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Evolution of Risk Management for Systemic Retinoids. Jill Lindstrom, MD Medical Officer Division of Dermatologic and Dental Drug Products FDA. Overview. Background Historical development of risk management for systemic retinoids Summary . Approved Systemic Retinoids.
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Evolution of Risk Management for Systemic Retinoids Jill Lindstrom, MD Medical Officer Division of Dermatologic and Dental Drug Products FDA
Overview • Background • Historical development of risk management for systemic retinoids • Summary
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
Risk Management Tools • Product labeling • Package Insert • Container, label • Targeted education • Patient brochures • Reminder systems • Stickers, informed consent • Controlled distribution
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 • 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
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
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
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)
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
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
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
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
cRMP : Other • Voluntary surveys • Patient • Pharmacy • Effectiveness assessed at one year • Performance benchmarks • Patient survey enrollment of 60% • Qualification sticker use approaching 100%
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
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
Isotretinoin RMP Chronology • 1982 – approved • 1988 – APPP • 2002 – cRMP • 2004 – AC recommend mandatory registration, controlled distribution, pregnancy registry
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
Soriatane (acitretin) • Third oral retinoid approved in US • October 28, 1996 • Indication: severe psoriasis • In women of childbearing potential, if unresponsive to other therapies
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
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
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
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