1. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 1 Evolution of Risk Management for Systemic Retinoids Evolution of Risk Management for Systemic Retinoids Jill Lindstrom, MD Medical Officer Division of Dermatologic and Dental Drug Products FDA Jill Lindstrom, MD Medical Officer Division of Dermatologic and Dental Drug Products FDA

2. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 2 OverviewOverview Background Historical development of risk management for systemic retinoids Summary Background Historical development of risk management for systemic retinoids Summary

3. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 3 Approved Systemic Retinoids Chemical name Trade nameDate approval (removal) Indication IsotretinoinAccutane5/7/1982Severe recalcitrant nodular acne Amnesteem11/2002 Sotret12/2002 Claravis4/2003 EtretinateTegison9/30/1986 (12/20/2002) Severe recalcitrant psoriasis AcitretinSoriatane10/26/1996Severe psoriasis BexaroteneTargretin12/29/1999Refractory CTCL

4. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 4 Retinoid Teratogenicity All approved systemic retinoids produce fetal abnormalities in animal studies Isotretinoin: potent human teratogen –High frequency of adverse outcomes –Severity of effect Mortality Structural malformations Impaired function –Large window of vulnerability All approved systemic retinoids produce fetal abnormalities in animal studies Isotretinoin: potent human teratogen –High frequency of adverse outcomes –Severity of effect Mortality Structural malformations Impaired function –Large window of vulnerability

5. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 5 Risk Management Tools Product labeling –Package Insert –Container, label Targeted education –Patient brochures Reminder systems –Stickers, informed consent Controlled distribution Product labeling –Package Insert –Container, label Targeted education –Patient brochures Reminder systems –Stickers, informed consent Controlled distribution

6. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 6 Historical Overview of Pregnancy Prevention Risk Management Isotretinoin as prototype –Indicated for severe recalcitrant nodular acne –Circumscribed 20-week course Three other oral retinoids Isotretinoin as prototype –Indicated for severe recalcitrant nodular acne –Circumscribed 20-week course Three other oral retinoids

7. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 7 IsotretinoinIsotretinoin First oral retinoid approved in US –May 7, 1982 –Indication: the treatment of severe recalcitrant nodular acne Initial risk management: labeling –Pregnancy category X –Contraindications –Warnings –Precautions First oral retinoid approved in US –May 7, 1982 –Indication: the treatment of severe recalcitrant nodular acne Initial risk management: labeling –Pregnancy category X –Contraindications –Warnings –Precautions

8. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 8 IsotretinoinIsotretinoin June 1983: first human malformation Risk management responses –Labeling: Teratogenicity information in package insert highlight boldface type Boxed warning –Targeted education: Dear Doctor/Pharmacist letters June 1983: first human malformation Risk management responses –Labeling: Teratogenicity information in package insert highlight boldface type Boxed warning –Targeted education: Dear Doctor/Pharmacist letters

9. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 9 Accutane Pregnancy Prevention Program (APPP) - components Labeling: Package Insert (boxed warning) –Negative pregnancy test 7d before treatment initiation –Monthly pregnancy testing and contraceptive counseling –Use of two forms of contraception for one month before, during and one month following treatment Labeling: package –Blister pack –“Avoid pregnancy” icon –Boxed warning Labeling: Package Insert (boxed warning) –Negative pregnancy test 7d before treatment initiation –Monthly pregnancy testing and contraceptive counseling –Use of two forms of contraception for one month before, during and one month following treatment Labeling: package –Blister pack –“Avoid pregnancy” icon –Boxed warning

10. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 10 APPP: Components (con’t) Targeted education: –Educational materials –Referral and reimbursement for contraceptive counseling Reminder systems: –Informed consent for female patients Patient survey Accutane Tracking Survey (assess prescriber use of PPP) Targeted education: –Educational materials –Referral and reimbursement for contraceptive counseling Reminder systems: –Informed consent for female patients Patient survey Accutane Tracking Survey (assess prescriber use of PPP)

11. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 11 APPP: Impact Impact –Initial rise in number of reported exposed pregnancies first year of implementation –Subsequent leveling of number of reported exposed pregnancies next 10 years –Number of patients treated with isotretinoin doubled same time period Impact –Initial rise in number of reported exposed pregnancies first year of implementation –Subsequent leveling of number of reported exposed pregnancies next 10 years –Number of patients treated with isotretinoin doubled same time period

12. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 12 APPP transition DODAC convened 9/2000 Recommended augmentation of isotretinoin RMP to include registration and controlled distribution precedent: Thalomid 2002: implementation of current risk management plan (cRMP) –S.M.A.R.T./S.P.I.R.I.T./A.L.E.R.T./I.M.P.A.R.T DODAC convened 9/2000 Recommended augmentation of isotretinoin RMP to include registration and controlled distribution precedent: Thalomid 2002: implementation of current risk management plan (cRMP) –S.M.A.R.T./S.P.I.R.I.T./A.L.E.R.T./I.M.P.A.R.T

13. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 13 cRMP : Components Labeling –Updates to PI, PPI and container labels –Medication Guide Targeted education –Instruction guides for prescribers and pharmacists –Patient brochures –Dear Doctor/Dear Pharmacist letters Labeling –Updates to PI, PPI and container labels –Medication Guide Targeted education –Instruction guides for prescribers and pharmacists –Patient brochures –Dear Doctor/Dear Pharmacist letters

14. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 14 cRMP : Components Reminders Systems –Updated patient informed consent forms –Prescriber checklist –Yellow stickers placed on prescriptions Prescribers: patient has been qualified Pharmacists: 30 day supply, no refills, fill w/in 7d of qual date Controlled distribution –Letter of Understanding signed by prescribers Attestation of relevant competencies and agreement to comply with RMP –Yellow stickers provider to prescriber upon receipt Reminders Systems –Updated patient informed consent forms –Prescriber checklist –Yellow stickers placed on prescriptions Prescribers: patient has been qualified Pharmacists: 30 day supply, no refills, fill w/in 7d of qual date Controlled distribution –Letter of Understanding signed by prescribers Attestation of relevant competencies and agreement to comply with RMP –Yellow stickers provider to prescriber upon receipt

15. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 15 cRMP : Other Voluntary surveys –Patient –Pharmacy Effectiveness assessed at one year Performance benchmarks –Patient survey enrollment of 60% –Qualification sticker use approaching 100% Voluntary surveys –Patient –Pharmacy Effectiveness assessed at one year Performance benchmarks –Patient survey enrollment of 60% –Qualification sticker use approaching 100%

16. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 16 cRMP: One Year Metrics Patient survey response rate: 36% Sticker use: >90% –Unsatisfactory surrogate endpoint –Poor correlation between sticker use and survey responses Number of reported exposed pregnancies unchanged Patient survey response rate: 36% Sticker use: >90% –Unsatisfactory surrogate endpoint –Poor correlation between sticker use and survey responses Number of reported exposed pregnancies unchanged

17. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 17 2004 DODAC/DSARM AC Recommended augmentation of cRMP –Registration of all patients, male and female –Registration of all pharmacies –Registration of all prescribers –Pregnancy registry Sponsors and FDA currently working to implement these recommendations Recommended augmentation of cRMP –Registration of all patients, male and female –Registration of all pharmacies –Registration of all prescribers –Pregnancy registry Sponsors and FDA currently working to implement these recommendations

18. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 18 Isotretinoin RMP Chronology 1982 – approved 1988 – APPP 2002 – cRMP 2004 – AC recommend mandatory registration, controlled distribution, pregnancy registry 1982 – approved 1988 – APPP 2002 – cRMP 2004 – AC recommend mandatory registration, controlled distribution, pregnancy registry

19. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 19 Tegison (etretinate) Second oral retinoid approved in US September 30,1986 Indication: treatment of severe recalcitrant psoriasis Pregnancy prevention RMP: –Boxed warning –Warnings, Contraindications, Precautions Withdrawn from US market Dec 20, 2002 Second oral retinoid approved in US September 30,1986 Indication: treatment of severe recalcitrant psoriasis Pregnancy prevention RMP: –Boxed warning –Warnings, Contraindications, Precautions Withdrawn from US market Dec 20, 2002

20. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 20 Soriatane (acitretin) Third oral retinoid approved in US October 28, 1996 Indication: severe psoriasis –In women of childbearing potential, if unresponsive to other therapies Third oral retinoid approved in US October 28, 1996 Indication: severe psoriasis –In women of childbearing potential, if unresponsive to other therapies

21. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 21 Soriatane (acitretin): RMP Sponsor was asked to implement RMP consistent w/best practice at that time (APPP) Soriatane PPP –Labeling: boxed warning, -BHCG, use of two forms of contraception during and 3yrs after treatment –Education: brochures; Med Guide (2003) –Reminders: patient informed consent Sponsor was asked to implement RMP consistent w/best practice at that time (APPP) Soriatane PPP –Labeling: boxed warning, -BHCG, use of two forms of contraception during and 3yrs after treatment –Education: brochures; Med Guide (2003) –Reminders: patient informed consent

22. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 22 Targretin (bexarotene) Fourth oral retinoid approved in US December 29, 1999 Indication: cutaneous manifestations of CTCL refractory to other systemic therapy RMP similar to APPP and SPPP –Labeling: boxed warning, -BHCG, 2 forms contraception before, during and after therapy –Education: Medication Guide (2003) –Limitation of amount dispensed to 30 days Fourth oral retinoid approved in US December 29, 1999 Indication: cutaneous manifestations of CTCL refractory to other systemic therapy RMP similar to APPP and SPPP –Labeling: boxed warning, -BHCG, 2 forms contraception before, during and after therapy –Education: Medication Guide (2003) –Limitation of amount dispensed to 30 days

23. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 23 SummarySummary All approved systemic retinoids are known or highly suspect potent human teratogens Risk management plans should incorporate current best practices Best practices for pregnancy prevention risk management have evolved Labeling Targeted education Reminder systems Controlled distribution All approved systemic retinoids are known or highly suspect potent human teratogens Risk management plans should incorporate current best practices Best practices for pregnancy prevention risk management have evolved Labeling Targeted education Reminder systems Controlled distribution

24. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 24 SummarySummary Current thinking on best practices for pregnancy prevention risk management: –Isotretinoin cRMP needs to be strengthened –DODAC-DSARM 2/2004 recommendations: Mandatory registration of all patients, prescribers, pharmacies Pregnancy registry Current thinking on best practices for pregnancy prevention risk management: –Isotretinoin cRMP needs to be strengthened –DODAC-DSARM 2/2004 recommendations: Mandatory registration of all patients, prescribers, pharmacies Pregnancy registry