An investigator received an updated investigator's brochure from the sponsor; the update did not include changes related to subject safety. Which of…

The investigator's reporting responsibilities to the Institutional Review Board/Independent Ethics Committee (IRB/IEC) are primarily focused on events and information that may alter the risk-benefit assessment or affect subject safety. An updated Investigator's Brochure (IB) that does not contain any new safety information or changes to the risk profile does not meet the criteria for prompt reporting. While the investigator must maintain the current IB in the study files and be familiar with its contents, this type of non-safety update is typically submitted to the IRB/IEC during the next scheduled continuing review, rather than as a separate, immediate notification.

A. The IRB/IEC: Notification is required for updates that could adversely affect subject safety or the risk-benefit balance; this update does not meet that threshold.

B. The Data Safety Monitoring Board (DSMB): The DSMB's mandate is to review safety data; an IB update with no new safety information does not require notification from the investigator.

C. The regulatory authority: The sponsor, not the investigator, is primarily responsible for submitting the IB and its updates to the relevant regulatory authorities (e.g., FDA).

1. International Council for Harmonisation (ICH) Harmonised Guideline for Good Clinical Practice E6(R2), Section 4.6.3: This section requires the investigator to provide the IRB/IEC with all documents subject to review. However, the urgency and method of submission are dictated by the content. For non-safety updates, this is typically handled at continuing review.

2. U.S. Food and Drug Administration, Code of Federal Regulations, Title 21, Part 56.108(a)(1): This regulation requires investigators to promptly report to the IRB "any unanticipated problems involving risks to human subjects or others." An IB update with no new safety information does not constitute an unanticipated problem involving risk.

3. U.S. Food and Drug Administration, Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs — Improving Human Subject Protection (January 2009), Section IV.B, "What should be submitted to the IRB?": The guidance states, "An amendment to an IB should be submitted to the IRB only when the amendment is relevant to the protection of human subjects (e.g., when the amendment contains a new or revised risk assessment)." This directly supports that an IB update without safety changes does not require submission.