Transcript Slide 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.)
Concluding Remarks and
Recommendations (cont.)
2.
3.
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
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
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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
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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
The End!
Comments/Questions/Discussion?