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
Chemical 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
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 (cont)

• 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

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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 gt90
• 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