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.