Scientific Publications by FDA Staff

Clin Cancer Res 2016 Jun 1;22(11):2623-9

Rendering the 3 + 3 design to rest: more efficient approaches to oncology dose-finding trials in the era of targeted therapy.

Nie L, Rubin EH, Mehrotra N, Pinheiro J, Fernandes LL, Roy A, Bailey S, de Alwis DP

Selection of the maximum tolerated dose (MTD) as the recommended dose for registration trials based on a dose-escalation trial using variations of an MTD/3 + 3 design often occurs in the development of oncology products. The MTD/3 + 3 approach is not optimal and may result in recommended doses that are unacceptably toxic for many patients and in dose reduction/interruptions that might have an impact on effectiveness. Instead of the MTD/3 + 3 approach, the authors recommend an integrated approach. In this approach, typically an adaptive/Bayesian model provides a general framework to incorporate and make decisions for dose escalation based on nonclinical data, such as animal efficacy and toxicity data; clinical data, including pharmacokinetics/pharmacodynamics data; and dose/exposure-response data for efficacy and safety. To improve dose-ranging trials, model-based estimation, rather than hypothesis testing, should be used to maximize and integrate the information gathered across trials and doses. This approach may improve identification of optimal recommended doses, which can then be confirmed in registration trials.