Predictive Potential of Cmax Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ2 Similarity Factor Method

Author:

Henriques Sara Carolina12ORCID,Paixão Paulo1ORCID,Almeida Luis2,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

Abstract

Pilot bioavailability/bioequivalence (BA/BE) studies are downsized trials that can be conducted prior to the definitive pivotal trial. In these trials, 12 to 18 subjects are usually enrolled, although, in principle, a sample size is not formally calculated. In a previous work, authors recommended the use of an alternative approach to the average bioequivalence methodology to evaluate pilot studies’ data, using the geometric mean (Gmean) ƒ2 factor with a cut off of 35, which has shown to be an appropriate method to assess the potential bioequivalence for the maximum observed concentration (Cmax) metric under the assumptions of a true Test-to-Reference Geometric Mean Ratio (GMR) of 100% and an inter-occasion variability (IOV) in the range of 10% to 45%. In this work, the authors evaluated the proposed ƒ2 factor in comparison with the standard average bioequivalence in more extreme scenarios, using a true GMR of 90% or 111% for truly bioequivalent formulations, and 80% or 125% for truly bioinequivalent formulations, in order to better derive conclusions on the potential of this analysis method. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling, accounting for different IOV levels. A redefined decision tree is proposed, suggesting a fixed sample size of 20 subjects for pilot studies in the case of intra-subject coefficient of variation (ISCV%) > 20% or unknown variability, and suggesting the assessment of study results through the average bioequivalence analysis, and additionally through Gmean ƒ2 factor method in the case of the 90% confidence interval (CI) for GMR is outside the regulatory acceptance bioequivalence interval of [80.00–125.00]%. Using this alternative approach, the certainty levels to proceed with pivotal studies, depending on Gmean ƒ2 values and variability scenarios tested (20–60% IOV), were assessed, which is expected to be helpful in terms of the decision to proceed with pivotal bioequivalence studies.

Publisher

MDPI AG

Subject

Pharmaceutical Science

Reference16 articles.

1. European Medicines Agency (EMA) (2023, August 29). 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) (2023, August 29). Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted under an ANDA. Draft Guidance. August 2021, Available online: https://www.fda.gov/media/87219/download.

3. Henriques, S.C., Albuquerque, J., Paixão, P., Almeida, L., and Silva, N.E. (2023). Alternative Analysis Approaches for the Assessment of Pilot Bioavailability / Bioequivalence Studies. Pharmaceutics, 15.

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

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

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