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Introduction to Patient-Reported Outcomes (PROs) March 2-4 2004, Karolinska Institutet, Sigtuna, Sweden Mesure de la qualité de vie liée à l’état de santé Olivier CHASSANY, MD, PhD Délégation à la Recherche Clinique (AP-HP) Hôpital Saint-Louis, Paris Définition de la Qualité de Vie liée à l’état de santé Définition de l’OMS (dénominateur minimal commun) « La santé, ce n’est pas seulement une absence de maladie, c’est aussi un état total de bien-être physique, psychologique et social » « La qualité de vie est la perception qu’a un individu de sa place dans l ’existence, dans le contexte de la culture et du système de valeurs dans lesquels il vit en relation avec ses objectifs, ses attentes, ses normes et ses inquiétudes » Définition de la Qualité de Vie liée à l’état de santé La mesure de la qualité de vie est : • Subjective (perception du patient) • Se mesure idéalement par auto-questionnaire • Multidimensionnelle • Dimensions minimales : physique, psychique et sociale • Dimensions spécifiques d’une pathologie ou condition Definition of Health-Related Quality of Life (HRQL) “Health is a state of complete physical, mental, and social well-being and not merely the absence of disease” (WHO 1948) The value assigned to duration of life as modified by the impairments, functional states, perceptions and social opportunities that are influenced by disease, injury, treatment, or policy (Pr Donald Patrick, Seattle USA) Agreement on multidimensionality and subjective assessment Mesure de la Qualité de Vie liée à l’état de santé Une question unique ne suffit pas : « Globalement, quelle est votre qualité de vie en ce moment ? » PAST • Health-Related Quality of Life (HRQL) is based on several decades of research • Many studies, especially using generic questionnaires made it possible to appreciate how diseases affected HRQL • Poor quality of clinical trials • Abuse of “Quality of Life” trials TODAY • Rationale for the Added Value of HRQL in clinical trials • Increased recognition of the patient’s perspective: Patient-Reported Outcomes (PRO) • Agreement (more or less) on HRQL definition, multidimensionality and subjective assessment • Availability of HRQL questionnaires correctly validated and translated for many diseases • Guidelines on how measuring HRQL in clinical trials • Increasing recognition of HRQL value by regulators • Huge literature (too much ?) Why should we measure the perception of patients ? • Changes in the therapeutic targets in the growing context of chronic diseases and palliative treatment in a rising old population • Nowadays, therapeutic benefits : • rarely curative, or prolonging survival, • but improving symptoms and functional status, and thus preserving or restoring HRQL • Availability of PRO questionnaires correctly validated and translated for many diseases • cancer • • • • • • • • AIDS heart failure Parkinson’s disease Alzheimer’s disease asthma COPD osteoarthritis diabetes … The impact on HRQL is not always foreseeable better HRQL lower HRQL Group health enrollees Cardiac arrest General population and is not systematically correlated with the severity of the disease as perceived by the medical community Moderate obesity Ulcerative colitis Myocardial infarct Angina Crohn's Hypothyroidism End-stage hemodialysis Rheumatoid arthritis Non-oxygen dependent COPD Physically disabled adults Back pain Chronic low back pain Oxygen dependent COPD Chronic pain non-responders Amyotrophic lateral sclerosis 0 5 10 15 20 25 30 35 Overall Sickness Impact Profile score Patrick D, Erickson P. Health status and health policy. Quality of life in health care evaluation and resource allocation. Oxford University Press, 1993. The impact on HRQL is not always foreseeable Physical Role Social functioning functioning functioning Patients w ith no chronic Health Mental health perceptions Bodily pain conditions (n = 2595) Hypertension (n = 2706) 10% Diabetes (n = 844) 0% Congestive heart failure (n = 297) Myocardial infarction (n -10% = 147) Arthritis (n = 2079) -20% Chronic lung problems -30% (n = 731) Gastrointestinal disorders (n = 696) * Back problems (n = 486) -40% Angina (n = 532) Stewart AL et al. Functional status and well-being of patients with chronic conditions. Results from the Medical Outcomes Study. JAMA 1989; 262: 907-913. Which are the arguments in favour of HRQL ? “Objective” measure “Subjective” measure Exercise test versus physical functioning, r = 0.40 Wiklund I et al. Clin Cardiol 1991. Slide presented with the authorization of Pr Ingela Wiklund Weak correlation between Patient-Reported Outcomes and physiological endpoints (n = 96) r BPQ CRQ 6-min walk test 0.17 0.07 Pre SaO2 0.14 0.17 Symptoms BPQ : Breathing Problems Questionnaire HRQL CRQ : Chronic Respiratory Disease Questionnaire Variability in exercise capacity contributed to only 3% of the variability in BPQ score Quality of life in elderly patients with COPD: measurement and predictive factors. Yohannes AM et al. Resp Med 1998. Correlation between glycemic control and perception of Quality of Life DQOLY (Diabetes Quality of Life for Youths) Hb1Ac Impact (23 items) r = - 0.21 Worry (23 items) r = - 0.28 Satisfaction (11 items) r = - 0.04 Grey M, et al. Personal and family factors associated with quality of life in adolescents with diabetes. Diabetes Care. 1998 ;21: 909-914. Niveau d’agrément de la perception d’un symptôme (douleur) entre patients et médecins Score de douleurs Agrément entre patients et leurs médecins généralistes Colopathie fonctionnelle r = 0,31 Maladie veineuse chronique r = 0,27 Chassany O, et al. Discrepancies between patient-reported outcomes (PROs) and clinician-reported outcomes in chronic venous disease (CVD), irritable bowel syndrome (IBS), and peripheral arterial occlusive disease (PAOD). Value in health. Under press Niveau d’agrément de la perception de la qualité de vie entre patients et médecins Score qualité de vie Agrément entre patients et leurs médecins généralistes Colopathie fonctionnelle (FDDQL) r = 0,28 Maladie veineuse chronique (CIVIQ) r = 0,17 Artériopathie chronique oblitérante des MI (CLAUS) r = 0.26 Chassany O, et al. Discrepancies between patient-reported outcomes (PROs) and clinician-reported outcomes in chronic venous disease (CVD), irritable bowel syndrome (IBS), and peripheral arterial occlusive disease (PAOD). Value in health. Under press Perception of pain : moderate agreement between IBS patients & physicians The physician is more disposed to bear the pain of his/her patient than the patient himself 6 Physician-Patient Difference Cross-sectional survey 239 IBS patients 57.5 ± 16 years 64% women r = 0.31 4 2 0 -2 -4 -6 -8 -10 -2 0 2 4 6 Patient's VAS 8 Tendency of physician to overestimate the pain IBS VAS (0-10, worst) Patients 3.9 ± 2.5 10 12 Tendency of physician to underestimate the pain Clinicians 3.0 ± 2.1 Chassany O, et ALFIS. Added value of patient’s perspective in irritable Bowel Syndrome. Qual Life Res 2003; 12: A821 Perception of Quality of Life by patients and clinicians in Irritable Bowel Syndrome HRQL impairment is over/under estimated by clinicians in IBS FDDQL (43 items) Daily activities Anxiety Diet Sleep Discomfort Coping Control Stress Global Patients (n = 239) 72 62 56 59 55 49 55 31 ± ± ± ± ± ± ± ± 21 22 23 16 15 13 23 25 56 ± 12 Clinicians (n = 163) 58 54 60 72 69 57 59 43 ± ± ± ± ± ± ± ± 35 28 26 26 25 26 26 27 59 ± 19 FDDQL : Functional Digestive Disorders Quality of Life 43 items / 8 domains, score 0-100 (best HRQL) Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Irritable Bowel Syndrome. Quality Life Res 2003; 12: A821 Perception of HRQL by patients and clinicians ? Survey among 239 IBS patients and 163 clinicians Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le patient pour le retentissement sur l'activité quotidienne 100,00 90,00 r = 0.43 Relation score FDDQL apprécié par le m édecin / score FDDQL apprécié par le patient pour le retentissem ent sur l'alim entation 100,00 r = 0.30 90,00 70,00 Daily Activities 80,00 Score FDDQL activité quotidienne 60,00 patient Diet 70,00 50,00 Scores égaux 40,00 Score FDDQL alimentation 60,00 patient 80,00 Scores égaux 50,00 40,00 30,00 30,00 20,00 20,00 10,00 10,00 0,00 0,00 0 1 2 médecin 3 4 5 0 1 2 m édecin 3 4 5 Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le patient pour le retentissement sur le sommeil Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le patient pour le degré d'anxiété 100,00 100,00 Anxiety 90,00 Sleep 90,00 80,00 80,00 70,00 Score FDDQL sommeil 70,00 Score FDDQL anxiété 50,00 Scores égaux 40,00 60,00 patient patient 60,00 Scores égaux 50,00 40,00 30,00 30,00 20,00 20,00 10,00 10,00 0,00 0 1 2 3 médecin 4 5 0,00 0 1 2 médecin 3 4 5 Perception of HRQL by patients and clinicians ? Survey among 239 IBS patients and 163 clinicians 100,00 Relation score FDDQL apprécié par le m édecin / score FDDQL apprécié par le patient sur la m aîtrise de sa m aladie Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le patient pour le retentissement sur la vie sociale 100,00 Social Life 90,00 Control 90,00 80,00 80,00 70,00 50,00 60,00 patient 60,00 patient Score FDDQL maîtrise maladie 70,00 Score FDDQL vie sociale/incofort Scores égaux Scores égaux 50,00 40,00 40,00 30,00 30,00 20,00 20,00 10,00 10,00 0,00 0,00 0 1 2 médecin 3 4 0 5 Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le patient sur la réaction face à la maladie 1 2 m édecin 3 4 5 Relation score FDDQL apprécié par le médecin / score FDDQL apprécié par le patient sur l'impact du stress 100,00 Coping 90,00 100,00 80,00 70,00 70,00 Score FDDQL réaction maladie Scores égaux 50,00 40,00 30,00 patient 60,00 patient Stress 90,00 80,00 60,00 50,00 Score FDDQL stress 40,00 Scores égaux 30,00 20,00 20,00 10,00 10,00 0,00 0 1 2 3 médecin 4 5 0,00 0 1 2 médecin 3 4 5 Perception of pain and HRQL by patients with IBS r = 0.63, p < 0.0001 100 FDDQL Global Score 239 IBS patients 57.5 ± 16 years 64% of women Global FDDQL: 56.1 ± 11.6 90 80 70 60 50 40 30 20 10 0 0 2 4 6 Patient's VAS 8 FDDQL : Functional Digestive Disorders Quality of Life 43 items / 8 domains, score 0-100 (best HRQL) Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Irritable Bowel Syndrome. Quality Life Res 2003; 12: A821 10 Perception of pain by patients and clinicians in Chronic Venous Insufficiency Patients Clinicians (n = 233) (n = 120) 4.22 ± 2.48 2.97 ± 1.92 r = 0.27 10 9 8 Pain VAS Physicians Pain perception is underestimated by clinicians in CVI 0 [best Pain] – 10 [worst Pain] 7 6 5 4 3 2 1 0 0 1 2 3 4 Pain VAS Patients 5 6 7 8 9 10 Perception of Quality of Life by patients and clinicians in Chronic Venous Insufficiency HRQL impairment is underestimated by clinicians CIVIQ Patients (n = 240) Clinicians (n = 120) Physical Function Pain Social Function Psychological Impact Global 44 ± 25 45 ± 20 38 ± 24 35 ± 23 39 ± 20 31 ± 22 30 ± 20 24 ± 21 26 ± 21 28 ± 19 CIVIQ : 20 items / 4 domains, score 0-100 (worst HRQL) Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Chronic Venous Insuffisiency Perception of Quality of Life by patients and clinicians in Chronic Venous Insufficiency Relation score CIVIQ apprécié par le médecin / score CIVIQ apprécié par le patient pour le retentissement activité physique Relation score CIVIQ apprécié par le médecin / score CIVIQ apprécié par le patient pour le retentissement douleur Impact of pain 100,00 100,00 90,00 90,00 80,00 80,00 70,00 70,00 Patients Patients Physical Function 60,00 patient patient 60,00 50,00 40,00 30,00 r = 0.29 20,00 50,00 40,00 r = 0.28 30,00 20,00 10,00 10,00 0,00 0 1 2 3 4 5 6 7 8 9 0,00 10 0 médecin Physicians Score CIVIQ activité physique 3 4 Physicians Scores égaux Score CIVIQ douleur Social Function 5 6 7 8 Scores égaux Psychological Function Relation score CIVIQ apprécié par le médecin / score CIVIQ apprécié par le patient pour le retentissement psychologique 100,00 100,00 90,00 r = 0.23 80,00 r = 0.23 90,00 80,00 Patients 70,00 60,00 patient patient 2 médecin Relation score CIVIQ apprécié par le médecin / score CIVIQ apprécié par le patient pour le retentissement vie sociale Patients 1 50,00 40,00 30,00 70,00 60,00 50,00 40,00 30,00 20,00 20,00 10,00 10,00 0,00 0,00 0 1 2 3 4 5 6 médecin Physicians Score CIVIQ vie sociale Scores égaux 7 8 9 0 1 2 3 4 5 6 7 médecin Physicians Score CIVIQ psychologique Scores égaux CIVIQ patients : 0 [best QoL] – 100 [worst QoL] - QoL physicians : 0 – 10 [maximal impact] 8 9 10 Perception of Quality of Life by patients and clinicians in Chronic Venous Insufficiency Relation entre le score global attribué par le patient et celui attribué par le médecin Global QoL score 100 90 80 Patients score patient 70 60 50 40 30 20 r = 0.33 10 0 0 1 2 3 4 5 6 7 score médecin nuage de points 8 Physicians droite de régression CIVIQ patients : 0 [best QoL] – 100 [worst QoL] QoL physicians : 0 – 10 [maximal impact] 9 10 Correlation of pain versus Quality of Life in patients with Chronic Venous Insufficiency Patients : pain vs QoL 100 CIVIQ global score 90 80 70 60 50 40 30 r = 0.78 20 10 0 0 1 2 3 4 5 6 Pain VAS CIVIQ : 0 [best QoL] – 100 [worst QoL] Pain VAS : 0 – 10 [worst pain] 7 8 9 10 Perception of pain by patients and clinicians Results of a survey in 3 chronic diseases Pain perception is underestimated by clinicians in irritable bowel syndrome (IBS) and chronic venous insufficiency and overestimated in peripheral arteriopathy Patients IBS Venous insufficiency Arteriopathy Pain : from 0 to 10 [worst pain] 3.9 ± 2.5 4.2 ± 2.5 3.5 ± 2.0 Clinicians 3.0 ± 2.1 3.0 ± 2.0 4.3 ± 2.1 Perception of HRQL by patients and clinicians in Peripheral Arteriopathy Occlusive Disease HRQL impairment is over-estimated by clinicians CLAU-S (43 items) Patients (n = 68) Clinicians (n = 61) Daily Life Pain Social Life Fear Mood 57 ± 28 64 ± 20 76 ± 18 65 ± 28 72 ± 24 66 ± 23 47 ± 27 55 ± 21 57 ± 26 56 ± 26 63 ± 28 54 ± 21 Global CLAU-S : 43 items / 5 domains, score 0-100 (best HRQL) Chassany O, Le Jeunne P, et ALFIS. Added value of patient’s perspective in Arteriopathy Patient-reported Outcomes (PROs) are in many conditions as important as other outcomes • Clinicians’ and patients’ perspectives although overlapping, are not similar • Clinicians tend to underestimate the pain intensity of their patients • Similarly, patient’s perception of pain cannot completely reflect the impact of QoL • Symptoms (e.g. pain) and QoL although overlapping to some extent measure different concepts • Patient’s perspective is a major outcome in the evaluation of therapies Weak correlation between HRQL & symptoms • e.g. Irritable Bowel Syndrome (IBS) • The absence of abdominal pain (e.g. during a consultation with a physician) may not be linked with a good HRQL. The patient : • May be anxious not to know when the next bout will occur • May be limited in his inter-personal life and his leisure's • Constrained to take drugs and to pay attention to food • The same is true in asthma, migraine, osteoarthritis, acne, heart failure, HIV (e.g. impact of lipodystrophia induced by antiretroviral therapy, even in patients who have not yet the side effect) … Chassany et al. Validation of a specific quality of life questionnaire in functional digestive disorders (FDDQL). Gut 1999. Cystic fibrosis : Correlation between different endpoints ClinicianReported Physiological Caregiver High resolution CT SaO2 0.84 FEV1 Maximal Capacity Exercise PatientReported Proxy MRC Satisfaction HRQL (QWB, Caregiver Dyspnea SIP) Family Scale 0.57 0.33-0.40 0.40 Chassany O. De la maladie chronique à la qualité de vie. Méthodes d’évaluation. Rev Mal Respir 2003; 20: S38-41. 0.75 Correlation between adolescent pulmonary function (FEV1) and perception of health 24 adolescents (11-18 yrs) with CF, their mothers, and their fathers completed the Child Health Questionnaire during routine CF clinic visits at 2 urban hospitals. Health Scale General health Physical functioning Role/social-physical Bodily pain Role/social-emotional Role/social-behavior Mental health Family activities Self-esteem Behavior problems Adolescents 0.73 0.37 0.47 0.42 0.39 -0.21 0.27 0.34 0.24 -0.04 Mothers 0.73 0.70 0.73 0.55 -0.01 0.03 0.28 0.37 0.05 -0.21 Fathers 0.54 0.64 0.60 0.37 0.11 0.06 -0.05 0.18 -0.23 -0.36 Adolescents with cystic fibrosis: family reports of adolescent quality of life and forced expiratory volume in one second. Powers PM et al. Pediatrics 2001; 107: E70. Correlation between adolescent vs mother and father reports of perceived adolescent Health 24 adolescents (11-18 yrs) with CF, their mothers, and their fathers completed the Child Health Questionnaire during routine CF clinic visits at 2 urban hospitals. Health Scale General health Physical functioning Role/social-physical Bodily pain Role/social-emotional Role/social-behavior Mental health Family activities Self-esteem Behavior problems Mothers 0.66 0.69 0.62 0.69 -0.12 0.48 0.33 0.45 0.41 0.71 Fathers 0.57 0.31 0.49 0.37 0.24 0.17 0.48 -0.09 0.65 0.66 Adolescents with cystic fibrosis: family reports of adolescent quality of life and forced expiratory volume in one second. Powers PM et al. Pediatrics 2001; 107: E70. Psycho-social impact of lipodystrophy • Erosion of self-image and self-esteem • Problems in social and sexual relations • Threat to loss of control • Forced HIV disclosure • Demoralization and depression • Clinicians’ minimization of the importance of lipodystrophy Collins E, Wagner C, Walmsley S. Psychosocial impact of the lipodystrophy syndrome in HIV infection. AIDS Read 2000; 10: 546-550 Factors associated with severe impact of lipodystrophy on the Quality of Life • 84 asymptomatic HIV patients with clinical lipodystrophy (LD) • Dermatology Life Quality of Life Index (DLQI) • Impact of body fat changes on – Influenced dressing – Produced feeling of shame – Disrupted Sexual life their HRQL 65% 49% 27% Blanch J et al. Factors associated with severe impact of lipodystrophy on the quality of life of patients infected with HIV-1. Clin Infect Dis 2004. Everything is all right, CD4, viral load… Impact of Lipodystrophy (HIV) on Quality of Life I don’t recognize Myself in mirror I look like a monster Everybody can see I’ve got HIV I’m thinking about stopping treatment I need a plastic Surgery The impact of Lipodystrophy (HIV) on HRQL is not adequately captured by other criteria International Classification Biological Markers Viral Load Patient-Reported Outcomes (PROs) ClinicianReported Lipodystrophy Sign Score CD4 CDC Lipodystrophy Satisfaction SF-12 Score Lipodystrophy Lipodystrophy Specific HRQL MOS-HIV Sign Score ABCD Score r=0.17 r=0.13 r=0.2-0.7 r=0.39 p=NS r=0.58 r=0.03 r=0.65 r=0.43 Duracinsky M, Chassany O. Agreement between patients’ and clinicians’-reported outcomes in lipodystrophy (HIV/AIDS). Value in Health 2004; 7: 641 Conclusion • Clinicians’ and patients’ perspectives although overlapping, are not similar • Lipodystrophy impacts QoL • Clinicians cannot infer the QoL of their patients neither from a biological marker nor from a clinical exam • The different PROs although overlapping, measure each a distinct concept • The patient's perspective is essential in medical decision making : the psychological and social distress related to the body changes must be measured in clinical trials, to make sure that life is not lengthened at the expense of its quality • ABCD questionnaire is validated in French HRQL as a survival predictor for patients with advanced head and neck carcinoma treated with radiotherapy Changes in the HRQL scales during radiotherapy were not significantly correlated with survival An increase in the baseline fatigue score of 10 points corresponded to a 17% reduction in the likelihood of survival (95%CI: 8-27%) Fang FM, et al. Quality of life as a survival predictor for patients with advanced head and neck carcinoma treated with radiotherapy. Cancer 2004; 100: 425-432. Health-Related Quality of Life predicts survival • 957 patients • AIDS Clinical Trials Group Protocol 204 • Randomized, double-blind comparing 3 prophylactic regimen against CMV • MOS-HIV – Physical Health Summary (PHS) – Mental Health Summary (MHS) • Each point increase in baseline decreased the risk of : MHS PHS Death 4% 4% CMV 2% Dropout 1% 1% Jacobson DL et al. Health-Related Quality of Life predicts survival, cytomegalovirus disease, and study retention in clinical trial participants with advanced HIV disease. J Clin Epidemiol 2003. Interview of a patient with pancreatic cancer Balance between aggressive therapy and HRQL 55 year male patient Diagnosed with pancreatic cancer (median survival 5 months) Interview : – “My Quality of Life is the most important” – “Chemotherapy will destroy everything” – “I want to investigate alternative therapies, such as nutrition supplements” • By the way, at the end of the consultation with Dr Gonzales, he had to pay 2800 $ (not taken in charge by any HMO/MCO, I presume) • The cancer of the patient was so advanced that he died before he could even start Dr Gonzales treatment Heard on Radio, 4 June 2004 Place of Patient-Reported Outcomes (PRO) Patient Outcomes Assessment Sources and Examples ClinicianReported For example • Global impression • Observation & tests of function Physiological For example • FEV1 • HbA1c • Tumor size CaregiverReported For example • Dependency • Functional status PatientReported • Global Impression • Functional status • Well-being • Symptoms • HRQL • Satisfaction with TX • Treatment adherence Acquadro C, et al. Incorporating the patient's perspective into drug development and communication: an ad hoc task force report of the Patient-Reported Outcomes (PRO) Harmonization Group meeting at the Food and Drug Administration, February 16, 2001. Value Health 2003; 6: 522-531. Slide from Laurie Burke, Director, Office of New Drugs, CDER, FDA Washington Define the conditions for which the measurement of HRQL/PRO in clinical trial is useful • Patient’s self-report is the primary or sole indicator of disease activity, e.g. dermatological disorders (psoriasis, acne), erection dysfunction • No objective marker or several possible markers of disease activity (migraine, osteoarthritis, asthma, menopause, heart failure) • Disease expressed by many symptoms (IBS) • To ensure that treatments prolonging survival (AIDS), do not adversely affect patients’ lives due to morbidity, functional or psychological impairments or side effects • The treatment does not seem to improve survival (cancer, rheumatoid arthritis, Parkinson’s disease), but it could improve HRQL, by reducing pain, anxiety, level of stress or by improving the functional status. Chassany O et ERIQA Working Group. Patient Reported Outcomes (PRO) and Regulatory Issues : A European Guidance Document for the improved integration of health-related quality of life assessment in the drug regulatory process. Drug Information Journal 2002. Osteoarthritis CPMP/EWP/784/97 II. Recommended primary/secondary efficacy endpoints a) Symptom modifying drugs PRO PRO • Pain attributable to the target joint is recommended as primary endpoint. Functional disability is an important additional primary endpoint. Pain should be measured by self-assessment with validated methods, such as VAS or Likert scale. • Functional disability A disease-specific and joint specific instrument such as the WOMAC…[…]…is recommended. Secondary endpoints include: Global rating, Flares, Physical signs including range of motion, Quality of Life, Consumption of medications for pain relief HRQL Irritable Bowel Syndrome (IBS) CPMP/EWP/785/97 (March 2003) 5. Recommended primary/secondary efficacy endpoints PRO HRQL Primary: The patient’s global assessment of symptoms and abdominal discomfort/pain should be used as the two primary endpoints. Statistically significant changes must be found in both parameters. Secondary (supportive): choice of secondary efficacy variables should be justified by the applicant and should include variables such as bloating/distension, stool frequency and urgency, and quality of life parameters. Health-related quality of life must, however, be considered most important secondary endpoints. Chronic Obstructive Pulmonary Disease (COPD) CPMP/EWP/562/98 (Dec 1999) VI. Recommended Primary and secondary endpoints: • In the major efficacy studies of symptomatic benefit the primary endpoint should reflect the clinical benefit the applicant wishes to claim in the future SPC. PRO • The Primary symptomatic benefit endpoint should be justified by referencing published data which support its validity; one example is the St George’s Respiratory Questionnaire. • There are a number of secondary endpoints which may provide useful information. These measure different aspects of the disease but they should be justified by referencing published data which support their validity; examples include…..symptom HRQL scales, exacerbation rates and QoL assessment. • Care should be taken with respect to statistical multiplicity if secondary endpoints become the basis for specific claims. Rheumatoid arthritis CPMP/EWP/556/95 rev 1 (Dec 2003) 3. Tools to measure efficacy (primary or secondary endpoints) PRO d) Patient’s global assessment of disease activity (VAS) e) Pain score (patient’s assessment : VAS, Likert Scale) g) Physical function (assessed by patient, e.g. HAQ, AIMS) 4. Supportive evidence for efficacy d) Emotional and social function (e.g. AIMS-1) e) Quality of life (RA-specific, e.g. AIMS, SF-36 or HRQL generic…) Checklist for designing, conducting and reporting HRQL - PRO in clinical trials HRQL / PRO objectives Statistical analysis plan • Added value of HRQL / PRO • Choice of the questionnaires • Hypotheses of HRQL / PRO changes • Primary or secondary endpoint • Superiority or equivalence trial • Sample size • ITT, type I error, missing data Study design • Basic principles of RCT fulfilled ? • Timing and frequency of assessment • Mode and site of administration... Reporting of results HRQL / PRO measure Interpreting the results • Description of the measure (items, domains…) • Evidence of validity • Evidence of cultural adaptation • Participation rate, data completeness • Distribution of HRQL / PRO scores • Effect size • Minimal Important Difference • Number needed to treat… Patient Reported Outcomes (PRO) and Regulatory Issues : A European Guidance Document for the improved integration of health-related quality of life assessment in the drug regulatory process. Chassany O et ERIQA Working Group. Drug Information Journal 2002. Define the conditions for which the measurement of HRQL/PRO in clinical trial is useful • Patient’s self-report is the primary or sole indicator of disease activity, e.g. dermatological disorders (psoriasis, acne), erection dysfunction • No objective marker or several possible markers of disease activity (migraine, osteoarthritis, asthma, menopause, heart failure) • Disease expressed by many symptoms (IBS) • To ensure that treatments prolonging survival (AIDS), do not adversely affect patients’ lives due to morbidity, functional or psychological impairments or side effects • The treatment does not seem to improve survival (cancer, rheumatoid arthritis, Parkinson’s disease), but it could improve HRQL, by reducing pain, anxiety, level of stress or by improving the functional status. Chassany O et ERIQA Working Group. Patient Reported Outcomes (PRO) and Regulatory Issues : A European Guidance Document for the improved integration of health-related quality of life assessment in the drug regulatory process. Drug Information Journal 2002. What is a HRQL questionnaire ? Subjective, multidimensional, self-assessed (whenever possible) QUESTIONNAIRE SF-36 (36 ITEMS, 8 DIMENSIONS) Abréviation Libellé Anglais Libellé Français Nombre d’items PF Physical Functioning Activités physiques 10 RP Role Physical Limitations dues à l’état physique 4 BP Bodily Pain Douleur physique 2 GH General Health Perception de l’état de santé 5 VT Vitality Vitalité 4 SF Social Functioning Vie et relations avec les autres 2 RE Role Emotional Limitations dues à l’état psychique 3 MH Mental Health Santé psychique 5 HT Health Transition Changement de l’état de santé 1 Faut-il choisir un questionnaire générique ou spécifique de qualité de vie ? SF-36 questionnaire générique - Étude chez 1032 patients ayant une colopathie fonctionnelle Fonction physique Limitations physiques Sommeil perturbé : 83% Douleur Prise d ’hypnotiques : 65% Santé générale Vitalité Fonction sociale Etat émotionnel Santé mentale Restrictions alimentaires : 83% Très gênantes : 65% 36 items (8 dimensions) Chassany O, et al. Gut 1999. Functional Digestive Disorders Quality of Life (FDDQL) - Activités quotidiennes - anxiété - Sommeil - Alimentation - Réaction face à la maladie - Contrôle de la maladie - Impact du stress 43 items (8 dimensions) When impact of lipodystrophy is measured by a generic instrument • 84 patients with lipodystrophy (LD) • HRQL measure : Spanish version of the Profil des Lebensqualität Chronichkranker (PLC) – 40 items – 6 dimensions : Physical Capacity, Psychological functioning, positive mood, social functioning, social well-being – Self-administered, but interviewer supervised to ensure that the questions were correctly understood and answered • LD had no influence on overall quality of life Blanch J et al. Impact of lipodystrophy on the quality of life of HIV-1 infected patients. JAIDS 2002. What is not quality of life ? • The abuse of the term HRQL in some clinical trials, whereas the questionnaire measured anything else – A listing of symptoms or of side effects cannot claim to measure HRQL – Satisfaction * • The following concepts cannot alone explore all HRQL : – physical or intellectual performance scale – handicap or functional incapacity scale – anxiety or depression scale – tiredness or pain scale – symptom bother scale * Treatment of penile curvature with Essed-Schroder tunical plication: aspects of quality of life from the patients' perspective. BJU Int 2004 What are we measuring ? HRQL or side-effects Measurement of quality of life in hypertensive patients. Bulpitt CJ et al. Br J Clin Pharmacol 1990; 30: 353-364. Justification of choice of instruments ? What are the hypotheses ? Randomized, DB, placebo-controlled study of GH replacement in 40 patients with acquired GH deficiency • Assessment at baseline and 18 months : • NHP (Nottingham Health Profile) • PGWB (Psychological General Well-being) • GHQ (General Health Questionnaire) • MMPI-2 (Minnesota Multiphasic Personality inventory) • Selection made on what ? • Psychometrics properties ? • Prior use in a similar population ? • Cover several different concepts ? • What where the hypotheses of score changes ? Baum HBA et al. Effects of physiological growth hormone therapy on cognition and quality of life in patients with adult-onset GH deficiency. J Clin Endocrinol Metab 1998; 83: 3184-9. Examples of generic HRQL questionnaires ? Name Items Dimensions Answers SIP Sickness Impact Profile 136 12 Yes/No* NHP Nottingham Health Profile 38 7 Yes/No* SF-36 Short-Form 36 (MOS) (Medical outcomes Survey) 36 8 Likert PGWB Psychological General Well-Being 22 6 Likert * Binary responses are unlikely to be sensible enough to detect a small change Attention à la longueur des questionnaires Nom du questionnaire Nb d’items SIP Sickness Impact Profile (questionnaire générique) 136 DSQOLS Diabetes Specific Quality of Life Scale 64 DCP Diabetes Care Profile NEWSQOL Newcastle Stroke-Specific Quality of Life Measure 56 SIS Stroke Impact Scale 64 HOPES HIV Overview of Problem situations AIDS-HAQ AIDS – Health Assessment Questionnaire 234 103-176 116 Content of HRQL questionnaires : Nottingham Health Profile (NHP) • Je me sens seul • Je suis de plus en plus découragé • Je me rends compte que plus rien ne me fait plaisir • J’ai des difficultés à entrer en contact avec les autres • J’ai l’impression de n’avoir personne de proche à qui parler • J’ai du mal à faire face aux événements • J’ai l’impression d’être une charge pour les autres • Je trouve que la vie ne vaut pas la peine d’être vécue ! c’est plus une échelle de dépression que de qualité de vie What are we measuring ? Improvement of lung function (FEV1, p < 0.0001) with added beclomethasone dipropionate (BDP) Temporary decrease of symptoms HRQL assessment : No improvement of NHP and ISP – NHP : 38 statements, 6 dimensions : physical mobility, pain, social isolation , emotional reactions, energy, sleep. • Answer by YES / NO – ISP (Inventory of Subjective Health) : 21 items related to subjective complaints : tiredness, chest and heart problems, gastric problems, indigestion, headache… • Is that measuring HRQL ? The influence of an inhaled steroid on quality of life in patients with asthma or COPD. Van Schayck CP et al. Chest 1995; 107: 1199-205. Choice of PRO instrument - What are we measuring ? Example of HIV / AIDS Fatigue Items related to intensity, circumstances, and consequences of fatigue. Psychometric properties of the HIV-related fatigue scale. Barroso J et al. J Assoc Nurses AIDS Care 2002. Cognitive function Dutch four-item MOS-HIV cognitive functional status subscale. The importance of cognitive self-report in early HIV-1 infection: validation of a cognitive functional status subscale. Knippels HM et al. AIDS 2002. Treatment satisfaction Weak correlation between severity of side-effects and score of satisfaction concerning these side-effects (r = 0.18) Validation of the HIV treatment satisfaction questionnaire. Woodcock A et al. Qual Life Res 2001. Doctor-Patient satisfaction Satisfaction among HIV-infected patients was not associated with QOL The doctor-patient relationship and HIV-infected patients’ satisfaction with primary care physicians. Sullivan LM et al. J Gen Intern Med 2000. MOS-HIV AIDS-HAQ HOPES FACIT (FAHI) HAT-QoL MQoL-HIV WHOQOLHIV Medical Outcomes Study HIV Health Survey AIDS-Health Assessment Questionnaire HIV Overview of Problem Situations HIV/AIDSTargeted Quality of Life Wu A Lubeck Ganz PA Functional Assessment HIV specific subscale Cella D Holmes WC Multidimensional Quality of Life Questionnaire for HIV/AIDS Smith World Health Organisation’s Quality of Life HIV instrument WHO Nb Items 1991 35 1992 116 1993 103-176 1996 55 1988 (1997) 34 (76?) 1997 40 2003 31 Dimensions 11 8 5 6 5 10 Gal Health Perception Disability Social Function Mental Health Cognitive Function Energy/Fatigue Pain Disease Worry Physical Function Psychosocial Function Sexual Function Medical interaction Marital Relationship Overall Function Disclosure worries Health Worries Financial Worries Life Satisfaction Mental Health Physical Health Physical Functioning Social Function Social Support Cognitive Function Financial Status Partner Intimacy Sexual Function Medical Care Based Gal Health Perception Physical Function Role Function Social function Cognitive function Pain Mental Health Energy/fatigue Health Distress Quality of Life Health Transition SF-36 Author Year Languages Danish, Dutch, English UK, French, German, Italian, Portuguese, Spanish Dutch, Spanish Functional Assessment of Cancer Treatment (FACT-G) French Cancer Rehabilitation Evaluation System (CARES) Italian, Portuguese, Spanish WHOQOL German, Spanish French MOS-HIV • • • • “Très” SF-36 “Très” physique Reflètant plus l’état de santé que la qualité de vie Pas de question sur – Le sommeil – Le traitement – La lipodystrophie Grossman HA et al. Quality of Life and HIV : current assessment tools and future directions for clinical practice. AIDS Read 2003. WHOQOL-HIV • Culturellement universel (Inde, Afrique, Asie, Amérique du Sud, …) • Multidimensionnel : – – – – – – Vos croyances personnelles donnent-elles un sens à votre vie ? Vous sentez-vous en sécurité dans votre vie de tous les jours ? Votre environnement est-il sain ? (pollution, bruit, salubrité, etc…) Avez-vous besoin d’argent pour satisfaire vos besoins ? Êtes-vous satisfait de vos moyens de transport ? Êtes-vous satisfait de l’endroit où vous vivez ? O’ Connell K et al. Preliminary development of the World Health Organisation’s Quality of Life HIV instrument (WHOQOL-HIV). Analysis of the pilot version. Social Science & Medicine 2003. WHOQOL-HIV • Spécifique du VIH ? – Un traitement médical vous est-il nécessaire pour faire face à la vie de tous les jours ? • Libellé compréhensible ? – Dans quelle mesure, êtes-vous tracassé par tout problème physique lié à votre infection par le VIH ? – Avez-vous assez d’énergie dans la vie de tous les jours ? – Avez-vous le sentiment d’être assez informé pour faire face à la vie de tous les jours ? – Comment trouvez-vous votre capacité à vous déplacer seul ? O’ Connell K et al. Preliminary development of the World Health Organisation’s Quality of Life HIV instrument (WHOQOL-HIV). Analysis of the pilot version. Social Science & Medicine 2003. Who measures what ? Complaint score Health Status Index Work satisfaction Psychological General Well-Being Profile of Mood Status Life satisfaction Psychomotor function Sleep Sexual function Life events Quality of life with three antihypertensive treatments. Fletcher AE et al. Hypertension 1999; 19: 499-507. (32 items) (5 items) (7 items) (22 items) (3 items) (7 items) (6 items) (8 items) Self Inter Inter Self Self Self Inter Self Self Who measures Well-Being ? Clinicians ?? N = 30 Analysis of Well-Being between indapamide and captopril. Lacourciere Y. Am J Med 1988; 84: 47-51. Who should fill-in questionnaire ? In studies evaluating sexual impairment induced by antihypertensive treatment in male patients, the answers given to nurses, by patients themselves and by their spouses were quite different... Rate of sexual dysfunction Nurses Low Who should fill-in questionnaire ? In studies evaluating sexual impairment induced by antihypertensive treatment in male patients, the answers given to nurses, by patients themselves and by their spouses were quite different... Rate of sexual dysfunction Nurses Low Patients Moderate Who should fill-in questionnaire ? In studies evaluating sexual impairment induced by antihypertensive treatment in male patients, the answers given to nurses, by patients themselves and by their spouses were quite different... Rate of sexual dysfunction Nurses Low Patients Moderate Patients (palm pilot) Higher Who should fill-in questionnaire ? In studies evaluating sexual impairment induced by antihypertensive treatment in male patients, the answers given to nurses, by patients themselves and by their spouses were quite different... Rate of sexual dysfunction Nurses Low Patients Moderate Patients (palm pilot) Higher Spouses Very high From Pr Ingela Wiklund (AstraZeneca) Item generation Scaling Item reduction Reproductibility Content validity Construct validity Discriminant validity Convergent validity Responsiveness Cultural adaptation Score résumé mental du SF-12 (MCS) • • • • • • • • • • Mean ABCD score To follow the rigorous procedures of development of HRQL or PRO questionnaires ABCD score vs nb of lipodystrophy regions 100 Factorial analysis ABCD Score ABCD 20 items a 1 ,723 2 ,084 3 ,284 4 ,177 b ,529 ,067 ,427 ,293 c ,696 ,359 ,152 ,290 d ,580 ,488 ,149 ,318 30 e ,625 ,143 ,471 ,096 20 f ,684 ,118 ,347 -,105 10 g ,609 ,195 ,381 ,125 0 h ,767 ,417 -,050 ,089 i ,181 ,323 ,728 ,132 j ,387 ,697 ,369 ,104 k ,110 ,293 ,740 ,119 l ,174 ,732 ,317 ,000 m ,181 ,775 ,298 ,121 n ,542 ,611 -,078 ,358 o ,195 ,731 ,265 ,249 p ,378 ,490 ,123 ,478 q ,778 ,412 -,101 ,290 r ,149 ,136 ,505 ,221 s ,241 ,247 ,339 ,662 t ,100 ,089 ,166 ,821 90 85 80 70 71 64 60 56 50 54 45 40 42 0 1 2 3 4 5 6 Number of lipodystrophy regions ABCD vs Mental Component Summary (MCS) SF-12, r=0.65 70 60 50 40 30 20 10 0 20 40 60 80 100 Score de qualité de vie ABCD Scientific Advisory Committee of the Medical Outcomes Trust. Assessing health status and quality-of-life instruments: attributes and review criteria. Qual Life Res 2002 Factor How measuring fatigue ? Identification of concepts Multiple causes • • • • • • • • • • Lack of rest or exercise Improper or inadequate diet Psychological stress (depression, anxiety) Use of recreational substances Anemia Abnormalities of the thyroid gland and hypogonadism Infections Side effects of medications Sleep disturbances Fever Fatigue description • • • • • • Lack of energy Sleepiness Tiredness Exhaustion Inability to get enough rest Weakness Specific fatigue questionnaire HRQL questionnaire : must have items related to fatigue Assessment and treatment of HIV-related fatigue. Adinofi A. J Assoc Nurses AIDS Care 2001. Determinants of the Quality of Life Various factors involved in the multidimensional HRQL construct 2nd illness Social support Personality traits Diabetes burden Coping with disease Control of disease Rose M, et al. Determinants of the quality of life of patients with diabetes under intensified insulin therapy. Diabetes Care. 1998; 21: 1876-85. Items about DIET can express different concepts Input of patients in item generation is critical Diabetes --> Cause --> Food --> consequence --> DIET I am able to keep my diet regimen under control Control of disease / self-management My diabetes and its treatment (e.g. diet) keeps me going out with friends / to restaurant / as much as I want Interference with social and personal relationships I find it hard to do all the things (e.g. diet) I have to do for my diabetes Coping with disease Watkins KW, et al. Effect of adults' self-regulation of diabetes on quality-of-life outcomes. Diabetes Care 2000; 23: 1511-5. Item generation of the FDDQL questionnaire Première version du questionnaire spécifique FDDQL dans les Troubles Fonctionnels Intestinaux (TFI) : les exemples suivants correspondent à des items peu clairs, doublement négatifs … • Il m'est facile de me décontracter et de ne plus penser à rien • Je n'angoisse pas à l’idée que mes vacances avec le changement des habitudes alimentaires, risquent d'aggraver ma maladie (douleurs, constipation ou au contraire diarrhée) • Je ne pense pas que ma maladie retentisse négativement sur mon travail Chassany O, et al. Gut 1999. Attention au libellé des questions Fatigue Symptom Inventory • Combien de temps dans la journée, en moyenne, vous êtes vous senti(e) fatigué(e) durant la dernière semaine ? Rate how much of the day, on average, you felt fatigued in the past week St-George Respiratory Questionnaire (50 items) • Sur l’année dernière, en moyenne sur une semaine, combien de “bons jours” vous avez eu ? Over the last year, in an average week, how many good days (with little chest trouble) have you had Fatigue symptom inventory Item scaling of HRQL questionnaires ? (Please check one box for each statement.) All of the time Most of the time Some of the time A little of the time None of the time (5) (4) (3) (2) (1) Item scaling of HRQL questionnaires ? (Please check one box for each statement.) All of the time Most of the time Some of the time A little of the time None of the time (5) (4) (3) (2) (1) Tout le temps Très souvent Quelquefois Rarement Jamais Item scaling and scoring of HRQL questionnaires ? Les modalités de réponses doivent permettre de détecter des petits changements • Réponse binaire : YES / NO peu sensible • Echelle verbale Likert en 5 à 7 points • Echelle visuelle analogique 0 1 2 3 4 Pas du tout Un petit peu Moyen Beaucoup Enormément Généralement, la réponse à un item est transformée en une valeur : entre 0 et 4 pour une échelle verbale à 5 points Les scores des dimensions sont obtenus par sommation des réponses aux items Pour faciliter la présentation des résultats, les scores des dimensions peuvent être transformés entre 0 et 100 Factorial analysis of Assessment of Body Change and Distress (ABCD) in Lipodystrophy (HIV/AIDS) Factorial analysis (n = 143) Lipodystrophy score (6 items) Correlation matrix Q1 Q2 Q3 Q4 Q5 Q2 Q3 Q4 Q5 Q6 0,512 -0,175 -0,117 -0,049 0,227 -0,151 0,070 0,188 0,260 0,231 0,327 -0,006 0,671 Facteurs Factors 1 2 Q1 -,210 ,789 0,101 Q2 ,065 ,841 0,028 Q3 ,573 -,265 Q4 ,855 ,090 Q5 ,882 ,151 Q6 ,088 ,558 2-factor structure 1- Lipoatrophy 2- Lipoaccumulation Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life questionnaire in Lipodystrophy (ABCD) Factorial analysis of Assessment of Body Change and Distress (ABCD) in Lipodystrophy (HIV/AIDS) Factors Composante Factorial analysis (n = 143) ABCD Quality of life score (20 items) 4-factor structure : 1- Acceptation, coping, satisfaction of appearance 2- Psychological, social and relational impact 3- Fear of future 4- Compliance with the treatment Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life questionnaire in Lipodystrophy (ABCD) a 1 ,723 2 ,084 3 ,284 4 ,177 b ,529 ,067 ,427 ,293 c ,696 ,359 ,152 ,290 d ,580 ,488 ,149 ,318 e ,625 ,143 ,471 ,096 f ,684 ,118 ,347 -,105 g ,609 ,195 ,381 ,125 h ,767 ,417 -,050 ,089 i ,181 ,323 ,728 ,132 j ,387 ,697 ,369 ,104 k ,110 ,293 ,740 ,119 l ,174 ,732 ,317 ,000 m ,181 ,775 ,298 ,121 n ,542 ,611 -,078 ,358 o ,195 ,731 ,265 ,249 p ,378 ,490 ,123 ,478 q ,778 ,412 -,101 ,290 r ,149 ,136 ,505 ,221 s ,241 ,247 ,339 ,662 t ,100 ,089 ,166 ,821 Item reduction Iterative process based on : • Distribution of answers • Content analysis (items and response options are relevant and comprehensive of the dimensions) • Factorial analysis (to support the hypothesized scale structure, i.e. the combination of items into dimensions) 1- Have you hesitated about going to public places ? 2- Have you felt embarrassed with your friends ? 3- Have you felt embarrassed with your family ? 4- Have you cancelled any journeys, weekends away or outings ? 5- Have your digestive problems affected your love life ? 6- Have your digestive problems affected your sex life ? 7- Have you had to cancel personal or professional meetings ? 8- Have you been embarrassed with your work colleagues ? 9- Have your digestive problems affected your relationship with work colleagues ? 0% Not at all / never / not applicable A little bit / rarely Moderately / sometimes 25% 50% Quite a bit / often 75% 100% Extremely / always During the development of a HRQL questionnaire in irritable bowel syndrome, patients were asked to answer these items ranging from “not at all” to “extremely.” Results are presented as a percentage of patients. Discriminant validity of the Functional Digestive Disorders Quality of Life questionnaire (FDDQL) Number of symptoms Scores moyens FDDQL 100 [1-5] [6-10] 80 > 10 60 40 20 0 Activ ité quotidiennes Anx iété Alimentation Sommeil Inconfort Réaction face Contrôle de à la maladie International study : France, Germany, Great Britain 391 IBS and dyspeptic patients Chassany O, et al. Gut 1999. la maladie Stress Discriminant validity of the Health Assessment questionnaire adapted to Sclerodermia (SSc HAQ) Score values (m ± SD) of the global SSc HAQ and HAQ-DI, according to the number of the following organ involvements (n=6): • Raynaud’s phenomenon • Digital ulcers • Gastro-intestinal • Pulmonary • Musculoskeletal • Hand contracture 3 2,5 0 1 2 3 4 5 6 2 1,5 1 0,5 0 SSc HAQ HAQ-DI Comparison using ANOVA (p < 0.0001 for both scores) (n=100 patients) HAQ-DI: Health Assessment Questionnaire – Disability Index; Global SSc HAQ = (8 HAQ-DI domains + 5 VAS)/13. Validation of French version of the scleroderma health assessment questionnaire (SSc HAQ). Georges C, Chassany O et al. Clinical Rheumatology, Under press. Discriminant validity of a Lipodystrophy specific quality of life questionnaire 100 Global Quality of Life score (ABCD) impairs with the number of sites of lipodystrophy (n = 155) 90 80 85 70 71 64 60 56 50 54 45 40 42 score min-max : 0-100 [0 = worse quality of life, 100 = good quality of life] ANOVA, p < 0.001 30 20 10 0 0 1 2 3 4 5 6 Number of lipodystrophy regions r = 0.39 Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life questionnaire in Lipodystrophy (ABCD) Convergent validity of a Lipodystrophy specific quality of life questionnaire Logical correlation between Global ABCD score and generic quality of life (SF-12) (n = 155) Score résumé physique du SF-12 (PCS) vs Mental Component 70 Summary (MCS), r = 0.65 60 50 40 30 20 vs Physical Component Summary (PCS), r = 0.101 60 50 40 30 20 10 0 20 40 60 80 Score de qualité de vie ABCD 100 0 20 40 60 80 100 Score de qualité de vie ABCD Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life questionnaire in Lipodystrophy (ABCD) Convergent validity of a Lipodystrophy specific quality of life questionnaire General Health Physical Function Role Physical Social Function Cognitive Function Pain Mental Health ABCD QoL score 0.51 0.37 0.21 0.63 0.48 0.48 0.68 Energy/Fatigue Health Distress Global QoL Health Transition 0.59 0.70 0.56 0.22 MOS-HIV Logical correlation between some dimensions of the MOSHIV, e.g. the health distress, mental health and social function (r > 0.6) Sensibilité au changement - Questionnaire d’éducation dans l’asthme (CHU Montpellier) Évolution des scores entre la première (n = 96), la 2e (n = 67) et la 3e visite (n = 21) au cours d’un programme d’éducation G3 G2 G1 F3 E1 B3 F2 0 F1 0 E3 20 E2 20 D3 40 D2 40 D1 60 H1 Scores des 6 domaines explorant le comportement face à des scénarios cliniques 70 H2 H3 I1 100 60 80 50 60 40 30 40 SG CONN ALT3 0 SG CONN ALT2 20 SG CONN ALT1 Score global SG CONN3 SG COMP ALT3 SG COMP ALT2 SG COMP ALT1 Sg COMP3 SG COMP2 0 SG COMP1 10 SG CONN2 20 I2 I3 Scores des 2 domaines explorant les connaissances SG CONN1 B2 60 B1 80 AC3 80 AC2 100 AC1 100 Cultural adaptation and Linguistic validation • • • • • Objective: Conceptual equivalence between the source questionnaire and the target version There is no consensus, however the major steps recommended remain the same Forward translation: – independent translations (source target language) – Reconciliation meeting to obtain a consensual version Backward translation: – independent translation (target source language) – Comparison of the source questionnaire with the "backward" translation to check the conceptual content of forward version Cognitive debriefing: – Structured and in-depth interviews to test their understanding / interpretation of the translation of each item Cultural adaptation - forward/backward translation Source (FR) Vous êtes-vous senti(e) mal dans votre peau ? Problem idiomatic expression Forward Have you felt ill at ease ? backward Vous êtes-vous senti mal à l’aise ? Problem Original concept is not correctly translated Final Have you felt unhappy with yourself ? Chassany O, et al. Validation of a specific quality of life questionnaire in functional digestive disorders Chassany O, et al. Gut 1999. (FDDQL). Gut 1999. Cultural adaptation - forward/backward Disease: Asthma - Original version developed in Canada Item: Here is a list of activities in which some people with asthma are limited, among them: « shoveling snow » • Canada (US) • Japan • Norwegian Shoveling the snow Cultural adaptation - forward/backward Disease: Asthma - Original version developed in Canada Item: Here is a list of activities in which some people with asthma are limited, among them: « shoveling snow » • Canada (US) Shoveling the snow • Japan Beat futons • Norwegian Cultural adaptation - forward/backward Disease: Asthma - Original version developed in Canada Item: Here is a list of activities in which some people with asthma are limited, among them: « shoveling snow » • Canada (US) Shoveling the snow • Japan Beat futons • Norwegian Going fishing Cultural Adaptation Cultural adaptation All of the time Most of the time Some of the time c. … upset that I can’t control my body. f. … confused about how much to exercise. g. … feel discomfort or pain. h. … embarrassed about how I look. i. … worry that my HIV is getting worse. j. … upset that people may think I am sick. a. … feel frustrated because clothes don’t fit A little of None of the time the time right. Cultural adaptation of Assessment of Body Change and Distress (ABCD) in Lipodystrophy (HIV/AIDS) Questionnaire ABCD : Item Q8c (Problème de la traduction de “upset”) Original MB CE Version 1 Version 4 Back DE Finale c. … upset that I can’t control my body. c …. je me suis senti(e) triste parce que je ne pouvais pas contrôler mon corps c. … j’ai été contrarié/e de me rendre compte que je n’avais plus le contrôle de mon corps c. … j’ai été contrarié/e inquiet(e) de me rendre compte que je n’avais plus le contrôle de mon corps. c. … j’ai été contrarié/e de ne plus avoir le contrôle de mon corps. c. … I was upset about losing control of my body c. … j’ai été contrarié/e de ne plus avoir le contrôle de mon corps. Def : To distress or perturb mentally or emotionally, to disturb, to sadden, to trouble, to offend, to disappoint Duracinsky M, Chassany O. Linguistic and psychometric validation in french of a specific quality of life questionnaire in Lipodystrophy (ABCD) Cultural adaptation How often did your asthma make you feel frustrated during the past week? To prevent from accomplishing a purpose or fulfilling a desire. To cause feelings of discouragement Literal translation in French : frustré Backward translation : offended, dispossessed, injured, shocked Responsiveness - specific questionnaires Specific questionnaire : responsiveness ? HRQL is not improved by drugs in Chronic heart failure ? MLwHF Placebo 6.25 mg 12.5 mg 25 mg (0-105) Baseline 47.7 45.8 43.9 43.6 Mortality at 6 months 16 14 12 Endpoint 10 8 40.4 38 36.5 38.2 Minnesota Living with Heart Failure MLwHF : 21 items, 0 (best) - 105 (worst) 6 4 2 g 25 m g 12 ,5 m g 25 m 6, Pl ac eb o 0 Bristow MR et al. Circulation 1996. Double-blind, placebo-controlled trial (n=345), 6 months, 3 doses of carvedilol (beta-blocker) Responsiveness - generic questionnaires Psychological General Well-Being (PGWB) & GERD HRQL is not improved by gastro-oesophageal reflux disease drugs ? Résolution des symptômes à 4 semaines 122 Global PGWB score 80% J0 60% 40% 20% 4 semaines 102 82 62 42 22 Ome 20mg 0% Ome 20mg Ome 10mg Cis 10mg 24% difference in pyrosis relief Galmiche JP, et al. Aliment Pharmacol Ther 1997. Ome 10mg Cis 10mg No difference in PGWB score . Predictive value of Quality of Life ? Is health-related quality of life among older, chronically ill patients associated with unplanned readmission to hospital ? 163 Australian, chronically ill patients (67 ± 16) discharged to home following acute hospitalization HRQL (SF-36) assessed at one month post-hospital Patients were followed-up for six months thereafter to determine subsequent incidence of unplanned readmission On multivariate analysis : SF-36 physical component score < 40 (OR = 2.2, p = 0.05) Is health-related quality of life among older, chronically ill patients associated with unplanned readmission to hospital ? Pearson S et al. Aust N Z J Med 1999; 29: 701-706 Specific Cystic Fibrosis Questionnaire (CFQ) French Cystic Fibrosis Questionnaire : • CFQ-14 for teenagers & adults • CFQ Child P : a parent-proxy evaluation for children aged 8-13 • 33 interviews patients & parents : - Item generation • Cross-sectional survey among 393 patients & parents : - Item reduction - Internal consistency, convergent and discriminant validity • 124 patients & 85 parents : - Subscale structure (Rasch analysis…) - Reproducibility and responsiveness 9 • • • • • • • • dimensions : physical functioning energy/well-being emotions social limitations role, embarrassment body image eating disturbances treatment burden Development of the Cystic Fibrosis Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Henry B, et al. Qual Life Res 2003; 12: 63-76. Cross-cultural adaptation of questionnaires is not enough ? • • • • Specific CFQ-14 developed in France Translated in German Studies in n = 197 and n = 103 adolescents/adults Construct validity : same 9 HRQL domains as in the French original CFQ-14 • Internal consistency : ranged from 0.71 to 0.94 • Clinical validity : supported by severely ill patients reporting lower HRQL than less ill patients The revised German Cystic Fibrosis Questionnaire: validation of a disease-specific health-related quality of life instrument. Wenninger K et al. Qual Life Res 2003; 12: 77-85. “Validated” scale is not enough • A validated scale doesn’t imply systematically that it is relevant for the population studied • e.g. even for the so well-known SF-36 applied in a given condition, the issue of its relevance should be addressed… – e.g. SF-36 in IBS – MOS-HIV validated before HAART • Moreover some scales are getting old… Choice of a PRO questionnaire - Importance of the sample included during the validation process Climbing upstairs 41,7% Doing housew ork 37,2% Having sex 32,4% Walking one block 31,6% Playing w ith children 29,1% Talking 28,7% Carrying groceries 28,7% Cooking 27,9% Doing regular social activities 27,9% Doing home maintenance 26,7% Dancing 26,7% Going for a w alk 26,3% Visiting w ith friends or relatives 23,9% Mopping or scrubbing the floor 20,2% Jogging, exercising, or running 19,4% Playing sports 17,4% Singing 17,0% Bicycling Playing w ith pets Importance of various areas of limitations due to asthma among Harlem emergency department users (n =247) mostly Afro-american patients with a low socioeconomic status and a lower compliance 10,9% 8,1% Asthma-related limitations in sexual functioning: an important but neglected area of quality of life. Meyer IH, et al. Am J Public health 2002; 92: 770-772. Study Design : specific issues related to HRQL / PRO measure • Eligibility criteria : if HRQL primary endpoint, set a minimal impairment of HRQL (as for other criteria, e.g. pain, asthma onset… ) • Timing and frequency of HRQL assessment : – At baseline, at the end of the study or at withdrawal • Length of the trial (relevance of short term trials ?) • Mode and site of HRQL administration : – Self-administered whenever possible – Assure the confidentiality – Before the medical consultation • Data monitoring and quality assurance • Procedures for prevention and handling of missing data Chassany O et ERIQA Working Group. Patient Reported Outcomes (PRO) and Regulatory Issues : A European Guidance Document for the improved integration of health-related quality of life assessment in the drug regulatory process. Drug Information Journal 2002. Basic principles of RCTs fulfilled ? Placebo effect is also strong for HRQL • Double-blind sham surgery-controlled trial designed to determine the effectiveness of transplantation of human embryonic dopamine neurons into the brains of persons with advanced Parkinson's disease • Study investigated the quality of life (HRQL) of participants during the 1 year of double-blind follow-up • In all cases, those who thought they received the transplant reported better HRQL (physical, emotional and social) scores McRae C, et al. Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry 2004; 61: 412-420 Statistical analysis plan : Estimating the adequate sample size • • • • HSQ (Health Status Questionnaire) before / after scores on 1300 patients All p values < 0.0001 Conclusion: all HRQL domains were significantly different across treatment groups • Problem: 1300 provide 80% power to detect a change of 1 unit on a 0-100 point scale JCO 2001 (anonymous) Importance of withdrawals and missing data N = 365 (394 randomized) Poorer HRQL scores Assessment of quality of life by patient and spouse... Testa MA et al. Am J Hypertens 1991; 4: 363-73. Statistical analysis plan : PRO multiplicity Salmeterol / COPD • • • • • • • SF-36 Assessment 3 months 6 months 9 months 12 months 36 8 (+1) dimensions Open label " Salmeterol 50 g " or SR Theophylline bid " Randomized (n = 178) Number of tests Completers (n = 145) HRQL (secondary) : SF-36 Mean changes between baseline and the 4 assessments over time, for each dimension : Student t test (n = ???) in favor of Salmeterol Physical Functioning (PF) Change in Health Perception (HT) Social Functioning (SF) Assessment 3 months 9 months 12 months p 0.02 0.03 0.04 Efficacy, tolerability and effects on HRQL of inhaled Salmeterol in COPD. Di Lorenzo G et al. Clin Ther 1998. Interpreting PRO results ? Zk vs Pl p Daytime symptoms (0 to 3 (severe)) - 0.14 < 0.001 Nighttime awakening (per wk) - 0.63 < 0.001 2 agonist use (puffs/day) - 0.64 < 0.001 FEV1 Morning PEF (BL : 362) 0.05 0.331 + 13,1 L/min < 0.001 Evening PEF (BL : 398 + 11,5 L/min < 0.001 Global AQLQ score (BL : 4.28) + 0.26 0.004 Zafirlukast improves asthma symptoms and HRQL in patients with moderate reversible airflow obstruction. Nathan RA et al. J Allergy Clin Immunol 1998. Marquis P, Chassany O, Abetz L. A comprehensive strategy for the interpretation of quality of life data based on existing methods. Value in Health 2004 ; 7 : 93-104. How to evaluate drugs when clinical relevance of results is not obvious ? Mean score ± SD p < 0.05 and IC95 HRQL Pain VAS YES ? p < 0.05 OK Responders MID Interpretation of results - Effect size • Treatment in claudication (Peripheral Arterial Occlusive Disease) • Phase III, randomized, double-blind, vs placebo Endpoint Effect Size Walking distance Specific HRQL questionnaire (CLAUS) 2.13 0.48 Effect size (Distribution-based approach) Dividing a difference between 2 groups by the SD Dossier for Drug Approval File for Approval - AFSSAPS Effect Size Small Moderate Large Benchmark > 0.20 > 0.50 > 0.80 Interpretation of results - Effect size Longitudinal validation study : Effect Size (ES) of a symptomatic specific questionnaire (EEV) and the SF-36 calculated from the change as perceived by over 100 patients with vertigo after 4 weeks of treatment Generic quality of life SF-36 European Evaluation of Vertigo (EEV) Global score Mental Health Role Emotional Instability Social Functioning Neurovegetative signs Vitality Health Perception Motion intolerance Bodily Pain Duration of illusion Role Physical Illusion of m ovem ent Physical Functioning 0 0,5 1 1,5 2 Effect size (Distribution-based approach) a difference between 2 groups by the SD FileDividing for Approval - AFSSAPS 0 0,2 0,4 0,6 0,8 Effect Size Small Moderate Large Benchmark > 0.20 > 0.50 > 0.80 Minimal Important Difference (MID) MID obtained from comparison with a Global Rating Answer to the GLOBAL RATING change* A very great deal Worse Better Interpretation of change -7 +7 Large Mean change in HRQL scale (range 1-7) 1.5 A great deal A good deal Moderately -6 -5 -4 +6 +5 +4 Moderate 1.0 Somewhat A little -3 -2 +3 +2 Small 0.5 Almost the same About the same -1 +1 * “Overall, has there been any change in your shortness of breath during your daily activities since the last time you saw us ?” Guyatt GH, Juniper EF. Several publications Minimal Important Difference (MID) or change DEPENDS ON WORDING Changes in AQLQ symptom-domain anchored to global Asthma control global Global category Average Worse Minimally worse No change Minimally improved Asthma change global n 3 - 0.04 0.13 49 0.35 102 0.78 135 1.48 18 Average n 3 - 1.05 0.18 11 0.33 45 0.42 86 0.85 121 Improved n = 343 (mild to moderate asthma) Global asthma control question : “How well is your asthma controlled?” Global asthma change question : “Overall has there been any change in your asthma since the beginning of the study ?” AQLQ : Response from 0 to 6 (poorly controlled / much worse) Barber BL et al. Qual Life Res 1996. Minimal Important Difference (MID) MID obtained from comparison with a Global Rating may be different according to : • Wording of the Global Rating • Improvement vs. worsening • Characteristics of patients (age, gender…) • Characteristics of disease (severity …) • Setting of the trial, type of intervention • Cross-cultural differences • Baseline level of scores … Currently, there is no consensus, whether to be relevant, MID should be > 0.5 on a range score from 1 to 7 Impact of the global on patient perceivable change in an asthmatic specific QOL questionnaire. Barber BL et al. Qual Life Res 1996. Minimal Important Difference (MID) PGWB (1) MID [range of the scale] Corresponding MID on a range scale 0-100 3 [0-110] (2) 8 [0-110] (3) SGRQ 4 [0-100] AQLQ (4) 0.5 [1-7] 2.7 7.3 4 7 CRQ 4) 0.5 [0-6] 7 6 [0-100] (GR : little better) 13 [0-100] (GR : much better) I-QOL (4) SF-36 10 [0-100] 6 13 10 Dyspnoea index (5) 1 [-3, +3] 14 VAS pain (4) 2 [0-10] 18 (1) Informal meeting with Harold Dupuy (Paris, June 2003), (2) group level, (3) individual level (4) values obtained by correlation with a global rating (GR) (5) Baseline and transitional dyspnoea index (BDI/TDI) How many and which PRO domains should improve for a claim ? (PAOD) • HRQL primary endpoint using the specific questionnaire : CLAU-S (9 domains, 80 items) 8 Naftidrofuryl Placebo 6 4 • Results : 2 domains significantly 2 improved with drug (daily life, p=0.004; pain, p=0.001) 0 • Should the planners have Domains The effects of naftidrofuryl on quality of life. Liard F et al. Dis Manage Health Outcomes 1997. ta lity Vi ue Fa tig sio n ty es ep r D e xie An cia l lif ts So pl ai n Pa C om lif ai ly D domains would improve? e hypothesized that only these 2 in -2 An ge r Arteriopathy Occlusive Disease 10 Change score • 234 Patients with Peripheral How many and which PRO domains should improve for a claim ? • 90 (6 x 15) statistical tests • Difference of 0.2 (range 1-7) at 3 months • No difference at 12 months Abstract “Aerobic grouptraining of elderly patients recovering from an acute coronary event beneficially influences physical fitness and several parameters expressing quality of life” Symptoms - Chest pain - Shortness of breath - Dizziness - Palpitation - Cognitive ability Alertness Quality of sleep Physical ability Daily ability Depression Self perceived health Ladder of life: future Fitness Physical activity J3 J12 NS <0.05 NS <0.05 NS NS NS NS NS NS NS NS <0.05 <0.01 NS NS NS NS NS NS NS NS NS NS NS NS NS NS Stahle A et al. Improved physical fitness and HRQL following training after acute coronary events. Eur Heart J 1999. How many and which PRO domains should improve for a claim ? Antacid in GERD • Randomized, placebocontrolled, double-blind trial • Primary endpoint : heartburn (diary) • Secondary endpoint : SF-36 questionnaire • Sample size > 230 • Duration : 28 days SF-36 domains PF RP BP HP VT SF RE MH Score differences at 4 wks antacid vs placebo <3 <7 <3 <3 <3 <3 <3 <4 p Effect size NS NS NS NS < 0.04 < 0.05 NS < 0.03 0.15 < 0.15 0.20 < 0.15 < 0.25 < 0.10 0.20 < 0.20 Justification of measuring HRQL at 4-wk (and not after 6 months of taking 3 to 6 pills/day) ? • Why no difference with placebo on Bodily Pain domain (BP) ? • Number Needed to Treat on the primary endpoint is 20 patients for one to reduce its heartburn by over 50% French Drug Agency 2003 • PROs are not a regulatory issue for EMEA, but… • Many PROs such as symptom scales are wellestablished since decades • But, nobody knows how to assess Pain : – Which tool ? (evidence of validation) – When ? – Period of time ? – Which question ? – Minimal important change ? • Osteoarthritis (10 mm on 0-100 mm VAS ?) • Irritable Bowel Syndrome (10% difference ?) Nobody knows if a 9 % difference of responders in IBS is worth giving a claim? • Tegaserod / Irritable Bowel Syndrome • Endpoints: – “did you have satisfactory relief of your overall IBS symptoms during last week?” – “did you have satisfactory relief of your abdominal discomfort or pain symptoms during last week?” • Responder : satisfactory relief for at least 3 out of the 4 first 4 weeks • Relief of overall IBS symptoms 33.7 vs 24.2 (placebo) 9.3% • Relief of abdominal discomfort/pain : 31.3 vs 22.1 9.1% European mutual procedure (2004-2005) Because PROs (including HRQL) are unavoidably part of the Approval decision Example of an IBS drug (mutual recognition) • Small difference on pain versus placebo (primary endpoint) • Tertiary endpoints (quality of life, satisfaction, utility and work productivity) bring consistency with the other endpoints, and they may thus reinforce the rather small clinical benefit observed on the co-primary endpoints, and thus enhance the benefit/risk ratio • Not only patients tend to feel a little bit better for pain and symptoms, but they express a small improvement in some aspects of their daily life, and they are a little bit more productive for work January 2005 5 key issues for Drug Approval Process HRQL (and PRO) to be considered as a credible criterion if there is enough evidence (in the file) about the : 1- Added-value of HRQL/PRO with respect to other criteria 2- Psychometric properties of the HRQL/PRO instruments 3- International validation of the HRQL/PRO instruments 4- Adequacy of the statistical analysis plan 5- Clinical significance of observed changes Based on a meeting with representatives of AFSSAPS, EMEA and ERIQA Working Group, Paris, 1999 Chassany O et ERIQA Working Group. Patient Reported Outcomes (PRO) and Regulatory Issues : A European Guidance Document for the improved integration of health-related quality of life assessment in the drug regulatory process. Drug Information Journal 2002. Review of a dossier : Example of misuse/abuse Anti-emetic (chimiotherapy) • National procedure • Module 2 (clinical overview) • Claim wanted : « XX gets an advantage in term of quality of life … » • Functional Living Index Emesis (FLIE) questionnaire presented as HRQL (secondary endpoint) → 18 items (9 same items for nausea and vomiting) → Certainly not multidimensional HRQL • Interest of measuring so-called HRQL the day after 5 days of anti-emetic treatment ? → very small if any September 2004 Review of a dossier : Example of misuse/abuse What are the results 1st study ? • 2 items with a statistical difference (+ 1 or 2 points on a 7-point scale at p = 0.07) XX vs comparator • No double-blind • At least 18 tests • Relevance of difference ? • Global score : statistical difference (p = 0.0885) What are the results 2nd study ? • No difference XX vs comparator • Double-blind • Intent to treat : 200 • FLIE analyzed in only 151-177 patients (n = 131 for global score) – Where are patients and why are they missing ? Review of a dossier : Example of misuse/abuse Conclusions • • • • Useless to measure HRQL at 5 days FLIE is not measuring HRQL but impact on daily function* Methodological flaws The allegation « XX gets an advantage in term of quality of life … » is not supported by data • A similar dossier of another anti-emetic (aprepitant) presented FLIE more as what it is really measuring : Patient-Reported Impact on Daily Life * Guideline on non-clinical and clinical development of medicinal products for the treatement of nausea and vomiting with cancer chemotherapy, CPMP/EWP/4937/03, February 2005 Guideline européenne sur la qualité de vie EMEA/CHMP/EWP/139391/2004 Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products Adoption by CHMP : July 2005 Date for coming into effect : January 2006 http://www.emea.eu.int Why there are so few HRQL mention in labelling ? • The lack of experience and training of the reviewers and regulators • The fears (legitimate) of the regulatory authorities to officially acknowledge the PRO and to take into account a subjective criterion by nature : – Whose clinical interpretation remains difficult – Whose good practices of advertising remain to be specified in a market where competition is rough – Without counting the possibility for a drug which would have shown a substantial benefit on HRQL/PRO, to have claim in terms of rate of refunding, or price Need for improving advertisements How is defined a upholding of Well-Being ? Physical Well-Being 1 single item ranging from 0 (very good) to 4 (very poor) French Drug Approval (1999) What were hypotheses ? In protocol : Quality of life = “Time lost from usual daily activities” Better result in placebo group : less time lost (not disclosed in the publication) Comparison of Proton Pump Inhibitors in Gastro-oesophageal Reflux Disease PRO endpoint, as useful as spirometry What can one wish for the future ? • Training of reviewers and regulators to HRQL & PRO WORKMAT : Educational Program for Reviewers • Appropriation and adaptation by regulatory agencies of the published recommendations Guidelines FDA European Position Paper (EWP) ? • Questionnaires constantly in adequacy with the beneficial and harmful effects of the new treatments • Choice among the various questionnaires, of those which have the best psychometric properties (responsiveness) • That HRQL and PRO be part of the daily medical-decision making What can one wish for the future ? Should we develop questionnaires for specific subgroups (e.g HIV) ? Women Quality of life among women living with HIV: the importance violence, social support, and selfcare behaviors. Gielen AC et al. Soc Sci Med 2001. Injection drug users Psychological distress and quality of life in drug-using and non-drug-using HIV-infected women. Vaarwerk MJ et al. Eur J Public Health 2001. Aging Successful aging among people with HIV / AIDS. Kahana E et al. J Clin Epidemiol 2001. Children - adolescents Evaluation of life quality for children infected by HIV: validation of a method and preliminary results. Nicolas J et al. Pediatr AIDS HIV Infect 1996. Family The family context of HIV: a need for comprehensive health. De Matteo D et al. AIDS Care 2002. According to religion Relationships of religion, health status, and socioeconomic status to the quality of life of individuals who are HIV positive. Flannelly LT et al. Issues Ment Health Nurs 2001. Measuring HRQL in routine oncology practice improves communication and patient well-being • Routine assessment of cancer patients' HRQL had an impact on physician-patient communication and resulted in benefits for some patients, who had better HRQL and emotional functioning Velikova G, et al. Measuring quality of life in routine oncology practice improves communication and patient well-being: a randomized controlled trial. J Clin Oncol 2004; 22: 714-724