FDA and OHRP have published regulations regarding research involving children as subjects, usually referred to as “Subpart D”. (21 CFR 50 Subpart D, 45 CFR 46 Subpart D). Under these regulations, an IRB may only approve pediatric research if it falls into one of three categories:
- Minimal risk (21 CFR 50.51, 45 CFR 46.404),
- Greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (21 CFR 50.52, 45 CFR 46.405), or
- 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 (21 CFR 50.53, 45 CFR 46.406).
If the IRB finds that the research cannot be approved under one of the above categories, but determines 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, there is a fourth option to obtain approval– referral to the FDA and/or OHRP (21 CFR 50.54, 45 CFR 46.407).
When research is referred under this process, the FDA Commissioner, the Secretary of the Department of Health and Human Services (HHS) (Secretary), or both consults with a panel of experts in pertinent disciplines and provides an opportunity for public review and comment. Then, a determination is made as to whether the research can proceed.
What is the 21 CFR §50.54, 45 CFR §46.407 referral process?
On March 30, 2023, FDA and OHRP published a Draft Guidance that describes the process for referral of research involving children as subjects and not otherwise approvable by an IRB. The Draft Guidance describes the required documents that must be provided to FDA and identifies IRBs and institutions as the organizations that are expected to make the 21 CFR 50.54, 45 CFR 46.407 referrals.
Current WCG policy is to encourage sponsors, rather than the IRB, to initiate communication with, and directly interact with, FDA, OHRP or both regarding research on investigational products under an IND or IDE.
When WCG IRB determines that a given protocol involving children is not approvable under21 CFR 50.51, 50.52, or 50.53 for FDA; 45 CFR 46.404, 46.405, or 46.406 for OHRP, our current process is to provide the sponsor with a detailed description of the reasons why the research is not approvable as currently written, and to recommend modifications to the protocol to secure approval.
If the sponsor does wish to make a 21 CFR 50.54/45 CFR 46.407 referral, WCG IRB will provide the sponsor with the IRB minutes, as required in the Draft guidance, and will be available to assist the sponsor as it navigates the referral process.
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