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Risk Management Program
for Lotronex®
(alosetron hydrochloride)
Tablets
Craig A. Metz, PhD
VP, US Regulatory Affairs
GlaxoSmithKline
A 1
Consultants
Robert Sandler, MD, MPH Elizabeth B. Andrews, MPH, PhD
University of North Carolina Research Triangle Institute
at Chapel Hill Epidemiology Program
RMP Advisory Board
Jerry Gurwitz, MD
Lin Chang, MD Meyers Primary Care Institute
University of California at University of Massachusetts
Los Angeles Epidemiology Program
Educational Program
James Lewis, MD
Georgetown University
Safety Review Committee
A 2
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
A 3
Presentation Outline
• Background
• RMP goals
• RMP
– Program elements
– Program results
• RMP implementation conclusions
• Issues
A 4
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• Product voluntarily withdrawn November 2000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
A 5
Rationale
• Mitigating risks associated with
complications of constipation and
ischemic colitis
• Doing so without creating extraordinary
barriers to patient access
A 6
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
A 7
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
A 8
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
A 9
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
A 10
Prescribing Program for
Lotronex TM (PPL)
A 11
A 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
A 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
A 14
Prescribing Program for Lotronex (PPL)
Patient Takes RX to
Patient & Physician Subsequent Rx
Pharmacy for
Sign Consent get sticker
dispensing
Steps: Steps: Steps:
1. Physician identifies 1. Pharmacist checks 1. Dr calls in to
appropriate patient for paper Rx with refill kits
PPL sticker
2. Patient reviews Med 2. Check against
Guide 2. Fills Rx PPL
enrollment
3. Physician counsels Retail pack includes:
patients on risks and 3. Kits refilled
benefits 1. Box
4. Patient & Physician 2. 30 Tablets
sign agreement 3. PI
5. Copy goes to patient 4. Med. Guide
and one in medical file
5. Patient Survey Card
6. Physician attaches PPL
sticker to Rx and gives
to patient No Refills allowed
7. Physician provides No Faxed, Elec.,
Follow-up Survey form or Phone Rx's allowed
to patient
A 15
Education
A 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
A 17
Patient Education
• Medication Guide
– Received from the physician
– Included in the product packaging
• Physician counseling
• Patient - Physician Agreement
A 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
A 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
A 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
A 21
Reporting and Collection of
Serious Adverse Events and
Adverse Events of Special Interest
Associated With the Use of
Lotronex
A 22
AE Reporting Conditions
• Different d-IBS population
• Better informed patients and physicians
• Physician agreement to report serious
AEs
• Patient survey (non-traditional source)
A 23
Report Sources for Adverse
Events
• Spontaneous Reporting
• Clinical trials
• Patient Follow-Up Survey Program
A 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
A 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
A 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
A 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
A 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 A 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)
A 30
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
A 31
Implementation of a Plan to
Evaluate the Effectiveness of
the Lotronex Risk
Management Program
A 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
A 33
Physician Roster
Comparison
A 34
Process for Analysis of Physician
Prescription Data
MD Sends
Vendor Sends GSK Matches
Enrollment
Physician Enrollment Data
Form to
Enrollment Data to Prescription
Database
Set to GSK Data
Vendor
GSK Purchases
Prescription
Data Set from GSK Submits
NDCHealth Quarterly
Report to FDA
A 35
Enrolled Prescribers
1600
1400
Number of
Physicians
1200 Prescribing
81% 81% 83% Number
1000 83% Enrolled
Prescribers
82%
79% 81% Prescribing
800 81%
82%
79%
600 78%
75%
400
200
63%
0
Nov- Dec- Jan- Feb- Mar- Apr- May- Jun- Jul- Aug- Sep- Oct- Nov- Dec-
02 02 03 03 03 03 03 03 03 03 03 03 03 03
Months
A 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
A 37
Prescribing Activity for Physicians
Enrolled in the PPL (N=5053)
3000 60%
50%
2500 50%
Percent Prescribing
Number Prescribing
2000 40%
1500 30%
1000 20%
11% 10%
500 7% 7% 10%
6%
4% 4% 3%
0 0%
0 1 2 3 4 5 6-10 11-15 >15
Total Number of Prescriptions
A 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)
A 39
Patient Follow-Up Survey
Program
A 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
A 41
Data Collection Flow Chart
Patient Prescribed
Lotronex & Receives
Pre-enrollment
Patient Submits Pre-
Enrollment Card to RTI & is If Pre-enrollment Card
Enrolled In Study Missing Key Contact
Information, Tracing
Baseline Questionnaire & Informed Consent & Operations Unit Attempts
Consent Not Returned Baseline Questionnaire to Complete Information
Within 2 Weeks Mailed to Patient
Baseline Questionnaire &
Call Center Places
Signed Consent Returned
Reminder Call to Patient
Within 4 Weeks
5-WK, 10-WK & Quarterly
Questionnaires Not
Follow-up Questionnaires
Returned Within 2-4 Weeks
Sent as Scheduled
Call Center Contacts
Quarterly Analysis
Patient to Complete
Conducted
Questionnaire by Phone
A 42
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
A 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%
1The 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.
A 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)
A 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)
A 46
Longitudinal Claims-Based
Observational Studies
A 47
Objectives
• Describe/characterize patients receiving
Lotronex
• Describe/characterize PPL compliance
• Incidence of events in patients treated
with Lotronex (vs. comparison group)
A 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
A 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
A 50
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
A 51
RMP Implementation
Conclusions
A 52
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
A 53
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
A 54
RMP Impact Issues
A 55
Issues
• Impact on practitioner
• Impact on patient
• Viability of RMP components
A 56
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
A 57
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?
A 58
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
A 59
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)
A 60
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
A 61
GOAL
To modify the RMP to improve
product access for appropriate
physicians and patients while
continuing to effectively
manage risk
A 62
