P-1

1
IsotretinoinAdvisory Committee

• February 26-27, 2004

2
Roche Presentation Agenda
Introduction Joanna Waugh
Isotretinoin Benefit/Risk Martin H. Huber, M.D.
Regulatory Overview Joanna Waugh
Overview of S.M.A.R.T. Program Susan Ackermann Shiff, Ph.D.
Review of Data from S.M.A.R.T. Program Martin H. Huber, M.D.
Recommendations Martin H. Huber, M.D.
3
Roche Presenters and Responders

• Susan Ackermann Shiff, Ph.D.Global Head Risk
  ManagementDrug Safety Risk Management
• Martin H. Huber, M.D.Vice President and Global
  HeadDrug Safety Risk Management
• Joanna WaughGroup Director,Regulatory Affairs

• Kay Bess, R.N. B.S.N.U.S. Head of
  Operations,Drug Safety Risk Management
• Karen Blesch, Ph.D.Director,Drug Safety Risk
  Management
• Tammy ReillyVice President,Dermatology and
  Oncology Operations
• Susan Sacks, Ph.D.Global Head Epidemiology,Drug
  Safety Risk Management

4
Outside Experts

• Diane Berson, M.D.Assistant Professor, Dept. of
  Dermatology,Weill Medical College of Cornell
  University,New York, NY
• Judith K. Jones, M.D., Ph.D.President, The Degge
  Group Ltd.Arlington, VA
• Victor J. Strecher, Ph.D., M.P.H.Professor,
  University of Michigan School of Public
  HealthAnn Arbor, MI

5
Isotretinoin Risk Management Programs
Isotretinoin Manufacturer Risk Management Program Approval Date
Accutane Hoffmann-La Roche Inc. S.M.A.R.T.1 October 2001
Amnesteem Mylan S.P.I.R.I.T. 2 November 2002
Sotret Ranbaxy I.M.P.A.R.T. 3 December 2002
Claravis Barr A.L.E.R.T. 4 April 2003
1. System to Manage Accutane Related
Teratogenicity 2. System to Prevent
Isotretinoin Related Issues and
Teratogenicity 3. Isotretinoin Medication Program
Alerting you to the Risks of Teratogenicity 4. Adv
erse Event Learning and Education Regarding
Teratogenicity
6
Proposal for Program Modification

• S.M.A.R.T. Approval Commitments Included
• Development of a back-up programfor a mandatory
  registry
• Follow-up advisory committee to discuss program
• Roche evaluated S.M.A.R.T. data and developed a
  proposal for program enhancements

7
Inter-Company Communication

• December 2003 FDA/Roche/generic companies
  reviewed data across risk management programs
• Roche and generic companies subsequently worked
  together on recommendations for program
  modification
• All companies agree need for a single program
• Recommendation generally agreed by all companies
• Details of implementation require
  furtherrefinement and discussion

8
Martin H. Huber, M.D.

• Vice President and Global HeadDrug Safety Risk
  ManagementHoffmann-La Roche Inc.

9
Presentation Overview

• Isotretinoin Benefit / Risk
• Regulatory Context and Evolution of Accutane
  Pregnancy Risk Management
• Overview of S.M.A.R.T. Program
• Review of Data from S.M.A.R.T. Program(April 1,
  2002 March 31, 2003)
• Recommendations

10
Isotretinoin Indication

• Isotretinoin is indicated for Severe Recalcitrant
  Nodular Acne (SRNA)
• Indicated only for patients who are unresponsive
  to conventional therapy, including systemic
  antibiotics
• Indicated only for those females who arenot
  pregnant and agree to not become pregnant

11
Medical Need for Isotretinoin

• The consequences of SRNA are serious
• Inadequately treated SRNA can lead to disfiguring
  scarring
• Isotretinoin is uniquely efficacious for severe
  recalcitrant nodular acne and currently no
  alternative therapies exist for these patients

12
Medical Need for Isotretinoin
Source DermNet
13
Specific Challenge for Isotretinoin

• Isotretinoin is a human teratogen
• The majority of female patients areof
  childbearing potential
• Therefore, pregnancy prevention measures
  including proactive risk managementare
  essential
• Changing behavior of patients

14
Public Health Goals

• No woman who is pregnant should receive
  isotretinoin therapy
• No woman should become pregnant during orfor 1
  month after receiving isotretinoin therapy

15
Joanna Waugh

• Group Director, Regulatory Affairs
• Hoffmann-La Roche Inc.

16
Presentation Overview

• Isotretinoin Benefit / Risk
• Regulatory Context and Evolution of Accutane
  Pregnancy Risk Management
• Overview of S.M.A.R.T. Program
• Review of Data from S.M.A.R.T. Program(April 1,
  2002 March 31, 2003)
• Recommendations

17
Accutane Pregnancy Risk Management

• Teratogenic risk of Accutane known since approval
  of drug in 1982
• Variety of risk management steps throughout
  product life cycle
• Proposed program includes risk management
  enhancements in response to S.M.A.R.T. data

18
Accutane Pregnancy Risk Management Milestones
Risk Management Milestones Date
Pregnancy Category X Contraindicatedin pregnant women October 1982
Black Box Warning February 1984
Pregnancy Prevention Program (PPP) October 1988
Two forms of contraception October 1988
Negative monthly pregnancy test October 1988
Avoid pregnancy symbol in packaging October 1988
Educational materials regarding contraceptives and pregnancy avoidance October 1988
Female patient informed consent form October 1988
Evaluation tools for effectiveness of PPP (Accutane Survey) October 1988
19
Accutane Pregnancy Risk Management Labeling
Milestones
Risk Management Milestones Date
Description of birth defects added April 1990
Recommended prescribing one month supply April 1990
Updated patient consent form to include additional requirements January 1994
Two negative pregnancy tests prior to initial prescription May 2000
Advisory Committee discussed pregnancy prevention September 2000
Medication Guide introduced January 2001
S.M.A.R.T. Risk Management Program October 2001
20
Development of S.M.A.R.T.

• September 2000 Advisory Committee discussed
  pregnancy prevention
• Roche put forward various proposals which
  included mandatory patient and prescriber
  registration
• FDA and Roche agreed the critical issue was to
  link a negative pregnancy test with each
  prescription and dispensing of Accutane

21
Elements of S.M.A.R.T.

• Link dispensing to negative pregnancy
  testing(via Accutane Qualification Sticker (QS))
• Enhanced education
• Enhanced informed consent
• Registration of prescribers

22
Susan Ackermann Shiff, Ph.D.

• Global Head Risk Management
• Drug Safety Risk ManagementHoffmann-La Roche Inc.

23
Presentation Overview

• Accutane Benefit / Risk
• Regulatory Context and Evolution of Accutane
  Pregnancy Risk Management
• Overview of S.M.A.R.T. Program
• Review of Data from S.M.A.R.T. Program(April 1,
  2002 March 31, 2003)
• Recommendations

24
Overview of S.M.A.R.T.
Registered, qualified prescriber
Qualified patient
Pharmacy
25
Prescriber Education
Mandatory Enrollment to Obtain Stickers

• S.M.A.R.T. Guideto Best Practices
• S.M.A.R.T. Letterof Understanding
• Accutane Qualification Sticker

26
Prescriber Attestation

• Know the risk and severity of fetal injury/birth
  defects from Accutane
• Know how to diagnose and treat the various
  presentations of acne
• Know the risk factors for unplanned pregnancy and
  the effective measures for avoidance of unplanned
  pregnancy
• Will properly use the S.M.A.R.T. proceduresfor
  Accutane

27
Female Patient Education

• For Women
• Single Booklet
• Contains all elements
• Education
• Contraception Information
• Informed Consent Forms
• Accutane Survey Enrollment Card
• Educational Reinforcement

28
AdditionalPatient Education Components

• Patient videos/storyboard (English/Spanish)
• Be Prepared, Be Protected (contraception
  education)
• Be Aware, The Risks of PregnancyWhile on
  Accutane
• 1-800 Number Accutane Information Line
• 1-800 Contraceptive Information Line
• Contraceptive counseling
• Accutane BlisterPak with pregnancy avoidance
  symbol
• Medication Guide (in BlisterPak)

29
Male Patient Education

• For Men
• Patient Product Information
• Consent Form
• Educational Reinforcement

30
Accutane Qualification Sticker

• The yellow self-adhesive Accutane Qualification
  Sticker signifies that the patient has been
  qualified as described in CONTRAINDICATIONS AND
  WARNINGS of the package insert

31
Accutane Qualification Criteria

• Female patients of childbearing potential
• must have
• Negative urine or serum pregnancy tests
• Selected and committed to use two forms of
  effective contraception for at least one month
  prior to, during and one month after
  discontinuation of therapy
• Signed patient information/consent forms
• Been informed of the purpose and importanceof
  participating in the Accutane Survey

32
Pharmacist Requirements

• Accutane Qualification
• Sticker
• No more than a 30-day supply only
• Dispense within 7 daysof qualification date
• No refills allowed
• Accutane Label
• No telephone or computerized prescriptions are
  permitted
• Opportunity to verify physician registrationvia
  1-800 number

33
Presentation Overview

• Accutane Benefit / Risk
• Regulatory Context and Evolution of Accutane
  Pregnancy Risk Management
• Overview of S.M.A.R.T. Program
• Review of Data from S.M.A.R.T. Program(April 1,
  2002 March 31, 2003)
• Recommendations

34
Instruments for Evaluationof S.M.A.R.T. Program

• Prescription Compliance Survey
• Accutane Survey
• Pregnancy Reports

35
Prescription Compliance Survey

• Description
• Quarterly survey of a random sample of pharmacies
  pertaining to use and completion of
  Qualification Sticker
• Quarterly audit of anonymous Accutane
  prescriptions from random sample of pharmacists
  participating in the survey

36
Prescription Compliance Survey

• Objective
• To assess prescribers and dispensing
  pharmacists compliance with appropriate useof
  the Accutane Qualification Sticker

37
Prescription Compliance Survey 1 Year Assessment
Metrics

• Primary
• 90 of all physicians will use the QS
• Secondary
• 90 of all physicians completely and correctly
  complete the QS
• 90 of all prescriptions are dispensedwith a
  Medication Guide
• Metric met Medication guide included
  inBlisterPak effective October 2002

38
Prescription Compliance Survey

• Results
• Qualification Sticker affixed to prescription
  97.2
• Qualification Sticker correctly completed 96.4
• No differences by survey waves
• No differences by age, gender, location and payer
• Conclusions
• All metrics for use of sticker exceeded
• The mechanics of the sticker work well

39
Instruments for Evaluationof S.M.A.R.T. Program

• Prescription Compliance Survey
• Accutane Survey
• Pregnancy Reports

40
Accutane Survey

• Description
• Developed by Slone Epidemiology Center
  (SEC),Boston University
• Implemented in 1989
• January 1989 present SEC
• October 2002 present SI International/Degge
• 2 Arms
• After Treatment
• During and After Treatment

Note SI International uses a questionnaire that
was modified to incorporate assessment of
activities specific to S.M.A.R.T.
41
Accutane SurveyObjectives

• Voluntary Survey
• To determine female patient awareness of the
  teratogenic risks of Accutane
• To measure compliance with key elements of
  S.M.A.R.T., including patient informed consent,
  pregnancy testing, contraception use,
  MedicationGuide, Qualification Sticker
• To calculate the rate of pregnancy among female
  Accutane users
• To identify risk factors for the occurrence of
  pregnancy

42
Accutane SurveyAssessment Metrics

• Primary
• Enrollment in the Accutane Survey should reach
  60by March 31, 2003
• Secondary
• Female patient representativeness
• Recall of Qualification Sticker affixed to
  Accutane prescription
• Recall of Pregnancy test
• Recall of receiving a Medication Guide
• Recall of using two forms of safe and effective
  contraception
• Enrolling in the Accutane Survey via the
  physician office,card in BlisterPak, and by
  toll-free telephone number

43
Accutane SurveyEnrollment Rate

• Method
• Number of enrollees divided by the numberof new
  female patient starts
• Results
• April 1, 2002 March 31, 2003 28.2
• April 1, 2001 March 31, 2002 17
• Conclusions
• Accutane Survey enrollment rate increased
  fromyear prior to S.M.A.R.T. but fell short of
  60 metric

44
Accutane SurveyMethods of Enrollment
Enrollment Method Pre-S.M.A.R.T. S.M.A.R.T.
Doctor 24 56
BlisterPak 74 43
Telephone 2 1
45
Accutane SurveyPatient Awareness
Start of Treatment

• What might Accutane do if it is taken during
• pregnancy?
• Cause birth defects 99
• Cause birth defects and miscarriage 46
• None of the above 1
• Did your doctor tell you that it is important not
  to
• become pregnant while taking Accutane?
• Yes 98

Source SI International
46
Accutane SurveyRecall of Pregnancy Test
Start of Treatment
Pre-S.M.A.R.T. S.M.A.R.T. S.M.A.R.T.
Pre-S.M.A.R.T. SEC SI/Degge
Any pregnancy test 81 92 88
Two pregnancy tests 64
No pregnancy tests 18 8 9
Unknown 1 lt1 3
47
Accutane SurveyPregnancy Risk Category
Start of Treatment
Total Under S.M.A.R.T. N5,197 Total Under S.M.A.R.T. N5,197
N
Hysterectomy or Post-Menopausal 241 5
Not sexually active 2,607 50
Sexually active 2,309 44
Unknown 40 1
Source SI International
48
Accutane SurveyPregnancy Risk Category
Start of Treatment

• Of the sexually active participants
• Using at least 2 forms of birth control 59
• Not using at least 2 forms of birth control 41

Source SI International
49
Accutane SurveyNon-Compliance with
S.M.A.R.T.Contraception Requirements by Age
Start of Treatment
Age 12-15 N471 () 16-19 N1374 () 20-29 N1949 () 30-39 N879 () 40-44 N242 () 45 N253 ()
Sexually active,no contraception 1 1 2 2 1 2
Sexually active, not using 2 formsof contraception 1 6 20 35 40 28
Not sexually active 97 82 40 19 14 11
Source SI International
50
Accutane SurveyQualification Sticker and
Pregnancy Testing Birth Control Use
Start of Treatment
AccutaneQSYes N5,058 AccutaneQSYes N5,058 Accutane QSNo N137 Accutane QSNo N137
n n
Any baseline pregnancy test 4,394 86.9 113 82.5
2 or more baseline pregnancy tests 3,019 60.0 74 54.0
Sexually active and using 2 or more forms of birth control 1,450 28.7 34 24.8
Became pregnant 20 0.4 2 1.5
Source SI International
51
Accutane SurveyPregnancy Testing
During Treatment
Pregnancy Test Categories N3,636
One pregnancy test 11
2 or more pregnancy tests 63
No pregnancy test 21
Unknown 5
Source SI International
52
Accutane SurveyPregnancy Risk Category
During Treatment

• Of the sexually active participants
• Using at least 2 forms of birth control 48
• Not using at least 2 forms of birth control 52

Source SI International
53
Accutane SurveyRecall of Qualification Sticker
During Treatment

• Recall of Qualification Sticker attachedto most
  recent Accutane prescription 99

Source SI International
54
Accutane SurveyConclusions

• Increased enrollment, but did not increase to 60
  
• Increased proportion of patients enrollingvia
  prescribers office
• Mechanics of sticker working well

55
Accutane SurveyConclusions (cont.)

• Understand need to avoid pregnancy
• Incomplete compliance with pregnancy testing and
  contraceptive requirements
• Little relation between patient recall of a
  Qualification Sticker and pregnancy testing
• Little relation between patient recall of a
  Qualification Sticker and her contraceptive
  practices

56
Martin H. Huber, M.D.

• Vice President and Global HeadDrug Safety Risk
  ManagementHoffmann-La Roche Inc.

57
Tools for Evaluation of S.M.A.R.T. Program

• Prescription Compliance Survey
• Accutane Survey
• Pregnancy Reports

58
Pregnancy Reports Methodology

• Data for pregnancy case reports come from
• Accutane Survey (Slone Epidemiology Center)
• Accutane Survey (The Degge Group, Ltd. and SI
  International)
• Spontaneous Reports via healthcare professionals
  and consumers

59
Methodology forPregnancy Classification

• Pre-S.M.A.R.T.
• Treatment started April 1, 2001 to March 31, 2002
  with the report received by August 15, 2002
• S.M.A.R.T.
• Treatment started April 1, 2002 to March 31, 2003
  with the report received by August 15, 2003
• Therapy start dates unknown
• Reports that came to Roche during April 1 to
  March 31 of Pre-S.M.A.R.T. and S.M.A.R.T.year
  one with unknown start date

60
Context for Pregnancy Reports

• Majority from spontaneous reporting
• Overall Accutane usage declined
  fromPre-S.M.A.R.T. to S.M.A.R.T. year one

Year Male (Net) Projected Female (Net) Projected
2000 284,925 278,252
2001 265,384 253,831
2002 227,473 218,673
2003 128,936 128,973
61
Pregnancy Case Reports Pre-S.M.A.R.T. vs.
S.M.A.R.T.
Pre-S.M.A.R.T. S.M.A.R.T.
Total number 150 183
Treatment initiation date known 94 94
Treatment initiation date unknown 56 89
62
Possible Explanations for Increased Number of
Pregnancy Reports

• Unlikely that increased number of pregnancy
  reports represent a true increase in the rateof
  exposed pregnancies
• More likely increased reporting frequency
• Increased awareness among physicians
• Increased participation in survey
• Increased education and awareness among patients

63
Source of Pregnancy Reports
94
94
56
89
Direct to Roche,consumer or others
Direct to Roche, health care professional
Pregnancy Case Reports
Accutane Survey
Pre- S.M.A.R.T.
S.M.A.R.T.
Pre- S.M.A.R.T.
S.M.A.R.T.
Known TherapyStart Date
Unknown TherapyStart Date
Source
Of the 33 S.M.A.R.T. pregnancies with known
Accutane initiation dates, 11 were reported to
SEC and 22 were reported to SI/Degge. Both
S.M.A.R.T. pregnancies with unknown Accutane
start dates were reported to SEC
64
Timing of Accutane ExposureRelative to
Pregnancy Pre-S.M.A.R.T. vs. S.M.A.R.T.
Pre-S.M.A.R.T. N150 S.M.A.R.T. N183
Patient pregnant prior to starting Accutane Therapy 28 (19) 24 (13)
Patient became pregnant while on Accutane Therapy 77 (51.3) 75 (41.0)
Patient became pregnant within 30 days after stopping Accutane therapy 44 (29.3) 58 (31.7)
Unknown 1 (lt 1) 26 (14)
65
Age of Pregnancy Cases Pre-S.M.A.R.T. vs.
S.M.A.R.T.
Age Range Pre-S.M.A.R.T. N150 S.M.A.R.T. N183
12 - 15 5 (3.3) 2 (1.1)
16 - 19 19 (12.7) 29 (15.8)
20 - 29 62 (41.3) 44 (24.0)
30 - 39 24 (16.0) 27 (14.8)
40 - 44 1 (0.5)
45 1 (0.5)
Unknown 40 (26.7) 79 (52.7)

Mean 24.5 24.8
Median 24.0 23.0
Range 14 - 39 14 - 50
66
Pregnancy Case Reports Summary
Education
Pregnancy Case Reports (n72)
Signed Female Informed Consent
ReceivedSpiral Notebook
Enrolled in Accutane Survey
22 cases had no data Source Roche Drug Safety
Yes
No
Unknown
67
Pregnancy Case Reports Summary
Compliance
Pregnancy Case Reports (n72)
Two BaselinePregnancy Tests
Monthly Follow-up Pregnancy Tests
Used Two Forms of Contraception
Qualification Sticker Attached to Prescription
22 cases had no data Source Roche Drug Safety
Yes
No
Unknown
68
Methods of Contraception
Methods of Contraception Pre-S.M.A.R.T. S.M.A.R.T.
Methods of Contraception Known Start Date (N94) Known Start Date (N94)
Abstinence 10 11
2 Forms (Primary Secondary) 17 30
2 Forms (Both Secondary) 0 0
1 Form (Primary) 18 18
1 Form (Secondary) 14 11
Unknown 27 19
None 8 5
Source Roche Drug Safety
69
Pregnancy Rate in the Accutane Survey

• Applies only to SEC Accutane Survey participants
• Number of Accutane exposed pregnancies per 1,000
  140 day Accutane treatment courses
• Number of Accutane exposed pregnancies per 1,000
  patients per year

Source Slone Epidemiology Center (SEC)
70
Pregnancy Rate in the Accutane Survey
Number of Pregnancies per 1,000 Patients per Year
Number of Pregnancies per 1000 Accutane Treatment
Courses
Enrollment Year
One Accutane Treatment Course is 140
days Source Slone Epidemiology Center (SEC)
71
Pregnancy Data Conclusions

• Moderate decreases were seen with S.M.A.R.T. in
  the number of women who initiated Accutane
  therapy while pregnant (improved intervention)
• Relative increase in number of pregnancies
  reported likely due to increased awareness with
  S.M.A.R.T. program (improved assessment)
• Pregnancy is associated with incomplete
  compliance with risk management parameters

72
Goal of Enhanced Program

• No woman who is pregnant should receive
  isotretinoin therapy
• Further enhance link of negative pregnancytest
  to dispensing
• No woman should become pregnant during
  isotretinoin therapy
• Enhance patient compliance with behavior
  component, more specifically, increased useof
  contraceptives

73
Presentation Overview

• Accutane Benefit / Risk
• Regulatory Context and Evolution of Accutane
  Pregnancy Risk Management
• Overview of S.M.A.R.T. Program
• Review of Data from S.M.A.R.T. Program(April 1,
  2002 March 31, 2003)
• Recommendations

74
Overview of Proposal

• Single information system that provides
• a verifiable link between
• Registered physician
• Results of a laboratory-conducted pregnancy test
  (females of childbearing potential)
• Registered patient
• Patient interaction with the educational and risk
  management evaluation component of the system
• Registered pharmacy
• Product dispensed

75
Patient PathFemales of Childbearing Potential
PotentialCandidateforAccutane
76
Patient PathFemales of Childbearing Potential
PotentialCandidateforAccutane

• Initial Visit
• Determine if childbearing potential
• Screening pregnancy test
• Educate patient
• Informedconsents

77
Patient PathFemales of Childbearing Potential
No
Registry
PotentialCandidateforAccutane

• Initial Visit
• Determine if childbearing potential
• Screening pregnancy test
• Educate patient
• Informedconsents

78
Patient PathFemales of Childbearing Potential
No
Registry
Pt. ID
PotentialCandidateforAccutane

• Initial Visit
• Determine if childbearing potential
• Screening pregnancy test
• Educate patient
• Informedconsents

Patient interacts with educational and risk
management component ofthe system

• Focus on reinforcement of compliance with2 forms
  of contraception

79
Patient PathFemales of Childbearing Potential
No
Registry
Pt. ID
PotentialCandidateforAccutane

• Initial Visit
• Determine if childbearing potential
• Screening pregnancy test
• Educate patient
• Informedconsents

Patient interacts with educational and risk
management component ofthe system

• Follow-up Visit
• Laboratory confirms pregnancy test
• Educate patient
• Patient receives prescription with Qualification
  Sticker with patient ID

• Focus on hard link to pregnancy test
• Focus on reinforcement of compliance with2 forms
  of contraception

80
Patient PathFemales of Childbearing Potential
No
Registry
Pt. ID

• Registered
• Pharmacy
• Verifies QS
• Verifies Rxis authorized
• Provides product information (NDC )
• Obtains confirmation
• Medication Guide
• Dispenses Rx

PotentialCandidateforAccutane

• Initial Visit
• Determine if childbearing potential
• Screening pregnancy test
• Educate patient
• Informedconsents

Patient interacts with educational and risk
management component ofthe system

• Follow-up Visit
• Laboratory confirms pregnancy test
• Educate patient
• Patient receives prescriptionwith Qualification
  Sticker with patient ID

81
Patient PathFemales of Childbearing Potential
No
Registry
Pt. ID
PotentialCandidateforAccutane

• Initial Visit
• Determine if childbearing potential
• Screening pregnancy test
• Educate patient
• Informedconsents

Patient interacts with educational and risk
management component ofthe system

• Follow-up Visit
• Laboratory confirms pregnancy test
• Educate patient
• Patient receives prescriptionwith Qualification
  Sticker with patient ID

• Registered
• Pharmacy
• Verifies QS
• Verifies Rxis authorized
• Provides product information (NDC )
• Obtains confirmation
• Medication Guide
• Dispenses Rx

30 Days Later
Patient receives Accutane(30 days)
82
Patient PathFemales of Childbearing Potential
No
Registry
Pt. ID
Patient interacts with educational and risk
management component ofthe system

• Follow-up Visit
• Laboratory confirms pregnancy test
• Educate patient
• Patient receives prescriptionwith Qualification
  Sticker with patient ID

PotentialCandidateforAccutane

• Initial Visit
• Determine if childbearing potential
• Screening pregnancy test
• Educate patient
• Informedconsents

• Registered
• Pharmacy
• Verifies QS
• Verifies Rxis authorized
• Provides product information (NDC )
• Obtains confirmation
• Medication Guide
• Dispenses Rx

30Days Later
Patient receives Accutane(30 days)
83
Patient PathMales Females of Non-childbearing
Potential
No
Registry
Pt. ID
PotentialCandidateforAccutane

• Determine ifqualified
• Educate patient
• Informed consent
• Patient receives prescriptionwith Qualification
  Sticker withpatient ID

• Registered Pharmacy
• Verifies QS
• Verifies Rxis authorized
• Provides product information (NDC )
• Obtains confirmation
• Medication Guide
• Dispenses Rx

30Days Later
Patient receives Accutane(30 days)
84
Pregnancy Registry

• Centralized system for reporting, confirming,and
  follow-up of all pregnancies
• Enhances failure-analysis efforts
• Facilitates calculation of an isotretinoin-exposed
  pregnancy rate

85
Evolution of PregnancyRisk Management
Program Features PPP S.M.A.R.T Proposed Program
Registration of Physician X X
Registration of Patient X
Registration of Pharmacy X
Educational Component X X X X X
Authorized Prescriber Check Mechanism X X X
Linking of Patient Ed./RM to Dispensing X X X
Linking of Pregnancy Test to Dispensing X X X
Limited to 30 Days Supply/No Refills X X
Use of Qualification Sticker X X
Auditing Mechanism X X X
Contraceptive Counseling X X X X
Pregnancy Reporting Decentralized Decentralized Centralized
86
Considerations of Proposed Program

• Benefits
• Improves links between dispensing and compliance
  with pregnancy testing and pregnancy prevention
  activities
• May improve data quality and reporting
• Provides real-time patient qualification
  assessment linked to dispensing
• Provides opportunities for enhanced risk
  management evaluation activities

• Challenges
• Prescriber / patient relationship
• Size of program
• Alternative sourcing

87
Conclusions

• Proposed program enhancements establish
• a verifiable link between
• Prescriber
• Patient
• Pharmacy
• Negative laboratory-conducted pregnancy test
• Patient interaction with the educational and risk
  management evaluation component of the system
• Product dispensed

88
Conclusions (cont.)

• Reduce the number of women who are pregnant when
  they receive their initial prescription
• Reduce the number of women who become pregnant
  during isotretinoin therapy
• Enhance pregnancy detection and follow-up
• Number of pregnancies may initially increase

89
Risk Management Model
Identify Issues and Put Them into Context
Assess Risk/ Assess Benefits
Evaluate Results
Engage Partners and Other Stakeholders
Identify and Analyze Options
Implement the Strategy
Select a Strategy
89
90
Backups
91
Estimated Rates of Unintended Pregnancies,
Unintended Births and Abortions
(Per 1,000 Women, Age and Marital Status, and
Percentage of Unintended Pregnancies Ended by
Abortion, by Characteristic, 1994)
Unintended Pregnancy Unintended Birth Abortion Endedby Abortion
Total 44.7 20.9 24.1 54.0
Age at Outcome Age at Outcome Age at Outcome Age at Outcome Age at Outcome
15-19 71.1 38.9 32.2 45.3
20-24 96.0 43.0 53.0 55.2
25-29 58.4 25.3 33.1 56.7
30-34 33.1 14.6 18.4 55.7
35-39 17.8 7.8 10.0 56.3
40 5.0 1.8 3.2 64.7
Numerator for rates is women aged 40 and older
denominator is women aged 40-44 Source Henshaw
S.K., Family Planning Perspectives, 1998