1. Quality of Life Assessment in Clinical Trials Adapted from www.biostat.wisc.edu/training/courses/542slides/09-qol.pdf Introduction to Clinical Trials Biostatistics and Medical Informatics University of Wisconsin at Madison

2. Why are we interested in Quality of Life (QOL)? The FDA has stated that efficacy with respect to overall survival and/or improvements in QOL might provide the basis for drug approval. The FDA has stated that efficacy with respect to overall survival and/or improvements in QOL might provide the basis for drug approval. Shaughnessy JA, Wittes RE, Burke G et al. Commentary concerning demonstration of safety and efficacy of Investigational anticancer agents in clinical trials. Journal of Clinical Oncology 1991 (9) 2225-32

3. Discussion Issues in QOL Background Background Data Collection Considerations Data Collection Considerations DeMets’ Perspective (Biostats professor at U Wisc) on QOL in clinical trials DeMets’ Perspective (Biostats professor at U Wisc) on QOL in clinical trials

4. Measuring QOL Happy Miserable How are you feeling today?

5. What is QOL? WHO: “Health is not only the absence of infirmity and disease, but also a state of physical, mental and social well-being.” WHO: “Health is not only the absence of infirmity and disease, but also a state of physical, mental and social well-being.” Multiple domains include: Physical, cognitive, emotional and social functioning, pain, sexual functioning, health perceptions, and symptoms about nausea and fatigue Multiple domains include: Physical, cognitive, emotional and social functioning, pain, sexual functioning, health perceptions, and symptoms about nausea and fatigue Fundamental Principle: QOL IS ASSESSED BY THE PATIENT Fundamental Principle: QOL IS ASSESSED BY THE PATIENT

6. QOL (1) Definition depends on context: Definition depends on context: Cancer vs. MI vs. hypertension Cancer vs. MI vs. hypertension Early instruments for measuring QOL were disease-specific Early instruments for measuring QOL were disease-specific Later instruments, “general health status” Later instruments, “general health status” POMS = Profile of Mood POMS = Profile of Mood SIP = Sickness Impact Profile SIP = Sickness Impact Profile Difficulties with Concept Difficulties with Concept No agreement on definition No agreement on definition Lack of standardized measures Lack of standardized measures

7. QOL (2) One definition (Levine and Croog) has two components: One definition (Levine and Croog) has two components: Functioning Functioning Social (major component): get along with family and friends Social (major component): get along with family and friends Physical: perform daily activities Physical: perform daily activities Emotional: stability and self-control Emotional: stability and self-control Intellectual: decision-making ability Intellectual: decision-making ability Perceptions Perceptions Life satisfaction: sense of well-being Life satisfaction: sense of well-being Health Status: compared to others Health Status: compared to others

8. Factors influencing QOL Interventions/Treatment Interventions/Treatment Disease Processes Disease Processes Labeling: diagnosis brings on ‘change’ Labeling: diagnosis brings on ‘change’ Concomitant Care Concomitant Care Non-related life events (e.g. death in the family) Non-related life events (e.g. death in the family)

9. Rationale in Clinical Trials QOL assesses effect of intervention/treatment QOL assesses effect of intervention/treatment Primary response (treatment less toxic?) Primary response (treatment less toxic?) Side effects (treatment toxic?) Side effects (treatment toxic?) Economic aspects (low risk/cost of treatment but high benefit?) Economic aspects (low risk/cost of treatment but high benefit?) Another setting: Treatment for pain Another setting: Treatment for pain Primary response (pain lessened?) Primary response (pain lessened?) Side effects (interact with disease? Other side effects?) Side effects (interact with disease? Other side effects?) Economic aspects Economic aspects

10. Assessing QOL Hardest part! Hardest part! Determine QOL objective Determine QOL objective Choose instrument to measure QOL Choose instrument to measure QOL Reliable, valid, responsive, feasible Reliable, valid, responsive, feasible Global measures, disease-specific measures, symptom checklists Global measures, disease-specific measures, symptom checklists Select assessment time points Select assessment time points Develop analysis plan Develop analysis plan

11. Data Collection Mode: self-administered vs. interview Mode: self-administered vs. interview Self-admin: Reading ability, fine-motor skills Self-admin: Reading ability, fine-motor skills Interview: Hearing problems, age/gender/ethnicity sensitivity, training of interviewer Interview: Hearing problems, age/gender/ethnicity sensitivity, training of interviewer Either: language Either: language Content Content Instrument validity, sensitivity, specificity Instrument validity, sensitivity, specificity Sensitivity of questions Sensitivity of questions Frame of reference (cognitive skills, privacy, cultural background) Frame of reference (cognitive skills, privacy, cultural background) Source(s) Source(s) Patient vs family vs health care provider Patient vs family vs health care provider

12. DeMets’ Perspective Off-the-shelf (i.e. general) instruments Off-the-shelf (i.e. general) instruments Designed to distinguish sickness from wellness Designed to distinguish sickness from wellness May not be sensitive to particular aspect of a given trial May not be sensitive to particular aspect of a given trial May not be validated or “normed” in population being tested May not be validated or “normed” in population being tested May ask silly questions for trial population May ask silly questions for trial population May take long time to complete May take long time to complete May impact negatively on compliance May impact negatively on compliance

13. DeMets Perspective “Tailor Made” Instruments “Tailor Made” Instruments Quick and simple Quick and simple Standardized but targeted to disease Standardized but targeted to disease Validated, normed to trial population Validated, normed to trial population Selects subsets of off-the-shelf instruments Selects subsets of off-the-shelf instruments Home-Made Instruments Home-Made Instruments Often designed by graduate student or comparable Often designed by graduate student or comparable Often too long Often too long Often not validated or ‘normed’ or field tested in the patient population of interest Often not validated or ‘normed’ or field tested in the patient population of interest

14. Analytic Issues “Measurement” “Measurement” QOL measured by multiple indicators QOL measured by multiple indicators Need validated overall ‘score’ Need validated overall ‘score’ Or, can use fancier multivariate methods Or, can use fancier multivariate methods Usually, treat ‘score’ as observed level of QOL and proceed with analysis. Usually, treat ‘score’ as observed level of QOL and proceed with analysis. Problems: Problems: sometimes the ‘score’ is not a valid measure of QOL in the patient population sometimes the ‘score’ is not a valid measure of QOL in the patient population These types of measures tend to be fraught with measurement error. These types of measures tend to be fraught with measurement error.

15. Other QOL issues Often interested in whether or not survival with poor quality of life is better than death without suffering. Often interested in whether or not survival with poor quality of life is better than death without suffering. “QALY”= Quality Adjusted Life Years “QALY”= Quality Adjusted Life Years Example: Example: Cancer: many patients would rather not get toxic therapies and have more enjoyable end of life Cancer: many patients would rather not get toxic therapies and have more enjoyable end of life The general idea is to down-weight time spent in periods of poor quality of life. The general idea is to down-weight time spent in periods of poor quality of life. Methodologically challenging: Methodologically challenging: How to determine the weights? How to determine the weights? Different settings might need different weights. Different settings might need different weights.

16. Quality Adjusted Survival QTWIST: Quality-Adjusted Time Without Symptoms of disease and Toxicity. QTWIST: Quality-Adjusted Time Without Symptoms of disease and Toxicity. Evaluate therapies based on both quantity and quality of life through survival analysis Evaluate therapies based on both quantity and quality of life through survival analysis Based on QALYs. Based on QALYs. Define QOL health states, including one with good health (minimal symptoms). Define QOL health states, including one with good health (minimal symptoms). Patients progress through health states and never back-track. Patients progress through health states and never back-track. Partition the area under the Kaplan-Meier Curve and calculate the average time spent in each clinical health state. Partition the area under the Kaplan-Meier Curve and calculate the average time spent in each clinical health state. Compare treatment regimens using weighted sums durations, weights are utility based. Compare treatment regimens using weighted sums durations, weights are utility based. Example: 5 year survival Example: 5 year survival 3 adjusted years of life Compare the average QTWIST in two treatment groups. Could be that on treatment A, people live longer, but QOL is worse. Quality of Life for Individual

17. References: www.biostat.wisc.edu/training/course s/542slides/09-qol.pdf www.biostat.wisc.edu/training/course s/542slides/09-qol.pdf Fairclough and Gelber, “Quality of Life: Statistical Issues and Analysis.” From Quality of Life and Pharmacoeconomics in Clinical Trials, Second Edition, ed. B. Spiker. 1996. Fairclough and Gelber, “Quality of Life: Statistical Issues and Analysis.” From Quality of Life and Pharmacoeconomics in Clinical Trials, Second Edition, ed. B. Spiker. 1996.