A 1 Alosetron /26 Elizabeth B. Andrews, Ph.D., M.P.H. Director, Worldwide Epidemiology

A 2 Alosetron /26 Risk Management Plan

A 3 Alosetron /26 GW Program of Responsible Product Stewardship Scientific foundation to understand the risks and predictors of serious events Scientific foundation to understand the risks and predictors of serious events Communication program to educate physicians, pharmacists and patients Communication program to educate physicians, pharmacists and patients Program evaluation to determine if and when additional efforts are warranted Program evaluation to determine if and when additional efforts are warranted

A 4 Alosetron /26 Epidemiologi c Research Communication Program Evaluation Systematic Evaluation Risk Definition Mechanisti c Studies Clinical Studies Risk Management Strategy An Integrated Approach Appropriate Use ProgramAppropriate Use Program Healthcare PractitionersHealthcare Practitioners PharmacistsPharmacists PatientsPatients Testing Comprehension of Communication VehiclesTesting Comprehension of Communication Vehicles Tracking Awareness and Source of KnowledgeTracking Awareness and Source of Knowledge Lotronex Utilization StudyLotronex Utilization Study Ongoing pharmacovigilanceOngoing pharmacovigilance

A 5 Alosetron /26 Epidemiologi c Research Communication Program Evaluation Systematic Evaluation Risk Definition Mechanisti c Studies Clinical Studies Risk Management Strategy An Integrated Approach Appropriate Use ProgramAppropriate Use Program Healthcare PractitionersHealthcare Practitioners PharmacistsPharmacists PatientsPatients Testing Comprehension of Communication VehiclesTesting Comprehension of Communication Vehicles Tracking Awareness and Source of KnowledgeTracking Awareness and Source of Knowledge Lotronex Utilization StudyLotronex Utilization Study Ongoing pharmacovigilanceOngoing pharmacovigilance

A 6 Alosetron /26 Epidemiologi c Research Program Evaluation Systematic Evaluation Risk Definition Mechanisti c Studies Clinical Studies Risk Management Strategy An Integrated Approach Communication Appropriate Use ProgramAppropriate Use Program Healthcare PractitionersHealthcare Practitioners PharmacistsPharmacists PatientsPatients Testing Comprehension of Communication VehiclesTesting Comprehension of Communication Vehicles Tracking Awareness and Source of KnowledgeTracking Awareness and Source of Knowledge Lotronex Utilization StudyLotronex Utilization Study Ongoing pharmacovigilanceOngoing pharmacovigilance

A 7 Alosetron /26 Epidemiologi c Research Systematic Evaluation Risk Definition Mechanisti c Studies Clinical Studies Risk Management Strategy An Integrated Approach Program Evaluation Communication Appropriate Use ProgramAppropriate Use Program Healthcare PractitionersHealthcare Practitioners PharmacistsPharmacists PatientsPatients Testing Comprehension of Communication VehiclesTesting Comprehension of Communication Vehicles Tracking Awareness and Source of KnowledgeTracking Awareness and Source of Knowledge Lotronex Utilization StudyLotronex Utilization Study Ongoing pharmacovigilanceOngoing pharmacovigilance

A 8 Alosetron /26 Epidemiologi c Research Communication Program Evaluation Systematic Evaluation Risk Definition Mechanisti c Studies Clinical Studies Risk Management Strategy An Integrated Approach Appropriate Use ProgramAppropriate Use Program Healthcare PractitionersHealthcare Practitioners PharmacistsPharmacists PatientsPatients Testing Comprehension of Communication VehiclesTesting Comprehension of Communication Vehicles Tracking Awareness and Source of KnowledgeTracking Awareness and Source of Knowledge Lotronex Utilization StudyLotronex Utilization Study Ongoing pharmacovigilanceOngoing pharmacovigilance

A 9 Alosetron /26 Recent launchRecent launch Interest highInterest high Many options consideredMany options considered Strategy consistent with the evidenceStrategy consistent with the evidence –Appropriate patients –Early recognition Risk Management Strategy Opportunity

A 10 Alosetron /26 Risk Definition Epidemiology Program

A 11 Alosetron /26 Contributions of Epidemiology Studies vs Clinical Trials Large numbers of patientsLarge numbers of patients Real world experienceReal world experience –more heterogeneous patients –treatment and compliance less controlled Estimate infrequent/rare eventsEstimate infrequent/rare events Explore risk factors for eventsExplore risk factors for events Trade depth (trial) for breadth (epidemiology)Trade depth (trial) for breadth (epidemiology)

A 12 Alosetron /26 Program of Epidemiology Research: Questions Addressed Frequency of complications of constipation in patients treated with Lotronex in actual practiceFrequency 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 populationFrequency of ischemic colitis in patients treated with Lotronex compared with other populations – persons with IBS, persons who consult GI specialists, general population Potential risk factorsPotential risk factors

A 13 Alosetron /26 General Study Designs Observational cohort studies to define incidence of complications of constipation and ischemic colitisObservational cohort studies to define incidence of complications of constipation and ischemic colitis Nested case-control studies to evaluate risk factorsNested case-control studies to evaluate risk factors

A 14 Alosetron /26 Methodologic Issues ChallengesChallenges –Spectrum of disease –ICD-9 code is non-specific ApproachesApproaches –Broad capture of ICD-9 codes –Development of computer algorithms –Validation through chart review

A 15 Alosetron /26 Epidemiology Commitments GW and FDA agreed to a Phase IV observational cohort studyGW and FDA agreed to a Phase IV observational cohort study 10,000 patients treated with Lotronex10,000 patients treated with Lotronex GW is modifying the study to include complications of constipationGW is modifying the study to include complications of constipation

A 16 Alosetron /26 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

A 17 Alosetron /26Datasource United HealthCare (UHC) Research DatabaseUnited HealthCare (UHC) Research Database Second largest health care company in the United States: >300,000 physicians, >14 million membersSecond largest health care company in the United States: >300,000 physicians, >14 million members UHC Research Database subset comprised of 7 million members since 1990 with medical and prescription coverageUHC Research Database subset comprised of 7 million members since 1990 with medical and prescription coverage Observational Cohort Study of Safety in Patients Receiving Lotronex

A 18 Alosetron /26 Study Conduct: Phase I Development of algorithms using computerized claims to identify patients with diagnoses under studyPhase I Development of algorithms using computerized claims to identify patients with diagnoses under study Phase II Incidence of events in patients receiving LotronexPhase II Incidence of events in patients receiving Lotronex Phase III Further characterize events in patients with IBS, and in general populationPhase III Further characterize events in patients with IBS, and in general population Observational Cohort Study of Safety in Patients Receiving Lotronex

A 19 Alosetron /26 Utilization Study Question: Descriptive study of utilization patterns over time in United HealthCareQuestion: Descriptive study of utilization patterns over time in United HealthCare Population: All persons receiving a prescription for LotronexPopulation: All persons receiving a prescription for Lotronex Analysis: Descriptive evaluation of users by :Analysis: Descriptive evaluation of users by : –Age –Gender –History of constipation –History of IBS-related visits and prescriptions

A 20 Alosetron /26 This study is also part of Program EvaluationThis study is also part of Program Evaluation Systematic evaluationSystematic evaluation First review December 2000, quarterly thereafterFirst review December 2000, quarterly thereafter Utilization Study

A 21 Alosetron /26 Epidemiology: Program of Research StudyPopulationTimeline 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) Complete risk factors in 6 million patients December 2000 general population and patients with IBS

A 22 Alosetron /26 Epidemiology: Program of Research (continued) StudyPopulationTimeline 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 Summer in GW Clinical Trials Clinical Trials 2000

A 23 Alosetron /26 Risk Definition Clinical Studies

A 24 Alosetron /26 Program of Clinical Studies Study on constipation managementStudy on constipation management –Laxatives –Interruption of therapy –Dose reduction Studies for other indications/populationsStudies for other indications/populations –Male IBS –Functional Dyspepsia

A 25 Alosetron /26 Risk Definition Mechanistic Studies

A 26 Alosetron /26 Mechanistic Studies Phase IV commitmentPhase IV commitment –Cultured endothelial cell integrity Mesenteric blood flow in humans with PET scanningMesenteric blood flow in humans with PET scanning Coagulation factorsCoagulation factors

A 27 Alosetron /26 Epidemiologi c Research Communication Program Evaluation Systematic Evaluation Risk Definition Mechanisti c Studies Clinical Studies Risk Management Strategy An Integrated Approach Appropriate Use ProgramAppropriate Use Program Healthcare PractitionersHealthcare Practitioners PharmacistsPharmacists PatientsPatients Testing Comprehension of Communication VehiclesTesting Comprehension of Communication Vehicles Tracking Awareness and Source of KnowledgeTracking Awareness and Source of Knowledge Lotronex Utilization StudyLotronex Utilization Study Ongoing pharmacovigilanceOngoing pharmacovigilance