Adaptive clinical trial designs for European marketing authorization
By William Chin, PhD, Scientific Coordinator, EUCRAF
Adaptive clinical trial design is a confirmatory clinical trials with flexible design and analysis plan, that is a frequently considered for clinical trials by sponsors. Typically, a scientific advice is requested by sponsor to involve regulators in the early planning of a clinical drug development program. At the EMA, scientific advice and protocol assistance procedures are offered to assist the implementation of adaptive clinical trials. A survey was conducted by Amelie Elsäßer et. al. looking at scientific advice letters on adaptive clinical trials in phases II or III and protocol assistance procedures issued between January 2007 and May 2012. The followings are the highlights of the survey's findings:
- The scientific advice and protocol assistance documents revealed that sponsors do not routinely follow the guidance from EMA's reflection paper.
- 59 scientific advices were identified that address adaptive study designs in phase II and phase III clinical trials in the period of 5.5 years, with the great majority of proposals were accepted (15, 25%) or conditionally accepted (32, 54%).
- Almost all were proposed as confirmatory phase III or phase II/III studies.
- The most frequently proposed adaptation was sample size reassessment, followed by dropping of treatment arms and population enrichment.
- The most frequent concerns raised by CHMP/SAWP were insufficient justifications of the adaptation strategy, type I error rate control and bias.
- When discussing adaptive designs the sponsor should demonstrate that the statistical approaches chosen control the type I error.
- A justification using extensive simulation studies comparing the adaptive design and the classical approaches is typically required to demonstrate that potential advantages of the more complex design.
- EMA generally encourages the use of innovative methods in earlier stages of drug development. Besides the SA and PA procedures, the Agency provides nonproduct-related platforms such as Innovation Task Force Meetings, Scientific workshops and Qualification Procedures to discuss new methodological approaches.
1. Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency, Amelie Elsäßer, Jan Regnstrom, Thorsten Vetter, Franz Koenig, Robert James Hemmings, Martina Greco, Marisa Papaluca-Amati, and Martin Posch. Trials. 2014; 15(1): 383. Published online Oct 2, 2014. doi: 10.1186/1745-6215-15-383
2. European Medicines Agency . Reflection Paper on Methodological Issues in Confirmatory Clinical Trials Planned with an Adaptive Design (CHMP/EWP/2459/02) 2007