Pharmacoeconomics Research: Its Role in Clinical Trials

Kent H Summers, PhD Associate Professor Purdue University, School of Pharmacy May 14, 2008

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

Economic Environment

Growing Constrained ?

Why Clinical Trials ?

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

Clinical Pharmaceutical Research

Phase 1 Phase 2 Phase 3 Phase 4 Safety Safety & Efficacy Treatment decisions Policy decisions

Can you assume that RCT results will be reflected in actual practice?

EFFECTIVENESS “Outcomes” studies EFFICACY RCTs

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 Can it work in clinical practice?

(proven in RCTs



ideal conditions) Effectiveness Does it work in real life?

Efficiency Does it contribute to a more efficient use of resources?

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

Pharmacoeconomics research information VALUE

• Is a pharmaceutical product worth its price?

• In which patients does it produce the optimal benefit (both cost and quality) ?

AMCP-format Formulary Submission Clinical Studies Safety Efficacy Effective ness???

Disease and Product Description Plan Data Economic Modeling Overall Product Cost and Value Submission Document Published Economic Evaluations Resource Utilization Costs Reporting Potential for Bias

Source: Mather et al,

AJMC

1999.

ECHO

Model of Outcomes Assessment Economic (Cost offsets, Productivity) Clinical (BP, FEV HbA1c) Humanistic (QoL, Satisfaction)

Source: Kozma C,

et al. Clin Ther

1993

Pharmacoeconomics CLINICAL ECONOMIC HUMANISTIC Efficacy Safety Side effects Work productivity Resources consumed Direct Medical Costs Satisfaction Quality of Life Bothersomeness, tolerability

Selection of costs (and outcomes) in an analysis depends on perspective

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

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

.

Types of Economic Analyses

Analytic Method

Cost - benefit (CBA) Cost effectiveness (CEA) Cost-utility (CUA) Cost minimization (CMA) Cost-of-illness

Input (Cost) Consequences Primary Concern

Monetary Monetary Monetary Monetary Monetary Clinical: life-year gained, % patients reaching goal Quality-adjusted life-year (QALY) gained Equal benefit

ASSUMED

Monetary Maximal increment in benefit for limited resources Least costly way to achieve objective; compare alternatives within 1 therapeutic category Societal allocation; compare alternatives across therapeutic categories Efficiency (e.g., generic, therapeutic substitution) Total cost identification

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

Denominator: CEA v. CUA

1.0

CUA QaLYs - patient 1 0 QaLYs - patient 2 Death Death Life-year Gained = CEA Time

CUA ratio denominator

Healthy Morbidity Mortality Quality-adjusted Life Year (QaLY) Gained

CUA: Cost/QALY "League Table"

Warfarin v. ASA (low risk MI patients) Surgical gall bladder v. lithotripsy Dual airbags v. driver side only tPA v. streptokinase $140,000 $69,000 $32,000 $4,300 Captopril v. none 0 Pneumococcal vaccination v. none $0 $410,000 $100,000 $200,000 $300,000 $400,000

Pharmacoeconomics CLINICAL ECONOMIC HUMANISTIC Efficacy Safety Side effects Work productivity Resources consumed Direct Medical Costs Satisfaction Quality of Life Bothersomeness, tolerability

Humanistic (“Intangible”) Outcomes

"Not everything that counts can be counted, and not everything that can be counted counts."

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

Clinician-reported

• •

Global impression Observation & tests of function

What are PrOs?

Outcomes Assessment: Sources and Examples Physiological

• •

FEV

•

HbA1c Tumor size Caregiver-reported Patient-reported

•

Dependency

•

Physical functional

•

status Emotional status & functioning

• •

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



Therefore, validation of data collection instruments vitally important!

Source: Acquadro, et al, ViH, 2003

The value of patient-reported outcomes (PROs):

• 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.

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)

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) ???

Multiple dimensions of HrQoL

FUNCTION Physical Function Quality of Life General well being AFFECT Psychological Function Social & Role Function



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?

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

Generic Instrument

------------------------------------------------------------------------------ • National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) – Confirmed reliability and validity for a number of common eye conditions

specific

– Validated in type 1 diabetes cohort of the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR)

Instrument

– 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.

EQ-5D

By placing a checkmark in one box in each group below, please indicate which statements best describe your own health state today.

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

EQ-5D: Visual Analog Scale (VAS)

Information available at product launch?

Phase 1 Phase 2 Phase 3 Phase 4 Registration Safety & Efficacy



Effectiveness?

Treatment decisions Policy decisions

Efficacy (from RCTs) Effectiveness (CE projections)

Economic Models

• • •

Inputs

Safety & Efficacy Data (RCTs) Epidemiology Cost of disease

Outputs

Cost / effectiveness

Basic Decision-analytic Model

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

Pharmacoeconomic Research: Product Examples

Brand

Prozac Actos Yentreve

Generic

fluoxetine pioglitazone duloxetine

Indication

major depressive disorder hyperglycemia in type 2 diabetes mellitus stress urinary incontinence

Example: Prozac (fluoxetine)

Phase 1 Phase 2 Phase 3 Phase 4 Registration Safety & Efficacy



Effectiveness?

Retrospective studies Prospective studies

Example: Prozac (fluoxetine) Kupfer Curve

Kupfer DJ. 1991

Example: Actos (pioglitazone)

Phase 1 Phase 2 Phase 3 Phase 4 Registration Safety & Efficacy



Effectiveness?

Economic Model

Example: Yentreve (duloxetine)

Example: Yentreve (duloxetine)

Urinary incontinence treatment management decisions based on:

• •

Number of incontinence episodes Impact on quality of life

Example: Yentreve (duloxetine)

Phase 1 Phase 2 Phase 3 Registration Safety & Efficacy



X Phase 4 Effectiveness?

QoL instrument development QoL in RCTs Treatment decisions Policy decisions

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

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