Isotretinoin Pregnancy Risk Management Program

1. Isotretinoin Pregnancy Risk Management Program

2. Isotretinoin Manufacturers

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

4. Agenda

5. Overview of iPLEDGE

6. 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

7. 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

8. Evolution of iPLEDGE

9. 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

10. 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

11. 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

12. 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 WARNINGSof 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

13. 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.

14. 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

15. 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

16. Pregnancy Reporting Resultsfor S.M.A.R.T.® Year-1 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

17. 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

18. 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

19. iPLEDGE Enhancements

20. iPLEDGE Enhancements (cont’d)

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

22. Development Process of iPLEDGE

23. 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

24. Labeling discussions Vendor selection Submission of program components DDMAC submissions FDA Interactions Celgene patent resolution Communications and interactions with stakeholders and SAB members iPLEDGE Development Milestones JointAdvisory CommitteeMeeting 1st SAB meeting Labeling supplement submitted Patient registration began 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

25. 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

26. 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

27. iPLEDGE Program

28. Who Is Part of iPLEDGE?

29. Patient Path:Females of Child-Bearing Potential PotentialPatientforIsotretinoin

30. PotentialPatientforIsotretinoin Patient Path:Females 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

31. PotentialPatientforIsotretinoin 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 Patient Path:Females 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

32. PotentialPatientforIsotretinoin 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 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 Patient Path:Females of Child-Bearing Potential iPLEDGE Pt. ID # Patient interacts with educational and risk management component ofthe system Prescriber enters pregnancy test results

33. PotentialPatientforIsotretinoin 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 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 Patient interacts with educational and risk management component ofthe system Prescriber enters pregnancy test results Patient Path:Females 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

34. PotentialPatientforIsotretinoin 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 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 Patient interacts with educational and risk management component ofthe system Prescriber enters pregnancy test results Patient Path:Females 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)

35. PotentialPatientforIsotretinoin 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 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 Patient interacts with educational and risk management component ofthe system Prescriber enters pregnancy test results Patient Path:Females 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)

36. 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

37. 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

38. 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)

39. iPLEDGE Education Materials

40. 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

41. Pharmacy Education For Pharmacists: • Pharmacist Guide • Prescription Bag Stickers • Pharmacy Process Flowchart

42. 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

43. 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

44. Program Requirements

45. Prescriber Registration and Activation * Patient registration commenced December 30, 2005

46. 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

47. Prescriber Requirements (cont’d) 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

48. Prescriber Requirements (cont’d) 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

49. Pharmacy Registration and Activation RSP = responsible site pharmacist

50. 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