FDA Guidance on PROs Breakfast Seminar 19 th  March 2009 Diane Wild, MSc Oxford Outcomes Ltd.,  Oxford, UK
Overview <ul><li>What are PROs? </li></ul><ul><li>Why and when to use them </li></ul><ul><li>The FDA draft guidance </li><...
PROs – FDA Definition <ul><li>A PRO is a measurement of any aspect of a patient’s health status that comes directly from t...
The PRO umbrella <ul><li>Conceptual confusion between QoL, HRQoL, functional status etc.  </li></ul><ul><li>The term patie...
Why use PROs <ul><li>Some treatment effects only known to the patient (e.g. pain, fatigue) </li></ul><ul><li>Patients prov...
For what purpose? <ul><li>Definition of entry criteria </li></ul><ul><li>Evaluation of efficacy </li></ul><ul><li>Evaluati...
Timing and frequency <ul><li>As events occur </li></ul><ul><li>At regular intervals </li></ul><ul><li>Baseline and end of ...
Taxonomy of PROs <ul><li>Concepts: </li></ul><ul><ul><li>Functional status (physical, psychological, social). </li></ul></...
QoL/HRQoL? <ul><li>FDA draft guidance – extremely complex. </li></ul><ul><li>QoL is distinct from HRQoL as it includes per...
Copyright ©1996 BMJ Publishing Group Ltd. Hickey, A. M et al. BMJ 1996;313:29-33 Fig 1--The segments represent five areas ...
Generic & Condition Specific <ul><li>Generic Measures </li></ul><ul><li>Designed for general use/broad base  </li></ul><ul...
HRQL of Patients with COPD vs.  General Population Norms   (SF-36) High scores = good HRQL
FDA Draft Guidance
Draft guidance – rationale for development <ul><li>FDAs thinking on how sponsors can develop and use study results measure...
Draft guidance contents (1) <ul><li>Selection of PROs </li></ul><ul><li>Development of PROs </li></ul><ul><li>Modification...
Assess Measurement Properties Assess score reliability, validity and ability to detect change.  Evaluate administrative & ...
Modifications – The FDA’s View <ul><li>Revising the PRO instrument’s measurement concept,  </li></ul><ul><li>Applying an i...
Draft guidance contents (2) <ul><li>Specific populations (children, cognitively impaired) </li></ul><ul><li>Study design (...
After the draft guidance <ul><li>Consultation period – comments sent to FDA </li></ul><ul><li>Series of papers in Value in...
PRO Review on Critical Path Preclinical Phase 2A Phase 2B Phase 3 Phase I Pre-IND EOP2B EOP2A EOP1 Initial PRO Submission ...
Approved Product Labels Label Claims Based on Patient-Reported Outcomes in EMEA and FDA Approvals Since 2000 Jane Scott et...
ePRO migration:level of evidence required to establish equivalence
Migration and Re-validation <ul><li>FDA guidance states “the extent of additional validation recommended depends on the ty...
ISPOR ePRO consensus group: Modification categories <ul><li>Minor  – no change in content or meaning (non substantive chan...
ISPOR ePRO consensus group: Levels of evidence <ul><li>Minor – Small scale cognitive debriefing and usability testing  </l...
Levels of Evidence <ul><li>Cognitive Debriefing </li></ul><ul><ul><li>Explores the way individuals understand, mentally pr...
Levels of Evidence <ul><li>Usability Testing </li></ul><ul><ul><li>Related to the software and device </li></ul></ul><ul><...
Levels of Evidence <ul><li>Equivalence Testing </li></ul><ul><ul><li>Administer paper and ePRO versions </li></ul></ul><ul...
Levels of Evidence <ul><li>Psychometric Evaluation  </li></ul><ul><ul><li>Factor structure </li></ul></ul><ul><ul><li>Inte...
Comparisons of ePRO and paper PRO <ul><li>Gwaltney et al 2008 – meta-analysis of 46 studies and 275 PROs </li></ul><ul><li...
Translation issues <ul><li>Translation can be significantly more wordy than source text – mixed modes of administration no...
Summary <ul><li>PROs useful umbrella term for a variety of measures </li></ul><ul><li>FDA draft guidance has helped to cla...
Contacts <ul><li>Diane Wild,  </li></ul><ul><li>Oxford Outcomes, </li></ul><ul><li>[email_address] </li></ul>
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FDA Guidance On PROs By Diane Wild, M Sc

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Describes PROs with examples of why and how to use them. Details FDA draft guidance for selection, development and validation of PROs. Features the levels of evidence of ePRO migration.

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FDA Guidance On PROs By Diane Wild, M Sc

  1. 1. FDA Guidance on PROs Breakfast Seminar 19 th March 2009 Diane Wild, MSc Oxford Outcomes Ltd., Oxford, UK
  2. 2. Overview <ul><li>What are PROs? </li></ul><ul><li>Why and when to use them </li></ul><ul><li>The FDA draft guidance </li></ul><ul><li>After the guidance was released </li></ul><ul><li>ePRO migration – levels of evidence </li></ul>
  3. 3. PROs – FDA Definition <ul><li>A PRO is a measurement of any aspect of a patient’s health status that comes directly from the patient (i.e., without the interpretation of the patient’s responses by a physician or anyone else) (FDA Draft Guidance, 2006). </li></ul>
  4. 4. The PRO umbrella <ul><li>Conceptual confusion between QoL, HRQoL, functional status etc. </li></ul><ul><li>The term patient reported outcomes was agreed by a group of interested parties (ISPOR, FDA etc) in September 2000. </li></ul><ul><li>PRO describes the source rather than the content. </li></ul>
  5. 5. Why use PROs <ul><li>Some treatment effects only known to the patient (e.g. pain, fatigue) </li></ul><ul><li>Patients provide a unique perspective on effectiveness (e.g. spirometry) </li></ul><ul><li>Formal assessment more reliable than informal interview </li></ul>
  6. 6. For what purpose? <ul><li>Definition of entry criteria </li></ul><ul><li>Evaluation of efficacy </li></ul><ul><li>Evaluation of adverse events </li></ul>
  7. 7. Timing and frequency <ul><li>As events occur </li></ul><ul><li>At regular intervals </li></ul><ul><li>Baseline and end of treatment </li></ul>
  8. 8. Taxonomy of PROs <ul><li>Concepts: </li></ul><ul><ul><li>Functional status (physical, psychological, social). </li></ul></ul><ul><ul><li>Symptoms/signs (frequency, severity, bothersomeness) </li></ul></ul><ul><ul><li>Health perceptions/perceived health status. </li></ul></ul><ul><ul><li>Satisfaction/preference for treatment </li></ul></ul><ul><ul><li>Adherence </li></ul></ul><ul><ul><li>QoL </li></ul></ul><ul><ul><li>HRQoL </li></ul></ul>
  9. 9. QoL/HRQoL? <ul><li>FDA draft guidance – extremely complex. </li></ul><ul><li>QoL is distinct from HRQoL as it includes perceptions of immediate environment, housing conditions etc </li></ul><ul><ul><li>Have you enough money to meet your needs? </li></ul></ul><ul><ul><li>How safe do you feel in your daily life? </li></ul></ul>
  10. 10. Copyright ©1996 BMJ Publishing Group Ltd. Hickey, A. M et al. BMJ 1996;313:29-33 Fig 1--The segments represent five areas of life nominated by the individual; the size of the segment can be adjusted to show the relative importance of each area for the individual's quality of life
  11. 11. Generic & Condition Specific <ul><li>Generic Measures </li></ul><ul><li>Designed for general use/broad base </li></ul><ul><li>Comparable across disease states </li></ul><ul><li>Disease Specific Measures </li></ul><ul><li>Designed for use within a particular disease </li></ul><ul><li>More sensitive to smaller clinically significant changes </li></ul><ul><li>Maybe more sensitive to specific impact of clinical variables </li></ul><ul><li>Relatively narrow focus may prevent sensitivity to treatment side-effects. </li></ul>
  12. 12. HRQL of Patients with COPD vs. General Population Norms (SF-36) High scores = good HRQL
  13. 13. FDA Draft Guidance
  14. 14. Draft guidance – rationale for development <ul><li>FDAs thinking on how sponsors can develop and use study results measured by PROs to support labelling claims. </li></ul><ul><li>To increase efficiency of discussions, streamline FDAs review and provide optimal information about the patients view of treatment benefit. </li></ul>
  15. 15. Draft guidance contents (1) <ul><li>Selection of PROs </li></ul><ul><li>Development of PROs </li></ul><ul><li>Modification of PROs </li></ul><ul><li>Validation of PROs </li></ul>
  16. 16. Assess Measurement Properties Assess score reliability, validity and ability to detect change. Evaluate administrative & respondent burden. Add, delete or revise items. Identify meaningful differences in scores. Finalise instrument formats, scoring, procedures & training materials. From FDA Draft PRO Guidance document 2006 Identify Concepts & Develop Conceptual Framework Identify concepts & domains that are important to patients. Determine intended population and research application. Hypothesize expected relationships among concepts. Create Instrument Generate items. Choose administration method, recall period & response scales. Draft instructions. Format instrument. Draft procedures for scoring & administration. Pilot test draft instrument. Refine instrument & procedures. Modify Instrument Change concepts measured, populations studied, research application, response options, recall period or method of administration. PRO
  17. 17. Modifications – The FDA’s View <ul><li>Revising the PRO instrument’s measurement concept, </li></ul><ul><li>Applying an instrument to a new population or condition, </li></ul><ul><li>Changing the PRO’s item content or formatting, </li></ul><ul><li>Changing the mode of administration, OR </li></ul><ul><li>Changing the target culture or language for application of the instrument </li></ul>Draft Guidance, Lines 570-671
  18. 18. Draft guidance contents (2) <ul><li>Specific populations (children, cognitively impaired) </li></ul><ul><li>Study design (blinding and randomisation, frequency of assessments etc) </li></ul><ul><li>ePROs (record keeping, maintenance and access issues) </li></ul><ul><li>Data analysis (missing data, interpretation etc) </li></ul>
  19. 19. After the draft guidance <ul><li>Consultation period – comments sent to FDA </li></ul><ul><li>Series of papers in Value in Health expanding on the issues in the guidance </li></ul><ul><li>ISPOR Task forces </li></ul><ul><ul><li>Content validity </li></ul></ul><ul><ul><li>Translation and linguistic validation </li></ul></ul><ul><ul><li>ePRO </li></ul></ul><ul><li>Final guidance will be released…… </li></ul>
  20. 20. PRO Review on Critical Path Preclinical Phase 2A Phase 2B Phase 3 Phase I Pre-IND EOP2B EOP2A EOP1 Initial PRO Submission (Updated) PRO submission Submit Final PRO Evidence Dossier PRO Selection/ Development PRO Validation/ Modification
  21. 21. Approved Product Labels Label Claims Based on Patient-Reported Outcomes in EMEA and FDA Approvals Since 2000 Jane Scott etal. Poster presented at ISPOR Athens 2008 37.8 8.9 7.6 3.4 85.6 17.6 16.1 1.1 8.5 yr Mean 331 76 65 29 728 150 137 9 Total 26 4 4 2 34 4 4 0 2008* 69 13 13 7 75 14 11 1 2007 42 5 5 0 98 18 15 4 2006 23 7 7 3 82 15 13 1 2005 36 11 8 6 114 23 20 0 2004 18 9 6 2 79 18 17 1 2003 38 10 10 0 79 15 14 1 2002 38 13 11 6 71 18 18 1 2001 31 4 1 3 96 25 25 0 2000 All Approvals Any PRO Signs & Symptoms HRQL All Approvals Any PRO Signs & Symptoms HRQL Year EMEA Approvals by Year FDA Approvals by Year PRO Claims in FDA and EMEA Product Labels Approved between 1 January 2000 and 2 June 2008
  22. 22. ePRO migration:level of evidence required to establish equivalence
  23. 23. Migration and Re-validation <ul><li>FDA guidance states “the extent of additional validation recommended depends on the type of modification made.” (pg 20, line 582-583 ) </li></ul><ul><li>Ambiguity </li></ul>
  24. 24. ISPOR ePRO consensus group: Modification categories <ul><li>Minor – no change in content or meaning (non substantive changes in instructions, minor changes in format) </li></ul><ul><li>Moderate – May change content or meaning (changes in item wording or changes in presentation that might alter interpretability, visual to aural) </li></ul><ul><li>Substantial – Clear change in content or meaning (substantial changes in response options or item wording) </li></ul>
  25. 25. ISPOR ePRO consensus group: Levels of evidence <ul><li>Minor – Small scale cognitive debriefing and usability testing </li></ul><ul><li>Medium – Formal assessment of equivalence and usability testing </li></ul><ul><li>Substantial – large scale usability testing and full psychometric testing </li></ul>
  26. 26. Levels of Evidence <ul><li>Cognitive Debriefing </li></ul><ul><ul><li>Explores the way individuals understand, mentally process and respond to items on a questionnaire (Willis 2005) </li></ul></ul><ul><ul><li>Similar to target sample </li></ul></ul><ul><ul><li>5-10 patients </li></ul></ul><ul><ul><li>Verbal probing technique </li></ul></ul><ul><ul><li>Needs to be documented </li></ul></ul>
  27. 27. Levels of Evidence <ul><li>Usability Testing </li></ul><ul><ul><li>Related to the software and device </li></ul></ul><ul><ul><li>Navigation of electronic platform </li></ul></ul><ul><ul><li>Scale should be based on the complexity of the physical and cognitive tasks required by the ePRO application </li></ul></ul>
  28. 28. Levels of Evidence <ul><li>Equivalence Testing </li></ul><ul><ul><li>Administer paper and ePRO versions </li></ul></ul><ul><ul><li>Parallel vs cross-over </li></ul></ul><ul><ul><li>Similar to target sample </li></ul></ul><ul><ul><li>Basic classical test theory techniques (internal consistency, means, standard deviations etc) </li></ul></ul>
  29. 29. Levels of Evidence <ul><li>Psychometric Evaluation </li></ul><ul><ul><li>Factor structure </li></ul></ul><ul><ul><li>Internal consistency </li></ul></ul><ul><ul><li>Test-retest </li></ul></ul><ul><ul><li>Construct validity </li></ul></ul><ul><ul><li>Responsiveness </li></ul></ul><ul><ul><li>MID </li></ul></ul>
  30. 30. Comparisons of ePRO and paper PRO <ul><li>Gwaltney et al 2008 – meta-analysis of 46 studies and 275 PROs </li></ul><ul><li>Very high correlations (.90) </li></ul><ul><li>Little evidence to suggest that size of computer screen, respondent age, or amount of computer experience had any impact </li></ul><ul><li>Respondents prefer ePRO over paper </li></ul>
  31. 31. Translation issues <ul><li>Translation can be significantly more wordy than source text – mixed modes of administration not recommended </li></ul><ul><li>Possibilities of combining linguistic validation steps with migration cognitive debriefing </li></ul>
  32. 32. Summary <ul><li>PROs useful umbrella term for a variety of measures </li></ul><ul><li>FDA draft guidance has helped to clarify and streamline review process </li></ul><ul><li>Level of evidence for equivalence of ePROs is dependent on changes required for migration </li></ul><ul><li>Growing evidence to suggest that equivalence is generally high and ePROs preferred by patients </li></ul>
  33. 33. Contacts <ul><li>Diane Wild, </li></ul><ul><li>Oxford Outcomes, </li></ul><ul><li>[email_address] </li></ul>

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