AIDS TREATMENT NEWS No. 093; December 15, 1989
John S. James
The clinical trials of ddI need hundreds of volunteers and will probably have to run for two years after the last subject is recruited. The same delay applies to all HIV treatments, and therefore becomes a death sentence for tens of thousands of people -- although some of them will be saved by the parallel track. (The public does not realize that the faster approval of AZT cannot be repeated, because today it would be unethical to give research subjects only a placebo when an approved treatment is available, and it is much harder to get definitive results when comparing a new treatment to an active control than to a placebo.)
In the design of the ddI trials, statisticians computed the numbers of subjects needed, assuming a two-year study. The fact that the numbers came from mathematical computations gave them an aura of infallibility, unchallengeable by ordinary mortals. But we can and must examine what these trials are trying to do, and why.
The trial design -- including the two years, the hundreds of subjects, and the consequent need for time-consuming and expensive coordination of many widely distant medical centers -- was created to produce a single bit of information, one yes-or-no answer. The question to be answered is whether, if the drug really does nothing at all, the chance of the trial falsely concluding that the drug does work (just by chance alone) is less than a given probability (usually five percent).
Is this the question that most needs answering? Should this question be allowed to add two years or more delay to every new HIV drug? Should this question serve as a gatekeeper which prevents other research from starting until it is answered? Should it be allowed to make research so costly in money, facilities, and (most importantly) qualified personnel, that it limits the trials to a handful of new drugs, when there will soon be dozens that clearly deserve followup?
The real issue with ddI is not whether it works. A growing working consensus holds that it probably does. And drugs do not begin multimillion dollar clinical trials unless pharmaceutical companies, which are in the business of evaluating drugs, believe in them. The most important questions now are long-term toxicity, and when and how to use ddI most effectively in various groups of patients.
Some of this information will come out of the ddI trials -- but only by accident. Because the trials will take so much time, long-term toxicity data will be produced. And restrictive entry criteria will assure us much information about using ddI in certain groups of patients, and none about using it in other groups. The whole structure of the trials is built around the need to get that one statistical bit of information, to be able to walk away with that single yes-or-no answer -- not to answer the questions which are most important now to patients and physicians.
Trials which studied long-term toxicity by design instead of by accident could be started much sooner, probably as a continuation of phase I, and could use many fewer patients. The time and money saved could be used to test several other drugs which otherwise will be neglected.
The medical world today is obsessed with one nightmare -- that a worthless drug will come into widespread use. This danger is real, as such cases have occurred many times in the past. The problems come from using this nightmare as the sole gatekeeper which controls everything else, regardless of all other elements in the real-world situation.
A Better Way
A rational program for clinical testing and early use of new drugs would probably involve an expanding circle of research and treatment, starting with dose and toxicity studies and, depending on results obtained, moving continuously into wider use in appropriate groups of patients. The research aspect would be most intensive at first; then gradually the treatment aspect would predominate.
This expanding circle of use, with research most intensive at first, is what already occurs with conventional phase I, II, III, and IV studies. But today's process is not rational or planned as a whole. It is full of arbitrary discontinuities, prohibitively burdensome requirements derived from theories, and deliberate blindness to the actual questions, issues, knowledge base, and opportunities of the specific drug, in its social and public-health context.
Note that we are not suggesting dropping the legal requirement that drugs show efficacy before they are marketed. That is a different issue. We are saying instead that narrow efficacy testing should not completely dominate clinical trials, should not be applied blindly and rigidly in ways that straightjacket and paralyze the entire research enterprise.
A coherent, rational design for an integrated research and treatment process, using to advantage the specifics of each situation and addressing the actual questions at issue, could get the most important answers far faster than the present system, and at a fraction of the cost. It could bring many more drugs into trials than the present system, which is seriously overloaded with unnecessarily costly trials. It could bring us years closer to better treatments for AIDS, thereby saving most of the lives which otherwise would be lost.
This is one of the central research issues we intend to address in 1990.
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