Quality of Life Measures in Clinical Trials

1. Quality of Life MeasuresinClinical Trials George A Wells Department of Epidemiology and Community Medicine University of Ottawa

2. Outcome Measures • Hard vs soft outcomes • Ranges of outcomes and their assessment • Statistical aspects • Criteria for development and selection of outcomes • Choosing efficacy parameters: types of endpoints

3. Patients desire the following… 1) to live as long as possible [death] 2) to be normally functioning [disability] 3) to be free of pain, psycological, physical, social and other symptoms [discomfort] 4) to be free of iatrogenic problems from treatments [drug s/e] 5) to remain solvent [destitution]

4. Statistical Aspects Levels of Measurement • nominal, ordinal, interval • discrete, continuous

5. … Statistical Aspects Relating two numbers (x,y) • incremental change x-y • proportional change (x-y)/y • percent change 100 (x-y)/y • proportion (of baseline) x/y • percent (of baseline) 100 x/y

6. Criteria for Development and Selection of Outcomes Comprehensive (content validity) - includes appropriate components of health Credibility (face validity) - appears sensible and interpretable Accuracy (criterion validity) - consistently reflects true clinical status of patients Sensitivity to change (discriminant validity) - detects smallest clinically important difference Biological sense (construct validity) - matches hypothesized expectations when compared with other indirect measures

7. Choosing Efficacy Parameters: Types of Endpoints • objective measurements (validated and accepted to represent appropriate efficacy criteria) • reduced or reversed disease progression • improved quality of life • reduced mortality • clinical global impression (physician, patient) • improved symptomatology of patient • biochemical measures (assessing underlying disease state)

8. Identifying the best endpoints … • influence physicians’ decision • combination of outcomes that’s most practical and useful • hard measurement • change in endpoint that would be clinically significant

9. Identifying the best endpoints … • References to quality of life • 1966-74 40 references • 1986-99 >10,000 references • FDA has 2 requirements for approving anticancer drugs: • improve survival • increase quality of life • Quality of life has been the focus of • numerous questionnaires and measurement instruments • many articles and conferences • policy • (increasingly) outcome in clinical trials

10. Quality of Life Endpoints in Clinical Trials • What is quality of life • Health measurement scales and quality of life • Generic versus specific quality of life • Advantages and disadvantages of quality of life measures

11. What is quality of life … Aristotle “… when it comes to saying in what happiness consists, opinions differ and the account given by the generality of mankind is not at all like that of the wise. The former take it to be something obvious and familiar, like pleasure or money or eminence and there are various other views, and often the same person actually changes his opinion. When he falls ill he says that it is health and when he is hard up he says it is money.” Pigou first coined the term QOL in 1920 in a book on economics and welfare

12. What is quality of life … World Health Organization (1948) Redefined health … “state of complete physical, mental and social well-being and not merely the absence of disease” Report on the President’s Commission on National Goals in the United States (1960) “… to examine the quality of individual’s lives” Elkington (1966) Editorial: Medicine and the Quality of Life … a single definition of quality of life remains elusive

13. What is quality of life … Kaplan “… impact of disease and treatment on disability and daily functioning …” Greer “… physical, emotional, social well-being after disease and treatment … ” Burlinger ”… impact of perceived health on an individual’s ability to live a fulfilling life …”

14. What is quality of life … Cella and Tulsky “… patients appraisal of and satisfaction with their current level of functioning compared to what they perceive to be possible or ideal…” Spilker “… the functional effect of an illness and its consequent therapy upon a patient as perceived by the patient …” Patrick and Erickson ”… the value assigned to opportunity, perceptions, functional states, impairment and death, associated with events or conditions as influenced by disease, injuries, treatment or policy …”

15. What is quality of life … Williams “… individuals perceptions of their position in life in the context of culture and value systems in which they live and in relations to their goals, expectations, standards and concerns …” Common theme: Patient centred and subjective

16. Domains Important in Measuring Quality of Life Schipper & Levitt • physical / occupational functioning • psychological functioning • sociability • somatic comfort

17. …Domains Important in Measuring Quality of Life Aaronson • disease, symptoms and treatment s/e • psychological functioning • sociability • somatic comfort

18. …Domains Important in Measuring Quality of Life Bonomi et al • physical • independence • social • psycological • spiritual • environmental

19. …Domains Important in Measuring Quality of Life Cella & Tulsky • physical concerns • functional ability • family well being • emotional well-being • spirituality • social functioning • treatment satisfaction • future orientation (planning, hope) • sexuality / intimacy • occupational functioning

20. Consensus Domains in Measuring Quality of Life • Physical function • Emotional / psychological function • Social • Symptoms of disease and treatment

21. Influences on Quality of Life 1) gender 2) culture 3) disease specific 4) spiritual 5) age

22. Properties of Quality of Life 1) multi-factorial / dimensions 2) subjective 3) time sensitive 4) patient centred 5) patients as their own control

23. Approaches / Concepts Used in Defining Quality of Life • Psychological approach • QOL reflects patients’ perceived illness side of the distinction between illness and disease (eg., hypertension) • Time-trade off utility concept • QOL is defined by patients’ willingness to trade-off years of life for suboptimal life • does not account for concepts such as adaptation • Ware’s community centred concept • QOL is defined by the ‘ripple’ effect of health events and interventions on the patients’

24. …Approaches / Concepts Used in Defining Quality of Life • Reintegration concept • reorganization of physical, psychological and social characteristics of an individual into a harmonious whole so that well adjusted living can be resumed after incapacitating illness / trauma • Calman’s principle • gap between patients’ expectations and achievements • gap between patients actual achievements and potential

25. Quality of Life Endpoints in Clinical Trials • What is quality of life • Health measurement scales and quality of life • Generic versus specific quality of life • Advantages and disadvantages of quality of life measures

26. Health Measurement • Reliability • Validity • Sensitivity to Change

27. Reliability Reflection of the amount of error, both random (mechanical inaccuracy, measurement mistakes) and systematic, inherent to any measurement Determines how reproducible is the scale under different conditions

28. Reliability The reliability coefficient expresses the proportion of the total variance in the measurements (denominator), which is due to true differences between subjects (numerator)

29. Reliability • Reproducibility • Test-retest reliability • Intra-rater reliability • Inter-rater reliability • Internal consistency of a scale (correlation among items composing an instrument)

30. Reliability: Reproducibility • Intra-class correlation (ICC) • (based on ANOVA) • Pearson’s r • Kendall’s index of concordance • Kappa coefficient • Bland and Altman

31. Reliability: Reproducibility • Other considerations: • Observations as fixed factor • test always done by same observers • same items completed by all • Observations as random factor • observer varies

32. Reliability: Reproducibility • Other considerations (cont’d): • Observer nested within subject • several subjects evaluated by several observers • no observer common to more than one subjects • One-way ANOVA • subject as grouping factor • multiple observations within each cell as ‘within-subject’ factor

33. Reliability: Reproducibility • Other considerations (cont’d): • multiple observations k • multiple items on questionnaire • multiple observers • repeated use of an instrument

34. Reliability: Internal Consistency • Represents the average of the correlations among all items in the measure • All the items should be ‘tapping’ different aspects of the same attribute • items should be moderately correlate with each other • each should correlate with the total scale score

35. Reliability: Internal Consistency • Item-total correlation • checks homogeneity of scale • correlation of individual item with scale score omitting that item • Pearson correlation (working rule: >0.2) • Split-half reliability • splits scale in half, each half is correlated with the other • Spearman-Brown • Kuder-Richardson 20 • scales with dichotomous items • Cronbach’s aplha • scales with ordinal items • should be >0.70 but <0.90 (item redundancy)

36. Reliability: Improving IT • Reduce error variance • observer training • elimination of extreme observers • improve scale design • Increase true variance • introduce items resulting in performance nearer middle of scale • modify descriptors on the scale • Increase number of items • as long as items not perfectly correlated

37. Validity Determine the degree of confidence we can place on inferences made based on the scores from the scale

38. Validity • Content • cover all domains of interest • sufficient number of items • inferred from experts • Criterion • test against a ‘gold’ standard • Concurrent • gold standard and the new instrument are applied at the same time • Predictive • Gold standard is applied in the future

39. Validity • Construct • if no gold standard exists • based on conceptual definition of construct to be measured • defines hypotheses of what should or should not correlate • Correlational Convergent • instrument tested should correlate with other methods that measure same concept Divergent • instrument should not correlate with other methods that measure different themes

40. Validity • Construct (cont’d) • Factorial analysis • examines how items measure one or more common themes • analysis forms the questions into groups or factors that appear to measure common themes with each factor distinct from the others • Multi-trait multi-method analysis • method for considering convergent and discriminant validity simultaneously

41. Validity • Evaluation using: • Correlations • Receiver operator characteristic (ROC) curves • 2x2 tables (sensitivity and specificity)

42. Sensitivity to Change Ability of an instrument to detect small but clinically important clinical Particularly important where subjective reports of health status is one of the primary outcomes of the trial

43. Sensitivity to Change • t-test • compares means at baseline and follow-up • Effect-size • relates changes in mean score (from baseline to follow-up) to the standard deviation of baseline score • ROC • Evaluate how a given change score can discriminate between patients who improve from those who do not

44. Quality of Life Endpoints in Clinical Trials • What is quality of life • Health measurement scales and quality of life • Generic versus specific quality of life • Advantages and disadvantages of quality of life measures

45. Generic versus Specific Generic Instrument designed to assess health related quality of life in a broad range of populations Specific Instrument designed for specific disease condition

46. Generic versus Specific Examples: Generic Sickness Impact Profile (SIP) Rand-36 Item Health Status Profile (SF-36) Examples: Specific Spitzer Quality of Life Index (QL) European Organization for Research and Treatment of Cancer Quality of Life (EORTC-QLQ)

47. Generic versus Specific • SIP • behaviourally based measure of health status • 136 items • 12 categories

48. Generic versus Specific • SF-36 • 36 items • 8 domains (health concepts): • Physical functioning • Bodily pain • Role limitation due to physical problems • Role limitation due to emotional problems • General mental health • Social functioning • Energy / fatigue • General health perception • 2 component scores: • Physical component score • Mental component score

49. Generic versus Specific • QL and EORTC-QLQ • cancer

50. Generic versus Specific Why use Generic or specific? • developed for appropriate population • differential weights given to each category • differential selection of categories Consequence: • specific indices are more responsive to change • generic indices give importance on overall well-being