The Politics of Treatment
Points of Departure
Targeting a Retrovirus (1984–1986)
April 24, 1984: A triumphant Margaret Heckler, secretary of health and human services, announced to the expectant reporters assembled at a Washington, D.C., press conference that the cause of AIDS had been found. This report of a virus linked to AIDS ushered in a new wave of debates—about who should receive credit for the discovery of the putative causal agent, which practices were most responsible for its transmission, and whether a retroviral causation was indeed sufficiently proven. But the general acceptance of the retroviral hypothesis of AIDS causation had still other implications that were both immediate and far reaching. Up until that point, medical treatment of people with AIDS had been aimed at controlling, as well as possible, the opportunistic infections and cancers that progressively devastated the bodies of immune-suppressed individuals. These were stopgap measures, at best—not only because many of the opportunistic diseases were difficult to treat, but also because each infection that subsided would generally be replaced by yet another. Lacking an understanding of the fundamental causes of immunosuppression, biomedical science had little hope of reversing the downward course of illness.
The discovery of Luc Montagnier's "LAV," Robert Gallo's "HTLV-III," and Jay Levy's "ARV" instantly changed the scientific agenda for AIDS research. Suddenly it became possible to use a new vocabulary,
one with words like "cure" and "vaccine." Perhaps the most extreme reactions came from politicians with a vested interest in promoting a triumphalist (and nationalist) account of scientific progress. A blood test for the virus would be available in a few months and a vaccine to prevent AIDS would be developed and ready for testing in about two years, announced Secretary Heckler, to the visible discomfort of some of the prominent scientists with her on the podium.
In fact, there were no insurmountable obstacles to the development of the blood test for antibodies to HTLV-III, which was licensed by the Food and Drug Administration (FDA) in just under a year. But those more familiar with the inherent difficulties of vaccine research knew that scientists had succeeded in designing reasonably effective prophylactic vaccines against only a dozen viral illnesses. The most recent such vaccine, against hepatitis B, had taken most of a decade to bring to market. Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), quickly sought to dispel illusions and dampen inflated expectations. "To be perfectly honest," he told the New York Times a few days after the press conference, "we don't have any idea how long it's going to take to developed a vaccine, if indeed we will be able to develop a vaccine."
A similar degree of uncertainty combined with high hopes surrounded the investigation of treatments for those already suffering from AIDS. The public and the media spoke of "cures," a term which conjured up images of penicillin-like drug that would quickly and efficiently rid the body of the invading microorganism. But unlike the bacteria and fungi that antibiotics treat, viruses—from the common ones, like the cold virus, to the rare and deadly ones, like Ebola—have seldom proven amenable to medical intervention. Viruses insinuate themselves into cellular DNA—the genetic code in the cell's nucleus—transforming infected body cells into factories for the production of more virus. To rid the body of a virus, therefore, requires eliminating every infected body cell without killing uninfected body cells—and scientists in 1984 had little to no idea about how such a task might be accomplished with HTLV-III. Indeed, at the time that the virus was discovered, only three antiviral agents of any kind were licensed for use in the United States, and none of them was entirely effective: amantadine, a drug used against influenza A; vidarabine, which was used against various viral infections of the eye; and acyclovir, a drug used for treating the herpes simplex virus.
The Logic of Treatment
The search for a treatment against an infectious agent can proceed according to a clear theoretical logic or a hit-and-miss pragmatism. At one extreme, researchers may use their knowledge of the pathogen and the disease process to synthesize a novel compound that will target the pathogen or interrupt the pathogenesis (the development of disease). If the newly synthesized drug acts against the infectious agent in vitro and proves to be not too toxic in animal testing, then it can be tried in humans to see if the theoretically predicted effect is observable in practice. At the other extreme, researchers may simply "see what works" by taking existing drugs whose potential efficacy seems plausible (for example, drugs wih known antiviral activity) and adding them to a test tube containing the infectious agent. Such evidence of activity of a drug against a pathogen in vitro is no guarantee, to be sure, that the drug will have any effect on a disease process inside of a living human being or that the human being will be able to tolerate the drug. But it is a good way of screening for promising therapeutic agents.
Since it takes time to synthesize new compounds, and since biomedical researchers knew little about the structure, properties, or life cycle of what would come to be called the human immunodeficiency virus (HIV), hit-and-miss pragmatism was the more likely pathway to quick results. But researchers did possess one crucial fact from the outset that could guide them in the selection of likely agents for testing: they believed they were dealing with a retro virus, composed not of DNA, like most viruses, but RNA. An ordinary DNA virus enters the nucleus of an infected cell and causes the cell to carry out the genetic instructions encoded in the virus's DNA; it transcribes its DNA into RNA, which is then assembled into proteins that form a new virus. But before a retrovirus can integrate itself into the nucleus of an infected cell and replicate, it first has to convert its RNA into DNA—to rewrite its own genetic code "backwards" in a process called reverse transcription. To complete that process, the virus relies on an enzyme it produces, called reverse transcriptase ; this enzyme, in other words, is absolutely essential to the process of viral replication. Inhibit the reverse transcriptase and you inhibit the viral spread: You don't "cure" the patient in the sense of ridding the body of already infected cells and restoring a functioning immune system, but you do—at least in theory—prevent the virus from going on to infect new cells. This
treatment strategy made particular sense if you assumed, as many researchers did, a straightforward model of how HIV caused immune system damage: if AIDS was the long-term result of HIV's direct cytopathic (cell-killing) effects on helper T cells (also called CD4 cells), then stopping the virus in its tracks should prevent the virus from killing more such cells, thereby keeping the immune system from deteriorating further.
It didn't take long for both National Cancer Institute (NCI) scientist and those connected with the Pasteur Institute in France to pursue this promising lead. In October 1984, a group of NCI researchers including Gallo and Samuel Broder, the director of the NCI, published an article in Science describing their in vitro studies with a drug called suramin, which was "known to inhibit the reverse transcriptase of a number of retroviruses." Suramin had been developed by the Bayer Company in Germany more than half a century ago, and, though never licensed in the United States, it had been used extensively in Africa and South America for the treatment of certain parasitic diseases. The NCI researchers found that when suramin was added to HTLV-III in the test tube, the virus became incapable of infecting and killing helper T cells.
Meanwhile, collaborators of Montagnier in France, having made similar assumptions about the logic of treating AIDS, began giving a compound directly to patients—antimoniotungstate, or HPA-23, which was known to incapacitate the reverse transcriptase of certain retroviruses that infect mice. By February 1985, they could offer a brief report in Lancet on a fifteen-day course of treatment with four patients. Comparing the before-and-after assays showed that the drug regimen appeared successful in curtailing the replication of LAV.
But the French researchers also had some words of caution against assuming any easy successes in the fight against AIDS. Even though "infection with LAV seems to be an essential step in the pathogenesis of AIDS," nonetheless a drug that acted against the virus "may not be able to cure the disease." This might be because antiviral therapy came too late, after the virus had already done irreparable damage to the immune system. Or it might be that the pathways from infection to development of AIDS involved more than just direct cell-killing. Perhaps LAV infection instigated "autoimmune mechanisms"—failures of the immune system to distinguish between body cells and invaders, leading the immune system to turn on itself and target other immune cells. In that case, "AIDS could prove to be self-perpetuating even in
the face of inhibition of LAV multiplication." Even if a compound like HPA-23 were eventually proven to be a safe and effective antiviral agent—even if it could be administered to humans in a clinically effective dose, even if its side effects proved tolerable, and even if the initial, promising results could be confirmed in controlled clinical trials with large numbers of patients—it still might not be sufficient to keep AIDS patients alive. "An antiviral won't be the miracle, but it will be absolutely obligatory," Jean Claude Chermann, one of the study coauthors and one of the discoverers of LAV, told Newsweek in April.
That month, more than two thousand researchers from thirty countries converged on Atlanta to attend the first of what would become an annual milestone: the International Conference on AIDS. Researchers in the United States and Europe reported at the conference that testing had begun, or was about to begin, with six drugs in small numbers of patients. These drugs, all of which had been found to have some inhibitory effect on the virus in the test tube, included suramin and HPA-23, as well as ribavirin, an antiviral drug made by a small Southern California pharmaceutical company.
Such studies were just the initial step on the long, uphill path to the marketing of a new drug in the United States. With the passage of the Pure Food and Drug Act in 1906 and the Food, Drug, and Cosmetic Act in 1938, the FDA had been empowered to require that drug manufacturers submit evidence from "adequate tests" showing that a drug was safe, before it could be licensed for sale. Since safety was a relative term, the FDA was expected to assess risk and benefits, which implied making some additional determination of whether the drug was indeed effective. In 1962, in response to public uproar after the drug thalidomide was found to cause birth defects, Congress passed an amendment to the Food, Drug, and Cosmetic Act called the Kefauver-Harris amendment. (Thalidomide had never been licensed in the United States, but some pregnant women participating in studies had received it.) Although the issue with thalidomide was one of safety, the effect of the Kefauver-Harris amendment was to shift the emphasis of drug regulation more heavily in the direction of requiring formal, scientific proof of efficacy.
As Harry Marks has described, by the early 1970s, "with the growth in influence of the National Institutes of Health and the rise of biostatistics as a distinct discipline …, the nature and methods of drug evaluation had achieved a form of scientific and bureaucratic orthodoxy." Usually, the FDA asked for evidence from at least three
"phases" of randomized clinical trials in human subjects performed sequentially: a small Phase I trial to study the drug's toxicity and determine a good dosage for drug absorption; a larger, longer Phase II trial to test the drug's efficacy; and a still larger Phase III trial to bolster the evidence of efficacy in comparison with other treatments for the condition. Each of these studies required planning, recruiting of subjects, careful monitoring, and interpretation and write-up; and the FDA often took its own good time to reach its conclusions, which it made on the basis of recommendations from expert advisory panels. Typically, it might take a drug six or eight years to leap the regulatory hurdles. Critics pointed to the paltry number of drugs that made it to market in the post-Kefauver-Harris environment and argued that U.S. standards were unjustifiably higher than those of other countries. Consumer protectionists responded that U.S. standards were appropriately high, since many countries around the world couldn't afford to perform elaborate drug tests and therefore relied on the FDA to determine what was safe and effective.
Just like medications, any potential vaccine against AIDS would have to pass through extensive testing that included various phases of clinical trials, before the FDA licensed its use. But as reports at the International Conference made clear, even Phase I trials were still a long way off. Researchers had, however, begun identifying "subunits" of the virus that might serve to generate a protective immune response. Using parts of the virus, it was generally assumed, was a safer strategy than using the whole virus: researchers could induce an immune response without having to worry about the risk of accidentally infecting the healthy vaccine recipient. One problem, however, was the recent discovery—Gallo called it "worrisome"—of considerable genetic variation among different strains of the virus. This raised the question of whether any particular subunit could generate protection against every strain. "We have a long way to go before AIDS is preventable or treatable," Dr. Martin Hirsch of Massachusetts General Hospital concluded in reviewing the conference, "but the first steps have been taken, and we are on our way."
The Genesis of Treatment Activism
Observers in gay and lesbian communities had other, more critical perceptions of the International Conference and the depth of the scientific and political commitment to finding treatments for AIDS. Secretary Heckler's statement at the conference regarding
the nation's priorities was widely reported—that AIDS must be stopped "before it spreads to the heterosexual community." Commentators familiar with other scientific conferences observed some distinctive aspects of this one: "The meeting was unusual for the remarkable mixture of participants—doctors and scientists of almost every discipline rubbing elbows with gay activists and media personalities," said the newsletter of the Bay Area Physicians for Human Rights, the gay doctors' group: "The unlikely combinations led to comments about 'strange bedfellows,' but there is no proof of the reality of that phrase."
Moments of levity notwithstanding, this was a threatening time for gay communities. With the availability of the HTLV-III antibody test, many would soon be learning for the first time that they were infected with the virus and faced with an uncertain future. At the same time, as the epidemic became more of a mainstream issue in the United States following reports of actor Rock Hudson's AIDS illness, fears of contagion on the part of the mass public multiplied, leading in many instances to stigmatization of homosexuals, whether healthy or ill. Gay rights and AIDS advocacy organizations feared that those testing positive for viral antibodies would be subject to discrimination, including loss of their jobs, housing, health insurance, and anonymity. In March 1985, the conservative commentator William F. Buckley Jr. proposed, in a notorious New York Times op-ed piece, that "everyone detected with AIDS should be tattooed in the upper forearm to protect common-needle users, and on the buttocks, to prevent the victimization of other homosexuals. …"
The activist response to AIDS by gays and lesbians dated to the earliest days of the epidemic (see chapter I). It rested on the firm base of gay rights activism constructed in the previous decade, with its sex-positive ethic and its suspicious take on medical claims. Now, in response to the new wave of provocations, many who had kept themselves at arm's length from such activism suddenly found themselves drawn into the fray. For a generation of relatively privileged, middle-class gay men, government had been something to restrict, to keep out of their "private" lives. As the boundary between private illness and public health exploded, these same men sought active governmental involvement to fund emergency AIDS research and to protect people with AIDS against discriminatory treatment. However, such assistance was far from the top of the agenda of the Reagan administration, which consistently requested modest funds for AIDS research only to see Congress boost the amounts on its own initiative. Lesbians,
often radicalized by feminism in general and influenced by the feminist health movement of the 1970s in particular, also mobilized in increasing numbers, frequently assuming leadership roles in AIDS struggles.
While the mainstream national gay rights organizations focused on issues of discrimination and budget appropriations, new voices emerged on the horizon. People with AIDS and their supporters discovered in early 1985 that ribavirin, one of the experimental drugs reported to inhibit reverse transcriptase, was available for two dollars a box in the farmacias of Mexico's border towns. Soon a steady stream of couriers were running shipments of ribavirin, along with an unapproved immune-boosting drug called isoprinosine, past U.S. customs and from there to AIDS patients all over the United States.
Elsewhere, wealthy gay men with connections found other pathways to therapies reported to have potential benefit. "There are some Americans in Paris these days who are not so much interested in abstract art or avant-garde literature as they are in saving their own lives," wrote Newsweek in August, a week after Rock Hudson became the most prominent "AIDS exile" to seek treatment with HPA-23. Embarrassed by stories of the "AIDS exiles," the FDA announced that it would permit the administration of HPA-23, along with the other antiviral AIDS drugs that had entered testing, on a "compassionate use" basis—a long-standing FDA mechanism for releasing experimental drugs on a case-by-case basis when requested by physicians for their terminally ill patients, in situations where no standard therapy is available. But the FDA spokesperson struggled to explain that the decision to permit compassionate use was in no way meant to suggest that HPA-23 actually worked . "There is no proven treatment for AIDS yet," he emphasized. "Everyone is assuming that this is a panacea, and there is none." The French, meanwhile, had been forced to discontinue HPA-23 in some patients because of its toxic effects on the blood and the liver.
The availability of drugs in other countries, however, only inclined the new AIDS activists to press for easier access by U.S. patients to a range of experimental compounds. Martin Delaney, at this time a Bay Area business consultant, former seminary student, and current ribavirin "smuggler," emerged as a key voice in these debates. "We don't know for sure how these drugs will work," Delaney told a community forum in the Castro district, the heart of San Francisco's gay community. "But it makes more sense than the next best thing, which is dying without trying anything." In October, Delaney held a press conference
to announce the opening of a new organization, Project Inform, which would conduct studies to determine the benefits of experimental drugs being used in the community, like ribavirin and isoprinosine. "No matter what the medical authorities say, people are using these drugs," Delaney told reporters skeptical of the idea of community-based research. "What we want to do is provide a safe, monitored environment to learn what effects they are having."
Some years back, Delaney himself had participated in an experimental trial of a drug to treat chronic hepatitis. The drug had cured his hepatitis but left him with permanent damage to the nerves in his feet. Delaney considered it a fair bargain; but the drug was thought too toxic, the trial was terminated, and the treatment never approved. It was an experience that would color Delaney's response to the AIDS epidemic. Who should decide what risks a patient can assume—the doctor or the patient?
Rights, Risks, and Ethics
The extensive literature on the ethics of clinical research reflects considerable emphasis on protection of human subjects in biomedical experimentation. This, however, is a rather recent development that has paralleled the rise in importance of the randomized clinical trial both in biomedical fact-making and in regulatory decision making. As historian David Rothman has described, the pivotal moment occurred in 1966 with the New England Journal of Medicine' s publication of a whistle-blowing review article by Henry Beecher, replete with disturbing, recent examples of unethical and potentially harmful experimental research. Beecher catalogued incidents of "investigators who had risked 'the health or the life of their subjects' without informing them of the dangers or obtaining their permission"—for example, withholding penicillin from servicemen with streptococcal infections as part of a study of an alternative therapy. These revelations were followed a few years later by public outrage and congressional hearings in response to news media disclosures about the Tuskegee syphilis study, conducted openly for decades under the auspices of the U.S. Public Health Service, in which hundreds of poor, black sharecroppers were denied existing treatment so that researchers could study the "natural history" of the disease. In 1974 Congress created the National Commission for the Protection of Human Subjects, which issued guidelines on research. In addition, the
NIH began requiring that each research center seeking federal funds for biomedical research on human subjects establish an "institutional review board" to evaluate the ethics of each proposed research "protocol" (the plan for the study).
As Rothman and Harold Edgar have noted, the irony in these protective measures and in the new regulatory regime at the FDA was that they ran counter to the egalitarian and libertarian trends of the 1960s and 1970s in general and to the critique of paternalistic medicine in particular. "Just when patients secured greater autonomy—the right to know a diagnosis, to accept or refuse treatment—the experts at the FDA and review boards controlled the right to regulate new drugs and research protocols." Soon AIDS patients and their advocates began rebelling against what they saw as well-intentioned but deadly paternalism. Activists like Delaney would exert a demand for greater patient autonomy by challenging medical authority from two directions at once. On one hand, they would insist that patients interested in trying experimental drugs should have the right to assume risks rather than endure the benevolent protection of the authorities. On the other hand, they would criticize certain approved and accepted research methods, like trials in which some patients received placebos, characterizing them as unethical for subjecting patients to unfair risks that the patients did not want to assume.
The State of the Art, 1985
As virologist and molecular biologists learned more about the life cycle of the virus, researchers began to speculate about other ways of halting its replication, besides interfering with reverse transcription. NCI researchers analyzed the different points of attack in an article published in September in Cancer Research . First, in order to infect a cell and begin replicating, the outer proteins of the virus (called the "envelope") had to bind to the surface of the cell. Perhaps this binding could be blocked through the use of antibodies; but since most AIDS patients produced antibodies to HTLV-III and became ill nonetheless, it might be that such antibodies were insufficiently protective. Second, after binding to the cell surface, the virus "enters the target cell by an as yet unknown mechanism." If this mechanism could be identified, perhaps entry could be blocked. Third, after reverse trasncription and integration of the viral DNA into the nucleus of the host cell, the virus proceeded to manufacture new viral proteins. The authors noted that this transcription process appeared to be
boosted by a protein, the product of a recently discovered viral gene called tat (for "transactivation"), a gene not found in other known retroviruses. A drug that interfered with this protein might also be an effective antiviral agent. Finally, the new viral proteins were processed and assembled into a fully formed new virus, which was released from the cell by budding. "Our knowledge of these steps is rudimentary at best," the NCI researchers acknowledged, though "interferons have been shown to inhibit the release of other retroviruses. …"
While this was all very nice in theory, the NCI researchers concluded that the best immediate bet remained the reverse transcriptase inhibitors, like suramin. Unfortunately, the early reports on suramin, based on a small Phase I toxicity study by NCI and NIAID, were proving to be mixed at best. The drug did seem to reduce viral replication in vivo as it had in vitro. But "it did not produce clinical or immunological improvement with the regimen used." A larger, Phase II trial would be needed to find out more about the efficacy of the drug. But the concerns about suramin were quickly confirmed a few months into the Phase II study. The drug was far too toxic: it appeared to have caused adrenal failure in several patients and may have hastened some patients' deaths. Later, some treatment activists would claim that the study had been poorly monitored and had subjected its participants to needless risk. The principal investigators, on the other hand, would offer the suramin study both as a cautionary tale and "as an example of how a clinical trial should be conducted": "Trials such as this one … prevent potentially harmful drugs from being distributed to large numbers of patients in the community."
Those skeptical about the viral hypothesis (see part one) interpreted the ongoing difficulties with treatment research as evidence of the inadequacies of the reigning causal models. "If we have agents that effectively inhibit the replication of this virus," said New York physician Dr. Joseph Sonnabend in a New York Native interview in October 1985, "but [those agents] make no impact on the course of this disease, I think it will make apparent, for some people, the actual role of HTLV-III in causing this disease." But research and media attention continued to focus on antiretroviral agents, and in early 1986, NCI researchers found themselves with a potential success on their hands.
"Waiting for the Right Disease"
Samuel Broder, the head of the NCI, had not been putting all his eggs in the suramin basket. In late 1984 he had put out the
word to the big pharmaceutical companies (the ones he considered capable of quickly bringing a drug to market): Send us anything you have on the shelf that might inhibit a retrovirus, and we'll do the assay to see if it halts replication of HTLV-III. Burroughs Wellcome, the North Carolina-based subsidiary of a large British firm called Wellcome PLC, submitted ten compounds, and in February 1985 one of Broder's researchers, Hiroaki Mitsuya, found that one of the compounds was a reverse transcriptase inhibitor with strong antiviral activity: azidothymidine, called 3&0374;-Azido-3&0374;-Deoxythymidine in full or just AZT for short.
AZT had a peculiar history. In the early 1960s, a researcher named Jerome Horwitz at the Michigan Cancer Foundation decided to design a drug that would keep cancer cells from duplicating. With funding from the NCI, and working with such unlikely ingredients as herring sperm, Horwitz and his coworkers synthesized a group of compounds called dideoxythymidines that were designed to look like nucleosides, the building blocks of DNA. In theory, these "nucleoside analogues" would substitute themselves for real nucleosides, thereby interfering with formation of DNA molecules. Without more DNA, the cancer cells would simply stop duplicating. In practice, the treatment was a complete failure. Horwitz gave AZT and the other dideoxythymidines to mice with leukemia, but the drugs showed no effect. "My colleagues and I said that we had a very interesting set of compounds that were waiting for the right disease."
Burroughs Wellcome had tested AZT against animal viruses but had dropped this line of inquiry since it was unrewarding. Now, after getting the good news about AZT from Broder, Burroughs Wellcome filed an "IND" (investigational new drug application) with the FDA. Phase I trials began in July 1985 with nineteen U.S. AIDS patients, under the auspices of the NCI and in collaboration with Duke University. Mitsuya announced the results of the six-week study on the last day of an AIDS conference the following January: AZT kept the virus from replicating in fifteen of the nineteen research subjects, boosting their immune systems (as measured by their T-cell counts) and relieving some of their symptoms. "It's not a dream drug," Mitsuya explained in a television interview, stressing the need for additional testing.
The formal publication of the study in Lancet in March 1986 spelled out more of the details. Researchers recently had discovered that AIDS was frequently accompanied by neurological impairments,
which indicated that the virus was also affecting cells in the brain. An effective therapy, therefore, would have to be capable of crossing a circulatory system defense called the "blood-brain barrier," a feat that many drugs could not accomplish. Fortunately, AZT did appear to cross the blood-brain barrier. In addition, though some subjects had experienced headaches or had developed low white cell counts, the drug could be tolerated relatively well. This was a relief, because AZT "might have been expected to produce intolerable side effects" (in the words of Jean Marx, the reporter for Science who described the trial), given the mechanism of drug action. AZT "fooled" the reverse transcriptase enzyme into using it, in place of the nucleoside it imitated, when transcribing the virus's RNA to DNA. Then, once AZT was added to the growing DNA chain, AZT's structure prevented any additional nucleosides from being added on: reverse transcription simply came to a halt at that point, and the virus stopped replicating. But the problem was that since AZT terminated DNA synthesis, one might logically anticipate that it would have harmful effects on the DNA in healthy cells.
Having shown initial evidence of relative drug safety , the researchers had accomplished the formal objectives of a Phase I trial. But there was nothing to prevent them from reporting the apparent good news about efficacy —the news that attracted media attention. "The results also suggest that at least some immunological reconstitution occurred in most of the patients …, and that a clinical response was obtained in some." However, these findings had to be treated cautiously, since simply being in a trial "may have a strong placebo effect in influencing such factors as appetite and sense of well-being, and it is even possible that improved nutrition may then induce changes in immune function." Only the next step—a so-called "placebo-controlled" Phase II study, conducted in "double-blind" fashion so that neither the subjects nor the researchers would know who was receiving AZT and who was receiving a placebo (a look-alike dummy pill)—could determine whether the observed clinical improvements were truly due to the drug. (This study would be funded by Burroughs Wellcome and conducted at a number of academic centers, including the University of Miami, where it was under the direction of Dr. Margaret Fischl, and the University of California at San Diego, under Dr. Douglas Richman.) The NCI researchers concluded with a summary of the questions that remained to be answered: "We cannot say whether AZT can be tolerated over a long time, whether viral drug resistance will
develop, or ultimately whether AZT will affect disease progression or survival in patients with HTLV-III-induced disease. These are issues which can be resolved only by appropriately controlled long-term studies."
Clinical Trials Take Center Stage (1986–1987)
"The general public, and even most AIDS organizations and activists, do not yet realize that we already have an effective, inexpensive, and probably safe treatment for AIDS." This was the characterization of AZT offered by John James, editor and publisher of a San Francisco-based newsletter called AIDS Treatment News (ATN ), in its third issue, published May 1986. Yet large-scale studies of AZT, James reported, were still several months away from starting, and "if all goes well, your doctor might be able to get AZT in about two years." This was hardly an acceptable time frame in James's view, and he offered a simple justification for his position: "We should point out that ten thousand people are expected to die of AIDS in the next year. And with deaths doubling every year, a little math shows that a two-year delay between when a treatment is known to work and when it becomes available means that three quarters of the deaths which ever occur from the epidemic will have been preventable."
Of course, James's grim logic hinged on the meaning of the deceptively straightforward phrase "when a treatment is known to work": what do we mean by "known," and what do we mean by "work"? As far as James was concerned, though the effects of long-term use indeed remained unknown, it was clear that AZT did something . But from the standpoint of researchers—at least when speaking in their official capacities—it was precisely the point of the next round of testing to determine whether AZT in fact worked. Furthermore, as James himself fully realized, the sort of evidence that impressed him would not get Burroughs Wellcome past the front door of the FDA.
A former computer programmer with no formal medical or scientific training, James had just launched what would become the most prominent grassroots AIDS treatment publication in the United States.ATN rapidly emerged as a crucial resource for doctors and patients alike; within a year, it had a circulation of thirty-five hundred.
The newsletter provided the latest inside word on the up-and-coming drugs as well as the alternative therapies that didn't make it into formal clinical trials. It would go on to engage as well in a sweeping and detailed critique of the federal drug-testing and regulatory enterprise. As Debbie Indyk and David Rier have noted in a study of grassroots AIDS publications like ATN , such organs of communication effectively "[circumvent] the assessment of gatekeepers such as [medical journal] reviewers and editors. …" The result has been not only that more, and more varied, material has made it "through the net," but that "researchers, clinicians, and patients often confront new data almost simultaneously—sometimes, patients even see it first. …"
In those early days, James had another pressing goal—to convince other activists and AIDS organizations that a new task confronted them. Already they had become experts about prevention strategies, antibody testing, antidiscrimination legislation, and the health care delivery system. Now it was time to learn a new set of tricks. "So far, community-based AIDS organizations have been uninvolved in treatment issues, and have seldom followed what is going on," wrote James in a call to arms in that same May 1986 issue. "With independent information and analysis, we can bring specific pressure to bear to get experimental treatments handled properly. So far, there has been little pressure because we have relied on experts to interpret for us what is going on. They tell us what will not rock the boat. The companies who want their profits, the bureaucrats who want their turf, and the doctors who want to avoid making waves have all been at the table. The persons with AIDS who want their lives must be there, too [emphasis added]." To "rely solely on official institutions for our information," James bluntly advised, "is a form of group suicide."
Over the following months, James elaborated this strategy for engagement with clinical research. It wasn't that the researchers conducting AIDS clinical trials were evil or incompetent, but that they were "too close to their own specialties and overly dependent on the continued good graces of funding sources" to be capable of generating or publicly communicating an objective assessment of treatment research issues. On the other hand, these researchers were crucial sources of data: "Physicians and scientists already have pieces of the information, and they need someone they can talk to who can put the pieces together and let people know what is going on." There was nothing pie-in-the-sky, James insisted, about proposing that lay activists could
become experts themselves: "Non-scientists can fairly easily grasp treatment-research issues; these don't require an extensive background in biology or medicine."
It was the right time to pay attention to the organization of clinical trials. With $100 million in federal funding, the NIH was in the process of setting up a nationwide network of fourteen research centers, dubbed AIDS Treatment Evaluation Units (ATEUs), which sought to enroll an additional one thousand of the nation's ten thousand living AIDS patients in government-sponsored Phase II trials of a select group of drugs, including AZT, foscarnet, HPA-23, and ribavirin. Following the standard NIH procedure for "extramural research" (so called to distinguish it from the NIH's own in-house or "intramural" research), NIH would farm out the work to researchers, mostly at academic centers, who had designed and submitted the study protocols and would serve as the principal investigators for the studies.
But the process of setting up the ATEUs was slow and chaotic. Since HIV was an infectious agent, the National Institute of Allergy and Infectious Diseases, under the leadership of Anthony Fauci, had claimed ownership of AIDS treatment research. NIAID, however, had never organized clinical trials on this scale, and Fauci would soon be subjected to intense criticism by activists for what appeared to be incompetence. If Fauci were less intent on amassing power within the federal health bureaucracy, some suggested, he would have left AIDS treatment research with the NCI, where it began, relying on that institute's proven expertise in organizing large, multisite clinical trials for cancer therapies.
The Gold Standard
Practically unknown before the Second World War, randomized clinical trials had rapidly, recently, and incontrovertibly become established as the "gold standard" in biomedicine. Such trials are presumed capable of establishing the risks and benefits of new drugs or of weeding out ineffective or dangerous drugs that doctors have prescribed on the basis of anecdotal evidence. Of course, sometimes anecdotal evidence is perfectly adequate: When an antibiotic brings about rapid miracle cures of diseases that are otherwise often fatal, doctors can safely trust the "evidence of their own eyes." But drugs with more marginal, or less rapid, effects are often harder to evaluate. If a patient gets somewhat better over the course of a few
months, is it the drug that is responsible or some other factor in the patient's life? Randomized clinical trials claimed to take the guesswork out of medical judgments.
These trials, many commentators have noted, are also crucial to the "scientization" of modern medicine—the legitimation of medicine as a fully scientific practice resting not just on the basic biological sciences but on the knowledge base generated by its own, distinct laboratory method. Studies that proceed through the right steps—beginning with the random assignment of patients to either the treatment arm or the control arm—are presumed to generate true knowledge, while those with procedural failings are not. This reification of method, Harry Marks has said in an analysis of the history of such trials, has tended to bracket the political judgments that the use of the method necessarily entails: "On what basis do we choose a significance level?" "On what basis do we integrate the findings from a given experiment with the relevant body of theoretical or empirical literature?" And insofar as the use of such trials has encouraged researchers to privilege "trustworthy answers to a simply put question" over "a contestable reply to a more complex inquiry," it has remained unclear whether the type of knowledge generated is useful—whether the trials provide meaningful guidance to the doctors, patients, and officials who would use them. In this sense, as Marks has argued, reliance on randomized clinical trial may beg the fundamental policy question: What is the problem to which they are the solution?
By 1986, as many as four hundred thousand to eight hundred thousand U.S. patients were enrolled in such trials every year. The number of clinical trials reported in the scientific literature had grown by 30 percent in the first half of the decade alone, from 3,414 in 1980 to 4,372 in 1985. The practical impact, as Dr. Sidney Wolfe of Ralph Nader's Health Research Group commented in 1986, was that "patients have much greater access to new treatments now than they did a decade ago." But a more subtle consequence of this steady expansion of clinical research was that it had shifted the social meaning of the trials.
To the study investigators and the research establishment, the trials were simply scientific experiments; but in the eyes of those suffering from serious illnesses, controlled clinical trials were an important means of access to otherwise unavailable drugs—drugs endowed with the glimmer of scientific promise by simple virtue of their novelty and the fact that they were being studied. So, for example, in December
1985, when the NCI announced a small study of a new experimental cancer treatment using interleukin-2, two thousand people telephoned within two days to find out how to get into the trial. The differing perceptions of the essential purpose of clinical trials would soon put people with AIDS and their representatives on a collision course with the FDA and medical researchers.
"Great Promise for Prolonging Life"
The announcement came on September 20, 1986, after several days of rumors and speculation, and it made front-page news around the country: Margaret Fischl's Phase II trial of AZT had been ended early, after the NIH's Data and Safety Monitoring Board—whose job it was to take periodic "peeks" at trials in progress —concluded that the drug was so effective that it would be unethical to keep the control group on placebos any longer. AZT "holds great promise for prolonging life for certain patients with AIDS," Dr. Robert Windom, the assistant secretary for health, told reporters, adding that he had asked the FDA to consider AZT for licensing as expeditiously as possible. But AZT, Windom also made clear, "is not a cure for AIDS."
The study had been conducted in double-blind fashion with 145 subjects getting AZT and 137 a sugar pill identical in appearance, according to the formal write-up, which appeared in the New England Journal of Medicine the following July. All the patients had AIDS or AIDS symptoms, and there was a similar range of T-cell counts in the two arms of the study. At the time the study was terminated, 19 patients in the placebo arm had died. Only 1 patient receiving AZT had died, and this was a remarkable difference. (It was also a statistically significant difference: the probability that these results might have occurred by chance was well beneath the accepted statistical threshold of one in twenty.) There had been a total of 45 new opportunistic infections in the placebo arm of the study, versus only 24 in the treatment arm. More problematically, "severe adverse reactions," particularly bone marrow suppression, had been observed in the study: a full 24 percent of the AZT recipients had experienced anemia, and 21 percent required blood transfusions. AZT use also caused nausea, myalgia, insomnia, and severe headaches.
With the support of the NIH and FDA, Burroughs Wellcome announced that it would supply AZT free of charge to any AIDS patient
who had suffered an attack of Pneumocystis carinii pneumonia, the most deadly of the opportunistic infections, during the past 120 days, pending the drug's formal approval. It would be distributed on a case-by-case basis only through physicians who submitted requests and agreed to supply data to Burroughs Wellcome; and the NIH set up a toll-free number for doctors to call to request the forms to file. Within weeks, after many doctors and people with AIDS protested that these criteria were arbitrary, Burroughs Wellcome agreed to expand the program to include any of the 7,000 people with AIDS who had suffered pneumocystis at any point.
On March 20, 1987, less than three years after the Heckler press conference announcing the discovery of HTLV-III, the FDA approved AZT for use in the 33,000 Americans diagnosed with AIDS, on the basis of a positive recommendation by the panel of experts on the FDA's Anti-Infective Advisory Committee. The drug had proceeded from in vitro studies to full approval in just two years and had been approved without a Phase III study. The United Kingdom, France, and Norway had also licensed AZT in the preceding weeks.
Burroughs Wellcome announced that it would sell its product under the brand name "Retrovir" at a price that would amount to eight thousand to ten thousand dollars per patient each year. The company refused to disclose its profit margins for AZT—a drug that, after all, had been invented by a federally funded cancer researcher in Detroit a quarter-century earlier, had been sitting on Burroughs Wellcome's shelves for years, and then had been shown effective against HIV in vitro by scientists at NCI and Duke University. One pharmaceutical industry analyst quoted in the New York Times estimated the profit at up to 40 percent and predicted that Retrovir would soon be "the company's largest contributor to revenue and earnings." It was widely assumed that the price reflected the company's assessment—shared by researchers and conveyed to patients by the media—that the life span of the drug was limited since new and better antiviral drugs would be available soon. In practice the price meant that only rich countries could afford to subsidize it. AZT was—and is—essentially unavailable to all those outside of the so-called first world.
The pricing of AZT was not the only point of controversy. "At least half of all AIDS patients that should be eligible to take the drug either cannot take it at all or must take a lower dose to prevent toxicity," reported a news article in Science . (It would later become apparent that the originally prescribed dosage of twelve hundred milligrams per
day was unnecessarily high.) "We found it nearly impossible to keep patients on the drug," said Jerome Groopman, a prominent researcher and clinican who tried giving AZT to fourteen patients on a compassionate use basis. "AZT may be a genie that we are letting out of the bottle," Dr. Itzak Brook of the FDA's Anti-Infective Advisory Committee told Time magazine in February. Brook had been both the chair of the committee and the sole dissenting vote on the recommendation to license the drug.
In a more formal commentary published in the Journal of the American Medical Association (JAMA ), Brook explained that the committee "recognized that the benefit in very sick patients outweighed the serious toxic effects, but it was concerned by the fact that the long-term efficacy and toxicity are, to date, unknown and require further studies." Moreover, many committee members, according to Brook, were concerned that once the drug was approved, HIV-infected people with mild symptoms or none at all might gain access to the drug (since once a drug is licensed, any physician can prescribe it to a patient, whether or not the patient fits the official "indications"). For mildly symptomatic and asymptomatic patients, there were as yet no data from which to conclude either that the drug had benefits or that the benefits exceeded the risks.
As Time suggested, halting the test early and offering the drug to patients in the placebo arm "robbed researchers of the chance to judge, under controlled conditions, any long-range effects of AZT, which might be as dangerous as the treated disease." In fact, as the Washington Post had reported, the days before the announcement of the study's outcome had been marked by serious, behind-the-scenes soul searching: some government officials and researchers had been so concerned about the impact that releasing the drug might have on the capacity to conduct future research that they had implored the media not to carry the story about the trial's findings until a policy decision had been reached, lest the publicity itself create irresistible pressure for the release of the drug. But research ethics, political realities, and the prevailing construction of belief precluded any alternative course of action. "I don't see how you can have a placebo group," said Dr. Charles Schable of the Centers for Disease Control (CDC), "because if you're pretty sure it's going to work, why should you not give it to people?"
The Politics of "Indifference"
To use the language preferred by those who are experts on clinical trials, the AZT study was no longer at an "indifference point" (or, it no longer maintained a state of "equipoise"). In order to conduct an ethical experiment on human beings in which one group receives Treatment A and the other receives Treatment B, "the clinical investigator [must] be in a state of genuine uncertainty regarding the comparative merits of treatments A and B." If this precariously balanced state does not hold—if the researcher has good reason to believe that one treatment is superior—then it would be considered unethical to subject either group to the putatively inferior treatment. When the Phase II AZT study began, it was technically at the indifference point: John James's belief that the drug was "known to work" notwithstanding, investigators like Fischl and Richman believed that there were no hard data supporting AZT's efficacy, since the suggestive results from the uncontrolled Phase I trial may simply have been due to a placebo effect and since that trial had lasted for only a few weeks. But once the Data and Safety Monitoring Board had "unblinded" the study to see the results so far, equipoise no longer held: clear statistical evidence showed a treatment difference between the AZT recipients and those given placebos.
The requirement that a trial could be conducted only when a state of equipoise existed was intended to protect the rights of human subjects by imposing an objective standard on the design of medical experimentation. In practice, like many such rules of scientific practice, this one was subject to negotiation and interpretation. After all, any time researchers test a drug, they do so because they have some reason to think it might work; indeed, probably few investigators take upon themselves the arduous task of designing and conducting a clinical trial unless, on some "gut level," they believe the study might succeed. At what point, therefore, do reasoned guesswork and personal belief come to violate a state of "genuine uncertainty"? Clearly, there is no firm, universally apparent, dividing line separating equipoise from its absence. So certain was Jonas Salk of the efficacy of his polio vaccine that he opposed conducting a double-blind, placebo-controlled trial, arguing that such a "fetish of orthodoxy" would unnecessarily doom some of those in the placebo group to contracting polio. Other researchers countered that in the absence of such a study, the vaccine would never achieve broad credibility among doctors and scientists.
Inevitably, the assessment of equipoise becomes a social and often political process, embedded in the complex interactions and negotiations that establish the credibility of treatments in different quarters.
More problematically still, there is no reason to assume that researchers and research subjects will be equally "indifferent" about the potential merits of therapies, or will be indifferent in quite the same way. "It is clear that research subjects may rationally prefer one treatment arm of a randomized clinical trial … rather than another even if there is no medical reason for the choice," commented medical ethicist Robert Veatch, pointing to patients' complex evaluations of side effects of drugs and quality-of-life concerns. "Only in the rarest of circumstances will active subjects really be indifferent to the two treatment options if indeed they really understand what these options are."
Placebos Under Attack
The fact that researchers and research subjects could differ in their understandings of equipoise was unlikely to lead to controversy in comparisons between two active treatments, one old and one new. But comparisons between a potentially active drug and an inert placebo were far more capable of sparking an uproar among patients with a life-threatening disease. The use of placebos in the Phase II AZT trial was one of the first such cases to be criticized by AIDS treatment activists. In blunt terms, in order to be successful the study required that a sufficient number of patients die: only by pointing to deaths in the placebo group could researchers establish that those receiving the active treatment did comparatively better. Furthermore, to avoid introducing confounding variables into the study, the protocol forbade participants to receive other medication during the study. All this made a certain sense from the standpoint of experimental design, but it was difficult to justify to those people occupying the dual social roles of "patient" and "research subject"—people who began with the assumption that the purpose of medicine was to help them. Researchers insisted that clinical trials should not be confused with treatment—that being a research subject is not the same as being a patient. But this was a difficult distinction to put across in the best of circumstances, and it did not resonate with people with AIDS who were fighting to stay alive. In essence, the same practices and procedures that gave biomedicine its credibility as a science were threatening the credibility of medicine as a healing profession.
Mathilde Krim, a New York cancer researcher who had become the co-chair of the American Foundation for AIDS Research (AmFAR), argued at a New York demonstration in summer 1986 that "the double-blind clinical trial on AZT is an insult to morality." But defenders of placebo-controlled trials characterized them as the quickest route to the truth and pointed to their track record in weeding out ineffective drugs that practicing physicians had believed in. Without the science of clinical trials in general, and without double-blind, placebo-controlled trials in particular, physicians were left with nothing but anecdotes and hunches. Douglas Richman, the AZT researcher at the University of California at San Diego, argued in 1988: "In the field of antiviral therapy alone, numerous anecdotal claims were made for the benefits of corticosteroids for chronic hepatitis B, of iododeoxyuridine for herpes simplex encephalitis, and cytosine arabinoside for disseminated herpes zoster. These clinical observations made by concerned physicians were proved to be erroneous in randomized, double-blind, placebo-controlled studies. In fact, the study drug in each case did more harm than the placebo."
The opposite error—erroneously rejecting an effective therapy—was also possible in the absence of placebo-controlled trials. Indeed, said Richman, if there had been no double-blind, placebo-controlled trials, AZT probably would have been discarded. Since AZT showed no impact on the rate of opportunistic infections for the first six weeks of the study and no impact on survival for an even longer period, it would have been easy to conclude from an uncontrolled study that AZT was toxic and ineffective. In response, some, such as Krim, argued that placebo controls weren't the only option for a controlled study. Data obtained from treatment groups could be compared with the medical records of matched cohorts of other AIDS patients who had been followed in the past in studies of the natural history of AIDS (a method called "historical controls"). Or patients in treatment groups could be compared against their own medical records from the weeks prior to their entry into the study. Similar methods had been employed successfully in research with cancer drugs.
Beyond the questions about whether double-blind, placebo-controlled trials were ethical, there began to emerge, in response to the Phase II AZT study, a growing concern about whether such trials were in practical terms possible . The essence of a double-blind trial is that neither the subject nor the investigator knows whether the subject is receiving the drug or the placebo. But how can such information be
disguised in the case of a relatively toxic drug that produces symptoms like nausea and headaches? And how do researchers anticipate the actions of patients understandably anxious about the possibility that they were squandering their remaining days swallowing sugar pills? Even before the trial had ended, rumors began to trickle in from various quarters: some patients were seeking to lessen their risk of getting the placebo by pooling their pills with other research subjects. In Miami, patients had learned to open up the capsules and taste the contents to distinguish the bitter-tasting AZT from the sweet-tasting placebo. Dr. David Barry, the director of research at Burroughs Wellcome, complaining implausibly that never before in the company's history had any research subject ever opened up a capsule in a placebo-controlled trial, quickly instructed his chemists to make the placebo as bitter as AZT. But patients in both Miami and San Francisco were then reported to be bringing their pills in to local chemists for analysis.
Presumably such practices were not invented by AIDS patients. But the prevalence of AIDS within relatively well-defined communities, and the growing sophistication of the emergent treatment underground, made it likely that strategies for "beating the system" diffused more rapidly and more extensively among AIDS patients than among, say, research subjects in cancer trials. (Ironically, such behavior also risked extending the length of the trial, by increasing the time required to show a statistically significant difference between the AZT group and the placebo group—an example of the clash between the individual and social good that makes such trials so vexing.)
Researchers insisted that their own monitoring methods revealed little abuse: blood tests identified few patients in the placebo arms of studies who had obtained the active drug. Still, reports of "noncompliance" raised serious questions about just how "objective" the much-vaunted double-blind trials really were. Those seeing only the tidy graphs and reading only the crisp prose in the New England Journal of Medicine might conceive of such trials as the essence of scientific rigor and, hence, the most solid basis for forming clinical and regulatory judgments. Those observing the conduct of a trial "from the inside" might conclude that knowledge was resting on something rather less solid than bedrock, and they might wonder why the research establishment chose to fetishize this mechanism for establishing biomedical truth.
The Repudiation of Victimhood
So-called noncompliance—of patients who don't take their medicine, as well as research subjects who don't follow the protocols—is a long-standing concern among medical professionals. But preoccupation with the issue has skyrocketed in recent years. In one study of the medical literature, Ivan Emke was able to find only 22 articles published in English on the topic of compliance before 1960. But "by 1978, 850 more had been published. Between 1979 and 1985, another 3,200 articles on compliance were published." Noncompliance has become a catchall category for things patients do that health providers find undesirable—a term that casts as much light on doctors' expectations as it does on patients' behavior.
As Emke has noted, doctors tend to discuss what they call the "problem of noncompliance" as if it were purely an individual issue involving specific troublesome patients. But as far back as the Popular Health Movement of the 1830s and 1840s, noncompliance has also appeared in "organized" forms. The feminist health movement of the 1970s and 1980s is, in Emke's words, "the clearest modern example": "It represents more than simply a questioning of the medical orthodoxy, but also involves the setting up of alternative clinics, the support of unique therapies, and the democratization of medical knowledge." The consequences of organized noncompliance for professional authority are suggested indirectly by an observation made by Eliot Freidson, the influential sociologist of medicine and the professions, who, writing in the 1960s, assumed there was a general absence of such organization among medical patients. Professional authority cannot function as such, said Freidson, unless "its clientele is a large, unorganized aggregate of individuals, leaving little possibility for the exertion of lay pressure to compromise occupationally preferred standards."
"Noncompliance" is a vague term, emphasizing what patients don't do, rather than what they do. It also suggests a zero-sum game, as if AIDS patients and their doctors had no interests in common. In practice, the relationship between patients with AIDS or HIV infection and community doctors has often been a close one—particularly in gay communities where the doctors themselves are sometimes gay and, in not a few cases, are also infected with HIV. Rather than speaking of noncompliance, it might be more accurate to describe a series of shifts in the nature of the doctor-patient relationship, accompanied and often
fueled by an unusual medical sophistication on the part of the patients.
As the extensive literature on the "doctor-patient relationship" suggests, there are many different models of such relationships. The doctor might be conceived as omnipotent or as simply an adviser to the patient. The patient might be imagined to be an inert object (as in surgery) or a competent decision maker (as in many chronic illnesses). But as professional ethics have changed in recent years, and as the balance of power in the doctor-patient relationship has shifted, doctors have been increasingly inclined to acknowledge the full subjectivity of their patients.
AIDS patients have encouraged this cultural shift. Like their feminist predecessors, people with AIDS practiced "self-help with a vengeance," as Indyk and Rier have nicely characterized it —an outright rejection of medical paternalism and an insistence that neither the medical establishment nor the government nor any other suspect authority would speak on behalf of people with AIDS or HIV. In 1985, groups of patients issued a "Founding Statement of People with AIDS/ARC" and a "Patient's Bill of Rights," which have been widely reprinted. The "Founding Statement" asserted: "We condemn attempts to label us as 'victims,' which implies defeat, and we are only occasionally 'patients,' which implies passivity, helplessness, and dependence upon others. We are 'people with AIDS."' People with AIDS insisted not only on their right to self-representation but also on the right to full explanations from health professionals, the right to anonymity and confidentiality, and the right to refuse specific treatments. Decision-making power, ultimately, had to reside with the person whose life was on the line. This was not an assumption to which doctors necessarily were averse, but the ingrained culture of professional practice often tended to militate against it. At a 1988 conference on AIDS held in London, an anthropologist held up two books side by side to illustrate the gap in perceptions: one was called AIDS: A Guide for Survival , the other, The Management of AIDS Patients . (Only two years later, as the balance of power and knowledge between doctors and patients shifted, AIDS Treatment News would publish an article for patients advising them how to go about "Managing Your Doctor." )
In explaining the medically "noncompliant" tendencies of groups like gay men and injection drug users with AIDS, some have emphasized their alienation from society: outcasts can be expected to rebel.
Others have stressed the desperation of those confronted with imminent death. Yet for many people with AIDS, having the capacity to challenge their doctors over the terms of their medical treatment may stem less from their oppression or desperation than from their relative social advantages. Barrie R. Cassileth and Helene Brown have made a similar point about cancer patients who pursue alternative therapies: "Contrary to the stereotype, … patients who seek unproven methods include the educated, the middle to upper class, and those who are not necessarily terminal or even beyond hope of cure or remission by conventional treatments." Such patients are overrepresented because "several features of these [alternative] cures require time, financial resources, and an educated, questioning approach to illness.…"
Similarly, many people with AIDS and their friends, lovers, and families are often equipped with the financial and cultural resources that permit them to reverse the unidirectional flow of power in the traditional doctor-patient relationship. Many are highly educated (though very often not in the hard sciences), highly motivated, and willing to work to learn the foreign language of biomedicine. "An offensive strategy began to emerge on the island of [hospital room] 1028," reported Paul Monette, in a memoir describing his lover's death, "especially as I took an increasingly hands-on role, pestering all the doctors: No explanation was too technical for me to follow, even if it took a string of phone calls to every connection I had. In school I'd never scored higher than a C in any science, falling headlong into literature, but now that I was locked in the lab I became as obsessed with A's as a premed student. Day by day the hard knowledge and raw data evolved into a language of discourse."
One New York doctor described the results of such autodidactic strategies as he witnessed them with his patients: "You'd tell some young guy you were going to put a drip in his chest and he'd answer: 'No, Doc, I don't want a perfusion inserted in my subclavian artery,' which is the correct term for what you proposed doing." In the eyes of some doctors, these were "bad" patients—troublesome know-it-alls who presumed to tell the doctor what to do. But others appreciated patients who took such an energetic interest in their own treatment. The emerging partnerships between patients and health practitioners—and more generally, the expanding expertise residing in gay communities—would hold profound consequences for the politics of knowledge-making in the coming years.
"Drugs Into Bodies"
Gaining Access (1987–1988)
"It's Not That Easy"
With the steady continuation of basic research on HIV, researchers learned an increasing amount about the life cycle of the virus and its genetic structure. Montagnier's discovery in 1986 of a second, distinct HIV virus—named HIV-2—also believed capable of causing AIDS, produced complications for therapeutic strategies, since there was no reason to believe that a treatment against HIV-1 would necessarily prove efficacious against HIV-2. In practice, treatment strategies focused simply on HIV-1, the virus associated with AIDS around the world; relatively little treatment-oriented research was devoted to HIV-2, found almost exclusively in West African countries.
In contrast to the rapid accumulation of knowledge about the properties and life cycle of HIV-1, researchers lacked a clear understanding of the pathogenesis of AIDS—the steps by which HIV directly or indirectly brought about the decline in the numbers of helper T cells and the destruction of immune functioning. Since the virus could be detected in only a tiny fraction of T cells, it began to seem unlikely that the direct cytopathic effect of HIV could adequately account for the observed T-cell decline. This anomaly was one of the factors that prompted one prominent retrovirologist, Dr. Peter Duesberg of the University of California at Berkeley, to argue in March 1987 that HIV could not be the cause of AIDS (see chapter 3).
A number of research findings in the period from 1986 to 1988
shed some light on the mysteries of pathogenesis, with implications for therapeutic strategies. Gallo and coauthors noted in 1987 that infection with the virus could cause T cells to clump together, forming "multinucleated giant cells" called syncytia. "As these gian cells cannot divide appropriately," wrote Gallo, "cell death results." Another clue to the question of how HIV could be so deadly when so few T cells were infected came with the discovery that HIV also infected the macrophages (from the Greek words for "big eater"), immune system scavenger cells present in the blood and other body tissues that surround and ingest foreign particles such as bacteria and protozoa. Since HIV could infect macrophages without killing them, macrophages could serve as reservoirs of infection within the body—"like beanbags, filled with hundreds of viral particles," in the words of Dr. Monte S. Meltzer of Walter Reed Army Institute of Research in Washington, D.C. An important implication was that a truly effective antiviral would presumably have to function within macrophages as well as in helper T cells.
Vaccine development also continued at a rudimentary stage, since researchers lacked basic information about what type of immune response a vaccine should stimulate and what type of viral preparation could most safely and effectively generate such a response. Was the goal to stimulate the "humoral" (antibody) arm of the immune system to generate an effective "neutralizing antibody" that could defend against HIV? Or was it to stimulate the "cell-mediated" arm (the arm that HIV itself attacks) to produce "killer T cells" that would be programmed to destroy an invading viral particle? Could either or both of these goals best be accomplished with whole virus or protein subunits, and should these be natural or genetically engineered? And once a candidate vaccine existed, how could it be tested to see if it worked? Chimpanzees were the only other species capable of being infected with HIV, but since they didn't develop AIDS, were they really a good "animal model" for AIDS research? Should researchers bypass animal testing and proceed directly to trials in humans? If so, the question of establishing efficacy became peculiarly tricky. One public health official admitted in 1986: "People have been talking vaccine, vaccine, vaccine for public consumption, and I have said it, too. But I always scratch my head and say this is not the kind of situation where it is going to be easy to do the testing."
After all, in order to prove that a vaccine is effective, researchers have to show a difference in infection rates, in a double-blind trial,
between those who received the vaccine and those who received a placebo. But in order to pass an ethics review, such a trial would have to include a "prevention component": each participant would have to be counseled on how to reduce the risk of HIV infection, and each would have to be strongly advised to practice these risk reduction techniques on the logic that he or she might be in the placebo group or might have received an ineffective trial vaccine. The difficulty, however, is that to the extent that the research subjects heed this counseling, there might be less of a difference in infection rates between the placebo group and the vaccine recipients. "The dilemma you might get into is that unless the volunteers continued with the practices that put them at risk, there would be nothing to study," commented Harold Jaffe of the CDC's AIDS program. It was a telling instance of the clash between the "scientific method" and the "real world": once the controlled experiment moved beyond the bounds of the laboratory walls, the iron logic that gave the experiment its scientific credibility proved difficult, if not impossible, to comply with—at least without threatening the moral credibility on which science, as a public institution, depends.
Meanwhile, NIAID's ATEU program for clinical trials of AIDS drugs, announced with some fanfare in 1986, had barely gotten off the ground—"delayed for months by technical, ethical and financial problems, bureaucratic sluggishness and lack of cooperation from [Burroughs Wellcome]," according to the lead of a front-page New York Times article. By April 1987 only 350 patients were enrolled in trials, as compared to the 1,000 that Fauci had promised would be enrolled by the first of the year. Activists chalked the delays up to NIAID's incompetence: unlike, say, the National Cancer Institute, NIAID simply didn't have the experience with running large, multicenter clinical trials. But some researchers insisted that clinical trials necessarily take time to design properly and that "there are no short cuts to the truth."
Fauci, paradoxically, put the blame on scientific progress: The licensing of AZT, in one fell swoop, had invalidated every existing protocol for tests of new antiviral drugs in AIDS patients. Now that AZT had become the standard of care for patients with advanced AIDS, it was no longer ethically acceptable to conduct placebo-controlled trials with such patients. Every protocol had to be rewritten to compare a group receiving the experimental drug with an "active control group" taking AZT. This was no minor substitution, since active-control trials
raised different methodological questions and demanded different statistical interpretation. "Months of work suddenly required complete revision," explained Fauci. The scientist also had sharp words for Burroughs Wellcome, expressing his "frustration" that the company "literally has complete control over what does or does not get done" in NIAID trials involving AZT. Burroughs Wellcome had been quick to supply the AZT when ATEU researchers wanted to try administering the drug in combination with acyclovir, another Wellcome product. But it took six months to get the company's permission to test AZT in combination with alpha interferon, a drug produced by a competing pharmaceutical company.
In 1987, Fauci took steps to put his own house in order. He abolished the ill-fated ATEU program for testing AIDS drugs and set up in its place a new network of researchers and research sites, called the AIDS Clinical Trials Group, or ACTG. And he hired away some of NCI's experts on clinical trials, including Dr. Daniel Hoth, an oncologist who was previously the chief of the investigational drug branch at NCI and who would run the ACTG program, and Dr. Susan Ellenberg, a biostatistician who would give expert advice on how to design the trials. "It was really like trying to build a space shuttle in Bangladesh," recalled Hoth some years later, after his departure from NIAID: "We were trying to do two things at once. One was to build the infrastructure and the second was to actually do the research. It was like being out in the Persian Gulf and you had scaffolding over the aircraft carriers at night and in the day [you were flying] missions."
From Hoth's perspective, part of the problem lay in the particular orientations of infectious-disease researchers and in how they differed from the oncologists with whom Hoth had worked in the past. Cancer researchers were used to running large, cooperative research projects; indeed, the average oncologist had at least a passing familiarity with such research since so many cancer patients were enrolled in trials. By contrast, many of the infectious-disease researchers who would run the government-funded trials at the various ACTG research sites around the country had little of this expertise. "So we were teaching people how to write protocols, how to deal with the FDA, how to think about strategic issues," Hoth recalled. Furthermore, it was obvious to oncologists "that you couldn't answer the most important questions by yourself because most of the important questions require very large trials"; cooperation, therefore, was the name of the game. But Hoth found the infectious-disease researchers to be resistant, at least
initially, to this fundamental truth. "They live in a publish or perish mode," said Hoth. "That drove them towards individual protocols rather than cooperation. So it was very hard for them to 'get' the concept of a cooperative group."
Criticism of the pace of drug testing continued throughout 1987 as patients pressed for studies of drugs ignored by the research establishment. Fauci complained to the press about the "misperception" that "if we're not testing every conceivable drug in a trial, we're falling short of our responsibility." As soon as any compound was reported to act against the virus in vitro, "everybody in New York and San Francisco is saying 'Why aren't you studying this? Thousands of people are dying in the streets, and this at least offers some hope. Why not try it?'" But "it's not that easy," Fauci insisted; most of these compounds proved to be of dubious value. In the words of Frank Young at the FDA, "the real problem is, where do you get the ideas and where do you get the compounds from?"
According to the Nobel Prize-winning molecular biologist David Baltimore, advances in AIDS drug treatment would come not through "random screening" of potential agents but rather through a more directed process of "rational drug development." As an example, many pointed to the biotechnology industry's latest contribution to AIDS research, a genetically engineered substance called soluble CD4, developed by the Genentech corporation in San Francisco. Soluble CD4 was designed to act as a "decoy" by imitating the CD4 molecule, the site on the immune system cells to which the virus binds. In theory, the virus would latch onto the soluble CD4 rather than attach itself to T cells; the effect of the drug on the virus, according to an enthusiastic NCI spokesperson, would be like "putting putty all over a porcupine." Samuel Broder was enthusiastic enough to tell the press: "It is one of the most important steps we have ever been able to take." Unfortunately, a good result in the test tube with a "rationally engineered" drug proved to be just as poor a predictor of in vivo success as the results of many drugs stumbled upon by chance. Soluble CD4 bombed out in clinical trials, proving completely ineffective in controlling HIV infection.
The NIAID-sponsored trials pursued scientifically safer and more predictable strategies. Since AZT had been shown to have efficacy, investigators focused attention on other dideoxynucleosides,
the family of nucleoside analogues to which AZT belongs. Two drugs in particular showed promise: dideoxycytidine (ddC) and dideoxyinosine (ddI). And since AZT's effect had been shown only in advanced cases of AIDS, it made sense to study the drug in less sick patients to see if it was beneficial to begin prescribing the drug earlier in the course of illness. Two large trials were begun: one, labeled "Protocol 016," studied AZT in mildly symptomatic HIV-infected patients; the other, "Protocol 019," focused on AZT use in asymptomatic patients. No one knew how many of such patients, if left untreated, would go on to develop AIDS. But whereas earlier in the epidemic authorities had suggested that perhaps 5, 10, or 20 percent of those infected would eventually develop AIDS, the experts increasingly were predicting that nearly every infected person might eventually do so. "Early intervention"—before the immune system had been severely compromised by the course of HIV infection—seemed therefore to make good intuitive sense. In fact, community-based treatment advocacy organizations like Project Inform had begun to stake their very identity on the notion of intervening early.
Ellen Cooper, the head of the FDA's Antiviral Drug Division, recalled that "there were a lot of people who would say to me at the agency, 'Well why are we even bothering to do studies in asymptomatics? … We know it's an antiviral, we know it works in more advanced patients. [Why not just] open up the indications to early patients?'" And in practice, some doctors had already begun prescribing AZT to HIV-infected patients who did not have AIDS, prompting bitter controversy between advocates and critics of the practice. "I know you don't get better by yourself," commented one Los Angeles doctor with a large AIDS practice, in a pithy expression of the practicing physician's interventionist orientation. Itzak Brook, the FDA advisory committee chair who had voted against approving the drug, was quick to say "I told you so": "This is just what I was afraid of," he commented to the New York Times . Samuel Broder of the NCI suggested that doctors and patients should simply sit back and wait: "The best thing to do now is to let the scientific community work this out." But Mathilde Krim, writing in a public policy journal, put the blame back on the NCI for having helped create the predicament in the first place: as far back as late 1985, NCI researchers had been discussing AZT in hopeful terms on national television, thereby enhancing the public's belief in the drug and raising the expectations of the patient community.
With HIV-infected people clamoring for AZT, the 016 (mildly
symptomatic patients) and 019 (asymptomatic patients) trials became more important than ever. They also became ever more difficult to conduct. Since there was no approved treatment for patients in these categories, AZT still had to be measured against a placebo. But compared to the original Phase II AZT trial with AIDS patients, these were larger and longer studies—necessarily so, since otherwise there would be "too few" deaths in the placebo arm to prove anything, given the relative health of the patients. Fischl's AZT trial had involved only 137 patients on placebos, and they were kept on it for twenty-four weeks at most. By contrast, the 019 study, conducted by Dr. Paul Volberding of the University of California at San Francisco, had 428 people in the placebo arm, and it was expected to run for several years.
Soon articles in the gay press were publicizing the plight of the "sacrificial lambs" in the AZT studies, sentenced by the research establishment to "death by placebo." Experts on clinical trials sought to emphasize the difference between the 016 and 019 studies and the earlier Phase II AZT study conducted with much sicker AIDS patients. That the patient community might find placebos difficult to countenance in trials of those facing "imminent death" was "entirely understandable," said Thomas Chalmers of the Harvard School of Public Health. But, he argued, "it is more difficult to understand that philosophy when one is dealing with asymptomatic patients … who may never develop AIDS and face a chance of being [made] sicker by a toxic and ineffective drug."
However, the trial participants—who had tested positive, who had gleaned from numerous newspaper accounts that they had a "time bomb" ticking away inside of them, and who, in their day-to-day lives, could see the presumed end results reflected in the bodies of the friends and lovers they visited in hospitals, reflected in the obituaries they read, and reflected in the funerals they attended—quite simply drew different conclusions. One subject in the 019 trial who had discovered he was in the placebo arm commented, "Fuck them. I didn't agree to donate my body to science, if that is what they are doing, just sitting back doing nothing with me waiting until I get PCP [Pneumocystis carinii pneumonia] or something." He told a reporter for the gay press that he had covertly begun taking dextran sulfate, an unapproved drug available through the treatment underground. Some community physicians expressed their incredulity on learning that participants in these studies were not permitted to take prophylactic medication to ward off pneumocystis pneumonia. One doctor described an experience
with one of his patients: "I said hello, and he handed me this lab slip from UCSF and started crying. He said they won't let me have aerosol pentamidine.… I looked at it, looked at him, and said, 'I don't believe you. Nobody would do that!' It drove me nuts!"
Dual Roles and "Double Agents"
The fundamental problem was that it was becoming more and more difficult for people with AIDS and HIV to occupy the dual roles of "patients" and "research subject." That these distinct roles might overlap without tension was always a convenient fiction. But in the cases of other illnesses such as cancer, the problem had been given more extended consideration. Most clinical research in cancer takes place on the "front lines" of patient care: a patient's own oncologist routinely enrolls him or her in research protocols that are integrated into the overall treatment plan. At least in theory, these oncologists are self-reflective about their role as what ethicist Robert Levine calls "double agents": they wear the hats of both "doctor" and "researcher" and must be responsible, simultaneously, to the abstract goal of knowledge and the concrete needs of their patients. Researchers in infectious disease also saw patients, but they were far less likely than oncologists to have extended experience with patients suffering from chronic, life-threatening illnesses. Until AIDS, as David Rothman and Harold Edgar have explained, "most the research in infectious diseases, although certainly not all, did not involve desperately ill patients willing to take high risks for the slimmest possibility of a gain. Inevitably, in the realm of infectious diseases, the commitment to placebo-based random trials did not have to come up against agonizing questions."
As these "agonizing questions" surfaced in trials like 016 and 019, community physicians not involved directly in clinical research (like the astonished doctor quoted above) found themselves caught smack in the middle between their own patients and the respected academic researchers conducting the trials. In more typical circumstances, these practitioners would likely have deferred to the academics, who enjoy high status within the broader medical community. (As Andrew Abbott has described it, such professionals reside closest to the profession's "pure" knowledge base and bask in its reflected glow. ) But the physicians on the front lines of the AIDS epidemic—the ones who saw hundreds of people with AIDS and HIV in their practices, who in some
cases were gay themselves and in some cases were HIV positive—found their loyalties sharply divided. Many of them reacted with sympathy as activists began to propose ways of easing the tension between the roles of "patient" and "subject"—ways of conducting research that might serve the ends of both science and ethics.
A Knowledge-Empowered Movement
A Lab of One's Own
By the mid-1980s, some groups of community physicians had banded together with patient groups to pioneer new forms of knowledge-making. Instead of waiting for NIAID to test drugs in its lengthy, cumbersome clinical trials at academic centers, primary-care physicians and people with AIDS decided to go about designing such trials themselves. "By integrating scientific trials with normal medical practice, community-based trials allow credible testing of treatment options with far less administrative delay than usually involved, and at far less cost," said John James in AIDS Treatment News . As Mary-Rose Mueller has detailed in an analysis of community-based research, this endeavor served as "a form of professional resistance [by community physicians] to academic medicine" and an opportunity for them to stake out a new jurisdiction within professional practice. At the same time, community-based research promised to bring scientific knowledge-production closer to popular control. Scientists' power, as Bruno Latour has emphasized, stems at least in some measure from their possession of laboratories; now the AIDS movement sought to build its own.
As John James explained in 1988, two very different models of community-based research had arisen. In San Francisco in 1985, researchers such as Donald Abrams, associated with the University of California at San Francisco and San Francisco General Hospital, had formed the County Community Consortium (CCC), a coalition of San Francisco physicians with AIDS practices. The original purpose had been to improve communication between researchers and doctors and disseminate information about treatments more rapidly. Over time, as some of the primary-care doctors became interested in participating in research, the CCC evolved into a mechanism for organizing community-based trials. The idea was that physicians would distribute drugs, monitor patients, and collect data as an integral part of their
regular clinical work with patients. And it wasn't a new idea: in many ways it resembled the community-based cancer research effort sponsored by the NCI, called the Community Clinical Oncology Program. "We have a distinct advantage in being able to follow up patients, because the research is being done where the patients are getting their primary care," commented Abrams, the head of the CCC. "So even if the patient stops participating in the study, we still know … what sort of outcomes they have…."
The second model was pioneered by people with AIDS in New York City, who worked together with a number of activist doctors, including the maverick Joseph Sonnabend. Frustrated by the slow pace of federally sponsored treatment research, they founded an organization called the Community Research Initiative (CRI), which opened its doors in May 1987 under the sponsorship of the local PWA Coalition, the advocacy group run by people with AIDS. From the start, people with AIDS or HIV infection participated in decision making about what trials CRI should conduct and even how they should be organized, "[setting] policies on placebo use, and [insisting] that trials under [CRI] sponsorship be effectively open to women and minorities, not only to gay men." The effect of such community participation, argued James, was to ensure smoother trials and higher levels of "compliance" with the protocols: "Such prior community involvement in policy issues around the selection and conduct of trials makes recruitment easier and increases patient-experimenter cooperation, for example by greatly reducing any need to 'cheat' in the study by taking other drugs without telling the researchers." Community-based research was not suited for high-tech trials requiring sophisticated lab tests that the average primary-care physician did not have the equipment to perform. But other trials, involving minimal data collection, could easily be conducted out of doctors' offices. Drug companies, also impatient with the NIAID trials system, proved interested in the concept as well, and soon CRI had a number of contracts to conduct studies for different companies, both large and small.
Still, community-based research invited skepticism. "Traditional researchers thought that community doctors would not be sophisticated enough to run trials," said Mathilde Krim, whose organization, AmFAR, would later become a chief funder of community-based research. "But actually they were highly sophisticated…. After all, they had been managing the disease for years." This sort of "hands-on" expertise did not, in itself, establish community-based research as
credible in the eyes of mainstream researchers or government health officials, who were more invested in a conception of medicine as "science," not "art." Rather, public demonstration of the credibility and viability of community-based AIDS research came with the testing of aerosolized pentamidine, a form of prevention against deadly pneumocystis pneumonia. It was a therapy that community-based research at the CCC and CRI effectively rescued after NIAID bungled its own efforts to test it.
In February 1987 researchers recruited by NIAID to participate in its clinical trials program rated research into prophylactic aerosolized pentamidine as a high priority: preventing pneumocystis pneumonia was a much better therapeutic strategy than simply treating people once they contracted the disease. But it wasn't until June the following year that researchers actually began to recruit patients into the NIAID trials, after more than a year of writing and rewriting the protocols and negotiating with Lyphomed, the manufacturer of the product. Meanwhile, in May 1987, a group of activists including Michael Callen, the well-known dissenter on the HIV hypothesis who was also on the board of CRI, had met with Anthony Fauci and pleaded for him to issue federal guidelines recommending pentamidine use to prevent PCP. When Fauci refused, citing the lack of data on efficacy, Callen returned to New York to tell his fellow board members: "We're going to have to test it ourselves." In San Francisco, the CCC had also launched its own study, a three-armed trial where patients received different doses of pentamidine but no one received a placebo. Denied funding by NIAID, the CCC received money for the trial from Lyphomed and the University of California.
In 1989, after examining study data from both the CCC and CRI, the FDA approved aerosolized pentamidine for prophylactic use against PCP—the first time in its history that the agency approved a drug based solely on data from community-based research. Before accepting the CRI's data, FDA representatives had visited the CRI's offices in New York and gone over their methods and their paperwork. They came away satisfied that "good science" was being done. This was essential for the legitimation of CRI, according to Dr. Bernard Bihari, a member of the board of directors: "Doing good science allowed us to establish our credibility."
Plaudits soon arrived from all quarters. "The Community Research Initiative … offers the possibility to combine the technical expertise of the research community with the outreach potential of community
health clinics and physicians in community practice," wrote the Presidential Commission on the HIV Epidemic in its 1988 report, urging direct federal funding of the community-based research programs. One member of the commission described CRI as "one of the best things to have come out of the AIDS effort." Said Anthony Fauci the following year: "What I see in the community programs is totally compatible with the mission of the NIH."
The successes of community-based research notwithstanding, those who cared about the overall progress of AIDS research could hardly afford to ignore the federal agencies that coordinated the bulk of the effort. In early 1987, deep concerns about NIAID's clinical trials and the FDA's regulatory requirements—not to mention the drug companies' obedience to the profit motive, the religious right's intolerance, and the Reagan administration's general indifference—combined to push AIDS activism into a new level of energy and organization. On the East Coast, the gay playwright and all-around rabblerouser Larry Kramer, who had helped found the Gay Men's Health Crisis at an earlier juncture in the epidemic, was one of the initiators of a new group in New York City, a radical activist organization called the AIDS Coalition to Unleash Power—better known by its acronym, "ACT UP." On the West Coast, a group of San Franciscans who called themselves the Citizens for Medical Justice began organizing a series of demonstrations against Burroughs Wellcome at its Bay Area offices, protesting the price of AZT. Citizens for Medical Justice then transformed itself into the AIDS Action Pledge, which in turn became the San Francisco chapter of ACT UP.
Soon there was an ACT UP/Chicago and an ACT UP/Houston, an ACT UP/New Orleans and an ACT UP/Seattle. Although AIDS activism has remained significantly stronger in the United States than elsewhere, most likely due to the greater strength of the gay and lesbian movement and the greater salience of identity politics in general in the United States, ACT UP eventually developed international dimensions. By the early 1990s there were also ACT UP chapters in Sydney, London, Paris, Berlin, Amsterdam, and Montreal. Each chapter was autonomous, though informal links connected them.
A magnet for radical, young gay men and women, ACT UP practiced an in-your-face politics of "no business as usual." Adopting
styles of political and cultural practice deriving from sources as diverse as anarchism, the peace movement, the punk subculture, the feminist health movement, and gay liberation "zaps" of the 1970s, ACT UP became famous for its imaginative street theater, its skill at attracting news cameras, and its well-communicated sense of urgency. "Silence = Death" read its characteristic slogan, set against the pink-triangle symbol of gay liberation (itself a symbolic appropriation of the patch worn by homosexuals in the Nazi death camps). ACT UP chapters typically had no formal leaders; in many cities, meetings operated by the consensus process.
As Joshua Gamson described in a participant-observation study of the San Francisco chapter, ACT UP shared the basic characteristics of so-called new social movements—"a (broadly) middle-class membership and a mix of instrumental, expressive, and identity-oriented activities." By "staging events and by carefully constructing and publicizing symbols," ACT UP "attacks the dominant representations of AIDS and of people with AIDS and makes attempts to replace them with alternative representations." Though the New Yorkers were particularly well connected to the art world and the communications media, ACT UP in general quickly perfected a highly dramaturgical style of activism and an abiding concern with techniques of expression.
On the national scene, the New York City chapter dominated, with more than 150 members at regular weekly meetings and a three hundred thousand-dollar budget by the end of 1988. But chapters in San Francisco, Los Angeles, and Boston were also prominent within the movement. Activists came from all walks of life. Yet as results from a survey of ACT UP/New York members conducted by Gilbert Elbaz suggest, "the group was predominantly gay, white male [with ages] between 26 and 35." Members were also "predominantly sero-negative, highly educated, and part of the new middle class." In Elbaz's sample of 413 activists, 80 percent were men and 78 percent were white. Thirty-five percent had done at least some postgraduate study. It was also a highly politicized group: More than half of Elbaz's respondents had participated in demonstrations before joining ACT UP; a good number had been involved in movements such as the peace movement and the feminist movement. Many of the women, in particular, had had experience with civil disobedience leading to arrest.
For some, radical AIDS activism provided a "home" within the gay and lesbian movement. Commented New York activist David Barr, a lawyer by training: "I can't tell you how many gay men … that I
know who said, 'ACT UP was the first time I've ever felt a part of a gay community.' That was certainly the case for me. I mean, the 'gay community' before that was always more alienating to me than anything else…." For others, like Michelle Roland, whose father had been jailed with Martin Luther King and who grew up reading United Farmworkers literature in her Berkeley home, joining the San Francisco chapter of ACT UP was a natural outgrowth of radical politics. But many, including Roland, have pointed to the deaths of close friends as the immediate, mobilizing incidents that provoked them to become involved. And they have recalled their frustration with the prevalent notion that since AIDS was inevitably fatal, all that could be done for people with AIDS was to provide palliative care.
The Discourse of Genocide
Especially in the early years of the epidemic, some had speculated openly that AIDS had emerged as an act of genocide—as a deliberate attempt, perhaps by government scientists, to eliminate "undesirable" populations by spreading an infectious agent among them. Now, with the rise of groups such as ACT UP, a new conception of genocide gained currency in activist rhetoric: genocide described the consequences of the failure of governmental and medical authorities to respond to the epidemic adequately. Genocide was not the product of anyone's action but the by-product of in action or willful neglect. As AIDS activists mobilized to focus public attention on the epidemic and convince a Republican administration to fund prevention, treatment, research, and social services, the new conception of genocide proved a useful framing device.
One of the prime enunciators of the charge of genocide-by-neglect was Larry Kramer, the New York activist. In a book entitled Reports from the Holocaust , Kramer argued that "a holocaust does not require a Hitler to be effective…. Holocausts can occur, and probably most often do occur, because of inaction . This inaction can be unintentional or deliberate." Kramer's sidestepping of the question of intentions in no way inclined him to be charitable toward those he considered perpetrators of genocide. Writing about Ronald Reagan and various government health officials, Kramer declared them all "equal to Hitler and his Nazi doctors performing their murderous experiments in the camps—not because of similar intentions, but because of similar results."
Genocide by neglect became one of the key frames employed by
ACT UP in its formative years of mobilization. If, by this logic, government officials were murderers, then people with AIDS were to be understood as casualties of state-sponsored violence. In this context, the Nazi-era pink triangle in the ACT UP logo took on additional resonance. Soon the stark image of a bloody palm print could be seen stickered to the backs of black leather jackets from New York to San Francisco, with the caption reading: "The U.S. government has blood on its hands."
The FDA under Fire
Though its targets were always multiple, throughout 1987 and 1988, ACT UP trained its attention particularly on the FDA, perceived to be the roadblock in the way of access to AIDS drugs. In March 1987, the FDA commissioner announced a new plan to create a special category of unapproved drugs called Treatment Investigational New Drugs (Treatment INDs), to be available on a compassionate use basis to patients with terminal illnesses whose doctors contacted the FDA. But in essence this was nothing more than a codification of existing, case-by-case compassionate use policies. AIDS activists were not mollified; "Drugs into bodies" was their war cry.
"Many of us who live in daily terror of the AIDS epidemic cannot understand why the Food and Drug Administration has been so intransigent in the face of this monstrous tidal wave of death," wrote Larry Kramer in an opinion piece published in the New York Times . "There is no question on the part of anyone fighting AIDS that the F.D.A. constitutes the single most incomprehensible bottleneck in American bureaucratic history…." "In addition to ribavirin, why is the F.D.A. withholding Ampligen; Glucan; DTC; DDC; AS 101; MTPPE and AL 721?" he asked in reference to some of the many experimental drugs that were rumored to be efficacious. Patients had no interest in paternalism, Kramer insisted: "AIDS sufferers, who have nothing to lose, are more than willing to be guinea pigs." Similarly, Martin Delaney, executive director of the San Francisco-based Project Inform, struck a chord that resonated deeply with U.S. political culture by painting the FDA as a would-be "Big Brother" and insisting on the individual's basic right to choose. In public debates and private meetings with AIDS clinical researchers and FDA officials, Delaney sought to reframe the very purpose of the FDA: rather than seek only to protect the public from ineffective or dangerous therapies, the FDA should take an active stance to promote the nation's health.
AIDS activists were not the only voices challenging the FDA. For years, conservatives from places ranging from the Heritage Foundation to the offices of the Wall Street Journal to—most recently—the corridors of the White House had been seeking to roll the "deregulation" bandwagon onward in order to focus on the pharmaceutical industry. The FDA was killing the drug companies and preventing useful products from getting to market, the argument ran; the best solution would be to repeal the Kefauver-Harris amendment, which had granted the FDA the authority to assess the safety and efficacy of drugs. "Especially considering who was the president, we had concern" about adding fuel to the deregulatory movement, recalled David Barr of ACT UP/New York: "But it wasn't enough concern that it would stop us from doing what we were doing." Soon an unlikely alliance had developed—usually tacit, but sometimes explicit—between AIDS treatment activists and conservatives, leaving consumer protection groups and traditional liberals on the other side.
When cancer treatment advocates connected to the ultraconservative John Birch Society had used similar grounds to press for access to laetrile in the 1970s, a confluence of interest with pro-market forces was perhaps less surprising. But when AIDS Treatment News plugged a Heritage Foundation report called "Red Tape for the Dying," describing it as proposing "a workable, politically possible change which could solve part of the AIDS 'drugjam,'" or when Project Inform began collaborating on a regulatory proposal with the Competitive Policy Institute, a conservative policy group, everything started to seem upside down, and liberal politicians might have been forgiven their bewilderment at becoming the target of criticism by their usual allies. Henry Waxman, the liberal chair of the health sub-committee of the House of Representatives, found himself in a peculiar plight when he raised objections to the Treatment IND proposal. The Wall Street Journal , suggesting that Waxman "has been to new-drug development in this country what the troll under the bridge was to forward progress in the Billy Goats Gruff," noted with evident glee: "If he opposes the administration initiative, it will be interesting to hear him explain it to AIDS victims in his West Hollywood constituency."
The FDA was being pressured from all sides, particularly by the increasingly flagrant flouting of the law by the AIDS treatment underground. Importing unapproved drugs had become an organized and global operation, with regular couriers flying in treatments such as dextran sulfate from places like Japan and then distributing them at
bargain prices to individuals all around the United States. Organizations called "buyers clubs" (sometimes also called "guerrilla clinics"), operating in a gray zone of legality, had sprung up in major cities around the United States, swapping information about treatments and selling a range of unapproved compounds and alternative therapies. By October 1987, Project Inform's newsletter reported ten such organizations in the United States, plus one in Vancouver and one in London. These organizations had benevolent motivations and, indeed, protected their customers from less scrupulous entrepreneurs seeking to profit from "quack" remedies. But the FDA was far from convinced of the wisdom of tolerating their operations. "This is a very fine line we're walking," said Frank Young, the FDA commissioner, acknowledging the practical limits of pursuing a strict enforcement policy against the buyers clubs: "Since there's nothing else available except AZT, we are trying to make available the opportunity for patients to get other drugs and treat themselves."
When Young appeared in Boston at the Lesbian and Gay Health Conference in July 1988, he confronted a hostile audience of one thousand; the first three rows were filled with ACT UP demonstrators holding signs saying "FDA, YOU'RE KILLING ME." While some demonstrators conducted a mock "die-in," others held up their watches with alarms ringing: for people with AIDS, time was running out. But to the surprise of the audience, Young had come to announce that the FDA would now permit the importing of unapproved AIDS drugs in small quantities for personal use. In a remark to a reporter after his talk, Young described his motivations: "There is such a degree of desperation, and people are going to die…. I'm not going to be the Commissioner that robs them of hope." But according to a reporter for Science , the change in policy "stunned" many in the research community: "One official in the federal government's AIDS Program went so far as to suggest that the FDA commissioner had gone 'temporarily insane.'"
AIDS activists, however, had no intention of letting up the pressure on the FDA—certainly not in response to the limited new policy of importation for personal use. Plans began in New York City, San Francisco, and elsewhere for a demonstration that would "shut down" the FDA. In an early example of what would prove to be periodic position papers on the state of AIDS research, ACT UP/New York distributed a thirty-five-page, closely argued document entitled the "FDA Action Handbook," designed to explain to the mass membership the medical and political justification for the action. "Many Federal agencies, not
to mention local and state ones, have been derelict in the fight on AIDS," wrote Jim Eigo and Mark Harrington, two of the authors: "Yet only one agency, the FDA, is actively blocking the delivery of promising drugs to PWAs and people with HIV infection." Sections of the handbook included discussion of topics such as "What Is the FDA?" "A Brief History of the FDA," "The Standard Drug Approval Process," "Drug Horror Stories," and "Exclusion of Women, People of Color, Poor People, People in Rural Areas, IV Drug Users, Hemophiliacs, Prisoners & Children from Experimental Drug Trials." The document is noteworthy for its use of "atrocity tales" and for its construction of an antagonist identity: "Like corporations, [government bureaucracies] consider the data of lives as raw material and grist for a perpetual-motion paper mill. Human need, suffering and death count for very little when compared to the imperatives of orderly process and well-maintained policies."
On October 11, 1988, following a national display of the Names Project AIDS Quilt on the Capitol Mall in Washington, D.C., more than a thousand demonstrators from around the country converged on FDA headquarters in Rockville, Maryland, to "seize control" of what some labeled the "Federal Death Administration." Protesters fell to the ground holding mock tombstones with caustic inscriptions: "I got the placebo. R.I.P."; "As a person of color I was exempt from drug trials." Two hundred demonstrators were arrested by police, who wore rubber gloves to protect themselves from the supposed risk of HIV infection.
It was a protest that, in the words of two chroniclers, "represented … a culmination of our early efforts. …" It also marked "a turning point in both recognition by the government of the seriousness and legitimacy of our demands and national awareness of the AIDS activist movement." The ACT UP/New York Media Committee had "distilled" the message of the "FDA Action Handbook" to explain it to the press in simple terms: Protesters demanded immediate access to drugs proven safe and theoretically effective in Phase I trials. Double-blind, placebo-controlled trials should be declared unethical and replaced with alternative trial designs. The FDA should make it clear that it would not tolerate trials that prohibited its participants from taking simultaneous prophylaxis against opportunistic infections. People from all affected populations—gays, injection drug users, and people with hemophilia; women and men; whites and people of color— must be given access to trials. Medicaid and private health insurance should cover experimental drug therapies.
"The meeting at the FDA two weeks later was very different," recalled David Barr, "because, not only had we been able to show our firepower out on the street, but when we sat down at the table we had a list of issues that we understood—we were very knowledgeable about them by that time. …" Significantly, activist strategies and tactics in negotiation with FDA officials differed considerably from the colorful display outside the building. That "was theater and we knew it was theater," explained Barr. "It was a much smaller group of people who were actually inside at the table, and we wouldn't go in there saying, `Okay, we want to go through these forty demands with you.' We were savvy enough to say [ahead of time], `What are our issues at this meeting with this group of people? Let's talk about these five things, and what is our priority'—and we learned how to do a meeting. …"
The simultaneous use of insider and outsider tactics meant, however, that activists needed to establish working relationships with the same people they had vilified in public statements and demonstrations. Similarly, activists needed to engage with the nuts and bolts of policies and research practices whose defects they had heretofore been content to paint with a broad brush. Though activists continued their bitter criticisms of government agencies and individual scientists, they resisted the notion—found, for example, in the animal rights movement —that the scientific establishment was "the enemy" in some absolutist sense. "I wouldn't exaggerate how polite we were," reflected Mark Harrington. "At the same time, I would just say that it was clear from the very beginning [that we recognized that], as Maggie Thatcher said when she met Gorbachev, `We can do business.' We wanted to make some moral points, but we didn't want to wallow in being victims, or powerless, or oppressed, or always right. We wanted to engage and find out if there was common ground."
Beyond the FDA
The Wall Street Journal made effective literary use of the iconography of the protest in its editorial two days afterward, which described the "battle between people who have all the time in the world and people who have little time left in their lives." But what the Journal may have failed to observe was how the activists themselves had already set their sights well beyond the walls of the FDA building. Though the main goal, to be sure, was access to treatments,
in pursuit of that goal activists had to engage with the researchers and the health professionals, the pharmaceutical houses and the insurance companies, NIAID and the NCI and the Department of Health and Human Services. For all its importance as a symbolic target, the FDA was just one player; and the demonstration in Rockville, for all its significance in the construction and legitimation of a nationwide movement, in a sense represented the end of an era. Arguments about competing philosophies of drug regulation would continue. But the more activists learned about the FDA's drug approval policies, the more they became enmeshed in debating the details of what counted, in the agency's eyes, as "good science." And the more they became concerned with the science of clinical trials, the more the focus of their energy shifted from the FDA to NIAID. "While the question of a person's freedom to use a treatment whether or not it works is indeed an important issue," commented AIDS Treatment News in 1988, heralding this new turn, "the more important question is what treatments do in fact work, and how can the evidence be collected, evaluated, and applied quickly and effectively."
Of course, these two issues—the ethics of access to therapies and the methodology of clinical trials—often came together in concrete ways. For example, some worried about the potential conflict between access and research: would unrestricted access to experimental treatments hamper researchers' abilities to conduct trials? After all, if every person with AIDS could obtain an experimental drug with a minimum of hassle, why would anyone enroll in a clinical trial? In effect, the capacity to conduct clinical trials presupposed coercion through control of the supply of the drugs. Researchers and health officials took this point for granted; for example, Ellen Cooper, the head of the FDA's Antiviral Drug Division, argued in JAMA that "a national policy of early widespread availability of unproved experimental agents would slow or even halt the completion of controlled clinical trials through which therapeutic advances are established and then improved on. …" Recalled Cooper: "I really understood, or emphathized with, where they were coming from, which is … the individual patient with a life-threatening disease." But in her view, it was a simple question of the greatest good for the greatest number; and the individual's right to treatment would have to take a back seat to research that could benefit the public at large.
AIDS activists protested the implicit coercion, suggesting, in Martin Delaney's words, that it was "morally offensive [to] use access to
treatment as a lever to force subjects into studies. The fact that such an argument is openly made demonstrates how detached the regulators' mindset has become." But to the extent that activists succeeded in swaying researchers and government officials on this point, they did so by turning the argument on its head. "The policy of restriction," said Delaney, addressing the 1988 meeting of the Infectious Diseases Society of America, "is itself destroying our ability to conduct clinical research." Delaney explained: "AIDS study centers throughout the nation tell of widescale concurrent use of other treatments; frequent cheating, even bribery, to gain entry to studies; mixing of drugs by patients to share and dilute the risk of being on placebo; and rapid dropping out of patients who learn that they are on placebo. … Such practices are a direct result of forcing patients to use clinical studies as the only option for treatment." If these policies continued, Delaney warned, "it will soon be impossible to conduct valid clinical AIDS research in the US."
This was a forceful argument that spoke to researchers' basic interests while playing on their fears. Continuing in his role as the defender of good science, Delaney proposed the solution: "If patients had other means of obtaining treatment, force-fitting them into clinical studies would be unnecessary. Volunteers that remained would be more likely to act as pure research subjects, entering studies not solely out of a desperate effort to save their lives." Their motivations for doing so might be altruism or a desire to obtain other tangible rewards of clinical trial participation, such as access to free, high-quality medical care.
Over the next few years, treatment activists would pursue a three-pronged agenda, one that Delaney's solution in many ways suggested. First, they would fight with the FDA over what counted as sufficient proof of safety and efficacy in a medical emergency, speeding up the approval of a number of drugs, particularly ones that treated opportunistic infections associated with AIDS. Second, in the case of experimental drugs still being tested, they would press for institutionalized mechanisms of "expanded access" outside of the framework of clinical trials. And third, they would seek to transform the clinical trials themselves, to make the trials more relevant, more humane, and more capable of generating trustworthy conclusions. This complex agenda would require a thoroughgoing engagement with the biomedical establishment—an encounter that would have important implications for the practice of medical research, the dynamics of the movement, and the establishment of certainty or uncertainty about specific experimental treatments.
Learning New Languages
The shift in attention from the FDA to NIAID raised important questions about the capacity of laypeople to intervene in science. Put bluntly, how did these activists know what they were talking about? What was the source of their expertise? It was one thing to educate oneself about one's own illness and thereby shift the dynamics of power in the relationship between doctor and patient. It was quite another to suggest that one had a role in the actual conduct of scientific research.
Part of the explanation lies in issues of organization, resources, and community. Patients with heart disease who want to share information or organize a critique of medicine have to seek out like-minded individuals and find points of commonality with them. People with AIDS—particularly in gay communities—already knew how to find one another, and they benefited from a history of political and social organization. By 1988 there was an entire infrastructure encompassing treatment publications and buyers clubs, advocacy groups and grassroots activists—a firm foundation that could then support the widespread dissemination of medical knowledge. And by this point, these organizations' knowledge about AIDS often exceeded that of the average practicing physician. "When we first started out, there were maybe three physicians in the metropolitan New York area who would even give us a simple nod of the head," said the director of a New York City buyers club in 1988: "Now, every day, the phone rings ten times, and there's a physician on the other end wanting advice. [From] me! I'm trained as an opera singer!"
This was the base on which the treatment activists could build as they turned their attention to clinical trial design. To be sure, not every AIDS treatment activist started without scientific training. Iris Long, for instance, had worked for twenty years as a pharmaceutical chemist before she decided to join ACT UP/New York; she quickly made herself indispensable as a teacher of raw recruits. Andy Zysman, who would become a key activist addressing issues of cancers associated with AIDS, was an emergency physician at Kaiser Hospital; he joked that his professional background caused him to be "viewed as a reactionary Republican" when he joined ACT UP/San Francisco. More typically, however, the stars of the treatment activist movement were science novices, but ones who were unusually articulate, self-confident, and well educated—"displaced intellectuals from other fields," according to Jim Eigo, a New York City treatment activist
with a background in the arts. Often these activists were able to parlay other social and personal advantages into a new type of credibility—to convert their "capital" from one form to another, as Bourdieu would put it.
The trajectory of Mark Harrington, a de facto leader of ACT UP/ New York's Treatment & Data Committee, exemplified one pathway to expertise among the key treatment activists. Harrington studied German critical theory in college at Harvard and had worked as a coffeehouse waiter and a freelance writer. When he discovered ACT UP, Harrington was writing scripts for a film company. "The only science background that might have proved relevant was [what I had] when I was growing up: my dad had always subscribed to Scientific American , and I had read it, so I didn't feel that sense of intimidation from science that I think a lot of people feel," Harrington recalled. Taking quick stock of his ignorance about science and the federal bureaucracy, Harrington stayed up one night and made a list of all the words he needed to understand. That list evolved into a fifty-page glossary that was distributed to ACT UP members. Harrington's frequent collaborator on the Treatment & Data Committee, Jim Eigo, authored poetic critiques of scientific practice that were peppered with references to Shakespeare. These were intellectuals, to be sure, but they represented the "humanistic" wing of the intelligentsia, a fact that shaped the contours of their engagement with the other, "technical" wing. They learned their science, but their engagement with it rested on moral principles and an ethic of commitment, which they juxtaposed with images of the clinical detachment of the scientists and the bureaucrats. "I have a face in my mind for every AIDS-related condition I can describe to you," said Eigo, "… every one the face of a friend." Science and bureaucracy, by contrast, were cold and passionless—epitomized, in activists' eyes, by the FDA's Ellen Cooper, whom some labeled the "Ice Queen."
Steven Shapin has noted, in an analysis of the historical constitution of the expert/lay divide, that the question of who possesses "cultural competence" in science is "one of the most obvious means by which we, and people in the past, discriminate between `science' and `the public….'" The most crucial avenue pursued by treatment activists in the construction of their scientific credibility has been precisely the acquisition of such competence—that is, learning the languages and cultures of medical science. Through a wide variety of methods—including attending scientific conferences, scrutinizing research protocols,
and learning from sympathetic professionals both inside and outside the movement—the key treatment activists have gained a working knowledge of the medical vocabulary. While activists have also insisted on the need to bring "nonscientific" language and judgments into their encounters with researchers, they have nonetheless assumed that the capacity to speak the language of the journal article and the conference hall is a sine qua non of their effective participation. In a learning approach that one activist, G'dali Braverman, has frankly characterized as "ass-backwards," activists often began with the examination of a specific research protocol in which patients had been asked to enroll and, from there, went on to educate themselves about the mechanism of drug action, the relevant "basic science" knowledge base (such as considerations of the viral replication cycle of HIV or the immunopathogenesis of AIDS), and the inner workings of "the system" of drug testing and regulation, including the roles of the pharmaceutical companies and the relevant government advisory committees.
Other activists have explicitly used the metaphors "foreign language" and "foreign culture" to describe their initiation into treatment activism. Brenda Lein, a San Francisco activist, described the first time she went to a local meeting of the Treatment Issues Committee of ACT UP: "And so I walked in the door and it was completely overwhelming, I mean acronyms flying, I didn't know what they were talking about. I thought, `Oh, they're speaking Greek and I'm never going to understand this language.' … Hank [Wilson] came in and he handed me a stack about a foot high [about granulocyte macrophage colony-stimulating factor] and said, `Here, read this.' And I looked at it and I brought it home and I kept going through it in my room and …, I have to say, I didn't understand a word." But after reading it "about ten times," Lein concluded: "Oh, this is like a subculture thing; you know, it's either surfing or it's medicine and you just have to understand the lingo, but it's not that complicated if you sit through it. So once I started understanding the language, it all became far less intimidating."
And indeed, the remarkable fact is that once they acquired a certain basic familiarity with the language of biomedicine, activists found they could also get in the doors of the institutions of biomedicine. Once they could converse comfortably about Kaplan-Meier curves and cytokine regulation and resistance-conferring mutations, activists increasingly discovered that researchers felt compelled, by their own
norms of discourse and behavior, to consider activist arguments on their merits. Not that activists were always welcome at the table—to quote Lein again: "I mean, I walk in with … seven earrings in one ear and a Mohawk and my ratty old jacket on, and people are like, `Oh great, one of these street activists who don't know anything…'" But once she opened her mouth and demonstrated that she could contribute to the conversation intelligently, Lein found that researchers were often inclined, however reluctantly, to address her concerns with some seriousness.
The "Impurities" of Activism
Few social movements are inclined to mix "moral crusades" with "practical crusades." Treatment activism in the late 1980s was distinctive for the powerful fusion of these two forms. A case in point was the presentation made by activists in early 1989 before a special governmental committee charged with reviewing procedures that concerned cancer and AIDS drugs—generally called the "Lasagna committee" after its chair, Dr. Louis Lasagna of Tufts University, in Massachusetts, an authority on clinical trials and FDA approval policies. What particularly caught Lasagna's attention was the extraordinary contrast between the AIDS activists and the spokespersons for other illnesses. On one hand, there was the "very well behaved," "well-dressed" woman dying of breast cancer, who testified before the committee in moderate tones about the need for new cancer therapies. On the other hand, there were the noisy AIDS activists who "came dressed in any old way almost proud of looking bizarre." The activists' "penchant for the dramatic" was well evidenced at the hearings, Lasagna later recalled: "About fifty of them showed up, and took out their watches and dangled them to show that time was ticking away for them." But the activists' message did not rest on theatrics alone. "I'd swear that the ACT UP group from New York must have read everything I ever wrote," said Lasagna. "And quoted whatever served their purpose. It was quite an experience."
Even as activists creatively blended moral and scientific claims-making, they were burrowing progressively deeper into the institutional structures of the federal health bureaucracies. In consequence, activist identities were being reshaped—that was part of what the construction of credibility entailed. As Mark Harrington recalled after contributing to the activists' testimony before the Lasagna committee:
"There was a lot of euphoria, but there was also a wistfulness about crossing over. From then on we were sort of inside/outside, and not just outside; and [we] sort of lost innocence. I knew that we would never be so pure and fervent in our belief that we were right, because we were actually going to be engaged and, therefore, be more responsible for some of the things that actually happened." As treatment activists sought to mobilize supporters and construct their own frames for the problems with AIDS research, they experienced the tensions—endemic to many social movements—between "prefigurative" and "accommodationist" politics. On one hand, they sought to "live their values" and see them inscribed on the inner workings of the institutions of medicine and science. On the other hand, they strove for effectiveness within the system as constituted. The tension between these goals would lead to cleavages and fractures in AIDS activist organizations over the succeeding years.
A broadly similar contradictory impulse could be observed in the educative strategies of the grassroots treatment organizations and in the conceptions of science that they put forward. Project Inform, for example, didn't simply advise people with AIDS or HIV infection what to do or what to think, it also sought to educate them about how to weigh scientific claims, read between the lines of the journal articles and the news reports, and make informed treatment decisions—how, in other words, to assess credibility in science. In the October 1987 issue of its publication, PI Perspectives , Project Inform set out the dilemma: "What is a reasonable strategy in the absence of hard scientific conclusions? How do I choose something that is likely to help without throwing money away?" It's not "reasonable," the article maintained, to put much faith in unscientific "personal testimonials"; "to avoid being misled by personal enthusiasm or stifled by the turgid pace of science, one must focus as much as possible on objective, measurable indicators." When considering a new treatment, one should first ask what formal research data are available on this treatment. Next, who conducted the research? ("We must look to the reputations of the authors and institutions they are working for.") Where was the research published? ("The best shows up in major journals, such as New England Journal of Medicine, Lancet, JAMA , and Science .") Do the research data lack "apparent validity"? ("Are there obvious internal inconsistencies or misleading statements"?) What controls were employed in the study? How many people were studied? Is there a plausible theory for the mechanism of antiviral action? How is antiviral
activity measured? ("Viral culture methods are notoriously inconsistent.")
In essence, Project Inform was proposing that people with AIDS or HIV infection pursue the same interpretive strategies as do doctors and scientists themselves when they read a scientific journal article: they should weigh the markers of credibility that attest to the validity of scientific claims. Indeed, if anything is surprising about Project Inform's advice, it is the utter conventionality of their assumptions about the telltale indicators of good science. There were no suggestions here, for instance, that forces may sometimes conspire to keep articles out of the prominent journals or that new ideas may spring from unlikely sources. Nor, in the reliance on "objective, measurable indicators," was there any truck with relativist notions about truth being in the eye of the beholder.
This strategy for the knowledge-empowerment of the movement represented one face of AIDS treatment activism and, indeed, one face of Project Inform. At times, the movement asserted its faith in science (or a particular, positivist conception of it): it believed that "only by following the rules of investigation will we ever be certain of a treatments' [sic ] usefulness. We differ with the scientific establishment mostly in regards to the pace of research and the degree of certainty required before a treatment should be made available." At other times, the movement posed fundamental challenges to the conventional scientific wisdom about who produces knowledge and what social practices ensure its validity. This unresolved tension—between reformist and revolutionary critiques of scientific practice—would surface with regularity in the debates over treatment in the years to come.
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.
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.
Clinical Trials and Tribulations
The Search for New Directions (1992–1993)
The ever fragile optimism of treatment activists strained to the breaking point in late 1991. The second generation of antiviral AIDS drugs—the non-nucleoside reverse-transcriptase inhibitors that had been engineered specifically to fight HIV and that had looked so promising in vitro—performed poorly in clinical trials. Merck's "L" drugs, nevirapine, and another drug called TIBO were all shown to have little individual efficacy against the virus because the viral gene that produced reverse transcriptase proved capable of mutating in a matter of days or weeks to resist these compounds. For some time now, the avowed goal had been to use the little-loved nucleoside analogues, AZT, ddC, and ddI, to keep people alive just long enough to get better drugs into circulation. Now people would have to depend on the first-generation drugs for much longer—while those who ceased benefiting from them would have no obvious therapeutic recourse standing between them and complete immune collapse.
The news about the non-nucleoside reverse-transcriptase inhibitors "was nothing short of shattering," said Theo Smart of ACT UP/New York. "So many hopes had been pinned to [these drugs'] effectiveness." "Researchers openly wondered, 'What are we going to do next?'" reported Jesse Dobson of ACT UP/Golden Gate and the Community Constituency Group, describing an ACTG meeting in late
1991. "Activists Despondent and the Movement Is Splintering" was the headline of one of a series of articles in the San Francisco Examiner by reporter Jayne Garrison, describing the state of affairs. Garrison quoted Peter Staley, a prominent New York activist: "As far as I'm concerned I'm going to die, Magic Johnson is going to die and the million Americans who are presently infected will die." Concluded Garrison: "So far, the virus is outsmarting science."
Martin Delaney, projecting the generally upbeat message of Project Inform, rejected the "gloom and doom" and stressed instead the continued importance of combination therapy with nucleoside analogues, the apparently large numbers of "long-term survivors" who had been living with HIV for a decade or more, and the promised protease inhibitors and tat inhibitors then on the horizon. Unfortunately, the ongoing saga of Hoffman-LaRoche's tat inhibitor—the only such drug in development—was hardly reassuring. For reasons that were inexplicable to the Johns Hopkins researchers who had been contracted to conduct the study, the company summarily postponed its Phase I trial in May 1991. Activists had generally found this company less cooperative than most; now they could only speculate that Hoffman-LaRoche wished to avoid subsidizing another parallel track program, having given out free ddC to more than three thousand AIDS patients.
At first the company announced that it would sell its tat inhibitor to the highest bidder; then, half a year later, Hoffman-LaRoche changed its mind, saying it would develop the drug after all. "Apparently the company decided that this drug was too good to sell—especially in view of the disappointing results with the competing class of non-nucleoside reverse-transcriptase inhibitors," suggested John James in AIDS Treatment News . But throughout 1992, Hoffman-LaRoche sat tight. In early 1993 activists declared open warfare on the company with the mass resignation of the members of the Community Advisory Board that the company had established. "There can be no more polite dialogue with your company," said TAG and ACT UP/New York in a letter sent to Hoffman-LaRoche in late January threatening a boycott of its products, laboratories, and home care services. In his column in the Advocate , Delaney proposed that the government seize the drug "in the national interest": "Eminent domain is frequently used to seize private property for such national emergencies as highway construction. Is AIDS less important?"
As John James observed, the lesson of the tat inhibitor extended
well beyond the cupidity or irresponsibility of a single company. Here was a type of drug that "leading AIDS scientists" considered to be "perhaps the single most promising approach to developing better AIDS treatments"; furthermore, potential tat inhibitors could easily be discovered through known screening methods. There was no reason, in theory, why there couldn't be fifty tat inhibitors in development; "instead, the whole pharmaceutical industry (or rather, that small part of it which has any interest in AIDS) seems to be waiting to see what happens with the only tat inhibitor drug now in human testing. …" It was a maddening picture: "In the middle of a major worldwide epidemic, the most promising approach to treatment development has been abandoned to a single project with a single drug in a single company." The problem was not just Hoffman-LaRoche; the problem was the whole notion that the "invisible hand" of the free market would somehow function in the service of the public good and not just private gain—a notion that the NIH was unwilling or unable to challenge. And, separate from the issue of political economy, there remained the additional, nagging question: Why did Hoffman-LaRoche seem to have "so little interest in its own drug"? "What might it know that we don't?" asked James.
A "New Paradigm" for Treatment Activism
In keeping with the grim news from the treatment front, the Eighth International Conference on AIDS, held in Amsterdam in June 1992, was "somber" in atmosphere. One striking expression of official pessimism came from the editor of JAMA , Dr. George Lundberg, who predicted that AIDS would remain a common disease a century from now. Lawrence Altman, covering the conference for the New York Times , noted some of the effects of discouragement: "Even demonstrators who have disrupted previous conferences and attacked health officials and scientists for their slow, step-by-step approach conceded that there was an urgent need to return to basic science," he wrote.
These were the sentiments that motivated the lengthy report "AIDS Research at the NIH: A Critical Review," prepared by Gregg Gonsalves and Mark Harrington and presented by the Treatment Action Group at the 1992 conference. The two authors had sat down and read every NIH grant that had funded AIDS research through each of
the NIH institutes, and they had tried to envision a logical, cohesive approach to organizing that research effort. "Since 1987," wrote Gonsalves and Harrington, "the activist critique of AIDS research has worked its way back: from drug approval at the regulatory level of the US Food + Drug Administration …, to expanded access for drugs still under study (Parallel Track), to the design and conduct of the controlled clinical trials themselves by the National Institutes of Health …, pharmaceutical companies, and community-based clinical trial centers." Now activists had come to realize that in order for their efforts to succeed, they would have to focus their attention on an even earlier phase of the research process: "If the reforms won by activists are not to become mere stratagems for craven pharmaceutical companies swiftly to develop and market a whole series of additional nucleoside analogues (d4T, FLT, 3TC, etc.), activists must become more involved in the basic research process itself, forcing academic and industrial researchers to turn their attention to novel treatment approaches to HIV-induced immune suppression.…" This was a tall order, one that "[required] that activists become as familiar with the $800 million AIDS program of the NIH as they have with its major clinical component," the ACTG. The ACTG "is but one eighth of the NIH AIDS program. A cure will never be tested by the ACTG unless it's discovered somewhere else first." Clinical trials were the late stage in the game—to get drugs into development, activists had to influence the course of basic AIDS research at the NIH, within NIAID as well as the various other agencies, like the National Cancer Institute, the National Institute of Child Health and Human Development, and the National Institute of Neurological Disorders and Stroke. "This is a new paradigm for AIDS activists," the TAG authors made clear: "We have to familiarize ourselves with a wide range of disciplines."
It was a significant shift, but a risky one, for the course of action that now seemed most crucial also appeared to be one in which activists were by no means guaranteed to succeed. Gonsalves and Harrington grasped the point clearly: "Activists' claim to expertise in clinical trials came out of lived experience. Most of us cannot claim the same for basic biomedical research." At best, activists could "hope to serve as catalysts for better and more coordinated work within the research realm, and as agitators with Congress and the Administration for enhanced resources in the public realm." Indeed, it was in the realm of public policy that the report itself had the most impact. Upon the election of President Bill Clinton, who had promised to prioritize
AIDS research, Senator Ted Kennedy made the TAG report the basis for an amendment tacked onto the NIH authorization bill. Following the blueprint laid out in the report, Kennedy called for a strengthened Office of AIDS Research within the NIH, which would have jurisdiction over all AIDS-related research in each of the NIH institutes.
The Science of "Concordology"
As treatment activists focused on such drugs as the non-nucleosides, the tat and protease inhibitors, and still more experimental approaches, controversy continued to swirl around AZT. This made sense: AZT was still, by far, the most commonly prescribed AIDS antiviral, and it was considered the best drug with which to begin antiretroviral therapy. The drug had a high profile, in part because Burroughs Wellcome's marketing of the drug was sophisticated and relentless: the company's efforts included promotional videos mailed to doctors, a toll-free "AIDS information" hot line designed to peddle the company's product, and mass media and billboard ad campaigns preaching the benefits of knowing one's antibody status and initiating antiretroviral treatment early. Yet questions about the drug's use had never fully been answered to the satisfaction of many.
Longtime opponents of AZT, including HIV dissenters such as John Lauritsen and Chuck Ortleb, attacked those who had climbed aboard the AZT bandwagon. Lauritsen labeled Project Inform and the Gay Men's Health Crisis as "gay quisling groups" for their endorsement of nucleoside analogues, while the Native referred to John James as an "AZT pimp." Such attacks became more vehement after some of the treatment activist groups began accepting donations from Burroughs Wellcome. In 1992 Project Inform received a $150,000 grant from the company to upgrade its computer equipment. TAG and ACT UP/Golden Gate received small donations, but TAG also brokered a $1 million grant from the company to AmFAR in support of community-based research. "If I have to take money from the devil to save my life and the lives of my friends, I'll do it," said Peter Staley of TAG. Yet even if the donations came without strings attached, the acceptance of such funds left treatment groups vulnerable to attack by opponents of AZT. One leaflet that made the rounds in San Francisco in 1992 and purported to come from a group called "ACT UP/Underground" described Burroughs Wellcome's "blood payment" to Project
Inform. In a memorable phrase, the leaflet accused the organization of having "promised to deliver its own community to nucleoside slavery, bound in the chains of corporate greed!"
At a different volume level, mainstream authorities continued to debate the merits of early intervention with AZT in people who were asymptomatic. "After 5 Years of Use, Doubt Still Clouds Leading AIDS Drug" was the New York Times headline of a 1992 article by Gina Kolata that charted the undercurrents of uncertainty. No study had yet demonstrated that AZT actually prolonged life in people who started taking the drug when they had fewer than 500 T cells, although the Veterans Administration study, once completed, indicated that AZT did prolong the length of the disease-free state. (Concerns about racial differences in response to AZT based on a preliminary report from the study were generally allayed by retrospective analyses of earlier studies that showed no treatment differences based on race.) This study was considered too small to provide a definitive answer to questions of survival; instead, researchers now looked to the completion of the Concorde study in Europe.
Meanwhile, doctors and patients grappled with uncertainties: Was it better to start treatment early, before the immune system had deteriorated and while the patient could more easily tolerate a serious drug, in the hope of delaying the onset of symptoms, thus keeping the patient healthy until more effective drugs arrived on the scene? Or was it better to wait, sparing outwardly healthy patients a toxic drug that could cause anemia or liver damage and avoiding the development of resistance, so that the drug would be effective later in the course of illness at the point when there was clearer evidence that it actually provided a benefit? As a 1992 survey of 448 physicians reveals, the vast majority simply followed the NIH guidelines and the FDA labeling, prescribing AZT for anyone with fewer than five hundred T cells per cubic millimeter. But doctors and patients who tracked the science of AIDS more closely were often less certain about the best course of action.
Still, nobody seemed quite ready for the news when the Concorde researchers released their preliminary report on April 1, 1993, in a brief letter to the editor in Lancet . Eight hundred seventy-seven patients, asymptomatic upon entry into the study, had been randomized into the "immediate treatment" arm of the study and had received one thousand milligrams of AZT daily; 872 had been placed in the "deferred treatment" arm, receiving a placebo unless they became symptomatic,
at which point they were put on AZT. In total, the study provided 5,328 person-years of data, making it the largest and longest study of its kind. The researchers reported that the patients in the "immediate treatment" arm experienced more of a CD4-count boost, on average, than those in the "deferred treatment" arm. However, "by contrast with the differences in CD4 count, there was no significant difference in clinical outcome between the two therapeutic strategies." The three-year survival rate was 92 percent for those who had begun taking AZT early and 93 percent for those who were put on the drug later. And similarly, there was no significant difference between the two groups in terms of disease progression and the development of opportunistic infections.
In the eyes of the Concorde investigators, Ian Weller in Britain and Jean-Pierre Aboulker in France, the study did not so much contradict 019 and the other studies of AZT use in asymptomatic patients as subsume them by proceeding for a longer period of time. The investigators had found an initial trend suggesting benefit in the early use of AZT, similar to that found by Paul Volberding in ACTG 019. But since the trend wasn't statistically significant, the trial was kept going, and as time passed the benefit simply disapeared. The bottom line, according to the Lancet report, was this: starting AZT early, as opposed to starting it later, did not extend survival or even the disease-free state. And CD4, the "surrogate marker" that had been employed in the licensing of ddI and ddC in the United States, could not be considered predictive of long-term treatment differences.
It was a painful moment that left many people dazed—or defensive, or angry, or jubilant, depending on their previous commitments in the AZT controversies. "Rarely have a mere eight paragraphs sparked such fury, hysteria and hyperbole," said an article in a San Francisco lesbian and gay newspaper. Not long afterward, one researcher with the World Health Organization would suggest that "a whole tropical rain forest has disappeared as a result of this study," which ushered in a brand new domain of scientific inquiry he dubbed "Concordology." And in the space of a few days following the report in Lancet , the stock value of Wellcome PLC dropped by more than $500 million.
Billed as the "definitive" study of AZT use in asymptomatic HIV infection, Concorde initially appeared to settle nothing; it seemed almost infinitely malleable in the interpretations it could generate. "You can interpret [Concorde] as your bias dictates," said the director of
inpatient services at San Francisco General Hospital. Weller, the British principal investigator, who described himself as having already been "very conservative in the use of zidovudine [AZT] monotherapy in asymptomatic patients," now said: "Those physicians like myself who tended to wait until symptoms appeared are going to be more sure they were doing the right thing." Douglas Richman, one of the principal investigators in the AZT studies in the United States, commented: "This is a chronic active persistent infection. It's incomceivable to me that not treating it is the way to go." One "knowledgeable and compassionate AIDS doctor told [GMHC's publication, Treatment Issues ] privately that he would continue to prescribe AZT for his asymptomatic patients even if it did not work. He said there was nothing else for him to do."
Those who wanted to score political points had plenty of opportunity. Larry Kramer, for instance, used the study to highlight the overall failure of the research effort in an overwrought editorial he penned for the Advocate , entitled "AZT Is Shit." Other responses followed predictable patterns. "Advocates of the AZT-is-poison school have had a field day," wrote Tim Kingston, a reporter for the San Francisco Bay Times . "Not only do they assert that early AZT intervention is ineffective, but also that all AZT treatment and all HIV antiretroviral therapies are ineffective." One example was the comment of HIV dissenter and AIDS activist Michael Callen, quoted in the Los Angeles Times: "Taking AZT is like aiming a thermonuclear warheard at a mosquito." A San Francisco gay newspaper whose AIDS writer had been opposed to AZT ran a cover graphic of a hand tipping a gigantic bottle of Retrovir (the brand name of AZT), with capsules spilling onto tombstones in a graveyard.
A Los Angeles-based group of AZT dissidents, called Project AIDS, International, sought to spread the word to AZT "victims": "You need to know your rights. Ask yourself the following questions: Were you misled by the U.S. studies or information that was given you through theFDA or CDC? Were you pressured into taking AZT … by your doctors or an AIDS organization? … If you have answered yes …, you have a right to compensation.…" In London, newspapers reported that the widow of a person with AIDS was suing Wellcome PLC, claiming that her husband had died from the effects of AZT. And a London group calling itself Gays Against Genocide picketed an AIDS organization and a hospital where a clinical trial of AZT in children was in progress, accusing their targets of "murder"
and "baby-killing," respectively. Meanwhile, opponents of these views argued that if Concorde did anything it disproved , once and for all, the notion that AZT is poison: after all, a large number of people had taken a high dose of AZT for four years and only a small percentage experienced adverse reactions to the drug.
European AIDS authorities, by and large, tended to accept the study conclusions as given. But U.S. authorities rushed to explain that nothing really had changed. Until more data were available, "no physician or patient should change the approach they're using based on this study," Daniel Hoth of NIAID told USA Today . David Kessler, the FDA commissioner, told the New York Times that the results of Concorde were not a surprise, since experts "have known that AZT has real but limited benefit"; this of course sidestepped the issue of the FDA's labeling of AZT for use in any HIV-infected person with fewer than five hundred T cells.
East Coast AIDS groups, less well-disposed overall to the nucleoside analogues, criticized the official "spin control." GMCH's publication, Treatment Issues , commented: "The blizzard of press releases responding to Concorde reveals the extent of the personal and professional investment many U.S. researchers have in AZT's efficacy. While one should expect a profit-driven corporation like Burroughs Wellcome to interpret the data favorably, U.S. government agencies should be held to a different standard." But West Coast groups like Project Inform and publications like AIDS Treatment News that were more committed to early intervention reacted quickly to the study, and they rushed out their methodological heavy artilerry. Fighting against the "black-boxing" of Concorde, they strove to highlight as much contingency, messiness, and uncertainty as they possibly could.
First, patients in the study had received an unusually high dose of AZT—twice the dose that had become standard by the time of the study's terminatinn. From the "pragmatic" perspective on clinical trials, this meant that the study had questionable relevance to the real-world treatment decisions of 1993. A larger concern was the modification of the study protocol in midcourse, after the results of ACTG 019 had come out. To satisfy ethical requirements, the Concorde investigators had allowed patients with fewer than five hundred T cells to choose at any point to begin open use of AZT rather than remain in the double-blinded trial. In all, 282 of the 872 patients in the deferred treatment arm had switched from placebo to AZT. The accepted statistical practice, however (called the "intent-to-treat" rule), was to
analyze patients as if they remained in the original groups to which they had been randomly assigned . That is, the 282 patients who began taking AZT prior to progression to illness were analyzed as if they had been on placebo all along.
The purpose of the intent-to-treat rule in biostatistics is to put the burden of proof on the drug whose efficacy is under investigation. For example, if some subjects in the placebo arm of a trial accidentally receive the study drug, researchers continue to count them in the placebo group. Then, if a difference in outcome is still found between the two arms of the study despite the blurring of regimens that occurred, the researcher can be especially confident about the results. The problem, however, is that if no difference is found, the researcher might reasonably wonder: is the drug really useless or did the contamination of the original study design prevent a true difference from manifesting itself? No one representing the Concorde study was suggesting that the change in the study protocol might account for the negative outcome—that if no placebo patients had switched to open-label AZT, the "deferred treatment" arm would have done worse relative to the "immediate treatment" arm. But to many U.S. researchers (and certainly to Burroughs Wellcome) this seemed eminently plausible. In effect, they argued, two roughly similar groups were being compared, so it was no surprise when the outcomes were similar.
John James also raised questions about the surrogate markers issue, which, as he noted, was so vital to the program of accelerated approval of new drugs. The Lancet letter had reported only that the median CD4 counts over time failed to predict the outcomes of the two arms of the study. Most U.S. researchers, wrote James, thought it was insufficient to look just at the median counts: "This question must be addressed by case-by-case analysis of whether individual patients whose T-helper counts rose after starting the drug seemed to show improved prognosis as a result." Meanwhile, treatment activists around the country worried that the initial reports from Concorde would fuel a backlash against the changes that had been instituted at the FDA to approved drugs more rapidly. "The spin, I predict, will be 'This is all the activists' fault," wrote Larry Kramer. "New York Times chameleon Dr. Lawrence Altman said as much in his ineptly reported article.…"
Altman had written a follow-up to his initial news article on Concorde, a commentary entitled "AIDS Study Casts Doubt on Value of Hastened Drug Approval in U.S." The article explained how Concorde
researchers had "persisted" against the prevailing construction of belief about AZT, continuing their study even after ACTG 019 had ended. That persistence had paid off in a finding that overturned the conventional wisdom. Furthermore, "in challenging the reliability of the CD-4 count in evaluating AZT, the Concorde study rekindled a long simmering dispute between many European and American researchers over the validity of surrogate markers in H.I.V. and AIDS," wrote Altman, noting that the British government had refused to license ddI on the basis of surrogate markers. Altman quoted Ian Weller, the British principal investigator, about the "lesson" in the Concorde study: "Don't stop trials too early…. Whatever the pressures are, keep going as long as possible."
Some reacted defensively to such charges, while others were despondent. Yet all the responses seemed to reflect the same underlying disquiet. It wasn't just the study; it was the whole state of the science, and Concorde was merely the last straw. An editorial in GMHC's Treatment Issues did a good job of capturing the sentiments that seemed to feed many of the reactions to the study: "Concorde underscores the uncertainty many AIDS researchers and clinicians feel. A few years ago, many physicians believed that the nucleoside analogs … would transform AIDS into a so-called 'chronic manageable' condition. There is now a deep and growing sense among many that some of the basic assumptions underlying AIDS drug development need to be reexamined."
These were the clouds hanging overhead as thirteen thousand people from 166 countries assembled in Berlin's vast and labyrinthine conference center in June for the Ninth International Conference on AIDS. A cover story by Science reporter Jon Cohen had set the stage for the scientific proceedings. "The more we learn, the less certain we are" was the message Cohen had gleaned from a survey he conducted of 150 leading AIDS researchers: "After more than a decade of struggling in frustration as the epidemic gallops on, researchers are being forced to reexamine assumptions they once held without question." Even as "politicians and AIDS activists [were] demanding results immediately," researchers confronted a series of "collapsing certainties," including the virtues of antiretroviral therapy in asymptomatics, the trustworthiness of surrogate markers in evaluating
treatments, and the reliability of certain key vaccine experiments. In addition, "many researchers who once believed almost all the damage caused by HIV could be explained by the virus's direct killing of cells now think indirect mechanisms must also be at work."
Progress certainly was being made in the understanding of pathogenesis, as conference presentations by top scientists such as Fauci and Jay Levy made clear. On one hand, better laboratory techniques such as PCR had revealed higher concentrations of infected cells throughout the body (and not just in the bloodstream); this lent credence to claims that direct cell-killing could play an important role in AIDS, while arguing against those, such as Duesberg, who had been maintaining that HIV could not be the true cause of AIDS if so few cells were infected (see chapters 3 and 4). On the other hand, few now thought that direct cell-killing was the only factor at work. Levy's recent, one hundred-page journal article on pathogenesis had listed more than a dozen factors he believed were involved in HIV-induced immune deficiency. HIV and its constituent proteins appeared to have a range of effects on both infected and uninfected cells, as well as on their associated cytokines; aberrant signaling by the cytokines then caused cascading effects throughout the immune system.
Better understanding could be gleaned, perhaps, from the study of so-called "long-term survivors" or "long-term nonprogressors"—this was a direction that activists had been promoting and that was increasingly emphasized in Berlin. "There's a growing sense that there is no magic bullet for AIDS, so we should shift research to see why some people do well …," said ACT UP/New York's Aldyn McKean. But as Robin Weiss had pointed out in an article on pathogenesis in Science , there might be nothing "special" about long-term survivors: since "the rates of progression … are also consistent with a stochastic, random occurrence of AIDS after HIV infection …, 'long-term' survival could be pure luck."
Gallo, in his address, offered a dazzling array of future, high-tech treatment possibilities. Gene therapy and "antisense" therapy might be used to prevent infection of cells. Drugs could be developed that targeted cellular products used by the virus, rather than directly targeting the virus. HIV-infected people could be given a genetically engineered protein of HHV-7 (human herpes virus, number seven), a virus that "competes" with HIV for CD4 receptor sites; the protein would then beat the virus to the CD4 molecules on the T cells and prevent infection.
This was all very nice, but what treatments were available in the short run? What could the assembled physicians (or at least, those from rich countries) go back and tell their patients, symptomatic or asymptomatic, about the options that were open to them? What was the "state of the art"? One crucial set of facts was offered by the Concorde researchers, who presented a range of data that went beyond the limited report in Lancet . Overall, the Concorde trial gained in credibility at the conference, though some found ways to bracket or qualify its findings. Martin Delaney claimed there were still data he would like to see, but that it "wasn't worth fighting about." Concorde was "just one of many studies out there" and not a particularly relevant one, at that. Concorde had asked "one question": Does a daily gram of AZT initiated early in the course of disease prevent progression? But since no one routinely took a gram a day of the drug, it wasn;t clear "what that means for early intervention in general or even for AZT."
The big story, however, was the result from ACTG 155. This was Margaret Fischl's Phase II study that many had been awaiting in order to see whether the AZT/ddC combination, licensed the previous year, would perform as well in a long-term study as surrogate marker evidence had predicted. At a satellite symposium held in Berlin on the eve of the international conference, Fischl tried to put the best face on the study's outcome. The sad facts were that 42 percent of the subjects receiving AZT, 43 percent of the subjects receiving ddC, and 39 percent of the subjects receiving the combination had progressed to serious illness or death; there was no statistically significant difference between the three treatment arms of ACTG 155. The subjects receiving the combination therapy did get a larger CD4 count boost, just as they had in the promising early study, ACTG 106. But they didn't live any longer in the end.
Nevertheless, Fischl framed the outcome as positive by stressing that the combination therapy did show an advantage in the subset of patients whose CD4 counts at the outset were between 150 and 300 per cubic millimeter. Since these were the subject with the highest initial CD4 counts in the study, the "spin" that Fischl was pushing was that patients benefited from the combination unless they were already too far along in their illness. NIAID supported this interpretation, issuing a press release with the headline: "Effectiveness of AZT/ddC Combination Depends on Pretreatment Immune Cell Count."
Yet as the distressing word of the study's overall findings spread
through the halls of the conference center, reporters witnessed the unusual spectacle of a NIAID representative yanking the press release from the media center and hastily replacing it with a new, more sober one: "The Effectiveness of AZT Alone, ddC Alone or AZT/ddC Combination Is Similar Overall for Patients with Advanced HIV Disease." Fischl, undeterred, repeated her original conclusions at the formal conference session. No sooner had she finished than activists from TAG sprang to the microphone. "The answer to the study you designed is that the study shows no difference between combo and monotherapy," insisted a furious David Barr. "You have staked your career on these drugs," yelled Barr. "I have staked my life."
Barr and other activists characterized Fischl's stratification of the subjects by CD4 count as a methodologically unjustifiable violation of the fundamental principles of randomization, indeed, as a post hoc fishing expedition for results that would make the study appear a success. As much as activists had wanted to believe in the combination therapy, they now had no patience for any sugarcoating of the bad news. (Or perhaps, to the extent that they felt disillusioned, Fischl provided a convenient focal point for their anger: it's more satisfying, after all, to direct one's wrath at a researcher who appears to be cheating than at a virus that appears to be winning.) "How much is Roche paying you?" yelled out activists in the audience, referring to Hoffman-LaRoche, the manufacturer of ddC, which had already been the target of an activist protest during the conference's opening ceremonies because of the company's slowness in conducting its own, postmarketing studies of ddC as required by the FDA.
Whether Fischl was casting about to salvage her study or describing a genuinely important auxiliary finding was, in some sense, beside the point. Activist rage had more to do with the predicament the patient community now found itself in. As Mark Harrington noted in a heated challenge to Fischl voiced from the conference floor, the response to Concorde by U.S. experts had been to play it down, to claim that, after all, combination therapy was the real standard of care for asymptomatics. "The truth is," said Harrington bitterly, "we have no standard of care for asymptomatics." There was no disputing Harrington's point, nor did the conference presentations on non-nucleosides, tat inhibitors, and protease inhibitors suggest that answers lay just around the corner. Insiders already knew the gossip about Hoffman-LaRoche's tat drug: after years of stalling, the company had finally
determined that the drug had no efficacy, at least at the dosage tried so far. And the results from the protease inhibitors were preliminary and carried little weight.
Doctors, Researchers, and "Cookbook Medicine"
The deep uncertainties about antiviral therapy were aired in Berlin at a "Meet the Experts" session entitled "When to Start Antiretroviral Treatment"—though as Martin Delaney aptly noted, it could just as well have been called "Whether to Start Antiretroviral Treatment." The session was an elaborate dance between practicing physicians requesting advice and experts reluctant to commit. Robert Yarchoan of the NCI listed the options as he saw them: You could begin monotherapy early. You could begin combination therapy early. Or you could wait for the development of symptoms or until the CD4 count dipped below 200 and then initiate either monotherapy or combination therapy. In short, no logical option could be ruled out! As Delaney noted, the more we knew about pathogenesis and the extent of covert infection, the more sense it made to intervene early; but the more we learned about the therapies that were available, the less confident we became about the current efficacy of doing so. The challenge of AIDS, said Delaney, was precisely "to make decisions in the face of uncertainty": "I think maybe 019 gave people the illusion we weren't dealing with uncertainty."
Some doctors in the audience stressed the virtues of case-by-case decision making on the basis of the "art" of clinical judgment—the strategy of "try it and see what happens." "I feel, personally, I learn more about how to treat a patient by treating the patient than by looking at the results of clinical trials," said one physician. Others were anxious for formal guidelines. A member of the audience pressed one of the panelists, the British researcher Anthony Pinching, to say what he would tell a patient who was asymptomatic and had a T-cell count of 300. Pinching explained that he would describe the various studies, analyze the patient's T-cell trend over time, and then present the patient with a choice. "Why do we need all this cookbook medicine?" asked Pinching: "I have yet to meet a patient who is unwilling to make a choice." And if the patient wanted to know your opinion? the questioner persisted. Pinching replied that, in his experience, there
were "two types of patients": "interveners" and "don't rock the boaters." "If they insist on advice, I try to identify their nature as one or the other."
It was a revealing comment and, by one reading, an enlightened response. Resisting doctors' cries for prescriptive advice, Pinching was emphasizing the patient's autonomy in deciding on a course of treatment. Against reliance on inflexible rules ("Do this if your T cells drop below 500, do that if they fall below 200"), Pinching was insisting on the uniqueness of the individual patient. And rather than speaking beyond the limits of his knowledge, Pinching was candidly exposing the extent of medical uncertainty. Yet the response was also more than a little disconcerting. Thirteen years into the epidemic, at the key international conference at which leading scientists reviewed the state of the art of antiretroviral treatment, the best advice about early intervention that an eminent AIDS authority could offer to the doctors of the world was a handy bit of folk wisdom about the psychological propensities of patients.
Living with Uncertainty (1993–1995)
AZT: More "Pieces of the Elephant"
Later that month, the NIH would ratify uncertainty as the new wisdom, dressing it in the language of bureaucratese. After a three-day meeting, an expert advisory panel offered up recommendations: Asymptomatic HIV-infected patients with three hundred to five hundred T cells should begin taking AZT. But not taking AZT, and continuing to monitor the immune system, was "an equally valid option." Patients in stable condition with more than three hundred T cells who were already taking AZT should stay on it, the panel recommended. However, the chair, Dr. Merle Sande of the University of California at San Francisco, told the New York Times that "stopping AZT for such people would be a medically sound and logical conclusion from the recommendations." In short, the NIH recommended that patients do X , but if they wanted to do not-X , that was "equally valid."
Sande blamed the current predicament on the competing conceptions of the purpose of clinical trials. He complained to Lawrence Altman that the various trials of the nucleoside analogues had been designed with FDA regulatory questions in mind, rather than the clinical
questions that doctors wanted answered: "We were in a hurry four to six years ago to get drugs approved, so the studies were designed in that way and not necessarily to answer the clinical medical questions that we face in making decisions today. … We are a prisoner of those studies." Altman's article suggested that much of the blame also lay with the activists for having pressed so hard to get drugs approved quickly. In fact, though, it had been activists who had insisted all along that clinical trials were asking the wrong questions—that they should be oriented to the real-life issues confronting patients and doctors rather than the thumbs-up/thumbs-down logic of FDA approval.
To complicate the picture further, barely a month after the new guidelines were issued the New England Journal published the results of the European-Australian Collaborative Group study, a three-year, double-blind, placebo-controlled study of AZT use in 993 asymptomatic patients with CD4 counts above four hundred per cubic millimeter upon entry. The study found that early administration of AZT did delay the onset of symptoms, supporting the view "that most patients with HIV infection should be treated," in the words of an accompanying editorial. The study did not address the issue of survival benefit. Merle Sande commented to the New York Times: "I think all the studies are showing the same thing: that there is a little benefit from AZT for a short period of time." Douglas Richman stressed the differences in endpoints and follow-up periods compared to those used in Concorde and said: "This study looks at another piece of the elephant. … But we can't say if five years from now the two curves of the two different patient groups won't come together. It's part of the complexity of a clinical investigation—but that's life in the big city."
"It's really resulted in incredible frustration," acknowledged Paul Volberding, the UCSF researcher, in 1994: "No one feels they know what to do. No one trusts the guidelines, even though the guidelines have been put together as best as people could do. People want an answer and there isn't one." Volberding's own long-term follow-up study of the participants in ACTG 019 (the study that first had suggested benefit from early use of AZT in asymptomatics) was, in fact, consistent with the results of Concorde. First presented in Berlin and published in JAMA in 1994, the follow-up concluded that the benefits of AZT were time-limited and that early administration conferred no additional survival benefit over late administration.
The overall credibility of AZT received a boost in early 1994, when NIAID announced the results of a trial called ACTG 076, which had
studied whether administration of the drug to pregnant women could prevent transmission of the virus to their fetuses. The results were striking: more than a quarter of the babies born to women who received a placebo became HIV positive, but only eight percent of the babies whose mothers received AZT became infected with the virus. The study left many questions unanswered: What, for example, were the long-term health risks to the baby when AZT was administered to a woman during pregnancy? Did the benefit outweigh the risks, given that, even without AZT, three-quarters of the babies would emerge seronegative? And the study ignited new controversy about the policy implications: Should all pregnant women now be required to take an HIV antibody test? Such questions notwithstanding, there was room for exultation. For the first time, in one particular context, AZT appeared to mean the difference between life and death.
Unfortunately for Burroughs Wellcome, news about ACTG 076 coincided with formal publication of the Concorde study. Burroughs Wellcome took the occasion to issue a spirited defense of its product: "Several independently sponsored studies have clearly demonstrated the benefits and advantages of early therapy," commented David Barry, the vice president of research, in a press release. There were indications, however, that doctors and patients were drawing different conclusions about the drug. JAMA reported that a study in the Canadian province of Ontario showed a 45 percent decline in the number of patients beginning therapy with AZT in the months following the preliminary report on Concorde. Even many patients who were symptomatic were apparently forgoing use of the drug. Burroughs Wellcome acknowledged that sales of the drug were down, particularly in the United States.
The Holy Grail of Statistics
As dissatisfied as activists were with AZT and its chemical cousins, in practice it was impossible for activists not to invest their energies in staking out positions on the use of antiviral drugs that were most readily available. The problem was that the data concerning combinations of nucleoside analogues such as AZT and ddC did not lend themselves to unambiguous interpretation. ACTG 155, Fischl's study of the AZT/ddC combination, was an important and telling illustration: debates about the significance of ACTG 155 demonstrated the interpretative flexibility that could make AIDS clinical trials a source of uncertainty rather than the mechanism by which uncertainty
was resolved. "People believe passionately on both sides of the question as to whether [the combination therapy] worked," Deborah Cotton, the dissenter on the Antiviral Advisory Committee, commented more than a year after the Berlin conference. "There are schools of thought. There are the believers and the nonbelievers, and … I don't think anything is going to change. I really don't."
The ACTG 155 researchers were quick to insist, and the published study was careful to point out, that the controversial subgroup analysis presented by Fischl in Berlin was not "post-hoc": "The three CD4 cell count subgroups were specified by the study chairpersons in June 1992, which was before any interim review of the primary end-point data," Fischl and her coauthors argued. But this did not settle the issue, because the subjects were not randomized into treatment arms from the outset according to this particular breakdown in CD4 counts. Biostatisticians are typically cautious about pulling subsets out of clinical trial populations after randomization—or at least, cautious about overinterpreting what they find. Susan Ellenberg, formerly the chief biostatistician for the ACTG trials at NIAID, praised the TAG activists' suspicion of subgroup analyses: "I think that that is the kind of thing that they have learned. They have become very methodologically astute," reflected Ellenberg.
Declaring that "several potential explanations exist for the overall findings in our study," the authors in fact presented a series of arguments for why combination therapy might be advantageous even though the trial seemed to suggest otherwise. Because patients had taken AZT before enrolling in the study, it was possible that they were already resistant to that drug. In that sense, what was really being studied was not combination therapy but ddC alone. Or perhaps the best time for combination therapy was simply earlier in the progression of HIV disease, before certain phenotypic changes in the virus associated with late-stage AIDS occurred. Finally, the report pointed to the consequences of "intent-to-treat" analysis. Because of the way the protocol was worded, many patients who experienced strong side effects from either AZT or ddC were taken off all their drugs. But in accordance with the logic of intent-to-treat, these patients were still counted as part of the treatment arm to which they were originally randomized. The effect was potentially to blur the difference between the different arms, creating a higher standard for establishing efficacy. But biostatisticians argued that to remove from analysis the patients who go off a drug can bias trial results, because there is no reason to assume that people who go off medications are typical of those who
remain. Some clinical researchers found the logic maddening all the same: How could they study the effects of a drug in patients who weren't even using it? "As a clinician, what I really want to know is, is a drug working while a patient is taking it—not six months after he stopped taking it," commented Martin Hirsch, a virologist and one of the principal investigators on ACTG 155.
The debate over intent-to-treat analysis was a perfect example of the clash in perspective between infectious-disease researchers and biostatisticians. "I don't think that statistics is the holy grail," complained Hirsch, at the same time affirming his strong general support for the methods of the randomized clinical trial. "Many of us clinicians think that an 'as-treated' analysis … gives us at least as much information that is useful clinically as does 'intent-to-treat.'" And indeed, the authors of the published report on ACTG 155 undertook "an exploratory analysis to gain insight into the possible association between early treatment cessation and treatment outcome." That is, they performed an "as-treated" analysis, ceasing to count people in the study two months after they stopped their treatment. The results: "combination therapy was associated with a significantly lower rate of disease progression or death than were either [AZT] or [ddC] monotherapy." In other words, from this standpoint, the study was quite simply a success, and combination therapy worked . Yet "caution should be used when interpreting this exploratory analysis," the authors quickly added, because "this type of analysis is known to be biased."
For all the careful disclaimers, what was noteworthy about the published report on ACTG 155 was how intent it seemed to be on reaffirming the conclusion from which everyone began—that combination therapy really was better. Douglas Richman insisted that the results from ACTG 155 were "compatible" with those from ACTG 106; he added that ACTG 106 had now been corroborated by the final results from the Burroughs Wellcome study of the AZT/ddC combination. By contrast, Mark Harrington of TAG argued that "the high baseline CD4 group (150–300)—the one with the claimed 'benefit' of combination therapy—was exactly the arm with the fewest clinical events, thus the least [statistical] power." Harrington's bottom line: "Combination therapy with AZT/ddC in the 155 population is 50% more toxic and no more effective than monotherapy with AZT alone."
What were the true "results" of ACTG 155? How, and in what way, can we take data produced by such an experiment and apply
them to the real-world dilemmas of patients who demand answers? The point here is that clinical trials do not occur in a vacuum—and when the environment in which trials are conducted and interpreted is so contentious, then these experiments, rather than settling controversies, may instead reflect and propel them. Consider the range of factors and pressures that structured the determination of the "meaning" of ACTG 155 as well as that of its precursor, ACTG 106: the methodological (and jurisdictional) disputes between infectious-disease researchers and biostatisticians; activist demands for access to drugs, plus or versus activist conceptions of "good science"; the social construction of hype; the profound need experienced by patients, and the kinds of pragmatic decisions that patients and research subjects make in response to their immediate perceptions of their interests; the marketing strategies of pharmaceutical corporations and the incentive structures to which these companies respond; the complicated role of practicing physicians in interpreting the data produced by clinical trials; the politics of regulation and deregulation; and the distinctive character of regulatory science as practiced by expert advisory bodies. In such an environment—given these stakes—is it any wonder that the interpretation of key trial results is often up for grabs? AIDS trials are not unique in this regard, as studies of cancer trials make clear. But insofar as the participation of knowledge-empowered activists increases the number of claims-makers and alters the distribution of credibility among them, AIDS trials may be particularly inclined toward conflicting readings.
East Coast, West Coast
From the perspective of TAG activists, the evidence from trials like ACTG and Concorde was clear enough: neither AZT monotherapy in asymptomatic patients nor combination therapy in patients at any stage of illness had been proven efficacious. And the predictive power of the CD4 surrogate marker, in their estimation, was in grave doubt. In the summer of 1994, as the FDA granted accelerated approval to yet another nucleoside analogue, d4T, and announced an upcoming meeting to review accelerated approval, TAG activists began making noise. In August, the finance magazine Barron's ran a cover story called "Rushing to Judgment," which quoted TAG members about the risks of accelerated approval. Similarly, Time magazine described the evolution of AIDS activists who in the past "threw
smoke bombs at the National Institutes of Health" but now were "changing their minds" about the fast-track drug approval policies they once had promoted. Alarmed, Project Inform circulated a "consensus statement" on the need for accelerated approval and gained the endorsement of AIDS activist organizations around the country.
At the Antiviral Advisory Committee meeting held in September 1994 more than forty activist groups presented their positions, including activists from the Midwest and the South who insisted that neither the East Coast nor the West Coast activists spoke for them on questions of access to drugs. Kessler assured the audience that accelerated approval would continue to be FDA policy, and he promised to issue clearer guidelines for companies to follow in preparing applications for such approval. TAG activists did not call for an end to accelerated approval, but they issued a hard-hitting evaluation of the program to date. Accelerated approval, these activists suggested, might well be creating structural incentives for drug companies to crank out mediocre drugs that resemble the mediocre AZT rather than invest in the development of novel treatments with other mechanisms of action. (Others responded that accelerated approval created greater incentives for small companies to move into AIDS research: the alternative, long-term Phase II studies, was too expensive and too much of a risk.) Furthermore, argued TAG members, some of the companies were ducking their responsibility to perform postmarketing studies. "We pay huge amounts of money and we suffer through major toxicities, and we have to take the drug company's word for it that the drugs work. That's supposed to be empowerment?" complained TAG member Spencer Cox in comments to the New York Times .
Preserving the policy of accelerated approval, as most players preferred to do, presumed finding a better surrogate marker or markers. By fall 1994, attention had focused on new, high-tech measures of viral load, such as assays that used PCR technology to quantify viral RNA. From the standpoint of Anthony Fauci (the most prominent backer of the use of CD4 counts as a surrogate marker in the early 1990s), viral load was "fundamentally … better as a marker. I don't think there's any question about it." Fauci explained: "There's a lot of virus floating around, and when you treat somebody, you can see dramatic decreases in that virus." Here Fauci was referring to an important, recent finding about the pathogenesis of HIV infection: rather than a slow, subdued "latency," it now appeared that HIV disease was characterized by "rapid turnover" of both virus particles and T
cells —what the New York Times described as "a pitched battle from the very start of infection," with hundreds of millions of virus particles and hundreds of millions of infected cells dying every single day. This new conception of the dynamics of HIV infection implied that viral load was a crucial indicator of disease progression.
Biostatistician Stephen Lagakos, while optimistic about the possible uses of these markers, also pointed to "overstatements" on the part of some of their advocates, and he described stories he had heard reporting "that some of the producers of these [marker tests are] trying to get clinicians to buy gobs of these kits and use them on everybody at $500 a crack." More emphatically, in an article subtitled "When Viral Load Is Crowned King," the Treatment Action Group railed in its newsletter against "frustrated scientists [who] have a new toy and biotechnology companies [who] have a new assay to sell." TAG was calling instead for large-scale trials—so-called "large simple trials" with as many as five thousand subjects—particularly for the upcoming protease inhibitors. The virtue of such trials, these activists argued, was that they could simultaneously tell us "if these new drugs prevent sickness and death" and "if the new viral load assays are useful predictors." Hoffman-LaRoche, manufacturer of a protease inhibitor called saquinavir, was in TAG's view "racing" to the FDA with "lukewarm" data, seeking accelerated approval on the basis of a single, twenty-four-week study. TAG proposed instead an expanded access program for saquinavir to accompany the larger, long-term studies.
By this point, the long-simmering dispute in tactics between East Coast groups such as TAG and the San Francisco activists had "become particularly intense and often bitter," as John James explained in AIDS Treatment News . In general terms, everyone avowed respect and support for his or her activist compatriots. But from the standpoint of the San Francisco activists, the TAG members had become scientific conservatives seeking to be more rigorous than thou. Said G'dali Braverman of ACT UP/Golden Gate: "There's an interesting evolution in terms of one's personal treatment activism. You reach that point where you start losing your sight of [the idea] 'We really are dealing with patients who need an option now,' and you start trying to think like a scientist." Such a tendency was "a difficult thing to temper," added Braverman. "You know why I really think there's a split?" reflected Brenda Lein of Project Inform. "Because the East Coast folks don't have a constituency of people living with HIV that
they work with on a day-to-day basis. I mean, I answer hotline calls from people who want access. They talk to each other."
Needless to say, TAG activists, many of whom were themselves living with AIDS and HIV infection, disputed these characterizations. They insisted they were not necessarily opposed to accelerated approval and certainly not to expanded access: Their motto was "access and answers." Nor did they oppose the right of the individual to have access to therapies. But they wanted to counterbalance that right against some conception of the greater good. And they criticized their San Francisco comrades for continuing to promote hype about up-and-coming drugs; they saw themselves as hard-nosed realists who had been burned too many times to ever contribute to the "hype cycle" again. This explained the venom behind TAG's attack on Margaret Fischl in Berlin—the sense on the part of activists that they were led to believe in combination therapy and manipulated into hopping onto a roller-coaster ride of exhilaration followed by despair. Mark Harrington made this point emphatically in his written critique of ACTG 155: "ACTG 155 was riddled with investigator bias and sponsor-disseminated hype from the very beginning. … Indeed, as early as August 1990, at a meeting with ACT UP, Roche's Dr. Whaijen Soo told us: 'I'd like to confide a remark of Margaret's. … The difference she sees among people on the ddC/AZT combination [in ACTG 106] is a big difference—like the difference between people on AZT versus placebo in the original trial. She can almost tell them apart by looking at their behavior.' Say that around the country for three years and you can create a huge demand for an unproved drug." TAG members were now vigilant against becoming the pawns of the pharmaceutical companies and resistant even to well-intentioned optimism. David Barr commented in 1994: "I've been pulled aside several times in the last couple of months [by people whispering], 'I'm really excited about the protease inhibitors.' … I have to say, 'Please, I understand you're saying that to me because you want to help me, but it doesn't help me .'"
Back to Basics
In the midst of cleavages on regulatory policies, activists could agree on one point: it was time for brand-new directions in AIDS research—new approaches that could arise only out of discoveries in basic science. Project Inform, for example, had begun assembling leading scientists and activists for periodic "Immune Restoration
Think Tank" meetings to brainstorm research directions in restoring immune system functioning. TAG had endorsed the emphasis on basic research in its report on NIH's AIDS research that it had presented in Amsterdam in 1992. A new report presented at the 1993 Berlin conference was all the more emphatic—and dramatic: "The world of basic research on AIDS is the final frontier for AIDS activists; it is here that we make our last stand," wrote Gregg Gonsalves. "We must forge a partnership with those scientists who have devoted their lives to studying the basic biology of HIV and the immune system and quicken the pace of discovery."
On the assumption that basic research, unlike clinical research, "has not had a powerful constituency to advocate on its behalf," TAG had conducted interviews with thirty-six researchers in the basic sciences—immunologists, virologists, and molecular biologists—most of them at work in academic settings. Above all, said Gonsalves, researchers stressed "the need to take basic AIDS research from the pristine in vitro laboratory setting to more difficult, but critical, work with wild-type HIV isolates and clinical samples, often using in vivo settings with animal models or humans." This was a restatement of the familiar problem—that scientists knew infinitely more about the structure of HIV than about how HIV causes AIDS. "In vivo veritas" was the slogan that TAG recommended: "Many of the interviewees criticized the relevance of in vitro work ('pristine, beautiful, irrelevant systems')."
The long-running activist critique of "purity," "cleanliness," and "elegance" was now applied to a new set of concerns: once again, as with clinical trials, activists were pressing for real-world "messiness" in place of pristine, ivory-tower science. Harrington had made this point in graphic fashion in a presentation the year before at the Amsterdam conference. Using slides of his own lymph tissue as backdrop, Harrington had demanded that scientists attend to "what is going on in our bodies, rather than exclusively in elegant and often artificial laboratory and animal models." With representational strategies such as these, activists could hope to bring the "politics of the body" to bear on the remotest regions of laboratory science.
Needless to say, not all clinical researchers were happy about the new activist agenda. "I think that … the basic science people now have the activist community in the palms of their hands," complained Donald Abrams in late 1993, "and they're going to run with it for a while. … I think it's too bad." However, activists were by no
means alone in articulating the need for a renewed emphasis on basic research. In May 1994, Gina Kolata wrote in the New York Times about a "new consensus … among many leading scientists that the nation's $1.3 billion AIDS research program is on the wrong track." The article cited an editorial just published in Nature by Bernard Fields, chair of the department of microbiology and molecular genetics at Harvard Medical School, entitled "AIDS: Time to Turn to Basic Science." "The focus on drugs and vaccines made sense a decade ago." wrote Fields, "but it is time to acknowledge that our best hunches have not paid off and are not likely to do so." Kolata also quoted Harold Varmus, the new head of the NIH: "Everyone agrees with Bernie's basic precept." And William Paul, the immunologist who recently had replaced Anthony Fauci as director of the newly reorganized Office of AIDS Research, said of the Fields manifesto: "We take that as our marching orders."
At the next International AIDS Conference, held in Yokohama, Japan, in August 1994, Paul made his priorities more explicit. This was the tenth annual conference; since the first such conference held in Atlanta in 1985, the number of cases of AIDS in the United States had climbed from about nine thousand to more than four hundred thousand. The number of AIDS cases around the world was now estimated at four million. "Realism was in the air," according to a commentary on the conference in Lancet ; and it was in a spirit of realism that Paul announced his intention to cut spending on clinical trials sponsored by the ACTG in order to put more money into the "revitalization and expansion" of basic research. Basic research was the "engine that will drive the entire AIDS research enterprise forward," Paul told the conference participants in his plenary lecture, reiterating the long list of fundamental, unanswered questions about HIV and the pathogenesis of AIDS.
What role could treatment activists play in facilitating the progress of basic science? Arguably, activists had a perspective on clinical trials that made them valuable contributors to the effort to conduct such trials smoothly and adequately. In focusing on basic research, however, it was less clear whether activists possessed a special vantage point from which to augment the production of knowledge. By one reading, the most activists could accomplish in this domain was to call for researchers to get on with it. For Martin Delaney, however, the point of Project Inform's Immune Restoration Think Tanks was not just to urge researchers to conduct basic research but to try to sketch
out, in discussion with them, the most fruitful avenues of inquiry. "We feel we have accomplished more and better research in this fashion than we ever could have achieved had we chosen to insist on being the researchers ourselves," said Delaney, suggesting a contrast with such earlier adventures as the "underground" trials of Compound Q.
To get a better feel for the conduct of basic research, TAG members actually began spending time in Anthony Fauci's laboratory at NIAID. "I don't think they make any pretenses that they're immunologists or microbiologists or virologists," said Fauci. "But they want to understand as much of the down-in-the-trenches science as they can." Activists didn't need to comprehend every detail or nuance of the research, Fauci explained, in order "to evaluate the broad strokes of the studies that come out." Activists themselves were forthright about the limitations as well as the possibilities inherent in this new approach. "I can't talk cell lines with the big boys, that's for sure, but who cares?" commented Derek Link of TAG. "That's not my role."
Aiding the activists as they negotiated relationships with the basic scientists was the relative accessibility and openness of these researchers. "Most basic scientists are very different than the star clinical researchers," explained Link. "These are people who labor away in a lab, pretty much in obscurity. They're thrilled to have somebody interested in their work. …" Brenda Lein of Project Inform echoed this observation: "If you think about it, it's sort of a lonely profession … because it's not like you go to a cocktail party as a scientist and people [say], 'Oh that's so fascinating, and what happened in the cell culture next?' And if you actually have someone who's interested, they're more than anxious to be able to talk about their work. … You know, there's not many people who get excited about epitope mapping. …"
Activists have cultivated these new relationships to bring the patient's perspective to the foreground in basic research—to force bench scientists to be fully cognizant of the day-to-day realities of sickness and suffering beyond the laboratory walls. In so doing, they have attempted to speed the process by which compounds move from the laboratory to testing in humans. "I probably wouldn't have four drugs in clinical trials without the activists having had some [effect on] me," commented Robert Gallo in 1994. Another way that activists influenced the knowledge-making processes of basic research was by performing a bridging, or "pollination," function, bringing together researchers from different specialty areas who were unfamiliar with
one another's work. Gallo, a participant in the Immune Restoration Think Tanks, agreed vigorously that activists have served as a "catalyst" that "forc[ed] people to communicate better" and to see beyond the limits of their individual specialty areas. Derek Link was also emphatic about the utility of this role: "There are numerous, numerous times when I'm talking to researcher X and saying, 'Researcher Y is now [working on such-and-such].' And [they say], 'Well, that's interesting.' And then there's some discussion about that."
"Cocktails" and "Synergy"
Basic research had produced one recent finding that held crucial implications for drug development: New techniques for measuring virus in the blood had indicated that HIV disease was characterized not by a long, subdued latency but by what researchers and reporters called a continuous "raging battle." Each day the immune system killed hundreds of millions of viral particles; each day the virus replicated to produce hundreds of millions more, killing T cells in the process. Gradually, the virus gained the upper hand in this high-cost war of attrition. Meanwhile, the more the virus replicated, the more it was likely to mutate. Simple math suggested that over the course of a few years, "every viable mutation at every position in the [viral] genome will occur," noted David Ho in a commentary in the New England Journal . The implication was that whatever individual antiviral drug researchers threw at the virus, it wouldn't take long before a mutant had emerged that was resistant to the drug. "Therefore, monotherapy as we know it is doomed to fail," argued Ho. "In the long run, effective treatment must instead force the virus to mutate simultaneously at multiple positions in one viral genome. This is best achieved by using a combination of multiple, potent antiretroviral agents." Ho envisioned a time in the near future when combinations of antivirals would be given to patients as early as possible, ideally just after infection, when the virus was most homogeneous. He argued forcefully that the relative lack of success of combinations of the nucleoside analogues (AZT, ddI, ddC, and d4T) was not an adequate test of the concept of early intervention. As soon as we had better antivirals, then it was, as Ho's article declared, "Time to Hit HIV, Early and Hard."
What made Ho optimistic were recent studies of protease inhibitors, as well as one nucleoside analogue combination, AZT plus 3TC. In trials, these drugs not only boosted CD4 counts, they also significantly
reduced viral load and did so to a greater extent than the approved therapies. Researchers were beginning to speak in optimistic terms of multidrug "cocktails"—such as AZT plus 3TC plus a protease inhibitor—that might inhibit viral replication for extended periods. "Psychologically we definitely have turned a corner," Robert Schooley, the new chair of the ACTG Executive Committee, told the Los Angeles Times in February 1995.
Promising results of two European AZT/3TC trials had been announced toward the end of 1994, and Glaxo, the Canadian drug company that manufactured 3TC, had established an expanded access program. TAG described the combination as "admittedly intriguing," but also warned that the results "are based solely on short-term surrogate marker changes: the same surrogate marker changes that brought us those all-powerful antiretrovirals AZT, ddI, ddC (a real winner) and d4T." Both Glaxo and Burroughs Wellcome were delighted by the apparent synergy of their respective products—especially after the 1995 merger that formed the world's largest pharmaceutical company, Glaxo Wellcome.
Meanwhile, by 1995 three companies—Hoffman-LaRoche, Merck, and Abbott—were conducting large-scale trials of protease inhibitors, and several other companies were following in their footsteps. Patient groups clamored for access to these drugs, but expanded access of the protease inhibitors posed special problems for the drug companies. These compounds were difficult to manufacture, and patients consumed them in much higher quantities than required with other antiviral drugs. In short, there just wasn't enough protease inhibitor to go around—at least, not without jeopardizing supplies for clinical trials. As a result, each of the three companies announced that it would hold a lottery to assign spots in its expanded access program. In summer 1995, 18,500 people competed for about 3,600 slots. Though lotteries seemed the most equitable solution in the short run, many observers expressed concerns about the pressures building for accelerated approval of the protease inhibitors, especially with rumors of the upcoming emergence of "underground" protease drugs.
As antiretroviral research embraced new possibilities, including an even newer class of drugs called integrase inhibitors, the pervasive gloom of 1993 and 1994 seemed to be lifting. And in late 1995, the Antiviral Advisory Committee recommended accelerated approval of two more drugs, based on the drugs' effects in boosting CD4 counts and lowering viral loads: 3TC (to be used in combination with AZT)
and saquinavir, the Hoffman-LaRoche protease inhibitor (also for use in combinations). FDA Commissioner Kessler took the opportunity to express his excitement about the protease inhibitors, calling them "the most active agents against HIV we have seen to date." With the agency's rapid endorsement of its advisory committee's recommendations, the number of approved antiviral AIDS drugs had risen from one in 1987 to six at the close of 1995.
Optimism increased in the early months of 1996, as the Antiviral Advisory Committee recommended approval of two other protease inhibitors, Abbott's ritonavir and Merck's indinavir. The FDA, then undergoing close scrutiny by Republican members of Congress concerned with speeding up the drug approval process, acted on the committee's recommendations in a matter of days. Indeed, approval of Merck's drug arrived just forty-two days after the company had first submitted its application to the agency. Abbott's drug, ritonavir, was given full (rather than accelerated) approval after an international study reported that the drug cut the death rate nearly in half in a group of 1,090 AIDS patients: the death rate was 4.8 percent among those who received ritonavir and 8.4 percent among those who received a placebo in place of the protease inhibitor. (Subjects in both groups were also free to take AZT or d4T if they chose.) Still, concerns remained about the long-term efficacy of ritonavir as well as the other protease inhibitors, given the likely development of resistance to the drugs.
None of these drugs was a "magic bullet"—a "penicillin" for AIDS; no expert expected that such a drug could be developed. From the perspective of Daniel Hoth, who came to NIAID originally from the National Center Institute, the development of antiretroviral AIDS therapies was—slowly but ineluctably—recapping the progress of cancer therapies. Clinicians started out with single-agent, palliative drugs: "That's cancer in the '50s. Then you go through another generation, you get some better drugs. And you start to get complete remissions, you start to get longer durations of partial remission. … And you gradually increase both the depth of the response … and the duration of it." This would be the likely pathway in the development of AIDS drugs, Hoth was convinced: "I think we're going to see a formal recapitulation of what happened in … cancer."
Whatever the speed of development of therapies, political and economic factors dictated that their distribution would be highly uneven. To the extent that existing antiretroviral therapies had important benefits—for
example, in the apparently sharp reduction of transmission of HIV from pregnant women to fetuses—such findings remained, in the mid-1990s, irrelevant to most of the world's population. As Science 's AIDS reporter Jon Cohen explained: "Poorer countries can't afford either AZT or the sophisticated clinics used in [ACTG] 076. In addition, 076 calls for repeatedly dosing the mother with AZT during her pregnancy, and many women in developing countries don't visit medical clinics until they are in labor—if then." Nor were the pharmaceutical companies likely to provide the solution. "I doubt very much that it will be Glaxo Wellcome giving away unlimited amounts of AZT," a company spokesperson told Cohen. In countries that spent only a handful of dollars per capita on health care in a year, what, then, was the likelihood that any antiretroviral therapy developed in the West would actually see widespread use? Even in the United States, with federally funded health insurance programs such as Medicaid under increasing attack, the ability of people with AIDS and HIV to afford multiple combinations of drugs that were each quite expensive seemed increasingly in doubt.
Promoting "Good Science"
The mid-1990s saw the U.S. public engrossed by popular nonfiction like The Hot Zone and Hollywood films such as "Outbreak," which presented terrifying images of the sudden and devastating illness caused by the rare Ebola virus. AIDS and the fears it had provoked in the 1980s were often the unspoken subtexts in these representations. Yet ironically the ongoing brutalities of the AIDS epidemic seemed to fade from the public eye—even as the number of cases in the United States passed the half-million mark and U.S. health authorities reported that AIDS had become the leading killer of twenty-five- to forty-four-year-olds. Seen less as a raging plague than as a chronic plight, AIDS, like homelessness and drug use, had merged into the background landscape of late-twentieth-century social life.
Activists struggled to bring AIDS back to center stage. For a while, it had seemed as if a Democratic administration might make a difference, that it might offer a different "political opportunity structure" for movement activism. But whatever President Clinton's sympathies, AIDS was far from the top of his agenda. One apparently promising step was the establishment of an eighteen-member presidential
commission, the National Task Force on AIDS Drug Development, designed to bring together representatives of government agencies, the pharmaceutical industry, the research community, and activist groups to recommend ways to streamline the discovery and testing of new AIDS drugs. The panel included Ben Cheng of Project Inform, Peter Staley of TAG, and Moisés Agosto of the National Minority AIDS Council and TAG. Daniel Hoth, who had left NIAID for private industry but was a member of the task force, noted the key difficulty confronting them: "Very few of the problems are amenable to executive proclamation." By early 1996 the group had disbanded, acknowledging that they had been unable to remove the obstacles that stood in the way of faster development of new AIDS drugs, and citing lack of clear support from President Clinton.
In debates over how to improve the drug development system, activists were just one player and held relatively few cards. The pharmaceutical companies, by contrast, could often push research as their interests dictated. Drug companies could collaborate with one another, sharing data when it suited their purposes: fifteen of them had formed an entity called the "Inter-Company Collaboration for AIDS Drug Development" to test combinations of drugs produced by different companies. But drug companies could also go their own ways or exit the arena altogether. Many biotechnology firms, for example, were finding the AIDS arena too risky and were choosing to invest their resources in more promising efforts.
By the mid-1990s, AIDS activism in general was in a period of decline, and the "treatment activist" subset looked considerably different from its incarnation in the late 1980s. The dominant wing of treatment activism—which encompassed groups such as TAG, Project Inform, and subgroups of ACT UP chapters around the country, along with representatives to the CCG and local community advisory boards—was small, committed, relatively expert, and relatively professionalized. As the mainstream treatment activist groups have moved into the mid-1990s, their work has proved to be a vital but less visible, and in many ways less hopeful, political endeavor.
There are many factors that have contributed to the current juncture. While all social movements confront the issue of burnout and renewal, few find that on a regular basis their leaders become ill or die. More generally, much of the difficulty has lain in the vicissitudes of the research process and the sheer intractability of the scientific problem. Garance Franke-Ruta, a TAG activist who was 17 when she first joined ACT UP, recalled the evolution: Activists first gained access
to the system at a time of relative optimism, when drugs such as AZT suggested the hope of keeping patients alive until a better drug came along. By the early 1990s, when the much-disliked and marginally effective AZT was still the first-line therapy, activists had come to adopt a longer view. "Most of us are just simply not going to see the answer to this in our lifetime," commented San Francisco activist G'dali Braverman. "And I think there was an excitement in the early days and this feeling that we could change everything—which we will! —and that we would live to see it and that the answers were already there, we just hadn't seen them, or hadn't been told them. We know better now."
With this perspective came a further shift in strategic thinking away from the simple strategy of "drugs into bodies" and toward the promotion of "good science." As Moisés Agosto put it, "A lot of treatment activists got involved [in the 1980s] believing that through their activism they were going to be able to save their lives." Strategies, therefore, were based significantly on the desire to get something—anything —through the pipeline—to get "drugs into bodies" fast enough to matter for the health of the current generation of activists. Agosto continued: "Now, my personal [belief] is, 'No, I'm not going to be able to save my life.'" In the ongoing tension between "access" and "answers," activist strategy had moved toward the opposite pole: "It's about having good science that develops good therapies [so] that we may have a cure or therapy someday."
In this current period of adjustment, groups such as TAG, ACT UP/Golden Gate, Project Inform, and others around the country have accelerated their engagement with the AIDS research effort, but the details of their work have receded from public view. As the issues become ever more complex and technical, they also become more difficult to summarize on a leaflet or in a sound bite. Nor has it proven easy to recruit new activists into a movement with such a high degree of accumulated technical expertise. "The training program is sink or swim," Derek Link commented. "People who are totally intimidated are not going to do well."
To the extent that polarization between "us" and "them" increases the tendency for social movement actors to sacrifice for the cause, the evolution of relatively more cooperative relationships between activists and their interlocutors in research and government may have made it somewhat harder for the movement to stoke the fires of passion. Some activists, such as the novelist Sarah Schulman, who are critical of those in groups like TAG believe that the decline in the use
of direct action techniques spelled the end of effective treatment activism. But others reject what they see as a fetishizing of confrontational direct action—trying to "scream a cure out of a test tube"—insisting that tactics should be suited both to the task at hand and to the stage in the evolution of the movement. "It would have been stupid to do a large demo when you could have picked up a phone and made a couple of phone calls and gotten just the same results," commented Harrington.
Implicit in this evaluation, however, is not simply a practical insistence on "doing what works," but also a transformed conception of the identity of the antagonist. In place of the charges of genoc ide that activists had used in the early days of ACT UP to frame their critiques of the research establishment, these activists were now often inclined to acknowledge the good intentions of researchers. "There's a new respect for the scientists," said Gregg Gonsalves in an interview in the gay magazine the Advocate: "There is more of a willingness to focus on the problems that the scientists are really facing rather than what we once thought of as the scientists' malice." If so, Anthony Fauci has certainly endorsed the change of heart. He told the same reporter: "I have to admit it's gratifying that people who are highly qualified—and most of the activists that I have gotten to know are—have come around to support us. … In the late '80s we were getting pushed around to put people in clinical trials for drugs that we really didn't think were very promising anyway. … Now that we are in agreement about the need for basic research, maybe we will have better drugs and vaccines one day."
Is this co-optation? Or is it well-advised realism that is the fruit of (sometimes bitter) experience? Garance Franke-Ruta's reflections suggest the ways in which the acquisition of the "realistic" perspective of the educated participant in science can constrain utopian imaginings, even as it paves the way for a more focused and sober activism: "When ACT UP started, people didn't know as much, and demanded much more. And there was something in ACT UP initially that was really wonderful, which was that out of ignorance of what is possible, you are sometimes able to do the impossible—whereas once you know what is possible and what is not possible, you let that define what it is that you're willing to ask for. So the more we learned, in some ways the less we were able to ask for , until eventually we knew so much that we felt—we feel—like sometimes we don't know that we can ask for anything [emphasis added]."
There is, of course, virtue in self-doubt and critical reflection. Scientists, too, could be heard reporting their own. "I think we got a little bit too cocky too early," a Princeton molecular biologist told the New York Times in 1994, describing the need to refocus on basic research. Such sentiments are a useful antidote to hubris and to a surplus of faith in what science can accomplish. Over the course of less than a decade and a half, researchers had vastly expanded the knowledge about AIDS, while treatment activists had garnered their own expertise and reshaped the conduct and contours of biomedical research. In the end, however, neither activists nor scientists could force a cure into being, no matter how committed their efforts or how sophisticated their interventions.