Pediatric Research: What's acceptable risk?

Mark Schreiner MD

I’ve been involved in clinical research for most of my career. How to protect children in research trials became personal to me in the 1990s when lead paint research in Baltimore children and the death of a patient in the original gene therapy trials halted a lot of clinical research at Johns Hopkins. I asked Mark Schreiner to write up today’s Pediatric Anesthesia Article of the Day. Mark has been intimately involved in the issues raised by today’s article for most of his career and I could think of no one better to review it. Myron Yaster MD

Original article

Schupmann W, Li X, Wendler D. Acceptable Risks in Pediatric Research: Views of the US Public. Pediatrics. 2022 Jan 1;149(1):e2021052687. doi: 10.1542/peds.2021-052687. PMID: 34961881.

The exposure to risk in the research context is regulated under the Common Rule (45 CFR 46 Subpart D) and FDA (21 CFR 50 Subpart D) regulations. Any child may participate in research that is no more than minimal risk (45 CFR 46.404). While this sounds simple, IRBs and ethicists disagree where to draw the line between minimal risk and greater than minimal risk. For example, the recent JAMA patient page1 includes “A behavioral study that may ask some sensitive questions” as one example of greater than minimal risk research. In my 35+ years serving on an IRB, including over 20 years as chair or vice-chair, I never reviewed a questionnaire that I considered greater than minimal risk. After all, children attend middle school where the social pressures exceed almost any level of distress that could be caused by a questionnaire.

This isn’t always the case. A friend of mine conducts research in Bosnia where questionnaires about war crimes could place the participants at high risk.  

Research that is greater than minimal risk (45 CRF 46.405) and which offers a potential for direct benefit to the participant may be approved by the IRB. The direct benefit must derive from the intervention that is greater than minimal risk, for example, participation in a drug or vaccine study for a disease without alternative treatment. Risky ancillary procedures can’t be justified by the benefit from the intervention. In other words, a brain biopsy for purely research procedures can’t be justified by the benefit of an experimental drug.

Research that is greater than minimal risk and which offers no potential for direct benefit to the participant (45 CFR 46.406) may be approved by the IRB only if the risks are no more than a minor increase above minimal, the intervention or procedures present experiences commensurate with the subject’s actual prior experiences, and the intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition and which is of vital importance for the understanding or amelioration of the subjects' disorder or condition. And, the child must assent to their participation. Since the definition of minimal risk is controversial, it is not surprising that a “minor increase” would be even less clearly defined.

There is a fourth category for research not qualifying under ¶406 which requires review/approval by a panel of experts and the Secretary HHS.

Shupmann, Li and Wendler address a different question than that faced by IRBs. They explored the level of risk that parents thought acceptable for children in general and for their own child in particular, for what they call “net-risk” research.” By net-risk they mean research or components of research that are greater than minimal and are without any direct benefit to the participant.  

A total of 1658 participants were presented with 1 of 4 scenarios involving blood draw and 3 riskier procedures – bone marrow biopsy, kidney biopsy and a single dose of an experimental drug – that would expose the subject to progressively greater risk. They were asked to imagine that their child was 10 years old with advanced, untreatable cancer. The blood draw is no more than minimal risk. The risks of the other procedures increased in frequency and severity. The parents were informed that 1 in 1000 children would have bleeding after the bone marrow biopsy. Aside for hematuria, the need for transfusion, hematoma, 0.7 - 1% of children would need some sort of surgical intervention after undergoing kidney biopsy. The risks of a single dose of the experimental drug included a 1 in 100 chance of death. I cannot imagine an IRB approving the study of a single dose drug with this level of risk. If a kidney biopsy was needed to assess the progress of an experimental treatment, it would possibly be approvable.

Unfortunately, not all relevant risks that an IRB would consider seem to have been included, such as the likelihood of post-procedure pain or need for sedation or general anesthesia for the biopsies. Also, the risk of death from a single dose of an experimental drug seem to be wildly inflated. The risk of death in Phase I clinical oncology studies is about 0.5% and many of those deaths are due to disease progression. It is doubtful that many IRBs would consider a kidney biopsy under sedation/GA with a 1% chance of surgical intervention as meeting the definition of a minor increase above minimal risk and a 1 in 100 chance of death from a single dose of an experimental drug is out of the question. 

The vast majority agreed that research was important and appropriate, in at least some circumstances, and 84.5% felt it appropriate to allow children to participate in research for the benefit of others. Despite this, few parents (9.6%) had a child who had previously participated in a research study. As the level of risk increased in the various scenarios, the percentage of respondents agreeing that the procedure was acceptable decreased - ~ 90% for the blood draw (a minimal risk procedure), ~69% for bone marrow biopsy down to ~50% for single drug dose. As far as their own child was concerned, fewer respondents expressed a willingness to enroll them in any of the research scenarios than who deemed those same procedures appropriate for children in general. For each scenario, the percent of respondents assessing the research as appropriate increased as the value of the hypothetical benefit to future patients increased from “reduce side effects for future cancer treatments”, “increase life by months to years”, to “cure for cancer”.

The authors noted that the level of support for research involving a hypothetical child with cancer exceeded the level of support from prior studies, one of which involved a child with a broken leg and the other a child in the ICU. Families of children with incurable conditions may be more willing to expose their child to greater risk in the hope that early phase research could offer their child a cure. The IRB’s job is to examine the risks and potential benefits objectively, and without the emotional overlay that parents bring. Exposing children who are vulnerable by virtue of their underlying disease shouldn’t be allowed to undergo increased level of risk for the benefit of others compared to healthy children.

References

1.      Thompson LA, Mercado R. What Parents Should Consider When Enrolling Children in Research. JAMA Pediatr. 2022 Mar 1;176(3):332. doi: 10.1001/jamapediatrics.2021.6025. PMID: 35099517