The FDA and HHS issued joint guidance that details the procedures regarding their review of proposed pediatric research that cannot be approved by an institutional review board (IRB) under the agencies’ pediatric research regulations.

Under both the FDA and HHS regulations, IRBs can approve pediatric research under three provisions:

• 21 C.F.R. §50.51 and 45 C.F.R. §46.404: Research not involving greater than minimal risk;
• 21 C.F.R. §50.52 and 45 C.F.R. §46.405: Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects;
• 21 C.F.R. §50.53 and 45 C.F.R. §46.406: Research involving no more than a minor increase over minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition.

If an IRB does not find that research involving children as subjects meets those requirements, the research may proceed only if:

• The IRB finds that the research presents a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting the health or welfare of children; and
• The FDA Commissioner and/or Secretary of the Department of Health and Human Services after consultation with a panel of experts in pertinent disciplines (e.g., science, medicine, education, ethics, law) and following opportunity for public review and comment, determines either:
  • • The research in fact satisfies one of the three provisions or
    • The following three conditions are met:
      • • The research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children;
        • The research will be conducted in accordance with sound ethical principles; and
        • Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians (21 C.F.R. §50.55 and/or 45 C.F.R. §46.408).

IRBs may refer research involving children as subjects to FDA and/or OHRP for review under 21 C.F.R. §50.54 or 45 C.F.R. §46.407, as applicable. “Regardless of the agency to which the referral is submitted, both FDA and OHRP intend to consult with each other on any referrals received under 21 C.F.R. §50.54 and 45 C.F.R. §46.407 to ensure the appropriate agency has been notified and to determine whether a joint review (i.e., a review by both FDA and OHRP) is needed,” the guidance said.

In cases in which the clinical study is determined to be both FDA-regulated and HHS-supported or -conducted, the “FDA and OHRP will coordinate their assessment of the referral as needed. In such cases, FDA and OHRP generally intend to conduct a joint review of the research and will follow the process for FDA-only assessment of referrals,” the guidance said.

When final, the guidance will replace the final guidance issued by the FDA in December 2006 entitled Guidance for Clinical Investigators, Institutional Review Boards and Sponsors: Process for Handling Referrals to FDA Under 21 C.F.R. §50.54: Additional Safeguards for Children in Clinical Investigations and the guidance issued by HHS’s Office for Human Research Protections (OHRP) entitled Children as Research Subjects and the HHS ‘407’ Process, which was released in May 2005.

Submit Referrals As Soon As IRB Determination Is Made

Both FDA and OHRP encourage IRBs to submit referrals as soon as an IRB determines that the clinical investigation can only proceed under 21 C.F.R. §50.54 or 45 C.F.R. §46.407 and to submit all documents electronically in optical character recognition-enabled versions.

Send documents to FDA at opt@fda.hhs.gov and to OHRP at OHRP@hhs.gov.

Referrals should include:

• The IRB’s explanation of why the clinical investigation or proposed research does not meet the requirements of 21 C.F.R. §50.51, §50.52, or §50.53 for FDA referrals and 45 C.F.R. §46.404, §46.405, or §46.406 for OHRP referrals;

• The IRB’s finding that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children;
• The research protocol, investigator’s name, current informed consent documents, including the parental/guardian permission form and, if being used, the assent form(s) and/or a description of the assent process;
• Other informative supporting documents, such as the IRB minutes pertinent to the clinical investigation or proposed research, correspondence between the IRB and the investigator, investigational product labeling, the investigator’s brochure (IB), and the IRB’s assessment of investigator qualifications and research site adequacy;
• IRB names and contact information (also include institution name for OHRP referrals);
• For FDA referrals only: Investigational New Drug application (IND) or Investigational Device Exemption (IDE) numbers assigned by FDA if applicable and known; and
• For OHRP referrals only: HHS application number (if applicable) and name of the HHS division conducting or supporting the research. Note: OHRP will notify the relevant HHS division supporting the research of the request for review of the research under 45 C.F.R. §46.407.

“Depending on to whom the referral was submitted, FDA or OHRP will conduct an initial assessment to determine whether there is adequate information to proceed with the referral. If the information submitted is insufficient to enable FDA or OHRP to conduct this initial assessment, the IRB (or institution) will be promptly notified of any needed information,” the guidance said.

“If the proposed research fulfills the criteria for consideration under the provisions of 21 C.F.R. §50.54 (FDA) or 45 C.F.R. §46.407 (OHRP), the referral will be accepted and the review process will be initiated,” the guidance said.

“For reviews conducted by FDA, FDA will notify the appropriate FDA office and/or review division to inform it that FDA has accepted a referral to review the clinical investigation under 21 C.F.R. §50.54. FDA will provide written confirmation to the referring IRB that FDA has accepted its referral. The IRB should inform the sponsor that a referral under 21 C.F.R. §50.54 has been accepted by FDA. For reviews conducted by OHRP, OHRP will notify the appropriate HHS division supporting or conducting the research of the referral acceptance under 45 C.F.R. §46.407. OHRP will provide written confirmation of acceptance to the referring IRB and/or referring institution through mail or email.”

If an IRB decides to withdraw a referral from FDA or OHRP, the agencies encourage the IRB (or institution) to include the reasons for withdrawal in its withdrawal request and in the IRB meeting minutes.

Process After Referrals Are Accepted Is Outlined

After a referral is accepted by the FDA, the Office of Pediatric Therapeutics (OPT) and the relevant FDA office or review division, will prepare for presentation of the clinical investigation to a joint meeting of FDA’s Pediatric Advisory Committee (PAC) and the Pediatric Ethics Subcommittee (PES). The review of referrals to OHRP will be conducted by an expert panel comprised of individuals selected for their expertise relevant to the specific referral.

The guidance noted that “although an IRB (or institution) may make a referral for review because of a particular aspect of the clinical investigation or proposed research (e.g., entry criteria, planned procedure), the agencies intend to request input and recommendations on the clinical investigation or proposed research in its entirety.”

After deliberation and discussion of the clinical investigation, the PAC/PES will vote on whether to recommend that the proposed clinical investigation may proceed under 21 C.F.R. §50.51, §50.52, §50.53 or §50.54. PAC/PES members will not write individual recommendations regarding whether the research meets the criteria in 21 C.F.R. §50.54(b)(1) or (2).

FDA staff will develop and send a memorandum that outlines the PAC/PES recommendation(s) as well as FDA staff comments and recommendations and relevant supporting documents to the FDA Commissioner (or delegee). “The memorandum may include recommended changes to the research protocol and/or changes to the parental/guardian permission and assent forms that the PAC/PES and/or FDA staff believe are necessary for the clinical investigation to proceed under Subpart D, as well as any suggested changes that might enhance the clinical investigation (e.g., strategies to ease study burden on patients and care providers, strategies to improve trial enrollment),” the guidance said.

The memorandum will request the Commissioner (or delegee) make a final determination as to whether, and if so, under which provisions of Subpart D, the clinical investigation may proceed. After the final determination is made, the FDA intends to forward the determination to the IRB and post the final determination on the FDA website within 90 days of the PAC/PES meeting or as soon as practicable thereafter. The agency also will post the PAC/PES transcripts and meeting documents on the FDA website when available.

After deliberation and discussion of the proposed research in OHRP panel meetings, each panel member will write an individual recommendation discussing whether the research meets the criteria of 45 C.F.R. §46.407(b)(1) or (2). OHRP will post the individual panel member recommendations in the docket where the recommendations will be open to public comment for 30 days.

OHRP will develop a recommendation for the Assistant Secretary for Health (ASH) based on panel deliberations, reports, public comments and its own analysis. The recommendation may include changes to the research protocol and/or changes to the parental/guardian permission and assent forms that an expert panelist or OHRP staff believe are necessary for the research to proceed under Subpart D, as well as any suggested changes that might enhance the research (e.g., strategies to ease study burden on patients and care providers, strategies to improve trial enrollment.

After review of the relevant materials and OHRP’s recommendation, the ASH, on behalf of the HHS Secretary, will make the final determination regarding whether the research may proceed under any of the four Common Rule categories for pediatric research. OHRP will inform the referring institution and/or IRB chair, the investigator and the HHS division supporting or conducting the research of the ASH’s determination and post its recommendation to the ASH and the ASH’s final determination in the established docket within 90 days of the expert panel meeting or as soon as practicable thereafter.

Guidance Details Differences in the Process for Joint Reviews

Joint FDA/OHRP reviews will follow the process for FDA-only assessment of referrals. Unique aspects of the joint review process include:

• FDA will communicate with the IRB and sponsor, and institution if appropriate, on behalf of both FDA and OHRP.
• FDA will post documents related to the joint review to the FDA website. OHRP will not post documents to a federal docket and will instead post a link to the FDA website on the OHRP website.
• FDA will convene a PAC/PES meeting, which will serve as the expert panel meeting for both FDA and OHRP.
  • • OHRP will participate with the FDA in the selection of members for the PAC/PES meeting.
    • OHRP will participate with FDA in the PAC/PES meeting.
• The ASH, acting on behalf of the Secretary, will make the determination whether the research is approvable under 45 C.F.R. §46.407 after the FDA Commissioner (or delegee) has determined whether the clinical investigation is approvable under 21 C.F.R. §50.54.
  • • After the PAC/PES makes its recommendation(s) on whether the clinical investigation may proceed under 21 C.F.R. Part 50, Subpart D, and 45 C.F.R. Part 46, Subpart D, FDA staff will submit a memorandum outlining the PAC/PES recommendation(s), FDA staff recommendations and the supporting documents to the FDA Commissioner (or delegee).
    • The FDA Commissioner (or delegee) will determine whether the clinical investigation may proceed under 21 C.F.R. §50.54.
    • FDA will forward a memorandum outlining the PAC/PES recommendation(s), FDA staff recommendations, and the Commissioner’s (or delegee’s) determination to OHRP.
    • OHRP will formulate a recommendation to the ASH based on the findings of the PAC, the FDA Commissioner’s (or delegee’s) determination, public comments, and OHRP internal review.
    • OHRP will send a memorandum with the PAC/PES recommendation(s), the FDA Commissioner’s (or delegee’s) determination, OHRP’s recommendation(s) and all supporting documents to the ASH. The ASH, acting on behalf of the Secretary, will make the determination whether the research may proceed under any of the four Common Rule categories for pediatric research.

Multisite Research Discussed

The guidance noted that “in some circumstances, research referred for review under FDA and/or HHS regulations might be conducted at multiple sites or institutions, and as such, be reviewed by more than one IRB.”

In those cases, “if an IRB for one or more of the clinical sites refers the research for review, the IRB should notify the sponsor or HHS division supporting or conducting the research. In this situation, FDA and OHRP strongly encourage the sponsor or relevant HHS division to notify all other study site IRB(s) and investigator(s) of the referral.”

For multisite research regulated by the FDA and conducted under an IND or IDE, if an IRB makes a referral under 21 C.F.R. §50.54, the “FDA will determine whether the clinical investigation may proceed (or continue, if enrollment has already begun at one or more sites) or will be placed on clinical hold,” the guidance said.

In the case of a referral regarding an investigation for which an IDE application (or supplement) is pending, the FDA also may consider other actions. “If FDA concludes that a clinical hold is appropriate, the agency generally intends to apply that clinical hold to all sites, regardless of whether IRBs other than the one that referred the protocol have approved the protocol,” the guidance said.

While the review is under way, the FDA will inform the sponsor whether the clinical investigation has been placed on clinical hold and the sponsor must then notify investigators if the clinical investigation has been placed on clinical hold. In addition, the sponsor also should inform the other study site IRBs.

For multisite research regulated by OHRP, that does not require, or is excepted from the requirement for, single IRB review under 45 C.F.R. §46.114, the HHS division supporting or conducting the research may consider the implications of the 45 C.F.R. §46.407 review process on the conduct of the research at other HHS supported sites and whether, if consistent with applicable law, to delay or suspend subject enrollment at these other sites pending the outcome of the review.

Similar Research Will Be Considered

The “FDA and OHRP recognize that there may be situations in which it would be appropriate for the Commissioner (or delegee) and/or the ASH to rely on previous PAC/PES or expert panel consideration of a similar research protocol in order to review a newly referred protocol,” the guidance said, noting Subpart D regulations do not specify that the expert panel review of the research must occur after the IRB referral for review.

According to the guidance, the FDA and/or OHRP will consider reviewing referred research “under an abbreviated process if the research is similar to research that FDA and/or OHRP has already reviewed under Subpart D and determined may proceed. This abbreviated process would necessitate that FDA and/or OHRP determine the newly referred research is sufficiently similar to the previously reviewed research such that the previous referral and review are applicable to the newly referred research,” the guidance said, adding that “such determinations are anticipated to be rare.”

If the FDA and/or OHRP conduct an abbreviated review process, the agencies will include in the information posted online the determination by the Commissioner and/or ASH for the previous referral as well as relevant background information from the previous referral. In addition, the agencies will publish a Federal Register notice to solicit public comments on the newly referred research. The docket will remain open for 30 days.

Based on a review of public comments, the FDA and/or OHRP may either decide a determination may be issued without additional PAC/PES or expert panel review, or that a new PAC/PES or expert panel review is needed.

If the determination is that no additional review is needed, the “FDA and/or OHRP will prepare a recommendation for the Commissioner (or delegee) and/or ASH and the subsequent final determination by the Commissioner (or delegee) and/or ASH regarding the newly referred protocol will be posted to the FDA website, with a reference to the FDA docket, and/or will be posted to the OHRP docket, as applicable.”

Submit electronic comments on the draft guidance to Docket No. FDA–2022–D–0142 on www.regulations.gov by May 30.