BRIEFING DOCUMENT

NONPRESCRIPTION DRUGS and REPRODUCTIVE HEALTH DRUGS ADVISORY COMMITTEE MEETING

16 DECEMBER 2003

 

PLAN B® (LEVONORGESTREL)

FOR EMERGENCY CONTRACEPTION

Rx-to-OTC SWITCH

 

 

 

 

 

 

 

 

 

14 November 2003

 

 

 

 

 

 

 

 

Women’s Capital Corporation

1990 M Street, NW

Suite 250

Washington, DC 20036

 

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION


 

TABLE OF CONTENTS

LIST OF APPENDICES. 7

1 Introduction and Background.. 8

1.1 Introduction.. 8

1.2 Executive Summary.. 8

1.2.1 Unintended Pregnancy. 8

1.2.2 Emergency Contraception. 9

1.2.2.1 Definition. 9

1.2.2.2 Awareness. 10

1.2.2.3 Emergency Contraception – History. 11

1.2.2.4 Emergency Contraception – Worldwide Experience. 12

1.2.2.5 Emergency Contraception – Access. 13

1.2.2.6 Pharmacy Access Programs. 15

1.2.2.7 Potential Impact of Expanded Access to Emergency Contraception. 16

1.2.2.7.1 Condom Use. 16

1.2.2.7.2 Sexually Transmitted Infections (STI) 19

1.2.2.7.3 Routine Birth Control Use. 19

1.2.3 Plan B: Post-Marketing Safety Experience. 20

1.2.3.1 Ectopic Pregnancy. 25

1.2.4 Plan B: Rx-to-OTC Switch. 26

2 CLINICAL Pharmacology of Levonorgestrel – MECHANISM OF ACTION.. 28

3 Well-Controlled, COMPARATIVE, Clinical STUDIES OF 0.75 MG LEVONORGESTREL for Emergency Contraception (NOT SPECIFICALLY DESIGNED TO SUPPORT AN Rx-to-OTC SWITCH). 32

3.1 Summary of Comparative Clinical Efficacy Studies of 0.75 mg Levonorgestrel for Emergency Contraception from NDA 21-045. 32

3.2 Controlled Studies of the Plan B Levonorgestrel Regimen for Emergency Contraception Since the Submission of NDA 21-045. 34

4 Studies Supporting the OTC Distribution of Plan B.. 34

4.1 Overview... 34

4.2 Plan B OTC Label Comprehension Study.. 37

4.2.1 Overview and Study Design. 37

4.2.2 Survey Overview.. 39

4.2.3 Survey Procedure. 39

4.2.4 Study Population. 40

4.2.5 Results – All Patients. 44

4.2.5.1 Communication Objectives. 44

4.2.5.2 Communication Objective 2. 46

4.2.5.3 Communication Objective 4. 47

4.2.5.4 Communication Objective 8. 49

4.2.6 Results by Literacy Level (as assessed by the REALM test) 50

4.2.6.1 Overview.. 50

4.2.6.2 Results - Communication Objectives. 53

4.2.7 Summary and Conclusions – Label Comprehension Study. 54

4.3 Plan B OTC Actual Use Study.. 56

4.3.1 Overview and Study Design. 56

4.3.2 Study Population. 60

4.3.3 Analysis of Primary Outcome Variables of Plan B OTC Actual Use Study. 64

4.3.3.1 Contraindicated Use. 64

4.3.3.2 Incorrect Use. 65

4.3.4 Analysis of Pregnancy During Plan B OTC Actual Use Study. 66

4.3.5 Additional Results of the Plan B OTC Actual Use Study. 68

4.3.6 Prior vs. Naïve Users. 69

4.3.7 Safety Results for the Plan B OTC Actual Use Study: Adverse Events. 70

4.3.8 Actual Use Study: Conclusion. 72

5 benefit/risk overview of plan b as an otc emergency contraceptive.. 74

5.1 Overview... 74

5.2 Risk Assessment of Plan B.. 74

5.3 Benefits of OTC Plan B.. 76

5.4 Discussion and Conclusions – Risks vs. Benefits. 77

6 plan b: Convenient Access, Responsible Education Program... 79

6.1 Introduction.. 79

6.2 CARESM Program Objectives. 80

6.3 Labeling/Packaging.. 81

6.3.1 Core messages. 82

6.3.2 Labeling refinements. 82

6.3.3 Additional sources of information. 83

6.4 Education.. 83

6.4.1 Educational Program to Healthcare Professionals. 83

6.4.2  Educational Campaign to Consumers. 84

6.4.3 Media Coverage. 85

6.5 Distribution.. 85

6.6 Monitoring.. 86

6.7 Summary and Conclusions. 88

7 References. 89

 

 


LIST OF TABLES

 

Table 1: Plan B Serious Adverse Events 28 July 2002 – 27 July 2003. 22

Table 2: Summary of Adverse Events by Body System... 24

Table 3: Well-Controlled Comparative Clinical Studies Previously Submitted in NDA 21-045. 32

Table 4: Efficacy Results for Comparative Clinical Trials from NDA 21‑045 (WHO #92908, WHO 1998b, Ho 1993). 33

Table 5: Sponsor Studies Supporting OTC Distribution of Plan B.. 35

Table 6: Socio-Demographic Characteristics of the Eligible Population in the Plan B OTC Label Comprehension Study.. 41

Table 7: Distribution of Eligible Subjects Seen at Mall and Clinic Settings, by Age Group.. 42

Table 8: Contraceptive History of the Eligible Population in the Plan B OTC Label Comprehension Study.. 43

Table 9: Percent of Subjects Who Understood Communication Objectives Related to Efficacy in the Plan B OTC Label Comprehension Study.. 45

Table 10: Correct Response Percentages for Questions 9, 21, 22, and 25 Making Up Communication Objective 2: Plan B is Intended as a Back Up Method and Should Not Be Used for Regular Birth Control.. 46

Table 11: Correct Response Percentages for Questions 10, 19, 20 and 29 Making Up Communication Objective 4: The First Pill Should Be Taken Within 72 Hours After Intercourse.. 48

Table 12: Correct Response Percentages for Question 15 Making Up Communication Objective 8: Plan B Should Not Be Used by Women with Unexplained Vaginal Bleeding... 49

Table 13: Socio-Demographic Characteristics of the Subjects Administered the REALM Test in the Plan B OTC Label Comprehension Study.. 52

Table 14: Percent of REALM Subgroup Who Understood Communication Objectives Related to Efficacy in the Plan B OTC Label Comprehension Study   53

Table 15: Socio-Demographic Characteristics of Screened and Enrolled Cohorts in the Actual Use Study (% of each subset). 63

Table 16: Efficacy Results for Actual Use Study and NDA Pivotal Study.. 68

Table 17: Contraceptive Methods Used Before and After Receiving Plan B.. 68

Table 18: Contraindicated and Incorrect Use Among Prior and Naïve Users of Emergency Contraception.. 70

Table 19: Percent of Subjects Reporting Adverse Events in Actual Use Study    (≥  5% reported for at least one subset). 71

Table 20: Interval Between Pill Doses in Actual Use Study and NDA Pivotal Clinical Trial.. 73

 


LIST OF FIGURES

 

FIGURE 1: PROBABILITY OF CONCEPTION ON SPECIFIC DAYS NEAR THE DAY OF OVULATION (WILCOX 1995)……………………………………………………………………..29

Figure 2: Instructions for Use Printed on the Outside of the Plan B OTC Actual Use Study Label*. 60

Figure 3: Pregnancy Analysis in Actual Use Study.. 67

 


LIST OF APPENDICES

 

APPENDIX 1: MECHANISMS OF ACTION

APPENDIX 2: LABEL COMPREHENSION QUESTIONS AND QUESTIONNAIRE

APPENDIX 3: LABEL COMPREHENSION STUDY LABEL

APPENDIX 4: ACTUAL USE STUDY LABEL

APPENDIX 5: PROPOSED OTC LABEL

APPENDIX 6: CATEGORIZATION OF VERBATIM TERMS FOR LABEL COMPREHENSION STUDY QUESTION #7

APPENDIX 7: PROPOSED PATIENT PACKAGE INSERT

APPENDIX 8: LABEL COMPREHENSION STUDY DATA TRANSCRIPTION CARD


1 Introduction and Background

 

1.1 Introduction

This briefing document summarizes information in support of the proposed Rx-to-over-the-counter (OTC) switch for the marketed emergency contraceptive, Plan BÒ and describes the proposed CARESM (Convenient Access Responsible Education) program intended to insure the appropriate and responsible use of Plan B.  Women’s Capital Corporation (“the sponsor”) proposes that expanded access to Plan B, combined with a well defined marketing and educational program, will provide a fundamentally improved approach to satisfying an unmet medical need that will result in the reduction of unintended pregnancies.

 

Barr also contends that Plan B is an ideal OTC candidate.  The unpredictable timing of the event leading to the need for emergency contraception, along with the following characteristics of Plan B strongly support the switch to OTC status:

·       Early use of Plan B increases efficacy

·       Plan B has an appropriate safety profile

·       Plan B has a compelling risk/benefit assessment

·       Plan B is not used chronically.

 

1.2 Executive Summary

1.2.1 Unintended Pregnancy

 

There are nearly three million unintended pregnancies each year in the United States, and about half of them end in abortion. Unintended pregnancy remains a major public health problem, affecting women in all reproductive age groups and socio-economic strata. Greater use of emergency contraception (EC) could theoretically prevent up to 70% of unintended pregnancies (Trussell 1992b).  Use of emergency contraception by American women is still relatively rare for a number of reasons, including generally limited information that this therapeutic option exists and restrictions on availability that limit access. 

 

In 1994, the last year for which complete data are available, 49% of all pregnancies in the U.S. are estimated to have been unintended and 54% of these pregnancies ended in abortion (Henshaw 1998). Abortion rates are highest among women who are aged 18-29, unmarried, low-income, and/or black or Hispanic. In addition, low-income women presenting for abortion are more likely to report problems accessing contraception (Jones 2002b). Based on 1994 data, Henshaw (1998) estimated that American women average 1.4 unintended pregnancies over their reproductive lifetime and that 43% of U.S. women will have an abortion by the time they reach 45 years of age (Henshaw 1998).

 

In addition, the incidence of contraceptive failures should not be underestimated.  More than half (53.7%) of U.S. women presenting for elective abortion were using a method of contraception in the month they became pregnant; of those who were not using a method, most had used contraception in the recent past. Of note, only 1.3% reported using emergency contraception (Jones 2002b).

 

 

1.2.2 Emergency Contraception

 

1.2.2.1 Definition

 

Emergency contraception is a therapy for women who have had unprotected sexual intercourse, including sexual assault or a contraceptive failure.  Pharmacologic methods of emergency contraception have included use of combination or progestin-only oral contraceptives, danazol, synthetic estrogens, conjugated estrogens, and antiprogestins.

 

1.2.2.2 Awareness

 

Levels of awareness regarding emergency contraception remain low, and few women are counseled about the method in advance by their doctors. A nationally representative survey found that just 68% of women aged 18-44 are aware that there is something they can do in the first few days after unprotected sex to prevent pregnancy (Kaiser 2003).  A 2000 survey that probed deeper into women’s “awareness” of emergency contraception found that while 74% of women aged 18-44 surveyed claimed to have heard of the “morning-after” pill, just 27% percent claimed to have heard of “emergency contraceptive” pills.  Furthermore, only 43% responded that emergency contraceptive pills were available in the United States, 30% knew that a prescription was required to obtain emergency contraception, and only 16% understood that emergency contraceptive pills needed to be taken within 72 hours after sexual intercourse (Kaiser 2000).  Another survey of 293 active duty members of a U.S. Air Force base found that while 64% had heard of EC, only 15% knew the correct timeframe for use (van Royen 2000).  A product that is so time dependent cannot be used effectively unless women are educated proactively.  These studies demonstrate that awareness and comprehensive understanding of emergency contraception and its uses is currently inadequate to insure responsible and effective use.

 

These low levels of awareness and knowledge about emergency contraception may, in part, be due to the fact that only 25% of gynecologists and 14% of general practice physicians reported that they talk about this method “always” or “most” of the time (Kaiser 2003a).  This may be due to physicians being too busy to discuss an event that may or may not be relevant for any given patient.  The lack of knowledge about emergency contraception is likely to result in a number of preventable unintended pregnancies, as a recent survey of U.S. women (n=10,683 usable questionnaires) obtaining abortions in 2000-2001 found that just 1.3% of women reported taking emergency contraceptive pills to prevent the pregnancy (Jones 2002b).  Despite the reported rates of unintended pregnancy, another survey from earlier this year found that only 6% of women aged 18-44 reported ever having used emergency contraception (Kaiser 2003b).

 

1.2.2.3 Emergency Contraception – History

 

Over the last several decades a variety of approaches to emergency contraception have been evaluated, including high-doses of estrogen, estrogen combined with progestin, progestin alone, antiprogestational agents and intrauterine devices (IUDs) (Van Look 1993; Glasier 1997).  Ovral® (0.5 mg norgestrel/0.05 mg ethinyl estradiol), a high-dose combined oral contraceptive approved for use in 1968, was a standard product used for emergency contraception in the U.S. from the mid-1970s.  Dosed as 2 tablets (total dose: 1.0 mg norgestrel/0.1 mg ethinyl estradiol) within 72 hours of unprotected sex, followed by another 2 tablets 12 hours after the first dose (total dose: 1.0 mg norgestrel/0.1 mg ethinyl estradiol) (generally referred to as the Yuzpe regimen after its Canadian developer), it was declared a safe and effective regimen by the FDA in 1997.  A combination product based on the Yuzpe regimen, Preven®, was approved by the FDA in 1998.  To date, all approved emergency contraceptive products are available by prescription only.

 

Beginning in the late 1980s, investigators recognized the potential of levonorgestrel as an emergency contraceptive in place of the standard Yuzpe regimen of combined high-dose oral contraceptives (containing estrogen and progestin).  Levonorgestrel has a long history of use in combination oral contraceptives and there are substantial data to support the drug’s efficacy in pregnancy prevention, including the efficacy of elevated doses used postcoitally. Using levonorgestrel 0.75 mg tablets already marketed by Gedeon Richter, Ltd., the World Health Organization (WHO) sponsored two well-controlled studies of levonorgestrel for emergency contraception, both of which were published (Ho 1993, WHO 1998b). The first of these studies was a single-center, randomized trial of levonorgestrel compared with the Yuzpe regimen in women requesting emergency contraception within 48 hours of unprotected intercourse. In this study, levonorgestrel was found to be as effective in preventing pregnancy as the Yuzpe regimen.

 

WHO subsequently conducted a multi-center, randomized, double-blind study (WHO #92908) in order to confirm and expand the findings of Ho et al. (1993). In this study conducted in 14 countries, 1,998 women from a wide variety of racial and ethnic groups participated.  Two separate doses of levonorgestrel 0.75 mg (taken 12 hours apart within 72 hours of unprotected sex) showed greater efficacy when compared with the Yuzpe regimen.  The results indicated that Plan B is 89% effective if used as labeled within 72 hours of unprotected sex. Plan B reduced the risk of pregnancy following a single act of mid-cycle unprotected sexual intercourse from 8%, on average, to 1.1%. The regimen was demonstrated to be more effective if treatment is initiated soon after unprotected sex than if treatment is delayed. Taken within 24 hours of coitus, the regimen reduced the risk of pregnancy by 95%, from about 8% to 0.4%. 

 

Plan B was approved by the U.S. Food and Drug Administration (FDA) in 1999 as a prescription product indicated for use following a contraceptive accident, failure to use a regular contraceptive method correctly or sexual intercourse without contraception, including cases of sexual assault. 

 

1.2.2.4 Emergency Contraception – Worldwide Experience

 

Levonorgestrel has a 40-year history of safe use in combined and progestin-only contraceptives. In addition, there is a 30-year history of clinical research on elevated doses of levonorgestrel for postcoital contraception and 20 years of foreign marketing experience for the 0.75 mg tablet manufactured by Gedeon Richter Ltd., which provide ample evidence of the safety and efficacy of 0.75 mg levonorgestrel tablets in postcoital pregnancy prevention. 

 

The extensive body of efficacy and safety data, from multiple studies by many different investigators, and covering a diverse population of women, provide considerable reassurance that Plan B should remain highly safe and effective in an OTC environment. The levonorgestrel regimen for emergency contraception is currently approved in 101 countries. In 33 of these countries it is currently sold without a prescription, by pharmacists, or OTC.  In Israel, Norway and Sweden, levonorgestrol is available OTC.  In 30 countries, including the UK and France, it is available directly from a pharmacist without a prescription.[1]  Of those countries where Plan B is currently sold without a prescription, the UK, Finland and Switzerland provide access to Plan B with age restrictions.  Clinical trials, medical literature and post-marketing surveillance by regulatory agencies indicate no clinically significant safety problems.  An evaluation of international post-marketing adverse events also shows that “real-life” usage of emergency contraception does not pose any safety concerns. 

 

 

1.2.2.5 Emergency Contraception – Access

 

Since the efficacy of emergency contraception has been found to be significantly affected by the amount of time between the unprotected sex-act and using emergency contraception, rapid access to the method is of critical importance to maximize efficacy.  A pooling of the results for the Yuzpe regimen (estrogen and progestin) of emergency contraception combined with Plan B found that each 12 hours of delay reduces efficacy by about 50% (p=0.02) (Piaggio 1999).  Treatment is completely ineffective once the process of implantation of a fertilized egg is underway, a process that begins within five to seven days after coitus (Grimes 2001, Raman-Wilms 1995, Bracken 1990). 

 

The majority of American women who must seek a prescription from a private physician and then fill it at a pharmacy face even greater barriers to timely use than do clinic populations where emergency contraception is well understood and provided at the time of the visit.  Even in the hospital and clinic setting, Shawe et al. (2001) found that only 4% of women accessing the method at a healthcare facility obtained it in the first 12 hours and only 37% did so in 12-24 hours.  A review of eight other studies found that only 27% to 61% of women accessed the method within 24 hours, 23% to 33% in 24 to 48 hours, and 10% to 25% in 49 to 72 hours (Ashok 2002, Arowojolu 2002, WHO 2002, Roizen 2001, Nanthakumaran 1998, Tydén 1998, Evans 1996, Roberts 1995).  Highlighting problems with access, a recent study from University of California, San Francisco (UCSF) found that 14% of 663 subjects reported wanting to use emergency contraception in the past but not doing so because of: inconvenience (17%), difficulty with the 72-hour limit (11%), the clinic was closed (7%), they did not know where to go (9%), and other reasons (15%) (UCSF 2003b).

 

Another aspect reflecting a logistical barrier to obtaining EC was recently published by Espey et al.  An assessment was performed to determine the immediate availability of prescription emergency contraception (Plan B and Preven) at pharmacies in Albuquerque, New Mexico.  A prescription for either Plan B or Preven was presented at 89 pharmacies and found that neither EC was immediately available at 89% of the pharmacies included in the study.  At those pharmacies where EC was not immediately available, only 53% predicted that they could obtain the product for the patient within 24 hours.  The authors concluded that “lack of availability at the pharmacy constitutes a major barrier to emergency contraception access.” (Espey, 2003)  Thus, any program designed to maximize the efficacy of Plan B must include education about appropriate use of Plan B, education about where and how to obtain Plan B and finally a mechanism to insure availability of Plan B at the pharmacy level.

 


1.2.2.6 Pharmacy Access Programs 

 

While emergency contraceptive pills are still prescription products in the United States, there are currently five states in the U.S. where a woman can walk in to a pharmacy and obtain emergency contraceptive pills without an advance prescription from a prescriber.  These five states are Alaska, California, Hawaii, New Mexico, and Washington State.  The changes made by each state relate to their existing pharmacy practice laws. Some states required legislative change, others required regulatory change, and one state, Washington, needed no formal change in law, but needed to bring about institutional acceptance for this new practice.

 

Pharmacy access to emergency contraception was initiated in 1997 in the United States:  

  • 1997 - Washington State initiated its pilot program, which became a self-sustaining program just two years later. 
  • 2000 - California initiated a pilot program with 70 pharmacies.
  • 2002 - California legislation took effect allowing a statewide effort; Alaska approved its first collaborative protocols allowing pharmacists to dispense emergency contraception.
  • 2003 - New Mexico approved a statewide protocol to allow for pharmacy access; Hawaii passed legislation that will allow women to access emergency contraception directly from a pharmacist as soon as a standardized protocol is developed.

 

A preliminary assessment of the first two months of the pharmacy access program in Washington State found that pharmacy access was key to greater utilization of emergency contraception: 42% of women (n=129) responding to a mail-in questionnaire indicated that without pharmacy access they would simply have waited to see if they became pregnant, and 16% said they did not know what they would have done (Wells 1998); among adolescents (aged 15-21, n=126), 22% would have waited to see if they got pregnant and 20% did not know what they would have done (Sucato 2001).

 

Additional data on adolescents accessing the services (n=126, aged 15-21), found that extended accessible hours to the regimen were utilized, as 45% obtained emergency contraception on the evening and/or the weekend.  In addition, although prior use of the method was common, repeated prior use was not: 32% had used emergency contraception 1 or more prior times, with 10% using it 2 or more prior times, and just 6% using it 3 or more prior times (Sucato 2001).

 

In addition, adolescents did not represent a disproportionate share of consumers accessing emergency contraception directly from a pharmacist in Washington State, as the mean age of women seeking services was 24.5 years, with only 13% under 18 years of age.  Timely access was met, as a review of 991 pharmacy records revealed that 70% of women received emergency contraception within 1 day of unprotected intercourse.  It appears that barriers were also removed, which likely contributed to the timely access, as 20% of respondents reported that they went to a pharmacist because their physician’s office was closed, 7% reported that their regular clinic or physician didn’t prescribe emergency contraception, and 14.8% reported that they had no regular clinic or physician (Downing 2000).

 

1.2.2.7 Potential Impact of Expanded Access to Emergency Contraception

 

1.2.2.7.1 Condom Use

Easier access to emergency contraception does not appear to undermine condom use. Easier access to emergency contraception as a backup (i.e., in the event of condom breakage, slippage, or leakage) may, in fact, allow more women to rely on condoms for both birth control and disease prevention (WCC/FHI 2002, UCSF 2003b, Raine 2000).

 

A number of studies provide information about the effects of emergency contraception on condom use. In the Plan B® OTC Actual Use Study, 10.3% of subjects who reported no condom use before admission were using condoms at follow-up, compared to only 4.7% of condom users who had stopped using the method (WCC/FHI 2002). This result is consistent with the literature. At the three‑month follow-up of 39 women given a Preven® emergency contraception kit to keep at home, 39% of those who had not reported condom use at last intercourse during enrollment did report condom use at last intercourse at the time of follow-up. Just 15% of those who had used a condom at last intercourse at enrollment were not using a condom after three months in the study, suggesting a net gain of 24% in condom use (Roye 2002, Roye 2001). In the 1994–1996 study in Scotland by Glasier et al. (1998) comparing women who received an off-label regimen of emergency contraception in advance with those who had to obtain it from the clinic, there was no difference between the two groups with respect to the use of condoms. A subsequent study of advanced provision by Raine et al. (2000), also using an off-label regimen, showed similar results among low-income minority adolescents and young adults in San Francisco. There was no difference between the advanced provision and clinic access groups with respect to the consistency of condom use at the four-month follow-up.

 

In the UCSF Emergency Contraception Access Study of Plan B (UCSF 2003b), the advanced provision and pharmacy access groups each showed a statistically significant decrease in rates of condom use at last sex from baseline to follow-up (p<0.007 and p<0.001, respectively), while the clinic access group remained relatively consistent over time (p<0.651). In this study, young women at high risk of unintended pregnancy and STI acquisition were given access to three free packages of Plan B.  Condom use at last intercourse was lightly lower in the advance provision group (48.9%) and pharmacy access group (50.6%) than in the clinic access group (55.7%) (p<0.097). No differences were shown, however, in frequency of condom use or current use of condoms. Primary and secondary endpoints were compared for adolescents (15–17 years) and young adults (18–24 years). At follow-up interviews six months (to a year) after enrollment, there were no significant differences between the two age groups in condom use since entering the study (p<0.519), condom use at last intercourse (p<0.933) or current use of condoms (p<0.938).  The impact on condom use was mixed, but adolescents appeared no more likely to modify their condom use than young adults.  In the study by Belzer et al. (2003) of adolescent mothers aged 14-20, also conducted with Plan B, there was no difference in condom use between subjects given Plan B in advance or those who had to return to a clinic setting to receive the product.

 

These and other studies of advanced provision, in which women self‑diagnosed their need for emergency contraception and used it without medical oversight—often many months after receiving counseling—provide further support that Plan B can be used safely, effectively and appropriately without medical supervision.  As noted above, the UCSF results (UCSF 2003b) could suggest that in particularly vulnerable populations prone to risky sexual behavior, easy cost-free access to emergency contraception, through advanced provision or free pharmacy access may increase slightly some types of risk-taking.

 

It cannot be assumed that OTC sale of Plan B in retail pharmacies would have a similar impact, since users would be required to pay for the product.  It is important to note that when compared to routine use of condoms or even oral contraceptives, Plan B is a very expensive form of “routine” birth control.  The cost of repetitive use of Plan B is in and of itself a deterrent to repeated use for most of the population.  The small decreases in consistent condom use observed in the recent UCSF Emergency Contraception Access Study (2003b) were not observed in the Glasier et al. (1998), Raine et al. (2000), or Belzer et al. (2003) studies. The explanation may be that in the Glasier, Raine, and Belzer studies, subjects were given only one course of treatment in advance, while in the UCSF study subjects were given three packages of Plan B in advance or a card allowing them access to up to three free packages at a pharmacy.  Plan B is packaged in single-use packages.  Women will need to consider cost when making their contraceptive choices.  Finally, the CARESM program will actively encourage the use of routine birth control through the distribution of written materials to consumers as well as a hotline and website providing responsible and accurate information.

 

1.2.2.7.2 Sexually Transmitted Infections (STI)

In the UCSF Emergency Contraception Access Study (2003b) comparing advanced provision, pharmacy access and standard clinic access, there was no evidence of a difference in the acquisition of an STI during the study among the three groups.  It is important to note that subjects were given access to three free packages of Plan B.  In the study population as a whole, 22.3% of participants had a history of STIs. During the study, a total of 156 participants (16.7%) acquired an STI (self-reported or by laboratory tests), including: 47 (14.9%) in the advance provision group, 58 (18.5%) in the pharmacy access group and 51 (16.7%) in the clinic access group. The differences were not statistically significant. There were no differences among the three groups when controlling for baseline history of STIs (p<0.427). When primary and secondary endpoints were compared for adolescents (15-17 years) and young adults (18-24 years) at follow-up interviews six months (to a year) after enrollment, there were no significant differences between the two age groups in sexually transmitted disease acquisition (p<0.719). 

 

1.2.2.7.3 Routine Birth Control Use

Studies also show that women with access to EC typically do not abandon regular contraception or use their chosen method less consistently.  A growing body of literature suggests that women with easier access to EC are more likely to use EC following an occasional episode of unprotected sex than women who must visit a clinic or doctor’s office for a prescription (Glasier 1998c, Raine 2000, Belzer 2003, Jackson 2003, Ellertson 2001a), but they are generally not more likely to abandon regular contraception (Belzer 2003, Jackson 2003, UCSF 2003b). Women who use EC following a pregnancy scare may actually be more likely to use an effective ongoing contraceptive method afterwards (Riain 1998, Rowlands 2000).  A number of studies also provided evidence that advanced provision did not increase the incidence of unprotected sex (Raine 2000, Belzer 2003, Jackson 2003).

 

The availability of Plan B in community pharmacies along with an appropriate and responsible education program will help raise awareness of emergency contraception and encourage its appropriate use.  Once women are educated about emergency contraception in the context of providing a clear understanding of how it fits into a responsible contraceptive strategy, eliminating the need for a prescription provides for more direct and timely access in the event of a contraceptive emergency.  Thus, the change to OTC availability of Plan B should not encourage the inappropriate use of this product but with responsibly designed educational and marketing programs, will maximize efficacy and thereby decrease the incidence of unintended pregnancies and potentially abortion.

 

1.2.3 Plan B: Post-Marketing Safety Experience

 

Plan B has been marketed as a prescription drug product in the U.S. since 1999.  During the most recent reporting period, 28 July 2002 to 27 July 2003, WCC received 216 initial post-marketing Adverse Drug Experience (ADE) reports containing 327 adverse events.  No deaths were reported.  These 216 reports included 191 nonserious and/or labeled events from the U.S. and 25 serious adverse events from the U.S. and Chemical Works of Gedeon Richter, Ltd. (Gedeon Richter), which markets levonorgestrel tablets in 40 countries worldwide, the Canadian Adverse Drug Reaction Monitoring Program (CADRMP), and the published literature. 

 

Table 1 lists the serious adverse event reports received during the reporting period.  The 25 serious adverse event reports included 35 adverse events.  Although the possibility of ectopic pregnancy is described under the warning section in the labeling for Plan B, ectopic pregnancies were considered serious adverse events and were reported to the FDA. 

Table 1: Plan B Serious Adverse Events 28 July 200227 July 2003

Event Description

Preferred Term(s)

Date Submitted

Ectopic pregnancy

Ectopic pregnancy

9/11/2002

Benign dermoid cyst, Ectopic pregnancy

Benign ovarian germ cell teratoma, Ectopic pregnancy

9/11/2002

Ectopic pregnancy

Ectopic pregnancy

9/11/2002

Ectopic pregnancy

Ectopic pregnancy

10/9/2002

Ectopic pregnancy

Ectopic pregnancy

11/12/2002

Ectopic pregnancy

Ectopic pregnancy

11/12/2002

Congenital anomaly

Congenital anomaly

12/9/2002

Itching, rash, hives

Itching, rash, hives

2/19/2003

Ectopic pregnancy

Ectopic pregnancy

3/6/2003

Unintended pregnancy, spontaneous abortion

Unintended pregnancy, abortion

3/6/2003

Ectopic pregnancy

Ectopic pregnancy

3/6/2003

Ectopic pregnancy

Ectopic pregnancy

3/18/2003

Fetus detached from uterine wall

Abruptio placentae

4/2/2003

Unintended pregnancy

Unintened pregnancy

4/16/2003

Ectopic pregnancy

 Ectopic pregnancy

4/16/2003

Unintended pregnancy, hospitalization after spot bleeding, induced abortion

 Unintended pregnancy, antepartum hemorrhage, induced abortion

5/6/2003

Ruptured tubal pregnancy

 Ruptured tubal pregnancy

5/21/2003

Right ruptured tubal pregnancy

Ruptured tubal pregnancy, vaginal bleeding

5/21/2003

Possibility of a right-sided ectopic pregnancy

 Abdominal pain, nausea, right ectopic pregnancy

5/21/2003

Unintended pregnancy, miscarriage

 Unintended pregnancy, missed spontaneous abortion

5/21/2003

Ectopic pregnancy, ovarian cystectomy

 Ectopic pregnancy

7/11/2003

Unintended pregnancy

 Unintended pregnancy

5/21/2003

Unintended pregnancy, premature rupture of membrane

Unintended pregnancy, caesarean section

5/28/2003

Ectopic pregnancy

Ectopic pregnancy, laparotomy, salpingectomy

5/28/2003

Ectopic pregnancy

Ectopic pregnancy

7/14/2003

The adverse events received by WCC (362 events in 216 reports) and all the serious adverse events (numbering 35 events in 25 reports) are summarized in the following table by WCC Preferred term (Table 2).

 


Table 2: Summary of Adverse Events by Body System

 

Preferred Term

Non-serious Events

 

15-Day Alert Events

Number of  Reported Events

Percentage of Total Events

Body as a Whole

Fatigue/asthenia

15

4.6

 

Cardiovascular System

 

 

 

Irregular rapid pulse

1

0.3

 

Gastrointestinal System

Nausea

34

10.4

1

Vomiting

8

2.5

 

Diarrhea/loose stools

7

2.1

 

Bloating/water retention

5

1.5

 

Stomachache

2

0.6

 

Metallic taste in mouth

1

0.3

 

Appetite loss

1

0.3

 

Neurological System

Headache

11

3.4

 

Dizziness/lightheaded

9

2.8

 

Emotional changes

2

0.6

 

Irritability

1

0.3

 

Shakiness in hands

1

0.3

 

Twitching in right eye

1

0.3

 

Blurred vision

1

0.3

 

Respiratory System

Labored breathing

1

0.3

 

Return of asthma symptoms

1

0.3

 

Dermatological

Rash/hives

3

0.9

1

Acne

1

0.3

 

Itching

3

0.9

1

Musculoskeletal System

Back pain

2

0.6

 

Mylagia

1

0.3

 

Genitourinary System

Menstrual irregularities

98

30.0

1

Abdominal pain/cramping

47

14.4

1

Unintended pregnancy

30

9.2

6

Preferred Term

Nonserious Events

15-Day Alert Events

Number of  Reported Events

Percentage of Total Events

Breast tenderness/pain

22

6.7

 

Ectopic pregnancy

 

 

16

Vaginal discharge

5

1.5

 

Vaginal pain

2

0.6

 

Abortion

 

 

3

Galoctorrhea

1

0.3

 

Urinary frequency

3

0.9

 

Hematuria

2

0.6

 

Urinary urgency

2

0.6

 

Congenital anomaly

 

 

2

Ovarian cyst

2

0.6

1

Dysuria

1

0.3

 

Abruptio placentae

 

 

1

Antepartum hemorrhage

 

 

1

TOTAL:

327

 

35

 

Post-marketing pharmacovigilance has not identified any unexpected adverse events.  Most adverse events reported were not life-threatening.  The only serious adverse event reported multiple times was ectopic pregnancy.  Ectopic pregnancy is included in the warning section of the label but is not thought to be associated with the use of Plan B.

 

1.2.3.1 Ectopic Pregnancy

 

The incidence of ectopic pregnancy in the United States general population is 2% of all pregnancies.  In routine (i.e., daily) users of progestin-only oral contraceptives, up to 10% of the pregnancies that occur are ectopic. This incidence is higher than with most other contraceptive methods (McCann and Potter 1994). Although the mechanism is uncertain, it may be due to the decreased activity of the fallopian tube cilia and changes in tubal motility that interfere with the transport of the ovum. 

 

There does not appear to be an increased risk of ectopic pregnancy with use of
Plan B. In clinical studies including more than 11,000 women who used Plan B for postcoital contraception there were 3 reported ectopic pregnancies of a total 198 pregnancies giving an ectopic pregnancy rate of 1.5%. 

 

Additional reports of ectopic pregnancy with use of Plan B have been received from the post-marketing setting.  The number of ectopic pregnancies is high compared to the number of unintended pregnancies reported to pharmacovigilance authorities. This is probably due to less reporting of unintended pregnancy because it is not usually considered a serious or unexpected adverse event, but a product failure. Ectopic pregnancies are much more likely to be reported than intrauterine pregnancies, since they are abnormal and thus more likely to be considered an adverse event. 

 

These data suggest no increased risk of ectopic pregnancy for levonorgestrel emergency contraception.  In addition, the proposed Plan B OTC label cautions women to be alert for symptoms of associated with ectopic pregnancy and to see their healthcare professional should any of these symptoms arise. 

 

In summary, post-marketing surveillance data support the safety and efficacy of Plan B as a prescription drug product.  Most adverse events were nonserious and not life-threatening.  Based on exposure, the incidence of ectopic pregnancy should not be expected to exceed that seen in the general population.  Based on existing safety data, the change from prescription to OTC availability for Plan B is not anticipated to have an adverse impact on the safety profile.

 

1.2.4 Plan B: Rx-to-OTC Switch

 

On 16 April 2003, Women’s Capital Corporation (WCC) submitted a Supplemental New Drug Application (sNDA) to change the status of Plan B from prescription only to OTC.  Two studies to support an Rx-to-OTC switch were developed through a highly interactive process with the FDA OTC Division.  The OTC Label Comprehension Study was undertaken to evaluate the ability of women to understand the instructions for use after reviewing a prototype OTC label (Appendix 3).  Since the dose and dosing regimen in the sNDA proposed labeling are identical to the approved prescription-only labeling, the goal of this study was to determine whether the proposed OTC labeling could be understood by the patient without medical screening or counseling from a healthcare professional.

 

The second study supporting the Rx-to-OTC sNDA was the OTC Actual Use Study, designed to provide information on the ability of the target population to self-select and appropriately use Plan B when labeled for OTC distribution.  The primary objective was to estimate the frequency of contraindicated and incorrect uses of Plan B when dispensed under simulated OTC conditions.  Repeat and prior use of emergency contraception, the impact of emergency contraception on regular contraceptive use, pregnancy and pregnancy outcome, and reports of adverse events were also evaluated in this study.

 

These two studies conducted to support the Rx-to-OTC switch provide substantial evidence that women (1) can self-diagnose their need for emergency contraception; (2) can understand the directions for use of an emergency contraceptive product; and (3) can self-administer the product in a manner likely to be safe and efficacious without medical screening or counseling from a healthcare professional
(see Section 4).

 

Plan B’s Rx-to-OTC switch is supported by leading U.S. medical organizations who agree that the current prescription requirement creates a major barrier to timely access and who agree that the levonorgestrel regimen is safe, easy to use and, if used quickly, highly effective in preventing pregnancy.  In addition, there is no evidence that levonorgestrel would harm a pregnant woman or a developing fetus if the product is taken accidentally during early pregnancy (Grimes 2001, Raman-Wilms 1995, Bracken 1990).  A number of organizations have passed resolutions in support of OTC status, including the American College of Obstetricians and Gynecologists, the American Academy of Family Physicians, the American College of Nurse-Midwives, the American Medical Association, the Association of Reproductive Health Professionals, the National Medical Association, and Physicians for Reproductive Choice and Health.  In addition, over 70 organizations have petitioned FDA to remove the prescription requirement for emergency contraception (CRLP 2001).

 

Barr proposes to support the OTC distribution of Plan B with the CARESM Program (Convenient Availability Responsible Education, see Section 6).  This program focuses on education at all levels in concert with increased availability at the pharmacy level.  This program has several major components intended to increase awareness about the appropriate and responsible use of Plan B, while insuring availability of Plan B at the pharmacy.  Education programs will be targeted to healthcare providers and consumers through their healthcare provider.  Barr recognizes that in order to responsibly sell and market this product, it is essential to provide education and increase availability without encouraging risky behavior.  Thus, the intent of the CARESM program is to insure that women are aware of Plan B, know how and when to use it, and understand how to easily obtain it in the most expeditious manner.  More detail is provided on the CARESM program in Section 6.

 

2 CLINICAL Pharmacology of Levonorgestrel – MECHANISM OF ACTION

 

It is likely that levonorgestrel emergency contraception, like other systemic methods of contraception, works in several different ways, depending on the cycle day of unprotected sex and the cycle day of treatment (Croxatto 2002d, see Appendix 1). The only mechanism of action that has been clearly demonstrated to prevent pregnancy is the impact of emergency contraception on the ovulatory process (Croxatto 2002d, Müller 2002, Croxatto 2002b, Trussell 2002, 2003c). In addition to suppressing or delaying ovulation, the drug may compromise the ovulatory process to the degree that fertilization is not possible, or interfere with sperm migration and function (Croxatto 2002d, Yeung 2002).

 

Text Box: Figure 1: Probability of Conception on Specific Days Near the Day of Ovulation (Wilcox 1995)
 
There are only six fertile days in the menstrual cycle – that is, days in which an act of sexual intercourse can give rise to pregnancy. These are the day of ovulation and the five preceding days (Figure 1, Wilcox 1995). Thus, in most cases spermatozoa spend one to five days in the female genital tract before encountering the ovum. This interval provides an opportunity to interfere with the migration and function of the sperm and/or with the process of ovulation. Emergency contraceptive pills may prevent the encounter of spermatozoa with the ovum; and, even if the two gametes do come in contact, fertilization may not proceed to completion.  (Croxatto, 2002d)

 

In human beings, fertilization is not very efficient: in ideal circumstances, when intercourse takes place during the most fertile days, the chance that fertilization will take place does not exceed 50%. On average, in couples not using any method of birth control, the chance of conception during any one cycle is approximately
25-30%.  Even with daily intercourse, most ovulatory menstrual cycles may be incapable of producing a conception (Wilcox 1995), as other factors (such as age) apparently have a strong role in determining fertility.  It is plausible that even minor alterations in reproductive processes will greatly lessen the likelihood of pregnancy. This possibility has been explored experimentally in a few studies, and emergency contraceptive pills have been shown to interfere with pre-fertilization events (Croxatto 2002d).

The only mechanism of action that has been clearly demonstrated to prevent pregnancy is the impact of emergency contraception on the ovulatory process (Croxatto 2002d, Müller 2002, Croxatto 2002b, Trussell 2002, 2003c). Current understanding of ovulation is that a mid-cycle surge of luteinizing hormone from the pituitary acts on a follicle in the ovary, setting into motion a series of coordinated events, and resulting in release of an oocyte and transformation of the empty follicle into the corpus luteum.  When the normal luteinizing hormone surge or any of the subsequent events is altered, the result can be ovulatory dysfunction and compromised fertilization.  Depending on the timing of the administration relative to the luteinizing hormone surge, levonorgestrel inhibits or postpones this luteinizing hormone surge, inhibits or postpones rupture of the follicle, interferes with the formation of the corpus luteum, or has no effect on these indices. (Croxatto 2002d)

 

Through the above mechanisms, levonorgestrel emergency contraception pills given during the preovulatory phase of the menstrual cycle have the capacity to interfere with the ovulatory process by suppressing or delaying ovulation.  Additionally, even if ovulation does occur, the drug may compromise the ovulatory process to the degree that fertilization is not possible.  Another mechanism by which levonorgestrel may work is by interfering with sperm migration and function. Interference with the fertilization process has not been directly demonstrated for levonorgestrel emergency contraception (Croxatto 2002d, Yeung 2002).

 

Sperm migration in women occurs in two phases. In the first phase, a few minutes after insemination some spermatozoa, aided by propulsive contractions of the genital tract, reach the fallopian tube. In the second phase, over several days, spermatozoa that have been stored in the crypts of the uterine cervix migrate in successive cohorts towards the fallopian tube. Only those from the second phase have the ability to fertilize.  Administration of levonorgestrel 3-10 hours after sexual intercourse has been shown to affect sperm migration between 3 and 9 hours after treatment. It reduced the number of spermatozoa recovered from the uterine cavity, increased the pH of the uterine fluid (which immobilized spermatozoa), and increased the viscosity of cervical mucus (which impeded further passage of sperm cells into the uterine cavity) (Kesserii 1974). Although the dose of levonorgestrel in this study was only 57% of the current levonorgestrel dosage, these results are highly relevant to the actions of levonorgestrel when administered as an emergency contraceptive.  If ovulation occurs after a woman has taken levonorgestrel, interference with the sustained phase of sperm migration could well reduce or eliminate the probability of fertilization. (Croxatto 2002d)

 

Levonorgestrel alters the endometrium to varying degrees depending on dose.  The impact of these endometrial changes on implantation is unclear.  There is little direct evidence that prevention of implantation is a mechanism of action for levonorgestrel emergency contraception (Croxatto 2002d, Ugocsai 2002, Kahlenborn 2002).  Alterations in endometrial receptivity that could interfere with implantation have been investigated, but only indirectly.  Some studies have found alterations in endometrial morphology or in the expression of certain progesterone-dependent molecules.  Whether such changes have a deleterious effect on endometrial receptivity is questionable.  Other studies have found either negligible alterations or none, and in the case of levonorgestrel, existing evidence does not support the hypothesis that it alters endometrial receptivity or impedes implantation. (Croxatto 2002d)

 

Overall, the available data suggest that the primary mechanisms of action likely interfere with the ovulatory process.  Since most of the risk of pregnancy is concentrated in the days leading up to and including the day of ovulation and since a direct effect on the process of ovulation has been demonstrated, it is likely that Plan B works primarily and perhaps exclusively prior to fertilization. The fact that emergency contraception is more effective the sooner it is used would also argue against important post-fertilization modes of action (Trussell 2003c, Croxatto 2002d).

 


3 Well-Controlled, COMPARATIVE, Clinical STUDIES OF 0.75 MG LEVONORGESTREL for Emergency Contraception (NOT SPECIFICALLY DESIGNED TO SUPPORT AN Rx-to-OTC SWITCH)

 

3.1 Summary of Comparative Clinical Efficacy Studies of 0.75 mg Levonorgestrel for Emergency Contraception from NDA 21-045

 

Two well-controlled studies were presented and summarized in NDA 21-045 (approved in July 1999). These randomized trials evaluated a two-dose regimen of levonorgestrel 0.75 mg tablets compared to the older Yuzpe regimen of combined high-dose oral contraceptives (Table 3) — the standard for emergency contraception at the time.

 

Table 3: Well-Controlled Comparative Clinical Studies Previously Submitted in NDA 21-045

Study

Regimens

Number of Subjects Included in Analysis

Design*

WHO #92908

(WHO 1998b)

- Two doses of   0.75 mg LNG 12 h apart

- Two doses of  EE 0.05 mg + NG 0.50 mg 12 h apart (Yuzpe)

976

 

979

 

AC, DB, MC, R

Ho et al.

(1993)

 

- Two doses of   0.75 mg LNG 12 h apart

- Two doses of EE 0.05 mg + NG 0.50 mg 12 h apart (Yuzpe)

410

 

424

AC, R, SC

 

 

* Abbreviations used in this table: AC=Active Control, DB=Double-Blind, EE= Ethinyl Estradiol, LNG=Levonorgestrel, MC= Multi-Center, NG=Norgestrol, R=Randomized, SC=Single-Center

 

The pivotal Plan B clinical study for NDA 21-045 was designed, coordinated, monitored and analyzed by the WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO #92908, WHO 1998b). It was conducted between 1995 and 1997 at 21 clinical sites in 14 countries on five continents. The earlier Ho et al. (1993) study was conducted at the Family Planning Association of Hong Kong.

 

In the pivotal multi-center study, 31 women (3.2% of the efficacy population) became pregnant in the Yuzpe group and 11 (1.1% of the efficacy population) became pregnant in the levonorgestrel group (Table 4). The crude relative risk of pregnancy (levonorgestrel/Yuzpe) was 0.36 (95% confidence intervals: 0.18–0.70). The Breslow-Day test of homogeneity across centers provided no evidence of a difference in ratios between centers. Since the upper one-sided 95% confidence bound levonorgestrel/Yuzpe was 0.70, which is less than 1, the levonorgestrel regimen was deemed to be more effective than the standard Yuzpe regimen.

 

Table 4: Efficacy Results for Comparative Clinical Trials from NDA 21‑045 (WHO #92908, WHO 1998b, Ho 1993)

 

WHO #92908

(WHO 1998b)

Ho et al.

(1993)

Levonorgestrel Group

Number of women

976

410

Number of pregnancies

11

12

Pregnancy rate in %

1.1

2.9

Number of observed/expected pregnancies§

11/76.3

8/19.8*

Prevented fraction in %

86

60

Yuzpe Group

Number of women

979

424

Number of pregnancies

31

15

Pregnancy rate  in %, (95% CI)**

3.2 (2.2, 4.5)

3.5

Number of observed/expected pregnancies§

31/74.2

9/22.0*

Prevented fraction in %, (95% CI)**

58 (41, 72)

59*

Comparison of Levonorgestrel to Yuzpe

Relative risk levonorgestrel/Yuzpe, (95% CI)**

0.36 (0.18–0.70)

--

 

  §    Expected pregnancies calculated using Dixon’s expected probabilities of pregnancy by cycle day.

 *  Among 331 women (levonorgestrel group) and 341 women (Yuzpe group) who had reliable menstrual dates.

** Abbreviation used in this table: CI=Confidence Interval

 

Significantly higher pregnancy rates were noted among women who delayed taking the treatment for two or three days after intercourse when the results from both the levonorgestrel and Yuzpe arms were combined (Piaggio 1999). This finding is biologically plausible: the longer the treatment is delayed, the more likely it is that the woman would have become pregnant at which time treatment is ineffective. These studies provide evidence of the high efficacy of Plan B, taken according to the currently approved labeling.

3.2 Controlled Studies of the Plan B Levonorgestrel Regimen for Emergency Contraception Since the Submission of NDA 21-045

 

Three other studies of the Plan B levonorgestrel regimen for emergency contraception have been completed since the submission of NDA 21-045 and a fourth study is undergoing final analysis:

1.     The Wu et al. (1999) study comparing the efficacy of two doses of 0.75 mg levonorgestrel with one 10 mg dose of mifepristone in 1,276 women

2.     The Arowojolu et al. (2002) study comparing the efficacy of two 0.75 mg doses with a single dose of 1.5 mg in 1,118 women at two sites in Nigeria

3.     The WHO (2002) multi-center study comparing the efficacy of two 0.75 mg doses with a single dose of 1.5 mg and a single dose of 10 mg mifepristone in 4,071 women at 15 sites in 10 countries

 

Two of the three studies, Arowojolu et al. (2002) and the multi-center international study conducted by WHO (2002) were designed, in part, to test alternate dosing regimens.  The new studies completed since the submission of NDA 21-045 support the high efficacy of levonorgestrel for emergency contraception.

 

4 Studies Supporting the OTC Distribution of Plan B

 

4.1 Overview

 

Plan B was approved by the FDA for marketing as a prescription product on 28 July 1999.  The proposed change in this supplement to the NDA is a prescription (Rx) to OTC switch for the use of Plan B as emergency contraception.  The dosage and instructions for use will remain the same, although the package and package insert have been modified to suit an OTC environment. 

 

The two OTC studies sponsored by WCC -- the Plan B OTC Label Comprehension Study and the Plan B OTC Actual Use Study (Table 5) -- were designed, coordinated and monitored by Family Health International (FHI).  These studies were designed to evaluate whether Plan B can be used safely and effectively without oversight by a licensed medical practitioner.  The Label Comprehension Study was conducted first to evaluate an OTC label prototype and women’s ability to understand the instructions for use (WCC/FHI 2001). The study was recently published (Raymond 2002a).  The ensuing modified label prototype was used for the Actual Use Study.

 

Table 5: Sponsor Studies Supporting OTC Distribution of Plan B

Study

Rationale

Number of Subjects

Recruited

Design*

Plan B OTC Label Comprehension Study

(WCC/FHI 2001; Raymond 2002a)

This study was designed to evaluate comprehension of the prototype OTC package label for Plan B.

663

 

(656 in analysis)

MC, OL

Plan B OTC Actual Use Study

(WCC/FHI 2002)

This study was designed to provide information on the ability of the target population to self-select and appropriately use Plan B when labeled for OTC use. The primary objective was to estimate the frequency of contraindicated and incorrect uses of Plan B when dispensed under simulated OTC conditions. Secondary objectives were to estimate the incidence of repeat use, pregnancy and adverse events.

665

 

(540 in efficacy analysis)

MC, OL

 

* Abbreviations used in this table: MC=Multi-Center, OL = Open Label, OTC = Over-The-Counter

 

As agreed upon at the meeting held on 5 February 2001 with the FDA Division of Reproductive and Urologic Drug Products (DRUDP), the Division of Over-the-Counter Drug Products and representatives of WCC, the Plan B OTC Actual Use Study was considered the pivotal study and its results are the primary source of data to support the Rx-to-OTC switch.  When used according to instructions, the approved dosage and regimen have been judged safe and effective by the FDA.  Therefore, the Actual Use Study was designed primarily to show that women could use the product appropriately and according to directions, without counseling or medical oversight. (A discussion of the study design can be found in Section 4.3.1 below).

 

The proposed OTC product labeling was developed according to current FDA content and formatting requirements (21 CFR 201.60–201.66) and was written to be understood by women of low literacy. Important efficacy information from the prescription product labeling is addressed in the proposed OTC labeling.

The OTC label used in the Label Comprehension Study was revised based on the results of that study, and the revised label was then used in the Actual Use Study (see Appendix 4).  The Actual Use Study OTC label was then submitted as part of
the sNDA.

 

On 15 October 2003, WCC submitted an amendment to the Rx-to-OTC sNDA application in response to an oral request from FDA made on 26 September 2003.  At that time, FDA requested a copy of the OTC prototype labeling from the Label Comprehension Study, the Actual Use Study, and the proposed commercial labeling.  These labels appear in Appendices 3, 4, and 5, respectively. 

 

Changes between the Actual Use Study prototype and the proposed OTC commercial labeling were:

·           The percentages listed for the incidence of side effects were removed, consistent with other OTC labeling. 

 

·           The statement on unusual vaginal bleeding appeared in the Warning section of the Plan B package for the Label Comprehension and Actual Use studies and in the proposed OTC product package.  A second statement concerning unusual vaginal bleeding was moved from the contraindications to the side effect section of the proposed OTC product package.

 

The package proposed in the sNDA is a 3¼² ´ 3² package (see Appendix 5).  Although the changes described above were made to the proposed OTC package, the size of the package studied was identical in both the Label Comprehension and Actual Use studies to that proposed for marketing in the sNDA. 

 

The sponsor is now proposing to insert this 3¼² ´ 3² package into a larger outer package.  The larger outer package will have identical labeling to the smaller inner package but in a larger and thus more legible font.  A package insert will also be included in the larger package.  Additional consumer-tested information will also be enclosed in the larger package.  Information on Plan B, its appropriate use, sexually transmitted diseases, and routine forms of birth control are proposed for inclusion.  Rough drafts of some of this additional information (not yet studied in the target population) appear in Appendix 7.  In addition, a card designed for the patient to record the time of the first dose and the projected time of the second dose will be provided. 

 

4.2 Plan B OTC Label Comprehension Study

 

4.2.1 Overview and Study Design

 

Prototype labeling for the Plan B OTC product was evaluated in the Label Comprehension Study (WCC/FHI 2001). The study took place in malls and family planning clinics in eight geographically representative U.S. cities between 18 June and 12 July 2001.  Every effort was made – including the use of enrollment quotas based on demographics – to enroll a target population that was highly diverse and adequate for subgroup analyses among all groups in the general population likely to be represented in the OTC population of Plan B users.  The focus of this study was to determine the proportion of subjects who demonstrated “understanding” of eleven prospectively defined communication objectives developed with the FDA that were thought to be important for safe and effective use of Plan B. These objectives addressed indications for use, contraindications, instructions, possible side effects, and management of serious complications of use.  All eleven communication objectives were defined prior to study initiation.  The results of the study were published (Raymond 2002a).

 

The eleven communication objectives were developed by consensus of WCC, FHI, and consultants.  The FDA had many comments and suggestions, particularly on the individual questions; most were incorporated.  Results of informal and formal pretests of the questionnaire were also considered in the finalization of the questions. 

 


The table that follows summarizes the definition used to define each communication objective.

Communication Objective

Responses that operationally define comprehension of the objective

1.      Plan B® is indicated for prevention of pregnancy after unprotected sex.

at least two of the following:  7, 14, 16, 19

2.      Plan B® is intended as a back up method and should not be used for regular contraception.

at least three of the following:  9, 21, 22, 25

3.      Plan B® does not prevent sexually transmitted diseases or HIV/AIDS.

13 and 27

4.      The first pill should be taken within 72 hours after intercourse. 

at least two of the following: 10 (if response  mentions 72 hours or 3 days), 29, (19 and 20)

5.      The first pill should be taken as soon as possible after intercourse.

10 (if response mentions as soon as possible) or 26

6.      The second pill should be taken 12 hours after the first.

30

7.      Plan B® should not be used by women who are already pregnant (because it will not be effective).

11 or 17

8.      Plan B® should not be used by women with unexplained vaginal bleeding

15

9.      Plan B® should not be used by women with allergy to any ingredient in the product.

18

10.    Side effects of Plan B® include nausea and vomiting.

(32 and 34) or nausea/vomiting mentioned in answer to 37, unless she answered "yes" to all of 32-36

11.    If severe abdominal pain develops, the user should seek medical care immediately.

31

 

A total of 663 interviews were conducted in the Label Comprehension Study.  To be eligible, subjects had to self-report that they were able to read English well enough to read an OTC product label. They also could not have a marketing or healthcare background or have previously participated in this study. Of those interviewed, 656 women between the ages of 12 and 50 met the inclusion criteria and were included in the analysis. Of the seven women not considered eligible, 3 were more than 50 years old, 2 did not read English, one had a healthcare/marketing background, and one provided missing data for all of the five questions regarding eligibility.  This resulting number of eligible subjects exceeded the target sample size of 575.  The target sample size was established to make possible the determination of the proportion of women who understood each communication objective with a 95% confidence interval (conservatively assuming that the proportion would be 50%).  The target also reflected advice from the FDA on the usefulness of subgroup analyses.  Most subjects (582; 89% of the total eligible subjects) were enrolled at malls.  The other 73 (11%) were enrolled at clinics.  Clinics were included because the ethics board of FHI required that minors enrolled at malls have parental consent to participate in the study.  This requirement was waived at clinics because minors can receive clinical services in that setting without parental consent.

 

4.2.2 Survey Overview

 

A standardized questionnaire was used to precisely guide conduct of the survey for each subject (see Appendix 2).  As described in detail below, a series of standardized questions were asked in a specific order after the subject had the opportunity to inspect or refer to various portions of the prototype OTC Plan B package
(see Appendix 2).  Answers to all open-ended questions were recorded verbatim and subsequently categorized (e.g., see Appendix 6).  Correct answers were prospectively defined.  At the suggestion of the FDA, “acceptable” answers to some questions were also defined (see Appendix 2).  Verbatim responses were categorized as acceptable before tabulation of results.

 

4.2.3 Survey Procedure

 

For the survey, each subject was given a prototype OTC Plan B package (see Appendix 3). Each woman was instructed first to look at the outside of the package (i.e., Appendix 3, Panels 1 and 13) as if she were thinking about whether to purchase the product in a pharmacy.  The subject was instructed to “take as much or as little time as you normally would in a drugstore.”  The package was retrieved, and the interviewer asked the subject to respond from memory to the following question “Without looking at the label, tell me what Plan B is used for?” (Question 7, see Appendix 2).

 

The package was then returned to the subject, and she was permitted to inspect the outside (i.e., Appendix 3, Panels 1 and 13), while the interviewer asked Questions 8-12 (see Appendix 2).

 

The subject was then told to open the package and review it as if she were about to use the product at home. She was permitted to refer to the entire label while the reviewer asked Questions 13-37 (see Appendix 2). The questions were both multiple choice and open‑ended.  After completing the product questionnaire, the interviewer recorded demographic information about the subject.  Finally, the subject was asked to complete a self-administered questionnaire about her sexual and contraceptive history.

 

4.2.4 Study Population

 

The socio-demographic characteristics of the 656 subjects who were analyzed in the Label Comprehension Study are summarized in Table 6.  Statistics are presented alongside the comparable distribution of women in the U.S. population.  Enrollment quotas were set to ensure that the study population included representative numbers of women with characteristics of particular interest (e.g., 17-25 years old). These quotas were based on a review of census data on the demographic characteristics of U.S. women of reproductive age and the desire to include sufficient women for subgroup analyses. 


 

Table 6: Socio-Demographic Characteristics of the Eligible Population in the Plan B OTC Label Comprehension Study

Demographic Breakdown

Label Comprehension Study Number of Women (%)

U.S. Women     (Age 12-50)*

Age (years)

12-16

76 (11.6)

12.3%

17-25

355 (54.1)

21.4%

26-50

225 (34.3)

66.3%

Race

Asian or Pacific Islander

30 (4.6)

4.4%

American Indian or Alaska Native

6 (0.9)

1.0%

Black

155 (23.6)

13.5%

White

324 (49.4)

72.8%

Other

115 (17.5)

¾

Refused/Missing

26 (4.0)

¾

Marital Status

Single

487 (74.2)

¾

Married

143 (21.8)

¾

Divorced

17 (2.6)

¾

Widowed

8 (1.2)

¾

Refused/Missing

1 (0.2)

¾

Ethnicity

Hispanic

154 (23.5)

13.1%

Not Hispanic

500 (76.2)

86.9%

Refused/Missing

2 (0.3)

¾

Highest Level of Education**

6th Grade or less

4 (0.6)

2%

7th - 8th Grade

26 (4.0)

3%

9th - 12th Grade (not completed high school)

148 (22.6)

14%

Completed high school or GED

199 (30.3)

28%

Vocation/Techical school

18 (2.7)

ND

Less than 4 years of college

117 (17.8)

29%

Completed college

105 (16.0)

17%

Graduate school

37 (5.6)

2%

Refused/Missing

2 (0.3)

ND

 

 *   Data is from the U.S. Census 2000.

**  Data from U.S. population include women age 15-54

ND = Not Done

 


Almost 12% of participants were between the ages of 12 and 16 years, a figure comparable to their proportion in the U.S. population of women, aged 12–50. Consistent with the aims of the Label Comprehension Study to enroll a sample of subjects most consistent with the primary target population expected to use Plan B, the proportion of women in the study age 17-25 was more than twice the proportion in that age group who make up the U.S. population. Black and Hispanic women were also over-represented relative to the general American population in an effort to ensure a study sample that reflected a heterogeneous cross-section of ethnicity.  The study also included overall a higher proportion of women with lower education than the general population. 

 

Subjects were seen at four clinics (N=73 subjects) and eight shopping malls (N=583 subjects).  Table 7 summarizes the distribution of subjects by age group who were seen in mall and clinic settings:

 

Table 7: Distribution of Eligible Subjects Seen at Mall and Clinic Settings, by Age Group

 

Age Group (in Years)

Study Setting

12-13

14-16

17-25

26-50

Mall (N=583)

2.7%

9.4%

51.3%

36.5%

Clinic (N=73)

1.4%

5.5%

76.7%

16.4%

 

As expected, subjects 17-25 years of age were represented to a larger proportion (76.7%) at clinics than at malls (51.3%).  This was almost certainly a result of the fact that women coming to clinics tended, in general, to be in 17-25 year old age group, as many of the clinics were situated near college campuses and this is the age group that clinics tend to draw from.  Note that the percentages associated with each distribution in the table above should be viewed with some caution, as the number of subjects seen at clinics is just 11% of the total number of eligible subjects seen in the Label Comprehension Study.

 

Study participants were likely users of an OTC product for emergency contraception given their sexual and contraceptive history (Table 8).  More than three-quarters (79%) of the women who responded to the sexual history questionnaire were sexually experienced; and, of these, most (71%) had experienced unprotected intercourse despite a desire not to become pregnant.  More than two-thirds had worried about an unintended pregnancy at some time in the past (70%).  More than half of subjects who had used oral contraceptive pills reported having missed taking pills and 40% of those who had used condoms had experienced a condom break. However, only 32 (6%) of the sexually experienced subjects had ever previously used emergency contraceptive pills.

 

Table 8: Contraceptive History of the Eligible Population in the Plan B OTC Label Comprehension Study

Sexual and Contraceptive History

Number (%)* Who Responded

Ever had sex

474 (79)

Had sex in past 3 months

383 (82)

Ever used ECPs

32 (6)

Ever used condom

410 (89)

Ever had condom break (of those who ever used a condom)

155 (40)

Ever used oral contraceptive pills

284 (61)

Ever missed oral contraceptive pill (of those who ever used oral contraceptive pills)

159 (57)

Ever used spermicide

89 (18)

Ever used injectable

83 (17)

Ever used withdrawal

204 (43)

Ever used rhythm

40 (8)

Ever used other method

54 (11)

Ever had unprotected sex but did not want pregnancy

314 (71)

Ever worried about unwanted pregnancy

315 (70)

Any pregnancy scare (condom break, missed pills, unprotected sex, worry about unwanted pregnancy)

390 (82)

 

 

* Percentages here are expressed as % of those who responded. The number of respondents varies by question with those providing conflicting responses or missing responses excluded.

 

In summary, demographic results suggest that the target population for the Label Comprehension Study was well represented and consistent with the study’s aim to enroll a representative, diverse group of subjects that would 1) include a significant contingent of the target population most likely to use Plan B, 2) include a representative group of subjects considered at greatest risk of failure to understand the labeled instructions for product use, and 3) not be biased by the inclusion of subjects with educational levels too high to obtain a fair assessment of label comprehension using proposed OTC label language. 

 

 

4.2.5 Results – All Patients

 

4.2.5.1 Communication Objectives

 

Results for the 11 prospectively defined communication objectives were tabulated based on assessment of the survey questions comprising the definition of each objective.

 

Table 9 summarizes the results associated with the percentage of correct responses obtained for each communication objectives.  In addition to presenting results for the entire 656 eligible subject sample, summary data have also been stratified by age grouping (12-16, 17-25, 26-50 years old), and setting (mall, clinic).

 


Table 9: Percent of Subjects Who Understood Communication Objectives Related to Efficacy in the Plan B OTC Label Comprehension Study

Objective

Age Group

Setting

Total
(N=656)

12-16
(n=76)

17-25
(n=355)

26-50
(n=225)

Mall
(n=583)

Clinic
(n=73)

1 Plan B is indicated for prevention of pregnancy after unprotected sex.*

86.8

93.5

95.6

93.5

93.2

93.4

2 Plan B is intended as a back up method and should not be used for regular contraception.

57.9

67.6

71.6

68.6

61.6

67.8

3 Plan B does not prevent sexually transmitted diseases or HIV/ AIDS.

93.4

96.6

92.0

94.3

97.3

94.7

4 The first pill should be taken within 72 hours after intercourse.

77.6

86.5

87.1

85.4

87.7

85.7

5 The first pill should be taken as soon as possible after intercourse.

84.2

83.7

81.3

83.4

79.5

82.9

6 The second pill should be taken 12 hours after the first.**

77.6

90.1

81.8

85.2

90.4

85.8

7 Plan B should not be used by women who are already pregnant.

97.4

99.4

97.8

98.6

98.6

98.6

8 Plan B should not be used by women with unexplained vaginal bleeding.

72.4

77.2

74.7

75.6

76.7

75.8

9 Plan B should not be used by women with allergy to any ingredient in the product.

90.8

91.5

91.1

91.1

93.2

91.3

10 Side effects of Plan B include nausea and vomiting.

90.8

93.0

84.0

88.5

98.6

89.6

11 If severe abdominal pain develops, the user should seek medical care immediately.

81.6

84.2

77.3

81.3

83.6

81.6

 *  Using an acceptable definition for question 7 from the full study report (WCC/FHI 2001)

** Using an acceptable definition for question 30 from the full study report (WCC/FHI 2001)

 

Subjects in the clinic and mall settings provided very similar correct response rates to the 11 objectives.  Thus, setting does not appear to have influenced the outcome.

 

Overall, consistent responses for each communication objective were observed across both age and study setting groupings.  For Objectives 2 and 8, the correct response rates were somewhat lower than for the other nine objectives across all subgroups.  Additional analysis of these findings led to the observation that one or more questions making-up the objective may have either been ambiguous or otherwise problematic for the subject to satisfactorily answer.  Objective 4 will also be addressed since the 12-16 age group demonstrated slightly lower correct response rates than the other subgroups evaluated.

 

4.2.5.2 Communication Objective 2

 

Communication Objective 2 focused on use of Plan B as a back up method that should not be used for regular contraception.  Correct response to at least three of the four questions comprising Communication Objective 2 operationally defined correct comprehension of this objective.  Low response percentages for Communication Objective 2 were seen for all subgroups (see Table 10).

 

Table 10: Correct Response Percentages for Questions 9, 21, 22, and 25 Making Up Communication Objective 2: Plan B is Intended as a Back Up Method and Should Not Be Used for Regular Birth Control

Age Group (Yrs)

Questions

12-16
(N=76)

17-25
(N=355)

26-50
(N=225)

Total
(N=656)

Overall Results, Correct Response for Objective 2: (correct response for at least 3 of the questions)

57.9%

67.6%

71.6%

67.8%

9:

According to the label, should Plan B be used as regular birth control? (NO)

77.6%

87.0%

85.3%

85.4%

21:

A woman is planning to have sex tonight. She usually uses condoms to prevent pregnancy. This time she plans to use Plan B instead because her husband complains about using condoms. Is this a correct use of Plan B ? (NO)

50.0%

49.6%

40.9%

46.6%

22:

A woman used Plan B every day instead of her usual birth control pills. Was this a correct use of Plan B ? (NO)

90.8%

91.0%

89.8%

90.5%

25:

A woman and her husband do not like using condoms, and the woman does not want to take birth control pills. They decide to use Plan B as their main contraceptive method. Is this a correct use of Plan B? (NO)

59.2%

65.6%

75.6%

68.3%

 

It is clear from this presentation that questions 21 and 25 presented more of a challenge to the women surveyed.  For the 12-16 year old group, 77.6% were able to correctly answer that Plan B was not a regular birth control method (Question 9); over 90% of them understood the scenario described in Question 22 to correctly answer that Plan B was not an “every day”, “regular” birth control method.  It could be speculated that the two younger age groups, particularly the youngest one, had an easier understanding of the proper use of Plan B when presented with a scenario that they could evaluate, rather than simply responding to a direct question.  In order to strengthen the message about appropriate use, however, the message that Plan B is not a substitute for regular contraception now appears in bold print within the current, proposed OTC label.  The sponsor is proposing to include additional information in the package discussing more effective and appropriate methods of birth control.

 

It is also interesting that, for Question 21, the correct response rate for the 26-50 year old age group (40.9%) is discernibly lower than for the two younger age groups (50.0% and 49.6%, respectively), and that this finding appears to be independent of education level.  It is possible that a greater number of older subjects are married or in long-term relationships and are more practical when it comes to sex.  These subjects may also be having sex less often than their younger counterparts.  As a result, older subjects may have seen Plan B as effective contraception for a “planned emergency”.  Although the product is not indicated for this use, it may shed some light into the perception that subjects have regarding whether an “emergency” is literally that or a “prevention” of an emergency (like keeping a fire extinguisher on hand in the unlikely event of fire).

 

4.2.5.3 Communication Objective 4

 

Table 11 displays the proportion of all subjects giving the correct answer to each question related to Communication Objective 4 for all subject and for each age group indicated.


 

Table 11: Correct Response Percentages for Questions 10, 19, 20 and 29 Making Up Communication Objective 4: The First Pill Should Be Taken Within 72 Hours After Intercourse

Age Group (Yrs)

Question

12-16
(N=76)

17-25
(N=355)

26-50
(N=225)

Total
(N=656)

Overall Results,Correct Response for

Objective 4: (at least 2 of the following: Question 10 (72 hours/3days), 29, (19 & 20))

77.6%

86.5%

87.1%

85.7%

10:

After unprotected sex, when is the best time to take the first tablet? (ASAP AND WITHIN 72 HRS OR 3 DAYS)

38.2%1

13.2%2

25.0%3

60.0%1

25.1%2

34.9%3

50.6%1

24.4%2

26.2%3

54.3%1

23.5%2

30.8%3

19:

A woman had unprotected sex 2 days ago and then used Plan B to prevent pregnancy. Was this a correct use of Plan B? (YES)

82.9%

86.2%

88.9%