# Presentation: 097212

## Risk Management Programfor Lotronex®(alosetron hydrochloride) Tablets

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

## 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**

## 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**

## Presentation Outline

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

## 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**Product voluntarily withdrawn November 2000 **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**

## Rationale

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

## 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**

## 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**

## 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 **

## 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**

## Prescribing Program for LotronexTM (PPL)

## Slide 12

**Notes:**
IBS is one of over 20 functional GI disorders.  Therefore  Hallmark symptoms of IBS are chronic or recurrent lower abdominal pain and discomfort associated with features of altered bowel function, such as urgency, altered stool consistency, altered stool frequency, and incomplete evacuation, as well as bloating. In functional GI disorders,  structural or biochemical abnormalities are not usually found

## 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**

## 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**

## Prescribing Program for Lotronex (PPL)

_**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 **

**Patient Takes RX to Pharmacy for dispensing**

_**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 **

**Subsequent Rx get  sticker**

_**Steps:**_
**1.****	****Dr calls in to refill kits **
**2.****	****Check against PPL enrollment   **
**3.****	****Kits refilled**

**Prescribing Program for Lotronex (PPL)**

## Education

## 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**

## Patient Education

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

## 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**

## 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**

## 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**

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

## AE Reporting Conditions

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

## Report Sources for Adverse Events

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

## 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**

## 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**

## 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**

## 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**

## 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 **

## 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)**

## Safety of LotronexConclusions

**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**

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

## 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**

## Physician Roster Comparison

## 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 Submits Quarterly Report to FDA**

**GSK Purchases Prescription Data Set from NDCHealth**

## Enrolled Prescribers

**Enrolled Prescribers**

**Prescribers**

**Months**

## 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**

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

**Number Prescribing**

**Total Number of Prescriptions**

**Percent Prescribing**

**Notes:**
Let’s review the recently approved Package Insert for LOTRONEX...

## 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)**

## Patient Follow-Up Survey Program 

## 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**

## Data Collection Flow Chart

## Patient Survey EnrollmentNovember 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**

## Summary of Survey Response Rates1

**	****	****Number of**
**	**** ****Number of ****	****Questionnaires**
**	**** ****Questionnaires ****	****Completed and****	****Response **
**Patient Population ****	**** Sent****1**** ****	****Returned****1****	****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.**

## 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)**

## 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)**
**	****	**

## Longitudinal Claims-Based Observational Studies

## Objectives

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

## 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 **

## 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**

## 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**

## RMP ImplementationConclusions

## 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**

## 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**

## RMP Impact Issues

## Issues

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

## 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**

## Prescriber ImpactGeneral Issues

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

## Prescriber ImpactPotential Barriers to Patient Access

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

## 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)**

## Program ViabilityClaims 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**

## GOAL

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

## Slide 63