1. Pharmacoeconomics Research: Its Role in Clinical Trials Kent H Summers, PhD Associate Professor Purdue University, School of Pharmacy May 14, 2008

2. Pharmacoeconomics Goal & Objectives Goal: To increase knowledge of pharmacoeconomics research to better understand the significance of this data collected in clinical trials Objectives Identify the role of economic and humanistic studies in drug product development Identify the types of health outcomes studies used in drug product development Identify where health outcomes studies are performed in the drug development process

3. Economic Environment Growing ? Constrained

5. Why Clinical Trials ? 1.Registration 2.Safety 3.Efficacy 4.Inform prescribing decisions 5.Inform drug policy decisions ???

6. Safety Safety & Efficacy Treatment decisions Policy decisions Clinical Pharmaceutical Research Phase 1 Phase 4 Phase 3 Phase 2

7. EFFICACY EFFECTIVENESS RCTs “Outcomes” studies Can you assume that RCT results will be reflected in actual practice?

8. Effectiveness The extent to which medical interventions achieve health improvements in real-life settings (usually differs from efficacy, as determined in controlled clinical trials). Efficacy Effectiveness Efficiency Can it work in clinical practice? (proven in RCTs  ideal conditions) Does it work in real life? Does it contribute to a more efficient use of resources?

9. Managed care’s interest in economic evaluations Formulary management may involve (and economic evaluations can inform decisions regarding): 1.requirement of prior authorization for payment of certain drugs or unusual dosages 2.limits on the quantity of product dispensed 3.tiered copayments, in which patients are required to pay less for cheaper medications (e.g., generic medications) and more for expensive brands. (How to select products for tier levels?) Also, the Food and Drug Administration Modernization Act of 1997 (FDAMA): promotion, AMCP-format formulary submission

10. Pharmacoeconomics research information VALUE Is a pharmaceutical product worth its price? In which patients does it produce the optimal benefit (both cost and quality) ?

11. Clinical Studies Effective- ness??? Efficacy Safety Submission Document Overall Product Cost and Value Published Economic Evaluations Reporting Potential for Bias Economic Modeling Resource Utilization Disease and Product Description Costs Plan Data Source: Mather et al, AJMC 1999. AMCP-format Formulary Submission

12. Economic (Cost offsets, Productivity) Clinical (BP, FEV HbA1c) Humanistic (QoL, Satisfaction) Source: Kozma C, et al. Clin Ther 1993 ECHO Model of Outcomes Assessment

13. Pharmacoeconomics CLINICALECONOMIC Safety Work productivity Direct Medical Costs Quality of Life Bothersomeness, tolerability HUMANISTIC SatisfactionEfficacy Resources consumed Side effects

14. Source: Lyles A, “Formulary Decision-Maker Perspectives: Responding to Changing Environments” (Chapter 7) in, Economic Evaluation in U.S. Health Care: Principles and Applications (Pizzi, Lofland, eds.), 2006 Selection of costs (and outcomes) in an analysis depends on perspective

15. Economic Analysis “A comparative analysis of alternative courses of action in terms of both their costs and consequences. ” Drummond et al., Oxford University Press, 1987:8.

16. Types of Economic Analyses

17. Cost Effectiveness Ratio Numerator Costs included depends on perspective Life-year Gained Payer’s Perspective Hospital costs Physician costs Lab costs Rx costs (if covered) Employers’ Perspective Hospital costs Physician costs Lab costs Rx costs (if covered) Indirect (productivity) costs Patients’ Perspective Deductible costs Co-insurance costs Co-pay costs Out-of-pocket costs Transportation costs

18. Denominator: CEA v. CUA Death 1.0 0 Life-year Gained = CEA QaLYs - patient 1 QaLYs - patient 2 QaLYs gained Quality-adjusted Life Years CUA Time

19. CUA ratio denominator Morbidity Mortality Quality-adjusted Life Year (QaLY) Gained Healthy

20. CUA: Cost/QALY "League Table"

21. Pharmacoeconomics CLINICALECONOMIC Safety Work productivity Direct Medical Costs Quality of Life Bothersomeness, tolerability HUMANISTIC SatisfactionEfficacy Resources consumed Side effects

22. "Not everything that counts can be counted, and not everything that can be counted counts." Humanistic (“Intangible”) Outcomes

23. Patient- reported Outcomes (PrOs) An umbrella term that includes outcome data reported directly by the patient. It is one source of data that may be used to describe a patient’s condition and response to treatment. It includes such outcomes as global impressions, functional status, well-being, symptoms, health-related quality of life, satisfaction with treatment and utilities. Source: MC Glossary

24. What are PrOs? Outcomes Assessment: Sources and Examples Clinician-reported Global impression Observation & tests of function Physiological FEV HbA1c Tumor size Caregiver-reported Dependency Physical functional status Emotional status & functioning Patient-reported Global impression Functional status Well-being Symptoms HrQoL Tmt satisfaction Utilities  PrOs = patient’s reports of a health condition and its treatment  Health-related Quality of Life (HrQoL) = patient’s evaluation of the impact of a health condition and its treatment on daily life  T Therefore, validation of data collection instruments vitally important! Source: Acquadro, et al, ViH, 2003

25. The patient’s perspective is a key element in medical diagnosis and treatment. PRO data are unique and complementary indicators of disease activity. PROs in clinical trials provide important data for evaluating the effectiveness of new treatment. Consistent with the definition of a scientific instrument, PRO measures provide precise, reliable, valid, and reproducible data. PRO data are essential for evidence-based practice. For new pharmaceuticals, PRO data from clinical trials support evidence-based practice. Professional organizations recognize the key role PRO data play in diagnosis and treatment, as evidenced by their clinical practice guidelines. The inclusion of PROs in clinical trials is sanctioned by professional organizations, as evidenced by their trial guidelines, including FDA. The value of patient-reported outcomes (PROs):

26. Why are PrOs important in drug development?  Clinical response endpoints, alone, can underestimate treatment benefit  PrOs represent logical extensions of clinical effects  To understand impact on quality, in addition to quantity of life (esp. Oncology)

27. Why will PrOs become increasingly important? IOM report (patient-centered care) FDA acceptance its use in promotion (FDAMA) FDA guidance for its measurement Future drug development: from chronic care (subject to price controls)  “lifestyle” drugs (out-of-pocket, less price restrictions, purchase decisions based on desires of patients) ???

28. Quality of Life Physical Function Social & Role Function Psychological Function General well- being Multiple dimensions of HrQoL AFFECT FUNCTION

29. HrQoL Measurement Issues  Health status: Medical Outcomes Studies Short Form, 36 questions (MOS SF-36) Multi-dimensional measurement of treatment impact Impact on function, affect Cross-condition comparisons Responsiveness?  Utilities (preference-based measures): EQ-5D Non-affected population’s understanding of disease impact? Single number (1 – 100) Cross-condition comparisons Responsiveness?  Condition-specific instruments: Clinically sensible Responsiveness Cross-condition comparisons? Interpretation? Usefulness in medication utilization decisions?

30. Example: Selection of HrQoL data collection instruments in eye disease studies SF-36 (health status), EQ-5D (utilities) –Validated and reliable –Widely used in quality of life studies –Not specific to ophthalmology ------------------------------------------------------------------------------- National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) –Confirmed reliability and validity for a number of common eye conditions –Validated in type 1 diabetes cohort of the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) –Strongly associated with vision, independent of retinopathy severity and other diabetic complications Linder M, et al. Arch Ophthalmol. 1999;117:1611-1616. Klein R, et al. Arch Ophthalmol. 2001;119:733-740. Sharma S, et al. Br J Ophthalmol. 2002;86:493-496. Generic Instrument Condition- specific Instrument

31. EQ-5D Mobility I have no problems in walking about o I have some problems in walking about o I am confined to bed o Self-Care I have no problems with self-care o I have some problems washing or dressing myself o I am unable to wash or dress myself o Usual Activities (e.g. work, study, housework, family or leisure activities) I have no problems with performing my usual activities o I have some problems with performing my usual activities o I am unable to perform my usual activities o Pain/Discomfort I have no pain or discomfort o I have moderate pain or discomfort o I have extreme pain or discomfort o By placing a checkmark in one box in each group below, please indicate which statements best describe your own health state today.

32. EQ-5D: Visual Analog Scale (VAS)

34. Registration Safety & Efficacy  Effectiveness? Treatment decisions Policy decisions Information available at product launch? Phase 1 Phase 4 Phase 3 Phase 2

35. Economic Models Inputs Safety & Efficacy Data (RCTs) Epidemiology Cost of disease Outputs Cost / effectiveness Efficacy (from RCTs) Effectiveness (CE projections)

36. Basic Decision-analytic Model

37. Pharmacoeconomics Goal & Objectives Goal: To increase knowledge of pharmacoeconomics research to better understand the significance of this data collected in clinical trials Objectives Identify the role of economic and humanistic studies in drug product development Identify the types of health outcomes studies used in drug product development Identify where health outcomes studies are performed in the drug development process

38. Pharmacoeconomic Research: Product Examples BrandGenericIndication Prozacfluoxetinemajor depressive disorder Actospioglitazonehyperglycemia in type 2 diabetes mellitus Yentreveduloxetinestress urinary incontinence

39. Registration Safety & Efficacy  Effectiveness? Retrospective studies Prospective studies Example: Prozac (fluoxetine) Phase 1 Phase 4 Phase 3 Phase 2

40. Example: Prozac (fluoxetine) Kupfer Curve Kupfer DJ. 1991

41. Registration Safety & Efficacy  Effectiveness? Economic Model Example: Actos (pioglitazone) Phase 1 Phase 4 Phase 3 Phase 2

43. Example: Yentreve (duloxetine)

44. Urinary incontinence treatment management decisions based on: Number of incontinence episodes Impact on quality of life Example: Yentreve (duloxetine)

46. Registration Safety & Efficacy  Effectiveness? Treatment decisions Policy decisions Example: Yentreve (duloxetine) Phase 1 Phase 4 Phase 3 Phase 2 X QoL instrument development QoL in RCTs

47. SUMMARY Clinical trials as a model of medication performance The following data collected in RCTs is very important: Side effects (even minor SEs, only potentially bothersome SEs) Event rates: unscheduled phone calls (e.g., to answer patient questions about potential SEs), physician office visits, ED visits, hospital admissions Secondary study endpoints, such as those collected in PrO instruments

48. Pharmacoeconomics Goal & Objectives Goal: To increase knowledge of pharmacoeconomics research to better understand the significance of this data collected in clinical trials Objectives Identify the role of economic and humanistic studies in drug product development Identify the types of health outcomes studies used in drug product development Identify where health outcomes studies are performed in the drug development process