1. Frank Bretz (Novartis) U Penn – April 13, 2016 Acknowledgment: Willi Maurer, Paul Gallo (Novartis) Adaptive Designs: The Swiss Army Knife Among Clinical Trial Designs?

2. Swiss Army Knife  Wiktionary: A tool that has many functions, one for every perceivable need.  Wikipedia: The term "Swiss Army knife" has entered popular culture as a metaphor for usefulness and adaptability. 2 | U Penn | Frank Bretz | April 13, 2016 * *Trade Registry Number: CHE-105.977.463

3. Outline  Adaptive designs over the years  Role of adaptive designs in clinical trials  Outlook 3 | U Penn | Frank Bretz | April 13, 2016

4. Outline  Adaptive designs over the years Disclaimer: In what follows, this is a (biased?) selection of references and not meant to be exhaustive  Role of adaptive designs in clinical trials  Outlook 4 | U Penn | Frank Bretz | April 13, 2016

5. Adaptive designs over the years Historical papers 5 | U Penn | Frank Bretz | April 13, 2016

6. Adaptive designs over the years Cross-industry collaborations 6 | U Penn | Frank Bretz | April 13, 2016

7. Adaptive designs over the years Landmark trials 7 | U Penn | Frank Bretz | April 13, 2016

8. Adaptive designs over the years Regulatory guidance documents 8 | U Penn | Frank Bretz | April 13, 2016

9. Adaptive designs over the years Books 9 | U Penn | Frank Bretz | April 13, 2016

10. Outline  Adaptive designs over the years  Role of adaptive designs in clinical trials Reference: Dette, Bornkamp, Bretz (2013) On the efficiency of two- stage response-adaptive designs. Statistics in Medicine 32, 1646-60  Outlook 10 | U Penn | Frank Bretz | April 13, 2016

11. Role of adaptive designs in clinical trials 11 | U Penn | Frank Bretz | April 13, 2016  In a slightly narrower context: What are the factors leading to good trial designs? How can we evaluate those factors?  In the following we elaborate further on Ph IIb Dose Finding (DF) trials … where until now traditional trial designs with few doses using pairwise comparisons based on relatively few patients prevail … while acknowledging that DF starts much earlier -Need for incremental dose response (DR) learning at project level requiring integrated planning and quantitative decision making -Need to design Ph I / Ph IIa studies in view of DF (and Ph III) Is it possible to define factors which influence whether to select a standard, or a novel approach for a given trial?

12. Role of simulations in designing clinical trials General considerations 12 | U Penn | Frank Bretz | April 13, 2016  Comprehensive, simulation-based evaluations to guide modern protocol design  Simulations are essential to understand the operating characteristics of a chosen trial design Compare different design options and / or fine tune the design parameters Evaluate robustness of a design w.r.t. deviation from assumptions  Limitations: Current limited availability of advanced clinical trial simulators -Need for case-by-case implementations leading to problems of resources, validation / reproducibility,... How to summarize, visualize and communicate the results of extensive simulation studies?

13. Role of analytical methods in designing clinical trials General considerations  Analytical results (where available) can confirm simulation results and provide additional insight Use simplified settings restricted to key factors Allows one to “see” the relationship between the parameters and possibly prove general results Overcomes numerical convergence problems often encountered in simulation studies 13 | U Penn | Frank Bretz | April 13, 2016

14. Role of analytical methods in designing clinical trials Example from Dette et al. (2013) 14 | U Penn | Frank Bretz | April 13, 2016

15. Role of analytical methods in designing clinical trials Example from Dette et al. (2013) 15 | U Penn | Frank Bretz | April 13, 2016

16. Role of analytical methods in designing clinical trials Example from Dette et al. (2013) 16 | U Penn | Frank Bretz | April 13, 2016

17. Outline  Adaptive designs over the years  Role of adaptive designs in clinical trials  Outlook 17 | U Penn | Frank Bretz | April 13, 2016

18. Conclusions  There is a role for adaptive clinical trial designs and they should be considered routinely in drug development  No single design / method uniformly best: relative performance depends on scenarios, assumptions, trial objectives,...  Innovative approaches are multifaceted that combine strengths from different areas, e.g. adaptive, model-based, Bayesian, optimal design, etc.  Individual techniques are available, but not used properly in combination as a toolbox approach 18 | U Penn | Frank Bretz | April 13, 2016

19. Conclusions 19 | U Penn | Frank Bretz | April 13, 2016  Clinical trial designs depend on a multitude of factors  Trial design optimization requires comprehensive simulations to evaluate operating characteristics and robustness of a chosen design compare different design options and/or finetune the design parameters  Analytical methods might be helpful, if available (but will never replace simulations due to complexity of clinical trial designs)  Further factors not considered here will impact the choice for or against a certain design: recruitment rate, time to read-out, drug supply, randomization,...

20. Adaptive Designs: The Swiss Army Knife Among Clinical Trial Designs?  It depends... Simple scissor Optimal tool for a specific task Swiss Army knife* Versatile tool that combines several individual functions in a single unit Giant Swiss Army knife* Functions for every perceivable need Looks impressive Highly impractible Very expensive 20 | U Penn | Frank Bretz | April 13, 2016 *Trade Registry Number: CHE-105.977.463