Isotretinoin Pregnancy Risk Management Program

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Isotretinoin Pregnancy Risk Management Program
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Isotretinoin 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
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Objectives

• Provide Advisory Committee with
• A program overview of iPLEDGE and
• Status update of iPLEDGE

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Agenda
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.
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Overview of iPLEDGE
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Isotretinoin 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

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iPLEDGE

• 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

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Evolution of iPLEDGE
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History 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

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February 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

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S.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

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S.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 month 
• 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

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S.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.

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Prescription 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

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Accutane 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

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Pregnancy 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
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Sponsors 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

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Feedback 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

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iPLEDGE 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
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iPLEDGE 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)
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Structure of iPLEDGE

• One centralized pregnancy risk management system
  for wholesalers, prescribers, pharmacies, and
  patients
• Educational Component
• Pregnancy Registry
• Program Evaluation Plan

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Development Process of iPLEDGE
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Program 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

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iPLEDGE 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
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Stakeholder 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

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Transition 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

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iPLEDGE Program
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Who Is Part of iPLEDGE?
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Patient PathFemales of Child-Bearing Potential
PotentialPatientforIsotretinoin
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Patient 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

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Patient 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

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Patient PathFemales of Child-Bearing Potential
iPLEDGE
Pt. ID
Patient interacts with educational and risk
management component ofthe system
Prescriber enters pregnancy test results
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Patient 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

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Patient 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)
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Patient 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)
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After 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

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Lost 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

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Patient 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)
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iPLEDGE Education Materials
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Prescriber 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

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Pharmacy Education

• For Pharmacists
• Pharmacist Guide
• Prescription Bag Stickers
• Pharmacy Process Flowchart

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Females 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

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Males 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

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Program Requirements
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Prescriber Registration and Activation
Patient registration commenced December 30, 2005
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Prescriber 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

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Prescriber 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

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Prescriber 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

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Pharmacy Registration and Activation
RSP responsible site pharmacist
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Pharmacy 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

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Pharmacy 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

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Wholesaler Registration

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Wholesaler 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

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Wholesaler 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

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Wholesaler 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

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Response 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
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Status Update
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iPLEDGE 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
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iPLEDGE 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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