Dilemmas and Divisions in Science and Politics
Combination Therapy and the "Surrogate Markers" Debate (1989–1992)
The Origins of a Bandwagon
By the late 1980s, the guiding assumption was that "combination therapy" was the most fruitful avenue of therapeutic investigation in treating HIV infection. AZT, the only approved antiviral, seemed to benefit patients for a while, until the virus mutated to resist the drug's action. Combining drugs would in theory delay the development of resistance while, perhaps, permitting lower doses of each drug to be used, thus reducing the exposure of the patient to toxic side effects. This was the model in fighting tuberculosis and other diseases; it was generally extrapolated to HIV infection. Researchers and activists alike were anxious to proceed with the testing of combinations of nucleoside analogues (drugs like AZT) as well as drugs with other mechanisms of action. But activists, researchers, government officials, and pharmaceutical companies would have to negotiate the crucial details of the testing process: What evidence was required to demonstrate the safety and efficacy of combination therapies? How quickly could these drugs be released?
At the Sixth International Conference on AIDS, held in San
Francisco in June 1990, researchers presented the preliminary results of a clinical trial called ACTG 106, a small-scale study of the combined use of AZT and ddC. One of the first in vivo studies to test a combination therapy, ACTG 106 was carried out in two sites, under the direction of Margaret Fischl at the University of Miami and Douglas Richman at the University of California at San Diego. As a preliminary study, the main purpose of the trial was not to determine efficacy but simply to monitor for toxicity and determine an appropriate dose for use in subsequent, larger studies. There were only fifty-six patients, and they were randomly assigned to six different "dosing regimens" of the combination therapy of AZT plus ddC and followed for an average of forty weeks. Because the study was not meant to measure efficacy, there was no control group.
The study succeeded in its explicit goal of determining an optimal dose and assuring that the side effects of the two drugs, while certainly unpleasant and potentially quite serious, were still manageable. (With AZT the main concern was liver damage; with ddC, peripheral neuropathy, or nerve damage in the hands and feet.) But this was not what attracted attention. "To everyone's surprise," according to John James, the editor of AIDS Treatment News, "not only did the combination seem safe, it also appeared to work much better than any other anti-HIV treatment known." Though the participants were severely immune suppressed, with fewer than 100 T cells per cubic millimeter upon entry, they experienced sharp increases in their T-cell counts—a mean increase of about 120 cells per cubic millimeter in the patients receiving higher doses. "Although these results must be interpreted with caution," the authors noted in the published report of the study, which finally appeared in early 1992, "the response rates of CD4 lymphocytes [helper T cells] seen in our patients differ sufficiently from those reported in previous studies to merit comment."
Activists were less restrained in expressing the widespread enthusiasm. "There was nothing at that point in time that was comparable to that sort of jump, particularly at late stage of disease. And at late stage of disease, everybody had run out of their options," recalled G'dali Braverman, an activist with ACT UP in San Francisco. The problem was that the study was small, lacking a control, and too short in duration to determine if the therapy prolonged life. Confirmation of the efficacy of AZT/ddC combination therapy would have to wait several years for the completion of ACTG 155, a much larger, Phase II study that was already under way. That study had randomly assigned patients, in blind fashion, to one of three treatments: AZT alone, ddC
alone, and the two drugs in combination. Meanwhile, according to John James, "long before the scientific paper was published, the results of [ACTG 106] had established a de facto standard of care among many of the best-informed patients and physicians." As James expressed it in the pages of AIDS Treatment News , researchers and people with AIDS simply "drew different practical conclusions" from ACTG 106. "Scientists who run clinical trials are interested in maintaining scientific standards, in doing studies correctly so that they get solid, trustworthy results. People with life-threatening illnesses, on the other hand, are interested in using whatever knowledge is available to make the best treatment decisions they can."
Belief in the efficacy of the ddC/AZT combination regimen swept through the AIDS movement with the force of a juggernaut. Of course, no doctor could prescribe ddC to his or her patients at this point. Some people with AIDS were able to obtain free ddC from the manufacturer, Hoffman-LaRoche, under the new parallel track program (also called "expanded access") that provided experimental drugs to people not in clinical trials. But one particular fact about ddC really fueled the bandwagon: unlike other nucleoside analogues, such as AZT and ddI, ddC could be manufactured cheaply and easily from common chemical ingredients.
Soon ddC was being pumped out of basement laboratories and passed on to the buyers clubs and, from there, distributed to people with AIDS and HIV around the country. And the FDA, for the most part, was turning a blind eye. If the estimate put forward by Derek Hodel, then director of the PWA Health Group, a New York City buyers club, can be trusted, as many as ten thousand people nationwide may have been receiving bootleg ddC by late 1991. Hoffman-LaRoche representatives were, not surprisingly, upset about the infringement on the company's patent, and they voiced concerns about quality control in the underground manufacturing process. Experts on clinical trials complained that the access to ddC threatened to undermine ongoing trials of the drug. After all, if you are in a ddC trial and become convinced that ddC works but don't know for sure whether you are receiving ddC or are in the control group, and if you can get ddC at bargain-basement prices around the corner, are you going to bother staying in the trial? Thomas Chalmers of Harvard University, a medical researcher and expert on clinical trials, told the New York Times that the buyers clubs were "terrible," "the most serious step backward I've seen in a long time."
One of the most noteworthy aspects of the controversy, however,
was the fact that a considerable number of practicing physicians tolerated, and even encouraged, the bootleg use. One San Francisco doctor well known for his involvement in AIDS care, Marcus Conant, acknowledged that as many as three hundred of his patients were taking bootleg ddC. "If I were in their shoes I would be doing the same thing," Conant told a reporter for Nature . A manufacturer of the bootleg drug told the gay newsmagazine the Advocate: "Doctors from around the country are calling us and their local buyers clubs to get ddC for their patients."
Some of these doctors may simply have been acknowledging the inevitable: given the existence of the buyers clubs, they no longer stood as the "gatekeepers" between their patients and the medication that might help them. At the same time, both doctors and patients recognized the practical virtues of cooperation: these were serious drugs, and it behooved patients to find doctors willing to monitor the use of their ddC in case of toxicity or adverse reactions. Other doctors may have found it easier to hand out the buyers club phone number than try to navigate Hoffman-LaRoche's restrictive parallel track program, which required complicated paperwork certifying that the patient had already tried both AZT and ddI and had failed on both drugs. Finally, many doctors quite simply believed that the AZT/ddC combination was state-of-the-art medicine and preferable to ddI, given the results from existing studies. "I'm not going to wait for my patients to lose any more T cells before advising them to get ddC on the underground," said one Washington, D.C., physician, delivering a personal manifesto. "For me and a lot of other doctors, we're out and we're not going back."
These community physicians had precisely the overlapping affiliations that the term suggests: they aligned themselves, in complicated ways, both with their communities and with their professions. Or to put it another way: by the early 1990s, AIDS treatment activism had become a movement that cut across professions, not just one that pitted professionals against laypeople. These physicians, moreover, were quick to insist on the evidence of their own eyes. Clinical trials or no clinical trials, their patients benefited from the combination therapy. Such attitudes, of course, have a long history, as practitioners have resisted the encroachment on their professional authority that the scientization of medicine represents. Medicine, in this view, is an "art," not a "science." "While science may be considered a symbol of legitimacy and source of power for the medical profession," Deborah Gordon has
noted, "physicians' clinical expertise may be regarded as their personal power and private magic." The tacit knowledge and skills of everyday practice, not the results of randomized clinical trials, were the basis of these doctors' claims to professional autonomy. They were the ones on the front lines of patient care; they saw themselves as best suited to make clinical judgments about what was best for their patients.
By late 1991, the credibility of the combination therapy—or at a minimum, widespread belief in its potential efficacy—had been established in the United States, less through the formal claims of infectious-disease researchers than through the interventions of less authoritative actors, including AIDS activists and community-based physicians. The FDA, meanwhile, though mandated to assure the safety and efficacy of drugs, was taking a backseat. In an intriguing analysis published sometime afterward, John James defended this peculiar, de facto endorsement of an underground drug as perhaps "the best possible solution to a deeper structural problem, a confusion about what we as a society use FDA approval for." Was the purpose of the FDA sanction to permit access to a drug, or to recommend a drug as the standard of care? "In theory the FDA does not regulate the practice of medicine"; in practice, doctors relied on FDA approvals to decide what to prescribe, while insurers often declined to reimburse the cost of a drug used outside of its indicated labeling. Given this basic confusion, what could the FDA do? "With only one small study available, it would have been difficult to say, 'Here, take this' to tens of thousands of people. Yet it would also be unacceptable to say, 'You can't have this' to those who had studied the matter and made an informed choice," James concluded. Much as a rumor on Wall Street can circulate uncontrollably and inflate the value of a stock, any positive signal from the FDA would have had widespread repercussions, augmenting the credibility of the drug. Since the FDA had no mechanism for permitting access to a drug without appearing also to recommend it, turning a blind eye to the buyers clubs was a convenient, and perhaps necessary, holding action.
Surrogate Markers to the Rescue
But how to get ddC, along with ddI and other new drugs, formally approved by the FDA? That was the true goal, in the eyes of most AIDS activists—not relying on compounds cooked up in somebody's kitchen. No one thought these drugs were magic bullets.
As Mark Harrington wrote in his column in the gay and lesbian magazine Outweek , "At best, [ddI] will be a less toxic alternative to AZT [and] at worst, it will be an alternative with less antiviral activity and unpleasant side effects." Nonetheless, the issue was "vitally important," wrote John James, "because there are tens of thousands of people unable to use AZT, or no longer able to benefit from it."
The obstacle, in James's view, lay "not with any one agency, company, or other institution, but with a professional consensus which crosses organizational boundaries"; this consensus, if not disrupted, would effectively prevent "any decisive treatment advance from being available for years." The entire research enterprise was geared toward what James called "dinosaur trials"—huge, costly, multicenter trials that would take years to complete. Why did the trials take so long and require so many subjects? As James explained in AIDS Treatment News , the chief impediment was that "the FDA has insisted on the slowest measure of clinical improvement," namely death or opportunistic infections in the control group. "This means that the drug being tested is not measured by improvements in the patients who receive it, but [opportunistic infections] or deaths in those who do not."
The alternative measure of drug efficacy that activists proposed was one with a long history in biomedicine but none whatsoever in AIDS: the use of "surrogate markers" to demonstrate the efficacy of a treatment. A drug shown to reduce serum cholesterol or blood pressure, for example, may be approved to treat heart disease on the assumption that such improvements correlate in the long run with an overall clinical benefit. Similarly, the amount of reduction in tumor size is sometimes used as a surrogate marker for the effectiveness of a cancer drug. Approving a drug on the basis of a surrogate marker necessarily implied greater uncertainty about the actual effects of the drug against the disease for which the marker is a stand-in. But it was a more or less accepted course of action for life-threatening diseases, since it could speed up the decision-making process considerably.
The difficulty, however, was that no marker had yet been proven to function as a surrogate for the effectiveness of an antiviral AIDS drug. A good marker would be one with "face validity" and "biological relevance"; it would also be easily measurable in some objective and reliable fashion. But a high-profile workshop called "Surrogate End-points in Evaluating the Effectiveness of Drugs against HIV Infection and AIDS," sponsored by the Institute of Medicine of the National
Academy of Sciences and held in September 1989, had failed to arrive at a consensus on such a marker or markers. Anthony Fauci, the director of NIAID and the government's point man on AIDS research, backed the most obvious and oft-discussed marker: CD4 counts (the technical name for T-cell counts). Another logical choice was the level of p24 antigen, the core viral protein, but it was found only inconsistently in the blood. Debate also focused on other indicators of disease progression in the blood of HIV-infected people, such as a rising "b2 microglobulin" count or "neopterin" count. But these latter measures were nonspecific, Fauci argued, since they are common in many illnesses. "Nobody dies from elevated levels of b2 -microglobulin or neopterin," said Fauci, "but nobody can make it without CD4 cells."
T-cell depletion was the very hallmark of AIDS; to an immunologist like Fauci, AIDS could almost be defined in terms of HIV's direct and indirect effects on T cells. Any drug that staved off T-cell decline had to have some value. To Fauci, and certainly to many activists, this made such intuitive good sense that any opposition seemed almost frivolous. The biostatisticians and the FDA regulators had their doubts, nonetheless. As a measure, CD4 counts were notoriously labile, fluctuating depending on the time of day the blood was drawn, how much sleep the patient had the night before, what the patient ate for breakfast, or which laboratory was doing the analysis. More fundamentally, as NIAID biostatistician Susan Ellenberg pointed out, the problem was that something might be a good prognostic marker of the future course of illness in the natural history of a disease (and no one doubted that CD4 counts filled this role in AIDS), but that didn't prove it could function as the endpoint of a clinical drug trial. That is, researchers can predict the future of an HIV-infected person (speaking in probabilistic terms) if they know his or her CD4 counts, but that doesn't necessarily mean they can predict the effect of a treatment on the person's prognosis simply by knowing the effect of the treatment on his or her CD4 counts. Such an association remained to be demonstrated.
Some of the New York activists, like Mark Harrington, promoted the use of surrogates but also argued that surrogate markers were only part of the answer. He called for careful attention both to quality-of-life indicators and the pathogenetic mechanisms of HIV infection that presumably underlay the surrogate markers. But others, particularly in San Francisco, saw surrogate markers as the critical issue. Martin Delaney, the director of Project Inform, for whom the virtue of CD4
as a surrogate marker was "intuitively correct," blasted what he saw as the head-in-the-sand insistence on definitive proof. "Such a view may be valid from a scientifically conservative, purist perspective," Project Inform's newsletter contended, "but it is hardly a progressive position in the context of a raging epidemic. … How much does one have to know about the scientific nature of combustion when the house is burning down?" Yet researchers and regulators presented examples from other diseases to argue that their concerns were more than mere pedantry. James Bilstad, an FDA official, described to a JAMA reporter in 1991 the recent "very disturbing" finding that certain cardiac arrhythmia drugs improved the commonly accepted surrogate markers for heart disease but tripled the risk of mortality from sudden cardiac arrest.
Books about AIDS drug development have tended to portray the struggle over surrogate markers as one in which stodgy defenders of the status quo were eventually won over by well-informed activists who were in possession of what was indisputably the "right" answer. No doubt this is partly because these books were published before 1993, when the use of CD4 as a surrogate marker was seriously challenged. However, from the start the issue of surrogate markers in AIDS clinical trials had scientific arguments on both sides that were passionately defended. (Indeed, activists themselves were not insensitive to the arguments against surrogate markers, particularly the sole reliance on CD4. James, for instance, was more impressed by a technique called quantitative PCR [polymerase chain reaction] that measured plasma viremia; he and others advocated combining laboratory markers with markers of apparent health, such as a doctor's ranking of the patient's overall state of being.) Here, once again, an activist victory depended on the capacity of activists to intervene in a complex scientific controversy by adding their moral authority—and political muscle—to one particular side in a methodological and epistemological controversy. The existence of competing expert interpretations of how knowledge was to be constituted gave AIDS activists an opening from which to conduct their campaign.
Activist pressure on the surrogate marker issue was destined, in turn, to hold profound consequences for the public negotiation of belief about the efficacy of drugs like ddI and ddC. The debates over whether ddI and ddC "worked" would proceed hand in hand with a debate over the very mechanisms by which efficacy might be established in an AIDS antiviral trial. Given these circumstances, controversy about the licensing and use of these drugs was almost inevitable.
In general, for a clinical trial to "work," its results must be taken to "stand for" the effects of a drug were the drug to be administered widely to patients outside the artificial, experimental setting. A trial resting on surrogate markers, therefore, derives its credibility from a two-stage process of representation: it must first be agreed that the short-term effect of the drug on the marker represents the long-term effect of the drug in reducing mortality—and then the trial results must be understood to reflect what would happen in the everyday world of patients who consumed the drug. When articulation of the linkage between "experiment" and "real world" becomes so complex—and when the stakes are nothing short of life and death—not only is there more space for argument about the meaning of trial results, but the capacity of "outsiders" to intervene and assert claims becomes all the more potent.
The "Future that we all Envisioned"
By 1991, the uncertainty about surrogate markers was on a collision course with the widely felt need to license ddI and ddC. Everyone knew these drugs had a certain value, activists contended; the issue was simply one of finding the appropriate mechanism for making them available. Expanded access, the San Francisco activists had decided, was a step in that direction but simply not good enough: It "only works when there is a public-spirited and well-financed drug company, willing to spend money to save lives when sales of the drug may be years away," wrote John James.
The Phase II trials—those vast, costly, and inefficient endeavors—were ultimately of little relevance, activists argued, because they were designed "to produce a single bit of information, one yes-or-no answer," namely, the question of statistical significance: in the event that these drugs were useless, was the chance of falsely concluding that they had benefit less than five percent? This, in James's view, was simply the wrong question to be asking. Doctors and patients needed pragmatic advice about the best ways in which to use these drugs. In that sense, "the real issue with ddI is not whether it works. A growing working consensus holds that it probably does.… The most important questions now are long-term toxicity, and when and how to use ddI most effectively in various groups of patients."
Particularly for San Francisco activists, two solutions to the "dinosaur trials" dilemma became effectively joined: the FDA could speed up approval by relying on a surrogate marker such as CD4 counts,
and it could make that approval conditional upon evidence to be obtained from subsequent studies. A proposal for a new FDA policy of "conditional approval" therefore emerged as a strategy for managing the greater uncertainty that the reliance on surrogates would entail. Such a policy, as activists imagined it, would put the burden on the drug companies to fund and conduct "postmarketing studies" to provide additional evidence of drug safety and efficacy. If evidence was not forthcoming, the FDA would revoke the license for the drug and it would be taken off the market. However, as soon as a drug was conditionally approved, the manufacturer could begin selling it and insurers would reimburse for it. The advantage over expanded access was that the latter program had provided only weak incentives for drug company cooperation. At most, as David Feigal of the FDA suggested, participation in expanded access enhanced a drug's credibility as an effective treatment: "It cements [the perception] that this is an up-and-coming drug, one valuable enough that it's being made available early." Conditional approval, by contrast, was designed with the explicit goal of enlisting the pharmaceutical companies by giving them a chance to do what they liked best: earn profits. The idea of conditional approval was quickly endorsed by the deregulation lobby and by the Quayle Competitiveness Council, the vice president's commission dedicated to the elimination of regulatory barriers for U.S. industries.
New York activists, who had pushed through the expanded access mechanism, were less enthusiastic about the idea. David Barr commented: "We have never said we are not interested in collecting good data. I have concern that if conditional approval is not done the right way we will lose our ability to collect data." Members of Congress who promoted consumer protection, such as Ted Weiss and Henry Waxman, were even more dubious. In April 1991, Waxman wrote to David Kessler, Bush's newly appointed head of the FDA and an advocate of change at the agency, expressing his concern that conditional approval, unlike the expanded access program, "could allow promotion and sale of drugs that did not meet previous standards for safety and efficacy." Soon afterward, Martin Delaney sent off a blistering letter to Waxman defending the policy and demanding that he cease and desist. Conditional approval "is not about lowered standards or opening the floodgates to harmful or worthless drugs," Delaney told Waxman. "It would be a very limited program accessible only in life-threatening situations and for drugs which show safety and clear
promise on the basis of surrogate markers." Insisting that Project Inform was not the "dupe" of the Republican party or the pharmaceutical industry, Delaney demanded that Waxman "put a muzzle" on one of his aides who had been speaking against the policy.
Meanwhile, as the various parties debated the merits and dangers of conditional approval, the question of surrogate markers also moved to the fore. By late 1990, Ellen Cooper, director of the Antiviral Drug Division, was describing herself as "encouraged" about the use of CD4 counts as a surrogate marker for AIDS antivirals, but she told JAMA that "we are not there yet" regarding reaching agreement in the research community. Delaney's analysis was that the FDA preferred to share the decision-making risk by forging a consensus with other federal agencies rather than go out on a limb. Cooper herself, however, seemed resistant to joining any consensus she did not genuinely support or to approving drugs based on standards she felt were inadequate. That, at least, was the general conclusion drawn when she suddenly resigned her position on December 19.
To consider the role of surrogate markers in approving antiviral AIDS drugs, the FDA convened a special meeting of the Antiviral Advisory Committee in February 1991. Among various scientific presentations was one by Anastasios ("Butch") Tsiatis, a statistician from Harvard, who had gone back over the data from the original Phase II AZT study. Tsiatis found that those patients whose T-cell counts went up after receiving AZT did better overall than those patients who did not experience a rise. In other words, by looking at the effect of AZT on CD4 counts, one could predict who would benefit most from AZT. On the other hand, it also appeared that the people who received AZT in the study experienced more of a benefit from the drug than the rise in CD4 alone could explain. But to Delaney, the issue wasn't whether CD4 told us everything as long it accurately predicted some significant portion of a drug's potential benefit.
"I think the reality is that we are not going to have this future that we all envisioned here," warned Martin Delaney in his testimony at the meeting, explaining that "body count" trials with survival as an endpoint simply were no longer feasible , regardless of whether they were desirable. "Survival … studies with each passing day of this epidemic become less and less possible. As more data accumulate on each of these drugs, as we take more time to compare one to the next, fewer and fewer patients are willing to sit still in studies that take two to three years. Fewer will stay on those studies as newer and better
compounds come along. …" Delaney was certainly right in insisting that regulators not conceive of AIDS antiviral trials as abstract laboratory experiments whose purity could be protected from external influences. These were concretely situated and inevitably messy enterprises, enormously dependent on the behavior and attitudes of the research subjects and carried out within a certain historical field of possibilities, with each trial having ramifications on concurrent and subsequent ones. Where Delaney was being more than slightly disingenuous was in his failure to acknowledge the extent to which organizations such as his own accelerated the kinetics (or the psychodynamics) of this system. Project Inform, for example, held regular "Town Meetings" and published reports in its newsletter detailing the latest thinking about the experimental AIDS drugs, in effect encouraging patients to believe or disbelieve, to comply with protocols or switch to other studies.
At the end of the day, the Antiviral Advisory Committee unanimously endorsed the use of CD4 counts as a surrogate marker for demonstrating the efficacy of nucleoside analogues in the treatment of AIDS. The way was paved for Bristol-Myers Squibb, the sponsor of ddI, and Hoffman-LaRoche, the maker of ddC, to file their applications with the FDA. Existing data on toxicity and efficacy, combined with CD4 data, would be enough to warrant licensing these drugs, Jim Eigo predicted. "Maybe a year down the road we'll find we made a mistake," David Barr told JAMA . "But the choice on the other side is no treatment." Ellen Cooper, who had sat out the meeting as a spectator, came up to Delaney toward the end. "You have to be careful with this, or you could do yourself more harm than good," she told him.
Between "Science" and "Policy"
A long and divisive two-day meeting of the Antiviral Advisory Committee in July 1991 resulted in the recommended licensing of ddI, though not by unanimous vote. The clincher came on the second day, when the committee considered data that had been obtained, on special FDA consent, from a peek at the ongoing Phase II trial. In the study, patients who had already been on AZT for twelve months or more were randomly assigned either to continue AZT or to receive ddI. The results so far showed a T-cell decline in those who stayed on AZT, compared with a modest rise in those who had been switched to ddI. After what Project Inform referred to as "endless hand-wringing by some committee members," the committee voted in
favor of approving ddI for adult and pediatric AIDS patients no longer responsive to AZT; the vote was five to two. As it almost always does, the FDA endorsed the recommendations of its advisory panel sometime afterward.
Project Inform's newsletter, commenting on the approval, called it "in many ways the single most important victory in 6 years of AIDS activism" and described the FDA as "courageous." Kessler himself characterized the vote as "a milestone in drug review." "We're in the midst of a medical emergency," Donald Abrams, one of those who voted for approval, told a reporter for JAMA . "One person dies of AIDS in the United States every 8 minutes," Abrams added, repeating what was in fact a common ACT UP slogan. Later, when asked about his vote, Abrams described his role in essentially political terms, as one of "representing" doctors and patients from San Francisco, groups that wanted ddI to be approved.
Normally, as Sheila Jasanoff describes it in a study of regulatory science, the use of independent scientific advisory bodies allows agencies such as the FDA to "harness the authority of science in support of its own policy preferences." The experts on these panels "seem at times painfully aware that what they are doing is not 'science' in any ordinary sense, but a hybrid activity that combines elements of scientific evidence and reasoning with large doses of social and political judgment." Nonetheless, the experts normally speak in the language of science, and this has the important effect of legitimating the policies that are ratified. In the case of ddI, however, the scientific basis was so contested and the political pressures so extreme that panelists sought to disentangle their separate roles as scientists and policymakers—to make clear that as far as they were concerned, their vote was a scientific endorsement of neither ddI nor the use of CD4 counts as a surrogate marker, but rather a pragmatic policy decision. The panelists were going to allow patients to assume the risks that patients themselves, their activist representatives, and their physicians were demanding that they be allowed to assume.
Some refused to take this step, however. Deborah Cotton, a Harvard Medical School professor who was one of the "no" votes, expressed concern that the approval had set a bad precedent that "creates incentives" for other drug companies to press for approval with inadequate data. She worried, moreover, that it would be "a real challenge to explain to participants in the controlled trials why it is so important for the trials to continue and for them to remain in them." Now, more than ever, it was necessary to complete the trials
and make sure that the effect of ddI on a surrogate marker would translate into a genuine clinical benefit and decreased mortality. But once the FDA had given its blessing to the drug, based on data that seemed to show that ddI was better than AZT for those who had been on AZT for some time, why would anyone stay in the trial, at the risk of being in the AZT arm? Why not just drop out of the study and have one's doctor prescribe ddI? Belief had now hardened into relative certainty; in such an environment, was a clinical trial possible?
Paul Meier, a statistician from the University of Chicago who said he voted for approval reluctantly, noted that the committee would have preferred to make the approval conditional upon future studies, "yet had to take full approval because there is no such option." He commented to the New York Times: "I really genuinely worry that we are ratcheting down what has been a good standard for the F.D.A." Some New York activists, while supporting the decision, were also concerned about the inconclusive nature of the data. "This whole situation makes all of us very nervous," David Barr told the New York Times .
The Genie in the Bottle
It was in the wake of these decisions that the FDA's Antiviral Advisory Committee sat down in April 1992 to consider the approval of ddC. First the committee turned back to ddI, looking at the data that had since been accumulated from the first of the Phase II trials to be completed. With a collective sigh of relief, the panel concluded that faith in ddI had apparently been borne out: its impact on CD4 counts had indeed predicted its clinical benefit. Nor had the approval of ddI impeded the successful completion of the trial, as committee members like Cotton had feared. "We took a risk in approving DDI and today I think that on balance we did it right," said Kessler, expressing the philosophy of what some were calling the "new FDA." "We cannot wait for all the evidence to come in when people are suffering and dying from these devastating diseases."
With renewed confidence in the use of CD4 counts as a surrogate marker, the committee then turned to ddC. A week before the meeting, Kessler had made official the new option of what would now be called not "conditional" but "accelerated" approval, along the lines originally proposed by activists. According to David Feigal, who would replace Ellen Cooper as head of the Antiviral Drug Division, Kessler emphasized that such approvals should indeed be thought of as "conditional."
But Kessler couldn't call the policy by that name for fear that third-party payers might decline to reimburse patients for their purchases of such drugs. Here again, the FDA was forced to be acutely sensitive to the vast financial and human consequences of the signals the agency sent out—despite the fact that, officially, "our approvals are not intended to be the basis for reimbursement decisions."
Hoffman-LaRoche asked that ddC be conditionally approved as a monotherapy (that is, for use by itself) for patients who were intolerant to AZT; but there was no evidence to support such a labeling, and the committee quickly nixed the idea. Instead, the committee turned to the evidence from ACTG 106 and other small studies that showed positive effects of ddC/AZT combination therapy on CD4 counts. Ironically, as Michael Botkin, an activist and writer on AIDS treatment issues for a San Francisco gay newspaper, described it, Burroughs Wellcome "[pulled] their rival's chestnuts out of the fire." In past years, Burroughs Wellcome had been decidedly uncooperative about research involving the use of AZT and the products of other companies. But with the growing interest in combination therapy, and with the widespread recognition that AZT alone was no solution to AIDS, the company stood to gain from an official endorsement of the ddC/AZT combination. They presented data from a study the company had commissioned that corroborated the results of ACTG 106 by showing the drug combination's effect on T-cell counts. By an eight to three margin, the committee voted in favor of conditional approval of ddC when used in conjunction with AZT. (Final approval would depend on the outcome of other studies, particularly ACTG 155.) As Botkin commented, that put Burroughs Wellcome in the "delightful position of proving that their rival's treatment is effective—but only when taken with their own product!"
The FDA ratified the advisory committee's recommendation on June 22, in what Health and Human Services Secretary Louis W. Sullivan described as "another step forward for patients with AIDS." Many treatment activists, like Delaney and James, were pleased by the outcome. Others were decidedly cynical. "For once, politics played in our favor," said G'dali Braverman of ACT UP/Golden Gate, adding that the Antiviral Advisory Committee meeting had a "scripted" feel, with dissenters being "strong-armed" by Kessler. In Botkin's analysis, Kessler had been seeking support from all sides, playing to the AIDS activists and the deregulation advocates by adopting accelerated approval, while placating consumer protectionists with simultaneous, well-publicized campaigns to beef up vitamin and food labeling.
Meanwhile, the underground ddC was a threat and a growing embarrassment. "The only answer, from Kessler's perspective, was to co-opt the buyers clubs by quickly approving ddC, thus demonstrating that the government is moving fast enough to introduce new AIDS treatments and that independent efforts aren't needed."
Comments by some committee members supported these activists' perceptions that the results had been foreordained. Deborah Cotton, who voted against approving ddC just as she had voted against ddI earlier, told Science that in her view, the committee had been asked to "pound [the data] into a scientific conclusion." FDA Commissioner Kessler "clearly wanted it," Cotton afterwards recalled. "David spent the entire two days at the table, which is usually how you tell that he's invested in an issue. …" From Cotton's standpoint, the ready reliance on surrogate markers was a mistake, because it threatened to delay the process of obtaining solid data about treatments. "We really have to ask whether relying on surrogate markers will hasten a cure or hinder it," Cotton told the reporter from Science: "We're getting into a situation of such complexity that we may have a large number of agents being used and no way of distinguishing among them." She added: "It's sad that we may have nothing to offer people in 1992. … It's sadder that in 2000 we may have nothing, too. In 2000 we'll look back and say, 'If only we'd done this in a more rational way.'"
Kessler assured the worriers that accelerated approval demanded careful postmarketing studies. If the surrogate marker evidence didn't hold up, the FDA would then "[put] the genie back in the bottle." Yet as Kessler's own phrasing perhaps inadvertently suggested, removing an approved drug from circulation might be easier said than done. Short of a truly catastrophic result in the postmarketing study, was it really likely that the political environment would permit the withdrawal of one of only three antiviral drugs approved against HIV? Or had the construction of belief passed the point of no return?
Inside and Outside the System
New Antiviral Research and the "Receding" Bottleneck
One irony in the push to license ddI and ddC is that, long before the drugs were approved, the hopes of researchers, doctors, and activists had moved well beyond the infertile terrain of the
nucleoside analogues. Officially, the research establishment continued to tout the potential virtues of combination therapy with the nucleosides and to promote the goal of turning AIDS into a "chronic manageable illness," though increasingly it appeared that the announcement in Montreal of its advent had been more than a little premature. Activists were less sanguine about the pace of progress. By the time of the San Francisco conference in 1990, ACT UP/New York had concluded: "This year, the hopes of many in the AIDS communities have reached a low ebb. It is clear to all that anti-HIV agents such as AZT, ddC and ddI will not, in any conceivable combination, stop the progression of HIV infection—at most, for those who are lucky, they will significantly slow it."
Writing in Outweek in 1990, New York activist Larry Kramer put the position in his own inimitably vituperative style. He accused researchers like Margaret Fischl and Paul Volberding of having "pumped AZT down the throats of AIDS patients like they were Strasbourg geese being fattened up for the kill." Kramer averred: "AIDS is not a manageable disease, and there is nothing at present that makes me think that it is going to be a manageable disease in my lifetime or the lifetime of the other 20 million HIV infected. ANYONE WHO TELLS YOU OTHERWISE IS A LIAR ."
ACT UP/New York's Treatment & Data Committee analyzed the predicament in the 1990 update of its AIDS Treatment Research Agenda , distributed at the San Francisco conference. The ACTG was concentrating its resources on "massive Phase II trials,of stop-gap first generation nucleoside analogues," to the exclusion of just about everything else. Hardly any compounds were in Phase I trials, even though dozens were known to act against HIV in vitro (the report listed sixty of them, along with many immune therapies, anti-infectives, and other drugs that awaited testing). Given the backlog, and given the ACTG's apparent priorities, the emergence of a new generation of antiviral treatments was necessarily years away. In that sense, the problem was no longer the FDA, the Treatment & Data Committee concluded. "As activists make increasing headway with regulators, the bottleneck in AIDS drug development seems to recede towards the beginning of the process, when compounds are taken from test tube and animal studies and administered to humans for the first time." Mixed metaphor though it may have been, this notion of the "receding bottleneck" served to orient treatment activists in the years to come.
For patients, the pace of AIDS antiviral research was measured in
relation to their own life expectancy; but researchers, whose point of reference was the rate of scientific progress for other diseases, found the advance of knowledge both swift and encouraging. "We have learned more about the AIDS virus than any other virus that affects humans," Dr. William Haseltine told New York Times reporter Gina Kolata in late 1990, reciting what had become almost a mantra in AIDS research circles. "Molecular biologists and drug development experts have climbed rapidly from a valley of despair to a peak of expectation in their struggle to combat the AIDS virus," wrote Kolata, focusing on a recent publication in Science by NCI scientists Hiroaki, Yarchoan, and Broder that identified "13 major chinks in [the virus's] armor, each one of which may in time yield to therapeutic attack." "There really is a large and growing menu" of ways to interrupt the cycle of viral replication, Broder told Kolata: "I think it's a very important time."
John James agreed there was room for "cautious" optimism, especially with regard to three promising sets of "designer drugs" that were farthest along in development. First, there were new drugs that acted at the same point in the virus's replication cycle (reverse transcription) as AZT, ddC, and ddI but didn't belong to the dideoxynucleoside family. These so-called non-nucleoside reverse-transcriptase inhibitors included the "L drugs" made by Merck (formally labeled "L-697, 661" and "L-697, 639") and a drug called nevirapine developed by Boehringer Ingelheim Pharmaceuticals.
Second, Hoffman-LaRoche had been developing a "tat inhibitor," which was designed to block the protein produced by the viral gene called tat . This protein, required for the replication of HIV, acted "downstream" of reverse transcriptase in the replication cycle; it was responsible for "transactivation," a speeding-up of the manufacture of the new viral particle. In vitro, the tat inhibitor was synergistic with AZT, meaning that the drugs might conceivably be given in combination to deliver a one-two punch against the virus. Unlike the reverse transcriptase inhibitors, a tat inhibitor would, in theory, work against chronically infected cells such as macrophages; such cells behave abnormally but are not killed by the virus. In addition, some believed that a tat drug also showed promise against Kaposi's sarcoma. Finally, Hoffman-LaRoche's drug seemed particularly promising because it was chemically related to diazepam (Valium), a well-known drug that had already been used extensively in humans.
The third exciting set of compounds, still under development, were called protease (or proteinase) inhibitors. These drugs would block the
action of a different enzyme, protease, that plays a role at yet a later stage in the viral life cycle. After being assembled, the newly produced virus that buds from the infected cell is in an immature state; the protease enzyme then processes the genetic material to complete the virus's development. Only at that point does the new virus become infectious. In the presence of a protease inhibitor, therefore, the new virus released into the bloodstream would be harmless, incapable of infecting other cells. At least, that was the theory being pursued by a number of pharmaceutical companies, including Hoffman-LaRoche.
These were the practical applications of the intense scrutiny of HIV by molecular biologists; one problem, however, was that scientific knowledge about the virus far outstripped an understanding of the immunopathogenesis of AIDS in the human body—that is, how the virus directly or indirectly contributed to the eventual collapse of immune functioning. As David Baltimore and Mark Feinberg wrote in an editorial in the New England Journal of Medicine toward the end of 1989: "Humans are genetically heterogeneous, lead idiosyncratic lives, and become infected through a number of routes, and important practical and ethical considerations constrain clinical experimentation. As a result, we are rapidly learning about the role of each of HIV's approximately 10,000 nucleotides, but remain largely ignorant of rudimentary aspects of the processes underlying the development of AIDS in humans." It was believed at the time, on the basis of blood work done with cohort studies, that there were three stages to "HIV disease." First, soon after infection with the virus, there was an initial stage of acute infection marked by a high viral load in the blood, a strong antibody response, and in many cases, symptoms such as a low-grade fever and swollen lymph glands. Then a long, middle stage of "latency" would set in, during which the viral load measurable in the blood was relatively low but the T-cell count gradually declined. In most cases this was succeeded—eventually—by a final stage of crisis, coincident with the onset of opportunistic infections (and, usually, a T-cell count below two hundred per cubic millimeter), in which the viral load once again became high. Increasingly it was also becoming apparent that "latency" was a misnomer, because although the infected person was outwardly healthy, and although the virus might indeed be dormant in some infected cells, the process of viral replication continued throughout the middle stage.
The implication of this clinical picture was that the infected person's immune system initially succeeded in controlling the infection and keeping the virus in check, but over time lost that ability quite
dramatically—for reasons that were not at all well understood, though hypotheses certainly abounded. Some, like Luc Montagnier, argued that simultaneous infection with other agents ("cofactors") speeded up the process of immune breakdown. Others pointed to syncytia formation (the clumping together of infected T cells) or to abnormalities with cytokines (the proteins released by immune system cells that signal other immune cells) or to autoimmune mechanisms. These competing hypotheses sometimes led to contradictory implications for treatment strategies. For example, researchers such as Jonas Salk were working on a "therapeutic vaccine" designed to bolster the immune response in people already infected with HIV; but those who believed that HIV progression was a result of "overactivation" of the immune system feared that such a therapy might actually make the infection progress faster. Clearly, in the absence of a good working knowledge of pathogenesis, it was difficult to elaborate a coherent therapeutic approach that aimed at preventing the development of AIDS and not just the replication of the virus.
A Seat at the Table
Treatment activists in the early 1990s followed the reports of novel therapies with intense interest. How could these drugs get into development faster? How could researchers be induced to focus on them and on the promising anti-infectives for treatment of opportunistic infections, rather than devote federal funds to what activists saw as increasingly arcane trials of different regimens of the nucleoside analogues? To have influence over such questions, activists needed a seat at the table—specifically, places on the committees of the ACTG, where decisions were made about the research priorities that determined how federal funds would be distributed. As activists saw it, the big names in AIDS antiviral research—Paul Volberding, Douglas Richman, Thomas Merigan, Margaret Fischl, Martin Hirsch—dominated the committees that voted, predictably, to fund the kinds of studies that these researchers did. Treatment activists wanted to situate themselves as a counterpower to assert their own priorities.
That they might achieve such a lofty goal was plausible only because the activists already were winning their credibility in the methodology wars—the debates over such matters as inclusion criteria, concomitant medication, and surrogate markers in clinical trial design. At the same time, activists hadn't simply studied science and "played nice." Throughout 1990, ACT UP put the same kind of direct
pressure on NIAID that the FDA had been made to endure a few years earlier. One thousand demonstrators from around the United States made a show of force at NIH headquarters in Bethesda, Maryland, on May 21, occupying the office of Daniel Hoth, Fauci's assistant and head of the ACTG program. Activists held banners and shouted slogans: "Ten years, one billion dollars, one drug, big deal." Eighty-two of them were arrested.
Demonstrations had an important function in building the movement and drawing in new activists. Yet it was difficult for treatment activists to frame their critique of NIAID and the ACTG effectively, in a way that would mobilize the masses and capture the media spotlight. In that sense, as John James noted, the change in the rallying site from Rockville in 1988 to Bethesda in 1990 represented "much more than just a different subway stop." "The public does not understand the NIH issues (by contrast to the FDA, which it can easily picture as the 'heavy' keeping promising treatments away from patients). NIH issues center [on] scientific judgments and priorities; it is hard for the public to judge whether or not criticisms have merit." In a word, any critique of NIAID and the ACTG demanded expertise . Even educating the AIDS movement base, let alone the general public, about the problems with the ACTG was a daunting task, though Harrington did his best in passionate screeds published in Outweek and the Village Voice . "The U.S. has poured over a quarter of a billion dollars into the AIDS Clinical Trials Group …, making it the most generously endowed clinical research network in history," wrote Harrington. "Yet the ACTG has managed only to test old drugs inefficiently and new drugs not at all…."
One of Harrington's recurrent themes was that the ACTG operated like a secret society, and he took it upon himself to air the dirty laundry. The ACTG was not some neutral advisory; its meetings were a political field, and the principal investigators who comprised its advisory committees all had vested interests. "Card-carrying virologists" dominated the all-powerful executive committee that made final decisions behind closed doors about which studies to fund. The executive committee ensured that the bulk of the resources went to the giant, high-profile trials of the antivirals, while researchers studying anti-ineffectives were starved for funds. The only solution, the activists insisted, was to throw open the doors of the ACTG and put community representatives on every last committee, from the executive committee on down.
To Fauci and others in NIAID, ACT UP members like Harrington
and Eigo, and certainly more mainstream figures such as Delaney, were known quantities. These activists had in some respects been incorporated into the AIDS establishment; by the time of the Sixth International Conference on AIDS in 1990, they spoke from the podium, rather than shouting from the back of the room. "When it comes to clinical trials, some of them are better informed than many scientists can imagine," Fauci himself insisted in a speech at the conference, adding that researchers "do not have a lock on correctness." For Fauci, there was no great threat in granting the activists' demand to attend ACTG meetings.
Indeed, Fauci may have deemed it both strategic and useful to incorporate a activists into the process: as he later commented, his assumption was that "on a practical level, it would be helpful in some of our programs because we needed to get a feel for what would play in Peoria, as it were." But many of the principal investigators sitting on the ACTG committees were leery of opening the door to the activists. In 1989, according to the account by Bruce Nussbaum, Fauci had told Hoth to get the researchers "used to the idea"—"to tell them that Eigo and Harrington were 'good guys,' smart enough to understand the science.…" But the researchers balked. Nussbaum quotes "one key member of the ACTG" as having told Hoth: "What are you going to do if you want to have a serious scientific discussion about a promising agent and you've got someone from the Provincetown PWA Coalition who thinks that [the drug] Peptide T is the greatest thing since sliced bread.…?"
After members of ACT UP/New York's Treatment & Data Committee crashed a meeting in late 1989, an initial compromise position was offered: a Community Constituency Group (CCG) would be formed, a demographically diverse advisory body of representatives from all communities affected by AIDS that would meer with the ACTG at its quarterly meetings. But by this point activists refused to accept token participation; they sought to open up the closed-door meetings of the key committees—and even to obtain voting rights for the activists, just as the principal investigators enjoyed. After a yearlong campaign that included the demonstration at the NIH campus, Fauci gave the activists what they wanted and forced the researchers to play along All ACTG meetings would be opened up, and each of the twenty-two representatives of the CCG would have a regular seat on one of the ACTG committees, including the executive committee. In exchange, according to Arno and Feiden's account, "Fauci wanted the rhetoric
toned down." These authors quote Fauci as saying: "If [activists] are trying to get into the system, they may have to modify some of their activist modes, but that doesn't mean they have to become Uncle Toms."
The Reconstitution of Identity
Victory or co-optation? Such a stark opposition is inadequate to capture the nuances and micropolitics of activist engagement with the ACTG. Activists certainly were aware of the risks; for some time, they had been elaborating a complex strategy of intervention as both "insiders" and "outsiders." The NIH demonstration was a case in point. Fauci told the New York Times that he "knew the leaders of the protest well and was surprised to hear 'irrational' language on the street from people he had worked with in meetings." But activists, and surely Fauci as well, knew that the language of the street and the language of the meeting room served different purposes and had different intended audiences. Activists, for their part, had been concerned about not jeopardizing the existing working relationships with NIH personnel, as Harrington later recalled: "When we did the NIH demo, Peter [Staley of ACT UP/New York] said, 'Oh, let's call Tony [Fauci] and go and have dinner with Tony and tell him about this demo.… In a way, we'll give him an advance heads-up. But we'll also be saying: "Look, even though we're doing this demo, we still want you to understand that we have a relationship where we can discuss and debate our issues.…"'"
Such maneuvering was a tricky business. Yet the politics of simultaneous insider and outsider activism might well have continued smoothly had it not been for two crosscutting sets of pressures. First, AIDS treatment activism was becoming increasingly diverse , and the establishment of the CCG would make it more so. But different constituencies had different priorities, goals, and degrees of access to federal officials—and, therefore, different opinions about the purposes and the relative merits of insider and outsider strategies. Second, AIDS treatment activism was becoming increasingly more complex (as John James had suggested in comparing NIH issues to FDA issues). The established treatment activists knew about much more than clinical trial methodology and design—by this point they could speak fluently about a host of technical issues that were surfacing in research on AIDS treatments. These activists had become experts of a sort, and
they could engage with researchers, government health officials, and pharmaceutical companies in a way that their fellow activists could not. The practical consequence was that it became harder for individual activists to locate themselves simultaneously on the inside and the outside. Activism tended toward a de facto division of labor—some people working on the inside, others on the outside—thus relocating the expert/lay divide to a position within the movement itself.
The Diversification of Treatment Activism
Treatment activism began in gay communities for the same reason that AIDS activism in general began in gay communities—because gays asserted "ownership" of the social problem and had the material and symbolic resources with which to organize themselves and confront adversaries. But even within the predominantly gay male social movement organizations like ACT UP, various constituencies had asserted their priorities. In New York City, for example, the Women's Caucus of ACT UP had been pursuing treatment issues since 1988 at some distance from the work of the Treatment & Data Committee (the home of Harrington, Barr, Eigo, and others), made up mostly, though not entirely, of men.
Activists in the Women's Caucus, and their counterparts around the country, confronted a complexly interwoven set of obstacles in bringing attention to the health needs of women with HIV and AIDS. In a book on women and AIDS, Gena Corea has described the "crazy-making politics of knowledge" that seemed to bar women from scientific consideration and medical treatment: the Centers for Disease Control's definition of AIDS, created largely with reference to the opportunistic infection contracted by gay men, systematically "exclude[d] the symptoms appearing exclusively in women," such as pelvic inflammatory disease. In very practical terms, this meant that women were not receiving the health and disability benefits that accrued from an AIDS diagnosis. ("Women don't get AIDS, they just die from it," to quote the ACT UP slogan.) However, the definition couldn't be changed to include women's symptoms, the CDC maintained, because of the absence of data proving a causal link between those symptoms and HIV infection. But the necessary data couldn't be generated , because "women of childbearing potential" had largely been excluded from clinical trials (putatively out of concern for their
potential fetuses), and when they were included, no pelvic exams were performed. This meant not only that we failed to learn about the effects of HIV in women, but also that women were denied access to experimental treatments that might have helped keep them alive.
Women activists linked their critique of these practices to an analysis of the history of the medical profession's treatment of women: women had long been considered medically "other." In the case of AIDS, activists charged, biomedicine ignored women except to consider them as "vectors" or "vessels"—as transmission routes to men or to babies, or as carriers of precious fetuses that required protection. Eventually, women activists pressed successfully for a change in the CDC case definition. They also pressured Daniel Hoth and Anthony Fauci to hold a National Conference on Women and HIV Infection in December 1990. According to Maxine Wolfe of the Women's Caucus: "Although men in ACT UP had, by now, been routinely meeting with NIAID officials, in order for women AIDS activists to get just a meeting with them we had to stage a sit-in at the offices of Dr. Daniel Hoth …, make constant phone calls, send him several letters threatening a repeat sit-in, and 'zap' him in front of 5,000 of his colleagues at the Sixth International AIDS Conference. …"
Gay men and lesbians of color also formed caucuses within ACT UP chapters around the country, and some of them, too, became concerned with treatment issues. But, as Cathy Cohen notes in her study, activists of color in ACT UP found themselves "in the precarious position of not being trusted by many in communities of color because of their ties to ACT UP and at the same time not being fully supported by influential members inside of ACT UP." And as Moisés Agosto, who became involved in AIDS activism after moving from Puerto Rico to New York City, discovered, it was often hard to convince members of racial minority communities of the need for activism on treatment issues, given the wide range of concerns confronting them. To the extent that these communities became open to AIDS activism, it was on issues of prevention and care. Treatment activism, Agosto found, was generally perceived as "an upper-middle class, white gay-boy thing to do"—though Agosto tried to demonstrate the importance of the work by translating treatment information into Spanish.
Finally, by the early 1990s, some hemophilia activists had also moved into the arena of treatment activism. Despite the very high incidence of HIV infection among people with hemophilia, this community had been slow to mobilize. Eventually people with hemophilia
would organize forcefully around the question of the culpability of the blood-banking industry in the infection of people with hemophilia through contaminated blood products, and they would pursue legal remedies. But "it's a very geographically dispersed community, there's not a lot of us, [and] we're dying at the rate of one a day, which is a lot considering that there were only probably eight or ten thousand of us infected to begin with," explained Jonathan Wadleigh, a founder of the key hemophilia activist group, the Committee of Ten Thousand. Gay men organizing an activist response didn't need to search far and wide to find others affected by AIDS. By contrast, "with an incidence of one in ten thousand [in the] population, normally you're lucky if you meet one person in a lifetime who has hemophilia."
When Wadleigh decided to begin attending meetings of ACT UP/Boston in the late 1980s, he was "often the only straight person" in the room as well as "the only person with hemophilia." But given the inaction he perceived on the part of the New England Hemophilia Foundation, Wadleigh "began to quickly associate [himself] more with the gay community and … to relate to the brand of activism that was going on there." Recognizing that the level of information about treatments in the hemophilia community was very low, Wadleigh started up a treatment newsletter, summarizing articles from the established grassroots publications such as AIDS Treatment News , the San Francisco AIDS Foundation's BETA , and Project Inform's PI Perspectives . He also became involved in methodological debates about the inclusion criteria for AIDS trials. Boilerplate language in trial protocols routinely excluded anyone with elevated liver enzymes—but people with hemophilia (along with injection drug users) quite often show signs of liver disease and hence have elevated enzyme levels. Wadleigh's fight to liberalize the entry criteria so that more people with hemophilia could participate in clinical trials was, in his view, one of his most significant contributions in the domain of treatment activism.
The Politics of Cleavage
In agreeing to establish a Community Constituency Group that would attend ACTG meetings, Hoth and Fauci proposed that the group include representatives of a wide range of constituencies—gays, racial minorities, women, injection drug users, people with hemophilia, and children. Whether NIAID officials deliberately sought
to dilute the impact of gay male treatment activism, or simply considered it good politics to broaden the community representation, the significance of the CCG was that it became the first place where activists from all these various communities came together to talk about AIDS treatments. Particularly for activists representing communities of color, this was a long-awaited opportunity to present their views before government officials and scientists, and their agenda was broad. The established treatment activists, however, saw it as inappropriate to use the CCG as a forum for issues beyond the purview of the ACTG. They wanted to talk about the science of clinical trials, and they urged the newcomers to "get up to speed." Almost immediately, tensions rose sharply.
At an AIDS Treatment Activist Conference held just prior to a CCG meeting, some called the ACT UP/New York Treatment & Data Committee's agenda a "white male" approach to health care, focused solely on drug development to the exclusion of issues like health care financing, which were of primary interest to women, minorities, and poor people. One ACTG committee meeting ended in chaos, when members of ACT UP/New York's Women's Caucus, most of them white, blasted a planned clinical trial of pregnant women with HIV as "bad science" and "unethical." (The study, ACTG 076, was designed to test the use of AZT in interrupting transmission of HIV from mother to fetus. The activists objected to, among others things, the apparent prioritizing of fetuses over adult women in clinical research.) In response, several African-American women who were involved in running the study denounced the activists, leading a number of black and Latino members of the CCG to cry that ACT UP was "racist."
On the local level, similar pressures fractured individual ACT UP chapters. Flush from its triumphs at the Sixth International Conference, where it had mobilized hundreds of people into the streets around the conference center for a weeklong series of demonstrations, ACT UP/San Francisco swelled with new members in the latter part of 1990 and then rapidly exploded. Ostensibly, the debate concerned whether the group should continue to operate according to the consensus process, allowing a single voice of dissent to paralyze decision making. At a deeper level, most commentators agreed, the split was between those (mostly gay white men who were HIV positive) who supported the basic goal of "drugs into bodies" and those (including many of the women and people of color in the group) who sought a more thoroughgoing engagement with the class-based inequities of the
U.S. health care system and with the racist, sexist, and homophobic dimensions of biomedicine and, indeed, of U.S. society as a whole. From the standpoint of the latter group, the privileged white men were insensitive to any issues but their own; from the vantage point of the former, the forces of political correctness were engaged in utopian phrase-mongering while they were busy saving lives. The former group seceded from ACT UP/San Francisco to constitute a new chapter, ACT UP/Golden Gate.
Similar splits soon occurred in ACT UP/Chicago and ACT UP/Portland. Meanwhile, women in the Women's Caucus of ACT UP/New York became increasingly disturbed by the incorporation of "the boys" into the ACTG system. Though the Women's Caucus members had succeeded in pressuring Fauci to hold the National Conference on Women and HIV Infection in December 1990, they had never enjoyed easy access to NIAID officials, and the conference itself proved to be a tense and acrimonious event. "So imagine our fury," wrote Risa Dennenberg, describing the occasion in Outweek , "when, like ships in the night, three of [us] collided in the lobby of the Sheraton at the close of the conference, with members of the Treatment and Data Committee of ACT UP/NY, who were, unbeknownst to us, heading to a social event with these same dreaded government bureaucrats."
Members of the Women's Action Committee proposed a six-month moratorium on face-to-face meetings with government officials—to the utter bewilderment and consternation of the Treatment & Data Committee. "As soon as we got the seat at the table, which we had fought for, and which had been a part of our rhetoric for years, there was a faction in ACT UP that didn't want us to claim it," Harrington recalled with disbelief, several years later. Soon afterward, the core of the Treatment & Data Committee split off to form a new, more exclusive organization, which they called the Treatment Action Group, or TAG. "In New York, we were running a participatory democracy with nine hundred people in the room," commented David Barr, recalling how painful it was to contemplate leaving ACT UP: "You know, you can only do it for so long. …"
Gender and racial divisions, as well as debates over internal participatory mechanisms, insider/outsider strategies, and overall priorities and goals, are the kinds of issues that can tear apart any social movement. What particularly complicated the internal battles of the AIDS movement was the additional overlay of the politics of expertise. It was not simply that some people were working on the inside while
others were outside—just as important, those who were on the inside were increasingly mastering specialized forms of knowledge with which their fellow activists on the outside did not come into contact. There resulted what Gilbert Elbaz, in an analysis of ACT UP/New York, has nicely described as a gap between the "lay expert" activists and the "lay lay" activists. Stratification by gender, race, class, and education helped to structure access to the "lay expert" identity. "[It's] interesting how similar they are to the people that they're fighting," reflected Michelle Roland, a San Francisco Bay Area treatment activist. "I mean, it's science. And who is raised in this culture to believe that they could be scientists? Smart white men. And who are the treatment activists? Smart white men. All with an education. … And then you have … the occasional woman who says, 'I can do it too!'"
The CCG should have been a place where possession of knowledge became equalized. In practice, people who not only came from very different backgrounds and had sharply differing priorities but also had widely varying degrees of exposure to biomedical science were thrown together and expected suddenly to perform. The CCG "was a great experiment," reflected David Barr, "but there were people at all different points within the learning curve." Barr explained: "You'd have somebody … who had AIDS, who knew a lot about AIDS, [but who] didn't know anything about AIDS research—you know, nothing. And never had seen a clinical trial, didn't live in a city where they did clinical trials, on the one end—and then Mark Harrington and Martin Delaney on the other." The solidification of knowledge-based hierarchies was furthered by the difficulties experienced by the first wave of autodidacts in developing a coherent educational strategy that would bring larger numbers of activists into the arena of knowledge-assessment. One activist who remained with ACT UP after others left to form TAG painted a picture of a Treatment & Data meeting circa 1990: the core group of activists "feverishly [tossing] acronyms at each other," complaining that they were overworked and in need of help; the "mostly silent majority of 20 or 30," sitting in the back of the room, "waiting for a revelation."
Another tendency accentuated by the organizational splits and the professionalization of treatment activism was the increasing emphasis on Western medicine and reliance on the pharmaceutical industry, to the relative exclusion of alternative treatments and non-Western conceptions of healing. The main ACT UP chapters had always had committees on alternative treatments, while Project Inform had promoted
Compound Q, derived from the root of a Chinese cucumber, and AIDS Treatment News had regularly and consistently promoted a range of nonpharmaceutical products. With the splits in the prominent ACT UP chapters, advocates of alternative and mainstream treatments often ended up in different camps. ACT UP/Golden Gate focused on the ACTG and the pharmaceutical companies, while interest in natural and alternative treatments was pursued mainly by ACT UP/San Francisco and other groups. Similarly, in New York, TAG focused on mainstream science, while alternative treatment activists found ACT UP to be a more congenial environment.
At a national level, too, there was often little room for discussing alternative treatments. Jason Heyman, a San Francisco activist who tried to address the issue at a CCG meeting, recalls being "told to leave the room" by a prominent East Coast treatment activist. In this case as in others, the dominant treatment activists had acquired the power to perform the "boundary work" that distinguished legitimate treatment issues from illegitimate ones. "They were a wall … between us and the establishment. They were keeping us out." Heyman had no objection, in principle, to the fact that activists had moved to the inside. But once they had done so, "they changed … and they looked at us differently. They were offended by us." And the irony was that "we were doing what they had done. We were just being rude and … coming in there and saying, 'Look, this is what we want'— which is just what they had done."
By 1992, the links connecting treatment activist experts with their grassroots base had become increasingly attenuated. Knowledge still flowed "downward" in the form of articles by the treatment activists that appeared in the gay press and the treatment newsletters. But there was less accountability to the broader movement. Perhaps predictably, perhaps inevitably, pressures to democratize science conflicted with pressures to establish new hierarchies of expertise. The tugs toward these different poles coincided with yet another tension, that which existed between "prefigurative" and "accommodationist" politics— between the appeal of a radical critique of medicine and the felt need to save lives now. By the early 1990s, it seemed that the voices of pragmatism had become dominant. Core groups of activists had established themselves as important contributors to the development of knowledge about AIDS treatments—but at the price of increasing distance from what was, in any case, a rapidly splintering movement.