FDA May Soon Require Dose Findings Studies for Oncology Product Approval
(Thursday, November 11, 2021)
Most cancer drugs are clinically evaluated at the highest dose possible, the Maximum Tolerated Dose (MTD), with the assumption that more is better. A white paper co-authored by several FDA oncology drug officials argues that the MTD approach is no longer appropriate and that prior to conducting registration studies, sponsors should conduct dose-finding studies to find the optimum dose which may be lower than the MTD. The White Paper lists several issues with the MTD approach particularly for new molecular targeted agents (MTAs) and immunotherapies that “often have target saturation limits below the MTD suggesting drugs can be given at lower doses with similar efficacy and potentially fewer side effects”. For all oncology products, FDA expects that dose-finding studies will be conducted prior to confirmatory/registration studies. The White paper present several suggestions to incorporate dose-finding studies in drug development programs to establish a therapeutic window based on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the product. At least two doses should be evaluated in a randomized manner in a Phase 2 study for dose selection for the registration study. The dose-finding study does not need to be statistically powered but should be sufficiently sized to find the minimally active dose based on evaluation of the dose/exposure – activity/toxicity relationships. Ideally the two doses selected should be 2-3 folds apart with one dose being the lowest dose expected to provide activity based on the PK/PD analysis, and the second dose being the highest dose expected to give increased activity with acceptable toxicity. The doses for the clinical studies should be calculated from non-clinical data from animal models or computational models. FDA plans to release dose optimization guidance for oncology drugs to further emphasize the recommendations made in the white paper. FDA expects pre-market dose-finding studies to be a part of the standard oncology drug development programs. The white paper also includes suggestions on overall development program such as the design of the Phase 1 and 2 trials, analysis of patient reported outcomes (PROs), pre-clinical study designs, post-approval studies, and strategies for customizing study designs based on the chemical structure of the drugs and heterogeneity of the target patient population. The MTD model for oncology drug development may not be completely dead but it would harder to argue the waiver of dose-finding clinical studies with FDA, going forward.
Dr. Mukesh Kumar
Founder & CEO, FDAMap
Linkedin: Mukesh Kumar, PhD, RAC