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preferred by those who are experts on clinical trials, the AZT study was no longer at an "indifference point" (or, it no longer maintained a state of "equipoise").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."