1. P-1 Isotretinoin Pregnancy Risk Management Program

2. P-2 Isotretinoin Manufacturers IsotretinoinManufacturerApproval Date AccutaneHoffmann-La Roche Inc.May 1982 AmnesteemMylan/GenpharmNovember 2002 SotretRanbaxyDecember 2002 ClaravisBarr Laboratories, Inc.April 2003

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

4. P-4 Agenda Overview of iPLEDGE Evolution of iPLEDGE Susan Ackermann Shiff, PhD Global Head, Risk Management, Hoffmann-La Roche Inc. I sotretinoin Product Manufacturers Group Development Process of iPLEDGE Christine Mundkur Sr. VP, Quality and Regulatory Counsel, Barr Laboratories, Inc. Isotretinoin Product Manufacturers Group iPLEDGE Program Status Update James Shamp Director, Covance, Inc.

5. P-5 Overview of iPLEDGE

6. P-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. P-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. P-8 Evolution of iPLEDGE

9. P-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. P-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. P-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. P-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 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

13. P-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. P-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. P-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. P-16 Pregnancy Reporting Results for S.M.A.R.T. ® Year-1 Pre-S.M.A.R.T. 1 N=150 S.M.A.R.T. 2 N=183 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%) Unknown1 (< 1%)26 (14%) 1 Treatment started April 1, 2001 to March 31, 2002 with the report received by August 15, 2002 2 Treatment started April 1, 2002 to March 31, 2003 with the report received by August 15, 2003

17. P-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. P-18 Feedback from Joint 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. P-19 iPLEDGE Enhancements Gaps from Previous RMPsRisk 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 RMPRegistry ensures education of prescribers, pharmacies, and patients

20. P-20 iPLEDGE Enhancements (cont’d) Gaps from Previous RMPsRisk 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)

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

22. P-22 Development Process of iPLEDGE

23. P-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. P-24 iPLEDGE Development Milestones 200420052006 FMAMJJASONDJFMAMJJASONDJFM Joint Advisory Committee Meeting FDA Interactions Celgene patent resolution Vendor selection Submission of program components Labeling discussions FDA issued White Paper Face-to-face meeting with FDA – Covance presented proposal to FDA Communications and interactions with stakeholders and SAB members Sponsors sent Dear Doctor Letter reinforcing use of existing RMP Labeling supplement approved Registration materials sent to wholesalers, prescribers, and pharmacies Patient registration began 1 st SAB meeting DDMAC submissions Labeling supplement submitted Mandatory registration/ activation

25. P-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. P-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. P-27 iPLEDGE Program

28. P-28 Who Is Part of iPLEDGE?

29. P-29 Patient Path: Females of Child-Bearing Potential Potential Patient for Isotretinoin

30. P-30 Patient Path: Females of Child-Bearing Potential Potential Patient for Isotretinoin Initial Registration Visit: Determine if childbearing potentialDetermine if childbearing potential Screening pregnancy testScreening pregnancy test Informed consentInformed consent Prescriber educates and registers patient (iPLEDGE educational kit including iPLEDGE ID card)Prescriber educates and registers patient (iPLEDGE educational kit including iPLEDGE ID card) Enter patient demographicsEnter patient demographics System enforced 30-day wait before 1 st RxSystem enforced 30-day wait before 1 st Rx Pt. ID # iPLEDGE

31. P-31 Patient Path: Females of Child-Bearing Potential Potential Patient for Isotretinoin 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 1 st Rx Pt. ID # Patient Confirmation Visit: Document 2 forms of contraception patient is committed to usingDocument 2 forms of contraception patient is committed to using Educate patientEducate patient Order laboratory conducted pregnancy testOrder laboratory conducted pregnancy test Patient receives RxPatient receives Rx Start 7 day window to fill RxStart 7 day window to fill Rx Second consentSecond consent iPLEDGE

32. P-32 Patient Path: Females of Child-Bearing Potential Potential Patient for Isotretinoin 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 1 st Rx 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 Patient interacts with educational and risk management component of the system Prescriber enters pregnancy test results iPLEDGE

33. P-33 Patient Path: Females of Child-Bearing Potential Potential Patient for Isotretinoin 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 1 st Rx 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 Patient interacts with educational and risk management component of the system Prescriber enters pregnancy test results Registered Pharmacy: Verifies Rx is authorizedVerifies Rx is authorized Provides product information (NDC #), quantity dispensed and day supplyProvides product information (NDC #), quantity dispensed and day supply Obtains RMA # and do not dispense after dateObtains RMA # and do not dispense after date Medication GuideMedication Guide Dispenses Rx prior to do not dispense after dateDispenses Rx prior to do not dispense after date iPLEDGE

34. P-34 Patient Path: Females of Child-Bearing Potential  23 Days Later Potential Patient for Isotretinoin 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 1 st Rx 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 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 Patient interacts with educational and risk management component of the system Prescriber enters pregnancy test results Patient receives Isotretinoin (30 days) iPLEDGE

35. P-35 Patient Path: Females of Child-Bearing Potential iPLEDGE Potential Patient for Isotretinoin Initial Registration Visit: Determine if childbearing potentialDetermine if childbearing potential Screening pregnancy testScreening pregnancy test Informed consentInformed consent Prescriber educates and registers patient (iPLEDGE educational kit including iPLEDGE ID card)Prescriber educates and registers patient (iPLEDGE educational kit including iPLEDGE ID card) Enter patient demographicsEnter patient demographics System enforced 30-day wait before 1 st RxSystem enforced 30-day wait before 1 st Rx Registered Pharmacy: Verifies Rx is authorizedVerifies Rx is authorized Provides product information (NDC #), quantity dispensed and day supplyProvides product information (NDC #), quantity dispensed and day supply Obtains RMA # and do not dispense after dateObtains RMA # and do not dispense after date Medication GuideMedication Guide Dispenses Rx prior to do not dispense after dateDispenses Rx prior to do not dispense after date Pt. ID # Patient Confirmation Visit: Document 2 forms of contraception patient is committed to usingDocument 2 forms of contraception patient is committed to using Educate patientEducate patient Order laboratory conducted pregnancy testOrder laboratory conducted pregnancy test Patient receives RxPatient receives Rx Start 7 day window to fill RxStart 7 day window to fill Rx Second consentSecond consent Patient interacts with educational and risk management component of the system Prescriber enters pregnancy test results Patient receives Isotretinoin (30 days)  23 Days Later

36. P-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. P-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. P-38 Patient Path: Males & Females of Non Child-Bearing Potential  23 Days Later Potential Patient for Isotretinoin Determine if childbearing potentialDetermine if childbearing potential Informed consentInformed consent Prescriber educates and registers patient (iPLEDGE educational kit including iPLEDGE ID card)Prescriber educates and registers patient (iPLEDGE educational kit including iPLEDGE ID card) Enter patient demographicsEnter patient demographics Prescriber confirms patientPrescriber confirms patient Registered Pharmacy: Verifies Rx is authorizedVerifies Rx is authorized Provides product information (NDC #), quantity dispensed and day supplyProvides product information (NDC #), quantity dispensed and day supply Obtains RMA # and do not dispense after dateObtains RMA # and do not dispense after date Medication GuideMedication Guide Dispenses Rx prior to do not dispense after dateDispenses Rx prior to do not dispense after date Pt. ID # Patient receives Isotretinoin (30 days) iPLEDGE

39. P-39 iPLEDGE Education Materials

40. P-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. P-41 Pharmacy Education For Pharmacists: Pharmacist Guide Prescription Bag Stickers Pharmacy Process Flowchart

42. P-42 Females of Child-Bearing Potential Patient 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. P-43 Males & Females of Non Child-Bearing Potential Patient 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. P-44 Program Requirements

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

46. P-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. P-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. P-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. P-49 Pharmacy Registration and Activation RSP = responsible site pharmacist

50. P-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

51. P-51 Pharmacy Requirements (cont’d) 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

52. P-52 Wholesaler Registration

53. P-53 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

54. P-54 Wholesaler Requirements (cont’d) 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

55. P-55 Wholesaler Requirements (cont’d) 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

56. P-56 Response to Stakeholder Feedback FeedbackSponsor Action AADDelegation of duties 7-day window definition Operational hurdles Ordering materials Creation of Office Staff Designee Function Under evaluation Being implemented Updated Prescriber Homepage NACDSCentralized chain pharmacy registration Electronic prescription authorization Alternative methods for centralizing registration process Under evaluation HDMAUpdates to list of eligible pharmacies/wholesalers 24-hour grace period for system updates

57. P-57 Status Update

58. P-58 iPLEDGE Implementation Dates Mandatory registration/activation date for wholesalers and pharmacies to distribute and receive product December 30, 2005 Patient registration beganDecember 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

59. P-59 iPLEDGE Registration and Activations as of February 8, 2006 Stakeholder Total Registrations Total ActivationsUniverse Retail Pharmacies 48,61342,49655,000 Prescribers20,23610,37836,000 Wholesalers199N/A298 Number of patients registered = 17,881

60. P-60