Equivalence Testing in Dose-Response Studies
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EQUIVALENCE TESTING IN DOSE-RESPONSE STUDIES EDWARD J. CHANNON Biostatistics and Data Management, BASF Pharma, Nottingham, United IGngdom
Some developments are described in the case of multidose equivalence studies (multiple doses of the test substance and one dose of the reference). If equivalence cannot be proven for the test substance at one of the doses studied, the procedure uses linear interpolation to examine intermediate doses. This greatly increases the power of the equivalence testing procedure, provided that equivalence for an intermediate dose only is considered an acceptable result of the study. The closed test procedure for equivalence testing of the doses studied is also described in order to clarify methods presented in other statistical publications. It is ojien dificult to specify the equivalence criterion (delta) precisely, although it is taken as a known constant in many statistical publications. It is recommended that results be presented in a form that allows them to be checked against several different values of delta. Key Words: Dose response; Active control equivalence; Equivalence testing; Multiple comparisons; Interpolation
INTRODUCTION ACTIVE CONTROL EQUIVALENCE (ACE) studies (1,2) are well established; both clinicians and statisticians accept them as valid. These studies usually involve two treatment groups (the test substance and an active control) and possibly a placebo control group. There is little in the literature referring to the test substance at more than one dose. A novel statistical approach is developed for the statistical analysis of such studies with adjustment for multiplicity. Although the need for multiple comparison tests that control the overall type I error remains controversial among statisticians, such tests are important in medical statistics.
Reprint address: Edward Channon, Biostatistics and Data Management, BASF Pharma. St. Nicholas Court, 27 Castle Gate, Nottingham NGl 7AR. United Kingdom. E-mail: [email protected].
Multiplicity is discussed by the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use in the E9 guideline (3), “Statistical Principles for Clinical Trials.” The guideline says that methods to avoid or reduce multiplicity are sometimes preferable when available but adjustment to the type I error should always be considered for any aspects of multiplicity that remain in confiiatory analyses. There are two relevant ICH guidelines (3,4), E9 and E4 (“Dose Response Information to Support Drug Registration”), but they do not cover multidose equivalence studies in great detail (although such trials are discussed in E9 under Section 3.3.2). The issues of equivalence testing (5,6) and dose-response testing have been well-covered in the literature. Although multiple comparison equivalence testing (7) and dose-response equivalence testing (8,9) have been devel-
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