Understanding FDA’s Draft Guidance on Ethical Considerations for Involving Children in Clinical Trials

In 2016, the Food and Drug Administration (FDA) approved Spinraza (nusinersen). It was the first drug to treat children with spinal muscular atrophy (SMA), a disease affecting children’s muscular strength and movement. While the FDA’s approval of nusinersen may not seem extraordinary, it was.

Nusinersen’s approval marked the first time nonclinical data supported conducting initial clinical trials involving children. Usually, when there aren’t data to support enrolling children in clinical trials, the risk threshold requires the prospect of direct clinical benefit. But for the nusinersen clinical trials, children were most likely to benefit, and so the clinical trials began without first collecting data on adult research participants.

Even though this was a big step for involving children in clinical trials, kids haven’t always been as fortunate. Until the 1980s, children had been excluded from research studies in an effort to protect them against research-related risks. As a result, many medicines weren’t tested to treat children, and instead, doctors routinely gave them medicines approved for adults, adjusting the dosing based on the child’s weight.

Today, many clinicians and researchers acknowledge giving children drugs with no supporting pediatric research data and adjusting dosing based on weight likely isn’t the most effective way to treat them. Even worse, ineffective dosing could cause unanticipated effects. The ethical way forward is to offer children[1] better opportunities to participate in clinical research.

On September 26, 2022, the FDA published a draft guidance summarizing ethical considerations for conducting clinical trials involving children. The FDA’s draft guidance intends to provide industry, sponsors, and institutional review boards (IRBs) with insight into protecting children who participate in clinical investigations[2]. This blog examines key considerations from this draft guidance to assist research and IRB professionals involved in pediatric clinical trials.

Why This Guidance Now?

Children are a vulnerable population: They can’t consent for themselves to enroll in clinical research. The regulations at 21 CFR part 50, subpart D summarize the additional safeguards for children in clinical investigations. Subpart D also outlines the threshold of risks to which children can be exposed. Naturally, IRBs, investigators, and sponsors should assess the risks associated with pediatric clinical trials. So, why has the FDA issued this draft guidance?

Pediatric studies are necessary. The FDA’s draft guidance suggests we’d be mistaken to believe that it’s unethical to start pediatric studies without adult data. “Children need access to safe and effective medical products, and health care professionals need data to make evidence-based decisions when treating children,” said Dionna Green, MD, Director of FDA’s Office of Pediatric Therapeutics, in the FDA news release about the draft guidance.

Including children in research requires studies to be ethically and scientifically sound. Sometimes, the specific clinical situation is not only appropriate but necessary to understand before determining whether to begin studies in children. The FDA’s guidance anticipates helping to streamline safe and effective medical products for children, thus guiding and encouraging innovation in pediatric clinical trials.

Ethically Sound and Scientifically Necessary

The FDA’s guidance condenses regulatory concepts to help IRBs, investigators, and sponsors interpret and apply them when reviewing clinical investigations enrolling children. The overarching goal aims to ensure they’re doing what’s right ethically and scientifically for children in clinical investigations.

The draft guidance encourages specialized IRB expertise in assessing pediatric research, stating, “IRBs should consider the purposes of the research and the setting where the research will be conducted and should be aware of the unique challenges of research involving children.”

It also suggests poorly designed pediatric studies may not be ethical, as they can expose children to unnecessary risks and are “unlikely to yield informative study results.” As an example, the guidance notes elements of well-designed studies include selecting appropriate control groups and endpoints relevant to the pediatric population.

Component Analysis

Several issues arise when assessing risks associated with a pediatric clinical investigation. The FDA advises sponsors and IRBs to conduct a component analysis. In other words, IRBs and sponsors should evaluate each part of a study separately to determine the prospect of direct benefit.

In the draft guidance, the FDA notes children enrolled in an active arm of a placebo-controlled study could have the prospect of benefiting directly from an investigational medical project. Potentially receiving direct benefit could feasibly justify a higher risk threshold. The active arm’s risks, then, should be evaluated as one component of the trial.

Children enrolled in the placebo arm likely won’t benefit directly. A component analysis evaluates this arm’s risks with a lower threshold, meaning the risks shouldn’t exceed minimal risk or a minor increase over minimal risk.

Next Steps for the Research Community: Comment on the Draft

The FDA’s newly published draft guidance emphasizes how IRBs, investigators, and sponsors can ensure pediatric studies are scientifically and ethically sound to include children in clinical research. Specifically, pediatric clinical studies should meet certain ethical standards to protect children as a vulnerable population in research.

The public can comment on the FDA’s draft guidance until December 27, 2022. Comments should be labeled with docket number FDA-2022-D-0738. More information can be found at regulations.gov.

[1] FDA’s regulations at 21 CFR 50.3(o) define children.

[2] FDA’s regulations define the term Clinical Investigation at 21 CFR 50.3(c). This blog post uses trial, clinical trial, and study interchangeably to mean clinical investigation.

Back to Resources