Clinical Investigation and Outcomes Research Health Outcomes Research

1. Clinical Investigation and Outcomes ResearchHealth Outcomes Research Marcia A. Testa, MPH, PhD Department of Biostatistics Harvard School of Public Health

2. The Discipline of Health Outcomes Research • Scientific inquiry evaluating the results of medical interventions and health care services. • Outcomes data are direct measures of whether medical treatments are beneficial

3. How Are Outcomes Results Used? • “Outcomes research seeks to understand the end results of particular health care practices and interventions. • Used to provide information on the quality of care so that it can be improved by determining • which health care services influence the probability of optimal patient outcomes • which produce optimal improvement in the patient's physiologic status, physical function, emotional and intellectual performance and comfort (comparative effectiveness research) 1. Outcomes Research Resource Guide, 1996/97 Edition, American Medical Association

4. Measuring Outcomes • Outcomes are a function of • baseline health status • patient clinical characteristics • patient demographics • psychosocial characteristics • treatment • health care setting • The GOAL of health outcomes research analysis is to isolate the relationship between outcomes and treatment.

5. Outcome Measures • Mortality – Survival time, Death event • Morbidity – Time to an Occurrence of a Clinical Events (e.g., Stroke, MI, Cancer) • Health Status – Physical, Mental and Emotional Health Functioning • Quality of Life – Health Status as Perceived by the Individual • Patient Satisfaction – Distance between Quality of Life and Individual Expectations • Health Economic Outcomes – Cost utility, cost effectiveness

6. Hematologic Malignancies & Anemia Comparative Effectiveness Trial

7. Hb Changes Figure 2. Mean hemoglobin (Hb) change (intent-to-treat; n = 269). aP < .0001 early versus late group. Postrandomization Months 1, 2, 3, and 4 values correspond with mean Hb between Weeks 0 (baseline) to Weeks 4, 5-9, 10-14, and 15-20, respectively. a P < 0.0001

8. Treatment, Fatigue, Symptoms bP < .01 late vs. early treatment. cP < .05 late vs. early treatment.

9. Treatment and Health Status bP < .01 late vs. early treatment. cP < .05 late vs. early treatment.

10. Treatment and QOL bP < .01 late vs. early treatment. cP < .05 late vs. early treatment.

11. Measuring Outcomes Outcome Full Health Death

12. Measuring Outcomes, Measuring Performance Improving Process (how we perform) Measurement Improving Outcomes (the results of our performance)

13. Clinical Patient Centered Economic The Consequences of Health Care and Medical Intervention

14. Clinical The Consequences of Health Care and Medical Intervention –Types of Outcomes Labs, Clinical Events, Physician Assessments

15. Patient Centered The Consequences of Health Care and Medical Intervention –Types of Outcomes Symptom reports, health status, quality of life, patient satisfaction

16. Well-being General Perceived Health Mental and Emotional Physical/ Symptoms Cognitive Work/Social Multi-faceted QOL Domains

17. Outcomes Research - 1996QOL is Recognized as Important

18. Outcome MeasuresFunctional Health Coverage • Generic health instruments are address larger health constructs and hence their causal links to specific treatment events may be more difficult to detect • Condition-specific instruments will vary with the condition being treated, and hence are typically more sensitive to treatment effects

19. Outcome MeasuresFormat Influencing Coverage • Fixed-Length or “Static” – number of questions is fixed – greater coverage requires greater number of questions • Dynamic instruments - use computer adaptive testing to restrict items based upon a Bayesian approach which selects the next question based upon the answer to the previous question • Combines the practicality of short form instruments with the sensitivity and target coverage of condition-specific instruments

20. Questionnaires and SurveysGeneric Instruments • Some outcomes survey questions, commonly referred to as “instruments”, focus on describing how individuals rate their health overall – or generic instruments • General health surveys such as the SF-36 are now used in research studies, population surveys, and some health plans to assess patients' overall level of functioning. • Translation of SF-36 into Arabic and the translation methods references are given in the Additional Resources Section of the Website.

21. Questionnaires and Surveys Condition-Specific Instruments • Developing outcome instruments for specific diseases has been an especially prolific research area • Such instruments are more likely than general health survey measures to be able to detect changes in the disease due to treatment

22. Steps in Designing an Outcome Research Study • Define a researchable question • Develop a conceptual model • Identify the critical dependent and independent variables • Identify appropriate measures for each • Develop an analysis plan • Indicate what is believed to cause the outcome • Identify critical pathways and what other factors are likely to affect the outcome • Identify which variables (in the outcomes function equation) are relevant to your hypothesis

23. The Conceptual Health Model • Environmental Behavioral, Social • Income • Social Support • Education • Health Access • Lifestyle • Medical Interventions • Specific medications • Surgery • Diet and Exercise • Case Management • Outcome Measures • Lab values • Symptoms • Functioning • Quality of life • Employment/Work • Patient Factors • Age • Gender • Occupation

24. OUTCOME Change The Outcomes Model Risk Adjustment Patient Characteristics Change Structure (Setting) Process (Treatment) Measurement

25. Outcomes Research - 1998Health Economic Benefits

26. Diabetes Outcomes Model • Treatment • Specific medications • Diet • Exercise • Case Management • Clinical Factors • Severity • Duration • Etiology • Comorbidity • Outcomes • HbA1c • Symptoms • Function • Complications • Quality of life • Employment/Work • Patient Factors • Age • Race • Gender • Occupation

27. REGIMEN BURDEN • Pain, Life-style, discomfort EFFICACY • Clinical Treatment Satisfaction Adherence 1c HEALTH STATUS • Self-Reported Symptom distress QUALITY OF LIFE • SIDE EFFECTS Functional status • Physical, Mental, • Adverse reactions Cognitive, Social Understanding Causal Pathways HEALTH ECONOMICS • Productivity • Health Care Utilization

28. Study Design 62 sites in the United States Glipizide GITS + diet vs Placebo + diet 16-week multicenter, randomized, double-blind, placebo-controlled, parallel titration study • 1-week washout o o o o • 3-week single-blind placebo o o o o o o o o o o o o o o o o o o o o o o o o o o • 4-week dose titration o o o o o o o o o o • 8-week maintenance o o o o o o o o Testa MA, Simonson DC. JAMA 1998; 280:1490-1496.

29. Study Design Maintenance Screening / Single-blind Dose titration Maintenance washout placebo 5-20 mg ■ ■ ■ ■ ■                  -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Week Randomization to placebo & diet or Glipizide GITS & diet (1:2)  Clinical and Laboratory Assessment ■ Health Economic Assessment Testa MA, Simonson DC. JAMA 1998; 280:1490-1496.

31. Patient Population Baseline Clinical Characteristics Placebo Glipizide GITS Number of Patients 201 393 Gender (M / F) (%) 60 / 40 55 / 45 Race (W / B / O) (%) 70 / 18 / 12 70 / 18 / 12 Emp / Ret / Unemp(%) 50 / 38 / 12 48 / 40 / 12 Age (yrs) 58 ± 12 59 ± 11 Duration DM (yrs) 5 ± 5 6 ± 6 FPG (mg / dL) 231 ± 66 218 ± 62 HbA1c (%) 8.7 ± 1.4 8.5 ± 1.5 Testa MA, Simonson DC. JAMA 1998; 280:1490-1496.

32. Clinical Results End of Week 15 Placebo Glipizide GITS P-Value FPG (mg / dL) 224 ± 66 161 ± 41 < 0.001 HbA1c (%) 9.3 ± 1.9 7.5 ± 1.2 < 0.001 Hypoglycemic 4.8 6 NS Symptoms (%) Glucose < 55 0 0 NS mg / dL (%) Testa MA, Simonson DC. JAMA 1998; 280:1490-1496.

33. HbA1c and Symptom Distress • EFFICACY • HbA1c • HEALTH STATUS • Self-Reported Symptom distress

34. Pharmacological SideEffects and Symptom Distress • EFFICACY • HbA1c • HEALTH STATUS • Self-reported Symptom distress • SIDE EFFECTS • Adverse reactions

35. Trembling Low blood sugar reaction Fast pulse, rapid heartbeat, palpitations Hypoglycemic symptoms, weight gain, feeling overweight Heartburn Wheezing or difficulty breathing Gaining weight Cold hands or feet Feeling overweight Constipation Swelling of feet or ankles Abdominal cramps Skin rash Decrease in appetite Mood swings Losing weight Flushing, sensation of heat Shortness of breath or breathing hard Increase in hunger Inability to sleep, insomnia Pains in legs or calves Lightheadedness Lethargy, no energy to do things Numbness or tingling of hands or feet Vomiting Nauseous, queasy, sick to stomach Diarrhea Itching, scratching Heart pounding, beating hard Nightmares Headaches Impaired or worsening vision Tired, feeling weary Muscle cramps Vertigo, sensation of spinning Dizziness when standing up Tightness,pain in chest Drowsy or sleepy Cold sweat, clammy skin Hyperglycemic symptoms, thirst, nocturia, blurred vision, fatigue Sugar in urine Foot cramps, foot pain Sweating, perspiring Confusion General weakness or fatigue Numbness of lips or mouth Blurred or double vision Crabby, short-tempered Getting up often during the night to urinate Being Thirsty Having to urinate frequently Sweet taste in mouth Drinking a lot of fluids Dryness of mouth, eyes or nose High blood sugar Mean HbA1c: 9.3 ± 1.9% 7.5 ± 1.2% Symptom Worsening With Glucose Lowering P = N.S. Symptom Improvement With Glucose Lowering P < .05 P < .01 P < .001 -0.2 0 0.2 0.4 0.6 0.8 1 SD Units Testa MA, Simonson DC. JAMA 1998; 280:1490-1496.

36. Impact on Quality of Life • EFFICACY • HbA1c • HEALTH STATUS • Self- Reported Symptom distress • QUALITY OF LIFE • Functional status • Physical, Mental, Cognitive, Social • SIDE EFFECTS • Adverse reactions

37. Change In QOL Scales With Therapy in Type 2 Diabetes 0.4 *** Overall Rating Mental Health Cognitive Function Perceived Health Symptom Distress 0.3 ** ** * 0.2 0.1 QOL Score (SD units) 0 * P < 0.05 ** P < 0.01 *** P < 0.001 -0.1 -0.2 -0.3 Placebo Glipizide GITS Testa MA, Simonson DC. JAMA 1998; 280:1490-1496.

38. Change in HbA1c and QOL In Patients with NIDDM 0.2 Favorable QOL * Response * * 0 No Change in QOL * -0.2 No Change in HbA1c QOL Global Outcome (Z-score) * -0.4 Unfavorable QOL -0.6 Response log-linear regression, r = .95, p < .01 -0.8 >1.5 -.5 to -1.5 1.5 to .5 <-1.5 .5 to -.5 Improved Worsened c (%) Change from Baseline HbA 1 HbA1c HbA1c Testa MA, Simonson DC. JAMA 1998; 280:1490-1496.

39. REGIMEN BURDEN • Pain, Life-style, discomfort EFFICACY • Clinical Treatment Satisfaction Adherence 1c HEALTH STATUS • Self-Reported Symptom distress QUALITY OF LIFE • SIDE EFFECTS Functional status • Physical, Mental, • Adverse reactions Cognitive, Social Understanding Causal Pathways HEALTH ECONOMICS • Productivity • Health Care Utilization

40. Production Losses Absenteeism (US $ / worker / month) Bed Days (US $ / 1000 person days) Restricted Activity Days (US $ / 1000 person days) $ Loss $1000's 100 4 1000 50 500 2 P = 0.01 Change (Week 15 – Baseline) 0 0 0 P < 0.001 P = 0.05 -2 -50 -500 Placebo Placebo Placebo Glipizide GITS Glipizide GITS Glipizide GITS $ Savings Testa MA, Simonson DC. JAMA; 1998;280:1490-1496.

41. Health Care Utilization Percent of Patients Reporting 1 or More Non-study-related Ambulatory Visits (clinic, ER, physician office) per Month 40 40 P = NS P = 0.002 Percent of Patients 30 30 20 20 Baseline Week 15 Baseline Week 15 Glipizide GITS Placebo Estimated savings = $11 per patient per month (assuming cost of $66 per ambulatory visit) Testa MA, Simonson DC. JAMA; 1998;280:1490-1496.

42. Summary • Use Outcomes Research to • Improve the quality of health care by changing treatment and services and by promoting preventive strategies • Outcomes are “probability statements” • Multifaceted • Requires integrating and consolidating many different components of health functioning • Outcomes may take time to develop, use intermediate outcomes if necessary

43. Summary • Use Outcomes Research to • Improve the quality of health care by changing treatment and services and by promoting preventive strategies • Outcomes are “probability statements” • Multifaceted • Requires integrating and consolidating many different components of health functioning • Outcomes may take time to develop, use an intermediate outcomes

44. Additional Resources and References • Online Questionnaires: SF12, LASA, EQ-5D. • SF-36 translated into Arabic by Saud Abdulaziz bin Al Abdulmoshin, 1997 • Coons SJ, Reliability of an Arabic Version of the RAND-36 Health Survey and Its Equivalence to the US English Version • Testa and Simonson, NEJM, 1996 • Testa and Simonson, JAMA, 1998 • Straus, Testa, Sarokhan et al., Cancer 2006