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Silver Spring, MD, United States

Nie L.,OB OTS CDER FDA | Rubin E.H.,Merck And Co. | Mehrotra N.,OCP OTS CDER FDA | Pinheiro J.,Johnson and Johnson | And 4 more authors.
Clinical Cancer Research | Year: 2016

Selection of the maximum tolerated dose (MTD) as the recommended dose for registration trials based on a doseescalation 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. © 2016 American Association for Cancer Research.

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