IAS 2013 - SymposiumHealth-Related Quality of Life

Why and how ?

Pr Olivier CHASSANYPatient-Reported Outcomes Research Unit, University Paris 7 & Hôpital Saint-Louis

Health : "A state of complete physical, mental, and socialwell-being not merely the absence of disease”

(World Health Organization (WHO) 1948)

“The value assigned to duration of life as modified by the impairments, functional states, perceptions and social opportunities that are influenced by disease, injury, treatment, or policy”

(Pr Donald Patrick, Seattle, USA)

Assessment of HRQL is:• Subjective (patient’s perception)• Self-reported in most conditions• Multidimensional

Health-Related Quality of Life (HRQL) - Definition

FDA & EMA Guidance on assessment of PRO/HRQL in clinical trials of drugs

2006http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003637.pdf

2009http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf

PRO HRQLFDA

Why should we measure the perception of patients in clinical trials ?

• Changes in the therapeutic targets in the growing context of chronic diseases and palliative treatment in a rising old population

• Cancer• HIV/AIDS• Heart failure• Parkinson’s disease • Alzheimer’s 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 / conditions

1. “Objective” markers versus PROs

2. Clinician-Reported Outcomes and proxies/caregivers versus PROs

3. Between PROs

What is the agreement between different perspectives ?

“Objective” measure Exercise test versus physical functioning, r = 0.40

“Subjective” measure

Wiklund I et al. Clin Cardiol 1991. Slide presented with the authorization of Pr Ingela Wiklund

“Objective” marker versus PRO

© Pr Ingela Wiklund

Patients39.0 ± 24.9(n=232)

GPs30.4 ± 21.0(n=307)

Difference8.6 (28%)

CorrelationKw = 0.31 (n=232)

Clinicians underestimate pain severity(Irritable Bowel Syndrome - IBS)

All values under the equality line indicate GP underestimation of pain by GPsPain values ranged between 0 (no pain) and 100 (severe pain)

Chassany O, Duracinsky M, et al. Discrepancies between PROs and Clinician-Reported Outcomes in chronic venous disease, irritable bowel syndrome, and peripheral arterial occlusive disease. Value in Health 2006.

Bendtsen P. Measuring health-related quality of life in patients with chronic obstructive pulmonary disease in a routine hospital setting: Feasibility and perceived value. Health Qual Life Outcomes. 2003

Patients' perception adds an information that is not captured by physicians or “objective” markers

The impact on HRQL is not always foreseeable

0 5 10 15 20 25 30 35

Overall Sickness Impact Profile score

Amyotrophic lateral sclerosis

Chronic pain non-responders

Oxygen dependent COPD

Chronic low back pain

Back pain

Physically disabled adults

Non-oxygen dependent COPD

Rheumatoid arthritis

End-stage hemodialysis

Hypothyroidism

Crohn's

Angina

Myocardial infarct

Ulcerative colitis

Moderate obesity

General population

Cardiac arrest

Group health enrolleesbetter HRQL lower HRQL

and is not systematically correlated with the severity of

the disease as perceived by the medical community

Good HRQL Bad HRQL

Patrick D, Erickson P. Health status and health policy. Quality of life in health care evaluation and resource allocation. Oxford University Press, 1993.

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 & 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.

Health Scale Mothers FathersGeneral health 0.66 0.57Physical functioning 0.69 0.31Role/social-physical 0.62 0.49Bodily pain 0.69 0.37Role/social-emotional -0.12 0.24Role/social-behavior 0.48 0.17Mental health 0.33 0.48Family activities 0.45 -0.09Self-esteem 0.41 0.65Behavior problems 0.71 0.66

Pain values ranged between 0 (no pain) and 100 (severe pain)QoL scores ranged between 0 (bad QoL) and 100 (good QoL)

Patients’ perception : Pain only partially reflected HRQL (Irritable Bowel Syndrome)

Patient-assessed QoL decreased as patient-assessed pain increased (r=0.71). However, patient-assessed QoL scores varied drastically for a given pain intensity, suggesting that pain intensity only partially reflected QoL.

4.1.2. Patient’s assessed outcome measures (cont’d)Efficacy of a new drug evaluated by patient is important when … even relatively limited extent of skin psoriasis may severely socially and psychologically disable the patient.

The assessment of HRQL scales specific for psoriasis may represent an added value for a new drug in comparative clinical trials, in addition to classical efficacy/safety measures. Patient-assessed drug efficacy may be a secondary or tertiary endpoint in pivotal clinical trial.

… Ideally, trials assessing psoriasis-specific HRQL should be designed to assess patient’s perspective in the evaluation of drug-effect in order to understand better the clinical significance of the benefit observed and to be sure that the administered treatment does not impact adversely on patient’s HRQL.

EMA guidelines : Psoriasis : Note for GuidanceCPMP/EWP/2454/02 (Nov. 2003)

HRQL

From Pr Ingela Wiklund (UBC)

Chassany O, et al. Validation of a specific QoL in functional digestive disorders (FDDQL). Gut 1999; 44: 527-533

1. Physical functioning2. Physical role functioning3. Bodily pain4. General health5. Vitality 6. Social role functioning7. Emotional role

functioning8. Mental health

Sleep and diet disturbances (83%)

Generic SF-36• 36 items• 8 domains

Irritable Bowel Syndrome

Functional Digestive Disorders Quality of Life (FDDQL)• 43 items (8 domains)

1. Daily activities 2. Anxiety3. Sleep4. Diet5. Abdominal Discomfort6. Coping with disease7. Control of disease8. Stress

Generic or specific questionnaire ? Importance of the content validity

- A “validated” scale doesn’t imply that it is relevant for the population studied- A single item is inadequate to capture all the aspects of HRQL

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

8,1%

10,9%

17,0%

17,4%

19,4%

20,2%

23,9%

26,3%

26,7%

26,7%

27,9%

27,9%

28,7%

28,7%

29,1%

31,6%

32,4%

37,2%

41,7%

Playing w ith pets

Bicycling

Singing

Playing sports

Jogging, exercising, or running

Mopping or scrubbing the f loor

Visiting w ith friends or relatives

Going for a w alk

Dancing

Doing home maintenance

Doing regular social activities

Cooking

Carrying groceries

Talking

Playing w ith children

Walking one block

Having sex

Doing housew ork

Climbing upstairs

Content validity - 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.

Number of lipodystrophy regions

6543210

Me

an

AB

CD

sco

re 100

90

80

70

60

50

40

30

20

10

0

4245

5456

64

71

85

Score de qualité de vie ABCD

100806040200Score

résum

é m

enta

l du S

F-1

2 (

MC

S)

70

60

50

40

30

20

10

ABCD vs Mental Component Summary (MCS) SF-12, r=0.65

Rigorous process of development & validation of HRQL & PRO questionnaires

• Content validity• Item generation• Scaling• Item reduction• Reproductibility• 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

Factorial analysis ABCD ScoreFactorABCD

20items 1 2 3 4a ,723 ,084 ,284 ,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

ABCD score vs nb of lipodystrophy regions

Conceptual Framework of Patient-Reported Outcomes in Paroxysmic Nocturnial Haemoglobinluria (PNH)

Cross-sectional study (n between 28 and 38)FSI: Fatigue Symptom InventoryBPI: Short form Brief Pain InventoryPSQ: Pittsburgh Sleep Quality IndexSTAIS: State-Trait Anxiety InventoryBDI: Beck Depression InventoryQoL: EORTC QLQ-C30 global score

Anaemia Fatigue

Sleep

Pain

Depression

Anxiety

QoLr = 0.241

0.452

0.419

0.589

0.644

0.786

Fatigue predicted by:• Pain• Sleep impairment• Anxiety / depression

Higgins, Stern, Penn State University

Fatigue Symptom Inventory• Rate how much of the day, on average, you felt fatigued

in the past week

St-George Respiratory Questionnaire (50 items)• Over the last year, in an average week, how many good

days (with little chest trouble) have you had

Fatigue symptom inventory

Understanding of items must be checked with patients

Interpretation of HRQL & 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.

What does mean this HRQL difference ?

Active treatment vs Placebo p

Daytime symptoms (0 to 3) - 0.14 < 0.001Nighttime awakening (per wk) - 0.63 < 0.001beta2 agonist use (puffs/day) - 0.64 < 0.001

FEV1 0.05 0.331Morning PEF (BL : 362) + 13,1 L/min < 0.001Evening PEF (BL : 398) + 11,5 L/min < 0.001

Global AQLQ score (BL : 4.28, range score 1-7) + 0.26 0.004

How to interpret PRO – HRQL results when relevance is not obvious ?

Mean score difference ± SD (p < 0.05) between 2 groups

MIDMinimal Important

Difference

Responders (%)

NNTNumber Needed to Treat

Effect Size

Anchor-basedDistribution-

basedPopulation-

based

Relate changes on a HRQL measure to known population

norms

Differences or changes for HRQL are inevitably smaller that for other endpoints (e.g. symptoms) being an indirect measure of the diseaseBut different interpretations will not save a small mean difference between groups

Minimal Clinically Important Difference (MID)

• Smallest difference in measure patients perceive as beneficial, and would mandate, in the absence of troublesome side effects and excessive cost, a change in patient’s management.

• Difference on HRQL corresponding to smallest change in status that shareholders (patients, clinicians, ...) consider important

Patrick DL, Erickson P: Health Status and Health Policy. Oxford University Press. New York 1993. pp 422-3Jaeschke R, Singer J, Guyatt GH: Measurement of health status - ascertaining the minimal clinically important difference. Controlled Clinical Trials. 1989; 10:407:415

Minimal Important Difference (MID)Mapping Changes in PROs scores to a single question

Guyatt GH, Juniper EF. Several publications

* Overall, has there been any change in your shortness of breath during your daily activities since the last time you saw us ?

Answer to the GLOBAL RATING change from -7 to +7*

Worse Better Interpretation of change

Mean change in HRQL scale (range 1-7)

A very great deal - 7 + 7 Large 1.5

A great dealA good dealModerately

- 6- 5- 4

+ 6+ 5+ 4

Moderate 1.0

SomewhatA little

- 3- 2

+ 3+ 2 Small 0.5

Almost the same - 1 + 1

About the same

23

Minimal Important Difference

(MID)

Comparison between

groups

Definition of responders

Comparison of 2 means

Comparison of 2 percentages

AQLQ(Asthma)

[1-7]0.5

Improvement higher than 0.5 (depends on

baseline value)

Number NeededTo Treat (NNT)

When defining a meaningful change on an individual patient basis (i.e. a responder), that definition is larger

than the MID for group mean comparison

Not the same

24

Minimal Important Difference

(MID)

Comparison between

groups

Definition of responders

Comparison of 2 means

Comparison of 2 percentages

PAIN(Osteoarthritis)

VAS (0-100)

10-20%10-15 mm (VAS)

30-50% decreasevs. baseline or value < 30 mm

Number NeededTo Treat (NNT)

When defining a meaningful change on an individual patient basis (i.e. a responder), that definition is larger

than the MID for group mean comparison

Not the same

Adjunctive treatment of partial-onset seizures in patients with epilepsy ≥ 12 years

European Approval (07/2012)

• Fycompa (perampanel)• Clear dose response for adverse events, captured by global assessments

European public assessment report (EPAR) - http://www.ema.europa.eu

Placebo 8mg 12mg

50% responder (frequency)

19% 35% 35%

SAE 5,6% 8,2%

Discontinuation for SAE

1,4% 4,2% 13,7%

CGIC * 27,4% 43,2% 35,7%

PGIC * 38,5% 51,6% 46,5%

* Much or very much improved CGIC - Clinical Global Impression of Change PGIC - Patient Global Impression of Change

• “The benefit on patients’ survival seen in the study was very limited and it did not outweigh the risk associated with the combination of erlotinib and gemcitabine, given the side effects of the treatment.”

EMA refusal of the marketing authorisation for TARCEVAerlotinib - EMA/284207/2006

HRQL• “The study did not show any improvement in

the quality of life of the patients treated.

• EMA major concerns for refusal of the marketing authorisation to TARCEVA in pancreatic cancer ?

• A clinical endpoint is an aspect of a patient’s clinical or health status that is measured to assess the benefit or harm of a treatment. A clinical endpoint describes a valid measure of clinical benefit due to treatment: the impact of treatment on how a patient feels, functions and survives.

Final EunetHTA guideline, Feburary 2013

European Network HTA Joint ActionWP5 - Methodology guidelines

”Clinical endpoints”

HTA : Health Technology AssessmentFor reimbursement purpose

Future: ePRO & eHealth