Designing the chemoprevention trials of tomorrow: Applying lessons learned from past definitive trials

Chemoprevention represents an important part of cancer medicine's future. The identification of chemopreventive agents holds tremendous promise for reducing the burden of cancer. Currently, 13 agents are FDA approved for the treatment of precancerous lesions or to reduce the risk of invasive cancer. The identification and availability of safe and effective chemopreventive agents rely upon their rigorous evaluation in phase I-IV clinical trials. Five critical elements must be considered in the design and conduct of any clinical trial: (a) agent or intervention to be tested for its ability to suppress the incidence of precancerous or cancerous lesions, inhibit their progression, or induce their regression; (b) biomarkers evaluated at the level of a tissue, cell, or biochemical product as secondary endpoints to evaluate the underlying biology of the preinvasive neoplastic lesion and/or the mechanisms underlying an agent's efficacy and/or toxicities; (c) the cohort of individuals at risk for cancer who are enrolled to participate in the trial; (d) design specifying how the various components are combined, implemented, and monitored; (e) endpoint-the primary goal of the trial that drives the sample size and power estimates. These elements can be remembered by the pneumonic "ABCDE." In this chapter, we discuss each of the five cardinal elements of trial design and evaluate previous trials in the context of these cardinal elements to glean lessons that can inform and enhance the design and conduct of future trials.