The "Future that we all Envisioned"
By 1991, the uncertainty about surrogate markers was on a collision course with the widely felt need to license ddI and ddC. Everyone knew these drugs had a certain value, activists contended; the issue was simply one of finding the appropriate mechanism for making them available. Expanded access, the San Francisco activists had decided, was a step in that direction but simply not good enough: It "only works when there is a public-spirited and well-financed drug company, willing to spend money to save lives when sales of the drug may be years away," wrote John James.
The Phase II trials—those vast, costly, and inefficient endeavors—were ultimately of little relevance, activists argued, because they were designed "to produce a single bit of information, one yes-or-no answer," namely, the question of statistical significance: in the event that these drugs were useless, was the chance of falsely concluding that they had benefit less than five percent? This, in James's view, was simply the wrong question to be asking. Doctors and patients needed pragmatic advice about the best ways in which to use these drugs. In that sense, "the real issue with ddI is not whether it works. A growing working consensus holds that it probably does.… The most important questions now are long-term toxicity, and when and how to use ddI most effectively in various groups of patients."
Particularly for San Francisco activists, two solutions to the "dinosaur trials" dilemma became effectively joined: the FDA could speed up approval by relying on a surrogate marker such as CD4 counts,
and it could make that approval conditional upon evidence to be obtained from subsequent studies. A proposal for a new FDA policy of "conditional approval" therefore emerged as a strategy for managing the greater uncertainty that the reliance on surrogates would entail. Such a policy, as activists imagined it, would put the burden on the drug companies to fund and conduct "postmarketing studies" to provide additional evidence of drug safety and efficacy. If evidence was not forthcoming, the FDA would revoke the license for the drug and it would be taken off the market. However, as soon as a drug was conditionally approved, the manufacturer could begin selling it and insurers would reimburse for it. The advantage over expanded access was that the latter program had provided only weak incentives for drug company cooperation. At most, as David Feigal of the FDA suggested, participation in expanded access enhanced a drug's credibility as an effective treatment: "It cements [the perception] that this is an up-and-coming drug, one valuable enough that it's being made available early." Conditional approval, by contrast, was designed with the explicit goal of enlisting the pharmaceutical companies by giving them a chance to do what they liked best: earn profits. The idea of conditional approval was quickly endorsed by the deregulation lobby and by the Quayle Competitiveness Council, the vice president's commission dedicated to the elimination of regulatory barriers for U.S. industries.
New York activists, who had pushed through the expanded access mechanism, were less enthusiastic about the idea. David Barr commented: "We have never said we are not interested in collecting good data. I have concern that if conditional approval is not done the right way we will lose our ability to collect data." Members of Congress who promoted consumer protection, such as Ted Weiss and Henry Waxman, were even more dubious. In April 1991, Waxman wrote to David Kessler, Bush's newly appointed head of the FDA and an advocate of change at the agency, expressing his concern that conditional approval, unlike the expanded access program, "could allow promotion and sale of drugs that did not meet previous standards for safety and efficacy." Soon afterward, Martin Delaney sent off a blistering letter to Waxman defending the policy and demanding that he cease and desist. Conditional approval "is not about lowered standards or opening the floodgates to harmful or worthless drugs," Delaney told Waxman. "It would be a very limited program accessible only in life-threatening situations and for drugs which show safety and clear
promise on the basis of surrogate markers." Insisting that Project Inform was not the "dupe" of the Republican party or the pharmaceutical industry, Delaney demanded that Waxman "put a muzzle" on one of his aides who had been speaking against the policy.
Meanwhile, as the various parties debated the merits and dangers of conditional approval, the question of surrogate markers also moved to the fore. By late 1990, Ellen Cooper, director of the Antiviral Drug Division, was describing herself as "encouraged" about the use of CD4 counts as a surrogate marker for AIDS antivirals, but she told JAMA that "we are not there yet" regarding reaching agreement in the research community. Delaney's analysis was that the FDA preferred to share the decision-making risk by forging a consensus with other federal agencies rather than go out on a limb. Cooper herself, however, seemed resistant to joining any consensus she did not genuinely support or to approving drugs based on standards she felt were inadequate. That, at least, was the general conclusion drawn when she suddenly resigned her position on December 19.
To consider the role of surrogate markers in approving antiviral AIDS drugs, the FDA convened a special meeting of the Antiviral Advisory Committee in February 1991. Among various scientific presentations was one by Anastasios ("Butch") Tsiatis, a statistician from Harvard, who had gone back over the data from the original Phase II AZT study. Tsiatis found that those patients whose T-cell counts went up after receiving AZT did better overall than those patients who did not experience a rise. In other words, by looking at the effect of AZT on CD4 counts, one could predict who would benefit most from AZT. On the other hand, it also appeared that the people who received AZT in the study experienced more of a benefit from the drug than the rise in CD4 alone could explain. But to Delaney, the issue wasn't whether CD4 told us everything as long it accurately predicted some significant portion of a drug's potential benefit.
"I think the reality is that we are not going to have this future that we all envisioned here," warned Martin Delaney in his testimony at the meeting, explaining that "body count" trials with survival as an endpoint simply were no longer feasible , regardless of whether they were desirable. "Survival … studies with each passing day of this epidemic become less and less possible. As more data accumulate on each of these drugs, as we take more time to compare one to the next, fewer and fewer patients are willing to sit still in studies that take two to three years. Fewer will stay on those studies as newer and better
compounds come along. …" Delaney was certainly right in insisting that regulators not conceive of AIDS antiviral trials as abstract laboratory experiments whose purity could be protected from external influences. These were concretely situated and inevitably messy enterprises, enormously dependent on the behavior and attitudes of the research subjects and carried out within a certain historical field of possibilities, with each trial having ramifications on concurrent and subsequent ones. Where Delaney was being more than slightly disingenuous was in his failure to acknowledge the extent to which organizations such as his own accelerated the kinetics (or the psychodynamics) of this system. Project Inform, for example, held regular "Town Meetings" and published reports in its newsletter detailing the latest thinking about the experimental AIDS drugs, in effect encouraging patients to believe or disbelieve, to comply with protocols or switch to other studies.
At the end of the day, the Antiviral Advisory Committee unanimously endorsed the use of CD4 counts as a surrogate marker for demonstrating the efficacy of nucleoside analogues in the treatment of AIDS. The way was paved for Bristol-Myers Squibb, the sponsor of ddI, and Hoffman-LaRoche, the maker of ddC, to file their applications with the FDA. Existing data on toxicity and efficacy, combined with CD4 data, would be enough to warrant licensing these drugs, Jim Eigo predicted. "Maybe a year down the road we'll find we made a mistake," David Barr told JAMA . "But the choice on the other side is no treatment." Ellen Cooper, who had sat out the meeting as a spectator, came up to Delaney toward the end. "You have to be careful with this, or you could do yourself more harm than good," she told him.