4
Clinical Research and Drug Regulation

In perhaps no other area has the impact of AIDS been more clear than in the identification, clinical testing, and regulation of new drugs. The effects have been so extensive and the pace of change so rapid that it is difficult to describe all the important events within the confines of a single chapter. Yet it is still too soon to identify changes that are merely transient phenomena versus those that will endure (Henninger, 1990). Although there are early indications that the changes witnessed in AIDS research may be affecting pharmaceutical development for other diseases, it remains unclear whether AIDS will appreciably alter the development of drugs in general, especially for conditions that are less lethal or less common.

Perhaps the most profound change wrought by AIDS in the area of drug development is simply the dramatic increase in public awareness, especially regarding the very existence, as well as the structure and purpose, of clinical trials. Terms such as "randomized," "placebo," and ''double-blind," although perhaps not household words, are nonetheless regularly used in the mass media. Debate about the ethics and scientific validity of clinical trials occurs not only among physicians, statisticians, and ethicists, but also among patients, activists, and politicians. AIDS has opened the arena of clinical investigation—the organization, ethics, and politics of research—to media and public scrutiny.

The impact of the HIV/AIDS epidemic on clinical research poses a series of important questions with broad implications for the practice of science and medicine. For example, to what extent have changes been



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The Social Impact of Aids in the United States 4 Clinical Research and Drug Regulation In perhaps no other area has the impact of AIDS been more clear than in the identification, clinical testing, and regulation of new drugs. The effects have been so extensive and the pace of change so rapid that it is difficult to describe all the important events within the confines of a single chapter. Yet it is still too soon to identify changes that are merely transient phenomena versus those that will endure (Henninger, 1990). Although there are early indications that the changes witnessed in AIDS research may be affecting pharmaceutical development for other diseases, it remains unclear whether AIDS will appreciably alter the development of drugs in general, especially for conditions that are less lethal or less common. Perhaps the most profound change wrought by AIDS in the area of drug development is simply the dramatic increase in public awareness, especially regarding the very existence, as well as the structure and purpose, of clinical trials. Terms such as "randomized," "placebo," and ''double-blind," although perhaps not household words, are nonetheless regularly used in the mass media. Debate about the ethics and scientific validity of clinical trials occurs not only among physicians, statisticians, and ethicists, but also among patients, activists, and politicians. AIDS has opened the arena of clinical investigation—the organization, ethics, and politics of research—to media and public scrutiny. The impact of the HIV/AIDS epidemic on clinical research poses a series of important questions with broad implications for the practice of science and medicine. For example, to what extent have changes been

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The Social Impact of Aids in the United States driven by scientific, ethical, economic, or political considerations? Has AIDS merely accelerated changes that were already occurring in cancer research, or do they represent a clear departure from the practices of the last two decades? When changes have occurred, have they been defined narrowly for AIDS or more broadly constructed? How can change be monitored in the future, and can the likely long-term critical impact of such change be predicted? This chapter begins with a brief historical perspective on clinical research and drug development prior to the advent of the HIV/AIDS epidemic. It is important that the interplay of politics, science, and ethics in this area be recognized as an ongoing dynamic during the twentieth century; it has been shaped by AIDS but it was not created by it. The chapter then describes drug development from 1981 through late 1991—the age of AIDS—and analyzes the impact of social institutions and events on the process and, conversely, the impact of the process on such institutions as the Food and Drug Administration and the National Institutes of Health. The development of social and political activism is examined as a major force for generating change. Finally, the chapter summarizes how key areas in clinical investigation and drug regulation have been shaped by the HIV/AIDS epidemic. HISTORICAL PERSPECTIVE1 Several developments of the post-World War II era establish a baseline for evaluating changes driven by the HIV/AIDS epidemic. Those developments relate to four major historical shifts: (1) the development of randomized clinical trials as orthodox research methodology, (2) changes in federal drug regulation, (3) the evolution of protections for human research subjects and the growing recognition of ethical dilemmas inherent in research, and (4) the rise of patient advocacy and the changing dynamics of patient-physician relationships. In the postwar era, and especially since 1960, considerable change has taken place in each of these areas. The AIDS epidemic has had powerful effects on clinical research and the culture of science. Randomized Clinical Trials Although experimental approaches to clinical medicine date to antiquity, it was only in the 1940s and 1950s that contemporary approaches to the evaluation of medical treatments and technologies were fully articulated and began to be put into practice. Randomized clinical trials—experiments in which human subjects are randomly assigned to experimental and nonexperimental (control) groups for purposes of comparison—offer researchers

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The Social Impact of Aids in the United States considerable advantages in evaluating new drugs and other medical technologies. First, variability among subjects will, on average, be equally distributed, thereby reducing the potential for selection bias. Second, because such studies are generally conducted on a double-blind basis (i.e., neither the researcher nor subject knows which group a given subject is in), randomized clinical trials offer a mechanism for reducing investigator bias (W.A. Silverman, 1985). Third, randomized clinical trials permit the use of sophisticated statistical tests of significance in the comparison of treatments. According to their proponents, prospective, double-blind trials offer the potential to place clinical medicine, at long last, on a truly scientific base (Marks, 1990). As biostatisticians have recognized, the development of randomized clinical trials was perhaps the most important methodologic advance associated with the scientific basis of therapeutics (Zelen, 1990). Despite these advantages, randomized clinical trials did not immediately become the basic rule of clinical investigation. Such studies were expensive to conduct, administratively complex, and required new skills that many investigators lacked. Furthermore, investigators expressed a critical awareness of the difficult ethical dilemmas posed by randomized trials. As statistician A. Bradford Hill (1951:279) explained: The first step in such a trial is to decide precisely what it hopes to prove, and secondly to consider whether these aims can be ethically fulfilled. It need hardly be said that the latter consideration is paramount and must never, on any scientific grounds whatsoever, be lost sight of. If a treatment cannot ethically be withheld then clearly no controlled trial can be instituted. Researchers, attuned to this question, attempted to specify those conditions under which a particular treatment could be withheld for the purposes of a randomized trial (Chalmers, Block, and Lee, 1972). According to most researchers, randomization could be justified only in instances in which there was genuine ignorance concerning the advantages and disadvantages of an experimental drug; only then could a researcher claim "therapeutic indifference" (Hill, 1963:1047): It must be possible ethically to give every patient admitted to a trial any of the treatments involved. The doctor accepts, in other words, that he really has no knowledge at all that one treatment will be better or worse, safer or more dangerous, than another. … If the doctor does not believe that, if he thinks even in the absence of any evidence that for the patient's benefit he ought to give one treatment rather than another, then that patient should not be admitted to the trial. Only if, in his state of ignorance, he believes the treatment given to be a matter of indifference can he accept a random distribution of patients to the different groups. … By certain omissions from a trial we may limit the generality of the answer given by it, but on

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The Social Impact of Aids in the United States ethical grounds that, in my experience, must be accepted [emphasis in original]. In order to retain this state of ignorance as the process of collecting data began, trials were designed to isolate researchers from findings. This was accomplished by establishing an advisory panel, usually including expert biostatisticians, to monitor the data as they accrued. Such panels were empowered to halt a trial at the earliest time that a scientific conclusion, usually defined as statistically significant, could be reached. In practice, despite this mechanism, such determinations about when a trial should be ended proved to be complex (Chalmers, Block, and Lee, 1972). In addition to the justification of therapeutic indifference, proponents of randomized trials also cited the fact that experimental preparations were sometimes scarce and that randomization offered a means of allocating drugs in a socially constructive manner (Rutstein, 1970). Such was the case with the Medical Research Council's streptomycin trials of 1946 (Hill, 1963:1043): When, in 1946, the Medical Research Council's Streptomycin in Tuberculosis Trials Committee set out to investigate the effect of that drug in pulmonary tuberculosis it was faced with no serious ethical problem. The antibiotic had been discovered two years previously … the published clinical results were distinctly encouraging though not conclusive. Yet overriding all this evidence in favour of the drug was the fact that at that time exceedingly little of it was available in Great Britain. … Except for that situation it would certainly on ethical grounds have been impossible to withhold the drug from desperately ill patients. With that situation, however, it would, the Committee believed, have been unethical not to have seized the opportunity to design a strictly controlled trial [emphasis in original]. Despite these early attempts to define clear ethical criteria for randomization, withholding unproven but potentially beneficial treatments has remained controversial. So-called treatment indifference is far more simple to establish in theory than in practice (Johnson, Lilford, and Brazier, 1991). Drugs are subjected to controlled trials because there is already some evidence that they may be effective. This hope, which may or may not be borne out through further investigation, nevertheless shapes the research environment, especially in instances in which there is little to offer patients with serious, life-threatening disease. Jonas Salk, for example, opposed double-blind trials of the vaccine he developed against polio. In Salk's mind, the research he had already conducted demonstrated the effectiveness of the vaccine; to conduct a full-fledged randomized trial, he concluded, would be merely a "fetish of orthodoxy" and would lead to more new and unnecessary cases of paralytic polio among the group receiving the placebo. Other researchers countered that without a full randomized clinical trial the

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The Social Impact of Aids in the United States effectiveness and safety of the vaccine would never have scientific and medical credibility, a requirement if doctors, parents, and children were to accept immunization (Carter, 1966; Brandt, 1978a). In this respect, it was argued that only through rigorous trials would it be possible to avoid "therapeutic anarchy," in which clinicians, based on experience and anecdote, would do as they saw fit. Randomized trials would add scientific evidence and legitimacy to clinical judgment (Feinstein, 1967). Proponents also pointed out that only randomization could adequately identify not only the beneficial impacts of experimental drugs but also their significant dangers and side effects (Chalmers, Block, and Lee, 1972). The difficult ethical considerations that attend randomized clinical trials remain a critical part of the debate concerning "therapeutic research," a term used to denote research conducted on subjects who, it is hoped, will benefit from the experimental preparation. When are randomized trials justified? How should they be organized? Is it ethical, in effect, to toss a coin to assign patients to a particular treatment? How can the conflicts between the desire to further scientific knowledge and the commitment to act in the interest of individual patients be resolved? Does the very act of randomization violate basic norms of the doctor-patient relationship (Fried, 1974; Schaefer, 1982)? In randomized clinical trials, conflicts inevitably arise between the group and the individual, between the desire for scientific advancement and an individual patient's welfare. Attempts have been made to moderate such conflicts, but they can never be absolutely and categorically resolved. All these issues were debated prior to the AIDS epidemic, but the epidemic gave them a new immediacy. What would be the nature of clinical research in the midst of the epidemic (Eckholm, 1986)? With the onset of the epidemic and the establishment of a research program, the techniques of drug evaluation and experimentation and the ethics of randomized clinical trials came under intense scrutiny. The Food and Drug Administration and the Politics of Drug Regulation Since the early twentieth century, federal regulation of food and drugs had been largely reactive to scandals and tragedies in which consumers of unsafe products were harmed. Upton Sinclair's The Jungle (1906) helped to spur Congress to pass the first major piece of protective legislation in 1906, which prohibited false and deceptive labeling of food products and medications (Pure Food and Drug Act, P.L. 59-384). Prior to that time, a vigorous market had existed for nostrums and patent medicines, many of which made sweeping claims for miracle cures. Nevertheless, the act had no provisions requiring evidence that a drug be safe or effective. The

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The Social Impact of Aids in the United States impact of the act was undermined by a Supreme Court ruling in 1912 requiring the Food and Drug Administration (FDA) to demonstrate not only that a particular claim was false, but also that it had been made with the intent to deceive. Promotional claims for useless and dangerous products, not surprisingly, continued to flourish (Quirk, 1980; Okun, 1986; Young, 1990). In 1938 Congress again took action, this time enacting the Food, Drug, and Cosmetic Act (P.L. 75-717), which required that drugs be established as safe through "adequate tests" prior to marketing. Unfortunately, a tragedy helped to break the legislative deadlock that preceded passage of this act. Elixir sulfanilamide, a new sulfa drug marketed for children, was suspended in a solvent that could lead to immediate death; by the time the drug was withdrawn, more than 100 deaths had occurred. With the new legislation, the FDA was mandated to review safety data on drugs and remove dangerous products from the market. Despite growing methodologic sophistication and rigor in the design and execution of drug trials during the 1950s and 1960s, it soon became clear that the public was still not always protected from pharmaceuticals that were either inadequately tested or produced. As late as the early 1960s, randomized clinical trials continued to be the exception rather than the rule in testing new therapeutic interventions. Spurred by another series of scandals, Congress in 1962 enacted the Kefauver-Harris amendments to the Food, Drug, and Cosmetic Act of 1938 (Harris, 1964; Quirk, 1980). The notorious "Cutter incident" of 1956, in which 11 children died as a result of being inoculated with improperly produced Salk polio vaccine, was a powerful indicator of the need for better governmental regulation of biologic and pharmaceutical products. This tragedy was soon followed by the thalidomide disaster; children born to mothers who had taken this sedative had severe congenital malformations (Insight Team, 1979). Although thalidomide had not been marketed in the United States, it had been made available in loosely conducted premarketing studies. Both incidents pointed to weaknesses in the federal regulatory process. The Kefauver-Harris amendments to the Food, Drug, and Cosmetic Act required for the first time that before FDA approval was granted, a company had to categorically demonstrate through animal and human studies that a drug was safe and efficacious. (Prior to 1962 federal law had required that drugs be safe, but no specification regarding efficacy was mandated.) The amendments were a major impetus for the conduct of randomized clinical trials, which soon became the only accepted criterion for evaluating new drugs. By 1970, with the growth in influence of the National Institutes of Health and the rise of biostatistics as a distinct discipline (Marks, 1990), the nature and methods of drug evaluation had achieved a form of scientific and

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The Social Impact of Aids in the United States bureaucratic orthodoxy. Moreover, as medical costs rose precipitously during these years, interest in comparing treatments, not just on the basis of efficacy, but also on the basis of costs, was heightened and spurred more trials. A report by the Office of Technology Assessment (1983) concluded that randomized clinical trials offered a particularly effective methodology for evaluating a full range of medical interventions and technologies. Furthermore, the report concluded, such trials should become the basis for evaluating standards of medical practice, as well as for public policy. The regulatory ethos established in the wake of the Kefauver-Harris amendments emphasized caution. The repercussions of approving a dangerous drug were typically perceived as being greater than those that would attend restricting the marketing of a potentially beneficial drug. Although some critics have recently called this view of regulation "paternalistic" (Delaney, 1989a,b), it reflected a growing recognition that the evaluation of pharmaceuticals was a complex scientific, political, and economic process. Individual patients and individual physicians, it was argued, could not make decisions about safety and effectiveness in a clear or objective manner. Any substantive evaluation required the aggregation and evaluation of large data sets. Thus, the government should mediate by establishing clear criteria, mandating trials, and evaluating industry claims before allowing drugs to be marketed. Rather than being seen as paternalistic, this approach was more often viewed as a significant role of the government in a consumer-oriented, government-regulated economy. In addition, as skepticism about medical technologies and interventions grew during the 1970s and 1980s, the FDA was often criticized for not being aggressive enough in its regulatory mission (Mintz, 1967; Silverman and Lee, 1974; Wolfe and Coley, 1980; U.S. Department of Health and Human Services, Advisory Committee on the FDA, 1991). The Kefauver-Harris amendments shifted the regulatory burden from premarket notification of a new drug to premarket approval. The legislation required "substantial evidence" of efficacy, including "adequate and well-controlled investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved." This change obviously required the development of detailed criteria and bureaucratic mechanisms to evaluate the safety and efficacy of drugs. Under the regulations established to meet the requirements of the amendments, companies or other researchers seeking to have a product approved must first submit an investigational new drug application. The application had to show that initial screening and animal testing for toxicity had been completed and offer a thorough justification and plan for testing human subjects. Generally, randomized clinical trials are divided into three phases: phase I trials typically assess data on safety; phase II trials evaluate efficacy; and

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The Social Impact of Aids in the United States phase III trials compare the prospective drug with standard therapy, usually on a randomized, double-blind basis. This process can take considerable time, and a variety of approaches to streamlining the procedures have been proposed. In the view of the pharmaceutical industry, which typically bears the costs of clinical trials, the Kefauver-Harris amendments raised the cost of researching, developing, and marketing new products. In the face of the AIDS epidemic, FDA's policies of cautious protection came under fire. Given attempts to modify regulatory practices, it will be critical in the future to monitor the potential effects of changes on new drug development, both for HIV and other diseases. How, in the context of the AIDS epidemic, has the FDA balanced its duties to ensure safe and effective drugs against its duty to make potentially beneficial agents available on a timely basis? (Edgar and Rothman, 1991). And how are changes in the regulatory environment likely to affect research and development in the pharmaceutical industry? Protecting Human Research Subjects Just as changes in the regulation of new drugs were spurred by a series of scandals, so, too, were attempts to protect human subjects driven by reports of serious abuses. Efforts to improve the regulatory capacities of the FDA were followed by a heightened public concern about the ethics of human subject research. Widespread reports of experiments in which research subjects were unaware of their involvement led to calls for more vigorous protections (Gray, 1975; Barber, 1976; Katz, 1984). Henry Beecher's (1966) review of unethical experimental protocols in the New England Journal of Medicine (see also Rothman, 1987b) was soon followed by exposes of the Public Health Service's Tuskegee syphilis experiment, in which some 400 African American sharecroppers were denied treatment in a study of the natural history of the disease (Brandt, 1978b; Jones, 1981; Thomas and Quinn, 1991). As a result of these reports, Congress in 1974 established the National Commission for the Protection of Human Subjects (Rothman, 1991; Jonsen, 1984). The commission devised general ethical principles for the conduct of human experimentation, which it issued in its 1978 "Belmont report" (National Commission for the Protection of Human Subjects, 1978). Three principles were to form the basis for the evaluation of experimental protocols and provide a guide for obtaining informed consent, establishing favorable risk-benefit ratios, and equitably selecting test subjects: respect for persons, beneficence, and justice. A central tenet of the Belmont report was the need to be rigorous in differentiating experimentation from therapy. The commission argued that therapeutic research had the potential of subjecting patients to risky and dangerous experimentation offered in the hope

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The Social Impact of Aids in the United States of therapeutic benefits. The heavy emphasis implicit in the work of the commission, as well as its formal title, was the need to protect individuals from potentially dangerous research—that is, that government must set limits on researchers and their prospective subjects. In this context, taking part in an experiment was typically viewed as a sacrifice that citizens, in the name of the public good, might periodically be called on to perform. Most commentators emphasized, however, that all too often the burden of medical progress fell inadequately on vulnerable populations—the uneducated and minorities (Katz and Capron, 1975). The commission reiterated its support for clinical investigation and scientific research, but it sought to establish clear principles on which to evaluate research on human subjects and specific mechanisms to protect human subjects from possible harm. The findings of the commission were supported by the federal government in the subsequent requirements for institutional review boards to evaluate research protocols in advance of their implementation. Any institution that received federal funds was required by law to establish such a board to review all proposed research on human subjects and to assess the procedures for obtaining each subject's informed consent. In fact, most research institutes, regardless of funding sources, did establish institutional review boards. The effect of the boards was to create a somewhat more restrictive environment for clinical investigation by establishing clear requirements for consultation and oversight. The era of autonomous research had come to an end. The HIV/AIDS epidemic suddenly and dramatically fractured the risk-aversive ethic of human experimentation, raising again fundamental questions regarding the nature of clinical investigation and research ethics (Levine, 1988). The epidemic created a constituency that would find the protections of the past too restrictive. It created a constituency of individuals eager to take risks with unproven therapies. In the midst of the AIDS epidemic, when access to clinical trials has become a bitterly contested question, it is worth remembering that only a short time ago the focus of discussion was the protection of research subjects from potentially dangerous experimental protocols. What the regulatory process had failed to recognize was that in certain specific situations individuals might be eager to have access to experimental drugs even if their safety and efficacy had yet to be proven by scientific criteria. The AIDS epidemic made clear that risk can only be defined in a very specific personal and social context. In this respect, an appropriate margin of safety for any set of clinical trials cannot be uniformly set.

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The Social Impact of Aids in the United States Patient Advocacy and Activism The critiques of medical experimentation articulated in the 1970s were not new, but they were being expressed with considerable vigor. Efforts to protect human research subjects were part of a larger social movement that reflected a shift in the medical balance of power. Many have called AIDS activism unique—and certainly in some ways it has been unprecedented—but it can be understood in the context of changes in medical relationships and authority that have characterized American medicine since the late 1960s (Jonsen, 1991; Rothman, 1991). Although there is no adequate history of the patient-doctor relationship, it is widely recognized that fundamental cultural changes in the nature of this relationship have occurred since the mid-1960s. Since that time, there have been several changes that reflect, if not characterize, a shift away from "medical paternalism": a growing skepticism by patients of medical and scientific authority; a deeper commitment to disclosure and consent by physicians; the legal codification of informed consent, as well as clearer promulgation of patients' "rights"; and the establishment of institutional mechanisms, such as internal review boards to protect human subjects. All these developments reflected significant change in the general practice of medicine and the nature of clinical investigation (Katz, 1984; Faden and Beauchamp, 1986). The rise of AIDS activism can be understood only in the context of the critical shifts in the medical culture just noted and the gay rights movement of the 1970s and 1980s (D'Emilio, 1983). The development of organized activist groups provided an institutional vehicle for articulating critiques of traditional research approaches and federal regulatory mechanisms (see Chapter 6). Those critiques reflected the powerful conflicts in values and priorities revealed by the epidemic, as well as a more general erosion of medical and scientific authority. This social process, as noted, was already under way before the onset of the epidemic; the sacrosanct world of scientific and medical investigation had been opened to public scrutiny, regulation, and criticism. Research, in this new context, would fundamentally require active participation and negotiation between researchers and subjects. The AIDS epidemic would severely strain virtually every assumption of what had come—over a 20-year period—to be the guiding, orthodox assumptions regarding clinical research and the regulation of new drugs. Every aspect of the process by which new pharmacologic agents were identified, evaluated, regulated, and allocated would be tested by the exigencies of epidemic disease. Questions basic to the epistemologic foundations of biomedicine—questions of verifiability, reproductibility, proof, variability, safety, and efficacy—would all be subject to debate and reevaluation. In

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The Social Impact of Aids in the United States this respect, the epidemic has already had a profound social impact on science and medicine. THE FIRST DECADE OF AIDS The recognition of the first case of AIDS in the summer of 1981 was an abrupt event, but a basic understanding of its cause, epidemiology, and natural history evolved over a period of 5 years. During that time, despite great limitations of knowledge, many treatments were pursued and some therapeutic successes claimed. Kaposi's sarcoma and Pneumocystis carinii pneumonia (PCP) were the two diseases that heralded the arrival of the epidemic. Both diseases had been seen before (in elderly and cancer patients, respectively), and drugs already licensed were commonly used to treat the disorders, generally with good results. Indeed, it was the sudden marked increase in requests for a drug long used to treat PCP, pentamidine, that provided one of the first pieces of evidence that AIDS was an epidemic disease. Frustration that PCP and other complications in AIDS patients were not amenable to conventional therapies led to a host of alternative approaches, including vitamins, holistic therapies, and imported, non-FDA-approved drugs. At the same time, the failures led scientists to consider the infectious and neoplastic aftermath of AIDS's destruction of the immune system as essentially insurmountable and to concentrate on the central immune defect underlying the disease as the proper focus for drug research. Heroic interventions, such as bone marrow transplants in twins (one infected with HIV and one not) and aggressive chemotherapy for Kaposi's sarcoma, were attempted. As patients continued to die despite these measures, AIDS increasingly came to be viewed as an untreatable disease, and medical and lay literature emphasized the need to respect the rights and needs of individuals with a fatal disease of short duration, including their right to refuse intubation and resuscitation, their need for companionship and personal assistance, and the need to create low-cost, compassionate, out-of-hospital care. The year 1985 was a landmark year in the epidemic. First, it was revealed that movie star Rock Hudson had AIDS and that he had traveled to France to obtain HPA-23, an antiviral agent that French researchers had hailed at a press conference as curing several patients with the disease. Patients in the United States, desperate for therapy, questioned why a potentially useful drug could not be brought into this country. Affected individuals became increasingly aware of the often painfully slow process of drug evaluation and licensing regulated by the FDA. When additional experience with HPA-23 did not confirm early promising results, however, the wisdom of traditional methods of drug testing seemed to be substantiated. Second, suramin, an agent that had been licensed for over 50 years and

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The Social Impact of Aids in the United States barriers to participation, as of the end of 1991 fewer than 7 percent of participants in the AIDS Clinical Trials Group trials were women. AIDS trials are not unique in having few women participants (Cotton, 1990a,b). Indeed, the norm in clinical trials for a wide variety of illnesses has been explicitly to exclude women. Despite NIH guidelines requiring that any research protocol not including women offer a justification for the exclusion, a study released by the U.S. General Accounting Office (1990) demonstrated that few federally sponsored studies complied with those guidelines. That report, widely covered by the media, resulted in congressional inquiry into the lack of inclusion of women in trials and the creation of a new post of assistant director of the NIH for women's research. Recent NIH directives require, not merely encourage, the participation of women (and minorities) in federally funded research (National Institutes of Health, 1990; Dresser, 1992). AIDS was not the cause of the debate concerning this issue, but it certainly sharpened that debate because AIDS is now a leading cause of death in women of childbearing age. Inclusion of pregnant women in AIDS trials has created an arena for debate concerning larger social issues. Because most cases of pediatric AIDS are a result of transmission of the virus from mother to fetus, proposals for treatment of the mother in an attempt to prevent such transmission have been offered. At the time of this writing, a study designed to treat pregnant women with AZT to prevent such transmission has recently begun. The protocol for this study (the so-called AIDS Clinical Trials Group protocol 076) has been the subject of more debate and controversy than that for any other AIDS trial; that 2-year debate illustrates the changing climate regarding treating pregnant women with experimental therapies. The trial was originally designed to treat newborn infants with either AZT or a placebo (chosen at random) for 6 weeks in an attempt to prevent or ameliorate HIV infection, because, at that time, most investigators were unwilling to treat pregnant women with AZT. Although some of this reluctance stemmed from concerns over maternal side effects (the drug causes anemia when given at high doses), even greater reservations were related to fetal toxicity, especially the possibility of inducing birth defects. Unfortunately, key information needed to assess the risk-benefit of treatment during pregnancy for mother and fetus was, and to a large degree still is, unavailable. Estimates of the overall risk of transmission from mother to fetus have decreased steadily from approximately 50 percent to 25-35 percent (Hardy, 1991), and preliminary data and extrapolation from other diseases have raised the possibility that the virus might be transmitted during the birth process itself. A registry of over 40 cases in which pregnant women had received AZT during at least part of their pregnancy revealed no cases of teratogenicity likely due to AZT. Armed with these admittedly limited data, the investigators for protocol 076 proposed including women in the

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The Social Impact of Aids in the United States third trimester of pregnancy, on a randomized basis, to receive either AZT or a placebo until the birth of the child. The newborn would then receive the same medication as the mother for an additional 6 weeks after birth. This design was chosen to decrease the risk of fetal malformation by starting therapy well after organ development was complete. Study organizers believed that the risk of giving AZT to an uninfected fetus was acceptable because of the inability to identify such fetuses and the relatively high likelihood of transmission. Thus, the pediatricians who designed the trial believed the study to be timely and ethical. Criticism of the design, however, was immediate and severe. Advocates of women with HIV disease and some AIDS Clinical Trials Group investigators argued that the focus of the protocol, including any risk-benefit analysis, should be the pregnant woman, not the fetus. Previously expressed concerns that women were considered of importance in the epidemic only in relation to their role as "vectors" of disease to their unborn children or as sexual partners seemed to them to be borne out by the design of protocol 076 (Mitchell, 1988). Critics also pointed out that AZT had been demonstrated to prolong life in patients with AIDS and to delay progression to AIDS in asymptomatic HIV-infected individuals with CD4 counts below 500. They argued that by randomizing pregnant women to receive AZT or a placebo, the design would deny some women essential therapy in order to determine the effects of the drug on preventing fetal transmission. To meet concerns that in this protocol, and others, decisions regarding the treatment of women were not being addressed by those qualified to make them, a working group composed of obstetrician-gynecologists, internists, and pediatricians was established within the AIDS Clinical Trials Group. The working group has since been raised to the level of a full scientific committee and presumably will be consulted regarding all studies in which pregnant women will be enrolled. Ultimately, the FDA asked its Anti-Viral Advisory Committee to review protocol 076. That review, in September 1990, resulted in recommendations to radically redesign the study. In general, the recommendations supported the view that women should be the focus of the trial. Thus, the committee recommended that women with AIDS or severe immune dysfunction be excluded and given AZT. Women with moderate immune dysfunction, although eligible, would be told that if they were not pregnant, AZT would often be recommended, although the risk of delaying therapy for 6 months was believed to be small. Randomization much earlier, just after the first trimester, was recommended to maximize the possible benefit in preventing fetal transmission. Advocates have recently voiced new doubts about the ethical propriety of the protocol. They point out that the carcinogenic effects of AZT in women are unknown because studies of AZT have included very few women.

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The Social Impact of Aids in the United States (Female rodents given a high dose of AZT for prolonged periods have developed cervical dysplasia.) Advocates argue that the prime group to be recruited for this study (HIV-positive women with more than 500 CD4 cells) receive no known benefit from AZT and face a possible hazard in its use, genital carcinogenesis. Again, they argue that the protocol subsumes the interests of the mother to those of the fetus. However this debate evolves and whatever final shape protocol 076 takes, it is clear that this experience has altered how pregnant women are viewed as trial subjects, and it has highlighted the lack of information on gender-specific treatment effects in women. Whether it will have far-reaching effects on how decisions are made regarding the use of experimental or standard therapies with pregnant women with other diseases is unclear, but given that the entire area of research in women's health is undergoing dramatic evolution, it is likely that developments regarding AIDS will be scrutinized and considered as possible models. Dissemination of Information Peer-Reviewed Reporting of Clinical Research Dissemination of information regarding research results has traditionally occurred first through peer-reviewed scientific and medical publications. This process begins with an author's writing and rewriting of a manuscript and submitting it to a journal, initial editorial consideration, and, usually, referral to outside reviewers. Editors then compile and compare reviews and make a final decision regarding publication. Papers may be accepted outright, accepted under the condition that changes are made, returned to the author for possible resubmission, or rejected outright. Rejected manuscripts are almost always submitted to other journals, beginning the time-consuming review process again. Once a paper is accepted for publication, considerable time usually occurs before it is actually published, often 6 months to 1 year. After publication, months to years may elapse before the results of the research make their way into clinical practice or are widely accepted and taught by the scientific community. Codification of results into textbooks and removal of outdated or even disproved information from textbooks may take longer. Although cumbersome, this process has on the whole been viewed as appropriate. Outside peer review—in theory and usually in practice—provides an objective assessment of the accuracy and relevance of research findings by experts in the same field. It has benefits for authors, who are often given advice by reviewers that strengthens or extends their work, and society benefits from the prevention of dissemination of information that is not sound. These advantages have been considered to outweigh the inherent

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The Social Impact of Aids in the United States disadvantage of delay. However, many people have questioned whether in the case of clinical research that appears to show a significant therapeutic benefit for serious diseases or that demonstrates a previously unknown toxicity of accepted therapy the slow and orderly process of peer review and publication is in fact appropriate. Studies pertaining to AIDS have not been the only ones in which disclosure before publication has been championed or actually occurred. Repeatedly in the past decade, authors, journalists, physicians, and public health officials have protested specific instances in which promising results were delayed from public announcement for months prior to journal publication. In response to these criticisms, some journals have adopted various "fast track" approaches to manuscript review and publication, in essence identifying some manuscripts as high priority and hastening them through the process. In addition, several government agencies have themselves asked for permission from journal editors to release information to the lay press and medical practicing communities before manuscript publication and in some cases, even before manuscript review. For example, in May 1988, the National Cancer Institute sent out a "Clinical Alert" informing the public that adding chemotherapy to initial surgery for women with node-negative breast cancer increased survival. Publication of the findings in the New England Journal of Medicine, which had agreed to the "Clinical Alert," did not occur until 9 months later. Similar announcements in the past 5 years have included information concerning a protective effect of corticosteroids for spinal cord injury, a news conference to announce an unexpected mortality from two widely used antiarrhythmic drugs in a large clinical trial, and announcements of termination of a clinical trial of AZT versus a placebo in delaying the progression to AIDS among HIV-positive asymptomatic subjects. Such announcements have been criticized, however, as not providing sufficient information to permit physicians and patients to proceed with clinical care, for which they would want to have detailed information, such as drug dosage, drug side effects and interactions, and any caveats concerning the applicability of the results to types of patients other than those included in the trial. In addition, although most promising studies that have been announced in this way had some level of review by such groups as independent data-safety monitoring boards, early release of their results came with the risk that the information would be found to be inaccurate, which would lead to the need for rapid retraction and, perhaps, to morbidity and mortality. The issue of whether a more pragmatic approach to traditional peer review is needed is just beginning to be fully considered. Some people have suggested that guidelines should define studies that are of sufficient importance and whose inherent design and internal review mechanism are

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The Social Impact of Aids in the United States of sufficient rigor that they should be singled out for rapid, intensive review and early disclosure of relevant results. It is likely that continued refinements, large and small, will be proposed that will alter the process of research review and dissemination. Because of the large number of AIDS-related clinical studies, including clinical trials, and the urgency of AIDS research, it is likely that much of the debate and change will take place in the context of the epidemic. Non-Peer-Reviewed Publications The dissemination of AIDS research information through AIDS-specific, nontraditional means has been explosive. Among the most interesting of these are patient-oriented publications, which started out very modestly but have grown in sophistication and influence as well as circulation. AIDS Treatment News (mentioned above), which is produced in San Francisco by John S. James (a former computer programmer), has a circulation of about 5,000. Another influential newsletter is San Francisco Project Inform's PI Perspective. Supported by a staff of 11 and numerous volunteers, it has a circulation of 50,000. Project Inform also operates an AIDS treatment hotline (Bishop, 1991). Many mainstream AIDS researchers and clinicians are subscribers to AIDS treatment newsletters, and a few even contribute to such publications. Often, these publications provide editorial comment on many aspects of the epidemic, such as regulation and access to drugs, HIV antibody testing among various groups at risk, and immigration and travel restrictions for HIV-positive individuals. Completion and updating of information regarding all known AIDS drugs has been done for several years by the American Foundation for AIDS Research through its AIDS/HIV Treatment Directory. The Public Health Service operates a toll-free hotline (1-800 TRIALS-A) that provides information on federally sponsored clinical trials and industry-sponsored efficacy trials. From the beginning of the epidemic, the problem of teaching busy practitioners about a new disease of rapidly growing prevalence and importance was appreciated. A variety of newsletters for primary care practitioners were established to meet this need, such as AIDS Alert, AIDS News, and AIDS Clinical Care (published by the Massachusetts Medical Society, publishers of the New England Journal of Medicine). These publications are uniquely suited to providing up-to-date information on AIDS through a mixed format of in-depth clinical reviews, annotated summaries of articles in leading peer-reviewed journals, and reporting of late-breaking stories of interest. They fill a gap between mass media reporting and traditional peer-reviewed journals and as such are uniquely suited to the exigencies of the epidemic.

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The Social Impact of Aids in the United States Science and Health Reporting in the Mass Media During the 1980s medical and scientific reporting in the mass media became increasingly well supported and sophisticated, changing from simple repetition of the abstracts and press releases that accompanied publication of articles in medical journals to careful and then highly critical commentary. Major newspapers often employ several full-time science and medical reporters, and local and network television shows regularly air health segments. As science and medicine have become big business, they have become big stories. Because of the dramatic nature of the HIV/AIDS epidemic, the changes it has generated in all aspects of science and medicine, and its extraordinary social ramifications, AIDS has become the biggest of those stories and as such has driven many of the media changes that have occurred (Kinsella, 1989). Ironically, there was almost total avoidance of AIDS by the media early in the epidemic. The turning point came in the mid-1980s, and it is often tied to the coverage given to Rock Hudson when it was learned that he had AIDS. Now, virtually all AIDS stories of importance and most minor ones are covered by the daily print media. Indeed, many AIDS researchers rely first and foremost on several key newspapers to keep themselves abreast of AIDS research news. The number of public service announcements, local and national "AIDS specials," and AIDS segments on major television news shows has been remarkable. Indeed, the Public Broadcasting System had for some time a regular feature, "AIDS Quarterly," hosted by anchor Peter Jennings; it has continued but is now the "Health Quarterly." CONCLUSIONS It is impossible at this juncture in the HIV/AIDS epidemic to reach any definitive conclusions about its long-term impact on clinical research and the regulation of new drugs. It is apparent that patient activism, a political climate favoring deregulation, and the exigencies of the AIDS epidemic have generated the most significant reevaluation of the research and regulation processes to occur since World War II. As this chapter shows, the AIDS epidemic has had profound effects on the conduct and nature of clinical research and on the regulation of drugs. First, not since randomized clinical trials became the orthodox mode of clinical investigation had the most basic approaches and assumptions regarding research methodologies been open to searching critique in the context of an epidemic disease. AIDS has led to a fundamental reconsideration of basic methodologies for establishing the efficacy and safety of pharmaceuticals. New approaches to experimentation—to shorten the time required, as well as to alter the criteria for assessment—are actively being

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The Social Impact of Aids in the United States explored. Moreover, the very legitimacy of randomization has been called into question as the ethics of withholding treatments has loomed large in the context of the epidemic. At this time it seems clear that randomized clinical trials will continue to have a significant role in clinical investigation, but that they will be designed in new ways in order to answer a revised set of questions. Moreover, it seems likely that the new methodologic approaches will not be limited to AIDS investigations, but, rather, will be diffused to other research fields. Although randomized clinical trials continue to offer significant scientific advantages for the evaluation of new drugs, it seems likely that in the context of AIDS, alternative approaches to clinical investigation will be proposed and evaluated in the years ahead. Second, there has been a dramatic shift in the face of the epidemic from a restrictive ethos for regulating new drugs to a new, less restrictive environment. Nevertheless, the balance between protection and access is likely to be the focal point of intense debate in the future. The evolution of the parallel track, expanded compassionate drug allocations, and the general trend to expedite trials—all are clear indicators of the impact that the HIV/AIDS epidemic has had on drug regulation. Although the epidemic has spurred these changes, it now seems likely that in certain instances attempts will be made to expedite the regulatory process for drugs for other diseases, especially those for life-threatening or previously untreatable conditions. Reports of toxicity, morbidity, or, especially, drug-related mortality, however, could lead to new restrictions in the future. Third, changes in clinical trials and the regulation of new drugs are obviously having a related impact on the pharmaceutical industry. Although the issue of the relationship between federal research and private industry has been most vocally raised in the instance of AZT, fundamental questions of public-private cooperation in research and development have been posed by the epidemic. To date, many of these complex issues have been resolved essentially on an ad hoc basis, but that public-private relationship, which is outside the scope of this chapter, merits much more attention. Moreover, the incentives and disincentives for the development of new drugs in a new regulatory environment also needs much more scrutiny. Fourth, to a degree that few could have anticipated, AIDS has influenced the nature and meaning of the ethics of human investigation. AIDS has forced clinical medicine to consider the variable of time in a new way: added to the normative care and precision of clinical investigation has been the new demand of urgency. The epidemic will not pause for the traditional modes of science; AIDS has forced the acceleration of the procedures and processes of clinical investigation, as well as the mechanisms of regulation. The scientific community has accepted the acceleration of clinical trial phases in the context of AIDS, recognizing the urgency of early access and allocation

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The Social Impact of Aids in the United States of new drugs for a disease that is fatal and principally strikes young people. Similar pressures were building prior to AIDS for early access to new cancer drugs. However, there is also serious concern in the research community that an effective research tool may be compromised and that the implications for both safety and efficacy of new therapeutic agents have not been fully assessed. Thus, the long-term impact of these changes is not known. Although, in the past, the very term ''therapeutic research" was held in disrepute, the lines between experimentation and therapy have now been blurred. Activists have chanted, "a drug trial is health care, too." The basic concept of human experimentation has been radically altered—from protecting individuals from research to attempting to ensure individuals access to research. These changes can be fully understood only in the context of the powerful and effective social and political activism that the HIV/AIDS epidemic has generated. NOTE 1.   This section is based in part on a paper prepared for the panel by Harry M. Marks of the Institute for the History of Medicine at the Johns Hopkins University, "Historical Perspectives on Clinical Trials" (August 1990). REFERENCES Abrams, D.I. (1990) Alternative therapies in HIV infection. AIDS 4:1179-1187. AIDS Coalition to Unleash Power (ACT-UP) (1989) A National AIDS Treatment Research Agenda. Paper distributed at the Fifth Annual International Conference on AIDS, Montreal, June 4-9. Annas, G.J. (1988) AIDS, judges and the right to medical care. Hastings Center Report 18(4):20-22. Arras, J.D. (1990) Noncompliance in AIDS research. Hastings Center Report 20:24-32. Barber, B. (1976) The ethics of experimentation with human subjects. Scientific American 234:25-31. Bayer, R. (1990) Beyond the burdens of protection: AIDS and the ethics of research. Evaluation Review 14:443-446. Beecher, H.E. (1966) Ethics and clinical research. New England Journal of Medicine 274:1354-1360. Bishop, K. (1991) Underground press leads way on AIDS advice. New York Times December 16:A-10. Bozette, S.A., F.R. Sattler, J. Chiu, A.W. Wu, D. Gluckstein, et al. (1990) A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. New England Journal of Medicine 321:1451-1457. Brandt, A.M. (1978a) Polio, politics, publicity, and duplicity: ethical aspects in the development of the Salk vaccine. International Journal of Health Services 8:257-270. Brandt, A.M. (1978b) Racism and research: the case of the Tuskegee syphilis study. Hastings Center Report 8:26-27. Carter, R. (1966) Breakthrough: The Saga of Jonas Salk. New York: Trident.

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The Social Impact of Aids in the United States Chalmers, T., J. Block, and S. Lee (1972) Controlled studies in clinical cancer research. New England Journal of Medicine 287:75-78. Cotton, P. (1990a) Examples abound of gaps in medical knowledge because of groups excluded from scientific study. Journal of the American Medical Association 263:1051, 1055. Cotton, P. (1990b) Is there still too much extrapolation from data on middle-aged white men? Journal of the American Medical Association 263:1049-1050. Delaney, M. (1989a) The case for patient access to experimental therapy. Journal of Infectious Diseases 159:416-419. Delaney, M. (1989b) Patient access to experimental therapy. Journal of the American Medical Association 261:2444-2447. D'Emilio, J. (1983) Sexual Politics, Sexual Communities: The Making of a Homosexual Minority in the United States, 1940-1970. Chicago: University of Chicago Press. Dresser, R. (1992) Wanted: single, white male for medical research. Hastings Center Report 22(1):24-29. Eckholm, E. (1986) Should the rules be bent in an epidemic? New York Times July 13:E30. Edgar, H., and D.J. Rothman (1991) New rules for new drugs: the challenge of AIDS to the regulatory process. In D. Nelkin, D.P. Willis, and S.V. Parris, eds., A Disease of Society: Cultural and Institutional Responses to AIDS. New York: Cambridge University Press. Faden, R.R., and T.L. Beauchamp (1986) A History and Theory of Informed Consent. New York: Oxford University Press. Feinstein, A. (1967) Clinical Judgment. Baltimore, Md.: Williams and Wilkins. Fried, C. (1974) Medical Experimentation: Personal Integrity and Social Policy. New York: American Elsevier. Gray, B. (1975) Human Subjects in Medical Research: A Sociological Study of the Conduct and Regulation of Clinical Research. New York: John Wiley and Sons. Green, S.B., S.S. Ellenberg, D. Finkelstein, A.B. Forsythe, L.S. Freedman, et al. (1990) Issues in the design of drug trials for AIDS. Controlled Clinical Trials 11:80-87. Gross, J. (1991) Turning disease into a cause: breast cancer follows AIDS. New York Times January 7:A1. Hand, R. (1989) Alternative therapies used by patients with AIDS (letter). New England Journal of Medicine 320:672-673. Hardy, L.M., ed. (1991) HIV Screening of Pregnant Women and Newborns . Committee on Prenatal and Newborn Screening for HIV Infection, Institute of Medicine. Washington, D.C.: National Academy Press. Harris, R. (1964) A Real Voice. New York: Macmillan. Henninger, D. (1990) Will the FDA revert to type? Wall Street Journal December 12:A16. Hill, A.B. (1951) The clinical trial. British Medical Bulletin 7:278-282. Hill, A.B. (1963) Medical ethics and controlled trials. British Medical Journal 1:1043-1049. Insight Team (of the Sunday Times of London) (1979) Suffer the Children: The Story of Thalidomide. New York: Viking Press. James, J.S. (1989) AIDS Treatment News. Berkeley, Calif: Celestial Arts. Johnson, N., R.J. Lilford, and W. Brazier (1991) At what level of collective equipoise does a clinical trial become ethical? Journal of Medical Ethics 17:30-34. Jones, J.H. (1981) Bad Blood: The Tuskegee Syphilis Experiment. New York: Free Press. Jonsen, A. (1984) Public policy and human research. Pp. 3-19 in J. Humber and R. Almeder, eds., Biomedical Ethics Reviews. Clifton, N.J.: Humana Press. Jonsen, A.R. (1991) Old Ethics, New Medicine. Cambridge, Mass.: Harvard University Press. Katz, J. (1984) The Silent World of Doctor and Patient. New York: Free Press. Katz, J., and A.M. Capron (1975) Catastrophic Diseases: Who Decides What?: A Psychological and Legal Analysis of the Problems Posed by Hemodialysis and Organ Transplantation . New York: Russell Sage Foundation.

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