00012_am.ppt 1 an assessment of the accutane (isotretinoin) pregnancy prevention program allen a....
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100012_am.ppt
An Assessment of theAn Assessment of theAccutane (Isotretinoin)Accutane (Isotretinoin)
Pregnancy Prevention ProgramPregnancy Prevention Program
Allen A. Mitchell, M.D.
Carla Van Bennekom, R.N., M.P.H.
Carol Louik, Sc.D.
Slone Epidemiology Unit
Boston University School of Public Health
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Pregnancy Prevention Program (PPP):Pregnancy Prevention Program (PPP):
– Introduced in fall, 1988
– Multi-component program
– Aimed at female patients and their physicians
– Unprecedented and novel approach
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Survey of Accutane Use in WomenSurvey of Accutane Use in Women
Sponsored by: Hoffmann-La Roche, Inc.
SEU Responsible for: - Design/Protocol
- Data Collection
- Data Processing
- Data Analysis
Guidance provided by: Independent Advisory Committee
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Slone Epidemiology UnitSlone Epidemiology UnitAccutane Survey Advisory CommitteeAccutane Survey Advisory Committee
1988 - 20001988 - 2000
Paul D. Stolley, M.D., Chair*University of Maryland School of MedicineBaltimore, MD
Edward L. Decker, Pharm.D.New England Medical CenterBoston, MA
Karen McKoy, M.D.Lahey ClinicBurlington, MA
Observers:
Charlotte Catz, M.D., NICHD
John Melski, M.D.Marshfield ClinicMarshfield, WI
Peter Pochi, M.D.Boston University School of MedicineBoston, MA
Robert S. Stern, M.D.Harvard Medical SchoolBoston, MA
José F. Corderó, M.D., CDC
*Dr. Stolley resigned as Committee Chair on July 19, 2000 because he has joined the FDA as a Senior Consultant.
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ObjectivesObjectives
To assess compliance with the Pregnancy Prevention Program
• Awareness of the teratogenic risk
• Patient and physician behaviors
• Pregnancy rate
• Pregnancy outcome
• Risk factors for pregnancy
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LimitationsLimitations
• No pilot testing
• No pre/post comparison
• What is “success”?
• Survey itself is an intervention
• Voluntary enrollment/? representativeness
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Accutane SurveyAccutane Survey
TIME PERIOD OF INTERESTTIME PERIOD OF INTEREST
(Duration of Follow-up)(Duration of Follow-up)
Accutane Treatment Potential Pregnancy (2 Trimesters)
0 1 2 3 4 5 6 7 8 9 10 11MONTHS
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To Encourage EnrollmentTo Encourage Enrollment
• Multiple/different opportunities
• Keep it simple
• Provide payment
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Enrollment OpportunitiesEnrollment Opportunities
1) Physician-generated
• All prescriptions originate with physician
• Logistically feasible
• Strong incentive
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Enrollment OpportunitiesEnrollment Opportunities
2) Toll-free telephone call
• Simple
• Quick
• Familiar
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Enrollment OpportunitiesEnrollment Opportunities
3) Package-generated
• Unique
• Direct to patient
• Bypasses physician
• May preferentially target women who
– were not encouraged by their physician
– may be relatively noncompliant
– are attracted by payment
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Follow-Up ApproachesFollow-Up Approaches
Frequent: During and After Treatment (DAT)
Advantage - Avoid recall bias
Disadvantage - ? Affect outcome beyond PPP
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Follow-Up ApproachesFollow-Up Approaches
Infrequent: After Treatment only (AT)
Advantage - Avoids intervention beyond PPP
Disadvantage - Potential recall bias
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Information Obtained at Follow-UpInformation Obtained at Follow-Up
DAT AT
Patient characteristics
Education + -
Doctor specialty + -
Pregnancy risk + -
Patient knowledge
Risk of birth defects + +
Avoid pregnancy + -
Compliance
Pregnancy testing + +
Contraception + +
Wait for next menstrual period + -
Pregnancy occurrence + +
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Accutane SurveyAccutane SurveyEnrollments: 1989-1999Enrollments: 1989-1999
0
10000
20000
30000
40000
50000
60000
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Cumulative enrollmentsthrough 6/30/00: >494,000
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Method of EnrollmentMethod of Enrollment
21%
76%
3%
Doctor-generated
Package-generated
Toll-free phone no.
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Follow-Up RatesFollow-Up Rates
During and After Treatment (“DAT”)
Number to date (6/00): 61,659
1/89 - 12/94 (telephone) 32,301
Completed Follow-Up: Tx start 98%
Tx middle 98%
6 mos.p Tx 93%
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Follow-Up RatesFollow-Up Rates
During and After Treatment (“DAT”)
1/95 - 6/00 (mail) 29,358
Completed Follow-Up: Tx start 98%
Tx middle 98%
6 mos.p Tx 97%
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Follow-Up RatesFollow-Up Rates
After Treatment (“AT”)
Number to date (6/00): 433,256
Completed Follow-Up: 6 mos.p Tx 80-86%
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Age of Enrollees by Enrollment YearAge of Enrollees by Enrollment Year
24
24.5
25
25.5
26
26.5
27
Mea
n a
ge
(yea
rs)
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000
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Highest Level of EducationHighest Level of Education
0
5
10
15
20
25
30
35
%
<12 years High schoolgraduate
Some college ortechnical school
Collegegraduate
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Type of PrescriberType of Prescriber
010
2030
4050
6070
8090
% Y
es
Dermatologist GeneralPractice
Family Practice Other
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Past Treatment for AcnePast Treatment for Acne
0102030405060708090
100
% Y
es
Any antibiotics Oral vitamin A Retin-A BenzoylPeroxide
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Pregnancy Risk CategoriesPregnancy Risk Categories
(at DAT 1)1/95 – 6/00(n=28,016)
3% Hysterectomy/postmenopausal
57% Not sexually active
40% Sexually active
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Pregnancy Risk CategoriesPregnancy Risk Categories
(at DAT 1)1/95 – 6/00(n=28,016)
57% Not sexually active: Using birth control 44%
Not using birth control 56%
100%
40% Sexually active: Using birth control 98%
Not using birth control 2%
100%
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Receipt of PPP InformationReceipt of PPP Information
1/95 – 6/00(n=28,386)
Patient brochure 92%
True/false test 42%
Birth Control brochure 53%
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Knowledge of Accutane RiskKnowledge of Accutane Risk
1/95 – 6/00(n=28,386)
May cause miscarriage 43%
May cause birth defects 99%
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Compliance with PPP – ICompliance with PPP – I
1/95 – 6/00(n=28,386)
Told to avoid pregnancy 99%
Signed consent form77%
Postpone Accutane until pregnancy test 67%
Postpone Accutane until next menstrual period 57%
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Compliance with Selected Measures of the PPPCompliance with Selected Measures of the PPP
0
10
20
30
40
50
60
70
80
90
100
% Y
es
1995 1996 1997 1998 1999 2000
Told to avoid pregnancy
Signed consent form
Postponed Accutane untilresults of pregnancy test known
Postponed Accutane until nextmentrual period
n=5,108 n=5,157 n=5,206 n=5,047 n=5,283 n=2,585
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Compliance with PPP – IICompliance with PPP – II
Pregnancy Testing1/95 – 6/00(n=27,073)
Serum 56%
Urine 9%
Both serum and urine 8%
Any 76%
None 24%
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Pregnancy Testing Before Starting Accutane by Pregnancy Testing Before Starting Accutane by Enrollment YearEnrollment Year
0
10
20
30
40
50
60
70
80
%
1995 1996 1997 1998 1999 2000
Any pregnancy test
No pregnancy test
n=5,108 n=5,157 n=5,206 n=5,047 n=5,283 n=2,585
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Knowledge and Compliance at Onset of TherapyKnowledge and Compliance at Onset of Therapy
1989 -1990(n=9,365)
% Yes Instructions from physicians Wait until pregnancy test results 78% Wait until next menstrual period 63% Behavior Any pregnancy test before therapy 60%
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Knowledge and Compliance at Onset of TherapyKnowledge and Compliance at Onset of Therapy
1989-1990 1991-1993 (n=9,365) (n=11,809) Instructions from physicians Wait until pregnancy test results 78% 85% Wait until next menstrual period 63% 75% Behavior Any pregnancy test before therapy 60% 67%
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Contraceptive StatusContraceptive StatusNoncontraceptors by Age GroupNoncontraceptors by Age Group
0
10
20
30
40
50
60
70
80
%
<15years
15-24years
25-34years
35-44years
45+years
Sexually active
Not sexually active
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Contraceptive StatusContraceptive StatusSurgical Sterility by Age GroupSurgical Sterility by Age Group
0
10
20
30
40
50
60
70
%
<15 years 15-24 years 25-34 years 35-44 years 45+ years
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Contraceptive StatusContraceptive StatusNonsurgical Contraception by Age GroupNonsurgical Contraception by Age Group
0
10
20
30
40
50
60
70
%
<15 years 15-24 years 25-34 years 35-44 years 45+ years
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Contraceptive StatusContraceptive StatusNonsurgical Contraception by Enrollment YearNonsurgical Contraception by Enrollment Year
0
10
20
30
40
50
60
%
1995 1996 1997 1998 1999 2000
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Among Nonsurgical Contraceptors, % Reporting Among Nonsurgical Contraceptors, % Reporting Oral Contraceptive Use by Enrollment YearOral Contraceptive Use by Enrollment Year
0
10
20
30
40
50
60
70
80
%
1995 1996 1997 1998 1999 2000
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Among ContraceptorsAmong Contraceptors% Reporting Use of 2+ Methods by Age Group% Reporting Use of 2+ Methods by Age Group
0
5
10
15
20
25
30
35
40
45
%
<15 years 15-24 years 25-34 years 35-44 years 45+ years
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Among ContraceptorsAmong Contraceptors% Reporting Use of 2+ Methods by Enrollment Year% Reporting Use of 2+ Methods by Enrollment Year
5
10
15
20
25
30
35
40
%
1995 1996 1997 1998 1999 2000
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Among the 27,439 women in DAT1,
6,549 (24%) reported no pregnancy test before starting Accutane
Of those, 3,958 (60%) did not wait until their next menstrual period
Of those,
1,554 (39%) were sexually active
and 39 (1%) were sexually active, not using birth control
Thus, among 27,439 women, 39 (0.1%) were sexually active, not using birth control, had no pregnancy test, and did not wait until their menstrual period before starting Accutane.
Proportion of the Most “At Risk” Women Who Are Proportion of the Most “At Risk” Women Who Are Noncompliant with Pregnancy Testing and Noncompliant with Pregnancy Testing and
Waiting to Start AccutaneWaiting to Start Accutane
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Pregnancies During Accutane TreatmentPregnancies During Accutane Treatment
1989 – 1999 Cohorts
Number of women completing follow-up 347,857
Number of pregnancies reported 1,019
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Number of Pregnancies ReportedNumber of Pregnancies Reportedby Enrollment Yearby Enrollment Year
0
20
40
60
80
100
120
Nu
mb
er o
f P
reg
nan
cies
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
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Accutane SurveyAccutane Survey
Characteristics of Pregnancies(n=1,019)
Pregnant at start of treatment 10%
No contraceptive use 23%
Contraceptive failure 66%
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Outcomes of Accutane Exposed PregnanciesOutcomes of Accutane Exposed Pregnancies
1989 – 1999 cohorts(n=1,019)
No. %
Therapeutic abortion 681 67
Spontaneous abortion 177 17
Liveborn 117 11
Ectopic 29 3
Unknown 15 1
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Pregnancy Rate During Accutane TreatmentPregnancy Rate During Accutane Treatment
1989 – 1999 Cohorts(Duration of Use <1 Year)
Number of women completing follow-up 339,994
Number of pregnancies reported 992
Rate per 1000 Accutane courses 2.8
Rate per 1000 person years 7.4
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Pregnancy Rates During Accutane Treatment Pregnancy Rates During Accutane Treatment by Ageby Age
1989 – 1999 Cohorts
Age (years) No. of women Pregnancy rate/1000 courses
<15 12,290 1.0
15-24 138,497 2.8
25-34 89,040 3.7
35-44 44,574 1.7
45+ 7,970 0.5
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Pregnancy Rate/1000 Person CoursesPregnancy Rate/1000 Person Coursesby Enrollment Yearby Enrollment Year
0
0.5
1
1.5
2
2.5
3
3.5
4
Rat
e/10
00 c
ou
rses
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
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Pregnancy Rate During Accutane Treatment Pregnancy Rate During Accutane Treatment by Contraceptive Methodby Contraceptive Method
1989 – 1999 Cohorts
Method No. of Women Pregnancy rate/1000 courses
None 113,247 1.7
Oral contraceptive 97,895 2.5
Tubal ligation 23,194 0.5
Condom 17,475 10.6
Vasectomy 15,965 0.3
Other 12,318 3.1
Unknown 4,622 2.5
Diaphragm 4,519 5.9
IUD 2,212 3.6
Rhythm 855 15.2
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Accutane SurveyAccutane Survey
Validity
• Follow-up rates are high• Responses consistent (AT vs. DAT)
– Knowledge– Behaviors– Pregnancy rates
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Accutane Survey vs. U.S. Female PopulationAccutane Survey vs. U.S. Female Population
Pregnancy Rates(per 1,000 women/years)
Accutane Survey U.S. Population*
7.4 105
*NCHS, 2000; women ages 15-44
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Accutane Survey vs. U.S. Female PopulationAccutane Survey vs. U.S. Female Population
Proportion Sexually Activeand
Not Using Contraception(n=26,074)
Accutane
Survey
U.S.
Population* Age: 15-24
25-34
35-44
<1
1
1
7
5
5
*National Survey of Family Growth, NCHS, 1995.
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Accutane Survey vs. U.S. Female PopulationAccutane Survey vs. U.S. Female Population
Among Contraceptors:Proportions using birth control pill
Accutane
Survey %
U.S. Population*
% Age: 15-24 73 49
25-34 53 33
35-44 20 8
*National Survey of Family Growth, NCHS (1995 Data).
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Major Factors Associated withMajor Factors Associated withSuccessful Contraception*Successful Contraception*
– Age (coital frequency, fecundity)
– Education
– Duration of method use
– Motivation
*Trussell J and Kost K: Studies in Family Planning 1987;18:237-183
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% of Pregnancies by Contraceptive Method% of Pregnancies by Contraceptive Method
27%
25%
33%
2%13%
No method
Condom
Oral contraceptive
Unknown method
Other
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Accutane SurveyAccutane Survey
Validity
• Follow-up rates are high• Responses consistent
– Knowledge– Behaviors– Pregnancy rates
• Pregnancy rates “rebound” after stopping Accutane
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Pregnancy Rates and Outcomes During and After Pregnancy Rates and Outcomes During and After Therapy with Isotretinoin in 122,582 Women,Therapy with Isotretinoin in 122,582 Women,
1989-19931989-1993
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1) What proportion of eligible women enroll in the Survey?
2) Do women in the Survey represent the larger population of Accutane users?
Accutane SurveyAccutane Survey
Representativeness
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Roche Consumer SurveyRoche Consumer Survey
Female Accutane Users1990 – 1991
(n=400)
Proportion reporting enrollment in survey:
239/400; 60%
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Consumer SurveyConsumer Survey
Accutane Survey
Enrolled Not enrolled
Age (mean) 29 31
Education (median) 14 14
Dermatologist prescribed 91% 88%
Sexually active 64% 54%
- Using contraception (96%) (92%)
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Consumer SurveyConsumer Survey
Contraceptive Methods(among 205 contraceptors; in %)
Accutane Survey
Enrolled Not enrolled
Birth control pill 40 16
Condom 10 12
Other barrier methods 9 8
Surgical sterilization 44 65
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United Health CareUnited Health Care
Population: 1.2 million women ages 12-59
1/90 – 6/96
5,095 women ages 12-59, who filled Accutane prescription between 1/90 and 6/96
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United Health CareUnited Health Care
Population: 1.2 million women ages 12-59
1/90 – 6/96
5,095 women ages 12-59, who filled Accutane prescription between 1/90 and 6/96
Proportion enrolled in Accutane Survey
Definite: 38.4%
Possible: 7.5%
Total: 45.9%
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United Health CareUnited Health Care
Accutane Survey: Enrolled vs. Not Enrolled
Accutane Survey
Enrolled* Not enrolled
Age (mean) 26.4 28.2
*“Definite” matches only.
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United Health CareUnited Health Care
Accutane Survey Enrollment Rates by Age
Age Enrolled
<20 38%
20-29 44%
30-39 41%
40-49 26%
50-59 14%
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SEU Accutane SurveySEU Accutane Survey
Is there selection bias favoring women at low risk?
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Characteristics of Survey ParticipantsCharacteristics of Survey ParticipantsAccording to Enrollment MethodAccording to Enrollment Method
Doctor-generated
Package-generated
Age (mean) 24.3 25.9
Prescriber –dermatologist 98% 88%
Signed consent 98% 71%
Pregnancy test before starting 84% 69%
Pregnancy rate (per 1000 courses) 2.5 2.8
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Among women who enrolled via the Medication Package, only 13% reported that they did so because of their doctor’s encouragement.
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Doctor Encouraged to Enroll in SurveyDoctor Encouraged to Enroll in Surveyby Age Groupby Age Group
0
10
20
30
40
50
60
% Y
es
<15 years 15-24 years 25-34 years 35-44 years 45+ years
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SummarySummary
Since 1989, 494,915 women have enrolled in the Accutane survey.
Follow-up rates are high.
Except for a slight decline in age, demographic characteristics have remained stable.
Awareness of teratogenic risk is high.
Compliance with pregnancy testing and contraceptive guidelines is variable but not decreasing.
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SummarySummary(cont’d)(cont’d)
Pregnancy rates are appreciably lower than U.S. population and have declined over time.
Data appear to be valid.
No evidence that Survey results are not representative.
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Future DirectionsFuture Directions
Increase enrollments– Increase payment at enrollment– Add payment upon completion– Modify doctor-patient enrollment procedures
Enroll women on multiple courses
Increase power and value of DAT follow-up5000/yr 25,000/yr
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Future DirectionsFuture Directions(cont’d)(cont’d)
Modify Survey questions– Oral contraceptive type– Refine pregnancy risk questions
Initiate regular feedback to prescribers to encourage them to value the Survey and enroll patients.
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Method of Enrollment by Enrollment YearMethod of Enrollment by Enrollment Year
0102030405060708090
%
Doctor-generated
Package-generated
Toll-free phone no.
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Age of Enrollees by Enrollment YearAge of Enrollees by Enrollment Year
05
1015202530354045
%
<20 years
20-29 years
30-39 years
40+ years
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Region of Residence by Enrollment YearRegion of Residence by Enrollment Year
0
5
10
15
20
25
%
New EnglandMid AtlanticSouth AtlanticEast South CentralWest South CentralMountainPacificWest North CentralEast North CentralOther
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Highest Level of Education by Enrollment YearHighest Level of Education by Enrollment Year
0
5
10
15
20
25
30
35
40
1995 1996 1997 1998 1999 2000
%
<12 years
High school graduate
Some college ortechnical school
College graduate+
n=5,108 n=5,157 n=5,206 n=5,047 n=5,283 n=2,585
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Past Treatment for Acne by Enrollment YearPast Treatment for Acne by Enrollment Year
0
10
20
30
40
50
60
70
80
90
100
% Y
es
1995 1996 1997 1998 1999 2000
Any antibiotics
Oral vitamin A
Retin-A
Benzoyl Peroxide
n=5,108 n=5,157 n=5,206 n=5,047 n=5,283 n=2,585
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Pregnancy Risk Category by Enrollment YearPregnancy Risk Category by Enrollment Year
0
5
10
15
20
25
30
35
40
% Y
es
1995 1996 1997 1998 1999 2000
Hysterectomy orpostmenopausal
Not sexually active,using birth control
Not sexually active, notusing birth control
Sexually active, usingbirth control
Sexually active, notusing birth control
n=5,023 n=5,087 n=5,144 n=4,987 n=5,220 n=2,555
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Oral Contraceptive Users by Sexual Activity StatusOral Contraceptive Users by Sexual Activity StatusAge 15-24 yearsAge 15-24 years
0
5
10
15
20
25
30
1995 1996 1997 1998 1999 2000
%
Sexually activeNot sexually active
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Doctor Encouraged to Enroll in SurveyDoctor Encouraged to Enroll in Surveyby Enrollment Methodby Enrollment Method
010
20304050
60708090
% Y
es
Doctor-generated Medicationpackage-genrated
Toll-free telephonenumber
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Number of Liveborns by Enrollment YearNumber of Liveborns by Enrollment Year
0
2
4
6
8
10
12
14
16
18
Nu
mb
er o
f L
iveb
orn
s
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
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% of Pregnancies by Contraceptive Method% of Pregnancies by Contraceptive Method
27%
2%
25%4%
1%
32%
1%
1%5% 2%
No methodRhythymCondomDiaphragmIUDOral contraceptiveVasectomyTubal ligationOther methodUnknown method
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Pregnancy Rate During Accutane Treatment by Pregnancy Rate During Accutane Treatment by Contraceptive Method by Enrollment YearContraceptive Method by Enrollment Year
0
5
10
15
20
25
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
No method
Oral contraceptive
Condom
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Pregnancy Rates According to Follow-UpPregnancy Rates According to Follow-Upby Enrollment Yearby Enrollment Year
1
1.5
2
2.5
3
3.5
4
4.5
5
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
DAT
AT
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Contraceptive Failure RatesContraceptive Failure Rates
Typical Use* Perfect Use* Accutane Survey†
Method (%) (%) (%)
Diaphragm 18 6 1.5
Condom (male) 12 3 2.8
IUD 0.1-2.0 0.1-1.5 0.9
Oral contraceptive pill
0.1-0.5 0.6
Female sterilization 0.4 0.4 0.1
Male sterilization 0.15 0.10 0.08*Percent pregnant in first year of use; Hatcher RA et al.: Contraceptive Technology, 17th Edition, 1994, p113.
†Rate per 100 woman-years.
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Compliance According to PregnancyCompliance According to PregnancyRisk CategoryRisk Category
(DAT1, 1995 – 2000)
Hyst.
Not sexually active, using birth control
Not sexually active, not using
birth control
Sexually active, using birth
control
Sexually active, not using birth
control Unk.
N 943 6,970 8,821 10,811 195 276
% % % % % %
Told to avoid pregnancy 95 99 99 99 99 99
Signed consent 51 81 78 76 69 79
Had pregnancy test N/A 82 70 76 70 64
Waited for test after starting N/A 74 58 70 63 53
Waited for next month after starting N/A 63 48 60 53 47
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Does the more intensive DAT follow-up Does the more intensive DAT follow-up itselfitself result in enhanced compliance?result in enhanced compliance?
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Accutane SurveyAccutane Survey
Pregnancy Rates According to Follow-Up
Follow-Up N Pregnancies Rate/1000 Courses
AT 292,955 848 2.8
DAT 46,989 144 3.0
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Pregnancy Rate in 30 Days Following AccutanePregnancy Rate in 30 Days Following Accutaneby Enrollment Yearby Enrollment Year
(n=338/338,959; Rate=1.0/1000 enrollees)
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
%
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Pregnancy Rate During TreatmentPregnancy Rate During TreatmentAmong Women on Accutane for 1-2 YearsAmong Women on Accutane for 1-2 Years
N=27/7,862, or 27/9,641 person-years of treatment
Rate=2.8/1000 person-years of treatment