1. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 IsotretinoinIsotretinoin Background and Regulatory History Jill Lindstrom, MD Medical Officer Division of Dermatologic and Dental Drug Products Background and Regulatory History Jill Lindstrom, MD Medical Officer Division of Dermatologic and Dental Drug Products

2. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 2 OverviewOverview Clinical background History of pregnancy prevention risk management Current isotretinoin pregnancy prevention risk management plan Guidelines for assessment Clinical background History of pregnancy prevention risk management Current isotretinoin pregnancy prevention risk management plan Guidelines for assessment

3. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 3 Isotretinoin--backgroundIsotretinoin--background Indication: treatment of severe recalcitrant nodular cystic acne Only drug moiety approved for this indication –innovator: Accutane - 1982 –generics: Amnesteem - 11/2002 Sotret - 12/2002 Claravis - 4/2003 –other related oral products are in development Indication: treatment of severe recalcitrant nodular cystic acne Only drug moiety approved for this indication –innovator: Accutane - 1982 –generics: Amnesteem - 11/2002 Sotret - 12/2002 Claravis - 4/2003 –other related oral products are in development

4. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 4 Courtesy of Dr. Diane Thiboutot

5. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 5

6. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 6

7. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 7

8. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 8 Courtesy of Dr. James Leyden

9. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 9 Courtesy of Dr. James Leyden

10. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 10 Isotretinoin Standard of Practice In practice, also used for non- nodular (but scarring) acne in addition to use for approved indication

11. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 11 Courtesy of Dr. James Leyden

12. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 12 Courtesy of Dr. James Leyden

13. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 13 Courtesy of Dr. Diane Thiboutot

14. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 14 Courtesy of Dr. Diane Thiboutot

15. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 15 Courtesy of Dr. Diane Thiboutot

16. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 16 Courtesy of Dr. Diane Thiboutot

17. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 17 Isotretinoin--mechanism of action Decreases sebum production Normalizes follicular hyperkeratinization and reduces follicular plugging Decreases Propionibacterium acnes colonization Anti-inflammatory Decreases sebum production Normalizes follicular hyperkeratinization and reduces follicular plugging Decreases Propionibacterium acnes colonization Anti-inflammatory

18. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 18 Courtesy of Dr. Diane Thiboutot

19. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 19 Courtesy of Dr. Diane Thiboutot

20. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 20 Isotretinoin--clinicalIsotretinoin--clinical Single course of therapy 15-20 weeks results in complete and prolonged disease remission in many patients

21. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 21 Isotretinoin--TeratogenIsotretinoin--Teratogen Increased risk of spontaneous abortion and premature birth Malformations: craniofacial, cardiac, thymus, CNS, functional 28% of exposed pregnancies affected at birth Indicated only for use in females who are not pregnant and males Increased risk of spontaneous abortion and premature birth Malformations: craniofacial, cardiac, thymus, CNS, functional 28% of exposed pregnancies affected at birth Indicated only for use in females who are not pregnant and males

22. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 22 History of Risk Management At approval in 1982 –animal data suggested teratogenicity –labeling: pregnancy category X contraindications warnings precautions At approval in 1982 –animal data suggested teratogenicity –labeling: pregnancy category X contraindications warnings precautions

23. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 23 History of Risk Management 1983 - 1987 –first report of infant malformation in 1983 –red warning stickers distributed to pharmacies –multiple Dear Doctor letters issued –labeling revised as additional data became available 1983 - 1987 –first report of infant malformation in 1983 –red warning stickers distributed to pharmacies –multiple Dear Doctor letters issued –labeling revised as additional data became available

24. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 24 History of Risk Management Pregnancy Prevention Program (PPP) 1988 Advisory Committee –Sponsor proposed Pregnancy Prevention Program (PPP) PPP components –Label/package package warnings avoid pregnancy icon blister pack 1988 Advisory Committee –Sponsor proposed Pregnancy Prevention Program (PPP) PPP components –Label/package package warnings avoid pregnancy icon blister pack

25. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 25 History of Risk Management Pregnancy Prevention Program (PPP) PPP components, con’t –Package Insert - boxed warning negative pregnancy test 7d before treatment initiation two reliable forms of contraception begin therapy on 2nd or 3rd day of next menses dispense 30 days supply pregnancy testing and contraceptive counseling monthly PPP components, con’t –Package Insert - boxed warning negative pregnancy test 7d before treatment initiation two reliable forms of contraception begin therapy on 2nd or 3rd day of next menses dispense 30 days supply pregnancy testing and contraceptive counseling monthly

26. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 26 History of Risk Management Pregnancy Prevention Program (PPP) PPP components, con’t –Informed consent for female patients –PPP kit for prescribers –Patient survey (SEU) –Accutane Tracking Survey - prescriber use of PPP PPP components, con’t –Informed consent for female patients –PPP kit for prescribers –Patient survey (SEU) –Accutane Tracking Survey - prescriber use of PPP

27. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 27 Number of Reported Pregnancies 1982-1999 by Year of Therapy (US) Data presented by Roche at 2000 Advisory Committee Meeting Reported Pregnancies Year Spontaneous Reports Accutane Survey

28. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 28 Estimated Number of Patients Using Accutane Number of Patients Data presented by Roche at 2000 Advisory Committee Meeting

29. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 29 History of Risk Management 2000 Advisory Committee Recommendations Dermatologic and Ophthalmic Drugs Advisory Committee convened on 9/2000 Recommended augmentation of isotretinoin risk management plan Communicated to Sponsor on Oct 6, 2000 Dermatologic and Ophthalmic Drugs Advisory Committee convened on 9/2000 Recommended augmentation of isotretinoin risk management plan Communicated to Sponsor on Oct 6, 2000

30. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 30 2000 Advisory Committee Recommendations Neuropsychiatric Risks Three points of action –amend informed consents - done –develop education program for prescribers - done –initiate research program - basic science groundwork needed Not the subject of this meeting Three points of action –amend informed consents - done –develop education program for prescribers - done –initiate research program - basic science groundwork needed Not the subject of this meeting

31. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 31 History of Risk Management 2000 Advisory Committee Recommendations Pregnancy prevention: two goals –no one should begin isotretinoin therapy if pregnant –effective pregnancy prevention will occur throughout the course of isotretinoin treatment Pregnancy prevention: two goals –no one should begin isotretinoin therapy if pregnant –effective pregnancy prevention will occur throughout the course of isotretinoin treatment

32. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 32 History of Risk Management 2000 Advisory Committee Recommendations Five point plan of action: –augmentation of patient education –registration of all patients –registration of prescribers –implementation of pregnancy registry –linkage of prescription to adequate pregnancy testing Five point plan of action: –augmentation of patient education –registration of all patients –registration of prescribers –implementation of pregnancy registry –linkage of prescription to adequate pregnancy testing

33. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 33 Current Risk Management Plan Approved for innovator Oct. 2001 –Accutane: S.M.A.R.T. –current risk management plan (RMP) Compelling need for enhanced pregnancy prevention risk management Based on extensive discussions and negotiations between Sponsor and FDA Approved for innovator Oct. 2001 –Accutane: S.M.A.R.T. –current risk management plan (RMP) Compelling need for enhanced pregnancy prevention risk management Based on extensive discussions and negotiations between Sponsor and FDA

34. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 34 2000 Advisory Committee Recommendations Points of Action - 1 A heightened educational program for each patient that includes verifiable documented written informed consent –augmented education and written informed consent is component of current RMP A heightened educational program for each patient that includes verifiable documented written informed consent –augmented education and written informed consent is component of current RMP

35. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 35 2000 Advisory Committee Recommendations Points of Action - 2 Complete registration of all patients, both male and female –intended to provide denominator for ascertainment of pregnancy rate –Sponsor proposed alternative proposal to estimate denominator using pharmacy databases and survey data avoided patient privacy issues assoc. w/registries increased survey enrollment integral to accuracy Complete registration of all patients, both male and female –intended to provide denominator for ascertainment of pregnancy rate –Sponsor proposed alternative proposal to estimate denominator using pharmacy databases and survey data avoided patient privacy issues assoc. w/registries increased survey enrollment integral to accuracy

36. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 36 2000 Advisory Committee Recommendations Points of Action - 3 Complete registration and certification of isotretinoin prescribers –Sponsor did not have authority to certify –Voluntary prescriber registration self-attestation of relevant competencies signed commitment to use the current RMP –Sponsor provides prescribers with information –Prescribers responsible for obtaining necessary education to achieve competencies in Letter of Understanding Complete registration and certification of isotretinoin prescribers –Sponsor did not have authority to certify –Voluntary prescriber registration self-attestation of relevant competencies signed commitment to use the current RMP –Sponsor provides prescribers with information –Prescribers responsible for obtaining necessary education to achieve competencies in Letter of Understanding

37. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 37 2000 Advisory Committee Recommendations Points of Action - 4 Comprehensive program to track fetal exposures to isotretinoin/formal registry –provide numerator for pregnancy rate –patient privacy and HIPAA concerns –Sponsor proposed extrapolation of numerator required survey response rate >60% –education of prescribers to increase awareness of survey –increased reimbursement for patient participation Comprehensive program to track fetal exposures to isotretinoin/formal registry –provide numerator for pregnancy rate –patient privacy and HIPAA concerns –Sponsor proposed extrapolation of numerator required survey response rate >60% –education of prescribers to increase awareness of survey –increased reimbursement for patient participation

38. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 38 2000 Advisory Committee Recommendations Points of Action - 5 Linkage of dispensing of isotretinoin to verification of adequate pregnancy testing –current RMP asks pharmacist to verify that patient has been qualified by prescriber –pharmacist does not independently review laboratory pregnancy test result –pharmacist participation is voluntary but encouraged Linkage of dispensing of isotretinoin to verification of adequate pregnancy testing –current RMP asks pharmacist to verify that patient has been qualified by prescriber –pharmacist does not independently review laboratory pregnancy test result –pharmacist participation is voluntary but encouraged

39. AE REPORTS MANUFACTURER One- time LOU 1 Rx w/ sticker 5 dispense isotretinoin & Med. Guide 7 PHARMACY SURVEY sticker Rx with PHARMACIST 6 stickers & educational materials 2`2` Contraception Counseling; Contraception Screening ß-HCG PATIENT 3 PATIENT SURVEY Second ß-HCG ; Informed consent 4 PHYSICIAN

40. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 40 Current Risk Management Plan Approved for innovator Oct 2001 –Accutane: S.M.A.R.T. Current RMP for generics contains essential elements –Amnesteem: S.P.I.R.I.T., Nov 2002 –Sotret: I.M.P.A.R.T., Dec 2002 –Claravis: A.L.E.R.T., April 2003 Approved for innovator Oct 2001 –Accutane: S.M.A.R.T. Current RMP for generics contains essential elements –Amnesteem: S.P.I.R.I.T., Nov 2002 –Sotret: I.M.P.A.R.T., Dec 2002 –Claravis: A.L.E.R.T., April 2003

41. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 41 Current Risk Management Plan Different names –S.M.A.R.T. (Accutane) –S.P.I.R.I.T. (Amnesteem) –I.M.P.A.R.T. (Sotret) –A.L.E.R.T. (Claravis) Different survey contractors –innovator: Degge/SI –generic: Slone Epidemiology Unit Midcourse changes in brand dispensed –patient confusion, multiple enrollment Different names –S.M.A.R.T. (Accutane) –S.P.I.R.I.T. (Amnesteem) –I.M.P.A.R.T. (Sotret) –A.L.E.R.T. (Claravis) Different survey contractors –innovator: Degge/SI –generic: Slone Epidemiology Unit Midcourse changes in brand dispensed –patient confusion, multiple enrollment

42. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 42 Assessment of Current RMP Sponsor instructed to submit comprehensive report on metrics after one year Advisory Committee in 2000 did not comment on benchmarks nor define “success” Establishing adequate benchmarks is challenging Sponsor instructed to submit comprehensive report on metrics after one year Advisory Committee in 2000 did not comment on benchmarks nor define “success” Establishing adequate benchmarks is challenging

43. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 43 Assessment of Current RMP Performance benchmarks Patient survey response rate: > 60% –success of current RMP contingent upon achievement of higher survey response rate –approval of current RMP based upon Sponsor’s assertion of achievability of Sponsor-identified threshold Patient survey response rate: > 60% –success of current RMP contingent upon achievement of higher survey response rate –approval of current RMP based upon Sponsor’s assertion of achievability of Sponsor-identified threshold

44. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 44 Assessment of Current RMP Performance benchmarks Use of qualification stickers –Stickers serve as surrogate endpoint for use of current RMP –Imperfect surrogate –Sponsor informed that threshold for success would approach 100% Use of qualification stickers –Stickers serve as surrogate endpoint for use of current RMP –Imperfect surrogate –Sponsor informed that threshold for success would approach 100%

45. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 45 Assessment of IPPRMP Performance benchmarks Fetal exposures to isotretinoin –goal that no one initiate isotretinoin therapy if pregnant may be achievable –goal that no one become pregnant while on isotretinoin therapy has added complexity of patient behavior Fetal exposures to isotretinoin –goal that no one initiate isotretinoin therapy if pregnant may be achievable –goal that no one become pregnant while on isotretinoin therapy has added complexity of patient behavior

46. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 46 ConclusionsConclusions Isotretinoin is a uniquely effective drug for the treatment of severe scarring acne Long history of risk management efforts to prevent fetal exposures to isotretinoin Current RMP introduced new tools Assessment of current program Isotretinoin is a uniquely effective drug for the treatment of severe scarring acne Long history of risk management efforts to prevent fetal exposures to isotretinoin Current RMP introduced new tools Assessment of current program