Evolution of Risk Management for Systemic Retinoids

1. Evolution of Risk Management for Systemic Retinoids Jill Lindstrom, MD Medical Officer Division of Dermatologic and Dental Drug Products FDA

2. Overview • Background • Historical development of risk management for systemic retinoids • Summary

3. Approved Systemic Retinoids

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

5. Risk Management Tools • Product labeling • Package Insert • Container, label • Targeted education • Patient brochures • Reminder systems • Stickers, informed consent • Controlled distribution

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

7. Isotretinoin • 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. Isotretinoin • 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. 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

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)

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

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

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

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

15. cRMP : Other • Voluntary surveys • Patient • Pharmacy • Effectiveness assessed at one year • Performance benchmarks • Patient survey enrollment of 60% • Qualification sticker use approaching 100%

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

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

18. Isotretinoin RMP Chronology • 1982 – approved • 1988 – APPP • 2002 – cRMP • 2004 – AC recommend mandatory registration, controlled distribution, pregnancy registry

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

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

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

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

23. Summary • 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. Summary • 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