June 16, 1994

David Kessler, MD
Commissioner
United States Food & Drug Administration
5600 Fishers Lane
Rockville, MD 20857

Dear Commissioner Kessler:

We are writing with reference to FDA’s plans to regulate the development of a new class of anti- HIV therapies known as “protease inhibitors,” and with specific reference to possible regulatory decisions regarding Hoffmann-LaRoche, Inc.’s Ro 31-8959 (“saquinavir”).

As has been noted, both in meetings with you and your staff and in FDA Advisory Committee hearings, many of us are very concerned about the level of data that will be required for marketing approval of new classes of antiretroviral treatments. As people with AIDS/HIV, advocates and physicians [sic], we believe that people with AIDS are entitled to information about new therapies that is sufficient to make necessary risk/benefit analyses regarding their treatment. In regulating the first generation of antiretroviral drugs, many felt that a reduced evidential standard was appropriate, due to the absence of available treatments; now, however, we believe that the development of protease inhibitors offers a new opportunity to re-think this regulatory process in ways that will ensure reasonable access to new drugs, while producing clinically relevant information about their use. We would like to offer an approach to developing these therapies that combines access with the fundamental principles of clinical research. We believe that this approach can allow us to move as expeditiously as possible towards integrating the access and informational requirements of industry, FDA, and people with AIDS/HIV.

Specifically, we are concerned that Hoffmann-LaRoche, Inc. intends to apply for Accelerated Approval based on changes in CD4+ levels and virological markers observed in ACTG study #229. We feel that such an approval would penalize people with AIDS/HIV by setting an inappropriately low standard of evidential requirements that would govern the regulation of this entire class of therapies. We urge you not to invite Hoffmann-LaRoche to apply for Accelerated Approval of saquinavir until we can complete further discussion between FDA, its Advisory Committee, the company and people with AIDS/HIV.

Saquinavir, unlike d4T or ddC, is not yet an appropriate candidate for an accelerated NDA because it has not been studied for safety in a broad enough patient population for a long enough time, because Hoffmann-LaRoche’s proposed follow-up studies are flawed, and because the use of surrogate markers to evaluate potential efficacy in ACTG 229 is completely untested in this class of therapies. The current ddC-controlled NV 14256A study does not use a validated control arm in this population and, like the projected AZTcontrolled SVI4604A study, it lacks statistical power to determine probable magnitudes of treatment effect.

People with AIDS/HIV require access to life-saving treatment information. We have learned through difficult experience that we cannot depend on the goodwill of pharmaceutical industry sponsors to produce the information that is necessary to make life-or death treatment decisions. We believe that inadequate characterization of new drugs places PWA/HIVs in a deadly double bind: if a drug offers unmeasured, then people who refuse treatment may be losing opportunities for added health and life. If a drug is only as good as, or even worse than placebo, then patients taking it may be wasting time and money, and risking premature morbidity and mortality.

We are concerned too that, should Saquinavir be granted Accelerated Approval, future clinical investigators would then be ethically required to test new protease inhibitors against Saquinavir, despite the lack of demonstrated clinical benefit. As we have seen with the nucleoside analogues, this would compound the problems of characterizing future therapies, and compromise the ability to obtain information about the utility of this entire class of therapies.

Instead of Accelerated Approval at the present time, we would suggest that sponsors of protease inhibitors combine strategies from past drug development processes in ways that are designed to produce maximal information at minimal cost. Instead of the traditional expanded access program, we would suggest a large, relatively simple comparing two doses of Saquinavir to placebo in all HIV-positive patients with <500 CD4+ cells/mm3 (see attached concept sheet). Such a study would not need to limit or exclude concomitant medications, other than excluding other protease inhibitors, and, indeed, would allow people in the study to receive any nucleoside analogue regimen they may wish to choose, in accordance with the 1993 PHS state-of-the-art guidelines. The study should be accompanied by a salvage protocol for patients who have failed on all standard therapies, or who have, less than 50 CD4+ cells/mm3. We believe that such a study, properly designed, could be faster and cheaper than the standard drug development process, could synthesize the twin goals of broad access and rapid, definitive answers, and could provide meaningful data on how best to use this new class of potential antiviral agents.

This issue is of particular concern in that Hoffmann-LaRoche has failed to honor previous agreements to conduct large-scale post-marketing studies to confirm the clinical efficacy of Zalcitabine [ddC]. Before FDA provides input to Hoffmann-LaRoche regarding an application for Accelerated Approval for Saquinavir, we ask that all parties consider this proposal. We are currently scheduling meetings with manufacturers of the various protease products, including Hoffmann-LaRoche, and would like to meet with FDA as soon as possible. Please [contact TAG] to set up a meeting in the coming weeks to further discuss these issues.

We now have a unique window of opportunity to plan prospectively a coherent, rapid and clinically useful development path for HIV protease inhibitors, and to learn from the lessons gained by five years of disappointing and contradictory research on nucleoside analogues. We must not let this opportunity slip by.

We look forward to working with you to resolve these issues.

Sincerely,

David Barr Gay Men’s Health Crisis
Spencer Cox Treatment Action Group
Lynda Dee AIDS Action Baltimore
Gregg Gonsalves Treatment Action Group
Derek Hodel AIDS Action Council
Mark Harrington Treatment Action Group
Derek Link Gay Men’s Health Crisis
Bruce Schackman Treatment Action Group

cc:

Dr. Janet Woodcock
Dr. Robert Temple
Dr. Randy Wykoff
Dr. David Feigal