Assessing treatment efficacy in the subset of responders in a randomized clinical trial

Background

Durability of response is a clinically relevant dimension of the treatment effect in randomized clinical trials; it is often measured by comparing among the responders the duration of response between the treatment arms. However, since the comparison groups are defined by response (a post-randomization event), it is subject to analysis-by-responder bias, especially if the proportion of responders differs between the arms.

Methods

Two simple methods are developed that use tumor shrinkage measurements in order to lessen analysis-by-responder bias by generating more comparable patient subsets in the control and experimental arms of the trial. These subsets are then used to estimate between-arm differences in response duration. In the subtraction method, responding patients with the least tumor shrinkage in the treatment arm with more responders are removed from the patient subset for that arm. In the addition method, non-responding patients with the most tumor shrinkage in the treatment arm with fewer responders are added to the patient subset for that arm. In both methods, the numbers of patients subtracted or added are such that the proportion of patients in the modified patient subset is the same as the proportion of responders in the other treatment arm.

Results

The methods are demonstrated on a hypothetical dataset where they are shown to eliminate analysis-by-responder bias, and on two published analyses of randomized trials that compared the duration of response between the treatment arms.

Conclusions

The proposed methods can lessen the analysis-by-responder bias. These methods to compare duration of response between treatment arms may provide a useful exploratory analysis to measure treatment efficacy among responders.

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