurring at therapeutic doses of the drug, deserves serious consideration during FDA's review of the drug. At present, however, there is little evidence that this mechanism is a common factor in the deaths associated with propoxy- phene. Indeed, there is no clear evidence to date demonstrating that the therapeutic use of propoxyphene, in the absence of tranquilizers or alcohol, has caused ac- cidental death. For example, although about one-third of the prescriptions for products containing propoxyphene are written for patients over age 60, these same patients experience only 8% of the deaths reported to be associated with propoxyphene. The largest incidence of deaths associated with propoxyphene products occurs among those in the 20-40 age range, who only receive about one- PAGENO="0458" 17010 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY third of the prescriptions, but experience roughly half the deaths. If propoxy- phene-associated deaths were predominantly accidental, one would expect a much higher proportion of the deaths to occur among users over 60, assuming that older users are at least as likely to have fatal accidents as younger users. The only serious health risk from propoxyphene other than the deaths de- scribed above is that the drug can cause physical dependence. Otherwise, it does not cause significant adverse reactions in many cases. Miller and Greenblatt (ref. 3 found that adverse reactions in hospitalized patients are infrequent and mild. Moreover, although the adverse reactions from propoxyphene that did occur were qualitatively similar to those from codeine and other analgesics used in the hospital setting, they occurred less frequently. Standard tolerance studies in volunteers revealed no significant difference between propoxyphene and place- bo. In contrast, Goodman and Gilman (ref. 4 state that in equianalgesic doses, propoxyphene and codeine may be expected to produce similar incidences of side effects. Thus, the principal harm posed by propoxyphene, and the basis of the HRG petition, are the deaths associated w-ith the use of the drug in suicide attempts or accidental overdosing or interactions with other nervous system depressants in drug abuse situations. B. Possible Harm From Immediate ~S'uspension of Propo~ypliene From the General Market The principal harm from immediate suspension of a drug is the loss to patients of the benefit of its therapeutic effectiveness. Therefore, to assess the harm from suspension of propoxyphene, it is necessary to evaluate the available information concerning its effectiveness. I recognize that the efficacy of analgesics is particularly difficult to assess. Pain is a subjective symptom. I am informed that although it can be quantita- tively measured for purposes of clinical trials, the conduct of such trials is com- plicated by the fact that any analgesic will have a large placebo effect, typically in the range of 30-35% of the patients. In addition, many experts believe that in the case of prescription analgesics, such as propoxyphene, the placebo effect associated with the drug is increased by the facts that the drug is prescribed by a physician after consultation w-ith the patient, that the capsules and tablets are colored rather than w-hite, and that the drug is dispensed by a pharmacist. Moreover, the overwhelming majority of prescriptions for products containing propoxyphene are for conipounds containing it in combination with another analgesic, such as aspirin or acetaminophen. These combinations are clearly effective because of these other analgesics, and propoxyphene may make an additional contribution to their efficacy. The literature on the efficacy of propoxyphene itself is mixed. HRG gives major attention to a literature review conducted by Miller et al. in 1970 (ref. 5). Miller cited 9 of 18 placebo controlled trials in which propoxyphene was found to be more effective than the placebo. Miller concluded that "[p]ropoxyphene is no more effective than aspirin or codeine and may even l)e inferior to these analgesics. . . . When aspirin does not provide adequate anal- gesia it is unlikely that propoxyphene w-ilI do so.' HRG also cites three subse- ~uent studies that found no significant difference between propoxyphene and placebo. On the other hand, a 1978 study by Sunshine et al. (ref. 6) found propoxyphene napsylate at 200 ing (twice the recommended dose) to be signifi- cantly better than placebo. The low'st dose used (50 mg) was slightly better than a placebo. The usual dose (100 mg) was not tested. In a second review of the literature in 1977, Miller (ref. 7) reported that three studies showed that propoxyphene is no more effeetive than a placebo and that five studies showed that it is as effective as (hut not more effective than) a standard analgesic. For purposes of this preliminary assessment of propoxyphene's efficacy in reaching an imminent hazard determination. I conclude that propoxyphene has some, but limited, efficacy. Thus, it is possible that there may l~e some risk to patients w-ho do not ade- quately resnond to (or. in relatively few cases canrot safely take) aspirin. acetaminophen, or other analgesics. and who w-ould l)e deprived of propoxypliene. Moreover, propoxyphene does induce some degree of physical dependence, so that suddent unavailability could lead to withdrawal symptoms for some patients. PAGENO="0459" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17011 Other patients who depend particularly on propoxyphene for relief from pain may experience some suffering as the result of the abrupt removal of the drug from the market. For these people, the most likely substitute for propoxyphene is codeine, which is widely believed to be even more addictive than propoxyphene. If presented with the sudden disappearance of propoxyphene from the market, physicians would still be reluctant to~ prescribe codeine for more than inter- mittent use, and patients would be reluctant to take it. C. Likelihood of Final Action to Withdraw the Drug front the General Market 2 The Bureau of Drugs in FDA has responsibility for initiating a withdrawal proceeding (21 CFR 314.200). but has not proposed that the NDA's for propoxy- phene be withdrawn. Possible grounds for withdrawal of these NDA's include (1) that evidence from clinical experience shows the drug to be unsafe, (2) that new evidence not available when the NDA's were approved, together with the original evidence supporting the approvals, demonstrates that the drug is no longer shown to be safe, and (3) that the new evidence, evaluated together with the evidence in the original NDA's, supports a finding that there is a lack of substantial evidence that the drug is effective. 21 U.S.C. 355(e) (1), (2), and (3). The issues concerning the safety and effectiveness of propoxyphene are diffi- cult and complex. Although the drug is associated with a large number of deaths, many of these deaths appear to be related to misuse of the drug rather than its use in accord- ance with the labeling directions. It is not clear that many of these deaths- those related to suicide attempts-would be prevented if propoxyphene were immediately removed from the market. In addition, the record currently does not contain sufficient evidence for me to make a finding of imminent hazard based on two as yet unresolved issues raised by HRG's petition: (1). The extent to which propoxyphene is dangerous, if at all, when used in accordance with the labeling; (2) The extent to which labeling restrictions are effective in controlling use of propoxyphene that may lead to death.3 On the basis of the information with respect to propoxyphene available to me at this time, I cannot conclude whether or not one or more of the new drug appli- cations is likely to be withdrawn. That determination cannot be made until the issues concerning the efficacy and safety of propoxyphene in light of all the data now available have been developed more fully. D. Potenial Alternative Means To Prevent Hazard During the period FDA is evaluating further the safety and efficacy of pro- poxyphene, three steps can be taken to protect the public health. I am concerned by the various dangers posed by propoxyphene; use in suicides, accidental deaths from the interaction of the drug with alcohol or other drugs that act on the ner- vous system, and dependence on the drugS Therefore, I am directing that these problems be addressed immediately without awaiting the final FDA decision on whether propoxyphene meets the statutory standards of safety and effectiveness. I believe that implementation of the following actions will reduce the hazards to the public health. First, the Department will promptly evaluate HRG's proposal to transfer pro- poxyphene from Schedule IV to Sclìedule II of the Controlled Substances Act. If this transfer were made, the production of propoxyphene w-ould be limited by government-detersnined quotas; all distribution of the drug would be on special order forms; and prescriptions for the drug would not be refillable and would have to be in writing (i.e., telephone prescriptions would be prohibited). The Assistant 2Because final responsibility for deciding whether the new drug applications for propoxvphene should he withdrawn is delegated to the Commissioner of Food and Drugs. I have not asked Dr. Kennedy to comment on this matter, and he has reserved Judgment unti' formal administrative procedures have developed a complete record for his review. In the phenformin case, the evidence (lid support a finding that phenformin was dangerous even if used in accordance with the labeling. In addition, the evidence shOred that phenformin was being used widely outside of the indications set out in the labeling. PAGENO="0460" 17012 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Secretary for Health, who has delegated authority to make drug scheduling rec- ommendations on behalf of the Department, will make a recommendation to the Department of Justice on propoxyphene in the near future, after consideration by FDA and its Drug Abuse Advisory Committee. Second, FDA will expeditiously prepare and distribute appropriate informa- tion for physicians, dentists, and pharmacists regarding the risks associated with the use of propoxyphene. This information will encourage physicians and dentists to reconsider the risks of and need for the drug in specific cases. It should also help deal with the problems of suicide and accidental deaths from drug interactions by making physicians and dentists more cautious in prescrib- ing the drug for patients who may be suicidal or who may be using alcohol or other drugs affecting the central nervous system. This information will also encourage pharmacists, when dispensing propoxyphene, to put on the container warnings against taking the drug in combination with tranquilizers or alcohol. Third, FDA will promptly prepare and distribute appropriate information for the general public, in the form of a published article or otherwise, regard- ing the risks associated with the use of propoxyphene. Although I believe these actions will help protect the public, I do not believe that the completion and evaluation of these actions are necessary before a de- cision on the suspension or withdrawal of the propoxyphene NDA's can be made. VI. Uonclusioiv At this time, I do not believe that there is sufficient evidence available show- ing that the continued use of propoxyphene constitutes so serious a threat to public health as to warrant the extraordinary action of summary suspension of general distribution of the drug. pending initiation and completion of the procedures to determine w-hether propoxyphene should be removed permanently from the general market. Based on the record currently before me, I am unable to declare propoxyphene an "imminent hazard." The Act carefully balances the safeguards against improvident withdrawals of NDA's and the need to protect the public health from significant risks. The suspension power vested in the Secretary should be used sparingly, when it is likely that the drug will ultimately be withdrawn from the market and im- mediate action will prevent serious harm during the pendancy of the withdrawal proceedings. The issues in the case of propoxyphene are in significant doubt. and I am not prepared to predict their outcome at this time. The fact that I am not granting the HRG petition at this time does not mean that further evidence cannot lead me to an opposite conclusion. If, in the course of FDA's further review of propoxyphene, new information is developed to show that propoxyphene meets the criteria for suspension, I will act promptly. Furthermore, the other steps that I have directed should reduce the risks that propoxyphene poses to the pub1ic health, while FDA holds its hearing to de- termine whether the drug should be removed from the market. Dated February 15, 1979. JOSEPH A. CALIFANO, Jr., Secretary of Health, Education, and Welfare. [From the New York Times, Feb. 18, 1979] A COMPANY AT WAR: How LILLY DEFENDED DARVON-MARSHALING FORCES IN "RED FLAG ALERT" (By Peter T. Kilborn) INDIANAPOLIs-In 1957, scientists of Eli Lilly & Company here introduced a painkiller that w-as safer and less addictive than the morphine and codeine that most physicians w-ere then prescribing. The generic name of the drug was propoxyphene hydrochloride, and the brand name. Darvon. In due course, it became the third most prescribed drug in the Fnited States. Then, on Nov. 21, 1978. the media relations director at Lilly, Russell Durbin, received a call from an Associated Press reporter in Washington. What, he asked, had Lilly to say about a petition to ban Darvon? Thus began a long and wrenching episode for the 103-year-old giant of the pharmaceutical industry. With insulin, the Salk nntipolio vaccine in the mid- 50's, and an ever-growing stable of antibiotics, Lilly has prided itself on doing PAGENO="0461" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17013 well for its stockholders by doing good for the sick. With what became a tor- rent of press calls, Lilly now found itself exposed to the scorching glare of public scrutiny, facing allegations that Darvon was on one hand even less ef- fective than aspirin in killing pain and on the other, more common even than h~'roin in killing people. Companies can be knocked to their knees in such confrontations: The Fire- stone Tire and Rubber Company was forced to recall its entire 500 line of radial tires last year in the face of compelling evidence that the tires were unsafe. But industry can also win now and then: Two years ago, the Food and Drug Administration ordered a ban of saccharin because it could cause cancer. Soft-drink companies, among others, argued that the risk was small in relation to the benefits of saccharin; they helped persuade Congress to order a mora- torium that remains in effect. Now here was Lilly, its brow to the barrel of a deadly serious adversary. The author of the petition was Dr. Sidney M. Wolfe, director of thern Health Research Group in Washington, a low-budget but high-impact consumer interest organization sponsored by Ralph Nader. Management considered Dr. Wolfe's assertions flawed and distorted readings of statistics on drug abuse, as well as a blatant attack on the company's integrity. Lilly's response to tile Wolfe allegations illustrates how companies have to proceed when the debate over them and their products moves `outside the com- fortable forum of the Government agencies that regulate them. The company would deal more with the question of the hazards of Darvon, than with the older, less inflammatory charges comparing it with aspirin. It would argue the case on the merits, but would also have to keep an eye on public relations. And the Lilly defense would show how two sides in such a dispute can take essentially the same information to reach entirely different conclusions. "What petition?" Mr. Durbin wondered as he fielded the reporter's call. But he got the gist of it, and he promised to get right back. He hurried from his office on the 10th floor of Lilly's meandering headquarters building to the serene, wood-layered 12th. Edgar G. Davis, vice president for corporate affairs, was standing outside his `office, ending a phone call at his secretary's desk and trying to get off to a meeting. The meeting would have to wait a moment now. "That was a red-flag alert," said Mr. Davis. He and Mr. Durbin reported the call to J. Richard Zapapas, group vice president. Mr. Zapapas in turn called Richard D. Wood, chairman and chief executive, who was out of the building attending a meeting of the Lilly Endowment, a foundation set up by heirs of the company founder, CoL Eli Lilly, who ~von his rank on the Union side in the Civil War. A committee that came to be called the Darvon Working Group would convene for the first time that afternoon, and Mr. Davis would be in charge. The bulk of Lilly's work ended last week, with completion of reams of docu- ments that make up the company's side of the case, and it has reason to be encouraged. Late last week, Joseph A. Califano Jr., Secretary of Health, Edu- cation and Welfare, denied Dr. Wolfe's call for a ban on Darvon. The debate, meanwhile, has shifted from the public arena, at least for n'ow, into the F.D.A. and the Drug Enforcement Administration, where Lilly feels it belongs. At best, however, Lilly won a draw. Mr. Califano didn't ban the drug, but he did order an intensive review that could lead to tighter restraints on its use. Darvon is still immensely profitable, and it accounted for $70 million of corporate revenues last year of $1.85 billion, putting Lilly near the top of the industry. But Darvon's heyday has passed. Sales fell to 1.17 billion pills and capsules last year from a peak of 1.57 billion in 1974, the result in part of studies showing that aspirin was often a better painkiller. Lilly's experience in defending its product on a public battleground took an enormous toll. "It becomes a gigantic P.R. war with blunt instruments," said Mr. Wood, 52, an urbane, meticulous, rather remote presence in the otherwise collegial environs of the Lilly executive suite. "It's dumb," lie said. "It's unfor- tunate. It's time-consuming. Doing this doesn't create anything. It's defensive." The effort diverted a score of Lilly executives, full time, from their normal responsil)ilities Lilly has been forced to allocate supplies of Mandol, a new antibiotic that was introduced in October, and Mr. Wood blamed the Darvon affair for stalling plans to expand production. Also delayed, he said, was the American debut of Cefaclor, an antibiotic that Lilly now sells only in Britain. Meanwhile, John bit, 53, secretary and general counsel of Lilly's pharmaceu- PAGENO="0462" 17014 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tical division, was distracted from F.D.A. negotiations seeking to define the rules governing research on recombinant DNA, the outer limit of drug industry re- search. It could offer a means of obtaining insulin from human cells, a far better source than the pancreases of swine and cattle now being used. James M. Gorrel, director of Government programs, dealt only with Darvon for two months. "The only mail I looked at," he said, "were things that were hand-carried in here and I was told, `This has something to do with Darvon.'" Typists in Lilly's Word Processing Center worked 480 hours of overtime, cranking out the documents for the Darvon defense. Two computer analysts did the equivalent of four months' work in two, reviewing Darvon data that Lilly computers spent 289 hours compiling. Over a 10-week period, the Lilly corporate jet, which normally flies one round-trip between Indianapolis and Washington a week, made eight extra trips, and Covington & Burling, Lilly's Washington law firm, committed one partner full time to the project and another half time. THE INDUSTRY'S NEMESIS The man who went after Lilly is the pharmaceutical industry's No. 1 nemesis. Dr. Wolfe helped bring about the ban, three years ago, of Red Dye No. 2, widely used in food then but found to cause cancer, and of phenformin, an oral diabetic drug that was found to hurt more people than it helped. He is a graduate of Cornell and of the Western Reserve medical school and did his residency and internship at the National Institutes of Health. He is a vigorous 41-year-old who runs the 400-meter dash for the Potomac Valley Seniors Track Club. "I've been aware for a long time that Darvon is not a very effective painkiller, and I never prescribed it to patients," said Dr. Wolfe. "Then I became aware of widespread abuse and of people dying from taking Darvon. I reviewed all the literature on Darvon-related deaths and concluded that more people were dying from Darvon than from any other drug." Dr. Wolfe actually delivered two petitions that day, both prepared by Michael Lipsett, a young lawyer now in his third year of medical school in San Diego. One went to Mr. Califano asking that the F.D.A. declare propoxyphene an im- minent hazard and ban it from the marketplace. If not that, Dr. Wolfe asked that the F.D.A. support the second petition, to the Justice Department and its Drug Enforcement Administration, urging that propoxyphene be reclassified to prohibit refills and over-the-phone prescriptions. He then delivered copies to the Washington press corps and to Senator Gay- lord Nelson, Democrat of Wisconsin, the drug companies' top political watchdog and chairman of the Senate Subcommittee on Monopoly and Anticompetitive Practices. "The object," said Dr. Wolfe, "was to get the question aired and to get people to ask what the F.D.A. was doing." Mr. Davis, 47, had been planning to take off the week between Christmas and New Year's, when Lilly shuts down. He and his wife were to go to Florida to join their three children, now at colleges in New England. Mr. Holt was planning to be in Florida as well as Dr. Robert H. Furman, 60, vice president for corporate medical affairs, had scheduled a ski week in Aspen. Now they would all stay in Indianapolis. The Davis children would come to Indianapolis, and their father would see them on Christmas Day. A STRATEGY SHAPES UP Mr. bit became Mr. Davis's executive officer on the working group. The 11 other members included Dr. Furman, Mr. Gorrel, Stephen A. Stitle, chief of the Washington office, William D. Cairns, director of public relations, Robert Luedke, director of market planning. and Charles E. Redman, director of scientific information services and one of Lilly's 450 Ph.D.'s. A strategy began to fall into place. Said Mr. Wood: `My job was to say, O.K.. here's the problem. Analyze what the petitions said. Make sure we have the proper people in the corporation paying attention to them. There's a psychology you have to put forward: We're on firm ground. We have to turn the charges around." Right from the start, there were problems. CBS News called when Mr. Durbin was upstairs alerting Mr. Davis. A correspondent, Leslie Stahl, wanted to inter- view a Lilly executive in Washington. But Mr. Stitle, a 33-year-old lawyer, was in Indianapolis that day, so Lilly lost an early round in the public relations war-a chance to air its case on network television. PAGENO="0463" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17015 The Darvon Working Group would meet every Monday at 2 p.m. and every Tuesday at 10:30 a.m. It, in turn, would report to the Darvon Policy Group, composed of Mr. Wood, Dr. Earl B. Herr, president of Lilly Research Labora- tories, Mr. Zapapas, Cornelius W. Patinga, an executive vice president, Eugene L. Step, president of the pharmaceutical division, C. Harvey Bradley Jr., the top corporate attorney, and Mr. Davis, who was the link between the two groups. The policy group, meeting every Tuesday at 8:30 a.m., would set straategy arid deadlines for the working group. In business school, such committees~ are called matrix organizations. Lilly management uses them to tackle temporary problems requiring expertise from several parts of the company. "The problem here is how do you reach out into the corporation and pull together the bits and pieces of information you need to make a solid case?" said Mr. Davis. "This was a major, unfounded threat, with implications for a product and the company," Mr. Davis said. "We knew we were right. And we knew we had to get the data to make that case." Dr. Wolfe's fatality data, the working group found, were built in part on material gathered for the Drug Enforcement Administration through the Drug Abuse Warning Network, known as DAWN. It collects medical examiners' reports on drug-related fatalities in 23 metropolitan areas. Dr. Wolfe had shown that fatalities involving propoxyphene, of which 95 percent is Lilly's Darvon, had soared 25 percent in 1977 to 590. That put it second oniy to heroin with 751, and because the network covers only big cities, where heroin use is concentrated, Dr. Wolfe figured that Darvon deaths in smaller communities pushed the Darvon toll above heroin's. He also contended that most of the deaths resulted from accidental overdoses. WHAT THE TAPE5 5HOWED "Our task,' said Mr. Luedke. "was to get the DAWN data study," the material from which the D.E.A. compiled the statistics that Dr. Wolfe used. The source was IMS America Ltd., leading experts in pharmaceutical market research and a company that both the Government and the industry consider reliable. Mr. Luedke asked IMS for the raw material, the 455,000 reports, recorded on 16-track computer tape, showing incidents of drug-related fatalities from 1974 through 1978. The tapes were then turned over to Dr. Redman, who, with a team of five analysts and statisticians, put them through the Lilly computer, updating them as Mr. Luedke obtained 1978 statistics in daily calls to IMS. The tapes did not exonerate Lilly. They showed hundreds of deaths each year from overdoses of propoxyphene. But DAWN's reports showed only the results for all of 1977, not for each quarter, and Lilly made a happy discovery: "By looking at the tapes," said Mr. Luedke, "we found most of the mentions in the first quarter, and that they then began to drop." The fall of Darvon-related deaths continued from then On, to the end of 1978. Lilly also went to Dr. Bryan S. Finkle, a toxicologist at the University of Utah, who, in an earlier study, had reported a rise in Darvon-related deaths in the early 1970's. Now he found a decline matching the Lilly analysis. He also found that most deaths resulted from massive overdoses, often in combination with alcohol or other drugs, indicating that many of the fatalities were probably suicides, not accidents. As for the heroin charge, Lilly found that in relation to the number of prescriptions filled, propoxyphene ranked way back in 11th place among all drugs as a cause of death. Lilly then wanted to see if its own warnings of the hazards of misusing Darvon had had any impact on physicians. They asked IMS to poll them. The sampling of 514 physicians showed that 88 percent were aware of warnings against the abuses of Darvon and that 91 percent considered the drug safe when used as prescribed. These developments broke in the days just before Christmas. Lilly had still not constructed an airtight case. It was clear that Darvon could at times be lethal with relatively small overdoses, as Dr. Wolfe charged, increasing the risk of acci- dental fatalities. And data from the IMS tapes still raised questions. Some medi- cal examiners don't file reports on drug-related deaths as promptly as others, so some doubt about the downward trend for 1978 remained. But time was getting short. On Friday, Dec. 29, Lilly would have to answer Dr. Wolfe's petitions in a preliminary submission to the F.D.A. and the D.E.A. The typists in the Word Processing Center began working right through the night then, cranking out the documents that the working group would assemble PAGENO="0464" 17016 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY into what came to be called the "Red Book." The company lawyer, Mr. Holt, marked the hours he worked those days in his pocket agenda. He logged 16 on one and 20 on another. THE RED BOOKS DEPART The Red Book, nearly an inch thick, was compiled and bound during the after: noon and evening the day before the deadline. At 12 :40 AM. 0cc. 29, Mr. Bolt took a box of 20 and left for the Indianapolis airport, and the books departed later that morning at 7 AM. on an American Airlines flight to Washington. Mr. Stitle met the flight and then hurried around the capital, delivering 10 copies to the F.D.A., three to the D.E.A., and a couple to Covington & Burling. By then, another shoe was falling. Mr. Stitle learned that Senator Nelson was likely to hold hearings on the Wolfe petitions. That would put the Darvon affair squarely before the public. Senator Nelson himself couldn't banish Darvon, but he could bring immense pressure on the regulators to do so, and he could certainly heat up the debate. "Originally, we thought we would have to do an analysis for the regulatory agencies involved," said Mr. Davis. "Now we had to be sure that the complex scientific view of things was communicated and developed with recognition that the data would be examined by people who were not regulators." And Dr. Furman added: "The Nelson hearings meant we would have to over- prepare. We would have to conjure up dirty questions, false accusations, mis- interpretations of things we have said." The Darvon Working Group proceeded with its final submission to the regula- tors, this one a blue book nearly 2 inches thick, but now much of the group's attention was shifting to Washington. Mr. Stitle began working hours like Mr. Bolt's. His 8-year-old son asked when daddy was coming home from vacation. Mr. Stitle didn't go on vacation but he never got home before 8-year-olds go to bed. INVITATION TO THE HEARINGS He and Mr. Davis, Dr. Furland and Raymond 0. Clutter, assistant corporate secretary and general counsel, made a trip to see the Nelson staff to brief it on their view of Darvon. "We've heard reports that you would look at this." Mr. Stitle recalled saying. "If you're going to have hearings, we want to appear." Mr. Stitle also visited other senators on the subcommittee. "These are the allegations," he told them. "These are Eli Lilly's view of the facts. Here's what Dr. Wolfe is saying. These are what we think the fallacies are." Senator Nelson wrote to Mr. Davis on Jan. 15 formally inviting Lilly to testify at the hearings. They would be held on Jan. 31, Feb. 1 (a Wednesday and Thurs- day), and on Feb. 5 (a Monday). Dr. Furman, who won a top debating award while a student at Union College in Schenectady, would speak for the company. Lilly decided. Dr. Wolfe would testify on the first day, but Lilly's turn wouldn't come until the third. That presented a problem: The press could be expected to cover the opening session, where it would report Dr. Wolfe's charges, but it would be six days before Lilly could present its side. This time, Lilly was ready. On the day that Dr. Wolfe appeared, Lilly had news releases ready giving its side of the issue, and to assure the company similar exposure on the networks, Mr. Davis stood ready to be interviewed. He made his debut on ABC, and moments later his secretary in Indianapolis received a call from a woman in Los Angeles who wanted to know if she could keep taking Darvon. Nevertheless, the hearings w'ere rough. It was clear even to Lilly that Darvon, after two decades on the market, was neither a fully effective nor entirely safe drug. "I would imagine that Darvon's days are probably numbered," observed Senator Lowell P. Weicker Jr., a Connecticut Republican and heir to the Squibb drug fortune, the panelist most sympathetic to Lilly's position. "We ourselves" said Dr. Furman, "will probably come up with a better product." PAGENO="0465" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 17017 40-224 0 - 70 - 30 PAGENO="0466" 17018 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY ELI LILLY & Co. [In millions) Year ended Net Dec. 31 Revenues income Earnings per share Quarter ended Net Revenues income Earnings per share Dividend 1978 1 $1, 852. 1 $277. 5 $3. 81 December 1978 1_ - - - $474. 4 $64. 5 $0. 89 $0.45 1977' 1,550.2 223.5 3.07 September 1978 416.1 59.8 .85 .40 1976 1,397.8 202.7 2.87 June1978 444.5 70.0 .99 .40 1975 1,267.2 184.0 2.66 March 1978 482.5 79.0 1.12 .40 1974 1, 148. 2 176. 1 2. 55 December 1977 `~ 391. 6 52. 9 . 73 . 355 Total assets, Dec. 31, 1977 $1, 752, 645, 000 Current assets 1, 203, 294, 000 Current liabilities 489, 384, 000 Stockholders equity 44, 361, 000 Stock price, Feb. 16, 1979 N.Y.S.E. consolidated close 513f Stock price, 52-week range 54-38~ Employees, Nov. 6, 1978 23, 300 `Restated. [From the New York Times, Feb. 18, 1979] THE WORLD OF DARVON Propoxyphene is a mild-to-moderate analgesic, or painkiller, that affects the central nervous system. The Darvoo1 brand of propoxyphene sold by Eli Lilly & Compaaay accounts for 95 percent of all propoxyphene sales in the United States and is available either as pure propoxyphene or mixed w-ith other analgesics. The other leading analgesics are acetasninophens, which are sold over the counter as Tylenol and Datril, and aspirin. Pharmacists fill about 18 million pre- scriptions for Darvon and Darvon compounds a year. It costs 10 to 20 tunes more than the over-the-counter analgesics. The propoxyphene molecule, w-hich Lilly discovered, is a close cousin of the methadone molecule. It is mildly addictive and can produce a euphoria. No one fully understansds the nature of pain, how analgesics subdue it or why One analgesic controls some types of pain better than another analgesic. Lilly has found that aspirin usually works better than propoxyphene in dealing w-ith inflammation. And Dr. Charles G. Moertel of the Mayo Clinic in Rochester, Minn., has show-n in tightly controlled studies than cancer patiesits realize snore pain relief from both asprin, acetaminophens. and codeine than they do from propoxyphene. But in relieving many other pains, such as those of arthritis and tooth extractions, propoxyphene ahs been found highly effective. One explanation for Darvon's effectiveness may he psychological. Because a doctor prescribes Darvon. patients may merely believe it works and, in a way, w-ill it to work. The bigger question concerning Darvon. however, is safety. Medical examiners in major cities have found traces of Darvon in the bodies of hundreds of persons believed to have died from drug overdoses. Lilly and the Food and Drug Administration say that the drug is never fatal w-hen taken in prescribed doses and w-hen not mixed with other potent drugs or alcohol. And Dr. Bryan S. Finkle. a prominent toxicologist, has pro- duced studies asserting that half the reported deaths are suicides. However, Dr. Sidney M. Wolfe, w-ho initiated the recent attack on Darvon. argues that the deaths are more likely accidental. His own studies contend .that the body stores propoxyphene longer than most drugs and that a fatal dose ~an l)e accumulated unintentionally. The F.D.A. will now explore those questiomas. The Secretary of Health, Educa- tion and Welfare, Joseph A. Califano Jr., has given the agency a June 1 deadline to decide whether to reclassify propoxyphene under the provisions of the Con- trolled Substances Act. Tw-o years ago, Darvooi was, added to Schedule IV of the act, which allow-s physicians to telephone prescriptions to pharmacies and allow-s consumers up to five refills per prescription. Dr. Wolfe wants it put in Schedule II, which w-ould prohibit both refills and telephone prescriptions. PAGENO="0467" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17019 DEPARTMENT OF DEFENSE, ASSISTANT SECRETARY OF DEFENSE, Washington~ D.C., January 22, 1979. HOn. GAYLORD NELSON, Chairman, Select Committee on Small Business, U.S. Senate, Washington, D.C. DEAR MR. CHAIRMAN: In your letter to the Secretary of Defense dated Janu- ary 8, 1979, you requested information on the usage and disposition of the drug Darvon and other preparations containing propoxyphene within the Department of Defense. We are unable to provide all of the data requested in questions 2 and 3. In instances where data are not provided, accounting records are not maintained individually by ; of drug; therefore, the retrieval of requisite information is inordinately expensive and time consuming. If the committee believes the excluded data to be absolutely necessary for its hearings, we will make every effort to assemble the additional information. However, the follow- ing is provided pursuant to your request. a. NSN 6505-00--89O-2O~24 Propoxyphene Hydrochloride, Aspirin and Phena- glycodol Capsules (Darvon-Tran), 500s was standardized in December 1964, reclassified to terminal status in January 1971 and deleted in August 1974. b. NSN 6505-00-913-7907 Propoxyphene Hydrochloride, Aspirin, Caffeine and Phenacetin Capsules (Darvon Compound-65), lOOs was standardized in Sep- tember 1965, reclassified to terminal status in March 1971 and deleted in Jiune 1971. c. NSN 6505-00-784-4976 Propoxyphene Hydrochloride, Aspirin, Caffeine and Phenacetin Capsules (Darvon Compound-65), 500s was standardized in January 1965, reclassified to terminal status in May 1971 and deleted in December 1971. ci. NSN 6505-00-958-2364 Propoxyphene Hydrochloride Capsules, USP, (Dar- von), 65 mg, 500s was standardized in January 1965 and recommended for re- classification to terminal status in~ February 1971. However, this item was not deleted since two services recommended retention. The item was retained since Propoxyphene Hydrochloride, 65 mg was never declared ineffective in a 65 mg dose and is considered by many physicians, both military and civilian, an effec- tive analgesic and alternative to Aspirin for patients unable to tolerate Aspirin, such as patients with gastrointestinal disorders, i.e. peptic ulcers. e. Any commercially available analgesic may be and probably is being pur- chased and used instead of these deleted drug products. Enclosure (1) provides a listing of all oral analgesic tablets and capsules currently standardized which are possibly betng used in place of the deleted items. f. Though not specifically requested one other Propoxyphene containing anal- gesic was also deleted. NSN 6505-00-725-6992 Propoxyphene Hydrochloride Capsules, lISP, (Darvon) 32 mg, 500s was standardized in January 1965, re- classified to terminal status in July 1970 and deleted in October 1974. g. Enclosure (2) provides a list of all drug products containing Propoxyphene currently in the Federal Supply Catalog. These products are identified by NSN, generic name and trade name. Date of standardization is also noted. h. The amount spent by DoD for preparations containing Propoxyphene for each year since fiscal year 1970 is not available. However, for fiscal year 1977 and fiscal year 1978 the amounts were $526,050 and $359,690 respectively. i. The proportions of Defense drug procurements purchased centrally and locally by the individual services are not readily available. This information is normally reported only as total medical supplies purchased from standard stock and open (local) purchase; drug purchases are not normally reported separately. Only the Navy has actual figures available on drug purchases and these are limited. For 17 Naval Regional Medical Centers, during the July-September 1978 period, 75 percent of drug purchases were from standard stock and 25 percent were from open purchase. For the Army to obtain this data would require a special report and extensive effort for Army medical activities worldwide. From the purchases reported for all medical supplies, the Air Force was able to extrapolate the drug portion and estimates 84 percent of drug purchases were from standard stock and 16 percent were from open purchase. I trust this information will satisfy your requirements. Sincerely, VERNON MC,KENZrE, Pr~noipal Deputy Assistant Secretary. Enclosure. PAGENO="0468" 17020 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ALTERNATIVE ANALGESIC TAB LETS AND CAPSULES IN THE FEDERAL SUPPLY CATALOG Generic name Trade name NSN Acetaminophen and codeine phosphate capsules, 500's Phenaphen No. 3 6505-01-041-262~ Acetaminophen and codeine phosohate tablets, 500's Tylenol No. 3 6505-00-147-834~ Acetaminophen tablets, USP, 0.325 g, 50's Tylenol 6505-O1-017-162~ Acetaminophen tablets, USP, 0.325 g, 1,000's Tylenol 6505_00_985_7301 Acetaminophen tablets, USP, 0.325 g, individually sealed, 250's Tylenol 6505-00--117-732~ Aspirin, aluminum hydroside gel, dried, and magnesium hydroxide Ascriptin 65O5-00-135-278~ Tablets, 500's. Aspirin, Caffeine, and phenacetin tablets, 1,000's Empirin Compound 6505-00-100-6245 Aspirin tablets, USP, 325 mg, 36's - 6505-01-016-2224 Axpirin tablets, USP, 0.324 g, 100's 6505-00-100-9985 Aspirin tablets, USP, 0.324 g, 1,000's, enteric csated Ecstrin 6505-00-063-5631 Aspirin tablets, USP, 0.324 g, 1,000's 6505-00-153-8750 Aspirin tablets, USP, 0.324 g, individually sealed, 100's 6505-00-118-1948 Butalbital, aspirin, caffeine, and phenacetin tablets, 30's Fiorinal 6505-00-117-8620 Butalbital, aspirin, caffeine, and phenacetin tablets, 1,000's Fisrinal 6505-00-962-4375 Butalbital, aspirin, caffeine, and phenacetin tablets, individually Fisrinal 6505-00-118-2129 sealed, 30's. Chlorzoxazone and acetaminophen tablets, 500's Parafon Forte 6505-00-764-3313 Codeine phssphate and aspirin tablets, 1,000's Ascodeeo-30 6505-00-149-0116 Codeine phosphate and asoirin tablets, individually sealed, 25's Ascodeen-30 6505-00-118-2347 Codeine sulfate tablets, NE, 30 mg, 100's 6505-00-118-2132 Codeine sulfate tablets, NF 30mg, individually sealed, 25's 6505-00-056-8056 Ethsheptazine citrate aod assirin tablets, 1,000's Zactirin 6505-00-687-7901 Ibuprofen tablets, 400 mo, 500's Motrin 6505-00-128-8035 Indomethacin capsules, NE, 25 mg 100's Indocin 6505-00-926-2154 Indomethacin capsules, NE, 25 mg, 1,000's Indocin 6505-00-931-0680 Indoniethacin capsules, NE, 25 mg, individually sealed, 100's Indocin 6505-00-118-2776 Meperidine hydrochloride tablets, USP, 50 my, 100's Demerol 6505-00-126-9375 Meperidine hydrochloride tablets, USP, 50 mg, individually sealed, 25's. Demersl 6505-00-851-6589 Naproxen tablets. 250 mg, 100's Naprosyn 6505-01-061-2198 Oxycodone hydrochloride, aspirin, caffeine, oxycodone terephthalate, Percodan 6505-01-030-9493 and phenacetio tablets, 100's. Oxycodone hydrochloride, aspirin, caffeine oxycodone terephthalate, Percordan 6505-01-030-9492 and pheoacetin tablets, 250's. Oxyphenbutazone tablets, NE, 100 mo, 1,000's~ Tandearil 6505-00-786-8747 Pentazocine hydrochloride tablets, NE, equivalent to 50 mg of peotazo- Talwin 6505-00-180-6030 doe, 100's. Pentazocine hydrochloride tablets, NE, equivalent to 50 mg of pentazo- Talwin 6505-01-008-5995 cine, individually sealed, 100's. Phenylbutazone tablets, USP, 100 mg, 100's Butazolidin 6505-00-181-7888 Phenylbutazone tablets, USP, 100 my, 1,000's Butazolidin 6505-00-181-7895 Propoxyphene hydrochloride capsules, USP, 65 mg, 500's Darvon 6505-00-958-2364 Propoxyphene hydrochloride capsules, USP, 65 mg. individually Darvon 6505-00-118-1207 sealed, 100's. Propoxyphene napsylate and acetamioophen tablets, 30's Darvocet-N 100 6505-00-111-8364 Propoxyphene napsylate and acetaminophen tablets, 500's Darvocet-N 100 6505-00-111-8359 Propxyphene napsylate and acetaminophen tablets, individually Darvocet-N 100 6500-00-111-8373 sealed, 100's. Propoxyphene napsylate and aspirin tablets, 30's Darvon.N with ASA 6505-00-083-5762 Propoxyphene napsylate and aspirin tablets, 500's Darvon.N with ASA 6505-00-212-6109 Propoxyphene napsylate tablets, NE, 100 my, 30's Darvso-N 6505-00-083-5750 Propoxyphene napsylate tablets, NF, 100 my, 500's Darvsn-N 6505-00-111-8383 Sodium salicylate tablets, NE, 0.324, gram, 1,000's 6505-00-299-8617 Solmetin sodium tablets, 200 mg, 500's Tolectin 6505-01-030-3241 PROPOXYPHENE DRUG PRODUCTS IN THE FEDERAL SUPPL Y CATALOG Date Generic name Trade name NSN standardized Propoxyphene hydrochloride capsules, USP, 65 mg Darvon 6505-00-958-2364 January 1965. 500's. Propoxyphene hydrochloride capsules, USP, 65 mg, Darvon 6505-00-118-1207 May 1973. individually sealed, 100's. Propoxyphene napsylate tablets, NE, 100 mg, 30's Darvon-N 6505-00-083-5750 February 1973. Propoxyphene napsylate tablets, NE, 100 mg, 500's._ Darvoo-N 6505-00-111-8383 July 1974. Propoxyphene napsylate and aspirin tablets, 30's Darvon-N with ASA 6505-00-083-5762 February 1973. Propoxyphene Napsylate and aspirin tablets, 500's~. - Darvon-N with ASA 6505-00-212-6109 July 1974. Propoxypheoe napsylate and acetaminophen tablets, Darvocet-N 100 6505-00-111-8359 August 1974. 500's. Propoxyphene napsylate and acetaminophen tablets, Darvocet-N 100 6505-00-111-8364 August 1974. 30's. Propoxyphene napsylate and acetaminophen tablets, Darvocet-N 100 6505-00-111-8373 August 1974. individually sealed, 100's. PAGENO="0469" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17021 CENTER FOR HUMAN ToxIcoLoGy, UNIVERSITY OF UTAH, salt Lake City, Utah, January 24, 1979. Dr. WILLIAM Q. STURNER, Medical Examiner's Office, Department of health, Provide ace, RI. DEAR BILL: This letter will formally introduce to you Dr. Yale Caplan who i~ serving as a consultant forensic toxicologist to the Center For Human Toxicology. The purpose of our joint activity is to assist the government. particularly the FDA 1)rug Abuse Advisory Committee and Senator Gaylord Nelson's Congres- sional Committee on various aspects of propoxyphemme toxicity. Time Cl-IT's assistance has been requested because of our past record in this field but unfortunately, time constraints have made it impossible for me to ful- fill their requests alone. Hence, theCHT has engaged Dr. Caplan, Dr. Garriott and Mr. Shaw for this purpose. I know of your personal concerns about tIme imivolvemnent of propoxyphene in medico-legal cases and, therefore, it seemed vital to inc that we obtain informatioll from your office and benefit from your opimous. I ask that you cooperate with I)r. Caplan and thereby assist time appropriate government offices to have before them as much authenticated data as possible concerning this drug. Thanks for your assistance. Best personal regards. Yours sincerely, BRYAN S. FINKLE, Ph. D., Director. DARVON RELATED DEATHs 1074: 131 Propoxyphene (Suicide) 1975: 1926 Propoxyphene (Suicide) 2234 Darvon, Propoxyphene (Suicide) 2367 Propoxyphene (Unclassified) 2981 Propoxyphene (Undetermined) 1976: 0058 Propoxyphene (Unclassified) 0200 Propoxyphene (Suicide) 0257 Propoxyphene (Unclassified) 0330 Propoxypliene (Suicide) 0589 Darvon (Suicide) 1033 Propoxyphene (Natural) 1172 Propoxyphene (Unclassified) 1266 Propoxyphene (Suicide) 1870 Propoxyphene (Suicide) 2046 Propoxyphene (Suicide) 2118 Propoxypheñe (Unclassified) 2303 Propoxyphene (Unclassified) 2405 Propoxyphene, Darvon (Suicide) 2496 Propoxyphene (Unclassified) 3185 Propoxyphene (Unclassified) 1977: 0191 Nor-propoxyphene (Suicide) 0307 Nor-propoxyphene (Unclassified) 0440 Propoxyphene (Suicide) 0564: Nor-propoxyphene (Accident) 0738 Propoxyphene (Suicide) 1403 Nor-propoxyphene (Accident 1406 Propoxyphene (Suicide) 1534 Nor-propoxyphene (Homicide) 1641 Nor-propoxyphene (Natural) 1701 Propoxyphene (Accident) 1783 Propoxyphene (Accident) 1892 Propoxyphene (Unclassified) 2168 Propoxyphene (Suicide) 2182 Propoxyphene (Suicide) 2412 Propoxyphene (Suicide) 2595 Propoxyphene (Suicide) 3182 Propoxyphene (Suicide) PAGENO="0470" 17022 COMPETITIVE PROBLEMS IN THE DRUG TNDUSTRY 1978: 0012 Propoxyphene (Suicide) 0500 Propoxyphene (Suicide) 0819 Propoxyphene (Accident) 1028 Propoxyphene (Unclassified) 1349 Propoxyphene (Suicide) 1596 Nor-propoxyphene (Natural) 2046 Propoxyphene (Unclassified) 3023 Propoxyphene (Suicide) 3461 Nor-propoxyphene (Natural) 1974: 1 Suicide. 1975: (4) 2 Suicides; 1 Unclassified; 1 Undetermined. 1976: (15) 1 Natural; 7 Suicides; 7 Unclassified. 1977: (17) 4 Accidents; 1 Homicide (GSW) 1 Natural; 9 Suicides; 2 Un- classified. 1978: (9) 1 Accident; 2 Naturals; 4 Suicides; 2 Unclassified. Total number of deaths in a 5-year period is 46. PAGENO="0471" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17023 ide ~ 8h~'1? ( ~ P~CcI'~,c ( D~C/b~'7~ 4~7~)~'~ ~ ~i' -. 9r. ~! ~ ~ $~i~CP ~ / j7,1~7t~ 3i/~c,ey~ / ~, ,q ~, / 7~ (Pt yL~A-~~ ~ (~i~ 9Y~i~y~ Pn'~'3~~~L V /~ 1 A~2:~ ~ ~ FH#~~'- £?~,;3/7~qL ~ ~ fxp~,t~ U 1111 BLOOi~ o~3~2~3~i. f~~Po~ ~ ~ PH,-~-e~'34sr/3 VJ~/-~-~ O~t~~4-~.; ~/~O,'/1~ ~ (1,L.4,~7'~t- -~ .- . 8'.~ ~ ~`~OI'~~ - ... ~i1/fC~ QS'fl"7/'- T'~'~"~ .P1/c,~'7'~- - - f~coo . * i,~27' *PX~/'~ (j/~/~L~ ii `(a~c~) *g-s~~~~ .~ L~s~,) ~ j~/~,-E/~ /8'3~J4 Xipi~y /,~c~r:~( C: C7~ E7C~ /~; 2C5~75& /le 2Z3jf-7c tiE ~3~7 -73~ ~fl~3'?O-7~ //E ~29F/-?5 `1- 3 t/-7.5~~ ,lEco5g-7c PAGENO="0472" 17024 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~&Oc1J ~ f~21~ Id.o1I-4~'~. ~ LI ,~ /A-~ ~ ~ c'1 e~-i~J (~, ía P,/~ e~s1-~f~ Sc. ~zo4~L (e. ~«= )~fle~ ~ ~ ~ ~LCC~) ~ fRoro~ 1.1 ~ ~P~X jc .3 -~ 1~/z,,t'~ ~ci34x'~3 I4~-~Ed~ ~(/.&~mr't~ f',oro»=~. (2 2 ~ ~ A- ~ PI~ ~-`~( $c i~oiJ ~3I&L~ f~'~7'~-r~ ~ (~ ~ /-`~1~ f~eo(o~L. J3~côD ~O~j'; ~r~CPCX O~/O~i~~". /-C~4C/'~ç O, `/ /`/O('d.JL VIZIA-E ~9.3V,~p'o /.`DA'P~b?d)( !-~ W1~,'~ c~/5T.-,7 A-~i? fl/l6P~y Sc. Po& - //7C rn- `-j13--)f9 /?t~ ~2CC'7(~' 1,'1r2f75~ 1-1E O~5-7~j~. flE &:33o--7~~ /7~~,o5-7i~ fl& /~233-7i~ flLobb I. ~ ~ a- L/ ~ p~ op~~ç 3 i~5-~ MoPox PAGENO="0473" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17025 ne//72-2~. ~1~bOD ~ / ~ ~`i~&/~ ~3. g4' ~ P~oe~x ~ ~ ,t?R (-`~(oP~'K Cci,q~&P~XJP~. .. Z-j~i~i~ ~ /`RoPo~ - .~ - - ~:Ai. ~ Pxorc,~ . ~-.. ~RD//)2EPiXJPE~ flvS . / £~ ~ ~ ~`I? f,~i' "J~'~-~~c . . . ~a1~i~ P~P~ I ~ ~p,~ipcx ~3LCOD f/3'~'~~'~ f.jZc~POY J'~7 ~9 ~ ,~j -~, r/z~c~'% u'~/4 )E 1j-. ~ .-~ /- e e ~ (1.53 ~ Ljt~E/~ ~ ~` ~ 1-~ E/~"°~ - ~ o ~ fi-~Pc~ . - ... - (c. ~ ~ ~- 0? ~ 1011 fl~f7.~5-~~ . !.~OO .10.lS in~.j'.. ~ . - -. f'f ~ ,~ loll . . t,,qii1I~ ~ ~ .~ - f/~/~ ~ L-It.LM ~ - ,`-t-,~ p~po~- ~ .~&~`) JIo~i>n~o It `~-" ~j) *~ ~ ci'c>:~ P2~oo1, ~ l-O'~,'I"/'~, (~;,~5 1~1~ -~ f',q ~`P~Y t-' /? i~- `~ -~ ,`. ,~ ~ ~ ~i'~x (~ qo,-n~~ ~ th- (~JO-?5~, - ~714~r3 7'X~ i (* ii-? ~ /7c~' /2E /82~- 7~ i5--4~~- 76J) t_.c PAGENO="0474" 17026 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I~'#' ~ fY1./f2.7~7 /76~ 2b~&?(~. ~Li~oV 10,~3&,me `~ )~Qc/'~ t_ - OX ~ ~ 0 /2~-1c~ /1E2//f~,~- J3L COD - (.(DPOY ~ ~ ~ j'i1~o(a~ ~ 7~57Yiz.~'~. /ai'P~ç J~ /C~f~ l~,ic-~ - - - -- s' . (~ ~i) ," - (t'. oz~ ~-n~ ~ 6',c ~P~' Y -,~. 1qi~717 ,`je 2/~~9-7~, ~1aao .~ o,oq ~`. ( 7,'(/1 c~ 4',7,P7y~ )/i~ - (`~,6q,~1~-'~, ~P,~poy L'X/~~-E t"~i& I? ~.. p~ /i -/3-1~7 Z3O3~Th T~LO0D ~ ~ i?Pit~'Cy i~ ,~-i~- ~ ~ p/I .-,R,1 ~-/t~ ~ ~ey~&~ - U~P/Aj~ tc~ i'~~Pox / ~. c-c -~ ~ ~ ~i' ,~`. ~ ? LivEt~ ~ ( o ~ /`.4~ f"-~ C ~7 #C~ ~ --- ~ ~ ~`_3~ .`-C/' P~~7'~cV g ~ ~t1- 2C I-7t~7 /1t~' `CY-7c, - J~LceD ~33,-i~---~ ~c rC.c~-~-~ 10/cjicy ..--~ ~ ,-c/~,(c#',V gs.'~ -~--~-(- ``~~ I ~- QD~~,'z~~- - Lc~~c~,~-e--t- (i-ii~) - rc.oi~-~-~- pc/I~'~( - LI~r~Ii~ - ~_ i3. - - -- ~- ---~-~`~T -Pici'ox PAGENO="0475" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17027 T~ 2i~-? ~7 flE ZY~-7c- ~ ~ L17,c~~1' A,~iP' X (C, I 3 `.. /I~: t,'~e/ - - - - 1~ti /3iCtO JY.1~ j-~/~PtY (_(j ."~ ,~) 1/ ~ - - ~ ~ UE/bL ,i ~ `~ L 6,/,6-~~1 " - - P~'~" -- -. &/L1E/~ ~ `~ ~ i~ - `~`~`~ i-: 7~3 .,`.. J I'/I1'~>' 3~. C- O.t:$~.~ Jif J~'tPiy ~ ei1i'/I"~'~ -- ~ i~",'e-y - - - - ~ J ~,Y~-.in ,61~,,~'I/~:y L ~. *~?~ /t."Pf//" (7 1~ ii 1.-~ /7-3 ~3-?c- 2 `7~ .`.5~--7c /3 1~'~2 ) 7~7lC~: 7,1ñZJ'--Z~ C,&,~'~'~- ~ ( ~ /~/,,A~?5 ç C'/~7~;ç~ j~~C/" Y J ~ ,(f,'~1PC1 I ~ / V. -~ -~ ~ 717 ~i? 6 C,~'3"- C' t,O,31 .-i~) * ~ ~/~CI~C~ ~7ff1c/'-C~L __j~)~ ~ ~ -*.---.. - (~;.&~/.-~--`~ /`~(~pcy - -~-~- - ~i2-7h~, flE ~,g.r- ~. - - *~_***;3~ç~i) - -? i- ~ 6 ) ~ -` - - ~ C/1~ ~`/3 -1 -~-~--~--- ~ .Jj~R-1f jt'~S~i ~ 1'/,I6PCY - - ~/C~' 4/1:~g~ . - *L'~'-;'~. ~ -- -- 1,1, ~ ` 5c. i--..é.~ 6-,,f.66~-,~tc,~/AC,~k .. -- I 1.5C-6~4 "~`~ L ~ ~ ~ - PAGENO="0476" 17028 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY t~A~ ~ e,~/z.i. iL~f!L.j~.~ ~ 2~ - (~c. ~ ~ 1-~r~ ~7~7~Y' .-.... ~ ~ c'? -`-j rc.pc~-~~~-: /~Cc7.~( ~ ~ 1<1,2 c.X2.~7~,6,-/~'~ ~ -~6 - (`i.7~~-.-~ j9AC~CY Ct 0 i,3-,-~ ~ - (C.~.- ~`~` t.(L~~ ~ ~ g~j(,1~2f ~ 1A'C L L £` 9/~ * /- (76 ~ ~ C'~ C.~ ~;-~ / ~.` i~Cü ~-`~ ~C 2.26 ~ 76k) L',,,_~ O-f~~ ~` -- ~ 1e~'f~6/~'/ - ~ ~ (` ~.C&, ~ `~/`,(tP ~7 11 `/~`-1C7 C~1~/.77 /i~ I~-02~? /y~ £f~/t1-)7 ~`~- Cr~-y-~i ~ 7~7 /&~7ct~j7 Tfl~52tF.7t~7 £~732-7-7 13t c-cc l.)/~ J':L- ?z- ~~-7'7 ~_I1- 7/,.-?t;' - --- ~ ~ ~6f2y -- ~`ti(~C14J) O,a/4~~t~p~y - ~ --- - ME ,/4/~~~:77 *~ .__ - 8~'tv 6i9,4~;~%-IxfA-6/cY ~***O~~*~,y 76,71/42t17212 /)~ /~~`J77 1~_~~; 0: C~ .~; - if PAGENO="0477" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17029 Ô/:~4I(~ ~A/'src.~ - c~ t~ ,-~ ,L~ ~, ~ ~ *~ *~. - -- - - ~ / 3 -~, ~ ~ - .------- - -~ ~ ~ 33 ~ 57 ///~PL ~ ~ ~ tf7f/(//C~~Y~"- 5 ~ -1 ~ /~3'~f~ ~ ~ e.7 ~ 5 /~ . - - - ~ 7i/s'~ `;/S-i L - - - - ~ ~~~/`As'~) ( ~ -,`~-i( - 1'*. /~ ,~ `~ ,~ S - I ~ ~ ~_ (:7-3 ~ - `1 ~5 ,i~--(-D / 4-,. l-Lt c_-I','- )~ ~/~/ ,~ & C L' i( ii ~ .7.,,.- ?i~-x7 /,`~ /C(.,-~~ 7/~7.~ic1(7(.7 *~~7e~ /(5//.7~ 7-/~~.~~.77f fl5,)6,.7~ t-'~ -2~i-7 7V ,`ic /71~j? f~j~.:3J77~ /~`/7-?) L!1~ 127:.271. /1a92/éI?-77 t-,3)-?7~ t/1--2i~ 37 - - -~ C /~tX3'4tç"!Y C!IY/~57&(C 5. ~ `,.-7.Z.~ (:4 1,~~ f-~ ~ -- - -~ -- 15'~C(: P,/E~~7f- 9-~)_~ ~ LILE~ - (~.21;Z,~~ ~,"~&`~Y'5Y J~! (~D *.. ~ ~.~i//~-'~ r'1~35-~)i `~,O/~ -. 1X/Lc ~ ,C-r5/-?ePtY - - .-( &.7~~)3 /5/fl5)~ - - - ,.~.-I.L.P,41 ~?~: * S (?~) (~74/1/~7~~. /2~(/7~)' ~ ~ r/~oPc~ ~ ,,~`I~~-)/ ~ - * I.?I-'(Ifj .. ~ ~ - . - * ~. ~3 ~ ~ * ~ ~ ~ ~ 1/,j ~ ~ ~ ,~-i.q ~#,2?;,~ -_ - PAGENO="0478" 17030 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY r~ C,~~'e,'cy h - 1/I I) ~ p~ôo ~ ~ ~1/C,~-1~ `/`v/7,-'";yzii-/- * - *.... ~ ~ ~C~I'~'C~'CY ~i;z/&-~7 2 f~ .1?i..C~p ~ c.~TV~'~ ~ /~~`,cP,(c/'v~ ~ ~ -., 5~ ~ - ~. p.~ ,.-`~` tR,,~ ~Jq~'J-l)~ .- J ~/7'~'~ ~ f'~ -~-~-~ i~'~;"œ- ~ ç /c~~q ,~ /-j~r~Z~f~Y `l-3,7ü 1) Ti1~T'/~V--77 ~ 1/ i~ tf-~ (a. -,~--, ~ ,~- ~_cc-~7 ~ ~ ~ q~-~ ,P~ e'?~") L1IJ"1~ -~ *~,icf /--1'~/"'P / £~~_j;, ~ `- C~.c.tT <, Ac~.?'C-~ ,L/ L/./~7 ~ ~ 3cc~ -7r /3 ~--~ ~ ~ ~ (/f7 :1 - - (?J~P~~/ev - `~ fl~ /~7~-7U - ~ )JrE~ .-;-~~; X-i~P~é' I ~~`-~- ~ ~ -1~--~, ~ - c)/~i/-i5 ~I3-2 ~t.2~i ~ -- - - ) I~.i/f-;~- /i.~ ?.~t,',v -3 ~i ri~ /I~~ - - - C. ~ ~2~'~e~' /1- !~ C. ~. /~ ** L~ .~J7,;',-, /7IJk'I5/PZ~) PAGENO="0479" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17031 (~CQ'~k~ P'~F~" ~_qf.7~'j `-IC~O-/L7F ~ tc.. ~ ..?:0~7d1t1 (c'35.-~-~~~. ~ ~ ~ * .hiv~#~:.. L,~~et ~ ~t~/~/~' ft ~ ,~ cPc~' - - * Jj',o,~r~y ~ (q.~J~-v~~,: * -. - Lt)~ ~ ~`j~ P,~1 (t)~ -* * * .8 ~ 3'7f'n-r~ P,?'I' Y (~C~'.~-r P.~i°'~ e ~ `~-~- - CO ~( -~ ~e ~P.~1(*.-"-*~ - -~ - tic W~-?~ ~ *~ ~`7~-'~ ~ -- Pc ile-4~' ,c~ * - - (2~c/te- ti~c~6~-~ ~(j~/1/~ti~&Y - o ~1~v `~ ?~`~ ~f'~ ~ ~ ~ ~ ro, i~' 414 V - - ~;~-~c -~ 4.-i.-~~- /t/'21i~~) - L ~" "~ -`~ `~` ~ ~ * - -- ~ ~ j~, ~I ~/(/ ( t~ (I~ /1 ~ / - - - * ~ ~ ~ PAGENO="0480" 17032 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ,de c( .~/~~/7f ~ ~ ~ ( o~f~*',. ~ I D/c~'7~~ ,4#*?l7.4~iF7)"J~~~ t~'" ~ 44/~yL47!= ~ ~ `~Li Cy~ ,1 ~ - - - ~r. e fi,~-~ ~~wc~.-4- $~cf J ~ / /7,v7i~13/7A,eYLM7~ / O ~ ,`9 ~ (7A~ tptyL,~ ~ ~ `7~23c~7-73 ~ (~i. ~ ~ V/CIA~'~ C ~O ~ e.~~*/74~ ~ q',~, ~ V ~ ~ ~I~coV ~ fj~.itc~ç .4 ° ~` ~` r,~',ie~ pu~,i~'-i-'--- pH~con,?iq,7t1~ ~ ~- ~ ~ aco'~ 7/1/1C~ Q1~7'~ y,(,Jt& ~,/t~-cVdA/~I7~L 1- 3 ~/-7~ `~`~ CO5~-7~ ~coo ~ pxe~P~')c O ~ 7~ - ~ 9c(3~ç) ô,~ ~T~) ~ J-~ / ~ E,~ ~ &. Cl ~ ~~ct f~; XLnf-.~y //~t,-7( PAGENO="0481" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17033 ~&ocv (o,3c.4,4~ ~L~?2~ jo,oti4'~ £i~c~d"~6 U ~ 1A'IE ~i ~ ) c'1 e 1~- ~ "vi ~ Sc. ~ (c~. ~ Piz~J'~ J7,~f~z~ L3~Jt~/~ ~ t~cC~) Ic's~/rn'~J't t'Roro)~ o ~ 7'n-~ ~`,9~- c~ji~th ~ ~ ~ 12/ ~1/,-7f~-- iif~i~t~ fr~'9r/7~r~ ~-o,c (~fei~ (g cs~1 P~n,1n~3 L4C'ê4' (/.L~~7~1',~ P,n70 ... ----* -. It. ~e ~ ~ F~ ~ C, ~ -- f3,co~, 7j~: ~ * - IRIL-b `~/./& ,,`~-A'?~3eôi'~~g . ~ ±_.. (~ Cf,pj~ `~, Li~~E~c ~,~O/W ~ ,ca fle j~-7~ t/i~ (~O-7S~, ,ie / ~ -/7-?~-7~~7 flLf7~~5'_7~. ~`7C. ./7~7~ flg/S7e2-.7~ PAGENO="0483" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17035 ~OLOO~i ~ `~ foA~~ t A-E6 - ..-~ f~#oPAolov -. JJL ~ - - ,~ IR f~~/~'A - ~ * e/'-h~ L'~~3-'~, it~~/ (~o(a~ ~ /~P~'c L~U'E#S 1~D~/5~~ -- - o~ .`n~ t~ ~,~p1'O Y - ~ a o . .~ c'. eq .~ ~ r'-~,'a~ (. 7/tA1 c~ 4,'~/7~if'7Y~ )/~ E - (`c',6q~.~1~,-'o ,1~dY * 1) /~ /1-. E ;? /6 ~- &l i? ~-#~ `~ f'i? `~`O)( f?ILOOr ~o.5q,~.,L.ei?PIz~'oY ~ e'~.- ..~` `~, Pd? z~.',?,! ~ ~ k~?1sevy~*-c~L~ trP/A.L -7?~~ Pi~Pcx / e. ~ `o Plr~ ,,`~? * * - q `~~`i:i ~ ~ 6 - - - * Ljc'Ei~ ~ i~a~ ( 0. QYC ~ /`/IL~A. IT.-'iiA-0 -, ~ -.*-...- - . *. *.~/7~9 ~ P'~POY ",3~ _r.~9~( ,e-~d'PA~rt~'.Y . .. -* . . ~ -~ /1?~ 5~ . -- J3~Zc~D 3St~-~' ~f,Qc/'c'~( ra.ci.-~ij.. ~cPc)' - ~ . ~J ~. ~- /-V.~ /~(1/tV _. -. ~3~1 ,v~-'. ~~y~47e- I ~ ~. L~t,~-~- ) - L~rE1~ -- L 13. fi.4~ LIC/.<.1 -~~- *1~1~,i~ -p, (~. ~ - - ~ ~ ci1 ~ --i~-~' ~ C - P C -j~ - - ~ * ?t:'-j~tt2&~y- - ~ ~ ~ - - * .1<112 C.Y;2,!=/f~/C~ -- g.3ç4; 0~;c6 (`i.77~. ?~CL U i /-~ ~e,~;'~2CJ'~v ~ piI'-A ~7?~;~- Ac~f(~~ ~ LiL~~< ~ #tC/C,:~O)~ 3lY~~y `~`~ ~`"~ 7li `/U~'~)C7 * ~ti- t(c ~ /-ic- (~qvf~.;)~ 1i~2Y-~7 Ai~ Cf~'-77 (.`j ,,-i 4;~;~;~ ~ (2~24.~-76i. U. /E7~~u o.CI~T~fti~' ~t1.-.~T~' 1~-~ ~c)7c~~ )7 *. . t1e,~ r- ~ ~ /~~4"i' r-~-~ ~ ~fl~:~7&'7 £?73~.77 * * * ~-/I,j~7c~j - ( ~ P~epc~ - .* * - ~ ,i;j~ t-3I'~~ *~ --. *- * **. ---- --. - ---- ~ - *O~~ f~tf~y~_ ~ ~ * . --- -.--...--- - * U~/& ~ .`o J'.t ~ ,~ ,I~/~:77 . * /3AC'C-L, 6t9./-ixf~(/cY * 71/-.i~/~' r-,~.7/i.~7 // `-~-~"7? -- ~.Lc-~-~- -- * 2~- ~ /~/~c~ PAGENO="0486" 17038 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY /.`v~- ~ Ct -2~)1~1~/~if6Y - -,-- -~ - - ~ /~(?(-~ (p.33 .~ - (`7.iv.i&-~,; /`rPcr t'/'i' L ~ r"~~'-~v c i~'.~'c~-Y i~/i~t~'c ~ ~ C/-~~ ,vz~ ,~ 71/C~~ ~ - (`~ 3-~ ~ ~- P~ci'~v - - - ~ ~ ( ~ j~'~'~~CK - `~ ~/~/ `~.`~Af~C1/'~V - - r *`-~-- L' i( ii ~ t 4-:~ A- ~ i°.Rc-pey - (3&ccp - ~ O ~ ) ~ ~#92/~'Y~.ipI~ - -* Li ~ ,0tiE,t~7/-~ ~ L/LE,~ ~ -- j._1~t1~. ~ ~ l~/I~.t~ .~t-4~jP~.) (`1. 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PAGENO="0489" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17041 THE UNIVERSITY OF KANSAS MEDICAL CENTER, COLLEGE OF HEALTH SCIENCES AND HOSPITAL, Kansas City, Kans., January 26, 1979. Senator GAYLORD NELSON, Senate Small Business Committee, Russell Senate Office Building, Washington, D.C. DEAR SENATOR NELsoN: Since I was unable to arrange for Committee time in order to present testimony concerning the future of propoxyphene, I would like to avail myself of the opportunity to submit written comments for consider- ation by the Committee and inclusion in the record of Committee proceedings. Past experience with federal hearings concerned with health matters has given me the impression that all too often the viewpoint of one interested group is missing-that of practicing physicians who are directly responsible to and for the patient. This perspective might provide information to the Committee which is not available from pharmaceutical company officers, research investi- gators or physicians who, because of lack of "real life" practice experience, must generate attitudes on the basis of something less. I suspect that considerable pressures are exerted upon committees such as yours by a wide variety of indi- viduals whose knowledge and experience is purely theoretical rather than being based on practical experience. The background for my comments includes 26 years of practice of family medicine in rural Colorado. This practice included almost the total spectrum of human health problems, ranging from being responsible for major surgery and obstetrics to caring for the multiple aches and discomforts associated with daily life. The problem of relieving pain-acute or chronic-arose daily, and over the years I have used many agents for this purpose. My choice of agent depended on the response of my patients rather than the advertised claims of the manu- facturer. Many different compounds were used and some were discarded as being ineffective or likely to produce side effects. Before writing any analgesic prescrip- tions, factors such as probable severity of pain, patient drug idiosyncracy or allergy, other medications being tñken, alcohol intake, psychic stability (es- pecially depressive conditions or addictive history) and probable duration of discomfort were all considered. This resulted in my need for a variety of anal- gesics so that each prescription could be tailored to meet the needs of the indi- vidual patients. My personal "analgesic armentarium" which worked quite effectively for me in something over a half million patient contacts is as follows: Comparative strength Agent Watch for Weakest analgesic Aspirin Allergy, Gl upset. Tylenol Teenage suicide agent. Strongest analgesic Propoxyphene compounds Alcoholism, concurrent tranquilizers. Stronger yet Codeine (~-l gr) compounds 10 percent nausea plus vomiting, constipation Strongest Meperidine (in patient) Frequent nausea plus vomiting. Morphine (in patient) Do. Each agent is valuable under certain conditions, and no one of them is satis- factory in all cases. Propoxyphene compounds fill a definite analgesic niche which OTC agents are too weak to fill. They are effective and have a low inci- dence of unpleasant side effects. Unavailal)ility of propoxyphene compounds would probably result in increased use of the more potent and addictive narcotic drugs, since the OTC agents lack sufficient pain relieving qualities to serve as a sul)Stitute. Since many patients with chronic illnesses (rheumatoid arthritis. chronic back pain, etc.) require propoxyphene compounds on a long-term basis. reasonably simple prescription access should exist. T believe that this presents minimal hazard in properly selected patients since I have never seen a major threat to life or health of a patient in this category due to accidental or purpose- foil overdose. Propoxyphene compounds are not a panacea for all patients or all pains; they do, however, provide a prescriber with effective alternatives and the ability to match the potency of the medication to the pain. My other area of concern is the ever increasing intrusion of the government into the practice of medicine with the resultant detrimental effect upon the PAGENO="0490" 17042 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY physician-patient relationship. I must echo the words of President Carter who this week in his State of the Fnion Address, commented that government regula- tion of private lives must he decreased. Such regulation is particularly disturbing when it originates with physicians who by virtue of a medical degree become instant experts on health care. Some regulation is obviously necessary when the public health and welfare are genuinely at risk, but whemi regulation of drugs is being considered, I beg for inclusion of the people w-ho use the compounds. who know from experience if they are effective and who are ultimately responsi- ble for the welfare of patients, in the policy making process. I thank the Committee for consideration of my comments and the demonstrated interest in assuring the availability of safe, effective and reasonably accessible therapeutic agents to the public. Should I be able to supply any further informa- tion, I w-ill be glad to do so. Sincerely, JAMES G. PRICE. M.D. Assoeia tc Professor. Departm en t of Fani ily Practice. Curriculum vitae enclosed. CURRICULUM VITAE-JAMES G. PRICE, M.D. Birth: 20 June 1926, Brush. Colorado, son of John H. Price, D.D.S. and Laurette Dodds Price. Married: Janet Alice McSween of Brush, Colorado. 1949: Four children. Education: Pre-Med.: University of Colorado, BA., 1948; Medical School: University of Colorado, M.D., 1951; Internship: Denver General Hospital. Denver. Colorado; Certified as Diplomate, American Board of Family Practice, 1972. Recertified, 1977. Academic Honors: Phi Delta Chi-National Chemistry Honorary. 1944; Phi Beta Kappa, 1948; Alpha Omega Alpha, 1950; Recipient, Silver and Gold Award for Outstanding Alumnus, Colorado University Alumni Association, 1975. Military: USNR, 1944-46. Local and State Medical Societies: Past President, Morgan County Medical Society; Colorado Medical Society Judicial Council-9 years; Colorado Blue Shield Advisory Committee-3 years: Colorado Academy of General Practice. President-1964, Board of Directors-7 years. National Medical Activities: American Academy of Family Physicians-Com- mission on Membership and Credentials-3 years; Vice-speaker. Congress of Delegates-1967-_65; Speaker, Congress of Delegates-_1969_72; President-elect- 1972-73; President-1973-74; Member of numerous committees of the Academy and its Board of Directors. Past Professional Activities: Advisory Board and Executive Committee, Intersociety Council for Heart Disease Resources (ICHD). Board of Directors and Chairman, University of Colorado Development. Fund, 1967-73. Author of section on small hospitals. "The Medical Staff in the Modern Hospital," McGraw Hill, 1967. Principle Speaker, 18th Annual Meeting of Directors of Cardiology, 1971. Speaker, AMA Meeting, "The Quality of Life: The Middle Years." Program Chairman. Family Health Foundation of America Conference on Primary Health Care. "A Time For Cooperative Effort." Washington. D.C., 1976. Participant, Speaker or Chairman in multiple other meetings concerning Family Practice. Associate Professor in Family Practice, TJniversity of Colorado. 1973-77. Family Physician in Private Practice. 1952-78. Current Activities: Associate Professor in Family Practice. University of Kansas Medical Center, Kansas City, Kansas, 1978. Board of Trustees, Family Health Foundation of America. Board of Directors, American Board of Family Practice. Chairman, Residency Review Committee for Family Practice, (member since 1971). PAGENO="0491" COMPETITIVE PROBLEMS, IN THE DRUG INDUSTRY 17043 Author, Nationally syndicated newspaper column: "Your Family Physician." Editorial Advisory Board, "Medical World News." Medical Editor, "AAFP Home Study Self-Assessment Program." Medical Consultant for Current health. PMA Commission on Sales Training Program. Parliamentarian for AAFP Congress of Delegates, 1977-78. President-American Board of Family Practice, 1979. FARMINGTON, CONN., January 31, 1979. Subject: Congressional action on Darvon. Mr. LOWELL WEICKER, Russell ~Senate Office Building, Washington, D.C. DEAR SENATOR WEICKER: Would you please see that a copy of this letter (in- closed) gets to the proper Congressional committee people, if you yourself are not involved in the hearing on Darvon and if possible, let me know who they are. I am strongly opposed to removing Darvon from the market or even putting it on the dangerous drug list (which would mean a visit to the doctor every time the prescription w-as filled). There is no truth to the statement of one of Ralph Nader's men that Darvon or one of its compounds is no more efficacious of relieving pain than aspirin. I have been ill and in severe pain for time last four years and if it were not for Darvocet (Darvon and tylenol combined) would have had to take a more severe analgesic which w-ould have been addictive. My husband is in 24-hours-a-day pain because of heart surgery and there is no drug 011 the market today that he could safely take except Darvon. For Mr. Nader to say that aspirin is just as good as Darvon is merely a theoretical statement by someone who has not been in pain year after year. I have noticed that after four years of imeing on Darvon, that the drug is not addictive, for when pain is not present because of my recovery, I simply forget to take the pills because they are not needed. Even if the statistics were true and not slanted in an adverse direction, limit- ing the use of Darvon does not solve the problem for those people who are in con- stant pain-it would force them to addictive medication. I assume that there are a great many in pain caused by arthritis who would present the same argument I have put forward. My SO-year-old mother is one such person and taking Darvon out of reach of people like her w-ould cause terrible hardship. I can only conclude that Mr. Nader has launched this campaign wrecklessly withoiTt giving any thought to those people who need this drug, and would have second thoughts if he were one of the tens of thousands of peple who must live with pain every day of their lives. Mr. Nader's action is a reprehensible cheap try for publicity and I believe his statistics are faulty. He should look into statistics on how much relief this drug offers safely to suffering people. Please see that my arguments against bannmg or limiting the use of Darvon are heard by the neces- sary people. My husband concurs with the thoughts of this letter and so thanking you in advance, we are: NORMAN R. TOFFOLON. SHIRLEY I. TOFFLLON. ELILILLY & CO., Indianapolis, md., January 26, 1979. Hon. GAYLORD NELSON, Chairman, select Committee on kS1maii Business. TJ.~S. genate, Washington, D.C. DEAR SENATOR NELSON: As requested in your letter of January 15, 1979 to Mr. Richard D. Wood, I am enclosing responses to items one, two, three, and four. Tn addition to the enclosed response to item one. we are still compiling more pub- lished and unpublished information, w-hich we will provide you promptly. The material supplied in response to item three is confidential commercial informa- tion which has not been publicly disclosed, and we respectfully request that the Committee preserve its confidentiality. Sincerely yours, EDGAE G. DAvIS, Vice President Corporate Affairs. PAGENO="0492" 17044 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY ELI LILLY AND Co., Indianapolis, md., January 80, 1979. Hon. GAYLORD NELSON, Chairman, Select Committee on Small Business, U.S. Senate, Washington, D.C. DEAR SENATOR NELSON: The information in this letter supplements Lilly's response to your inquiry of January 15, 1979, to Mr. Richard D. Wood. In respond- ing to your inquiry, we provided information with my letter of January 26, and indicated with respect to item 1 that we would provide additional published and unpublished information promptly. The following is an addendum to the mate- rials previously furnished in response to item 1. The initial new drug application for Darvon (propoxyphene hydrochloride), submitted in March 1957, contains information about studies of cardiac function, as a part of the general pharmacologic effects of the drug. Anesthetized dogs given continuous intravenous infusions of propoxyphene until death had no pronounced changes in their ECGs (electrocardiograms), and it was concluded that the compound produced no deleterious cardiac effects. Minor EGG changes were observed when the animals were near death. Additional cardiac studies were reported in the IND (Investigational New Drug) filings for Darvocet and the NDA for Darvon-N in 1968. In the Darvocet md, a study in anesthetized cats given 5 mg/kg I.V. showed some EGG changes; at 0.5 mg/kg these changes were not noted. In the Darvon-N NDA, a similar study in anesthetized cats given the same dose of propoxyphene I.V. revealed no signifi- cant effects on cardiac rhythm. In addition, no significant effects on cardiac rhythm were seen in the ECG's of conscious dogs given 40 mg/kg orally. Studies in progress have shown that the prolongation of the PR interval pro- duced by intravenous administration of propoxyphene hydrochloride in con- scious dogs is not blocked by the anticholinergic drug atropine or the opiate antagonist naloxone. Preliminary experiments were also initiated to explore the therapeutic potential of propoxyphene and norpropoxyphene as antidysrhythmic agents. The compounds are weakly active and no further studies are planned to explore this activity. The foregoing information completes our response to question number 1. Very truly yours, EDGAR G. DAVIS, Vice President, Corporate Affairs. RESPONSE To ITsaI No. 1 The following discussion of the pharmacology and toxicology of propoxyphene and norpropoxyphene describes the unpublished information Lilly has about studies of the cardiac effects of propoxyphene and norpropoxyphene in humans and animals. In man propoxyphene is rapidly metabolized to norpropoxyphene, the principal metabolite. Norpropoxyphene has little analgesic ("opiod") activity (1/2 to 1/40 that of propoxyphene, depending on the assay method utilized), while its local anesthetic activity is two to three times that of the parent compound. The "opioid" effects are antagonized by agents such as naloxone, whereas local anesthetic effects `are not. At certain concentrations propoxyphene and nor- propoxyphene delay cardiac conduction and diminish myocardial contractility in animals. Review of reports of human propoxyphene overdose that include cardiac or ECG findings suggests that respiratory depression, apnea, anoxia, and acidosis are primarly responsible for the cardiac and ECG abnormalities observed. It is suggested that more attention he paid to the correction of acidosis in the management of propoxyphene overdose. Serial ECG tracings in subjects on large doses of propoxyphene in a heroin-detoxification program, and 24-hour Holter monitoring of the EGG in two volunteers given propoxyphene every four hours for one week, failed to reveal any significant ECG changes. Propoxyphene is an opioid possessing a pharmacological and toxicological profile similar to the chemically related methadone. It is well absorbed orally in animals and man and rapidly metabolized by N-demethylation in the liver to norpropoxyphene, the major plasma metabolite in the dog and man. PAGENO="0493" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17045 HUMAN PHARMACOLOGY After the administration of a single dose of propoxyphene in man, plasma propo~çyphene concentrations reach peak levels around 2 hours and decrease thereafter, with a half-life of 6 to 12 hours. Peak plasma concentrations of nor- propoxyphene are noted within a half to one hour following peak propoxyphene concentrations. The half-life of norpropoxyphene is 30 to 36 hours. In human subjects given a loading dose of propoxyphene (300 mg napsylate [N] or 195 mg hydrochloride [HOl]) followed by 100 mg N or 65 mg HC1 at four- hour intervals for 31 doses (5 days), peak plasma concentrations of norpropoXy- phene between 1.0 and 1.2 micrograms/mi (with the hydrochloride) and between 0.75 and 1.0 micrograms/ml (with the napsylate) were noted at about 120 hours. Single daily doses of 125 mg norpropoxyphene administered to humans for 7 days resulted in peak plasma concentrations of norpropoxyphene of 0.2a to 0.55 micrograms/mnl and did not elicit any overt adverse effect. ANIMAL PHARMACOLOGY AND TOXICOLOGY In acute toxicity studies the oral LD50 values for propoxyphene HOl in mouse, rat, and dog are 282, 230, and 100 mg/kg, respectively, and are approximately equivalent to 35, 29, and 12 times the maximum recommended dose of 8 mg/kg! day for humans. Propoxyphene napsyl;ate in acute doses is about one-half as toxic as the hydrochloride salt, especially in dogs, due to the more gradual ab- sorption of the napsylate salt. Animals given lethal doses of propoxyphene die following clonic and tonic convulsions. - - - - Acute toxicity studies in rodents reveal that the LD50 for pro~oxyphene is lower than that for norpropoxyphene, and in the rat this difference is of the order 4 to 5 times (on a molecular basis). The acute lethality of norpropoxyphene in mice is not reduced by naloxone. Dogs tolerated large daily oral doses of either the hydrochloride or napsylate salt of propoxyphene (equivalent to 35-70 times the maximal human dose) for as long as two years. In a few dogs some fatty change, usually of slight degree. was noted in the liver. The oral administration in dogs of increasing doses of propoxyphene, begin- ning with 20 mg/kg/day and increasing to 60 mg/kg/day in 5 to 15 mg/kg incre- mnents at intervals of three to four days over a period of 17 days. resulted in maximal plasma norpropoxyphene concentrations of 16-20 microgi~ains/ml, at which time propoxyphene concentrations were 2 to 3 micrograms/mi. (It should 1)e recalled that the starting dose of, 20 mg/kg/day is 21/2times the recommended human dose.) The dogs remained ambulatory on this enormous dosage regimen, free of any evidence of circulatory~ impairment, although they lost weight due to anorexia and occasional emesis, noted usually only after the first incremental dose, along with sedation and tremor. Tissue analyses for propoxyphene and nor- propoxyphene indicated higher concentrations in pl:asma than in the following tissues: brain, heart, kidney, liver, lung. Highest concentrations of 1)0th com- pounds were observed in the liver. Slightly increased serum glutamate pyruvate transaminase and alkaline phosphatase values were observed, hut glucose, bili- ruhin, creatinine, or BUN remained unchanged. Animal studies indicate that norpropoxyphene has little analgesic ("opioid") property (1/2 to 1/~ that of propoxyphene, depending on the assay method util- ized I. while its local anesthetic properties are two to three times that of the parent compound. Opiate effects are antagonized by naloxone, nalorphine. and levallorphan. whereas local anesthetic effects are not. The toxicological effects of propoxyphene relate to its analgesic (opioid) properties, which are shared to a much lesser degree by norpropoxyphene, and are readily reversed by antagonists such as naloxone. The local anesthetic prop- erties, shared by both propoxyphene and norpropoxyphene, but to a greater extent by norpropoxyphene, lack specific antagonists. Since (1) 1)0th propoxy- phene and norpropoxyphene possess local anesthetic effects not reversible by specific antagonists and (2) in view of the higher plasma and tissue concentra- tions of norpropoxyphene attained during chronic propoxyphene administra- tion, as well as (3) the relatively long half-life of norpropoxyphene, the possible role of the local anesthetic properties of the parent compound and its principal metabolite in propoxyphene-induced toxicity merits further study. The local anesthetic effects of norpropoxyphene have been compared with standard local anesthetic agents ,such as dibucaine, cocaine, and lidocaine, by PAGENO="0494" 17046 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY measurement of inhibition of cervical-sympathetic nerve action potential ampli- tude in the rat (Nickander, R., J. Pharm. & Exper. Ther., 200:245-253, ~977). Dibucaine was the most potent local anesthetic tested, while lidocaine was the least potent. Norpropoxyphene was more potent than propoxyphene, and both were more potent than cocaine in this system. Compounds possessing local anesthetic activity also modify cardiac conduc- tion. Since electrocardiographic changes have been reported in some cases of propoxyphene overdosage in humans, the possibility arises that the local an- esthetic effect of norpropoxyphene (and propoxyphene) might contribute to the toxicity or lethality of propoxyphene overdose, by a deleterious effect on cardiac conducting tissue. The effects of propoxyphene and of norpropoxyhene on cardiac conduction have been studied in vivo and in. vitro (Holland and Steinberg, To~cicol. & Appl. Pharm., 47:161-171, 1979. Propoxyphene and norpropoxyphene, 1O~ to 1O~ molar, (0.34-34 ~ig/ml) decreased Vmax,1 action potential duration, and cellular re- fractorIness of isolated canine Purkinje fibers in vitro. Norpropoxyphene was more potent with respect to reduction of Vmax, while the shortening of the action potential duration (at 95% repolarization) was similar for both pro- poxyphene and norpropoxyphene. The decrease in the effective refractory period by either compound was approximately equivalent, and thus the ratio of ef- fective refractory period to action potential duration was essentially unaltered by either compound. Both propoxyphene and norpropoxyphene have negative inotropic and chrono- tropic effects on guinea pig atria in vitro. Atrial rate of contraction (ED~0) was slowed 50 percent by propoxyphene 3.5/1.3X10-5M (11.7/4 pg/ml) and by norpropoxyphene 5.6/lOX 10~M (18.7/5.3 pg/ml). Atrial tension development was decreased by 50% In the presence of 1.4O/O1.01X10~ (46.7/0.3 pg/ml) propoxyphene or 7.9/2.OX10~ (26.3/6.7 pg/mi) norpropoxyphene. Thus, propoxy- phene had a slightly greater negative chronotroprc effect and a lesser negativi inotropic effects. Amsterdam et al. (Clin. Res., 25 :A204. 1977) observed a decrease in tension developed in vitro by cat right ventricular papillary muscle with either pro- poxyphene or norpropoxyphene at 10~ molar (34 ~g/ml). After washout, tension was promptly restored with isoproterenol. Neither propoxyphene nor norpro- poxyphene altered the time to peak tension of the contracting muscle. Lund-Jacobson (Acta Pharmacol. & Toxicol., 42 :171178, 1978) compared the effects of infusions of equimolar doses of propoxyphene and norpropoxyphene on the EGG in conscious rabbits. Prolongation of QRS, intermitted A-V block and ventricular extrasystoles were observed during both propoxyphene aw1 norpropoxyphene infusion. The ECG changes were determined to be independent of respiratory depression and were view-ed as resembling those seen in quinidine intoxication. The QRS prolongation correlated with plasma concentrations of propoxyphene and norpropoxyphene, although direct time comparisons were not made~ The effects of propoxyphene and nornropoxyphene infusions 0.72 to 7.2 pr/kg were studied in unanesthetized dogs. (Signs of centeral nervous system toxicity appeared in all dogs receiving the 7.2 pg/kg infusion of propoxyphene.) The effects of the 7.2 pg/kg doses of propoxyphene and norpropoxyphene on the P-R interval (atrioventricular conduction time) were similar, i.e., it was increased about 35 milliseconds. Plasma propoxyphene concentrations during the infusion of 7.2 pg/kg were 3.5/0.4 pg/ml. Plasma concentrations of norpro- poxyphene were one-fourth those of propoxyphene. When the lower doses of propoxyphene were infused, heart rate diminished, while the 7.2 pg/kg dose increased the heart rate about 25 beats per minute. Norpropoxyphene at the high dose increased heart rate less markedly, that is. about 16 beats per minute. The QT~2 increased slightly with increasing doses of propoxyphene. and the QRS duration was not significantly increased. His bundle conduction, A-H arid H-V intervals, were prolonged by both pro- poxyphene and norpropoxyphene. Norpropoxyphene was significantly more potent in prolonging H-V intervals than propoxyphene. If the infusion of either propoxyphene or norproxyphene was increased beyond 7.3 pg/kg to a total of 16.3 ag/kg, second degree A-V nodal block usually appeared. 1 MaxImum rate of rise of the action potential. 2 QTc=QT interval thvide(l by (R-R interval). PAGENO="0495" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17047 CLINICAL REPORTS Since it has been suggested that the negative inotropic and dromotropic effects attributable to the local anesthetic effects of propoxyphene and norpropoxyphene may play a role, in certain cases, in the demise of individuals consuming exces- sive amounts of propoxyphene, case reports wherein cardiac abnormalities were reported in association with propoxyphene overdose are reviewed below. In 1964 McCarthy and Kennan (J.A.M.A., 187:164-165, 1964) published one of the first reports of fatal propoxyphene overdose. A 15-year-old girl took 1280 mg propoxyphene hydrochloride with suicidal intent. When she arrived at the emergency room she was comatose and cyanotic with shallow respiration. Per- sistent generalized convulsions Legan almost immediately, and succinylchohne chloride was given intravenously in an effort to relax the respiratory muscles so that artificial ventilation could be established. Cardiac arrest occurred at this point. An endotracheal tube was inserted, and artificial ventilation and external cardiac massage immediately begun. Nalorphine and levarterenol were admin- istered intravenously. Shortly thereafter blood pressure was noted at 90/40 mm Hg, pulse 120 per minute. The patient remained deeply comatose with continued convulsive seizures separated by periods of apnea. Intravenous and intramuscular diphenylhydantoin aiid intravenous paraldehyde were administered to control convulsions. Peritoneal dialysis was begun, during which a bigeminal cardiac rhythm was noted that "responded well to intravenous procaine amide hydro- chloride" (an antiarrhythmic agent with local anesthetic properties). The pa- tient's course was slowly downhill, complicated by electrolyte imbalance and in- fection, and she expired 5 days later. Autopsy revealed cerebral edema, atelectasis, focal pneumonia, pleural effusion, and necrosis of the brain. The authors ascribed the episode of cardiac arrest to the severe hypoxia. They also observed that the bigeminal rhythm was easily controlled with procaine amide and that this rhythm disturbance had been noted previously and should be considered in the management of such patients. Comment: The cardiac arrest and bigemial rhythm almost certainly were engendered by the severe anoxia and cyanosis (and the acidosis that undoubtedly developed). It would seem unlikely that the bigeminal rhythm was caused by the local anesthetic effects of propoxyphene or norpropoxyphene inasmuch as the abnormal rhythm was reported to have responded well to intravenous procaine amide, itself a local anesthetic. Qureshi (J.A.M.A., 188:470-471, 1964) reported cardiac and other findings in an 18-year-old woman who ingested 832 mg propoxyphene hydrochloride at one time in a suicidal attempt. She promptly became disoriented and had generalized convulsions followed by cyanosis, coma, and circulatory shock. At examination, heart rate was 110, and apical systolic murmur, respirations slow and shallow with cyanosis. More convulsions, coma, and deep cyanosis followed. ECG re- vealed sinus tachycardia, nonspecific ST-T changes, and QRS 0.2 seconds, sug- gestive of intraventricular conduction delay. Appropriate measures were taken to counteract ONS depression and shock, and the patient improved and was dis- charged after an uneventful course, apparently well, three days later. With clinical improvement the EGG returned to normal. Comment: In his commentary the author notes that "the cardiac findings in this case may have been due to a direct toxic effect of propoxyphene on the heart; however, the possibility that these cardiac manifestations may have been due to myocardial hypoxia associated with the respiratory depression cannot be excluded." Sigurd and Jensen (Danish Med. Bull. 18 :166-168, 1971) reported a case of propoxyphene poisoning "complicated by circulatory arrest caused by asystole followed by reversible heart pump failure." The patient was a 45-year-old man ~~ithout known heart disease who was jailed because of public drunkenness only to be discovered 91/2 hours later tO be comatose. It was determined later that he had taken a barbiturate and propoxyphene, in addition to alcohol, in an attempt to commit suicide. On admission he was cyanotic and deeply comatose. Cyanosis rapidly became ~severe, and cardiac arrest occurred; an EGG at that time revealed no cardiac electrical activity. Cardiopulmonary resuscitation measures were undertaken. including intravenous bicarbonate solution and adrenalin IV. and intracardially. The EGG then revealed widened QRS and absent P waves, rate 80 per minute, no perceptible pulse. A solution of isoprena- line in isotonic glucose was infused, and the EGG then showed less-widened PAGENO="0496" 17048 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY QRS, absent P waves, rate 150, and a "well filled pulse." The patient continued to improve slowly (BP 130/80 mm Hg on second day), but lie remained uncon- scious during the first two days, without convulsions. The ECG subsequently revealed "tall double-peaker P waves" which remained unchanged during the nine days he was on the ward. At no time were signs of myocardial iscilemla seen in the ECG and no rise occurred in serum lactate dehydrogenase. His hospital course was complicated by a psychosis and transient renal func- tional impairment in association with a mild diabetes insipidus-like syndrome possibly as a result of the anti-ADH effect of propoxyphene. (Bower et al., Proc. Soc. Exp. Biol. and Med., 120 :155-157. 1965; McCarthy and Keenan. yule sepia). Propoxyphene was detected in the urine by thin layer chromatography, and serum barbiturate was 0.3 mg% (as aprobarbitate, W.H.O.). No plasma electro- lyte data are included in the report. Comment: The patient ingested three CNS-depressant agents in attempting suicide and was not seen medically for 10 hours or more. He was comatose and cyanotic, and cardiac arrest occurred within momcnts following admission. Undoubtedly the myocardium had sustained injury during the long interval of coma and anoxia. Acidosis was treated promptly, and cardiopulmonary resuscita- tion ultimately saved his life. There were many factors, obviously, contributing to inyocardial ischemia and injury (cardiac arrest persisted 8 minutes). The role, if any, of the local anesthetic effects of propoxyphene and norpropoxyphene in the disturbance of cardinc function in this patient can only he surmised. Phe serial electrocardiograms presented in this report suggest the presence of hyperkalemia. The infusion of glucose and the intravenous bicarbonate that the patient received would have tended to improve the ECG. Any hyponatremia accompanying the mild diabetes insipidus syndrome that developed would en- hance any electrocardiographic manifestation of hyperkalemia. Gustafson and Gustafson (Acta Med. Scand., 200 :241-248, 17G) reviewed pertinent laboratory and clinical findings in eleven cases (10 patients, one of whom was admitted twice) of propoxyphene overdose observed at University hospital in Lund, Sweden. None had ingested propoxyphene alone (5 had in- gested one or more additional CNS-depressant drugs). In addition, alcohol intake was reported in six. The principal clinical findings consisted of (1) coma (six patients were in deep coma on admission, four of whom had taken tablets containing barbiturate and one a phenothiazine preparation), (2) depressed respiration, 15/minute or less, in 7 cases (two patients were apneic and severely acidotic and required a mech- anical respirator), (3) circulatory abnormalities. (4) metabolic acidosis, (5) convulsions. (The absence of any mention of cyanosis is curious in view of the presence of respiratory depression and periods of apnea.) With respect to cardiovascular function: One patient on first admission had a systolic blood pressure of 80 mm Hg. On second admission he manifested circula- tory arrest (ventricular fibrillation) associated with severe acidosis. Sinus tachy- cardia was present on admission in five patients, and in the remaining cases the heart rate was normal. The ECG revealed QRS w-idening in four patients (two Of whom had severe acidosis), and in one patient a bundle branch block was noted on admission that was present at discharge 33 hours later, suggesting the prior existence of this conduction defect. Acidosis was noted in four patients (one of whom was admitted with acidosis on two occasions). Convulsions w-ere noted in only one patient, and severe acidosis was present in this patient. The two patients with severe acidosis merit additional discussion. One was a 21-year-old man who was first admitted (case 1) comatose after excessive inges~ tion of alcohol and a propoxyphene-barbiturate-aspirin preparation. Systolic blood presure was 80 mm Hg, but there were no signs of respiratory depression. He recovered over a 20-hour period, uneventfully. However, he was adthitted again (case 5) 8 months later, again having imbided heavily and having taken 650 mg propoxyphene, 3.5 gin aspirin, and 500 mg vinbarbital. On admission he was pulseless and apneic. Defibrillation was successful, and intracardiac adre- nalin and intravenous isoprenaline were administered. At this time the ECG re- vealed widened QRS (0.14 seconds), but an hour later the ECG showed sinus rhythm and normal QRS. Mechanical respiration was continued, and a metara- minol drip established to maintain blood pressure. However, his cardiac function ceased 15 hours later. Plasma propoxyphene concentration on admission was 0.74 micrograms/mi, norpropoxyphene 0.39 micrograms/ml. PAGENO="0497" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17049 The second patient (case 7) was a 16-year-old girl who, after drinking alcohol, attempted suicide by ingesting about 4.5 grams of propoxyphene. She convulsed shortly thereafter and on admission one hour later was comatose and apueic. She was severely acidotic. Systolic blood pressure was 100 mm Hg, and the ECG revealed sinus tachycardia, widened QRS (0.12 seconds), and prominent S waves (except iii lead III). Mechanical respiration was instituted, and subsequent seizures were controlled with intravendus diazepam. She responded well to treat- ment, acidosis subsided, and the ECG was normal in six hours. She was charged after two days. Her plasma propoxyphene concentration was 0.51 micro- grams/mi; and her norpropoxyphene concentration, 0.79 micrograms/mi,- 2.5-to 3 hours after ingestion. Propoxyphene and norpropoxyphene analyses were carried out utilizing the gas chromatograph-mass spectrometer technique of Wolen (Toxicol. Appi. Pharmacol, 19 :480, 1971). Highest plasma concentrations were found in the fatal case; and the patient with the second-highest concentration, over 0.5 micro- grams/mi, had very severe symptoms. In discussing the clinical symptomatology the authors note that cardiac arrest may occur secondary to respiratory depres- sion and apnea and that QIIS widening and ventricular bigeminy have been ob- served in humans taking excessive doses of propoxyphene. Comment: The development of respiratory depression and apnea, when exces- sive propoxyphene has been ingested either alone or with CNS-depressant agents, results in severe anoxia and acidosis. While the use of a narcotic antagonist to reverse the opiate-indicated respiratory depression is of prime importance, the need to correct acidosis needs emphasis. Acidosis depresses mnyocardial contrac- tility, diminishes cardiac responsiveness to catecholamines, and predisposes to ventricular fibrillation. The importance of correcting acidosis under conditions of anoxia with acute cardiopulmonary failure cannot be overemphasized. The use of intravenous sodium bicarbonate in cardiopulmonary resuscitation is described in The Heart, J. Willis Hurst, Ed., 4th Edition, 1978, McGraw Hill, New York. FINKLE STUDY In a review of 1,022 medical examiner cases associated with propoxyphefiè overdose, Finkle et at. (J. Forensic Sci., ~21 :~06-~42, 1~76) observed a small group of cases exhibiting a common pattern of symptoms prior to death, the most striking of which was a survival time of 15 minutes or less, that is, "sudden death." He examined various toxicologic and epidemiologic aspects in 52 cases, in all of which death apparently occurred within 15 minutes (interval from time last seen alive until death) of unexplained cause or causes. Age and sex distributions differed from those observed for the total study population, inasmuch as the greatest proportioii of males was noted in the 21-25 and 46-SO age groups. Body weights were not remarkable. In 4 of the 10 cases for which there was a medical history, "a heart condition" was noted. Single instances of hypertension, asthma, epilepsy, paraplegia, ulcers, and "recent head injury" were also noted. The drug abuse histories were noteworthy in that 44% had a documented history of abusing some substance (34% for total study group). Respiratory arrest, the predominant symptom (85%), was alniost twice as fre- quent. Seizure frequencies were about the same. Coma was observed less fre- quently (15% vo. 40%), but this may be due to the brief survival. The authors concluded that "the final collapse is centrally mediated and rarely cardio- vascular." There was a very high incidence of the use of other drugs in these "sudden death" cases; 85 percent had some other drug in addition to propoxyphene, in contrast to 76 percent for all cases. In the sudden death group, 52 percent had alcohol involved, in contrast to 42 percent in thi'e total group. The other drugs, determined by case investigation or by chemical analysis, were predominantly central nervous system depressants. In 40 percent of the cases, concentrations of drug (by laboratory analysis), other than propoxyphene or alcohol, were significantly high in and of themselves. Diazepam was the most f~equent. The data indicate that alcohol and other drugs played a major role in these cases. The particular importance of alcohol in the sudden death cases is attested to by the fact that blood alcohol concentrations were predominantly associated with lower propoxyphene concentrations. In 75 p~rcent of the sudden death cases associated with alcohol, plasma propoXyi)hene concentrations were less than 2.5 micrograms/mi., whereas in the total study group 72 percent of the sudden death cases associated with alcohol had values less than 7.0 micrograms/mi. 40-224 0 - 70 - 32 PAGENO="0498" 17050 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TENNANT STUDY Propoxyphene napsylate has been evaluated by Tennant (J. Nati. Med. Assn., 66 :23-27, 1974; J.A.M.A., 232 :1019-1022, 1975) for heroin detoxification and maintenance. Under double-blind conditions, 29 adults w-ere admitted to a 180- day maintenance program. About 1/4 of the patients remained in the study more than 90 days; a few remained for as long as two years. The maximum daily dose of propoxyphene napsylate w-as 1200 mg, starting w-ith 400 mg per day. Patients who received a single dose of 000 mg reported short-term dysphoria, but other- wise no serious toxic effects w-ere noted. Electrocardiograms, chest X-ray, and electroencephalograms were evaluated before and at the third and sixth month of the study. Tile ECG tracings were reviewed by a cardiologist and no changes were observed, nor were changes observed in tile other examinations. ECG MONITORING The electrocardiographic effects of propoxyphene were observed in two male volunteers, ages 56 and 60, admitted for study to tile Lilly Clinic, Wishard Memorial Hospital, Indianapolis. Tile tw-enty-four-hour ECG w-as recorded for each subject, using Holter monitors. After a six-day control period, a single 300 mg dose of propoxyphene napsylate w-as given, and blood stainples w-ere obtained at arious intervals over tile next 48 hours. Maximum concentrations of propoxyphene and norpropoxyphene observed in these two subjects were 0.25 and 0.37 (propoxyphene) and 1.1 and 1.4 (norpropoxyphene) micrograms/mi, respectively. From day 9 through day 15 the subjects received propoxyphene napsylate 10 mg every 4 hours (i.e., 600 mg/day). Day 16 through day 25 served as the posttreatment control period. Neither subject manifested any change in P-R, QRS, or QT~ during the period of propoxyphene administration, in comparison with pretreatment or posttreatment control tracings. Ventricular premature beats were observed slightly more frequently in one subject during treatment, while a slight decrease in ectopy was noted in the other. Neither change is significant. GENERAL COMMENT Bigeminal cardiac rhythm has been described relatively frequently in cases of propoxyphene overdose, and it is of some interest to note that in the case reported by McCarthy and Keenan "a bigeminal rhythm developed l)ut it responded u-eli to intravenously administered procaine amide hydrochloride"-an antiarrhyth- mic agent with potent local anesthetic effects. Serial ECG tracings in heroin addicts on propoxyphene napsylate detoxifica- tion-maintenance programs involving large doses of propoxyphene for periods of many weeks to several months do not indicate ai~y effects on conduction or other aspects of cardiac electrophysiology. Twenty-four-hour Holter ECG monitoring of volunteers on usual therapeutic doses of propoxyphene for several days yields no indication of any effect of propoxyphene on cardiac conduction or function. The possil)iiity that norpropoxypheiie cardiotoxicity plays a role in propoxy- phene toxicity merits further study. Certainly there are measurable, although relatively minor, effects on myocardial conduction, demonstrable by in vitro and in vivo animal experiments. Reports of human toxicity that provide cardiac and electrocardiographic commentary stronrly suggest that cardiocirculatory prob- lems-such as cardiac arrest, ventricular fibrillation, and arrhythmias-arise mainly from severe anoxia. due to respiratory depression and apnea, acidosis, which may be severe, and electrolyte imbalance. Central nervous system depres- sion per ~e may directiy interfere w-ith cardiopulmonary and circulatory func- tion. The impression is gained tilat prompt correction of acidosis has not received the therapeutic attention that it merits. Management of any cardiac dysfunction ill these cases would be greatly enhanced by correction of acidosis. While the local anesthetic effects of nonpropoxyphene on cardiac conduction might assume somewhat greater significance in an individual severely toxic from drug overdose, tile major threats to adequate cardiac function in this situation remain, namely, anoxia and acidosis and. later on. electrolyte imbalance. REsPoNsE TO ITEM No. 2 Sales volume of Lilly propoxyphemie ill major population areas. and the dollar volume of sales of Lilly propoxyphene per unit of population ill tile 24 Standard Metropolitan Statistical Areas comprising the DAWN system. PAGENO="0499" COMPETITIVE PROBLEMS IN THE DRIJG INDIJSTRY 17051 Following is information relative to the sales of Lilly propoxyphene in the 24 Standard Metropolitan Statistical Areas comprosing the Dawn system which are also the major po~iulation areas in the United States. It must be understood that Lilly products including Darvon, are sold through approximately 400 service wholesale drug distributors. Lilly does not sell its products directly to community pharmacies or hospitals. The attached table reflects Lilly dollar sales of its propoxyphene to whole- ,salers located within the geographic boundaries of each of the 24 SMSA's. Since the pharmaceutical market is highly competitive, wholesalers located within a specific SMSA sell and distribute Lilly products outside the boundaries of the SMSA in which they are located. Conversely, wholesalers located outside sell and distribute Lilly products inside the SMSA. Iii addition to the movement of merchandise across SMSA boundaries in both directions, people move across these boundaries also. In our highly mobile society, some people who live within the boundaries may work and purchase goods and services outside the area and some whO live outside may work and purchase goods inside. Therefore, because of the movement of 1)0th merchandise and people in and out of the areas, the sales reflected in the tal)le should not be relied upon to be indicative of the availability or consumption of Lilly's propoxyphene within the SMSA. LILLY SALES OF PROPOXYPHENE TO WHOLESALERS LOCATED IN STANDARD METROPOLITAN STATISTICAL AREA (SMSA) [In thousandsi Sales SMSA 1977 1978 Atlanta $593 $1,791 Buffalo 548 545 Denver 943 1,078 Minneapolis-St. Paul 843 858 SanAntonio 356 396 Boston 1,216 1,448 Chicago 1,455 1,282 Dallas 731 824 Washinnton,D.C 917 1,177 Indianapolis 514 363 Cleveland 1,495 1,768 Miami Norfolk 232 249 Los Angeles 1, 716 2, 146 NewYork 2,957 2,737 Detroit 2,584 3,017 Kansas City 1,471 1,608 New Orleans 922 830 Oklahoma City 854 783 Philadelphia 1, 865 1, 721 Phoenix 461 466 San Diego 362 438 San Francisco 612 619 Seattle 290 381 RESPONSE TO ITEM No. 3 ADVERTISING AND PROMOTION EXPENSES FOR LILLY PR0P0XYPHENE (Figures deleted at request of Eli Lilly and Co.) Note: Advertising and promotional expenditures include such expenses as samples, product literature, journal advertising, direct mail, exhibits and visual aids. Company records for the information requested are no longer available for the years 1957 through 1909. RESPONSE TO ITEM No. 4 Propoxyphene was initially classified by the World Health Organizaiton (WHO), in a document actually published in March, 1950, as a dependence- producing substance (Exhibit A, pages 9 and 10 retyped) based on chemical PAGENO="0500" 17052 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY structure, pharmacologic data, and the preliminary impressions of Dr. Nathan B. Eddy (Exhibit B). Since the United States was obligated by international agreement to implement the WHO recommendation, the United States Treasury Department published February 29, 1956, a proposed rule in the Federal Register seeking to declare propoxyphene, among other drugs, an addiction-forming or an addiction-sustaining drug, similar to morphine and that it was an opiate (Exhibit C). A hearing was held May 3, 1956, by the Treasury Department, Bureau of Narcotics in which Eli Lilly and Company presented evidence which indicated there was no evidence to sustain a conclusion that propoxyphene possessed addiction-producing or addiction-sustaining qualities similar to morphine (tran- script available). The new drug application for propoxyphene was approved September 9, 1957, and marketing began in the fall of 1957. In March of 1962, the Treasury Department, Bureau of Narcotics published in the Federal Register its determination that propoxyphene was not an opiate (Exhibit D). Following this determination, the WHO in 1964 withdrew its initial evaluation on the basis of five years of experience, repeated observations of the use of propoxyphene, and the United States determination (1~xhibit E, pages 5 and 8). WHO reaffirmed that controls on propoxyphene were unnecessary in 1969 and 1970. The WHO Scientific Group reported in 1972 that dependence liability and frequently of nonmedical use of propoxyphene was low. EXHIBIT A (Note.-Exhibit A, an article entitled "Expert Committee on Drugs Liable to Produce Addiction," has been omitted because of its poor readability. Relevant parts of pages 9 and 10 have been re-typed and appear below.) WORLD HEALTH ORGANIZATION TECHNICAL REPORT SERIES No. 102-ExPERT Co~r- MITTEE ON DRUGS LIABi~ To PRODUCE ADDICTION, SIXTH REPORT, MARCH 1956 5.2.2 4-DIMETHYLAMINO-1 , ~-DIPHENYL-3-METHYL-2-PROPIONOXYBUTANE Referring to the notification of the Government of the United States of America, the Committee was of the opinion that 4-dimethylamino-1,2-diphenyl~3~methyl~2~ propionoxybutane, because it (1) will only partially suppress the abstinence phenomena of a known morphine addiction, and (2) will in part sustain a mor- phine addiction, must be considered as having no greater addiction liability than codeine, and that 4-dimethylamino-3-1,2-diphenyl~3~methyl~2~propjonoxybutane and its salts are assimilable to the drugs mentioned in Group II of the 1931 Convention. Therefore, The Expert Committee on Drugs Liable to Produce Addiction: Recommends that its opinion with respect to 4-dimethylamino-1,2-diphenyl-3~ methyl-2-propionoxybut-ane and its salts be communicated to the Secretary-Gen- eral of the United Nations. UNITED STATES NOTIFICATION WITH RESPECT TO NINE NEW SYNTHETIC DRUGS Pursuant to Paragraph 1 of Article 1 of the Protocol signed at Paris on 19 November 1948, bringing under international control drugs outside the scope of the Convention of 13 July 1931, as amended by the Protocol Signed at Lake Success on 11 December 1946, the United States Government presents a notifi- cation that the following named drugs, and their respective salts, all of which are or may be used for medical or scientific purposes and to which the Conven- tion of 13 July 1931 does not apply. are considered liable to the same kind of abuse and productive of the same kind of harmful effects as the drugs specified in Article 1. Paragraph 2, of the said Convention: Ethyl-2,2-diphenyl-4.morpliounobutyrate 4-Dimethylamino-1,2-diphenyl~3~methy1~2~propjonoxy butane l,3-Dimethyl-4-phenyl-4-propionoxyhexamethylenejmine 4-Carbethoxy-1-methyl-4-phenylhexamethyleneimine 4-Carbethoxy-1,3-dimethyl-4-phenylhexamethyleneimjne 4-Oarbmethoxy-1,2-dimethyl-4-pl-ienylhexamethyleneimjne 3-Hydroxy-N-phenethylmorphjnan 1-{2-(p-aminophenyl) -3thylJ-4-earbethoxy-4-phenylpiperjdjne 4-Carhethoxy-1- (2-hydroxy-2-phenyl-ethyl)-4-phenylpiperjdine This notification is respectfully submitted for appropriate decision as to the status of the new drugs and of their respective salts under the Convention of 13 July 1931, as amended by the Protocol of 1946. PAGENO="0501" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17053 Suggestion for an international nonproprietary name for each of the above- named drugs will be submitted at a later date. EXHIBIT B (This letter is from Mr. Anslinger, U.S. Commissioner of Narcotics to WHO. Dr. Eddy's study is attached.) There are enclosed two copies of reports on the above-named drugs (identified as Enclosures A to E respectively) submitted by Dr. Nathan B. Eddy of the Na- tional Institutes of Health, United States Public I-Iealth Service, Bethesda, Mary- land, U.S.A. H. J. ANSLINGER, U.S. Commissioner of Narcotics, Representative of the Un4ted States on the Commission on Narcotic Drugs of the United Nations. Enclosures. ADDICTION LIABILITY OF ALPHA~4~DIMETHYLAMINO4,2-DIPHENYL-3-METHYL-4- PROPIONYLOXYBUTANE (LILLY 16298, PROPOXYPHENE) A. EFFECTS OF SINGLE DOSES IN NONADDICTED PATIENTS Since this drug is very irritating, only the oral route was used. The compound was administered in single doses to 13 nontolerant former addicts in doses rang- ing betwen 50 to 400 mg. Table I shows the results of 25 trials. It is evident that this compound is fairly inert. Even the two subjects who were given a dose of 200 mg. at 8:30 a.m. followed by 400 mg. at 9:00 am., said "It is like water," although both complained of a slight headache. One subject who received 150 mg. one week and 200 mg. the following week, complained of diarrhea on both occasions. B. SUPPRESSION OF SYMPTOMS OF ABSTINENCE FROM MORPHINE Eleven subjects who had been stabilized in 240-280 mg. of morphine daily were given a total dose of 1200 mg. of No. 16298 during the first 24 hours after abrupt withdrawal of morphine. The drug was administered orally, in doses of 200 mg at intervals of four hours, except at~ night when the interval was six hours. In a similar study using the same patients, the dose was increased to a total of 2400 mg. given in divided doses of 400 mg. In a control experiment, the same subjects were given placebo capsules which resembled the No. 16298 capsules on a com- parable schedule. In a positive control experiment, nine of these 11 subjects were given morphine injections on a four-hour schedule and they were informed only that another compound was being tested. The results of this experiment with the 400 mg. dose of No. 16298 (2400 mg. in 24 hours) are illustrated in Figure 1. Intensity of abstinence was reasusred by the Himmelsbach scoring system, beginning at the 14th hour of abstinence and continuing at hourly intervals to the 24th hour. The figure illustrates that when morphine was given the score fluctuated between 3 to 8 points. When placebo injections were given instead of morphine the intensity of abstinence rose to 30 points at the end of 24 hours. When No. 16298 was ad- ministered in doses of 400 mg., every four hours, the intensity of abstinence was significantly reduced beginning with the 14th hour and continuing through the 24th hour. Two of 9 subjects to whom this dose was given showed excessive seda- tion and a depressed respiration of Cheyne-Stokes type. It was necessary to reduce the dose to 200 mg. twice for one patient and once for the other patient. Although all the other patients who received this high dosage showed depressed respiration, it did not become sufficientjy serious to warrant discontinuation of the experiment. With the 200 mg. dose (total 1200 mg.) the abstinence scores from the 14th through the 24th hour were as follows: 14, 13, 14, 15, 16, 17, 18, 20, 20, and 23. These scores are very similar to those obtained with a 400 mg. dose except at the 14, 15, and 16th hour of abstinence. With the small dose, there was no serious depression of respiration hut definDe sedative effects were present. All of the patients in whom No. 16298 was substituted stated that it was bene- ficial in that they slept more and were less nervous than they had been when no medication was given. None of them stated, however, that the effect of the com- PAGENO="0502" 17054 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY pound resembled that of a narcotic drug and none experienced a morphine-like "euphoria" at any time during substitution of No. 16298. C. SUMMARY AND CONCLUSION 1. In doses ranging up to 400 mg. orally compound No. 16298 did not induce symptoms of morphine-like "euphoria" or behavior resembling that seen after administration of morphine in nontolerant former opiate addicts. 2. In doses of 200 and 400 mg. administered at intervals of approximately four hours, compound No. 16298 significantly suppressed the intensity of abstinence from morphine. The slight difference in the degree of depression by doses of 400 mg. as compared with doses of 200 mg. suggests that this drug would be incapable of completely suppressing symptoms of abstinence from morphine. When admin- istered in repeated doses of 400 mg. during substitution tests definite sedative and, in some subjects, pronounced respiratory depressant effects were observed. 3. ConcZusio~v.-Compound No. 16298 has addiction liability, as indicated by its ability to suppress signs of abstinence from morphine. However, its overall addic- tion liability is estimated to be no greater and is probably less than that of codeine. TABLE 1.-SINGLE DOSES OF C OMPOIJND 16298 ORALLY Number oT Dose (milligrams) subjects Response 50 100 6 2 Negative. Do. 150 200 250 200 plus 400 1 5 5 5 2 Negative except 1 subject; diarrhea. 2 subjects slightly drowsy; 1 diarrhea. 1 subject slightly dizzy. Both complained of a light headache, "It is like water." . but both sold, 1 200 mg were given at 8:30 a.m. and 400 mg additional were given at 9 a.m. For practical purposes the total dose was 600 mg. PAGENO="0503" I-,,, 14 15 16 17 lB 19 20 21 22 23 24 HOURS ABSTINENT The IcUer S signifies that this poInf is st~iiSticaiIv slgnifIc~~nt as compared to a corresponding ~oint for a pl~~c~bo. EXHIBIT C-PROPOSED RULE MAKING DEPARTMENT OF THE TREASURY, BUREAU OF NARCOTICS [21 CFR Ch. 11] PIPERIDYL METHADONE, AND OTHER DRUGS NOTICE OF PROPOSED RULE MAKING Notice is hereby given, pursuant to the provisions of section 1 of the act of March 8, 1946 (60 Stat. 38; 26 U.S.C. 4731), section 4 of the Administrative Procedure Act (60 Stat. 238; 5 U.S.C. 1003), and by virtue of the authority vested in me by the Secretary of the Treasury (12 F.R. 1480), that a determi- nation is proposed to be made that each of the following-named drugs has an addiction-forming or addiction-sustaining liability similar to morphine and is an opiate: (1) 4.4-diphenyl-6-piperidine-3-heptanone (piperidyl methadone). (2) Isopropyl 1-methyl-4-phenylpiperidine-4-carboxylate. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17055 30 25 20 15 l0 5 U 0 Lu z 1- (I) co Li~ 0 >- I- (I) z U F- z S S / ~0 .,,/ MORPHiNE PAGENO="0504" 17056 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (3) 3-diethylamino-1.1-di (2-thienyl)utene (diethylthiambutene). (4) 1,3-dimethyl-4-phenyl-4-propionoxyhexamethyleneimine, (5) 3-hydroxy-X-phenethylmorphinan. (6) Ethyl 2.2-diphenyl-4-rnorpholinobutyrate. (7) 4-dimethylamino-1.2-diphenyl-3-methyl-2-propionoxybutane~ (8) Ethyl 1-[2- (p-aminophenyl)-ethyl]-4-phenylpiperidine-4-carboxylate. Consideration will be given to any written data, views, or arguments. I)ertain- ing to the addiction-forming or addiction-sustaining liability of each of the above- named drugs, which are received by the Commisisoner of Narcotics prior to March 29, 1956. Any person desiring to be heard on the addiction-forming or addiction-sustaining liability of any of the above-named drugs w-ill l)e accorded the opportunity at a hearing in the office of the Commissioner of Narcotics. 1300 E Street, NW., Washington 25 D.C.. at 10 :00 am. March 29, 1956. provided that each person furnishes written notice of his desire to be heard, to the Com- missioner of Narcotics. Washington 25. D.C.. not later than 20 days from the publication of this notice in the Federal Register. If no written notice of a de- sire to 1)e heard shall be received within 20 days from the date of publication of this notice in the Federal Register. no hearing shall l)e held. but the Commis- sioner of Narcotics shall proceed to make a recommendation to the Secretary of the Treasury for a finding under section 1 of the act of March 8, 1946. (60 Stat. 38: 26 U.S.C. 4731) [SEAL] G. W. CUNNINGHAM, Acting Corn missioner of Narcotics. [P.R. Doe. 56-1532; Filed. Feb. 28, 1956; S :50 a.m.] EXHIBIT D DEPARTMENT OF THE TREASURY, BUREAU OF NARcoTIcs - [21 CFR Part 305] PROPOXYPHENE (4-DIMETHYLAMINO-1,2-DIPHENYL-3-METHYL-2- PROPIONOXYBUTANE) FOUND NOT TO BE AN OPIATE The Bureau of Narcotics published in the Federal Register (21 P.R. 1321) a notice of a proposed finding that the substance 4-dimethylamino-1.2-diphenyl-3- methyl-2-propionoxybutane (also known as propoxyphene) had an addiction- forming or addiction-sustaining liability similar to morphine and should be classified as an opiate. Eli Lilly and Company entered a protest with respect to the proposed findng and requested an opportunity to be heard on the matter. A hearing u-as held pursuant to this notice. On the basis of all the evidence, including technical data o~ere at the hearing, plus the fact that there has been no evidence of any danger to the public wel- fare regarding addiction liability during the approximately five years pro- poxyphene has been on the market. I have concluded that this substance should not be found to be an opiate. Also taken into consideration in making this deter- mination has been the resolution recommending such action, adopted at the January 1962 meeting of t.he Committee on Drug Addiction and Narcotics of the National Research Council. National Academy of Sciences. [SEAL] HENRY L. GIORDANO, Acting Commissioner of Narcotics. Approved: March 17, 1962. JAMES A. REED, Assistance Secretary of the Treasury. [P.R. Doe. 62-2870: Filed. Mar. 23, 1962: 8:30 a.m.] PAGENO="0505" COMPETITIVE PROBLEMS, IN THE DRUG INDUSTRY 17057 [21 CFR Part 3071 NORPETHIDINE (NORMEPERIDINE) APPLICATIONS FOR LICENSE TO MANUFACTURE Notice is herel)y given pursuant to the I)r0v151o115 of section 8 of the Narcotics Manufacturing Act of 1900 (74 Stat. 62) and 21 CFR 307.93 that an application for a license to manufacture the llarcotic drug Norpethidine (normeperidilie), basic class No. 34, has been submitted by each of the following named companies: Merck Chemical Division, Merck & Co., Inc., 126 East Lincoln Avenue, Raliway, N.J. Mallinckrodt Chemical Works, Second and Mallinckrodt Streets, St. Louis 7, Mo. Winthrop Laboratories Division of Sterling Drug Co., 1450 Broadway, New York 18, N.Y. and that such applications are being,' favorably considered. Within twenty days from the date of publication of this notice in the Federal Register, any interested person may file a written protest with both the Com- missioner of Narcotics and the applieaiits, against favorable consideration of the applications. Any such protest shall specify with particularity the facts relied upon as showing that the licenses if granted to tl1e applicants would not be in the public interest. Such interested person at the time of filing may request a hearing as to his protest. If 110 written notice of a desire to be heard shall be received within twenty days from date of publication of this notice in the Federal Register, no hearing shall be held. [SEALI HENRY L. GIORDANO, Acting Commissioner of Narcotics. Approved: March 17, 1962. JAMES A. REED, Assistant ~S'ecretarij of the Treasury. [FR. Doe. 62-2869; Filed Mar. 23, 1962; 8:50 a.m.] PAGENO="0506" 17058 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY EXHIBIT E HId 111th Org. :echn. Rep. Set., 1964, 273 IVORLD HEALTH ORGANIZATION TECHNICAL REPORT SERIES No. 273 WHO EXPERT COMMITTEE ON ADDICTION -PRODUCING DRUGS Thirteenth Report WORLD HEALTH ORGANIZATION G~8VA PAGENO="0507" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17059 The World Health Organizatioc (WHO) is a specialized agency of the United Nations. Its work is carried out by three organs the World Health Asseivbly, the supreme authority, to which all Member States send delegates; the Executive Board, the executive organ of the Health Assembly, consisting of 24 persons designated by as many Member States; and a Secretariat undcr the Director-General. ~VHO's activities include programmes relating to a wide variety of t'ublic health qucstions; communicable and chronic degenerative diseases, radiation and isotopes, maternal and child health, mental health, dcntal health, veterinary public health, social and occupa- tional health, nutrition, nursing, environmental health, public health administration, professional education and training, and health cdii- cation of the public. In addition, WHO undertakes or participates in certain technical work of international significance, such as the compilation of an international pharmacopoeia, the setting up of biological standards and of various other international standards (pesticides and pesticide-spraying equipment, drinking-water, food additives), the control of addiction-producing drugs, the exchange of scientific information and the publication of medical literature, the drawing up of international sanitary regulations, the revision of the international list of diseases and causes of death, the collection and dissemination of epidcmiological information, and statistical studies on morbidity and mortality. The Director-General has authority to establish expert advisory panels on particular subjects and to select and appoint their members, who undertake to contribute by correspondence and without r& muneration information or reports on developments within their own specialties. They serve in their personal capacity and not as represent- atives of governments or other bodies. Expert committees are convened to advise on particular subjects; their members are selected by the Director-General from the advisory panels, the choice being governed by the agenda of each committee. The selection of members of both expert advisory panels and committees is based primarily upon their ability and technical experience, with due regard to adequate geo- graphical distribution. Reports of expert committees, while not necessarily expressing the views of the Organization, are taken into consideration In developing programmes- PAGENO="0508" 17060 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WORLD HEALTH ORGANIZATION TECHNICAL REPORT SERIES No. 273 WHO EXPERT COMMITTEE ON ADDICTION-PRODUCING DRUGS Thirteenth Report Page `1. NotificatIons 3 2. Work of international bodies concerned with narcotic drugs 5 3. Single Convention on Narcotic Drugs, 1961 . 8 4. Terminology In regard to drug abuse 9 5. Considerations governing the medical use of narcotics . . 10 6. Khat (CoMa eduiLt) 10 7. Abuse of hallucinogenic agents . . . . . .. . . . . . . 11 I. Coded Information on narcotics 11 L International Classification of Diseases . 12 Annul:.Typesotdrugdependoncs . . . . . . . . 13 Anest 2: List of drugs under tnternatIo~1 narcotics coatesl 17 WORLD HEALTH ORGANIZATION OENEVA 1964 PAGENO="0509" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17061 WHO EXPERT COMMII7EE ON ADDICTION.PRODUCING DRUGS Geneva, 25.30 November 1963 Members: Dr N. B. Eddy, Consultant on Narcotics, National Institutes of Health, Bethesda, Md., USA (Chairman) Dr L. Goldberg, Professor of Research on Alcohol and Analgesics, Karolinsk* Institutet, Stockholm, Sweden (Rappor:eur) Dr M. Granier-Doycux, Professor of Pharmacology and Toxicology, Depart- ment of Pharmacology and Toxicology, Faculty of Medicine, Central University of Venezuela, Caraàs, Venezuela Dr P. Kiclholz, Profcssor of Psychiatry, University of Basic, Switzerland Dr A. D. Macdonald, Professor of Pharmacology, University of Manchester, England Dr B. Mukerji, Director, Chittaranjan National Cancer Research Centre; Professor of Pharmacology, Calcutta, India Dr V. V. Vasil'eva, Professor of Pharmacology, Second Moscow Institute of Medicine, Moscow, USSR (Vice-Chairman) Representatives of the United Nations: Mr W..J. Duke, Chief of Section, Division of Narcotic Drugs, United Nations, Geneva Mr 0. 1. Braenden, Ph.D., Division of Narcotic Drugs, United Nations, Geneva Representative of the Permanent Central Opium Board and the Dreg Supervisory Body: Mr A. Lande, Dr jur., Secretary of these two bodies, Geneva Dr H. Halbach, Dr med., Dr big., Chief Medical Officer, Addiction. Producing Drugs, WHO (Secrst~y) ` Unable to attend: Dr 0. Joachlmoglu, ProfessoT Emeritus of Phannacology; formerly Chair' man, Superior Health Council, Ministry of Social Welfare, Athens, Greece PRiNTVD 01 SWrTZULA~4D PAGENO="0510" 17062 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WId 111th Org. techa,. Rep. 5cr., 1964, 273 WHO EXPERT COMMITTEE ON ADDICTION. PRODUCING DRUGS Thirteenth Report The WHO Expert Committee on Addiction-Producing Drugs met in Geneva from 25-30 November 1963. Dr P. Dorolle, Deputy Director-General, on behalf of the Director. General, opened the session and welcomed the members of the Committee, the representatives of the Secretary-General of the United Nations, and the representative of the Permanent Central Opium Board and the Drug Super. visory Body. Dr N. B. Eddy was elected Chairman, Dr V. V. Vasil'eva Vice-Chairman, and Dr L.' Goldberg Rapporteur. 1. Notifications I 1-Diniet1i~'Iamino.3-pIzenylindane 1 Referring to the notification of the Government of Canada, the Corn. * mittee considered the accompanying reports, which included data on tests for physical dependence carried out with 1-dimethylamino-3-phenylindane in the monkey an.d in man. In view of the negative character of the evidence submitted and in the absence of any indication ~of the convertibility of l-dimethylamino.3-phenylindane into a product capable of producing addic- tion, the Committee was of the opinion that J-dirnethylamino-3-phenylin. dane should not now be regarded either as an addiction-producing drug or as one capable of conversion into an addiction-producing drug. Therefore, The WHO Expert Committee on Addiction-Producing Drugs RECOMMENDS that its opinion with respect to l-dimethylamino4- phenylindane be communicated to the Secretary-General of the United Nations. .2 J?roxyproplne' In its twelfth report,3 the Committee considered that the information at its disposal was insufficient for it to reach a definite conclusion with respect Also designated as N,N.dimethyl.3.phenyl-J-indanamine. $ International non.propncta.ry name proposed (or J-12-(2-hydroxyethoay)elh)1,. phenyl-4-propionylpiperidine. $ Wid Huh Org. ieclin. Rep. 5cr., 1962, 229, 4 (section 1.2). PAGENO="0511" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17063 4 ADDICTION-PRODUCING DRUGS to the addiction liability of droxypropine and decided to defer its opinion. Data on tests for physical dependence in the monkey have nov. been sup- plemented by clinical tests. In the light of the negative character of the e'~ idence presented and in the absence of any indication of the convertibility of droxvpropine into a product capable of producing addiction, the Com- mittee concluded that droxypropine should not now be regarded as an addiction-producing drug or as one capable of conversion into an addiction- producing drug. Therefore, The WHO Expert Committee on Addiction-Producing Drugs RECOMMENDS that its opinion with respect to droxypropine be com- municated to the Secretary General of the United Nations. 1 .3 Fentanyl 1 Referring to the notification of the Government of Bel~um, the Com- mittee considered that fentanyl (1) produced morphine-like effects, and (2) can be substituted for morphine in a known addiction. Evidence on these points was derived in part from experiments in monkeys. Experience has shown that results obtained in the monkey correlate with those in man, so that, when the former are unequivocal, they may be accepted as evidence of what is to be expected in man. Consequently, the Committee was of the opinion that fentan'l must be considered to be an addiction-producing drug comparable to morphine and that fentanyl and its salts should fall under the regime laid down in the 131 Convention for the drugs specified in Article 1. paragraph 2, Group I. Therefore, The \VHO Expert Committee on Addiction-Producing Drugs RECOMMENDS that its opinion with respect to fentanyl and its salts be communicated to the Secretary General of the United Nations. 1.4 Norpipanone2 Referring to the notification of the Government of Hungary, the Corn-* mittee considered that norpipànone (1) produced morphine-like effects, and 2) can be substituted for morphine in a known addiction. Evidence on these points was derived in p.nrt from experiments in monkeys. Experi- ence has shown that results obtained in the monkey correlate with those in man, so that, when the former are unequivocal, they may be accepted as evidence of what is to be expected in man. In addition, the chemical International non-proprietary name proposed for l-phenethyl-4-N-propionylanilino- piperidme. 2 International non.proprietary name proposed for 4,4-diphenyl-6-piperidino-3- hexanone. PAGENO="0512" 17064 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THIRTEENTH REPORT structure of norpipanone bears an extremely close relationship to that of other drugs known to be addiction producing.' Consequently the Com- mittee was of .the opinion that norpipanone must be considered to be an addiction-producing drug comparable to morphine and that norpipanone and its salts should fall under the regime laid down in the 1931 Convention for the drugs specified in Article 1, paragraph 2, Group I. Therefore, The WHO Expert Committee on Addiction-Producing Drugs RECOMMENDS that its opinion with respect to norpipanone and its salts be communicated to the Secretary-General of the United Nations. 1.5 Dextropropoxyphene 2 The Committee considered-again the evidence with respect to the abuse liability of dextropropoxyphene.3 It concluded that on the basis of five years of marketing experience and repeated observations at the Addiction Research Center, Lexington, Ky., USA, in comparison with other sub. stances, the risk of dextropropoxyphene to public health appeared to be sufficiently low as not now to require international narcotics control. 2. Work of International Bodies concerned with Narcotic Drugs 2. 1 The reports of the seventeenth4 and eighteenth ~ sessiOns of the Corn. mission on Narcotic Drugs of the Economic and Social Council, the relevant resolutions of the Economic and Social Council,6 and the reports of the Pcrmanent Central Opium Board ~ ° and Drug Supervisory Body~ were I WId 111th Org. icc/tn. Rep. Ser., 1956, 102, 10 (section 5.2.3). ` International non-proprietary name for (+)4.dimethylamino-3.meihyl.l,2.dL. phenyl.2-propionoxybutane. $ Wld 111th Org. icc/tn. Rep. 5cr., 1958, 142, 7 (section 5.1 .3). ` United Nations, Commission on Narcotic Drugs (1962) Report of the Seventeenth Session (May.June 1962)-( Economic and Social Council. Official Re~ords: thirty-fourth session. Supplement No. 9), Geneva (Document E/3648). ~ United Nations, Commission on Narcotic Drugs (1963) Report of the Eighteenth Setsiog, (ApPil.P,~4a.y 1953)-.(Scanomfc and Social Council. Official Records: thIrty.si.rcth session. Supplement No. 9), Geneva (Document f/3773). ` United Nations, Economic and Social Council (1963) Official Records: thirty- sixth session, 2 July. 2 August 1963. Supplement No. 1 : Resolutions, Geneva, p. 21 (Docu- ment E/3$l6). United Nations, Permanent Central Opium Board (1961) Report to the Economic and Social Council on the Work of the Board in 1961, Geneva (Document E/OB/17). $ United Nations, Permanent Central Opium Board (1962) RepQrt to the Economic and Social Council on the Work of the Board In 1962, Geneva (Document E/OB/18). * United Nations, Drug Supervisory Body (1961, 1962) Estimated World Require. nwnss for Narcotic Drugs In 1962 and 1963, Geneva (Documents E/DSB/19 & 20). PAGENO="0513" COMPETITIVE PROBLEMS :~ THE DRUG INDUSTRY 17065 6 ADDICTION-PRODUCING DRUGS summarized by the Secretary. Several items referred to in these reports were relevant to the Committee's present agenda. 2.2 With reference to the recent regional conference on coca leaf problems and the relevant resolution of the Economic and Social Council,1 the Committee noted with satisfaction that there is now general agreement on the harmfulness of coca leaf chewing and that the problems connected th~cewith are to be recarded as a concomitant of unfavourable socio-econo- mic circumstances, with detrimental effects on the individual as well as the society. The.general acceptance of this point of view should help in directing efforts towards the betterment of thô underlying environmental conditions, wherever possible as part of the general social and economic development of the areas concerned, and towards the eventual solution of the coca leaf problem. 2.3 With reference to the economic significance of coca leaves arising out of a possible increase in .the legal production of cocaine for medical purposes, the Committee wished to draw attention to the fact that the medical needs for cocaine have decreased considerably in the past few decades, as a consecuence of the cont~nuin~ develonrncnt of synthetic local anaesthetics v. luch can replace cocaine in the majority of its therapeutic indications. Therefore, further reduction in the legal manufacture of cocaine is likely and desirable, and this should diminish opportunity for diversion to illicit uses. The Committee was disturbed by the fact that in spite of this there is an upward trend in the abuse of cocaine, particularly in combination with other dru2s. 2.4 The Committee was glad to note that the Commission on Narcotic Drugs and the Permanent Central Opium Board 2were now placing increased emphasis on the sociological and economic aspects of drug abuse. It expressed the hope that the Commission's resolution ~ requesting member states of the United Nations or ,f the specialized agencies to encourage research on these aspects of the problem would contribute to the elucidation of the epidemiology of drug abuse already called for both by the WHO Expert Committee on Addiction-Producing Drugs' and by the WHO Study Group on the Treatment and Care of Drug Addicts.3 United Nations, Economic and Social Council (1963) Official Records: thirty. sixth irssiun, 2 July - 2 August 1963. Supplement No. 1 Resolutions, Geneva, p. 21 (Docu- ment E/3816). $ United Nations, Permanent Central Opium Board (1963) Report to she Economic and Social Council on the Work of the Board in 1963. Geneva (Docun$ent E/OB/19). United Nations Commission on Narcotic Drug (1962) Report of the Seventeenth Session, Resolution 2 (XVII) (Document E/3648, p. 22). * Wid filth Org. techn. Rep. Ser., 1960, 188, 11. ` Kid HIM Org. techn. Rep. See., 1957, 131, 11. 40-224 0 - 79- 33 PAGENO="0514" 17066 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THIRTEENTH REPORT 7 2.5 In connexion with the Commission's resolution on the control of barbiturates'the Committee wished to point out that there were a number of non-barbiturate sedatives, hypnotics and other drugs with sedative effect which had been shown to be abused and to produce ill-effects similar to those of the barbiturates. This was of particular significance where the sedative effect was not the one for which the drug was primarily used in medicine, but could be made use of properly under some circumstances, and might also lead to abuse. This may be illustrated by certain of the anti- histamines developed as anti-allergic agents, but exhibiting sufficient sedative action to be used, and abused, as sedatives. Another pertinent case is the recent observation of an epidemic-like outbreak of abuse of hypnotic drugs in a particular region. Methaquälone originally developed as an anti- malarial is currently advertised as a sedative and although introduced into that region only a year ago is now reported to constitute about four-fifths of the total amount of hypnotic drugs abused-in the group studied. 2.6 Sudden changes in the drug of choice for abuse amongst groups within a population or in circumscribed areas such as referred to above tend to show, in the Committee's view, the relevance of sociological and environ- mental factors, as distinct from individual motives, in the etiology of drug abuse.. Such fluctuations thus indicate the need for immediate national control measures, as repeatedly recommended by the Committee, for drugs of abuse not under international control (barbiturates 2 or other sedatives ~ and amphetamines 4), 2.7 With regard to the proposal made in the Commission on Narcotic. Drugs for an investigation into the causative role of psychoactive substances in accidents, especially road accidents, the Committee believed that such investigations could profitably be combined with similar studies on the role of alcohol. 2.8 The Committee took cognizance of the 1963 edition of the Multi- lingual list of narcotic drugs under international control.6 The list has been greatly expanded, partly by the inclusion of names of new drugs, but more particularly by additional names for drugs already known. The list is a help- ful tool for anybody working in this field. The Committee hopes that this document will be kept up to date. 1 United Nations Commission on Narcotic Drugs (1962) Report of the Sebentee'nM Session, Resohiilon.4 (XVII) (Doiument £13648, p.31). ~ Wid HiM Org. teclrn. Rep. 3cr., 1957, 116. 10 (sections 9 & 10). ~ Wid HiM Org. tee/tn. Rep. Se,., 1958, 142, ~0 (section 6). ~ Wid HIM Org. tic/tn. Rep. Sir., 1961, 211, 9 (section 2.2). ~ United Nations (1963) NarcotIc di'atgs under International control. Multilingual list (Docunssot E/CN.71436). PAGENO="0515" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17067 8 ADDICTION-PRODUCING DRUGS 3. Single Corn~entiou oá Narcotic Drugs, 1961 3.1 In the course of the preparations for the coming into force of the Single Convention, WHO was invited 1to make recommendations regarding amendments to the schedules annexed to that treaty instrument. The Com- mittee considered the following changes necessary.. 3.2 Schedule I The followin~ items should be added: Fentan)l (l-pheneth~I-4- `~-propsonv1aniIinopiperidine) \fethadone-!nterrncdiatc ~4-cvano-2-dimethvlaminc-4,4-diphenylbutane) Moramide-Intermediate (2-me~hyI-3-morphoIino-I,l.diphenylpropane carboxylic acid) Noracvmcthadol ((-~)-a-3-acetoxy-6-methylamino-4,4-diphenyIheptane) Norpiparione (4,4-diphenvl-6-piperidine-3-hexanone) Pcthidine-Intermediate-A (4-cyano-l-methyl-4-phenvlpiperidine) Pethidine-Intermediate-B (4-phenylpiperidine-4-carboxylic acid ethyl ester) Pethidine-Intermediate-C (l-methyl-4-phenylpiperidine-4-carboxylic acid) The following text should be added (after the entry "Trimeperidine"): "Any other product obtained from any of the phenanthrene alkaloids of opium or ec~onirc a!k~i1oids of the coca leaf, not listed in Schedule 1 or II, and neither made nor utilized exclus~~ely for authorized domestic research, unless the rovernment concerned finds that the product in question does not have morphine-like or cocaine-like effects." In the entry "Concentrate of Poppy Straw" the words "when such material is made available in trade" should be deleted. 3.3 Schedule II Nicocodine (6-nicotinylcodeine) should be added. Dextropropoxyphene ((+)-4-dimethylamino-3-methyl-1,2-diphenyl-2- propionoxybutane) should be deleted. 34 Schedule II! Of the substances listed in section (1), dextropropoxyphene should be deleted. The rest o section (1) should read as follows: "When compounded with one or more other ingredients and containing not more than 100 milligrams of the drug per dosage unit and with a concentration of not more than 2.5 per cent in individual preparations." 1 United Nations, Commission on Narcotic Drugs (1962) Report of the Seventeenth Session (May-June 1962)-EconomIc and Social Council, Official Recordi, :hlny-fowsh session, Supplement No. 9, Geneva (Document E/3648, p. 36). PAGENO="0516" 17068 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THiRTEENTH REPORT 9 In section (2) the following words should be deleted: "in such a way that the preparation has no, or a negligible, risk of abuse. and in such a way that the drug cannot be recovered by readily applicable means in a yield which would Constitute a risk to public health." In section (3) the words "Solid dose" should be deleted; 4. Terminology in Regard to Drug Abuse Drug dependence" to replace the terms "drug addiction" and "drug habituation" The WHO Expert Committee ort Addiction-Producing Drugs in 1952 attempted to formulate a definition of addiction a~'plicable to drugs under international control, which it later (1957) 2 revised. The Expert Committee sought also to differentiate addiction from habituation and wrote a defini- tion of the latter which, however, failed in ~ractice to make a clear dis- tinction. The definition of addiction gained some acceptance. but confusion in the use of the terms addiction and habituation and misuse of the former continued. Fu~ther, the list of drugs abused increased in number and~ diversity. These difficulties have become increasingly apparent and various attempts have been made to find a term that could be applied to drug abuse generally. The component in common appears to be dependence, hether psychic or physical or both. Hence, use of the term "drus denendence ", with a modifying phrase linking it to a particular drug type i~ order to differentiate one class of drugs from another, has been gi~en most careful consideration. "Drug dependence" is defined as a state arising from repeated ad- ministration of a drug on a periodic or continuous basis. Its characteristics will vary with the agent involved and this must be made clear by designating the particular type of drug dependence in each specific case-for example, drug dependence of morphine type, of cocaine type. of cannabis type. of barbiturate type, of amphetamine type, etc. (See Annex 1 for descriptions of specific types of drug dependence.) The Expert Committee recommends substitution of the term "drug dependence" for the terms "drug addiction" and "drug habituation It must be emphasized that drug dependence is a general term selected for its applicability to all types of drug abuse and carries no connotation of the degree of risk to public health or need for a particular type of drug control. The agents controlled internationally continue to be those that are morphine-like, cocaine-like, and cannabis-like, however produced, the use of which results in drug dependence of morphine type, drug dependence 1 Wid 111th Oi'g. :echn. Rep. Se,., 1952, 57, 9 (section 6.1). ~ Wid 111th Org. :echn. Rep. 5cr., 1957, 116, 9 (sectIon 5). PAGENO="0517" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17069 10 ADDICTION4 ..~DUCING DRUGS of cocaine type, and drug depcndev~ of cannabis type. Other types of drug dependcncc ~barbiturate, amphetar.~ne, etc.) continue to present problems, but their description under the gen~al term ~` drug dependence" does not in any way affect the measures tak~i to solve them. The general term will help to indicate a relationship by irawing attention to'~ common feature associated with drug abuse* and at~ the same time permit more exact description and differentiation of ;nçcific characteristics according to th& nature of the agent involved. S. Considerations Governing the Medical Use of Narcotics The Committee has on many occa ;ions stressed the medical aspects of the treatment of addicts and the precautionary attitude that should be adopted by physicians in this connexion and in the use of narcotics generally in their practice. Its attention was drawn to a recent report setting forth in considerable detail the whole philosophy of the use of narcotics in medical practice.1 It was felt that this report, constituted a useful guide towards the attainment of the objectives that the Committee has stressed. 6. Khat (Catha edulis) - The Committee studied a report by the Secretariat on the medical aspects of the habitual chewing of khat leaves. In this report the somatic and psychic symptoms brought about by the chewing of the leaves were reviewed and explained as the effects of the specific active principles con~ tamed in the leaves. Besides tannins in appreciable amounts, it has been possible to identify (±)-norpseudoephedrine (catbine) and a chemically and pharmacologically closely related substance, which disappears when the plant is dried and is presumably a step in the biosynthesis of cathine. These two substances are amphetamine4ike in respect of structure and pharmaco- dynamics, but there is evidence that their effects are less powerful than those produced by equivalent amounts of, fo example, methamphet~. amine. The Committee considered that while khat and pure' amphetamine substances produced medical effects that were similar although of different degree, the lower activity of khat was due in the main to differences in dosage, route of administration, and the circumstances in which the one or the other were consumed. In addition, khat produced gastro-intestinal symptoms, due partly to its high content of tannins. `Councilon Mental Health (1963) Narcoiks aed medical practice. I. Amer. med. Au., 185, 976. PAGENO="0518" 17070 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THiRTEENTH REPORT 11 The Committee realized that the habitual chewing of khat had led, in some areas, to socio-cconomic phenomena detrimental to the individual and the community, such as loss of man hours and diversion of income, with malnutrition and aggravation of disease as consequences. The Committee was of the opinion that the problems connected with khat and with the amphetamines' should be considered in the same light because of the similarity of their medical effects, even thouah there are quantitative differences and specific socio~economic features; this is all the more desirable since the problems with respect.to khat are confined at present to a few countries in one region. 7. Abuse of Hallucinogenic Agents The Committee took note of the increasingly frequent reports of poorly controlled clinical administration and non-medical use of lysergic acid diethylamide (LSD-25). In spite of warnings, irregular use is reaching alarming proportions. The Committee was particularly disturbed by the publicity given to the uncontrolled use of this drug and the damace that the indiscriminate use of so powerful an agent has already produced. The problem is at present a local one. In the Comrniace~s opinion, immediate measures with respect to distribution and availability are necessary. Other instances of indiscriminate use of aeerits with related e~ects, such as pevoti (mescaline), Piptadenia peregrina (hufotenine), and Rivca coriin- bosa were noted. The misuse in these instanèes ap7ears to be less widespread than in the case of LSD~25, but a watch should be kept and corrective measures taken where necessary. 8. Coded Information on Narcotics As indicated in previous reports,25 the Committee maintains an interest in the availability of a centralized source of information on drug dependence in all its aspects, including the agents involved, with easy means of fast retrieval. Coded data (about 8(X)O items) on a large part of the material accu- mulated, have now been transferred to an iBM card system, and the com- plete bibliographic material microfilmed. Co-operation with the American 1 Wid Hith Org. icc/In. Rep. Ser., 1956, 102, 12 (section 7); 1957, 116, 9 (section 7). ` Wid Hith Org. tic/in. Rep. Sir., 1957, 116. 11 (section ii). ~ Wid Hit/i Org. 1cc/in. Rep. Se,., 1958, 142, 11 (section 9). Wid Hith Org. tee/ui. Rep. Se,., 1959, 160, 10 (section 7), 14 (Annex 2). ~ Wid Him Org. sec/in. Rep. Sir., 1962, 229. 12 (section $). PAGENO="0519" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17071 12 ADDICTI0N~PR9DUCING DRUGS S~cial Health .Association, the Alcoholism and Drug Addiction Research Foundation, Toronto, and the United Nations Division of Narcotic Drugs, has been worked out. This will greatly expedite further work and increase the completeness of coverage of published material in this field. Sets of IBM cards and the microfilm will shortly be available at cost. 9. International Classification of Diseases The Committee was informed of the preparation of the eighth revision of the classification, and would draw attention to the diversity of the items listed under "316. Drug Addiction ", not all of which are considered addiction-producing in a legal or pharmacological sense. Referring to the recommendation in the present report that the term "drug dependence" be substituted for " drug addiction ",the Committee would invite attention to the application of this recommendation in the international classification of diseases, thereby bringing into better harmony the list of diverse items referred to above. PAGENO="0520" 17072 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Annex 1 TYPES OF DRUG DEPENDENCE Drug dependence of morphine type is described as a state arising from repeated administration of morphine, or an agent with morphine-like effects, on a periodic or continuous basis. Its characteristics include: (I) an over.powcrin~ desire or need to continue taking the drug and to obtain it by any means; the need can be satisfied by the drug taken initially or by another with morphine-like properties; (2) a tendency to increase the dose owing to the development of toler- ance; (3) a psychic dependence on the effects of the drug related to a sub- jective and individual appreciation of those effects; and (4) a physical dependence on the effects of the drug requiring its pres.. ence for maintenance of homeostasis and resulting in a definite, charac- teristic, and self-limited abstinence syndrome when the drug is withdrawn. The abstinence syndrome is the most characteristic and distinauishing feature of drug dependence of morphine type. It appears within a few hOurs of the last dose of drug taken, reaches peak intensity in 12 hours or more, and subsides spontaneously. most often within a week, the time course varying with the duration of action of the specific morphine.like agent involved. The abstinence syndrome may also he precipitated in a matter of minutes and made to take a more rapid time course by the ad- ministration of a specific antagonist while continuing the administration of the agent responsible for the dependence. The complex of symptoms which constitute the abstinence syndrome includes: yawning, Iacriination, rhinor- rhoea, perspiration, mydriasis. tremor, gooseflesh, anorexia, anxiety, rest- lessness, nausea, emesis, diarrhoea, hot flushes, rise In body temperature, Increase in respiratory rate an4 In systolic blood pressure, abdominal or other muscle cramps, and dehydration and loss of body-weight. Drug dependence of barbkurste type is described as a state arising from repeated administration of a barbiturate, or an agent with barbiturate-like effect, on a continuous basis, generally in amounts exceeding therapeutic dose levels. Its characteristics include: (1) a strong desire or need to continue taking the drug; the need can be satisfied by the drug taken initially or by another with barbiturate.likc properties; 13 PAGENO="0521" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17073 14 ADDICTION-PRODUCING DRUGS (2) a tendency to increase the dose, partly owing to the development of tolerance; (3) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects; and (4) a physical dependence on the effects of the drug requiring its pres- ence for maintenance of homeostasis and resulting in a definite, charac- teristic, and self-limited abstinence syndrome when the drug is withdrawn. The abstinence syndrome is the most characteristic and distinguishing feature of drug dependence of barbiturate type. It begins to appear within the first 24 hours of cessation of drug taking, reaches peak intensity in two or three days, and subsides slowly. There is at present no known agent that will precipitate the barbiturate abstinence syndrome during continua- tion of drug administration. The complex of symptoms which constitute the abstinence syndrome, in approximate order of appearance, are: anxiety, involuntary twitching of muscles, intention tremor of hands and fingers, progressive weakness, dizziness, distortion in visual perception, nausea, vomiting, insomnia, weight loss, and a precipitous drop in blood pressure on standing; convulsions of a grand mal type andfor a delirium resembling alcoholic delirium tremens may occur. * Drug dependence of cocaine type is described as a state arising from repeated administration of cocaine or an agent with cocaine-like properties, on a periodic or continuous basis. Its characteristics include: (1) an overpowering desire or need to continue taking the drug and to obtain it by any means; (2) absence of tolerance to the effects of the drug during continued administration; in the more frequent episodic use, the drug may be taken at short intervals, resulting in the build-up of an intense toxic reaction; * (3) a psychic dependence on the effects of' the drug related to a sub. * jective and individual appreciation of those effects; and (4) absence of a physical dependence and hence absence of an abstinence syndrome on abrupt withdrawal; withdrawal Is attended by a psychic * disturbance manifested by craving for the drug. Drug dependence of amphetamine type is a state arising front repeated administration of amphetamine or an agent with amphetamine-like effects on a periodic or continuous basis. Its characteristics include: (1) a desire or need to continue taking the drug; (2) consumption of increasing amounts to obtain greater excitatory and euphoric effects or to combat: more effectively depression and fatigue, accompanied in some measure: by the development of tolerance; PAGENO="0522" 17074 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ThiRTEENTH REPORT 15 (3) a psychic dependence on the effects of the drug related to a subjective and individual appreciation of the drug's effects; and (4) general absence of physical dependence so that there is no charac~ teristic abstinence syndrome when the drug is discontinued. Drug dcpendcnce of cannabis type is described as a state arising from repeated administration of cannabis or cannabis substances, which in some areas is almost exclusively periodic, in others more continuous. Its charac- teristics include: (1) a desire (or need) for repeated administration of the drug on account of its subjective effects, including the feeling of enhanced capabilities; (2) little or no tendency to increase the dose, sincethere is little or no development of tolerance; (3) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects; (4) absence of physical dependence so that there is no definite and characteristic abstinence syndrome ~`. hen the drug is discontinued. These are concise descriptions which could be expanded. particularly with reference to differences in decree accordin~ to dose and duration of administration and to p~otency among agents within a partict!ar type. The differences between morphine and codeine are a good example cf the latter. Descriptions of drug dependence of other types cotld ~e written, e.g., for certain sedatives not chemically classified as barbiturates, or for alcohol, to name only two. The characteristics of dependence of the non- barbiturate sedative type are essentially identical with the characteristics of dependence of the barbiturate type and a separate description seems at present unnecessary. Alcohol is outside the terms of reference of this expert committee, but is nevertheless an agent that can admittedly cause psychic and physical dependence. All the descriptions of types of drug dependence have been confined to medical aspects only, but socio-economic characteristics and implications should not be overlooked. They vary according to the drug type and there are variations in the individual and social harm that accompany drug dependence of different types: With morphine, the harm to the individual is in the main indirect, ansing from preoccupation with drug taking; personal neglect, malnutrition and infection are frequent consequences. For society also, the harm may be related to the preoccupation of the individual with drug taking; disruption of interpersonal relationships, economic loss, and crimes against property are frequent consequences. With the barbiturates, the detrimental effect on the individual stems in part from his preoccupation with drug taking, but more particularly from PAGENO="0523" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17075 16 ADDICTION-PRODUCING DRUGS persistent effects of the drug-ataxia, dysarthria, and impairment of mental function, with confusion, loss of emotional control, poor judgment, and occasionally a toxic psychosis. The harm to society is related to l~oth the individual's preoccupation with drug taking and the drug's effect on inter- personal relationships. With cocaine, the individual detrimental effect may be indirect, resulting from the individual's preoccupation with drug taking, again with malnutri- tion and infection as frequent consequences, or direct, a severe toxic reaction accompanying rapid and repeated administration in episodic drug use. The harm to society is related to preocàupation with drug taking by the indi- vidual, wjth economic loss and crimes against society as consequences. When drug dependence of cocaine type is brought about through chewing of coca leaves, anorexia, a change in working habits, and loss in weight are additional characteristics. The amphetamines tend to cause anorexia, persistent and exaggerated psychomotor disturbances, and disruption of mental function, even to the occurrence of a toxic psychosis. For society, the harm is related in part to the drug's psychomotor effects (involvement in accidents, for example). With cannabis, lasting disturbance of mental function has been alleged but not proven. Distortion of perception, one of the effects of the drug, may lead to disruption of interpersonal relationships, and abuse of the drug to criminal behaviour. The risk to public health should be and usually is of paramount impor- tance as a criterion for the establishment of control for a dependence. producing drug of any of the types described and in deciding on the degreo of control. At the same time, socio-economic factors and social harm asso- ciated ~with drug dependence and drug abuse must be taken into account and may determine the appropriateness of control in a particular case. The socio-economic factors largely determine society's attitude towards the individuals involved in drug abuse, but they are not characteristics that need to be considered in medical and scientific differentiation of the types of drug dependence. PAGENO="0524" 17076 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Annex 2 LiST OF DRUGS UNDER ~TERNAflONAL NARCOTICS CONTROL1 Common name or LVN * Chemical designation Ex~rrr Comrirree `n Ad~;icr~ ,~ Producing Drugs (`~`nrrol regime Reference $ G;oup J~ acetyldih, drocodeir.e acetylmethadol * aIl~lprodine alphacctylmethadol alphameprodine * alphamethadol alphaprodine anileridine' berizethidine' benryirnorphine betacetylmethadol S betameprodine * betarnethadol' betaprodine * cannabis clortitazene cocaine coca leaf codeine codeine-N-oxide desomorphine S dextromorarnjde' acetyldihydrocodeine 3-acetoxy-6-dimctlv, amino- 4,4-diphen)lhcrtane 3-allyl-l-mneth~ l-4-rhen)l- 4-propionoxypipcridine a~3.aceroxy.6~dimcthylamino~ 4,4-d rhenylheptane a-3_cthv1.l.methy14~phenyl_ 4-propionoxypiperidine a-6-d imethylarnino- 4,4-d,phenyl-3-heptanol a-i .3-dirnethyl4-phenyl. 4-propionoxypiperidine l-(p-aminophenethyl)- 4-m*tcnylniperidine- 4-cirbox~Iic acid ethyl ester 1 -(2-ben7yloxyethyl)- 4-phen~1ptrct~ine- 4.carbox~.i acid ethyl ester 3-ben7y!morphine ~-3-aceto~ -6-dimethylamino- 4.4-diphcn.Iheptar.e P.l.elhyl.l.melh~ l4.~ihcny!. 4-propiono'ypircridir.e ~-6-dimethylamino- 4,4-diphen)l-3-heptanol ~-l .3-dirneihyl-4-phenyl- 4-propionoxypiperidine Cannabis sariva L. p-chlorbenzyl-l-diemhyl- aminciethy1.5nitrobcnzimid~ azole methyl ester of benzoylecgonine 3-methylmorphine dihydrodeoxymorphine (-- )-4-12-methyl-4-ow- 3,3-diphen~l-4-tl-pyrrolI- din) l)but)l]morphotine 10 4 7 4 7 10 4 3 5 ii 8 1949, 19. 30 1949, 19. 31 1960, 188, 3 1954. 76. 7 1957. 116, 8 1954, 76. 7 1949, 19, 30 1957. 116, 7 1960, 188, 4 1954, 76. 7 1952. 57, 7 1955, 95, 8 1949, 19. 30 1961. 211. 4 1958. 142. 8 11 I II 193 193 193 193 193 ~93: I 93 193 193 193 193t 193~ 193 ~ 193 192 193 193 192 193 193 193 193 * Proposed internationgl non.j,roprietary name (INN). $ For details such as synonyms and the date of coming into force of international control, Multilingual list of narcotic arags under inrernario'mat control UN docirnient E;CN 7/3411 and of drugs wider international control (published annually by the UN, Division of Narcotic Dru respectively. $ The references given in this column are to World Health Organization: Technical Report Ser with the exception of the report published in 1949 which appeared in Official Records of the Wi Health Organization, No. 19. 17 PAGENO="0525" 18 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17077 ADDICTION-PRODUCING DRUGS Common name or INN * Chemical designation Expert Committee on Addiction- Producing Drugs - Control regime Report eumber Referencet Group Con- vention - 11 6 9 4 6 11 diarnpromide * * diethyithiambutene * dihydrocodeine dihydromor,hine dihydromorphine esters dirnenoxadol N-(2.(methylphençthYlaminO)- propyl]-propionanslide 3-diethylamino-1.l-di- (2'-thicnyl)-l-bUtefle 7,8.dihydrocodeine 7.8-dihydromorphine dirnepheptanol * dimethylthiambutene dioxaphetyl. butyrats diphenoxylate dipipanone ecgonine ecgonine esters ethyintethyl- thiambutens ethylmorphiM CtOnit*zCD etoxeridins fentanyl $ furethidine heroin hydrocodonc hydrocodonc esters hydromorphinol hydromorphone s hydromorphone esters bydroxypethidine 5 1 1931 1 1931 11 1931 1 193! 1 1931 I 1931 1 1931 I. 1931 1 1931 1* 1931 1 1931 I 1931 1 1931 1 1931 11 1931 1 1931 I 1931 I 1931 1 1931 2.dimethylaminoethYl 1-ethoxy-1 .1-diphenylacetate 6-dintethylamino- 4,4-diphenyl-3-heptanOl 3-dimethylamino-1.1di- (2.thienyl)-I-butenc ethyl 4-rnorpholino- 2,2.diphenylbutyrate 1.(3.cyano.3.3.diphenyl- propyl).4-phenylpipcridrne- 4-carboxylic acid ethyl ester 4,4.diphenyl-6-piperidino- 3-heptanone (-).3-hydroxytropane- 2-carboxylate 3-eihylntethylamino-1.1-di. (2'-thienyl)-1-buterte 3-ethylmorphine 1-diethylaminoethyl-2-p- ethoxybenzyl-5-nitro- hcnzimidazole 142-(2-hydroxycthoxy)elbYlI 4.phcnylplFerldlne- 4-carbonylic acid ethyl ester I ~phenethyl-4-N. propicnylanilinopiperid&ne l-(2-tetrahydrofurfuryl- oxyethyl)-4-phenylpipendrnc 4-carboxylic acid ethyl ester diacetylmorphine dihydrocodeinone 14-hydroxydihydromorphine dihydromorphinóne 4-(m-hydroxyphenyl)- 1-methylpiperidine- 4-carboxyhc acid ethyl cater 6.dimethylamino-5-methyl- 4,4-diphenyl-3-hexanorie 4-(m-hydroxyvhenyl)f~"~"1 4 11 1961. 211. 5 1956. 102. 10 1949, 19. 30 1959. 160. 9 1949. 19. 31 1954. 76. 9 1956. 102. 9 1961. 211. 5 1955. 95. 8 1954. 76, 9 1961. 211. 7 1938. 142. 9 1964. 273. 4 1960. 18*. 3 19~1. 211. 7 1949. 19.30 1949, 19. 31 1949. 19. 30 1952. 57, 6 $ 13 10 11 I 1 I I isomethadone ketobemidone levomethorphan * 1931 1931 1931 1931 1925 1925 1931 1931 1931 1931 3 1 I I 4-propionylpiperidine (-)3.metho~.N-piethy1- morphinan `The references given In this column are so World Health O,ga,cjzatloa: T~hnkal Report Series with the exception of ths report published In 1949 which appeared In Ogclml Records of the Wor$è Health Organizetion, No. 19. PAGENO="0526" 17078 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THIRTEENTH REPORT 19 . ~ INN' -Chemical designation Expert Com,nir,'ee On 4aitrz:on- Produc:nx Drugs Control regime Report num~~er Relerrnce Group Con- vention (-).4-(2-methyl-4.oco. 3 .3-diphenyl-4- (-pyrrolidinyl). butyljmorpholine (-)-3-hydro~y.N-phenacyI. morphinan (-)-3-hydroxy-N-methyj. morphinan 2-hydro~y-2.5,9-trjmethyI. 6.7-benzomorphan. 6-dimcih.Iamino.4,4-diphenyl. 3-heptanone 4-cyano-2-dirriethvlamjno. 4.4-diphenylbutane 6.methyl-t~'-deoxymorphine 6-methyldihydrontorphine 5-methyldihydromorphinone 2-methyl-3-morpholino. 1 ,1-diphenylproparie carboxylic acid 142-enorpholinoethyl)- 4-phenylpiperidine- 4-carboxylic acid ethyl ester 8 10 3 10 12 4 S 12 .8 1958, 142, 8 1960. 188. 5 1952. 57. 6 1960. 18*. 6 1949. 19. 30 1962. 229. 7 1954. 76. 6 1955. 95. 5 1949. 19. 30 1962. 2.29. 7 195*, 142. 8 I I I I *1 I 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 levomctramide levophenacyl_ rnorphan levorphanol' metazocine' methadooc methadone. intermediate methyldesorphine' methyldihydro. morphine' metopon rnoramde- intermediate morpheridine - morphine morphine esters morphine ethess rnorphir,e.N.oajde morphine-N-oxide dcri~3uves morbhzne ~entsvalent nttro~n derivsti~ myrophine' nicocodinc nicomorphine' noracymethadol' norcodeine' norlevorphanol' normethadooe' Dormorphine' norpipanuoe' opium oxycodone osycodone esters oxymorphone' pethidine'. Inyristylbenrylmorphine 6-nicotinylcodeine 3.6-dtnicotinylmorphine (±)-a-3-acetoxy6-methyl. amrno-4,4.dtphcnylhepune N-demcthylcodeine (- )-3-hydroxyrnorphinan 1 1931 1 1931 I 1931 1 1931 1 1931 1 1931 5 1955.95.6 II 1931 12 1962. 229. 6 II 1931 9 1959. 160. 4 1 1931 12 1962. 229. 5 I 1931 9 1959. 160. 5 11* 1931 10 1960. 118. 6 1 1931 ~imewyisminu~,,.ciprwnyj. 5 1955, 95, 7 1 1931 3-hexanone demethylmorphlne 9 1959. 160, 5 1 1931 4.4.dipheny1.6.piperi~jr~o.3. 13 1964, 273. 4 1 1931 hexanone 1925 I4-hydroxydihydroco~ej~o~~ 1 1931 1 1931 14-hydroxydihydromorphjr,an, 5 1955, 95, 6 I 1931 1-meth)14-pheriylpiperidinc. 1 1949, 19. 30 1 1931 4-carboxylic acid ethyl ester `The refesennes ~ve~ In this colump ar~ to World F1&,~ O~anir,aisp~: Technical Report Serle~ with ths exnepUon or the ierore oubhsned tn 1949 whIch appeared in 09km.! Records of the 14*, Health Or t.tzataea, No. 19. $ Reco~nded by WHO Ibr this control reshne. PAGENO="0527" 20 COMPETITIVE PROBLEMS, IN THE DRUG INDUSTRY 17079 ADDICTION-PRODUCING DRUGS Common name . - or INN * Expert Committee ~ .thCUOfl- Chemical Ignation Producing Drugs Re~orij Re~cc' ontrol ~ GruP[~n 12 1962. 229. 7 12 1962. 229. 7 5 1955. 95. 9 * pethidine- s,ntermed,ate-A pethidinc- intermediate-B pcthidine- intermediate-C pethidine- intermediate-C. esters of phenadoxonc phenampromlde phenazocinc phenomorphan ° phenoperidinc° photco.dinc piminodinc proheptazine properldine ° rscsmsthorphan raccmoramide racsmorphan thebacon ° thebalne trimeperldlns 4.cyano-I-methyl- 4-phenylpiperidinc 4-phenylpiperidine- 4-carboxylic acid ethyl ester 1~rnethyI-4-pheny1pipcrid1ne 4-carboxylic acid 6-rnorpholino-4.4-diphenyl- 3-heptanone N-(1-methyl-2-piperidinO- ethyt)propionaniLide 2'-hydroxy-5,9-dimethyl- 2-phcnethyl-6,7-benzO- morphan 3-hydroxy-N-phenethyl- morphinan 1-(3~hydroxy-3-pheny1propyI)- 4-phenylpiperidine- 4-carboxytic acid ethyl ester morpholinylethylmorphine 4.phenyl-1-(3-phcnylaminO- propyl)piner.idine-4-carboxyllC acid ethyl ester 1,3-diniethyl-4-phenyl- 4-propionoxyaztscyclohept*nO I-methyl-4-phenytplperldlne- 4-carboxylac acid isopropyl ester (k)~3.tpotho~y.ti'mcthYl' morphlniin (i:)-4-[2-methyl4-oxo' 3,3-diphcnyl-4-(1-pyrrofldlny0- butyljmotpholinc (±)-3-hydroxy-N.mcthyl- morphinan acetyldihydrocodelnone 3,6-dlmethyl-8-dchydro- morphine ~,2,5-trlmethy1-4-pheny1- 4-proplonoxyplpefidlfle I I I I I I I I II I *.I. I I I I I. I I 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 1931 `I 10 6 11 3 10 6 5 3 8 3 8 1949. 19. 31 1961. 211. 7 1960. 188. 6 .1956. 102. 8 1961. 211. 8 1952. 57. 5 1960. 188. 7 1.956. 102. 11 1955. 95. 9 1952, 81, 7 1958. 142. 8 1952. 57. 6 1958. 142. 9 `the references ijven In this column ae to World Health Orgssnlzaflo,i: Tgchnlcal Reiort SerIes with the exception of ;he rçport published In 1949 whIch app~red In ODlc$ai Records of the WO~(t~ Health Organization, NO. 19. PAGENO="0528" 17080 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY * WHO PUBLICATIONS SUBSCRIPTIONS AND PRICES 1964 Global Subscription The global subscription covers all WHO publications, ie., the combined subscription "C" and, in addition, the Monograph Series, Public Health Papers, Annual Epidernzo. logical and Vital Statistics, and any other occasional publications. £32 5120.00 Sw. ft. 375.-.. 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Is.oaavs 40-224 0 - 79 34 PAGENO="0530" 17082 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From the Federal Register. vol. 44. No. 43, Mar. 2, 1979] [Docket No. 77N-0266; DESI 10996] PROPOXYPHENE PUBLIC HEARING Agency: Food and Drug Administration (FDA). Action: Notice of Public Hearing. Summary: The Commissioner of Food and Drugs announces that FDA will hold a public hearing to receive information and opinions from interested per- sons on the issues of the safety and effectiveness of propoxyphene-containing drug product and whether additional regulatory action is needed in regard to these drugs. The hearing is part of an extensive review of propoxyhene under- taken at the direction of the Secretary. Dates: The public hearing will be held on April 6, 1979, at 9 am. Written or oral notices of participation are due no later than March 23, 1979. Address: The public hearing will be held at the Snow Room (Room 5051), HEW North Building, 330 Independence Avenue SW, Washington, D.C. Written notices of participation should be sent to the Hearing Clerk (HFA- 305), Food and Drug Administration, Department of Health, Education, and Welfare, Rm. 4-65, 5600 Fishers Lane, Rockville, MD 20857. Oral notices of participation will be accepted from persons who find insufficient the time avail- able for submitting a written notice. For further information or to give a notice of appearance oraliy, contact: Robert Nelson, Bureau of Drugs (HFD-120), Food and Drug Administration, Department of Health Education, and Welfare, 5600 Fishers Lane, Rockville, MD 20857, 301-443-3800. Supplementary information: TERMINOLOGY In this notice, DPX, the abbreviation for the dextrorotatory insomer (dextro- propoxyphene) to which is attributed the analgesic effect of propoxyphene, is used to denominate propoxyphene-containing products generally. In some instances, the notice clearly specifies individual drug products or groupings of drug products containing DPX (e.g., .comtdnation drugs, or the drugs in the hydrochloride or the napsylate salt forms). BACKGROUND Propoxyphene (NPX) hydrochloride alone and in combination with aspirin, phenacetin, and caffeine was first marketed ill 1957 `by Eli Lilly & Go. (hereinafter referred to as "Lilly"). Under the law applicable at that time, the drug products (Darvon, Darvon Compound, and Darvon Compound-65) were approved for marketing based solely on evidence of safety. When demonstration of efficacy became a requirement in 1962, DPX was among the drugs reviewed for FDA by the National Academy of Sciences/National Research Council (NAS/NRC). In the Federal Register of April 8, 1969 (34 FR 6264), FDA announced the con- clusion that DPX products (with the exception of the 32-milligram (mg) dose of propoxyphene hydrochloride) were effective "for the relief of mild to moderate pain.' In 1972, because of misleading claims made by Lilly, FDA required the firm to issue the following statements to physicians in a "Dear Doctor" letter: "There is no substantial evidence to demonstrate that 65 milligrams of Darvon is more effective than 650 milligrams of aspirin (two 5-grain tablets), and the preponder- ance of evidence indicates that it may be somewhat less effective. The preponder- ance of evidence indicaites that Darvon is somewhat less potent than codeine. The best available evidence is that Darvon is approximately two-thirds as potent as codeine. Furthermore, there is no substantial evidence that, when administered at equianalgesic doses, Darvon produces a lower incidence of side effects than codeine." In the Federal Register of December 27, 1972, (37 FR 28526) FDA announced a change in the labeling requirements for these products and acknowledged the limited effectiveness of the 32-mg dose of DPX hydrochloride in that: "recent studies have shown that this dose does have an analgesic effect in a certain fraction of the population with mild to moderate pain. While 32 milligrams of proproxyphene is a weak analgesic dose, only the physician attending a par- PAGENO="0531" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17083 ticular patient can determine by titrating the dose whether that individual pa- tient is one of the minority who will respond adequately to the 32-milligram dose, or is one of the majority who will require at least 65 `milligrams to achieve ade- quate analgesia." Because of the abuse potential of DPX-containing `products, they were placed in Schedule IV of the Controlled Substances Act in 1977. In an April 7, 1978 Federal Register notice (43 FR 14739), FDA revised labeling requirements to add warnings on adverse reactions; warnings on interaction with alcohol, tran- quilizers, sedative/hypnotics, and other central nervous system depressants; and information on management of overdosage. In the early 1970's after approval `of new drug applications (NDA's) `based on bj'onvailability studies, Lilly marketed new product's containing the napsylate salt of DPX, either alone (Darvon-N) `or in combination with aceta'minophen (Darvoeet~N) or aspirin (Darvon-N with A~SA). Since then, `more than 50 abbreviated new drug applications (ANDA's) have been submitted and approved for over 30 `~me-too" manufacturers `of D'PX products marketed under a variety `of trade names. Through the years, DPX-contining, products have become among the `most frequently prescribed prescription drugs in the United `States. They peaked in popularity from 1973 to 1975, when retail prescriptions `totalled over 39 million annually. While the `total number of prescriptions ha's declined in `recent years (total for 1978 is 31 million), DPX products are still very `popular. among the 200 most proscribed drugs `for the yea'rs 1972 `through 1977 is shown in Table 1. TABLE 1.-RANK AMONG THE TOP 200 MOST PRESCRIBED DRUGS I 1972 1973 1974 1975 1976 1977 Darvocet-N (propoxyphene napsyiate with acetaminophen) 87 24 20 18 2 12 Darvon 32 mg and 65 mg (propoxyphene hydrochloride)_ 35 47 68 71 78 93 Darvon Compound-65 APC 2 3 3 6 15 20 I Source: National Prescription Audit, MS America. 2 Darvocet-N was divided into two groups (50 and 100) for the year 1977 only. The 1977 rank for Darvocet-N 100 was 18; for Darvocet-N 50 it was 169. The 1977 ranking of 12 for Darvocet-N was derived by aggregating data for Darvocet-N 50 and 100, in order to simplify the comparison with previous years. RECENT DEVELOPMENTS During the 1970's clinical experience with DPX and publication of additional studies on the drug have given rise to some questions about its safety and efficacy. The reservations that FDA expressed in requiring certain labeling changes, described above, exemplify one result of such developments; another is the Drug Enforcement Administration's placement of DPX products in Schedule IV of the Controlled Substances Act. On November 21, 1978, the Secretary of Health, Education, and Welfare was petitioned by the Health Research Group (HRG). Washington, D.C., to suspend approval of the NDA's for DPX-containing products under section 505(e) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 355(e), on the ground that the continued marketing of these drugs represents an imminent hazard to the public health. Alternatively, ~RG requested that if the Secretary did not suspend approval of the NDA's, he would support HRG's petition to DEA that DPX be re- scheduled as a Schedule II narcotic under the Controlled Substances Act (Ref. 1). In response to the request of the Secretary for recommendations concerning these issues, FDA reviewed the following: Data cited by HRG ;~ other available reports of studios on DPX in the scientific literature; information available from the Drug Enforcement Administrations Drug Abuse Warning Network (DAWN) data submitted by Lilly on fatalities resulting from DPX products; information presented before the Monopoly and Anticompetitive Activities Subcommittee of the Select Committee on Small Business, U.S. Senate, on January 31, February 1 and 5, 1979; and information considered at FDA's Drug Abuse Advisory Oom- mittee meeting on February 13, 1979. On February 15, the Secretary announced his decision that evidence currently available does not warrant his invoking the imminent hazard provision of the Act. However, he directed FDA to take several specific actions to warn the public PAGENO="0532" 17084 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of the nature and degree of risk now known to be associated with DPX use and abuse. In addition, the Seeretarey ordered FDA to hold a public hearing on the effectiveness, modes of use, and safety of DPX, and to conduct and complete a comprehensive study of the scientific data on DPX. Highlights of material being studied by FDA are summarized in the following sections on "efficacy studies" and "safety". EFFICACY STUDIES Pro poa~yphene 1. Early studies on DPX seemed to establish that the ((rug was an effective, though mild, analgesic-This was demonstrated by the conclusion of the NAS/ NRC Panel on Drugs for Relief of Pain (Ref. 2). The chairman of the panel was Louis Lasagna, M.D., and expert in the field of clinical pharmacology and anal- gesia. William T. Beaver, M.D., a member of the panel and also an expert in the field of analgesia, concluded as follows in 1966: "In summary, dextropropoxy- phene is a mild oral analgesic w-hich is of questionable efficacy in doses lower than 65 milligrams. The drug is definitely less potent than codeine, the best available estimates of the relative potency of the two drugs indicating that dextropropoxyphene is approximately `A to 2/3 as potent as the latter drug. Like- wise, dextropropoxyphene in 32 milligram to 65 milligram doses is certainly no more, and possibly less, effective than the usually used doses of aspirin or A.P.C." (Ref.3). 2. Further reviews of 1970 anl 1972 confirmed previous views of DPX as effec- tive for mild to moderate pain. The methodology for the clinical assay of anal- gesic efficacy w-as less sophisticated at thnt time, however, and many of the early studies would not meet today's criterial as adequate aiid well controlled (21 GFR 314.111). Thus, in a review paper publi~hed in 1970 by Miller et al., less than 10 percent of the published reports of DPX hydrochloride that were reviewed consisted of double-blind placebo comparisons. Miller cited 9 of 18 placebo-con- trolled trials in which DPX was more effective than placebo and concluded that "Propoxyphene is iio more effective than aspirin or eodeine and may even be inferior to these analgesics * ~ ~ When aspirin does not provide adequate anal- gesia it is unlikely that Propoxyphene will do so" (Ref. 4). Prior to the 1972 labelling changes. Dr. Beaver again reviewed for FDA the pul)lislled scientific literature on DPX products and concluded that they were effective (Ref. 5). At the time of these reviews, it appeared that most of the studies that did not demonstrate efficacy showed significant niethodological problems or lack of assay sensitivity in that they were unable to (listinguish between a codeine or aspirin "standard" and placebo. However, some recent stu(lies have not shown these problems; they appear adequate and well controlled and repeatedly demonstrate the efficacy of other analgesics but have not done so with DPX. 3. Three recent "negative" studies are cited in the HRG petition.-The first is a 1972 study by Moertel et al., in which DPX was compared to other marketed analgesics and placebo in a single-dose trail in cancer patients. DPX, ethohepta- zine, and promazine were not superior to placebo in the relief of pain. Aspirin (650 mg) was found to be the most effective agent, followed by pentazocine. acetaminophen, phenacetin, mefenamic acid, and codeine (Ref. 6). Hopkinson et al. in a study reported in 1973, compared single doses of DPX hydrochloride (5 mg), acetaminophen (650 mg), DPX plus acetaminophen, and placebo in 200 patients with postepisiotomy pain and found that DPX was sta- tistically no better than placebo in the relief of pain (Ref. 7). Gruber, in a two-dose study in 46 patients, compared DPX napsylate (50 to 100 mg) to codeine (30 or 60Mg) and placebo. He found that although there was no measurable difference betweeen either active drug and placebo after the first dose, both drugs were superior in effect to placebo after the second dose (the drugs were not significantly different from each other) (Ref. 8). 4. Not all recent reports are negative.-A 1978 study by Sunshine et al. found DPX napsylate at 200 ing (twice the recommended dose) to be significantly better than placebo. The lowest dose used (50 mg) was slightly better than placebo, but the usual dose (100 mg) was not tested (Ref. 9). These reports reinforce the con- clusions of Beaver in 1966 that the results of DPX efficacy studies "of apparently suitable design. . . are to a degree contradictory" (Ref. 3). In a second review- by Miller in 1977. three studies showed DPX to be no more effective than placebo, and in five other DPX was as effective as the standard PAGENO="0533" COMPETITIVE PROBLEMS IN THE DRUG IND~STRY 17085 agent (Ref. 10). Beaver, in his recent Senate testimony (Ref. 11), note five recent positive studies (Baptisti, 1971; Berry, 1975; Winter, 1973; Young, 1978: and Wang, 1974). Propowyphene combinations 1. For DPX combinations, the efficacy issue is not whether they are effective per se since it is presumed they are at least as effective as the aspirin, acetamino- phen, or APO component. Rather, the question is whether the DPX component contributes to the efficacy of the combination, as required by 21 CFR 300.50 (fixed combination prescription drugs). 2. A 1971 review of studies by Beaver contains one of the earlier views on the efficacy of DPX combinations. Beaver nOted several positive studies (Brooke and Brooke, 1066; Gruber, 1962; i\Iarrs. 1959) and concluded that "although the design and results of available studies comparing combinations of DPX and either aspirin or APC with their individual constituents leave much to be desired, there is substantial evidence that these combinations are more effective than their constituents administered separately" (Ref. 5). 3. Three references are cited in the HRG petition: Hopkinson et al. found that there was no significant difference between the efficacy of acetaminophen alone and that of acetaminophen in combination with DPX. (Acetaminophen alone or in combination with DPX was significantly more effective than DPX alone and placebo (Ref.7)). In a 1974 study of the efficacy of combination drugs containing aspirin, Moertel et al. found that DPX napsylate (100 mg) did not significantly increase the analgesic effect of 650 mg aspirin. (Three compounds, codeine, pentazocine, and oxycodone, did significantly increase the aspirin's analgesic eflect; in addition to DPX napsylate, other substances that did not increase aspirin's analgesic effect were ethoheptazine, pentobarbital, and caffeine.) Moertel noted the "conflicting evidence in the literature regarding the effectiveness of propoxyphene" and con- cluded that "it remains to be clearly established that its popularity reflects true analgesic effectiveness" (Ref. 12). On the other hand, Bauer et al. in 1974 reported the results of a study that did show that the addition of DPX to the anti-inflammatory analgesics (aspirin at three different doses and penacetin at three doses, plus or minus caffeine) pro- duced a significant increase in analgesia. This was a factorial efficacy study of DPX, aspirin, and APC in 610 subjects by two investigators in two separate institutions. DPX was never tested alone, however, and the increased analgesia of the DPX combinations was accompanied by a significant increase in side effects. The authors noted that the aspirin-containing products were packaged improperly, but the possible loss of efficacy due to pharmaceutical instability was not tested by chemical analyses. This positive multifactorial study of the contribution of DPX to the efficacy of DPX combinations is large, contains 10 medication test groups but no placebo control, and has other methodological weaknesses. According to the authors, the data obtained at the two institutions "differed significantly and possibly should not be pooled". Nevertheless, the results were pooled and no assessment of individual studies is possible. Moreover, the most effective treatment group used DPX napsylate at 200 mg (twice the recommended dose). There was also a failure of the relative potency assay assessment for the different doses of aspirin, thought possibly due to the in- stability of the aspirin due to the defective packaging (Ref. 13). 4. A review by Miller in 1977 found that only the Bauer study showed a con- trihution of DPX to the DPX-APO combinations. As noted above, however, the problems of design ~nd analysis in: the Bauer study are substantial. Miller con- cluded that in the interim since his 1970 review, no newly published studies showed that DPX contributed significantly to the efficacy of DPX-aspirin or DPX-acetminophen combinations. In fact, he found that the only recent well- designed studies (Moertel and Hopkinson) showed no contribution of DPX to the efficacy or the combinations of DPX to the efficacy of the combinations (Ref. 10). SAFETY Concerns about the safety of DPX center primarily upon its relationship to the deaths of DPX users, rather than upon side effects associated with the drug, which have been thought to be relatively minimal when the drug is used as di- rected at the recommended doses. Concerning side effects, for example, Miller PAGENO="0534" 17086 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and GreenNatt reported that adverse reactions to DPX in hospitalized patients were infrenquent and mild. The adverse reactions, although qualitatively simi- lar, occurred less often than with codeine and other analgesics used in hospital- ized patients. Standard tolerance studies in volunteers revealed no significant differences between DPX and placebo (Ref. 14). In contrast, Goodman and Gil- man state that in doses eciuianalgesic to codeine it is likely that the incidence of side effects would be similar to those of codeine (Ref. 15).. Reports of deaths in connection with DPX use have frequently relied upon statistics received from the Drug Abuse Warning Network (DAWN) system. This system, from which data are cited in the HRG petition, is a large-scale data-col- lecting system, initiated in September of 1972 and operated for the Federal Gov- ernment on contract by IMS America, Ambler, PA DAWN collects data from over twenty large metropolitan areas in the continental United States and tab- ulates them as the number of "mentions" of a drug after persons have been in contact with or treated by one or three types of facilities: emergency rooms in non-Federal short-term general hospitals (as defined by the American Hospital Association), offices of medical examiners or coroners, and crisis intervention centers. An "episode" is either a drug-related death or a drug-related visit to an emergency room, and a "mention" is the report of a drug associated with an epi- sode. If three drugs were renorted for one episode, for example, three drug men- tions would be recorded. Certain analytical problems `nay arise because of fac- tors such as the lack of precision in reporting (e.g. the names of the drugs in- volved may be given to an emergency room in jargon that makes it impossible to as- sign the mention precisely to a particular drug or drugs) and the limitations in the system itself (e.g. the number and characteristics of the facilities reporting to the DAWN system have not remained constant). Despite these problems. DAWN data are regarded as useful in identifying trends or indicating the development of drug problems. Although the data are not measures of the absolute size of a drug problem, they illuminate aspects of the nature of such a problem, and are helpful in making comparisons among drugs. The DAWN data which follow in- clude only mentions from emergency rooms and medical examiners or coroners, excluding crisis intervention center reports. Althourh for many analyses it is appropriate to limit the data for a given period to that reviewed from consistent reporters, that was not done in this case because of the importance of not omitting any useful information. Table 2 compares DAWN data on coroners' reports of deaths (associated with DPX alone or in conjunction with other factors) with data on emergency room visits. Although there is a slight increase in deaths in 1977 compared with the previous 3 years, this difference is of questionable significance. In most instances, other substances (e.g. tranquilizers) are also implicated in the deaths. TABLE 2.-CORONERS' REPORTS AND EMERGENCY ROOM VISITS IN WHICH PROPOXYPHENE (DPX) IS MENTIONED 1 Year Coroners' reports Emer gency room visits Total DPX only Percent Total DPX only Percent 1974 1975 1976 1977 574 582 477 531 155 137 116 179 27.0 23.5 24.3 33.7 3,565 3,508 3,572 3,434 1,352 1,259 1,318 1,292 37.9 35.9 36.9 37.6 I Source: DAWN data, MS America. Comparisons on safety of DPX and other drugs are shown in Tables 3 and 4. Not only are total DAWN mentions (coroner and emergency room) for the drugs provided, but also comparisons indicating the ratios of DPX-associated deaths to prescriptions dispensed. The data indicate that DPX is the most frequently mentioned single drug on coroner's reports. However, the ratio of DPX-asso- ciated deaths (coroners' mentions) to dispensed prescriptions is low-er than that for the barbiturates. ethclilorvynol. glutethimide. methaqualone. amitriptycline, doxepin, and pentazocine, as show-n in Table 3. When comparisons are made according to drug groupings, as in Table 4. the 1)ropoxyphene rafio is consider- ably lower than that for three other drug groups ("barbiturates," "other seda- tive/hypnotics," and "antidepressants"). PAGENO="0535" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17087 TABLE 3.-COMPARISON OF PROPOXYPHENE WITH OTHER DRUGS; ASSOCIATIONS WITH EMERGENCY ROOM (ER) MENTIONS AND CORONER MENTIONS (DEATHS), 19771 Coroner mentions Rank: Coroner Coroner Coroner mentions! mentions! mentions! Total Emergency emergency million million prescriptions room Coroner room prescrip- prescrip- Drug (millions) mentions mentions mentions tions tions Barbiturates: Secobarbital 1. 2 2, 457 350 0. 14 292 3 Pentobarbital 1. 3 946 272 . 29 209 4 Secobarb/amobarb 1.0 3, 093 326 .11 326 2 Amobarbital * 3 : 130 123 . 95 410 1 Phenobarbital 7. 8 2, 989 254 . 08 32. 6 9 Benzodiazepines: Diazepam 53. 6 21, 678 418 . 02 7. 8 18 Chlordiazepoxide 13. 0 3, 411 54 . 02 4. 2 22 Flurazepam 13. 6 4, 643 80 02 5. 9 19 Other sedative!hypnotics: Meprobamate 8. 2 1, 238 95 . 08 11.6 16 Methaqualone 1. 0 2, 405 62 . 03 62. 0 6 Ethchlorvynol 1. 7 2, 202 135 . 06 79. 4 5 Glutethimide 1.8 639 94 .15 52.2 7 Chloral hydrate 2. 0 618 35 . 06 17. 5 13 Tranquilizers!antidepressants: Trifluoperazine 3. 0 1, 072 6 . 01 2. 0 24 Thioridazine 6. 8 2, 175 74 . 03 10. 9 17 Chlorpromazine 4. 7 2, 404 64 . 03 13. 6 15 Amtriiptyline 9. 0 3, 281 386 . 12 42. 9 8 imipramine 4.6 921 74 .08 16.1 14 Doxepin 4.1 1,397 104 .07 25.4 10 Haloperidol 1. 6 1, 058 3 . 01 1. 9 25 Analgesics: Morphine . 6 134 0 Codeine and codeine compounds.... 49. 8 3, 597 274 . 08 5. 5 20 Fiorinal 7.5 1,204 0 Fiorinal with codeine 2. 3 130 1 . 01 . 43 26 Pentazocine 3.5 1,079 71 .07 20.3 11 Pentazocine compound . 7 4 0 Aspi'in NA 7,184 156 .02 Acetaminophen NA 2, 559 77 . 03 Propoxyphene 33. 5 4, 179 607 . 15 18. 1 12 Other: Diphenhydramine 10. 8 1, 113 23 . 02 2. 1 23 Diphenylhydantoin 8. 6 2, 271 41 . 02 4. 9 21 Methapyrilene!scopolamine (OTC). NA 1, 725 1 I Source: DAWN and NPA data. TABLE 4.-COMPAR1SON OF PROPOXYPHENE WITH 0TH ER DRUG GROUP INGS; ASSOC IATIONS WITH D EATHS, 1977 a - ~ Drug group Total prescriptions Coroner mentions Coroner mentions! million prescriptions Group rank Barbiturates2 3.8 1,071 282.0 1 (Secobarbital, pentobarbital, amobarbital, and seco! amobarbital.) Other sedative/hypnotics2~_ (Methaqualone, ethchlorvynol, glutethimide, and chloral hydrate.) Benzodiaepines (Diazepam, flurazepam, and chlordiazepoxide.) Major tranquilizers (Chlorpromazine, thioridazine, trifluoperazine, and haloperidol.) Antidepressants (Amitriptyline, imipramine, and doxepin.) Other common prescription analgesics (Fiorinal with or without codeine, codeine with or without other analgesics, and pentazocine with 6.5 80. 2 16. 1 17. 7 63. 8 326 552 147 564 346 50.0 7.0 9. 0 32. 0 5. 0 2 6 5 3 7 or without other analgesics.) Propoxyphene with or without other analgesics 33. 5 607 18. 1 4 1Source: DAWN and NPA data. 2 Phenobarbital and meprobamate were intentionally excluded since their predominant use, as anticonvulsant and "muscle relaxant," respectively, differs from other drugs in the same pharmacologic category. PAGENO="0536" 1.7088 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The circumstances under which the DPX-related deaths occurred are a matter of special interest. Particularly relevant are considerations such as whether other drugs or alcohol were also involved, whether an overdose of DPX was taken, and to what extent the deaths were intentional. Although it is impossible to determine precisely the answers to such questions, some generalizations can be made from available data. 1. DPX is a common cause of drug-associated death. These cases involve both suicide and accidents, but a majority of the deaths appear to be intentional. Thus, a tabulation of the 72 DPX-related deaths reported in 1971-1975 by the San Francisco Coroner's Office indicates that `18 Percent of them were suicides (this compares with 10 codeine-related deaths, of which 50 percent were suicides). Analysis of data available from different sources, as shown in Table 5, supports the hypothesis that a substantial propnrtion of l)PX deatins are the result of use l)y those in younger age groups, for suicidal purposes or associated with abuse. Thus, 8-22 percent of the deaths are in the 10-19 age group, which accounts for only 7 percent of the prescriptions; 48-58 percent of the deaths are in the 20-39 age group with approximately 30 percent of the DPX prescriptions. Regardless of age considerations, however, it is apparent that DPX is one of the prescription drugs most frequently associated with suicide and accidental deaths, ranking behind only the barbiturates as a group in total number and behind only l)arhitllrates. other sedative-hypnotics and antidepressants in deaths per million prescriptions dispensed (Table 4). TABLE 5.-PROPOXYPHENE: REPORTED PRESCRIBING, EMERGENCY ROOM VISITS, AND ASSOCIATED DEATHS, BY AGE Percentages by age groups Category 0 to 9 10 to 19 20 to 29 30 to 39 40 to 49 50 to 59 GOandover Reported prescribing of propoxyphenel_ 1 7 239 3 26 35 Emergency room vinitn for suicide gen- turen4 37 40 11 6 4 1 (Total equals 505.) DAWN emergency room data 5 24 40 19 10 66 (Total equals 16, 113.) Deaths: FDA: Probable suicides reported 7 (total equals 173, 50 percent male, 50 Percent female) 22 37 20 14 8 FDA: Probable accidental deaths~ (total equals 48, 40 percent male, 60 nercent female) 13 13 34 17 6 2 Finkle data: Propoxyphene-annoci- ated deaths 8 (total equals 1,022, 45 percent male, 55 percent fe- male). 2 12 27 21 20 11 8 DAWN medical enaminer data (total equals 1,964) 8 35 23 17 17 National Disease and Therapeutic Index, IMS America. 2 Thin figure in for the age group 20 to 39. 2 This figure in for the age group 40 to 59. 4 FDA National Clearinghouse for Poison Control Centers. Drug Enforcement Administration, Drug Abuse Warning Netv.'ork, January 1975 to August 1978. This figure is for the age group 50 and over. FDA spontaneous adverse reaction reporting program. (In 15 percent of the reports age wan not reported.) 8 Reference 17. 2. A majority of the DPX-related deaths appear to have occurred when DPX was taken in conjunction with alcohol or other drugs. Thus, information from various sources, shown in table 6, indicates that in al)out 12-28 percent of the deaths, DPX alone was involved; in the others alcohol and/or other drugs were also present. PAGENO="0537" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17089 TABLE 6.-DEATHS ASSOCIATED WITH PROPOXYPHENE (DPX) Category S ource of data Baselt et al.1 Hine et al.2 Finkle et al.3 FDA DAWN medical examiner reports reports of of accidental or unexpected acci- deaths S dental deaths 1975 1976 1977 Total cases Years involved 29 1973-74 72 1971-75 1,022 1972-75 48 229 187 179 1969-77 1975 1976 1977 Mean age Percent male 38 58 35 56 25 45 30 40 Due to DPX alone: Number 8 14 244 15 56 27 29 Percent of total 28 19.6 24 27 24 12 16 Due to DPX and ethyl alcohol: Number 5 23 238 15 36 40 29 Percentof total 17 32 23 31 16 21 16 Due to DPX and other drug only: Number 8 17 349 10 101 87 79 Percent of total 28 23.6 34 21 44 47 44 Due to DPX and ethyl alcohol plus other drug(s): Number 8 18 191 6 32 26 28 Percent of total 28 25 18 12 14 14 16 1 Reference 16. 2 Reference 18. Reference 17. 4 FDA spontaneous adverse reaction reporting program. 5 Drug Enforcement Administration, Drug abuse Warning Network. 3. At present there is no clear evidence of deaths attributed to DPX products alone when takeis iso recomunended (loses and without alcohol or tranquilizers also l)eing iuivolved. There are, however, several accidental" deaths that have occurred apparently as a result of the consuunptiooi of DPX in quantities only slightly iii excess of recoonunended therapeutic dosage, usually combined with alcohol or tranquilizers or both. Dr. Larry Lewunan, Multnonaala County (Ore- gon) Medical Exauniner, in testiuaoony before the Senate Subcooouoaittee cited previously iua this siotice, presented data in support of this possibility (Ref. 11). While reports such as this are very infrequent, given the wide availability of DPX, they raise couscern that death of persons takiuag the drug at or near the recoonuosended doses may be more common thuaua is ciirreiitly appreciated. 4. The mechanisuas of deaths in cases of DPX overdose is commonly attributed to respiratory depressioua, a typical action of narcotics. This theory is sub- stantiated by a large aauuoul)er of case reports frouaa a wi(le variety of sources. However, the possibility of a speciflc:aisd priunary cardiotoxic effect, independent of respiratory depression has been raised. The demonstration of dose-related ~rogressive condition block appears clear in experinneoatal animals, and iaa soune patiemats with acutely toxic overdoses there are reported electrocardiographic (ECG) chaaoiges. This is not sonexpected ioa view of the local anesthetic activity of 1)0th! DPX and its primary metàbolite oiorpropoxyphene. It Ions been postu- lated that, with chronic dosing, DPX accuunulates to aaear toxic levels and ad- versely affects mnyocardial conduction, but this hans not been the experience in heroin addicts on long-term, highs-dose DPX oaapsylate maintenance. Moreover, when there are ECG changes in DPX overdoses and the CNS depressant effects are reversed by naloxone, the ECG changes rapidly revert to normal when respiration returns (or is mechanically supported) and acidosis is corrected. Therefore; the cardiac changes are uoiost likely se~omadary to hypoxia rather than noi'propoxypheuae toxicity, which would take at least several hours to be reversi- ble. Moreover, as shown in Table 5, only a small percentage of the deaths are in the over GO age group which accounts for 35 percent of the reported prescribing. This population would be presumably more sensitive to any cardiovascular toxicity associated with DPX, but the paucity of deaths in thus age group is notable. Cardiotoxicity at a thoerapeutic dose has not beeoa observed. 5. DPX can produce psychological and physical dependence of the opiate type when taken for an extended period of time. It will substitute for other opiates in addicted persons, but only to a limited extent. Because of the al)use potential of DPX, it was placed in Schedule IV of the Controlled Substances Act. The PAGENO="0538" 17090 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Health Research Group believes the restrictions of Schedule IV are not sufficient to protect the public from the dangers of DPX use and has proposed it be trans- ferred to the most restricted control, Schedule II. REFERENCES The following items specifically cited in this notice, as well as a number of other items related to the DPX hearing, are on file and available for inspection in the office of the Hearing Clerk, at the address specified at the beginning of this notice. 1. l'etition from Health Research Group, Washington, D.C., to Secretary J. Califario, November 21, 1978. 2. National Academy of Sciences/National Research Council; Report of Panel on 1)rugs for the Relief of Pain on Darvon Compound, NDA 10-996. 3. Beaver, W. T., "Mild Analgesics, A Review of Their Clinical Pharmacology (Part. IT) ," American Journal of Medical Science, 25 :576-599, 1966. 4. Miller, R. R., A. Feingold and J. Paxinos, "Propoxyphene Hydrochloride," Journal of American Medicine, 213(6) :990-1006, 1970. 5. Beaver, W. T., Memorandum to Henry E. Simmons, Director, Bureau of Drugs, Food and Drug Administration, May 18, 1971. 0. Moertel, C. G., D. L. Ahmann, W. F. Taylor, and N. Schwartau, "A Compara- tive Evaluation of Marketed Analgesic Drugs," The New England Journal of Medicine, 286 :813-15, 1972. 7. Hopkinson, J. H., IV, et al., "Acetaminophen Versus Propoxyphene Hydro- chloride for Relief of Pain in Episiotomy Patients," The Journal of Clinical Pharmacology, 113 :251-263, 1973. 8. (1ruber, C. M., Jr., "Codeine and Propoxyphene in Postepisiotomy Pain," The Journal of the American Medical Association, 237: 2734-35, 1977. 9. Sunshine, A. J. Slafta and C. Gruber, Jr., "A Comparative Analgesic Study of Propoxyphene, Fenoprogen, the Combination of Propoxyphene and Fenopro- fen, Aspirin, and Placebo," The Journal of Clinical Pharamacology, 18 :556-563, 1978. 10. Miller, R. R., "Propoxyphene, A Review," American Journal of Hospital Pharmacy, 34:413-423, 1977. 11. Propoxyphene Hearings (January 31, February 1 and 5, 1979) of the Mo- nopoly and Anticompetitive Activities Subcommittee of the Select Committee on Small Business, U.S. Senate. 12. Moertel, C. G., D. L. Ahmann, W. F. Taylor, and N. Schwartau, "Relief of Paiii by Oral Medications," The Journal of the American Medical Association, 229(1) :55-59, 1974. 13. Bauer, R. 0., A. Baptisti, Jr., and C. M. Gruber, Jr., "Evaluation of Propoxy- phene Napsylate Compound in Postpartum Uterine Cramping," The Journal of Medicine. 5 :317-328, 1974. 14. Miller, R. and D. J. Greenblatt, "Drug Effects in Hospitalized Patients: Experiences of the Boston Collaborative Drug Surveillance Program, 1966-1975," John Wiley & Sons, New York, pp. 162-164, 1975. 15. Jaffe, J. H. and W. R. Martin, "Narcotic Analgesic and Antagonists," in "The l'harmacological Basis of Therapeutics," 5th Ed., Edited by Goodman, T~. S., and A. Gilman, MacMillan Publishing Co., Inc., New York, pp. 270-271, 1975. 16. Baselt, H. C. and J. A. Wright, J. B. Turner, and R. H. Cravey, "Propoxy- pheiie and Norpropoxyphene Tissue Concentrations in Fatalities Associated with Propoxyhene Hydrochloride and Propoxyphene Napsylate," Archives of Tocvi- cology, 74 :145-152, 1975. 17. Finkel, B. S., K. L. McCloskey, G. F. Kiplinger, and I. F. Bennett, "A National Assessment of Propoxyphene in Postmortem Medicolegal Investigation, 1972-1975," Journal of Forensic Sciences. 21(4) :706-742, 1976. 18. fine, C. H., J. A. Wright, D. J. Allison, B. G. Stephens, and A. Pasi, Anal- ysis of Fatalities due to Acute Narcotism in a Major Urban Area (umpub.). PUBLIC HEARINGS The Food and Drug Administration announces that a public hearing will be held to obtain additional information and recommendations relevant to con- sideration of further regulatory actions on DPX-containing drug products. The PAGENO="0539" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 17091 hearing is open to all interested persons. Participants are invited to comment on the material presented in this notice and to contribute any additional well- documented information that will be of use to the Commissioner in evaluating efficacy, assessing risks, and analyzing risk/benefit considerations associated with the use of DPX and DPX-containing combinations. Specifically, the ob- jective of the hearing will be to gather evidence on the following issues: 1. Is there "new evidence of clinical experience, not contained in the NDA's or not available to the Food and Drug Administration until after such appli- cations were approved, or are there tests by new methods, or tests by methods not deemed reasonably applicable when the applications were approved which when evaluated together with the evidence available when the applications were approved, reveal that the drug is not shown to be safe for use under the conditions of use upon the basis of which the applications were approved"? (21 CFR 314.115(b) (2)). Specifically, how niany of the deaths associated with DPX are suicides; how many are accidents resulting from abuse or misuse; and how many are accidents resulting from normal use? Are there any deaths resulting from DPX taken at recommended doses, either alone or in combination with alcohol and other drugs? What are the blood levels of DPX and its major metalbolite, norpropoxyphene, that are associated with death, and what is the relationship of these levels to those observed when the drug is taken at recommended doses? What is the mechanism of death in these cases? Is it only respiratory depression, or is there a previously unrecognized effect on cardiac conduction? Are there differences in risk among DPX-containing salts and combinations? 2. Is there "lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recom- mended, or suggested in the labeling thereof"? (21 CFR 314.115(b) (3)). Spe- cifically, is there scientific evidence that DPX contributes to the analgesic effect of combination products containing aspirin, acetaminophen, or APC, as required by the FDA fixed-combination policy? (21 CFR 300.50(a)). Are there any differ- ences in effectiveness or other benefits among particular salts or combinations of DPX? In addition, the agency is interested in receiving testimony on whether ad- ditional regulatory action is needed at this time with respect to DPX-containing products. Such action could include, but is not necessarily limited to, removal of some or all of these products from the market, rescheduling under the Con- trolled Substances Act to Schedule III or II, the placing of new warnings in the labeling for physicians or a limitation in the labeling to use in patients who cannot tolerate other analgesics, and/or providing patients with warnings or other information. In a related, though separate, proceeding, the issue of whether DPX should be placed in Schedule II of the Controlled Substances Act, 21 U.S.C. 801 et seq. is being considered by the FDA's Drug Abuse Advisory Committee, which held an initial meeting on the subject on February 13, 1979 and will hold its second and final such meeting on April 17, 1979 to enable FDA to meet a June 1, 1979 deadline set by the Secretary of Health, Education, and Welfare for recommendations on scheduling of DPX. Because that issue is being fully con- sidered in that particular context, it is requested that participants at this hearing not focus primarily on the scheduling issue. The record of another related proceeding, the testimony at the propoxyphene hearings on January 31, February 1~and 5, 1979 of the Monopoly and Anticompeti- tive Activities Subcommittee of the Select Committee on Small Business of the U.S. Senate, is already the subject of review and study by FDA. For that reason, it will be unnecessary for participants to duplicate any of that testimony at this hearing. The hearing will begin at 9 am. on April 6, 1979, in the Snow Room (Room 5051), HEW North Building, 330 Independence Ave., SW., Washington, D.C. The presiding officer will be Ronald Kartzinel, M.D., Ph. D., Director of the Division of Neuropharmacological Drug Products, Bureau of Drugs, FDA. Persons wishing to comment or present views at the hearing must file by March 23, 1979, a written notice Of participation under 21 CFR 15.21 with the Hearing Clerk (HFA-305). Food and Drug Administration, Room 4-65, 5600 Fishers Lane, Rockville, MD 20857. The Envelope containing the notice should be prominently marked "Propoxyphene Hearing." The notice of participation should contain the following: Hearing Clerk Docket No. 77N-0266; the name, address and telephone number of the person desiring to make a statement; busi- PAGENO="0540" 17092 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ness or professional affiliation, if any; the subject of the presentation; and the approximate amount of time being requested for the presentation. A notice of participation may be telephoned to Mr. Robert Nelson, 301-443- 3800 by persons who find there is insufficient time to submit the require infor- mation in written form. Individuals and organizations with common interests are urged to consolidate or coordinate their presentations. The agency may require joint presentations by persons with common interests. It will allocate the time available for the hearing among the persons who properly file a notice of participation and will make a schedule of the hearing available to those persons. Persons may use their allotted time on any aspect of the proposed action, consistent with the conduct of a reasonable and orderly hearing. Formal written statements on the issues may be presented to the presiding officer on the day of the hearing for inclusion in the record. The time available for the hearing may make it impossible to accommodate all those desiring to appear. The Commissioner encourages those not appearing in person to submit their information in written form for inclu- sion in the administrative record of the drug. The hearing will be open to the public. At the discretion of the presiding officer, and as time permits, any interested person in attendance may speak on matters relevant to the issue under consideration after scheduled parties have presented their views. In order to permit time for all interested persons to submit data, information, or views, on the subject matter of the hearing, the administrative record of the public hearing will remain open for 45 days after the hearing is held. Dated: February 26, 1979. DONALD KENNEDY, Commissioner of Food and Drugs. [FR Doc.79-6246 Filed 3-1-79 ;8 :45 am] 0