IDENTIFYING THE MAXIMUM SAFE DOSE: A MULTIPLE TESTING APPROACH

Abstract

Identifying the maximum safe dose (MAXSD) is an objective of both randomized clinical dose-finding studies for the safety endpoint and toxicological studies. MAXSD is defined as the highest experimental dose with no significant increased safety effect relative to the placebo or control group. In safety assessment, the primary control of the false-negative error rate is more important than that of the false-positive rate. Therefore, we propose a multiple testing procedure for equivalence in the many-to-one design with a priori ordered contrasts (shifted control vs. dose), where the acceptable risk δ is defined in advance. Tests for shifted and ratio hypotheses are presented and discussed.

Keywords:

• Maximum safe dose
• No-observed-adverse-effect dose (NOAED)
• Multiple testing
• Stepwise testing procedure
• Intersection-union test

Acknowledgments

Partly supported by a grant from Volkswagenstiftung, Hannover, Germany, and by a grant from Bundesinstitut fuer Gesundheitlichen Verbraucherschutz, Berlin, Germany, for the first author.