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Another meeting with the (FDA) Commissioner, Rockville, MD, 11 July 1994. Bruce Schackman insisted that we all prepare overheads for our presentations, so we did. We took the train to Washington, D.C., and the Metro to Rockville. There we met Lynda Dee, resplendent in a peach-colored summer suit (with matching earrings, shoes and pocket book, no doubt), and Ellen Cooper at the new AmFAR CBCT office across the street from DAIDS, for a pre-meeting. The FDA met us in the Chesapeake Room in the Parklawn Building at 3:30.

David Barr pointed out that, as currently implemented, the Accelerated Approval regulations have failed to ensure that sponsors generate information about clinical utility post-marketing. People with HIV need access to information as well as to “un”-validated treatments. David Kessler took copious notes.

Gregg Gonsalves pointed out that the d4T hearing was badly programmed, and that the indication for which d4T was approved (salvage) is not the indication for which efficacy data may be forthcoming (second line). David Feigal pointed out that Bristol-Myers Squibb had promised to withdraw d4T from the market if BMS-019 does not prove clinical efficacy. “What if, as seems more likely, BMS-019 is inconclusive?” we queried. We don’t want market withdrawal — we simply want greater certainty that even modest treatment benefit will eventually be discovered.

David Feigal said the FDA Antiviral Drugs Advisory Committee would meet in the fall to review the current status or surrogate markers, expanded access and Accelerated Approval. Gregg Gonsalves pointed out that the 1962 Kefauver amendments were still the law of the land. He showed Tom Fleming’s analysis of the 16 randomized nucleoside trials which provided the basis for the 1993 state-of-the-art (SOTA) guidelines. In only two of the studies did CD4 rises correlate with a survival benefit. The overall predictability of CD4+ T-cell changes was 50 percent, no better than tossing a coin.

Spencer Cox showed overheads detailing problems with Accelerated Approval, and possible solutions. Surrogate markers (specifically, CD4) had proved disappointing. FDA should convene a periodic review of CD4 and other, newer potential markers, such as viral load measurements. FDA should require sponsors to hold a pre-phase II advisory committee hearing on their development plans is they were planning on applying for Accelerated Approval. The FDA could insure a “black box” on the labeling noting that accelerated-approval drugs had not yet been clinically validated (they had done this with d4T’s label). Finally FDA might consider fining sponsors who failed to meet their post-marketing commitments. Commissioner Kessler questioned whether FDA had authority to do this.

Michael Ravitch presented some problems with the Inter-Company Collaboration (ICC) master protocol. David Feigal said that Ed Skolnick, at the National Task Force meeting in April, was receptive to randomizing this study. Michael riposted that David Barry had sent several condescending letters to the effect that randomization and controlling were unnecessary fetishes. David Kessler asked to see these letters, which we will forward to him. FDA was receptive to urging the ICC to design a better master protocol.

We discussed Roche’s potential NDA for Saquinavir. FDA cannot disclose matters from on-going discussions with pharmaceuticals. “We made it clear with Accelerated Approval that we were not seeking any less data, but only a different kind of data,” Feigal said.

Wrapping up, David Kessler returned to the importance of the point about how Accelerated Approval needed to ensure the eventual development of answers, not only access, and indicated he would reflect on our concerns in a forthcoming article on Accelerated Approval. Speaking the next day to a reporter, Kessler noted that the community wants access to information, not just to potential new treatments.

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