On January 14, 2009, the Food and Drug Administration issued a guidance concerning the types of adverse events that should be reported to Institutional Review Boards (IRBs) responsible for overseeing clinical trials of new prescription drugs and medical devices.  The newly finalized Guidance follows several years of IRB complaints that they were receiving a large volume of adverse event (AE) reports, many of which lacked any meaningful analysis. IRBs had expressed concern that the indiscriminate reporting of AEs was inhibiting, rather than enhancing, their ability to protect the health and welfare of human subjects. FDA therefore decided to issue a Guidance on the matter, which clarifies when an AE should be considered an “unanticipated problem” and thus reportable to the study’s IRB (the final Guidance revises a draft version released in April 2007). This Guidance is entitled Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs – Improving Human Subject Protection and is available here.

First, the Guidance stresses that in order to be an “unanticipated problem,” the AE should be serious and unexpected, and it should have implications for the conduct of the clinical trial (for example, by requiring a protocol amendment). According to the FDA, an isolated AE “ordinarily does not meet [those] criteria” because the implications for the study as a whole cannot be interpreted. Therefore, FDA now recommends that investigators and sponsors undertake an aggregate analysis of similar events to determine whether the AE is significant for the study as a whole. If so, the AE should be reported to the IRB as an unanticipated problem, along with the relevant analysis.

Other circumstances would also warrant a report to the IRB. FDA recommends that the following AEs be considered “unanticipated problems”:

• A single event that is serious and unexpected, uncommon, and strongly associated with drug exposure (e.g., angioedema, hepatic injury, or Stevens-Johnson syndrome);

• A single event that is serious and unexpected, not commonly associated with drug exposure, but uncommon within the study population (e.g., tendon rupture);

• An AE included in the study investigator’s brochure, the study protocol, or the informed consent documents but which occurs with more specificity or severity than previously observed (a discussion of the divergent characteristics of the AE should accompany the report);

• A serious AE included in the study investigator’s brochure, the study protocol, or the informed consent documents but which occurs at a clinically significant increased rate when compared to the expected rate (a discussion of the divergence from the AE’s expected rate should accompany the report); and

• Any other AE or safety finding (e.g., based on animal data) that would cause the sponsor to modify the study investigator’s brochure, the study protocol, or the informed consent documents or that would cause the IRB to take other action to protect human subjects.

Finally, the Guidance also clarifies the responsibilities of participants in a multicenter study.  While FDA regulations require the investigator to report unanticipated problems to the IRB, in multicenter studies a single investigator may not have the information necessary to determine whether a new AE should be reported. As a result, FDA says that an investigator may rely on the sponsor’s assessment of the AE and can submit the sponsor’s report determining that an AE constitutes an unanticipated problem. Should the sponsor submit such a report to the IRB – and the investigator has actual knowledge of the submission and all parties explicitly agreed that the sponsor could submit reports to the IRB – FDA states that it intends to exercise enforcement discretion and not hold the investigator responsible for not submitting a duplicate copy of that report to the IRB. 

If you have any questions about this Guidance or clinical trial regulations more generally, please do not hesitate to contact one of the following Arent Fox attorneys:

Wayne H. Matelski
matelski.wayne@arentfox.com
202.857.6340

Brian P. Waldman
waldman.brian@arentfox.com
202.857.8971

Lisa A. Estrada
estrada.lisa@arentfox.com
202.828.3424

Joanne S. Hawana
hawana.joanne@arentfox.com
202.715.8951