Statistical aspects of bioequivalence--a review. 1992

A W Pidgen
Department of Clinical Pharmacology, Hoechst UK Ltd, Milton Keynes, UK.

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.

UI MeSH Term Description Entries
D008297 Male Males
D010599 Pharmacokinetics Dynamic and kinetic mechanisms of exogenous chemical DRUG LIBERATION; ABSORPTION; BIOLOGICAL TRANSPORT; TISSUE DISTRIBUTION; BIOTRANSFORMATION; elimination; and DRUG TOXICITY as a function of dosage, and rate of METABOLISM. LADMER, ADME and ADMET are abbreviations for liberation, absorption, distribution, metabolism, elimination, and toxicology. ADME,ADME-Tox,ADMET,Absorption, Distribution, Metabolism, Elimination, and Toxicology,Absorption, Distribution, Metabolism, and Elimination,Drug Kinetics,Kinetics, Drug,LADMER,Liberation, Absorption, Distribution, Metabolism, Elimination, and Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D013223 Statistics as Topic Works about the science and art of collecting, summarizing, and analyzing data that are subject to random variation. Area Analysis,Estimation Technics,Estimation Techniques,Indirect Estimation Technics,Indirect Estimation Techniques,Multiple Classification Analysis,Service Statistics,Statistical Study,Statistics, Service,Tables and Charts as Topic,Analyses, Area,Analyses, Multiple Classification,Area Analyses,Classification Analyses, Multiple,Classification Analysis, Multiple,Estimation Technic, Indirect,Estimation Technics, Indirect,Estimation Technique,Estimation Technique, Indirect,Estimation Techniques, Indirect,Indirect Estimation Technic,Indirect Estimation Technique,Multiple Classification Analyses,Statistical Studies,Studies, Statistical,Study, Statistical,Technic, Indirect Estimation,Technics, Estimation,Technics, Indirect Estimation,Technique, Estimation,Technique, Indirect Estimation,Techniques, Estimation,Techniques, Indirect Estimation
D013810 Therapeutic Equivalency The relative equivalency in the efficacy of different modes of treatment of a disease, most often used to compare the efficacy of different pharmaceuticals to treat a given disease. Bioequivalence,Clinical Equivalency,Equivalency, Therapeutic,Generic Equivalency,Clinical Equivalencies,Equivalencies, Clinical,Equivalencies, Therapeutic,Equivalency, Clinical,Therapeutic Equivalencies,Bioequivalences,Equivalencies, Generic,Equivalency, Generic,Generic Equivalencies

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