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.