Risk Management Program for Lotronex

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Risk Management Programfor Lotronex(alosetron
hydrochloride) Tablets

• Craig A. Metz, PhD
• VP, US Regulatory Affairs
• GlaxoSmithKline

2
Consultants

• Robert Sandler, MD, MPH
• University of North Carolina at Chapel Hill
• RMP Advisory Board
• Lin Chang, MD
• University of California at Los Angeles
• Educational Program
• James Lewis, MD
• Georgetown University
• Safety Review Committee

• Elizabeth B. Andrews, MPH, PhD
• Research Triangle Institute
• Epidemiology Program
• Jerry Gurwitz, MD
• Meyers Primary Care Institute
• University of Massachusetts
• Epidemiology Program

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Presentation Themes

• Successful Risk Management Program (RMP)
  implementation
• Appropriate prescribers
• Appropriate patients
• Appropriate behavior
• RMP Impact
• Safety profile
• Prescriber
• Patient
• Program elements
• Continual RMP evaluation and revision

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Presentation Outline

• Background
• RMP goals
• RMP
• Program elements
• Program results
• RMP implementation conclusions
• Issues

5
Background

• Product voluntarily withdrawn November 2000
• Supplemental New Drug Application submitted
  December 2001
• Joint GI Drugs Advisory Committee/Drug Safety and
  Risk Management Subcommittee Meeting - April 2002
• Supplemental NDA approved June 2002
• Product reintroduced November 2002 under a RMP
  with a revised indication statement

6
Rationale

• Mitigating risks associated with complications of
  constipation and ischemic colitis
• Doing so without creating extraordinary barriers
  to patient access

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RMP Goals

• Making Lotronex available to those patients for
  whom the benefitrisk ratio is favorable
• Prescribing of Lotronex to appropriate patients
  by qualified physicians
• Educating physicians, pharmacists, and patients
  about the risk and benefits of Lotronex and how
  to manage those risks
• Providing a framework for ongoing RMP evaluation

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Revised Indication

• Because of serious gastrointestinal adverse
  events, some fatal, reported with use of this
  drug, Lotronex is indicated only for women with
  severe diarrhea-predominant irritable bowel
  syndrome (IBS) who have
• chronic IBS symptoms (generally lasting 6 months
  or longer), and
• had anatomic or biochemical abnormalities of the
  gastrointestinal tract excluded, and
• failed to respond to conventional therapy

9
Revised Indication (continued)

• Diarrhea-predominant IBS is severe (less than 5
  percent of IBS is considered severe) if it
  includes diarrhea and one or more of the
  following
• frequent and severe abdominal pain/discomfort
• frequent bowel urgency or fecal incontinence
• disability or restriction of daily activities due
  to IBS
• In men, the safety and effectiveness of Lotronex
  have not been established

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RMP Key Components

• Enrollment of qualified physicians in a physician
  prescribing program
• A program to educate physicians, pharmacists, and
  patients about IBS and the benefits and risks of
  Lotronex
• A reporting and collection system for serious
  adverse events associated with the use of
  Lotronex
• A plan to evaluate the effectiveness of the RMP
  for Lotronex

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

• Physician signs attestation form
• I attest
• I can diagnose and treat IBS
• I can diagnose and manage IC
• I can diagnose and manage constipation and
  complications of constipation
• Acceptance of certain responsibilities
• I will educate
• I will complete the Patient Physician Agreement
  (PPA) process
• I will report serious adverse events
• I will affix stickers

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Prescribing Program for Lotronex (PPL)

• Prescribing Kit
• Key Steps Card
• Prescribing Information
• Medication Guides
• Patient/Physician Agreement Forms
• Prescribing Program Stickers
• Patient Follow-Up Survey Program Pre-Enrollment
  Cards

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Prescribing Program for Lotronex (PPL)
Patient Physician Sign Consent
Patient Takes RX to Pharmacy for dispensing
Subsequent Rx get sticker
Steps 1. Physician identifies appropriate
patient 2. Patient reviews Med Guide
3. Physician counsels patients on risks and
benefits 4. Patient Physician sign agreement 5.
Copy goes to patient and one in medical file 6.
Physician attaches PPL sticker to Rx and gives to
patient 7. Physician provides Follow-up Survey
form to patient
Steps 1. Pharmacist checks for paper Rx with PPL
sticker 2. Fills Rx Retail pack
includes 1. Box 2. 30 Tablets 3. PI 4. Med.
Guide 5. Patient Survey Card No Refills allowed
No Faxed, Elec., or Phone Rx's allowed
Steps 1. Dr calls in to refill kits 2. Check
against PPL enrollment 3. Kits refilled
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Education
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Physician Education

• Educational modules
• LOTRONEX (alosetron hydrochloride) Tablets
  Understanding the Risks and Benefits
• Current Thinking About IBS An Educational Review
  on Irritable Bowel Syndrome
• Dear Physician letters (345,000)
• Reminder letters for non-enrolled prescribers

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Patient Education

• Medication Guide
• Received from the physician
• Included in the product packaging
• Physician counseling
• Patient - Physician Agreement

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Pharmacist Education

• 113,000 Dear Pharmacist letters
• 25,000 outbound telephone calls
• National Boards of State Pharmacists Newsletters
• Reminder letters to pharmacies in vicinity of
  non-enrolled prescribers

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Other Educational Activities

• Telephone conference series with physicians
• Speaker program with physicians
• Information booths at professional society
  meetings
• GI specialty sales force
• Lotronex.com
• Call centers
• FAQs
• Medical information
• PPL questions

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Other Educational Activities

• Independent grants for IBS education
• Professional society symposia
• American College of Gastroenterology
• American Gastroenterological Association
• Educational monographs
• University based IBS web site
• Teleconference series
• CD-rom series

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Reporting and Collection of Serious Adverse
Events and Adverse Events of Special Interest
Associated With the Use of Lotronex

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AE Reporting Conditions

• Different d-IBS population
• Better informed patients and physicians
• Physician agreement to report serious AEs
• Patient survey (non-traditional source)

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Report Sources for Adverse Events

• Spontaneous Reporting
• Clinical trials
• Patient Follow-Up Survey Program

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Reporting Adverse Events

• Diagnoses of special interest
• ischemic colitis
• mesenteric ischemia, occlusion or infarction
• serious constipation
• complications of constipation
• Outcomes of special interest
• intestinal or anorectal surgery
• death

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Reporting Serious Adverse Events

• Mandatory (per regulations)
• Expedited reports for serious, unexpected
  spontaneous reports
• Expedited reports for serious, unexpected,
  attributable survey and clinical trial reports
• Voluntary (per approval letter June 7, 2002)
• Expedited reporting for all events of special
  interest

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Reporting Adverse Events Patient Survey

• Patient survey is intended to measure patient
  knowledge, behavior and RMP process elements
• Patients occasionally describe AEs in the course
  of the survey
• RTI de-identifies the AE report and forwards to
  GSK
• GSK assesses AEs for seriousness and special
  interest diagnoses
• RTI requests patient consent for GSK follow-up
  with prescriber
• AEs are reported to FDA as warranted

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

• Approximately 10,000 patients treated(34,000 Rx)
• 127 post-marketing AE cases
• 37 (29) considered serious
• 19 (15) with diagnoses and outcomes of special
  interest

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Diagnoses of Special Interest (N16)

• 8 ischemic colitis
• 6 medically confirmed
• 6 with colonoscopic/biopsy findings
• 3 hospitalized
• No mesenteric ischemia
• No serious constipation
• 8 complications of constipation
• 3 medically confirmed
• 3 fecal impaction
• 3 intestinal obstruction
• 1 ileus
• 1 ulcerated colon
• 3 hospitalized
• 3 seen in ER only

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Outcomes of Special Interest (N4)

• 1 surgery - unconfirmed exploratory laparoscopy
  in a consumer who reported intestinal obstruction
• 3 deaths
• 2 family member reports from Patient Survey
• multiple myeloma
• AIDS
• 1 physician report
• pulmonary embolism suspected (obese patient with
  complex medical history)

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Safety of LotronexConclusions

• No new safety issues
• AE cases of special interest
• Qualitatively similar (IC and CoC)
• Generally less severe outcomes
• Review of individual cases suggests prompt and
  appropriate management

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Implementation of a Plan to Evaluate the
Effectiveness of the Lotronex Risk Management
Program
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RMP Evaluation Components

• A retrospective study to compare the roster of
  physicians identified in a general prescription
  database as prescribers of Lotronex with the
  roster of physicians enrolled in the PPL
• Patient Follow-Up Survey Program
• Longitudinal Claims-Based Observational Studies

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Physician Roster Comparison
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Process for Analysis of Physician Prescription
Data
MD Sends Enrollment Form to Database Vendor
Vendor Sends Physician Enrollment Data Set to GSK
GSK Matches Enrollment Data to Prescription Data
GSK Purchases Prescription Data Set from NDCHealth
GSK Submits Quarterly Report to FDA
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Enrolled Prescribers
Prescribers
Months
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Prescribers of Lotronex Distribution of
Physician Specialties (Quarter October
2003-December 2003)

• Percentage of Percentage of Percentage of
• Total Total Total
• Prescriptions Prescriptions Prescriptions
• Number of from All from Enrolled by Non-Enrolled
• Specialty Prescriptions Prescribers Prescribers
  Prescribers
• Gastroenterologist 5,420 62 59 3
• Primary Care Physician 2,627 30 23 7
• Other 719 8 5 4
• Total 8,766 100 87 13

GP, family practice, internal medicine Most
frequent specialties obstetricians,
gynecologists, institutions, general surgery,
psychiatry Prescriptions within the quarter
divided by 8,766 Total Prescriptions
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Prescribing Activity for Physicians Enrolled in
the PPL (N5053)
Percent Prescribing
Number Prescribing
Total Number of Prescriptions
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Follow-Up for Non-PPL Prescribers

• Non-PPL prescriber identified
• First occurrence
• Enrollment kit forwarded to prescriber
• Reminder letter forwarded to local pharmacy
• Second occurrence
• Reminder letter forwarded to prescriber
• Third occurrence
• Firmer reminder letter forwarded to prescriber
• 75 comply (25 enroll, 50 stop prescribing)

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Patient Follow-Up Survey Program
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Objectives

• Assess patient knowledge of the risks and
  benefits of Lotronex
• Assess patient behavior in relation to
  recommendations in the RMP
• Assess the extent to which the patient satisfies
  the product labeling requirements for treatment
  with Lotronex

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Data Collection Flow Chart
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Patient Survey EnrollmentNovember 2002-December
31, 2003

• 42 (3701/8911) of all patients with a
  prescription for Lotronex pre-enrolled in the
  Survey Program
• 55 issued by the prescribing physicians office
• 18 were over the age of 65 years
• 7 (266) of pre-enrollees were male
• 0.2 (21) patients under the age of 18
• 36 of patients completed a BL questionnaire

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Summary of Survey Response Rates1

• Number of
• Number of Questionnaires
• Questionnaires Completed and Response
• Patient Population Sent1 Returned1 Rate
• Baseline respondents 3,559 3,174 89
• Week 5 follow-up respondents 2,247 2,186 97
• Week 10 follow-up respondents 2,047 2,001 98
• Quarter 1 follow-up respondents 1,388 1,354 98
• Quarter 2 follow-up respondents 527 515 98

1 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.
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.
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Compliance with RMP Process

• Indicators of Compliance with RMP N ()
• Signed a Patient Physician Agreement (PPA) 2,982
  (93)
• Discussed possible risks of Lotronex with
  doctor 3,083 (96)
• Discussed with doctor how Lotronex can help 3,091
  (97)
• Discussed with doctor reasons to stop
  Lotronex 3,019 (95)
• Discussed when to call the doctor 3,004 (94)
• Received medication guide from doctor 2,880 (91)
• Received medication guide from pharmacist 2,857
  (90)
• Read the medication guide (if received) 2,860
  (98)
• Recalled prescription with blue sticker 2,731
  (87)

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Patient Appropriateness

• Baseline Compliance with Females Males
• Treatment Criteria N () N ()
• Met treatment and severity criteria 2,296
  (90) 153 (84)
• Criteria for treatment
• Have diarrhea 2,596 (95) 173 (87)
• IBS ? 6 months 2,795 (98) 206 (97)
• Previous treatments for IBS 2,736 (96) 203 (96)
• Inadequate relief of symptoms 2,592 (97) 192
  (98)
• Severity conditions
• Cramps or bloating 2,491 (87) 172 (81)
• Accidents 2,672 (93) 189 (89)
• Somewhat or very hard life 2,772 (98) 202 (98)
• ALL 3 SEVERITY CONDITIONS 1,834 (80) 119 (78)

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Longitudinal Claims-Based Observational Studies
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Objectives

• Describe/characterize patients receiving Lotronex
• Describe/characterize PPL compliance
• Incidence of events in patients treated with
  Lotronex (vs. comparison group)

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Longitudinal Claims-based Observational Studies

• Database Source Description
• Ingenix Database Comprises approximately 4.2
  million insured patients.
• PA PACE Program Approximately 221,000 patients
  over the age of 65
• NJ Medicaid Approximately 200,000 patients over
  the age of 65 years
• PAAD Programs Approximately 65 are from PAAD and
  35 are from Medicaid
• HMO Research 3.9 million insured
• Network Center for ? Harvard Pilgrim Health Care
  
• Education ? Fallon Community Health Plan
• Research on ? Group Health Cooperative of Puget
  Sound
• Therapeutics (CERT) ? Health Partners
• ? Henry Ford Health Systems
• ? Kaiser Permanente Georgia
• ? Kaiser Permanente Northwest
• ? Kaiser Permanente Colorado
• ? Lovelace Health Systems

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Progress Through September 30, 2003

• Database Source Status
• PA PACE Program/ Identified 4 users of
• NJ Medicaid and Lotronex (PACE)/
• PAAD Program Results not yet available
• (NJ PAAD)
• HMO Research Network Identified 28 users of
  Lotronex
• CERT
• Ingenix Database Identified 89 users of Lotronex

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Observations

• 121 users / 277 dispensings
• 89 female
• 69 of first dispensings by gastroenterologist
• 70 (64 / 91) patient records contained signed
  PPA
• Program viability currently impacted by low
  product uptake

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RMP ImplementationConclusions
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RMP Implementation Summary

• All elements of the RMP have been successfully
  implemented
• 80 of prescribers in PPL
• 87 of prescriptions from PPL prescribers
• Patient Follow-Up Survey Program
• key product use information delivered
• patients selected were appropriate for treatment

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RMP Implementation Summary

• Patient/Physician behavior consistent with RMP
  goals
• Adverse events of special interest are few and
  outcomes generally less severe
• Continual RMP evaluation and revision
• follow-up for non-prescribers
• revisions to Patient Survey questionnaires
• AE reporting for Patient Survey

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RMP Impact Issues
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Issues

• Impact on practitioner
• Impact on patient
• Viability of RMP components

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Sources of RMP Feedback

• Physician directed qualitative research
• Physician directed quantitative research (data
  analysis ongoing)
• Patient directed qualitative research
• Clinical trials
• Sales force interactions
• Customer Response Center (CRC)
• Key opinion leaders

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Prescriber ImpactGeneral Issues

• Physician attestation process
• Perception of unique liability transfer from GSK
  to prescriber
• Actual use being reserved for most severed-IBS?
• Affront to professional training
• Unnecessary duplication of licensure process
• Is there a less intrusive way to assure
  prescribing by appropriate physicians?

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Prescriber ImpactPotential Barriers to Patient
Access

• Impact of RMP on clinical practice patterns
• Uncertainty regarding RMP origin/purpose
• Product labeling
• Uncertainty regarding 5 severity qualifier

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Patient Impact

• Primary focus on risk in product labeling
• Language tends to frighten rather than inform
• Feedback from field research
• Observations from current clinical trials
• 28 of screened patients refused to participate
• Requirement to sign a special document
  (Patient-Physician Agreement)

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Program ViabilityClaims Based Observational
Studies

• Low physician/patient uptake has had a serious
  effect on the observational studies
• Currently only 10,000 patients treated yielding
  121 patients in observational studies
• 2,000 patients required to support analysis
• Means that 155,000 patients need to be treated
• 15 years required at the current rate of product
  use

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GOAL

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

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