Between-Batch Bioequivalence (BBE): a Statistical Test to Evaluate In Vitro Bioequivalence Considering the Between-Batch
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Research Article Between-Batch Bioequivalence (BBE): a Statistical Test to Evaluate In Vitro Bioequivalence Considering the Between-Batch Variability Jonathan Bodin,1 Stéphanie Liandrat,2 Gabriel Kocevar,1 and Céline Petitcolas2,3
Received 15 April 2020; accepted 13 July 2020 Abstract.
Bioequivalence testing is an essential step during the development of generic drugs. Regulatory agencies have drafted recommendations and guidelines to frame this step but without finding any consensus. Different methodologies are applied depending on the geographical region. For instance, in the EU, EMA recommends using average bioequivalence test (ABE), while in the USA, FDA recommends using population bioequivalence (PBE) test. Both methods present some limitations (e.g., when batch variability is nonnegligible) making it difficult to conclude to equivalence without subsequently increasing the sample size. This article proposes an alternative method to evaluate bioequivalence: between-batch bioequivalence (BBE). It is based on the comparison between the mean difference (Reference − Test) and the Reference between-batch variability. After presenting the theoretical concepts, BBE relevance is evaluated through simulation and real case (nasal spray) studies. Simulation results showed high performance of the method based on false positive and false negative rate estimations (type I and type II errors respectively). Especially, BBE has shown significantly greater true positive rates than ABE and PBE when the Reference residual standard deviation is higher than 15%, depending on the between-batch variability and the number of batches. Finally, real case applications revealed that BBE is more efficient than ABE and PBE to demonstrate equivalence, in some wellknown situations where the between-batch variability is not negligible. These results suggest that BBE could be considered as an alternative to the state-of-the-art methods allowing costless development.
KEY WORDS: between-batch variability; equivalence test; in vitro bioequivalence; nasal spray; statistical test.
INTRODUCTION In the pharmaceutical industry, generics are becoming more and more important, mainly driven by countries’ regulations for giving patients easier access to drugs. From an industrial point of view, the final goal is to have a generic product that complies with all the regulatory requirements and is safe for the patient, i.e., has the same final therapeutic effect than the brand-name product. One way to prove the equivalence, without long and expensive clinical trials, is to conduct in vitro bioequivalence evaluation between the Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-020-00486-5) contains supplementary material, which is available to authorized users. 1
Data Science Department, Seenovate, Lyon, France. Nemera, Insight Innovation Center, La Verpilliere, 20 avenue de la gare, 38290, La Verpilliere, France. 3 To whom correspondence should be addressed. (e–mail: [email protected]) 2
Innovator (R
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