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