A Survey of Population Pharmacokinetic Reports Submitted to the USFDA: An Analysis of Common Issues in NDA and BLA from 2012 to 2021.

Background And Objective: Population pharmacokinetic (PopPK) analysis is one of the important components of regulatory submission. The purpose of this study was to survey PopPK analysis reports in new drug applications (NDAs) and biological licensing applications (BLAs) submitted to the US Food and Drug Administration (FDA) and to retrieve the information regarding PopPK-related issues in the US FDA review reports.

Methods: We surveyed NDAs and BLAs over the period from 2012 to 2022 from Drug@FDA databases and extracted the review reports from the website. We explored the issues identified in these reports and sorted them into four categories: (i) data used for PopPK analysis, (ii) base model development, (iii) final model development, and (iv) model evaluation. The percentage of the issues in each category and the total issues were calculated.

Results: Data from a total of 317 applications were analyzed. Of these, 122 applications had at least one PopPK-related issue, and the count went up to 168 issues. The proportion of issues for each category was ranked as follows: model evaluation (39%, 65 of 168), final model development (34%, 57 of 168), data used for PopPK analysis (14%, 24 of 168), and base model development (13%, 22 of 168). The most common issues were related to the goodness-of-fit plots, covariate selection, and high shrinkage of ETA, accounting for 17.9%, 15.5%, and 11.3% of the total issues, respectively.

Conclusion: The findings from this study may help the applicant understand the FDA's thinking on the PopPK analysis.