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42 – Evaluating Teachers and Teaching Methods
FDA and Innovative Designs: Case Study of a Missed Opportunity
Andre Rogatko
Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
Galen Cook-Wiens
Cedars Sinai Medical Center
Mourad Tighiouart
Cedars Sinai Medical Center
Steven Piantadowski
Cedars Sinai Medical Center
The standard 3+3 or "modified Fibonacci" up-and-down (MF-UD) method of dose escalation is by far the most used design in dose-finding cancer early trials. MF-UD was the state-of-the-art in 1971 when it was first used in cancer clinical studies. Since then, over one hundred methodological papers proposing or evaluating dose escalation designs have been published and MF-UD has always shown inferior performance when compared with its competitors regarding maximizing number of patients treated at optimal doses and minimizing number of patients under or overdosed. A consequence of using less effective designs is that more patients are treated with doses outside the therapeutic window. We present a case study where the FDA rejected the proposal to use Escalation with Overdose Control (EWOC), an established dose-finding method which has been extensively used in FDA-approved first in human trials and imposed a suboptimal design, a variation of the MF-UD, known as accelerated titration (AT) design. We show through extensive simulation studies that the AT design has poor operating characteristics relative to two versions of EWOC under several scenarios.