AIDS TREATMENT NEWS No. 093; December 15, 1989
John S. James

From Access to Oversight?

Last January we predicted that access would be the major treatment issue of 1989. At that time it was already clear that no major treatment advance would be approved in 1989; one could know that by looking at the drugs in the clinical-trials pipeline. Therefore, the issue would be whether people could use promising treatments while they were still experimental -- treatments like ddI which probably work but will take years to acquire statistical proof that they do.

Great progress on access was made last year, thanks largely to two key events: Fauci's proposal for a parallel track, and the ddI program developed by Bristol-Myers in cooperation with the FDA, AIDS activists, front-line physicians, and others. Major problems remain, and questions, issues, and conflicts around access will be very much with us in 1990. But we think that another issue may become central next year -- the need for better definition, design and management of the clinical trials, so that they can respond better to the needs of the public-health emergency.

We see resources as the most important single issue of 1990 -- money for prevention, research, treatment, and other care. Since we are not experienced in financing issues, we will follow the lead of service organizations and others. We are familiar with research, however, and here we believe that effective scientific and administrative oversight of the trials will become a critical issue. It has been the most important issue all along, but until now little has been said about it. Pressures are building to end the silence:

* No major approvals in 1990. It is already clear that no important HIV treatment will be approved in 1990 under current procedures. ddI and ddC are now farthest ahead, but approval for each must wait for (among other things) trials which will probably take two years. And neither of these clocks has started yet, because each only starts when the last patient called for by the respective protocol has been recruited and entered into the study.

As we will show below, this problem does not arise from any law of nature, but from unexamined assumptions in an overlooked meeting place between scientific study design and public policy. Critical options have been ignored because policy makers lack the scientific background to develop them, scientists lack the authority, and institutions lack the incentive. The growing AIDS case load and continually worsening emergency are increasing the pressures to bring the light of public examination and debate into some previously dark corners.

* Parallel track limitations. A pivotal event of 1989 was the proposal by Anthony Fauci, M. D., Director of the National Institute of Allergy and Infectious Diseases (NIAID), for "parallel track" access to promising treatments while they are still being tested in clinical trials. Until Fauci's proposal, the dominant idea had been that no early or compassionate access should be allowed for AIDS treatments, because otherwise people would not volunteer for clinical trials. Much of this thinking had been based on a misreading of the case of the drug ganciclovir, made available for compassionate use to thousands of people over a several-year period to prevent blindness from AIDS-related cytomegalovirus (CMV). The pharmaceutical industry wrongly assumed that ganciclovir's developer, Syntex Corporation of Palo Alto, CA, was being punished by the FDA for making an AIDS drug available through compassionate use.

Since an analysis of the new drugs in the pipeline showed that no important HIV treatment would be fully approved for several years, this prevailing mindset was a death sentence for tens of thousands of people. Fauci's parallel track proposal broke this mental logjam and opened a door for new thinking throughout government and industry. The head of the world's largest AIDS trials program had proposed that some early access could be allowed without damaging the trials. The new openness allowed the development of the system for early access to ddI -- a development unprecedented both in its speed, and in its bringing together of many different interests, getting some of the people involved talking to each other for the first time, to produce results.

Parallel track is urgently necessary. But it will not solve all the problems:

(1) Parallel track requires the good will of the company which has the exclusive rights to each new drug. The company must spend money to save lives, with no certainty of reward. Many will be unwilling to do so.

(2) Individuals receive the drug without charge but pay for required physician time and laboratory tests. Third-party payers will probably learn to identify these expenses and refuse them as "experimental," meaning that parallel track may be even more limited by social class than standard medical care. It will be difficult to define standards of care if crucial parts of care come to be delivered on an optional, "experimental" basis.

(3) The most important question is what drugs to use and how to use them. Clinical trials are supposed to help answer these questions. There are no trials designed to address the needs of parallel track. Parallel track lives only on the crumbs of knowledge which happen to fall out of trials designed for something else. (This isn't as bad as it sounds, however; clinical-trial design has so lost its way that standard medical practice lives largely on such crumbs, also.)

Despite these reservations, we totally support the parallel track. It is a life and death issue and there is no alternative ready to go. Sometimes a second-best solution is infinitely better than no solution at all. Parallel track is an emergency stop-gap until the entire system of clinical trials can be rethought and redesigned.

* The clinical-trials logjam. Those who run the major Federal system of AIDS clinical trials, the AIDS Clinical Trials Group (ACTG) system in NIAID, are quick to admit that the system is overloaded and cannot keep up with the important new drugs coming out of the laboratory. People are tired from overwork due to inadequate staff; tasks which everyone agrees are important are postponed or eliminated. The problems only look worse in the future as there will be more people with AIDS, more new drugs to try, but no more and maybe even less support from Congress.

Behind this problem is the fact that new-drug approval in the United States has become so elaborate and inefficient that it costs an average of $120 million for each new drug approved. The ACTG system, started from scratch to provide grants for testing AIDS drugs, cannot be expected to test dozens of new drugs under these rules with the limited resources available.

* Serious administrative problems. At a closed ACTG meeting on November 6-8, 1989, it was announced that no major new trials could start for six to nine months -- an estimate which may be optimistic. The reason is that the statistical and data- processing center for the ACTG system was being moved from Triangle Research Institute to Harvard University, and the new center would not be ready until then. This delay most seriously impacts trials for opportunistic infections, since other trials were not ready to go anyway.

In any system adequate to meet the needs of the emergency, no such delay would be tolerated.

* Questions about lack of results. A December 12 memo from ACT UP/New York to Federal agencies and others begins with the sentence, "After three years supported by hundreds of millions of public funds, the AIDS Clinical Trials Group (ACTG) has yet to develop data leading to a single new treatment for any HIV related condition."

We are not close enough to the ACTG to evaluate its performance independently. But ACT UP's Treatment and Data Committee is very well informed about the ACTG system and its problems.

Needed: Effective Oversight

It seems clear that some capable and independent oversight body needs to examine and analyze the record, point out problems or improvements needed, and see that the changes are made.

The National Commission on AIDS will not do this job. It is working in other areas and has no interest in oversight of research.

The well-regarded Institute of Medicine of the National Academy of Sciences has a committee to investigate the ACTG system. It remains to be seen whether this group will be effective.

The entire area of clinical research needs a thorough examination by top scientists and top administrators, with the staff, resources, authority, and independence to do the job.

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