IAS 2013 - Symposium
Health-Related Quality of Life
Why and how ?
Pr Olivier CHASSANY
Patient-Reported Outcomes Research Unit,
University Paris 7 & Hôpital Saint-Louis
Health-Related Quality of Life (HRQL) Definition
Health : "A state of complete physical, mental, and social
well-being not merely the absence of disease”
(World Health Organization (WHO) 1948)
“The value assigned to duration of life as modified by the
impairments, functional states, perceptions and social
opportunities that are influenced by disease, injury,
treatment, or policy”
(Pr Donald Patrick, Seattle, USA)
Assessment of HRQL is:
• Subjective (patient’s perception)
• Self-reported in most conditions
• Multidimensional
FDA & EMA Guidance on assessment of
PRO/HRQL in clinical trials of drugs
FDA
PRO
HRQL
2009
http://www.fda.gov/downloads/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/
UCM193282.pdf
2006
http://www.ema.europa.eu/docs/en_GB/d
ocument_library/Scientific_guideline/2009/
09/WC500003637.pdf
Why should we measure the perception of
patients in clinical trials ?
• Changes in the therapeutic targets in the growing
context of chronic diseases and palliative treatment
in a rising old population
• Cancer
• Nowadays, therapeutic benefits :
• HIV/AIDS
• rarely curative, or prolonging
• Heart failure
survival,
• Parkinson’s disease
• but improving symptoms and
• Alzheimer’s disease
functional status, and thus
• Asthma
preserving or restoring HRQL
• COPD
• Osteoarthritis
• Availability of PRO questionnaires
• Diabetes …
correctly validated and translated for
many diseases / conditions
What is the agreement between different
perspectives ?
1. “Objective” markers versus PROs
2. Clinician-Reported Outcomes and
proxies/caregivers versus PROs
3. Between PROs
“Objective” marker versus PRO
“Objective” measure
© Pr Ingela Wiklund
Wiklund I et al. Clin Cardiol 1991.
“Subjective” measure
Exercise test versus physical functioning, r = 0.40
Slide presented with the authorization of Pr Ingela Wiklund
Clinicians underestimate pain severity
(Irritable Bowel Syndrome - IBS)
Patients
39.0 ± 24.9
(n=232)
GPs
30.4 ± 21.0
(n=307)
Difference
8.6 (28%)
Correlation
Kw = 0.31
(n=232)
Pain values ranged between 0 (no pain) and 100 (severe pain)
All values under the equality line indicate GP underestimation of pain by GPs
Chassany O, Duracinsky M, et al. Discrepancies between PROs and Clinician-Reported Outcomes in chronic venous disease, irritable
bowel syndrome, and peripheral arterial occlusive disease. Value in Health 2006.
Patients' perception adds an information that is not
captured by physicians or “objective” markers
Bendtsen P. Measuring health-related quality of life in patients with chronic obstructive pulmonary disease in a routine hospital setting:
Feasibility and perceived value. Health Qual Life Outcomes. 2003
The impact on HRQL is not always foreseeable
better HRQL
lower HRQL
Group health enrollees
Cardiac arrest
and is not systematically
correlated with the severity of
the disease as perceived by the
medical community
General population
Moderate obesity
Ulcerative colitis
Myocardial infarct
Angina
Crohn's
Hypothyroidism
End-stage hemodialysis
Rheumatoid arthritis
Non-oxygen dependent COPD
Physically disabled adults
Back pain
Chronic low back pain
Oxygen dependent COPD
Chronic pain non-responders
Amyotrophic lateral sclerosis
0
Good HRQL
5
10
15
20
25
Overall Sickness Impact Profile score
30
35
Bad HRQL
Patrick D, Erickson P. Health status and health policy. Quality of life in health care evaluation and resource allocation. Oxford
University Press, 1993.
Correlation between adolescent vs. mother & father
reports of perceived adolescent health
24 adolescents (11-18 yrs) with CF, their mothers, and their fathers completed
the Child Health Questionnaire during routine CF clinic visits at 2 urban hospitals.
Health Scale
General health
Physical functioning
Role/social-physical
Bodily pain
Role/social-emotional
Role/social-behavior
Mental health
Family activities
Self-esteem
Behavior problems
Mothers
0.66
0.69
0.62
0.69
-0.12
0.48
0.33
0.45
0.41
0.71
Fathers
0.57
0.31
0.49
0.37
0.24
0.17
0.48
-0.09
0.65
0.66
Adolescents with cystic fibrosis: family reports of adolescent quality of life and forced expiratory volume in one second. Powers
PM et al. Pediatrics 2001; 107: E70.
Patients’ perception : Pain only partially
reflected HRQL (Irritable Bowel Syndrome)
Patient-assessed QoL
decreased as patientassessed pain
increased (r=0.71).
However, patientassessed QoL scores
varied drastically for a
given pain intensity,
suggesting that pain
intensity only partially
reflected QoL.
Pain values ranged between 0 (no pain) and 100 (severe pain)
QoL scores ranged between 0 (bad QoL) and 100 (good QoL)
EMA guidelines : Psoriasis : Note for Guidance
CPMP/EWP/2454/02 (Nov. 2003)
HRQL
4.1.2. Patient’s assessed outcome measures (cont’d)
Efficacy of a new drug evaluated by patient is important when … even
relatively limited extent of skin psoriasis may severely socially and
psychologically disable the patient.
The assessment of HRQL scales specific for psoriasis may represent an
added value for a new drug in comparative clinical trials, in addition to
classical efficacy/safety measures. Patient-assessed drug efficacy may be a
secondary or tertiary endpoint in pivotal clinical trial.
… Ideally, trials assessing psoriasis-specific HRQL should be designed to
assess patient’s perspective in the evaluation of drug-effect in order to
understand better the clinical significance of the benefit observed and to
be sure that the administered treatment does not impact adversely on
patient’s HRQL.
From Pr Ingela Wiklund (UBC)
Generic or specific questionnaire ?
Importance of the content validity
Generic SF-36
• 36 items
• 8 domains
1.
2.
3.
4.
5.
6.
7.
Physical functioning
Physical role functioning
Bodily pain
General health
Vitality
Social role functioning
Emotional role
functioning
8. Mental health
Irritable Bowel
Syndrome
Functional Digestive
Disorders Quality of Life
(FDDQL)
• 43 items (8 domains)
1. Daily activities
2. Anxiety
Sleep and diet
disturbances (83%)
3. Sleep
4. Diet
5.
6.
7.
8.
Abdominal Discomfort
Coping with disease
Control of disease
Stress
- A “validated” scale doesn’t imply that it is relevant for the population studied
- A single item is inadequate to capture all the aspects of HRQL
Chassany O, et al. Validation of a specific QoL in functional digestive disorders (FDDQL). Gut 1999; 44: 527-533
Content validity - Importance of the sample included
during the validation process
Climbing upstairs
41,7%
Doing housew ork
37,2%
Having sex
32,4%
Walking one block
31,6%
Playing w ith children
29,1%
Talking
28,7%
Carrying groceries
28,7%
Cooking
27,9%
Doing regular social activities
27,9%
Doing home maintenance
26,7%
Dancing
26,7%
Going for a w alk
26,3%
Visiting w ith friends or relatives
23,9%
Mopping or scrubbing the floor
20,2%
Jogging, exercising, or running
19,4%
Playing sports
17,4%
Singing
17,0%
Bicycling
Playing w ith pets
Importance of various areas
of limitations due to asthma
among Harlem emergency
department users (n =247)
mostly Afro-american
patients with a low socioeconomic status and a lower
compliance
10,9%
8,1%
Asthma-related limitations in sexual functioning: an important but neglected area of quality of life.
Meyer IH, et al. Am J Public health 2002; 92: 770-772.
Mean ABCD score
Rigorous process of development & validation of
HRQL & PRO questionnaires
Score résumé mental du SF-12 (MCS)
• Content validity
• Item generation
• Scaling
• Item reduction
• Reproductibility
• Construct validity
• Discriminant validity
• Convergent validity
• Responsiveness
• Cultural adaptation
ABCD score vs nb of
lipodystrophy regions
100
Factorial analysis ABCD Score
ABCD
20
items
a
1
,723
2
,084
3
,284
4
,177
b
,529
,067
,427
,293
c
,696
,359
,152
,290
d
,580
,488
,149
,318
30
e
,625
,143
,471
,096
20
f
,684
,118
,347
-,105
10
g
,609
,195
,381
,125
0
h
,767
,417
-,050
,089
i
,181
,323
,728
,132
j
,387
,697
,369
,104
k
,110
,293
,740
,119
l
,174
,732
,317
,000
m
,181
,775
,298
,121
n
,542
,611
-,078
,358
o
,195
,731
,265
,249
p
,378
,490
,123
,478
q
,778
,412
-,101
,290
r
,149
,136
,505
,221
s
,241
,247
,339
,662
t
,100
,089
,166
,821
90
85
80
70
71
64
60
56
50
54
45
40
42
0
1
2
3
4
5
6
Number of lipodystrophy regions
ABCD vs Mental Component Summary
(MCS) SF-12, r=0.65
70
60
50
40
30
20
10
0
20
40
60
80
100
Score de qualité de vie ABCD
Scientific Advisory Committee of the Medical Outcomes Trust. Assessing health status and
quality-of-life instruments: attributes and review criteria. Qual Life Res 2002
Factor
Conceptual Framework of Patient-Reported Outcomes
in Paroxysmic Nocturnial Haemoglobinluria (PNH)
Pain
Anaemia
r = 0.241
0.452
0.589
Anxiety
0.644
Fatigue
QoL
0.786
Sleep
Cross-sectional study (n between 28 and 38)
FSI: Fatigue Symptom Inventory
BPI: Short form Brief Pain Inventory
PSQ: Pittsburgh Sleep Quality Index
STAIS: State-Trait Anxiety Inventory
BDI: Beck Depression Inventory
QoL: EORTC QLQ-C30 global score
0.419
Depression
Fatigue predicted by:
• Pain
• Sleep impairment
• Anxiety / depression
Higgins, Stern, Penn State University
Understanding of items must be checked with
patients
Fatigue Symptom Inventory
• Rate how much of the day, on average, you felt fatigued
in the past week
St-George Respiratory Questionnaire (50 items)
• Over the last year, in an average week, how many good
days (with little chest trouble) have you had
Fatigue symptom inventory
Interpretation of HRQL & PRO results ?
Active treatment
p
vs Placebo
Daytime symptoms (0 to 3)
- 0.14 < 0.001
Nighttime awakening (per wk)
- 0.63 < 0.001
beta2 agonist use (puffs/day)
- 0.64 < 0.001
FEV1
Morning PEF (BL : 362)
Evening PEF (BL : 398)
0.05
+ 13,1 L/min
+ 11,5 L/min
0.331
< 0.001
< 0.001
+ 0.26
0.004
Global AQLQ score
(BL : 4.28, range score 1-7)
What does mean this HRQL difference ?
Zafirlukast improves asthma symptoms and HRQL in patients with moderate reversible airflow obstruction. Nathan
RA et al. J Allergy Clin Immunol 1998.
Marquis P, Chassany O, Abetz L. A comprehensive strategy for the interpretation of quality of life data based on
existing methods. Value in Health 2004 ; 7 : 93-104.
How to interpret PRO – HRQL results
when relevance is not obvious ?
Mean score difference ± SD
(p < 0.05) between 2 groups
Distributionbased
Effect Size
Anchor-based
MID
Minimal Important
Difference
Responders
(%)
Populationbased
Relate changes on a
HRQL measure to
known population
norms
NNT
Number Needed to Treat
Differences or changes for HRQL are inevitably smaller that for other endpoints (e.g.
symptoms) being an indirect measure of the disease
But different interpretations will not save a small mean difference between groups
Minimal Clinically Important Difference (MID)
• Smallest difference in measure patients perceive as beneficial,
and would mandate, in the absence of troublesome side
effects and excessive cost, a change in patient’s management.
• Difference on HRQL corresponding to smallest change in status
that shareholders (patients, clinicians, ...) consider important
Patrick DL, Erickson P: Health Status and Health Policy. Oxford University Press. New York 1993.
pp 422-3
Jaeschke R, Singer J, Guyatt GH: Measurement of health status - ascertaining the
minimal clinically important difference. Controlled Clinical Trials. 1989; 10:407:415
Minimal Important Difference (MID)
Mapping Changes in PROs scores to a single question
Answer to the
GLOBAL RATING
change from -7 to +7*
Mean change in
HRQL scale
(range 1-7)
Worse
Better
Interpretation
of change
A very great deal
-7
+7
Large
1.5
A great deal
A good deal
Moderately
-6
-5
-4
+6
+5
+4
Moderate
1.0
Somewhat
A little
-3
-2
+3
+2
Small
0.5
Almost the same
-1
+1
About the same
* Overall, has there been any change in your shortness of breath during your daily
activities since the last time you saw us ?
Guyatt GH, Juniper EF. Several publications
When defining a meaningful change on an individual
patient basis (i.e. a responder), that definition is larger
than the MID for group mean comparison
Comparison
between
groups
Minimal
Important
Difference
(MID)
0.5
AQLQ
(Asthma)
[1-7]
Comparison of
2 means
Definition of
responders
Not the same
Improvement higher
than 0.5 (depends on
baseline value)
Comparison of
2 percentages
Number Needed
To Treat (NNT)
23
When defining a meaningful change on an individual
patient basis (i.e. a responder), that definition is larger
than the MID for group mean comparison
Comparison
between
groups
Minimal
Important
Difference
(MID)
10-20%
10-15 mm (VAS)
PAIN
(Osteoarthritis)
VAS (0-100)
Comparison of
2 means
Definition of
responders
Not the same
30-50% decrease
vs. baseline or
value < 30 mm
Comparison of
2 percentages
Number Needed
To Treat (NNT)
24
Adjunctive treatment of partial-onset seizures in
patients with epilepsy ≥ 12 years
European Approval (07/2012)
• Fycompa (perampanel)
• Clear dose response for adverse events, captured by global assessments
50% responder
(frequency)
Placebo
8mg
12mg
19%
35%
35%
5,6%
8,2%
SAE
Discontinuation
for SAE
1,4%
4,2%
13,7%
CGIC *
27,4%
43,2%
35,7%
PGIC *
38,5%
51,6%
46,5%
* Much or very much improved
CGIC - Clinical Global Impression of Change
PGIC - Patient Global Impression of Change
European public assessment report (EPAR) - http://www.ema.europa.eu
EMA refusal of the marketing authorisation for TARCEVA
erlotinib - EMA/284207/2006
• EMA major concerns for refusal of the marketing
authorisation to TARCEVA in pancreatic cancer ?
• “The benefit on patients’ survival seen in
the study was very limited and it did not
outweigh the risk associated with the
combination of erlotinib and gemcitabine,
given the side effects of the treatment.”
• “The study did not show any improvement in
the quality of life of the patients treated.
HRQL
European Network HTA Joint Action
WP5 - Methodology guidelines
”Clinical endpoints”
• A clinical endpoint is an aspect of a patient’s clinical or health status that
is measured to assess the benefit or harm of a treatment. A clinical
endpoint describes a valid measure of clinical benefit due to treatment:
the impact of treatment on how a patient feels, functions and survives.
HTA : Health Technology Assessment
For reimbursement purpose
Final EunetHTA guideline, Feburary 2013
Future: ePRO & eHealth