Author Archives: Kenan Aktulun

HRP recently engaged in extensive correspondence with the FDA regarding the following statements that appeared in one of the later iteration’s of the FDA’s guidance document “Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency”:

Where an IND safety report is required to be submitted to FDA under 21 CFR 312.32, the investigator must [emphasis added] also send that IND safety report to the IRB. The IRB may have additional reporting requirements regarding COVID-19 during the clinical trial.

And

In addition, investigators are required under 21 CFR 312.66 to report all “unanticipated problems involving risk to human subjects or others” to the IRB. FDA considers a serious and unexpected adverse event that meets the criteria for sponsor reporting to FDA and all investigators in an IND safety report under 21 CFR 312.32, and would generally consider a serious adverse event that meets the criteria for safety reporting for an IND-exempt bioavailability/bioequivalence study under 21 CFR 320.31(d)(3), to be an “unanticipated problem[ ] involving risk to human subjects or others” that therefore must [emphasis added] be reported to the IRB by the investigator.

We discussed the disconnect between the above statements and the information provided in FDA’s still-active 2009 guidance document: “Adverse Event Reporting to IRBs – Improving Human Subject Protection” including the following:

In general, an AE observed during the conduct of a study should be considered an unanticipated problem involving risk to human subjects, and reported to the IRB, only if it were unexpected, serious, and would have implications for the conduct of the study (e.g., requiring a significant, and usually safety-related, change in the protocol such as revising inclusion/exclusion criteria or including a new monitoring requirement, informed consent, or investigator’s brochure).An individual AE occurrence ordinarily does not meet these criteria because, as an isolated event, its implications for the study cannot be understood [emphasis added].

While recognizing that the AE reporting to IRBs guidance remains active, FDA pointed to changes that were made to the IND Safety Reporting Regulations in 2010 and the subsequent 2012 guidance “Guidance for Industry and Investigators – Safety Reporting Requirements for INDs and BA/BE Studies” which states:

Although the rule on IND safety reporting does not directly address safety reporting by investigators to IRBs, questions have arisen about its impact on adverse event reports to IRBs, particularly with respect to the specific adverse events considered to be “unanticipated problems” that must be reported to the IRB. In general, a report that meets the criteria for reporting in an IND safety report should also be considered an “unanticipated problem” and reported to the IRB by the investigator.

We discussed the implications for IRBs, including the volume of IND Safety Reports, safety reports that do not involve or impact “local” subjects or the conduct of the research, and whether IRBs are expected to report these IND Safety Reports as unanticipated problems to “appropriate institutional officials, and the Food and Drug Administration” per 21 CFR 56.108(b).

FDA reiterated their position that IND Safety Reports submitted to the FDA should also be submitted to IRBs as unanticipated problems noting that the IRB “may decide to take action to safeguard participants that was not taken by the sponsor (e.g., stop administering an investigational drug, revise informed consent form).”  Because of the changes made to the IND regulations regarding what must be submitted to the FDA in an IND Safety Report, FDA does not believe that many of these reports will be uninformative.

Regarding reporting to the FDA, the FDA offered that an IRB could include in its written procedures that sponsor submission of the IND Safety Report to the FDA fulfills the prompt reporting requirement as long as the IRB confirms that the sponsor has submitted the report.  Regarding reporting to institutional officials, the FDA offered that the IRB could also address in its procedures when and to whom IND Safety Reports will be reported.

To that end, HRP has modified our SOPs, forms, and checklists accordingly and incorporated procedures for Chair or designee review and acknowledgment of these reports, when the reports do not involve or impact local subjects, or significantly impact the conduct of the research, and additional actions are not needed to ensure the protection of subjects enrolled at sites overseen by an IRB.

HRP recently sought clarification from NIH and OHRP regarding the process for organizations to request exceptions from the revised Common Rule requirement for single IRB for cooperative research.

While NIH was previously able to grant exceptions from its own single IRB policy, it is unable to grant exceptions to the revised Common Rule requirement.  HHS interprets the regulatory text (see excerpt below) to mean that exceptions not based in law may only be granted at the Department or Agency Head level.

45 CFR 46.114(b)(2) The following research is not subject to this provision:

(i) Cooperative research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe); or

(ii) Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.

Requests for exceptions for HHS agencies and offices are managed by OHRP while the decisions are made at the Department Head level (i.e., the Office of the Secretary).  A listing of HHS agencies and offices is available here: https://www.hhs.gov/about/agencies/hhs-agencies-and-offices/index.html.  At this time, requests for HHS exceptions may be emailed to OHRP at OHRP@HHS.gov.  OHRP anticipates that few exceptions will be granted.  It is unclear whether SACHRP’s 2018 recommendations on the topic will be taken into consideration.

Decisions regarding single IRB exceptions for other Common Rule Departments or Agencies (see list below) must also be made at the department or agency head level.  Organizations seeking such exceptions should reach out to the department or agency supporting the research for guidance on the process.

• Department of Homeland Security
• Department of Agriculture
• Department of Energy
• NASA
• Department of Commerce
• Social Security Administration
• Agency for International Development
• Department of Housing and Urban Development
• Department of Labor
• Department of Defense
• Department of Education
• Department of Veterans Affairs
• Environmental Protection Agency
• National Science Foundation
• Department of Transportation
• Office of the Director of National Intelligence
• Central Intelligence Agency
• Consumer Product Safety Commission