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Patient Reported Outcomes Lowell E. Schnipper, M.D. Berenson Professor of Medicine Harvard Medical School Chief, Hematology-Oncology Beth Israel Deaconess Medical Center Question PROs and HRQoL is of diminishing importance in the era of emerging targeted therapies? True? False? Patient Reported Outcomes: Why? Cancer often an incurable illness Improvement in patients HRQoL is an expectation of appropriate therapy Palliation is often the goal HRQoL is the product of Patient Reported Outcomes Value to the Clinical Trials Process Provide information about toxicity Symptom relief These often are primary or secondary clinical trial endpoints In the clinical setting HRQoL assessments can have predictive value for survival Subjectivity and Objectivity HRQoL is not subjective in the usual sense of the term It can be measured accurately in an individual, and in a group It is “subjective” in that it derives from the human subject of research or clinical practice 1. What is HRQOL? 2. What Should You Measure? 3. How Should You Measure it? 4. How is it incorporated into clinical research Health-Related Quality of Life (HRQOL) Assessment Health Related Quality of Life (HRQoL) Includes a number of domains Physical functioning: ranges from normal to complete impairment Psychological well-being (depression, anxiety, fear of recurrence) Social functioning P. Ganz, personal communicationt HRQoL Dimensions Physical FunctioningSpirituality Occupational/Role FunctioningFutureOrientation Social FunctioningSexuality/Intimacy Emotional Well-being Health Concerns Symptom StatusFamily Well-Being Financial ConcernsSatisfaction w/Care Global/Overall Perception of Quality of Life HRQOLHRQOL FunctionalFunctional StatusStatus GlobalGlobal RatingsRatings SymptomsSymptoms Quality of LifeQuality of Life What Should You Measure? HRQOL Assessment Definitions Instrument = Questionnaire “Item” = Question “Domain” = Dimension = Area of Behavior or Experience “Cross-Sectional Design” Compares 2 or More Populations at One Point in Time “Longitudinal Design” Assesses Changes in HRQOL Over Time in 1 or More Populations Types of QOL Instruments Health profiles-descriptive questionnaires-measures by a simple metric different aspects of HRQoL across multiple domains Generic, multi-dimensional Disease-specific, multi-dimensional Condition-specific, multi-dimensional uMeasure of Functioning Focus May be Generic or Disease-Specific Functional Status Domain Specific Linear Analog Self-Assessment Place an “X” at a point on the line that best represents how you have felt over the past two weeks. Your Mood HappyMiserable X Simple Average Sum or Mean of Item or Subscale Scores to Yield a Global Score This Approach Weights each Item Proportional to its Variance in the Population Under Study Example: Quality of Life Index Aggregated Scores Quality of Life Index Quality of Life Index HRQOLHRQOL Symptoms Functional Status Global Ratings Symptoms Focus: Disease (e.g., asthma, CHF, cancer, lung cancer) Type of symptom (e.g., pain) Dimension(s): Frequency Severity Distress Interference with activities HRQOLHRQOL Symptoms Functional Status Global Ratings Single Assessment of Overall Health or HRQOL Global Ratings Example: E-V-G-F-P How would you describe your overall state of health CHECK ONE? Excellent Very Good Good Fair Poor Why Should You Measure It? HRQOL Assessment Operational Definition HRQOL Assessment Adds Value IF HRQOL Data Can Influence Overall Conclusions of the Study HRQOL: Value Added Nature of the Value Added Depends on Overall Study Goals evaluating the effectiveness of interventions characterizing treatment-specific outcomes for use in shared decision making characterizing the burden of illness predicting patient outcomes quality-adjusting survival for resource allocation and other policy decisions Study Goals Question HRQoL is relevant to which type(s) of clinical trials: a.Phase I b.Phase Ib/II c.Randomized phase II trial d.Prospective randomized trial e.All of the above Depends On 1. Phase of the Trial 2. Natural History of Disease Evaluating Effectiveness Type of Clinical Trial and PRO Phase I: not critical-goal is primarily to define MTD or optimal biologic dose Phase II: can be used but not essential An opportunity to collect pilot data for use in phase III trial Phase III-HRQOL data is essential in this context Tailoring study design to the natural history of the disease l3 paradigms: Chronic and/or recurrent, non-lethal diseases Lethal but curable diseases Lethal, incurable diseases Chronic and/or recurrent, non- lethal diseases Effectiveness: relief of disease-related symptoms minimal treatment-related toxicity What outcomes do you need? Primary: Disease-related symptoms Secondary: Treatment-related symptoms Global rating Functional status Utilities (if CEA is planned) Chronic and/or recurrent, non- lethal diseases Lethal but curable diseases Effectiveness: cure rates minimize toxicity Lethal but curable diseases What outcomes do you need? Primary: Survival Secondary: Utilities (if CEA analysis is planned) treatment-related symptoms, functional status Lethal, incurable diseases Effectiveness: palliation prolongation of survival J. Weeks July 2006 Lethal, incurable diseases What outcomes do you need? Primary: Survival Functional status Disease-related symptoms Global rating Secondary: Utilities (if CEA is planned) J. Weeks July 2006 Information Patients Need Nature of Alternative Treatments Likely Outcomes from Treatments Descriptive Information for Each of the Possible Outcomes simple, transparent measures Supporting Shared Decision Making Characterizing the Burden of Illness To “Benchmark” Study Population generic health status measures To Identify Patient Needs domain-specific measures symptom-specific measures Predicting Outcomes Baseline HRQoL has been Shown to be an Independent Predictor for survival 30:473-83. EuroQoL (EQ-5D): Health Policy (1990);16:199-208. HRQoL Instruments Cancer-specific instruments Responsive to disease-related changes Cannot be used across populations with chronic disease Several are in common use because they are reliable and have been validated: Functional Living Index-Cancer: Shipper;JCO (1984); 2:427- 483 Modular instruments: combine a generic or “core” instrument applicable to a broad range of cancer patients with cancer-type specific questions FACT-C Gunnars, Acta Oncologica (2001);40:175-84. EORTC QLQ-C30, Aaronson JNCI (1993);85:365-367. HRQoL Instruments Domain Specific Instruments Designed to address one specific aspect of HRQoL Examples: Multi-dimensional Fatigue Inventory (MFI) McGill Pain Questionnaire Uses of HRQoL Instruments Outcome measure RCT evaluating treatment outcomes To qualify quantity of survival (e.g.,cost-effectiveness) Assess late physical/psychological problems Predictor Intervention Other Considerations Is the proposed analysis too taxing for the subject? must questionnaire be completed serially in light of possible attrition Is a proxy needed? will population include children, low literacy, non-English speaking, visually impaired, or cognitively impaired adults? HRQOL Assessment Other Considerations (contd) timing of assessments consistency across patients/groups critical responses influenced by recent experiences missing data avoid at all costs generally cannot be assumed to be at random specify methods for dealing in advance! multiple comparisons specify primary endpoints in advance HRQOL Assessment Make Your Final Choice Psychometric (responsive, valid, reproducible) properties validated in your population known and used in your field HRQOL Assessment Patient Reported Outcomes: Methodological Challenges The variety of questionnaires available Choice of time points Incomplete data (data attrition) Lack of pre-defined endpoints Response-shift over time of patient perceptions of HRQoL Psychological defenses tend to conserve perception of good HRQoL Question In a longitudinal study the best way to deal with response shift is to: a.Increase the sample size to dilute this effect b.Anticipate it by changing the scales used at longitudinal time points when making HRQoL measurements c.Use a pre-test (then test) and post-test set of questions at a follow-up visit to assess the degree of change (shift) in baseline attitude of HRQoL d.None of the above Examples from Examples from Completed TrialsCompleted Trials Developing a HRQoL instrument: Principles Phase III Breast Ca Trial 1. Dimensions: Physical, emotional and social well-being 2. Importance: items (questions) must reflect importance to patients 3. Quantifiable: summary scores must be amenable to statistical analysis 4. Validity: the instrument should be a true measurement of HRQoL 5. Reproducibility: the instrument should yield similar results in comparable patients 6. Responsiveness: the instrument should detect clinically important changes 7. Simplicity: the questionnaire should be short JCO 6:1798-1810, 1988 Developing a HRQoL instrument: Principles Item selection: Interview patients and determine what issues are important Winnow redundancies Breast cancer Questionnaire (BCQ): hair loss, emotional dysfunction, physical symptoms, trouble and inconvenience associated with treatment, fatigue, nausea, positive well-being BCQ contained 30 questions, Likert scale administered by an interviewer, and took 10-15 minutes: 7 points-patients asked to recall how they had been feeling over a defined period (2 weeks in this case). Maximum score on scale equates with most minimal deficit Final score expressed as mean of the score on the 30 questions JCO 6:1798-1810, 1988 Developing a HRQoL instrument: Principles Co-administration of several additional questionnaires, e.g., Spitzer QoL, Rand Physical and Emotional Status, Karnofsky score (by physician) Each questionnaire was administered at intervals throughout study treatment period and up to 72 weeks. JCO 6:1798-1810, 1988 Developing a HRQoL instrument: Principles BCQ had the best correlations with the Rand Physical and Emotional surveys and the Spitzer QoL instrument (Correlation coefficients approx. 0.6) Not surprisingly the prolonged treatment demonstrated a significant dip in QoL using the BCQ and Karnofsky scores during the extended treatment period. The BCQ correlated better with the patients assessments of her QoL. JCO 6:1798-1810, 1988 Prednisone +/- Mitoxantrone in Hormone Resistant Prostate Cancer Randomized controlled trial Palliation as an end points: 2 point reduction in the McGill-Melazak Pain questionnaire Approval of Mitoxantrone for this indication based upon positive QoL findings Tannock, JCO (1996);14:1756-64 Prednisone +/- Mitoxantrone in Hormone Resistant Prostate Cancer Instruments employed: Prostate Cancer-Specific QoL Instrument with 9 linear self-assessment scales (pain, physical activity, appetite, constipation, etc.) EORTC/QLQ-C30: contains multi-item domains for physical function, emotional function, pain, global QoL Tannock, JCO (1996);14:1756-64 Prednisone +/- Mitoxantrone in Hormone Resistant Prostate Cancer Results: Favored M+P for pain (38% reduction), physical activity, constipation and mood QoL parameters (PS, pain intensity and serum alk Phos) significant predictors of OS-PSA was not! Could be expanded to include cost effectiveness (cost per quality adjusted life year gained) Tannock, JCO (1996);14:1756-64 Question In the mitoxantrone/Prednisone trial just discussed, how would do you account for missing data? Question a. Anticipate attrition, identify a proxy at the point at which the patient is unavailable b. the sample size should be large enough to dilute the effect of missing data c. anticipate loss of patient availability and identify proxies at the start of the study d. use of a proxy will never provide validated data in a study in which HRQoL is an important endpoint R R A A N N D D OO MM I I Z Z E E Bilateral Orchiectomy* + FlutamideBilateral Orchiectomy* + Flutamide *Within one week of registration*Within one week of registration . . Bilateral Orchiectomy* + PlaceboBilateral Orchiectomy* + Placebo JNCI 1998; 90: 1537-44 SWOG 8894: Hormonal Therapy of Advanced SWOG 8894: Hormonal Therapy of Advanced Metastatic Prostate CancerMetastatic Prostate Cancer SWOG 9039: QOL Companion to S8894 Activation History Therapeutic trial, S8894, opened 12/89 Therapeutic trial, S8894, opened 12/89 QOL Companion study, S9039, opened QOL Companion study, S9039, opened 10/9010/90 290/1387 patients registered to 290/1387 patients registered to therapeutic trialtherapeutic trial QOL sam