SACHRP Recommendations on Draft Guidance “Ethical Considerations for Clinical Investigations of Medical Products Involving Children Guidance for Industry, Sponsors, and IRBs”

Background

On Sept 26, 2022, the Food and Drug Administration (FDA) issued a draft guidance for industry, sponsors, and institutional review boards (IRBs) entitled “Ethical Considerations for Clinical Investigations of Medical Products Involving Children.” (Draft Guidance) This draft guidance describes FDA's current thinking regarding ethical considerations for clinical investigations of drugs, biological products, and medical devices involving children. The Draft Guidance is intended to assist industry, sponsors, and IRBs when considering the enrollment of children in clinical investigations of medical products.

Additional safeguards for children are included in 21 CFR part 50, subpart D (Additional Safeguards for Children in Clinical Investigations). IRBs are required to follow these regulations when reviewing clinical investigations of FDA-regulated medical products that are intended to enroll children.

The FDA subpart D regulations include undefined terms, such as minor increase over minimal risk that are understood and applied inconsistently by members of the regulated community. In addition, it has been understood that FDA expects IRBs to apply component analysis in its review of research with children.¹

SACHRP has provided recommendations on various aspects of research with children, including the assessment of risk and the application of component analysis in research subject to the Department of Health and Human Services regulations found in 45 CFR 46, subpart D.² While 21 CFR 50, subpart D generally parallels 45 CFR 46, subpart D, clinical research subject to 21 CFR 50 is typically limited to clinical investigations of medical products. However, the previous SACHRP recommendations are generally applicable to FDA regulated research involving children.

Discussion

SACHRP is pleased that FDA is considering publishing guidance on the requirements for research involving children, “Ethical Considerations for Clinical Investigations of Medical

Products Involving Children Guidance for Industry, Sponsors, and IRBs” and below, SACHRP offers its commentary and recommendations for FDA’s consideration.

As a general comment, SACHRP notes that the Draft Guidance is also applicable to the community of investigators who conduct investigator-initiated research with children, and who may be unfamiliar with the nuanced requirements of 21 CFR 50, subpart D. Therefore, SACHRP recommends that investigators be clearly identified in the title of the guidance in addition to industry, sponsors and IRBs.

SACHRP also considered whether the regulated community would benefit from joint OHRP-FDA guidance on Subpart D. However, FDA-regulated pediatric clinical trials represent a specific subset of all research involving children and do not generally include most social-behavioral-educational research studies with children that are regulated by 45 CFR 46.    SACHRP agrees that these differences would complicate the document and lead to the delay in the advancement of any guidance, therefore, SACHRP recommends that OHRP consider developing its own guidance on the application of 45 CFR 46, Subpart D that addresses the issues that are germane to research with children that is not FDA regulated.

Principle of Scientific Necessity

The Draft Guidance frames the principle of scientific necessity within the ethical principle of justice as well as two regulatory requirements: the equitable selection of subjects (21 CFR 56.111(a)(3)) and minimization of risk (21 CFR 56.111(a)(1)).  The Draft Guidance argues that “Children should not be enrolled into a clinical investigation unless their participation is necessary to answer an important scientific and/or public health question directly relevant to the health and welfare of children.” SACHRP agrees that the inclusion of children in research should be justified by scientific necessity and its inclusion in the Draft Guidance is important.

SACHRP notes that in addition to scientific necessity, the inclusion of children in research also serves to generate data that informs the pediatric labeling of medical products. SACHRP recommends highlighting this aspect of conducting research with children and highlighting the importance of developing medical products for pediatric patients while providing appropriate protections to children enrolled in clinical investigations.

Risk Categories for Interventions or Procedures without Prospect of Direct Benefit

21 CFR 50.53 permits clinical investigations or procedures involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects' disorder or condition when the risk represents a minor increase over minimal risk, along with other conditions. Unlike the term minimal risk, the term minor increase over minimal risk is not defined within the regulation. IRBs have been left to independently interpret the term.  This has led to the inconsistent application of the term within

the IRB community and produced discordant results when multiple IRBs have reviewed pediatric protocols.³

In order to make a determination that proposed research is approvable under 21 CFR 50.53 the IRB must find that (1) the risk represents a minor increase over minimal risk and (2) 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. (21 CFR 50.53(a) and (b))

One challenge of the minor increase requirement lies in the manner in which it relates to the definition of minimal risk. As defined at 21 CFR 50.3(k), minimal risk “means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” In the pediatric setting, SACHRP has previously recommended (and FDA has adopted this recommendation in the Draft Guidance) that the definition of minimal risk when applied to Subpart D should be interpreted as “those risks encountered during daily life by normal, average, healthy children living in safe environments or during the performance of routine physical or psychological examinations or tests.”⁴ A minor increase over minimal risk is not defined in the regulations.  The Draft Guidance indicates that a minor increase “should be understood to mean a slight increase over minimal risk that poses no significant threat to the child’s overall health or well-being” and that any research-related harms should be transient and reversible.  SACHRP agrees with this understanding of a minor increase over minimal risk.

Once an IRB has found that an intervention or procedure constitutes a minor increase over minimal risk, a second challenge is that the IRB must then find 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.” (21 CFR 50.53(b)) When making this finding, the IRB must assess whether the research experiences are reasonably similar to those procedures and interventions that children with the condition or disorder as a class have or are expected to experience.  For example, the risks of a “research only” muscle biopsy in children with a muscle disorder such as Duchenne muscular dystrophy (DMD) generally has been considered a minor increase over minimal risk and the procedure meets the “commensurate” criterion.  Alternatively, for a child who would not otherwise undergo a muscle biopsy (e.g., a child with asthma), this procedure would not meet the “commensurate criteria” even though it would be considered no more than a minor increase over minimal risk in children with DMD.         

SACHRP recommends that the Draft Guidance reflect previous SACHRP recommendations regarding the “commensurate criteria.”⁵ In those recommendations, SACHRP stated that “in applying the commensurate criteria IRBs should determine that research interventions or procedures are reasonably similar to those procedures and interventions that children with the condition or disorder as a class have or are expected to experience.”

Prospect of Direct Benefit

The Draft Guidance states:

“[The] Prospect of direct benefit should result from the research intervention or procedure being studied (e.g., the investigational drug or medical device) and not from ancillary interventions or procedures, such as physical exams done as part of the trial. For research interventions or procedures that are considered to offer prospect of direct benefit, the IRB must find not only that the risk is justified by the anticipated benefit to the child, but the relation of the anticipated benefit to the risk is at least as favorable as any available alternatives (21 CFR 50.52). When evaluating if an intervention or procedure offers a prospect of direct benefit, the IRB should consider whether the evidence establishing proof of concept about a potential beneficial effect is sufficient, and whether the proposed dose (particularly for drugs) and duration of exposure to the intervention or procedure are adequate to offer a potential clinical benefit to the individual child. For a medical device clinical investigation, the device characteristics should be compatible with the child’s age and developmental stage such that a benefit is anticipated.

It is less clear how “prospect” is understood in the context of the regulations.  In the context of an FDA regulated clinical trial, should this be understood narrowly as requiring evidence of a clinical benefit or are there surrogate measures of clinical benefit that may be considered? Also, should IRBs conclude that participation in a clinical research study may confer an “inclusion benefit” that may be considered a direct benefit? While the Draft Guidance indicates that direct benefit which justifies the risks of the research intervention cannot come “from ancillary interventions or procedures, such as physical exams done as part of the trial,” some may argue that there may be an inferred direct inclusion benefit due to study activities such as additional monitoring of the disease or condition under study.

Given the impact of finding that proposed research offers the prospect of direct benefit on the implementation of research with children, SACHRP recommends that the Draft Guidance provide additional direction for the evaluation of the prospect of benefit, taking into consideration previous SACHRP recommendations which consider the "prospect of direct benefit" in context versus as an isolated term.⁶ The guidance should make clear that the direct benefit should be a clinical benefit, and that any surrogate measures of that clinical benefit should be supported and justified. The guidance should also clarify that the benefit must be the result of the procedure/intervention and not attributed to, for example, a subject’s mere inclusion in the research. Although the Draft Guidance states that direct benefit which justifies the risks of the research intervention cannot come from “ancillary interventions or procedures, such as physical exams done as part of the trial,” SACHRP recommends that the guidance extend this to include examples such as additional monitoring that might be required by a clinical trial or the benefit of closer oversight of a child’s disease or condition due to the frequency of study visits. The Draft Guidance should be clear that any such “inclusion benefits” would not convey direct benefit for the purpose of justifying the risks of the research intervention.

Assessment of Risk for Interventions or Procedures with a Prospect of Direct Benefit

SACHRP endorses allowing the use of data from nonclinical studies in the assessment of risks when there is a lack of clinical safety data.

Component Analysis

SACHRP is pleased that the Draft Guidance addresses the concept of component analysis. The Draft Guidance provides sound direction on the application of component analysis and does a good job of highlighting the nuances of the component analysis model. 

The concept of “component analysis” is rooted in the deliberations of the National Commission⁷ and has been mentioned in past FDA guidance⁸ and addressed in previous SACHRP recommendations.⁹ However, there has not been clear guidance specifically on this topic available to the regulated community.  Many sponsors and investigators are unfamiliar with component analysis, leading to confusion when IRBs make determinations about the permissibility of multiple research procedures and interventions in research with children.  This confusion can also extend to IRBs that do not routinely review clinical investigations involving children, as the term component analysis is not a defined regulatory term and is not otherwise described in Subpart D.  While the regulations at § 50.52 and 53 describe the assessment of the risk to children that is “presented by an intervention or procedure that does not hold out the prospect of direct benefit” (emphasis added), portions of the regulated community may not understand that this means that the review should be completed using component analysis.

Some may read the Draft Guidance and conclude that the FDA appears to that the use of a placebo is equivalent to withholding effective therapy. However, there are examples of clinical investigations where the use of a placebo is ethically more complex. For example, there is a difference between the use of a placebo while withholding known effective treatment versus research where the placebo (or investigational drug) is used, in conjunction with a known effective treatment, as an add-on to assist in masking randomization to different treatment arms.

The ICH E10 (Choice of Control Group) includes several examples of study designs that may include a placebo.¹⁰ Based on what the FDA has said in the Draft Guidance about “placebo” and “prospect of direct benefit,” it is not clear how the FDA would expect IRBs to apply Subpart D to various study designs that utilize placebo. Given the significance of the use of placebos in an IRB’s determinations regarding prospect of direct benefit, SACHRP recommends that FDA provide other examples of the use of a placebo in different study designs, and the resulting analysis, as reflected in ICH E10 Choice of Control Group. Other examples of the use of component analysis would be helpful, whether in this or future guidance or other venues.

Parental/Guardian Permission and Child Assent

The regulations state that “assent” means a child has provided affirmative agreement to participate in a clinical investigation; mere failure to object should not be construed as assent (21 CFR 50.3(n)). Unless the IRB waives the requirement, adequate provisions must be made for soliciting assent from the children if the IRB determines that the children are capable of providing assent (21 CFR 50.55(a), taking into account the ages, maturity, and psychological state of the children involved. This judgment may be made for all children to be involved in clinical investigations under a particular protocol, or for each child, as the IRB deems appropriate. (21 CFR 50.55(b))

SACHRP recommends that the Draft Guidance clarify that the reference to children 7 years of age and older often being considered capable of assent does not constitute an absolute threshold. IRBs may determine that in some circumstances children younger than 7 are capable of assent, but in other circumstances the age at which obtaining assent is appropriate will be older than 7.  IRBs need to make determinations based on the circumstances of the proposed research and the population being studied, taking into consideration the ages, maturity, and psychological state of the children involved in the clinical investigation. (21 CFR 50.55(b))

SACHRP recommends that the Draft Guidance include commentary on issues that arise when there is discordance between the wishes of the parent/guardian and the child regarding participation, e.g., when a parent/guardian gives permission but child does not give their assent or where a child wishes to participate in research but the parent/guardian refuses to give their permission.  The guidance should direct investigators to engage with the IRB when such scenarios are encountered. Although the regulations do not require assent when the research offers the prospect of direct benefit, there may be circumstances when the child’s refusal to give assent should be respected even when parents give permission.

Design Considerations for Clinical Investigations

SACHRP recommends that the Draft Guidance include considerations of the research setting, including relevant local laws that apply to clinical investigations, including parental rights, children’s rights and privacy, the age of majority, the care of children (e.g., mandatory reporter laws), and educational policies and rights (relevant to pediatric outcomes in conditions such as ADHD).  There may also be other local issues that can have an impact on study design due to their effect on the target subject population.

Clinical Investigations of Drugs

The analysis of single dose pharmacokinetic (PK) studies in the Draft Guidance is of value to the regulated community, and SACHRP agrees that many single-dose studies intended to collect PK data in children do not offer prospect of direct benefit.

Clinical Investigations of Medical Devices

SACHRP appreciates the inclusion of issues related to clinical investigations of medical devices in addition to drugs.  This not only promotes harmonization across FDA centers but makes clear that there can be unique issues in research with medical devices.

¹  The Preamble to 21 CFR 50 Subpart D Final Rule in 2013 included a discussion of component analysis. There has been no other separately published guidance. https://www.federalregister.gov/documents/2013/02/26/2013-04387/additional-safeguards-for-children-in-clinical-investigations-of-food-and-drug

²  https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2005-july-28-letter-appendix-b/index.html Appendix B: Recommendations regarding risk in research involving children

³  In December 2008 the FDA’s Pediatric Advisory Committee reviewed a clinical investigation entitled “Children's Oncology Group Protocol ASCT0631: A Phase 111 Randomized Trial of Granulocyte Colony Stimulating Factor (G-CSF) Stimulated Bone Marrow vs. Conventional Bone Marrow as a Stem Cell Source in Matched Sibling Donor Transplantation.” Prior to the Advisory Committee review, there was disagreement regarding the approvability of the participation of healthy donors in the research under 21CFR50.53.

⁴  https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2005-july-28-…

⁵  Ibid

⁶  https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2005-july-28-…

⁷  https://repository.library.georgetown.edu/bitstream/handle/10822/559373…

⁸  Guidance for Industry Acute Bacterial Otitis Media: Developing Drugs for Treatment https://www.fda.gov/media/71197/download

⁹  https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2005-july-28-letter-appendix-b/index.html

¹⁰  https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-10-choice-control-group-clinical-trials-step-5_en.pdf