Isotretinoin

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Isotretinoin

• Background and Regulatory History
• Jill Lindstrom, MD
• Medical Officer
• Division of Dermatologic and Dental Drug Products

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Overview

• Clinical background
• History of pregnancy prevention risk management
• Current isotretinoin pregnancy prevention risk
  management plan
• Guidelines for assessment

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Isotretinoin--background

• Indication treatment of severe recalcitrant
  nodular cystic acne
• Only drug moiety approved for this indication
• innovator Accutane - 1982
• generics
• Amnesteem - 11/2002
• Sotret - 12/2002
• Claravis - 4/2003
• other related oral products are in development

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Courtesy of Dr. Diane Thiboutot
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Courtesy of Dr. James Leyden
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Courtesy of Dr. James Leyden
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IsotretinoinStandard of Practice

• In practice, also used for non-nodular (but
  scarring) acne in addition to use for approved
  indication

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Courtesy of Dr. James Leyden
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Courtesy of Dr. James Leyden
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Courtesy of Dr. Diane Thiboutot
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Courtesy of Dr. Diane Thiboutot
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Courtesy of Dr. Diane Thiboutot
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Courtesy of Dr. Diane Thiboutot
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Isotretinoin--mechanism of action

• Decreases sebum production
• Normalizes follicular hyperkeratinization and
  reduces follicular plugging
• Decreases Propionibacterium acnes colonization
• Anti-inflammatory

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Courtesy of Dr. Diane Thiboutot
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Courtesy of Dr. Diane Thiboutot
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Isotretinoin--clinical

• Single course of therapy 15-20 weeks results in
  complete and prolonged disease remission in many
  patients

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Isotretinoin--Teratogen

• Increased risk of spontaneous abortion and
  premature birth
• Malformations craniofacial, cardiac, thymus,
  CNS, functional
• 28 of exposed pregnancies affected at birth
• Indicated only for use in females who are not
  pregnant and males

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History of Risk Management

• At approval in 1982
• animal data suggested teratogenicity
• labeling pregnancy category X
• contraindications
• warnings
• precautions

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History of Risk Management

• 1983 - 1987
• first report of infant malformation in 1983
• red warning stickers distributed to pharmacies
• multiple Dear Doctor letters issued
• labeling revised as additional data became
  available

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History of Risk Management Pregnancy Prevention
Program (PPP)

• 1988 Advisory Committee
• Sponsor proposed Pregnancy Prevention Program
  (PPP)
• PPP components
• Label/package
• package warnings
• avoid pregnancy icon
• blister pack

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History of Risk Management Pregnancy Prevention
Program (PPP)

• PPP components, cont
• Package Insert - boxed warning
• negative pregnancy test 7d before treatment
  initiation
• two reliable forms of contraception
• begin therapy on 2nd or 3rd day of next menses
• dispense 30 days supply
• pregnancy testing and contraceptive counseling
  monthly

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History of Risk ManagementPregnancy Prevention
Program (PPP)

• PPP components, cont
• Informed consent for female patients
• PPP kit for prescribers
• Patient survey (SEU)
• Accutane Tracking Survey - prescriber use of PPP

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Number of Reported Pregnancies 1982-1999 by Year
of Therapy (US)
Spontaneous Reports
Reported Pregnancies
Year
Data presented by Roche at 2000 Advisory
Committee Meeting
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Estimated Number of Patients Using Accutane
Number ofPatients
Data presented by Roche at 2000 Advisory
Committee Meeting
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History of Risk Management2000 Advisory
Committee Recommendations

• Dermatologic and Ophthalmic Drugs Advisory
  Committee convened on 9/2000
• Recommended augmentation of isotretinoin risk
  management plan
• Communicated to Sponsor on Oct 6, 2000

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2000 Advisory Committee RecommendationsNeuropsych
iatric Risks

• Three points of action
• amend informed consents - done
• develop education program for prescribers - done
• initiate research program - basic science
  groundwork needed
• Not the subject of this meeting

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History of Risk Management2000 Advisory
Committee Recommendations

• Pregnancy prevention two goals
• no one should begin isotretinoin therapy if
  pregnant
• effective pregnancy prevention will occur
  throughout the course of isotretinoin treatment

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History of Risk Management2000 Advisory
Committee Recommendations

• Five point plan of action
• augmentation of patient education
• registration of all patients
• registration of prescribers
• implementation of pregnancy registry
• linkage of prescription to adequate pregnancy
  testing

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Current Risk Management Plan

• Approved for innovator Oct. 2001
• Accutane S.M.A.R.T.
• current risk management plan (RMP)
• Compelling need for enhanced pregnancy prevention
  risk management
• Based on extensive discussions and negotiations
  between Sponsor and FDA

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2000 Advisory Committee RecommendationsPoints of
Action - 1

• A heightened educational program for each patient
  that includes verifiable documented written
  informed consent
• augmented education and written informed consent
  is component of current RMP

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2000 Advisory Committee RecommendationsPoints of
Action - 2

• Complete registration of all patients, both male
  and female
• intended to provide denominator for ascertainment
  of pregnancy rate
• Sponsor proposed alternative proposal to estimate
  denominator using pharmacy databases and survey
  data
• avoided patient privacy issues assoc.
  w/registries
• increased survey enrollment integral to accuracy

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2000 Advisory Committee RecommendationsPoints of
Action - 3

• Complete registration and certification of
  isotretinoin prescribers
• Sponsor did not have authority to certify
• Voluntary prescriber registration
• self-attestation of relevant competencies
• signed commitment to use the current RMP
• Sponsor provides prescribers with information
• Prescribers responsible for obtaining necessary
  education to achieve competencies in Letter of
  Understanding

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2000 Advisory Committee RecommendationsPoints of
Action - 4

• Comprehensive program to track fetal exposures to
  isotretinoin/formal registry
• provide numerator for pregnancy rate
• patient privacy and HIPAA concerns
• Sponsor proposed extrapolation of numerator
• required survey response rate gt60
• education of prescribers to increase awareness of
  survey
• increased reimbursement for patient participation

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2000 Advisory Committee RecommendationsPoints of
Action - 5

• Linkage of dispensing of isotretinoin to
  verification of adequate pregnancy testing
• current RMP asks pharmacist to verify that
  patient has been qualified by prescriber
• pharmacist does not independently review
  laboratory pregnancy test result
• pharmacist participation is voluntary but
  encouraged

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PHYSICIAN
Second ß-HCG Informed consent
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AE REPORTS
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Current Risk Management Plan

• Approved for innovator Oct 2001
• Accutane S.M.A.R.T.
• Current RMP for generics contains essential
  elements
• Amnesteem S.P.I.R.I.T., Nov 2002
• Sotret I.M.P.A.R.T., Dec 2002
• Claravis A.L.E.R.T., April 2003

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Current Risk Management Plan

• Different names
• S.M.A.R.T. (Accutane)
• S.P.I.R.I.T. (Amnesteem)
• I.M.P.A.R.T. (Sotret)
• A.L.E.R.T. (Claravis)
• Different survey contractors
• innovator Degge/SI
• generic Slone Epidemiology Unit
• Midcourse changes in brand dispensed
• patient confusion, multiple enrollment

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Assessment of Current RMP

• Sponsor instructed to submit comprehensive report
  on metrics after one year
• Advisory Committee in 2000 did not comment on
  benchmarks nor define success
• Establishing adequate benchmarks is challenging

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Assessment of Current RMPPerformance benchmarks

• Patient survey response rate gt 60
• success of current RMP contingent upon
  achievement of higher survey response rate
• approval of current RMP based upon Sponsors
  assertion of achievability of Sponsor-identified
  threshold

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Assessment of Current RMPPerformance benchmarks

• Use of qualification stickers
• Stickers serve as surrogate endpoint for use of
  current RMP
• Imperfect surrogate
• Sponsor informed that threshold for success would
  approach 100

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Assessment of IPPRMPPerformance benchmarks

• Fetal exposures to isotretinoin
• goal that no one initiate isotretinoin therapy if
  pregnant may be achievable
• goal that no one become pregnant while on
  isotretinoin therapy has added complexity of
  patient behavior

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Conclusions

• Isotretinoin is a uniquely effective drug for the
  treatment of severe scarring acne
• Long history of risk management efforts to
  prevent fetal exposures to isotretinoin
• Current RMP introduced new tools
• Assessment of current program