FDA and Innovative Designs: Case Study of a Missed Opportunity

• Activity Number: 226
• Type: Topic Contributed
• Date/Time: Monday, August 5, 2013 : 2:00 PM to 3:50 PM
• Sponsor: Biometrics Section
• Author(s): Andre Rogatko*+ and Galen Cook-Wiens and Mourad Tighiouart
• Companies: Samuel Oschin Comprehensive Cancer Institute At Cedars-Sinai Medical Center and Cedars Sinai Medical Center and Cedars Sinai Medical Center
• Keywords: dose finding cancer ; EWOC ; FDA ; accelerated titration ; escalation with overdose control ; phase I trials

Abstract

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.