ADJUSTING FOR NON-COMPLIANCE AND CONTAMINATION IN RANDOMIZED CLINICAL TRIALS

Abstract

A method of analysis is presented for estimating the magnitude of a treatment effect among compliers in a clinical trial which is asymptotically unbiased and respects the randomization. The approach is valid even when compliers have a different baseline risk than non‐compliers. Adjustments for contamination (use of the treatment by individuals in the control arm) are also developed. When the baseline failure rates in non‐compliers and contaminators are the same as those who accept their allocated treatment, the method produces larger treatment effects than an ‘intent‐to‐treat’ analysis, but the confidence limits are also wider, and (even without this assumption) asymptotically the efficiencies are the same. In addition to providing a better estimate of the true effect of a treatment in compliers, the method also provides a more realistic confidence interval, which can be especially important for trials aimed at showing the equivalence of two treatments. In this case the intent‐to‐treat analysis can give unrealistically narrow confidence intervals if substantial numbers of patients elect to have the treatment they were not randomized to receive. © 1997 by John Wiley & Sons, Ltd. Stat. Med., Vol. 16, 1017–1029 (1997).