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FDA BIOLOGIC ADVERSE EXPERIENCE REPORTING REGS WILL REQUIRE 15-DAY REPORTS FOR SERIOUS AND UNEXPECTED EVENTS; PROPOSAL SIMILAR TO DRUG REPORTING RULES

Executive Summary

FDA will require biologic manufacturers to report to FDA within 15 working days any serious unexpected adverse events and any "significant increase in frequency" of serious expected events, under a proposed rule published in the March 29 Federal Register. The proposed rule would require other adverse experiences to be reported periodically, at a frequency based on the product's length of marketing. Under the proposal, "all manufacturers having a biological product license under Section 601.20" will be required to meet the reporting requirements. FDA is proposing to exempt from the reporting requirements manufacturers of licensed in vitro diagnostics and whole blood and its components. Once final, the reg will make the adverse experience reporting requirements for biologics very similar to the present reporting procedures for drugs. FDA's current biologics regs do not require adverse experience reporting except for fatalities resulting from blood collection or transfusion. Reporting is also required for certain childhood vaccines under the National Childhood Vaccine Injury Act of 1986. FDA noted that vaccine manufacturers subject to reporting under the NCVIA will also be required to report adverse events in accordance with the proposed reg, but that duplicate reports will not be required. * The proposed rule defines an "adverse experience" as any "adverse event associated with use of a biological product in humans, whether or not considered product related, including an adverse event occurring in the course of the use of a product in professional practice, an adverse event occurring from overdose, abuse, or withdrawal, and any significant failure of pharmacologic action." A "serious" adverse experience is described by FDA as one "that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly or cancer." An "unexpected" event is defined as "an adverse experience that is not listed in the current labeling for the biological product and includes an event that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differs from the event because of greater severity or specificity." * The proposed reg notes that in order for manufacturers to meet the reporting requirement for any "significant" increase in frequency, they will "be required to review periodically the frequency of reports of 'serious' adverse experiences that are 'expected.'" The agency plans to require manufacturers to conduct the review "at least as often as the periodic cycle." For adverse experiences not subject to the 15-day reporting requirements, FDA proposes periodic reporting "at quarterly intervals for the first three years following licensure of the product, and at annual intervals thereafter." FDA noted that in certain cases it may modify the periodic requirements to "provide for increased surveillance of biological products when the circumstances so warrant." The proposal would require the quarterly reports "within 30 days of the close of the quarter, the first quarter beginning on the date of issuance of the product license, and annual reports within 60 days of the anniversary date of issuance of the product license." FDA is also proposing to require that manufacturers include in their periodic reports "information about the quantity of a biological product distributed under a product license" to enable "FDA to estimate more accurately the incidence of a biological product's adverse effects." Under the proposed rule, literature reporting is limited to "'serious and unexpected' adverse experiences and any 'significant increase in frequency' of a serious, expected adverse experience, i.e., those subject to the 15-day alert reporting requirement." FDA proposes limiting literature reporting to adverse experiences appearing in scientific journals as "case-reports" or as the result of a formal clinical trial in instances of unexpected serious events. Literature reports of significant increases in frequency would be limited to "scientific and medical journals containing reports of formal clinical trials, or epidemiologic studies or analysis of experience in a monitored series of patients." In conjunction with the proposed rule, the agency has issued a draft guidance for reporting adverse reactions to biologicals. The guideline elaborates on the reporting requirements outlined in the proposed rule and describes the procedures for submitting the information to FDA. Among the issues addressed in the guideline is how a manufacturer determines when there is a "significant" increase in the occurrance of an adverse event. The agency suggests two specific approaches (an arithmetic and a statistical test) that may be used when only two reporting periods are compared. When adverse reaction reports are available for three or more comparable reporting periods, the agency suggests use of statistical methods, such as cusum methods, regression analysis, or time series analysis, that "incorporate all the available information and assess the presence of a significant positive trend in the frequencies" of adverse reactions. The draft guideline can be obtained from FDA's Congressional, Consumer, and International Affairs Staff (HFB-142), at Park Bldg., room 158, 5600 Fishers Lane, Rockville, MD 20857. The agency is accepting comments on both the draft guideline and proposed rule through May 29.
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