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Risk Management Program for Lotronex ® (alosetron hydrochloride) Tablets

Risk Management Program for Lotronex ® (alosetron hydrochloride) Tablets. Craig A. Metz, PhD VP, US Regulatory Affairs GlaxoSmithKline. Robert Sandler, MD, MPH University of North Carolina at Chapel Hill RMP Advisory Board Lin Chang, MD University of California at Los Angeles

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Risk Management Program for Lotronex ® (alosetron hydrochloride) Tablets

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  1. Risk Management Programfor Lotronex®(alosetron hydrochloride) Tablets Craig A. Metz, PhD VP, US Regulatory Affairs GlaxoSmithKline

  2. 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 Consultants

  3. 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

  4. 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 Background • Product voluntarily withdrawn November 2000 • Supplemental New Drug Application submitted December 2001 • Joint GI Drugs Advisory Committee/Drug Safety and Risk Management Subcommittee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

  7. RMP Goals • Making Lotronex available to those patients for whom the benefit:risk 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

  8. 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

  10. 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

  11. Prescribing Program for LotronexTM (PPL)

  12. 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

  13. 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

  14. 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

  15. Education

  16. 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

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

  18. 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

  19. 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

  20. 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

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

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

  23. Report Sources for Adverse Events • Spontaneous Reporting • Clinical trials • Patient Follow-Up Survey Program

  24. 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

  25. 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

  26. 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

  27. 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

  28. Diagnoses of Special Interest (N=16) • 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

  29. Outcomes of Special Interest (N=4) • 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)

  30. 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

  31. Implementation of a Plan to Evaluate the Effectiveness of the Lotronex Risk Management Program

  32. 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

  33. Physician Roster Comparison

  34. 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

  35. Enrolled Prescribers Prescribers Months

  36. 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

  37. Prescribing Activity for Physicians Enrolled in the PPL (N=5053) Percent Prescribing Number Prescribing Total Number of Prescriptions

  38. 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)

  39. Patient Follow-Up Survey Program

  40. 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

  41. Patient Prescribed Lotronex & ReceivesPre-enrollment Patient Submits Pre-Enrollment Card to RTI & is Enrolled In Study If Pre-enrollment Card Missing Key Contact Information, Tracing Operations Unit Attempts to Complete Information Baseline Questionnaire & Consent Not Returned Within 2 Weeks Informed Consent & Baseline Questionnaire Mailed to Patient Call Center Places Reminder Call to Patient Baseline Questionnaire & Signed Consent Returned Within 4 Weeks Questionnaires Not Returned Within 2-4 Weeks 5-WK, 10-WK & Quarterly Follow-up Questionnaires Sent as Scheduled Call Center Contacts Patient to Complete Questionnaire by Phone Quarterly Analysis Conducted Data Collection Flow Chart

  42. 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 physician’s 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

  43. 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.

  44. 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)

  45. 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)

  46. Longitudinal Claims-Based Observational Studies

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

  48. 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

  49. 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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