Nonprescription Drugs And Reproductive Health Drugs Joint Advisory Committee Meeting December 16, 2003

1. Nonprescription Drugs And Reproductive Health Drugs Joint Advisory Committee MeetingDecember 16, 2003 Plan B® (LEVONORGESTREL) For Emergency Contraception RX-to-OTC SWITCH

2. Plan B®: RX-to-OTC Switch Carole S. Ben-Maimon, M.D. President and COO, Barr Research On behalf of Women’s Capital Corporation

3. Agenda • Background Review • How Plan B Prevents Pregnancy • Rationale for OTC Switch • Risk/Benefit Assessment • Vivian Dickerson, M.D., President-Elect, American College of Obstetricians and Gynecologists and Director, Obstetrics and Gynecology, University of California Irvine Medical Center • Clinical Trials • Label Comprehension • Actual Use • Health Consequences of Plan B OTC • David Grimes, M.D., FACOG, FACPM, Vice President of Biomedical Affairs, Family Health International and Clinical Professor, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine • CARE Program

4. What Is Emergency Contraception? Emergency contraception is: • Therapy for women who do not wish to become pregnant and who have had unprotected sexual intercourse • Contraceptive accident • Sexual assault

5. Contraceptive Accident • 53% of unintended pregnancies resulted from contraceptive accident • Contraceptive accidents include method accidents and user accidents • Many contraceptive accidents are immediately recognizable: • Condom break/slip • Missed/late OCs • Late injection • Dislodgment of patch, ring, diaphragm • Failure of spermicide to melt • Failed withdrawal Source: Henshaw 1998

6. Public Health Problem Unintended Pregnancies: • Over 3,000,000/year in US; • Condom failure 15%, OC failure 8% (first year typical use) • ~800,000 unintended pregnancies in teens • In 2002, 215,000 US women were victims of rape, attempted rape, or sexual assault; • Half result in abortion; • Up to 50% of unintended pregnancies could be prevented by greater use of EC Source: Trussell 2004, Nat’l Vital Statistics Report 2003, Nat’l Crime Victimization Survey, 2002, Henshaw 1998, Trussell 1992

7. Approved Emergency Contraceptives Two FDA Approved RX ECs: • Preven®– Approved 1998, Based on Yuzpe method • 2 x Levonorgestrel 0.25mg/Ethinyl Estradiol 0.05mg tablets within 72 hrs of unprotected sex followed by 2 more tablets 12 hrs later • Plan B® – Approved 1999 • 1 x Levonorgestrel 0.75mg tablet within 72 hrs of unprotected sex followed by 1 more tablet 12 hrs later

8. How Plan BPrevents Pregnancy Risk of pregnancy highest in the days leading up to and including the day of ovulation Probability of Conception on Specific Days Near the Day of Ovulation (Wilcox 1995) Sources: Wilcox 1995, Trussell 2003, Croxatto 2002

9. How Plan B Prevents Pregnancy Direct Evidence: • Interference with the ovulatory process – demonstrated in several studies Hypothetical Mechanisms: • Interference with fertilization by affecting sperm migration – no direct evidence • Interference with implantation – no direct evidence

10. Early Use of Plan B Increases Efficacy WHO Trial: LNG Regimen Source: WHO 1998

11. RX Setting OTC Setting Locate prescriber available and willing to prescribe EC Identify need Contact prescriber • Additional potential requirements: • Office visit • Pregnancy test • Medical exam • Counseling Obtain prescription Locate pharmacy that stocks EC Purchase product Barriers With RX Use

12. Plan B® Has a Compelling Risk/Benefit Assessment Vivian Dickerson, M.D., President-Elect, American College of Obstetricians and Gynecologists and Director, Obstetrics and Gynecology, University of California Irvine Medical Center

13. Regulatory Requirements for Non-Prescription Marketing • Have an acceptable safety profile based on RX history • Have a low potential for abuse and misuse • Have an appropriate therapeutic index for safety • Have a positive benefit to risk ratio • Treat a condition that is self-recognizable, self-limiting and requires minimal HCP intervention The drug must:

14. Plan B Meets Requirements for OTC Use • Post-marketing and clinical trial safety data demonstrate an acceptable safety profile • There is a low potential for abuse or misuse • The benefits of OTC availability strongly outweigh the risks • Consumers can properly self-select the product for its intended use and can correctly use the product • Label Comprehension Study • Actual Use Study

15. Plan B: Safety and Efficacy Studies Over 7,000 subjects have participated in clinical studies: * Plan B NDA Supportive Study ** Plan B NDA Pivotal Study

16. Plan B is Safe & Effective • Plan B is 89% effective in preventing pregnancy if used as labeled within 72 hours of unprotected sex • Plan B has a well characterized safety profile, common AEs include: • Nausea • Abdominal pain • Fatigue • Headache • Menstrual changes • No deaths associated with Plan B regimen • No increased risk of ectopic pregnancy with Plan B • Professional screening does not impact efficacy or safety

17. Ectopic Pregnancy and Plan B • Plan B is a progestin-only EC • 6 trials of Plan B with systematic follow-up of pregnancies • 7,889 evaluable participants • 133 pregnancies • 2 ectopic (1.5%, consistent with background rate) • Post-marketing information for Plan B confirms low incidence of ectopic pregnancy

18. Plan B:RX-to-OTC Switch Studies The Plan B RX-to-OTC application is supported by two studies:

19. Label Comprehension Study DESIGN • PURPOSE:To evaluate comprehension of a prototype label of the Plan B OTC product • POPULATION: Women ages 12 to 50 surveyed in eight U.S. cities • Sampling included minority women and those at high risk for poor label comprehension • INSTRUMENT: Questionnaire

20. Label Comprehension Study Demographics of Eligible Subjects REALM* n=395 * Rapid Estimate of Adult Literacy in Medicine (Davis 1993)

21. Label Comprehension Study Objectives • Prevention of pregnancy after unprotected sex • Back up method (not regular contraceptive) • Does not prevent STIs/AIDS • 1st pill taken within 72 hours • 1st pill taken ASAP • 2nd pill taken 12 hours after 1st • Not for use in pregnant women • Not for use in women with unexplained vaginal bleeding • Not for use in women with allergy to product • Side effects include nausea and vomiting • If severe abdominal pain develops, seek immediate medical care

22. Label Comprehension Study

23. Label Comprehension Study

24. Label Comprehension Study

25. Plan B is Intended as a Back up Method & not for Regular Contraception

26. Plan B is Intended as a Back up Method & not for Regular Contraception

27. Plan B Label Changes PANEL 2 BOLDED

28. The First Pill Should be Taken within 72 Hours after Intercourse *ASAP 23.7% (≤8th grade); 36.6% (>8th grade); 26.4% (total)

29. Label Comprehension Study Results • Intent to treat analysis shows: • Satisfactory response rates for all objectives • 80% or greater response rate for 9 of 11 objectives Conclusion • Study demonstrates adequate label comprehension in all populations evaluated • Based on the results, the label was modified to enhance comprehension in the Actual Use Study

30. Label Comprehension Study Actual Use Study Plan B Label Changes PANEL 1 ENLARGED

31. Plan B Label Changes PANEL 4 BOLDED

32. Plan B Label Changes PANEL 6 BOLD

33. Label Comprehension Study Actual Use Study Plan B Label Changes Contraception  Control PANEL 13

34. Actual Use Study • PURPOSE: To determine if women seeking EC could self-select and use the product appropriately and safely when labeled for OTC distribution • OBJECTIVE: Estimate the frequency of contraindicated and incorrect use of Plan B • DESIGN: Non-comparative case series study • LOCATIONS: –5 Planned Parenthood affiliates – 5 pharmacies (Seattle, WA)

35. Actual Use Study Study Procedures • Initial Screening – • Given information about the study, not the product • Reviewed “Drug Facts Panel” on a sealed prototype product • Decided to receive or not receive Plan B without counseling • Signed Informed Consent • Received study product and Study Data Card • Follow-up contact at 1 week and 4 weeks

36. Actual Use and Label Comprehension Studies * Data from U.S. Census 2002 ** Label Comprehension Study  women aged 14-44

37. 665 Screened 585 Enrolled 80 Not Enrolled 42 Lost-to-Follow-Up 543 Provide Follow- up Information 509 Time between sex and 1st pill 523 Time between 1st and 2nd pill 540 Used Plan B 506 All Times Actual Use Study Analysis Cohorts

38. Actual Use Study Contraindicated Use • Was Plan B used according to outer package label? • Contraindications to use included: • Already pregnant • Allergy to any ingredient in Plan B • Any unusual vaginal bleeding

39. Actual Use Study Contraindicated Use • 99% of classifiable study subjects did not have contraindications to Plan B • 7 subjects with contraindications to Plan B: • 1 pregnant at time of Plan B use • 6 unexplained vaginal bleeding • 3 prior emergency contraceptive users

40. Actual Use Study Correct Use • Using Plan B according to strict interpretation of directions:

41. Actual Use Study Time From Sex Act to 1st Pill * Source: Reanalysis of study data submitted in approved NDA 21-045 (WHO 92908)

42. Actual Use Study Time Interval Between 1st and 2nd Pill * Source: Reanalysis of study data submitted in approved NDA 21-045 (WHO 92908)

43. Actual Use Study Pregnancy Analysis • 10 Pregnancies (of 526) • Pregnancy Rate: 1.9% • 95% Confidence Interval (0.92%, 3.47%) • Of 10 pregnancies: • 4 elective abortions • 1 called study pregnancy registry • 6 lost to follow-up • WHO (#92908) Clinical Trial 1.1%

44. Actual Use Study: Conclusions • Study design simulated OTC environment • Subjects were representative of the OTC population likely to use Plan B • Subjects were able to self-select and use the product correctly • The results are similar to the WHO pivotal trial • Plan B should be as safe and effective in an OTC setting as it is in the current RX setting

45. Health Consequences Of Over-the-Counter Levonorgestrel Emergency Contraception David Grimes, M.D., FACOG, FACPM Vice President of Biomedical Affairs, Family Health International and Clinical Professor, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine

46. Take-Home Message Access to and use of emergency contraception improves the health of women. Emergency contraception helps prevent unintended pregnancy, which carries substantial medical risks.

47. Maternal Mortality • Pregnancy remains a risky business • U.S. maternal mortality rate in 1999: 13 deaths per 100,000 live births • 4200 deaths reported to CDC from 1991 to 1999 Source: Chang et al. MMWR Surveill Summ 2003; 21:1

48. Maternal Morbidity In the U.S.: • 43% of women have some type of morbidity during childbirth hospitalization • 25% of women are hospitalized during pregnancy for a complication of the pregnancy Sources: Danel et al. Am J Public Health 2003;93:631 Scott et al. Obstet Gynecol 1997;90:225

49. In Contrast… Emergency contraception has no important medical harms, either in terms of morbidity or mortality Source: Grimes. N Engl J Med 2002;347:846

50. Induced Abortion: an Index of Unwanted Pregnancy • 862,000 abortions reported to CDC in 1999 • Ratio: 256 abortions per 1000 live births (1 in 5 pregnancies) • Rate: 17 abortions per 1000 women aged 15-44 yr (about 2%) Source: Elam-Evans et al. MMWR Surveill Summ 2002;51:1