ICH E11A: Pharma groups want more information on data extrapolation, pediatric biomarkers

Regulatory NewsRegulatory News | 06 November 2022 |  By 

Two US pharmaceutical industry groups note that they are generally supportive of the International Council for Harmonization (ICH) guideline on pediatric extrapolation in drug development but suggest that the guidance should address a broader subset of the population and not just focus on extrapolating data from adults. The groups called for more information on using biomarkers for the pediatric population and for including the estimands concept in the final guidance.
These comments were made in response to the US Food and Drug Administration (FDA) call for feedback on the ICH E11A, which was released for comment in April 2022 (RELATED: ICH drafts guideline on pediatric extrapolation in drug development, Regulatory Focus, 6 April 2022).
The guideline establishes a framework for extrapolating drug development data from adult trials to pediatric populations.
FDA received comments from the Pharmaceutical Research and Manufacturers of America (PhRMA) and the Biotechnology Innovation Organization (BIO), as well as Otsuka Pharmaceuticals and PTC Therapeutics.
Guideline supported
Both BIO and PhRMA voiced their support for the guidance. BIO said the group “appreciates that this guidance explains how pediatric extrapolation can be applied practically to support the safety and efficacy of a product in pediatric populations in a manner that will advance pediatric drug development globally. We also support the acknowledgement that extrapolation decision-making is complex, that knowledge evolves over time, and that gaps in information at the time of the initial pediatric development plan may be addressed during the execution phase of such a plan.”
Comments from PhRMA expressed appreciation for  efforts to “facilitate harmonized methodologies and strategies to incorporate pediatric extrapolation into overall drug development plans…. International harmonization through ICH is particularly important because it helps ensure alignment among ICH Member regions, preserves efficiency in biopharmaceutical development and speeds patient access to needed medicines.”
Groups want more subsets studied for extrapolating data
However, both groups would like the guidance to focus on extrapolating data from a broader population subset and not just adult populations.
Comments from PhRMA note that “the draft guidance is predominantly focused on the extrapolation of adult treatment effect to pediatric populations. However, PhRMA believes that it would be useful for the draft guidance to describe situations wherein extrapolation is done between two pediatric sub-populations.”
BIO’s comments recommend that the guidance be revised to address extrapolating data from small populations, such as those being treated for rare diseases. The group recommended that this data “would be helpful as a training example.”
More information on biomarkers needed
Groups also wanted more clarity on developing biomarkers for the pediatric population.
PhRMA “requests the draft guidance include a discussion highlighting the factors sponsors should assess in selecting a biomarker. Specifically, the guidance would benefit from the inclusion of an example where a biomarker can be measured in pediatric patients but not in adult patients and is used as the primary endpoint for pediatric patients.”
BIO similarly “requests that the final guidance includes an example for a situation where a biomarker can be measured in pediatric patients but not in adults and is used as the primary endpoint for pediatric patients.
PhRMA and BIO want estimands addressed
Both groups also call for the incorporation of the estimand concept from ICH E9(R1); ICH issued ICH E9(R1) training materials meant to improve the planning, design, analysis, and interpretation of clinical trials by defining suitable estimands in January 2022 (RELATED:  ICH guide provides clarity on estimands, sensitivity analyses, Regulatory Focus, 31 January 2022).
This guideline defines estimands as a “precise description of the treatment effect reflecting the clinical questions posed by a given trial objective [and] summarizes at a population level what the outcomes would be in the same patients under different treatment conditions being compared.”
BIO states that “this concept is important when establishing the main questions of interest and the analytical methods tasked with answering them and believe it should be referenced in the final guidance.”
PhRMA similarly notes that the estimand concept “is important in establishing the main question of interest.”
Otsuka requests more information on endpoints
In their comments, Otsuka Pharmaceuticals suggested that the guidance should include more detail on extrapolating data from secondary or exploratory endpoints to the pediatric population.
According to the draft guidance, “for many pediatric drug development programs, the primary endpoint(s) in the target pediatric population is/are different from that in the reference population. When this is the case, a comparison of one or more components of the primary endpoint(s) and/or secondary/exploratory endpoint(s) can be used to understand the relationship between the different endpoints.”
According to their comments, Otsuka officials would like to know if FDA could “elaborate on how the similarities of components of a primary endpoint or secondary/exploratory endpoint help the extrapolation of the primary endpoint when it is known that the primary endpoint in the target pediatric population is different from that in the reference population?”


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