Figure 1. Plan B Label used in the Actual Used Study
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:
Report date:
Sponsor: Women’s Capital Corporation
(The sponsorship was transferred to the Barr Research in Nov, 03)
Investigators: Family Health International (FHI),
Study sites: Five Family Planning Clinics sites (five states in US):
Planned Parenthood League of
Planned Parenthood Centers of
Planned Parenthood of
Planned Parenthood of Central and
Planned Parenthood of
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);
STUDY OBJECTIVES
To estimate the frequency of contraindicated and incorrect use of Plan B when dispensed under OTC-like conditions.
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.
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
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:
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
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.
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.
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.
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
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 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).
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
2. Missing
package: Study drug packages (dispensed or returned) were accounted for all
sites except at the
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 |
|
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) |
|
|
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”. |
Subject
|
|
Clinical Site
|
Pharmacy Sites
|
Total
|
|||||
|
Grand Rapid
|
|
|
|||||