A A 11

Risk Management ProgramRisk Management Programfor Lotronexfor Lotronex®®

(alosetron hydrochloride) (alosetron hydrochloride) TabletsTablets

Craig A. Metz, PhDCraig A. Metz, PhDVP, US Regulatory AffairsVP, US Regulatory Affairs

GlaxoSmithKlineGlaxoSmithKline

A A 22

ConsultantsConsultants

Robert Sandler, MD, MPHRobert Sandler, MD, MPHUniversity of North Carolina University of North Carolina at Chapel Hillat Chapel HillRMP Advisory BoardRMP Advisory Board

Lin Chang, MDLin Chang, MDUniversity of California at University of California at Los AngelesLos AngelesEducational ProgramEducational Program

James Lewis, MDJames Lewis, MDGeorgetown UniversityGeorgetown UniversitySafety Review CommitteeSafety Review Committee

Elizabeth B. Andrews, MPH, PhDElizabeth B. Andrews, MPH, PhDResearch Triangle InstituteResearch Triangle InstituteEpidemiology ProgramEpidemiology Program

Jerry Gurwitz, MDJerry Gurwitz, MDMeyers Primary Care InstituteMeyers Primary Care InstituteUniversity of MassachusettsUniversity of MassachusettsEpidemiology ProgramEpidemiology Program

A A 33

Presentation ThemesPresentation Themes

•Successful Risk Management Program (RMP) Successful Risk Management Program (RMP) implementationimplementation

– Appropriate prescribersAppropriate prescribers

– Appropriate patientsAppropriate patients

– Appropriate behaviorAppropriate behavior

•RMP ImpactRMP Impact

– Safety profileSafety profile

– PrescriberPrescriber

– PatientPatient

– Program elementsProgram elements

•Continual RMP evaluation and revisionContinual RMP evaluation and revision

A A 44

Presentation OutlinePresentation Outline

•BackgroundBackground

•RMP goalsRMP goals

•RMPRMP

– Program elementsProgram elements

– Program resultsProgram results

•RMP implementation conclusionsRMP implementation conclusions

•IssuesIssues

A A 55

BackgroundBackground

•Product voluntarily withdrawn November 2000 Product voluntarily withdrawn November 2000

•Supplemental New Drug Application submitted Supplemental New Drug Application submitted December 2001December 2001

•Joint GI Drugs Advisory Committee/Drug Joint GI Drugs Advisory Committee/Drug Safety and Risk Management Subcommittee Safety and Risk Management Subcommittee Meeting - April 2002Meeting - April 2002

•Supplemental NDA approved June 2002Supplemental NDA approved June 2002

•Product reintroduced November 2002 under a Product reintroduced November 2002 under a RMP with a revised indication statementRMP with a revised indication statement

A A 66

RationaleRationale

•Mitigating risks associated with Mitigating risks associated with complications of constipation and complications of constipation and ischemic colitisischemic colitis

•Doing so without creating extraordinary Doing so without creating extraordinary barriers to patient accessbarriers to patient access

A A 77

RMP GoalsRMP Goals

•Making Lotronex available to those patients Making Lotronex available to those patients for whom the benefit:risk ratio is favorablefor whom the benefit:risk ratio is favorable

•Prescribing of Lotronex to appropriate Prescribing of Lotronex to appropriate patients by qualified physicians patients by qualified physicians

•Educating physicians, pharmacists, and Educating physicians, pharmacists, and patients about the risk and benefits of patients about the risk and benefits of Lotronex and how to manage those risksLotronex and how to manage those risks

•Providing a framework for ongoing RMP Providing a framework for ongoing RMP evaluationevaluation

A A 88

Revised IndicationRevised Indication

•Because of serious gastrointestinal adverse Because of serious gastrointestinal adverse events, some fatal, reported with use of this events, some fatal, reported with use of this drug, Lotronex is indicated only for women drug, Lotronex is indicated only for women with severe diarrhea-predominant irritable with severe diarrhea-predominant irritable bowel syndrome (IBS) who have:bowel syndrome (IBS) who have:– chronic IBS symptoms (generally lasting chronic IBS symptoms (generally lasting

6 months or longer), and6 months or longer), and– had anatomic or biochemical had anatomic or biochemical

abnormalities of the gastrointestinal tract abnormalities of the gastrointestinal tract excluded, andexcluded, and

– failed to respond to conventional therapyfailed to respond to conventional therapy

A A 99

Revised Indication (continued)Revised Indication (continued)

•Diarrhea-predominant IBS is severe (less than Diarrhea-predominant IBS is severe (less than 5 percent of IBS is considered severe) if it 5 percent of IBS is considered severe) if it includes diarrhea and one or more of the includes diarrhea and one or more of the following:following:– frequent and severe abdominal frequent and severe abdominal

pain/discomfortpain/discomfort– frequent bowel urgency or fecal frequent bowel urgency or fecal

incontinenceincontinence– disability or restriction of daily activities due disability or restriction of daily activities due

to IBSto IBS• In men, the safety and effectiveness of In men, the safety and effectiveness of

Lotronex have not been established Lotronex have not been established

A A 1010

RMP Key ComponentsRMP Key Components

•Enrollment of qualified physicians in a Enrollment of qualified physicians in a physician prescribing programphysician prescribing program

•A program to educate physicians, A program to educate physicians, pharmacists, and patients about IBS and the pharmacists, and patients about IBS and the benefits and risks of Lotronexbenefits and risks of Lotronex

•A reporting and collection system for serious A reporting and collection system for serious adverse events associated with the use of adverse events associated with the use of LotronexLotronex

•A plan to evaluate the effectiveness of the A plan to evaluate the effectiveness of the RMP for LotronexRMP for Lotronex

A A 1111

Prescribing Program for Prescribing Program for LotronexLotronexTMTM (PPL) (PPL)

A A 1212

A A 1313

Prescribing Program for Lotronex (PPL)Prescribing Program for Lotronex (PPL)

•Physician signs attestation formPhysician signs attestation form– ““I … attest”:I … attest”:

• I can diagnose and treat IBSI can diagnose and treat IBS• I can diagnose and manage ICI can diagnose and manage IC• I can diagnose and manage constipation and I can diagnose and manage constipation and

complications of constipationcomplications of constipation

– Acceptance of certain responsibilitiesAcceptance of certain responsibilities• I will educate …I will educate …• I will complete the Patient Physician Agreement I will complete the Patient Physician Agreement

(PPA) process(PPA) process• I will report serious adverse eventsI will report serious adverse events• I will affix stickersI will affix stickers

A A 1414

Prescribing Program for Lotronex (PPL)Prescribing Program for Lotronex (PPL)

•Prescribing Kit:Prescribing Kit:– Key Steps CardKey Steps Card– Prescribing Prescribing

InformationInformation– Medication GuidesMedication Guides– Patient/Physician Patient/Physician

Agreement FormsAgreement Forms– Prescribing Program Prescribing Program

StickersStickers– Patient Follow-Up Patient Follow-Up

Survey Program Survey Program Pre-Enrollment CardsPre-Enrollment Cards

A A 1515

Patient & Physician Patient & Physician Sign ConsentSign Consent

Steps:Steps:

1.1. Physician identifies Physician identifies appropriate patientappropriate patient

2.2. Patient reviews Med Patient reviews Med Guide Guide

3.3. Physician counsels Physician counsels patients on risks and patients on risks and benefitsbenefits

4.4. Patient & Physician Patient & Physician sign agreementsign agreement

5. Copy goes to patient 5. Copy goes to patient and one in medical fileand one in medical file

6. Physician attaches PPL 6. Physician attaches PPL sticker to Rx and gives sticker to Rx and gives to patientto patient

7. Physician provides 7. Physician provides Follow-up Survey form Follow-up Survey form to patient to patient

Patient Takes RX to Patient Takes RX to Pharmacy for Pharmacy for

dispensingdispensing

Steps:Steps:

1.1. Pharmacist checks Pharmacist checks for paper Rx with for paper Rx with PPL stickerPPL sticker

2.2. Fills RxFills Rx

Retail pack includes:Retail pack includes:

1.1. BoxBox

2.2. 30 Tablets30 Tablets

3.3. PIPI

4.4. Med. GuideMed. Guide

5.5. Patient Survey CardPatient Survey Card

No Refills allowed No Refills allowed

No Faxed, Elec.,No Faxed, Elec.,or Phone Rx's allowed or Phone Rx's allowed

Subsequent Rx Subsequent Rx get stickerget sticker

Steps:Steps:

1.1. Dr calls in to Dr calls in to refill kits refill kits

2.2. Check against Check against PPL PPL enrollment enrollment

3.3. Kits refilledKits refilled

Prescribing Program for Lotronex (PPL)Prescribing Program for Lotronex (PPL)

A A 1616

EducationEducation

A A 1717

Physician EducationPhysician Education

•Educational modulesEducational modules

– LOTRONEXLOTRONEX®® (alosetron hydrochloride) (alosetron hydrochloride) Tablets: Understanding the Risks and Tablets: Understanding the Risks and BenefitsBenefits

– Current Thinking About IBS: An Educational Current Thinking About IBS: An Educational Review on Irritable Bowel SyndromeReview on Irritable Bowel Syndrome

•Dear Physician letters (345,000)Dear Physician letters (345,000)

•Reminder letters for non-enrolled prescribersReminder letters for non-enrolled prescribers

A A 1818

Patient EducationPatient Education

•Medication Guide Medication Guide

– Received from the physicianReceived from the physician

– Included in the product packagingIncluded in the product packaging

•Physician counselingPhysician counseling

•Patient - Physician AgreementPatient - Physician Agreement

A A 1919

Pharmacist EducationPharmacist Education

•113,000 Dear Pharmacist letters113,000 Dear Pharmacist letters

•25,000 outbound telephone calls25,000 outbound telephone calls

•National Boards of State National Boards of State Pharmacists NewslettersPharmacists Newsletters

•Reminder letters to pharmacies in Reminder letters to pharmacies in vicinity of non-enrolled prescribersvicinity of non-enrolled prescribers

A A 2020

Other Educational ActivitiesOther Educational Activities

•Telephone conference series with physiciansTelephone conference series with physicians•Speaker program with physiciansSpeaker program with physicians• Information booths at professional society Information booths at professional society

meetingsmeetings•GI specialty sales forceGI specialty sales force•Lotronex.comLotronex.com•Call centersCall centers– FAQsFAQs– Medical informationMedical information– PPL questionsPPL questions

A A 2121

Other Educational ActivitiesOther Educational Activities

• Independent grants for IBS educationIndependent grants for IBS education

– Professional society symposiaProfessional society symposia

•American College of GastroenterologyAmerican College of Gastroenterology

•American Gastroenterological AssociationAmerican Gastroenterological Association

– Educational monographsEducational monographs

– University based IBS web siteUniversity based IBS web site

– Teleconference seriesTeleconference series

– CD-rom seriesCD-rom series

A A 2222

Reporting and Collection of Reporting and Collection of Serious Adverse Events and Serious Adverse Events and

Adverse Events of Special Interest Adverse Events of Special Interest Associated With the Use of Associated With the Use of

LotronexLotronex

A A 2323

AE Reporting ConditionsAE Reporting Conditions

•Different d-IBS populationDifferent d-IBS population

•Better informed patients and physiciansBetter informed patients and physicians

•Physician agreement to report serious Physician agreement to report serious AEsAEs

•Patient survey (non-traditional source)Patient survey (non-traditional source)

A A 2424

Report Sources for Adverse Report Sources for Adverse EventsEvents

•Spontaneous ReportingSpontaneous Reporting

•Clinical trialsClinical trials

•Patient Follow-Up Survey ProgramPatient Follow-Up Survey Program

A A 2525

Reporting Adverse EventsReporting Adverse Events

•Diagnoses of special interestDiagnoses of special interest– ischemic colitisischemic colitis– mesenteric ischemia, occlusion or mesenteric ischemia, occlusion or

infarctioninfarction– serious constipationserious constipation– complications of constipationcomplications of constipation

•Outcomes of special interestOutcomes of special interest– intestinal or anorectal surgeryintestinal or anorectal surgery– deathdeath

A A 2626

Reporting Serious Adverse Reporting Serious Adverse EventsEvents

•Mandatory (per regulations)Mandatory (per regulations)– Expedited reports for serious, unexpected Expedited reports for serious, unexpected

spontaneous reportsspontaneous reports– Expedited reports for serious, unexpected, Expedited reports for serious, unexpected,

attributable survey and clinical trial reportsattributable survey and clinical trial reports

•Voluntary (per approval letter June 7, 2002)Voluntary (per approval letter June 7, 2002)– Expedited reporting for all events of Expedited reporting for all events of

special interestspecial interest

A A 2727

Reporting Adverse Events Reporting Adverse Events Patient SurveyPatient Survey

• Patient survey is intended to measure patient Patient survey is intended to measure patient knowledge, behavior and RMP process elementsknowledge, behavior and RMP process elements

• Patients occasionally describe AEs in the course of Patients occasionally describe AEs in the course of the surveythe survey

• RTI de-identifies the AE report and forwards to GSKRTI de-identifies the AE report and forwards to GSK

– GSK assesses AEs for seriousness and special GSK assesses AEs for seriousness and special interest diagnoses interest diagnoses

– RTI requests patient consent for GSK follow-up RTI requests patient consent for GSK follow-up with prescriberwith prescriber

– AEs are reported to FDA as warrantedAEs are reported to FDA as warranted

A A 2828

Post-Marketing Surveillance Post-Marketing Surveillance (Nov 20, 2002 - Feb 6, 2004)(Nov 20, 2002 - Feb 6, 2004)

•Approximately 10,000 patients treatedApproximately 10,000 patients treated(34,000 Rx)(34,000 Rx)

•127 post-marketing AE cases 127 post-marketing AE cases – 37 (29%) considered serious37 (29%) considered serious– 19 (15%) with diagnoses and outcomes of 19 (15%) with diagnoses and outcomes of

special interestspecial interest

A A 2929

Diagnoses of Special Interest (N=16)Diagnoses of Special Interest (N=16)•8 ischemic colitis8 ischemic colitis– 6 medically confirmed6 medically confirmed– 6 with colonoscopic/biopsy findings6 with colonoscopic/biopsy findings– 3 hospitalized3 hospitalized

•No mesenteric ischemiaNo mesenteric ischemia

•No serious constipation No serious constipation •8 complications of constipation 8 complications of constipation – 3 medically confirmed3 medically confirmed– 3 fecal impaction3 fecal impaction– 3 intestinal obstruction3 intestinal obstruction– 1 ileus1 ileus– 1 ulcerated colon1 ulcerated colon– 3 hospitalized3 hospitalized– 3 seen in ER only 3 seen in ER only

A A 3030

Outcomes of Special Interest (N=4)Outcomes of Special Interest (N=4)

•1 surgery - unconfirmed exploratory 1 surgery - unconfirmed exploratory laparoscopy in a consumer who reported laparoscopy in a consumer who reported intestinal obstructionintestinal obstruction

•3 deaths3 deaths– 2 family member reports from Patient 2 family member reports from Patient

SurveySurvey•multiple myelomamultiple myeloma

•AIDSAIDS

– 1 physician report1 physician report• pulmonary embolism suspected (obese patient pulmonary embolism suspected (obese patient

with complex medical history)with complex medical history)

A A 3131

Safety of LotronexSafety of LotronexConclusionsConclusions

•No new safety issuesNo new safety issues

•AE cases of special interestAE cases of special interest

– Qualitatively similar (IC and CoC)Qualitatively similar (IC and CoC)

– Generally less severe outcomesGenerally less severe outcomes

– Review of individual cases suggests Review of individual cases suggests prompt and appropriate managementprompt and appropriate management

A A 3232

Implementation of a Plan to Implementation of a Plan to Evaluate the Effectiveness of Evaluate the Effectiveness of

the Lotronex Risk the Lotronex Risk Management ProgramManagement Program

A A 3333

RMP Evaluation ComponentsRMP Evaluation Components

•A retrospective study to compare the roster A retrospective study to compare the roster of physicians identified in a general of physicians identified in a general prescription database as prescribers of prescription database as prescribers of Lotronex with the roster of physicians Lotronex with the roster of physicians enrolled in the PPLenrolled in the PPL

•Patient Follow-Up Survey ProgramPatient Follow-Up Survey Program

•Longitudinal Claims-Based Observational Longitudinal Claims-Based Observational StudiesStudies

A A 3434

Physician Roster Physician Roster ComparisonComparison

A A 3535

Process for Analysis of Physician Process for Analysis of Physician Prescription DataPrescription Data

MD Sends MD Sends Enrollment Enrollment

Form to Form to Database Database VendorVendor

Vendor Sends Vendor Sends Physician Physician

Enrollment Data Enrollment Data Set to GSKSet to GSK

GSK Matches GSK Matches Enrollment Data Enrollment Data to Prescription to Prescription

DataData

GSK Submits GSK Submits Quarterly Quarterly

Report to FDAReport to FDA

GSK Purchases GSK Purchases Prescription Prescription

Data Set from Data Set from NDCHealthNDCHealth

A A 3636

63%

75%

78%

82%81%

79% 81% 82%81% 81%

83%83%

79%

0

200

400

600

800

1000

1200

1400

1600

Nov-02

Dec-02

Jan-03

Feb-03

Mar-03

Apr-03

May-03

Jun-03

Jul-03

Aug-03

Sep-03

Oct-03

Nov-03

Dec-03

Number of Physicians Prescribing

Number Enrolled Prescribing

Enrolled PrescribersEnrolled PrescribersP

resc

rib

ers

Pre

scri

ber

s

MonthsMonths

A A 3737

Prescribers of Lotronex: Prescribers of Lotronex: Distribution of Physician Specialties Distribution of Physician Specialties

(Quarter October 2003-December 2003)(Quarter October 2003-December 2003)

Percentage ofPercentage of Percentage ofPercentage of Percentage ofPercentage ofTotalTotal TotalTotal TotalTotal

PrescriptionsPrescriptions PrescriptionsPrescriptions PrescriptionsPrescriptionsNumber ofNumber of from Allfrom All from Enrolledfrom Enrolled by Non-Enrolledby Non-Enrolled

SpecialtySpecialty PrescriptionsPrescriptions Prescribers***Prescribers*** Prescribers***Prescribers*** Prescribers***Prescribers***

GastroenterologistGastroenterologist 5,4205,420 62%62% 59%59% 3%3%

Primary Care Physician*Primary Care Physician* 2,6272,627 30%30% 23%23% 7%7%

Other**Other** 719719 8%8% 5%5% 4%4%

TotalTotal 8,7668,766 100%100% 87%87% 13%13%

* * GP, family practice, internal medicineGP, family practice, internal medicine**** Most frequent specialties: obstetricians, gynecologists, institutions, general surgery, Most frequent specialties: obstetricians, gynecologists, institutions, general surgery,

psychiatrypsychiatry****** Prescriptions within the quarter divided by 8,766 Total PrescriptionsPrescriptions within the quarter divided by 8,766 Total Prescriptions

A A 3838

Prescribing Activity for Physicians Prescribing Activity for Physicians Enrolled in the PPL (N=5053)Enrolled in the PPL (N=5053)

10%7%

11%

3%4%4%7%6%

50%

0

500

1000

1500

2000

2500

3000

0 1 2 3 4 5 6-10 11-15 >15

0%

10%

20%

30%

40%

50%

60%

Nu

mb

er P

resc

rib

ing

Nu

mb

er P

resc

rib

ing

Total Number of PrescriptionsTotal Number of Prescriptions

Per

cen

t P

resc

rib

ing

Per

cen

t P

resc

rib

ing

A A 3939

Follow-Up for Non-PPL PrescribersFollow-Up for Non-PPL Prescribers

•Non-PPL prescriber identified Non-PPL prescriber identified

– First occurrenceFirst occurrence

• Enrollment kit forwarded to prescriberEnrollment kit forwarded to prescriber

•Reminder letter forwarded to local pharmacyReminder letter forwarded to local pharmacy

– Second occurrenceSecond occurrence

•Reminder letter forwarded to prescriberReminder letter forwarded to prescriber

– Third occurrenceThird occurrence

• Firmer reminder letter forwarded to prescriberFirmer reminder letter forwarded to prescriber

•75% comply (25% enroll, 50% stop prescribing)75% comply (25% enroll, 50% stop prescribing)

A A 4040

Patient Follow-Up Survey Patient Follow-Up Survey Program Program

A A 4141

ObjectivesObjectives

•Assess patient knowledge of the risks Assess patient knowledge of the risks and benefits of Lotronexand benefits of Lotronex

•Assess patient behavior in relation to Assess patient behavior in relation to recommendations in the RMPrecommendations in the RMP

•Assess the extent to which the patient Assess the extent to which the patient satisfies the product labeling satisfies the product labeling requirements for treatment with requirements for treatment with LotronexLotronex

A A 4242

Data Collection Flow ChartData Collection Flow Chart

Baseline Questionnaire & Baseline Questionnaire & Consent Not Returned Consent Not Returned

Within 2 WeeksWithin 2 Weeks

Call Center Places Call Center Places Reminder Call to PatientReminder Call to Patient

Questionnaires Not Questionnaires Not Returned Within 2-4 WeeksReturned Within 2-4 Weeks

Call Center Contacts Call Center Contacts Patient to Complete Patient to Complete

Questionnaire by PhoneQuestionnaire by Phone

Patient Prescribed Patient Prescribed Lotronex & ReceivesLotronex & Receives

Pre-enrollmentPre-enrollment

Informed Consent & Informed Consent & Baseline Questionnaire Baseline Questionnaire

Mailed to PatientMailed to Patient

Baseline Questionnaire & Baseline Questionnaire & Signed Consent Returned Signed Consent Returned

Within 4 WeeksWithin 4 Weeks

5-WK, 10-WK & Quarterly 5-WK, 10-WK & Quarterly Follow-up Questionnaires Follow-up Questionnaires

Sent as ScheduledSent as Scheduled

Quarterly Analysis Quarterly Analysis ConductedConducted

Patient Submits Pre-Patient Submits Pre-Enrollment Card to RTI & is Enrollment Card to RTI & is

Enrolled In StudyEnrolled In StudyIf Pre-enrollment Card If Pre-enrollment Card Missing Key Contact Missing Key Contact Information, Tracing Information, Tracing

Operations Unit Attempts Operations Unit Attempts to Complete Informationto Complete Information

A A 4343

Patient Survey EnrollmentPatient Survey EnrollmentNovember 2002-December 31, 2003November 2002-December 31, 2003

•42% (3701/8911) of all patients with a 42% (3701/8911) of all patients with a prescription for Lotronex pre-enrolled in the prescription for Lotronex pre-enrolled in the Survey ProgramSurvey Program

– 55% issued by the prescribing physician’s 55% issued by the prescribing physician’s officeoffice

– 18% were over the age of 65 years18% were over the age of 65 years

– 7% (266) of pre-enrollees were male7% (266) of pre-enrollees were male

– 0.2% (21) patients under the age of 180.2% (21) patients under the age of 18

•36% of patients completed a BL 36% of patients completed a BL questionnairequestionnaire

A A 4444

Summary of Survey Response RatesSummary of Survey Response Rates11

Number ofNumber of

Number of Number of QuestionnairesQuestionnaires Questionnaires Questionnaires Completed andCompleted and Response Response

Patient Population Patient Population Sent Sent11 ReturnedReturned11 RateRate

Baseline respondentsBaseline respondents 3,5593,559 3,1743,174 89%89%

Week 5 follow-up respondentsWeek 5 follow-up respondents 2,2472,247 2,1862,186 97%97%

Week 10 follow-up respondentsWeek 10 follow-up respondents 2,0472,047 2,0012,001 98%98%

Quarter 1 follow-up respondentsQuarter 1 follow-up respondents 1,3881,388 1,3541,354 98%98%

Quarter 2 follow-up respondentsQuarter 2 follow-up respondents 527 527 515 515 98%98%

11 The allotted timeframes for return of completed questionnaires for the baseline, week 5, week The allotted timeframes for return of completed questionnaires for the baseline, week 5, week 10, and quarterly questionnaires are 4 weeks, 4 weeks, 11 weeks, and 11 weeks, respectively. 10, and quarterly questionnaires are 4 weeks, 4 weeks, 11 weeks, and 11 weeks, respectively. Therefore, the numerators and denominators for the response rates calculation include only Therefore, the numerators and denominators for the response rates calculation include only mailed questionnaires for which the allotted time frame was completed by December 31, 2003.mailed questionnaires for which the allotted time frame was completed by December 31, 2003.

A A 4545

Compliance with RMP ProcessCompliance with RMP Process

Indicators of Compliance with RMPIndicators of Compliance with RMP N (%)N (%)

Signed a Patient Physician Agreement (PPA) Signed a Patient Physician Agreement (PPA) 2,982 (93)2,982 (93)

Discussed possible risks of Lotronex with doctorDiscussed possible risks of Lotronex with doctor 3,083 (96)3,083 (96)

Discussed with doctor how Lotronex can helpDiscussed with doctor how Lotronex can help 3,091 (97)3,091 (97)

Discussed with doctor reasons to stop LotronexDiscussed with doctor reasons to stop Lotronex 3,019 (95)3,019 (95)

Discussed when to call the doctorDiscussed when to call the doctor 3,004 (94)3,004 (94)

Received medication guide from doctor Received medication guide from doctor 2,880 (91)2,880 (91)

Received medication guide from pharmacistReceived medication guide from pharmacist 2,857 (90)2,857 (90)

Read the medication guide (if received)Read the medication guide (if received) 2,860 (98)2,860 (98)

Recalled prescription with blue stickerRecalled prescription with blue sticker 2,731 (87)2,731 (87)

A A 4646

Patient AppropriatenessPatient Appropriateness

Baseline Compliance withBaseline Compliance with FemalesFemales Males Males Treatment CriteriaTreatment Criteria N (%)N (%) N (%)N (%)

Met treatment and severity criteria Met treatment and severity criteria 2,296 (90)2,296 (90) 153 (84)153 (84)

Criteria for treatment:Criteria for treatment:Have diarrheaHave diarrhea 2,596 (95)2,596 (95) 173 (87)173 (87)IBS IBS 6 months 6 months 2,795 (98)2,795 (98) 206 (97)206 (97)Previous treatments for IBSPrevious treatments for IBS 2,736 (96)2,736 (96) 203 (96)203 (96)Inadequate relief of symptomsInadequate relief of symptoms 2,592 (97)2,592 (97) 192 (98)192 (98)

Severity conditions:Severity conditions:Cramps or bloatingCramps or bloating 2,491 (87)2,491 (87) 172 (81)172 (81)AccidentsAccidents 2,672 (93)2,672 (93) 189 (89)189 (89)Somewhat or very hard life Somewhat or very hard life 2,772 (98)2,772 (98) 202 (98)202 (98)ALL 3 SEVERITY CONDITIONSALL 3 SEVERITY CONDITIONS 1,834 (80)1,834 (80) 119 (78)119 (78)

A A 4747

Longitudinal Claims-Based Longitudinal Claims-Based Observational StudiesObservational Studies

A A 4848

ObjectivesObjectives

•Describe/characterize patients Describe/characterize patients receiving Lotronexreceiving Lotronex

•Describe/characterize PPL complianceDescribe/characterize PPL compliance

•Incidence of events in patients treated Incidence of events in patients treated with Lotronex (vs. comparison group)with Lotronex (vs. comparison group)

A A 4949

Longitudinal Claims-based Observational Longitudinal Claims-based Observational StudiesStudies

Database SourceDatabase Source DescriptionDescription

Ingenix Database Ingenix Database Comprises approximately 4.2 million insured patients.Comprises approximately 4.2 million insured patients.

PA PACE ProgramPA PACE Program Approximately 221,000 patients over the age of 65Approximately 221,000 patients over the age of 65NJ Medicaid &NJ Medicaid & Approximately 200,000 patients over the age of 65 yearsApproximately 200,000 patients over the age of 65 yearsPAAD ProgramsPAAD Programs Approximately 65% are from PAAD and 35% are from MedicaidApproximately 65% are from PAAD and 35% are from Medicaid

HMO Research HMO Research 3.9 million insured3.9 million insuredNetwork Center for Network Center for Harvard Pilgrim Health Care Harvard Pilgrim Health Care Education & Education & Fallon Community Health Plan Fallon Community Health Plan Research on Research on Group Health Cooperative of Puget Sound Group Health Cooperative of Puget Sound Therapeutics (CERT) Therapeutics (CERT) Health Partners Health Partners

Henry Ford Health Systems Henry Ford Health Systems Kaiser Permanente Georgia Kaiser Permanente Georgia Kaiser Permanente Northwest Kaiser Permanente Northwest Kaiser Permanente Colorado Kaiser Permanente Colorado Lovelace Health Systems Lovelace Health Systems

A A 5050

Progress Through September 30, 2003Progress Through September 30, 2003

Database SourceDatabase Source StatusStatus

PA PACE Program/PA PACE Program/ Identified 4 users ofIdentified 4 users of

NJ Medicaid and NJ Medicaid and Lotronex (PACE)/Lotronex (PACE)/

PAAD Program PAAD Program Results not yet availableResults not yet available

(NJ PAAD)(NJ PAAD)

HMO Research Network HMO Research Network Identified 28 users of LotronexIdentified 28 users of Lotronex

CERTCERT

Ingenix DatabaseIngenix Database Identified 89 users of LotronexIdentified 89 users of Lotronex

A A 5151

ObservationsObservations

•121 users / 277 dispensings121 users / 277 dispensings

•89% female89% female

•69% of first dispensings by 69% of first dispensings by gastroenterologistgastroenterologist

•70% (64 / 91) patient records contained 70% (64 / 91) patient records contained signed PPAsigned PPA

•Program viability currently impacted by Program viability currently impacted by low product uptakelow product uptake

A A 5252

RMP ImplementationRMP ImplementationConclusionsConclusions

A A 5353

RMP Implementation SummaryRMP Implementation Summary

All elements of the RMP have been All elements of the RMP have been successfully implementedsuccessfully implemented

80% of prescribers in PPL80% of prescribers in PPL

87% of prescriptions from PPL prescribers87% of prescriptions from PPL prescribers

Patient Follow-Up Survey Program Patient Follow-Up Survey Program

– key product use information deliveredkey product use information delivered

– patients selected were appropriate for patients selected were appropriate for treatmenttreatment

A A 5454

RMP Implementation SummaryRMP Implementation Summary

Patient/Physician behavior consistent with Patient/Physician behavior consistent with RMP goals RMP goals

Adverse events of special interest are few Adverse events of special interest are few and outcomes generally less severeand outcomes generally less severe

Continual RMP evaluation and revisionContinual RMP evaluation and revision

– follow-up for non-prescribersfollow-up for non-prescribers

– revisions to Patient Survey revisions to Patient Survey questionnairesquestionnaires

– AE reporting for Patient SurveyAE reporting for Patient Survey

A A 5555

RMP Impact IssuesRMP Impact Issues

A A 5656

IssuesIssues

•Impact on practitionerImpact on practitioner

•Impact on patientImpact on patient

•Viability of RMP componentsViability of RMP components

A A 5757

Sources of RMP FeedbackSources of RMP Feedback

•Physician directed qualitative researchPhysician directed qualitative research•Physician directed quantitative research Physician directed quantitative research

(data analysis ongoing)(data analysis ongoing)•Patient directed qualitative researchPatient directed qualitative research•Clinical trialsClinical trials•Sales force interactionsSales force interactions•Customer Response Center (CRC)Customer Response Center (CRC)•Key opinion leadersKey opinion leaders

A A 5858

Prescriber ImpactPrescriber ImpactGeneral IssuesGeneral Issues

•Physician attestation processPhysician attestation process– Perception of unique liability transfer from Perception of unique liability transfer from

GSK to prescriberGSK to prescriber•Actual use being reserved for most severeActual use being reserved for most severe

d-IBS?d-IBS?

– Affront to professional trainingAffront to professional training– Unnecessary duplication of licensure Unnecessary duplication of licensure

processprocess– Is there a less intrusive way to assure Is there a less intrusive way to assure

prescribing by appropriate physicians?prescribing by appropriate physicians?

A A 5959

Prescriber ImpactPrescriber ImpactPotential Barriers to Patient AccessPotential Barriers to Patient Access

• Impact of RMP on clinical practice patternsImpact of RMP on clinical practice patterns

•Uncertainty regarding RMP origin/purposeUncertainty regarding RMP origin/purpose

•Product labelingProduct labeling

– Uncertainty regarding 5% severity qualifierUncertainty regarding 5% severity qualifier

A A 6060

Patient ImpactPatient Impact

•Primary focus on risk in product labelingPrimary focus on risk in product labeling– Language tends to frighten rather than Language tends to frighten rather than

informinform• Feedback from field researchFeedback from field research

•Observations from current clinical trialsObservations from current clinical trials

– 28% of screened patients refused to 28% of screened patients refused to participateparticipate

•Requirement to sign a special document Requirement to sign a special document (Patient-Physician Agreement)(Patient-Physician Agreement)

A A 6161

Program ViabilityProgram ViabilityClaims Based Observational StudiesClaims Based Observational Studies

•Low physician/patient uptake has had a serious Low physician/patient uptake has had a serious effect on the observational studieseffect on the observational studies

•Currently only 10,000 patients treated yielding Currently only 10,000 patients treated yielding 121 patients in observational studies121 patients in observational studies

•2,000 patients required to support analysis 2,000 patients required to support analysis

– Means that 155,000 patients need to be treated Means that 155,000 patients need to be treated

– 15 years required at the current rate of 15 years required at the current rate of product useproduct use

A A 6262

GOALGOAL

To modify the RMP to improve To modify the RMP to improve product access for appropriate product access for appropriate physicians and patients while physicians and patients while continuing to effectively continuing to effectively manage riskmanage risk