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Updated: FDA Finalizes Guidance on Physiologically Based Pharmacokinetic Analyses

Posted 04 September 2018 | By Ana Mulero 

Updated: FDA Finalizes Guidance on Physiologically Based Pharmacokinetic Analyses

A US Food and Drug Administration (FDA) notice on Friday finalized 2016 guidance on the recommended format and content for physiologically based pharmacokinetic (PBPK) analyses.
 
The Federal Register notice suggested the draft version, revealed in December 2016, received revisions that took into consideration issues and concerns raised during the comment period, closed with about a dozen comments, including from the European Medicines Agency (EMA).
 
Several pharmaceutical companies such as Amgen, Sanofi, Merck, Roche, Novartis and Bayer also submitted comments to FDA, calling for additional consistency, flexibility and clarifications.
 
The notice announcing the draft version of FDA’s guidance pointed to recommendations in five sections: executive summary, materials and methods, results, discussion and appendices.
 
Faith Bland, regulatory manager at Amgen, requested “consistency in outlining the sections FDA expects in to be included in the PBPK study report” because “the introduction of this [draft guidance] document outlines five sections to be included; however, Section Ill includes six.”
 
The final version was published Sunday and the sixth section—introduction—is one of several changes FDA made in support of standardization on its evaluation process for PBPK analysis reports. A substantial amount of information was nixed from the draft version as well.
 
The “introduction” section includes a new component regarding the use of previously submitted PBPK study reports for cross-referencing drugs on different intended uses at different stages.
 
Finalized recommendations brought the number of elements to include in description of simulation conditions up to seven, compared to five in the draft guidance.
 
The software-specific section also now involves just four elements under the final guidance vs. seven in the draft version. The ordering in this section was modified from “FDA does not require” to “FDA does not recommend the use of any particular software for PBPK modeling.”
 
The final guidance also clarifies that these analyzes can be used in support of “applications including, but not limited to, investigational new drug applications (INDs), new drug applications (NDAs), biologics license applications (BLAs), or abbreviated new drug applications (ANDAs).”
 
Inclusion of the aim of a PBPK analysis is one of the recommendations made by EMA in its submitted comment, under the assumption that reports “will be the same to the two agencies and therefore that it could be of value to have a more harmonized view of what to include.”
 
Other suggestions EMA made relate to how FDA intends to handle “sensitivity analysis of multiple components,” and specifying methodological approaches for model verification as well as how model results should be confirmed by sponsors.

Article updated on 9/4 with information on the final guidance.

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