Transcript HRQL

Introduction to Patient-Reported Outcomes
(PROs)
March 2-4 2004, Karolinska Institutet, Sigtuna, Sweden
Mesure de la qualité de vie
liée à l’état de santé
Olivier CHASSANY, MD, PhD
Délégation à la Recherche Clinique (AP-HP)
Hôpital Saint-Louis, Paris
Définition de la Qualité de Vie liée à l’état de santé
Définition de l’OMS (dénominateur minimal commun)
« La santé, ce n’est pas seulement une absence de
maladie, c’est aussi un état total de bien-être
physique, psychologique et social »
« La qualité de vie est la perception qu’a un individu
de sa place dans l ’existence, dans le contexte de la
culture et du système de valeurs dans lesquels il vit en
relation avec ses objectifs, ses attentes, ses normes et
ses inquiétudes »
Définition de la Qualité de Vie liée à l’état de santé
La mesure de la qualité de vie est :
• Subjective (perception du patient)
• Se mesure idéalement par auto-questionnaire
• Multidimensionnelle
• Dimensions minimales : physique, psychique et
sociale
• Dimensions spécifiques d’une pathologie ou
condition
Definition of Health-Related Quality of Life (HRQL)
“Health is a state of complete physical, mental, and
social well-being and not merely the absence of disease”
(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)
Agreement on multidimensionality and subjective
assessment
Mesure de la Qualité de Vie liée à l’état de santé
Une question unique ne suffit pas :
« Globalement, quelle est votre qualité de vie en
ce moment ? »
PAST
• Health-Related Quality of Life (HRQL) is based
on several decades of research
• Many studies, especially using generic
questionnaires made it possible to appreciate how
diseases affected HRQL
• Poor quality of clinical trials
• Abuse of “Quality of Life” trials
TODAY
• Rationale for the Added Value of HRQL in clinical trials
• Increased recognition of the patient’s perspective:
Patient-Reported Outcomes (PRO)
• Agreement (more or less) on HRQL definition,
multidimensionality and subjective assessment
• Availability of HRQL questionnaires correctly validated and
translated for many diseases
• Guidelines on how measuring HRQL in clinical trials
• Increasing recognition of HRQL value by regulators
• Huge literature (too much ?)
Why should we measure the perception of
patients ?
• Changes in the therapeutic targets in the
growing context of chronic diseases and
palliative treatment in a rising old population
• Nowadays, therapeutic benefits :
• rarely curative, or prolonging
survival,
• but improving symptoms and
functional status, and thus
preserving or restoring HRQL
• Availability of PRO questionnaires
correctly validated and translated
for many diseases
• cancer
•
•
•
•
•
•
•
•
AIDS
heart failure
Parkinson’s disease
Alzheimer’s disease
asthma
COPD
osteoarthritis
diabetes …
The impact on HRQL is not always foreseeable
better HRQL
lower HRQL
Group health enrollees
Cardiac arrest
General population
and is not systematically
correlated with the
severity of the disease
as perceived by the
medical community
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
5
10
15
20
25
30
35
Overall Sickness Impact Profile score
Patrick D, Erickson P. Health status and health policy. Quality of life in health care evaluation and resource allocation.
Oxford University Press, 1993.
The impact on HRQL is not always foreseeable
Physical
Role
Social
functioning
functioning
functioning
Patients w ith no chronic
Health
Mental health
perceptions
Bodily pain
conditions (n = 2595)
Hypertension (n = 2706)
10%
Diabetes (n = 844)
0%
Congestive heart failure
(n = 297)
Myocardial infarction (n
-10%
= 147)
Arthritis (n = 2079)
-20%
Chronic lung problems
-30%
(n = 731)
Gastrointestinal
disorders (n = 696) *
Back problems (n = 486)
-40%
Angina (n = 532)
Stewart AL et al. Functional status and well-being of patients with chronic conditions. Results from the Medical Outcomes
Study. JAMA 1989; 262: 907-913.
Which are the arguments in favour of HRQL ?
“Objective” measure
“Subjective” measure
Exercise test versus physical functioning, r = 0.40
Wiklund I et al. Clin Cardiol 1991.
Slide presented with the authorization of Pr Ingela Wiklund
Weak correlation between Patient-Reported
Outcomes and physiological endpoints
(n = 96)
r
BPQ
CRQ
6-min walk test
0.17
0.07
Pre SaO2
0.14
0.17
Symptoms BPQ : Breathing Problems Questionnaire
HRQL
CRQ : Chronic Respiratory Disease Questionnaire
 Variability in exercise capacity contributed to only 3% of
the variability in BPQ score
Quality of life in elderly patients with COPD: measurement and predictive factors. Yohannes AM et al. Resp Med 1998.
Correlation between glycemic control and
perception of Quality of Life
DQOLY (Diabetes
Quality of Life for Youths)
Hb1Ac
Impact
(23 items)
r = - 0.21
Worry
(23 items)
r = - 0.28
Satisfaction
(11 items)
r = - 0.04
Grey M, et al. Personal and family factors associated with quality of life in adolescents with diabetes. Diabetes Care. 1998
;21: 909-914.
Niveau d’agrément de la perception d’un
symptôme (douleur) entre patients et médecins
Score de douleurs
Agrément entre patients
et leurs médecins
généralistes
Colopathie fonctionnelle
r = 0,31
Maladie veineuse chronique
r = 0,27
Chassany O, et al. Discrepancies between patient-reported outcomes (PROs) and clinician-reported outcomes in chronic venous
disease (CVD), irritable bowel syndrome (IBS), and peripheral arterial occlusive disease (PAOD). Value in health. Under press
Niveau d’agrément de la perception de la qualité
de vie entre patients et médecins
Score qualité de vie
Agrément entre patients
et leurs médecins
généralistes
Colopathie fonctionnelle
(FDDQL)
r = 0,28
Maladie veineuse chronique
(CIVIQ)
r = 0,17
Artériopathie chronique
oblitérante des MI (CLAUS)
r = 0.26
Chassany O, et al. Discrepancies between patient-reported outcomes (PROs) and clinician-reported outcomes in chronic venous
disease (CVD), irritable bowel syndrome (IBS), and peripheral arterial occlusive disease (PAOD). Value in health. Under press
Perception of pain : moderate agreement
between IBS patients & physicians
The physician is
more disposed
to bear the pain
of his/her patient
than the patient
himself
6
Physician-Patient Difference
Cross-sectional survey
239 IBS patients
57.5 ± 16 years
64% women
r = 0.31
4
2
0
-2
-4
-6
-8
-10
-2
0
2
4
6
Patient's VAS
8
Tendency of physician to
overestimate the pain
IBS
VAS (0-10, worst)
Patients
3.9 ± 2.5
10
12
Tendency of
physician to
underestimate
the pain
Clinicians
3.0 ± 2.1
Chassany O, et ALFIS. Added value of patient’s perspective in irritable Bowel Syndrome. Qual Life Res 2003; 12: A821
Perception of Quality of Life by patients and
clinicians in Irritable Bowel Syndrome
HRQL
impairment is
over/under
estimated by
clinicians in
IBS
FDDQL (43 items)
Daily activities
Anxiety
Diet
Sleep
Discomfort
Coping
Control
Stress
Global
Patients
(n = 239)
72
62
56
59
55
49
55
31
±
±
±
±
±
±
±
±
21
22
23
16
15
13
23
25
56 ± 12
Clinicians
(n = 163)
58
54
60
72
69
57
59
43
±
±
±
±
±
±
±
±
35
28
26
26
25
26
26
27
59 ± 19
FDDQL : Functional Digestive Disorders Quality of Life
43 items / 8 domains, score 0-100 (best HRQL)
Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Irritable Bowel Syndrome.
Quality Life Res 2003; 12: A821
Perception of HRQL by patients and clinicians ?
Survey among 239 IBS patients and 163 clinicians
Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le patient pour
le retentissement sur l'activité quotidienne
100,00
90,00
r = 0.43
Relation score FDDQL apprécié par le m édecin / score FDDQL apprécié par le
patient pour le retentissem ent sur l'alim entation
100,00
r = 0.30
90,00
70,00
Daily Activities
80,00
Score FDDQL
activité
quotidienne
60,00
patient
Diet
70,00
50,00
Scores égaux
40,00
Score
FDDQL
alimentation
60,00
patient
80,00
Scores
égaux
50,00
40,00
30,00
30,00
20,00
20,00
10,00
10,00
0,00
0,00
0
1
2
médecin
3
4
5
0
1
2
m édecin
3
4
5
Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le
patient pour le retentissement sur le sommeil
Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le patient
pour le degré d'anxiété
100,00
100,00
Anxiety
90,00
Sleep
90,00
80,00
80,00
70,00
Score FDDQL
sommeil
70,00
Score FDDQL
anxiété
50,00
Scores égaux
40,00
60,00
patient
patient
60,00
Scores égaux
50,00
40,00
30,00
30,00
20,00
20,00
10,00
10,00
0,00
0
1
2
3
médecin
4
5
0,00
0
1
2
médecin
3
4
5
Perception of HRQL by patients and clinicians ?
Survey among 239 IBS patients and 163 clinicians
100,00
Relation score FDDQL apprécié par le m édecin / score FDDQL apprécié par le
patient sur la m aîtrise de sa m aladie
Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le patient pour
le retentissement sur la vie sociale
100,00
Social Life
90,00
Control
90,00
80,00
80,00
70,00
50,00
60,00
patient
60,00
patient
Score FDDQL
maîtrise maladie
70,00
Score FDDQL vie
sociale/incofort
Scores égaux
Scores égaux
50,00
40,00
40,00
30,00
30,00
20,00
20,00
10,00
10,00
0,00
0,00
0
1
2
médecin
3
4
0
5
Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le patient
sur la réaction face à la maladie
1
2
m édecin
3
4
5
Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le
patient sur l'impact du stress
100,00
Coping
90,00
100,00
80,00
70,00
70,00
Score FDDQL
réaction
maladie
Scores égaux
50,00
40,00
30,00
patient
60,00
patient
Stress
90,00
80,00
60,00
50,00
Score FDDQL
stress
40,00
Scores égaux
30,00
20,00
20,00
10,00
10,00
0,00
0
1
2
3
médecin
4
5
0,00
0
1
2
médecin
3
4
5
Perception of pain and HRQL by patients with IBS
r = 0.63, p < 0.0001
100
FDDQL Global Score
239 IBS patients
57.5 ± 16 years
64% of women
Global FDDQL:
56.1 ± 11.6
90
80
70
60
50
40
30
20
10
0
0
2
4
6
Patient's VAS
8
FDDQL : Functional Digestive Disorders Quality of Life
43 items / 8 domains, score 0-100 (best HRQL)
Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Irritable Bowel Syndrome.
Quality Life Res 2003; 12: A821
10
Perception of pain by patients and clinicians in
Chronic Venous Insufficiency
Patients
Clinicians
(n = 233)
(n = 120)
4.22 ± 2.48
2.97 ± 1.92
r = 0.27
10
9
8
Pain VAS Physicians
Pain perception is
underestimated by
clinicians in CVI
0 [best Pain] – 10 [worst Pain]
7
6
5
4
3
2
1
0
0
1
2
3
4
Pain VAS Patients
5
6
7
8
9
10
Perception of Quality of Life by patients and
clinicians in Chronic Venous Insufficiency
HRQL impairment is underestimated by clinicians
CIVIQ
Patients
(n = 240)
Clinicians
(n = 120)
Physical Function
Pain
Social Function
Psychological Impact
Global
44 ± 25
45 ± 20
38 ± 24
35 ± 23
39 ± 20
31 ± 22
30 ± 20
24 ± 21
26 ± 21
28 ± 19
CIVIQ : 20 items / 4 domains, score 0-100 (worst HRQL)
Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Chronic Venous Insuffisiency
Perception of Quality of Life by patients and
clinicians in Chronic Venous Insufficiency
Relation score CIVIQ apprécié par le médecin / score CIVIQ apprécié par le
patient pour le retentissement activité physique
Relation score CIVIQ apprécié par le médecin / score CIVIQ apprécié par le
patient pour le retentissement douleur
Impact of pain
100,00
100,00
90,00
90,00
80,00
80,00
70,00
70,00
Patients
Patients
Physical Function
60,00
patient
patient
60,00
50,00
40,00
30,00
r = 0.29
20,00
50,00
40,00
r = 0.28
30,00
20,00
10,00
10,00
0,00
0
1
2
3
4
5
6
7
8
9
0,00
10
0
médecin
Physicians
Score CIVIQ activité physique
3
4
Physicians
Scores égaux
Score CIVIQ douleur
Social Function
5
6
7
8
Scores égaux
Psychological Function
Relation score CIVIQ apprécié par le médecin / score CIVIQ apprécié par le
patient pour le retentissement psychologique
100,00
100,00
90,00
r = 0.23
80,00
r = 0.23
90,00
80,00
Patients
70,00
60,00
patient
patient
2
médecin
Relation score CIVIQ apprécié par le médecin / score CIVIQ apprécié par le
patient pour le retentissement vie sociale
Patients
1
50,00
40,00
30,00
70,00
60,00
50,00
40,00
30,00
20,00
20,00
10,00
10,00
0,00
0,00
0
1
2
3
4
5
6
médecin
Physicians
Score CIVIQ vie sociale
Scores égaux
7
8
9
0
1
2
3
4
5
6
7
médecin
Physicians
Score CIVIQ psychologique
Scores égaux
CIVIQ patients : 0 [best QoL] – 100 [worst QoL] - QoL physicians : 0 – 10 [maximal impact]
8
9
10
Perception of Quality of Life by patients and
clinicians in Chronic Venous Insufficiency
Relation entre le score global attribué par le patient et celui attribué par le médecin
Global QoL score
100
90
80
Patients
score patient
70
60
50
40
30
20
r = 0.33
10
0
0
1
2
3
4
5
6
7
score médecin
nuage de points
8
Physicians
droite de régression
CIVIQ patients : 0 [best QoL] – 100 [worst QoL]
QoL physicians : 0 – 10 [maximal impact]
9
10
Correlation of pain versus Quality of Life in
patients with Chronic Venous Insufficiency
Patients : pain vs QoL
100
CIVIQ global score
90
80
70
60
50
40
30
r = 0.78
20
10
0
0
1
2
3
4
5
6
Pain VAS
CIVIQ : 0 [best QoL] – 100 [worst QoL]
Pain VAS : 0 – 10 [worst pain]
7
8
9
10
Perception of pain by patients and clinicians
Results of a survey in 3 chronic diseases
Pain perception is underestimated by clinicians in
irritable bowel syndrome (IBS) and chronic venous
insufficiency and overestimated in peripheral
arteriopathy
Patients
IBS
Venous insufficiency
Arteriopathy
Pain : from 0 to 10 [worst pain]
3.9 ± 2.5
4.2 ± 2.5
3.5 ± 2.0
Clinicians
3.0 ± 2.1
3.0 ± 2.0
4.3 ± 2.1
Perception of HRQL by patients and clinicians in
Peripheral Arteriopathy Occlusive Disease
HRQL impairment is over-estimated by clinicians
CLAU-S (43 items)
Patients
(n = 68)
Clinicians
(n = 61)
Daily Life
Pain
Social Life
Fear
Mood
57 ± 28
64 ± 20
76 ± 18
65 ± 28
72 ± 24
66 ± 23
47 ± 27
55 ± 21
57 ± 26
56 ± 26
63 ± 28
54 ± 21
Global
CLAU-S : 43 items / 5 domains, score 0-100 (best HRQL)
Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Arteriopathy
Patient-reported Outcomes (PROs) are in many
conditions as important as other outcomes
• Clinicians’ and patients’ perspectives although
overlapping, are not similar
• Clinicians tend to underestimate the pain intensity of
their patients
• Similarly, patient’s perception of pain cannot
completely reflect the impact of QoL
• Symptoms (e.g. pain) and QoL although overlapping
to some extent measure different concepts
• Patient’s perspective is a major outcome in the
evaluation of therapies
Weak correlation between HRQL & symptoms
• e.g. Irritable Bowel Syndrome (IBS)
• The absence of abdominal pain (e.g. during a consultation
with a physician) may not be linked with a good HRQL.
The patient :
• May be anxious not to know when the next bout will occur
• May be limited in his inter-personal life and his leisure's
• Constrained to take drugs and to pay attention to food
• The same is true in asthma, migraine, osteoarthritis, acne,
heart failure, HIV (e.g. impact of lipodystrophia induced
by antiretroviral therapy, even in patients who have not
yet the side effect) …
Chassany et al. Validation of a specific quality of life questionnaire in functional digestive disorders (FDDQL). Gut 1999.
Cystic fibrosis : Correlation between different
endpoints
ClinicianReported
Physiological
Caregiver
High
resolution
CT
SaO2
0.84
FEV1
Maximal
Capacity
Exercise
PatientReported
Proxy
MRC Satisfaction HRQL
(QWB,
Caregiver Dyspnea
SIP)
Family
Scale
0.57
0.33-0.40
0.40
Chassany O. De la maladie chronique à la qualité de vie. Méthodes d’évaluation.
Rev Mal Respir 2003; 20: S38-41.
0.75
Correlation between adolescent pulmonary
function (FEV1) and perception of 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
Adolescents
0.73
0.37
0.47
0.42
0.39
-0.21
0.27
0.34
0.24
-0.04
Mothers
0.73
0.70
0.73
0.55
-0.01
0.03
0.28
0.37
0.05
-0.21
Fathers
0.54
0.64
0.60
0.37
0.11
0.06
-0.05
0.18
-0.23
-0.36
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.
Correlation between adolescent vs mother and
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.
Psycho-social impact of lipodystrophy
• Erosion of self-image and self-esteem
• Problems in social and sexual relations
• Threat to loss of control
• Forced HIV disclosure
• Demoralization and depression
• Clinicians’ minimization of the importance of
lipodystrophy
Collins E, Wagner C, Walmsley S. Psychosocial impact of the lipodystrophy syndrome in HIV infection. AIDS
Read 2000; 10: 546-550
Factors associated with severe impact of
lipodystrophy on the Quality of Life
• 84 asymptomatic HIV patients with clinical
lipodystrophy (LD)
• Dermatology Life Quality of Life Index (DLQI)
• Impact of body fat changes on
– Influenced dressing
– Produced feeling of shame
– Disrupted Sexual life
their HRQL
65%
49%
27%
Blanch J et al. Factors associated with severe impact of lipodystrophy on the quality of life of patients
infected with HIV-1. Clin Infect Dis 2004.
Everything
is all
right, CD4,
viral load…
Impact of Lipodystrophy
(HIV) on Quality of Life
I don’t recognize
Myself in mirror
I look like
a monster
Everybody can see
I’ve got HIV
I’m thinking about
stopping
treatment
I need a plastic
Surgery
The impact of Lipodystrophy (HIV) on HRQL is not
adequately captured by other criteria
International
Classification
Biological
Markers
Viral
Load
Patient-Reported
Outcomes (PROs)
ClinicianReported
Lipodystrophy
Sign Score
CD4
CDC
Lipodystrophy
Satisfaction
SF-12
Score Lipodystrophy
Lipodystrophy
Specific HRQL MOS-HIV
Sign Score
ABCD Score
r=0.17
r=0.13
r=0.2-0.7
r=0.39
p=NS
r=0.58
r=0.03
r=0.65
r=0.43
Duracinsky M, Chassany O. Agreement between patients’ and clinicians’-reported outcomes in lipodystrophy (HIV/AIDS). Value in
Health 2004; 7: 641
Conclusion
• Clinicians’ and patients’ perspectives although overlapping,
are not similar
• Lipodystrophy impacts QoL
• Clinicians cannot infer the QoL of their patients neither
from a biological marker nor from a clinical exam
• The different PROs although overlapping, measure each a
distinct concept
• The patient's perspective is essential in medical decision
making : the psychological and social distress related to the
body changes must be measured in clinical trials, to make
sure that life is not lengthened at the expense of its quality
• ABCD questionnaire is validated in French
HRQL as a survival predictor for patients with advanced
head and neck carcinoma treated with radiotherapy
Changes in the HRQL scales during radiotherapy
were not significantly correlated with survival
An increase in the baseline fatigue score of
10 points corresponded to a 17% reduction
in the likelihood of survival (95%CI: 8-27%)
Fang FM, et al. Quality of life as a survival predictor for patients with advanced head and neck
carcinoma treated with radiotherapy. Cancer 2004; 100: 425-432.
Health-Related Quality of Life predicts survival
• 957 patients
• AIDS Clinical Trials Group Protocol 204
• Randomized, double-blind comparing 3 prophylactic
regimen against CMV
• MOS-HIV
– Physical Health Summary (PHS)
– Mental Health Summary (MHS)
• Each point increase in baseline decreased the risk of :
MHS
PHS
Death
4%
4%
CMV
2%
Dropout
1%
1%
Jacobson DL et al. Health-Related Quality of Life predicts survival, cytomegalovirus disease, and study
retention in clinical trial participants with advanced HIV disease. J Clin Epidemiol 2003.
Interview of a patient with pancreatic cancer
Balance between aggressive therapy and HRQL
55 year male patient
Diagnosed with pancreatic cancer (median survival 5 months)
Interview :
– “My Quality of Life is the most important”
– “Chemotherapy will destroy everything”
– “I want to investigate alternative therapies, such as nutrition
supplements”
• By the way, at the end of the consultation with Dr Gonzales, he had
to pay 2800 $ (not taken in charge by any HMO/MCO, I presume)
• The cancer of the patient was so advanced that he died before he
could even start Dr Gonzales treatment
Heard on Radio, 4 June 2004
Place of Patient-Reported Outcomes (PRO)
Patient Outcomes Assessment
Sources and Examples
ClinicianReported
For example
• Global
impression
• Observation &
tests of function
Physiological
For example
• FEV1
• HbA1c
• Tumor size
CaregiverReported
For example
• Dependency
• Functional
status
PatientReported
• Global Impression
• Functional status
• Well-being
• Symptoms
• HRQL
• Satisfaction with TX
• Treatment adherence
Acquadro C, et al. Incorporating the patient's perspective into drug development and communication: an ad hoc task force
report of the Patient-Reported Outcomes (PRO) Harmonization Group meeting at the Food and Drug Administration, February
16, 2001. Value Health 2003; 6: 522-531.
Slide from Laurie Burke, Director, Office of New Drugs, CDER, FDA Washington
Define the conditions for which the measurement
of HRQL/PRO in clinical trial is useful
• Patient’s self-report is the primary or sole indicator of disease activity,
e.g. dermatological disorders (psoriasis, acne), erection dysfunction
• No objective marker or several possible markers of disease activity
(migraine, osteoarthritis, asthma, menopause, heart failure)
• Disease expressed by many symptoms (IBS)
• To ensure that treatments prolonging survival (AIDS), do not
adversely affect patients’ lives due to morbidity, functional or
psychological impairments or side effects
• The treatment does not seem to improve survival (cancer, rheumatoid
arthritis, Parkinson’s disease), but it could improve HRQL, by
reducing pain, anxiety, level of stress or by improving the functional
status.
Chassany O et ERIQA Working Group. Patient Reported Outcomes (PRO) and Regulatory Issues : A
European Guidance Document for the improved integration of health-related quality of life assessment in
the drug regulatory process. Drug Information Journal 2002.
Osteoarthritis
CPMP/EWP/784/97
II. Recommended primary/secondary efficacy endpoints
a) Symptom modifying drugs
PRO
PRO
• Pain attributable to the target joint is recommended as
primary endpoint. Functional disability is an important
additional primary endpoint.
Pain should be measured by self-assessment with validated
methods, such as VAS or Likert scale.
• Functional disability
A disease-specific and joint specific instrument such as the
WOMAC…[…]…is recommended.
Secondary endpoints include:
Global rating, Flares, Physical signs including range of motion,
Quality of Life, Consumption of medications for pain relief
HRQL
Irritable Bowel Syndrome (IBS)
CPMP/EWP/785/97 (March 2003)
5. Recommended primary/secondary efficacy
endpoints
PRO
HRQL
Primary: The patient’s global assessment of symptoms
and abdominal discomfort/pain should be used as the two
primary endpoints. Statistically significant changes must be
found in both parameters.
Secondary (supportive): choice of secondary efficacy variables
should be justified by the applicant and should include variables
such as bloating/distension, stool frequency and urgency, and
quality of life parameters. Health-related quality of life
must, however, be considered most important
secondary endpoints.
Chronic Obstructive Pulmonary Disease (COPD)
CPMP/EWP/562/98 (Dec 1999)
VI. Recommended Primary and secondary
endpoints:
• In the major efficacy studies of symptomatic benefit the
primary endpoint should reflect the clinical benefit the applicant
wishes to claim in the future SPC.
PRO
• The Primary symptomatic benefit endpoint should be justified
by referencing published data which support its validity; one
example is the St George’s Respiratory Questionnaire.
• There are a number of secondary endpoints which may provide
useful information. These measure different aspects of the
disease but they should be justified by referencing published
data which support their validity; examples include…..symptom
HRQL
scales, exacerbation rates and QoL assessment.
• Care should be taken with respect to statistical multiplicity if
secondary endpoints become the basis for specific claims.
Rheumatoid arthritis
CPMP/EWP/556/95 rev 1 (Dec 2003)
3. Tools to measure efficacy (primary or secondary
endpoints)
PRO
d) Patient’s global assessment of disease activity (VAS)
e) Pain score (patient’s assessment : VAS, Likert Scale)
g) Physical function (assessed by patient, e.g. HAQ,
AIMS)
4. Supportive evidence for efficacy
d) Emotional and social function (e.g. AIMS-1)
e) Quality of life (RA-specific, e.g. AIMS, SF-36 or
HRQL
generic…)
Checklist for designing, conducting and reporting
HRQL - PRO in clinical trials
HRQL / PRO objectives
Statistical analysis plan
• Added value of HRQL / PRO
• Choice of the questionnaires
• Hypotheses of HRQL / PRO changes
• Primary or secondary endpoint
• Superiority or equivalence trial
• Sample size
• ITT, type I error, missing data
Study design
• Basic principles of RCT fulfilled ?
• Timing and frequency of assessment
• Mode and site of administration...
Reporting of results
HRQL / PRO measure
Interpreting the results
• Description of the measure (items, domains…)
• Evidence of validity
• Evidence of cultural adaptation
• Participation rate, data completeness
• Distribution of HRQL / PRO scores
• Effect size
• Minimal Important Difference
• Number needed to treat…
Patient Reported Outcomes (PRO) and Regulatory Issues : A European Guidance Document
for the improved integration of health-related quality of life assessment in the drug
regulatory process. Chassany O et ERIQA Working Group. Drug Information Journal 2002.
Define the conditions for which the measurement
of HRQL/PRO in clinical trial is useful
• Patient’s self-report is the primary or sole indicator of disease activity,
e.g. dermatological disorders (psoriasis, acne), erection dysfunction
• No objective marker or several possible markers of disease activity
(migraine, osteoarthritis, asthma, menopause, heart failure)
• Disease expressed by many symptoms (IBS)
• To ensure that treatments prolonging survival (AIDS), do not
adversely affect patients’ lives due to morbidity, functional or
psychological impairments or side effects
• The treatment does not seem to improve survival (cancer, rheumatoid
arthritis, Parkinson’s disease), but it could improve HRQL, by
reducing pain, anxiety, level of stress or by improving the functional
status.
Chassany O et ERIQA Working Group. Patient Reported Outcomes (PRO) and Regulatory Issues : A
European Guidance Document for the improved integration of health-related quality of life assessment in
the drug regulatory process. Drug Information Journal 2002.
What is a HRQL questionnaire ?
Subjective, multidimensional, self-assessed
(whenever possible)
QUESTIONNAIRE SF-36 (36 ITEMS, 8 DIMENSIONS)
Abréviation
Libellé Anglais
Libellé Français
Nombre
d’items
PF
Physical Functioning
Activités physiques
10
RP
Role Physical
Limitations dues à l’état physique
4
BP
Bodily Pain
Douleur physique
2
GH
General Health
Perception de l’état de santé
5
VT
Vitality
Vitalité
4
SF
Social Functioning
Vie et relations avec les autres
2
RE
Role Emotional
Limitations dues à l’état psychique
3
MH
Mental Health
Santé psychique
5
HT
Health Transition
Changement de l’état de santé
1
Faut-il choisir un questionnaire générique ou
spécifique de qualité de vie ?
SF-36
questionnaire
générique
-
Étude chez 1032
patients ayant une
colopathie
fonctionnelle
Fonction physique
Limitations physiques
Sommeil perturbé : 83%
Douleur
Prise d ’hypnotiques : 65%
Santé générale
Vitalité
Fonction sociale
Etat émotionnel
Santé mentale
Restrictions alimentaires : 83%
Très gênantes : 65%
36 items (8 dimensions)
Chassany O, et al. Gut 1999.
Functional Digestive
Disorders Quality of Life
(FDDQL)
- Activités quotidiennes
- anxiété
- Sommeil
- Alimentation
- Réaction face à la
maladie
- Contrôle de la maladie
- Impact du stress
43 items (8 dimensions)
When impact of lipodystrophy is measured by a
generic instrument
• 84 patients with lipodystrophy (LD)
• HRQL measure : Spanish version of the Profil des
Lebensqualität Chronichkranker (PLC)
– 40 items
– 6 dimensions : Physical Capacity, Psychological
functioning, positive mood, social functioning, social
well-being
– Self-administered, but interviewer supervised to
ensure that the questions were correctly understood
and answered
• LD had no influence on overall quality of life
Blanch J et al. Impact of lipodystrophy on the quality of life of HIV-1 infected patients. JAIDS 2002.
What is not quality of life ?
• The abuse of the term HRQL in some clinical trials,
whereas the questionnaire measured anything else
– A listing of symptoms or of side effects cannot
claim to measure HRQL
– Satisfaction *
• The following concepts cannot alone explore all HRQL :
– physical or intellectual performance scale
– handicap or functional incapacity scale
– anxiety or depression scale
– tiredness or pain scale
– symptom bother scale
* Treatment of penile curvature with Essed-Schroder tunical plication: aspects of
quality of life from the patients' perspective. BJU Int 2004
What are we measuring ? HRQL or side-effects
Measurement of quality of life in hypertensive patients.
Bulpitt CJ et al. Br J Clin Pharmacol 1990; 30: 353-364.
Justification of choice of instruments ?
What are the hypotheses ?
Randomized, DB, placebo-controlled study of GH replacement in 40
patients with acquired GH deficiency
• Assessment at baseline and 18 months :
• NHP (Nottingham Health Profile)
• PGWB (Psychological General Well-being)
• GHQ (General Health Questionnaire)
• MMPI-2 (Minnesota Multiphasic Personality inventory)
• Selection made on what ?
• Psychometrics properties ?
• Prior use in a similar population ?
• Cover several different concepts ?
• What where the hypotheses of score changes ?
Baum HBA et al. Effects of physiological growth hormone therapy on cognition and quality of life in patients
with adult-onset GH deficiency. J Clin Endocrinol Metab 1998; 83: 3184-9.
Examples of generic HRQL questionnaires ?
Name
Items
Dimensions
Answers
SIP
Sickness Impact Profile
136
12
Yes/No*
NHP
Nottingham Health Profile
38
7
Yes/No*
SF-36 Short-Form 36 (MOS)
(Medical outcomes Survey)
36
8
Likert
PGWB Psychological General
Well-Being
22
6
Likert
* Binary responses are unlikely to be sensible enough to detect a small
change
Attention à la longueur des questionnaires
Nom du questionnaire
Nb d’items
SIP
Sickness Impact Profile (questionnaire
générique)
136
DSQOLS
Diabetes Specific Quality of Life Scale
64
DCP
Diabetes Care Profile
NEWSQOL
Newcastle Stroke-Specific Quality of Life
Measure
56
SIS
Stroke Impact Scale
64
HOPES
HIV Overview of Problem situations
AIDS-HAQ
AIDS – Health Assessment Questionnaire
234
103-176
116
Content of HRQL questionnaires :
Nottingham Health Profile (NHP)
• Je me sens seul
• Je suis de plus en plus découragé
• Je me rends compte que plus rien ne me fait plaisir
• J’ai des difficultés à entrer en contact avec les autres
• J’ai l’impression de n’avoir personne de proche à qui
parler
• J’ai du mal à faire face aux événements
• J’ai l’impression d’être une charge pour les autres
• Je trouve que la vie ne vaut pas la peine d’être
vécue !
c’est plus une échelle de dépression que de qualité de
vie
What are we measuring ?
Improvement of lung function (FEV1, p < 0.0001) with added
beclomethasone dipropionate (BDP)
Temporary decrease of symptoms
HRQL assessment : No improvement of NHP and ISP
– NHP : 38 statements, 6 dimensions : physical mobility, pain, social
isolation , emotional reactions, energy, sleep.
• Answer by YES / NO
– ISP (Inventory of Subjective Health) : 21 items related to subjective
complaints : tiredness, chest and heart problems, gastric problems,
indigestion, headache…
• Is that measuring HRQL ?
The influence of an inhaled steroid on quality of life in patients with asthma or COPD. Van Schayck CP et al.
Chest 1995; 107: 1199-205.
Choice of PRO instrument - What are we
measuring ? Example of HIV / AIDS
Fatigue
Items related to intensity, circumstances, and consequences of fatigue.
Psychometric properties of the HIV-related fatigue scale. Barroso J et al. J Assoc Nurses AIDS Care 2002.
Cognitive function
Dutch four-item MOS-HIV cognitive functional status subscale.
The importance of cognitive self-report in early HIV-1 infection: validation of a cognitive functional status
subscale. Knippels HM et al. AIDS 2002.
Treatment satisfaction
Weak correlation between severity of side-effects and score of satisfaction
concerning these side-effects (r = 0.18)
Validation of the HIV treatment satisfaction questionnaire. Woodcock A et al. Qual Life Res 2001.
Doctor-Patient satisfaction
Satisfaction among HIV-infected patients was not associated with QOL
The doctor-patient relationship and HIV-infected patients’ satisfaction with primary care physicians.
Sullivan LM et al. J Gen Intern Med 2000.
MOS-HIV
AIDS-HAQ
HOPES
FACIT
(FAHI)
HAT-QoL
MQoL-HIV
WHOQOLHIV
Medical Outcomes
Study HIV Health
Survey
AIDS-Health
Assessment
Questionnaire
HIV Overview
of Problem
Situations
HIV/AIDSTargeted Quality
of Life
Wu A
Lubeck
Ganz PA
Functional
Assessment
HIV specific
subscale
Cella D
Holmes WC
Multidimensional
Quality of Life
Questionnaire for
HIV/AIDS
Smith
World Health
Organisation’s
Quality of Life
HIV instrument
WHO
Nb Items
1991
35
1992
116
1993
103-176
1996
55
1988 (1997)
34 (76?)
1997
40
2003
31
Dimensions
11
8
5
6
5
10
Gal Health
Perception
Disability
Social Function
Mental Health
Cognitive Function
Energy/Fatigue
Pain
Disease Worry
Physical
Function
Psychosocial
Function
Sexual
Function
Medical
interaction
Marital
Relationship
Overall Function
Disclosure
worries
Health Worries
Financial Worries
Life Satisfaction
Mental Health
Physical Health
Physical Functioning
Social Function
Social Support
Cognitive Function
Financial Status
Partner Intimacy
Sexual Function
Medical Care
Based
Gal Health
Perception
Physical Function
Role Function
Social function
Cognitive function
Pain
Mental Health
Energy/fatigue
Health Distress
Quality of Life
Health Transition
SF-36
Author
Year
Languages
Danish, Dutch,
English UK,
French, German,
Italian,
Portuguese,
Spanish
Dutch, Spanish
Functional
Assessment
of Cancer
Treatment
(FACT-G)
French
Cancer
Rehabilitation
Evaluation
System (CARES)
Italian,
Portuguese,
Spanish
WHOQOL
German, Spanish
French
MOS-HIV
•
•
•
•
“Très” SF-36
“Très” physique
Reflètant plus l’état de santé que la qualité de vie
Pas de question sur
– Le sommeil
– Le traitement
– La lipodystrophie
Grossman HA et al. Quality of Life and HIV : current assessment tools and future directions for clinical
practice. AIDS Read 2003.
WHOQOL-HIV
• Culturellement universel (Inde, Afrique, Asie, Amérique du
Sud, …)
• Multidimensionnel :
–
–
–
–
–
–
Vos croyances personnelles donnent-elles un sens à votre vie ?
Vous sentez-vous en sécurité dans votre vie de tous les jours ?
Votre environnement est-il sain ? (pollution, bruit, salubrité, etc…)
Avez-vous besoin d’argent pour satisfaire vos besoins ?
Êtes-vous satisfait de vos moyens de transport ?
Êtes-vous satisfait de l’endroit où vous vivez ?
O’ Connell K et al. Preliminary development of the World Health Organisation’s Quality of Life HIV
instrument (WHOQOL-HIV). Analysis of the pilot version. Social Science & Medicine 2003.
WHOQOL-HIV
• Spécifique du VIH ?
– Un traitement médical vous est-il nécessaire pour faire face
à la vie de tous les jours ?
• Libellé compréhensible ?
– Dans quelle mesure, êtes-vous tracassé par tout problème
physique lié à votre infection par le VIH ?
– Avez-vous assez d’énergie dans la vie de tous les jours ?
– Avez-vous le sentiment d’être assez informé pour faire face à
la vie de tous les jours ?
– Comment trouvez-vous votre capacité à vous déplacer seul ?
O’ Connell K et al. Preliminary development of the World Health Organisation’s Quality of Life HIV
instrument (WHOQOL-HIV). Analysis of the pilot version. Social Science & Medicine 2003.
Who measures what ?
Complaint score
Health Status Index
Work satisfaction
Psychological General Well-Being
Profile of Mood Status
Life satisfaction
Psychomotor function
Sleep
Sexual function
Life events
Quality of life with three antihypertensive treatments.
Fletcher AE et al. Hypertension 1999; 19: 499-507.
(32 items)
(5 items)
(7 items)
(22 items)
(3 items)
(7 items)
(6 items)
(8 items)
Self
Inter
Inter
Self
Self
Self
Inter
Self
Self
Who measures Well-Being ? Clinicians ??
N = 30
Analysis of Well-Being between indapamide and captopril.
Lacourciere Y. Am J Med 1988; 84: 47-51.
Who should fill-in questionnaire ?
In studies evaluating sexual impairment induced by
antihypertensive treatment in male patients, the answers
given to nurses, by patients themselves and by their
spouses were quite different...
Rate of sexual dysfunction
Nurses
Low
Who should fill-in questionnaire ?
In studies evaluating sexual impairment induced by
antihypertensive treatment in male patients, the answers
given to nurses, by patients themselves and by their
spouses were quite different...
Rate of sexual dysfunction
Nurses
Low
Patients
Moderate
Who should fill-in questionnaire ?
In studies evaluating sexual impairment induced by
antihypertensive treatment in male patients, the answers
given to nurses, by patients themselves and by their
spouses were quite different...
Rate of sexual dysfunction
Nurses
Low
Patients
Moderate
Patients (palm pilot)
Higher
Who should fill-in questionnaire ?
In studies evaluating sexual impairment induced by
antihypertensive treatment in male patients, the answers
given to nurses, by patients themselves and by their
spouses were quite different...
Rate of sexual dysfunction
Nurses
Low
Patients
Moderate
Patients (palm pilot)
Higher
Spouses
Very high
From Pr Ingela Wiklund
(AstraZeneca)
Item generation
Scaling
Item reduction
Reproductibility
Content validity
Construct validity
Discriminant validity
Convergent validity
Responsiveness
Cultural adaptation
Score résumé mental du SF-12 (MCS)
•
•
•
•
•
•
•
•
•
•
Mean ABCD score
To follow the rigorous procedures of development
of HRQL or PRO questionnaires
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
How measuring fatigue ? Identification of
concepts
Multiple causes
•
•
•
•
•
•
•
•
•
•
Lack of rest or exercise
Improper or inadequate diet
Psychological stress
(depression, anxiety)
Use of recreational substances
Anemia
Abnormalities of the thyroid
gland and hypogonadism
Infections
Side effects of medications
Sleep disturbances
Fever
Fatigue description
•
•
•
•
•
•
Lack of energy
Sleepiness
Tiredness
Exhaustion
Inability to get enough rest
Weakness
Specific
fatigue
questionnaire
HRQL questionnaire :
must have items related
to fatigue
Assessment and treatment of HIV-related fatigue. Adinofi A. J Assoc Nurses AIDS Care 2001.
Determinants of the Quality of Life
Various factors involved in the
multidimensional HRQL construct
2nd
illness
Social
support
Personality
traits
Diabetes
burden
Coping
with
disease
Control
of disease
Rose M, et al. Determinants of the quality of life of patients with diabetes under intensified insulin therapy.
Diabetes Care. 1998; 21: 1876-85.
Items about DIET can express different concepts
Input of patients in item generation is critical
Diabetes --> Cause --> Food --> consequence --> DIET
I am able to keep my diet regimen under control
Control of disease / self-management
My diabetes and its treatment (e.g. diet) keeps me going out
with friends / to restaurant / as much as I want
Interference with social and personal relationships
I find it hard to do all the things (e.g. diet) I have to do for my
diabetes
Coping with disease
Watkins KW, et al. Effect of adults' self-regulation of diabetes on quality-of-life outcomes. Diabetes Care 2000; 23: 1511-5.
Item generation of the FDDQL questionnaire
Première version du questionnaire spécifique FDDQL dans les Troubles
Fonctionnels Intestinaux (TFI) : les exemples suivants correspondent à
des items peu clairs, doublement négatifs …
• Il m'est facile de me décontracter et de ne plus
penser à rien
• Je n'angoisse pas à l’idée que mes vacances avec le
changement des habitudes alimentaires, risquent
d'aggraver ma maladie (douleurs, constipation ou au
contraire diarrhée)
• Je ne pense pas que ma maladie retentisse
négativement sur mon travail
Chassany O, et al. Gut 1999.
Attention au libellé des questions
Fatigue Symptom Inventory
• Combien de temps dans la journée, en moyenne, vous êtes
vous senti(e) fatigué(e) durant la dernière semaine ?
Rate how much of the day, on average, you felt fatigued in the past week
St-George Respiratory Questionnaire (50 items)
• Sur l’année dernière, en moyenne sur une semaine,
combien de “bons jours” vous avez eu ?
Over the last year, in an average week, how many good days (with little
chest trouble) have you had
Fatigue symptom inventory
Item scaling of HRQL questionnaires ?
(Please check one box for each statement.)
All of the time
Most of the time
Some of the time
A little of the time
None of the time





(5)
(4)
(3)
(2)
(1)
Item scaling of HRQL questionnaires ?
(Please check one box for each statement.)
All of the time
Most of the time
Some of the time
A little of the time
None of the time





(5)
(4)
(3)
(2)
(1)
Tout le
temps
Très
souvent
Quelquefois
Rarement
Jamais
Item scaling and scoring of HRQL questionnaires ?
Les modalités de réponses doivent permettre de détecter
des petits changements
• Réponse binaire : YES / NO  peu sensible
• Echelle verbale Likert en 5 à 7 points
• Echelle visuelle analogique
0
1
2
3
4
Pas du tout
Un petit peu
Moyen
Beaucoup
Enormément
Généralement, la réponse à un item est transformée en une
valeur : entre 0 et 4 pour une échelle verbale à 5 points
Les scores des dimensions sont obtenus par sommation des
réponses aux items
Pour faciliter la présentation des résultats, les scores des
dimensions peuvent être transformés entre 0 et 100
Factorial analysis of Assessment of Body Change
and Distress (ABCD) in Lipodystrophy (HIV/AIDS)
Factorial analysis (n = 143)
Lipodystrophy score (6 items)
Correlation matrix
Q1
Q2
Q3
Q4
Q5
Q2
Q3
Q4
Q5
Q6
0,512
-0,175
-0,117
-0,049
0,227
-0,151
0,070
0,188
0,260
0,231
0,327
-0,006
0,671
Facteurs
Factors
1
2
Q1
-,210
,789
0,101
Q2
,065
,841
0,028
Q3
,573
-,265
Q4
,855
,090
Q5
,882
,151
Q6
,088
,558
2-factor structure
1- Lipoatrophy
2- Lipoaccumulation
Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life
questionnaire in Lipodystrophy (ABCD)
Factorial analysis of Assessment of Body Change and
Distress (ABCD) in Lipodystrophy (HIV/AIDS)
Factors
Composante
Factorial analysis (n = 143)
ABCD Quality of life score (20
items)
4-factor structure :
1- Acceptation, coping,
satisfaction of appearance
2- Psychological, social and
relational impact
3- Fear of future
4- Compliance with the treatment
Duracinsky M, Chassany O. Linguistic and psychometric validation in
french of a specific quality of life questionnaire in Lipodystrophy (ABCD)
a
1
,723
2
,084
3
,284
4
,177
b
,529
,067
,427
,293
c
,696
,359
,152
,290
d
,580
,488
,149
,318
e
,625
,143
,471
,096
f
,684
,118
,347
-,105
g
,609
,195
,381
,125
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
Item reduction
Iterative process based on :
• Distribution of answers
• Content analysis (items and response options are relevant and
comprehensive of the dimensions)
• Factorial analysis
(to support the hypothesized scale structure, i.e.
the combination of items into dimensions)
1- Have you hesitated about going to public places ?
2- Have you felt embarrassed with your friends ?
3- Have you felt embarrassed with your family ?
4- Have you cancelled any journeys, weekends away or outings ?
5- Have your digestive problems affected your love life ?
6- Have your digestive problems affected your sex life ?
7- Have you had to cancel personal or professional meetings ?
8- Have you been embarrassed with your work colleagues ?
9- Have your digestive problems affected your relationship with work colleagues ?
0%
Not at all / never / not applicable
A little bit / rarely
Moderately / sometimes
25%
50%
Quite a bit / often
75%
100%
Extremely / always
During the development of a HRQL questionnaire in irritable bowel syndrome, patients were asked to answer these
items ranging from “not at all” to “extremely.” Results are presented as a percentage of patients.
Discriminant validity of the Functional Digestive
Disorders Quality of Life questionnaire (FDDQL)
Number of
symptoms
Scores moyens FDDQL
100
[1-5]
[6-10]
80
> 10
60
40
20
0
Activ ité
quotidiennes
Anx iété
Alimentation
Sommeil
Inconfort
Réaction face Contrôle de
à la maladie
International study : France, Germany, Great Britain
391 IBS and dyspeptic patients
Chassany O, et al. Gut 1999.
la maladie
Stress
Discriminant validity of the Health Assessment
questionnaire adapted to Sclerodermia (SSc HAQ)
Score values (m ± SD) of
the global SSc HAQ and
HAQ-DI, according to the
number of the following
organ involvements (n=6):
• Raynaud’s phenomenon
• Digital ulcers
• Gastro-intestinal
• Pulmonary
• Musculoskeletal
• Hand contracture
3
2,5
0
1
2
3
4
5
6
2
1,5
1
0,5
0
SSc HAQ
HAQ-DI
Comparison using ANOVA (p < 0.0001 for both scores) (n=100 patients)
HAQ-DI: Health Assessment Questionnaire – Disability Index;
Global SSc HAQ = (8 HAQ-DI domains + 5 VAS)/13.
Validation of French version of the scleroderma health assessment questionnaire (SSc HAQ).
Georges C, Chassany O et al. Clinical Rheumatology, Under press.
Discriminant validity of a Lipodystrophy specific
quality of life questionnaire
100
Global Quality of Life score (ABCD)
impairs with the number of
sites of lipodystrophy
(n = 155)
90
80
85
70
71
64
60
56
50
54
45
40
42
score min-max : 0-100
[0 = worse quality of life,
100 = good quality of life]
ANOVA, p < 0.001
30
20
10
0
0
1
2
3
4
5
6
Number of lipodystrophy regions
r = 0.39
Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life
questionnaire in Lipodystrophy (ABCD)
Convergent validity of a Lipodystrophy specific
quality of life questionnaire
Logical correlation between Global ABCD score and
generic quality of life (SF-12) (n = 155)
Score résumé physique du SF-12 (PCS)
vs Mental Component
70
Summary (MCS), r = 0.65
60
50
40
30
20
vs Physical Component
Summary (PCS), r = 0.101
60
50
40
30
20
10
0
20
40
60
80
Score de qualité de vie ABCD
100
0
20
40
60
80
100
Score de qualité de vie ABCD
Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life
questionnaire in Lipodystrophy (ABCD)
Convergent validity of a Lipodystrophy specific
quality of life questionnaire
General Health
Physical Function
Role Physical
Social Function
Cognitive Function
Pain
Mental Health
ABCD QoL
score
0.51
0.37
0.21
0.63
0.48
0.48
0.68
Energy/Fatigue
Health Distress
Global QoL
Health Transition
0.59
0.70
0.56
0.22
MOS-HIV
Logical correlation between
some dimensions of the MOSHIV, e.g. the health distress,
mental health and social
function (r > 0.6)
Sensibilité au changement - Questionnaire d’éducation
dans l’asthme (CHU Montpellier)
Évolution des scores entre la première (n = 96), la 2e (n = 67) et la 3e
visite (n = 21) au cours d’un programme d’éducation
G3
G2
G1
F3
E1
B3
F2
0
F1
0
E3
20
E2
20
D3
40
D2
40
D1
60
H1
Scores des 6 domaines explorant le
comportement face à des scénarios cliniques
70
H2
H3
I1
100
60
80
50
60
40
30
40
SG CONN ALT3
0
SG CONN ALT2
20
SG CONN ALT1
Score
global
SG CONN3
SG COMP ALT3
SG COMP ALT2
SG COMP ALT1
Sg COMP3
SG COMP2
0
SG COMP1
10
SG CONN2
20
I2
I3
Scores des 2 domaines explorant
les connaissances
SG CONN1
B2
60
B1
80
AC3
80
AC2
100
AC1
100
Cultural adaptation and Linguistic validation
•
•
•
•
•
Objective: Conceptual equivalence between the source
questionnaire and the target version
There is no consensus, however the major steps recommended
remain the same
Forward translation:
– independent translations (source  target language)
– Reconciliation meeting to obtain a consensual version
Backward translation:
– independent translation (target  source language)
– Comparison of the source questionnaire with the "backward"
translation to check the conceptual content of forward version
Cognitive debriefing:
– Structured and in-depth interviews to test their understanding
/ interpretation of the translation of each item
Cultural adaptation - forward/backward
translation
Source (FR)
Vous êtes-vous senti(e) mal dans votre peau ?
Problem
idiomatic expression
Forward
Have you felt ill at ease ?
backward
Vous êtes-vous senti mal à l’aise ?
Problem
Original concept is not correctly translated
Final
Have you felt unhappy with yourself ?
Chassany O, et al. Validation of a specific quality of life questionnaire in functional digestive disorders
Chassany
O, et al. Gut 1999.
(FDDQL).
Gut 1999.
Cultural adaptation - forward/backward
Disease: Asthma - Original version developed in Canada
Item: Here is a list of activities in which some people
with asthma are limited, among them: « shoveling
snow »
• Canada (US)
• Japan
• Norwegian
Shoveling the snow
Cultural adaptation - forward/backward
Disease: Asthma - Original version developed in Canada
Item: Here is a list of activities in which some people
with asthma are limited, among them: « shoveling
snow »
• Canada (US)
Shoveling the snow
• Japan
Beat futons
• Norwegian
Cultural adaptation - forward/backward
Disease: Asthma - Original version developed in Canada
Item: Here is a list of activities in which some people
with asthma are limited, among them: « shoveling
snow »
• Canada (US)
Shoveling the snow
• Japan
Beat futons
• Norwegian
Going fishing
Cultural Adaptation
Cultural adaptation
All of
the
time
Most of
the
time
Some
of the
time





c. … upset that I can’t control my body.





f. … confused about how much to exercise.





g. … feel discomfort or pain.





h. … embarrassed about how I look.





i. … worry that my HIV is getting worse.





j. … upset that people may think I am sick.





a. … feel frustrated because clothes don’t fit
A little of None of
the time
the
time
right.
Cultural adaptation of Assessment of Body Change
and Distress (ABCD) in Lipodystrophy (HIV/AIDS)
Questionnaire ABCD : Item Q8c
(Problème de la traduction de “upset”)
Original
MB
CE
Version 1
Version 4
Back DE
Finale
c. … upset that I can’t control my body.
c …. je me suis senti(e) triste parce que je ne pouvais pas contrôler mon corps
c. … j’ai été contrarié/e de me rendre compte que je n’avais plus le contrôle de mon
corps
c. … j’ai été contrarié/e inquiet(e) de me rendre compte que je n’avais plus le
contrôle de mon corps.
c. … j’ai été contrarié/e de ne plus avoir le contrôle de mon corps.
c. … I was upset about losing control of my body
c. … j’ai été contrarié/e de ne plus avoir le contrôle de mon corps.
Def : To distress or perturb mentally or emotionally, to disturb, to
sadden, to trouble, to offend, to disappoint
Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life
questionnaire in Lipodystrophy (ABCD)
Cultural adaptation
How often did your asthma make you feel frustrated
during the past week?
To prevent from accomplishing a purpose or fulfilling a desire. To
cause feelings of discouragement
Literal translation in French : frustré
Backward translation : offended, dispossessed, injured,
shocked
Responsiveness - specific questionnaires
Specific questionnaire : responsiveness ?
HRQL is not improved by drugs in Chronic heart failure ?
MLwHF Placebo 6.25 mg 12.5 mg 25 mg
(0-105)
Baseline
47.7
45.8
43.9
43.6
Mortality at 6 months
16
14
12
Endpoint
10
8
40.4
38
36.5
38.2
Minnesota Living with Heart Failure
MLwHF : 21 items, 0 (best) - 105 (worst)
6
4
2
g
25
m
g
12
,5
m
g
25
m
6,
Pl
ac
eb
o
0
Bristow MR et al. Circulation 1996.
Double-blind, placebo-controlled
trial (n=345), 6 months, 3 doses of
carvedilol (beta-blocker)
Responsiveness - generic questionnaires
Psychological General Well-Being (PGWB) & GERD
HRQL is not improved by gastro-oesophageal reflux disease drugs ?
Résolution des symptômes à 4
semaines
122
Global PGWB score
80%
J0
60%
40%
20%
4 semaines
102
82
62
42
22
Ome
20mg
0%
Ome 20mg Ome 10mg
Cis 10mg
24% difference in pyrosis relief
Galmiche JP, et al. Aliment Pharmacol Ther 1997.
Ome
10mg
Cis 10mg
No difference in PGWB score
.
Predictive value of Quality of Life ?
Is health-related quality of life among older,
chronically ill patients associated with unplanned
readmission to hospital ?
163 Australian, chronically ill patients (67 ± 16) discharged
to home following acute hospitalization
HRQL (SF-36) assessed at one month post-hospital
Patients were followed-up for six months thereafter to
determine subsequent incidence of unplanned readmission
On multivariate analysis :
SF-36 physical component score < 40 (OR = 2.2, p = 0.05)
Is health-related quality of life among older, chronically ill patients associated with unplanned readmission
to hospital ? Pearson S et al. Aust N Z J Med 1999; 29: 701-706
Specific Cystic Fibrosis Questionnaire (CFQ)
French Cystic Fibrosis Questionnaire :
• CFQ-14 for teenagers & adults
• CFQ Child P : a parent-proxy evaluation
for children aged 8-13
• 33 interviews patients & parents :
- Item generation
• Cross-sectional survey among 393 patients
& parents :
- Item reduction
- Internal consistency, convergent and
discriminant validity
• 124 patients & 85 parents :
- Subscale structure (Rasch analysis…)
- Reproducibility and responsiveness
9
•
•
•
•
•
•
•
•
dimensions :
physical functioning
energy/well-being
emotions
social limitations
role, embarrassment
body image
eating disturbances
treatment burden
Development of the Cystic Fibrosis Questionnaire (CFQ) for assessing quality of life in pediatric and adult
patients. Henry B, et al. Qual Life Res 2003; 12: 63-76.
Cross-cultural adaptation of questionnaires
is not enough ?
•
•
•
•
Specific CFQ-14 developed in France
Translated in German
Studies in n = 197 and n = 103 adolescents/adults
Construct validity : same 9 HRQL domains as in
the French original CFQ-14
• Internal consistency : ranged from 0.71 to 0.94
• Clinical validity : supported by severely ill patients
reporting lower HRQL than less ill patients
The revised German Cystic Fibrosis Questionnaire: validation of a disease-specific health-related quality of life
instrument. Wenninger K et al. Qual Life Res 2003; 12: 77-85.
“Validated” scale is not enough
• A validated scale doesn’t imply systematically
that it is relevant for the population studied
• e.g. even for the so well-known SF-36
applied in a given condition, the issue of its
relevance should be addressed…
– e.g. SF-36 in IBS
– MOS-HIV validated before HAART
• Moreover some scales are getting old…
Choice of a PRO questionnaire - 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.
Study Design : specific issues related to
HRQL / PRO measure
• Eligibility criteria : if HRQL primary endpoint, set a minimal
impairment of HRQL (as for other criteria, e.g. pain, asthma
onset… )
• Timing and frequency of HRQL assessment :
– At baseline, at the end of the study or at withdrawal
• Length of the trial (relevance of short term trials ?)
• Mode and site of HRQL administration :
– Self-administered whenever possible
– Assure the confidentiality
– Before the medical consultation
• Data monitoring and quality assurance
• Procedures for prevention and handling of missing data
Chassany O et ERIQA Working Group. Patient Reported Outcomes (PRO) and Regulatory Issues : A
European Guidance Document for the improved integration of health-related quality of life assessment in
the drug regulatory process. Drug Information Journal 2002.
Basic principles of RCTs fulfilled ? Placebo
effect is also strong for HRQL
• Double-blind sham surgery-controlled trial
designed to determine the effectiveness of
transplantation of human embryonic dopamine neurons
into the brains of persons with advanced Parkinson's
disease
• Study investigated the quality of life (HRQL) of
participants during the 1 year of double-blind follow-up
• In all cases, those who thought they received the
transplant reported better HRQL (physical,
emotional and social) scores
McRae C, et al. Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial.
Arch Gen Psychiatry 2004; 61: 412-420
Statistical analysis plan : Estimating the
adequate sample size
•
•
•
•
HSQ (Health Status Questionnaire)
before / after scores on 1300 patients
All p values < 0.0001
Conclusion: all HRQL domains were
significantly different across treatment groups
• Problem: 1300 provide 80% power to detect
a change of 1 unit on a 0-100 point scale
JCO 2001 (anonymous)
Importance of withdrawals and missing data
N = 365
(394 randomized)
Poorer HRQL scores
Assessment of quality of life by patient and spouse... Testa MA et al. Am J Hypertens 1991; 4: 363-73.
Statistical analysis plan : PRO multiplicity
Salmeterol / COPD
•
•
•
•
•
•
•
SF-36
Assessment
3 months
6 months
9 months
12 months
36
8 (+1) dimensions
Open label
"
Salmeterol 50 g
"
or SR Theophylline bid
"
Randomized (n = 178)
Number of tests
Completers (n = 145)
HRQL (secondary) : SF-36
Mean changes between baseline and the 4 assessments over time, for
each dimension : Student t test
(n = ???)
in favor of Salmeterol
Physical Functioning (PF)
Change in Health Perception (HT)
Social Functioning (SF)
Assessment
3 months
9 months
12 months
p
0.02
0.03
0.04
Efficacy, tolerability and effects on HRQL of inhaled Salmeterol in COPD. Di Lorenzo G et al. Clin Ther 1998.
Interpreting PRO results ?
Zk vs Pl
p
Daytime symptoms (0 to 3 (severe))
- 0.14 < 0.001
Nighttime awakening (per wk)
- 0.63 < 0.001
 2 agonist use (puffs/day)
- 0.64 < 0.001
FEV1
Morning PEF (BL : 362)
0.05
0.331
+ 13,1 L/min < 0.001
Evening PEF (BL : 398 + 11,5 L/min < 0.001
Global AQLQ score (BL : 4.28)
+ 0.26
0.004
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 evaluate drugs when clinical relevance of
results is not obvious ?
Mean score ± SD
p < 0.05
and IC95
HRQL
Pain VAS
YES
?
p < 0.05
OK
Responders
MID
Interpretation of results - Effect size
• Treatment in claudication (Peripheral Arterial
Occlusive Disease)
• Phase III, randomized, double-blind, vs placebo
Endpoint
Effect Size
Walking distance
Specific HRQL questionnaire (CLAUS)
2.13
0.48
Effect size (Distribution-based approach)
Dividing a difference between 2 groups by the SD
Dossier for Drug Approval
File for Approval - AFSSAPS
Effect Size
Small
Moderate
Large
Benchmark
> 0.20
> 0.50
> 0.80
Interpretation of results - Effect size
Longitudinal validation study : Effect Size (ES) of a symptomatic specific
questionnaire (EEV) and the SF-36 calculated from the change as
perceived by over 100 patients with vertigo after 4 weeks of treatment
Generic quality of life SF-36
European Evaluation of Vertigo (EEV)
Global score
Mental Health
Role Emotional
Instability
Social Functioning
Neurovegetative
signs
Vitality
Health Perception
Motion intolerance
Bodily Pain
Duration of illusion
Role Physical
Illusion of
m ovem ent
Physical Functioning
0
0,5
1
1,5
2
Effect size (Distribution-based approach)
a difference
between 2 groups by the SD
FileDividing
for Approval
- AFSSAPS
0
0,2
0,4
0,6
0,8
Effect Size
Small
Moderate
Large
Benchmark
> 0.20
> 0.50
> 0.80
Minimal Important Difference (MID)
MID obtained from comparison with a Global Rating
Answer to the
GLOBAL RATING
change*
A very great deal
Worse
Better
Interpretation
of change
-7
+7
Large
Mean change in
HRQL scale
(range 1-7)
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
About the same
-1
+1
* “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
Minimal Important Difference (MID) or change
DEPENDS ON WORDING
Changes in AQLQ
symptom-domain
anchored to global
Asthma
control
global
Global category
Average
Worse
Minimally worse
No change
Minimally improved
Asthma
change
global
n
3
- 0.04
0.13 49
0.35 102
0.78 135
1.48 18
Average
n
3
- 1.05
0.18 11
0.33 45
0.42 86
0.85 121
Improved
n = 343 (mild to moderate asthma)
Global asthma control question : “How well is your asthma controlled?”
Global asthma change question : “Overall has there been any change in
your asthma since the beginning of the study ?”
AQLQ : Response from 0 to 6 (poorly controlled / much worse)
Barber BL et al. Qual Life Res 1996.
Minimal Important Difference (MID)
MID obtained from comparison with a Global Rating
may be different according to :
• Wording of the Global Rating
• Improvement vs. worsening
• Characteristics of patients (age, gender…)
• Characteristics of disease (severity …)
• Setting of the trial, type of intervention
• Cross-cultural differences
• Baseline level of scores …
Currently, there is no consensus, whether to be relevant,
MID should be > 0.5 on a range score from 1 to 7
Impact of the global on patient perceivable change in an asthmatic specific QOL questionnaire.
Barber BL et al. Qual Life Res 1996.
Minimal Important Difference (MID)
PGWB (1)
MID
[range of the scale]
Corresponding MID on a
range scale 0-100
3 [0-110] (2)
8 [0-110] (3)
SGRQ
4 [0-100]
AQLQ (4)
0.5 [1-7]
2.7
7.3
4
7
CRQ 4)
0.5 [0-6]
7
6 [0-100] (GR : little better)
13 [0-100] (GR : much better)
I-QOL (4)
SF-36
10 [0-100]
6
13
10
Dyspnoea index (5)
1 [-3, +3]
14
VAS pain (4)
2 [0-10]
18
(1) Informal meeting with Harold Dupuy (Paris, June 2003), (2) group level, (3) individual level
(4) values obtained by correlation with a global rating (GR)
(5) Baseline and transitional dyspnoea index (BDI/TDI)
How many and which PRO domains should
improve for a claim ?
(PAOD)
• HRQL primary endpoint using
the specific questionnaire : CLAU-S
(9 domains, 80 items)
8
Naftidrofuryl
Placebo
6
4
• Results : 2 domains significantly
2
improved with drug (daily life,
p=0.004; pain, p=0.001)
0
• Should the planners have
Domains
The effects of naftidrofuryl on quality of life. Liard F et al.
Dis Manage Health Outcomes 1997.
ta
lity
Vi
ue
Fa
tig
sio
n
ty
es
ep
r
D
e
xie
An
cia
l
lif
ts
So
pl
ai
n
Pa
C
om
lif
ai
ly
D
domains would improve?
e
hypothesized that only these 2
in
-2
An
ge
r
Arteriopathy Occlusive Disease
10
Change score
• 234 Patients with Peripheral
How many and which PRO domains should
improve for a claim ?
• 90 (6 x 15) statistical tests
• Difference of 0.2 (range 1-7)
at 3 months
• No difference at 12 months
Abstract “Aerobic grouptraining of elderly patients
recovering from an acute
coronary event beneficially
influences physical fitness and
several parameters expressing
quality of life”
Symptoms
- Chest pain
- Shortness of breath
- Dizziness
- Palpitation
- Cognitive ability
Alertness
Quality of sleep
Physical ability
Daily ability
Depression
Self perceived health
Ladder of life: future
Fitness
Physical activity
J3
J12
NS
<0.05
NS
<0.05
NS
NS
NS
NS
NS
NS
NS
NS
<0.05
<0.01
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
Stahle A et al. Improved physical fitness and HRQL following training after acute coronary events.
Eur Heart J 1999.
How many and which PRO domains should
improve for a claim ?
Antacid in GERD
• Randomized, placebocontrolled, double-blind
trial
• Primary endpoint :
heartburn (diary)
• Secondary endpoint :
SF-36 questionnaire
• Sample size > 230
• Duration : 28 days
SF-36
domains
PF
RP
BP
HP
VT
SF
RE
MH
Score differences at
4 wks antacid vs
placebo
<3
<7
<3
<3
<3
<3
<3
<4
p
Effect size
NS
NS
NS
NS
< 0.04
< 0.05
NS
< 0.03
0.15
< 0.15
0.20
< 0.15
< 0.25
< 0.10
0.20
< 0.20
Justification of measuring HRQL at 4-wk (and not after 6 months of
taking 3 to 6 pills/day) ?
• Why no difference with placebo on Bodily Pain domain (BP) ?
• Number Needed to Treat on the primary endpoint is 20 patients for
one to reduce its heartburn by over 50%
French Drug Agency 2003
•
PROs are not a regulatory issue for EMEA,
but…
• Many PROs such as symptom scales are wellestablished since decades
• But, nobody knows how to assess Pain :
– Which tool ? (evidence of validation)
– When ?
– Period of time ?
– Which question ?
– Minimal important change ?
• Osteoarthritis (10 mm on 0-100 mm VAS ?)
• Irritable Bowel Syndrome (10% difference ?)
Nobody knows if a 9 % difference of
responders in IBS is worth giving a claim?
• Tegaserod / Irritable Bowel Syndrome
• Endpoints:
– “did you have satisfactory relief of your overall IBS
symptoms during last week?”
– “did you have satisfactory relief of your abdominal
discomfort or pain symptoms during last week?”
• Responder : satisfactory relief for at least 3 out of
the 4 first 4 weeks
• Relief of overall IBS symptoms 33.7 vs 24.2
(placebo)  9.3%
• Relief of abdominal discomfort/pain : 31.3 vs 22.1 
9.1%
European mutual procedure (2004-2005)
Because PROs (including HRQL) are
unavoidably part of the Approval decision
Example of an IBS drug (mutual recognition)
• Small difference on pain versus placebo (primary endpoint)
• Tertiary endpoints (quality of life, satisfaction, utility and work
productivity) bring consistency with the other endpoints, and
they may thus reinforce the rather small clinical benefit
observed on the co-primary endpoints, and thus enhance
the benefit/risk ratio
• Not only patients tend to feel a little bit better for pain
and symptoms, but they express a small improvement
in some aspects of their daily life, and they are a little
bit more productive for work
January 2005
5 key issues for Drug Approval Process
HRQL (and PRO) to be considered as a credible criterion
if there is enough evidence (in the file) about the :
1- Added-value of HRQL/PRO with respect to other criteria
2- Psychometric properties of the HRQL/PRO instruments
3- International validation of the HRQL/PRO instruments
4- Adequacy of the statistical analysis plan
5- Clinical significance of observed changes
Based on a meeting with representatives of AFSSAPS, EMEA and ERIQA Working Group, Paris, 1999
Chassany O et ERIQA Working Group. Patient Reported Outcomes (PRO) and Regulatory Issues : A
European Guidance Document for the improved integration of health-related quality of life assessment in
the drug regulatory process. Drug Information Journal 2002.
Review of a dossier : Example of misuse/abuse
Anti-emetic (chimiotherapy)
• National procedure
• Module 2 (clinical overview)
• Claim wanted : « XX gets an advantage in term of
quality of life … »
• Functional Living Index Emesis (FLIE) questionnaire
presented as HRQL (secondary endpoint)
→ 18 items (9 same items for nausea and vomiting)
→ Certainly not multidimensional HRQL
• Interest of measuring so-called HRQL the day after 5 days
of anti-emetic treatment ?
→ very small if any
September 2004
Review of a dossier : Example of misuse/abuse
What are the results 1st study ?
• 2 items with a statistical difference (+ 1 or 2 points on a
7-point scale at p = 0.07) XX vs comparator
• No double-blind
• At least 18 tests
• Relevance of difference ?
• Global score : statistical difference (p = 0.0885)
What are the results 2nd study ?
• No difference XX vs comparator
• Double-blind
• Intent to treat : 200
• FLIE analyzed in only 151-177 patients (n = 131 for
global score)
– Where are patients and why are they missing ?
Review of a dossier : Example of misuse/abuse
Conclusions
•
•
•
•
Useless to measure HRQL at 5 days
FLIE is not measuring HRQL but impact on daily function*
Methodological flaws
The allegation « XX gets an advantage in term of quality
of life … » is not supported by data
• A similar dossier of another anti-emetic (aprepitant)
presented FLIE more as what it is really measuring :
Patient-Reported Impact on Daily Life
*
Guideline on non-clinical and clinical development of medicinal products for the treatement of
nausea and vomiting with cancer chemotherapy, CPMP/EWP/4937/03, February 2005
Guideline européenne sur la qualité de vie
EMEA/CHMP/EWP/139391/2004
Reflection paper on the regulatory guidance
for the use of health-related quality of life
(HRQL) measures in the evaluation of
medicinal products
Adoption by CHMP : July 2005
Date for coming into effect : January 2006
http://www.emea.eu.int
Why there are so few HRQL mention in labelling ?
• The lack of experience and training of the reviewers and
regulators
• The fears (legitimate) of the regulatory authorities to
officially acknowledge the PRO and to take into account a
subjective criterion by nature :
– Whose clinical interpretation remains difficult
– Whose good practices of advertising remain to be
specified in a market where competition is rough
– Without counting the possibility for a drug which
would have shown a substantial benefit on
HRQL/PRO, to have claim in terms of rate of
refunding, or price
Need for improving advertisements
How is defined a
upholding of Well-Being ?
Physical
Well-Being
1 single item ranging
from 0 (very good)
to 4 (very poor)
French Drug Approval (1999)
What were hypotheses ?
In protocol :
Quality of life =
“Time lost from
usual daily
activities”
Better result
in placebo
group :
less time
lost (not
disclosed in
the publication)
Comparison of Proton Pump Inhibitors
in Gastro-oesophageal Reflux Disease
PRO endpoint, as useful as spirometry
What can one wish for the future ?
• Training of reviewers and regulators to HRQL & PRO
WORKMAT : Educational Program for Reviewers
• Appropriation and adaptation by regulatory agencies of
the published recommendations
Guidelines FDA
European Position Paper (EWP) ?
• Questionnaires constantly in adequacy with the beneficial
and harmful effects of the new treatments
• Choice among the various questionnaires, of those which
have the best psychometric properties (responsiveness)
• That HRQL and PRO be part of the daily medical-decision
making
What can one wish for the future ?
Should we develop questionnaires for
specific subgroups (e.g HIV) ?
Women
Quality of life among women living with HIV: the importance violence, social support, and selfcare behaviors. Gielen AC et al. Soc Sci Med 2001.
Injection drug users
Psychological distress and quality of life in drug-using and non-drug-using HIV-infected women.
Vaarwerk MJ et al. Eur J Public Health 2001.
Aging
Successful aging among people with HIV / AIDS. Kahana E et al. J Clin Epidemiol 2001.
Children - adolescents
Evaluation of life quality for children infected by HIV: validation of a method and preliminary
results. Nicolas J et al. Pediatr AIDS HIV Infect 1996.
Family
The family context of HIV: a need for comprehensive health. De Matteo D et al. AIDS Care 2002.
According to religion
Relationships of religion, health status, and socioeconomic status to the quality of life of
individuals who are HIV positive. Flannelly LT et al. Issues Ment Health Nurs 2001.
Measuring HRQL in routine oncology practice
improves communication and patient well-being
• Routine assessment of cancer patients' HRQL had an
impact on physician-patient communication and
resulted in benefits for some patients, who had better
HRQL and emotional functioning
Velikova G, et al. Measuring quality of life in routine oncology practice improves communication and patient well-being: a
randomized controlled trial. J Clin Oncol 2004; 22: 714-724