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Mesure de la qualité de vie liée à l’état de santé

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.

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Mesure de la qualité de vie liée à l’état de santé

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  1. 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, PhDDélégation à la Recherche Clinique (AP-HP)Hôpital Saint-Louis, Paris

  2. 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 »

  3. 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

  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 l’état 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 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 ?)

  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 • 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

  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 d’agrément de la perception d’un symptôme (douleur) entre patients et médecins 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 d’agrément de la perception de la qualité de vie entre patients et médecins 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 r = 0.31 • Cross-sectional survey • 239 IBS patients • 57.5 ± 16 years • 64% women 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 patient’s 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 patient’s 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 < 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 patient’s 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 patient’s 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. 100 90 80 70 60 CIVIQ global score 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 Pain VAS 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 patient’s 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, 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

  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 Proxy Caregiver Family MRC Dyspnea Scale 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 d’évaluation. Rev Mal Respir 2003; 20: S38-41.

  31. 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. 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. 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. 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. 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% Factors associated with severe impact of lipodystrophy on the Quality of Life 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. I’m thinking about stopping treatment Impact of Lipodystrophy (HIV) on Quality of Life Everything is all right, CD4, viral load… I don’t recognize Myself in mirror I look like a monster Everybody can see I’ve 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 CD4 CDC MOS-HIV r=0.2-0.7 r=0.39 r=0.17 r=0.13 p=NS r=0.65 r=0.58 r=0.03 r=0.43 Duracinsky M, Chassany O. Agreement between patients’ and clinicians’-reported outcomes in lipodystrophy (HIV/AIDS). Value in Health 2004; 7: 641

  37. 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 Conclusion

  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 (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.

  39. 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% Health-Related Quality of Life predicts survival 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 • FEV1 • HbA1c • Tumor size • For example • Global • impression • Observation & • tests of function • 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 • • 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.

  43. 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 WOMAC…[…]…is recommended. Secondary endpoints include: Global rating, Flares, Physical signs including range of motion, Quality of Life, Consumption of medications for pain relief Osteoarthritis CPMP/EWP/784/97 PRO PRO HRQL

  44. 5. Recommended primary/secondary efficacy endpoints 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. Irritable Bowel Syndrome (IBS)CPMP/EWP/785/97 (March 2003) PRO HRQL

  45. 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 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 scales, exacerbation rates and QoL assessment. Care should be taken with respect to statistical multiplicity if secondary endpoints become the basis for specific claims. Chronic Obstructive Pulmonary Disease (COPD) CPMP/EWP/562/98 (Dec 1999) PRO HRQL

  46. 3. Tools to measure efficacy (primary or secondary endpoints) 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 generic…) Rheumatoid arthritis CPMP/EWP/556/95 rev 1 (Dec 2003) 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 • • 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.

  49. What is a HRQL questionnaire ? Subjective, multidimensional, self-assessed (whenever possible)

  50. Faut-il choisir un questionnaire générique ou spécifique de qualité de vie ? Chassany O, et al. Gut 1999. 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%

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