1. Plan B ® Actual Use and Behavior Studies NDA 21-045 NDAC & ACRHD Joint Meeting December 16, 2003 Jin Chen, MD, PhD Division of OTC Drug Products NDAC & ACRHD Joint Meeting December 16, 2003 Jin Chen, MD, PhD Division of OTC Drug Products Center for Drug Evaluation and Research

2. NDAC & ACRHD December 16, 2003 2 OutlineOutline Plan B Actual Use Study Behavior studies associated with emergency contraception Plan B Actual Use Study Behavior studies associated with emergency contraception

3. NDAC & ACRHD December 16, 2003 3 Actual Use Study Principles Simulate OTC setting Assess –self-diagnosis –self-selection –self-medication –safety –efficacy (rarely) Multi-center, open-label, single-arm, uncontrolled trial Simulate OTC setting Assess –self-diagnosis –self-selection –self-medication –safety –efficacy (rarely) Multi-center, open-label, single-arm, uncontrolled trial

4. NDAC & ACRHD December 16, 2003 4 Actual Use Study Principles (cont.) Study Population: anticipated OTC users Geographically diverse OTC-like settings Minimal exclusion criteria Subgroups (low literacy, age) Unlimited product access Minimal intervention from healthcare professionals Study Population: anticipated OTC users Geographically diverse OTC-like settings Minimal exclusion criteria Subgroups (low literacy, age) Unlimited product access Minimal intervention from healthcare professionals

5. NDAC & ACRHD December 16, 2003 5 Plan B Actual Use Study Objectives Primary Objectives: –Self-selection –Timing of doses Secondary Objectives: –Adverse events –Multiple use –Pregnancy rate Additional Observation: –Contraceptive behaviors Primary Objectives: –Self-selection –Timing of doses Secondary Objectives: –Adverse events –Multiple use –Pregnancy rate Additional Observation: –Contraceptive behaviors

6. NDAC & ACRHD December 16, 2003 6 Plan B Actual Use Study Design/Procedure Conducted in 5 family planning clinics across US & 5 pharmacies in WA Female subjects of reproductive age Purchased 1 package of Plan B 4-week Follow-up (2 contacts) Data collection by phone and diary card Conducted in 5 family planning clinics across US & 5 pharmacies in WA Female subjects of reproductive age Purchased 1 package of Plan B 4-week Follow-up (2 contacts) Data collection by phone and diary card

7. NDAC & ACRHD December 16, 2003 7 Subject Enrollment 665 Screened subjects 80 (12%) Not Enrolled 585 (88%) Enrolled 94% from clinics 6% from pharmacies

8. NDAC & ACRHD December 16, 2003 8 Demographics of Enrolled Subjects (n=585) Age: 14-44 yrs (22±5) Education: –87% ≥ HS education –13% had 9 th -11 th grade education Prior EC experience: 40% Age: 14-44 yrs (22±5) Education: –87% ≥ HS education –13% had 9 th -11 th grade education Prior EC experience: 40%

9. NDAC & ACRHD December 16, 2003 9 Subject Follow-Up (n=585) 93% (n=543) at least one follow-up contact –86% (n=501):2 follow-up contacts –2% (n=12):≥ 3 follow-up –5% (n=30):only 1 follow-up 7% (n=42) lost to follow-up 92% (n=540) used Plan B 93% (n=543) at least one follow-up contact –86% (n=501):2 follow-up contacts –2% (n=12):≥ 3 follow-up –5% (n=30):only 1 follow-up 7% (n=42) lost to follow-up 92% (n=540) used Plan B

10. NDAC & ACRHD December 16, 2003 10 ResultsResults Self-Selection Timing of Dosing Adverse Events Contraceptive Behavior Pregnancy Rate Self-Selection Timing of Dosing Adverse Events Contraceptive Behavior Pregnancy Rate

11. NDAC & ACRHD December 16, 2003 11 ResultsResults Self-Selection Timing of Dosing Adverse Events Contraceptive Behavior Pregnancy Rate Self-Selection Timing of Dosing Adverse Events Contraceptive Behavior Pregnancy Rate

12. NDAC & ACRHD December 16, 2003 12 Self-Selection (n=540) 95% of users (n=514) correctly self-selected: Unprotected intercourse (40%) Condom broke or slipped (45%) Missed taking OC pills (7%) Withdrawal method (4%) 95% of users (n=514) correctly self-selected: Unprotected intercourse (40%) Condom broke or slipped (45%) Missed taking OC pills (7%) Withdrawal method (4%)

13. NDAC & ACRHD December 16, 2003 13 Self-Selection (cont.) (n=540) 5% of users (n=26) incorrectly self-selected: 1.3% (n=7) had label contraindication: –6 unexplained vaginal bleeding –1 pregnancy 0.4% (n=2) took Plan B before unprotected intercourse 3% (n=17) provided non-specific reasons 5% of users (n=26) incorrectly self-selected: 1.3% (n=7) had label contraindication: –6 unexplained vaginal bleeding –1 pregnancy 0.4% (n=2) took Plan B before unprotected intercourse 3% (n=17) provided non-specific reasons

14. NDAC & ACRHD December 16, 2003 14 ResultsResults Self-Selection Timing of Doses Adverse Events Contraceptive Behavior Pregnancy Rate Self-Selection Timing of Doses Adverse Events Contraceptive Behavior Pregnancy Rate

15. NDAC & ACRHD December 16, 2003 15 Timing of Dose per Label (n=540) 92% (n=499) – 1 st pill < 72 hours 72% (n=387) – 2 nd pill at 12 hours after 1 st pill 68% (n=366) – both pills according to the label dosing regimen 92% (n=499) – 1 st pill < 72 hours 72% (n=387) – 2 nd pill at 12 hours after 1 st pill 68% (n=366) – both pills according to the label dosing regimen

16. NDAC & ACRHD December 16, 2003 16 Timing of Dose (Alternate 2 nd Dosing Analysis) 92% (n=499) – 1 st pill < 72 hours 93% (n=500) – 2 nd pill between 6-18 hours after 1 st pill 87% (n=469) – both pills according to the alternate 2 nd dosing interval 92% (n=499) – 1 st pill < 72 hours 93% (n=500) – 2 nd pill between 6-18 hours after 1 st pill 87% (n=469) – both pills according to the alternate 2 nd dosing interval

17. NDAC & ACRHD December 16, 2003 17 ResultsResults Self-Selection Timing of Dosing/use Adverse Events Contraceptive Behavior Pregnancy Rate Self-Selection Timing of Dosing/use Adverse Events Contraceptive Behavior Pregnancy Rate

18. NDAC & ACRHD December 16, 2003 18 Adverse Events (AEs) (n=540) No serious AEs No new safety signals Most common AEs (transient): –Abdominal pain (14%) –Nausea (12%) –Headache (11%) –Fatigue/tiredness (8%) No serious AEs No new safety signals Most common AEs (transient): –Abdominal pain (14%) –Nausea (12%) –Headache (11%) –Fatigue/tiredness (8%)

19. NDAC & ACRHD December 16, 2003 19 ResultsResults Self-Selection Timing of Dosing/use Adverse Events Contraceptive Behaviors Pregnancy Rate Self-Selection Timing of Dosing/use Adverse Events Contraceptive Behaviors Pregnancy Rate

20. NDAC & ACRHD December 16, 2003 20 Contraceptive Behaviors (n=543) Behavior 1 month before study 1 month during study ≥ 1 sex act w/o contraception 60%20% Withdrawal method 28%10% Condom use79%90%

21. NDAC & ACRHD December 16, 2003 21 Contraceptive Behaviors (cont.) Subjects tended to use more effective contraception methods 1.7% of enrolled subjects (n=10) requested Plan B more than once during 3-month enrollment period Subjects tended to use more effective contraception methods 1.7% of enrolled subjects (n=10) requested Plan B more than once during 3-month enrollment period

22. NDAC & ACRHD December 16, 2003 22 ResultsResults Self-Selection Timing of Dosing/use Adverse Events Contraceptive Behavior Pregnancy Rate Self-Selection Timing of Dosing/use Adverse Events Contraceptive Behavior Pregnancy Rate

23. NDAC & ACRHD December 16, 2003 23 Pregnancy Rate (n=540) Confirmed pregnancy (n=10):1.9% Unknown pregnancy status:2.6% (n=14, at the end of the study) Confirmed pregnancy (n=10):1.9% Unknown pregnancy status:2.6% (n=14, at the end of the study)

24. NDAC & ACRHD December 16, 2003 24 SummarySummary 95% of users correctly self-selected Plan B 68% of users took 1 st pill within 72 hours and 2 nd pill at 12 hours after the 1 st pill 87% of users took 1 st pill within 72 hours and 2 nd pill between 6-18 hours 95% of users correctly self-selected Plan B 68% of users took 1 st pill within 72 hours and 2 nd pill at 12 hours after the 1 st pill 87% of users took 1 st pill within 72 hours and 2 nd pill between 6-18 hours

25. NDAC & ACRHD December 16, 2003 25 Summary (cont.) No serious AEs and no new safety signals Subjects tended to use more effective contraception No significant differences among demographic subgroups: –Self-selection –Timing of dose/use –AEs –Adverse contraceptive behaviors No serious AEs and no new safety signals Subjects tended to use more effective contraception No significant differences among demographic subgroups: –Self-selection –Timing of dose/use –AEs –Adverse contraceptive behaviors

26. NDAC & ACRHD December 16, 2003 26 Limitations of Plan B Actual Use Study Short follow-up period Purchased only 1 package of Plan B No literacy testing 94% of subjects from clinics Short follow-up period Purchased only 1 package of Plan B No literacy testing 94% of subjects from clinics

27. NDAC & ACRHD December 16, 2003 27 Contraceptive Behavior Studies in Literature 8 behavior studies on advance provision of emergency contraception 5 published, 2 unpublished and 1 abstract 5 studies conducted in US 1 study each from UK, India, and Ghana 8 behavior studies on advance provision of emergency contraception 5 published, 2 unpublished and 1 abstract 5 studies conducted in US 1 study each from UK, India, and Ghana

28. NDAC & ACRHD December 16, 2003 28 Contraceptive Behavior Studies Study Design Study Populations: Family planning clinics/hospital-based clinics Ages 15-45 years Sample size from 160 to 1083 subjects Study Populations: Family planning clinics/hospital-based clinics Ages 15-45 years Sample size from 160 to 1083 subjects

29. NDAC & ACRHD December 16, 2003 29 Contraceptive Behavior Studies Study Design (cont.) Randomized controlled design –Treatment group: advance provision of 1 or 3 courses of EC pills –Control group: Rx EC access EC education for all subjects Follow-up period from 2-12 months Randomized controlled design –Treatment group: advance provision of 1 or 3 courses of EC pills –Control group: Rx EC access EC education for all subjects Follow-up period from 2-12 months

30. NDAC & ACRHD December 16, 2003 30 Contraceptive Behavior Studies Results Subjects with advanced EC provision were more likely to use EC did not have more unprotected sex did not decrease condom use did not switch to less effective contraception Subjects with advanced EC provision were more likely to use EC did not have more unprotected sex did not decrease condom use did not switch to less effective contraception

31. NDAC & ACRHD December 16, 2003 31 Contraceptive Behavior Studies Complement the AU Study: Longer follow-up period Relative large sample size Advance EC provision Complement the AU Study: Longer follow-up period Relative large sample size Advance EC provision

32. NDAC & ACRHD December 16, 2003 32 Limitations of Contraceptive Behavior Studies Conducted in clinics EC education (verbal and written) 3 foreign studies 6 studies provided 1 course of EC Conducted in clinics EC education (verbal and written) 3 foreign studies 6 studies provided 1 course of EC