Targeted Pregnancy Prevention Program SM for Women on Accutane ® (isotretinoin)

1. Targeted Pregnancy Prevention ProgramSM for Women on Accutane® (isotretinoin) Eileen Enny Leach, MPH September 18, 2000

2. Targeted Pregnancy Prevention Program • Created from an analysis and revision of the 1988 Pregnancy Prevention ProgramSM • Revised program targeted to both: • small percentage of patients who do notavoid pregnancy • physicians who are having difficulty assessingand predicting an individual patient’s behavior • Goal: Prevention of pregnancy

3. Accutane Product Labeling • 1982 - 1987 • Launched with Category X with strong Warnings based on animal data • Revised to include data as it became available • 1988 Risk Management Pregnancy Prevention ProgramSM for Women on Accutane® (isotretinoin) (PPP)

4. 1988 Label ChangeElements • Pregnancy test required 7 daysbeforestarting Accutane • Two reliable forms of birth control • Begin therapy on 2nd or 3rd day of next menses • One month prescription only • Monthly pregnancy testing • Monthly contraceptive counseling

5. 1988 Accutane Package Elements • Blister pack for 10, 20, 40mg

6. 1988 Accutane Package Elements • Blister pack for 10, 20, 40mg • “Avoid pregnancy” logo at each pill site

7. 1988 Accutane Package Elements • Blister pack for 10, 20, 40mg • “Avoid pregnancy” logo at each pill site • Black box warnings

8. 1988 Accutane Package Elements • Blister pack for 10, 20, 40mg • “Avoid pregnancy” logo at each pill site • Black box warnings • Line drawings of birth defects

9. 1988 Risk Management SystemPregnancy Prevention ProgramSM (PPP)for Women on Accutane®(isotretinoin)

10. 1988 Risk Management SystemPregnancy Prevention ProgramSM (PPP) for Women on Accutane®(isotretinoin) • Assists in meeting requirements of label • Developed in cooperation with the American College of Obstetrics and Gynecology • Initiated Accutane Survey (patient survey) • Accutane Tracking Survey (prescriber survey)

11. Pregnancy Prevention ProgramSMfor Women on Accutane®(isotretinoin) • 97% of prescribers use at least one component of the PPP* • Reduced pregnancy rate from† • 1989 4.0 per 1000 • 1998 2.1 per 1000 * Accutane Prescriber Tracking Survey †Accutane Survey (incidence rate based on 1000 140-day courses)

12. Review of Individual Reports3 Pregnancies per 1000 Female Patients • Confusion about timing of pregnancy test • False negatives • Did not wait until 2nd or 3rd day of menses • Misinformation about contraceptive methods • Received more than one month supply • No monthly pregnancy testing orcontraceptive counseling Accutane Survey and Roche Accutane Drug Safety Database

13. Review of Individual ReportsWomen Who Reported Pregnancy During Accutane Therapy 3 Pregnancies per 1000 Female Patients Reasons Women Became Pregnant • Unsuccessful at abstinence • Used ineffective contraception • Used contraception inconsistently • Had unexpected sexual activity • Had a failure of the contraceptive method

14. All Pregnancies Reported in the US (annually) Women, in the US, whobecame pregnant (3.6 million) 45% Women who reported unwanted or mistimed pregnancies

15. 5% Women who reported pregnancies with typical use of birth control pills All Pregnancies Reported in the US (annually) Women, in the US, whobecame pregnant (3.6 million) 45% Women who reported unwanted or mistimed pregnancies

16. Accutane-Exposed Pregnancies • Pregnancy rate for women taking Accutane • 3 pregnancies per 1000 • Pregnancy rate 0.3%

17. Women Who Reported Pregnancies3 Pregnancies per 1000 Female Patients • 91% reported receiving warnings prior to start of treatment that the drug could cause birth defects if used during pregnancy • Mean age 26.3 years* *Roche Accutane Drug Safety Database (1991-1998)

18. Considerations for Risk Managementfor Accutane • Accutane is a known teratogen • Female Accutane patients are usually of childbearing potential • 91% of surveyed women believe they know about contraception* • 37% chose the least effective birth control method* * Lewin Survey 2000

19. Risk Management Options • Selective and targeted • Should not negatively impact: • the compliant patient • the current success of the program

20. Identify Issues and Put Them into Context Evaluate Results Assess Risk/ Assess Benefits Engage Partners and Other Stakeholders Implement the Strategy Identify and Analyze Options Select a Strategy Risk ManagementModel Source: Presidential/Congressional Commission on Risk Assessment and Risk Management, Framework for Environmental Health Risk Management — Final Report, Vol. 1, 1997.

21. Women Who Reported Pregnancies*3 Pregnancies per 1000 Female Patients Pregnant at time of initial office visit Information not available Did not wait to begin therapy before next menstrual cycle Became pregnant during therapy *Roche Accutane Drug Safety Database

22. 26% Targeting Patients at Risk3 Pregnancies per 1000 Female Patients Pregnant at the time of initial visit (14%) or did not wait unit the next menses (12%) = 26% Issue: Pregnancy testing

23. 64% Targeting Patients at Risk3 Pregnancies per 1000 Female Patients = 64% Pregnancy occurred during therapy • 11% reported they believed they would be able to maintain abstinence • 34% reported failure to use contraception on the perceived day of conception • 33% occurred while using one form of contraception • 51% reported contraception failure • 61% occurred while using one form of contraception

24. Targeted Pregnancy Prevention ProgramProvisions • Revise Accutane labeling • two safe, effective forms of birth control • negative results from two pregnancy tests • Provide urine pregnancy test kits • Introduce an Office Implementation System • Package for one month supply using unit dosing • Encourage enrollment in Accutane Survey • Provide educational materials for prescribersand patients

25. 100% 1988 LabelElements of Label 1988 LabelElements of Label 2000 Label ChangeElements of Label • Two pregnancy tests required at specified times • No Rx until confirmation of a negative result from a second pregnancy test • Two safe, effective forms of contraception • One primary and one secondary

26. Primary Tubal ligation Partner’s vasectomy Birth control pills Injectable/implantablebirth control products IUD Secondary Diaphragms with spermicide Latex condoms with spermicide Cervical caps withspermicide Effective Forms of Contraception Accutane Package Insert, May 2000

27. 100% 2000 Label ChangeElements of Label • Two pregnancy tests required at specified times • No Rx until confirmation of a negative result from a second pregnancy test • Two safe, effective forms of contraception • One primary and one secondary • Reinforce one month prescription only

28. 100% One Month Supply with Unit Dosing

29. 100% 2000 Label ChangeElements of Label • Two pregnancy tests required at specified times • No Rx until confirmation of a negative result from a second pregnancy test • Two safe, effective forms of contraception • One primary and one secondary • Reinforce one month prescription only • Reinforce monthly pregnancy testing and monthly contraceptive counseling

30. Please check as completed Initial pregnancy test–Negative 2nd pregnancy test–Negative Monthly pregnancy test–Negative Patient has joined the Survey Patient has seen the Be Prepared, Be Protected video Patient has been counseled about avoiding pregnancy Monthly Contraception Assessment Patient is not sexually active Patient is sexually active LMP: Choice of contraception: Primary Secondary Change in method/new method Counseling on contraception failure rates Progress Notes

31. Primary and Secondary Method Contraception Rx Consider Accutane Therapy (1) (3) Yes SexuallyActive WithoutContraception Pregnancy Prevention Program 10 Steps ContraceptiveCounseling (2) SexuallyActive With Contraception CounselingeitherPrescriber orContraceptiveCounseling Office Implementation System

32. Primary and Secondary Method (2nd Day of Menses or 11 Days Post Sexual Activity with No Birth Control) Contraception Rx Consider Accutane Therapy 1st UrinePregnancy Test 2nd UrinePregnancy Test (3) (1) Yes Neg. PPP 10 Steps SexuallyActive WithoutContraception ContraceptiveCounseling (2) (4) (5) SexuallyActiveWith Contraception Pos. Pos. No Rxfor Accutane No Rxfor Accutane CounselingeitherPrescriber orContraceptiveCounseling Send forContraceptiveCounseling Office Implementation System

33. Primary and Secondary Method AccutanePatient Survey SEU Contraception Rx Consider Accutane Therapy No (2nd Day of Menses or 11 Days Post Sexual Activity with No Birth Control) (3) (1) Accutane Prescription Given Yes 1st UrinePregnancy Test 2nd UrinePregnancy Test PPP 10 Steps Neg. SexuallyActive WithoutContraception ContraceptiveCounseling (6) Patient Enrolls (2) (4) (5) Pos. Pos. PharmacistDispenses SexuallyActiveWith Contraception No Rxfor Accutane No Rxfor Accutane (7) Take Accutane(30 days) Send forContraceptiveCounseling CounselingeitherPrescriber orContraceptiveCounseling (8) Revisit Monthly2-5 • Assess acne • Review patient Musts, check contraceptive use • Pregnancy Tests = Neg (9) Office Implementation System

34. Primary and Secondary Method Contraception Rx Consider Accutane Therapy No (2nd Day of Menses or 11 Days Post Sexual Activity with No Birth Control) AccutanePatient Survey SEU (3) (1) Yes 1st UrinePregnancy Test 2nd UrinePregnancy Test PPP 10 Steps AccutanePrescriptionGiven Neg. Neg. SexuallyActive WithoutContraception ContraceptiveCounseling (6) (2) Patient Enrolls (4) (5) Pos. Pos. SexuallyActiveWith Contraception PharmacistDispenses No Rxfor Accutane No Rxfor Accutane (7) Lab Monitoring Take Accutane(30 days) Send forContraceptiveCounseling CounselingeitherPrescriber orContraceptiveCounseling (8) RevisitMonthly2-5 (9) • Assess acne • Review patient Musts,check contraceptive use • Pregnancy Tests = Neg Office Implementation System

35.          The 10-Step Office Implementation System SelectingAppropriatePatients PatientEducation Steps 1. Qualification checklist 2. Important Information About Your Treatment with Accutane (isotretinoin) 3. Self-evaluation Quiz 4. Contraceptive Counseling Referral Program 5. Information/Consent Form 6. Accutane Patient Survey 7.Be Prepared, Be Protected video 8. Preventing Pregnancy, a Guide to Contraception 9.Contraception Knowledge Test 10. Accutane InfoLine and Confidential Contraceptive Counseling Line REVISED REVISED NEW NEW NEW NEW

36. Targeted Pregnancy Prevention ProgramSMfor Women on Accutane®(isotretinoin)Prescriber Assessment and Intervention Skills Guide to Best Practices for Prescribers • Contraception education • Assessment and intervention skills • How to initiate and have a conversation about sexual activity • Method for using support materials

37. Targeted Pregnancy Prevention ProgramContraception Knowledge and Behavior Be Smart, Be Safe, Be Sure • Provides step-by-step process for: • Qualification checklist • Accutane information • Self-evaluation Quiz • Contraception CounselingReferral Program • Information/Consent Form • Accutane Patient Survey • Contraception Knowledge Test

38. Pregnancy Test KitInstructions • Monoclonal and polyclonal antibodies(> 25 mIU/mL hCG) • Easy to perform,easy to evaluate • Standardized against WHO International Reference Preparation • 99% accurate at 11 days post conception

39. Women Who Reported Pregnancy During Accutane Therapy Reasons Women Became Pregnant • Unsuccessful at abstinence • Used ineffective contraception • Used contraception inconsistently • Had unexpected sexual activity • Had a failure of the contraceptive method

40. Targeted Pregnancy Prevention ProgramKnowledge About Contraception Preventing Pregnancy: A Guide to Contraception • Patient responsibilities • Birth defects • Avoiding pregnancy • Myths, methods and failure rates • Contraceptive Counseling Line

41. New Birth Defect Line Drawings

42. Roche Education Initiatives • Prescriber • Office Staff • Pharmacist

43. Prescriber Education • Guide to Best Practices for Prescribers • Database of registered prescribers (name, address, and CME number) • Roche Professional Representatives –Office Visit • Dermatology Resident Program • Peer reviewed journal articles for CME • Web site CME

44. Office Staff Education • Contraception Counseling Certificate Program • CEU for Registered Nurses • Certificate for RNs, LPNs, Medical Assistants • Dermatology Nurses’ Association • CEU provider unit • Presented at regional and state chapters levels

45. Pharmacist Education • Distribution of professional materials to: • Pharmacy Groups • Individual Pharmacists • Pharmaceutical Associations • CEU articles in pharmacy journals

46. Chronology of Actions • March 1999:Roche submitted Targeted PPP to the FDA • March 2000:Roche announced Targeted PPP at the American Academy of Dermatology • April 2000:Roche distributed urine pregnancy test kits • Immediately addressed 26% of pregnancies

47. Chronology of Actions • May 2000:FDA approved label change • June 2000:Distribution of “Dear Doctor” letterDistribution of contraception video • July 2000:Individual prescriber and office staff training

48. Chronology of Actions • October 2000:Roche will launch educational materials • Addresses prescriber assessment and intervention skills relative to contraception • Targets female Accutane patients’ contraception knowledge and behavior • Provides an “Office Implementation System”

49. Process Metrics – Achieving Goals • Prescribers • Office Staff • Pharmacists • Accutane Survey • Roche Call Center • Behavioral Research

50. Prescriber Metric Goals • Prescriber notification of targeted program Sept. 2000 • Roche professional representative officevisit for message reinforcement • 90% of prescribing dermatologists Jan. 2001 • Remaining prescribers Mar. 2001 • CME credit programs dermatologists, primary care prescribers, reproductive health prescribers, pediatricians Jun. 2001 • Dermatology Resident Education Programs Dec. 2002