a 1 alosetron 2000 6/26 elizabeth b. andrews, ph.d., m.p.h. director, worldwide epidemiology

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Elizabeth B. Elizabeth B. Andrews,Andrews,

Ph.D., M.P.H.Ph.D., M.P.H.Director, Worldwide Director, Worldwide EpidemiologyEpidemiology

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Risk Risk Management Management

PlanPlan

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GW Program of GW Program of Responsible Product Responsible Product

StewardshipStewardship•Scientific foundationScientific foundation to understand the to understand the risks and predictors of serious eventsrisks and predictors of serious events

•Communication programCommunication program to educate to educate physicians, pharmacists and patientsphysicians, pharmacists and patients

•Program evaluationProgram evaluation to determine if and to determine if and when additional efforts are when additional efforts are warrantedwarranted

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EpidemioloEpidemiologic gic

ResearchResearch

CommunicatiCommunicationon

Program Program EvaluationEvaluation

Systematic Systematic EvaluationEvaluation

Risk Risk DefinitionDefinition

MechaniMechanistic stic

StudiesStudies

Clinical Clinical StudiesStudies

Risk Management StrategyRisk Management StrategyAn Integrated ApproachAn Integrated Approach

• AppropriatAppropriate Use e Use ProgramProgram

• Healthcare Healthcare PractitionePractitionersrs

• PharmacistPharmacistss

• PatientsPatients

• Testing Testing Comprehension Comprehension of of Communication Communication VehiclesVehicles

• Tracking Tracking Awareness and Awareness and Source of Source of KnowledgeKnowledge

• Lotronex Lotronex Utilization StudyUtilization Study

• Ongoing Ongoing pharmacovigilancpharmacovigilancee

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ResearchResearch






StudiesStudies











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ResearchResearch





StudiesStudies












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ResearchResearch




StudiesStudies













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ResearchResearch






StudiesStudies











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•Recent launchRecent launch

• Interest highInterest high

•Many options consideredMany options considered

•Strategy consistent with the Strategy consistent with the evidenceevidence

– Appropriate patientsAppropriate patients

– Early recognitionEarly recognition

Risk Management Risk Management Strategy OpportunityStrategy Opportunity

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Risk DefinitionRisk DefinitionEpidemiology Epidemiology

ProgramProgram

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Contributions of Contributions of Epidemiology Studies vs Epidemiology Studies vs

Clinical TrialsClinical Trials•Large numbers of patientsLarge numbers of patients•Real world experienceReal world experience– more heterogeneous patientsmore heterogeneous patients– treatment and compliance less treatment and compliance less

controlledcontrolled•Estimate infrequent/rare eventsEstimate infrequent/rare events•Explore risk factors for eventsExplore risk factors for events•Trade depth (trial) for breadth Trade depth (trial) for breadth (epidemiology)(epidemiology)

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Program of Epidemiology Program of Epidemiology Research: Questions Research: Questions

AddressedAddressed•Frequency of complications of Frequency of complications of constipation in patients treated with constipation in patients treated with Lotronex in actual practiceLotronex in actual practice

•Frequency of ischemic colitis in Frequency of ischemic colitis in patients treated with Lotronex patients treated with Lotronex compared with other populations – compared with other populations – persons with IBS, persons who persons with IBS, persons who consult GI specialists, general consult GI specialists, general populationpopulation

•Potential risk factorsPotential risk factors

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General Study DesignsGeneral Study Designs

•Observational cohort Observational cohort studies to define incidence studies to define incidence of complications of of complications of constipation and ischemic constipation and ischemic colitiscolitis

•Nested case-control studies Nested case-control studies to evaluate risk factorsto evaluate risk factors

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Methodologic IssuesMethodologic Issues

•ChallengesChallenges

–Spectrum of diseaseSpectrum of disease

– ICD-9 code is non-specificICD-9 code is non-specific

•ApproachesApproaches

–Broad capture of ICD-9 codesBroad capture of ICD-9 codes

–Development of computer Development of computer algorithmsalgorithms

–Validation through chart reviewValidation through chart review

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Epidemiology Epidemiology CommitmentsCommitments

•GW and FDA agreed to a GW and FDA agreed to a Phase IV observational Phase IV observational cohort studycohort study

•10,000 patients treated 10,000 patients treated with Lotronexwith Lotronex

•GW is modifying the study GW is modifying the study to include complications of to include complications of constipationconstipation

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Observational Cohort Study of Observational Cohort Study of Safety in Patients Receiving Safety in Patients Receiving

LotronexLotronexObjectivesObjectives

1.1. Incidence and risk factors for Incidence and risk factors for complications of constipation in complications of constipation in patients receiving Lotronex patients receiving Lotronex

2.2. Incidence and risk factors for Incidence and risk factors for ischemic colitis in patients ischemic colitis in patients receiving Lotronexreceiving Lotronex

3.3. Incidence of these events in the Incidence of these events in the general population and in patients general population and in patients with IBS not receiving Lotronexwith IBS not receiving Lotronex

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Datasource Datasource •United HealthCare (UHC) Research United HealthCare (UHC) Research

DatabaseDatabase•Second largest health care company in Second largest health care company in

the United States: >300,000 physicians, the United States: >300,000 physicians, >14 million members>14 million members

•UHC Research Database subset comprised UHC Research Database subset comprised of 7 million members since 1990 with of 7 million members since 1990 with medical and prescription coveragemedical and prescription coverage


LotronexLotronex

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Study Conduct:Study Conduct: •Phase IPhase I

Development of algorithms using Development of algorithms using computerized claims to identify patients computerized claims to identify patients with diagnoses under studywith diagnoses under study

•Phase IIPhase IIIncidence of events in patients receiving Incidence of events in patients receiving LotronexLotronex

•Phase IIIPhase IIIFurther characterize events in patients Further characterize events in patients with IBS, and in general populationwith IBS, and in general population


LotronexLotronex

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Utilization Study Utilization Study •Question:Question:

Descriptive study of utilization Descriptive study of utilization patterns over time in United patterns over time in United HealthCare HealthCare

•Population:Population:All persons receiving a prescription All persons receiving a prescription for Lotronex for Lotronex

•Analysis:Analysis:Descriptive evaluation of users by :Descriptive evaluation of users by :– AgeAge– GenderGender– History of constipationHistory of constipation– History of IBS-related visits and History of IBS-related visits and

prescriptionsprescriptions

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•This study is also part of This study is also part of Program EvaluationProgram Evaluation

•Systematic evaluationSystematic evaluation

•First review December First review December 2000, quarterly thereafter2000, quarterly thereafter

Utilization Study Utilization Study

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Epidemiology:Epidemiology:Program of ResearchProgram of Research

StudyStudy PopulationPopulation TimelineTimeline

Phase IV Study of Safety Phase IV Study of Safety UHC ResearchUHC Research •• First First interim interim in 10,000 patients in 10,000 patients DatabaseDatabase report report treated with Lotronex treated with Lotronex •• 7 million members 7 million members December 2000 December 2000

Disease frequency/ Disease frequency/ GPRD (UK)GPRD (UK) •• Complete Completerisk factors in risk factors in •• 6 million patients 6 million patients December 2000 December 2000 general population general population and patients with IBSand patients with IBS

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Epidemiology:Epidemiology:Program of Research Program of Research

(continued)(continued)StudyStudy PopulationPopulation TimelineTimeline

Disease frequency Disease frequency TN MedicaidTN Medicaid •• Complete Fall Complete Fall and risk factorsand risk factors •• 1.4 million patients 1.4 million patients 2002 2002

Disease frequency Disease frequency Mayo Clinic &Mayo Clinic & •• Complete Fall Complete Fall and risk factors and risk factors FoundationFoundation 2002 2002

•• Residents of Residents of Olmstead County Olmstead County

Case control study Case control study Patients in GWPatients in GW •• Initiate Summer Initiate Summerin GW Clinical Trials in GW Clinical Trials Clinical TrialsClinical Trials 2000 2000

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Risk DefinitionRisk DefinitionClinical StudiesClinical Studies

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Program of Clinical Program of Clinical StudiesStudies•Study on constipation Study on constipation

managementmanagement–LaxativesLaxatives– Interruption of therapyInterruption of therapy–Dose reductionDose reduction

•Studies for other Studies for other indications/populationsindications/populations–Male IBSMale IBS–Functional DyspepsiaFunctional Dyspepsia

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Risk DefinitionRisk DefinitionMechanistic Mechanistic

StudiesStudies

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Mechanistic StudiesMechanistic Studies

•Phase IV commitmentPhase IV commitment–Cultured endothelial cell Cultured endothelial cell integrityintegrity

•Mesenteric blood flow in Mesenteric blood flow in humans with PET scanninghumans with PET scanning

•Coagulation factorsCoagulation factors

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ResearchResearch






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a 1 alosetron 2000 6/26 elizabeth b. andrews, ph.d., m.p.h. director, worldwide epidemiology

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