Development and validation of new patient related outcomes

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2. Development and validation of new patient related outcomes Thierry Troosters

3. Outline • What are patient reported outcomes • The researchers perspective • Regulators perspective • PRO science: Validating new PRO’s • The example of PROactive

4. PROs and other outcomes Pathology LF What the disease means to the patient Troosters Respir Medicine 2010 Watz AJRCCM 2008

5. PROs and other outcomes Classical outcomes Lung function CT-scan (Bio-markers) Pathology LF Classical outcomes Exercise capacity Patient Reported Outcomes Few are available What the disease means to the patient

6. PRO: definition A report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. FDA guidance document 2009 www.fda.gov

7. PROs: Insight in effect Patient reported outcome tools may help capturing events that happen outside a ‘clinical contact’ (e.g. Exacerbations, side effects)

8. PROs: Insight in effect Patient reported outcome tools may help capturing events that happen outside a ‘clinical contact’ (e.g. Exacerbations) 48 EXACT PRO Frequency and severity of exacerbations 44 Mean Daily EXACT total scores 40 36 1 7 14 21 28 Day Leidy AJRCCM 2011

9. PROs: Insight in effect Patient reported outcome tools may help capturing events that happen outside a ‘clinical contact’ Some (side-) effects of interventions are only known to the patient Aquadro Value Health 2003

10. PROs: Insight in effect Patient reported outcome tools may help capturing events that happen outside a ‘clinical contact’ Some (side-) effects of interventions are only known to the patient Aquadro Value Health 2003 PROs often integrate several ‘physiologic’ effects of interventions

11. PROs: Insight in effect CRDQ vs QF R=0.17 CRDQ vs 6MWD R=0.27

12. 11 ml.yr-1 PROs: Insight in effect 42 ml.yr-1 * 1.71 ± 0.24 points.yr-1 1.05 points.yr-1 53 ml.yr-1 0.66 ± 0.23 points.yr-1 Troosters ERJ 2010

13. PROs: Insight in effect Exacerbations Mood Fear Lungfunction gas exchange Symptoms Musclefunction PhysicalActivity HRQoL ExerciseTolerance Cardiovascularfunction Health Beliefs Body composition Selfefficacy Past behavior Social support

14. PROs: Insight in effect More integration of different additive/complementary effects More confounders not directly related to the intervention Mood Fear Lungfunction gas exchange Symptoms Musclefunction PhysicalActivity HRQoL ExerciseTolerance Cardiovascularfunction Health Beliefs Body composition Selfefficacy Past behavior Social support

15. PROs: The regulator’s perspective PROs are nowadays essential to support efficacy Patient reported outcomes to support labeling claims: -Very stringent methodology for development -Subject to regulatory approval -Intermediate feedback is possible (qualification process)

16. Outline • What are patient reported outcomes • The researchers perspective • Regulators perspective • PRO science: Validating new PRO’s • The example of PROactive

17. PROs: Very strict guidance on development

18. PROs: Very strict guidance on development Clear concept and conceptual model Does the PRO assess something relevant to patients? Items that are understood by patients and reflect their experience With specific attention to Content and Scoring Culturally sensitive translations Focus groups and patient interviews form the basis Literature and experts are supportive

19. PROs: Very strict guidance on development Identify concepts & develop conceptual framework PRO Modify instrument (concept, population, method of administration) Create the instrument (items, scales, format, pilot) Assess measurement properties (Redundancy, revise, MCID, training materials) PATIENT INPUT IN EVERY STAGE IS VITAL http://www.fda.gov/cber/gdlns/prolbl.htm

20. An example: PROactive capturing PA • PROactive aims at developing PROs that capture physical activity • Question 1 Do patients consider physical activity or a change thereof relevant/important? Proactive WP2D 2011

21. An example: PROactive capturing PA Proactive WP2D 2011

22. An example: PROactive capturing PA • PROactive aims at developing PROs that capture physical activity • Question 1 Do patients consider physical activity or a change thereof relevant/important? • Question 2 What is physical activity from a patient perspective

23. An example: PROactive capturing PA • Any bodily movement produced by the skeletal muscles that results in energy expenditure • Amount and Intensity of physical activity are important to maintain health • Physical activity should be considered as a ‘vital sign’ • WHAT DOES ‘PHYSICAL ACTIVITY’ MEAN TO PATIENTS? Caspersen Public Health Rep 1985. Haskell Circulation 2007 CDC Physical activity plan March 2010

24. PROs: Very strict guidance on development Cognitive debriefing Country 1 Cognitive debriefing Country 2 Individual interv. Country 1 Focus group Country 1 Cognitive debriefing Country 3 Focus group Country 2 Language used by COPD patients Dimensions relevant to patients with COPD Cognitive debriefing Country 4 Individual interv. Country 2 Initial Item list Transcribed / translated / Analyzed Transcribed / translated / Analyzed Focus group Country 3 Cognitive debriefing Country 5 Individual interv. Country 3 Cognitive debriefing Country … Focus group Country 4 Report/ Adapt where needed Literature review Valid and acceptable Activity monitor Expert input Expert input Item list to initial validation (WP4)

25. Physical inactivity: Patient perspective Concept Physical Activity Amount of activity Walking outdoors Household Chores Leisure activities Dressing Bathing Consequences Emotional -Feeling sad -Feeling frustrated -Feeling dependent -Embarassement Influencing factors Disease related -Comorbidity -Exacerbations -Severity Symptoms / difficulty General dyspnea/Fatigue Symptoms with specific activities Difficulties with activities Consequences Social -Feeling Isolated -Others helping -Feeling dependent -Others not understanding Influencing factors External -Climate -Air quality Need for adaptation Need for breaks Slow down Help from others Aids

26. Physical inactivity: Patient perspective Concept Physical Activity 24 items Amount of activity Walking outdoors Household Chores Leisure activities Dressing Bathing Symptoms / difficulty General dyspnea/Fatigue Symptoms with specific activities Difficulties with activities Need for adaptation Need for breaks Slow down Help from others Aids

27. Physical inactivity: Patient perspective Concept Physical Activity Amount of activity Walking outdoors Household Chores Leisure activities Dressing Bathing Questionnairs available Monitors available Symptoms / difficulty General dyspnea/Fatigue Symptoms with specific activities Difficulties with activities Questionnaires available Need for adaptation Need for breaks Slow down Help from others Aids New dimention

28. The validation process • Content validity of the items • Validity of the items • Response options preferably linear • Sensitivity to change

29. The validation process

30. The validation process; an example CAT 21 Items 21 items capturing the most important aspects of a patient’s COPD health Individual interviews Focus groups 17 Items Administered in 6 countries in 1490 patients 4 items with Floor- Ceiling – Poor Item to total correlation 14 Items 3 items with High inter item correlation (measuring the same thing) 8 Items 6 items Performing poorly on scoring properties Leaving 8 items with minimal bias for age, gender, country Jones Eur Respir J 2009

31. The validation process • Content validity of the items • Validity of the items • Sensitivity to change • Response options preferably linear • MID with several interventions • Version control (languages!)

32. The validation process Patient perception of improvement may differ between interventions Troosters ERJ 2011

33. Summary • Patient reported outcomes do highlight unique features of the effects of interventions • Methodology to develop PROs has been described recently in much detail by regulators • PROs have the benefit of integrating several subtle physiologic changes • At the expense of having more potential confounders not directly related to the intervention • PROactive is a new PRO that aims at capturing the effects of interventions on PA