Discounting phase 2 results when planning phase 3 clinical trials
Article first published online: 29 MAY 2012
Copyright © 2012 John Wiley & Sons, Ltd.
Volume 11, Issue 5, pages 373–385, September/October 2012
How to Cite
Kirby, S., Burke, J., Chuang-Stein, C. and Sin, C. (2012), Discounting phase 2 results when planning phase 3 clinical trials. Pharmaceut. Statist., 11: 373–385. doi: 10.1002/pst.1521
- Issue published online: 17 SEP 2012
- Article first published online: 29 MAY 2012
- Manuscript Revised: 8 MAY 2012
- Manuscript Accepted: 8 MAY 2012
- Manuscript Received: 28 SEP 2011
- bias adjustment;
- launch criteria for phase 3 trials
Sample size planning is an important design consideration for a phase 3 trial. In this paper, we consider how to improve this planning when using data from phase 2 trials. We use an approach based on the concept of assurance. We consider adjusting phase 2 results because of two possible sources of bias. The first source arises from selecting compounds with pre-specified favourable phase 2 results and using these favourable results as the basis of treatment effect for phase 3 sample size planning. The next source arises from projecting phase 2 treatment effect to the phase 3 population when this projection is optimistic because of a generally more heterogeneous patient population at the confirmatory stage. In an attempt to reduce the impact of these two sources of bias, we adjust (discount) the phase 2 estimate of treatment effect. We consider multiplicative and additive adjustment. Following a previously proposed concept, we consider the properties of several criteria, termed launch criteria, for deciding whether or not to progress development to phase 3. We use simulations to investigate launch criteria with or without bias adjustment for the sample size calculation under various scenarios. The simulation results are supplemented with empirical evidence to support the need to discount phase 2 results when the latter are used in phase 3 planning. Finally, we offer some recommendations based on both the simulations and the empirical investigations. Copyright © 2012 John Wiley & Sons, Ltd.