P21: Comparative Analyses of Bioequivalence Assessment Methods for IVPT Data

For topical, dermatological drug products, an in-vitro option to determine bioequivalence (BE) between test and reference products is recommended. In particular, In Vitro Permeation Test (IVPT) data analysis uses a reference-scaled approach for two primary endpoints, cumulative amount (AMT) and maximum flux (Jmax), which takes the within subject variability into consideration.
In December 2022, FDA released a new guidance, specific to IVPT studies (www.fdanews.com/10-21-22-InVitroPermeationTestStudiesdraftguidance.pdf), that presents in detail the statistical analysis method applicable to both balanced and unbalanced IVPT data. We are currently working on expanding the IVPT statistical analysis method to data coming from other types of studies, such as in-vivo dermal Open-Flow Microperfusion (dOFM) and microdialysis. Based on existing open questions from drug development submissions over the studies mentioned above, new research is presented on the following topics on the IVPT study data:
1. The development of objective criteria (i.e., statistical tests) to determine and characterize outliers
2. The optimized use of an adaptive design with sample size re-estimation that leverages data from both the pilot and the pivotal IVPT studies
3. The adaptation of the bioequivalence (BE) assessment to a model-based approach using a mixed effects model that accounts for both the skin donors and their corresponding replicate skin sections.
We aim to address these questions by both simulated and real data. The performance of the introduced tests in terms of statistical power will be discussed.

In Vitro Permeation Test (IVPT)

Reference-Scaled Bioequivalence Test

Adaptive Design

Outliers

Mixed Effects Model 

Clinical Trial Design (e.g., Innovative/Complex Design, Estimands, Master Protocol)

ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop 2023