1. An Assessment of the Accutane (Isotretinoin) Pregnancy 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

2. Pregnancy Prevention Program (PPP):
Introduced in fall, 1988
Multi-component program
Aimed at female patients and their physicians
Unprecedented and novel approach

3. Does the PPP work?

4. Survey 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

5. Slone Epidemiology Unit Accutane Survey Advisory Committee 1988 - 2000
Paul D. Stolley, M.D., Chair*
University of Maryland School of Medicine
Baltimore, MD
Edward L. Decker, Pharm.D.
New England Medical Center
Boston, MA
Karen McKoy, M.D.
Lahey Clinic
Burlington, MA
Observers:
Charlotte Catz, M.D., NICHD
John Melski, M.D.
Marshfield Clinic
Marshfield, WI
Peter Pochi, M.D.
Boston University School of Medicine
Boston, MA
Robert S. Stern, M.D.
Harvard Medical School
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.

6. Objectives 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

7. Limitations No pilot testing No pre/post comparison What is “success”?
Survey itself is an intervention
Voluntary enrollment/? representativeness

8. Accutane Survey
Design

9. Accutane Survey TIME PERIOD OF INTEREST (Duration of Follow-up)

10. To Encourage Enrollment
Multiple/different opportunities
Keep it simple
Provide payment

11. Enrollment Opportunities
1) Physician-generated
All prescriptions originate with physician
Logistically feasible
Strong incentive

12. Enrollment Opportunities
2) Toll-free telephone call
Simple
Quick
Familiar

13. Enrollment 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

14. Follow-Up Approaches Frequent: During and After Treatment (DAT)
Advantage - Avoid recall bias
Disadvantage - ? Affect outcome beyond PPP

15. Follow-Up Approaches Infrequent: After Treatment only (AT)
Advantage - Avoids intervention beyond PPP
Disadvantage - Potential recall bias

17. Information Obtained at Follow-Up
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

18. Accutane Survey
Results

19. Accutane Survey Enrollments: 1989-1999
Cumulative enrollments
through 6/30/00: >494,000

20. Method of Enrollment

21. Follow-Up Rates During and After Treatment (“DAT”)
Number to date (6/00): 61,659
1/ /94 (telephone) 32,301
Completed Follow-Up: Tx start 98%
Tx middle 98%
6 mos.`p Tx 93%

22. Follow-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%

23. Follow-Up Rates After Treatment (“AT”) Number to date (6/00): 433,256
Completed Follow-Up: 6 mos.`p Tx %

24. Results: Demographics
Accutane Survey
Results:
Demographics

25. Age 1/89 – 6/00 (n=494,915)
Mean (years) 25.6
Median (years) 24

26. Age of Enrollees by Enrollment Year

27. Highest Level of Education

28. Type of Prescriber

29. Past Treatment for Acne

30. Pregnancy Risk Categories (at DAT 1) 1/95 – 6/00 (n=28,016)
3% Hysterectomy/postmenopausal
57% Not sexually active
40% Sexually active

31. Pregnancy Risk Categories (at DAT 1) 1/95 – 6/00 (n=28,016)
57% Not sexually active: Using birth control %
Not using birth control %
100%
40% Sexually active: Using birth control %
Not using birth control %

32. Results: Women’s Knowledge
Accutane Survey
Results:
Women’s Knowledge

33. Receipt of PPP Information 1/95 – 6/00 (n=28,386)
Patient brochure 92%
True/false test 42%
Birth Control brochure 53%

34. Knowledge of Accutane Risk 1/95 – 6/00 (n=28,386)
May cause miscarriage 43%
May cause birth defects 99%

35. Accutane Survey
Results:
Compliance

36. Compliance with PPP – I 1/95 – 6/00 (n=28,386)
Told to avoid pregnancy 99%
Signed consent form %
Postpone Accutane until pregnancy test 67%
Postpone Accutane until next menstrual period 57%

37. Compliance with Selected Measures of the PPP

38. Compliance with PPP – II Pregnancy Testing 1/95 – 6/00 (n=27,073)
Serum %
Urine %
Both serum and urine 8%
Any %
None %

39. Pregnancy Testing Before Starting Accutane by Enrollment Year

40. Knowledge and Compliance at Onset of Therapy 1989 -1990 (n=9,365)

41. Original Medication Package

42. Revised Medication Package

43. Knowledge and Compliance at Onset of Therapy

44. Compliance with PPP - III
Contraceptive Status, By Age

45. Contraceptive Status Noncontraceptors by Age Group

46. Contraceptive Status Surgical Sterility by Age Group

47. Contraceptive Status Nonsurgical Contraception by Age Group

48. Contraceptive Status Nonsurgical Contraception by Enrollment Year

49. Among Nonsurgical Contraceptors, % Reporting Oral Contraceptive Use by Enrollment Year

50. Among Contraceptors % Reporting Use of 2+ Methods by Age Group

51. Among Contraceptors % Reporting Use of 2+ Methods by Enrollment Year

52. Proportion of the Most “At Risk” Women Who Are Noncompliant with Pregnancy Testing and Waiting to Start Accutane
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.

53. Accutane Survey
Results:
Pregnancies

54. Pregnancies During Accutane Treatment 1989 – 1999 Cohorts
Number of women completing follow-up 347,857
Number of pregnancies reported 1,019

55. Number of Pregnancies Reported by Enrollment Year

56. Accutane Survey Characteristics of Pregnancies (n=1,019)
Pregnant at start of treatment 10%
No contraceptive use 23%
Contraceptive failure 66%

57. Outcomes 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

58. Pregnancy 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

59. Pregnancy Rates During Accutane Treatment by 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

60. Pregnancy Rate/1000 Person Courses by Enrollment Year

61. Pregnancy rate/1000 courses
Pregnancy Rate During Accutane Treatment by Contraceptive Method – 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
Diaphragm
4,519
5.9
IUD
2,212
3.6
Rhythm
855
15.2

62. Accutane Survey
Validity

63. Accutane Survey Validity
Follow-up rates are high

64. Accutane Survey Validity
Follow-up rates are high
Responses consistent (AT vs. DAT)
Knowledge
Behaviors
Pregnancy rates

65. Accutane Survey vs. U.S. Female Population Pregnancy Rates (per 1,000 women/years)
U.S. Population*
7.4
105
*NCHS, 2000; women ages 15-44

66. Accutane Survey vs. U.S. Female Population Proportion Sexually Active and Not Using Contraception (n=26,074)

67. Accutane Survey vs. U.S. Female Population Among Contraceptors: Proportions using birth control pill

68. Major Factors Associated with Successful Contraception*
Age (coital frequency, fecundity)
Education
Duration of method use
Motivation
*Trussell J and Kost K: Studies in Family Planning 1987;18:

69. % of Pregnancies by Contraceptive Method

70. Accutane Survey Validity
Follow-up rates are high
Responses consistent
Knowledge
Behaviors
Pregnancy rates
Pregnancy rates “rebound” after stopping Accutane

71. Pregnancy Rates and Outcomes During and After Therapy with Isotretinoin in 122,582 Women, 1989-1993

72. Accutane Survey Representativeness

73. Accutane Survey Representativeness
1) What proportion of eligible women enroll in the Survey?
2) Do women in the Survey represent the larger population of Accutane users?

74. Roche Consumer Survey Female Accutane Users 1990 – 1991 (n=400)
Proportion reporting enrollment in survey:
239/400; 60%

75. Consumer Survey Accutane Survey Enrolled Not enrolled Age (mean) 29 31
Education (median) 14
Dermatologist prescribed
91%
88%
Sexually active
64%
54%
- Using contraception
(96%)
(92%)

76. Consumer 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

77. United Health Care Population: ³1.2 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

78. United Health Care Population: ³1.2 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%

79. United Health Care Accutane Survey: Enrolled vs. Not Enrolled
Age (mean)
26.4
28.2
*“Definite” matches only.

80. United Health Care Accutane Survey Enrollment Rates by Age
Enrolled
<20
38%
20-29
44%
30-39
41%
40-49
26%
50-59
14%

81. SEU Accutane Survey
Is there selection bias favoring women at low risk?

82. Characteristics of Survey Participants According to Enrollment Method
Doctor-generated
Package-generated
Age (mean)
24.3
25.9
Prescriber –dermatologist
98%
88%
Signed consent
71%
Pregnancy test before starting
84%
69%
Pregnancy rate (per 1000 courses)
2.5
2.8

83. Among women who enrolled via the Medication Package, only 13% reported that they did so because of their doctor’s encouragement.

84. Doctor Encouraged to Enroll in Survey by Age Group

85. Summary
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.

86. Summary (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.

87. Future 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-up
5000/yr  25,000/yr

88. Future Directions (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.

90. Method of Enrollment by Enrollment Year

91. Age of Enrollees by Enrollment Year

92. Region of Residence by Enrollment Year

93. Highest Level of Education by Enrollment Year

94. Past Treatment for Acne by Enrollment Year

95. Pregnancy Risk Category by Enrollment Year

96. Oral Contraceptive Users by Sexual Activity Status Age 15-24 years

97. Doctor Encouraged to Enroll in Survey by Enrollment Method

98. Number of Liveborns by Enrollment Year

99. % of Pregnancies by Contraceptive Method

100. Pregnancy Rate During Accutane Treatment by Contraceptive Method by Enrollment Year

101. Pregnancy Rates According to Follow-Up by Enrollment Year

102. Contraceptive Failure Rates
Typical Use*
Perfect Use*
Accutane Survey†
Method
(%)
Diaphragm 18 6
1.5
Condom (male) 12 3
2.8
IUD
0.9
Oral contraceptive pill
0.6
Female sterilization
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.

103. Compliance According to Pregnancy Risk 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
Signed consent 51 81 78 76 69 79
Had pregnancy test
N/A 82 70 64
Waited for test after starting 74 58 63 53
Waited for next month after starting 48 60 47

104. Does the more intensive DAT follow-up itself result in enhanced compliance?

105. Accutane Survey Pregnancy Rates According to Follow-Up
Pregnancies
Rate/1000 Courses AT
292,955
848
2.8
DAT
46,989
144
3.0

106. Pregnancy Rate in 30 Days Following Accutane by Enrollment Year (n=338/338,959; Rate=1.0/1000 enrollees)

107. Pregnancy Rate During Treatment Among 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

108. United Health Care Accutane Survey Enrollment Rates by Age