ePro Adaptive Design


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ePro Adaptive Design

  1. 1. Using ePRO in Adaptive Trial Design CBI 4 th PRO Conference Dwight Cooper Global Director, Technical Services PHT Corporation (617) 973-1838 [email_address] 28 May 2009
  2. 2. Using ePRO in Adaptive Trial Design <ul><li>Traditional ePRO Trial Design </li></ul><ul><li>Adaptive Trial Designs </li></ul><ul><li>Types of Designs </li></ul><ul><li>Barriers to Use </li></ul><ul><li>Benefits ePRO Provides </li></ul>
  3. 3. Traditional “Non-Adaptive” ePRO Design <ul><li>Most Electronic Diaries use a Fixed Design </li></ul><ul><li>Elements of a fixed ePRO Design that do not change… </li></ul><ul><li>Subject Facing Functionality </li></ul><ul><ul><li>Diary questions and response choices, branching logic </li></ul></ul><ul><ul><li>Diary schedule, windows of availability, alarms </li></ul></ul><ul><ul><li>Translated diary text for each supported language </li></ul></ul><ul><li>Functionality for Site Personnel </li></ul><ul><ul><li>Questionnaires and response choices </li></ul></ul><ul><ul><li>Visit workflow, schedule of questionnaires available at each visit </li></ul></ul><ul><ul><li>Review screens, calculations, eligibility criteria </li></ul></ul>
  4. 4. Adapting ePRO Design via Mid Study Changes <ul><li>The original design can be modified via Software Updates </li></ul><ul><li>Common Examples of Mid-Study Changes… </li></ul><ul><li>Protocol Amendment </li></ul><ul><ul><li>More Frequent Data Collection; e.g. weekly diary merged into evening diary </li></ul></ul><ul><li>Global Expansion of Trial </li></ul><ul><ul><li>New Countries, Languages </li></ul></ul><ul><ul><li>Increase Subject Number Range </li></ul></ul><ul><li>Incorporate Feedback from Sites and Subjects </li></ul><ul><ul><li>Add more Rescue Medication choices </li></ul></ul><ul><ul><li>Update Instructions to Improve Comprehension and Usability </li></ul></ul>
  5. 5. Adaptive Trial Design <ul><li>What is it? </li></ul><ul><li>An adaptive trial design is flexible to accommodate anticipated changes during the study by analyzing data as it is collected </li></ul><ul><li>How does it work? </li></ul><ul><li>Interim analyses are performed to evaluate whether to adapt the trial design </li></ul><ul><li>What is the advantage? </li></ul><ul><li>Decision making occurs within the study before all data are collected rather than after study completion </li></ul>
  6. 6. Types of Adaptive Trial Designs <ul><li>Protocol Amendment </li></ul><ul><ul><li>Sample Size recalculation </li></ul></ul><ul><ul><li>Change primary endpoint </li></ul></ul><ul><ul><li>Change statistical parameters </li></ul></ul><ul><li>Seamless Phase II / III design </li></ul><ul><li>Adaptive dose escalation </li></ul><ul><ul><li>To identify maximum tolerated dose </li></ul></ul><ul><li>Drop loser </li></ul><ul><ul><li>Inferior treatment groups are dropped </li></ul></ul><ul><li>Randomization probability recalculation </li></ul>
  7. 7. Adaptive Trial Design <ul><li>An Example of Adaptive Dose Escalation </li></ul><ul><li>&quot;3+3&quot; trial design to identify maximum tolerated dose </li></ul><ul><li>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 </li></ul><ul><li>If there is one instance of limiting toxicity in the first group, three more patients are added at the same dose </li></ul><ul><li>If two (or all three) in any group show dose-limiting toxicity, the next lower dose is declared the maximum tolerated </li></ul><ul><li>There are many variations on this kind of adaptive design </li></ul>
  8. 8. Barriers to Using Adaptive Designs <ul><li>Adaptive trial designs are more time consuming to plan and execute </li></ul><ul><li>Adaptive designs are more complicated both computationally and logistically </li></ul><ul><li>Careful planning is needed to ensure the adaptive design is statistically sound and free from bias </li></ul><ul><li>Timely and reliable data collection is mandatory to support interim analyses </li></ul><ul><li>Simulation may be required to verify the design prior to implementation </li></ul><ul><li>There’s resistance to change - the old way works </li></ul>
  9. 9. Benefits ePRO Provides for Adaptive Trials <ul><li>For trials using adaptive designs and collecting endpoint data from patients, ePRO provides more reliable, timely data collection </li></ul><ul><li>ePRO’s ability to reduce data variance can amplify the benefits of adaptive designs – the signal in the data can be detected earlier </li></ul><ul><li>ePRO systems provide real-time access to the clinical data needed for interim analyses </li></ul><ul><li>ePRO systems can limit user access to clinical data, to prevent unblinding that could introduce bias or compromise trial integrity </li></ul><ul><li>Ability to automatically “flip the switch” on alternative workflow based on interim trial results </li></ul><ul><ul><li>Branching logic or workflow changes can be pre-programmed within the eDiary </li></ul></ul><ul><ul><li>Software updates can be employed to modify design aspects that were not initially planned for change </li></ul></ul>
  10. 10. Example of an Adaptive ePRO Trial <ul><li>Adaptive Frequency of Dosing </li></ul><ul><li>Evening Diary includes two separate responses for intake of Morning and Evening Study Medication </li></ul><ul><li>Adaptive design can trigger branching logic in Evening Diary </li></ul><ul><li>Interim Analysis performed to determine if Study Medication should be taken once or twice daily </li></ul><ul><li>Adaptive design can suppress collection of Evening Study Medication response </li></ul>
  11. 11. Example of an Adaptive ePRO Trial Adaptive branching logic for one daily dose Standard branching logic for two daily doses