(T1430-02-09) Evaluation of Methods for Assessing Pre-Dose Steady-State Drug Concentration Attainment in Bioequivalence Studies in Abbreviated New Drug Application (ANDA) Submissions

Purpose: For generic drug products with safety considerations administrated in healthy subjects, the FDA typically recommends conducting steady-state bioequivalence (BE) studies that enroll patients who have been receiving the treatment with the reference standards. The design of a steady-state BE study requires appropriate dose administration and sampling plans to demonstrate achievement of steady-state concentration. In general, the Agency has not recommended specific methods to evaluate pre-dose steady-state achievement. The objective of this project is to 1) summarize commonly used approaches and 2) explore the impact of method(s) to evaluate pre-dose steady-state attainment on the BE conclusion through case studies.

Methods: The data submitted from years 2010 to 2024 were evaluated. Information was collected on study design, including dose regimen and number of pre-dose plasma drug samples, as well as the methods used to evaluate the steady-state attainment by applicants and/or assessors in steady-state studies, based on the identified drug products. Additionally, focus was on ANDAs for oral dosage form drug products with apparent fluctuating pre-dose concentrations. Furthermore, statistical analyses for case studies were performed using different individual level approaches:1) regression analysis; and/or 2) ratio method – after linear regression, inclusion of subject(s) with the negative slope and additional exclusion based on ratio of pre-dose levels showing increasing trend (e.g., considered increasing if Day 0/Day -1 ≥1.25 AND Day -1/Day-2 ≥1.00).

Results: Sixty ANDAs for 15 drug products were identified with steady-state BE study designs. Among these ANDAs, 87% pertained to oral dosage form drug products such as tablets, capsules, suspension, sublingual formulations, while the remaining 13% were for intramuscular or intravenous injections. Regarding pre-dose steady-state evaluation by applicants, 40% did not conduct steady-state analysis (e.g., provided justification using steady-state information in product labeling), 28% conducted population-level analysis, employing methods such as the Helmert method or repeated measure ANOVA. Meanwhile, 32% conducted individual level analysis, utilizing techniques such as linear regression analysis or stepwise test for linear trend (after linear regression, inclusion of subject whose Day 0/Day -1 ratio is within a certain limit). Among 52 applications for oral dosage form drug products, 7 ANDAs exhibited apparent fluctuating pre-dose concentrations. The linear regression method and ratio method were able to identify the patients with increasing or decreasing concentration trend who did not reach the steady-state, although different number of subjects were identified based on the method used. However, there was no trend that one method identifies more subjects who did not reach pre-dose steady-state comparing to the other method. Case studies indicated that different methods have no impact on the BE conclusion, likely due to sufficient power ensured at the study planning stage.

Conclusion: The project identified that the applications often employ various methodologies to evaluate pre-dose steady-state attainment. At this time, there is no definitive method that stands out as the most appropriate for evaluating the pre-dose steady-state achievement. Further research may be necessary to identify the most appropriate method to evaluate the pre-dose steady-state achievement which will enhance the regulatory evaluation of BE studies, ensuring safe, effective, and high-quality drug product to the patients.

Acknowledgements: The views and opinions presented here represent those of the presenters and should not be considered to represent advice or guidance on behalf of the U.S. Food and Drug Administration.