Eight years later, FDA revises draft guidance on pediatric clinical pharmacology studies
07 Sep 2022
The FDA on Wednesday released updated draft guidance focusing on how sponsors of new drugs and biologics can best identify the appropriate pediatric doses of their developing products, as well as how to use disease and exposure-response knowledge from prior studies to inform future pediatric development.
The new 25-page draft guidance builds on a version from 2014 and public comments, the agency said, expanding on the section around ethical considerations for conducting such studies, and adding a section on drug-drug interactions, as well as generally tweaking the writing and organization of the original draft.
“Multiple-dose PK-PD studies can be designed to offer a prospect of direct benefit, but the dose and duration of exposure to the investigational product should be sufficient to result in potential changes in the clinical manifestations of the condition or in disease-specific biomarkers that reflect a clinical benefit,” new language added to the draft says.
“For example, the duration of the PK-PD study could be extended, or perhaps combined as the lead-in phase to an efficacy trial, to provide a suitable duration of drug exposure that offers a sufficient prospect of direct clinical benefit to justify the risks,” the new draft added.
Companies including Merck, Novartis and Sanofi originally sought clarifications on the older draft, with Merck urging the FDA to provide more on the considerations that have to be factored into the planning and design of pediatric clinical pharmacology studies within the context of the clinical studies for a specific pediatric indication and the entire pediatric development program.
The new draft also removes the line, “If there is uncertainty about whether extrapolation of efficacy is appropriate, a single adequate and well-controlled study using a clinical endpoint may be necessary,” to clarify that, “While it is helpful and provides additional evidence to support extrapolation, formally establishing and documenting similarity in exposure-response in adults and target pediatric population is not a requirement in order to consider some degree of extrapolation.”
In general, the guidance lays out the three options for pediatric dose selection (PK only, PK and PD with partial extrapolation, and PK/efficacy approach without extrapolation), as well as quantitative approaches (i.e., pharmacometrics), noting that pediatric clinical pharmacology studies should be conducted in individuals with the disease which the drug is intended to treat, or in rare instances, in those who are at risk of this disease.
As far as drug-drug interactions, the new draft notes that considering potential ethical concerns for standalone DDI studies in pediatrics, “quantitative approaches such as PBPK analyses should be explored to address pediatric DDIs during drug development when differences in DDI are expected.”
In addition to this updated draft guidance, the FDA also recently released four new ICH-related draft guidance documents, including one on drug interactions and one on pediatric extrapolation, as well as one final ICH guidance on heart-related questions.
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