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Isotretinoin

Isotretinoin. Background and Regulatory History Jill Lindstrom, MD Medical Officer Division of Dermatologic and Dental Drug Products. Overview. Clinical background History of pregnancy prevention risk management Current isotretinoin pregnancy prevention risk management plan

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Isotretinoin

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  1. Isotretinoin Background and Regulatory History Jill Lindstrom, MD Medical Officer Division of Dermatologic and Dental Drug Products

  2. Overview • Clinical background • History of pregnancy prevention risk management • Current isotretinoin pregnancy prevention risk management plan • Guidelines for assessment

  3. Isotretinoin--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

  4. Courtesy of Dr. Diane Thiboutot

  5. Courtesy of Dr. James Leyden

  6. Courtesy of Dr. James Leyden

  7. IsotretinoinStandard of Practice • In practice, also used for non-nodular (but scarring) acne in addition to use for approved indication

  8. Courtesy of Dr. James Leyden

  9. Courtesy of Dr. James Leyden

  10. Courtesy of Dr. Diane Thiboutot

  11. Courtesy of Dr. Diane Thiboutot

  12. Courtesy of Dr. Diane Thiboutot

  13. Courtesy of Dr. Diane Thiboutot

  14. Isotretinoin--mechanism of action • Decreases sebum production • Normalizes follicular hyperkeratinization and reduces follicular plugging • Decreases Propionibacterium acnes colonization • Anti-inflammatory

  15. Courtesy of Dr. Diane Thiboutot

  16. Courtesy of Dr. Diane Thiboutot

  17. Isotretinoin--clinical • Single course of therapy 15-20 weeks results in complete and prolonged disease remission in many patients

  18. Isotretinoin--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

  19. History of Risk Management • At approval in 1982 • animal data suggested teratogenicity • labeling: pregnancy category X • contraindications • warnings • precautions

  20. 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

  21. History of Risk ManagementPregnancy Prevention Program (PPP) • 1988 Advisory Committee • Sponsor proposed Pregnancy Prevention Program (PPP) • PPP components • Label/package • package warnings • avoid pregnancy icon • blister pack

  22. History of Risk ManagementPregnancy 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

  23. History of Risk ManagementPregnancy 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

  24. Accutane Survey Number of Reported Pregnancies 1982-1999 by Year of Therapy (US) Spontaneous Reports ReportedPregnancies Year Data presented by Roche at 2000 Advisory Committee Meeting

  25. Estimated Number of Patients Using Accutane Number ofPatients Data presented by Roche at 2000 Advisory Committee Meeting

  26. History of Risk Management2000 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

  27. 2000 Advisory Committee RecommendationsNeuropsychiatric 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

  28. History of Risk Management2000 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

  29. History of Risk Management2000 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

  30. 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 andFDA

  31. 2000 Advisory Committee RecommendationsPoints 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

  32. 2000 Advisory Committee RecommendationsPoints 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

  33. 2000 Advisory Committee RecommendationsPoints 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

  34. 2000 Advisory Committee RecommendationsPoints 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

  35. 2000 Advisory Committee RecommendationsPoints 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

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

  37. 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

  38. 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

  39. 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

  40. Assessment of Current RMPPerformance 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

  41. Assessment of Current RMPPerformance 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%

  42. Assessment of IPPRMPPerformance 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

  43. Conclusions • 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

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