that identify inheritable genetic defects, may have consequences for research participants, family members, and family relationships that emerge or intensify after the study ends. Long-term consequences are also an important concern for many cancer treatments (see, e.g., the recent report on long-term survivors of childhood leukemia [Pui et al., 2003]). The identification of studies that warrant long-term follow-up and the design and sponsorship of such studies should be recognized as elements of a comprehensive system for protecting human participants in research.

Adverse Event Reporting

In a general sense, an adverse event is an occurrence that causes harm to a patient or research participant or that has the potential to do so. The focus is usually on serious, unexpected problems (e.g., not described in the research protocol) that appear to be associated with the research. The reporting of adverse events in clinical studies is a complex topic, and the role of IRBs in relation to adverse events is not well-defined, which causes considerable frustration and uncertainty. As observed in a popular handbook for IRB members, “guidance [to IRBs] from federal authorities has been both confusing and contradictory” (Amdur and Bankert, 2003, p. 64).

Without mentioning adverse events as such, both DHHS and FDA regulations require that IRBs have written procedures for the prompt reporting to the IRB, appropriate institutional officials, and the relevant Department or Agency head of “any unanticipated problems involving risks” to human research participants or others (e.g., investigators) (45 CFR 46.103(b)(5); 21 CFR 56.108(b)(1)). The regulations also require prompt reporting to the investigator, appropriate institutional officials, and the Department or Agency head of any suspension or termination of an individual research protocol related to “unexpected serious harm” (45 CFR 46.113; 21 CFR 56.113). In separate regulations relating to investigational new drugs, FDA specifies additional requirements for investigators or research sponsors to report unanticipated or unexpected adverse experiences,


JCAHO, 2003). In the Best Pharmaceuticals Act of 2002 (P.L. 107-109), FDA was directed to review adverse events reports for the year after a drug was granted pediatric exclusivity (as described in Chapter 2). FDA staff have reported to the FDA Pediatric Advisory Subcommittee on several products. For some of the products, staff asked the subcommittee whether an additional year of follow-up was advisable, given the small number of reports (Iyasu, 2003). Staff also reported on the limitations of the current monitoring system. The limitations include the questionable quality of individual reports, biased or selective reporting and underreporting, and an inability to calculate problem rates because the system lacks denominator data (i.e., data identifying the number of individuals who are, for example, taking a particular drug).

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