030: Evaluation of Subject Populations Enrolled in Bioequivalence Studies for Generic Drug Development

Enrolling general population rather than healthy subjects in pharmacokinetic (PK) bioequivalence (BE) studies may be beneficial to generic drug developers by allowing flexibility in subject enrollment and increasing generalizability of BE data. However, general population includes subjects with predisposing conditions and/or concurrent medications that can introduce uncertainty in PK findings and increase the risk of adverse events if these risks were not carefully considered when enrolling this study population. The purpose of this project is to explore the necessity of including general population as a study population option in PK BE studies by evaluating the protocols of BE studies from recently approved abbreviated new drug applications (ANDAs) for generic drug development in comparison to that recommended in published Product-Specific Guidances (PSGs).

Description of Methods & Materials:

Published and revised PSGs were retrieved from FDA databases to generate a list of oral drug products with PSGs that recommend general population. For the pilot evaluation, four drugs that had been on the market for at least 5 years and had ANDAs with an approved status date of January 2020 or after were identified from the list. The ANDAs were then filtered for BE studies that were conducted after the PSG had been published or revised to recommend general population. BE studies that met the criteria were evaluated for determining the study population enrolled. Differences in eligibility criteria in BE studies and inconsistencies in recommendations among PSGs were noted.

Data & Results:

A total of six approved ANDAs for esomeprazole delayed-release tablet, pregabalin extended-release tablet, lamotrigine orally disintegrating tablet, and tadalafil tablet met the criteria for review. Of the six ANDAs, there were zero (0) PK BE studies that enrolled general population. Overall, the eligibility criteria for subject enrollment appeared to be similar among BE studies for these ANDAs (e.g., absence of significant disease, normal physical exam and laboratory values). The identified discrepancies were smoking status (light smokers vs. non-smokers), acceptable body mass index ranges, and contraception comments. The current evaluation also identified discrepancies (e.g., general population, healthy subjects, or healthy general population) in study population recommendations among PSGs of drug products with the same active ingredients and indications.

Interpretation, Conclusion or Significance:

This pilot evaluation suggests that the generic pharmaceutical industry enrolls healthy subjects for their PK BE studies regardless of the test product’s PSG recommendation, indicating that general population as an option for subject recruitment in BE studies for generic drug development may not be necessary for the four drugs evaluated from the current survey. Further analysis of additional ANDAs is needed to determine the status of including general population as a study population option on generic drug development.