1. 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 Olivier CHASSANY, MD, PhD Délégation à la Recherche Clinique (AP-HP) Hôpital Saint-Louis, Paris

2. 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

3. 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 Définition de la Qualité de Vie liée à l’état de santé

4. “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 Definition of Health-Related Quality of Life (HRQL)

5. Une question unique ne suffit pas : « Globalement, quelle est votre qualité de vie en ce moment ? » Mesure de la Qualité de Vie liée à l’état de santé

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. 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. The impact on HRQL is not always foreseeable

11. “Objective” measure Exercise test versus physical functioning, r = 0.40 “Subjective” measure Wiklund I et al. Clin Cardiol 1991. Which are the arguments in favour of HRQL ? Slide presented with the authorization of Pr Ingela Wiklund

12. Weak correlation between Patient-Reported Outcomes and physiological endpoints Quality of life in elderly patients with COPD: measurement and predictive factors. Yohannes AM et al. Resp Med 1998. Symptoms BPQ : Breathing Problems Questionnaire HRQLCRQ : Chronic Respiratory Disease Questionnaire  Variability in exercise capacity contributed to only 3% of the variability in BPQ score

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 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 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

16. Cross-sectional survey 239 IBS patients 57.5 ± 16 years 64% women Perception of pain : moderate agreement between IBS patients & physicians r = 0.31 Chassany O, et ALFIS. Added value of patient’s perspective in irritable Bowel Syndrome. Qual Life Res 2003; 12: A821 Tendency of physician to underestimate the pain Tendency of physician to overestimate the pain The physician is more disposed to bear the pain of his/her patient than the patient himself

17. Perception of Quality of Life by patients and clinicians in Irritable Bowel Syndrome Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Irritable Bowel Syndrome. Quality Life Res 2003; 12: A821 FDDQL : Functional Digestive Disorders Quality of Life 43 items / 8 domains, score 0-100 (best HRQL) HRQL impairment is over/under estimated by clinicians in IBS

18. r = 0.43 r = 0.30 Perception of HRQL by patients and clinicians ? Survey among 239 IBS patients and 163 clinicians 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. 239 IBS patients 57.5 ± 16 years 64% of women Global FDDQL: 56.1 ± 11.6 Perception of pain and HRQL by patients with IBS r = 0.63, p < 0.0001 Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Irritable Bowel Syndrome. Quality Life Res 2003; 12: A821 FDDQL : Functional Digestive Disorders Quality of Life 43 items / 8 domains, score 0-100 (best HRQL)

21. Perception of pain by patients and clinicians in Chronic Venous Insufficiency Pain perception is underestimated by clinicians in CVI 0 [best Pain] – 10 [worst Pain] r = 0.27

22. Perception of Quality of Life by patients and clinicians in Chronic Venous Insufficiency Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Chronic Venous Insuffisiency CIVIQ : 20 items / 4 domains, score 0-100 (worst HRQL) HRQL impairment is underestimated by clinicians

23. r = 0.29 Physical Function Perception of Quality of Life by patients and clinicians in Chronic Venous Insufficiency Physicians Patients Impact of pain Physicians Patients r = 0.28 Social Function Physicians Patients r = 0.23 Psychological Function Physicians Patients r = 0.23 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 Physicians Patients r = 0.33 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 CIVIQ : 0 [best QoL] – 100 [worst QoL] Pain VAS : 0 – 10 [worst pain] Patients : pain vs QoL r = 0.78

26. Perception of pain by patients and clinicians Results of a survey in 3 chronic diseases Pain : from 0 to 10 [worst pain] Pain perception is underestimated by clinicians in irritable bowel syndrome (IBS) and chronic venous insufficiency and overestimated in peripheral arteriopathy

27. Perception of HRQL by patients and clinicians in Peripheral Arteriopathy Occlusive Disease Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Arteriopathy CLAU-S : 43 items / 5 domains, score 0-100 (best HRQL) HRQL impairment is over-estimated by clinicians

28. 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 Patient-reported Outcomes (PROs) are in many conditions as important as other outcomes

29. Weak correlation between HRQL & symptoms Chassany et al. Validation of a specific quality of life questionnaire in functional digestive disorders (FDDQL). Gut 1999. 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) …

30. High resolution CT SaO 2 FEV 1 Maximal Capacity Exercise MRC Dyspnea Scale Proxy Caregiver Family Satisfaction HRQL (QWB, SIP) Physiological Clinician- Reported Caregiver Patient- Reported 0.84 0.75 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. Cystic fibrosis : Correlation between different endpoints

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. 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 Psycho-social impact 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 dressing65% –Produced feeling of shame49% –Disrupted Sexual life27% 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 look like a monster I don’t recognize Myself in mirror Everybody can see I’ve got HIV I’m thinking about stopping treatment Everything is all right, CD4, viral load… I need a plastic Surgery Impact of Lipodystrophy (HIV) on Quality of Life

36. The impact of Lipodystrophy (HIV) on HRQL is not adequately captured by other criteria Viral Load CDC Lipodystrophy Sign Score Lipodystrophy Sign Score Lipodystrophy Satisfaction Score Lipodystrophy Specific HRQL ABCD Score Biological Markers International Classification Clinician- Reported Patient-Reported Outcomes (PROs) r=0.17 p=NS r=0.13 r=0.03 MOS-HIV SF-12 r=0.58 r=0.2-0.7 r=0.65 r=0.39 CD4 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. 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 (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. 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 : MHSPHS 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- Reported Clinician- Reported Global Impression Functional status Well-being Symptoms HRQL Satisfaction with TX Treatment adherence For example Global impression Observation & tests of function Caregiver- Reported For example Dependency Functional status Physiological For example FEV 1 HbA1c Tumor size Patient Outcomes Assessment Sources and Examples 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 HRQL PRO

44. Irritable Bowel Syndrome (IBS) CPMP/EWP/785/97 (March 2003) 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. 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. Subjective, multidimensional, self-assessed (whenever possible) What is a HRQL questionnaire ?

50. Chassany O, et al. Gut 1999. - Fonction physique - Limitations physiques - Douleur - Santé générale - Vitalité - Fonction sociale - Etat émotionnel - Santé mentale 36 items (8 dimensions) Sommeil perturbé : 83% Prise d ’hypnotiques : 65% SF-36 questionnaire générique Étude chez 1032 patients ayant une colopathie fonctionnelle 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) Restrictions alimentaires : 83% Très gênantes : 65% Faut-il choisir un questionnaire générique ou spécifique de qualité de vie ?

51. When impact of lipodystrophy is measured by a generic instrument Blanch J et al. Impact of lipodystrophy on the quality of life of HIV-1 infected patients. JAIDS 2002. 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

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. 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 ? Justification of choice of instruments ? What are the hypotheses ? 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. NameItemsDimensionsAnswers SIPSickness Impact Profile136 12 Yes/No* NHPNottingham Health Profile387Yes/No* SF-36Short-Form 36 (MOS)368Likert (Medical outcomes Survey) PGWBPsychological General226Likert Well-Being * Binary responses are unlikely to be sensible enough to detect a small change Examples of generic HRQL questionnaires ?

56. Attention à la longueur des questionnaires Nom du questionnaireNb d’items SIPSickness Impact Profile (questionnaire générique) 136 DSQOLSDiabetes Specific Quality of Life Scale64 DCPDiabetes Care Profile234 NEWSQOLNewcastle Stroke-Specific Quality of Life Measure 56 SISStroke Impact Scale64 HOPESHIV Overview of Problem situations103-176 AIDS-HAQAIDS – Health Assessment Questionnaire116

57. 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 Content of HRQL questionnaires : Nottingham Health Profile (NHP)

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. 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 ? What are we measuring ?

59. 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. Choice of PRO instrument - What are we measuring ? Example of HIV / AIDS

61. 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.

62. WHOQOL-HIV 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. 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 ?

63. WHOQOL-HIV 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. 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 ?

64. 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 StatusSelf Life satisfaction(3 items)Self Psychomotor functionInter 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. Who measures what ?

65. N = 30 Who measures Well-Being ? Clinicians ?? 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. ABCD vs Mental Component Summary (MCS) SF-12, r=0.65 To follow the rigorous procedures of development of HRQL or PRO questionnaires 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 Factorial analysis ABCD ScoreABCD score vs nb of lipodystrophy regions

72. 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 How measuring fatigue ? Identification of concepts Assessment and treatment of HIV-related fatigue. Adinofi A. J Assoc Nurses AIDS Care 2001.

73. Determinants of the Quality of Life Control of disease Coping with disease Personality traits Social support 2 nd illness Diabetes burden Rose M, et al. Determinants of the quality of life of patients with diabetes under intensified insulin therapy. Diabetes Care. 1998; 21: 1876-85. Various factors involved in the multidimensional HRQL construct

74. Control of disease / self-management Items about DIET can express different concepts Input of patients in item generation is critical Diabetes --> Cause --> Food --> consequence --> DIET Watkins KW, et al. Effect of adults' self-regulation of diabetes on quality-of-life outcomes. Diabetes Care 2000; 23: 1511-5. 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 Interference with social and personal relationships Coping with disease

75. 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. Item generation of the FDDQL questionnaire

76. 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 Attention au libellé des questions

77. Item scaling of HRQL questionnaires ?

78. Tout le temps Jamais QuelquefoisRarementTrès souvent Item scaling of HRQL questionnaires ?

79. 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 Item scaling and scoring of HRQL questionnaires ?

80. Factorial analysis (n = 143) Lipodystrophy score (6 items) Factorial analysis of Assessment of Body Change and Distress (ABCD) in Lipodystrophy (HIV/AIDS) 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 (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 Factors 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)

82. 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) Item reduction 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. International study : France, Germany, Great Britain 391 IBS and dyspeptic patients Chassany O, et al. Gut 1999. Discriminant validity of the Functional Digestive Disorders Quality of Life questionnaire (FDDQL)

84. Validation of French version of the scleroderma health assessment questionnaire (SSc HAQ). Georges C, Chassany O et al. Clinical Rheumatology, Under press. 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. 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 Discriminant validity of the Health Assessment questionnaire adapted to Sclerodermia (SSc HAQ)

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 < 0.001 Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life questionnaire in Lipodystrophy (ABCD) r = 0.39

86. Logical correlation between Global ABCD score and generic quality of life (SF-12) (n = 155) Convergent validity of a Lipodystrophy specific quality of life questionnaire vs Physical Component Summary (PCS), r = 0.101 Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life questionnaire in Lipodystrophy (ABCD) vs Mental Component Summary (MCS), r = 0.65

87. Logical correlation between some dimensions of the MOS- HIV, e.g. the health distress, mental health and social function (r > 0.6) Convergent validity of a Lipodystrophy specific quality of life questionnaire

88. Sensibilité au changement - Questionnaire d’éducation dans l’asthme (CHU Montpellier) Scores des 6 domaines explorant le comportement face à des scénarios cliniques Évolution des scores entre la première (n = 96), la 2 e (n = 67) et la 3 e visite (n = 21) au cours d’un programme d’éducation 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. 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. Gut 1999. Cultural adaptation - forward/backward translation Chassany O, et al. Validation of a specific quality of life questionnaire in functional digestive disorders (FDDQL). Gut 1999.

91. Canada (US) Shoveling the snow Japan 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 »

92. Canada (US) Shoveling the snow JapanBeat 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 »

93. Canada (US) Shoveling the snow JapanBeat futons NorwegianGoing fishing 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 »

94. Cultural Adaptation Cultural adaptation

95. 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 Cultural adaptation of Assessment of Body Change and Distress (ABCD) in Lipodystrophy (HIV/AIDS) 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. Double-blind, placebo-controlled trial (n=345), 6 months, 3 doses of carvedilol (beta-blocker) Minnesota Living with Heart Failure MLwHF : 21 items, 0 (best) - 105 (worst) Specific questionnaire : responsiveness ? HRQL is not improved by drugs in Chronic heart failure ? Responsiveness - specific questionnaires

98. 24% difference in pyrosis relief Galmiche JP, et al. Aliment Pharmacol Ther 1997.. Responsiveness - generic questionnaires Psychological General Well-Being (PGWB) & GERD HRQL is not improved by gastro-oesophageal reflux disease drugs ? No difference in PGWB score

99. 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) Predictive value of Quality of Life ? 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 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. 9 dimensions : physical functioning energy/well-being emotions social limitations role, embarrassment body image eating disturbances treatment burden

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 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…

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. 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 Basic principles of RCTs fulfilled ? Placebo effect is also strong for HRQL 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. 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) Statistical analysis plan : Estimating the adequate sample size

107. N = 365 (394 randomized) Poorer HRQL scores Importance of withdrawals and missing data 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 < 0.05 and IC 95 Pain VAS OK YES p < 0.05 HRQL Responders MID ?

111. Treatment in claudication (Peripheral Arterial Occlusive Disease) Phase III, randomized, double-blind, vs placebo File for Approval - AFSSAPS Interpretation of results - Effect size Dossier for Drug Approval Effect size (Distribution-based approach) Dividing a difference between 2 groups by the SD

112. File for Approval - AFSSAPS Interpretation of results - Effect size Effect size (Distribution-based approach) Dividing a difference between 2 groups by the SD European Evaluation of Vertigo (EEV) Generic quality of life SF-36 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

113. Minimal Important Difference (MID) MID obtained from comparison with a Global Rating 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 ?”

114. DEPENDS ON WORDING 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) or change

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 > 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. (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) Minimal Important Difference (MID)

117. How many and which PRO domains should improve for a claim ? The effects of naftidrofuryl on quality of life. Liard F et al. Dis Manage Health Outcomes 1997. 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, p=0.004; pain, p=0.001) Should the planners have hypothesized that only these 2 domains would improve?

118. J3J12 Symptoms - Chest pain NSNS - Shortness of breath<0.05NS - Dizziness NSNS - Palpitation<0.05NS - Cognitive abilityNSNS AlertnessNSNS Quality of sleepNSNS Physical abilityNSNS Daily abilityNSNS DepressionNSNS Self perceived healthNSNS Ladder of life: futureNSNS Fitness<0.05NS Physical activity<0.01NS 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. How many and which PRO domains should improve for a claim ?

119. Antacid in GERD Randomized, placebo- controlled, double-blind trial Primary endpoint : heartburn (diary) Secondary endpoint : SF-36 questionnaire Sample size > 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 How many and which PRO domains should improve for a claim ?

120. Many PROs such as symptom scales are well- established 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 ?) PROs are not a regulatory issue for EMEA, but…

121. 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% Nobody knows if a 9 % difference of responders in IBS is worth giving a claim? European mutual procedure (2004-2005)

122. 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 Because PROs (including HRQL) are unavoidably part of the Approval decision January 2005

123. 5 key issues for Drug Approval Process Based on a meeting with representatives of AFSSAPS, EMEA and ERIQA Working Group, Paris, 1999 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 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. HRQL (and PRO) to be considered as a credible criterion if there is enough evidence (in the file) about the :

124. 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 Review of a dossier : Example of misuse/abuse September 2004

125. What are the results 1 st 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 2 nd 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

126. 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 Review of a dossier : Example of misuse/abuse

127. 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 Guideline européenne sur la qualité de vie

128. 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 Why there are so few HRQL mention in labelling ?

129. Need for improving advertisements French Drug Approval (1999) Comparison of Proton Pump Inhibitors in Gastro-oesophageal Reflux Disease Physical Well-Being What were hypotheses ? How is defined a upholding of Well-Being ? 1 single item ranging from 0 (very good) to 4 (very poor) In protocol : Quality of life = “Time lost from usual daily activities” Better result in placebo group : less time lost (not disclosed in the publication) Seen on TV This Drug improves your Quality of life !

130. PRO endpoint, as useful as spirometry

131. 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

132. 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 self- care 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. What can one wish for the future ?

133. 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 Measuring HRQL in routine oncology practice improves communication and patient well-being