New FDA guidelines offer ethical roadmap for including children in clinical trials

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Regulatory news

| September 26, 2022 | By Mary Ellen Schneider

The US Food and Drug Administration (FDA) has released draft guidelines outlining a series of ethical considerations for conducting clinical trials involving children.

The guidelines, published September 26, 2022, are intended to assist industry, sponsors and Institutional Review Boards (IRBs) when conducting or reviewing clinical investigations of drugs, biologics and medical devices involving children. It was developed by the FDA’s Office of Pediatric Therapeutics with input from the agency’s Centers for Drugs, Biologics, and Devices.

The issue of including children in clinical trials has been a challenge for the industry, as sponsors seek to balance the need to provide factual information about the impact of medical products on children and their protection against potential harm in research studies. (RELATED: Bioethics Council calls for reforms for clinical trials involving childrenRegulatory guidance May 27, 2015)

“Children need access to safe and effective medical products and healthcare professionals need data to make evidence-based decisions when treating children. However, children are a vulnerable population who cannot provide consent and have additional safeguards when participating in a clinical investigation,” Dionna Green, MD, director of the Office of Pediatric Therapeutics, said in a statement. “The best way to provide children with safe and effective treatment options is to include them in clinical research and provide those additional safeguards to protect them during clinical trials.”

Scientific necessity

The draft guidelines highlight several “fundamental concepts” that IRBs should consider when reviewing clinical investigations involving children, including the principle of scientific necessity. The FDA advises IRBs to consider scientific need, which covers fair subject selection and risk minimization, before weighing risks and benefits.

“Children should not be enrolled in a clinical investigation unless their participation is necessary to answer an important scientific and/or public health question directly related to the health and well-being of children. For example, for products under development for use in adults and children, if efficacy in adults can be extrapolated to children, then adult efficacy studies should be conducted to minimize the need for collect efficacy data in children,” the FDA wrote in the draft guidance.

Additionally, procedures that are already performed as part of clinical care should be used to meet research needs, as appropriate, the FDA suggested.

Benefits and risks

The draft guidelines also consider risk categories for interventions or procedures with no prospect of direct benefit, including minimal risk and minor increase over minimal risk. The standard for minimal risk is that the procedure presents no greater risk than would be experienced in the daily life of a healthy child in a safe environment. The use of an investigational drug is unlikely to be considered minimal risk, according to the guidelines, but a medical device may meet this standard, depending on whether it is intended for diagnostic or therapeutic purposes and depending on the way which it is used. A minor increase above the minimal risk means that there is no significant threat to a child’s well-being and that any potential harm would be transient and reversible. Examples of these interventions include collection of urine by catheter or bone marrow aspiration with topical pain relief.

“The investigator’s setting and level of experience are important factors to consider when evaluating whether an intervention or procedure meets the criteria of minor increase versus minimal risk” , the FDA wrote in the draft guidance.

To determine that an intervention has the prospect of a direct benefit, an IRB must decide that the risk is justified by the expected benefit to the child and that the expected benefit/risk ratio is “at least as favorable as all alternatives available”.

When considering the risk for interventions with a perspective of direct benefit in children, IRBs and sponsors should consider available safety data. A risk analysis should include data collected from healthy adults, adults with the same conditions, or adults and children treated with the same medicine or device for a different indication. However, if this type of data is not available, non-clinical studies may be considered, according to the draft guidelines. These include non-clinical studies of maximum tolerated doses or device performance and safety, studies in juvenile animals that support the pediatric age groups studied, and non-clinical studies of sufficient duration to support the treatment of chronic diseases.

The FDA has also advised sponsors and IRBs to conduct a “component analysis” when considering risks and benefits, which examines each part of the research study separately to assess whether it offers the prospect of a direct benefit. If a specific intervention or procedure does not offer the prospect of direct benefit, the risk should be limited to a minor increase over the minimal risk and meet these conditions.

“The risks associated with the administration of a placebo in a clinical investigation should be part of the risk component analysis. For example, if an intravenous catheter will be placed only to administer a placebo and is not required for clinical management or is not required for routine clinical care, the risk of catheter insertion and management must be taken considered as part of the risk assessment,” the FDA wrote. “A peripheral IV catheter should generally be considered minimal risk or a minor increase over minimal risk, whereas a central IV catheter should generally be considered to exceed the minor increase above the minimum risk threshold.”

If an intervention in a pediatric protocol exceeds the standards of minor increase over minimal risk with no prospect of direct benefit, the protocol is not approvable by an IRB. However, the investigation may be able to proceed under certain conditions, provided the IRB and the FDA Commissioner conclude that “the research presents a reasonable opportunity to further the understanding, prevention, or mitigation of harm.” a problem affecting the health or well-being of children”. the research is conducted according to ethical principles, and the consent of the children and the permission of the parents/guardians are received.

The draft guidelines also describe the elements of parental/guardian authorization and child assent, the design of pediatric clinical investigations, and considerations for the use of non-therapeutic procedural sedation.

Public comments on the draft guidance should be identified by filing number FDA-2022-D-0738 and sent to regulation.gov by December 27, 2022.

Draft guidelines on children in clinical trials

© 2022 Society of Regulatory Affairs Professionals.

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