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Rescuing Accelerated Approval: Moving Beyond the Status Quo

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A Report to the FDA Antiviral Drugs Advisory Committee


By Spencer Cox, Dennis Davidson, Gregg Gonsalves, Mark Harrington, Carlton Hogan, Rebecca Pringle Smith

12-13 September 1994 Silver Spring, Maryland

Moving Beyond the Status Quo: A Statement of Principles on AIDS Drug Development

Gregg Gonsalves, TAG

We believe that the development of a new class of antiretroviral agents, the protease inhibitors, offers a unique opportunity to improve the way we study drugs for HIV infection, incorporating lessons learned from the development of the nucleoside analogues AZT, ddl, ddC and d4T. We firmly support the right to earlier and broader access to experimental therapies for HIV infection that has been achieve through the use of novel regulatory mechanisms, including parallel track and accelerated approval. We also support the right of people with HIV infection to have access to the information they need to make well-informed treatment decisions about the drugs available to them.

People with HIV have a right to the earliest possible access to new therapies shown to be safe and which show a reasonable measure of antiviral activity in human subjects. However, the status quo has been unable to provide reliable evidence of the clinical efficacy of antiretroviral agents forcing people with HIV infection to make treatment decisions in the dark. While maintaining early access to new therapies through parallel track and accelerated approval, we believe we must supplement these mechanisms to give people with HIV the answers they need about the drugs they put into their bodies.

Accelerated approval allows the marketing of experimental drugs for HIV infection based on a suggestion of efficacy by sanitary changes in surrogate markers. However, the accelerated approval regulations require pharmaceutical companies to conduct studies to reliably confirm the clinical benefit of the drugs approved under this mechanism. Unfortunately, the agents granted accelerated approval by the Food and Drug Administration have not demonstrated clinical benefits for the indication for which they were licensed nor have the pharmaceutical sponsors of these agents initiated studies to resolve the unanswered questions about their use. There is currently no viable mechanism in place to compel pharmaceutical companies to demonstrate the clinical benefits of their agents as required by the accelerated approval regulations.

We must build upon our successes with expanded access and accelerated approval and finally offer people with HIV early access to new antiretroviral therapies and answers to the fundamental unresolved questions about these agents: is taking these drugs likely to be more helpful or more harmful than taking nothing at all? The Food and Drug Administration must insure that people with HTV will have these basic questions answered while maintaining early access to experimental therapies.

Right now, there is little credible scientific evidence on the clinical benefits of the currently approved antiretroviral therapies. Four drugs that no one knows how to use. The vast majority of people with HIV in the United States, if they receive medical care at all, are treated at public clinics, emergency rooms or in private practices with little experience in HIV disease. Primary-care providers in these settings are wary of prescribing drugs with unknown therapeutic effects and known toxicities. Only with credible information on their clinical benefits will these agents be offered to people with HIV from communities under-served by the medical profession, especially women and people of color, who are not connected with primary-care providers who have large HIV case loads and are willing to experiment with these new agents at their own discretion or at their patient's request.

Clinical research on anti-HTV drugs has not served people with HIV well in the past. Major questions remain unresolved after over five years of research on the currently approved antiretroviral therapies. Will these drugs keep me healthier and alive for longer than taking nothing at all? If they will, what agents are best to start with and when? When do you switch from one drug or drug combination to another? The list goes on. If we are to give people with HIV the information they need to keep them healthy and Irving longer, we are going to have to take a hard look at how we do clinical research. We cannot afford to continue to make the mistakes we have made in the past with the protease inhibitors and any other new classes of drugs that will enter the pipeline in the coming years.

Past studies of antiretroviral agents were designed to look for "home-run" or "magic bullet" drugs, with enormous effects. We were wishing and hoping for a penicillin for AIDS. We still are. However, the drugs developed for HTV infection have not been "home-runs," but they may be "singles" or "doubles." We have been unable to find out if the drugs we have may have small to moderate benefits (or on the other hand, small to moderate harmful effects) because the trials were designed only to look for something bigger and better. However, major effects may come incrementally: one moderate effect on top of another as four singles together get you to home base.

We can do better. Several proposals have been made. One series of proposals is for large, simple trials to evaluate antiretroviral therapies, including those from the Treatment Action Group (TAG) in New York City and the American Foundation for AIDS Research (AmFAR). What these have in common is that they are trying to give us answers about drugs with small to moderate effects. Preliminary results on the protease inhibitors do not indicate that they are "home-run" drugs. We need to be prepared to find out what benefits they can offer so we will not have several protease inhibitors on the market in several years without any information on their clinical usefulness.

Such trials also offer a way to validate new viral surrogate markers now in development. To show that a surrogate marker is a useful predictor of the clinical benefit of a drug, you need to conduct a trial that can show a drug can slow progression of disease or extend survival in which these markers are used. These markers cannot be scientifically and reliably validated in any other way. Once the new viral markers are credibly validated, it will be possible to further speed the development and approval of new drugs.

We can keep AIDS drug development as it is now and pretend nothing is wrong with the status quo. Those with vested interests would be happy to see no changes, even if they are changes for the better. Or we can move beyond the status quo and try to speed the development of and access to new experimental therapies for HIV infection while we also finally offer people with HTV accurate and reliable information that can save their lives.