HOECHST-ROUSSEL's MERITAL APPROVAL WAS BASED ON THREE PIVOTAL STUDIES OUT OF 17, FDA's TEMPLE TESTIFIES ON HILL; REP. WEISS ASKS FDA TO REVIEW FIRM's REPORTING

FDA based its December 1984 approval of Hoechst-Roussel's antidepressant Merital (nomifensine) on three pivotal studies out of 17 clinical trials performed in the U.S., the agency's Drug Research & Review Office Director Robert Temple, MD, testified at a congressional hearing on May 22. Speaking before Rep. Weiss' (D-NY) House Govt. Operations/Intergovernmental Relations Subcmte., Temple noted that the "review of nomifensine was not an easy one, and the time to approval was about six years." Efficacy evaluations were "complicated by a large number of studies that could not distinguish nomifensine from placebo," he said, but the test drug "did not appear less effective than the standard agent," imipramine. Ultimately, FDA concluded "five adequate and well controlled studies . . . demonstrated effectiveness," although two had "weaknesses," he said. Temple distinguished "null" studies from negative studies. The remaining Merital trials were not negative, he said; their "assay sensitivity" was not sufficient to demonstrate a difference between either nomifensine or imipramine and placebo. Hoechst-Roussel voluntarily withdrew the product from the world market last January due to reports of fatal hypersensitivity reactions. Weiss questioned FDA about the size of the pivotal studies. He said that one of the three studies included only six patients who were treated with nomifensine and whose results could be analyzed, and another trial included just 19. Temple insisted that the studies showed statistically significant evidence of efficacy. However, FDA Biostatistician Richard Stein, PhD, acknowledged that in his judgment the results of one pivotal study, which included a predominance of elderly males, could not be extrapolated to the general depressed patient population. FDAer Leber Does Not Understand Recall: Other Antidepressants Have Side Effects Also Neuropharmacological Drugs Div. Director Paul Leber, MD, said he did not understand Hoechst-Roussel's recall. "I don't know why Hoechst pulled the drug," Leber said. "I believe," he testified, "on the basis of evidence available to us, this was an effective antidepressant; there is no doubt it had a panoply of risks that were unattractive, but so do the other marketed drugs." Leber explained that "the whole point of getting a new class of antidepressant on the market is based on the idea that there are treatments that don't work out there . . . [and] have many unpleasant, untoward side effects and at best work in only 70% of the depressed patient population." Perhaps "someday we'll understand the etiology and pathogenesis of depression, and we'll be able to make a targeted drug," he said. "But at the present time, we're really hoping to get out there a drug that might work." Due to the "problems about the prevalence of the type of depression that might respond to a given drug, it may be very hard to show the efficacy of drugs. We still don't know which drugs to use for what particular treatment. As a matter of fact this subject is a matter of ongoing discussion in academia." Consequently, Leber continued, one of the things FDA "can do as an agency, I think, is to say if the drug works, if it has proven efficacy, and its risks are adequately labeled; it belongs out there in the hands of practitioners and patients who can make the judgment at the bedside. It's very hard for [FDA] to to decide whether or not a drug which might be useful should be held back because we have some global estimate of this metaphor called 'risk/benefit.' It's an ad hoc decision in every case. This drug had been marketed for a long time in Europe with a very good safety record" before FDA approved it. Noting that Merital was approved in December of 1984, Weiss criticized FDA's recent trend toward releasing a flurry of approvals at the end of the year. Since 1980, 30% of new chemical entities have been approved in the month of December, whereas only 0.8% have been approved in January, Weiss pointed out. FDA has "set up a criterion for yourselves of demonstrating increased numbers of approvals. When you get down to December and you're not satisfied with your numbers, you go pall mall about approving drugs in December," he charged, adding: "I just don't think that's really an appropriate way for you to conduct your business." Temple responded that "it's inconceivable that an approval decision can be made" in a month. "The major action on a decision occurs either at the time that we send an approvable letter or, if there is no approvable letter, an approval letter." Approvable letters for Merital were issued in the months of April and August, Temple noted. Although 16 of 30 new chemical entity approvals in 1985 were approved in December, when approvable letter dates are considered, he said, "the apparent incredible number of activities in December is substantially less impressive." Temple said "there were seven approvables of first approval actions in December," six in November, six in August, four in May, and "a scattering in July, September and October." Therefore, "the guts of the actions, the hard part . . . were spread out reasonably well over the part of the year from about May to December," Temple continued. On the other hand, "it is certainly true that a lot of things happen quicker toward the end of the year. Our finding is, for example, that companies come to meetings faster, they tend to agree to our labeling suggestions faster -- a lot of things happen. They obviously have deadlines in mind," he said. Weiss urged FDA to review the Hoechst-Roussel's handling of the situation with an eye toward recommending Justice Dept. prosecution for delays in submitting adverse reaction reports the firm had received. Temple answered: "Yes, we will review [FDA files], particularly the material you have put together." The congressman noted that a Swiss medical journal reported in 1983 that 51 Merital patients were examined and found to have formed antibodies to the drug, indicating allergic response. Hoechst-Roussel submitted the report in December 1984. Weiss also charged that adverse reports of hemolytic anemia were reported last January in a routine submission though the company knew of them in the fall of 1985. Temple testified that even if FDA had known of the Swiss report indicating 100% antibody formation in Merital patients, it probably would not have changed the approval decision. Furthermore, he said, even increased reports of hemolytic anemia might not have changed the decision. FDA decisionmaking, he explained, relies more on what effect a drug has on people than on its mechanism of action. "While the mechanism is considered interesting and perhaps important, it is not considered something that tells you per se . . . whether the drug has a big problem," Temple said. "Obviously you don't want to form antibodies if you can help it, but a lot of drugs do; the question is always, 'What does it do?' . . . [and] mechanism doesn't tell you anything about severity or frequency." For example, the fact that "penicillin causes 50% of the people who get it to develop antibodies is hardly reassuring by itself," he noted. "It happens though that most people who get penicillin and use it don't have unacceptable adverse reactions, so the drug is useful." Regardless of the mechanism, Temple continued, at the time of FDA approval, "in six years of marketing [in Europe] . . . people had not died of fever, people had not died of hemolytic anemia," and the reactions were reversible.