1. Concluding Remarks and Recommendations 1. General recommendations: Consider adaptive dose response designs in exploratory development more often Whenever possible use an approach that incorporates a model for the dose response.  Model assumptions can be either monotonic or umbrella shaped  That + trial specific objectives would determine the choice of particular methodology Consider several methodologies as AD candidates and pick the best-performing one  Define the dose assignment mechanism prospectively and fully evaluate its operational characteristics through simulation prior to initiating the study  Relative performance of various adaptive design methods is an area of ongoing research (PhRMA ADRS WG etc.)

2. Concluding Remarks and Recommendations (cont.) 2. Benefits of adaptive designs in exploratory development: Establishing POC & exploring D-R can be accomplished in one trial Often with less time/resources than 2 separate trials Even if resources are the same, quality of information extracted about D-R may be better; leading to increased probability of success (PoS) in subsequent trials 3. Benefits of adaptive designs in (Phase I) oncology : Balance between individual and collective ethics:  maximum information from the minimal number of patients Identify MTD more precisely limit allocation to extreme doses (above MTD) Improve chances of success of Phase II-III trials

3. Concluding Remarks and Recommendations (cont.) 4. Adaptive trial logistics Needs to be workable  Response observable reasonably quickly relative to patient entry Allow ample time for planning !!! Simulations require substantial time commitment from statistician  Extensive discussion with clinical needed to frame the problem  Simulations often require custom programming  Limited ready–to-use software options exist (none of them is perfect!) Be aware of dynamic allocation issues Drug Supply & Labeling more complicated Regulatory issues: less important in early development, however should not be completely ignored

4. Adaptive Design Software Options CytelSim (in development)  NOW: available only as a Merck in-house tool  FUTURE (TBD): may become commercially available Decimaker (fully supported product)  developed by ClinBay as R-based product  http://www.decimaker.com D-optimal design software (free)  http://haggis.umbc.edu/cgi-bin/dinteractive/inna1.html EWOC software (free)  http://sisyphus.emory.edu/software_ewoc.php MD-Anderson Cancer Center software (free)  http://biostatistics.mdanderson.org/SoftwareDownload http://biostatistics.mdanderson.org/SoftwareDownload  Variety of methods available, including  Phase I/II dose-finding based on efficacy and toxicity  CRM

5. The End! Comments/Questions/Discussion?