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2. The Development of Drugs The number and kinds of new molecular entities entering into development are to a large extent a direct result from the activities undertaken and the judgments made in the drug discovery phase. In view of the close relationship between research and development, let us consider some characteristics of drug research and discovery before going into the development process. Although research in various biomedical disciplines relevant to drug discovery takes place in academic, governmental and industrial laboratories, the development process is largely industry sponsored and takes place in industrial divisions and in clinical research settings, often in academic institutions. Historically, close relationships between industry, academia and government have been crucial to drug discovery and development (87~. During the twentieth century the interdependence of industrial, academic, and governmental research has intensified (47,134~. On the one hand, industrial laboratories exploit basic biomedical and clinical knowledge accumulated in academic and governmental settings, including the discovery of biologically active compounds (93~. On the other hand, basic research findings are also made in industrial laboratories, whereas the availability of new drugs often permits advances in basic, non-industrial, research to be made (31~. This reciprocal relationship refutes the popular perception that equates basic research with academia, and subsequently, in a linear fashion, equates applied research and drug development with industry. With the emergence of the biotechnology industry, the reality of this complex interdependence has received new prominence. it, ~ ~ Since the origin of the pharmaceutical industry in the nineteenth century, the nature of the drug discovery process has changed substantially. In the second half of this century drug discovery has, to a large extent, moved away from the random screening of thousands of compounds -- the prevalent mode of operation in Paul Ehrlich's days -- to the more rational design of drugs. This transition was made possible by a burgeoning number of research tools (such as electron microscopes, X-ray crystallography, and molecular modeling) advances in biochemical theo~, and an increasing knowledge of physiological processes in health and disease. However, both serendipity and empirical processes of trial and error remain important elements of drug discovery today ~ A powerful incentive for industrial collaboration with Federal laboratories, such as NTH, in R&D projects was provided by the Federal Technology Transfer Act of 1986. 8

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(130). According to Maxwell (96), four drug discovery approaches can be identified at present: 1. The basic approach This approach entails studies to elucidate new biochemical leads or biomedical hypotheses, which may lead to the synthesis of new compounds. 2. Screening of compounds This screening is usually targeted, i.e. based on a distinct rationale, for instance, blocking of a particular receptor. Because compounds may show unexpected therapeutic activity in other areas, it can be valuable also to perform some general screening. 3. Molecular modification Because the first candidate in a therapeutic class is rarely optimal, the objective of molecular modification is to discover improved agents from a "lead compound", with, for instance, a longer duration of action and/or greater selectivity. Maxwell distinguishes between "enlightened opportunism" and "unenlightened opportunism". The former refers to the molecular modification of pharmacological compounds, identified at an early stage of their development, in order to develop an improved agent. The latter refers to making a close chemical variation of a drug, which often is already widely diffused on the market. This distinction, however, is not always easy to make (see below), since much of this research seek] to overcome shortcomings of the marketed drug. 4. Clinical observations The final source of new drugs can be the clinical observation that a (new) compound has unexpected therapeutic actions in patients9. 9 The following examples would come under this category: "all the main classes of psychotherapeutic drugs (tranquilizers and anti-depressants); thiazide drugs for diabetes insipidus; anti-parkinson action of amantadine; anti- inflammatory action of steroids and pheny~butazone; anti-gout action of abopurinol; anti-arrhythmic action of phenytoin and lidocaine; uricosuric action of probenecid; acetazolamide for glaucoma and epilepsy; diazepam for status epilepticus; protective effects of beta blockers (and the probable protective effects of platelet modulators, including aspirin) against myocardial infarction and coronary death; use of aspirin and sulfinpyrazone in preventing stroke; non surgical closure of patent ductus arteriosus in premature babies by indomethacin". See, Wardell WM, Sheck LE. (138~. 9

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1 - - 1 That these strategies are not mutually exclusive can be illustrated by the discovery and development of beta-blockers. In the late 1940s, clinical research on nerves revealed that the stimulation of one set of nerve pathways, producing epinephrine and norepinephrine, made the heart beat faster and increased the need for oxygen. This research also suggested the existence of two types of receptors in the human body, alpha and beta receptors, that mediated the effects of norepinephrine and epinephrine (1~. This work resulted in the hypothesis by Black, one of the 1988 Nobel laureates for Medicine or Physiology, that blocking one of these receptors, would diminish the heart's demand for oxygen, possibly providing relief to angina sufferers. Black and his colleagues at Imperial Chemical Industries (ICI) tried to develop analogues of an earlier discovered compound dichloro- proteronol (118~. This compound had been found to have beta- adrenergic blockade activity, but also had partial agonist (sympathomimetic) activity. They first developed pronethalol (15), which was found to have considerable human side effects, such as nausea, vomiting and light-headedness. They then developed propanolol (16), first marketed as Inderal, which was free of the agonist activity of dichloro-protereronol and the side effects of pronethalol. The discovery and development of beta- blockers thus demonstrates the importance of "the basic approach" and the interaction with strategies 2 and 3. In the words of the Nobel committee's citation, "while drug development had earlier mainly been built on chemical modification of natural products, they (the laureates) introduced a more rational approach based on the understanding of basic biochemical and physiological processes" (109~. Following the introduction of beta-blockers into clinical practice, it was observed that beta-blockers also played a role in lowering blood pressure, preventing heart attack and coronary death. Finally, the proliferation of various beta- blockers has resulted in a number of more selective drugs as well some as so-called "me-too'' drugs (54~. a One caution needs to be made in this respect. As the research and development process is so lengthy, a number of companies may have started working on a clinical problem at roughly the same time, but reach the market at somewhat different times. Regarding beta-blockers, for instance, the British {CI and the Swedish ASTRA started roughly at the same time, but ICI was first to market. Astra's subsequent beta-blocker can not be simply defined as a me-too drug. 10

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Over time, the drug discovery and research process has become increasingly complex and sophisticatedly. Interesting compounds are extensively screened both in vitro and in Volvo for pharmacological and toxicological effects~2. There has been a rapid increase in the number and kinds of toxicological tests (~S,153,154~. Following short-term animal tests, long-term animal studies are initiated to detect possible mutagenicity, carcinogenicity, and teratogenicity. These studies often continue for a number of years concurrent with initial human trials. In testing biotechnology-based drugs, however, toxicology studies in animals do not always make sense when the new biologicals are products of human genes and are functionally species specific. More in general, animal tests sometimes have variable relevance for predicting the effects of an agent in humans. The changes in preclinical testing are reflected in the time spent in this stage of the research process and the costs incurred. While the duration of preclinical (animal) tests was approximately one year in the mid 1960s, it increased to approximately three and a half years in the early 19SOs, with a concomitant increase in costs (76,95~. Yet, uncertainty remains a crucial element in drug discovery and preclinica] research: the attrition rate traditionally has been such that of roughly each 10,000 compounds synthesized, 1,000 wait go into animal research, and only 10 wait initiate human testing (141~. In the United States, the decision to proceed with the development of a compound, including its clinical evaluation, in first instance involves a drug company and the Food and Drug Administration (FDA). Subsequently it engages clinical investigators, Institutional Review Boards (IRBs), and the research subjects themselves. The 1962 amendments to the Food, Drug and Cosmetic (FD&C) Act require a sponsor to apply to the FDA for permission to initiate human testing with an Investigational New Drug (IND). The purpose of such an IND application is to protect human subjects, in part by making sure that the proposed clinical investigations are as efficient as possible to minimize the numbers of patients exposed to the risks of such trials. An 7~ Drug discovery and preclinical research is governed directly by federal Good Laboratory Practices (GEP) regulations, however, the investigational new drug regulations exert strong feedback pressures on how research is undertaken, especially to~cologica] research. ]2 Patent protection is extremely important to drug research. Usually patents are filed early in the research process, preferably when there is a clear distinction between the active and inactive compounds. There are 3 types of patents: of a compound; of the use of a compound for a specific purpose; of procedural methods of manufacture. 11

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IND application must contain essentially all of the information then known (the mean size of an IND is 1,250 pages) on the nature of the new compound, formulation and identification methodologies, stability information, manufacturing methods, the methods and results of preclinical animal studies, the proposed clinical development plan for trials, and the identity and qualifications of clinical investigators~3. The FDA classifies IND applications according to a compound's chemical type and its potential benefit, to determine priority for review. In principle, clinical trials can start 30 days after the FDA receives an IND application, unless the agency orders a "clinical hold". After an IND application has been approved, a multi-stage process of clinical investigation starts: the demarcation lines ~ . .~ . w between tne various phases are somewhat fluid. Human testing is initiated with Phase ~ studies, which ordinarily last between 6 months and ~ year. These studies usually involve 20 to 100 healthy human volunteers, except in the case of drugs with potentially high toxicity levels -- such as neoplastic or AIDS drugs -- where it is considered ur~ethica] to subject healthy humans to the risk of these side effects, and thus patients are involved from the beginning. The objective of Phase ~ studies is to provide information on the dose of an experimental drug that might be used, how often, and especially on potential side effects. While drug absorption, metabolism, excretion, and some effects on tissues and organs are measured, a major concern is acute side effects in humans. Drug administration begins at very low single doses (for instance, one-eighth of the lowest dose that has caused a measurable effect in the most sensitive animal species), followed by multiple doses if no adverse effects are encountered as the dose is increased (83~. Safety concerns in this phase may include acute cardiovascular reactions, gastrointestinal `disturbances, CNS disturbances, bronchopulmonary reactions and anaphylactic reactions (154~. These studies generally involve both laboratory testing and clinical observation. ]3 Part 312, Title 21, the Code of Federal Regulations, specifies the procedures surrounding a "Notice of Claimed Investigational Exemption for a New Drug". Over the years the IND regulations have continuously been revised, resulting in a very complex system of requirements. Concerns were put forward that the interpretation of these regulations were unduly delaying the drug development process. An attempt was therefore made to rewrite these regulations in 1987, but according to the former legal counsel of the FDA this rewrite did not result in any significant changes (10,42~. 12

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Development was discontinued during Phase I studies of 20 percent of the drugs that initiated human testing 14~136~. The reasons for these discontinuations are in safety (S percent of the 20 percent), efficacy (6 percent of the 20 percent), and lack of commercial interest (6 percent of the 20 percent). Not uncommonly, chemical and pharmacological research on back- up compounds is pursued in case the compound undergoing development is discontinued due to side effects or lack of efficacy. For example, the anti- arthritic drug, pirox~cam, was the third member of a new chemical series (the oilcans), but the first one to make it to the market. Simultaneous with Phase ~ clinical studies, technical development activities take place to improve a particular compound's formulation. In developing a suitable tablet or capsule formulation, a number of physical, chemical, and pharmacology issues need to be resolved, such as the use of stabilizing agents (e.g., anti-ox~dants), micro-encapsulation, or the development of slow release forms to achieve the optimum rate of absorption. Phase IT clinical studies involve a few hundred patients and usually they may take several months to two years. The main emphasis in Phase IT studies is to examine the efficacy of a compound in treating the clinical problem for which it is intended75. At this point, the endpoints are selected that wall be pursued both in Phase rat and in Phase TIT studies. A major issue is the choice of endpoint, should one focus solely on intermediate endpoints, such as changes in biochemical, physiological and anatomical parameters, or should one also include clinical endpoints, such as effect on mortality, morbidity, or quality of life. These decisions, involving complex considerations regarding the disease, 14 This FDA study (136), analyzed a cohort of 172 NCEs initiating human testing in the years during 1976 through 1978. Not unexpectedly, new molecular entities developed outside of the US are less likely to be discontinued than US- developed ones (14% versus 24%), as the foreign developed entities have- usualI~ already been clinically tested outside the US. 1 One of the major changes embodied in the 1962 amendments was to include the provision that a sponsor needs to provide Insubstantial evidence!' of "effectiveness" as weld as of "safety" (Federal Food, Drug, and Cosmetic Act, as amended, Sec. 505 Odds. While effectiveness refers to the probability of benefits under average conditions of use, efficacy refers to this under ideal conditions of use. The law uses the term effectiveness to make explicit that drugs are approved and labeled for use under the genera] conditions of medical practice, not the more idealized conditions often found in an investigational setting (107~. Extending this argument, it is for this very reason that we will use the term efficacy in the context of pre-marketing clinical investigations. 13

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the time frame of treatment, and the scientific and regulatory acceptability of the relationship between intermediate endpoints and disease treatment. They can have a considerable impact on the scope of the development process. Traditionally, a number of intermediate endpoints, such as lowering blood sugar in diabetes or lowering blood pressure in severe hypertension, have been accepted as valid by the various parties involved in drug development. In other, more recent cases involving intermediate endpoints, such as clot lysis in myocardial re-infarction or the increase of hematocrit levels in anemic dialysis patients, there has been considerable disagreement about their value. For instance, in the development of recombinant erythropoietin (epo), a stimulator of red blood cell development, a nine-center, 300 patient efficacy trial demonstrated significant increase of hematocrit levels, while none of the patients developed antibodies to epo. The FDA found hematocrit increase alone insufficient proof of efficacy, and required additional evidence of clinical benefit. The company was able to demonstrate a reduction in the number of transfusions, and improvements in exercise tolerance and patient welI-being. The license application is being reviewed (38~. A number of factors may influence the acceptability of the kind of endpoints to pursue. For example, in hyper-cholesterolemia clinical endpoints such as myocardial infarction (death) may take a long time to develop, and thus practical reasons dictate the use of intermediate endpoints such as reduction of EDL-cholesterol. In this case the acceptability of intermediate endpoints is heightened because the association between the intermediate endpoint and the clinical problem is perceived to be strong (33~. The crucial question, however, often is not whether to pursue intermediate or clinical endpoints, but which endpoint should be pursued at which stage in the development process (especially pre- or post-approval). This question is important because the traditional notion of what constitutes valid clinical endpoints is evolving. Since many therapeutic agents for today's chronic `degenerative diseases only treat symptoms, the focus in clinical evaluations is shifting toward measuring long-term benefits and risks. Furthermore, it is increasingly apparent that risks and benefits should be measured not only in terms of reducing mortality, but in terms of improving functional status and quality of life. Such quality of life studies are becoming more important in the pharmaceutical area. Recent examples are provided by quality of life evaluations of auranofin and captopri] (12~. Phase II studies also attempt to detect short-term side effects. The safety concerns in Phase IT and in Phase ITI studies include cumulative organ toxicity, hypersensitivity reactions, metabolic abnormalities, endocrine disturbances, and if women of childbearing age are involved, teratogenicity (154~. 14

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The Food, Drug and Cosmetic Act requires "substantial evidence ... of safety and effectiveness ... consisting of adequate and well-controlled investigations". Phase IT studies mostly are double-blinded, randomized controlled clinical trials. While placebo-controf is the design of choice, the agency will accept no- treatment controls, standard treatment, and even historical controls (107~. The well-designed randomized controlled trial (RCr) is generally regarded as the statistically most powerful method to determine efficacy26 (102~. The essence of a RCr is that patients are randomly assigned to a treatment group, which receives the experimental drug or a control group, which receives a placebo, standard treatment or no treatment. According to Chalmers (27), a clinical trial is ideally quadruple-blinded: the therapy is disguised to physicians and patients (double-blinded), as is the randomization process and the ongoing results. Both randomization and blinding reduce biases; the differences in health outcome can thus be attributed to the intervention, within the limits of statistical methodology. In a welI-designed trial, the numbers of patients and the endpoints are chosen to obtain clinically important and statistically significant results. The degree of complexity in determining efficacy and safety depends on the therapeutic class to which the experimental drug belongs. At one end of the spectrum are the anti-infectives. Efficacy testing of these compounds is a relatively straightforward assessment of whether the compound kills the microorganism at the site of infection. Due to the acute nature of most infections, there may be less need for chronic toxicity testing. At the other end of the spectrum are psycho-pharmacological drugs. Determination of efficacy in psychiatric diseases, with a complex interplay of neurobiological, environmental and psychological factors, is difficult. There are fewer objective tests for psychiatric disorders and one often deals with 'soft' measures, thus a drug is subject to a wider range of tests. As these drugs may often be taken for long periods, chronic toxicity tests are needed. These varying degrees of complexity are reflected in the duration of the development process; for example, the development of psychopharmacological agents takes 3.1 years longer than cardiovascular drugs, and 7.3 years longer than anti-infective agents (76~. ]6 Were are a number of design variations, such as crossover, stratified, matched and factorial designs (56~. ]7 Randomization reduces selection and blinding reduces observer bias. ~8 For example, the size should be such as to avoid both Type ~ errors (the likelihood that an observed difference is due to chance) and Type IT errors (the chance that a difference of interest is missed due to too few patients). 15

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Within the total clinical development spectrum the highest drop out rate for new molecular entities occurs during Phase IT studies when 39 percent are discontinued (136~. The FDA analysis lists as reasons for these discontinuations safety (13%), efficacy (12%) and economic considerations (15%~. That efficacy and 'lack of commercial interest' are prominent reasons is not unexpected if one considers that the main objective of Phase IT studies is to determine efficacy, and that the line between "no efficacy" and "not enough efficacy to be competitive" may be quite fluid. With the rising costs of development (see Chapter 5), increasingly studies of the potential market for a drug occur during Phase IT and Phase ITI studies. The relative prominence of safety reasons is in part due to the fact that the results of long term animal studies are usually obtained at this point in the development continuum. At the end of Phase IT studies, a recent change in the U.S. regulatory scheme permits a sponsor to obtain a so-called Treatment IND for comoouncIs intended] to treat immediately life-threatening ~iseases~9. @ ~ ~ .~ ~ ~ - ~ ~ - ~ ~ This system makes experimental drugs available at a reasonable cost before marketing approval for terminally ill patients not enrolled in clinical trials. A recent example of a Treatment IND drug is pentostatin, for patients with hairy cell leukemia. With drugs for very serious (but not immediately life-threatening) diseases, a sponsor may request a treatment IND in the course of Phase ITI studies. During Phase IT and Phase Ill clinical studies much industrial effort is directed, usually by chemists and engineers, toward process optimalization and 'scaling up' for productions. The scaling up for ail efficient production process, Involving pilot plant operations and various other process and quality control measures, is a crucial part of the development process. By the time an investigational drug is ready for Phase Ill studies, quite a good picture of its safety and efficacy usually has emerged, at least for a market approval decision. Only 5% of the compounds initiating Phase Ill trials are ]9 The agency already had some experience with such an approach, for instance, since the mid 1970s promising anticancer drugs (so-called group C cancer drugs) were distributed on a limited basis prior to approval through the National Cancer Institute (152~. 20 The process by which a compound is initially synthesized and milligrams to grams of materials are made at the laboratory bench is not only quantitatively but is also qualitatively different from the large-scale production process. For instance, laboratory chemists may use reagents to prepare small quantities of a compound, that can not be used in a large-scale production setting, which may need to produce a ton of a particular compound per year. 16

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discontinued. These trials commonly involve up to several thousand patients (2,000 - 3,000), usually they are multi-center trials, and often they are multinational in scope. On average they last between ~ to 4 years. The purpose of these controlled trials and open (uncontrolled) studies is two-fold; to further carte a compound's therapeutic effects, for example by studying dose levels and schedules in larger patient groups, and to provide information on the side effects and possible toxicity of the drug candidate. These Phase Ill studies are important in determining what wall be in a package insert for the drug and thus what market claims can be made for a new entity in advertising. There are inherent limits to how much can be known about a drug prior to its general use in everyday practice. It is weld accepted that the detection of delayed or rare (less than 1:10,000) adverse events may require long time periods of exposure, a latent period to have expired or the exposure of thousands of patients. Wardell(139) points out that a sample size of 306,000 for each group would be needed to detect a difference between an incidence rate of I/10,000 and 2/10,000 at the 90% power level (using a two-sidec} test, a = 0.05~. Some serious toxicity may occur much less frequently, for instance chioramphenicol induced aplastic anemia probably occurs only in 1:40,000 to 1:50,000 exposures (84~. However, for side effects of drugs that have less than fatal consequences but are medically important the important difference to detect is between 1:500 and 1:1000 or 1:10,000. Furthermore, as Wiener(149) argues, failure to detect adverse effects in Phase IT! studies may be more than a matter of time and numbers. Side effects may be influenced by environmental factors, and variations in physician or patient characteristics (such as differing pharmaco-genetic profiles, or the use of other drugs, etc.~. The occurrence of these side effects may go unnoticed in carefully controlled and selected pre-marketing studies; their detection will require actual patient care settings. While the full picture of the risks involved may become apparent only with the widespread diffusion of a drug, this argument equally can be made about benefits. The full range of information on effectiveness of a drug cannot be expected to emerge in Phase IT! clinical trials that are designed to test the null hypothesis of efficacy. The eligibility criteria for these trials almost invariably excludes a spectrum of at risk patients, such as those with multi-morbiclities, those using many drugs, and special patient croups. such as I-- r--7 ~ pregnant women, newborn, children or the very of. Thus, the findings of RCrs may not easily be applicable to the total patient population, especially if linearity cannot be assumed in extrapolation (91~. It follows that pre-marketing clinical studies are of necessity incomplete in developing information that can _, 2 Increasingly, if a drug is expected to be used extensively in a particular population such as the elderly, it is studied in that specific population. 17

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be used to optimize medical use of a drug. A marketing approval decision therefore can never be an all benefits known and no-risk situational. At the end of Phase Ill trials a New Drug Application (NDA) or, in the case of a biological, a Product License Application (PLA) is usually submitted to the regulator agency, with a request for approval to market a specific compound for the indications specifies] in the application. The FDA ranks NDAs according to their review priority (41~. A drug, for instance, that is a "new molecular entity", not previously marketed in the United States, and that promises to provide "important therapeutic gain" (i.e. may diagnose or treat a disease not adequately treated or diagnosed by any marketed drug), receives the highest priority rating. An NDA contains detailed information on the laboratory formulation and chemistry of the drug, the results of all investigations, the manufacturing process, quality control procedures, the labelling of the drug, and samples of the drug in its proposed dose and form. Commonly an NDA encompasses over 100 volumes of information containing 60,000 pages each. Electronic NDAs, which contain the data in machine readable form, are becoming more common and may prove important in facilitating the FDA review process. This review process involves a team consisting of at least a medical officer, a pharmacologist and a chemist24. If 22 Unless, of course one would be willing to delay the marketing of new drugs for extremely long periods of time. This, however, would increase another kind of risk, i.e., the risk of not having a new or improved drug available on the market. 23 The following classification of TNDs, and also of New Drug Applications, exists according to chemical type: 1.a new molecular entity not marketed before in the US; 2.a new derivative from an active ingredient already marketed; 3.a new formulation of a drug already on the market; 4.a new combination of 2 or more compounds; S.a duplicate of an already marketed drug; 6.a new indication of use for an existing drug. With regard to the potential benefit, the following distinction is made: A."important gain", i.e. may effectively treat or diagnose a disease not adequately diagnosed or treated by any marketed drug; B."modest gain", i.e. offers modest, but read advantage over existing products; C."little or no gain", i.e. essentially offers similar therapeutic benefit as already marketed drug. Orphan drugs, i.e. drugs developed for rare diseases (in principle with less than 200,000 american patients), are handled under a different system, which explicitly incorporates marketing and tax advantages for the sponsor. Such systems also exist in other regulatory schemes, within the U.K. Committee on the Safety of Medicines, e.g., the "fast track" system. 24 The chemist in the team, among other things, requests an inspection 18

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applications concern significant new drugs or involve complex issues, they may be referred to an advisory committee for review and. recommendations (79~. With regard to biologics, licensing committees are used to provide the expertise as appropriate to the product. The FDA review time on average takes 2.5 to 3 years (76~. After a new drug is approved for marketing, coverage and reimbursement decisions by third-party payers can affect the diffusion of a drug and hence the development continuum25. These decisions should be placed within the context of a country's health care reimbursement policies. At present, these policies are changing in an attempt to contain health care costs; see, for instance, Medicare's prospective payment system, pro-generic substitution laws, and restrictive hospital formularies. With these changes, coverage is becoming a more important decision point in the process, as illustrated by the heated debate surrounding Medicare's decision not to authorize extra reimbursement for tissue plasminogen activator (TPA). One consequence is that cost analyses and cost effectiveness studies are becoming a much more prominent part of a drug's evaluation; for instance, cimitidine.. However, these analyses and their influence on decision making are outside the scope of this paper26. Following the marketing approval decision, a new drug generally diffuses into clinical practice (with the active help of marketing professionals). With the present-day chronic diseases, some of the most important therapeutic information, both on rare and delayed. side effects and on long-term effectiveness, can be. prodded only after a new drug has been used in everyday practice. The objective of so-called Phase IV (or post-marketing) studies is to report to be made to ensure that the sponsor adheres to good manufacturing practices (43~. 25 At this point a firm needs to also determine its price. The pricing ~ . ~ . ~ ~ . ~ . ~. . ~ ~ ~ ~ ~ . mechanisms, and the subsequent drug prices, as well as the health insurance or social security schemes differ considerably per country. In the US, there are few government restrictions on setting drug prices. In Britain, however, the prices of drugs are controlled under the Price and Profit Regulation Scheme. Under this scheme, the government and the specific pharmaceutical industry agree upon a reasonable rate of return. This scheme thus institutes a target rate of return (in essence it controls profits), and it allows price increases only to work through new products, thus providing an incentive to innovate (98~. 26 One development deserves mentioning as it directly influences drug development. In view of rising health care costs, 3rd party payers are some- times refusing to reimburse even the routine costs of medical care associated with clinical trials of experimental drugs. 19

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provide this information. This can be done by performing additional controlled clinical trials or by using observational (non-experimental) surveillance systems. The importance of these studies is underlined by the fact that new indications often are discovered only in clinical practice and subsequently drugs may be prescribed for these (unapproved) indications. One should realize that the FDA only regulates the introduction of new drugs and not their use in medical practice. Only experimental Phase IV studies may be used to request approval for a new indication and to change the drug labelling. In addition, these studies have sometimes been encouraged by manufacturers from a marketing standpoint, to create a pool of physicians familiar with the drug (99~. Most industrialized countries have some kind of post-marketing surveillance system to detect potential adverse effects. Such a system generally depends on a variety of methodological approaches, as no single method is fully effective. One approach depends on adverse effect reporting (75~. In the United States, physicians traditionally report suspected adverse effects voluntarily to the company (the FD&C Act requires manufacturers in turn to immediately report these effects to the FDA). In addition, physicians may voluntarily report suspected adverse effects directly to the regulatory agency, the medical literature, or to disease or specialty registries27. While advantages of adverse effect reporting are its potential coverage of the entire population and low operation costs. important weaknesses are found in incompleteness and , _ ~ . . . ~ ~ . . ~ inaccuracy. For example, due to a variety of factors, there is considerable under-reporting; the overall return on the U.K. Yellow Card System is estimated to be only 10 percent. - ~ ^^ warn adverse ettect reporting one also cannot measure the incidence of the risk. Furthermore, this reporting is by nature a hypothesis generating activity, the subsequent testing of the hypothesis will depend on other methods. Methodological approaches for further analysis of adverse events reported by physicians or manufacturers (and for monitoring signals of suspected adverse effects) include experimental and observational methods. While experimental methods have especially been applied to further examine efficacy post approval, risk measurements in specific patient populations are sometimes also undertaken. At present, however, there is increasing interest in epidemiological studies, such as case control and cohort studies. to measure adverse drug effects28. The advantage of cohort studies is that they can establish the likely 27 In the United Kingdom, for example, the well-established system of physician reporting to the Committee on the Safety of Medicines operates through the so-called Yellow Card system. 28 Cohort studies compare people exposed to a drug with those unexposed, 20

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incidence of the risk. Disadvantages are that they are potentially expensive and may yield the results more slowly than case control studies. Case control studies are useful if the frequency of events is very rare (up to 1:10,000~. Disadvantages are that controls are often difficult to establish and the studies can not establish absolute risk. The proliferation of large-scale automated data bases, such as those maintained by HMOs or Medicaid, may open up exciting possibilities to study a drug under general conditions of use. These data bases may contain demographic data, drug prescription data, or patient hospital admission and discharge data. With advances in computer capabilities, it is increasingly possible to link different data bases, for instance, pharmacy record with medical record data bases (20~. In essence, the Drug Surveillance Research Unit, initiated by Inman (72) in the United Kingdom in 1980, is based on this principled. In the same vein, the FDA has carried out a number of hypothesis testing studies using Medicaid and other medical record linkage data bases. Industry is also increasing its efforts in pharmaco-epidemiological research. As these large- scale data bases exist for other reasons, their operating costs are much lower than those associated with registries. In addition, they may lack the reporting bias and the inadequate follow-up that renders case studies problematic (146~. However, limitations exist in the adequacy of the data collected in these data bases (see below). As argued above, Phase IV studies also need to examine the long-term effectiveness of a drug. Since the early 1970s, the FDA has sometimes requested post-approval research as a condition of approval, often with good reason (see, for instance, the approval of levo dope). Studies done post approval to examine the benefits of a drug, in different patient populations or using different dosages, are usually an extension of the type of studies done and analyze differences in adverse events between both groups. Case control studies compare groups exhibiting a particular event with those not exhibiting this event, and then they examine differences in exposure to a particular drug. See, Report Joint Commission on Prescription Drug Use, for an extensive discussion of these methods (74~. 29 This system has become a second national scheme to detect adverse drug reactions (ADRs) greater than one in 10,000, and to evaluate the balance of risks and benefits of a drug. Using prescription based cohorts as a starting point, this system actively solicits responses from physicians. The response rate is 70%, approximately 22,000 general practitioners report regularly, and the system catches nearly 50 million people. Monitored events are followed up by analysis of the medical records of the patients. 21

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pre-marketing approval (94~. In addition a number of large-scale randomized trials have also been undertaken post approval that were funded not by the sponsor, but, for instance, by. the National Heart Lung and Blood Institute. In view of the very high costs associated With these large-scale trials, between $10 million and $100 million dollars, the number of such RCrs is limited (86~. Furthermore, as mentioned above, the RCr may not always be most helpful as a foundation for therapeutic decisions. It has therefore been proposed that modern observational methods could play an important complementary role to the RCr for assessing the effectiveness of a drug. Major weaknesses traditionally associated with these methods have made the determination of. the cause-and-effect relationships between drug use and outcomes more difficulty. However, in recent years there have been advances in the design and the execution of observational studies, which may address some of these weaknesses (see Chapter 5~. 30 For example, the series of cases has been found to be subject to different kinds of physician and patient bias. Cohort studies, for example, may include limitations such as the exact specification of the cohorts, limited quality of the data in terms of reproducibility and validity, difficulty to analyze the attributable agents, and the occurrence of detection bias. The US Surgeon General's first report on smoking listed 5 supporting criteria to establish a cause-effect relationship: consistency of the association; temporal relationship between cause and effect; coherence with existing insights; specificity of the relationship; strength of the association. See also, Feinstein (45~. 22