FDA finalizes population pharmacokinetics guidance

Regulatory NewsRegulatory News | 03 February 2022 |  By 

The US Food and Drug Administration (FDA) on Thursday finalized guidance on population pharmacokinetics, more than two decades after first issuing draft guidance on the topic.
In 2019, the agency revised the 20-year-old draft, noting that the number of applications relevant for population PK analysis had increased, as had the sophistication and reliability of PK analysis methods, in the intervening years. (RELATED: FDA revises 1999 draft guidance on population pharmacokinetics, Regulatory Focus 11 July 2019; Population pharmacokinetics: drugmakers seek clarity and additions to revised FDA guidance, Regulatory Focus 17 September 2019)
“Population PK analyses can quantify the impact of intrinsic and extrinsic patient factors on the exposure of a drug. In conjunction with supporting exposure-response data, population PK data can be used to identify patient factors that result in a clinically significant change in drug exposure and inform the proper use of drugs,” FDA said in the Federal Register notice announcing the final guidance.
The guidance itself addresses the data and model requirements for population PK analyses submitted as part of new drug applications (NDAs), biologic license applications (BLAs) or abbreviated new drug applications (ANDAs). The guidance also touches on the content of the PK report and labeling recommendations resulting from such analyses.
The agency said it considered comments on the revised draft guidance when it finalized the document. “Changes from the draft to the final guidance include greater detail on the use of population PK modeling for biologics, handling of time-varying covariates, additional methods and terminology typically used for population PK analyses, and updates to the format and content for submitting population PK reports,” it said.
“The focus of this guidance is on the use of this approach in explaining the variability in drug concentrations observed among human trial subjects from intrinsic factors, extrinsic factors, differences in dosing, and routes of administration,” the agency writes in the guidance.
One of the chief recommendations the Pharmaceutical Research and Manufacturers of America (PhRMA) made in its comments to the draft guidance was a request for more specific examples and references to the literature to support the technical statements made in the guidance.
While the final guidance does not include many additional examples, many of the examples it provides have been expanded upon from those in the draft guidance.
The final guidance revises the structure of the expected content of the population PK study report provided in a table toward the end of the document. The Synopsis section has now been merged with the Executive Summary, and the Data and Methods sections have been combined into a new Materials and Methods section with several revised components. The appendix section of the study report has also been expanded, and now includes more examples of appropriate materials for inclusion in that section, such as a “listing of samples removed from the study analysis and reasons for removal” and a “run record describing the steps during model development.”
The final guidance also expands on the use of novel methodologies and applications of population PK analyses. “There are many novel applications of population PK analyses beyond those described in this guidance. For example, application of population PK, model-based approaches can be an alternative for evaluating the bioequivalence of long-acting injectables, products with sparse PK sampling, or other scenarios when non-compartmental analysis (NCA) becomes challenging,” FDA writes. In such cases, “The model’s intended use and its regulatory impact determine the level of robustness needed for model evaluation.”
Guidance, Federal Register notice


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