Genentech's TPA Faced Tougher Test Before FDA

WASHINGTON—False assumptions, deficient data, lack of guidelines and a bureaucratic handoff all figured in a federal advisory panel's decision last month not to recommend approval of tissue plasminogen activator (TPA), widely touted as biotechnology's first "blockbuster" drug. The Food and Drug Administration (FDA) panel's action stunned Genentech Inc., the South San Francisco company that had hoped to begin marketing the blood clot-dissolving drug this summer. The company said it hopes to satisfy the panel's objections within, eight months, but some biotech industry analysts say the decision has set back Genentech's efforts by more than a year, providing an opportunity for competitors to catch up. The FDA advisory panel said May 29 that, although Genentech had provided adequate data showing that TPA dissolves blood clots, its studies did not show that the drug prolongs patients' lives or protects their cardiovascular function. Earlier that day, the panel had recommended approval for intravenous use of streptokinase, an older, less efficient clot-dissolving agent previously approved only for direct coronary artery injection in treating heart attack patients. Observers say Genentech's presentation suffered in comparison with the well-crafted studies adduced in support of streptokinase. Genentech officials had assumed that data showing TPA's clot-dissolving properties would be sufficient to obtain FDA approval, based on the agency's acceptance of similar data in approving streptokinase in 1982 and on its original assurance that mortality data on TPA would not be needed. But by an 8-to-1 vote, the FDA advisory panel of cardiologists and academicians recommended that Genentech be required to produce more persuasive data from clinical studies now underway. Such advice is not binding on FDA Commissioner Frank Young but is said to carry great weight. Genentech applied in 1983 for FDA approval of TPA. The agency's office of biologics held the application until last year, when it asked the cardio-renal division for "a consult" concerning some of the medical aspects, according to Joyce Bagley of the office's division of product certification. The cardio-renal division in turn sent the matter to its advisory group of outside experts. Although the FDA often seeks guidance from such panels about pending drug approvals, "we almost always wait until all the information is there before going to the advisory panel," said an official in the division. The highly publicized case of TPA was different, however. "The [cardio-renal] division brought it to the panel because they didn't want to have to say [no] to the company. They wanted the panel to," said Bruce Mackler, counsel to the Association of Biotechnology Companies in Washington. The handoff within the agency changed the rules of the game, observers agree. FDA spokeswoman Faye Peterson said the biologics group works closely with companies on production and safety issues, whereas cardiologists are more interested in knowing whether a product prolongs life. "This was one of the problems that caused the glitch," said Robert Kupor, a biotech analyst with Cable Howse & Regan in Seattle. "In the end, the decision was made by a group that never talked to Genentech." The original approval for streptokinase, by contrast, came from the office of biologics rather than the cardio-renal division, noted Joan Standaert, executive secretary of the advisory panel. Yet Genentech's studies contributed to the problem. Most data involved patients treated with TPA made before 1985, when the company found a more efficient way to produce the drug. Genentech contends that the variants are essentially the same. Genentech also relied heavily on studies it had not commissioned, including some performed by the National Institutes of Health. But "NIH does its studies for its own reasons, which are not necessarily related to the drug approval process," noted Standaert, who voted against recommending approval. Other data involved clinical trials performed in combination with angioplasty, in which a balloon catheter is used to enlarge narrowed sections of blood vessels. Those were unacceptable, Peterson said, because it's difficult to trace which effects result from TPA and which from the angioplasty. Genentech, although it has had three products approved by the FDA, still lacks the regulatory experience of major pharmaceutical firms. It also was proceeding without benefit of the guidelines formerly issued by the FDA to companies seeking approval for new drugs. The Reagan administration's anti-regulatory emphasis has cut down on such guidelines, an FDA official noted, and none were available for streptokiase or TPA. Genentech's rivals see some salient lessons as they develop their own clot-dissolving drugs. "It helps to be the second instead of the first," said Nan Ducharme, a spokeswoman for Integrated Genetics of Framingham, Mass., which is testing a second-generation version of TPA in clinical tri als in Japan. "It's a matter of [learningj how much information and in what form it's required." Bennett is a science writer in Washington, D.C.

Genentech's TPA Faced Tougher Test Before FDA

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