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

Regulatory NewsRegulatory News

| September 26, 2022 | Through Maria Ellen Schneider

The US Food and Drug Administration (FDA) has issued draft guidelines outlining a number of ethical considerations for conducting clinical trials in children.

The guidance, published on September 26, 2022, aims to support industry, sponsors and institutional review boards (IRBs) in conducting or reviewing clinical trials of drugs, biological products and medical devices involving children. It was developed by the FDA’s Office of Pediatric Therapeutics with input from the agency’s Drug, Biologics and Device Centers.

The issue of including children in clinical trials has been a challenge for industry as sponsors attempt to balance the need to provide evidence-based information about how medical devices affect children with protection from potential harm in research studies. (TIED TOGETHER: Bioethics Council calls for reforms for clinical trials in childrenRegulatory focus May 27, 2015)

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

scientific necessity

The draft guidance highlights several “key concepts” that IRBs should consider when reviewing clinical trials involving children, including the principle of scientific necessity. The FDA recommends that IRBs consider scientific necessity, which includes appropriate subject selection and risk minimization, before assessing risk and benefit.

Also Read :  China's economic recovery in the eyes of entrepreneurs, bankers and urban households-Xinhua

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

In addition, procedures already performed as part of clinical care should be used for research purposes, where appropriate, the FDA recommends.

benefits and risks

The draft guidelines also review risk categories for interventions or procedures with no prospect of direct benefit, including minimal risk and small increase versus minimal risk. The minimum risk standard is that the procedure poses no risk greater than what a healthy child would experience in everyday life 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 could meet this standard depending on whether it is designed for diagnostic or therapeutic purposes and how it is used. A small increase above minimal risk means that there is no significant threat to a child’s well-being and any potential harm would be temporary and reversible. Examples of these procedures are urine collection via a catheter or bone marrow aspiration with topical pain relief.

Also Read :  Life lessons from Mahatma Gandhi that parents can teach their children

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

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

When assessing the risk of interventions likely to have a 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 medical conditions, or adults and children treated with the same drug or device for a different indication. However, if this type of data is not available, non-clinical studies can be considered according to the draft guideline. This includes non-clinical studies of the maximum tolerated doses or device performance and safety, studies in juvenile animals supporting the pediatric age groups being studied, and non-clinical studies of sufficient duration to support the treatment of chronic conditions.

The FDA also advised sponsors and IRBs when evaluating risks and benefits to conduct a “component analysis,” which looks at each part of the research study separately to assess whether it offers the prospect of direct benefit. If a particular intervention or procedure promises no direct benefit, the risk should be limited to a small increase over the minimum risk and these conditions should be met.

Also Read :  Ukrainian First Lady Olena Zelenska on Russia's war, educating Ukraine's children and her country's future - 60 Minutes

“The risks associated with the administration of a placebo in a clinical trial should be part of the component analysis of risk. For example, if an intravenous catheter is placed only for placebo administration and is not required for clinical management or for routine clinical care, the risk of catheter insertion and management should be considered as part of the risk assessment. ‘ the FDA wrote. “A peripheral intravenous catheter should generally be considered to represent minimal risk or a small increase over the minimum risk, while a central intravenous catheter should generally be considered to have a small increase above the minimum risk threshold.”

If an intervention in a pediatric protocol exceeds the standards of modest increase versus minimal risk with no prospect of direct benefit, the protocol cannot be approved by an IRB. However, the investigation may proceed under certain conditions, provided that the IRB and the FDA commissioner conclude that “the research presents a reasonable opportunity to advance the understanding, prevention, or alleviation of a problem affecting health or children’s well-being affected”. the research is conducted in an ethical manner and the consent of the children and permission of their parents/guardians is obtained.

The draft guidelines also outline the elements of parent/guardian permission and child consent, the design of pediatric clinical trials, and considerations for the use of non-therapeutic procedural sedation.

Public comments on the draft guidance should be identified with file number FDA-2022-D-0738 and submitted to Regulations.gov by December 27, 2022.

Draft guide to children in clinical trials

© 2022 Regulatory Affairs Professionals Society.