Adaptive randomization for multiarm comparative clinical trials based on joint efficacy/toxicity outcomes

Biometrics. 2009 Sep;65(3):876-84. doi: 10.1111/j.1541-0420.2008.01175.x. Epub 2009 Jan 23.


We present an outcome-adaptive randomization (AR) scheme for comparative clinical trials in which the primary endpoint is a joint efficacy/toxicity outcome. Under the proposed scheme, the randomization probabilities are unbalanced adaptively in favor of treatments with superior joint outcomes characterized by higher efficacy and lower toxicity. This type of scheme is advantageous from the patients' perspective because on average, more patients are randomized to superior treatments. We extend the approximate Bayesian time-to-event model in Cheung and Thall (2002, Biometrics 58, 89-97) to model the joint efficacy/toxicity outcomes and perform posterior computation based on a latent variable approach. Consequently, this allows us to incorporate essential information about patients with incomplete follow-up. Based on the computed posterior probabilities, we propose an AR scheme that favors the treatments with larger joint probabilities of efficacy and no toxicity. We illustrate our methodology with a leukemia trial that compares three treatments in terms of their 52-week molecular remission rates and 52-week toxicity rates.

MeSH terms

  • Biometry / methods*
  • Controlled Clinical Trials as Topic / methods*
  • Data Interpretation, Statistical*
  • Endpoint Determination / methods*
  • Humans
  • Outcome Assessment, Health Care / methods*
  • Proportional Hazards Models*
  • Research Design*
  • Treatment Outcome