The Transformation of AIDS Research

Credit Where Credit is Due

That treatment activists have succeeded in establishing their scientific credibility and their cultural competence in biomedicine is widely acknowledged by a range of eminent researchers and government health officials. Although such testimonials appear sincere, they

need not, of course, be taken entirely at face value. However, even the most cynical interpretation would suggest that these authorities see the activists as important enough to merit flattery. (This, too, is a credibility tactic that researchers can employ.) Anthony Fauci has made clear that "there are some [activists] who have no idea what the hell they're talking about," but he was nonetheless happy to grant that "there are some that are brilliant, and even more so than some of the scientists."^[14] Robert Gallo has called Martin Delaney "one of the most impressive persons I've ever met in my life, bar none, in any field. … I'm not the only one around here who's said we could use him in the labs."^[15] Gallo described the level of scientific knowledge attained by certain treatment activists as "unbelievably high": "It's frightening sometimes how much they know and how smart some of them are."^[16] Prominent academic researchers also typically acknowledge the gradual acquisition of scientific competence on the part of key activists. "Mark Harrington is a perfect example," recalled Douglas Richman. "In the first meeting [of the Community Constituency Group] he got up and gave a lecture on CMV … that I would have punished a medical student for—in terms of its accuracy and everything else—and he's now become a very sophisticated, important contributor to the whole process."^[17] Reflected John Phair, a former chair of the ACTG Executive Committee: "I would put them up against—in this limited area—many, many physicians, including physicians working [with] AIDS. They can be very sophisticated."^[18]

Praise of treatment activists by biomedical authorities is one measure of the activists' acquisition of credibility. But real-world consequences speak louder: What difference has it made to have activists involved in issues of AIDS research and drug development? How has biomedical research been reconfigured as a result? Examples prove to be numerous: The arguments of AIDS activists have been published in scientific journals and presented at formal scientific conferences. Their publications have created new pathways for the dissemination of medical information. Their pressure has caused the prestigious journals to release findings faster to the press. Their voice and vote on review committees have helped determine which studies receive funding. Their efforts have led to changes in the very definition of "AIDS" to incorporate the HIV-related conditions that affect women. Their interventions have led to the establishment of new mechanisms for regulating drugs, such as expanded access and accelerated approval. Their arguments have brought about shifts in the balance of power between

competing visions of how clinical trials should be conducted. Their close scrutiny has encouraged basic scientists to move compounds more rapidly into clinical trials. And their networking has brought different communities of scientists into cooperative relationships with one another, thereby changing patterns of informal communication within science. Though activists have never sought or established absolute jurisdiction over any contested scientific terrain, they have, to use Andrew Abbott's term, won the rights to an "advisory jurisdiction" analogous to the relation of the clergy to medicine or psychiatry. Of course, as Abbott notes, advisory jurisdictions are characteristically unstable, "sometimes a leading edge of invasion, sometimes the trailing edge of defeat."^[19]

The Politics of Access

Drug regulation is one arena where the sheer effect of activism would be hard to dispute. Activists were not the only ones calling for change in the FDA, but they were the key players in pushing for the approval of AIDS drugs at an earlier stage in the drug development pipeline. And although some procedures allowing early access to experimental therapies were already on the FDA's books, others, such as expanded access and accelerated approval, are new to medicine as a result of AIDS, and have resulted in the provision of such therapies to much larger groups of patients than had been the case in the past. (Expanded access has since been instituted for drugs treating other diseases, such as Alzheimer's, while a drug for multiple sclerosis has received accelerated approval.^[20] This book has not focused on drugs that treat or prevent opportunistic infections, but it is perhaps there that the significance of activist efforts has been felt most keenly: earlier access to anti-infective drugs, though not without risk, has meant a longer life and better quality of life for many people with AIDS and HIV.^[21] In addition, activist efforts (for better or worse) propelled the adoption of interpretative mechanisms such as surrogate markers that, in turn, have hastened the approval process. Absent the AIDS activists, CD4 counts would not have been accepted as a surrogate marker of treatment efficacy in 1991; without the adoption of the CD4 marker, the AZT/ddC combination would not have been licensed in 1992.

Finally, activists have insisted on broadening the demographic characteristics of clinical trial participants, hence broadening access to experimental therapies. In fiscal year 1988, 82 percent of the new

subjects recruited into ACTG trials were white. By 1994, only 56 percent were white (26 percent were African-American, 16 percent were Hispanic/Latino, and 2 percent were "other"). Over the same period, the ratio of men to women in trials was reduced from about thirteen to one to about five to one.^[22] While activists cannot take all the credit for the demographic diversification of trials, there can be little doubt that politicization of the issue by activists brought about a climate in which change became perceived as a necessity. The minutes of the ACTG Executive Committee meetings recorded Daniel Hoth's exhortations to investigators to diversify trials: on one occasion Hoth noted that the ACTG was "under a great deal of political pressure to address this issue successfully"; on another, he described a phone conversation with the assistant secretary of health, "who had called to ask what the ACTG was doing to increase minority participation."^[23] These new emphases at NIAID were matched by changes at the FDA: in March 1993 agency officials announced that, instead of excluding women of childbearing age from trials, they would henceforth insist on their inclusion in nearly all new drug applications. "We now believe that there are ways to protect the fetus and to include women in studies at the same time," David Kessler told the press.^[24]

Beyond the very real concerns about risks to patients, the key criticism of expedited access to experimental therapies has focused on the potential threat to the research process. If, for example, patients were able to obtain drugs like ddI and ddC through expanded access programs, why would they bother to sign up for long-term clinical trials? This criticism ignores the other reasons why patients might enroll in trials—for example, altruism or the desire to obtain access to high-quality medical care and intensive monitoring of their medical condition. But in the end, as Anthony Fauci notes, "the proof of the pudding is that we were right. [Expanded access] hasn't hampered anything"; research subjects have enrolled and the trials have still been completed.^[25]

"Situated Knowledges" and the Lure of Science

Besides drug regulation, the other arena in which the hand of activism has most heavily been felt is the design and methodology of clinical trials. Here, activists have trained their attention on a range of apparently narrow and technical questions: Was there truly

a scientific necessity to exclude potential research subjects with abnormal lab test values? Was there anything from a statistical standpoint that prevented patients from taking concomitant medications or being enrolled in more than one trial at a time? By raising these questions, activists, sometimes with support from biostatisticians, have helped bring changes to the world of AIDS trials, making the procedures that governed them more similar to those already in place for cancer trials. "The way I looked at it is that, when the wind is blowing hard, you can either bend or you can break," recalled former NCI and NIAID biostatistician Susan Ellenberg. "I think we bent a lot in terms of the way we normally do trials. I think we stood firm in terms of the most important principles. …"^[26]

By pressing researchers to develop clinically relevant trials with designs that research subjects would find acceptable, activists have helped to ensure more rapid accrual of the required numbers of subjects and to reduce the likelihood of noncompliance on the part of those participating. And by working toward methodological solutions that satisfy, simultaneously, the procedural concerns of researchers and the ethical demands of the patient community, AIDS activists have, at least in specific instances, improved a tool for the production of knowledge in ways that even researchers acknowledge. In this sense, AIDS activists' efforts belie the commonplace notion that only the insulation of science from "external" pressures guarantees the production of secure and trustworthy knowledge.

In the aftermath of the Concorde trial, with its implication that changes in CD4 counts are not, as activists had maintained, an adequate surrogate marker for antiviral drug efficacy, there were suggestions that AIDS activists had muddied the waters of knowledge in their haste to see drugs approved. Activist insistence on the use of surrogate markers had "set back AIDS research for ten years," researcher and Antiviral Advisory Committee member Donald Abrams grumbled with some hyperbole in late 1993.^[27] Yet any such assessment must consider the larger picture. Absent the activists, what sort of knowledge strategies would have been pursued? Pristine studies addressing less-than-crucial questions? Methodologically unimpeachable trials that failed to recruit or maintain patients? Inevitably, there are risks inherent in the interruption of the status quo. But these must be weighed against all the other attendant risks, including those that might have followed from letting normal science take its leisurely course while an epidemic raged.

In their critiques of "pure" or "clean" or "elegant" science, and in their invocation of the "real world" and "pragmatic" decision making, AIDS activists have emphasized the local and contextual character of usable scientific knowledge. In the mainstream conception of science epitomized by the randomized clinical trial, true knowledge is produced through abstraction and the transcendence of particularities. In the alternative conception that develops out of activist critiques, reliable knowledge is produced through close attention to the concrete social, moral, and political context: better science comes about because of the focus on individual patients and their needs, desires, and expectations. This alternative conception of science is willing to surrender claims to universal validity in exchange for knowledge that bears some local and circumscribed utility.^[28]

At the same time, as some of the treatment activists have moved "inward" to cooperate closely with researchers and have become increasingly sensitized to the logic of biomedical research, their conceptions of the scientific process have turned in a more conventionally positivist direction. This development has led to cleavages within the movement about how to approach the politics of knowledge. "I've seen a lot of treatment activists get seduced by the power, get seduced by the knowledge, and end up making very conservative arguments," contends Michelle Roland, formerly active with ACT UP in San Francisco. "They understand the science and the methodology, they can make intelligent arguments, and it's like, 'Wait a minute … okay, you're smart. We accept that. But what's your role?'"^[29] Ironically, insofar as activists start thinking like scientists and not like patients, the ground for their unique contributions to the science of clinical trials may be in jeopardy of erosion. ACTG researcher John Phair notes that activists "have given us tremendous insight into the feasibility of certain studies" but adds that "some of the activists have gotten very sophisticated, and then [they] forget that the idea might not sell" to the community of patients.^[30]

Can one be both activist and scientist? Is the notion of a "lay expert" a contradiction in terms?^[31] There are no simple answers here, nor should we expect there to be. But arguably, it was not possible for key treatment activists to become authorities on clinical trials and sit on the ACTG committees without, in some sense, growing closer to the worldview of the researchers—and without moving a bit away from their fellow activists engaged in other pursuits. It is no surprise that activists with this degree of intellectual sophistication are themselves reflexively engaged in the consideration of precisely such issues.

Michelle Roland commented on the differentiation of activism in intriguing terms: "I hold on to the very strong belief that the only way that I'm going to do really good work is if there are people who do not know what I know—[people] who are always coming from that very emotional, very bottom-line place, to keep reminding me about that place."^[32]

Trials and Truth-Making

In the end, it remains somewhat unclear precisely what approaches to, or conceptions of, science activists would like to promote. Are AIDS activists really just trying to "clean up" science by eliminating "biases" that academic researchers are introducing? Or to supplant "clean science" with something that answers to different epistemological and ethical aspirations? It may be the tension between these conflicting and ambiguously defined goals, more than anything else, that characterizes the activist engagement with the AIDS research effort. The attempt to wrestle with such ambiguities is apparent in activists' views of the randomized clinical trial as a technology for producing knowledge. Generally speaking, activists have rejected a narrow, positivist conception of the clinical trial as a controlled laboratory experiment, pure and simple. But not many of them are prepared to replace the randomized clinical trial with an entirely different method of assessing drugs.^[33]

By contrast, in her analysis of controversial cancer trials, Evelleen Richards concludes with a call to curtail our reliance on the randomized clinical trial. Since the notion of a "definitive" clinical trial, she claims, is a myth that primarily serves the interest of professional legitimation, it would be better "to learn to live with the reality of uncertainty" and to introduce political, ethical, and subjective criteria into the evaluation of treatments. This "implies a more prominent role for non-experts, for patients and the public at large, in the processes of assessment and decision making. …"^[34] Quite similarly, AIDS activists have emphasized the artifactual and historical character of the clinical trials methodology, and they have placed a spotlight on the perception of the patient as a genuine participant in clinical research and not just the object of study. Yet—perhaps especially as they have become enculturated into the biomedical research process—most AIDS treatment activists share with doctors and researchers a profound investment in the belief that the truth about treatments is, in principle, knowable through some application of the scientific

method. Though many in the AIDS movement have at particular moments argued in favor of tolerating uncertainty as the necessary tradeoff for access to experimental drugs, in the end few activists, and perhaps few people with AIDS or HIV infection, are sanguine about the prospect of "[living] with the reality of uncertainty." This is not surprising, since activists and people with AIDS and HIV are confronted daily by a burning need to know whether given treatments "work" or not. The activist critique of the randomized clinical trial unseats that methodology from the pinnacle on which it is sometimes placed, but it also assumes (I think rightly) a greater role for such trials than analysts such as Richards would recommend.

Just how radical, then, is the critique of science offered by AIDS treatment activists? The question is hard to answer, especially as positions shift over time and vary significantly between individuals and groups. But what sparks the ambivalence between radical and reformist perspectives on science are just these painful ironies that vex efforts to influence clinical practice. On one hand, engagement with clinical research has always been driven by the dictates of expediency and dire need: activists have no time for the leisurely pursuit of truth; they'll settle for today's best guess. Yet on the other hand, treatment activists—particularly the New Yorkers with the Treatment Action Group, but to some extent nearly all of them—have increasingly become believers in science (however understood), and they desperately want clinical trials to generate usable knowledge that can guide medical practice. "My doctors and I make decisions in the dark with every pill I put in my mouth," complains David Barr, and this is not an easy way to live.^[35]

Insofar as activists want to rely on the knowledge generated by clinical trials, they must wrestle with the consequences of their own interventions. Do such actions enhance activists' capacity to push clinical research in the directions they choose? Or do activists and researchers alike become subject to the unintended effects of their words and deeds, trapped within evolving systems whose trajectories no one really controls? Here is a worst-case scenario of the spiraling effects of community-based interventions in the construction of belief in antiviral drugs—a caricature sketch, to be sure, but one that combines elements from a number of cases: Drug X performs well in preliminary studies, and a NIAID official is quoted as saying that X is a promising drug. The grassroots treatment publications write that X is the up-and-coming thing; soon everyone in the community wants access to

X, and activists are demanding large, rapid trials to study it. Everyone wants to be in the trial, because they believe that X will help them; but researchers want to conduct the trial in order to determine whether X has any efficacy. Those who cannot get into the trial demand expanded access, while others begin importing X from other countries or manufacturing it in clandestine laboratories. As X becomes more prevalent and emerges as the de facto standard of care, physicians begin to suggest to patients that they get hold of it however they can. Meanwhile, participants in the clinical trial of X who fear they are receiving a placebo or an inferior drug mix and match their pills with those of other participants. When the trial's investigators report potential treatment benefits, activists push for accelerated approval of X, leaving the final determination of X's efficacy to postmarketing studies. But who then wants to sign up for those studies, when everyone now believes that the drug works , since, after all, the FDA has licensed it and any doctor can prescribe it?

In seeking to control this troubling escalation, the recent moves on the part of TAG activists to extricate themselves from the "hype cycle" seem particularly important. "One disturbing but inevitable result of the urgency engendered by the AIDS crisis," wrote Mark Harrington in late 1993, "is that both researchers and community members tend to invest preliminary trials with more significance than they can possibly bear."^[36] To the extent that activists can develop a critique of this phenomenon and communicate the relative uncertainty of such trials to the broader public of HIV-infected persons, it may be possible to imagine a clinical trials process that more fully reflects the interests of those who are most in need of answers.^[37]

On the other hand, the turn toward positivism in the statements of some TAG members—the emphasis on "rigor," "objectivity," and "rule-following" as the guarantors of success^[38] —seems not only inadequate but inconsistent with the goal of not making more of trial results than we ought. As the earlier optimism about finding solutions to AIDS has given way to disappointment or resignation, it is understandable that some activists would find the lure of "good science" vastly preferable to the subordination of scientific judgment to the exigencies of the moment, however profound. The trick, though, is to encourage trials that are both ethical and well designed without reifying the method so as to suggest that such trials will provide degrees of certitude that they simply cannot provide. As Brian Wynne has suggested, the solution cannot be to further the myth that clinical

knowledge-production is a fully rule-bound enterprise. Rather, the only way forward is to open the "black box" of clinical research, expose the uncertainty and the value choices, and then convince people of the considerable importance of participating in such research even after they understand just how messy it truly is and how bounded is the usability of the knowledge produced by it.^[39]