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Bioequivalence: An overview of statistical concepts
Rani Shubha, Pargal A
Abstract
Bioequivalence (BE) means the absence of a greater-than-allowable difference between the systemic bioavailability of a test product and that of a reference product. Studies to test the BE of drug products, and the statistical basis for their design, analysis and interpretation, have evolved over the last two decades. A crossover design is preferred over a parallel-group design as it segregates the inter-subject variation (which is not product-dependent) from the intra-subject variation (which is product-dependent). The value of testing two one-sided null hypotheses of non-equivalence at a significance level of 0.05, and the importance of estimating a 90% confidence interval of the ratio (test/reference) of mean AUC and Cmax values, and of the difference between mean Tmax values, are now recognized and form the current standards for BE. The number of subjects required for a BE study with the desired power (at least 0.80) and significance level (0.05), depends on the expected deviation of the test product from the reference product and the error variance associated with the bioavailability parameters (AUC, Cmax, Tmax etc.) of the drug substance. At present, according to the Indian regulatory authority, the number of subjects required to conduct a BE study is 12 which is inadequate for most drug substances by the current international standards and criteria. This review expounds the foregoing principles of BE testing.
Keywords
Bioequivalence study designs, comparative bioavailability, statistical analysis
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