ePro Adaptive Design
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Transcript of ePro Adaptive Design
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Make the Most of Every Patient
Using ePRO inUsing ePRO inAdaptive Trial DesignAdaptive Trial Design
CBI 4th PRO Conference
Dwight CooperGlobal Director, Technical ServicesPHT Corporation(617) [email protected]
28 May 2009
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Using ePRO in Adaptive Trial Design
Traditional ePRO Trial Design
Adaptive Trial Designs
• Types of Designs
• Barriers to Use
• Benefits ePRO Provides
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Traditional “Non-Adaptive” ePRO Design
Most Electronic Diaries use a Fixed Design
Elements of a fixed ePRO Design that do not change…Elements of a fixed ePRO Design that do not change…
• Subject Facing Functionality– Diary questions and response choices, branching logic
– Diary schedule, windows of availability, alarms
– Translated diary text for each supported language
• Functionality for Site Personnel– Questionnaires and response choices
– Visit workflow, schedule of questionnaires available at each visit
– Review screens, calculations, eligibility criteria
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Adapting ePRO Design via Mid Study Changes
The original design can be modified via Software Updates
Common Examples of Mid-Study Changes…Common Examples of Mid-Study Changes…
• Protocol Amendment– More Frequent Data Collection; e.g. weekly diary merged into evening diary
• Global Expansion of Trial– New Countries, Languages
– Increase Subject Number Range
• Incorporate Feedback from Sites and Subjects– Add more Rescue Medication choices
– Update Instructions to Improve Comprehension and Usability
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Adaptive Trial Design
What is it?• An adaptive trial design is flexible to accommodate anticipated
changes during the study by analyzing data as it is collected
How does it work?
• Interim analyses are performed to evaluate whether to adapt the trial design
What is the advantage?
• Decision making occurs within the study before all data are collected rather than after study completion
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Types of Adaptive Trial Designs
• Protocol Amendment– Sample Size recalculation
– Change primary endpoint
– Change statistical parameters
• Seamless Phase II / III design
• Adaptive dose escalation– To identify maximum tolerated dose
• Drop loser– Inferior treatment groups are dropped
• Randomization probability recalculation
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Adaptive Trial Design
An Example of Adaptive Dose Escalation
"3+3" trial design to identify maximum tolerated dose"3+3" trial design to identify maximum tolerated dose
• In a 3+3 trial, three patients start at a given dose. If no dose-limiting toxic effects are seen, three more patients are added at a higher dose
• If there is one instance of limiting toxicity in the first group, three more patients are added at the same dose
• If two (or all three) in any group show dose-limiting toxicity, the next lower dose is declared the maximum tolerated
There are many variations on this kind of adaptive design
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Barriers to Using Adaptive Designs
• Adaptive trial designs are more time consuming to plan and execute
• Adaptive designs are more complicated both computationally and logistically
• Careful planning is needed to ensure the adaptive design is statistically sound and free from bias
• Timely and reliable data collection is mandatory to support interim analyses
• Simulation may be required to verify the design prior to implementation
• There’s resistance to change - the old way works
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Benefits ePRO Provides for Adaptive Trials
• For trials using adaptive designs and collecting endpoint data from patients, ePRO provides more reliable, timely data collection
• ePRO’s ability to reduce data variance can amplify the benefits of adaptive designs – the signal in the data can be detected earlier
• ePRO systems provide real-time access to the clinical data needed for interim analyses
• ePRO systems can limit user access to clinical data, to prevent unblinding that could introduce bias or compromise trial integrity
• Ability to automatically “flip the switch” on alternative workflow based on interim trial results
– Branching logic or workflow changes can be pre-programmed within the eDiary
– Software updates can be employed to modify design aspects that were not initially planned for change
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Example of an Adaptive ePRO Trial
Adaptive Frequency of of Dosing
• Evening Diary includes two separate responses for intake of Morning and Evening Study Medication
• Adaptive design can trigger branching logic in Evening Diary
• Interim Analysis performed to determine if Study Medication should be taken once or twice daily
• Adaptive design can suppress collection of Evening Study Medication response
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Example of an Adaptive ePRO Trial
Adaptive branching logic
for one daily dose
Standard branching logic
for two daily doses