Clearing Muddy Waters: The Need to Reconceptualize Minor Increase over Minimal Risk in Pediatric Rare Disease Research

The regulations dictating acceptable levels of risk in pediatric research were developed to protect pediatric research participants from unnecessary or excessive harms. These special protections were adopted in 1983 by the Department of Health and Human Services (DHHS) as part of what is generally referred to as Subpart D of the Common Rule (DHHS 2018), and have not undergone any evaluation or substantive revision in over 35 years. As pathways for drug development become more complex and with more innovative interventions, investigators and institutional review boards (IRBs) are increasingly evaluating complex protocols with research interventions for children that may represent, “a minor increase over minimal risk, without the potential for direct benefit.” Determinations of what interventions represent a minor increase are subjective, and as evidenced by the two research ethics cases in this issue (Johnson et al. 2020; Wilfond et al. 2020), the pathway for approving studies that may involve more than a minimal increase in risk, without potential for immediate direct benefit, is poorly defined.

Clearly it is not the intent of the regulations to prevent progress in pediatric research. Quite the opposite in fact as they were developed to prevent harms and address ethical issues raised by research involving children in prior centuries (Fleischman and Collogan 2008). In 1979 the National Commission published the Belmont Report with a section establishing children as a potentially vulnerable group in need of special protections due to their diminished autonomy. It further laid out that research involving children could be justified if it resulted in effective ways of treating pediatric illnesses or fostered the healthy development of children. Further, the Report concluded that the enrolled children need not be the direct beneficiaries of the research.

Although the Common Rule was revised in 2018, the pediatric sub-protections adopted with Subpart D of 45 CFR 46 were not changed. The two case studies in this issue focus on circumstances when IRBs are being asked to consider the approvability of drug studies with pediatric populations who are not expected to directly benefit based on current study design. Here the regulations dictate that “Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition” must involve no more than a minor increase in risk, the intervention be commensurate to experiences the participants have related to their actual or expected condition, and that the intervention will yield knowledge about the disorder or condition that is vital to understanding said disorder (FDA 2019).

It is under these regulations that the concept of minimal risk is defined as “the probability and magnitude of harm or discomfort anticipated in the research is 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” (FDA 2019). However, empirical research has shown a lack of consensus by IRBs on the definition and evaluation of minimal risk and minor increase over minimal risk (Janofsky and Starfield 1981; Shah et al. 2004). Minimal risk is often conceptualized as the risks associated with the daily lives of normal, healthy, average children. However, this conceptualization may not align with the regular (i.e. commensurate) daily health risks encountered by children with a chronic, serious, or life-threating disorder. For example, children with an implanted central venous catheter–such as a child undergoing chemotherapy or receiving care in the intensive care unit, have very different daily health risks (i.e. infection, thrombosis, etc.) than a healthy child without such an implanted device. During component analysis for research interventions without the potential for direct benefit, additional guidance is needed to reduce the subjectivity IRBs apply when evaluating minor increases in risk.

For example, in the first case, the investigator has designed a Phase I safety/toxicity of plerixafor followed by apheresis in children with sickle cell disease (SCD)—the matter at hand is whether it is ethically acceptable to study a drug in a population that will not receive direct benefit from the study itself, but rather sets the foundation for future gene transfer/editing research and whether such a study is approvable under the current criteria of acceptable levels of risk (Wilfond et al. 2020). Data from adults with SCD suggests the drug is well-tolerated, although patients may experience an increased risk of vaso-occlusive (VOC) pain crisis secondary to repeated apheresis collections but the VOC were mild, and patients responded to standard therapy. Given that patients with SCD have a daily risk of VOC, does a small increase in the risk of VOC as an adverse event represent only a minor increase in risk? For example, what if risks to participants were minimized (i.e. study infusion within one week of chronic transfusion therapy when a VOC is less likely) is this enough to justify an assessment of only a minor increase in risk? In the second case, regarding the use of low dose interleukin-2 (LD IL-2) (Johnson et al. 2020) in adolescents with pediatric-onset systemic lupus erythematosus (SLE), the question of how to define minimal risk is raised along with how to balance potential research risks in the context of rare pediatric diseases with limited effective treatment options. The FDA proposed that the researcher first conduct additional efficacy studies in adults; an approach some commentary authors felt would not yield any appreciable benefits for the research overall given the different biology of pediatric SLE.

It is evident that efforts to protect pediatric research participants from unnecessary risk has had the unintended consequence of placing additional burdens on investigators involved in rare disease pediatric research. These cases demonstrate the limitations of the current regulations. The subjective nature of assessing what represents only a “minor increase over minimal risk” and how to apply this to the ill-child experience continues to present challenges to consistent review at the IRB level and additional guidance is needed. The diverse opinions outlined in the case commentary responses, as with previous research (Janofsky and Starfield 1981; Shah et al. 2004), demonstrate the lack of consensus around this concept of minor increase over minimal risk and the author responses point to the fact that there is more than one approach to determining the level of risk. While two authors (Nelson 2020; Unguru 2020) assessed the respective cases and found that both trials exceed the threshold for a minor increase over minimal risk, others (Porter et al. 2020; Matsler and Young 2020; Sharma and Johnson 2020; Lee and Ginsberg 2020) assert that these trials could be considered below the threshold each pointing out the subjective nature of the term “minimal risk.”

As research on rare pediatric diseases continues to progress and expand, there is a clear need to address this lack of consensus. Although some have advocated for the use of the 45 CFR 46.407 panel in such cases, increasing the use of this type of review is not a practical long-term solution considering the ever-evolving landscape of clinical trial design and the increasing interest in pediatric therapeutics for serious or rare diseases. Given the specific issues around the interpretation of “minor increase over minimal risk”, we suggest it is time to convene key stakeholders (OHRP, FDA, NIH, IRBs, patients, families, clinician-researchers, advocacy groups, etc.) for a summit with the goal of developing additional guidance–perhaps via clarifying recommendations from the Secretary’s Advisory Committee on Human Research Protections (SACHRP 2005) or potentially modifying Subpart D with additional clarifications for 45 CFR 46.406. Bringing together federal policy makers and human subjects research experts who have experience evaluating research designs alongside clinician-researchers, patients, and affected family stakeholders could help bring to light the differing perspectives. Together it may be possible to define a clear pathway that allows for IRBs and federal agencies to conduct risk assessments, without increasing use of the 407 process, around what is a reasonably commensurate minor increase over minimal risk within the daily life of affected populations of children with rare or serious illness who, as a disease class, stand to benefit from research innovation.

DISCLOSURE STATEMENT

Liza-Marie Johnson and Benjamin S. Wilfond are the coeditors and Devan M. Duenas is the managing editor.

Additional information

Funding

The challenging cases in research ethics series is supported by the Institute of Translational Health Sciences [UL1 TR002319] with a CTSA award from the National Center for Advancing Translational Research.