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BIOMEDICAL POLITICS Unproven AIDS Therapies: The Food and Drug Administration and ddI Jeffrey Levi The scientific decision-making process in the case of the acquired immune deficiency syndrome (AIDS) has been characterized by unprecedented involvement of the persons affected by the disease. Initially, the AIDS crisis involved one group of people who were already politically organized—in this instance, gay men. Most other diseases affect a far more heterogeneous population from the start. By the time the first AIDS case was diagnosed in 1981, gay men, together with lesbians, had become a growing political presence in U.S. society and were already psychologically and strategically primed to challenge the system. Indeed, gay men came to the AIDS crisis with a predisposition to question and distrust the health and scientific establishments. In many of the larger cities across the nation, gay men had formed gay health clinics some 10 to 15 years before the advent of AIDS because of their distrust of the medical establishment in treating gays for sexually transmitted diseases. Past actions by health agencies fueled the distrust. For example, the Public Health Service (PHS), of which all the federal agencies responding to AIDS are a part, including the Food and Drug Administration (FDA), was, until late 1990, responsible for enforcement of a ban on immigration by homosexuals based on the determination that gays and lesbians are mentally ill—even though the Jeffrey Levi is a Washington-based health policy consultant working with several groups on AIDS issues, including the National Gay and Lesbian Task Force, the Gay Men's Health Crisis, and the Institute of Medicine.
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BIOMEDICAL POLITICS American Psychiatric Association removed homosexuality from its list of illnesses in 1976. It is from this past experience that AIDS activists of all stripes—from mainstream lobbying organizations to street groups using direct action (demonstrations and civil disobedience)—came to challenge some of the fundamental assumptions of the public health community's response to AIDS: from traditional public health control measures to how research ought to be conducted to determining who should make decisions about access to experimental therapies.1 Decision making regarding early release of dideoxyinosine (ddI), a promising antiretroviral drug that has been seen as a potential replacement for the often highly toxic drug zidovudine (AZT) in the treatment of human immunodeficiency virus (HIV) infection, occurred in a context of more general discussions within the AIDS scientific and activist communities about early access to experimental treatments for persons with AIDS that were to be offered on a "parallel track" with ongoing clinical trials. In effect, ddI became a prototype for early access before a model for implementing the broader parallel track program was developed or approved by the relevant government agencies. The success of the parallel track concept will be closely linked to the improvised approach developed for ddI. The support for early release of ddI and the general notion of parallel track represented a remarkable shift in attitudes among government researchers and regulators, a change inspired by discussions with and pressure from the AIDS activist community. The endorsement of parallel track by top PHS officials occurred in a context of agency jockeying for support from the AIDS activist community. Parallel track and early release of ddI have also resulted in an unusual confluence of interests among AIDS activists, regulators, drug companies, and some key scientific researchers. Government officials saw early release as a means of showing compassion and responsiveness at a time when existing research and regulatory structures seemed rigid and uncaring. Drug companies and top government regulators saw early access as another step toward the reduced regulation of the pharmaceutical industry that was a hallmark of Frank Young's tenure as FDA commissioner. Finally, activists saw parallel track as providing greater autonomy in decision making for persons with HIV infection. This paper reviews and describes the decision-making process that led to the early release of ddI. It is not an attempt to judge the merits of early release of ddI or the entire parallel track concept. Rather, it is meant to paint a picture of how and why decisions were made, with the hope that it might provide a basis for better, more rational decision making in the future. To lay the groundwork for the discussion of early release of ddI, the
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BIOMEDICAL POLITICS paper first reviews the history of increased drug regulation in the United States. It then discusses the trend toward deregulation during the Reagan administration that coincided with the AIDS crisis, the initial discussions and pressures for creation of a parallel track, and, finally, the process leading to early release of ddI. The paper also assesses some of the motivations of the actors involved. The sources for the paper are primarily interviews of participants in the process conducted by the author. The outcome is necessarily the author's synthesis—but one that, it is hoped, reflects what actually happened when the analysis of the individual participants and the public record are pieced together.2 THE DRUG REGULATION PROCESS Federal regulation of the drug industry in the United States 3 is a product of twentieth-century legislation that, until the 1980s, produced increasingly tight restrictions on pharmaceutical companies. Prior to this century, regulation of the food and drug industries was left to state and local governments, but as the federal role increased, the state role in this area began to disappear.4 Each significant federal initiative for closer regulation of the drug industry coincided with a major catastrophe with a drug, which brought political pressure for greater premarketing protection of consumers. The first major federal legislation designed to protect consumers was the Food and Drugs Act of 1906. No premarketing approval was proposed; the law merely required that drugs meet official standards of strength and purity. The next major legislation was the Federal Food, Drug, and Cosmetic Act of 1938, prompted by the elixir sulfanilamide scandal in 1937. In this case the drug was marketed without any safety testing and caused the death of 107 persons because it contained a chemical commonly used in antifreeze. The 1938 law required that a manufacturer prove the safety of a drug before it was marketed. Thus, from 1938 until 1962, regulation was focused on safety and involved minimal review by the FDA. A manufacturer simply sent a new drug application to the agency, and if there was no response within 60 days, the drug was deemed to be approved. The FDA had authority to veto an application, and it also had the option of using informal authority to try to convince a company not to market a product. In 1962, in reaction to the thalidomide scandal overseas, the Kefauver amendments to the Food, Drug, and Cosmetics Act resulted in a requirement that manufacturers demonstrate not only the safety of a drug but also its efficacy.5 This requirement led to far more complex clinical trials and the regulatory system that is the basis for today's drug approval process.
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BIOMEDICAL POLITICS The Drug Approval Process Today A pharmaceutical company wishing to begin human clinical trials of a new drug must first submit an investigational new drug (IND) application to the FDA. The IND must contain laboratory data on the drug, the results of any animal studies or foreign trials, and the proposed research protocols for trials in humans. Trials may begin within 30 days of submission of an IND if the FDA does not order a hold on clinical trials. Although not required by regulation, there are generally three stages to the clinical trials process. During Phase I, initial safety studies are conducted, usually among a small number of healthy patients, with gradual increases in dosage to determine safe levels. These trials average between six months and one year. Because they normally take place among healthy research subjects, usually no data are collected regarding efficacy. If a drug is considered toxic, however, as is the case for many cancer and AIDS drugs, Phase I trials are conducted among those who are already sick. As a result, some information regarding efficacy may be obtained, which is the basis for some of the pressure for early release of experimental drugs. These trials were not designed to test for efficacy, however, and as a result it is risky to draw any firm conclusions about the potential usefulness of a drug from Phase I trials. About 29 percent of drugs do not continue in trials past the Phase I stage. Phase II trials test the effectiveness of the drug and provide further evidence on safety. These studies, which usually take up to two years and involve several hundred patients with the disease for which the therapy is intended, are designed to assess the value of the drug as a treatment. Another 39 percent of drugs under development fail at this stage. Phase III trials are long-term safety and efficacy studies, involving thousands of patients at numerous research centers, that are designed to assess the risk-benefit value of the drug. They take between one and three years. Very few drugs (3 to 5 percent) fail at this stage. Indeed, there are some in the scientific community who believe that the distinction between Phase II and Phase III trials is often artificial and that, in fact, the two phases run into one another at a certain point in the research process. At the end of Phase III, the FDA begins its formal review of the data. A new drug application (NDA) is the basis for the agency's final approval of a drug for marketing. The NDA summarizes the findings of all the research, and the FDA has 180 days to approve the application. After the drug is placed on the market, the FDA and the pharmaceuti-
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BIOMEDICAL POLITICS cal company monitor it for unexpected toxicities, which could cause the FDA to revoke the marketing approval. In some instances, the FDA may even require what are called Phase IV, or postmarketing, studies to learn more about the drug. Speeding Up the Process: The “Bush Initiative” The length of the drug approval process has been a source of frustration to the drug industry for many years and a source of anger to many advocates for patients with life-threatening diseases. Partially in response to this pressure, and with the urging of the President 's Task Force on Regulatory Relief, chaired by then Vice President George Bush, the FDA announced in the fall of 1988 new regulations to expedite availability of promising therapies for patients with life-threatening and serious diseases. In a sense, the purpose of the regulations was to short-circuit the three clinical trials phases and, in the words of then FDA Commissioner Frank Young, “be able to reach a scientifically defensible decision to approve or disapprove marketing of drugs intended to improve the outcome in such diseases, based on the results of well-designed Phase II controlled trials ” (Young, 1989). Essentially, the new approach assumes that patients and physicians will use a different risk-benefit analysis for drugs to treat life-threatening illnesses and will be willing to use those drugs with less complete data than are usually available for approved drugs. The FDA's new regulations called for early consultation between the FDA and drug sponsors in the preclinical stage to ensure a clear understanding between regulators and industry as to the data required for approval. The regulations also permitted submission of an NDA after Phase II. If the drug were approved, the FDA might still require postmarketing studies (referred to as Phase IV above). As mentioned earlier, the distinctions among the clinical trials phases are considered artificial by some, and so it is difficult to assess how dramatic this change will be. On the other hand, the more active involvement of the FDA in the design of trials is also dependent on the willingness of the sponsoring company to work actively with the FDA early in the process and on the availability of FDA personnel, who are already stretched thin owing to agency understaffing. It is too early to know what effect the new procedures are having on drug approval times. Prelicensing Availability Under ordinary circumstances, access to a drug that is still in the investigational (IND) stage is limited to those patients participating in
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BIOMEDICAL POLITICS the clinical trials. The FDA, however, has a number of regulatory options to make the drug more widely available under certain circumstances. The primary vehicle is the treatment IND, which allows distribution of a promising therapy to limited populations before completion of an NDA. Prior to 1987, the uses and criteria for a treatment IND were relatively vague, which left tremendous discretion to the FDA regulators. The FDA issued new regulations in 1987 that attempted to clarify procedures and standards. According to these regulations, a treatment IND can be issued at any time between the end of Phase I trials and the submission of an NDA for promising therapies to treat the desperately ill—those with immediately life-threatening illnesses—provided there is no comparable or satisfactory alternative therapy that has already been licensed. The FDA also has a special mechanism for early access to promising cancer treatments. Known as Group C drugs, these agents are investigational drugs under development at the National Cancer Institute that are shown to have a certain level of efficacy but are some time away from full NDA approval. The primary criticism of the treatment IND process offered by patient advocates, particularly in the AIDS community, was that the standard of proof for treatment INDs was almost as high as that for an NDA and that in practice the treatment IND was functioning simply as a bridge between Phase III and the NDA while the FDA reviewed the data. Some in the FDA and in the research community were concerned that if treatment INDs were granted any earlier, the ability to collect good research data might be compromised and would delay even further the final NDA for a drug. This concern was based on the assumption that if a drug were available outside of clinical trials, few people would enroll in randomized trials because there was no guarantee of actually receiving the drug in question.6 It is in this context—with frustration over the length of time it took new drugs to move through the entire drug approval process and a feeling that existing mechanisms for early release of promising drugs were not being sufficiently employed—that AIDS activists began to call for a new mechanism for earlier release of AIDS drugs in the drug development process. This new mechanism is what became known as parallel track. PARALLEL TRACK The concept of parallel track—a system for expanded access to experimental therapies—originated in the AIDS activist community and
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BIOMEDICAL POLITICS posed some fundamental challenges to assumptions within the scientific community about how clinical research should be conducted and how access to drugs should be regulated. The most formal iteration of the parallel track concept came from the Treatment and Data Committee of the New York-based AIDS activist organization ACT UP (AIDS Coalition to Unleash Power), a direct action group more often seen protesting government policies than developing them. But the Treatment and Data Committee had also acquired a reputation for substantive understanding of AIDS drug development issues, and, more often than not, this arm of ACT UP could be found at the conference table at the National Institutes of Health (NIH), the FDA, or the PHS, particularly during the course of the discussions around parallel track and early access to ddI. Jim Eigo, a leader of the Treatment and Data Committee, defined parallel track as follows: “At the beginning of phase two (efficacy) trials, this parallel track would make investigational AIDS drugs available to people with HIV disease who are ineligible for the drugs' clinical trials and have no reasonable treatment alternatives” (Eigo, 1989). As Eigo explains it, the parallel track concept grew out of the failure of existing mechanisms to “deliver drugs to people with serious or life-threatening conditions who have no treatment alternative before full FDA marketing approval” (Eigo, 1989). It was first presented in April 1988 to principal investigators and officials of the National Institute of Allergy and Infectious Diseases (NIAID), the lead NIH agency working on AIDS. This presentation was the start of a long series of discussions and an education process directed at the NIH leadership, in particular NIAID's director Anthony Fauci, primarily through conversations with ACT UP and Project Inform's Martin Delaney. (Delaney, who heads the San Francisco-based group, is one of the leading voices for greater patient access and autonomy in decision making regarding the use of experimental therapies.) Fauci was probably the most critical player in the transformation of parallel track from an idea advocated by outsiders to one embraced by the federal public health establishment. He initially held the standard scientific community view on these proposals—that scientific controlled trials were the only way to establish the effectiveness of a drug and that expanded access could not be allowed to compete with these trials. Fauci believed the success of those trials was paramount as well as the most compassionate route in the long term, and would ultimately help more people than would be helped through early access. Through his conversations with the activists, however, Fauci became convinced that expanded access would not have to compromise the integrity of the trials if the parallel track was limited to those who could
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BIOMEDICAL POLITICS not otherwise participate in a clinical trial. There was also, at this time, growing concern within the NIH-funded AIDS clinical trials program that patients were not complying with the trial protocols. If patients did not see the clinical trials as their only means of obtaining a drug, it might be possible to conduct more efficient trials and have better patient compliance. Although there were hints from NIH officials at the Fifth International AIDS Conference in Montreal in early June 1989 that there might be more flexibility in NIH's position regarding earlier access, the formal declaration of a change of heart occurred in a speech given by Fauci in San Francisco later that month. “My commitment to carefully designed, controlled clinical trials for AIDS has not changed,” said Fauci. “Such trials are absolutely essential if we are going to get the answers needed by physicians who are treating patients.” But, he declared, “[a]t the same time, we have to be creative and flexible so we can provide increased access to promising drugs to patients who cannot participate in clinical trials” (Zonana and Cimons, 1989). Once Fauci broke the ice, there was almost a bandwagon effect on the rest of the PHS leadership. Fauci had given no warning to his colleagues in the FDA or to Dr. James Mason, the assistant secretary for health. Mason, who was Fauci's boss, reportedly was angry at receiving no advance notice that such a major initiative was going to be announced without prior consultation or approval. FDA Commissioner Young, eager to maintain his leadership position as an early advocate of quick access to experimental drugs, was quoted as saying, “I've been pushing it [parallel track] as much as Tony has” (Kolata, 1989a). Fauci presented his endorsement of the concept in principle without detailing how the program would actually work. Essentially, he announced that early release would not interfere with NIH's conduct of scientifically sound clinical trials and that personally he felt there was a moral obligation to make such therapies available earlier. He then tossed the ball into the FDA's court, correctly saying that, from a legal standpoint, all decisions regarding early release had to come from the regulatory agency, not the research arm. This maneuver was a source of considerable annoyance on the part of the other branches of the PHS, which were now handed a hot political potato with no prior warning or discussion. Overnight, Fauci became the hero of the activist community and, from the perspective of the FDA at least, made the regulators into the stumbling block to reform. It was not just the regulators and his political superiors in the assistant secretary's office whom Fauci took by surprise. Little if any groundwork had been laid within the research community or within the NIH AIDS program. This lack of preparation left considerable room for open op-
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BIOMEDICAL POLITICS position (or covert backbiting) to the proposal from the traditional research community. Indeed, some principal investigators in the AIDS Clinical Trials Group (ACTG) of NIAID suggested that Fauci was undercutting good science. Fauci did not have direct discussions on this topic with the principal investigators until the regular meeting of the ACTG the following month.7 There has been some suggestion that Fauci, in announcing the parallel track initiative, was trying to abate the rather harsh personal criticism he had been receiving from the activist community. In a sense the activists were the squeaky wheel that got the attention. Little was done to address the consequences of a parallel track endorsement to the rest of Fauci's political base—or the impact on internal agency morale of such a surprise announcement. It fell to the assistant secretary's office, through its National AIDS Program Office (NAPO), to try to produce a bureaucratic consensus on parallel track and ensure that the PHS was speaking with one voice. Essentially, Fauci was told that, although NIH should participate in discussions on parallel track, FDA and NAPO would be taking the lead roles. The need for a PHS-wide consensus was heightened by the pressures of a congressional hearing, a common mechanism to force decisions within the bureaucracy. Congressman Henry Waxman called a hearing on parallel track for July 19, 1989. As chair of the House health subcommittee, Waxman was the key AIDS legislator in the House and was concerned about the momentum Fauci's idea had gained. He was also wary of how such a policy was to be implemented and how the broader research community would react. At the hearing, Mason presented an administration position on parallel track that was astonishingly similar in its broad outlines to that of the AIDS activist community. Said Mason, “As contemplated, the availability of investigational therapeutic agents through this mechanism would be limited to those persons for whom there are no satisfactory alternative drugs or therapies available to treat that stage of disease and who, for some reason, are not eligible for or not able to participate in a clinical trial” (Mason, 1989). Although initially parallel track seemed like a simple proposal, NAPO and the FDA soon realized that its formulation was going to be quite complex, and that nailing down the details of the policy was going to take some time. At the hearing on July 19, Mason announced that the many unresolved questions around parallel track—which ranged from safety monitoring of released drugs, informed consent, and specific patient eligibility criteria to liability and reimbursement issues —would be presented to an expanded meeting of the FDA's Anti-Infective Drugs Advisory Committee on August 17. In preparatory meetings with PHS,
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BIOMEDICAL POLITICS activist, and research community representatives, however, it became clear to NAPO officials that a much lengthier process would be needed. The August 17 meeting became, instead, a public forum for the discussion of the various options and positions, pro and con, on the parallel track concept. At that meeting, NAPO Director James Allen announced that a smaller working group would be established to develop guidelines for parallel track that included the PHS agencies as well as researchers, activists, care providers, and pharmaceutical company representatives. The concepts of parallel track and ddI were first linked publicly after Fauci's San Francisco speech. When asked what would be a likely first candidate for parallel track, Fauci suggested ddI, although at the time only very preliminary discussions were taking place at FDA and with the drug's manufacturer, Bristol-Myers, regarding some form of early release. While ddI was always closely linked with the concept of parallel track, once it became clear that it would take time to develop the concept into a working system, ddI and parallel track decoupled, at least in terms of a bureaucratic response. As early as the July 19 congressional hearing, Assistant Secretary Mason stated that efforts to release ddI would not be constrained by any delays in the parallel track discussions. In a sense, ddI and parallel track were on parallel tracks of their own. As discussions were held at the NAPO level regarding guidelines for the parallel track policy, the FDA, NIH, Bristol-Myers, and AIDS activists were negotiating protocols for the early release of ddI. In these talks everyone took pains to make it clear that the ddI package was not meant to be the prototype for parallel track. Nevertheless, everyone also was very conscious that the success or failure of early release of ddI would greatly influence the outcome of the overall parallel track policy development. PARALLEL TRACK: PROS AND CONS Because attitudes toward parallel track are so closely tied to attitudes about early release of ddI, it is important to consider how the various players perceived parallel track before looking at some of the specifics of the decision making regarding ddI. The Food and Drug Administration The push for support of parallel track as a separate, new mechanism came from the commissioner's office. Frank Young's tenure at FDA had been marked by efforts to speed up the drug review process and reduce the level of regulation without compromising the safety and ef-
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BIOMEDICAL POLITICS ficacy standards required by law. His 1987 effort to create greater flexibility in the use of treatment INDs, as discussed earlier, was met with skepticism by some patient groups who felt that FDA was merely repackaging old ineffective concepts and with criticism by some members of Congress and consumer advocates who believed FDA was allowing questionable reductions in safety and efficacy. Young clearly communicated to career officials in charge of the drug review process that he wanted them to act expeditiously on parallel track and early release of ddI. At this juncture, Young was increasingly an embattled commissioner, with his administration of the FDA under close scrutiny by congressional oversight committees. He perceived the AIDS activist community as a source of strong support, perhaps the last stronghold, and was eager, if not anxious, to be seen moving the bureaucracy along on this issue.8 Alone, however, Young could only do so much. Considerable power in the federal bureaucracy is held by career officials, who make most of the regulatory decisions. In the minds of many activists, as well as some at NIH, one of the stumbling blocks to quicker approval or access to promising drugs was Ellen Cooper, then head of the Anti-Viral Drug Products Division. Cooper was perceived by some to be rigid in her adherence to traditional standards and inflexible in adapting to the new pressures associated with the AIDS epidemic. This perception changed somewhat during the course of the negotiations around release of ddI. Activists sensed a change of heart, and Cooper felt the activists were finally listening to what she had been saying all along. Certainly, career officials at the FDA were angry with Fauci at his refusal to consult with them before his speech on parallel track. They had heard of the proposal and had actually sought out discussions with Fauci but were ignored. Yet despite some lingering frustration and anger, the bureaucrats were pushed forward by deadlines on both the parallel track and ddI fronts set by the political appointees, including their own commissioner. This haste was a source of annoyance, as some felt that their responsibility to ensure that all decisions were based on sound data or policy was being undermined. To some career FDA officials, parallel track was simply the articulation of what had been their intent all along. In their view, the mechanisms for early release were there but had not been formalized, a condition that in some ways made the system potentially more flexible. In fact, they traced some of the difficulties in early access to Young's formalization of the treatment IND rules. This policy, they said, created false expectations among the AIDS activists and resulted in pressures to totally overhaul the system. These officials were concerned that parallel track might be hard to
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BIOMEDICAL POLITICS ess that had been agreed to for ddI release was going to be a prototype against which the ultimate parallel track initiative would be measured. It may not have been the systematic structure they envisioned for parallel track—and they felt very strongly that a systematic structure was needed—but it at least provided an opportunity to pilot-test some of the structure's components. In a certain sense, the activists helped create something new by their participation in the early release negotiations. The system may always have been open to this kind of input or may always have had this level of flexibility, as government and company officials often claimed; but in the case of ddI the activists achieved an unprecedented level of involvement by consumer and patient advocates in the drug regulation process, normally a very tightly held series of negotiations, and forced real-world considerations into the decision making of the regulators and the sponsor. Several fortunate political circumstances enhanced the activists' influence. There was a bidding war for community support between Young and Fauci that gave the activists an advantage, even if they were not conscious manipulators of that competition. In addition, ddI had gotten good press, which created public and media interest in how negotiations were faring. And above all, Bristol-Myers was a relatively open company. From a policymaking perspective, some questions can certainly be raised. The personal imperative that motivated many of the activists involved in the process added urgency to the discussions. But some activists also recognized that there may have been a fuzzy line between good policy and what they as individuals needed; for example, were accommodations being made, one activist asked himself, because they met his personal medical needs or because they also represented appropriate modifications in the protocols? Major precedent-setting changes were occurring in drug access policy. Both the ddI and parallel track decisions were made as though there was no carryover to diseases other than AIDS. The limited experience of the activists in broader health advocacy issues may have closed off opportunities for broader reform—or created problems for other disease groups. Even within the context of AIDS, decisions were made based on the immediate urgency of finding an alternative to AZT, while at the same time precedents were being set for future AIDS-related decisions. It is not entirely clear whether the activists were aware of the situational nature of the alliances they were making. Bristol-Myers may appear to be aligned with their concerns at this stage of the drug development process, but the company's decision was based on sound business imperatives and not on moral factors alone. It is not incon-
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BIOMEDICAL POLITICS ceivable that those same imperatives may drive a wedge between Bristol-Myers and the activists later in the process. Similarly, the activists seemed dependent on the support of FDA Commissioner Frank Young, particularly to push the career officials to accept earlier access. Young's sudden departure from the scene startled them—and taught them what many advocacy groups and career bureaucrats with longer experience have known for some time: political appointees come and go, and their value is of limited duration. Educating and building alliances with career officials may be more painstaking and less public, but they can, over the long term, provide lasting support. Given the substantial discretion that career officials have at a regulatory agency such as the FDA, it is not at all clear what impact Young's departure and a long transition period at the agency will have on the influence of the activists on future drug policy decisions. There is also a question of accountability with regard to the activists who participated in the early release negotiations. Although nominally affiliated with specific organizations, they were very much a part of the negotiating process as individuals who were respected for their expertise on the issues and for their ties to certain parts of the AIDS constituency. Through force of intelligence and personality they won their way into the decision-making process—a measure of their capabilities. But it left them open to second-guessing from other activists and to questions from players on the other side of the negotiating table as to how much political strength they were bringing to the process. In a sense, whatever naivete the activists brought to the negotiations regarding the drug industry and bureaucratic politics was matched by the other participants' assumption that the activists were responsible to an organizational structure similar to that of their own employers. CONCLUSIONS All of the key players in the decision-making process publicly express support for the final outcome—early access to ddI. The process by which this decision was constructed lends itself to several general observations. Competition and closely controlled decision making may move an agenda in the short term, but they may undermine long-term support. The competition between Fauci and Young caused Fauci to seek relatively little counsel beyond his inner circle regarding parallel track for fear Young would jump ahead of him. Young, for his part, pushed the FDA bureaucracy to move as quickly as possible on the ddI treatment IND so he could prove that he could make parallel track work before there was even a parallel track structure. In a sense, the strength of support
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BIOMEDICAL POLITICS from these two top health officials prevented the process from becoming bogged down in haggling over details. But that support also had its negative side: the lack of stability that accompanies dependence on a political appointee (Young) and the result of Fauci's lack of consultation with the academic community, whose long-term backing of parallel track remains very much in doubt. A process that allowed the academic community in particular to buy into the concept early on—to allow them, perhaps, the opportunity to be educated by the activists, as Fauci was—might have caused some frustration among the activists over delays, but it might also have assured a longer-term commitment, once the media and the politicians were no longer focusing on the subject. A broader definition of decision makers produces better policy outcomes The level of involvement in the ddI process by community physicians and advocates was unprecedented in FDA history, and all those who were part of the process agreed that the final outcome was the better for it. In particular, the New York meeting in late July that brought the FDA together with community physicians has been cited as introducing a critical and welcome real-world element to the discussion. FDA officials needed to hear from peers and fellow physicians, not just activists, to be convinced finally of the need for this level of expanded access. Yet no permanent mechanism currently exists to assure this level of involvement for future AIDS drugs or for drugs for any other disease. Ellen Cooper, who has often been perceived by many as an obstacle to just this kind of involvement, is one who believes that there is a need for all relevant participants to meet on a more formal basis. By participants, she means the drug's sponsor, researchers, and patient advocates. At some point, the legally empowered decision makers need to make their choices, but those choices will be better if they are informed by the input of all interested parties. Logically, she feels, the FDA should call this group together. Yet because, at least in the context of AIDS, FDA is often perceived as part of the problem, an independent group may need to facilitate the process. Even if the proposed parallel track guidelines are adopted, they would institutionalize advocacy involvement in only part of the drug access process. Broader solutions need to be proposed and debated, outside the context of a specific decision on one drug. The advocacy and activist groups, in facing the immediacy of the AIDS crisis, often neglect the longer-term value of institutionalizing their gains. Pressure for change needs to come from the outside, because even though regulators have been supportive of much that has happened in this individual case, the tendency is to fall back on familiar patterns that seem safer, even if not always better. Evaluation of new initiatives is too often an afterthought. In this case,
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BIOMEDICAL POLITICS a fairly far-reaching change in standard procedures has been implemented without setting up evaluation mechanisms. The success or failure of the ddI experiment will affect the future of early access, but there is currently no independent means of assessing and auditing what is occurring. Advocates for the various points of view within the research, regulatory, pharmaceutical, and activist constituencies will be left to argue over whether problems arising during this experiment (such as difficulties in recruiting patients) are the result of the early access program or other causes. This new early access process is too critical a change to be left to this kind of debate. It may be too soon to draw conclusions, but it is not too soon to identify the data that should be collected and how they ought to be evaluated. EDITOR'S NOTE: As of January 1991 clinical trial results suggest that ddI has promising retroviral activity and is generally well-tolerated. NOTES 1. Not all AIDS activists come from the gay community, just as AIDS is not a gay disease. But within the AIDS constituency, much of the pressure around early access to experimental drugs has, indeed, come from the gay community. More fundamental issues of access—to primary care and to clinical trials—are also part of the AIDS constituency 's agenda and have been pushed by the needs and advocacy of those minority and poverty community representatives active in the AIDS effort. These are antecedents, in a sense, to access to the experimental drugs that are the subject of this paper. 2. Among the individuals interviewed for this paper were James Allen, director of the National AIDS Program Office, and his deputy, Bruce Artem; Ellen Cooper, director of the Anti-Viral Drug Products Division of the FDA; Margaret Hamburg, then special assistant to Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and now with the New York City Health Commission; Jay Lipner, a New York activist attorney; Tim Westmoreland, counsel to the House Subcommittee on Health and the Environment; Paul Worrell, of Bristol-Myers; and Frank Young, former commissioner of the FDA. The author, as an AIDS consultant working with several groups, including the National Gay and Lesbian Task Force and Gay Men's Health Crisis, also attended a number of the key meetings in question and had numerous conversations with participants in the ddI early release and parallel track process over the period under discussion in this paper. 3. The history of federal drug regulation and description of the regulatory process in this section draw heavily on an issue brief by the National Health Policy Forum (NHPF), “The Pharmaceutical Industry, ” and a talk by Peter Barton Hutt, at an NHPF panel on January 11, 1990 in Washington, D.C. 4. The AIDS crisis, however, brought a shift in thinking about the state role in drug regulation in this regard. Reflecting frustration with the slow pace
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BIOMEDICAL POLITICS of federal drug approval for AIDS treatments, in 1987 the California legislature created its own version of the FDA in the hope that California-based pharmaceutical companies might move their drugs through an expedited state process. 5. The FDA had not permitted distribution of thalidomide in the United States, even without the additional authority and requirements granted with the Kefauver amendments. 6. Randomized trials are considered the “gold standard” for drug research. They involve assignment of patients to different parts of a study, to compare a new drug with a placebo (i.e., no treatment) or to compare the new drug with standard or current therapy. Patients are randomly assigned to a particular group, and researchers are not supposed to know to which study a patient is assigned. 7. This is not to say, however, that Fauci was caught by surprise at the attention his speech drew from the media. On the contrary, he personally called key AIDS reporters to make sure they would be covering the speech. 8. There was certainly some division within the AIDS activist community about Frank Young. New activists—such as those from ACT UP—had only relatively recent experience working with Young and saw him as trying sincerely to support their efforts and as responsive to the public demonstrations they undertook. Those with a longer history of AIDS lobbying were a bit more skeptical. They perceived Young as being supportive only as long as the interests of the AIDS community coincided with those of the pharmaceutical industry. And they had had some difficult experiences with Young in the early days of the AIDS epidemic around the licensing of the original antibody test for HIV. 9. “Guidelines for the Parallel Track Program for AIDS and HIV-Related Treatments,” memo to James Mason, M.D., Assistant Secretary for Health, August 17, 1989, from the AIDS Action Council, ACT UP/New York, ACT UP/San Francisco, AIDS Project Los Angeles, American Association of Physicians for Human Rights, American Civil Liberties Union AIDS Project, American Foundation for AIDS Research, Community Research Alliance, Gay Men's Health Crisis, Human Rights Campaign Fund, Lambda Legal Defense and Education Fund, Mobilization Against AIDS, National Association of People with AIDS, National Gay and Lesbian Task Force, National Gay Rights Advocates, Project Inform, and San Francisco AIDS Foundation. 10. Ibid. 11. The NIH had a role in research protocol design only because ddI Phase II trials are being done through the NIH's ACTG system. Had Bristol-Myers decided to do the trials privately, there might have been no NIH role. REFERENCES Cimons, M. 1989. Coalition proposes criteria for AIDS drug trials. Los Angeles Times, August 17, 1989. Eigo, J. 1989. Testimony before the Energy and Commerce Committee, Subcommittee on Health and the Environment, U.S. House of Representatives, July 19, 1989.
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BIOMEDICAL POLITICS Food and Drug Administration Anti-Infectives Advisory Committee. 1989. Transcript of August 17, 1989 meeting. Kolata, G. 1989a. AIDS studies head seeks wide access to drugs in tests. New York Times, June 26, 1989. Kolata, G. 1989b. Innovative AIDS drug plan may be undermining testing. New York Times, November 21, 1989. Mason, J. O. 1989. Testimony before the Energy and Commerce Committee, Subcommittee on Health and the Environment, U.S. House of Representatives, July 19, 1989. Schram, N. R. 1989. Lives, research hinge on limiting new AIDS drug. Los Angeles Times, September 27, 1989. Science. July 28, 1989. Quick release of AIDS drugs. Page 347. Young, F. 1989. Testimony before the National Committee to Review Current Procedures for Approval of New Drugs for Cancer and AIDS, January 4, 1989. Zonana, V. F., and M. Cimons. 1989. Ease AIDS drug rules, health chief urges. Los Angeles Times, June 24, 1989.
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BIOMEDICAL POLITICS Commentary Leon Eisenberg The decision by the FDA to make ddI available early in the drug evaluation process is unique in that the “user” community (patients and potential patients) played a decisive role in the outcome. For this discussion, the bureaucratic dispute about whether the decision was implemented by an existing mechanism that permitted release for “compassionate use” or whether it represented the de novo creation of a parallel clinical trial is irrelevant. The important point is that the FDA responded to patient-generated pressure for release of ddI with only meager safety data and before randomized controlled trials (RCTs) had been completed. The FDA action was strongly opposed by those committed to RCTs as the only scientific way to evaluate efficacy and safety in a chronic disease with a highly variable course and duration. Moreover, even many of those who had been reluctantly persuaded by the case for compassionate use because of the dire prognosis of AIDS were concerned about the precedent-setting consequences of this action would this step mean that the FDA would subsequently release other drugs before thorough testing and thereby expose patients to unwarranted risk? The epidemiology of AIDS and the historical moment of its appearance combined to create a singular set of circumstances. The first cases were exclusively male homosexuals; thereafter the syndrome was successively recognized in other population groups (transfusion recipients, hemophiliacs, intravenous (IV) drug users and their heterosexual partners, children born to infected mothers). The most recent case data (January 1990) show that gays Leon Eisenberg chairs the Department of Social Medicine at Harvard University.
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BIOMEDICAL POLITICS are still overrepresented in the caseload; the Centers for Disease Control attributes 60 percent of the 121,000 U.S. AIDS cases to male homosexual or bisexual behavior. What gave this situation particular relevance was that white middle-class gays had organized an effective political movement before the disease was first recognized. Consequently, they were in a position to speak out—and they had powerful reasons for doing so because the federal response to the epidemic was grossly inadequate. In contrast to self-declared, politically active gays, many of the other AIDS patient constituencies (e.g., IV drug addicts, bisexuals, and men who engage in homosexual behavior but do not identify themselves as gay) were not and are not represented in health care decisions. Almost all diseases are differentially distributed in populations. But there is no other instance in recent memory of an epidemic of an infectious disease that has been so narrowly focused on a self-conscious, politically experienced patient group, one that has spoken out forcefully in its own interests. It is not that concern for patients has been absent from prior FDA deliberations. Indeed, concern for health is the raison d'être of the FDA. Nor have patients lacked advocates. To the contrary, physician specialists have spoken up on behalf of their patients. What is different in the case of ddI is that for the first time patients spoke for themselves in the decision-making process. Traditionally in FDA deliberations the dialogue has been confined to civil servants, pharmacologists, clinicians, and pharmaceutical representatives. With ddI, patient spokespersons in effect forced their way to the negotiating table, where the authenticity of their experience gave them a special expertise. Permitting laypersons to participate in a technical decision, even when they are highly educated, raised questions in the regulatory community. Can dialogue be meaningful when the premises from which each group starts are not shared, and often not understood, by the others? Furthermore, the gay spokespersons had no mandate to represent other AIDS patients—for example, drug users and closet gays in the minority communities, whose lives are also at risk but who are largely excluded from access to standard treatments no less than to experimental ones. If the decision to proceed with the parallel track can be hailed in one sense as a victory for a more democratic process, what are its potential costs? Three risks can be foreseen: (1) the parallel track may impede or even block completion of the RCT; (2) early access to ddI may expose more patients to the risk of severe toxicity; and (3) the precedent may return to haunt us if it is applied unwisely. Let us consider each in turn. Although gay advocates do not speak with a single voice, many agree that RCTs are necessary to evaluate drug efficacy and safety. They share the concern of clinical investigators that the ability to obtain ddI outside of trials may markedly decrease enrollment in clinical trials. Why should a patient agree to a 50-50 chance of getting the highly touted new drug in the RCT
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BIOMEDICAL POLITICS when he or she can be sure of receiving it through the parallel track? If enough RCT volunteers were to default, that would be a misfortune for all HIV-positive patients. Will that happen? Is it happening? As of the fall of 1990, there is no answer. Recruitment of participants for the ddI RCT has been slow; the same has been true, however, of earlier trials of other drugs. What about undue toxicity? Recent reports indicate that the death rate among those in the parallel track is some 10 times higher than among those in the RCT. The explanation, however, is anything but certain. Criteria for admission into the RCT rule out patients with advanced disease, but such patients are allowed to receive the drug through the parallel track. The observed higher death rate in the parallel track may thus represent nothing more than the worse initial prognosis of the enrollees. The example of suramin, however, should remind policymakers that an RCT was necessary to discover that drug 's unacceptably high toxicity. The death rate from pancreatitis has also been much higher among those in the parallel track and probably does represent ddI poisoning. Again, this may be a dose-related phenomenon or interaction with stage of disease. Even if ddI use has caused pancreatitis and subsequent deaths, the fundamental question remains: does the chance to reverse a fatal disease justify the risk? Some patient advocates contend that life with advanced AIDS has such little value that hastening death is no tragedy. Unfortunately, during the FDA discussions, there was no agreement to spell out in advance (1) what data would justify abandoning the parallel track and (2) what evidence from the parallel track could properly be admitted into the evaluation process. Lack of such agreement led to predictable responses to the first mortality data. Those who had been against the parallel track from the first contended that the high mortality warranted its discontinuation; gay activists argue that the hope for benefit justified the risk. At present, whether ddI will prove to be a safe, effective drug is not clear. What is more important for public health in the long run is the way we evaluate the parallel track as a response to clamor for access to new drugs. Surely this mechanism should be neither adopted nor abandoned without a close reading of the ddI story. Did it allow very sick patients to obtain a useful agent months before its official release? Did it lead to avoidable deaths because toxicity exceeded utility? Could either outcome have been predicted from the data on hand when the decision was made? Whether ddI leads to early salvage or undue toxicity, should patients be given access to an agent they want to use when the risk is considerable and efficacy is uncertain? The recent example of laetrile raises serious questions about the wisdom of such a strategy. The danger is less the confraternity of charlatans ready to peddle expensive nostrums to credulous patients than the risk that even nontoxic nostrums, through their illusory promise of ready cure at no discomfort, can lead to great harm by diverting patients from appropriate (but unpleasant) treatment protocols.
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BIOMEDICAL POLITICS Commentary Peter F. Carpenter This case study is a well-researched, balanced, unbiased review of the decision-making process that allowed release of the AIDS drug ddI for use prior to approval of the new drug application. The case is an excellent example of the difficulties involved in attempting to achieve an appropriate balance between the needs of individuals (people with AIDS), who desire access to an unproven therapy, and the needs of society, which must ensure proper testing of pharmaceutical products before they are made available for use outside of controlled clinical trials. There is no “right answer” to this dilemma: rather, the decision will reflect both the specific circumstances of the disease and of the unproven therapy. In the case of ddI, the expected outcome for patients who did not use the unproven therapy was sufficiently severe that none of the therapy's anticipated side effects would have been more serious than the outcome without therapy. In addition, more active involvement (than might have occurred even a few years ago) of patients in the decision-making process was a factor in shifting the balance toward making the drug available. The case study also illustrates the importance of finding solutions within established rules, rather than forcing a change. Such an approach is not only face saving but, more importantly, avoids the often unexpected or unintended consequences of what was thought to be a simple change. However, the case Peter F. Carpenter, a former pharmaceutical company (ALZA) and federal government (Office of Management and Budget) executive, is a visiting scholar at the Center for Biomedical Ethics at Stanford University.
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BIOMEDICAL POLITICS does not carefully analyze the historical precedent of the availability of unapproved cancer drugs. These so-called Class C drugs and the controversy surrounding their use are, in many ways, quite similar to the ddI dilemma. It is unfortunate that we have failed to apply directly both the process and the substance of the lessons learned in developing the Class C system to ddI and other AIDS drugs. Some key elements in the process examined by Jeffrey Levi were the identification of concerned constituencies, clarity regarding the issue, and the role of certain key players in making things happen. A previously weak constituency, the gay community, consolidated recent increases in its political strength and was highly motivated by the impact of AIDS on its members to represent itself forcefully. The general public and the general scientific community, however, have not been represented in the process to date, which may have important long-term implications. The willingness of individuals in positions of formal power to engage in dialogue with the advocates of change was a procedural step that was critical in this decision-making process. In addition, the recognition that existing rules could be interpreted to accommodate the desired outcome was essential in reaching a timely decision. These procedural steps can and should be generalized to other decisions involving biomedical innovations. The two most important shortcomings of the ddI decision-making process were its failure to include representatives from all constituencies and to make provisions for evaluation. For example, the broader scientific community was not formally involved in the ddI decision and it is now beginning to question the apparent decision to move away from the “gold standard” of randomized controlled clinical trials, particularly in light of reports of adverse reactions among individuals receiving the drug outside of clinical trials. The FDA has published a formal proposal to revise its rules to permit the general application of the procedure used in the ddI case. The review process that the proposal will undergo could bring to light important constituencies that did not participate in the original ddI decision. Second, it is necessary and important to have a prospective evaluation mechanism to assess the soundness of the decision based on the actual results versus the expected results. The following potential process guidelines emerge from this case: Participants in the decision-making process should clearly identify the issue being addressed or, if they are starting from substantially different definitions, develop a convergent definition. It is necessary to separate the specific from the general—realizing that the solution will later need to be generalized. It is important to encourage dialogue among the broadest range of constituencies. There is value in finding ways to use interpretations of existing policy as the solution rather than developing totally new policies.
Representative terms from entire chapter: