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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
PROs and other outcomes
Smoking
Steps.day-1 ( n )
Genes
Noxious gases
12000
Exacerbation
10000
LF
Pathology
8000
COPD
6000
4000
Symptoms
2000
increased
breathing
requirements
0
Ctrl
I
II
III
IV
skeletal muscle
dysfunction &
Comorbidity
Troosters Respir Medicine 2010
Watz AJRCCM 2008
reduced
activity
de-conditioning
What the disease
means to the
patient
PROs and other outcomes
Smoking
Classical outcomes
Lung function
CT-scan
(Bio-markers)
Classical outcomes
Exercise capacity
Patient Reported Outcomes
Few are available
Genes
Noxious gases
Exacerbation
Pathology
LF
COPD
Symptoms
increased
breathing
requirements
skeletal muscle
dysfunction &
Comorbidity
reduced
activity
de-conditioning
What the disease
means to the
patient
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
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
Mean Daily EXACT total scores
happen outside a ‘clinical contact’ (e.g. Exacerbations)
48
EXACT PRO
Frequency and severity of exacerbations
44
40
36
1
7
14
Day
21
28
Leidy AJRCCM 2011
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 (tot)
CRDQ vs QF
CRDQ vs 6MWD
R=0.17
R=0.27
20
60
15
50
10
40
30
5
20
0
10
-5
-10
0
-15
-10
-20
-100
-200
-100-50 0
100
0
200 50 300
 6MWD (m)
100
400
PROs: Insight in effect
1 .6
46
S G R Q to ta l (units)
42 ml.yr-1 *
F E V 1 (L )
1 .5
11 ml.yr-1
1 .4
53
1 .3
ml.yr-1
1 .2
1.71 ± 0.24 points.yr-1
42
1.05 points.yr-1
38
34
0.66 ± 0.23 points.yr-1
1 .1
p la c e b o
1 .0
30
0
12
24
36
T im e (M o n th s)
48
tio tr o p iu m
0
12
24
36
48
T im e (Mo n th s)
Troosters ERJ 2010
PROs: Insight in effect
Exacerbations
Muscle function
Cardiovascular
function
Body composition
Mood
Fear
Lung function
gas exchange
Symptoms
Physical
Activity
Exercise
Tolerance
Health
Beliefs
Past
behavior
HRQoL
Self
efficacy
Social
support
PROs: Insight in effect
More integration of different additive/complementary effects
More confounders not directly related to the intervention
Muscle function
Cardiovascular
function
Body composition
Mood
Fear
Lung function
gas exchange
Symptoms
Physical
Activity
Exercise
Tolerance
Health
Beliefs
Past
behavior
HRQoL
Self
efficacy
Social
support
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
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
Modify instrument
(concept, population, method of
administration)
PRO
Assess measurement properties
(Redundancy, revise, MCID, training materials)
PATIENT INPUT IN EVERY STAGE IS VITAL
http://www.fda.gov/cber/gdlns/prolbl.htm
Create the instrument
(items, scales, format, pilot)
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
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
Caspersen Public Health Rep 1985.
Amount and Intensity of physical activity are important
to maintain health
Haskell Circulation 2007
Physical activity should be considered as a ‘vital sign’
CDC Physical activity plan March 2010
WHAT DOES ‘PHYSICAL ACTIVITY’ MEAN TO PATIENTS?
PROs: Very strict guidance on development
Individual interv.
Country 2
Individual interv.
Country 3
Focus group
Country 1
Focus group
Country 2
Language used by
COPD patients
Dimensions relevant to
patients with COPD
Focus group
Country 3
Focus group
Country 4
Transcribed / translated / Analyzed
Individual interv.
Country 1
Transcribed / translated / Analyzed
Cognitive debriefing
Country 1
Cognitive debriefing
Country 2
Cognitive debriefing
Country 3
Initial
Item list
Cognitive debriefing
Country 4
Cognitive debriefing
Country 5
Cognitive debriefing
Country …
Report/ Adapt where needed
Literature review
Expert input
Valid and acceptable
Activity monitor
Expert input
Item list to initial
validation (WP4)
Physical inactivity: Patient perspective
Concept Physical Activity
Amount of activity
Influencing factors
Disease related
-Comorbidity
-Exacerbations
-Severity
Walking outdoors
Household Chores
Leisure activities
Dressing
Bathing
Consequences
Emotional
-Feeling sad
-Feeling frustrated
-Feeling dependent
-Embarassement
Symptoms / difficulty
Influencing factors
External
-Climate
-Air quality
General dyspnea/Fatigue
Symptoms with specific activities
Difficulties with activities
Need for adaptation
Need for breaks
Slow down
Help from others
Aids
Consequences
Social
-Feeling Isolated
-Others helping
-Feeling dependent
-Others not understanding
Physical inactivity: Patient perspective
Concept Physical Activity
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
24 items
Physical inactivity: Patient perspective
Concept Physical Activity
Amount of activity
Walking outdoors
Household Chores
Leisure activities
Dressing
Bathing
Symptoms / difficulty
General dyspnea/Fatigue
Symptoms with specific activities
Difficulties with activities
Questionnairs available
Monitors available
Questionnaires available
Need for adaptation
Need for breaks
Slow down
Help from others
Aids
New dimention
The validation process
•
•
•
•
Content validity of the items
Validity of the items
Response options preferably linear
Sensitivity to change
The validation process
Item
generation
Statistical
validation
Further
validation
• Generate the concept
• Focus groups and interviews (initial item pool)
• Cognitive debriefing (revised initial item pool)
• Consolidate items that fit with framework
• Take out redundant items or those with floor/ceiling effect or poor
scoring characteristics
• Verify pre-specified hypothesis
• Check for responsiveness / MID
• Language controls
The validation process; an example CAT
21 Items
17 Items
21 items capturing the most important aspects of a
patient’s COPD health
Individual interviews
Focus groups
Administered in 6 countries in 1490 patients
4 items with
Floor- Ceiling – Poor Item to total correlation
3 items with
High inter item correlation (measuring the same thing)
14 Items
6 items
Performing poorly on scoring properties
8 Items
Leaving 8 items with minimal bias for age, gender,
country
Jones Eur Respir J 2009
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!)
The validation process
Patient perception of improvement may differ between interventions
 SGRQ (points)
0
Rehab
NETT LVRS*
LVRvalve
-5
LVRbiol
-10
-15
-20 -10
0
10
20
30
40
50
60
70
 6MWD (m)
Troosters ERJ 2011
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
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Development and validation of new patient related …