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Problems With Protease Inhibitor Development Plans

February 1995

By David Barr, Spencer Cox, Gregg Gonsalves, Mark Harrington, Derek Link, Michael Ravitch & Theo Smart
Edited by Mark Harrington for the National Task Force on AIDS Drug Development

From the Introduction

The development of protease inhibitors offers the National Task Force on AIDS Drug Development the opportunity to best fulfill its promise of shepherding a coordinated effort to develop new drugs for HIV disease. If it rises to this opportunity, the Task Force could help coordinate the development of a new and possibly exciting class of drugs that may lengthen and improve the quality of life of millions of HIV-infected people. By articulating the significant problems we face in developing the protease inhibitors and then implementing a coordinated strategy towards addressing these problems, the Task Force could present an approach to drug development heretofore unseen, an approach that would place quality research and concern for public health above all other concerns. If the Task Force fails to take this opportunity today, then it has failed in its overall mission, has wasted precious resources and time, and most importantly, has lied to those of us so desperately looking for leadership in the fight against AIDS.

This report provides an analysis of the current development plans for protease inhibitors and raises many of the important questions that must be addressed if these drugs are going to be developed responsibly. Once again, a small and committed group of community activists has undertaken the challenging task of collecting the information, analyzing it and asking the questions that remain outstanding. The first and most puzzling question is why are we the only ones doing this? Certainly there are statisticians who can question the statistical power of the proposed studies better than we. Certainly there are researchers who can more expertly articulate concern about the appropriateness of the control arms. There must be virologists who can debate what the impact of lowering levels of virus may have on disease progression. There are several government agencies which are charged with the responsibility to protect the public health by devising, implementing and reviewing drug development plans to ensure that these potentially important new therapies are studied not just quickly, but well. Yet here is the first report that takes a comprehensive approach to protease development. We had to fight just to ensure that the agenda of this meeting would allow for a full discussion of the issues raised herein. How sad, how discouraging.

After attending a meeting at which the largest drug company in the world presented its meager plans for protease development, I wondered how those doctors felt about their work. Do they believe that their trials are sufficient to answer critical questions about their drug? Does the FDA believe that sufficient data exist to approve drugs on the basis of changes in viral load? If not, what are they doing about it? Is the NIH comfortable about having no role at all in this effort, one of the most important aspects of AIDS drug development? The Task Force presents us with our only opportunity to look at these drugs, not as individual products in a race toward the marketplace, but as a class of therapies about which several issues must be resolved if we are going to be able to use any one of these drugs effectively. The Task Force can articulate the issues and determine which parties can best answer each specific question. These questions include not only the validation of the markers, the issue of cross-resistance, and the appropriate statistical power of the clinical studies, but also questions about drug supply, expanded access, standards for accelerated approval and a framework for post-marketing study design, execution and analysis.

Some individuals within the community of which I am a part, in their desperation, seem willing to forego any standards whatsoever, just for the opportunity of putting a new pill into their mouths. I, for one, am not willing to accept a standard of care based on desperation. I still want to know if the pill works. Not just for myself, but because there are tens of millions of people who will be faced with making these difficult treatment decisions long after I am gone. They will want to live long, productive lives. They will want to believe that when their doctor gives them medicine, it will work. We have a responsibility to them. A responsibility to learn from our mistakes in the past. A responsibility to look past our own desperation, ambition or greed. A responsibility to the public health.

Early access and accelerated approval of protease inhibitors must be part of any development plan. Let me say that again, lest someone did not hear it the first time — early access and accelerated approval of protease inhibitors must be part of any development plan. The Task Force can play an important role in determining how best to provide access quickly, given the high demand and the real problems of drug supply. However, just as I am desperate for the earliest access possible to these drugs, I am equally desperate to know what a moderate and time-limited treatment-induced reduction in viral load means, how best to approach the problems of drug resistance, and how to obtain meaningful information about using these drugs in combination with the existing standard of care. Very few other parties in this debate seem committed to obtaining this information. If that is not true, then prove it. Begin here, at the place where all the relevant players are represented. If not here, then where? If not now, then when?

To read the rest of this report, please download the pdf.

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