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