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FDA BREAKS TPA APPROVAL BLOCK: AD HOC ADVISORY GROUP CALLED IN TO SUPPLEMENT ADVISORY COMMITTEE AND IN-HOUSE REVIEW; FDA OK FOLLOWS FIVE-MONTH RE-REVIEW

Executive Summary

FDA's expedited effort to resolve the questions on recombinant TPA raised by its Cardio-Renal Advisory Committee culminated in approval of the product within five months of its initial rejection and within seven weeks of the sponsor's final submission of supplemental data. FDA Commissioner Young announced approval of Genentech's Activase (alteplase) on Nov. 13. "FDA did move exceptionally rapidly, proactively, in this process," Young declared at a Nov. 13 press conference. "Usually, after a negative advisory committee recommendation, it takes at the minimum of one year, to seven years on the outside, to have that particular recommendation answered and revised by other studies." Young specifically recognized the work of Center for Biologics/Associate Director for Research Elaine Esber, MD. "I believe that an awful lot of credit goes to Dr. Elaine Esber, under whose leadership the program was taken at the Center for Biologics," he said. Young also cited "cooperation" from NIH, "rapid action" on the part of Genentech, and an additional review by a special panel of consultants. The agency's objective in the re-review of the TPA application was to answer four questions raised by the advisory committee at its May 29 meeting. According to FDA's press conference version of the TPA re-review story, the decision could provide a model for future efforts by FDA to coax out information on significant, but initially incomplete, NDAs. Crucial safety information on intracranial bleeding episodes associated with TPA use, according to Young, came from an in-progress study sponsored by NIH, the TIMI II trial. "We needed a study that was blinded, was still not open," Young explained. "We were able to get very good cooperation from NIH to open up that study so we could know what happened with large numbers of people that were treated at the 100 mg dose." At the May meeting, Genentech submitted some data from studies that used a 150 mg dose. "At that time, there was a thought that [the rate of intracranial bleeds or strokes] could be as high as 4%, maybe 1.9%," Young remarked. "We now know that by using 100 mg instead of 150 mg the incidence of stroke is less than 0.5%." Regarding the question of whether clot lysis alone showed efficacy for TPA, Young said that the agency was able, "through very rapid action on the part of Genentech, to get a study that was almost completed at Johns Hopkins, submitted." That question, Young noted, "is no longer relevant because . . . we now know from Johns Hopkins data and some Australian data that TPA clearly improves heart function." An additional finding of the 140-patient Hopkins study was that similar clinical results were obtained with both the roller-bottle and suspension-culture forms of TPA ("The Pink Sheet" June 8, p. 9). While seeking approval to market the latter, Genentech, at the May 29 meeting, had presented data from clinical trials in which both formulations were used. "The final data submission by the company was Sept. 29, 1987 -- seven weeks ago," FDA said in its Nov. 13 approval announcement. "During this period, to aid in the evaluation of the data, FDA used outside experts to ensure that the medical community's views were fully represented." Young said that four months after the May advisory committee meeting, FDA convened a Sept. 2 meeting of the consultant panel. At that first meeting, the ad hoc group also rejected approval, deciding that the supplemental data were not sufficient. "We had a third meeting at the end of September which [found] all of the questions . . . answered," Young reported. The Sept. 2 meeting of the outside consultants indicates the tight schedule to which FDA was adhering. Throughout the summer, Young said publicly that the agency might have enough data to make a decision on the drug by Labor Day. By coincidence, the Sept. 2 review of the TPA application came at a propitious time for FDA. The day before, FDA approved Merck's application for Mevacor, grabbing the media's attention away from some of the close TPA-watching and editorializing that surrounded the review. Genentech's silent forebearance of the early September setback probably aided the company's cause. From the period immediately after the May 29 meeting until final approval, Genentech maintained a discreet posture toward the progress of the application. That helped set a better tone than existed prior to the May 29 meeting, when the company let expectations in the medical and financial communities get out of control. The company showed its sensitivity to FDA's position in the highly publicized review by keeping a low profile at the government's Nov. 13 press conference. Genentech officials visited FDA during the first week of November to discuss whether a joint press conference with FDA would be appropriate. Agency officials reportedly reminded Genentech that FDA has shied away from joint announcements in recent years. The agency did hold several joint press conferences at the beginning of the decade. To avoid any last minute public relations problems with FDA, Genentech delayed any comment on approval until after FDA's press conference on Friday morning. Genentech has agreed to undertake further Phase IV studies on TPA. Young said the agency is "looking forward very much in the next few weeks in negotiating and working with [the company] in designing the appropriate studies so that they will go on and we'll see some comparison studies." While Young attempted to portray the review as an extraordinary effort to work with a company to bring a submission up to approval standards, he continues to be plagued by the editorial campaign waged by The Wall Street Journal. Young was asked at the Nov. 13 press conference to comment on allegations that FDA officials improperly discussed Genentech's Activase application with members of the advisory committee at dinner the night before the May 29 meeting. The commissioner responded: "Basically, it was a dinner to celebrate the retirement of a chairman who had served seven years and the advisory committee was there with a few FDAers. There was no agenda, there were no business topics discussed." QUESTIONS ON TPA RAISED BY THE CARDIO-RENAL DRUGS ADVISORY COMMITTEE AT ITS MAY 29 MEETING AND RESPONSES PROVIDED BY FDA AT ITS NOV. 13 PRESS CONFERENCE 1. Is there an undue risk of intracranial bleeding using TPA? Safety data from more than 2,000 patients at a dose of 100 milligram from TIMI II and other studies not available at the Advisory Committee meeting has convinced FDA scientists that there is not an undue risk of intracranial bleeding using TPA. 2. Can clot lysis along serve as evidence of effectiveness for TPA? The question is no longer relevant because new data were made available from the Johns Hopkins and Australian studies showing that TPA clearly improves heart function in patients treated. 3. Did the two different methods of manufacturing TPA have any effect on the clinical results? The Hopkins study showed no differences in clinical effects using products manufactured by roller bottle or suspension culture methods. In addition, efficacy data have now been generated to support licensing of TPA prepared by the suspension culture method which will be used comercially. 4. Has a proper dose of TPA been established? 100 milligrams administered over a period of three hours.

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