Statistical aspects of bioequivalence--a review

Xenobiotica. 1992 Jul;22(7):881-93. doi: 10.3109/00498259209053147.

Abstract

1. Over the past 20 years a number of statistical methods have been proposed for use in bioequivalence testing. This review examines these methods and reflects current thinking of regulatory authorities. 2. The standard bioequivalence study is conducted as a controlled, single-dose crossover design in a small number of healthy male adults. Blood and/or urine samples are taken at predetermined times for drug/metabolite assay from which pharmacokinetic parameters are derived and compared statistically. Sample size calculations should be determined by the error variance associated with the primary characteristic to be studied, the significance level, the power of the test and the deviation from the reference product compatible with safety and efficacy. 3. In general, bioequivalence is assessed using three parameters namely, Cmax, tmax and AUC. Urinary excretion data may also be used if the amount excreted unchanged is significant. These parameters are best obtained using a simple model-independent approach. 4. The parameters of Cmax and AUC should be logarithmically transformed prior to analysis. For tmax, parametric statistical procedures are not appropriate. 5. Classical hypothesis testing using the power approach is not applicable to the practical problem under consideration in bioequivalence trials. 6. Classical 90% confidence limits and the 2 one-sided t-test approach are operationally identical and are the methods of choice for assessing bioequivalence (Cmax and AUC). When tmax is an important parameter from the clinical point of view then the use of non-parametric confidence intervals is recommended.

Publication types

  • Review

MeSH terms

  • Adult
  • Humans
  • Male
  • Pharmacokinetics
  • Statistics as Topic / methods
  • Therapeutic Equivalency*