Title: Isotretinoin Pregnancy Risk Management Program
1Isotretinoin Pregnancy Risk Management Program
2Isotretinoin Manufacturers
Isotretinoin Manufacturer Approval Date
Accutane Hoffmann-La Roche Inc. May 1982
Amnesteem Mylan/Genpharm November 2002
Sotret Ranbaxy December 2002
Claravis Barr Laboratories, Inc. April 2003
3Objectives
- Provide Advisory Committee with
- A program overview of iPLEDGE and
- Status update of iPLEDGE
4Agenda
Overview of iPLEDGE Evolution of iPLEDGE Susan Ackermann Shiff, PhDGlobal Head, Risk Management, Hoffmann-La Roche Inc.Isotretinoin Product Manufacturers Group
Development Process of iPLEDGE Christine MundkurSr. VP, Quality and Regulatory Counsel, Barr Laboratories, Inc. Isotretinoin Product Manufacturers Group
iPLEDGE Program Status Update James ShampDirector, Covance, Inc.
5Overview of iPLEDGE
6Isotretinoin Public Health Goal
- To eliminate fetal exposure to isotretinoin by
ensuring that - No female patient starts isotretinoin therapy if
pregnant - No female patient on isotretinoin therapy becomes
pregnant
7iPLEDGE
- The system of checks and balances, documentation
- and verification that requires
- Mandatory registration of prescribers, patients,
pharmacies and wholesalers - Mandatory monthly laboratory pregnancy tests
verified by prescriber - Mandatory interactive educational questions about
contraception and birth defects each month - Authorization for a prescription to be dispensed
only after the patient has met all criteria
8Evolution of iPLEDGE
9History of Isotretinoin Pregnancy Risk Management
- Approved in 1982
- For Severe Recalcitrant Nodular Acne (SRNA)
- Only for patients who are unresponsive to
conventional therapy, including systemic
antibiotics - Warnings about teratogenicity were included from
the beginning 1982 - Formal Pregnancy Prevention Program with
voluntary survey, educational materials 1988 - Frequent, incremental enhancements based on
experience - SMART program instituted 2002
10February 2004 Joint Advisory Committee Meeting
- Roche provided 1-year results for SMART
- Sponsors proposed a single enhanced pregnancy
risk management program for all isotretinoin
products - Registry for prescribers, pharmacies, and
patients - Pregnancy registry
- Advisory Committees agreed with Sponsors
proposal with feedback
11S.M.A.R.T. Risk Management Program
- Prescriber Requirements
- S.M.A.R.T. Guide to Best Practices
- S.M.A.R.T. Letter of Understanding
- Registration
- Accutane Qualification Sticker
- Pharmacist Requirements
- No more than a 30-day supply
- Dispense within 7 days of qualification date
- No refills, telephone or computerized
prescriptions allowed
12S.M.A.R.T. Risk Management Program
- Patient Requirements
- Doctor must affix a yellow qualification sticker
to the isotretinoin prescription each month,
which signifies that the patient has been
qualified as described in CONTRAINDICATIONS AND
WARNINGS of the package insert - Female patients of childbearing potential must
have - A negative pregnancy test each monthÂ
- Committed to using two effective forms of
contraception simultaneously - Signed an informed consent form
- Informed of the purpose and importance of
participating in the Accutane Survey
13S.M.A.R.T. Evaluation
- The effectiveness of the S.M.A.R.T. program was
- evaluated using the following
- The Prescription Compliance Survey
- A S.M.A.R.T.-revised Accutane Survey
- Pregnancy case reports for a time period before
S.M.A.R.T. vs. during S.M.A.R.T.
14Prescription Compliance Survey
- Results
- Qualification Sticker affixed to prescription
97.2 - Qualification Sticker correctly completed 96.4
- Conclusions
- All metrics for use of sticker exceeded
- The mechanics of the sticker work well
15Accutane Survey
- Results
- Increased enrollment (28), but did not increase
to 60 - 9 of female patients who recalled the
qualification sticker did not recall a pregnancy
test prior to initiation of therapy - Conclusions
- Understand need to avoid pregnancy
- Incomplete compliance with pregnancy testing and
contraceptive requirements
16Pregnancy Reporting Resultsfor S.M.A.R.T. Year-1
Pre-S.M.A.R.T.1 N150 S.M.A.R.T.2 N183
Patient pregnant prior to starting ACCUTANE therapy 28 (19) 24 (13)
Patient became pregnant while on ACCUTANE therapy 77 (51.3) 75 (41.0)
Patient became pregnant within 30 days after stopping ACCUTANE therapy 44 (29.3) 58 (31.7)
Unknown 1 (lt 1) 26 (14)
1Treatment started April 1, 2001 to March 31,
2002 with the report received by August 15,
2002 2Treatment started April 1, 2002 to March
31, 2003 with the report received by August 15,
2003
17Sponsors Proposal for Program Enhancements
- Further tighten existing links between pregnancy
testing and dispensing of drug - Reinforce patient commitment to using two forms
of contraception - Single risk management program for isotretinoin
- Limited participation with voluntary patient
survey - Centralized pregnancy reporting
- Root Cause Analysis
18Feedback fromJoint Advisory Committee Meeting
- Advisory Committees agreed with Sponsors
proposal - with the following additional feedback
- Registration of all health care professionals
prescribing or dispensing isotretinoin - Comprehension testing of the educational
materials - Mandatory patient follow-up survey
- Launch of program should not be delayed by a
pilot program or cost analysis
19iPLEDGE Enhancements
Gaps from Previous RMPs Risk Management Enhancements
Tighten pregnancy testing link Laboratory-conducted pregnancy test Pregnancy test results entered into system
Reinforce patient contraception use Patient and prescriber entries for the primary form must match Patient must answer monthly education questions
Single pregnancy RMP Registry ensures education of prescribers, pharmacies, and patients
20iPLEDGE Enhancements (contd)
Gaps from Previous RMPs Risk Management Enhancements
Limited survey participation Patient must answer monthly education questions
Centralized pregnancy reporting iPLEDGE Pregnancy Registry with RCA Prescribers must report all isotretinoin exposed pregnancies Lost to follow-up plan ? ensure best attempt to follow-up all Females of Child-Bearing Potential (FCBP)
21Structure of iPLEDGE
- One centralized pregnancy risk management system
for wholesalers, prescribers, pharmacies, and
patients - Educational Component
- Pregnancy Registry
- Program Evaluation Plan
22Development Process of iPLEDGE
23Program Magnitude
- Coordination and governance of 4 competitor
manufacturers of isotretinoin - Selection of appropriate vendor with capabilities
to design and implement a complex program - Development and design of novel computer-based
platform - Potential annual registry participation by
- 298 wholesaler distribution centers
- 36,000 prescribers
- 55,000 retail pharmacies
- 200,000 patients/year
24iPLEDGE Development Milestones
2004 2004 2004 2004 2004 2004 2004 2004 2004 2004 2004 2005 2005 2005 2005 2005 2005 2005 2005 2005 2005 2005 2005 2006 2006 2006
F M A M J J A S O N D J F M A M J J A S O N D J F M
JointAdvisory CommitteeMeeting
Patient registration began
1st SAB meeting
Labeling supplement submitted
FDA issued White Paper
Labeling supplement approved
Mandatory registration/activation
Face-to-face meeting with FDA Covance presented
proposal to FDA
Sponsors sent Dear Doctor Letter reinforcing
use of existing RMP
Registration materials sent to wholesalers,
prescribers, and pharmacies
25Stakeholder Feedback
- Solicited feedback from SAB including members
from - American Academy of Dermatology
- Dermatology Nurses Association
- Society of Dermatology Physician Assistants
- Obstetrician/Gynecologist (contraception
specialty) - National Association of Chain Drug Stores
- National Community Pharmacists Association
- Healthcare Distribution Management Association
- Teratologist
- Epidemiologist
- Patient Advocate
- Majority of feedback received as stakeholders
became knowledgeable of program capabilities - Feedback and recommendations continue to be
discussed
26Transition from Previous Risk Management
Programs to iPLEDGE
- Time needed for stakeholder uptake of iPLEDGE
and conversion from existing programs - Registration
- Education materials
- Activation
- Training appropriate office staff
- Planning patient education and transitions
27iPLEDGE Program
28Who Is Part of iPLEDGE?
29Patient PathFemales of Child-Bearing Potential
PotentialPatientforIsotretinoin
30Patient PathFemales of Child-Bearing Potential
iPLEDGE
Pt. ID
- Initial Registration Visit
- Determine if childbearing potential
- Screening pregnancy test
- Informed consent
- Prescriber educates and registers patient
(iPLEDGE educational kit including iPLEDGE ID
card) - Enter patient demographics
- System enforced 30-day wait before 1st Rx
31Patient PathFemales of Child-Bearing Potential
iPLEDGE
Pt. ID
- Patient Confirmation Visit
- Document 2 forms of contraception patient is
committed to using - Educate patient
- Order laboratory conducted pregnancy test
- Patient receives Rx
- Start 7 day window to fill Rx
- Second consent
32Patient PathFemales of Child-Bearing Potential
iPLEDGE
Pt. ID
Patient interacts with educational and risk
management component ofthe system
Prescriber enters pregnancy test results
33Patient PathFemales of Child-Bearing Potential
iPLEDGE
Pt. ID
- Registered Pharmacy
- Verifies Rx is authorized
- Provides product information (NDC ), quantity
dispensed and day supply - Obtains RMA and do not dispense after date
- Medication Guide
- Dispenses Rx prior to do not dispense after date
34Patient PathFemales of Child-Bearing Potential
iPLEDGE
Pt. ID
- Registered Pharmacy
- Verifies Rx is authorized
- Provides product information (NDC ), quantity
dispensed and day supply - Obtains RMA and do not dispense after date
- Medication Guide
- Dispenses Rx prior to do not dispense after date
?23 Days Later
Patient receives Isotretinoin(30 days)
35Patient PathFemales of Child-Bearing Potential
iPLEDGE
Pt. ID
- Registered Pharmacy
- Verifies Rx is authorized
- Provides product information (NDC ), quantity
dispensed and day supply - Obtains RMA and do not dispense after date
- Medication Guide
- Dispenses Rx prior to do not dispense after date
?23 Days Later
Patient receives Isotretinoin(30 days)
36After Isotretinoin Therapy
- Obtain monthly laboratory pregnancy test
immediately after the last dose of isotretinoin - Must continue to use 2 forms of contraception for
30 days after the last dose of isotretinoin - Obtain final laboratory pregnancy test 30 days
after the last dose of isotretinoin - Prescriber must enter both laboratory pregnancy
test results in the iPLEDGE system
37Lost to Follow-up Procedure Females of
Child-Bearing Potential
- For Prescribers
- Two (2) telephone attempts will be made to
contact the prescriber - If unable to contact, a traceable letter will be
sent to the prescriber and follow-up will focus
directly on the FCBP patient - For Patients
- Two (2) telephone attempts will be made to
contact the patient - If unable to contact, a traceable letter will be
sent to the patient and follow-up will be
considered final
38Patient Path Males Females of Non
Child-Bearing Potential
iPLEDGE
Pt. ID
PotentialPatientforIsotretinoin
- Determine if childbearing potential
- Informed consent
- Prescriber educates and registers patient
(iPLEDGE educational kit including iPLEDGE ID
card) - Enter patient demographics
- Prescriber confirms patient
- Registered Pharmacy
- Verifies Rx is authorized
- Provides product information (NDC ), quantity
dispensed and day supply - Obtains RMA and do not dispense after date
- Medication Guide
- Dispenses Rx prior to do not dispense after date
?23 Days Later
Patient receives Isotretinoin(30 days)
39iPLEDGE Education Materials
40Prescriber Education
- For Prescribers
- Guide to Best Practices for Isotretinoin
- Prescriber Contraception Counseling Guide
- Prescriber Checklists for FCBPs, and for Male
Patients and Males Females of Non
Child-Bearing Potential (FNCBP) - Recognizing Psychiatric Disorders in Adolescents
and Young Adults Guide - Educational DVD
- Prescriber Process Flowchart
41Pharmacy Education
- For Pharmacists
- Pharmacist Guide
- Prescription Bag Stickers
- Pharmacy Process Flowchart
42Females of Child-Bearing PotentialPatient
Education
- For FCBPs
- The iPLEDGE Program Guide to Isotretinoin
for Female Patients Who Can Get Pregnant - The iPLEDGE Program Birth Control Workbook
- The iPLEDGE Program Contraception Referral Form
and Contraception Counseling Guide - Patient ID Card
- Patient Information/Informed Consent Form (for
all patients) - Patient Information/Informed Consent About Birth
Defects (for female patients who can get
pregnant) - Patient Flowchart
43Males Females of Non Child-Bearing
PotentialPatient Education
- For Females who can not become pregnant and for
Men - The iPLEDGE Program Guide to Isotretinoin for
Male Patients and Female Patients Who Cannot Get
Pregnant - Patient Information/Informed Consent Form (for
all patients) - Patient ID Card
- Patient Flowchart
44Program Requirements
45Prescriber Registration and Activation
Patient registration commenced December 30, 2005
46Prescriber Requirements
- To prescribe isotretinoin, prescribers must
- Register with and activate iPLEDGE initially
- Reactivate annually
- Counsel all isotretinoin patients as required by
iPLEDGE - Prescribe no more than a 30-day supply of
isotretinoin to a patient during each monthly
office visit - Update patient records in the system in a timely
manner - Meet all other iPLEDGE requirements for
participating prescribers
47Prescriber Requirements (contd)
- For All Patients
- Register patient in iPLEDGE
- Signify that patient has signed Patient
Information/Informed Consent form - Signify that patient has received appropriate
education and counseling on isotretinoin and
program requirements, using appropriate iPLEDGE
patient education materials
48Prescriber Requirements (contd)
- For Females of Child-Bearing Potential
- Signify patient has signed additional Patient
Information/Informed Consent About Birth Defects - Signify patient has received appropriate
contraception counseling - Signify patient has selected and committed to
using 2 forms of contraception for 30 days prior
to, during, and for 30 days after discontinuing
treatment - Signify patient has had a negative in-office or
laboratory screening pregnancy test - There must be a 30-day run-in before receiving
first prescription - Signify patient undergoes monthly laboratory
pregnancy testing - Must be CLIA-certified lab
49Pharmacy Registration and Activation
RSP responsible site pharmacist
50Pharmacy Requirements
- To receive and dispense isotretinoin, each
individual pharmacy must - Have a designated Responsible Site Pharmacist
(RSP) - Register with and activate iPLEDGE initially
- Reactivate annually
- Meet all other iPLEDGE requirements for
participating pharmacies, including - Authorize all prescriptions through iPLEDGE
- Dispense no more than a 30-day supply of
isotretinoin to any patient at any time - Dispense all prescriptions with the isotretinoin
Medication Guide included with the product
51Pharmacy Requirements (contd)
- Responsible Site Pharmacist (RSP)
- Registers the pharmacy with the iPLEDGE program
- Activates the pharmacy registration initially and
annually - Attests that all program requirements are
understood - Trains all pharmacists who participate in the
filling and dispensing of isotretinoin
prescriptions and keeps a log or record of the
staff who have been trained
52Wholesaler Registration
53Wholesaler Requirements
- To receive and distribute isotretinoin,
wholesalers must - Register with iPLEDGE annually
- Meet all iPLEDGE requirements for wholesaler
distribution - NOTE In iPLEDGE, the term wholesaler refers
to wholesalers, distributors, and/or warehousing
chain pharmacy distributors
54Wholesaler Requirements (contd)
- Must distribute only FDA-approved isotretinoin
product - Must ship only to
- Pharmacies licensed in the US and registered and
activated in iPLEDGE - Other iPLEDGE-registered wholesalers with prior
written consent from the manufacturer - NOTE A list of registered and activated
pharmacies is provided electronically to
wholesalers on a daily basis, to facilitate
checking pharmacy status upon receipt of an order
55Wholesaler Requirements (contd)
- Must comply with inspection of wholesaler records
for verification of compliance by the
manufacturer (or delegate) - Must agree to return to manufacturer (or
delegate) any undistributed product if
registration is revoked or if the wholesaler
chooses to not register annually - Must agree to provide isotretinoin inventory (NDC
code and quantity on hand) and product flow data
to iPLEDGE for every location that has
isotretinoin - NOTE This is ONLY required for isotretinoin and
will NOT be shared except with the manufacturers
(or delegate) and FDA
56Response to Stakeholder Feedback
Feedback Sponsor Action
AAD Delegation of duties 7-day window definition Operational hurdles Ordering materials Creation of Office Staff Designee Function Under evaluation Being implemented Updated Prescriber Homepage
NACDS Centralized chain pharmacy registration Electronic prescription authorization Alternative methods for centralizing registration process Under evaluation
HDMA Updates to list of eligible pharmacies/wholesalers 24-hour grace period for system updates
57Status Update
58iPLEDGE Implementation Dates
Mandatory registration/activation date for wholesalers and pharmacies to distribute and receive product December 30, 2005
Patient registration began December 30, 2005
Request for product to be returned from unregistered wholesalers and pharmacies and registered pharmacies with no intentions of activating December 31, 2005
Request for product to be returned from registered but un-activated pharmacies January 31, 2006
Last date an isotretinoin prescription can be dispensed under SMART, ALERT, SPIRIT, or IMPART February 28, 2006
Mandatory registration/activation date for prescribers, pharmacies, and patients to prescribe, dispense, or receive isotretinoin March 1, 2006
59iPLEDGE Registration and Activations as of
February 8, 2006
Stakeholder Total Registrations Total Activations Universe
Retail Pharmacies 48,613 42,496 55,000
Prescribers 20,236 10,378 36,000
Wholesalers 199 N/A 298
- Number of patients registered 17,881
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