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Abstract

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 often difficult 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.

Keywords

Dose response Active control equivalence Equivalence testing Multiple comparisons Interpolation

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References

Chuang-Stein

Clinical equivalence—a clarification. Drug Inf J. 1999;33:1189–1194.

Hwang

Morikawa

Design issues in noninferiority/equivalence trials. Drug Inf J. 1999;33:1205–1218.

Committee for Proprietary Medicinal Products. Note for Guidance on Statistical Principles for Clinical Trials. (ICH topic E9). London: European Medicines Evaluation Agency; 1998.

Committee for Proprietary Medicinal Products. Note for Guidance on Dose-Response Information to Support Drug Registration. (ICH topic E4). London: European Medicines Evaluation Agency; 1994.

Ebbutt

Frith

Practical issues in equivalence trials. Stat Med. 1998;17:1691–1701.

Röhmel

Therapeutic equivalence investigations: statistical considerations. Stat Med. 1998;17:1703–1714.

Dunnett

Tamhane

Multiple testing to establish superiority/equivalence of a new treatment compared with k standard treatments. Stat Med. 1997;16:2489–2506.

Bauer

Rohmel

Maurer

Hothorn

Testing strategies in multi-dose experiments including active control. Stat Med. 1998;17(18):2133–2146.

Hsu

Berger

Stepwise confidence intervals without multiplicity adjustment for dose-response and toxicity studies. J Am Stat Assoc. 1999;94(446); 468–482.

10.

Senn

Statistical Issues in Drug Development. Chichester: Wiley; 1997:207–217.

11.

Committee for Proprietary Medicinal Products. Points to Consider on Biostatistical/Methodological Issues Arising from Recent CPMP Discussions on Licensing Applications: Superiority, Non-inferiority and Equivalence. (Draft). London: European Medicines Evaluation Agency; 1999.

12.

Jones

Jarvis

Lewis

Ebbutt JA

Trials to assess equivalence: the importance of rigorous methods. Br Med J. 1996;313:36–39.

13.

Committee for Proprietary Medicinal Products. Points to Consider on Biostatistical/Methodological Issues Arising from Recent CPMP Discussions on Licensing Applications: Choice of Delta. (concept paper). London: European Medicines Evaluation Agency; 1999.

14.

Hauck

Anderson

Some issues in the design and analysis of equivalence trials. Drug Inf J. 1999;33(1): 109–118.

15.

Marcus

Peritz

Gabriel

. On closed testing procedures with special reference to ordered analysis of variance. Biometrika. 1976;63:655–660.

16.

Hochberg

Tamhane

Multiple Comparison Procedures. New York: John Wiley; 1987; pages 54, 132, 294.

17.

SAS Institute Inc. SAS/STAT user's guide, Version 6. Fourth edition, Vol. 2. Cary, NC: SAS Institute Inc.; 1989.

18.

Wolfram

The Mathematica Book. 3rd ed. Cambridge: Wolfram Media/Cambridge University Press; 1996.

19.

Williams

A test for difference between treatment means where several dose levels are compared with a zero dose control. Biometrics. 1971;27:103–117.

20.

Williams

The comparison of several dose levels with a zero dose control. Biometrics. 1972;28:519–531.

Equivalence Testing in Dose-Response Studies

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