Pediatric subjects participating in HHS-funded or FDA-regulated studies are afforded additional protections not codified in subpart A of the Federal Policy for the Protection of Human Subjects (the Common Rule). On September 18, 2019, PRIM&R hosted a webinar, Pediatric Risk Determination: IRB Considerations and Cases. Presented by Rich Gormon, MD, and Donna L. Snyder, MD, this webinar helped attendees understand pediatric subpart D regulations, identify criteria for pediatric approvable research, and evaluate if the interventions or procedures in a protocol hold the prospect of direct benefit.

After the webinar, the speakers responded to attendee questions time didn’t permit us to address live. We’re pleased to share those responses with the readers of Ampersand.

Is 10 weeks a typical turnaround for 21 CFR 50.54 determinations?

No, the case presented was the first 21 CFR 50.54 review completed in such a short time period. FDA saw some urgency in resolving the issue because the children in the study were having significant issues with venous access. This was the first FDA only review; previous reviews additionally involved the Office of Human Research Protections (OHRP). Coordination across agencies was not required, potentially contributing to the shortened timeline. This was also the first review that included a commercial sponsor. The sponsor was motivated to address the issue quickly to avoid any lapses in dosing for patients who might need implanted venous access to continue to participate in the study.

Does risk exist in a vacuum? Minimal risk seems pretty straight forward. But minor increase over minimal risk is a little fuzzier. Does that definition change with severity of disease or lack of therapeutic options?

Minor increase over minimal risk was defined by the National Commission in the 1977 Report and Recommendations in Research Involving Children as “a risk which, while it goes beyond the narrow boundaries of minimal risk determined by the Commission, poses no significant threat to the child’s health or well-being.” The Commission went on to say that “the research activity must be commensurate with (i.e., reasonably similar to) procedures that the prospective subjects and others with the specific disorder or condition ordinarily experience (by virtue of having or being treated for that disorder or condition).” This concept is reiterated in 21 CFR 50.53 (b): “The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations.” IRBs have some latitude in the interpretation of what interventions or procedures meet requirements under 21 CFR 50.53 but often the assessment is made in the context of the specific disease and available treatment options.

In the case study presented, if the original IRB had approved implanted venous access, with or without sedation, would that have been enough for the FDA to initiate a clinical hold? Gaining IV access in children 96 times seems to be more likely more than a minor increase over minimal risk than the indwelling catheter.

The IRB and the FDA make two independent determinations. A protocol can be submitted to the FDA and the IRB at the same time. The IRB could approve the study and the FDA could put the study on hold. FDA would not issue a clinical hold based on the IRB action, but FDA would issue a clinical hold if there was a safety issue that met requirements under 312.42 for a clinical hold. If the FDA puts a study on hold, the study cannot proceed, so even if the IRB approves the study, the sponsor can’t enroll patients in the study until the clinical hold issue is resolved.

The protocol described in the case presentation was initially amended by the sponsor in 2015 after the sponsor received feedback from FDA that use of implanted venous access in the placebo arm did not offer a benefit and exceeded a “minor increase over minimal risk” and thus did not meet requirements under 21 CFR 50.52 or 21 CFR 50.53. Gaining IV access 96 times was considered acceptable by both the FDA and IRBs reviewing the study at the time. As noted in the presentation, the protocol was revised in 2017 and submitted to an IRB to include implanted venous access in the treatment and placebo arms because gaining peripheral venous access in the children in the study was becoming increasingly difficult. This protocol amendment that included implanted venous access was referred to FDA for review under 21 CFR 50.54 in March 2017. At the Pediatric Ethics Subcommittee (PES)/Pediatric Advisory Committee (PAC) meeting discussing the protocol under 21 CFR 50.54, a committee member did comment that the 92 weekly infusions potentially exceeded a “minor increase over minimal risk” given the difficulties in gaining IV access encountered by the study subjects. The PES/PAC did not consider the indwelling catheter as a “minor increase over minimal risk.” The study required approval by the FDA commissioner under 21 CFR 50.54 to proceed. The determination allowed the investigator in collaboration with the parent to determine what method of administration (peripheral or indwelling catheter) was best for the child.

Is component analysis done at the level of each procedure but on the level of each “arm” of the protocol study design?

21 CFR 50.52 specifically notes that direct benefit is assessed at the level of each intervention or procedure in a clinical investigation. As per 21 CFR 50.52: “Any clinical investigation within the scope described in 50.1 and 56.101 of this chapter [21 CFR] in which more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject…” Component analysis should be applied to any research related interventions or procedures that are included in a clinical investigation to determine if they offer a prospect of direct benefit or not. Any intervention or procedure that does not offer a prospect of direct benefit must not exceed a “minor increase over minimal risk” as per 21 CFR 50.53 unless reviewed under 21 CFR 50.54. Typical interventions or procedures to consider are administration of a study drug or placebo, MRIs with contrast, CT scans, use of non-therapeutic procedural sedation, and biopsies. When considering use of a placebo, the method (oral, injection) and duration of administration should be considered when assessing the risk.

In terms of fetal research, when are one or both parental signatures required?

FDA regulations do not include special protections for pregnant women and fetuses in clinical investigations. However, the Common Rule does include special protections, “Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research,” specified under 45 CFR 46, subpart B.  Most IRBs would consider it prudent to follow GCP specific recommendations and the Common Rule regulations for pregnant women and fetuses in clinical investigations. Under subpart B, only the signature of the pregnant woman is required when the research “holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means.” Signatures of both the pregnant woman and father are required “if the research holds out the prospect of direct benefit solely to the fetus …. except that the father’s consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest.”

Are there special considerations for evaluating a protocol that includes both children and adults?

Considerations for including children in a protocol that study both children and adults are the same as those for a study that only includes children; is there sufficient prospect of direct benefit to the child to justify the risks and is the balance of the risk to benefit at least as favorable as the available alternatives (21 CFR 50.52). Drug companies are encouraged to include adolescents and sometimes younger children in clinical trials for products that are in development if there are enough data to support a favorable benefit/risk determination. Depending on unmet need and severity of disease, children could be included early in a therapeutic development program. The FDA makes this determination on a product and disease specific basis. Historically, waiting until efficacy is established in adults before starting development in children has resulted in products being used off-label in children during the ensuing time delay for the pediatric drug studies. It is a matter of social justice to include children in adult trials to facilitate the availability of data to support safe and effective use in children when it there is a scientific basis and clinical need to do so.

PRIM&R thanks Dr. Gormon and Dr. Snyder for sharing their expertise.

The recording of this webinar is available for individuals to purchase in PRIM&R’s online store. If you would like to purchase the webinar for group viewing, please download the order form (PDF) and send it to registration@primr.org.

PRIM&R would like to thank Advarra for supporting this webinar. Advarra is the premier provider of IRB, IBC and global research quality and compliance consulting services in North America.

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