On a Primary Efficacy Endpoint
- PDF / 394,922 Bytes
- 6 Pages / 504 x 719.759 pts Page_size
- 103 Downloads / 209 Views
0092-86 I5/2001 Copyright 0 2001 Drug Information Association Inc.
ON A PRIMARY EFFICACY ENDPOINT* KALLAPPAM. KOTI, PHD United States Food and Drug Administration, Rockville, Maryland
In some confirmatory clinical trials, data on the number of episodes of a particular type during baseline and treatment phase periods are collected. The primary eflcacy variable proposed by the sponsor to compare the test drug with placebo is Y = ( B - T)/(B + T), where B and T are x-day rates of episodes for baseline and the treatment phase, respectively. In this article, it is argued that this eflcacy variable does not have clinical interpretation as required by the International Conference on Harmonization (ICH) E9 guidelines (I). It is claimed that the difference D = B - T would be a natural and legitimate eflcacy endpoint as it represents a reduction in the frequency of episodes. The relative difference RD = D/B is also examined for its feasibility. It is indicated that using Y as the dependent variable instead of D (or RD) lowers the p-values for the pooled t-test and the Wilcoxon test. It is concluded that the proposed eflcacy variable Y is obscurant in nature and introduces statistical bias in favor of the test drug. The arguments against the use of the response variable Yare also valid for clinical trials designed to increase the rate of an outcome. Key Words: Paired data; ANOVA; Wilcoxon test; P-value; Statistical bias
INTRODUCTION WE CONSIDER CLINICAL trials that are conducted to compare the efficacy of test drugs with placebo in reducing the frequency of episodes of a particular type. These episodes may be of partial seizures, panic disorder, or migraine attacks. Usually, these clinical trials are randomized, double-blind, placebo-controlled, parallel-group, multicenter trials comprising x-day baseline phase and z-day treatment phase. The Food and Drug Administration (FDA) regulations require that the pharmaceutical company sponsoring a test drug needs to identify an appropriate efficacy variable in order to establish
*The views expressed here are those of the author and not necessarily those of the FDA. Reprint address: Kallappa M. Koti, PhD, HFD-710, Room 15B45, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. E-mail: KotiK@ cder.fda.gov.
the efficacy of the drug. We have seen the following efficacy variable several times in our routine review work at the Food and Drug Administration. Let B denote the number of episodes recorded during the x-day baseline period. Let T = (Number of episodes during the z-day treatment phase+z)x x. Here T may be described as a rate. The primary efficacy variable proposed by the sponsor is Y = (B - T)/(B + T). The motivation behind choosing Y is unclear. This variable is also mentioned and discussed to some extent in Berry (2). The efficacy variable Y is described as response ratio. Sometimes the right hand side of Y is multiplied by 100 and it is called the symmetrized percent change. It is suggested that the data be analyzed using analysis of covariance. If the un
Data Loading...
