Provider groups, researchers raise concerns about extrapolating adult data in children

Regulatory NewsRegulatory News | 05 January 2023 |  By 

Clinicians and researchers are voicing concerns that the US Food and Drug Administration (FDA) has overemphasized the role for extrapolating adult data in pediatric populations as part of recent draft guidance on ethical considerations for conducting clinical trials that involve children.
 
In September 2022, FDA issued draft guidance aimed at assisting industry, sponsors and institutional review boards (IRBs) when conducting or reviewing clinical investigations of drugs, biological products and medical devices in pediatric populations. (RELATED: New FDA guidance offers ethical roadmap for including children in clinical trials, Regulatory Focus 26 September 2022)
 
The guidance explores the principle of scientific necessity, noting that “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.”
 
In public comments on the draft guidance, the American Academy of Pediatrics (AAP) wrote that the document could give the “impression that if a product has been shown to be effective in adults, it unnecessary to evaluate it in children.” While extrapolation is an important tool, the “framing” in the draft guidance does not address issues of adverse effects and long-term problems that may result from medications only tested in adults. “The guidance should clarify that very often there are important scientific questions in pediatrics that can be addressed through pediatric studies,” wrote AAP President Moira Szilagyi.
 
The Leukemia & Lymphoma Society (LLS) praised the draft guidance but commented that the agency had relied heavily on the assumption that it was possible to extrapolate effectiveness in children from data in adults. “LLS firmly believes that children should not be approached as little adults, and our funded research reflects this belief,” wrote Brian Connell, executive director of federal affairs at LLS.
 
In 2022, LLS launched the Pediatric Acute Leukemia (PedAL) Master Clinical Trial, building off the success of a study in adults. The research revealed that pediatric AML functions differently on a molecular level than adult AML. “LLS urges the Agency to include language in this guidance, recognizing the molecular differences that exist in many childhood diseases, as oftentimes pediatric diseases like AML must be viewed as entirely different conditions from their adult counterpoints,” Connell wrote. “These differences should be considered when evaluating the prospect of direct benefit and when weighing the principle of scientific necessity in trial design.” 
The Advanced Medical Technology Association (AdvaMed), which represents medical device and diagnostics manufacturers, recommended that the FDA add information on when adult data can be extrapolated for pediatric use for medical devices, building off the 2016 guidance “Levering Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices.”
 
“To de-risk pediatric medical device development, additional guidance and information from FDA on when children are required for a study to generate evidence of the prospect of direct benefit versus when extrapolation is appropriate would be valuable,” commented Tara Federici, Vice President of Technology and Regulatory Affairs at AdvaMed. “This could be done via examples of both where extrapolation is acceptable and where it may not be. These examples should also include examples of when anatomic or physiological correlations between adults and children may allow for extrapolation or not.”
 
Adolescents, assent, other issues
 
The Pharmaceutical Research and Manufacturers of America (PhRMA) asked for more specifics from FDA about how to operationalize the guidance. The group requested that FDA provide specific examples of balancing equitable selection with risk minimization for adolescents being included in an adult trial.
 
The Biotechnology Innovation Organization (BIO) also called on FDA to provide more information about the ethical considerations related to including adolescents in clinical trials, noting that physiologically adolescents may have limited or no difference in genotypic or phenotypic expression of disease from adults, in certain disease settings. “Language around ethical considerations when the science supports adolescent inclusion in adult studies could be helpful to potentially bring treatments to more patients,” wrote Alex May, Director of Science & Regulatory at BIO.
 
The Pediatric Trials Network, which is administered by the US National Institutes of Health, raised concerns that the draft guidance would categorize procedures that would have previously been considered minimal risk, requiring just single parent consent, as minor increase over minimal risk, requiring two parents to consent. “Two parent consent substantially impacts enrollment; thus, a change in approach could have profound impact on the ability to successfully conduct pediatric clinical trials,” wrote Danny Benjamin, chair of the Pediatric Trials Network.
 
The AAP called on the agency to offer more information on the assent process that could be used by IRBs in determining if a child is capable of providing assent for participation in a clinical trial. “At a minimum, the draft guidance should offer some basic guidance for how to assess a child’s capacity to assent to research participation and describe how assent should be elicited and documented,” Szilagyi wrote. “The assent process can be particularly challenging in certain populations of children, such as children in foster or kinship care, and special attention to these issues would be of particular value to ensure these children are included in clinical research.”
 
Comments on draft guidance

 

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