Mesure de la qualit

1
Mesure de la qualité de vie liée à létat de
santé
Introduction to Patient-Reported Outcomes
(PROs) March 2-4 2004, Karolinska Institutet,
Sigtuna, Sweden
Olivier CHASSANY, MD, PhDDélégation à la
Recherche Clinique (AP-HP)Hôpital Saint-Louis,
Paris
2
Définition de la Qualité de Vie liée à létat de
santé
Définition de lOMS (dénominateur minimal
commun)  La santé, ce nest pas seulement une
absence de maladie, cest aussi un état total de
bien-être physique, psychologique et
social   La qualité de vie est la perception
qua 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 
3
Définition de la Qualité de Vie liée à létat 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 dune pathologie ou
  condition

4
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
5
Mesure de la Qualité de Vie liée à létat de santé
Une question unique ne suffit pas
 Globalement, quelle est votre qualité de vie
en ce moment ? 
6
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
7
TODAY
Rationale for the Added Value of HRQL in
clinical trials Increased recognition of the
patients 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
?)
8
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

• cancer
• AIDS
• heart failure
• Parkinsons disease
• Alzheimers disease
• asthma
• COPD
• osteoarthritis
• diabetes

• 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

9
The impact on HRQL is not always foreseeable
and is not systematically correlated with the
severity of the disease as perceived by the
medical community
Patrick D, Erickson P. Health status and health
policy. Quality of life in health care evaluation
and resource allocation. Oxford University Press,
1993.
10
The impact on HRQL is not always foreseeable
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.
11
Which are the arguments in favour of HRQL ?
Subjective measure
Objective 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
12
Weak correlation between Patient-Reported
Outcomes and physiological endpoints
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.
13
Correlation between glycemic control and
perception of Quality of Life
Grey M, et al. Personal and family factors
associated with quality of life in adolescents
with diabetes. Diabetes Care. 1998 21 909-914.
14
Niveau dagrément de la perception dun 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
15
Niveau dagrément 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
16
Perception of pain moderate agreement between
IBS patients physicians

• Cross-sectional survey
• 239 IBS patients
• 57.5 16 years
• 64 women

r 0.31
The physician is more disposed to bear the pain
of his/her patient than the patient himself
Tendency of physician to underestimate the pain
Tendency of physician to overestimate the pain
Chassany O, et ALFIS. Added value of patients
perspective in irritable Bowel Syndrome. Qual
Life Res 2003 12 A821
17
Perception of Quality of Life by patients and
clinicians in Irritable Bowel Syndrome
HRQL impairment is over/under estimated by
clinicians in IBS
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
patients perspective in Irritable Bowel
Syndrome. Quality Life Res 2003 12 A821
18
Perception of HRQL by patients and clinicians ?
Survey among 239 IBS patients and 163 clinicians
r 0.43
r 0.30
Daily Activities
Diet
Anxiety
Sleep
19
Perception of HRQL by patients and clinicians ?
Survey among 239 IBS patients and 163 clinicians
Social Life
Control
Coping
Stress
20
Perception of pain and HRQL by patients with IBS
r 0.63, p lt 0.0001
239 IBS patients 57.5 16 years 64 of women
Global FDDQL 56.1 11.6
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
patients perspective in Irritable Bowel
Syndrome. Quality Life Res 2003 12 A821
21
Perception of pain by patients and clinicians in
Chronic Venous Insufficiency
r 0.27
Pain perception is underestimated by clinicians
in CVI
0 best Pain 10 worst Pain
22
Perception of Quality of Life by patients and
clinicians in Chronic Venous Insufficiency
HRQL impairment is underestimated by clinicians
CIVIQ 20 items / 4 domains, score 0-100 (worst
HRQL)
Chassany O, Le Jeunne P, et ALFIS. Added value of
patients perspective in Chronic Venous
Insuffisiency
23
Perception of Quality of Life by patients and
clinicians in Chronic Venous Insufficiency
Impact of pain
Physical Function
Patients
Patients
r 0.29
r 0.28
Physicians
Physicians
Social Function
Psychological Function
r 0.23
r 0.23
Patients
Patients
Physicians
Physicians
CIVIQ patients 0 best QoL 100 worst QoL -
QoL physicians 0 10 maximal impact
24
Perception of Quality of Life by patients and
clinicians in Chronic Venous Insufficiency
Global QoL score
Patients
r 0.33
Physicians
CIVIQ patients 0 best QoL 100 worst QoL
QoL physicians 0 10 maximal impact
25
Correlation of pain versus Quality of Life in
patients with Chronic Venous Insufficiency
Patients pain vs QoL
r 0.78
CIVIQ 0 best QoL 100 worst QoL Pain VAS
0 10 worst pain
26
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
Pain from 0 to 10 worst pain
27
Perception of HRQL by patients and clinicians in
Peripheral Arteriopathy Occlusive Disease
HRQL impairment is over-estimated by clinicians
CLAU-S 43 items / 5 domains, score 0-100 (best
HRQL)
Chassany O, Le Jeunne P, et ALFIS. Added value of
patients perspective in Arteriopathy
28
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, patients perception of pain cannot
  completely reflect the impact of QoL
• Symptoms (e.g. pain) and QoL although overlapping
  to some extent measure different concepts
• Patients perspective is a major outcome in the
  evaluation of therapies

29
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.
30
Cystic fibrosis Correlation between different
endpoints
Clinician- Reported
Patient- Reported
Physiological
Caregiver
FEV1
HRQL (QWB, SIP)
High resolution CT
SaO2
Maximal Capacity Exercise
MRC Dyspnea Scale
Proxy Caregiver Family
Satisfaction
0.75
0.57
0.84
0.33-0.40
0.40
Chassany O. De la maladie chronique à la qualité
de vie. Méthodes dévaluation. Rev Mal Respir
2003 20 S38-41.
31
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.
Correlation between adolescent pulmonary function
(FEV1) and perception of health
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.
32
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.
Correlation between adolescent vs mother and
father reports of perceived adolescent Health
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.
33
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
34
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 their HRQL
• Influenced dressing 65
• Produced feeling of shame 49
• Disrupted Sexual life 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.
35
Impact of Lipodystrophy (HIV) on Quality of Life
Everything is all right, CD4, viral load
I dont recognize Myself in mirror
I look like a monster
Everybody can see Ive got HIV
I need a plastic Surgery
36
The impact of Lipodystrophy (HIV) on HRQL is not
adequately captured by other criteria
International Classification
Patient-Reported Outcomes (PROs)
Biological Markers
Clinician- Reported
Lipodystrophy Sign Score
Lipodystrophy Satisfaction Score
Viral Load
SF-12
Lipodystrophy Specific HRQL ABCD Score
Lipodystrophy Sign Score
CDC
CD4
MOS-HIV
r0.2-0.7
r0.39
r0.17
r0.13
pNS
r0.65
r0.03
r0.58
r0.43
Duracinsky M, Chassany O. Agreement between
patients and clinicians-reported outcomes in
lipodystrophy (HIV/AIDS). Value in Health 2004
7 641
37
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

38
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 (95CI 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.
39
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.
40
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
41
Place of Patient-Reported Outcomes (PRO)
Patient Outcomes AssessmentSources and Examples
Patient- Reported
Clinician- Reported
Caregiver- Reported
Physiological

• Global Impression
• Functional status
• Well-being
• Symptoms
• HRQL
• Satisfaction with TX
• Treatment adherence

• For example
• Global
• impression
• Observation
• tests of function

• For example
• FEV1
• HbA1c
• Tumor size

• For example
• Dependency
• Functional
• status

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
42
Define the conditions for which the measurement
of HRQL/PRO in clinical trial is useful
Patients 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,
Parkinsons 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.
43
Osteoarthritis CPMP/EWP/784/97

• II. Recommended primary/secondary efficacy
  endpoints
• a) Symptom modifying drugs
• 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 WOMACis recommended.
• Secondary endpoints include
• Global rating, Flares, Physical signs including
  range of motion, Quality of Life, Consumption of
  medications for pain relief

PRO
PRO
HRQL
44
Irritable Bowel Syndrome (IBS)CPMP/EWP/785/97
(March 2003)

• 5. Recommended primary/secondary efficacy
  endpoints
• Primary The patients 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.

PRO
HRQL
45
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.
• The Primary symptomatic benefit endpoint should
  be justified by referencing published data which
  support its validity one example is the St
  Georges 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 scales, exacerbation rates and
  QoL assessment.
• Care should be taken with respect to statistical
  multiplicity if secondary endpoints become the
  basis for specific claims.

PRO
HRQL
46
Rheumatoid arthritis CPMP/EWP/556/95 rev 1 (Dec
2003)

• 3. Tools to measure efficacy (primary or
  secondary endpoints)
• d) Patients global assessment of disease
  activity (VAS)
• e) Pain score (patients 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 generic)

PRO
HRQL
47
Checklist for designing, conducting and reporting
HRQL - PRO in clinical trials

• HRQL / PRO objectives
• Added value of HRQL / PRO
• Choice of the questionnaires
• Hypotheses of HRQL / PRO changes
• Study design
• Basic principles of RCT fulfilled ?
• Timing and frequency of assessment
• Mode and site of administration...
• HRQL / PRO measure
• Description of the measure (items, domains)
• Evidence of validity
• Evidence of cultural adaptation

• Statistical analysis plan
• Primary or secondary endpoint
• Superiority or equivalence trial
• Sample size
• ITT, type I error, missing data
• Reporting of results
• Participation rate, data completeness
• Distribution of HRQL / PRO scores
• Interpreting the results
• 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.
48
Define the conditions for which the measurement
of HRQL/PRO in clinical trial is useful
Patients 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,
Parkinsons 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.
49
Subjective, multidimensional, self-assessed
(whenever possible)
What is a HRQL questionnaire ?
50
Chassany O, et al. Gut 1999.
Faut-il choisir un questionnaire générique ou
spécifique de qualité de vie ?
Étude chez 1032 patients ayant une colopathie
fonctionnelle
Functional Digestive Disorders Quality of Life
(FDDQL)
SF-36 questionnaire générique
- Fonction physique - Limitations physiques -
Douleur - Santé générale - Vitalité - Fonction
sociale - Etat émotionnel - Santé mentale 36
items (8 dimensions)
- Activités quotidiennes - anxiété - Sommeil -
Alimentation - Réaction face à la maladie -
Contrôle de la maladie - Impact du stress 43
items (8 dimensions)
Sommeil perturbé 83 Prise d hypnotiques 65
Restrictions alimentaires 83 Très gênantes
65
51
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.
52
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
53
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.
54
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.
55
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) 36 8 Likert (Medical outcomes
Survey) PGWB Psychological General 22 6 Likert
Well-Being Binary responses are unlikely to
be sensible enough to detect a small change
56
Attention à la longueur des questionnaires
Nom du questionnaire Nb ditems
SIP Sickness Impact Profile (questionnaire générique) 136
DSQOLS Diabetes Specific Quality of Life Scale 64
DCP Diabetes Care Profile 234
NEWSQOL Newcastle Stroke-Specific Quality of Life Measure 56
SIS Stroke Impact Scale 64
HOPES HIV Overview of Problem situations 103-176
AIDS-HAQ AIDS Health Assessment Questionnaire 116
57
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
• Jai des difficultés à entrer en contact avec
  les autres
• Jai limpression de navoir personne de proche
  à qui parler
• Jai du mal à faire face aux événements
• Jai limpression dêtre une charge pour les
  autres
• Je trouve que la vie ne vaut pas la peine dêtre
  vécue !
• cest plus une échelle de dépression que de
  qualité de vie

58
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.
What are we measuring ?

• Improvement of lung function (FEV1, p lt 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 ?

59
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.
60
(No Transcript)
61
MOS-HIV

• Très SF-36
• Très physique
• Reflètant plus létat 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.
62
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 dargent pour satisfaire vos
  besoins ?
• Êtes-vous satisfait de vos moyens de transport ?
• Êtes-vous satisfait de lendroit où vous vivez ?

O Connell K et al. Preliminary development of
the World Health Organisations Quality of Life
HIV instrument (WHOQOL-HIV). Analysis of the
pilot version. Social Science Medicine 2003.
63
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 dénergie dans la vie de tous les
  jours ?
• Avez-vous le sentiment dêtre 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 Organisations Quality of Life
HIV instrument (WHOQOL-HIV). Analysis of the
pilot version. Social Science Medicine 2003.
64
Who measures what ?
Complaint score (32 items) Self Health Status
Index (5 items) Inter Work satisfaction (7
items) Inter Psychological General
Well-Being (22 items) Self Profile of Mood
Status Self Life satisfaction (3
items) Self Psychomotor function Inter Sleep
(7 items) Self Sexual function (6
items) Self Life events (8 items)
Quality of life with three antihypertensive
treatments.Fletcher AE et al. Hypertension 1999
19 499-507.
65
Who measures Well-Being ? Clinicians ??
N 30
Analysis of Well-Being between indapamide and
captopril.Lacourciere Y. Am J Med 1988 84
47-51.
66
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...

67
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...

68
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...

69
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...

70
From Pr Ingela Wiklund (AstraZeneca)
71
To follow the rigorous procedures of development
of HRQL or PRO questionnaires
Factorial analysis ABCD Score
ABCD score vs nb of lipodystrophy regions
Item generation Scaling Item reduction
Reproductibility Content validity Construct
validity Discriminant validity Convergent
validity Responsiveness Cultural adaptation
Scientific Advisory Committee of the Medical
Outcomes Trust. Assessing health status and
quality-of-life instruments attributes and
review criteria. Qual Life Res 2002
72
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.
73
Determinants of the Quality of Life
Various factors involved in the multidimensional
HRQL construct
Personality traits
Social support
2nd illness
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.
74
Items about DIET can express different concepts
Input of patients in item generation is critical
Diabetes --gt Cause --gt Food --gt consequence --gt
DIET
I am able to keep my diet regimen under
control My diabetes and its treatment (e.g.
diet) keeps me going out with friends / to
restaurant / as much as I want I find it hard
to do all the things (e.g. diet) I have to do for
my diabetes
Control of disease / self-management
Interference with social and personal
relationships
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.
75
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 lidée 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.
76
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 lannée 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
77
Item scaling of HRQL questionnaires ?
78
Item scaling of HRQL questionnaires ?
Jamais
Tout le temps
Quelquefois
Rarement
Très souvent
79
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
• 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

0? Pas du tout 1? Un petit peu 2? Moyen
3? Beaucoup 4? Enormément
80
Factorial analysis of Assessment of Body Change
and Distress (ABCD) in Lipodystrophy (HIV/AIDS)
Factorial analysis (n 143) Lipodystrophy score
(6 items)
Correlation matrix
Factors
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)
81
Factorial analysis of Assessment of Body Change
and Distress (ABCD) in Lipodystrophy (HIV/AIDS)
Factors

• 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)
82
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)

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.
83
Discriminant validity of the Functional Digestive
Disorders Quality of Life questionnaire (FDDQL)
International study France, Germany, Great
Britain 391 IBS and dyspeptic patients
Chassany O, et al. Gut 1999.
84
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 (n6)
• Raynauds phenomenon
• Digital ulcers
• Gastro-intestinal
• Pulmonary
• Musculoskeletal
• Hand contracture

Comparison using ANOVA (p lt 0.0001 for both
scores) (n100 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.
85
Discriminant validity of a Lipodystrophy specific
quality of life questionnaire
Global Quality of Life score (ABCD) impairs with
the number of sites of lipodystrophy (n 155)
score min-max  0-100 0 worse quality of
life, 100 good quality of life ANOVA, p lt 0.001
r 0.39
Duracinsky M, Chassany O. Linguistic and
psychometric validation in french of a specific
quality of life questionnaire in Lipodystrophy
(ABCD)
86
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)
vs Physical Component Summary (PCS), r 0.101
vs Mental Component Summary (MCS), r 0.65
Duracinsky M, Chassany O. Linguistic and
psychometric validation in french of a specific
quality of life questionnaire in Lipodystrophy
(ABCD)
87
Convergent validity of a Lipodystrophy specific
quality of life questionnaire
Logical correlation between some dimensions of
the MOS-HIV, e.g. the health distress, mental
health and social function (r gt 0.6)
88
Sensibilité au changement - Questionnaire
déducation dans lasthme (CHU Montpellier)
Évolution des scores entre la première (n 96),
la 2e (n 67) et la 3e visite (n 21) au cours
dun programme déducation
Scores des 6 domaines explorant le comportement
face à des scénarios cliniques
Scores des 2 domaines explorant les connaissances
Score global
89
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

90
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 laise
? 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 (FDDQL). Gut 1999.
Chassany O, et al. Gut 1999.
91
Disease Asthma - Original version developed in
CanadaItem Here is a list of activities in
which some people with asthma are limited, among
them  shoveling snow 
Cultural adaptation - forward/backward

• Canada (US) Shoveling the snow
• Japan
• Norwegian

92
Disease Asthma - Original version developed in
CanadaItem Here is a list of activities in
which some people with asthma are limited, among
them  shoveling snow 
Cultural adaptation - forward/backward

• Canada (US) Shoveling the snow
• Japan Beat futons
• Norwegian

93
Disease Asthma - Original version developed in
CanadaItem Here is a list of activities in
which some people with asthma are limited, among
them  shoveling snow 
Cultural adaptation - forward/backward

• Canada (US) Shoveling the snow
• Japan Beat futons
• Norwegian Going fishing

94
Cultural adaptation
Cultural Adaptation
95
Cultural adaptation of Assessment of Body Change
and Distress (ABCD) in Lipodystrophy (HIV/AIDS)
Questionnaire ABCD Item Q8c (Problème de la
traduction de upset) 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)
96
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
97
Bristow MR et al. Circulation 1996.
Responsiveness - specific questionnaires
Specific questionnaire responsiveness ?HRQL is
not improved by drugs in Chronic heart failure ?
Double-blind, placebo-controlled trial (n345), 6
months, 3 doses of carvedilol (beta-blocker)
98
Responsiveness - generic questionnaires
Psychological General Well-Being (PGWB)
GERDHRQL is not improved by gastro-oesophageal
reflux disease drugs ?
24 difference in pyrosis relief
No difference in PGWB score
Galmiche JP, et al. Aliment Pharmacol Ther 1997. .
99
Is health-related quality of life among older,
chronically ill patients associated with
unplanned readmission to hospital ?
Predictive value of Quality of Life ?
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 lt 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
100
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.
101
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.
102
Validated scale is not enough

• A validated scale doesnt 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

103
Importance of various areas of limitations due to
asthma among Harlem emergency department users (n
247)mostly Afro-american patients with a low
socio-economic status and a lower compliance
Choice of a PRO questionnaire - Importance of the
sample included during the validation process
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.
104
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.
105
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
106
Statistical analysis plan Estimating the
adequate sample size

• HSQ (Health Status Questionnaire)
• before / after scores on 1300 patients
• All p values lt 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)
107
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.
108
Statistical analysis plan PRO multiplicity
Salmeterol / COPD Open label Salmeterol 50 ?g
or SR Theophylline bid Randomized (n
178) Completers (n 145) HRQL (secondary)
SF-36 Mean changes between baseline and the 4
assessments over time, for each dimension
Student t test
Efficacy, tolerability and effects on HRQL of
inhaled Salmeterol in COPD. Di Lorenzo G et al.
Clin Ther 1998.
109
Interpreting PRO results ?
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.
110
How to evaluate drugs when clinical relevance of
results is not obvious ?
Mean score SD
p lt 0.05 and IC95
Pain VAS
HRQL
Responders
MID
YES
?
p lt 0.05
OK
111
Interpretation of results - Effect size
Treatment in claudication (Peripheral Arterial
Occlusive Disease) Phase III, randomized,
double-blind, vs placebo
Effect size (Distribution-based
approach) Dividing a difference between 2 groups
by the SD
Dossier for Drug Approval
File for Approval - AFSSAPS
112
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)
Effect size (Distribution-based
approach) Dividing a difference between 2 groups
by the SD
File for Approval - AFSSAPS
113
Minimal Important Difference (MID)
MID obtained from comparison with a Global Rating
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
114
DEPENDS ON WORDING
Minimal Important Difference (MID) or change

• 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.
115
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 gt 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.
116
Minimal Important Difference (MID)

• (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)

117
How many and which PRO domains should improve for
a claim ?
234 Patients with Peripheral Arteriopathy
Occlusive Disease (PAOD) HRQL primary endpoint
using the specific questionnaire CLAU-S (9
domains, 80 items) Results 2 domains
significantly improved with drug (daily life,
p0.004 pain, p0.001) Should the planners
have hypothesized that only these 2 domains would
improve?
The effects of naftidrofuryl on quality of life.
Liard F et al. Dis Manage Health Outcomes 1997.
118
How many and which PRO domains should improve for
a claim ?

• J3 J12
• Symptoms
• - Chest pain NS NS
• - Shortness of breath lt0.05 NS
• - Dizziness NS NS
• - Palpitation lt0.05 NS
• - Cognitive ability NS NS
• Alertness NS NS
• Quality of sleep NS NS
• Physical ability NS NS
• Daily ability NS NS
• Depression NS NS
• Self perceived health NS NS
• Ladder of life future NS NS
• Fitness lt0.05 NS
• Physical activity lt0.01 NS

• 90 (6 x 15) statistical tests
• Difference of 0.2 (range 1-7) at 3 months
• No difference at 12 months
• Abstract Aerobic group-training of elderly
  patients recovering from an acute coronary event
  beneficially influences physical fitness and
  several parameters expressing quality of life

Stahle A et al. Improved physical fitness and
HRQL following training after acute coronary
events. Eur Heart J 1999.
119
How many and which PRO domains should improve for
a claim ?

• Antacid in GERD
• Randomized, placebo-controlled, double-blind
  trial
• Primary endpoint heartburn (diary)
• Secondary endpoint SF-36 questionnaire
• Sample size gt 230
• Duration 28 days

• 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
120
PROs are not a r