Risk management program for lotronex alosetron hydrochloride tablets
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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

Risk Management Programfor Lotronex®(alosetron hydrochloride) Tablets

Craig A. Metz, PhD

VP, US Regulatory Affairs



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
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
Presentation Outline

  • Background

  • RMP goals

  • RMP

    • Program elements

    • Program results

  • RMP implementation conclusions

  • Issues


  • Product voluntarily withdrawn November 2000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


  • Mitigating risks associated with complications of constipation and ischemic colitis

  • Doing so without creating extraordinary barriers to patient access

Rmp goals
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
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
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
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 lotronex ppl
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 ppl1
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 ppl2
Prescribing Program for Lotronex (PPL)

Patient & Physician Sign Consent

Patient Takes RX to Pharmacy for dispensing

Subsequent Rx get sticker


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


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


1. Dr calls in to refill kits

2. Check against PPL enrollment

3. Kits refilled

Physician 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
Patient Education

  • Medication Guide

    • Received from the physician

    • Included in the product packaging

  • Physician counseling

  • Patient - Physician Agreement

Pharmacist education
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
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 activities1
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

Risk management program for lotronex alosetron hydrochloride tablets

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

Ae reporting conditions
AE Reporting Conditions Adverse Events of Special Interest Associated With the Use of Lotronex

  • 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
Report Sources for Adverse Events Adverse Events of Special Interest Associated With the Use of Lotronex

  • Spontaneous Reporting

  • Clinical trials

  • Patient Follow-Up Survey Program

Reporting adverse events
Reporting Adverse Events Adverse Events of Special Interest Associated With the Use of Lotronex

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

  • 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
Reporting Adverse Events Adverse Events of Special Interest Associated With the Use of LotronexPatient 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
Post-Marketing Surveillance Adverse Events of Special Interest Associated With the Use of Lotronex(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
Diagnoses of Special Interest (N=16) Adverse Events of Special Interest Associated With the Use of Lotronex

  • 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
Outcomes of Special Interest (N=4) Adverse Events of Special Interest Associated With the Use of Lotronex

  • 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
Safety of Lotronex Adverse Events of Special Interest Associated With the Use 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

Implementation of a plan to evaluate the effectiveness of the lotronex risk management program

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

Rmp evaluation components
RMP Evaluation Components the Lotronex Risk Management Program

  • 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

Physician Roster Comparison the Lotronex Risk Management Program

Process for analysis of physician prescription data
Process for Analysis of Physician Prescription Data the Lotronex Risk Management Program

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

Enrolled prescribers
Enrolled Prescribers the Lotronex Risk Management Program



Prescribers of lotronex distribution of physician specialties quarter october 2003 december 2003
Prescribers of Lotronex: the Lotronex Risk Management ProgramDistribution 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
Prescribing Activity for Physicians Enrolled in the PPL (N=5053)

Percent Prescribing

Number Prescribing

Total Number of Prescriptions

Follow up for non ppl prescribers
Follow-Up for Non-PPL Prescribers (N=5053)

  • 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)

Objectives (N=5053)

  • 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 Prescribed Lotronex & Receives (N=5053)Pre-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

Patient survey enrollment november 2002 december 31 2003
Patient Survey Enrollment (N=5053)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 rates 1
Summary of Survey Response Rates (N=5053)1

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.

Compliance with rmp process
Compliance with RMP Process (N=5053)

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
Patient Appropriateness (N=5053)

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)

Objectives (N=5053)

  • Describe/characterize patients receiving Lotronex

  • Describe/characterize PPL compliance

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

Longitudinal claims based observational studies1
Longitudinal Claims-based Observational Studies (N=5053)

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
Progress Through September 30, 2003 (N=5053)

Database Source Status

PA PACE Program/ Identified 4 users of

NJ Medicaid and Lotronex (PACE)/

PAAD Program Results not yet available


HMO Research Network Identified 28 users of Lotronex


Ingenix Database Identified 89 users of Lotronex

Observations (N=5053)

  • 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 (N=5053)Conclusions

Rmp implementation summary
RMP Implementation Summary (N=5053)

  • 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 summary1
RMP Implementation Summary (N=5053)

  • 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

Issues (N=5053)

  • Impact on practitioner

  • Impact on patient

  • Viability of RMP components

Sources of rmp feedback
Sources of RMP Feedback (N=5053)

  • 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
Prescriber Impact (N=5053)General 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?

Prescriber impact potential barriers to patient access
Prescriber Impact (N=5053)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
Patient Impact (N=5053)

  • 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
Program Viability (N=5053)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

Risk management program for lotronex alosetron hydrochloride tablets
GOAL (N=5053)

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