Attachment B: Commentary on FDA Draft Guidance, “General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products,” released December 9, 2014, docket number FDA-2013-D-1275-0002

SACHRP would like to thank FDA for putting out this timely guidance on clinical pharmacology pediatric studies. The FDA regulation 21 Part 50 Subpart D, Additional Safeguards for Children in Clinical Investigations, delineates the categories of acceptable clinical investigations with children. At the same time, FDA regulations and policy require clinical pharmacology investigations with pediatric subjects in order to appropriately understand and develop medications for children. At times there is tension between these two important FDA directives, and this guidance will help to provide understanding of FDA’s expectations for these pediatric studies. SACHRP has several comments on this important guidance.

First, SACHRP notes that the guidance, on page 1 lines 17 to 19, is directed only at sponsors, rather than also addressing investigators and IRBs. We believe that it would be appropriate for this guidance to also be directed at investigators and IRBs, as there has been substantial debate over the years on the interpretation of 21 Part 50, Subpart D, and the corresponding HHS regulations at 45 CFR 46, Subpart D. In particular, IRBs will benefit from Section IV of the guidance on ethical considerations, pages 7 to 10.

Second, on lines 252 to 254, page 8, the guidance states “However, FDA has an independent responsibility to assess the compliance of the proposed clinical trial under 21 CFR 50 subpart D.” When a clinical investigation is presented to an IRB, the IRB does not know if FDA has considered the application of subpart D when providing the sponsor with permission to proceed with the study under an IND. As a procedural matter, it would be useful if there were notification to the sponsor and the IRB that the FDA considered Subpart D in its assessment of the proposed investigation.

Third, on line 261to 264, page 8, it says “In both cases, administration of an experimental drug or biological product is always considered to represent more than minimal risk and thus is not approvable by an IRB under 21 CFR 50.51.” While we agree that in nearly all cases an experimental drug will represent more than minimal risk, we question whether FDA should categorically rule it out as a possibility.

Fourth, on lines 296 to 297, page 9, the draft guidance discusses Case 1, involving research that involves a minor increase over minimal risk under 21 CFR 50.53. The guidance says “An example of a clinical pharmacology study that may be conducted under 21 CFR 50.53 is the pharmacokinetics of a single dose of an over-the-counter cough and cold product.” Because only one example is given, this will end up being the sole example that will be available to sponsors and IRBs to use for consideration of what constitutes a minor increase over minimal risk. Because the example uses an over the counter drug in the example, sponsors and IRBs may assume that only approved products qualify as having the potential to represent a minor increase over minimal risk. SACHRP believes that some investigational products may also qualify as representing a minor increase over minimal risk, and that it would be useful for FDA to provide an example of the risk profile of an investigational product that would qualify for this category.

There have been previous recommendations that have provided recommendations regarding procedures and situations that would qualify as a minor increase over minimal risk. The National Human Research Protections Advisory Committee (NHRPAC) recommendation “ Clarifying Specific Portion of 45 CFR 46 Subpart D that Governs Children’s Research”,[1] provides a chart which classifies common procedures as involving minimal risk, a minor increase over minimal risk, and more than a minor increase over minimal risk. This document does not address the risks of drugs or devices, however it could be used as a model for providing examples of drugs as well. In addition, SACHRP previously made the following recommendation regarding this issue on July 28, 2005[2]:

• Criteria for "minor increase over minimal risk" should include the following (a) the procedure does not meet minimal risk criteria, and (b) the investigator has presented sufficient evidence about the procedures, population, and the qualifications of research personnel to assure the IRB that:
  1. The increase in the probability and magnitude of harm is only slightly more than minimal risk.
  2. Any potential harms associated with the procedure will be transient and reversible in consideration of the nature of the harm (restricted to time of procedure or short post-experimental period).
  3. There is no or an extremely small probability that participants will experience as severe the potential pain, discomfort, stress, or harm associated with the procedure.

SACRHP believes that it would be useful if FDA provided more examples in this guidance on this important issue, or references the previous committee recommendations as further guidance.

Fifth, on lines 303 to 331, page 9 and 10, the draft guidance discusses Case 2, involving research with a prospect of direct benefit. It would be helpful if the draft guidance described or provided examples of the types of information that may or may not be used to support the IRB finding of a prospect of direct benefit. For example, could arguments based on mechanism of action and disease pathophysiology or genetics, data from adult trials involving the same or similar conditions, results from academic pilot studies in pediatric patients, patient experiences with an expanded access program or reports of off-label clinical use serve as justifications for a prospect of direct benefit in some situations? What level of therapeutic response may qualify as a prospect of direct benefit? Would it be acceptable to combine a PK protocol with a separate extension protocol and consider the two protocols together as qualifying to provide a prospect of direct benefit for the PK protocol?

Sixth, SACHRP is pleased that the FDA has included reference to the theory of component analysis in this draft guidance at lines 313 to 319 on pages 8 and 9. SACHRP [3] has endorsed the use of component analysis in the assessment of pediatric risk in research. SACHRP encourages FDA to provide a fuller description of the substantive and procedural elements of component analysis, and also more guidance on this important subject for sponsors and IRBs.

Finally, SACHRP notes that section IV of this draft guidance does not address the requirement under 21 CFR 50.53(b) that “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.” In the experience of the SACHRP members, this is sometimes a difficult regulatory requirement to satisfy, and FDA commentary on its interpretation would be valuable to the regulated community. For instance, it would help if FDA explained that the proper viewpoint was the experience from the child’s perspective, rather than the purpose of the research. If it is the child’s perspective, then taking a tablet that is experimental is similar to taking a tablet that is approved.

The CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects provides a useful statement on this requirement in its commentary on guideline 9:

The requirement that the research interventions be reasonably commensurate with clinical interventions that subjects may have experienced or are likely to experience for the condition under investigation is intended to enable them to draw on personal experience as they decide whether to accept or reject additional procedures for research purposes. Their choices will, therefore, be more informed even though they may not fully meet the standard of informed consent. [4]

A similar explanation from FDA would be valuable to sponsors and IRBs in interpreting this regulatory requirement.