Adverse Event Reporting

Adverse event collection and reporting is a fundamental aspect of drug development and of human subjects protection. The clinical investigator is the individual who identifies, evaluates, and documents adverse events experienced by study participants at his or her site and who is responsible for updating the IND sponsor and the IRB as appropriate, as set forth in federal regulations (at 21 CFR 312.64).

The sponsor is responsible for submitting safety information to FDA. The timing and reporting format will depend on the nature of the adverse event. The sponsor must report to FDA in writing all serious and unexpected adverse event information associated with the use of the investigational product within 15 calendar days of receipt of the information. Any unexpected life-threatening or fatal event associated with the use of the investigational product must be reported by telephone (or facsimile) within 7 calendar days of receipt of the information (as per 21 CFR 312.32). The telephone and written reports constitute expedited reports. Although causality assessment is integral to expedited reporting, a determination that a given investigational product caused or was associated with an adverse event in the course of a clinical study is not always possible. The most reliable way to assess the contribution of a test article to an adverse event is by comparing adverse event rates and severity in treatment and control groups. Randomized controlled trials, however, are infrequent in early phases of clinical testing. Although one cannot always be certain that there is a relationship between the administration of the study product and the adverse event, the level of suspicion required for reporting is quite low. Except if there is no reasonable possibility that the product caused or contributed to an unexpected serious adverse event, that event must be reported to the FDA according to specified time frames.

The sponsor is also required to submit to the IND an annual report that includes a summary of the most frequent and the most serious adverse events (21 CFR 312). The ICH guideline entitled "E3: Structure and Content of Clinical Study Reports" describes the manner in which safety data for individual studies should be organized and presented to regulatory authorities in marketing applications [17]. A marketing application includes an integrated summary of the entire safety experience for the product. FDA, as part of the ICH process, is developing a guideline entitled "The Common Technical Document for the Registration of Pharmaceuticals for Human Use" that addresses, among other items, formatting of integrated safety data [18]. Once marketed, a passive surveillance system allows for the continued collection and reporting of safety information [19]. For some products, such as ones that pose unique long-term risks, a more active type of postmarketing follow-up will be required.

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