Design of placebo-controlled randomized trials of anticancer agents: Ethical considerations based on a review of published trials

Background Limited information exists about the design of placebo-controlled cancer trials. Through a systematic review of trials published in 2013, we describe placebo use in randomized trials testing anticancer agents and analyze strategies that increase exposure to the experimental regimen. Methods Trials were classified as add-on (placebo in combination with standard treatment) or placebo-only. Strategies to allow more than half of the participants to receive the experimental regimen were reviewed. The risk-benefit ratio of receiving the experimental agent was considered favorable if the difference in primary outcome was significant (p <= 0.05), neutral if there was no significant difference in the primary outcome and the experimental agent did not add substantial toxicity, and unfavorable otherwise. Results Eighty trials were included (32,694 participants). Most trials were add-on (69%). The risk-benefit outcome was favorable, neutral, and unfavorable to the experimental agent in 52%, 32%, and 16% of placebo-only trials and 25%, 53%, and 22%, respectively, of add-on trials. Four strategies increased exposure to the experimental regimen: one-way crossover (23%), uneven randomization (21%), three-arms (13%), and randomized discontinuation design (4%); these strategies were used more often in placebo-only trials. Conclusion A minority of participants received placebo alone and strategies to increase experimental exposure were used commonly. Fewer than half of the studies had favorable outcomes, thus defending the use of placebo controls, when there is no established treatment. Strategies that increase patient exposure to experimental agents rather than placebo may expose them to non-beneficial, sometimes toxic, experimental agents.