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.)

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

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

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  D-optimal design software (free)  EWOC software (free)  MD-Anderson Cancer Center software (free)   Variety of methods available, including  Phase I/II dose-finding based on efficacy and toxicity  CRM

The End! Comments/Questions/Discussion?