New FDA guidance offers ethical roadmap for including children in clinical trials

Regulatory NewsRegulatory News | 26 September 2022 |  By 

The US Food and Drug Administration (FDA) has issued draft guidance outlining a series of ethical considerations for conducting clinical trials that involve children.
The guidance, published on 26 September 2022, is aimed at assisting industry, sponsors and institutional review boards (IRBs) when conducting or reviewing clinical investigations of drugs, biological products, and medical devices that involve children. It was developed by FDA’s Office of Pediatric Therapeutics with contributions from the agency’s drug, biologics and device centers.
The issue of including children in clinical trials has been challenging for industry as sponsors seek to balance of the need to provide evidence-based information on how medical products impact children with protecting them from potential harm in research studies. (RELATED: Bioethics Council Calls for Reforms for Clinical Trials Involving Children, Regulatory Focus 27 May 2015)
“Children need access to safe and effective medical products and health care professionals need data to make evidence-based decisions when treating children. However, children are a vulnerable population who can’t provide consent for themselves and are afforded 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 by including them in clinical research and providing these additional safeguards to protect them during clinical trials.”
Scientific necessity
The draft guidance highlights several “fundamental concepts” that IRBs should consider when reviewing clinical investigations involving children, including the principle of scientific necessity. FDA advises that IRBs consider scientific necessity, which covers the equitable selection of subjects and the minimization of risk, before assessing risk and benefit.
“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. For example, for products that are being developed for use in adults and children, if effectiveness in adults can be extrapolated to children, then effectiveness studies in adults should be conducted to minimize the need to collect effectiveness data in children,” FDA wrote in the draft guidance.
Additionally, procedures that are already being performed as part of clinical care should be used to be research needs, when appropriate, FDA suggested.
Benefits and risks
The draft guidance also reviews risk categories for interventions or procedures without the prospect of direct benefit, including minimal risk and minor increase over minimal risk. The standard for minimal risk is that the intervention does not pose a risk greater than what would be experienced in daily life for a healthy child in a safe environment. The use of an investigational drug is unlikely to be considered minimal risk, according to the guidance, but a medical device might meet this standard, depending on whether it is designed for diagnostic or therapeutic purposes and how it is used. A minor increase over minimal risk means there is no significant threat to a child’s wellbeing and any potential harms would be transient and reversible. Examples of these interventions including urine collection via catheter or bone marrow aspirate with topical pain relief.
“The setting and the experience level of the investigator are important factors to consider when making an assessment as to whether an intervention or procedure meets criteria as a minor increase over minimal risk,” FDA wrote in the draft guidance.
To determine that an intervention has the prospect of direct benefit, an IRB must decide that the risk is justified by the anticipated benefit to the child and that the expected benefit-risk balance is “at least as favorable as any available alternatives.”
When considering risk for interventions with a prospect 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 drug or device for a different indication. However, if that type of data are not available, nonclinical studies can be considered, according to the draft guidance. These include nonclinical studies on the maximum tolerated doses or device performance and safety, juvenile animal studies that support the pediatric age groups being studies, and nonclinical studies of sufficient duration to support treatment for chronic conditions.
FDA also advised sponsors and IRBs to conduct a “component analysis” when considering risks and benefits, which looks at each part of the research study separately to evaluate whether it offers the prospect of direct benefit. If a specific intervention or procedure does not offer prospect of direct benefit, the risk should be limited to a minor increase over minimal risk and meet those conditions.
“The risks associated with administration of a placebo in a clinical investigation should be part of the component analysis of risk. For example, if an intravenous catheter will be placed solely to administer placebo and is not needed for clinical management or is not needed for routine clinical care, the risk of the insertion and management of the catheter should be considered as part of the risk assessment,” FDA wrote. “A peripheral intravenous catheter should generally be considered as minimal risk or a minor increase over minimal risk, whereas a central intravenous catheter should generally be considered to exceed the minor increase over minimal risk threshold.”
If an intervention in a pediatric protocol exceeds the standards of minor increase over minimal risk without the 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 alleviation of a problem affecting the health or welfare of children,” the research is conducted according to ethical principles, and the assent of children and the permission of parents/guardians is received.
The draft guidance also outlines the elements of parent/guardian permission and child assent, the design of pediatric clinical investigations, and considerations for use of non-therapeutic procedural sedation.
Public comments on the draft guidance should be identified with docket number FDA-2022-D-0738 and sent to by 27 December 2022.
Draft guidance on children in clinical trials


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