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
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
The End!
Comments/Questions/Discussion?