AIDS TREATMENT NEWS No. 065 - September 23, 1988
John S. James

An important book which reviews both sides is Ethics and Regulation of Clinical Research, by Robert J. Levine, M. D., published by Yale University Press, New Haven, Connecticut, 1988. Dr. Levine is Professor of Medicine at Yale, and a well-known ethicist.

A chapter on randomized clinical trials (RCTs) includes a four-page section titled "Excessive Reliance on RCTs", which reviews papers by scientists proposing other study designs. These scientists see randomized trials as a valuable tool -- but imposed excessively on U. S. medical research by the FDA and the National Cancer Institute of the NIH, "agencies which control the entry of new therapies into the practice of medicine", "through their refusal to accept data developed with other methods". Others have shown through statistical studies that randomized trials have often failed to prove what they claimed to have proved.

One analyst described the conflict between "pragmatic" researchers (including most clinicians), and "fastidious" ones (including biostatisticians), with the fastidious school dominating clinical trials. The result is "clean" study designs which do not reflect actual medical practice. And a larger problem, though barely hinted at in Dr. Levine's book, is that the practical difficulties of meeting "fastidious" study requirements often cause grave delays, or even prevent important research from being done at all.

The arguments we have heard against more practical designs are:

* That each separate drug must first be tested by itself to show efficacy; it is not OK to test a treatment consisting of a combination of drugs not already tested and approved separately. (This argument supports the commercial needs of pharmaceutical companies, which want each of their products tested and approved by itself, not in combination with competitors' products.)

* That new antivirals cannot be tested in doctors offices. Instead, such "phase I" trials often hospitalize patients in medical centers for the first weeks, for elaborate testing. (We agree with this procedure for new, high-tech drugs such as CD4 or DDI -- but not for herbs, foods, common chemicals already in human use, or prescription drugs -- which already have long records of human use, with toxicities either unimportant or known.)

* The only good way to prove efficacy is with a randomized clinical trial, meaning that patients who volunteer do not know which of two or more treatments they are going to get (one may be a placebo). (We agree that such trials have a major place -- but they involve great practical difficulties which have often delayed results for years. Most of the delays and difficulties can be avoided by tight, scientifically designed trials built around the kinds of medical intervention which patients would be receiving anyway.)

The mainstream drug trials commonly take a year or much more before they even begin, to get approvals and funding. Many have such impractical entry criteria that it takes months to recruit even a single patient; these studies are doomed before they start, but they go through the motions anyway, giving the impression that something is being done. Other trials do collect potentially useful data, but keep it secret for a year or more until the slowest trial centers complete their last patients. Then results can take months to analyze, sometimes because the only people important enough to make decisions are too busy to find mutually acceptable times to meet. Finally the results must be kept quiet and unavailable to most physicians and patients for the months or more until publication. And even after publication there is no organized way to get the results to the attention of most of the physicians who could use them.

This system usually takes years to test each interesting possibility -- if it ever does. This slow "turn-around time" has a disastrous effect of research results and productivity, because years are required for each full cycle of idea, test, and evaluation, and many such cycles may be needed to get practical results.

These problems represent poor management, not good science.

The research establishment is now coming to accept the concept of community-based trials -- a concept endorsed by the Presidential Commission on the HIV Epidemic. But we fear that this establishment wants to keep community-based trials in the same straightjacket as conventional studies.

If community trials are required to repeat the unfeasible designs and procedures common in mainstream trials, they will be just a pale, underfunded imitation of the ineffectual system we already have.

Dr. Levine's section on excessive reliance on randomized trials mentions an alternative design, called observational case control studies, which is practically identical to the drug-trial proposals developing in the AIDS community:

"This design entails systematic observation of patients as they are treated by practicing physicians. Inclusion and exclusion criteria exactly like those used for RCTs are used to determine who will be observed. After the outcome has been esta- blished, patients are sorted by outcome, e.g., fatalities and survivors. Causes of the outcome are evaluated as in case-con- trol studies."

Anyone organizing community-based trials should scan Ethics and regulation of Clinical Trials and the literature it cites (the book has over 700 references). The AIDS community does have authoritative scientific support for the kinds of studies which need to be done.

880923
ATN06502

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 1988. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .