Gay Men's Health Crisis "Treatment Issues"; Vol. 8, No. 7 - August 1994
Gabriel Torres, M.D. and Dave Gilden

The "accelerated approval" policy of the Food and Drug Administration has resulted in the marketing of nucleoside analogues based primarily on short-term, modest influence on CD4 counts. Information as to how well these drugs work in clinical practice is rarely published despite FDA requirements that companies conduct post-marketing studies.

Protease inhibitors will not be a cure for AIDS or HIV. Like nucleoside analogues, they present physicians and persons with HIV with a great conundrum. How are we to determine when and how well they work? How easily can HIV evolve to overcome this new therapeutic challenge?

A Large Simple Trial

To answer such questions, New York's Treatment Action Group (TAG) is proposing a large two-year clinical efficacy trial comparing various protease inhibitors to a placebo in a sample of approximately 18,000 people with HIV. This "large simple trial" (LST) would go beyond previous parallel track or expanded access programs that have allowed people failing standard therapies to receive experimental drugs even before FDA approval.

The phase II/III LST efficacy trial could commence immediately after the preliminary Phase I safety trials were completed. The trial would be open to nearly anyone with HIV, and participants could take any drugs they desired in addition to the protease inhibitor. While the proposed trial would offer access to the experimental protease inhibitor to thousands of people, one-third of the trial participants would receive placebo rather than protease inhibitor in blinded fashion, i.e. neither doctors nor participants would know who was in the placebo arm. But TAG also proposes a non-placebo trial comparing different doses of the protease inhibitors for people who have CD4 counts of less than 50, who cannot tolerate any of the nucleoside analogues, or who have reached advanced disease in the large simple trial.

The data collected in the LST would be much more extensive than that previously gathered from expanded access participants. This information on clinical outcome (incidence of opportunistic infections, death, etc.) would be recorded by people's usual physicians and would reflect the effects that protease inhibitor have during actual use by the public. The trial furthermore would lend itself to subset analysis, in which particular subgroups would be monitored for the predictive power of laboratory tests (such as for HIV levels in the blood (see below) and improvements in immune response), drug-drug interactions, and specific toxic reactions that might normally go unobserved.

By TAG's own admission, the LST proposal is a work-in-progress that needs further development and analysis. The group felt it had to act fast. The proposal's initial impetus was reports that Hoffmann- La Roche was considering seeking accelerated approval for its protease inhibitor, saquinavir, on the basis of the data from the government-funded trial ACTG 229 - a trial with somewhat ambiguous results. [See Treatment Issues, June 1994.]

The Drawbacks

Although the LST concept has a number of attractive features, there are also a number of immediate drawbacks. Conducting a large trial would consume huge amounts of resources in terms of research dollars, human bodies exposed to an experimental drug, and attention diverted from other potential therapies inching their way through the pipeline. No one has ever organized large simple trials among HIV positive patients in the U.S., nor has anyone ever analyzed the costs in detail. A more "traditional" expanded access program would also be very costly.

The diverse, volatile factors influencing recruitment of volunteers for such a study are also unknown: A smaller LST evaluating immediate versus delayed AZT therapy in San Francisco is presently having difficulty enrolling patients. A large simple trial of protease inhibitors risks becoming similarly out-dated before enough people sign up for it.

Protease inhibitors are enormously expensive to produce, and the resource question has loomed large in TAG's discussions with drug companies over its proposal. Hoffmann-La Roche postponed a meeting with community representatives on the East Coast. The company has long claimed that the difficulty and expense in producing its saquinavir product limits its ability to expand supply. Roche is conducting two large multi-center trials, however, involving a total of 4,200 participants. These trials will collect data on disease progression and survival, although TAG questions whether their size will be large enough to really document saquinavir's benefits given the drug's medium level of effect on HIV. (Saquinavir may be more effective at higher doses, according to initial observations of a high-dose saquinavir trial being conducted at Stanford University.)

Merck & Co., whose protease inhibitor (L-524) is the next furthest along in development, did meet with TAG recently, but Merck officials plan on following their previously laid-out development strategy. The company, which has had, to its credit, extensive and open discussions with community representatives, does not want to go the accelerated approval route with the FDA. Merck wants to thoroughly test its drug, including completing small trials that document L-524's effect on physical symptoms, before seeking marketing approval. It will therefore probably be two or three years before L-524 is for sale, and in the meantime, Merck is planning no expanded access program. L-524 may be a very useful tool against HIV, but it will not be a cure or "home-run" drug. The company's position is that, at this time, L-524's potential does not appear great enough to merit what it claims is the substantial investment in rapidly expanding production at this time.

TAG representatives came away from the Merck meeting very disappointed. "We wanted both access and answers [as to how the drug works], and we're getting neither," one said. Access and Information

Are there other methods of screening protease inhibitors and other promising medications in a more efficient and rapid manner? One option might be to conduct a smaller placebo-controlled trial in people with advanced AIDS. Data collection for this trial would center on the ordinarily high incidence of opportunistic infections and deaths in the group. The results might provide a "quick-and- dirty" answer as to whether protease inhibitors provide any clinical benefit to this population. However, there are serious practical and ethical questions about a placebo study in such seriously-ill patients.

If the trial ends with positive data, it would encourage both drug developers and trial participants since both would have benefited, at least temporarily. But the study population in this case has high initial HIV levels and rates of replication. If not completely suppressed, the virus could rapidly rebound as it develops drug- resistant mutations and spreads into the fresh crop of uninfected CD4 cells. One fears a replay of the AZT story, in which rapid FDA approval, widespread use outside of the populations in which the drug had been tested, and the absence of long-term data, led to eventual disappointment.

New technology may help avoid the disappointments of the past. Tests such as "quantitative polymerase chain reaction" and "branched chain DNA" measure HIV levels in the blood and can be used to correlate changes in viral burden with antiretroviral therapy. These tests offer the possibility of continuously and directly monitoring the effect of protease inhibitors (and other experimental drugs) on HIV activity from the beginning of a clinical trial. Yet it remains to be seen how closely levels of HIV correlate with disease state, and more importantly, whether short term reductions in HIV viral load can provide real benefits in terms of disease progression and survival. HIV viral burden will have to be evaluated within the context of other variables, including immune system parameters (such as CD4 count) and, most importantly, clinical outcome.

Still, the final, definitive trials - that demonstrate under real- world conditions, whether protease inhibitors work, when is the best time to initiate therapy, and how to combine these compounds with existing therapies - will necessarily follow the large simple trial concept. Such trials need not be conducted prior to a drug's approval by the FDA, but they should already be underway and their continuation assured. Cooperation between industry, government agencies, patients from diverse communities and primary care providers will be essential in completing these trials.

One of the best contributions of the TAG proposal is the debate it has sparked over expanded access and accelerated approval. There are no easy ways to balance the different demands for quick access to drugs and more information about their use. Once a treatment is available in the community, it is difficult to organize the studies needed to document its effect. The time to thrash out this issue is now, not when protease inhibitors start coming before FDA Antiviral Drugs Advisory committee for approval.

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