The Critique of Pure Science
AZT and the Politics of Interpretation (1989–1990)
Signs of Rapprochement
By early 1989, it began to appear that AIDS treatment activists had won a partial convert to the cause: Anthony Fauci himself, the head of NIAID and the government's AIDS research program. To a greater extent than his counterparts at the FDA, Fauci had cultivated good relations with treatment activists, opening up channels of communication with people like Martin Delaney of Project Inform and Mark Harrington and Jim Eigo of ACT UP/New York's Treatment & Data Committee. "In the beginning, those people had a blanket disgust with us," Fauci told the Washington Post in 1989: "And it was mutual. Scientists said all trials should be restricted, rigid and slow. The gay groups said we were killing people with red tape. When the smoke cleared we realized that much of their criticism was absolutely valid." When activists complained about the FDA's slowness in approving a drug called ganciclovir that appeared to prevent blindness in people with AIDS suffering from a viral infection of the retina called CMV retinitis, Fauci went to bat for them and helped to put pressure on the FDA. In an article in the journal Academic Medicine published early in 1989, Fauci defended established scientific methods but also acknowledged some of the points that activists had been making. "Clearly, there is a need for greater access to clinical trials of
investigational drugs by a broader spectrum of the infected population," wrote Fauci.
The turning point came at the Fifth International Conference on AIDS, held in Montreal in June. Activists took center stage at the conference—disrupting the opening ceremony, staging protests against pharmaceutical companies that had been identified as profit-hungry, and presenting formal poster sessions with titles like "AIDS Drugs and the Politics of Biomedicine" and "Drug Regulation Gone Wrong: The Saga of Ganciclovir." Behind the scenes, Larry Kramer of ACT UP/New York met with Fauci—a man he had called "an incompetent idiot" and worse in print—and solidified Fauci's support for "parallel track," a new concept that had been developed by Jim Eigo and other New York activists.
The parallel track program was, in effect, the solution to the sort of dilemma that Martin Delaney had described at the meeting of the Infectious Diseases Society a few months before (a meeting that Fauci had attended): when researchers coerced people into trials by giving them no other means of access to experimental treatments, participants likely wouldn't comply with the study protocols, and as a result the data would be unreliable. To avoid such difficulties, as Fauci told the press in June, a parallel track program "would provide promising drugs to some people with AIDS at the same time as the drugs are undergoing rigorous [Phase II] clinical trials." Patients would be eligible to receive free drugs in the parallel track program "if they were unwilling or unable to participate in the normal clinical trial"—for example, because they failed to qualify for the study or because they lived too far from the study centers.
In essence, Fauci adopted the activist line on this issue, as his comments quoted in the front-page New York Times article made evident: "'Previously, there was a great concern that if we did this, then no one would be in the clinical trial,' Dr. Fauci said. But he added that he has changed his mind and now thinks it is unnecessary 'to hold a gun to their heads' to induce people to join clinical trials." Fauci explained that NIAID could pursue parallel track under its own authority without the need for any new, enabling legislation; indeed, he was prepared to start the program soon with the drug ddI, pending support from the manufacturer, Bristol-Myers. Unlike the FDA's more limited compassionate use policies, parallel track promised to provide large numbers of AIDS patients with easy access to drugs that had passed only Phase I trials. "I came out and stuck myself out on a limb … and
everybody here in Washington fell off their seats and said 'What is he doing?'" Fauci later recalled. But "I thought it was the right thing to do, and I figured the only way we could get it done was to just say that I was in favor of it and apologize later. And as it turned out, I didn't have to apologize, because everybody then jumped on the bandwagon…."
Optimism among activists about their successes in changing federal policies was matched by more upbeat attitudes on the part of researchers and clinicians about therapeutic prospects. With AZT, with prophylaxis against PCP, and with better treatment strategies against other opportunistic infections, AIDS patients were living longer. Other antivirals like ddI and ddC were on the horizon. By combining or alternating the use of these and other drugs (as was often done in cancer treatments and for some bacterial infections), doctors might be able to keep the virus in check while preventing the onset of drug resistance. In Montreal, a new conventional wisdom emerged: HIV infection might soon become a "chronic manageable illness," not fully curable but something that a person might live with.
AZT: "The Time Has Come"
This notion that HIV disease could soon become a chronic manageable illness received a sharp boost in August 1989 with the release of the latest news about AZT. "The drug AZT can delay the onset of AIDS in people who are infected with the virus but have no symptoms," began a front-page New York Times article. ACTG 019, as the ACTG-sponsored study of AZT use in asymptomatic HIV-infected patients was dubbed, had just been halted upon the discovery by the Data and Safety Monitoring Board that the participants on placebo had been twice as likely to develop AIDS-related symptoms as those taking AZT. Just a few weeks earlier, ACTG 016 had also been ended, with the conclusion that AZT helped prevent HIV-infected people with mild symptoms from progressing to full AIDS. Out of 713 people in that study, 36 taking a placebo had progressed to AIDS, versus only 14 of those on AZT. Dr. Jerome Groopman had called it "the first clear proof that early intervention makes a difference." Now, with the results from 019, the verdict seemed to be in. "Today we are witnessing a turning point in the battle to change AIDS from a fatal disease to a treatable one," said Dr. Louis Sullivan, the Bush administration's secretary of health and human services. It was
indeed a turning point, though 019 would prove to be one of the most-debated studies in the history of AIDS clinical trials.
The 019 study finally made its way into the New England Journal the following April, with Paul Volberding of San Francisco listed as the first author. About 1,500 patients at thirty-two trial sites around the country had participated in the study for an average time of fifty-five weeks. Though none of them had AIDS symptoms upon entry, all of them were immune deficient, with T cell counts below five hundred per cubic millimeter of blood. One third had received fifteen hundred milligrams a day of AZT—by the time the study ended, this was generally believed to be an unnecessarily high dose—and 14 patients in that group had developed an AIDS-defining illness. Another third had received five hundred milligrams a day, with 11 developing AIDS. And of the final third, the patients on placebo, 33 had developed AIDS. AZT did not stop patients, as an aggregate, from developing AIDS, but it appeared to slow the process down, at least over a fifty-five-week period. Furthermore, the subjects receiving AZT (either high or low doses) showed, on average, statistically significant increases in their T-cell counts as well as decreases in their "p24 antigen levels" (p24 is one of the core proteins that make up HIV, so a measure of p24 is a crude measure of how much virus is present in the bloodstream—also called the "viral load"). These markers provided additional evidence that AZT was boosting immune functioning while curtailing viral replication.
What about the rumors of "cheating" by patients seeking to avoid the placebo? Did this skew the study and make the results untrustworthy? "There were lots of stories circulated in the press about people sharing drugs, analyzing drugs," recalled Volberding. But lab tests to detect the presence of AZT in the blood of the placebo patients suggested that drug sharing in fact "was an incredibly small problem." In any event, noncompliance actually strengthened the results of the study, the authors of the study results argued, since it "would tend to give results that underestimate the true effect of zidovudine" (the generic pharmaceutical name for AZT). Noncompliance effectively blurred the differences between the treatment arm and the placebo arm, so the demonstration of a statistically significant difference became all the more impressive.
Volberding and his coauthors included a series of important disclaimers. Since the trial had been ended early, there was still no definitive evidence about the long-term benefits or safety of AZT: "Thus,
it is possible that the eventual risks of disease progression in the three treatment groups could become similar after a longer time period." This might prove true particularly if AZT were to lose its effectiveness after extended use, as the virus mutated to resist the drug. (Such "resistance-conferring mutations" had already been observed in the test tube.) Finally, said the authors, "it is possible that even if zidovudine persistently delays the onset of AIDS, it may not have an ultimate effect on survival." On first glance, this was a surprising and paradoxical notion: how could a drug delay the progression to AIDS without extending the patient's life span? Volberding and his coauthors didn't elaborate, but the implication was that once progression did occur, the downhill course might then be rapid. Such cases were not unknown in cancer treatment research, where a drug might shrink the size of a tumor yet not confer any survival benefit upon the patient.
The accompanying editorial, by Dr. Gerald Friedland, acknowledged these various uncertainties and also spoke of the psychological implications of putting asymptomatic people on AZT: "The decision to start therapy … converts an apparently healthy person into a patient probably committed to lifelong treatment." The initiation of therapy in effect transformed the infected person's identity; this was not an act to be undertaken lightly. Nor was there any hard evidence from 019 about the best time to take such action: Was it when the patient's T-cell count dropped to seven hundred per cubic millimeter? Five hundred? Three hundred? But despite these words of caution, the overall tone of the editorial was upbeat, and the title conveyed the basic message: "Early Treatment for HIV: The Time Has Come." Friedland wrote: "The results of this study strongly support a recommendation to institute zidovudine therapy at a dose of five hundred mg per day [the lower, less toxic dose used in the study] in persons with asymptomatic HIV infection and CD4+ cell counts [T-cell counts] below five hundred per cubic millimeter."
Treatment recommendations in an editorial in the New England Journal carry considerable authority, but in a certain sense these were moot. Everyone had known about the study for eight months. Moreover, in early 1990 the FDA's new Antiviral Advisory Committee (one of more than forty standing committees of experts charged with giving independent scientific advice to the agency) had already recommended changing the labeling for AZT to include all HIV-positive patients with T-cell counts below five hundred. Despite concerns about the development of drug resistance, the vote this time was unanimous.
The FDA's Ellen Cooper had reservations about the recommendation—after all, the vast majority of people in each arm of the study had done well over the course of fifty-five weeks; the percentage of "events" (progression to AIDS) was small. Did it really make sense to begin mass administration of AZT to hundreds of thousands of relatively healthy people in order to prevent a small fraction of them from progressing to AIDS each year? As Cooper would later acknowledge, this was ultimately less a scientific question than "a matter of judgment and generalization." In the end, the FDA adopted the advisory committee's recommendations on March 2, and the NIH issued new guidelines for physicians concerning when to prescribe AZT. Burroughs Wellcome's potential market thereby increased by a factor of more than ten: In the United States alone, there were fifty thousand reported living AIDS patients, but an estimated six hundred thousand HIV-infected people with no AIDS-defining illnesses and with T-cell counts below five hundred. In England, the stock value of parent company Wellcome PLC increased by 1.4 billion pounds.
In practice, the findings of the 019 study, announced only in preliminary form to the media by NIAID, had provided the basis for regulatory policy making before the full results had even appeared in a peer-reviewed journal, where they could be scrutinized by other experts. Project Inform praised NIAID for its "efforts to release important news without waiting the extra 6 months or more needed for acceptance and printing of a completed journal article." For some time, activist groups had been insisting on the rights of people with AIDS to have access to medical data, and they had criticized the tendencies of some medical journals to monopolize control of information by threatening not to publish studies that had been disclosed to the press. But others, both within the AIDS movement and the scientific establishment, would condemn the practice of "science by press release." As far as Fauci was concerned, however, he really didn't have much of a choice, given the widespread interest in the 019 trial and the extensive monitoring of science by the AIDS movement: "Very, very quickly, everyone would have known the study was terminated. … It would have been unacceptable to everyone to make them guess why."
Poison? Or Just Mediocre?
In fact, neither NIAID's press conference, nor the FDA's approval, nor even the article in the New England Journal and the
accompanying editorial succeeded in bringing closure to debates about AZT. This was true both within the AIDS movement and among the scientific establishment. In gay communities, controversy about AZT had been bubbling away ever since the original licensing of the drug in early 1987 for use by people with full-blown AIDS. The New York Native , the gay newspaper most closely associated with the promotion of heretical views, had been calling AZT a "poison." Its administration "was an act of genocide on the scale of the kinds of 'medical experiments' conducted in Nazi Germany," the newspaper argued. "AZT's alleged benefits are not backed up by hard data, and are not sufficient to compensate for the drug's known toxicities. … Do not take, prescribe, or recommend AZT," read the Native 's cover in June 1987; an article by John Lauritsen, the HIV dissenter and ally of Peter Duesberg's, accompanied it.
Since Lauritsen did not believe that HIV caused AIDS (see part one), it followed that he would not support the use of an anti-HIV agent as a treatment for the syndrome—especially one that was a DNA chain terminator with potentially serious effects on healthy body cells. But Lauritsen, like Sonnabend, Callen, and other HIV dissenters, also argued that the Phase II AZT study had been methodologically flawed in ways that cast doubt on its substantive conclusions. "In practice, the study became unblinded almost immediately," wrote Lauritsen, recapitulating the various rumors about problems in conducting that study. Though, as with 019, it could be maintained that any noncompliance by participants actually strengthened the results, Lauritsen turned the argument around by proposing that the failure to maintain perfect double-blind conditions had pernicious effects on the research process. Since the research staff knew from lab test results which patients were receiving AZT and which were taking the placebo, he argued, they may have provided better overall care to the AZT patients, whether "unconsciously or deliberately"; this difference in care, rather than the administration of AZT, might explain the difference in progression to AIDS.
Lauritsen's was a textbook case of how to deconstruct a scientific study. "Scientists constantly face uncertainty," Susan Leigh Star has emphasized. "Their experimental materials are recalcitrant; their organizational politics precarious; they may not know whether a given technique was correctly applied or interpreted; they must often rely on observations made in haste or by unskilled assistants." Yet precisely because contingency, confusion, misgivings, and indecision tend to be "written out" of scientists' published work as part of their normal
persuasive practice, nonscientists often have mistaken notions about the degree of certainty behind the knowledge that science generates. As Harry Collins has concluded, "There is a relationship between the extent to which science is seen as a producer of certainty and distance from the research front." Thus one strategy for undercutting the credibility of scientific claims is to bring the audience in for a closer look, so as to recapture the contingency and messiness: "Irrespective of whether the critic describes 'truly disqualifying' acts of clumsiness or incompetence, or irrelevant details, the mere act of describing an experiment as a piece of ordinary life reduces its power to convince."
Although dissenters in the AIDS causation controversy universally rejected AZT, criticisms of the drug were not limited to this group. Particularly in New York City—which Martin Delaney characterized as "almost unique in the nation in its anti-AZT hysteria" —there were numerous pockets of suspicion of AZT. Throughout the epidemic, the New York gay community had been—depending on one's perspective—either more radical in its skepticism toward authority or more possessed of a debilitating paranoia than its counterparts in San Francisco and elsewhere around the country. From early on, New Yorkers had seemed to show more interest in conspiratorial theories about the origins of AIDS. With the advent of the HIV antibody test in 1985, even the more mainstream organizations like the Gay Men's Health Crisis had advised against taking the test, on the grounds that those testing positive might be rounded up and quarantined or at least discriminated against; by contrast, San Francisco organizations like the AIDS Foundation had taken a more neutral approach, while Project Inform had advocated in favor of testing as the necessary first step in a program of early intervention. Randy Shilts has suggested that such political and attitudinal differences reflected the relative degrees of comfort of the two gay communities as they evolved in the years before the epidemic, with New Yorkers more "closeted" and concerned about threats to their social privilege and San Franciscans more out-of-the-closet, secure, and influential vis-à-vis their city government.
Whatever the structural or psychosocial roots of these dispositions, they surfaced as well in debates over AZT. Though the "AZT is poison" argument was always a minority view among treatment activists and the communities at large, it was less of a fringe perspective on the East Coast than it was on the West Coast. Indeed, a 1989 gay health conference at Columbia University in New York erupted into a debate between Delaney and Sonnabend over AZT. Interestingly, Delaney agreed that there were "some problems" with the original AZT study
but also "[took] some responsibility for those problems": "We as a community screamed and hollered to move that drug through the system and study it as fast as humanly possible." Counseling pragmatism over a methodological purism, Delaney told the audience that to obsess about any deficiencies in that study "is a little like having study groups on the Council of Trent."
In its treatment newsletter, PI Perspectives , Project Inform expanded on the view that it was willing to accept a certain degree of uncertainty about drugs as a trade-off for more rapid approval: "Patients and their advocates, including Project Inform, pushed the regulatory and research system hard to make AZT available as soon as possible. We should not be surprised that the drug came into common use while our understanding of it was still very crude." The irony is that, when it was first approved, "there was widespread belief that AZT would be quickly replaced by other drugs with similar benefits and fewer side-effects." That hope had proven to be misplaced, so now patients and advocacy groups found themselves having to make the best of a not so great situation, forced to depend on a mediocre drug. But in response to this predicament, Project Inform advocated judicious risk taking over what it saw as denial and defeatism.
Having committed itself to an interventionist therapeutic strategy, Project Inform in a sense depended on AZT, the only approved anti-HIV drug and the only such drug with widespread public credibility. AZT was, at the moment, an "obligatory passage point": Project Inform needed the drug to advance the group's mission. With the news about ACTG 019, Project Inform pushed its critique of the AZT dissidents: "This latest information should (but won't) sound the death knell for the views of those who have bitterly opposed AZT for the last 3 years." The only real question now, Project Inform's newsletter proposed, was whether every HIV-positive person shouldn't begin immediate AZT use, even if his or her T-cell count was higher than five hundred per cubic millimeter. "At the very least, it is one rationally supportable course of action, perhaps more so than the opposite view."
Two Committees, Two Conclusions
Critiques by the AZT dissidents would continue after the results of the 019 study were announced. But perhaps more noteworthy (though in practice little noted at the time outside of the scientific press) was the lack of consensus in mainstream science about the merits of early intervention with the drug. All mainstream authorities
agreed that AZT should be prescribed to patients with AIDS. But should it be recommended for use by every HIV-infected person with fewer than five hundred T cells (let alone those with more than five hundred T cells)? Here the gap in perception was not between the two coasts of the United States, but rather between the opposite shores of the Atlantic Ocean. While the New England Journal of Medicine had promoted the message that the "time had come" for early intervention, Lancet , the most important British medical journal, suggested that "clinicians should change their prescribing habits with caution." The 019 study, according to Lancet , had simply shown that AZT could prevent a small number of people from progressing to AIDS over a short time period. Could these results be extrapolated to the majority of patients, who would progress more slowly in any case? Did the drug really halve the progression rate, or did it simply delay progression for a period of months until the onset of drug resistance?
According to Anthony Pinching, a British immunologist and AIDS clinical trials investigator, the difference in judgment "was exacerbated by the 8-month delay between the announcement of some preliminary results and publication [of the study]"—a delay that Europeans, including the British, had found irritating. During this time, while the rest of the world was waiting to see the data, the NIH and the FDA had effectively given their blessing to AZT use in asymptomatics. In the United States, hopes had coalesced into certainty; elsewhere, scientists and patients were in limbo. At root, said Pinching in an editorial about "knowledge and uncertainty" in AZT use, the problem was that U.S. authorities had "extrapolated" beyond the limits of the actual data—even if one considered the full data from the published study. They had been led beyond the limits of legitimate scientific deduction by "the widespread desire to see progress achieved and the wish to be seen to have made such progress." To illustrate his point about extrapolation, Pinching listed fifteen questions about AZT use in asymptomatics that still remained to be answered, even after the conclusion of 019.
The issue of what remained to be answered was very much on the minds of researchers throughout Europe, for some of them were smack in the middle of their own study when the media began trumpeting the news about the termination of 019. A consortium of researchers in Britain, Ireland, and France was conducting a trial dubbed "Concorde" that was substantially similar to 019. As in the United States, the European researchers had dealt with the ethics of placebo-controlled
trials; as in the United States, the Europeans had had to justify to community groups why such trials were necessary in studying AZT use in asymptomatics. But now—even after the results from 019 had been reported—the Concorde researchers were intent on continuing the study. As far as they were concerned, a state of equipoise still held: "The results we have seen," said Jean-Pierre Aboulker, the head of the study on the French side, "do not allow us to give a strict recommendation to give AZT." In deference to those who trusted the results of 019, they would modify the protocol to allow participants to begin "open-label" use of AZT, if they chose not to run the risk of being given the placebo. This change would introduce methodological complications into the interpretation of the data. But it would satisfy ethical objections while allowing Concorde to continue.
"Two committees looking at one set of data have come to radically different conclusions about the anti-AIDS drug AZT," was how a reporter for Science characterized the transatlantic dispute. In practice, everyone agreed on which questions they would like to have answered—questions about long-term risks and benefits, about the development of resistance, about whether early use would squander the limited efficacy of the drug against the virus. The different actions taken had to do with different judgments about the implications of what was known and what wasn't. How and when should a particular balance of certainty and uncertainty about a drug inform clinical practice? And what is the feasibility of continuing a placebo-controlled trial, once a specific (but not conclusive) benefit had been shown?
"I think there is generally a greater skepticism in the U.K. about the value of treatments than in the U.S.," commented biostatistician Susan Ellenberg, reflecting a widespread perception in the U.S. biomedical community. "I think there is much more reluctance [in Britain] to treat unless it is absolutely necessary." Such cultural differences were compounded by differences in the sheer magnitude of the epidemic in the two countries, not to mention the more vociferous character of AIDS treatment activism in the United States. Continuing the 019 trial "was not a conceivable possibility when the data were first seen … by those of us who were on the executive committee of the ACTG," researcher Martin Hirsch later recalled. "There was no choice but to stop the study given what the results were. … If we had withheld that kind of information we would have been strung up on trees. And if we had given out the information and said we were going to continue the placebo control trial anyway, we would have been strung up even
quicker." Similarly, the principal investigator for Concorde in Britain, Dr. Ian Weller, suggested to Science that the large numbers of AIDS patients in the United States had generated greater pressures there for the immediate translation of research into results. And once the formal guidelines had been issued, all the remaining uncertainties, though never denied, had in a practical sense been bracketed, largely to be ignored by the media, most practicing physicians, and most patients. Concorde, by contrast, chose to put uncertainty in the foreground. With the goal of obtaining definitive answers about early intervention with AZT, the Concorde trial would keep running all the way to 1993. Ironically, the results of Concorde, when finally available, would provoke more controversy than any AIDS antiviral study ever.
Activism and the Manufacture of Knowledge (1989–1991)
Methodology to the Rescue
As treatments activists followed, or contributed to, the debates surrounding AZT, they also devoted increasing attention to new drugs, such as ddI and ddC, that appeared likely to be the next additions to the therapeutic armamentarium of HIV antivirals. Since these drugs were chemically related to AZT, few thought that any of them would be an ideal therapy; but nothing else was anywhere near approval, and ddI and ddC at least showed promise. Perhaps they could provide alternatives for those who couldn't tolerate AZT's toxicity or for those who, over time, had stopped benefiting from AZT. Or perhaps some combination of these nucleoside analogues would prove more effective than AZT alone. Throughout 1989 and 1990, as AIDS treatment activists pursued the approval of these drugs as well as others that treated opportunistic infections, they became ever more enmeshed in the minutiae of clinical trial design—a set of topics that, increasingly, they would debate face-to-face with researchers and officials from the NIH and the FDA. This direct engagement with the terms of clinical research would both establish the scientific credibility of the activists (or certain of their representatives) and ultimately alter the pathways by which specific treatments came to seem credible in different quarters.
As with the parallel track initiative, a turning point came with the Montreal conference in the summer of 1989. ACT UP/New York had
distributed an AIDS Treatment Research Agenda blasting the ACTG program and detailing the activists' demands: more compounds in clinical trials, an end to placebo-controlled trials that required "body counts" to prove efficacy, greater access to clinical trials by all social groups affected by the epidemic, and more flexible protocols with broader entry requirements. Susan Ellenberg, the chief biostatistician assigned to the ACTG trials at NIAID, recalled seeking out the ACT UP/New York document in Montreal in response to her own curiosity: "I walked down to the courtyard and there was this group of guys, and they were wearing muscle shirts, with earrings and funny hair. I was almost afraid. I was really hesitant even to approach them. …" But after picking up the document, Ellenberg quickly found herself "scribbling madly in the margins." Though most of her marginal notes reflected dismay at activists' failure to understand, "there were many places where I found it was very sensible—where I found myself saying, 'You mean, we're not doing this?' or 'We're not doing it this way?'"
Ellenberg brought the ACT UP report back to Bethesda and shared it with her colleagues in a working group of statisticians who had been meeting to discuss challenges posed by the AIDS epidemic. "I've never been to such a meeting in my life," said Ellenberg. According to David Byar, the chief of the biometry branch of the Division of Cancer Prevention and Control at NCI: "I think anybody looking at that meeting through a window who could not hear what we were saying would not have believed that it was a group of statisticians discussing how trials ought to be done. There was enormous excitement and wide divergence of opinion." Soon afterward, with Fauci's consent, Ellenberg expanded her Statistical Working Group by inviting representatives from ACT UP and other community-based organizations to participate.
In a sense, the agenda of these meetings of the Statistical Working Group was to find methodological common ground that would satisfy competing ethical concerns. In more public arenas, activists were effective in seizing the moral high ground, and researchers were easily put on the defensive. Activist theater—like serving "Kool-AID" at public speeches by ACTG researchers to compare them to Jim Jones orchestrating mass suicide in Jonestown, Guyana—acted on researchers' sensitivities but risked alienating them as well. In more private negotiations, by contrast, there was at least tacit acknowledgment of ethical claims on both sides.
On one hand, activists often criticized trials in terms of the rights of research subjects; on the other, researchers defended the trials with utilitarian arguments about the benefit to society. But as Rebecca Smith of ACT UP/New York and AmFAR, who became close to several of the biostatisticians, explained in a letter published in Science , the solution was precisely to find points of convergence between "the immediate short-term needs of people with AIDS" and the "long-term goals of medical research." To the extent that methodological solutions could be engineered that would make all parties comfortable, people with AIDS and HIV infection would willingly participate in the trials and conform to the protocols, and scientific knowledge would be advanced.
Still, AIDS researchers often found this agenda threatening. At a 1990 community forum on clinical trials held in San Francisco, Donald Abrams commented: "My concern is we may never be able to study anything again to see if it works." But ACT UP/San Francisco member Michelle Roland argued at the same conference that perhaps the problem had less to do with any inherent limitations of science than with the ways in which doctors are socialized to imagine that clinical trials ought to be conducted. "We need to design realistic clinical trials that do a better job of meeting people's needs," said Roland, calling for a "revolution in clinical trial design." She acknowledged that such trials were "going to be more difficult to analyze. But we've got to do it."
The biostatisticians at NIH proved to be an important ally in this struggle: they did not always agree with activists, but some of them also had their criticisms of biomedical researchers. In the view of these biostatisticians, the reliance of principal investigators on "overly narrow and unimaginative" rules for conducting clinical trials betrayed their failure to entirely comprehend the underlying statistical principles. "Statisticians had been trying to say a lot of these things for years," Rebecca Smith recalled. "And we came along, and from a somewhat different perspective said a lot of them." Or as Ellenberg put it: "What the activists wanted pretty much was what we wanted too, and what we had every confidence that we were eventually going to be able to pursuade the investigators of. …"
At a panel discussion at the 1990 Annual Meeting of the Society for Clinical Trials to which Ellenberg invited activists, Jim Eigo explained the kinds of obstacles that stood in the way of carrying out effective AIDS research. "Investigators have traditionally had to deal with people
who are sick in a single way"; they therefore had been able to study the effect of a single drug on a single condition. But in the case of AIDS, where patients might be taking a range of drugs to treat their opportunistic infections, this was an "unreasonable preference" and one that had "made a shambles of the efforts to enroll AIDS clinical trials." Investigators routinely eliminated people who were on various medications and then found they could not fill their trials, explained Eigo, giving an example of recent trials for the antiviral drug ddI: at one New York site researchers had screened 150 people with AIDs and found only 3 who were "eligible" to participate in the study.
The point was that activist had insights about "accrual" of subjects into studies and "compliance" with the conditions of studies, two of the most vexing issues for clinical investigators: What trials would patients sign up for? Under what conditions could patients be relied on to follow the study protocols? It wasn't that researchers couldn't speculate about the answers to these questions; as one prominent researcher, Douglas Richman, insisted: "It's not like we're completely out to lunch. We sit and we talk to the patients. We've got some incredibly good nurses at the study center who spend all their time with the patients and think about the inefficiencies and the problems with the protocols and why patients are not happy with some protocols and happy with others." In practice, however, many researchers had tended to view accrual as essentially a technical problem and compliance as a management issue. From the investigators' standpoint, noncompliant subjects were "bad" subjects; from the activists' perspective, "noncompliance can be taken as a surrogate marker of the extent to which [doctors] have been able to explain things to patients." In fact, "if people don't comply," said Rebecca Smith, "that means they're not buying in, on some level."
Activists, as the research subjects' representatives or as subjects themselves, possessed grounded knowledge that many researchers found valuable in the design of trials—"an extraordinary instinct … about what would work in the community," as Anthony Fauci summarized it, and "probably a better feel for what a workable trial was than the investigators [had]." This was the expertise that researchers began to find attractive, and that made it worthwhile for activists to be invited onto the local community advisory boards and institutional review boards that oversaw protocols for clinical trials at hospitals and research centers. Furthermore, activists could work as intermediaries, helping to explain to people with AIDS and HIV exactly what a
clinical trial was and how one might decide whether to participate. Rebecca Smith considered one of her most important activist projects to be the production of a booklet called "Deciding to Enter an AIDS/ HIV Drug Trial." Published by the AIDS Treatment Registry in New York, this booklet was designed precisely to give people with HIV the capacity to make an informed decision about whether to participate in clinical research. It offered an overview of the drug approval process, a glossary of terms, and a long checklist of questions that the potential research subject should consider.
The Questions of Real Importance
Of course, activists also had quite a bit of learning to do about clinical trials, and biostatisticians played an important role in that education process. Both Susan Ellenberg of NIAID and Mark Harrington of ACT UP/New York pointed to David Byar (who died of AIDS himself in August 1991) as the key "charismatic" figure who helped bridge the gap between worlds. Byar suffered no fools—whether statisticians, activists, or researchers—but was happy to expound on the inner logic of the controlled clinical trial until his audience grasped the issues. Inevitably, the greater exposure to the science of clinical trials caused activist opinions to begin to shift.
An interesting example concerned the debate over the ethics of placebos. The idea that placebo-controlled trials were inherently unjust in life-threatening illnesses had endowed treatment activists with a moral claim, and it had made for some catchy slogans. But ironically, the same argument that had helped mobilize the AIDS movement to pay attention to clinical trial design had little currency once activists sat down at the table with the wizards of statistics. Simply by accepting the terms of the debate—that properly conducted, controlled trials should guide the selection of therapies—treatment activists became bound, at least to some extent, by the inner logic of these evaluative methods. And that logic, as David Byar insisted, at times favored the use of placebos as the shortest route to a meaningful answer: placebos were "sometimes … in the patients' best interest, whether they realize it or not, and no matter how many signs they paint and march around New York City with. …"
As D. Bruce Burlington of the FDA explained, the FDA did not necessarily insist on placebo controls as the only mechanism for conducting a controlled study that could lead to a drug's approval. For
example, "the agency can, and frequently does, accept … the historically controlled trial," where patients receiving an experimental treatment are compared with a matched group of untreated patients who were followed at some point in the past. But drug sponsors relying on historical controls "bear the burden of establishing the natural history of the disease," that is, proving that the progression of illness within the untreated cohort was representative of the disease in question. The problem, according to Burlington, was that AIDS had no single, constant natural history, given "the dramatic changes in demographics and the marked improvement in diagnosis and management of [HIV-infected] patients." The natural history of AIDS was in flux; so what would the treatment group be compared against?
Some activists, like Jim Eigo, rethought their assumptions: at another panel discussion in 1991, he acknowledged that although he originally had seen no need for placebos ever, he now recognized the virtues of using them in certain situations, where a short trial could rapidly answer an important question. More generally, activists maintained that the point was not so much placebos versus no placebos, but whether a trial asked a meaningful, real-world question that the patient community wanted answered. As Eigo put it in 1989 at a symposium entitled "Methodological Issues in AIDS Clinical Trials," sponsored by NIAID and the FDA: "If every arm of every trial asked a question of real importance to people with acquired immune suppression, enough of those people would find every arm of every trial a viable treatment option and, therefore, if they knew about the trial, could be accrued for that trial." This, in a sense, was a new definition of "equipoise" reframed from the vantage point of the community of patients rather than the community of scientists. If a trial compared different treatment options (including one option that was the control), if patients didn't know which option was best, if patients wanted to know which option was best, and if every option provided patients with quality medical care in all other respects, then patients would sign up for the study, regardless of the type of controls used. The prescription, therefore, was for better and more profound communication between researchers and the subject population (or their activist representatives) before studies got off the ground—indeed, before they were even proposed. "When we talk about methodology," Mark Harrington told the participants at the "Methodological Issues" conference, "we usually talk about how we are going to answer the questions that we set out to ask." This begs the prior question of "how
… we decide what are the important questions. As patients become more involved in the design and execution of clinical trials," said Harrington, "it is crucial to recognize that patients' questions are very important and deserve to be answered."
The questions that regulators or researchers wanted answered were often too academic, too removed from the day-to-day realities of patient care; and the resulting trials didn't provide participants with attractive options. Only an active engagement and negotiation between researchers, doctors, and the AIDS movement could ensure that the most important therapeutic questions were being studied; only such an engagement could rescue researchers from the not infrequent difficulties in recruiting patients to participate in their trials. As Paul Volberding acknowledged in his presentation at the same conference, "examples abound of clinical trials that are elegant in their design but fail because of limited accrual of subjects."
Credibility and Representation
Even if researchers were dubious about the patient community's ability to gauge what research was most important, they certainly recognized the practical virtues of cooperation and negotiation in order to ensure accrual. In this sense, a basic "credibility achievement" of treatment activists has been their capacity to present themselves as the legitimate, organized voice of people with AIDS or HIV infection (or, more specifically, the current or potential clinical trial subject population). This point is easily missed, but important, since the three groups—activists, people with AIDS or HIV, and clinical trial participants—overlap but are not isomorphic, and it is a complicated question whether in fact activists do meaningfully represent the diverse groups in the United States that are affected by HIV. Even within gay communities, the question of representation can be complex, in part because the activists are often politically more radical than the gay mainstream on whose behalf they speak, and in part because gay researchers and health professionals may also make plausible claims to representation. "What right do these people have to think that they are representing the gay community, when I'm also here and just on the other side of the fence?" Donald Abrams complained.
Looking back at her experience with treatment activism, Michelle Roland reflected with some candor, "I never represented 'people with AIDS.' I represented activists . And those are different people, you
know. They are a subset of people with AIDS." Yet the extraordinary success of treatment activists (who have always been a relatively small group and whose ranks have been further depleted by burnout, illness, and death over the years) stemmed in large part from their capacity to convince the biomedical establishment not only that they spoke for the larger body of patients but also that they could mobilize hundreds or thousands of angry demonstrators to give muscle to their specific requests. And once activists monopolized the capacity to say "what patients wanted," researchers could be forced to deal with them in order to ensure that research subjects would both enroll in their trials in sufficient numbers and comply with the study protocols. On the basis of their credibility, activists constructed themselves as an "obligatory passage point" standing between the researchers and the trials they sought to conduct. Of course, by the same token, the activists wanted to see the trials conducted, so the point, really, is that the relationship became a powerfully symbiotic one.
Access, Heterogeneity, and Pragmatism
One area in which activists succeeded in placing considerable and effective pressure on the biomedical establishment was the question of opportunity to participate in clinical trials. In part this concern grew out of the earliest debates about the true purpose of trials: were they scientific experiments or a means of access to unapproved treatments? The activists engaged in debating clinical trial design had no desire to pose the question in either/or terms, and certainly they were in favor of conducting experiments. On the other hand, they objected to the exclusion of individuals from trials on grounds that seemed to them arbitrary. Typically, the protocols specified various lab test levels as cutoffs for entrance into a study; a person with results outside the normal or expected range on these lab tests was excluded, ostensibly in order to avoid the introduction of extraneous variables into the study. In some cases, such rules actually threatened to derail the study. At the "Methodological Issues" conference, Harrington gave an example of a worthwhile study that was enrolling at a "snail's pace" because the protocol required that potential participants test positive for the p24 antigen, a marker of active viral replication, but one that in practice is hard to detect.
Principal investigators insisted on the virtues of "clean data." But in the name of this lofty goal, people who were currently taking other
medications, or had taken them in the past, found themselves excluded by study protocols, while sometimes those enrolled in studies who took so much as an aspirin without explicit permission were threatened with expulsion. Terry Sutton, a San Francisco activist who was going blind from CMV retinitis but who was denied entry to a test of a drug to treat that condition because he had already used another (unsuccessful) drug, summed up his frustration: "The idea of clean data terrifies me, because it punishes people for trying to treat early. My roommate … has made the decision not to treat early because of the pure subject rule. What he says is 'I want to be a pure subject so that I can get access to the best protocol once it starts to move.' You only get to be a pure subject once."
Rebecca Smith described a similar, but more hopeful story that pointed to the virtues of activist intervention. A patient who believed that his AIDS-related dementia was being kept in check by AZT also wanted to take an experimental drug to prevent blindness from CMV infection of his eyes. But in order to enroll in the trial for the CMV drug, he was told by his doctor that he would have to go off AZT. The patient "told me that … he was being asked to choose between his vision and his sanity," Smith recalled. But with Smith's support, the patient persisted, asking his doctor if there was any medical reason that one couldn't take both drugs, and whether anyone had ever studied the conjoined effects of the drugs. The end result of these discussions was the enrollment of the patient in a new study that alternated regimens of the two therapies.
In the skirmishes over these poignant dilemmas, activists found an ally in some of the biostatisticians. David Byar, for example, argued that as long as a study had been properly randomized from the outset, research subjects could simultaneously receive other medications, such as PCP prophylaxis, without threatening the statistical interpretation of the study results. Similarly, Byar insisted there was no statistical barrier to the simultaneous participation of patients in multiple trials, and he argued against excluding potential research subjects simply because they had abnormal results on lab tests. "Sometimes rigid entry criteria are defended because the investigators desire to study homogeneous groups, but this reasoning is usually difficult to justify," said Byar. "It is important to study patients with abnormal baseline values, because such patients will receive treatments shown to be effective, and we need to know in advance whether or not they can tolerate them."
Byar's argument pointed to a larger debate between two competing understandings of the very purpose of clinical trials—a debate with a history independent of AIDS or AIDS activism. In a 1983 article in the Annals of Internal Medicine , Dr. Alvan Feinstein, a professor at the Yale University School of Medicine and an authority on clinical trials, had distinguished between two warring conceptions of such trials, which he called the "pragmatic" and "fastidious" perspectives. Proponents of the first perspective look to trials "to answer pragmatic questions in clinical management." The trial design, in their view, should "incorporate the heterogeneity, occasional or frequent ambiguity, and other 'messy' aspects of ordinary clinical practice." Those who approach clinical trials with the perspective that Feinstein called fastidious "fear that [the pragmatic] strategy will yield a 'messy' answer. They prefer a 'clean' arrangement, using homogenous groups, reducing or eliminating ambiguity, and avoiding the spectre of biased results" in order to produce rapid and secure findings. This theoretical dichotomy was linked to an even older power struggle that Harry Marks has characterized as intrinsic to the history of the use of controlled trials in medicine—between academic researchers who would like to impose scientific judgment on clinical practice and primary-care physicians who struggle to preserve autonomy over clinical decision making.
Feinstein's distinction between fastidious and pragmatic clinical trials was described by Dr. Robert Levine, a professor of medicine and ethicist at Yale University, in his 1986 book, Ethics and Regulation of Clinical Research ; from there, the distinction made its way into the pages of AIDS Treatment News . The pragmatic perspective made sense to activists, as it did to community physicians with whom they were often allied. Clinical trials are experiments, to be sure, but they are real-world experiments with real-world implications. They should be designed not to answer ivory-tower theoretical questions but to inform day-to-day clinical practice and help patients and doctors make meaningful decisions when confronted with treatment dilemmas. If, for example, patients in the real world take different pills simultaneously, why not study the combined effects of the drugs? By contrast, many FDA regulators, academic researchers, and researchers for drug companies were more inclined, by training and institutional logic, to adhere to the dictates of fastidiousness. But by the late 1980s, many parties to the controversy could appreciate that there were valid arguments on each side. Indeed, Paul Volberding, in his talk at the
"Methodological Issues" conference, presented the case of entry restrictions as a simple trade-off: strict entry criteria promised an efficient trial, but one that might lack generalizability; broad criteria meant that findings would be generalizable but that the trial would be less efficient in the short run.
What was "real" and what was "artificial"? Precisely because every scientific experiment is by definition a stand-in for reality, any experimental method is, in principle, open to being taken apart by those who claim reality is not adequately represented. In this case, where there was an ongoing dispute between experts about which method was truer to "nature," activist pressure stood a good chance of tipping the balance. Because activists were able to enroll allies from fields such as biostatistics and bioethics, they succeeded in endowing the pragmatic perspective with additional credibility. "Once statisticians and activists started to talk, [this] was one of the things that there was immediate agreement on, from different points of view," recalled Ellenberg. "The activists were screaming that people couldn't get into trials…. The statisticians [were concerned] that the results of the trials weren't going to apply to anybody…." Working together, activists and biostatisticians successfully called for a number of modifications in trial design, many of which were already in common use in trials for other illnesses such as cancer. These included the use of broader entry criteria, more diverse subject populations, and concomitant medication.
The Politics of Purity
Taking on a more profound challenge, one suggested by Terry Sutton's poignant comment, activists interrogated the presuppositions of scientific "cleanliness." Did "clean" data come only from "pure" subjects? Was "messy," "impure" science necessarily bad science? The debate between fastidious and pragmatic approaches to clinical trials already pointed to these questions; AIDS treatment activists pressed them even further. People with AIDS were not in awe of that "strange and abstract god, clean data," Jim Eigo told a Senate health subcommittee. Similarly, John James argued that "Good Science, like God, patriotism, and the flag, are rhetorical devices designed to be impossible to argue against—devices often used in the absence of a good case on the merits." Academic researchers could be counted on to come up with "elegant" research designs, but were these the ones that would most effectively answer the burning questions?
The metaphors varied, but the implication, in each case, was similar: the defense of science put forward by mainstream researchers was an ideology designed to promote the kind of science they happened to do as the only kind that could be called science. Purity and cleanliness, in this sense, were not intrinsic to the scientific project; they were legitimating metaphors that imbued modern scientific institutions with an appearance of the sacred.
Building on concepts like Feinstein's notion of "pragmatic" trials, activists hinted at (though never fully described) what they saw as a preferable kind of science, which would be more accurate, more useful, and more responsible. This science would be less preoccupied with the formal rules that prevent "contamination" and more open to the varying of experimental design in recognition of practical barriers, ethical demands, and other "real-world" exigencies. "The truth is that [clinical trial] research is muddy, and people need to start acknowledging that," San Francisco activist Michelle Roland explained. "You can't get good clean answers, the world does not work that way. Patients tend to not work that way unless you totally manipulate them. And this is not a population that is going to be easily manipulated. So you either have muddy research that you know is muddy, and you can at least say, 'This is where it's muddy,' or you have muddy research and you don't even know how muddy it is."
The championing of "real-world messiness" was also the strategy of Martin Delaney of Project Inform when he decided, in 1989, to conduct research on "Compound Q" (tricosanthin), a drug obtained from a Chinese cucumber that had been shown to kill HIV-infected macrophages in the test tube. Believing that the official study of Compound Q was too small and that it was using inadequate dosages, Project Inform initiated its own study with the cooperation of a number of doctors and laboratories and forty-two participants in three cities. No placebo controls were used. The following year, Delaney reported his cautiously optimistic findings at the main panel on clinical trials at the Sixth International Conference on AIDS, in San Francisco. Delaney acknowledged that Project Inform had "stretched the rules" by including research participants who were simultaneously taking other medications. But rather than accept that such procedures contaminated the study, Delaney argued that the "real-world conditions" of his study were precisely its virtues and the warrants of its validity. "This is the real-world laboratory," Delaney proclaimed. "This is not the artificial world of clinical trials."
Needless to say, the Compound Q trial sparked considerable controversy, and it prompted an FDA investigation, though in the end Project Inform was allowed to proceed. At an earlier juncture in the study, when two participants went into comas, Delaney was blasted by Paul Volberding, who was directing the official study of the drug at the University of California at San Francisco. "It doesn't take a genius to hand out drugs," said Volberding, "but it takes a certain amount of discipline to ask questions in a rigorous way." And at the AIDS Conference, Delaney was attacked by co-panelist Arnold Relman, editor of the New England Journal of Medicine , who defended the "proven methods of science." "Let's not go back to the days of black magic," Relman exhorted. For his part, Delaney continued to defend his "real-world laboratory," but the experience of designing and conducting a study also made an impact on him. "The truth is, it does take a lot longer to come up with answers than I thought before," he admitted at a community forum in 1990.
Heterogeneity and Social Difference
Having campaigned against narrow inclusion criteria, activists pushed the question of access to trials even further: they opened up the issue of the social demographics of clinical trial participants. In public, the research establishment was on weak ground in this debate: since AIDS activists had successfully promoted the notion that access to trials was potentially beneficial, ordinary notions of equality and justice suggested that this social good should be distributed widely and fairly. Just the opposite was in fact the case, at least in the trials funded through NIAID's ACTG program.
As a 1989 front-page Los Angeles Times exposé by Robert Steinbrook had revealed, "blacks, Latinos and intravenous drug users, the groups increasingly afflicted with AIDS virus infections, are significantly under-represented in federally sponsored AIDS clinical trials…." Using documents obtained from NIAID under the Freedom of Information Act, Steinbrook showed that while blacks and Latinos accounted for 42 percent of adult U.S. AIDS patients, they made up only 20 percent of the research subjects in the ACTG trials. Only II percent of the ACTG subjects were injection drug users, though this population accounted for 28 percent of AIDS cases. A later study by New York activists that was presented at the Seventh International Conference on AIDS in 1991 showed that women comprised only 6.7
percent of ACTG trial participants. While women accounted for only 9.8 percent of overall AIDS cases according to the CDC's statistics, activists argued that many actual cases of women with AIDS were not captured by the CDC's surveillance definition.
In fact, most trials were populated largely by adult, white gay men who had contracted HIV through sexual transmission. Other demographics groups, such as men of color and women and children of all races, were underrepresented; so were those who had contracted HIV through drug use or contaminated blood products. The reasons for these exclusions were multiple. Certainly it didn't help that there were no AIDS Clinical Trials Units in five of the thirteen cities that contributed the greatest numbers to the CDC's statistics for U.S. AIDS cases—Houston, Philadelphia, Atlanta, Dallas, and San Juan, Puerto Rico. Injection drug users were rarely targeted for recruitment because they were considered to be "bad" research subjects. "They are alienated, disorganized and distrustful," one doctor told the New York Times in 1988. "They don't keep appointments; you can speculate about why, but they just don't do it." (In response, other doctors maintained that those drug users who were participating in drug treatment programs made perfectly good research subjects.) Some observers also cited "real-life barriers" to the participation of working-class and poor people in trials, including the cost of transportation and the lack of child care.
In the case of minority groups, particularly African-Americans, it also could not be assumed that people were anxious to volunteer for trials. Whites may have been banging on the doors demanding to be put to use as "guinea pigs," but many blacks had vivid historical memories of precisely what such use entailed. As one Dallas health educator testified before the National Commission on AIDS, "So many African American people that I work with do not trust hospitals or any of the other community health care service providers because of that Tuskegee Experiment." The fact that many researchers had targeted Africa as the site of origin of AIDS aroused further distrust in African-American communities. In one survey of black church members, 35 percent of the respondents expressed agreement with the claim that AIDS might actually be a form of genocide perpetrated by the U.S. government on minority communities. Given such sentiment, it was unlikely that the AIDS Clinical Trials Units would draw many African-Americans simply by posting an announcement and waiting for the phone to ring. At a minimum, serious recruitment
would have required a concerted outreach effort that presupposed gaining the trust of community leaders.
Finally, the very same reforms in the protection of human subjects that incidents such as the Tuskegee study had engendered also created pressures to exclude various groups from clinical research. According to this logic, experimentation was something that vulnerable populations were to be protected from . Children, for example, were generally not to be the subjects of clinical trials until after a drug had been proven safe and effective in adults. (Partly as a result, AZT was not widely distributed to children with AIDS in the United States until October 1989, more than three years after adults had gained broad access to the drug. )
The situation with women was even more restrictive. Until 1986, women "of childbearing age"—regardless of whether they were pregnant or had any intention of becoming so—were barred from trials as a matter of course out of fear of causing damage to fetuses (or out of fear of resulting lawsuits). Though the NIH formally changed its rules in response to protests, research protocols (for AIDS and other illnesses) often continued to exclude women, and the FDA continued to ban women from early research on new drugs. Some women with AIDS charged that even after they had offered to undergo sterilization, they were still told they would be unable to join the clinical trials for drugs that the women considered to be promising.
In practice, such policies meant not only that women lacked access to experimental therapies that might help them but also that doctors lacked certainty about the effects of drugs in women's bodies. "American women have been put at risk," said Representative Pat Schroeder, citing a study begun in 1981 that sought to investigate the role of aspirin use in preventing heart attacks, which had enrolled twenty-two thousand male doctors. "[NIH] officials told us women were not included in this study because to do so would have increased the cost," commented a congressional investigator. "However, we now have the dilemma of not knowing whether this preventive strategy would help women, harm them, or have no effect." Another female member of Congress, Olympia Snowe, described a federally funded study on the relation between obesity and cancer of the breast and uterus; the pilot study had used only men. "Somehow I find it hard to imagine that the male-dominated medical community would tolerate a study of prostate cancer that used only women as research subjects," Snowe commented.
Men's and women's bodies are manifestly different, and it seemed not unreasonable to suggest that drugs might have different effects in the different genders. Some experts claimed that the same was true for members of different racial groups; Asians, for example, were said to metabolize an antidepressant drug called desipramine more slowly. As to whether such differences might reveal themselves with AIDS therapies, researchers remained uncertain. Anthony Fauci would comment in 1994 that such a basic question as "whether the drug has an antiviral effect" is something "you could determine … by giving it to people who live on … Park Avenue and 69th Street in New York City and not worry about the rest of the world…." But that's different, Fauci went on to say, from the question of precisely how best to use particular drugs in particular populations—an issue to be determined by administering drugs to a heterogeneous collection of patients.
Whether or not there truly are significant variations in how drugs affect different social groups, the fact remains that the existence of such variations is widely considered plausible by a society that increasingly tends to understand social difference as something rooted in biology. The body of a gay white man, therefore, was seen as an inappropriate location for generating predictions about the effects of a drug on a straight white man, or a gay Latino man, or a gay white woman. The complexities involved in such debates became evident in 1991, when yet another AZT study, conducted in Veterans Administration hospitals by the Department of Veterans Affairs, purported to find a difference in response to AZT between white and minority patients. "AIDS Study Suggests Drug May Have Racial Limits," declared a Washington Post headline. Dr. Wayne Greaves, an infectious disease specialist at Howard University in Washington, D.C., told the New York Times that he would "counsel black and Hispanic patients that in light of the new data they had to decide for themselves whether to take the drug." But as scientists and activists scrutinized the data, they discovered that the Veterans Administration researchers had in fact made their claims about a racial category they called "minority." Lacking sufficient numbers of Latinos and African-Americans to draw statistically significant conclusions, the investigators had simply decided to lump the two groups together. Ron Johnson of New York City's Minority Task Force on AIDS blasted the "sloppy" methodology: "Until they do a credible study, they're just playing with us, throwing out confusing and conflicting bits of information." Underlying this response, however, was the prior reification of racial
categories: "black" and "Hispanic" were considered to be "real" markers of biological difference (and thus potential predictors of differences in response to treatment), in a way that the hybrid category "minority" was not.
The issue was indeed one of credibility, as Johnson indicated, and in U.S. society at the time, a drug would simply not be perceived as credible across the board if it had not been tested in a diverse range of social groups. As Vivian Pinn-Wiggins, a pathologist at Howard University and the president of the National Medical Association (an organization mainly of African-American physicians) put it in 1990, "some of our physicians are a little leery" of certain medications because "we can't be certain whether minorities have been participants" in the clinical trials. Of course, as Ellen Cooper pointed out at the "Methodological Issues" conference, there are many kinds of heterogeneity, and there are no a priori grounds for singling out particular instances, such as racial and gender differences, and assuming that there are the ones that will manifest differences in response to treatments. These categories are simply the ones with greater social and political salience.
Two sets of issues came together in the debate over homogeneity and heterogeneity in a study population: the need for a morally credible policy promoting fair access to experimental drugs and the need for a scientifically credible policy for acquiring generalizable data. Between these two sets of issues, AIDS treatment activists had plenty of room to play. Defenders of the notion that a "clean" trial required a homogeneous research population, by contrast, found themselves increasingly on the defensive. The activist critique demonstrated the back-and-forth movement between ethical and epistemological claims-making that AIDS treatment activism had perfected: heterogeneous trials were not only fairer, they were also better science. Though it would not always prove so easy, in this case, the goals of "access" and "answers" could be made to coincide.
Old Dogs and New Tricks
Two astonishing, back-to-back "Sounding Board" articles in the New England Journal of Medicine in October 1990 attested to the activist success in shifting biomedical norms governing the acquisition of knowledge through AIDS clinical trials. One article, by David Byar and many prominent biostatisticians, argued for restructuring
the "phases" of the FDA approval process, dismissed the requirement of homogeneity in a clinical trial population, and called for more flexible entry criteria. The authors concluded with a call for "patients and their organizations to participate in the planning of clinical trials. Such participation is likely to ensure greater agreement with the objectives and design of the trial and to make people with AIDS more aware of the opportunities to enter trials."
The other article, by Thomas Merigan, an ACTG researcher from Stanford, was called "You Can Teach an Old Dog New Tricks: How AIDS Trials Are Pioneering New Strategies." Praising the "new level of rapport" and the "partnership of patients, their advocates, and clinical investigators," Merigan argued that "all limbs [of a trial] should offer an equal potential advantage to patients, as good as the best available clinical care"; that no one in a trial should be denied treatment for opportunistic infections; that trials should not be "relentlessly pursued as originally designed" when "data appeared outside the trial suggesting that patients would do better with a different type of management"; and that "the entry criteria for trials should be as broad as scientifically possible to make their results useful in clinical practice."
Medical ethicists had also come on board; they wrote elsewhere of "the beginnings of a new consensus … on basic principles and policies that ought to guide HIV/AIDS clinical research." Such principles emphasized the "routine use of community consultation," but also called specifically for such practices as broad entry criteria for trials. One ethicist, Robert Levine, argued against "boilerplate exclusions" that ruled out whole groups of potential research subjects on the basis of abnormal lab test values—and acknowledged that the issue "didn't occur to me until I had it explained to me by Mark Harrington."
Few of these "reforms" were actually new, and many were standard practice in cancer research. As Byar commented, the reaction to his paper in the New England Journal was "Well, that's not terribly exciting, I mean we knew that stuff already." But, Byar continued, "there was plenty of evidence that if they knew it, they weren't using it." What the two articles marked was not the birth of new ideas but the successful passage of those ideas into commonsense understandings about how AIDS trials should be done. Moreover, these were the ideas that had been pushed by the activists, and their ascension was widely understood as a testament to the activists' forceful argumentation and successful mastery of the arcana .
On one hand, activists had "denaturalized" the randomized clinical trial—taken it off its pedestal and subjected its presuppositions to scrutiny. Clinical trials "are a product of recent history," argued Jim Eigo in a presentation at the conference of the American Academy for the Advancement of Science: they are not an "unassailable gold standard." On the other hand, activists had presented themselves as the collective voice of reason that could restore order to the scientific method. Theirs was "not a call for the abolition of clinical trials," Eigo assured his listeners at the same conference, but "rather a call for their revision and augmentation."
In retrospect, this was a high point—though few activists marked it at the time, being preoccupied with keeping themselves, their friends, and their lovers alive. Activists had reframed how clinical research should be conceived, and they had established the proposition that the desires of the patient community must be factored into the design of clinical trials. They had situated themselves as an "obligatory passage point" on questions of trial methodology, and they had enrolled at least a number of statisticians, ethicists, researchers, and government officials behind their program. For the moment, it appeared that activists could be the voice of principled morality for their communities and the voice of principled science in the inner circles of biomedicine—without undue strain arising out of conflict between these roles. The challenges of the early 1990s would pose complications to this impressive agenda.