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1Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Evolution of Risk Management for Evolution of Risk Management for Systemic RetinoidsSystemic Retinoids
Evolution of Risk Management for Evolution of Risk Management for Systemic RetinoidsSystemic Retinoids
Jill Lindstrom, MDMedical Officer
Division of Dermatologic and Dental Drug ProductsFDA
Jill Lindstrom, MDMedical Officer
Division of Dermatologic and Dental Drug ProductsFDA
2Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
OverviewOverviewOverviewOverview
• Background
• Historical development of risk management for systemic retinoids
• Summary
• Background
• Historical development of risk management for systemic retinoids
• Summary
3Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Approved Systemic RetinoidsApproved Systemic RetinoidsApproved Systemic RetinoidsApproved Systemic RetinoidsChemical name Trade name Date approval
(removal)Indication
Isotretinoin Accutane 5/7/1982 Severe recalcitrant nodular acne
Amnesteem 11/2002
Sotret 12/2002
Claravis 4/2003
Etretinate Tegison 9/30/1986 (12/20/2002)
Severe recalcitrant psoriasis
Acitretin Soriatane 10/26/1996 Severe psoriasis
Bexarotene Targretin 12/29/1999 Refractory CTCL
4Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Retinoid Teratogenicity Retinoid Teratogenicity Retinoid Teratogenicity 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
5Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Risk Management ToolsRisk Management ToolsRisk Management ToolsRisk 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
6Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Historical Overview of Pregnancy Historical Overview of Pregnancy Prevention Risk ManagementPrevention Risk Management
Historical Overview of Pregnancy Historical Overview of Pregnancy Prevention Risk ManagementPrevention 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
7Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
IsotretinoinIsotretinoinIsotretinoinIsotretinoin
• 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
8Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
IsotretinoinIsotretinoinIsotretinoinIsotretinoin
• 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
9Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Accutane Pregnancy Prevention Accutane Pregnancy Prevention Program (APPP) - componentsProgram (APPP) - components
Accutane Pregnancy Prevention Accutane Pregnancy Prevention Program (APPP) - componentsProgram (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
10Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
APPP: Components (con’t)APPP: Components (con’t)APPP: Components (con’t)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)
11Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
APPP: ImpactAPPP: ImpactAPPP: ImpactAPPP: 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
12Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
APPP transitionAPPP transitionAPPP transitionAPPP 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
13Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
cRMP : ComponentscRMP : ComponentscRMP : ComponentscRMP : 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
14Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
cRMP : ComponentscRMP : ComponentscRMP : ComponentscRMP : 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
15Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
cRMP : OthercRMP : OthercRMP : OthercRMP : 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%
16Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
cRMP: One Year MetricscRMP: One Year MetricscRMP: One Year MetricscRMP: 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
17Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
2004 DODAC/DSARM AC2004 DODAC/DSARM AC2004 DODAC/DSARM AC2004 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
18Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Isotretinoin RMP ChronologyIsotretinoin RMP ChronologyIsotretinoin RMP ChronologyIsotretinoin 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
19Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Tegison (etretinate)Tegison (etretinate)Tegison (etretinate)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
20Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Soriatane (acitretin)Soriatane (acitretin)Soriatane (acitretin)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
21Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Soriatane (acitretin): RMPSoriatane (acitretin): RMPSoriatane (acitretin): RMPSoriatane (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
22Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
Targretin (bexarotene)Targretin (bexarotene)Targretin (bexarotene)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
23Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
SummarySummarySummarySummary• 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
24Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004
SummarySummarySummarySummary
• 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
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