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Development and validation of new patient related outcomes Thierry Troosters

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

Troosters Respir Medicine 2010 Watz AJRCCM 2008 PROs and other outcomes LF COPD Exacer- bation Genes Smoking Noxious gases Symptoms reduced activity de-conditioning skeletal muscle dysfunction & Comorbidity increased breathing requirements Pathology What the disease means to the patient

LF COPD Exacer- bation Genes Smoking Noxious gases Symptoms reduced activity de-conditioning skeletal muscle dysfunction & Comorbidity increased breathing requirements Pathology What the disease means to the patient Classical outcomes Lung function CT-scan (Bio-markers) Classical outcomes Exercise capacity Patient Reported Outcomes Few are available PROs and other outcomes

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

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

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

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: 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

PROs: Insight in effect CRDQ vs QF R=0.17 CRDQ vs 6MWDR=0.27

1.71 ± 0.24 points.yr ± 0.23 points.yr -1 Troosters ERJ ml.yr -1 * 53 ml.yr ml.yr points.yr -1 PROs: Insight in effect

Lung function gas exchange Muscle function Cardiovascular function Body composition Symptoms Physical Activity Exercise Tolerance Exacerbations HRQoL Social support Fear Mood Self efficacy Health Beliefs Past behavior PROs: Insight in effect

Lung function gas exchange Muscle function Cardiovascular function Body composition Symptoms Physical Activity Exercise Tolerance HRQoL Social support Fear Mood Self efficacy Health Beliefs Past behavior PROs: Insight in effect More integration of different additive/complementary effects More confounders not directly related to the intervention

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)

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

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

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

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

An example: PROactive capturing PA Proactive WP2D 2011

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

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 Haskell Circulation 2007 CDC Physical activity plan March 2010

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

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

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

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

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

Item generation Generate the concept Focus groups and interviews (initial item pool) Cognitive debriefing (revised initial item pool) Statistical validation Consolidate items that fit with framework Take out redundant items or those with floor/ceiling effect or poor scoring characteristics Verify pre-specified hypothesis Further validation Check for responsiveness / MID Language controls

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

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

Patient perception of improvement may differ between interventions Troosters ERJ 2011

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 Summary