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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, History of Risk Management –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 –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

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

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

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

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

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

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

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

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

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

Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, Current Risk Management Plan Approved for innovator Oct –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 –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

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

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

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

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

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

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

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

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

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

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

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

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

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