Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies

Author:

Henriques Sara Carolina12ORCID,Albuquerque João23,Paixão Paulo1ORCID,Almeida Luís2,Silva Nuno Elvas1ORCID

Affiliation:

1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal

2. BlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, Portugal

3. Centro de Estatística e Aplicações, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal

Abstract

Pilot bioavailability/bioequivalence (BA/BE) studies are usually conducted and analysed similarly to pivotal studies. Their analysis and interpretation of results usually rely on the application of the average bioequivalence approach. However, due to the small study size, pilot studies are inarguably more sensitive to variability. The aim of this work is to propose alternative approaches to the average bioequivalence methodology, in a way to overcome and reduce the uncertainty on the conclusions of these studies and on the potential of test formulations. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling. Each simulated BA/BE trial was analysed using the average bioequivalence approach. As alternative analyses, the centrality of the test-to-reference geometric least square means ratio (GMR), bootstrap bioequivalence analysis, and arithmetic (Amean) and geometric (Gmean) mean ƒ2 factor approaches were investigated. Methods performance was measured with a confusion matrix. The Gmean ƒ2 factor using a cut-off of 35 was the most appropriate method in the simulation conditions frame, enabling to more accurately conclude the potential of test formulations, with a reduced sample size. For simplification, a decision tree is also proposed for appropriate planning of the sample size and subsequent analysis approach to be followed in pilot BA/BE trials.

Publisher

MDPI AG

Subject

Pharmaceutical Science

Reference21 articles.

1. European Medicines Agency (EMA) (2022, September 15). Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr **). London. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf.

2. U.S. Food and Drug Administration (FDA) (2022, September 15). Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted under an ANDA. Draft Guidance, Available online: https://www.fda.gov/media/87219/download.

3. Chow, S.C., and Liu, J. (2008). Design and Analysis of Bioavailability and Bioequivalence Studies, Chapman and Hall/CRC.

4. Average Bioequivalence Evaluation: General Methods for Pilot Trials;Pan;J. Biopharm. Stat.,2006

5. Pilot and Repeat Trials as Development Tools Associated with Demonstration of Bioequivalence;Fuglsang;AAPS J.,2015

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