Model-based approach for two-stage group sequential or adaptive designs in bioequivalence studies using parallel and
Florence Loingeville1, Manel Rakez2, Thu Thuy Nguyen3
1ULR 2694 - METRICS : Evaluation of Health Technologies and Medical Practices, University of Lille, CHU Lille, Lille, France.
Statistical Methods in Medical Research
|July 14, 2025
Summary
This study shows that model-based TOST (MB-TOST) is a viable alternative to non-compartmental analysis TOST (NCA-TOST) for bioequivalence studies. Two-stage designs, including group sequential and adaptive designs, reduce sample size, especially for highly variable drugs.
Area of Science:
- Pharmacokinetics and Bioequivalence
- Statistical Methods in Drug Development
- Clinical Trial Design
Background:
- Non-compartmental analysis (NCA) with two one-sided tests (TOSTs) is standard for pharmacokinetic (PK) bioequivalence (BE) analysis.
- Sample size determination for BE studies relies on assumptions of between/within subject variability (B/WSV).
- Group sequential (GS) and adaptive designs (ADs) offer interim analysis benefits when prior information is limited.
Purpose of the Study:
- To extend group sequential (GS) and adaptive designs (ADs) to model-based TOST (MB-TOST) for PK BE analysis.
- To evaluate the performance of MB-TOST and NCA-TOST within GS and AD frameworks.
- To compare sample size, type I error, and power across different designs and variability levels.
Main Methods:
- Simulated parallel and two-way crossover designs for a one-compartment PK model.
- Evaluation of NCA-TOST and MB-TOST with one-stage, GS, and AD approaches.
- Assessment under three different levels of initial between/within subject variability (B/WSV).
Main Results:
- Both NCA-TOST and MB-TOST maintained controlled type I error and adequate power in two-stage GS and AD designs.
- Two-stage designs, particularly ADs, reduced sample size compared to traditional methods, especially for highly variable drugs.
- Many AD trials terminated at Stage 1, indicating efficiency gains.
Conclusions:
- MB-TOST is a potentially viable alternative to NCA-TOST for BE assessment in two-stage designs.
- Two-stage GS and AD approaches are effective for sample size reduction in BE studies, especially with high B/WSV.
- The findings support the use of MB-TOST within advanced trial designs for more efficient BE evaluations.
Keywords:
Bioequivalencecombination of p-values testnonlinear mixed effects modelsample size re-estimationtwo-one sided testtwo-stage designtype I error controlMore Related Videos
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