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NSAID ADVERSE REACTION REPORT DATA MAY REFLECT ADVERSE REACTION PROFILES AS WELL AS CONTROLLED POST MARKET TECHNIQUES, FDA's TEMPLE TELLS ADVISORY CMTE.

Executive Summary

Statistical compilations of nonsteroidal anti-inflammatory drug (NSAID) adverse reaction reports may reflect adverse reaction profiles as well as controlled post mkaret surveillance techniques, FDA Office of Drug Research and Review Director Robert Temple, MD, suggested at an Arthritis Drugs Advisory Cmte. meeting April 29. Commenting on a system of compiling NSAID adverse reaction reports developed by FDA staffer John Harter, MD, Temple said that "nobody receives signals or accepts signals that aren't fairly large. I think that is not different from what one does with cohort or case control studies. My feeling is that it remains to be shown whether a five-fold or a ten-fold signal here isn't just as meaningful as a two or three-fold signal in some kind of cohort study or case control study." While he acknowledged that the system of compiling adverse reaction data for NSAIDs contains "problems that come when you start looking closely at the data," Temple concluded that "sometimes you turn up a very large multiple of what you expect, five or ten fold, and I think the history is that those may well be meaningful, and have been" in the past. The April 29 advisory cmte. discussion was devoted to a review of Harter's tabulation of 1984 ADR reports for the NSAID class. At an initial discussion of the data last fall ("The Pink Sheet" Oct. 29, 1984, p. 3), the cmte. concluded that the therapeutic ranking of individual NSAID drugs could not be based upon ADR report comparisons derived from Harter's compilation of data. Commenting on the potential usefulness of the adverse reaction tabulations, Harter said: "To do something with the signals that come out, you have to go from looking at the terms to looking at the cases. That is always an interesting process and it is one in which my rule of thumb is [that] I think one case out of ten in this system is useful." Requirement For Reporting Of ADRs Within 15 Days Leads To Duplicate Reports In System -- Harter In 1984, FDA's voluntary reporting system received 16,911 ADR terms associated with NSAIDs. Harter ranked 10 approved NSAIDs on the basis of cases per million U.S. prescriptions rather than on ADR terms as long as there was a minimum average of two cases per drug. In Harter's tabulations, any drug that fell within a range of 10% of another drug's number of cases per million prescriptions was tied in rank with that drug. Referring to his ranking of NSAIDs, Harter said: "It's not that important anyway, it just indicates those that are close to each other. Sometimes there's not much that separates them all." Harter, with the assistance of several drug mfrs., discussed the "artefactual blips" that are evident in this ranking of the NSAID class. "Blips exist when somebody has got a percentage that's higher or a number that's higher than the other drugs in a class," Harter explained. Many of these blips, when dissected by Harter and the company representatives, were attributed to flaws inherent in the system or by the data fed into the system. In response to a question posed by cmte. member Edith Schwartz, PhD, Tufts University School of Medicine, on the importance of foreign data, Harter responded that it is important to expand the data base so that "subset questions" (the more uncommon, unique problems) can be addressed. On this same issue, Temple commented that since there is a life cycle to reporting rates, an additional two year's experience gained in a foreign country might prove very useful: "One thing you might ask if a drug happened to be approved elsewhere earlier was whether what appears to be a hot spot in U.S. data is persisting as a hot spot in foreign data." Harter highlighted for the cmte. the difficulties in trying to interpret ADR report data. Among these were the problems created by duplicate reports getting into the system, the difficulties in obtaining foreign data, and the spottiness of the data that is received. To illustrate this last problem, Harter showed how in a breakdown of upper gastro-intestinal ADR reports, in fully one-third of the cases the drug's indication was not specified. "What's striking here is that the non-reported is a very big category; and even for drugs that are almost surely used most of the time for rheumatoid or osteoarthritis, the number's zero for most of them," Temple commented. In response to a question from cmte. member Leslie Dornfeld, MD, Harter said that he is working to refine the system to allow for more representative comparisons between specific drugs. "What we are trying to do is take the first three years of marketing of a drug and monitoring it against the first three years of any other member of the class." Another refinement, he said, would be "to look at only serious reactions and leave the nauseas and the things that are by themselves sort of non-specific and show up in a lot of different body systems, leave them out of that and just pick certain terms and look at the first three years." Harter observed that "duplicate reports, [are] a big problem for us. Companies that are most aggressive about meeting the 15 day reporting requirement" under FDA's recently revised adverse reaction reporting regs "have to send us preliminary reports about cases because they don't have follow-up. And then what happens is a report will get in there two or three times because the follow-up case has added information . . . and a case can get in there under a slew of terms."

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