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Executive Summary

FDA's guidelines for adverse drug reaction reporting under the new NDA regs will provide two alternate definitions of "increased frequency " -- which is a trigger for filing a 15-day alert report, FDA Drugs & Biologics Epidemiology and Biostatistics Associate Director Gerald Faich, MD, told the Food & Drug Law Institute's (FDLI) Annual Pharmaceutical Update meeting May 13 in New York City. Under the reg, which becomes effective May 23, mfrs. are required to submit 15-day alert reports for a "significant" increase in frequency of "serious and expected" reactions as well as for "serious and unexpected" adverse drug experiences. The agency will propose "a statistical approach, which speaks to 95% confidence levels, or an arithmetic approach," Faich said. The arithmetic approach would define "increased frequency" as a doubling in a comparison period over "what would be expected. . . after adjusting for market share." The FDAer explained that the length of the comparison period depends upon how long a drug has been marketed. "If you are a newly marketed drug, you compare it to clinical trials," Faich told the meeting. "If you are a drug that's been on the market at least one quarter, you compare it to the prior quarter for the first three years. If you've been on the market for three years, you compare it to the prior year." In his presentation, Faich described the revised reporting requirements and highlighted sections of the forthcoming guidelines. However, he cautioned that since the guidelines are still several months away from publication, many of his remarks "have to be viewed as preliminary." Faich mentioned that while the regs are not totally explicit about how often increased frequency should be analyzed, "what they do say is at least as frequently as periodic reports." In cases of "increased frequency," the 15-day alert report should be in the form of a "narrative," Faich said. If a serious "unlabeled" (not in current labeling) reaction is reported, a form 1639 must be submitted. Describing the periodic report, Faich identified four essential components: (1) form 1639s that were not submitted in the 15-day report, meaning domestic non-serious or domestic serious at normal frequency; (2) an index or a line listing of those 1639s; (3) a narrative summary of what has been submitted in that new period report as well as the 15-day reports during the interval; and (4) a narrative of actions taken related to ADRs. The rewrite requires that periodic reports be filed quarterly during the first three years after approval, and yearly thereafter. Faich noted that, in general, the regs do not apply retrospectively. However, "if you've got an NCE [new chemical entity] approved in the last three years," Faich explained, "you are under quarterly reporting until the third anniversary, then you go to annual . . .If you've got a non-NCE approved during the last three years, you are on annual reporting. And if you've got a new drug approved after May 23, you are on quarterly reporting for three years and then annual." The FDAer pointed out that the period reports explicitly exclude all reporting of ADRs that derive from studies, foreign sources or the literature. Foreign Sources Reguire 15-Day Reports Accordingly, the only reports an applicant would have to make from those three sources are reports that qualify as 15-day reports. (See chart outlining reporting reguirements,) "This happens to be one of the biggest single clarifications in the rewrite related to ADR reporting," he emphasized. "You do not need to report to FDA adverse reaction reports from a foreign source unless it's a serious unlabeled reaction or unless its frequency is elevated [above what would have been expected in that foreign setting] and it was a serious reaction listed in the label. The same is true for literature and studies of any sort." Chart omitted.

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