On September 25, the US Food and Drug Administration (FDA) released a draft guidance, “Ethical Considerations for Clinical Investigations for Medical Products Involving Children.” The draft guidance is intended to help industry, sponsors, and IRBs when considering enrolling children in clinical investigations of drugs, biological products, and medical devices. Public comments are being accepted until December 27, 2022. 

When finalized, the guidance “will provide the agency’s perspective on the ethical considerations for including and protecting children in clinical trials.” This is important language—the FDA has made clear that it is critical to include children in clinical research to develop products and treatments that are safe and effective for children, specifically. At the same time, children are a vulnerable population who cannot consent for themselves, requiring additional research protections.  

Therefore, the guidance’s main function is to provide a detailed description of the “ethical framework” for research involving children codified in the requirements in 21 CFR 50, subpart D (Additional Safeguards for Children in Clinical Investigations).  

Fundamental concepts in subpart D’s framework
As part of that explanation, the guidance also elaborates on its current thinking on “fundamental concepts” involved in subpart D’s framework that IRBs should consider when reviewing clinical investigations involving children. Those concepts include: 

• The principle of scientific necessity; 
• Risk categories for procedures without the prospect of direct benefit, including minimal risk and minor increase over minimal risk; 
• The prospect of direct benefit; 
• Assessment of risk for interventions with a prospect of direct benefit; 
• Component analysis; 
• Potential for review under 21 CR 50.54 (the provisions under which a clinical investigation not otherwise approved by an IRB because it exceeds minor increase over minimal risk and does not offer the prospect of direct benefit may proceed if specific criteria are met); and 
• Parental/guardian permission and child asset.  

FDA outlines several factors IRBs should consider for regulatory criteria
The guidance goes on to describe how IRBs should apply the framework of subpart D to pediatric clinical investigations. More specifically, FDA outlines and explains the following factors IRBs should consider when determining if the regulatory criteria for clinical investigations have been met: 

• The type, source, and amount of data that support conducting the pediatric clinical investigation. 
• Design considerations, with an eye to the fact that clinical investigations involving children should always be designed to maximize the amount of information gained and minimize the number of subjects involved.  
• Study procedures, including a discussion of the important distinction, given FDA’s ethical framework, between study procedures that are carried out as part of routine clinical care and procedures done solely for research purposes, and examples of ways to minimize risk.  

Tools and examples for sponsors, IRBs and investigators
All in all, the draft guidance is thorough, detailed, and well-illustrated, with examples. When final, it should prove extremely useful to sponsors, IRBs, and (though they are not named as a target) investigators involved in the conduct of pediatric clinical research.  

FDA is providing some additional educational tools to help the community understand what is in the draft guidance, including a Guidance Snapshot, part of their Guidance Snapshot Pilot | FDA as well as a podcast.  

Make your voice heard  
This is the regulated community’s chance to weigh in on FDA’s draft guidance on ethical consideration for pediatric clinical investigations. Submit your comments here. The deadline for submitting comments is December 27, 2022. 

PRIM&R will be submitting our comments on this draft guidance, and if we can, we will share those comments here on the blog before the due date so you can reference them. The guidance will also be discussed in Session A05, A Case Study Exploring the Ethical Considerations for Pediatric Clinical Trials, at 2022 PRIM&R Annual Conference. In the meantime, please share any thoughts about these guidelines and how you foresee them affecting your work.