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11 Attitudinal Factors That Influence the Utilization of Modern Evaluative Methods KENNETH L. MELMON This volume has focused on assets and liabilities of data gathering method- ologies and the ultimate application of the data to modify use of drugs, devices, and procedures. The medical profession's attitudes may affect the gathering and application of data. The profession's actions seem to reflect a disincentive to data gathering in spite of the fact that doctors and their patients have the most to gain from the acquisition of important outcome information. I believe the pro- fession has unwittingly, yet emphatically, developed and perpetuated a serious deficiency in gathering and assimilating the available data necessary to make optimal medical decisions. The origin of the disincentive and its effects are the subjects of this chapter. The theme of the conference on which this volume is based contains two assumptions: (1) fundamental understanding of the development of technology will improve effectiveness and efficiency of the development; and (2) the meth- ods of clinical evaluation are key determinants of whether and how new tech- nologies~rugs, devices, or procedures- are developed and applied. The majority of the conference discussion concerned itself with the method- ologies for clinical evaluation that can be used mainly to fulfill the needs of a regulatory process, but secondarily to help in medical decision making. We have not asked whether the regulatory process is sufficient for gathering data necessary for the optimization of medical practice or how attitudes of medicine are pervasive in affecting what methods of clinical evaluation are used or disre- garded. I will argue that data generation sufficient for regulation of new chemi- cal entities seems to be the major determinant of the methods of clinical evalua- tion used and who uses them. Those data are satisfactory for regulatory' purpos- 135
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36 KENNETH L. MELMON es but fall far short of what is needed to optimize physician decision making on the use of new drugs, devices, or procedures (1-3~. We must clearly separate what is necessary for adequate regulation of new drugs, procedures, and devices from what is necessary for good medical prac- tice. We also must make it clear that the agency of regulation is not legally responsible for the best possible use of an approved device, procedure, or drug. Morally, if not legally, the profession is responsible for the nuances of use that optimize the medical value of new technologies. We should clearly be aware that the Food and Drug Administration (FDA) does not need post-marketing surveillance data (PMS) on drug effects to justify its decisions for release of a drug to the market. Indeed, if the FDA does not need PMS to justify or cross- check the validity of decisions to release drugs, it needs even less information about the post-marketed effects of devices or procedures. THE FOOD AND DRUG LAW AND CLINICAL EVALUATION I believe that the Food, Drug, and Cosmetics Act is thoughtful and appropri- ate. The mandates of the act and the performance of the FDA in relation to the mandates are adequate for their intended purposes. Some will argue that the FDA's actions are inadequate, but few, if any, would suggest greater complica- tions to the process. Should we tamper with the regulatory process so that it collects additional information to ensure optimal use of a drug, a procedure, or a device? I believe that, if we tamper with the regulatory process to meet medical needs, it would so distort the process and focus of regulation that soon it would become impossible for the agency to regulate as effectively as it does today. In fact, some would say that the passive behavior of the profession already has dis- torted the process and crippled it by asking more than legitimately can be expected from the agency based on the food and drug act. Because it may not understand them, the medical profession does not seem to have defended the minimal and legitimate regulatory requirements needed for marketing a drug. In the hearings that I have been involved with that examine the regulatory process, I have never heard an individual representing medicine saying, "Senator, despite your responsibility in writing the food and drug act, you misunderstand what we can and should expect from the regulatory process. You even misunderstand what you should expect of the process. You condemn regulators for not knowing everything about a marketed drug before it is mar- keted. Yet to expect more than is known today at the time of marketing may lead to fewer drugs being developed and no better use of those drugs than today." The regulators are and should be the determinants of the regulatory methods and process in the context of the food and drug act and its amendments. Most scholarly reviews of the process conclude that methods used for clinical evalua- tion of new chemical entities are quite sufficient for the regulatory responsibili- ties that have been assigned to the agency. But inherent restrictions within the
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INFLUENTIAL A17lTUDlNAL FACTORS 137 legislation mean that the process does not include gathering data upon which to base the optimal practice of medicine. The FDA, by mandate of the food and drug act, works without an explicit definition of safety and efficacy of a new chemical entity. This open-ended expectation translates into the most reasonable and economical strategy for industry to use. The null hypothesis is used to prove or disprove the potential for efficacy of a new chemical. The approval is valid because the method is efficient and the most likely medical use of a new entity cannot be anticipated and therefore cannot be tested for. In a practical sense, one usually considers toxicity the unwanted effects that are found in the process of proving efficacious actions that can be attributed to the chemical entity. Obviously, testing the null hypothesis for efficacy often requires exposure of relatively few patients (usual- ly fewer than 1,000) to a drug and those often for only brief periods. Thus, it is not surprising that information adequate to prove some of a drug's potential value will not predict the full spectrum of the drug's effects (positive or detrimental) when it is used in the field. The FDA's own studies in 1983 bear out some of the shortcomings of the information about drug toxicity developed during testing for efficacy (see below). While the data are more than sufficient to approve a drug for important efficacy, complete efficacies and the demogra- phy of toxicity remain undefined. A second restriction on the regulatory agency is that it may not interfere with the practice of medicine. This law-based admonition means that the agency in effect has only a binary response to any information obtained about effects of marketed drugs. The agency can allow the whole profession to take it or leave it. That is, the F DA can only totally restrict the drug from the market or leave it on for unrestricted use. The agency usually is not in a position to restrict distri- bution of the drug, or to restrict use to subsets of practitioners or patients. It should not be in such a position. Medicine must find the optimal use of a marketed drug while it is being used. Medicine should continue to have this latitude to modulate indications, and put toxicity of marketed drugs into perspective (2,4~. We should not be sur- prised that the vast majority of marketed drugs ultimately are used for unap- proved purposes and in unapproved dosages, as IMS America told the Joint Commission on Prescription Drug Use. Because the FDA cannot regulate the optimal use of a drug, there are few incentives for it to search for post-marketed effects of drugs. Nevertheless, that search does uncover important uses for the practice of medicine (nuances of efficacy and toxicity) that usually are less dra- matic than would be needed to label the drug as an eminent public health haz- ard. Only in the latter circumstance is banning truly "legal" or at least justifi- able. Although the FDA may be perceived by medicine as an agency that should help gather data to make therapeutic maneuvers as good as possible, that is not their duty. In fact, to unrestrictedly hand them this task could create important conflicts of interest for them. The agency could then be blamed by politicians
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38 KENNETH L. MELMON for having data that allow initial acceptance of a drug, but later appear to "justi- fy" modulation of medical practice or question established use patterns of the drug. In each instance the agency is restrained from further action by law. Yet if the agency tries to make up for the deficiencies in information used by the profession, the medical officers of the agency become vulnerable to politically driven criticism. The spokespersons for the medical profession have to begin thinking serious- ly about the information they want that will be sufficient for the best possible use of marketed drugs. They can start by appreciating the wisdom of the food and drug act and publicly protecting the performance of the agency in its most important legal functions. Medicine then must develop a clear understanding of the effects that the two restrictions on the food and drug act have as determinants of company strategy used to develop a new chemical entity. Medicine must also come to understand the legitimacy of the restrictions and the responsibility they place on medicine to systematically gather post-marketing data. Medicine must grapple with the fact that the majority of uses of prescription drugs are for unapproved indica- tions. Perhaps that situation is created because the profession is uneducated. But it is more likely that the profession is perceptive and is getting its informa- tion on the new uses of drugs from medically based sources that are not interest- ed in or adequate for regulatory purposes. Those sources, by using interven- tional and observational techniques, can provide legitimate data about how to use a drug, a device, or procedure only after the technique is made generally available. WHAT IS THE VALUE OF THE EVIDENCE PROVIDED BY PRE-MARKETING AND POST-MARKETING STUDIES? In pre-marketing studies the manufacturer is simply and legitimately chal- lenged to show a biological effect that is likely to have some medical meaning. In the context of that efficacy, the experiments must show whether the drug is basically safe. Thus, an objective of the experiment is to use the drug for as short a period as possible and in the smallest possible doses in diseases that allow ready measurement of efficacy. The unexpected effects of a drug, if they are to appear in pre-marketing test- ing, will have to occur almost every time the drug is given, or at least 1:100 to 1:500 times that the drug is given. To know events that occur as infrequently as 1:10,000 or 1:50,000 exposures can be medically important, but these events can be found only after the drug is used in the practice of medicine (51. Inevitably there will be legitimate major medical limitations of pre-market- ing data for the understanding of a drug once it moves into the field. When the drug is used in patients with a variety of other diseases for which useful therapy is available, and when alternative therapy and devices might be applied to the same indication for which the new drug is used, we cannot predict whether the
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INFLUENTIAL ATTITUDINAL FACTORS 139 efficacy expressed in the designed careful studies will be seen. We cannot pre- dict the adversity caused by such drugs in complicated field situations. When adverse effects occur, we cannot predict whether they occur only in the context of expected efficacy or whether they occur in situations for which the drug was never intended or proven efficacious in the first place. Being able to dissect these kinds of events and to link efficacy with toxicity in the field sit- uation is a key factor in appropriate management of the drug by the profession. Alvan Feinstein (6) alluded to medical situations in which we cannot fairly or thoroughly test a drug, device, or procedure before it is used in the field. The medical community is the only resource we can call on to verify that the poten- tial efficacy attributed to a pre-market drug actually expresses itself after the drug is marketed. Testing a drug on the fetus would be unconscionable. Many diseases are chronic and slow to respond definitely to any intervention. Therefore, it becomes impractical, if not impossible, to subject patients with these diseases to protracted pre-marketing testing (5~. Surrogate endpoints must instead be used to test, for example, for efficacy in the treatment of hyperten- sion and osteoporosis. The legitimate effects of drugs on such diseases often may best be estimated by using the observational techniques this conference has focused on. Despite the fact that they are not used for regulatory purposes, observational studies complement experimental studies of drug effects. It is impossible to mimic what will happen in the field during the experimental study of a new chemical entity when some type of efficacy is proved or disproved. Observational studies can fill crucial gaps in our understanding of what drugs will do in practice settings, many of which are unavailable for intentional exper- imental study. DISINCENTIVES AND INCENTIVES TO THE GATHERING OF POST-MARKETING DATA If expectations of pre-marketing studies are legitimate, and if the FDA is truly restricted from interference with the practice of medicine, then the agency has a disincentive to find effects that better serve as modulators of appropriate use than as signals of unbalanced danger. The additional important effects of a drug that make it useful to medicine may actually muddy regulatory waters. Thus, the agency needs to hope that the medical community will worry about itself enough to effectively find the true information about efficacy and toxicity in the field. Those hopes have been answered in the United Kingdom and Scandinavian countries but despite their logic and feasibility have not been sys- tematically applied in the United States. Yet, the most relevant and abundant signals created by drugs, devices, and procedures only occur in our midst and by our orders.
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140 KENNETH L. MELMON The major disincentives for the FDA to gather more data than is necessary to vouch for defined efficacy with acceptable toxicity stem from the political over- sight of the agency. Congressional hearings and the efforts of some public caus- es over newly found data on drugs can be framed in such a way as to be unfairly demoralizing to the agency. If new and more important efficacy is revealed of a marketed drug, the overseers can ask why it was not found sooner; when serious adverse effects that are not serious enough to be considered imminent public health hazards are revealed, the overseers condemn the regulators for releasing the drug in the first place. Even with such criticism, the agency is not usually able to use the new data to relabel the agent for new indications nor is it empowered to restrict use of the drug unless the information is gathered to meet precise and sometimes unnecessary specifications. Why then should the agency accept responsibility to gather data that would be more useful to medicine (to modulate its behavior with the drug) or to industry (to define the most appropri- ate market for the drug)? The law and the restrictions on regulatory action on marketed drugs are fore- most in creating disincentives for the FDA to reach out for more information after a drug is approved. The agency has every right to expect academics, orga- nized medicine, or industry to pick up the challenge to get the needed data, because each of those parties generates the data, can easily access it, and has so much more to gain than the agency from getting and understanding the meaning of the data from the field. Yet each party may have its reasons for wishing to avoid responsibility for gathering and interpreting field data. Academics seem to have unjustly relegat- ed the fields of epidemiology, general health services research, and pharma- coepidemiology to the outer fringes of legitimate scholarship. Industry has been quite suspicious of post-marketing surveillance, probably because they feared additional data would be used in some regulatory or quasi-regulatory manner. Perhaps another industry concern about PMS is that those in industry may not have confidence in the medical value and effects of some of their prod- ucts. The latter concern certainly could be valid if study were to focus on some of the popular drug-indication pairs that intuitively seem senseless, e.g., the rather widespread uses of B-12 in the absence of real indications or antibiotics for the treatment of viral diseases. In this day and age of costly and effective drugs, one has to wonder why PMS is not a regular part of industrial developmental strategy to define efficacy and gather data in order to defend against some unjustifiable swipes at entities considered for banning. Conversely, certainly Sterling-Winthrop would have benefited if aspirin's cardiovascular effects were established decades ago. So would it have been valuable for industry and medicine if cyclosporine's effects on Type I diabetes, low-dose heparin's prophylactic actions on pulmonary emboli in hospitalized patients, etc. were known long before today. Only absence of interest retards recognition of additional similar market-expanding and therapy-optimizing data on other drugs.
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INFLUENTIAL ATTITUDINAL FACTORS 141 Organized medicine's lack of effective interest in PMS is difficult to under- stand. How can medicine restrain itself from pressuring academia and industry to get and use, as soon as possible, the inevitably useful data on medical maneu- vers? Sadly the profession has not awakened fully to the value of PMS that will help to optimize the use of chemical entities, diagnostic or therapeutic proce- dures, and devices. yenning very convincingly pointed out the considerable barrier we have constructed against recognizing and using unexpected signals caused by marketed drugs. As he studied medically substantial adverse drug reactions of the last decade (incidence 1:500 - 1:10,000), he demonstrated how quickly leads on unexpected events caused by newly marketed drugs are found and confirmed but how slowly medicine's habits change to accommodate the new information (7~. Even worse than yenning's observation about our defects in using data about drugs is the way that medicine discovered the amazingly severe adverse responses to practolol. The drug caused three impressive diseases that were not seen spontaneously—complete blindness, recurrent complete small bowel obstruction requiring surgery, and severe pulmonary failure. These diseases were caused by fibrous overgrowth of the cornea, the serosal surface of the bowel, or the interstitial areas of the lung. In spite of the fact that the incidence of these events was 1:500, and that the events were initiated shortly after the therapy, it took several years of hundreds of thousands of courses of treatment per year with practolol before the first case was suspected. Once physicians were told of the first incidence, they rapidly confirmed the observation. But overcoming what seems like the embarrassment of the first suspicion or obser- vation took truly herculean efforts. These examples show that in spite of many discoveries of important effects of drugs after marketing, the profession does not understand the limitations of the regulatory process and the need to be sensitive and tuned to receive and use those data. Medicine does not seem to understand that possibly the most impor- tant information about a drug only will be seen in the process of its use in the field. The profession is not taking advantage of the information that is generat- ed. We are not minimizing the time that it takes to see the event and to transfer the knowledge into clinical action. The American medical profession has provided very scanty new information about effects of drugs. What we usually do is to simply confirm and report the effects that already have been described. The profession has not shown that it has accepted its role in melding data used for regulatory purposes with PMS information. CONSEQUENCES OF SHIRKED RESPONSIBILITY BY ACADEMICS AND THE PROFESSION Politicians readily focus on the regulatory agency's actions. Any open review guarantees publicity and involves little political risk. After all, the pub-
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42 KENNETH L. MELMON kc naturally is at least as concerned about safe and efficacious drugs as they are about safe airplanes. But if the medical profession does not describe the limits of the expectations of pre-marketed study of drugs and devices, how can the public? It appears that doctors do not know enough about marketed drugs when they use them, do not press for systematic post-marketing surveillance, and almost never balk at or criticize verbal attacks on the agency and its staff. Thus, the way is cleared for a politician's sharp lance. The FDA knows the limitations of pre-marketing studies and the futility of extending them to guarantee that all important medical effects of drugs will be known before the drugs are marketed. The agency can and has explained that, in order to find drug effects that occur 1:10,000 times a drug is used in a pre- marketing phase, it requires at least 30,000 instead of the usual 2,000-4,000 subjects for experiments. To get an expected incidence of 1:40,000 with a rela- tive risk of 2 (incidence data in chloramphenicol-induced aplastic anemia), 3,000,000 subjects would have been needed (5~. Clearly the profession did not explain what easily could have been expected from it. Few, if any, from our profession stood up for or even behind the FDA to defend the regulatory pro- cess when critics said much more should be known about drugs before they are marketed. When academics and the medical profession shirk responsibility for under- standing limitations of the regulatory process and leave post-marketing data gathering to whatever sporadic collection occurs, the pressure on the FDA to know more increases. The agency's expectations of itself for knowing more about drugs and devices than is known after potential efficacy is established is only natural. Yet the drive to learn more runs counter to the legal terms of the food and drug act. The ambivalence these countercurrent drives create probably is responsible for certain irrational behavior of the agency. Many in industry and some in academia complain that trivial, unnecessary, and time consuming pre-marketing expectations of drug testing frequently add inordinate delays to drug development. This disgruntlement is most likely to occur when the same chemical entity already has been released in a foreign market. Some believe that the delay in release at home is simply to bide time while PMS takes place on foreign soil. By such delay, effects caused by the drug that only can be seen in the field may be revealed. If they occur in the 1:100 to 1:10,000 range and are truly severely adverse, the FDA has in its delay tactics developed a substitute process for lack of systematic PMS in the United States. It simultaneously escapes unjustified but inevitable criticism from polit- ical oversight groups that always want the FDA to know more. The American medical profession has become dependent on monitoring of drugs outside of the United States. Although William Inman is not the only source of information on marketed drugs, it is amazing how much the Western World relies on one man for such vital data. The deficiency of PMS does not simply lead to suboptimal decisions by doctors, it may also contribute to wide- ranging negative effects of technology transfer into the medical field. In spite
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INFLUENTIAL A7TlTUDINAL FACTORS 143 of the availability of cost-effective and valid methodologies, we can count on the fact that they will not be well applied. Fewer data than are needed will be gathered to justify and extend the early decisions to market a drug or device or validate the use of a procedure. In a meeting in New Milton, England, in 1986 Ollie Miettinen and Walter Spitzer gathered data that demonstrated that drug banning also is often based on inade- quate inflation (84. The fault for irrational decisions to ban lies not solely with the accusations that a drug may have dangerous properties but also with the absence of organized data that refute or validate that accusation. It was not wrong to be worried about possible hepatic and anaphylactic potential of Xomax and the phocomelia produced by thalidomide. But it was professionally incorrect not to have collected data to balance the decisions. We should have known whether the adverse effects were valid and collected data that demon- strated expected efficacy and potential unanticipated efficacies in very impor- tant diseases. If we had been systematic in our data gathering, we would have known today whether Xomax, as opposed to other non-steroidal anti-inflamma- tory agents, truly could have reduced the incidence of myocardial infarction, pulmonary embolism, and stroke that was attributed to it only after the drug was withdrawn from the market (9~. We would have known today whether thalido- mide could have a major role as an immunosuppressant. It might have become uniquely useful for some of the most vexing problems in medicine (rheumatoid arthritis, type I diabetes mellitus, multiple sclerosis, lepromatous leprosy, rejec- tion of transplantation, etc.) (10~. We have a dearth of safe drugs available for immunosuppression and many transplant patients would have been at no risk for thalidomide's potential to cause birth defects. Unsubstantiated banning can cre- ate disincentives and increased risk and cost of technology transfer into our field. We will never know the true value of Xomax and thalidomide because the signals they were creating in the field have ceased. Are we next going to elimi- nate coumadin from men with prostatic cancer because we do not want to cause bleeding in patients with myocardial infarction? The FDA itself contributes evidence of its frustration related to where the line should be drawn on its responsibilities. In 1983, the agency studied the value of pre-marketing studies of 16 recently marketed drugs. The drugs repre- sented 30 percent of the FDA approvals from 1975to 1981. They were drawn from categories that comprise 40 percent of drug use in the United States. The agency concluded that the average time to the release of the drug was 8.2 years, and that half of the time was spent in Phases I and II. During those phases, rela- tively little was learned about the efficacy of the chemical, but everything that would be discovered about adverse reactions showed up. No additional adverse reactions were discovered in Phase III when efficacy truly was being tested. Furthermore, the data collected about the quantity of adverse responses exag- gerated those that would be found during short-term drug use and underestimat- ed those for the long-term drug use in the field. Not surprisingly, adverse and
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44 KENNETH L. MELMON efficacious effects that followed long-term use were not detected in the pre-mar- keting tests. To compensate for the deficiency of pre-marketing studies, the agency, probably with tongue in cheek or at least with some frustration, con- cluded that Phase III studies should be extended. But this conclusion was inval- idated by their own data. They had shown that drop-out rates were at least 30 percent if Phase III studies extended beyond 12 to 18 months. Thus, Phase III studies could not be straightforwardly extended into Phase IV. If that was to be done, only the patient group at least risk to continued drug use would be the subjects of Phase IV. What is the FDA to do without careful, systematically executed PMS studies using combinations of the methodologies described in this conference? What can we do about the likely fact that the agency knows the profession does not have but could use better data about the drugs and devices we have at our disposal? GATHERING BETTER INFORMATION ON USE AND EFFECTIVENESS DOES NOT MEAN CHANGING REGULATORY POLICY The major factors that lead to overextension of the legitimate efforts of the FDA as they attempt to evaluate the ultimate effects of drugs, devices, and pro- cedures also lead to underutilization of available and useful methodologies. The factors can be summarized succinctly. First, there is no systematic post- marketing surveillance in the largest single marketplace for drugs, devices and procedures. Second, the medical profession has shown little, if any, leadership in developing or using post-marketing signals. The origin of such disinterest probably lies in the misunderstanding by the profession of regulatory responsi- bilities and the power of pre-marketing testing. We may have developed inap- propriate confidence in the sufficiency of the regulatory process for providing data that can be used to optimize medical practice. We certainly have misunder- stood by underestimating the profession's role in generating the data we need and relieving the regulatory agency from half-hearted and incomplete post-mar- keting functions. Finally, because of the fundamental flaws in our expectations of the regulatory groups, medicine has forced compensatory moves that are costly in every sense of the word. I believe that any serious student (from academia, industry, or government) of the regulatory process has to respect the intent of the food and drug act, the development of the FDA, and the functions and the effect of the process as it responds to the law. The scholar also would have to conclude that what may be adequate for regulatory purposes is inadequate for medical purposes and even for evolving regulatory purposes (self regulatory and/or governmental regulato- ry purposes) once a drug or device is approved or a procedure appears. Answers to the problem of adequate data about the use of medical tools must come from the profession. We (the profession) and the industry must back appropriate regulatory decisions. To do this and to generate the ways and
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INFLUENTIAL ATTITUDINAL FACTORS 145 means to deploy the methodologies discussed in this meeting we must: (1 ) understand the value of signals generated by new technologies not only at the time of their initial use but also well through their history. (Where would we be today if aspirin had been banned early in its use because it caused gas- trointestinal bleedings; (2) understand the profession's role in monitoring events and interpreting generated signals; (3) educate ourselves and the govern- ment and non-governmental politicians to respect the process and judge it on solid bases that do not employ the temptation to make a drama of science; (4) play a modulatory role to ensure that those who have the courage and sense to use the tools available to them have the wisdom to use them well or optimally; and (5) show the industry not only how to gather and use post-marketing data to help physicians understand how best to use their tools but also to define the market for a product and protect its life so it can be fully utilized. Criticism should always be available to those who help create opportunity in our environment, but it should not be restricted from self. Applied well, criti- cism would greatly enhance the efficiency and extent of generation of knowl- edge and the rate, extent, and use of technology transfer. REFERENCES 1. United States Congress. Senate. Final Report of the Joint Commission on Prescription Drug Use for the Subcommittee on Health & Scientific Research of the Committee on Labor & Human Resources. U.S. Government Printing Office: Washington, D.C., 1980: 1-153. Strom BL, Melmon KL, Miettinen OS. Post marketing studies of drug efficacy: Why? American Journal of Medicine 1985;78:475-480. Snell ES. Postmarketing development of medicine. Pharmacy International February 1986;33-37. Strom BL, Melmon KL, Miettinen OS. Post marketing studies of drug efficacy: How? American Journal of Medicine 1984;77:703-708. Strom BL (ed). Pharmacoepidemiology. New York: Churchill Livingstone, 1989:423. 6. Feinstein A. Remarks made during roundtable discussion. Institute of Medicine conference on "Improving the Translation of Research Findings into Clinical Practice: The Potential and Problems of Modern Methods of Clinical Investigation." May 1989, Washington, D.C. 7. yenning GR. Identification of adverse responses to new drugs. Parts I-m. British Medical Journal 1983;268:199-202, 289-292, 365-368, 458-460. 8. Melmon KL. Adverse effects of drug banning. Journal of Clinical Epidemiology 1989;42~9~:921-923 9. Inman WHW, Rawson NSB. Zomepirac and cardiovascular deaths. Lancet 1983;2:908. 10. Mechanisms of reactions in leprosy. Lancet 1972;2:580-581. 2. 3. 4. 5.
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Representative terms from entire chapter: