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.