Study #9727: Plan B OTC Actual Use Study

(Volumes 27-30 of sNDA 21-045)

 

Title:                        Phase 3 Non-Comparative Case Series Study of Plan B Levonorgestrel Emergency Contraceptive Pills Provided Using a Simulated Over-The-Counter Approach

 

Study date:               November 5, 2001 to April 11, 2002

Report date:             September 30, 2002, updated January 30, 2003

 

Sponsor:                   Women’s Capital Corporation

                                 (The sponsorship was transferred to the Barr Research in Nov, 03)

 

Investigators:            Family Health International (FHI), Research Triangle Park, NC

                                

Study sites:               Five Family Planning Clinics sites (five states in US):

         Planned Parenthood League of Massachusetts, Boston, MA

         Planned Parenthood Centers of West Michigan, Grand Rapids, MI

         Planned Parenthood of Houston and SE Texas, Houston, TX

         Planned Parenthood of Central and Northern Arizona, Phoenix, AZ

         Planned Parenthood of Western Washington, Seattle, WA

                                 Five pharmacy stores

         Longs Drugs stores (in 5 cities of WA)

 

Study Design:           Open-label, one-arm, uncontrolled multi-center clinical trial

 

GCP:                        Yes

 

Study Drug:              Plan B (0.75-mg Levonorgestrel tablet); Lot #: W110004

 

 

STUDY OBJECTIVES

 

Primary Objective:

 

To estimate the frequency of contraindicated and incorrect use of Plan B when dispensed under OTC-like conditions.

 

Secondary Objective:

 

To estimate repeat use, pregnancy, and adverse events when Plan B is dispensed under OTC-like conditions.

 

Additional Observation

 

To collect and compare uses of emergency and regular contraception at enrollment and follow-up.

METHODS

 

Study Procedure (Table 1)

 

1.     Investigators used a written script to inform women presenting to the study sites about the study. Each woman who expressed an interest in study participation reviewed the Plan B label and then completed a Screening Form.. 

 

2.   Eligible subjects who wished to purchase Plan B were asked to sign the Informed Consent Form, and then to complete a Background Questionnaire.

 

3.   Each subject could purchase only one package of Plan B at a time.  To purchase more, women had to repeat the enrollment process. Each woman received a Study Data Card (with stamped/addressed envelope) to complete after using Plan B and then to mail to the study site. Study staff did not provide instructions on how to use Plan B  (other than the package label) unless the subject specifically asked a question; the questions and answers were recorded on a data form.

 

4.     Subjects who purchased Plan B were contacted one week and four weeks later either by telephone or were seen in person at the study site, questioned about Plan B use, adverse events and pregnancy status. Information about prior and concomitant medications was collected but not interrupted (no restriction and no special instruction). Subjects with an uncertain pregnancy status or with adverse events (Aes) received weekly follow-up until the issue was resolved.

 

5.    Subjects were told about monetary compensation for study participation after completing the Screening Form. They received $40 (for the clinic sites) or $45 (the pharmacy sites) compensation after both contacts.

 

 

Table 1. Schedule of Study Procedures

 

Procedure	Screening	Week 1 (5-8 days)	Week 4 (28 days or later	Weekly thereafter (if necessary)
Collect baseline and background data	X
Determine eligibility	X
Informed consent	X
Provision of Plan B if eligible	X
Provision of Study Data Card	X
Collect information on use of product		X	X
Collect information on adverse events		X	X	X
Collect information on pregnancy		X	X	X

 

 

Investigators

 

Family Health International (FHI) designed the study, distributed Plan B, and monitored the sites. They made at least 2 site visits during the study to monitor the progress of study, to confirm that the sites were following the protocol, and to review the data. Study staffs were trained separately at each site according to a standardized training curriculum.

 

Plan B Dispensing

 

Each subject enrolled in the study was initially allowed to purchase only one package of Plan B containing two 0.75-mg levonorgestrel tablets (a single bath with lot #W110004). The package design was the same as the approved Rx package but printed with the proposed OTC labeling (Figure 1).  No patient package insert was provided with the study product.

 

Subjects were allowed to continue their routine medication. Information was collected about medication used in the week before enrollment and concomitantly during the study. Subjects could repeat the enrollment process at a later time to qualify to purchase more Plan B.

 

Subject Screening and Enrollment

 

Admission criteria: A woman who met the following 5 criteria was eligible to receive Plan B:

 

1. Requested emergency contraception for personal use.
2. Had not previously participated in the Plan B Label Comprehension study.
3. Could read English, according to her own judgment.
4. Was willing to complete questionnaires and to be contacted or return to the study site in one week and four weeks for follow-up.
5. Wanted the study product after reading the text on the outside of the study package label.

 

The subjects were allowed to enroll repeatedly while the study sites were open. The same subject number was used for the “re-enrolled” subjects. Supportive documents included informed consent and contact information at the admission re-visits. The intervals between uses were recorded, but the data were not statistically analyzed due to low number of repeated users.

 

 

Figure 1. Plan B Label used in the Actual Used Study

 

 

Minor subjects: Subjects aged 15 or younger were excluded from 2 sites (Phoenix and Houston) because parental consent for this age was required. The other clinical sites did not impose age restrictions. No specific measures were taken to recruit minors at the sites so that the population would be representative of that seeking emergency contraception.                                                

 

Assessment of Self-Selection/De-Selection

 

Self-selection: Subjects were asked to review the drug package, to complete the Screening Form and to determine whether or not the product was appropriate for them. The validity of the self-selection decision was determined based on the reasons that the subject requested and used Plan B.

 

Self-deselection: Contraindicated uses were evaluated for assessment of self-deselection, as follows:

 

Determination of Pre-existing pregnancy: Pre-existing pregnancy was evaluated at screening time (last menstrual period and usual menstrual cycle length), at follow-up contact (menstrual profile, pregnancy test results since last menstrual period (LMP), other reasons to suspect pregnancy), and by estimated fertilization date (pregnancy at least 14 days after fertilization)

 

Unexplained vaginal bleeding: At the earliest follow-up contact, the medical monitor determined the onset of “any unusual” vaginal bleeding, and how it was unusual, before subject took the first pill.

 

Allergic to the product: Information on allergy to all medications, foods and Plan B was collected during both follow-up contacts to avoid influencing behavior.

 

The reasons to deselect Plan B in those subjects who did not request or who received Plan B but did not use it were not evaluated in the study.

 

Assessment of Correct/Incorrect use

 

The date and time of coitus and subsequent ingestion of each pill were collected. The following questions were asked to collect data about intentional and unintentional incorrect use:

 

Did you use Plan B according to all the instructions on the box? If no, what instruction did you not follow?

Did you know you were not following the instructions when you took the Plan B pills or did you realize that only after you took the pills?

 

Primary analyses of incorrect use: the subjects did not follow the dosing schedule: “Take the first tablet as soon as possible within 3 days (72 hours) after unprotected sex; Take the second tablet 12 hours after you take the first tablet”.

 

Secondary analyses of incorrect use: First tablet up to 72 hours after intercourse and second tablet up to 16 hours after the first; First tablet up to 72 hours after intercourse and second tablet up to 6-18 hours (the rationale for this timing was not provided in the report) after the first; First tablet up to 120 hours after intercourse and second tablet up to 24 hours after the first.

 

Subjects with unclassifiable use patterns were excluded in the analyses.

 

Safety Assessment

 

Adverse events were defined as medical problems that started or worsened after Plan B use

 

Adverse events were recorded in the Study Data Cards and were collected during the follow-up contacts (week 1, week 4 and thereafter for some subjects), and recorded in the “Adverse Events Notes page” by study staff, reviewed and then transferred to the Adverse Events data form by the clinician. The frequency, severity (mild, moderate or severe), and seriousness, and the relevance to the drug treatment were analyzed.

 

Site staffs did not investigate discrepancies of AE reports between the cards and the follow-up contacts unless the cards indicated the possibility of an unusual, serious, or severe event.

 

Adverse events were coded in COSTART terminology. The 95% confidence limits around frequencies within body system class were calculated by the exact binomial method.

 

Concomitant Medications: Medications used by enrolled subjects during the week before enrollment and during the follow-up period were coded according to the WHO Anatomical Therapeutic Chemical Classification system.

 

Efficacy Assessment

 

At the follow-up contacts, information about menstrual history, pregnancy test results since LMP, and any suspected pregnancy were collected and evaluated by medical monitors.

 

Criteria to determine pregnancy (any of the following):

 

a.      Did not have menses following product use

b.     Had a positive pregnancy test

c.      Had any other evidence of pregnancy, such as ultrasound, abortion.

d.     Had no evidence ruling out pregnancy as assessed by site staff.

 

 

 

Estimate Fertilization Date

 

Pregnancy occurring before Plan B use was determined by the estimated fertilization date (based on data collected from all pregnant subjects) or date of sexual intercourse. There was no diagnostic examination (ultrasound and/or blood/urine test) to confirm the fertilization date.

 

Criteria to exclude pregnancy

 

a.      Had a menstrual period after Plan B use

b.     Had a negative pregnancy test at least 2 weeks after the products

c.      Other information (not specified in the report), confirmed by medical monitor individually

 

Undetermined pregnancy:

 

Subjects who did not meet the above inclusion and exclusion criteria to determine pregnancy were classified as “undermined pregnancy” and were followed up until pregnancy status was clarified.

Sexual and Contraceptive behaviors

 

Information about sexual behavior and contraception methods before (one month) and after (4 weeks) Plan B use were collected using multiple questions containing the following parameters:

 

Had sex: Subjects had sex with or without contraception during specific interval.

 

Had at least one sex act without contraception: included any subject who was classified as having had sex in the specified interval but indicated that she did not use any contraception at least once.

 

Used a “more effective” method: oral contraceptive pills, Depo-Provera, Lunelle, vasectomy, or intrauterine device at any time during the interval.

 

Used a “less effective” method: other than “more effective” methods, including those who did not indicate use of any method.

 

Used a specific contraceptive method: included any subject who indicated that she had used that method at any time in the specified interval.

 

Used no condoms: included any subject classified as having had sex in the specified interval who was not classified as ever having used condoms in that interval.

 

Subjects’ reports of abstinence (“yes” answers to “have not had sex: in the past month, since receiving Plan B, or since One Week contact”) were not included in these classifications because some subjects gave contradictory responses.

 

Data Collection

 

Data were collected by the investigators using the following forms at the study sites. Data recorded on all forms received at FHI were entered into the computer with Clintrial 4.3 software; the data entry system was validated by FHI data management staff.

 

Plan B Study Screening Form

Plan B Study Background Questionnaire

Plan B Study Disposition Form

Plan B Study One Week Contact Form

Plan B Study Four Week Contact form

Plan B Study Data Card

Plan B Study Data Card Transcription Form

Plan B Supplemental Contact Form

 

 

Study Data Card: Information about the LMP, the sex act prompting use of the product, timing of ingestion of each tablet, and pregnancy test were collected. Information was transcribed onto Study Data Card Transcription Form during site visits by FHI.

 

Site staffs were instructed not to investigate discrepancies between the information obtained at the follow-up contacts and on the cards.

 

Data Audit: There was computer hardware problem (p029, vol. 27) during the study, which may have compromised some data entries. It was/is unclear how much of the study data were affected by this problem. FHI conducted an audit analysis, showing the error rate was 0.011-0.036% of 95% CI.  The sponsor stated that this was less than the pre-defined 0.05% (audited 61,336 data points from key data fields for the primary outcomes).

 

Data Analyses

 

Statistical analyses: Data were summarized in tabular forms with SAS (version 8.0). The mean, median, minimum-maximum, and standard deviation (SD) were calculated for continuous variables and frequency tables were used for categorical data. For proportions, exact binomial 97.5% confidence intervals were calculated.

[See statistical review for certain statistical issues].

 

Definition of analysis populations:

 

Screened Population: All subjects screened in the study and no one was excluded.

 

Enrolled Population: All subjects who enrolled in this study (i.e., received study product).

 

Per-Protocol Population: The Enrolled Population excluding subjects enrolled with violations of any of the study admission protocol criteria.

 

Incomplete Follow-up Population: All subjects who did not complete follow-up procedures (i.e., did not complete both scheduled contacts and all required supplemental contacts or did not mail in the Study Data Card).

 

Lost to Follow-up Population: All subjects who provided no follow-up data.

 

Missing Data: Analyses of contraindication use, incorrect use, and pregnancy included only subjects with sufficient data to allow classification of the status of the outcome. The sponsor assumed that subjects with missing data had the same outcomes as subjects who provided data.

 

Data obtained at visits that were outside the “per protocol” time windows were included in the primary outcome analysis. In all analyses, the data from the Study Data Cards were used only if the corresponding data from the contact visits were missing (except where otherwise noted).

 

 

Deviations from the Study Protocol

 

1.     Informed Consents: Two versions of the Informed Consent forms were used, one (amendment #1) at 4 clinical sites and pharmacy sites and another at the Boston site (using the final version, amendment #2), as listed in Table 2. The IRB at each site approved the consent form that the site actually used. (Reviewer: the discrepancies were minor and may not affect either subject welfare or the integrity of the data).

 

2.     Missing package: Study drug packages (dispensed or returned) were accounted for all sites except at the Houston site where 2 packages were missing.

 

3.     Evaluable population: In the protocol, this was all screened subjects who met all eligibility criteria, who used the product, and who completed both follow-up contacts. In the actual analysis, the evaluable population included those subjects who received and used the study product and completed one or both follow-up contacts.

 

4.     Repeat users: The number of repeat uses was low and thus no separate analysis was conducted in the report.

 

5.     An analysis of “deliberate incorrect and contraindicated uses” was proposed in the protocol, but the final report focused on “unintentional incorrect and contraindicated use”.

 

 

Table 2. Differences between the informed consents used in different study sites

 

Deviations	Boston Site	All others
Version of Consent Form used	Amendment #2 (final)	Amendment #1
Consult health care professionals	“Please let us know if you would like to speak with a pharmacist/clinician at any time during the research study."	"You may speak with a pharmacist/clinician at any time during the research study."
Ask additional contact	verbally inform each subject at the four-week contact (at all sites)	Grand Rapids, Seattle, and the pharmacies, but others, did not specifically state that subjects might have additional contacts after the one-month contact.
State special warning	No special warnings were used in the informed consent.	“Make sure that you understand the risks and side effects of the package insert instructions before you take the pill. If you have any questions, call [name] or the clinic/pharmacy”.

 

RESULTS

 

Subject

 

Enrollment: A total of 665 women were screened at least once in the 5 clinical sites and 5 pharmacy sites; 585 (88%) subjects met all eligibility criteria and 80 (12%) were ineligible. The distribution of screened subjects and their eligibility were summarized in Table 3. Of the 80 ineligible subjects, 38 women who indicated eligibility did not sign the informed consent and thus became ineligible; the other 42 failed to meet one or more criteria listed in Table 4.

 

Table 3. Subjects Screened and Enrolled in Each Study Site

 

	Clinical Site						Pharmacy Sites	Total
	Boston	Grand Rapid	Houston	Phoenix	Seattle	Total
Screened Subjects	129	125	170	123	79	626	39	665
Eligible Subjects	111	117	138	111	72	549	36	585
	86.0%	93.6%	81.2%	90.2%	91.1%	87.7%	92.3%	88.0%
Ineligible Subjects	18	8	32	12	7	77	3	80
	14.0%	6.4%	18.8%	9.8%	8.9%	12.3%	7.7%	12.0%

 

 

Table 4. Reasons that screened subjects did not receive Plan B

 

	Clinical Sites N=626	Pharmacy Sites N=39	Total N=665
Ineligible subjects	77	3	80
Did not sign the consent form (but eligible)	ND	ND	38
Did not think they should receive Plan B	42	0	42
Change mind	2	0	2
Indication	10	0	10
Instruction	1	0	1
Side effect	7	0	7
Want more info	17	0	17
Other options	1	0	1
No reason recorded	4	0	4

Data were extracted from text and Table 1.3 (vol. 28, p011). ND: no data available.

 

Subject Disposition: The disposition of subjects is summarized in Figure 2 and Table 5. Of the 585 eligible subjects, 576 (98%) were enrolled at first screening into the study (received the study product). Nine eligible subjects declined to participate in the study but 6 of them ultimately received prescription Plan B. Of the 80 ineligible subjects, 60 received prescription Plan B, 9 received the study product, 9 received no treatment and 2 received oral contraceptive pills.

 

Table 5. Subjects Who Received Treatment

 

Eligibility	Subjects Screened	Subjects Received Study Plan B	Subjects Received Rx Plan B	Subjects not Received Plan B
Eligible	585	576	6	3
Ineligible	80	9	60	11
Total	665	585	66	14

 

 

Demographics: The demographic characteristics of screened and enrolled populations are summarized in Tables 6 and 7. The mean age of the enrolled subjects was 22.1±5.0 (14-44) years old. Seventy-four percent of subjects were 17-25 years old and 5% were ages 14-16. Approximately 74% of the enrolled subjects had at least some college education and 0.3% had less than a 9^th grade education. 

 

The demographic characteristics between the screened and enrolled populations (Table 6), and between the incomplete follow-up/lost to follow-up populations and the screened population seemed to be comparable.

 

All subjects ages 14-16 were in middle school or high school. Nine percent of subjects age 17-44 had less than an 11^th grade education; 0.2% had less than an 8^th grade education and 8.6% had completed 9^th-11^th grade (Table 7).

 

 

Figure 2. Disposition of Subjects

(Adapted from the sponsor’s Figure 1 in page 070 of vol. 27)

Table 6. Demographics of Screened and Enrolled Populations

(Adapted from the sponsor’s Table F in page 44 of vol. 27)

 

 

Table 7. Demographics of Enrolled Subjects by Age

(% of enrolled subjects in parentheses)

 

Characteristics	Age (years)		Total N=585
	14-16 N=29	17-44 N=556
Education
≤ 8th Grade	1 (3.4)	1 (0.2)	2 (0.3)
9th-11th Grade	28 (96.6)	48 (8.6)	76 (13.0)
High school/Graduated	0	77 (13.8)	77 (13.2)
Vocational/Technical School	0	9 (1.6)	9 (1.5)
Some college	0	290 (52.2)	290 (49.6)
Finished college	0	95 (17.1)	95 (16.2)
Graduate School	0	36 (6.5)	36 (6.2)
Race*
Asian	2 (6.9)	35 (6.3)	37 (6.3)
American Indian/Alaskan Native	2 (6.9)	8 (1.4)	10 (1.7)
Black	3 (10.3)	55 (9.9)	58 (9.9)
Native Hawaiian or pacific Islander	0	10 (1.8)	10 (1.7)
White	23 (79.3)	424 (79.3)	447 (76.4)
Missing	1 (3.4)	38 (6.8)	39 (6.7)
Prior EC Use
Ever	8 (27.6)	226 (40.6)	234 (40)
Never	21 (72.4)	330 (59.4)	351 (60)

Data were extracted from Table 2.2c and g (p027 and p035 of vol. 28). * Some subject listed more than 1 race.

 

 

Compliance of Follow-up Contacts (Figure 3, Table 8)

 

Of the 585 enrolled subjects (576 eligible and 9 ineligible), 42 subjects (7.4%) did not provide follow-up data, constituting the Lost to Follow-up Population; 501 subjects (85%) completed both contacts, but only 262 subjects (45%) provided contact information within the per-protocol time windows (5-8 days for the first contact and ≥ 28 days for the second contact).  Contacts were by phone (98%) and in person (2%).

 

Compliance with the follow-up schedule was less complete for subjects age ≤ 16 years and subjects with less than a high school education (Table 9). There were no significant differences in the follow-up compliance among those of different races, ethnicity and history of emergency contraceptive pill (ECP) use.

The compliance for the 1^st contact was much better at the clinics than at the pharmacies.

 

A total 322 subjects (55% of enrolled population) completed follow-up contacts (2 contacts and required supplemental contacts) and mailed the Study Data Card.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 3. Incomplete or Lost Follow-up Subjects

The figure was adapted from the sponsor’s Figure 2 in page 071 of vol. 27. “Complete follow-up” was referred to those subjects who completed ≥ 2 follow-up contacts as well as mailed in the study data cards.

 

 

 

Table 8. Compliance of Follow-up Contacts

(% of enrolled population)

 

Follow-up Contact	Clinical Sites N=550	Pharmacy Sites N=35	All sites N=585
0 Contact	7.1%	11.4%	7.4%
1 Contact	5.3%	0	5.0%
≥ 2 Contacts (Total)	85.5%	88.6%	85.6%
≥ 2 Contacts (per protocol)†	46.5%	17.1%	44.8%
Timing of 1st Contact
5-8 days	52.5%	17.1%	50.4%
Mean days (Min-Max)	11.0±7.9 (4-81)	21.3±21.6 (6-92)	11.6±9.5 (4-92)
Timing of any 2nd Contact
≥ 28 days	80.7%	88.6%	81.2%
Mean Days (Min-Max)	32.5±8.0 (12-94)	38.5±14.2 (28-92)	32.9±8.6 (12-94)
Study Data Card Received	57.8%	51.4%	57.4%

Data are extracted from the sponsor’s Table 1.4a (vol. 28, p012).

†The 1^st contact at 5-8 days and the 2^nd contact at ≥28 days

 

 

Table 9. Follow-up Compliance in Subjects by Ages and Education Levels

(% of enrolled population)

No. of Follow-up Contacts	Age (years)		Education Levels		Prior EC Use		Total N=585
	14-16	17-44	< HS	≥ HS	Ever	Never
	N=29	N=556	N=78	N=507	N=234	N=351
0	24.1	6.5	19.2	5.5	9	6.3	7.4
1	20.7	4.1	11.5	3.9	4.7	5.1	5.0
2	55.2	87.2	66.7	88.6	85.0	86.0	85.6
≥ 3	0	2.2	2.6	2.0	1.3	2.6	2.1

Data are extracted from Tables 1.4c and 1.4f (vol. 28, p012).

 

Disagreements between Follow-up Contact and the Study Data Card

 

Approximately 57% of the enrolled subjects (336/585) returned the Study Data Card. Most of the returned cards (80%) contained at least one discrepancy compared to the follow-up contact. Approximately 50% of the returned cards included adverse event information that differed from the follow-up contact information; however, all AEs from the cards and the follow-up contacts were included in analysis (as seen in Safety section of this review). The overall discrepancy of data (excluding AEs) obtained from the Study Data Card was 41% (138/336) compared to the data from follow-up contacts (Table 10).

 

Table 10. Discrepancies between data (excluding AEs) obtained from

the Study Data Card and the Follow-up Contacts

(% of 336 subjects who returned the Study Data Card)

 

Parameters	No Discrepancy	Discrepancy	Data from Card only	Data from Contact only
Onset data of menstrual period before Plan B use	61.9	33.6	1.5	3.0
Date of sex act that caused subject to want Plan B	80.1	13.1	6.3	0.6
Date and time 1st Plan B pill taken	76.5	19.0	0.9	3.6
Date and time 2nd Plan B pill taken	69.3	25.0	1.8	3.9
Had menstrual period after taking Plan B	69.3	18.8	0.3	11.6
Onset date of menstrual period after taking Plan B	73.8	19.3	1.5	5.4
Date and results of pregnancy test	81.3	3.6	3.6	11.6
All information combined	20.2	41.1	12.5	26.2

Data were extracted from Table 4.1a in page 094 of vol. 28.

 

 

Due to the low return rate of the Study Data Cards, there was greater available data from follow-up contacts for the final analyses. Considering this may have introduced interview bias into the results, the Agency sent a request to the sponsor on Oct 1, 2003 to provide data analyses based on data from the Study Card only. As per the sponsor’s response on Oct 17, 2003, the incorrect use analysis using data recorded on the Study Card was no higher than that from the follow-up contact data as stratified by age, educational levels and Ever/Never EC experience.

 

Reproductive History

 

Approximately 68% of the enrolled subjects had no history of pregnancy before the first screening, and 84% had no living children (Table 11).

 

Table 11. Gravidity History of Enrolled Subjects

(% of enrolled population)

 

	Clinical Sites N=550	Pharmacy Sites N=35	Total N=585
Previous Pregnancy
0	68.4	65.7	68.2
1	18.4	11.4	17.9
≥ 2	12.4	22.9	13.0
Missing	0.9	0.0	0.9
Living Children
0	84.7	71.4	83.9
1	8.5	14.3	8.9
≥ 2	5.5	14.3	6.0
Missing	1.3	0	1.2

Data are extracted from the sponsor’s Table 2.6a in page 047 of vol. 28.

 

 

Emergency Contraceptive History

 

About 60% of subjects had no previous experience using an emergency contraception (EC) (Tables 12 and 13). The demographic characteristics of Ever and Never EC users were comparable.

 

Of those with previous EC experience, 2% of subjects used it within the past month and 8% within the last 1-3 months (Table 14).

 

Subjects with prior emergency contraceptive use were more likely to have had at least one act of sexual intercourse without contraception in the past month (p<0.05) and to have a positive pregnancy history (p< 0.01). There were no significant differences in condom use between ever EC users and never EC users (Table 15).

 

 Table 12. Demographics of subjects with and without

Previous Emergency Contraceptive Use Experience

(% of the enrolled population)

 

Characteristics	Ever EC Use	Never EC Use	Total
	N=234 (40%)	N=351 (60%)	N=585 (100%)
Age (years)
14-16	3.4	6.0	5.0
17-25	75.2	73.8	74.4
26-30	13.7	14.2	14.0
31-35	5.6	3.1	4.1
≥ 36	2.1	2.8	2.6
Education
Some College	52.6	47.6	49.6
Finished College	13.7	17.9	16.2
High school	12.0	14.0	13.2
9th-11th Grade	12.0	13.7	13.0
Graduate School	8.1	4.8	6.2
Technical School	1.3	1.7	1.5
≤ 8th Grade	0.4	0.3	0.3
Missing	0	0	0
Race*
White	71.8	79.5	76.4
Black	13.7	7.4	9.9
Asian	5.1	7.1	6.3
Others	3.4	3.4	3.4
Missing	7.3	6.3	6.7
Marital Status
Single	86.3	90.9	89.1
Married	7.3	4.6	5.6
Others	6.4	4.2	5.1
Missing	0	0.3	0.2

Data are extracted from the sponsor’s Table 2.2g (vol. 28, p035). Some subjects had more than 1 race.

Table 13. History of Previous Emergency Contraceptive Use

(% of enrolled population)

 

	Clinical Sites	Pharmacy Site	Total
Never Used	60.7	48.6	60.0
Ever Used	39.3	51.4	40.0
(Times)      1	25.3	31.4	25.6
2	10.4	11.4	10.4
3	2.2	5.7	2.4
≥ 4	0.9	2.9	1.0
Missing	0.5	0	0.5

Data are extracted from the sponsor’s Table 2.6a (vol. 28, p047).

 

 

Table 14.  Time since the Last Emergency Contraceptive Use

(% of enrolled population)

 

Months Since Last Use	Clinical Sites N=550	Pharmacy Site N=35	Total N=585
< 1	2.2	2.9	2.2
1-3	7.8	14.3	8.2
> 3	29.3	34.3	29.6
Total	39.3	51.4	40.0

Data were extracted from the sponsor’s Table H (vol. 27, p046) and Table 2.6a (vol. 28, p047).

 

Table 15. Reproductive and Contraceptive History

of Previous Emergency Contraceptive Users

(% of enrolled population with or without previous ECP use)

 

Characteristics	Ever ECP Use	Never ECP Use	Total
	N=234 (40%)	N=351 (60%)	N=585 (100%)
Pregnancy History†
None	62.0	72.4	68.2
1	19.7	16.8	17.9
≥ 2	18.4	9.4	13.0
Missing Data	0	1.4	0.9
Living Children
None	80.3	86.3	83.9
1	10.7	7.7	8.9
≥ 2	9.0	4.0	6.0
Missing Data	0	2.0	1.2
Contraceptive Method
Condoms	76.5	80.3	78.8
Withdrawal	29.9	26.8	28.0
Oral Contraceptive Pills	22.2	20.5	21.2
Spermicide	7.7	8.5	8.2
Emergency Contraception	5.6	0	2.2
Natural Family Planning	2.6	1.7	2.1
DepoProvera or Lunelle	2.6	1.1	1.7
Other	0.4	0	0.2
At least one sex act without Contraception during past month‡	65.8*	56.1	60.0

Data are extracted from the sponsor’s Table 2.6g (vol. 28, p054).

† p < 0.003 by Kruskal-Wallis test and ‡  p =  0.02 by Chi-square test compared between Ever ECP and Never ECP.

History of Contraception

 

A total of 536 subjects (92% of the enrolled population) used a contraceptive method in the previous month  (Table 16); and the most common method was the condom (79% of the enrolled population). The Lost to Follow-up population and the entire enrolled population were comparable in their histories of contraception, emergency contraception, pregnancy, and sex without contraception.

 

Table 16. History of Contraceptive Methods in Previous Month

(% of the enrolled population)

 

Contraceptive Method	Clinical Sites N=550	Pharmacy Sites N=35	Total N=585
Condoms	79.6	65.7	78.8
Withdrawal	29.1	11.4	28.0
Oral Contraceptive Pills	20.9	25.7	21.2
Spermicide	8.5	2.9	8.2
Emergency Contraception	2.2	2.9	2.2
Natural Family Planning	2.2	0	2.1
DepoProvera or Lunelle	1.3	8.6	1.7
Other	0.2	0	0.2
At least one sex act without contraception	60.2	57.1	60.0

Data were extracted from the sponsor’s Table I (vol. 27, p046) and Table 2.6a (vol. 28, p048).

 

 

Reasons to request Plan B (Table 17): The major reasons for the 585 enrolled subjects to request Plan B during the recruitment visit were “condom broke/slipped” (37%), “unprotected sex” (33%), “prevent pregnancy” (17%), and “Oral Contraceptive Pills (OCP) problem” (4%). The sponsor stated that subjects with the reason “prevent pregnancy” did not intend to use Plan B before sexual intercourse.

 

 Ninety-seven percent had a correct reason to request Plan B (after excluding those subjects who provided “unspecified” reasons). See Table 17.

Reasons to use Plan B (Table 18): Approximately 98% of 540 subjects who used Plan B after enrollment had single (91%) or multiple sex acts (7%). The main factors to prompt the subjects to take Plan B were “condom broke/slipped”, “used no contraception”, and “missed OCPs”. Correct self-selection calculated by exclusion of the reasons “Other” and “Doesn’t remember/missing data” was 95% (514 of 540 users).

 

Overall, the factors prompting subjects to seek and use Plan B were similar among those of different ages, races, ethnicity, educational levels, or ever/never EC use experience (Tables 17 and 18).

 

 

Table 17. Reasons to Request Plan B at Screening/Enrollment by Subgroups

(% of the enrolled population)

 

Reason to Request Plan B	Study Sites		Eligibility		Age (year)		Education		Prior EC Use		Total N=585
	Clinics N=550	Pharmacy N=35	Ineligible N=9	Eligible N=576	≤ 16 N=29	≥ 17 N=556	< HS N=78	≥ HS N=507	Ever N=234	Never N=351
Condom broke or slipped	37.1	42.9	44.4	37.3	31.0	37.8	34.6	37.9	32.5	40.7	37.4
Unprotected sex	33.3	31.4	11.1	33.5	27.6	33.5	23.1	34.7	37.6	30.2	33.2
Prevent pregnancy	17.1	14.3	11.1	17.0	27.6	16.4	28.2	15.2	18.8	15.7	16.9
OCP problem	3.8	5.7	11.1	3.8	3.4	4.0	5.1	3.7	3.8	4.0	3.9
Mistake/accident	2.4	0.0	11.1	2.1	6.9	2.0	3.8	2.0	2.1	2.3	2.2
Contraceptive failure (unspecified)	1.8	0.0	0.0	1.7	0.0	1.8	0.0	2.0	1.7	1.7	1.7
Withdrawal	1.5	0.0	11.1	1.2	0.0	1.4	2.6	1.2	0.0	2.3	1.4
Prevention, unspecified	1.3	0.0	0.0	1.2	3.4	1.1	2.6	1.0	0.9	1.4	1.2
Unspecified	1.3	0.0	0.0	1.2	0.0	1.3	0.0	1.4	1.7	0.9	1.2
Sex, unspecified	0.5	2.9	0.0	0.7	0.0	0.7	0.0	0.8	0.4	0.9	0.7
Backup to spermicide	0.2	0.0	0.0	0.2	0.0	0.2	0.0	0.2	0.4	0.0	0.2
Missed injection	0.0	2.9	0.0	0.2	0.0	0.2	0.0	0.2	0.0	0.3	0.2

Data were extracted from Tables 2.10a, b, c, f and g (p061-p069 of vol. 28). The information was collected during the screening/enrollment visits.

 

Table 18.  Reasons to Prompt Plan B Use after Enrollment by Subgroups

(% of subjects who used the product)

 

Reason to use Plan B	Study Sites		Eligibility		Age (year)		Education		Prior EC Use		Total N=540
	Clinics N=510	Pharmacy N=30	Ineligible N=7	Eligible N=533	≤ 16 n=22	≥ 17 n=518	< HS n=64	≥ HS n=476	Ever N=213	Never N=327
Reason to Prompt Plan B Use (Total Responses)	100	100	100	100.0	100.0	100.0	100.0	100.0	100.0	100.0	100.0
Single sex act	91.6	86.7	85.7	91.4	95.5	91.1	92.2	91.2	91.1	91.4	91.3
Multiple sex acts	6.9	10.0	0.0	7.1	4.5	7.1	4.7	7.4	8.5	6.1	7.0
Other reason	0.8	3.3	14.3	0.8	0.0	1.0	1.6	0.8	0.0	1.5	0.9
Missing data	0.8	0.0	0.0	0.8	0.0	0.8	1.6	0.6	0.5	0.9	0.7
Nature of Contraception Failure (Total Responses)	98.6	100	85.7	98.9	100.0	98.6	96.9	98.9	99.5	98.2	98.7
Condom broke/slipped	44.9	50.0	42.9	45.2	54.5	44.8	46.9	45.0	39.9	48.6	45.2
Used no contraception	39.8	36.7	28.6	39.8	27.3	40.2	28.1	41.2	44.6	36.4	39.6
Missed OCPs	7.1	3.3	0.0	6.9	9.1	6.8	10.9	6.3	7.0	6.7	6.9
Withdrawal	3.7	0.0	0.0	3.6	9.1	3.3	7.8	2.9	3.8	3.4	3.5
Other	2.5	10.0	14.3	2.8	0.0	3.1	3.1	2.9	4.2	2.1	3.0
Doesn’t remember/missing	0.6	0.0	0.0	0.6	0.0	0.6	0.0	0.6	0.0	0.9	0.6

Data were extracted from Table 5.2a, b, c, f and g (p106- of vol. 28). The information was collected during the follow-up contacts. OCPs: oral contraceptive pills.

Contraindicated Use: There are three contraindications listed in the Warnings section of the proposed OTC label, and subjects should have deselected this product if they had any of them. A total of 523 (97%) of 540 users provided sufficient data for evaluation of contraindications after the first screening. Seventeen subjects (3.1% of 540) had insufficient data for evaluation and were excluded from analysis. The results by age, educational level, and previous EC experience were summarized in Table 19.

 

Seven subjects with contraindications (1.3% of 523 users) unintentionally used Plan B. The contraindicated users were in the “eligible” group; six of them were at least age 17 and had at a high school education or greater.  By including 3.1% subjects with missing data, the maximum percentage of contraindicated use would be 4.4%.

 

Pregnancy: One subject was already pregnant when she used Plan B.

 

Unexplained vaginal bleeding: Six subjects had unexplained vaginal bleeding before use: one after intercourse, one early menses, and 4 unexplained bleeding.

Allergy: No subjects were allergic to Plan B.

 

The sponsor stated that they did not have information on the 45 subjects (585-540) who purchased Plan B but did not use it because of contraindications.

 

 

Table 19. Contraindicated Use of Study Product

(% of subjects who used the product)

 

	Age (years)		Education		Prior ECP Use		Total
	≤ 16	≥ 17	< HS	≥ HS	Ever	Never
Users	22	518	64	476	213	327	540
Total Contraindicated Use†
Intentional	0	0	0	0	0	0	0
Unintentional	1 (4.5)	6 (1.2)	1.6	1.3	1.4	1.2	7 (1.3)
Insufficient data	3 (13.6)	14 (2.7)	9.4	2.3	2.8	3.4	3.1
Pregnancy at time of Use
Yes	0	1 (0.2)	0	0.2	0	0.3	0.2
No	86.4	97.7	93.8	97.7	98.1	96.6	97.2
Insufficient data	13.6	2.1	6.3	2.1	1.9	3.1	2.6
Unexplained vaginal Bleeding
Yes	1 (4.5)	5 (1.0)	1.6	1.1	1.4	0.9	1.1
No	21 (95.5)	511 (98.6)	96.9	98.7	98.1	98.8	98.5
Insufficient data	0	0.4	1.6	0.2	0.5	0.3	0.4
Allergy to Plan B
Yes	0	0	0	0	0	0	0
No	100	99.0	96.9	99.4	99.1	99.1	99.1
Insufficient data	0	1.0	3.1	0.6	0.9	0.9	0.9

Data were extracted from the sponsor’s Tables 5.5c, f and g in page 122-127 of vol. 28.

† “Intentional” indicates that subjects correctly recognized contraindications before use and “Unintentional” indicates that subject incorrectly recognized contraindications before use.

 

Correct/Incorrect Plan B Use

 

Of the 585 enrolled subjects 540 took 2 pills or 1 pill (only one subject). A total of 506 subjects (94% of 540 users) provided sufficient data for evaluation of correct use and the remainder were excluded from the analysis.

 

Two subjects took the first pill before sexual intercourse (103 hours and 12.5 hours respectively). As shown in Table 20, the first pill was taken at 34.8±21.1 hours (-103 to 175 hours) in relation to the timing of sexual intercourse and the second pill was taken 12.5±3.2 hours (0-36 hours) after the first pill.

 

There was similar timing of Plan B use among those of different ages, ethnicities, races, educational levels and with/without emergency contraceptive experience.

 

 

Incorrect Use Analysis as per Protocol (Tables 21a & 21b): The per-protocol analysis for correct use (to take the first pill <72 hours after sex and the 2^nd pill at 12 hr after the first pill), demonstrated that the correct use rate was 67.8% (366 of 540 users) and the incorrect use was from 26% (140 of 540).  The incorrect use rate was 32% in a more conservative analysis that included the 34 subjects with missing data (140+34 of 540) Most errors were related to the timing of the 2^nd dose.

 

Of the 26% incorrect uses, 1.3% (7 subjects) were intentional and 24.6% (133 subjects) were unintentional.

 

A re-analysis of the data based on the 506 subjects who used Plan B and provided sufficient follow-up data (Table 21b), demonstrated that the correct and incorrect use rates were 72% (366 of 506) and 28% (140 of 506), respectively.

 

Therefore, overall correct and incorrect use rates would be 68-72% and 26-32%, respectively.

 

The correct/incorrect use rates did not demonstrate clinically significant differences among the subgroups stratified by age, educational level, and previous EC experience.

 

 

Table 20. Disposition of Plan B in the Enrolled Population

(% of enrolled population)

 

	Age (years)		Education		Prior ECP Use		Total
	≤ 16	≥ 17	< HS	≥ HS	Ever	Never
Enrolled Subjects	29	556	78	507	234	351	585
Gave product away
Yes	0	1.3	0	1.4	1.3	1.1	1.2
No	75.9	92.3	80.8	93.1	89.7	92.6	91.5
No data	24.1	6.5	19.2	5.5	9.0	6.3	7.4
Number of pills taken
0	0	0.5	0	0.6	0.4	0.6	0.5
1	0	0.2	0	0.2	0	0.3	0.2
2	75.9	93.0	82.1	93.7	91.0	92.9	92.1
No data	24.1	6.3	17.9	5.5	8.5	6.3	7.2
The first pill taken†
Subject (%)	65.5	88.1	71.8	89.3	88.5	86.0	87.0
Hours after sex act	40.2±19.2 (11.5-70)	34.6±21.2 (-103-175)	35.0±18.1 (5-70)	34.8±21.5 (-103-175)	34.1±18.7 (-12.5-88)	35.3±22.7 (-103-175)	34.8±21.1 (-103-175)
The second pill taken‡
Subject (%)	72.4	90.3	78.2	91.1	88.9	89.7	89.4
Hours from the 1st pill	12.1±0.5 (11-14)	12.5±3.3 (0-36)	12.9±3.0 (11-24.5)	12.5±3.2 (0-36)	12.6±3.1 (0-36)	12.5±3.2 (0-36)	12.5±3.2 (0-36)

Data were extracted from the sponsor’s Tables 5.1c, 5.1f and 5.1g in page 101-105 of vol. 28.

† including subjects who took at least one pill; subjects may take pills before sex.

‡ including subjects who took pills and the interval between pills was not negative.

 

Table 21a. Incorrect Use of Plan B by Primary Definition

(% of subjects who used the product, including those who provided insufficient data)

 

	Age (years)		Education		Prior ECP Use		Total N=540 No. (%)
	≤ 16 N=22	≥ 17 N=518	< HS N=64	≥ HS N=476	Ever N=213	Never N=327
Total Correct Use, no. (%)	17 (77.3)	349 (67.4)	43 (67.2)	323 (67.9)	142 (66.7)	224 (68.5)	366 (67.8)
Total Incorrect Use, no. (%)	3 (13.6)	137 (26.4)	16 (25.0)	124 (26.1)	63 (29.6)	77 (23.5)	140 (25.9)
Intentional†	0	1.4	0	1.5	1.9	0.9	7 (1.3)
Unintentional‡	13.6	25.1	25.0	24.6	27.7	22.6	133 (24.6)
Missing data	9.1	6.2	7.8	6.1	3.8	8.0	34 (6.3)
Timing for the first pill after sex act
> 72 hours	0	1.9	0	2.1	1.9	1.8	10 (1.9)
< 72 hours	86.4	92.7	87.5	93.1	95.3	90.5	499 (92.4)
Missing data	13.6	5.4	12.5	4.8	2.8	7.6	31 (5.7)
Interval between the second and first pill
</> 12 hours	13.6	25.7	25.0	25.2	29.1	22.6	136 (25.2)
At 12 hours	81.8	71.2	70.3	71.8	68.5	73.7	387 (71.7)
Missing data	4.5	3.1	4.7	2.9	2.3	3.7	(3.1)

Data were extracted from the sponsor’s Tables 5.8c, 5.8f and 5.8g in page 133-137 of vol. 28.

† “Intentional” was that subjects correctly recognized the instruction before use;

‡ “Unintentional” was that subject incorrectly recognized the instruction before use.

 

Table 21b. Incorrect Use of Plan B by Primary Definition

(% of subjects who used the product, excluding those who provided insufficient data from denominator)

 

	Age (years)		Education		Prior ECP Use		Total No. (%)
	≤ 16	≥ 17	< HS	≥ HS	Ever	Never
Valid Users*	20	486	59	447	207	301	506
Total Correct Use, no. (%)	17 (85.0)	349 (71.8)	43 (72.9)	323 (72.2)	142 (68.6)	224 (74.4)	366 (72.3)
Total Incorrect Use, no. (%)	3 (15.0)	137 (28.2)	16 (27.1)	124 (27.7)	63 (30.4)	77 (25.6)	140 (27.7)
Intentional†	0	1.4	0	1.6	1.9	1.0	7 (1.4)
Unintentional‡	15.0	26.7	27.1	26.2	28.5	24.6	133 (26.3)
Timing for the first pill after sex act
> 72 hours	0	2.1	0	2.2	1.9	2.0	10 (2.0)
< 72 hours	95.0	98.8	94.9	99.1	98.1	98.3	499 (98.6)
Interval between the second and first pill
</> 12 hours	15.0	27.4	27.1	26.8	30.0	24.6	136 (26.9)
At 12 hours	90.0	75.9	76.3	76.5	70.5	80.0	387 (76.5)

Data were reprocessed based on the sponsor’s Tables 5.8c,f,g, 5.10a in page 133-140 of vol. 28.

* “Valid users” were subjects who used the product and provided sufficient data: Valid Users = (Total Users – Users with missing data).

† “Intentional” was that subjects correctly recognized the instruction before use;

‡ “Unintentional” was that subject incorrectly recognized the instruction before use.