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Concluding Remarks and Recommendations

Concluding Remarks and Recommendations. 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

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Concluding Remarks and Recommendations

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  1. Concluding Remarks and Recommendations • 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.) • 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 • 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.) • 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 • Variety of methods available, including • Phase I/II dose-finding based on efficacy and toxicity • CRM

  5. The End! Comments/Questions/Discussion?

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