1. Got outcome measures? What Clinicians & Investigators Want Lisa M. Shulman, M.D. The Eugenia Brin Professor in Parkinson’s Disease and Movement Disorders Department of Neurology University of Maryland School of Medicine

2. Disconnect Between Impairment & Disability Worse

3. Clinical Reality: Advanced Disease Severity Reported Disability… None to Severe Worse

4. Clinical Reality: Advanced Disease Severity Reported Health-Related QoL… Lo to Hi Worse Better

5. A Clinical Reality: Similar disease severity, but different experiences People with similar disease severity report very different levels of physical function and QoL

6. Why? Age Other Medical Conditions Treatment Side-Effects Quality of Medical Care Optimism & Resilience Support System Self-Management Skills Finances Responsibilities Depression, Anxiety Activity Level Emotional Stressors

7. Discrepancy Between Outcomes Impairment vs. Disability/QoL Reporting Investigators View: Poses a dilemma in trial outcomes Clinicians View: Important data in the clinical setting – Isn’t preservation of QoL in the setting of chronic illness our objective? Should a treatment be provided when… – Symptoms are reduced but benefit is not demonstrated on HRQoL measures? – Outcomes reveal statistical differences that are not clinically important?

8. Efficacy vs. Clinical Effectiveness Efficacy trials – Study relatively short term efficacy and safety under controlled, closely observed circumstances in selected populations Difficult to extrapolate data to normal use Effectiveness trials – Reports the proportion of patients with a meaningful response & tolerable side effects, willing to continue therapy

9. Many Efficacy, Few Effectiveness Trials Regulatory trials not sufficient to answer practical questions 1.Which antidepressant or anticonvulsant is best for neuropathic pain? 2.Does failure to respond to one drug preclude response to another drug? 3.What is the optimum sequence of interventions to produce the greatest benefit in the shortest time? Moore, Pain 2010

10. Testing several drugs, doses, titration options Patients with insufficient benefit or unacceptable AEs proceed to another treatment Primary outcome - proportion achieving symptomatic relief with tolerable side effects for each treatment Best Initial Drug & Sequence…….. C > A > D > B Example – Clinical Effectiveness Study Design Moore, Pain 2010

11. Outcome Measures Tension between Specificity & Generalizability Measuring the right endpoint requires specificity – Example: “improving functional status” is too general – Better: Functional walking capacity (distance 6MW) or IADL performance (shopping/traveling in the community) But, measures may also be too specific – Focus on a narrow domain with limited impact – Focus on a single disease, sacrificing comparability

12. Specificity Can finite resources support the development of domain & disease-specific measures for all conditions? – Fatigue in MS, PD, heart failure… – Pain in cancer, arthritis, neuropathy… – Depression in stroke, epilepsy, COPD… February, 2011

13. Generalizability Symptom Clusters - Multiple Symptom Scales Common symptom clusters appear together across most chronic diseases – Fatigue, sleep, depression, anxiety, pain, concentration – Cluster symptoms exacerbate one another Shulman, 2001

14. Generalizability / Comparability Brief Measures of Symptom Clusters Measures symptom severity and impact

15. Generalizability Composite Outcomes Combining 2 or more component outcome measures into a single measure – Pros: addresses limited resources for trials – may answer questions in less time with less subjects – Cons: Meta-analysis of 40 trials (Cordoba, BMJ, 2010) “The use of composite outcomes in trials is problematic” Components not of similar importance (70%) Problems in reporting of composite outcomes (40%) Exaggerates how well interventions work

16. Patient-Reported Outcome Measures The Investigator’s view: – PROs provide distinct information regarding efficacy, effectiveness and quality of survival The Clinician’s view: – PROs are important because health care decisions should be based on the needs of our patients

17. PROs – Not Just For Research Integration into Clinical Practice Collecting patient-reported data and delivering it to clinicians in real time For screening, monitoring & enhancing the patient-doctor relationship PROMIS-based RCT in Advanced Cancer NCI R01 CA60068-09

18. Outcome Measures Innovation, Evolution & Progress Ridley, Wall Street Journal, 2/5/11 Key Lesson of Adulthood: The Need to Unlearn

19. Outcome Measures Different Views & Perspectives Do we have different objectives? – Clinicians – Clinical Investigators – Industry – Public Policymakers – Scientists – Patient Advocates

20. Medical Research Model The Efficacy – Effectiveness Gap Grants, Scientists, Patients Clinical Research Trials Publications- Clinician Awareness of Evidence Changes in Clinical Practice Improvement in Patient Well-Being & Function Evidence of Efficacy Evidence of Clinical Effectiveness Adapted from Weiss, Am J Psych 2007 Is it possible to bridge this gap – to learn more about effectiveness when studying efficacy?

21. Clinically Important Differences Measurement of MIDs may reconcile disconnects between: – Impairment and QoL – Efficacy & Effectiveness Linking efficacy outcomes to meaningful change Guyatt, Qual Lif Res. 2007

22. Needed – More Analysis of CID for Outcome Measures in Neurology

23. What do clinicians & investigators want? Survey of 20 Neurologist - Investigators What do you want in the outcome measures for your patients? 1.A better measure of symptoms 2.A better measure of function 3. A better measure of well-being (HR-QoL) 4. A better measure of clinically important changes 5. Convenience (brief, easy, reasonable cost) 6.Easy to interpret for you 7.Easy to interpret for your patients

24. What do clinicians & investigators want?

25. What Clinicians & Investigators Want Bridging the gap between – Efficacy & Effectiveness – Meaningful changes for people

26. The Clinician’s Perspective Managers and trialists may be happy for treatments to work on average; patients expect their doctors to do better than that. Evans, 1995