Elizabeth B. Andrews, Ph.D., M.P.H.

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Elizabeth B. Andrews,Ph.D., M.P.H.

• Director, Worldwide Epidemiology

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Risk Management Plan
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GW Program of Responsible Product Stewardship

• Scientific foundation to understand the risks and
  predictors of serious events
• Communication program to educate physicians,
  pharmacists and patients
• Program evaluation to determine if and when
  additional efforts are warranted

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Risk Management StrategyAn Integrated Approach
Communication
Program Evaluation
Risk Definition

• Appropriate Use Program
• Healthcare Practitioners
• Pharmacists
• Patients

• Testing Comprehension of Communication Vehicles
• Tracking Awareness and Source of Knowledge
• Lotronex Utilization Study
• Ongoing pharmacovigilance

Mechanistic Studies
Clinical Studies
Epidemiologic Research
Systematic Evaluation
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Risk Management StrategyAn Integrated Approach
Communication
Program Evaluation
Risk Definition

• Appropriate Use Program
• Healthcare Practitioners
• Pharmacists
• Patients

• Testing Comprehension of Communication Vehicles
• Tracking Awareness and Source of Knowledge
• Lotronex Utilization Study
• Ongoing pharmacovigilance

Mechanistic Studies
Clinical Studies
Epidemiologic Research
Systematic Evaluation
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Risk Management StrategyAn Integrated Approach
Program Evaluation
Risk Definition
Communication

• Appropriate Use Program
• Healthcare Practitioners
• Pharmacists
• Patients

• Testing Comprehension of Communication Vehicles
• Tracking Awareness and Source of Knowledge
• Lotronex Utilization Study
• Ongoing pharmacovigilance

Mechanistic Studies
Clinical Studies
Epidemiologic Research
Systematic Evaluation
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Risk Management StrategyAn Integrated Approach
Risk Definition
Program Evaluation
Communication

• Appropriate Use Program
• Healthcare Practitioners
• Pharmacists
• Patients

• Testing Comprehension of Communication Vehicles
• Tracking Awareness and Source of Knowledge
• Lotronex Utilization Study
• Ongoing pharmacovigilance

Mechanistic Studies
Clinical Studies
Epidemiologic Research
Systematic Evaluation
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Risk Management StrategyAn Integrated Approach
Communication
Program Evaluation
Risk Definition

• Appropriate Use Program
• Healthcare Practitioners
• Pharmacists
• Patients

• Testing Comprehension of Communication Vehicles
• Tracking Awareness and Source of Knowledge
• Lotronex Utilization Study
• Ongoing pharmacovigilance

Mechanistic Studies
Clinical Studies
Epidemiologic Research
Systematic Evaluation
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Risk Management Strategy Opportunity

• Recent launch
• Interest high
• Many options considered
• Strategy consistent with the evidence
• Appropriate patients
• Early recognition

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Risk DefinitionEpidemiology Program
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Contributions of Epidemiology Studies vs Clinical
Trials

• Large numbers of patients
• Real world experience
• more heterogeneous patients
• treatment and compliance less controlled
• Estimate infrequent/rare events
• Explore risk factors for events
• Trade depth (trial) for breadth (epidemiology)

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Program of Epidemiology Research Questions
Addressed

• Frequency of complications of constipation in
  patients treated with Lotronex in actual practice
• Frequency of ischemic colitis in patients treated
  with Lotronex compared with other populations
  persons with IBS, persons who consult GI
  specialists, general population
• Potential risk factors

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General Study Designs

• Observational cohort studies to define incidence
  of complications of constipation and ischemic
  colitis
• Nested case-control studies to evaluate risk
  factors

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Methodologic Issues

• Challenges
• Spectrum of disease
• ICD-9 code is non-specific
• Approaches
• Broad capture of ICD-9 codes
• Development of computer algorithms
• Validation through chart review

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Epidemiology Commitments

• GW and FDA agreed to a Phase IV observational
  cohort study
• 10,000 patients treated with Lotronex
• GW is modifying the study to include
  complications of constipation

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Observational Cohort Study of Safety in Patients
Receiving Lotronex

• Objectives
• 1. Incidence and risk factors for complications
  of constipation in patients receiving Lotronex
• 2. Incidence and risk factors for ischemic
  colitis in patients receiving Lotronex
• 3. Incidence of these events in the general
  population and in patients with IBS not receiving
  Lotronex

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Observational Cohort Study of Safety in Patients
Receiving Lotronex

• Datasource
• United HealthCare (UHC) Research Database
• Second largest health care company in the United
  States gt300,000 physicians, gt14 million members
• UHC Research Database subset comprised of 7
  million members since 1990 with medical and
  prescription coverage

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Observational Cohort Study of Safety in Patients
Receiving Lotronex

• Study Conduct
• Phase IDevelopment of algorithms using
  computerized claims to identify patients with
  diagnoses under study
• Phase IIIncidence of events in patients
  receiving Lotronex
• Phase IIIFurther characterize events in patients
  with IBS, and in general population

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Utilization Study

• QuestionDescriptive study of utilization
  patterns over time in United HealthCare
• PopulationAll persons receiving a prescription
  for Lotronex
• AnalysisDescriptive evaluation of users by
• Age
• Gender
• History of constipation
• History of IBS-related visits and prescriptions

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Utilization Study

• This study is also part of Program Evaluation
• Systematic evaluation
• First review December 2000, quarterly thereafter

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EpidemiologyProgram of Research

• Study Population Timeline
• Phase IV Study of Safety UHC Research First
  interim in 10,000 patients Database report
  treated with Lotronex 7 million members
  December 2000
• Disease frequency/ GPRD (UK) Completerisk
  factors in 6 million patients December 2000
  general population and patients with IBS

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EpidemiologyProgram of Research (continued)

• Study Population Timeline
• Disease frequency TN Medicaid Complete Fall
  and risk factors 1.4 million patients 2002
  
• Disease frequency Mayo Clinic Complete Fall
  and risk factors Foundation 2002
  Residents of Olmstead County
• Case control study Patients in GW Initiate
  Summerin GW Clinical Trials Clinical Trials
  2000

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Risk DefinitionClinical Studies
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Program of Clinical Studies

• Study on constipation management
• Laxatives
• Interruption of therapy
• Dose reduction
• Studies for other indications/populations
• Male IBS
• Functional Dyspepsia

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Risk DefinitionMechanistic Studies
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Mechanistic Studies

• Phase IV commitment
• Cultured endothelial cell integrity
• Mesenteric blood flow in humans with PET scanning
• Coagulation factors

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Risk Management StrategyAn Integrated Approach
Communication
Program Evaluation
Risk Definition

• Appropriate Use Program
• Healthcare Practitioners
• Pharmacists
• Patients

• Testing Comprehension of Communication Vehicles
• Tracking Awareness and Source of Knowledge
• Lotronex Utilization Study
• Ongoing pharmacovigilance

Mechanistic Studies
Clinical Studies
Epidemiologic Research
Systematic Evaluation