Conditions: Contraception
Keywords: Daily birth control
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 189
Healthy volunteers: yes

Brief summary:
This study is designed to assess whether consumers select and use norgestrel 0.075 mg, a progestin only pill for contraception, in a manner consistent with the OTC package directions in an Over-the-Counter (OTC)-like setting.

Detailed description:
Subjects will be primarily recruited via passive recruiting methods, such as in-store posters, direct mail postcards, and digital space advertising.

Respondents to advertisements will either call Clinical Research Organization (CRO) call center or visit the study website for initial screening (during which data regarding age, gender, and minimal study exclusion criteria will be collected) and scheduling of an in-person enrollment visit at a local participating research site.

During the face-to-face enrollment visit, potential subjects who meet the inclusion and exclusion criteria for the study will be given an (empty) study medication package and will be allowed as much time as they need to review the information on the outside of the entire package. Subjects will then be asked if the product is OK or not OK for them to use.

Qualified subjects then will be allowed to purchase (pharmacy sites) or be given (clinic sites) the study product.

Approximately 47 sites will be used, comprising retail pharmacy research sites and women's health clinics or adolescents' clinics.

Arms:
arm 1: Norgestrel 0.075 mg tablets to be taken orally, one tablet daily at the same time everyday for up to 16 weeks

Interventions: intervention 1: Norgestrel 0.075 mg tablets
Intervention descriptions: intervention 1: All subjects enrolled in the use phase of this open-label study will be given the opportunity to purchase and take one Norgestrel 0.075 mg tablet daily up to 16 weeks.

Subjects will use the investigational product based on their understanding of the directions on the outer packaging called the Drug Facts Label and information inside the product packaging called the Consumer Information Leaflet.

Protocol document:
Prot_000.pdf: 
 
HRA Pharma 
 
 
OPILL® ACTUAL USE TRIAL PROTOCOL 
 
 
Title: 
A Multi-Center Oral Contraceptive Pill Use Trial 
Conducted In an OTC Naturalistic Environment 
(OPTION) 
Compound: 
Norgestrel 0.075 mg 
Protocol Number: 
151042-001 
Protocol Version / Date: 
Final v. 1.2 / 15 Dec 2017 
Sponsor’s Name and 
Address:  
Laboratoire HRA Pharma 
15 rue Béranger 75003 PARIS  
France 
Pharmacovigilance Contact 
Information 
HRA Pharma Pharmacovigilance  
15 rue Béranger 75003 PARIS, France 
fax : + 33 1.42.77.03.52  
e-mail : pharmacovigilance@hra-pharma.com 
 
Principal Investigator 
Russell Bradford, MD, MSPH 
PEGUS Research, Inc. 
331 S. Rio Grande, Ste 100 
801-487-9899 
 
24-Hour Adverse Event 
Reporting Number 
888-804-1674 
 
 
The information contained in this document is proprietary and confidential and is intended for the 
exclusive use of the designated addressee.  Any disclosure, reproduction, distribution, or other 
dissemination of this information outside of HRA Pharma or its Affiliates, Licensees, or their 
Regulatory Agencies is strictly prohibited.  If you have received this document in error, please 
contact HRA Pharma. 


Rx-to-OTC Switch Opitto (norgestrel 0.075 mg)
Actual Use Trial Protocol
Authors:
Russell D. Bradford, MD, MSPH
Vice President, Medical Affairs
PEGUS Research, Inc.
Approval:
Sarah Farnsworth.
Vice President, Scientific Affairs
PEGUS Research, lnc.
Virna Gamalinda
Senior Medical Officer Women Health
Laboratoire HRA Pharma
Wr¿<
CONFIDENTIAL
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DN: cn=Sarah Fatnsworth, o=pEGUS
Research, lnc., ou=VP, Scientific Affairs,
emðll=FôrnsworthS@pegus.com, c=US
Reason: I am approvlng this document
Date: 201 8.02.2ó I 7 :23:28.07'00'
Signatures
Signature
Signature
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Date
Final v. 1.2,15D8C2017
PEGUS Research, lnc.
CONFIDENTIAL
Page 2 of 91


Rx-to-OTC Switch Opill® (norgestrel 0.075 mg) 
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PEGUS Research, Inc. 
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Document History 
Document 
Version / Date 
Summary of Changes 
Final protocol 
Version 1.0 
N/A 
Amended protocol 
Version 1.1 
Incorporated IRB 
Recommendations. 
General wording and flow changes 
of the document to better clarify 
study procedures. 
Section 1.2: Dosing information 
about norgestrel 0.075 and how it 
is currently a prescription 
medication. 
Section 3.3: Information regarding 
that subjects must personally enroll 
in this study, and certify that they 
are seeking the study product for 
their own use.  Representative 
buyers (such as family members 
and/or male partners, etc.) will not 
be allowed. 
Section 5.3.2: Information 
regarding the “Mock Purchase” of 
the study and how that pertains to 
potential subjects specifically 
adolescents.  
Section 12.3: Informed consent 
documents will be presented 
electronically, and signatures 
gathered digitally, however, all 
consent procedures (including 
obtaining informed consent from a 
parent or legal guardian, if 
necessary) will be conducted in 
person.  An archived copy of the 
signed informed consent document 
will be made available to subjects 
digitally. 


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Amended Protocol 
Version 1.2 
Section 3.3, 3.3.1:  Revised to 
incorporate exclusion of subjects 
younger than 12. 
Section 3.6:  Clarify the rationale 
for when CIL and reminder card 
are available to subjects. 
Section 4.3.3: Revised to clarify 
that subjects will return study 
materials, any unused IP and 
empty packaging to the study site. 
Sections 5.3.3, 5.4.3.2, 6.4, 6.5, 
8.2 : Text revised to reflect that the 
results of the end of study home 
pregnancy test will be recorded in 
the online medication use / 
electronic diary 
Section 5.4.1:  Text revised to 
allow for sites to collect relevant 
details around an AE and report 
back to PEGUS Research staff. 
Section 5.4.2: Text added to clarify 
that subjects without easy access 
to the internet will be provided a 
device for use in the study. 
Sections 5.4.4, 6.8: Clarified that 
subjects who fail to return for an 
end of study visit will be contacted 
and reminded.  
Section 9.3.3.6: Clarified timeframe 
for pregnancy determination. 
Section 10.1: Clarified that 
interviews will not be conducted in 
the absence of an active internet 
connection. 
Section 12.3:  Clarified that PII will 
not be retained for subjects who do 
not pass screening or who do not 
qualify for use phase, and clarified 
language outlining consent 
procedures for minors who are not 


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“children” according to local law 
and regulation. 
Section 12.4:  Addition of language 
describing the ability of subjects to 
opt in for future contact if there are 
related research opportunities. 


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Protocol Summary 
Study Title A Multi-Center Oral Contraceptive Pill Use Trial Conducted In an 
OTC Naturalistic Environment (OPTION) 
Background and 
Rationale 
Opill® (norgestrel 0.075 mg) is proposed for an Rx-to-OTC switch.  
This combined Self-Selection (SS) / Actual Use Trial (AUT) will be 
conducted to demonstrate appropriate consumer selection and 
use behavior as guided by OTC labeling when using the product 
in the absence of a physician or other learned intermediary.  This 
study will be conducted to obtain measurements of self-selection 
and consumer behaviors related to the actual use of the product 
compliance with key communication messages presented in the 
Drug Facts Label (DFL). 
Objectives and 
Endpoints 
The objective of this study is to evaluate the adequacy of the 
proposed OTC labeling to guide appropriate consumer selection 
and use behavior by measuring pre-specified endpoints.  The 
designation of the following endpoints as primary or secondary 
endpoints or other measures is based on the potential clinical 
consequences raised if a consumer were to fail to heed the label 
instructions.  Endpoints are designated either as Self-Selection 
endpoints or Actual Use endpoints. 
Primary Endpoints 
A. Self-Selection:  Proportion of self-selection population who
make a correct selection decision regarding use of the
product
B. Actual Use:  Use of the study medication every day
C. Actual Use:  Use of the study medication at the same time
of day
D. Actual Use:  Use of the study medication without an
extended break or any break between packs
Secondary Endpoints 
A. Actual Use:  Proportion of user population who do not use
study medication together with another form of hormone-
containing birth control
B. Actual Use:  Proportion of user population who report
using a barrier method of contraception (or abstaining
from intercourse) for the first 48 hours after starting to use
the study medication
C. Self-Selection/Actual Use:  Proportion of self-selection
population taking one of the “ask a doctor or pharmacist
before use” products who do not select (and cite that as
the reason for not selecting), who select but do not use
(and cite that as the reason for not using), or who report
contacting a healthcare provider or pharmacist about use
of the product


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D. Self-Selection/Actual Use: Proportion of self-selection
population who report having liver problems who either do
not select (and cite that as the reason for not selecting),
who select but do not use (and cite that as the reason for
not using), or who report contacting a healthcare provider
about use of the product
E. Actual Use:  Proportion of user population who experience
one of the “Talk to a doctor” conditions listed within the
“When using this product” or “Stop use and ask a doctor”
sections of the label who report contacting a healthcare
provider and/or stop use as directed by the label
F. Actual Use:  Number of pregnancies reported during the
course of the study
Other Measures 
A. Actual Use:  Character and frequency of adverse events
as reported by the user population
B. Actual Use:  Patterns of use, including discontinuation
rates and reasons for discontinuation
C. Actual Use:  Proportion of user population who experience
severe vomiting or diarrhea within 4 hours of taking their
daily pill who report using a barrier method of
contraception every time they have sex (or abstain from
intercourse) for the next 48 hours
D. Actual Use:  Characterize healthcare seeking behavior
among subjects
Study Design This is an observational open-label, multi-center, 16-week study 
designed to mimic an OTC-like environment in which consumers 
will make a selection (and purchase decision, in the case of 
pharmacy sites) about the product based on their reading of the 
DFL and other information on the outer package, and then, if they 
choose to, take Opill® home and use the product aided by the 
OTC labeling (DFL, Consumer Information Leaflet (CIL) and 
reminder card).  The study will increase understanding regarding 
how consumers will use the medication in an OTC-like 
environment. 
Number of 
Participants 
A total of approximately 900 subjects will be allowed to proceed to 
the use phase of the study.  Assuming that about 80% of those 
who proceed to the use phase will both use the study medication 
and participate in at least one follow-up telephone call that will 
yield an actual use population of approximately 720 subjects 
among which to evaluate the primary endpoints.  In an effort to 
achieve an adequate subgroup of adolescent users (age 12-17), 
adult purchasers will be constrained to no more than 725.  Efforts 
will be made to enroll an adolescent subgroup of approximately 
175 use phase participants (or more, should a higher proportion 
naturally occur). Additionally, among adolescents, a sample of 50 
use phase subjects age 12-15 will be sought. 


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Methods Subjects will be primarily recruited via passive recruiting methods, 
such as in-store posters, newspaper advertisements, direct mail 
postcards, and digital space advertising. Respondents to 
advertisements will either call PEGUS Research or visit a study 
website for initial screening (during which data regarding age, 
gender, and minimal study exclusion criteria will be collected) and 
scheduling of an in-person enrollment visit at a local participating 
research site.  Approximately 46 sites will be used, comprising 
retail pharmacy research sites and women’s health clinics or 
adolescents’ clinics in geographically diverse locations. 
Challenging goals for enrollment of adolescent subjects have 
been established.  Experience suggests that the methods of 
advertising that are typically used in an AUT will not be sufficient 
to enroll a large enough cohort of adolescents.  The requirement 
to recognize that a study advertisement could apply to them and 
to respond, schedule an appointment, and actually show up for 
that appointment often proves to be beyond what most 
adolescents will do (particularly among adolescents that are 
seeking the product without a parent’s involvement).  Because 
enrolling a sufficient number of adolescents in the study is 
important, a small number of women’s health clinics or adolescent 
clinics (approximately 10 in total) will be included as study sites.  
In those clinics, active recruitment will be implemented, wherein 
clinic staff will offer adolescents who are seeking oral 
contraception the opportunity to participate in the study. 
During the face-to-face enrollment visit, potential subjects who 
meet the inclusion and exclusion criteria for the study will be 
given an (empty) Opill® package and will be allowed as much time 
as they need to review the information on the outside of the entire 
package (including the DFL).  Subjects will then be asked if the 
product is OK or not OK for them to use.  For subjects at 
pharmacy sites, those who report that it is OK for them to use will 
be told the cost of the investigational product and will be asked if 
they would like to purchase it for their own use.  Reasons for any 
non-purchase decision will be recorded.  For subjects at clinic 
sites, those who report that it is OK for them to use will be asked 
if they would like to obtain it for their own use.  Following the 
selection decisions, in response to a structured questionnaire, 
subjects will provide limited medical history, current medication 
use, and demographic information.  The Rapid Estimate of Adult 
Literacy in Medicine (REALM)1 or Rapid Estimate of Adolescent 
Literacy in Medicine (REALM-Teen)2 will then be administered.  
Subjects will be asked to sign the informed consent.  Subjects 
that sign consent will take a urine-based pregnancy test. 
Qualified subjects then will be allowed to purchase (pharmacy 
sites) or be given (clinic sites) the study product to take home and 
told they may return to the site at any time for resupply.  Subjects 
will be allowed to purchase/obtain up to eight 28-count (four-week 
supply) packages during the study period, although that limit will 


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not be communicated to subjects unless they attempt to 
purchase/obtain more than that.  While any request for more than 
8 packages will be denied, the request and reason for it will be 
recorded. Subjects will record their use of the product using an 
online medication use diary. 
Subsequent contact will be via four telephone interviews 
conducted by trained nurse interviewers working from a central 
research site at weeks 4, 8, 12, and 16.  Interviewers will contact 
subjects by telephone to conduct scripted interviews to gather 
information on if, how and when the subject took the product, any 
adverse events (AEs), concomitant medications, and other 
actions the subject may have taken related to the use of the 
product.   
Once all steps of the final telephone interview are completed, the 
subject will be asked to take a self-administered urine-based 
home pregnancy test and record the results in their electronic 
diary. Subjects will then be prompted to return to the study site for 
an additional end-of-study pregnancy test and to return any 
unused study medication or empty packaging. If the subject does 
not complete a home pregnancy test but does return to the site for 
the end of study visit and associated pregnancy test, no additional 
follow-up will be done.  If the subject does not record the end of 
study home pregnancy test and fails to return to the site for the 
end of study visit, a nurse interviewer will follow up and request 
that they complete a self-administered urine-based pregnancy test 
at home, report the results in their electronic diary, and return to 
the site for the end of study visit. 
Statistical 
Analysis 
A summary of the disposition of subjects (including responders, 
self-selection population, use phase subjects and users) and 
reasons for exclusion from these populations will be provided.  
Demographic characteristics, medical history and other 
background information will be summarized for the self-
selection, use phase and user populations. 
Frequencies and percentages will be presented for categorical 
data. Mean, standard deviation (SD), median and range will be 
presented for numerical data. 
Frequencies, percentages and 2-sided 95% confidence 
intervals (CIs) will be calculated for the primary and secondary 
endpoints using the Exact method.  For the primary endpoints, 
it will be concluded that the established target threshold is 
reached if the lower limit of the CI of the point estimate is equal 
to or exceeds the value of the pre-determined threshold. 
Endpoints and demographics will be presented for subgroups of 
interest, with subjects dichotomized on the corresponding 
variables, which include (but are not necessarily limited to): 


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literacy, gender, age (adolescent vs. adult women), and history of 
hormonal birth control use. 
A more detailed description of planned data analysis procedures 
will be found in the Statistical Analysis Plan which will be 
approved and signed before the database is locked. 
Study Duration The duration of this study is expected to be approximately 10 
months (from first subject enrolled in the study until last subject 
last visit), with subject recruitment proposed to start in Q1 2018 
and end in Q3 2018.  The actual overall study duration or subject 
recruitment period may vary. 
CRO PEGUS Research, Inc. 
331 South Rio Grande, Suite 100 
Salt Lake City, UT  84101 
Date 15 Dec 2017 


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Schedule of Activities 
 
The schedule of activities table below provides an overview of the protocol visits and procedures.  Refer to the STUDY 
PROCEDURES and ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment 
required for compliance with the protocol.  The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the well-being of the subject. 
Visit Identifier 
Recruitment  Enrollment 
Visit / First 
Purchasea 
 
Week 
4 
 
Week 
8 
Week 
12 
Week 
16 
End of 
Treatment / 
Early 
Terminationf 
End of 
Study 
Visit 
After Study 
Completion 
  
 
Day 1 
28±4 
Days 
56±4 
Days 
84±5 
Days 
112±5 
Days 
 
 
 
Initial screening and scheduling 
X 
 
 
 
 
 
 
 
 
Review screening / study inclusion 
criteria 
 
X 
 
 
 
 
 
 
 
Subject reviews outer packaging and 
makes selection and purchase 
decision 
 
X 
 
 
 
 
 
 
 
Collect demographics 
 
X 
 
 
 
 
 
 
 
Collect current/regular relevant 
medications and associated 
conditionsb 
 
X 
 
 
 
 
 
 
 
Administer REALM or REALM-Teen 
test c 
 
X 
 
 
 
 
 
 
 
Study exclusion/inclusion criteria 
assessed for eligibility to continue 
 
X 
 
 
 
 
 
 
 
Subject signs informed consent  
 
X 
 
 
 
 
 
 
 
Enrollment pregnancy testd 
 
X 
 
 
 
 
 
 
 
Purchase transactione/Product 
dispensed 
 
X 
 
 
 
 
 
 
 
Subject uses study diary 
 
X 
→ 
→ 
→ 
→ 
X 
 
 
Interim telephone interviews  
 
 
X 
X 
X 
X 
 
 
 
End-of-study telephone interview 
 
 
 
 
 
 
X 
 
 
Concomitant medications 
 
X 
→ 
→ 
→ 
→ 
X 
 
 
Adverse Events 
 
X 
→ 
→ 
→ 
→ 
X 
 
 


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Visit Identifier 
Recruitment  Enrollment 
Visit / First 
Purchasea 
 
Week 
4 
 
Week 
8 
Week 
12 
Week 
16 
End of 
Treatment / 
Early 
Terminationf 
End of 
Study 
Visit 
After Study 
Completion 
  
 
Day 1 
28±4 
Days 
56±4 
Days 
84±5 
Days 
112±5 
Days 
 
 
 
Self-administered end-of-study 
pregnancy test 
 
 
 
 
 
 
 
X 
 
Return study drug and materials 
 
 
 
 
 
 
 
X 
 
Site-administered end-of-study 
pregnancy test 
 
 
 
 
 
 
X 
 
 
Reimbursement for cost of study 
medication (after all subjects 
complete the study) 
 
 
 
 
 
 
 
 
X 
Abbreviations: → = ongoing/continuous event; REALM = Rapid Estimate of Adult Literacy in Medicine; REALM-Teen = Rapid Estimate of 
Adolescent Literacy in Medicine 
a. 
Day relative to first purchase of study medication (Day 1). 
b. 
Subjects will be asked to provide a list of any medical conditions they have and any medications they are taking.  Females only. 
c. 
REALM1 or REALM-Teen2 test will be conducted for all subjects regardless of self-selection and purchase decision. 
d. 
Subjects with a positive pregnancy test at enrollment will be asked to make a selection decision again to better assess self-selection and then 
will be excluded from the use phase. 
e. 
Subjects will be allowed to purchase or be dispensed any amount of study medication up to a total of 8 packages at any time during their use 
phase. 
f. 
Early termination interview will be conducted during the study if the subject is discontinued or withdraws consent prior to Week 16. 
 
 
 


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Glossary and Abbreviations 
 
AAFP 
American Academy of Family Physicians 
ACCP 
American College of Clinical Pharmacy 
ACOG 
The American Congress of Obstetricians and Gynecologists 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
AMA 
American Medical Association 
APHA 
American Public Health Association 
ASRM 
American Society for Reproductive Medicine 
AUT 
Actual Use Trial 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIL 
Consumer Information Leaflet 
CIOMS 
Council for International Organizations of Medical Sciences 
COC 
Combined Oral Contraceptive 
CRF 
Case Report Form 
CRO  
Contract Research Organization  
DCI 
Data Collection Instrument 
DFL 
Drug Facts Label 
DMP 
Data Management Plan 
EDC 
Electronic Data Capture 
EDP 
Exposure During Pregnancy 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FD&C 
Food, Drug and Cosmetics (US Federal act) 
GCP  
Good Clinical Practice  
HBC 
Hormonal Birth Control 
HIV 
Human Immunodeficiency Virus 
HPO 
Hypothalamic-Pituitary-Ovarian 
HRT 
Hormone Replacement Therapy 
ICH 
International Council on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IP 
Investigational Product 
IUD 
Intrauterine Device 
LCS 
Label Comprehension Study 
LNG-IUS 
Levonorgestrel-releasing Intrauterine System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHANES 
National Health and Nutrition Examination Survey 


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OTC 
Over-the-Counter 
PHI 
Personal Health Information  
PII 
Personally Identifiable Information  
POC 
Progestin Only Contraceptive 
POP 
Progestin Only Pill 
PT 
Preferred Term 
PV 
Pharmacovigilance 
RCT 
Randomized Control Trial 
REALM 
Rapid Estimate of Adult Literacy in Medicine 
REALM-Teen 
Rapid Estimate of Adolescent Literacy in Medicine 
Rx 
Prescription 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SLE 
Systemic Lupus Erythematosus 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SSS 
Self-Selection Study 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
US / USA 
United States / United States of America 
US SPR 
US Selected Practice Recommendations for Contraceptive Use 
USPS 
Unites States Postal Service 
USMEC 
United States Medical Eligibility Criteria (for Contraceptive Use) 
WHO 
World Health Organization 
 
 
 


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Table of Contents 
1 
INTRODUCTION ................................................................................................... 19 
1.1 
Indication ..................................................................................................... 19 
1.2 
Dose ............................................................................................................ 19 
1.3 
Background and Rationale ........................................................................... 19 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 19 
2.1 
Objectives .................................................................................................... 19 
2.2 
Endpoints ..................................................................................................... 19 
 
Primary Endpoints ............................................................................ 19 
 
Secondary Endpoints ....................................................................... 20 
 
Other Measures ................................................................................ 20 
2.3 
Rationale Underlying Selection and Prioritization of Study Endpoints .......... 20 
3 
STUDY DESIGN .................................................................................................... 26 
3.1 
Naturalistic Design ....................................................................................... 27 
3.2 
Study Sites................................................................................................... 27 
 
Site Training and Procedural Integrity ............................................... 28 
3.3 
Subject Selection ......................................................................................... 28 
 
Self-Selection Phase / Initial Enrollment Visit Inclusion Criteria ........ 29 
 
Use Phase Exclusion Criteria ........................................................... 29 
 
Recruitment Methods ....................................................................... 30 
3.4 
Randomization ............................................................................................. 30 
3.5 
Data Collection ............................................................................................ 30 
3.6 
Test Materials .............................................................................................. 31 
3.7 
Study Administrative Structure ..................................................................... 31 
4 
STUDY TREATMENTS .......................................................................................... 31 
4.1 
Allocation to Treatment ................................................................................ 31 
4.2 
Breaking the Blind ........................................................................................ 32 
4.3 
Drug Supplies .............................................................................................. 32 
 
Formulation and Packaging .............................................................. 32 
 
Preparation and Dispensing ............................................................. 32 
 
Drug Storage and Accountability ...................................................... 32 
4.4 
Drug Administration ..................................................................................... 33 
 
Compliance ...................................................................................... 33 
4.5 
Concomitant Medication(s) .......................................................................... 33 
4.6 
Rescue/Escape/Salvage Therapy ................................................................ 33 
4.7 
Batch recall .................................................................................................. 33 
5 
STUDY PROCEDURES ......................................................................................... 34 
5.1 
Telephone Screening of Passively Recruited Potential Subjects .................. 34 


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5.2 
Active Recruitment of Potential Subjects ...................................................... 34 
5.3 
Study Period ................................................................................................ 34 
 
Enrollment Visit, Self-Selection/Purchase Decision .......................... 34 
 
Mock Purchase................................................................................. 34 
 
After Purchase Decision and Before Study Entry .............................. 35 
5.4 
Use Phase ................................................................................................... 36 
 
Unscheduled Study Site Visits .......................................................... 36 
 
Online Medication Use Diary ............................................................ 36 
 
Telephone Interviews ....................................................................... 37 
 
End of Study Visit ............................................................................. 37 
5.5 
Subject Withdrawal (Early Termination) ....................................................... 38 
5.6 
Study Flow ................................................................................................... 40 
6 
ASSESSMENTS .................................................................................................... 41 
6.1 
Screening Assessment ................................................................................ 41 
6.2 
Enrollment Interview .................................................................................... 41 
6.3 
Reading Level Assessment .......................................................................... 41 
6.4 
Pregnancy Testing ....................................................................................... 43 
6.5 
Medication Use Diary ................................................................................... 43 
6.6 
Interim Follow-up Telephone Interviews ....................................................... 43 
6.7 
End-of-Study/Early Termination Telephone Interview .................................. 44 
6.8 
End-of-Study Visit ........................................................................................ 44 
7 
ADVERSE EVENT REPORTING ........................................................................... 44 
7.1 
Adverse Events ............................................................................................ 44 
7.2 
Reporting Period .......................................................................................... 45 
7.3 
Definition of an Adverse Event ..................................................................... 45 
7.4 
Abnormal Test Findings ............................................................................... 46 
7.5 
Serious Adverse Events ............................................................................... 46 
 
Protocol-Specified Serious Adverse Events ...................................... 46 
7.6 
Hospitalization ............................................................................................. 47 
7.7 
Severity Assessment ................................................................................... 48 
7.8 
Causality Assessment .................................................................................. 48 
7.9 
Exposure During Pregnancy ........................................................................ 48 
7.10 Withdrawal Due to Adverse Events .............................................................. 49 
7.11 Eliciting Adverse Event Information .............................................................. 49 
7.12 Reporting Requirements .............................................................................. 49 
 Serious Adverse Event Reporting Requirements .............................. 50 
 Non-Serious Adverse Event Reporting Requirements ...................... 50 
 Sponsor Reporting Requirements to Regulatory Authorities ............. 50 


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8 
DATA MANAGEMENT ........................................................................................... 51 
8.1 
EDC System ................................................................................................ 51 
8.2 
Electronic Diary System ............................................................................... 51 
8.3 
Data Management Plan ............................................................................... 51 
8.4 
Conceptual Approach to Self-Selection ........................................................ 51 
8.5 
Classification Activities ................................................................................. 52 
 
Selection Decision ............................................................................ 52 
 
Appropriate to Use ........................................................................... 53 
 
Physician Mitigation .......................................................................... 55 
 
Coding of Open-ended Responses ................................................... 55 
9 
DATA ANALYSIS/STATISTICAL METHODS ......................................................... 55 
9.1 
Sample Size Determination .......................................................................... 56 
9.2 
Analysis Populations .................................................................................... 56 
9.3 
Endpoint Analysis ........................................................................................ 56 
 
Primary Endpoint Analysis ................................................................ 57 
 
Target Thresholds ............................................................................ 61 
 
Secondary Endpoint Analysis ........................................................... 71 
 
Other Measures Analysis ................................................................. 73 
9.4 
Safety Analysis ............................................................................................ 73 
9.5 
Interim Analysis ........................................................................................... 73 
9.6 
Missing Data ................................................................................................ 73 
9.7 
Open-ended Data ........................................................................................ 73 
10 DATA HANDLING AND RECORD KEEPING ......................................................... 73 
10.1 Data Collection Instruments / Electronic Data Record .................................. 73 
10.2 Study Documentation ................................................................................... 74 
10.3 Confidentiality of Study Documents and Electronic Records ........................ 74 
11 QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 75 
12 ETHICS .................................................................................................................. 75 
12.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ........ 75 
12.2 Ethical Conduct of the Study ........................................................................ 75 
12.3 Subject Information and Consent ................................................................. 76 
12.4 Opt in for Future Research Contact.............................................................. 78 
12.5 Liability and Insurance ................................................................................. 78 
12.6 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
 
78 
12.7 Mandatory Reporting ................................................................................... 78 
13 SPONSOR DISCONTINUATION CRITERIA .......................................................... 79 
14 PUBLICATION OF STUDY RESULTS ................................................................... 79 


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14.1 Communication of Results by the Sponsor................................................... 79 
15 EMERGENCY CONTACTS ................................................................................... 79 
16 STUDY DURATION AND DATES .......................................................................... 79 
17 REFERENCES ...................................................................................................... 80 
18 APPENDICES ........................................................................................................ 82 
18.1 Mock Package and Drug Facts Label ........................................................... 82 
18.2 Consumer Information Leaflet ...................................................................... 86 
18.3 Reminder Card ............................................................................................ 91 
 
List of In-Text Tables and Figures 
 
Figure 1  Study Procedures Flowchart .......................................................................... 40 
 
Table 1  Endpoint Rationale .......................................................................................... 21 
Table 2 REALM Test Grade-equivalent Reading Levels ................................................ 42 
Table 3 REALM-Teen Test Grade-equivalent Reading Levels ...................................... 42 
Table 4 Self-Selection Decision Outcomes .................................................................... 52 
Table 5  Two-sided 95% CIs for Various Sample Sizes Around 85% Point Estimate ..... 56 


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1 
INTRODUCTION 
Opill® (norgestrel 0.075 mg; currently approved as Ovrette®, with the new proposed 
proprietary name Opill®) is proposed for a prescription to over-the-counter (Rx-to-OTC) 
switch.  This study is designed to assess whether consumers in a simulated OTC 
environment will self-select and use the product in a manner consistent with the OTC 
labeling.  A Drug Facts Label (DFL) for the nonprescription version of Opill® has been 
drafted and evaluated in pivotal label comprehension studies (LCS).  This protocol 
describes the next stage of the development program, a pivotal self-selection study 
(SSS) and actual use trial (AUT), which will provide measures of how and when 
consumers select to use and use the product in an OTC-like setting. 
1.1 
Indication 
The proposed labeled “Purpose” for nonprescription norgestrel 0.075 mg is “Daily Birth 
Control Pill”.  The proposed labeled “Use” for nonprescription norgestrel 0.075 mg is “for 
daily use by women to prevent pregnancy”. 
1.2 
Dose 
Norgestrel 0.075 mg (previously marketed under the tradename Ovrette®), taken daily, is 
an approved prescription progestin-only oral contraceptive pill (POP).  The current 
prescription formulation and dose is proposed for the Rx-to-OTC switch.  The safety and 
efficacy of the study product at that dose were established with the initial approval of the 
product for prescription use. 
1.3 
Background and Rationale 
This SSS/AUT is designed to demonstrate that consumers will select and use Opill® in a 
manner consistent with the OTC labeling.  
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The objective of this study is to evaluate the adequacy of the proposed OTC labeling to 
guide the behavior of subjects in an OTC-like setting when selecting and using Opill®. 
2.2 
Endpoints 
The determination of primary and secondary endpoints has been made based on the 
potential clinical consequences of a consumer failing to heed each key label instruction.  
The rationale behind selection and prioritization of endpoints is summarized below in 
Section 2.3 (a full detailed rationale for primary endpoints is presented in Section 
9.3.2).  The appropriateness of behaviors will be assessed by measuring the endpoints 
as per the endpoint analysis described in Section 9.3. 
 Primary Endpoints 
A. Self-Selection:  Proportion of self-selection population who make a correct 
selection decision regarding use of the product 


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B. Actual Use:  Use of the study medication every day 
C. Actual Use:  Use of the study medication at the same time of day 
D. Actual Use:  Use of the study medication without an extended break or any break 
between packs 
 Secondary Endpoints 
A. Actual Use:  Proportion of user population who do not use study medication 
together with another form of hormone-containing birth control. 
B. Actual Use:  Proportion of user population who report using a barrier method of 
contraception (or abstaining from intercourse) for the first 48 hours after starting 
to use the study medication. 
C. Self-Selection/Actual Use:  Proportion of self-selection population taking one of 
the “ask a doctor or pharmacist before use” products who do not select (and cite 
that as the reason for not selecting), who select but do not use (and cite that as 
the reason for not using), or who report contacting a healthcare provider or 
pharmacist about use of the product. 
D. Self-Selection/Actual Use: Proportion of self-selection population who report 
having liver problems who either do not select (and cite that as the reason for not 
selecting), who select but do not use (and cite that as the reason for not using), 
or who report contacting a healthcare provider about use of the product. 
E. Actual Use:  Proportion of user population who experience one of the “Talk to a 
doctor” conditions listed within the “When using this product” or “Stop use and 
ask a doctor” sections who report contacting a healthcare provider and/or stop 
use as directed by the label. 
F. Actual Use:  Number of pregnancies reported during the course of the study. 
 Other Measures 
A. Actual Use:  Character and frequency of adverse events as reported by the user 
population. 
B. Actual Use:  Patterns of use, including discontinuation rates and reasons for 
discontinuation. 
C. Actual Use:  Proportion of user population who experience severe vomiting or 
diarrhea within 4 hours of taking their daily pill who report using a barrier method 
of contraception every time they have sex (or abstain from intercourse) for the 
next 48 hours. 
D. Actual Use:  Characterize healthcare seeking behavior among subjects. 
 
2.3 
Rationale Underlying Selection and Prioritization of Study Endpoints 
The determination of endpoints and prioritization as primary, secondary or other 
measures has been made based on the potential clinical consequences of a consumer 
failing to heed each key label instruction.  Each endpoint is listed in Table 1 below, with 
the DFL messages relevant to the endpoint, followed by the rationale underlying the 
classification as primary, secondary or other measure.  Please note that the rationale in 
the table below describe the reasons for measuring each endpoint and their 
classifications.  Descriptions of how each endpoint is calculated is found in Section 9.3. 
 


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Table 1  Endpoint Rationale 
Endpoints 
Relevant DFL Message(s) 
 
 
Primary 
 
A 
Self-Selection:  Proportion of self-selection 
population who make a correct selection 
decision regarding use of the product  
 
Use 
For daily use by women to prevent 
pregnancy 
 
Allergy alert: Do not use if you are allergic to 
this product or any of its ingredients. 
 
Do not use 
● if you are male 
● if you have ever had any cancer 
● if you are already pregnant or think you 
may be pregnant 
● as an emergency contraceptive (to prevent 
pregnancy after unprotected sex)  
 
 
 
 
Rationale:  This endpoint measures the ability of subjects to make a correct self-selection 
decision based on their own medical profile and history and the label inclusion and 
exclusion criteria.  This is important to the extent that data about safe and effective use of 
the product are linked to the elements inherent to correct selection (or non-selection).  
Therefore, general self-selection is designated as primary endpoint.   
 
Please note that the criteria upon which initial selection is judged include the absolute 
contraindications, as translated from the prescription labeling contraindications section to 
the proposed DFL.  Two conditional contraindications from the prescription labeling are 
presented in other sections of the DFL to reflect their conditional nature, namely, 
unexplained intermenstrual bleeding and liver problems.  Evaluation of the instructions 
regarding those two messages is evaluated individually based on subject behavior in 
discrete endpoints. 
 
 
 
B  Actual Use:  Use of the study medication 
every day  
 
Directions 
● Take 1 tablet at the same time every day  
● this product will work best to prevent 
pregnancy when taken exactly as directed  
● if you are more than 3 hours late taking 
your tablet or miss taking your tablet on 1 or 
more days: 
● take 1 tablet immediately, as soon as 
you remember that you missed it 
● then go back to taking your daily tablet at 
your usual time 
● use a condom (or another barrier 
method) every time you have sex during 
the next 2 days (48 hours), because it 
takes 2 days for Opill® to start working 
again 
 
 
 
 
Rationale:  This endpoint is designed to measure the extent to which subjects comply with 
the instruction to take one tablet every day.  This endpoint is relevant to several key 
messages from the DFL which are directly related to efficacy of the product.  A woman who 
does not follow the instructions to take one tablet every day and is engaging in sexual 


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intercourse may put herself at risk of unintended pregnancy.  Therefore, adherence to this 
message is designated as a primary endpoint. 
 
 
 
C  Actual Use:  Use of the study medication at 
the same time of day 
Directions 
● Take 1 tablet at the same time every day   
● this product will work best to prevent 
pregnancy when taken exactly as directed 
● if you are more than 3 hours late taking 
your tablet or miss taking your tablet on 1 or 
more days: 
● take 1 tablet immediately, as soon as 
you remember that you missed it 
● then go back to taking your daily tablet at 
your usual time 
● use a condom (or another barrier 
method) every time you have sex during 
the next 2 days (48 hours), because it 
takes 2 days for Opill® to start working 
again 
 
 
 
 
Rationale:  This endpoint is designed to measure the extent to which subjects comply with 
the instruction to take the product at the same time every day.  While it is not clear the 
extent to which failure to heed this instruction is clinically relevant, pharmacodynamics of 
other progestin only pills (POPs) suggest that they may be most efficacious if taken no 
more than 3 hours after the time of day the previous day’s dose was taken.  Therefore, 
adherence to this message is designated as a primary endpoint. 
 
 
 
D 
Actual Use:  Use of the study medication 
without an extended break or any break 
between packs 
Directions 
● Take 1 tablet at the same time every day  
● Never skip your daily tablet 
● to prevent pregnancy, take this product 
every day, even when you bleed or have 
spotting 
● When you finish this pack, start the next 
one the following day without a break 
 
 
 
 
Rationale:  This endpoint is intended to ensure that women understand that this product is 
taken daily, without any breaks, and adhere to that instruction.  The endpoint assesses 
whether users understand not to take breaks between pills as it is important that 
consumers do not miss several days in a row for any reason.  It is being assessed in part 
because, some consumers may be accustomed to or familiar with the pattern of use for 
some combined oral contraceptives (COCs) where pills containing active ingredients are 
taken for 21 (or more) days followed by a pill-free break of 4-7 days (or 4-7 days of inactive 
pills). If a woman fails to heed the instructions not to skip pills, to take the product every 
day even if they bleed or have spotting, or to start the next pack the day after finishing a 
pack, and takes breaks in her use of the product, she may, if sexually active, put herself at 
risk of unintended pregnancy.  Therefore, adherence to this message is designated as a 
primary endpoint.  Please note that all cases of missed pills at any time will be captured in 
primary endpoint B above, so that this endpoint represents a special case in which multiple 
pills are missed in a row or pills are missed in between packs. 
 
 
 
 
 
 
Secondary 
 
A 
Actual Use:  Proportion of user population 
who do not use study medication together 
Do not use 


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with another form of hormone-containing 
birth control 
● together with another birth control pill, 
vaginal ring, patch, implant, injection or an 
IUD (intra-uterine device) 
 
 
 
 
Rationale:  This endpoint measures whether subjects use the study product concomitantly 
with another hormone-containing birth control method.  This is designated as a secondary 
endpoint for several reasons.  While the concomitant use of a POP with another hormonal 
method of birth control or with an intrauterine device (IUD) is unnecessary, and would 
represent unnecessary expense, it is not unsafe.  There would be no medical 
consequences of taking Opill® while using another contraceptive method since its 
concomitant use would not interfere with the efficacy of the other method or with the 
efficacy of Opill®, and adding a relatively small dose of progestin to another method would 
be unlikely to alter the pattern of side effects of either method.  Because failure to heed this 
message would not result in a safety concern or a reduction in efficacy, this endpoint is 
designated as secondary. 
 
 
 
B 
Actual Use:  Proportion of user population 
who report using a barrier method of 
contraception (or abstaining from 
intercourse) for the first 48 hours after 
starting to use the study medication 
Directions 
● Use a condom (or another barrier method) 
every time you have sex during the first 2 
days of use (48 hours) after you start your 
first pack of this product, because it takes 2 
days for this product to start working 
 
 
 
 
Rationale:  This endpoint measures how well subjects follow the instruction to use a 
condom or another barrier method every time they have sex during the first two days of 
use of the study product.  The rationale for the instruction is that it takes 48 hours of 
product use for the establishment of full contraceptive efficacy.  Use of a barrier method 
during the first 48 hours of POP use is recommended to reduce the risk of pregnancy 
during that time period. 
 
While it is not possible to quantify the relative increase in the risk of contraceptive failure if 
a woman were to fail to heed this instruction, the risk of pregnancy with a single act of 
intercourse even when no contraceptive method is used is low.  Therefore, this endpoint is 
designated as secondary. 
 
 
 
C 
Self-Selection/Actual Use:  Proportion of 
self-selection population taking one of the 
“ask a doctor or pharmacist before use” 
products who do not select (and cite that 
as the reason for not selecting), who select 
but do not use (and cite that as the reason 
for not using), or who report contacting a 
healthcare provider or pharmacist 
Ask a doctor or pharmacist before use if  
● you are taking a prescription drug to:   
● prevent seizures (phenytoin, 
carbamazepine, barbiturates, primidone, 
topiramate, oxcarbazepine) 
● treat tuberculosis (rifampin, rifabutin) 
● treat HIV/AIDS  
● treat pulmonary hypertension (bosentan) 
● you are taking a supplement containing St. 
John’s Wort (an herbal ingredient) 
● you have used an emergency 
contraceptive containing ulipristal acetate in 
the past 5 days 
 
 
 
 
Rationale:  This secondary endpoint measures how well subjects follow the instruction to 
ask a doctor or pharmacist when taking one of the listed drugs of interaction.  The 
interaction with POPs of some medications, such as certain anticonvulsants, antiretroviral 
therapies (e.g. efavirenz) and drugs for the treatment of tuberculosis (TB) (e.g. rifampicin) 
may reduce the effectiveness of the contraceptive [USMEC 2016].  While use of these 
medications may reduce the effectiveness of POPs, it does not present a safety risk to 
users.  Failing to obey these instructions may result in an increased risk of pregnancy, 


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although this increased risk of pregnancy has not been quantified.  Pregnancy is relatively 
contraindicated in women with these conditions taking these drugs, so use of any 
contraceptive method, even with reduced efficacy, is beneficial.  This endpoint is 
designated as secondary also because the number of subjects expected to fall into this 
population is small and the study is not powered to provide for a narrow confidence interval 
around the estimate of these behaviors, due to this small denominator. 
Please note that the denominator for this endpoint is the self-selection population, to 
account for subjects who may decide not to select the product based on this warning 
(which would be a correct behavior), but subjects taking these medications will be allowed 
to select the study product and use it, with adherence to the warning evaluated based on 
whether or not they report discussing with a doctor or pharmacist. 
 
 
 
D 
Self-Selection/Actual Use:  Proportion of 
self-selection population who report having 
liver problems who either do not select 
(and cite that as the reason for not 
selecting), who select but do not use (and 
cite that as the reason for not using), or 
who report contacting a healthcare provider 
about use of the product 
Ask a doctor before use if you have 
● liver problems 
 
 
 
 
Rationale:  This endpoint measures how well subjects who report liver problems follow the 
instruction to consult a healthcare provider about use of the product.  This is designated as 
a secondary endpoint because the types of liver problems potentially adversely affected by 
POP use, hepatocellular adenoma and carcinoma, are rare and the potential clinical 
consequences of those with such liver problems taking a POP are theoretical and also rare 
(White et al, 2012).  Women with these specific conditions are likely to be under the care of 
a physician with regular follow up, which is likely to include discussion about any 
medication being used.  If this instruction is ignored by a consumer in this very small 
population, the consequence is theoretical worsening of the prognosis of their 
hepatocellular adenoma and carcinoma.  While the DFL directs all women with “liver 
problems” to “Ask a doctor before use” out of an abundance of caution, for women with 
"liver problems" other than hepatocellular adenoma and carcinoma, harmful effects are 
unlikely. This endpoint is designated as secondary also because the number of subjects 
expected to fall into this population is very small and the study is not powered to provide for 
a narrow confidence interval around the estimate, due to this small denominator. 
 
Please note that the denominator for this endpoint is the self-selection population, to 
account for subjects who may decide not to select based on this warning (which would be 
a correct behavior), but subjects reporting liver problems will be allowed to select the 
product and use it, with adherence to the warning evaluated based on whether or not they 
report discussing with a doctor and following the doctor’s advice. 
 
 
 
E 
Actual Use:  Proportion of user population 
who experience one of the “Talk to a 
doctor” conditions listed within the “When 
using this product” or “Stop use and ask a 
doctor” sections who report talking with a 
healthcare provider and/or stop use as 
directed by the label 
When using this product 
● You are likely to experience changes in 
your menstrual periods 
● Talk to a doctor AND continue taking this 
product every day if you have these 
unexpected bleeding symptoms: 
●unexplained vaginal bleeding between 
your periods before you started using this 
product 
● repeated vaginal bleeding brought on by 
sex 


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● periods that lasts more than 8 days or 
are unusually heavy 
● have not had any periods for 2 months or 
you think you may be pregnant – do a 
pregnancy test or talk to a doctor 
● Talk to a doctor if you 
● have sudden or severe pain in your lower 
belly – see a doctor immediately (you could 
have an ectopic pregnancy) 
● start having migraines with aura 
(headaches that start with changes in 
vision) or your migraine headaches get 
worse 
● Stop use and ask a doctor if you 
● become pregnant 
● develop yellowing of your skin or whites 
of your eyes (especially with fever, 
tiredness, loss of appetite or dark colored 
urine) 
 
 
 
 
 
Rationale:  This endpoint measures how well subjects follow the instruction to consult a 
healthcare provider and/or stop use of the product in the face of certain label-defined 
conditions.  This is a composite endpoint measuring subjects’ adherence to related 
instructions, namely asking a healthcare provider and/or stopping use of the product in 
response to a variety of possible conditions, none of which are likely to be independently 
seen in this study in significant numbers. While the frequency of each condition and the 
appropriate behavioral response will be reported independently as part of this endpoint, the 
calculated endpoint measure will be the composite.  It is designated as a secondary 
endpoint for a number of reasons.  Only one of the conditions that consumers are directed 
to talk to a doctor about, or stop use and ask a doctor about, are potentially caused by, or 
exacerbated by, use of the study product (i.e, cholestasis).  The others are included in the 
labeling as they might be a sign of an underlying condition that should be evaluated by a 
healthcare provider.  Additionally, for most of these conditions (apart from pregnancy and 
jaundice which develops during treatment) there is no contraindication to continued use.  In 
the case of pregnancy, while there is obviously no contraceptive benefit to use of the study 
product while pregnant, neither would there be expected to be any risk incurred by such 
use.  In the case of jaundice that develops during treatment, such cases are expected to 
be exceptionally rare.  As with the other elements of the endpoint, if any such cases occur, 
they will be identified and reported independently.  However, the expected frequency of 
these conditions argues for their inclusion as part of this composite measure.     
 
 
 
F 
Actual Use:  Number of pregnancies 
reported during the course of the study 
 
 
 
 
 
Rationale:  This endpoint is intended to characterize the pregnancies that may occur during 
the course of the study.  While it does not directly measure behavior related to messages 
on the DFL, it is of interest.  Please note that as efficacy of the product has already been 
established, this study is not powered as an efficacy study.  Therefore, conclusions related 
to efficacy cannot be drawn. 
 
 
 
 
 
 
Other Measures 
 


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A 
Actual Use:  Character and frequency of 
adverse events as reported by the user 
population 
 
 
 
 
 
Rationale:  This endpoint is intended to characterize the type and frequency of adverse 
events among subjects in the use phase of this study.  There is no reason to expect that 
rates or character of adverse events will differ from those expected in the prescription 
environment.  This endpoint is designated an “other measure” as it is not a direct measure 
of participants' compliance with label directions. 
 
 
 
B 
Actual Use:  Patterns of use (e.g., starting 
and stopping, discontinuation rates and 
reasons for discontinuation) 
 
 
 
 
 
Rationale:  This endpoint is intended to characterize more general patterns of use, such as 
how and when subjects start to use the study product, how often subjects discontinue use 
and why, as well as to identify any unexpected uses (attempted use as an emergency 
contraceptive, if there is any such use, for example).  Importantly, discontinuation, as 
contrasted to non-compliance, is not contrary to labeling; a woman is free to discontinue 
the product at any time, for whatever reason.  This is designated as an “other measure.” 
 
 
 
C 
Actual Use:  Proportion of user population 
who experience severe vomiting or 
diarrhea within 4 hours of taking their daily 
pill who report using a barrier method of 
contraception every time they have sex (or 
abstain from intercourse) for the next 48 
hours 
Directions 
● If you vomit for any reason or have severe 
diarrhea within 4 hours of taking your daily 
tablet, use a condom (or another barrier 
method) every time you have sex for the 
next 2 days (48 hours), because the 
medicine may not have been fully absorbed 
 
 
 
 
Rationale:  This endpoint is intended to measure how well subjects follow the instructions 
to use a condom (or another barrier method) every time they have sex for the next 48 
hours if they have vomited or had severe diarrhea within 4 hours of taking the product.  
This is designated as an "other measure," as the study product is not expected to cause 
vomiting or diarrhea.  This message is intended for any woman for whom vomiting or 
severe diarrhea happen to occur within four hours of taking a pill (conditions expected to 
be quite uncommon and unrelated to product use), as vomiting or severe diarrhea may 
interfere with absorption of that dose.  The risk for unintended pregnancy among a woman 
who fails to heed this message is expected to be very low. 
 
 
 
D 
Actual Use:  Characterize healthcare 
seeking behavior among subjects 
 
 
 
 
 
Rationale:  This endpoint is intended to characterize how subjects in this study typically 
interact with healthcare providers and how they do so under study conditions.  This is 
designated as another measure, as it is of general interest but unrelated to any DFL 
message.  
 
 
 
3 
STUDY DESIGN 
This is an observational, open-label, multi-center, 16-week study designed to create as 
much as possible an OTC-like environment in which participants will make an initial self-
selection and purchase decision about Opill® based only on their reading of the outside 
of the package including the DFL.  Qualified participants who choose to do so will then 


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purchase the study medication, leave the study site and use the product on their own, 
guided by the OTC labeling.  The study is designed to assess if, when and how subjects 
use the medication in an OTC-like environment. 
It is important to note that none of the information gathered at screening, enrollment, or 
during the 16-week study period will be discussed with subjects until the End-of-Study 
interview. 
3.1 
Naturalistic Design 
This trial is a multi-center trial conducted in a naturalistic environment.  Study 
characteristics and procedures were designed to make it as naturalistic as possible.  
Some of the key naturalistic elements include the following: 
• 
There are minimal exclusionary criteria imposed on participants, making this trial 
nearly an all-comers study to mimic the likely OTC population. 
• 
The study will be conducted in retail pharmacies, representing typical locations 
where consumers now commonly purchase OTC medicines (adult and 
adolescent subjects) and women’s health and adolescent clinics (adolescent 
subjects). 
• 
The proposed OTC packaging and labeling is the only product information 
provided to participants during the study.  Participants will only review the outer 
packaging including DFL at the initial visit.  Study staff will not provide any 
additional information or encouragement regarding product selection at that visit.  
Staff will not answer participant questions about the study medication and will 
instead refer subjects to the labeling. However, any questions related to the “Ask 
a doctor or pharmacist before use” section of the DFL that are asked of study 
staff in their capacity as healthcare provider or pharmacist will be recorded. 
• 
After purchasing the study product, participants will take the package with them 
when they leave the site.  The package will include the outer packaging, 
(Appendix 18.1) and, inside the package, the consumer information leaflet (CIL, 
Appendix 18.2), a reminder card (which highlights key messages about directions 
for use from the DFL, Appendix 18.3) and study medication. 
3.2 
Study Sites 
Approximately 36 retail pharmacy study sites will be chosen for this study as such sites 
provide an environment that is considered typical of those from which consumers may 
expect to find this product following approval.  Additionally, approximately 10 women’s 
health clinics or adolescent clinics will be chosen to serve as recruitment and enrollment 
sites for some adolescent subjects.  Study sites will be selected to provide geographic 
and demographic diversity and to be representative of literacy in the general population.  
Sites will be selected from approximately 10 geographic regions in the US.  Each site 
has a private office or a suitable semi-private area where the enrollment visit will be 
carried out privately and without distraction.  The study area will also have all of the 
necessary computer equipment and a high-speed internet connection to accommodate 
the electronic data capture (EDC) system. 


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 Site Training and Procedural Integrity 
PEGUS Research will select sites and train the site staff after approval by the Sponsor.  
All study staff will receive study-specific training.  All training will be documented and 
retained in the study files. 
3.3 
Subject Selection 
Actual use trials are designed to determine how well the population of likely consumers 
is able to apply the information in nonprescription drug labeling to guide their own 
behavior.  Participants should therefore represent a wide range of demographic 
characteristics. 
In order to mimic the OTC marketplace as much as possible, initial participant selection 
will be self-driven by consumer response to advertising for the indication (e.g. “Are you 
looking for a birth control pill without a prescription? You may qualify to participate in a 
confidential research study on a prescription strength over-the-counter birth control 
pill.”).  In this way, the study sample is generated in the same way that the potential 
users of an OTC oral contraceptive would self-identify and purchase.  This generates a 
sample that is most likely to be representative of the eventual user population.  Given 
that adolescents are an important subgroup in the study, adult (18+) participants will be 
constrained to no more than 725 purchasers, allowing for an adolescent sample (age 12-
17) of 175.  Among adolescents, the enrollment goal for those ages 12-15 will be 50.  If 
passive recruitment of adolescents to study pharmacies is not robust enough to meet 
sample size goals, as is anticipated, staff within the women’s health or adolescent clinic 
sites will be allowed to invite adolescents to participate in the study if the adolescent 
patient identifies a need for contraception in the context of a clinical visit and expresses 
a preference for an oral contraceptive.  In those cases, clinicians will not instruct 
subjects about how to use the study product, they will simply inform potential subjects 
(adolescents seeking an OC in the clinic setting) about the study and extend the 
invitation to participate. 
While it is unusual in an AUT to allow for active recruitment on the part of clinicians, the 
targets requested by the Food and Drug Administration (FDA) for adolescent enrollment 
are challenging and may well make this supplemental recruitment measure necessary.  
In order to minimize the potential for bias, clinicians will be trained to not counsel 
potential subjects about the use of oral contraceptives in general, and to not provide 
specific counseling about the study product.  This supplemental mechanism of 
recruitment is unlikely to have any impact on the primary endpoints of the study.  The 
usual concern about active clinician recruitment in an AUT is that it may bias self-
selection.  In this particular case, any potential bias affecting self-selection would be in 
the negative direction as subjects may indeed select the product mistakenly thinking that 
the clinician has recommended it, when, in fact, the product is not right for them.  In 
order to estimate any impact of clinician referral on self-selection endpoints, data will be 
presented separately for subjects recruited in this manner. 
Please note, subjects must personally enroll in this study, and certify that they are 
seeking the study product for their own use.  Representative buyers (such as family 
members and/or male partners, etc.) will not be allowed. 


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 Self-Selection Phase / Initial Enrollment Visit Inclusion Criteria 
In order to enroll a sample as representative as possible of the likely OTC consumer 
population, the study inclusion criteria are defined as broadly as it is feasible.  Subjects 
must meet the following initial screening study inclusion criteria:  
1. Able to read, speak and understand English  
2. 12 years of age or older 
3. Can see well enough to read information on the label  
4. Another member of the respondent’s household has not participated in this study 
5. Consumer or someone else in the household does not work for a market 
research or advertising company, public relations firm, news organization, 
pharmacy or pharmaceutical company, medicine manufacturer, as a healthcare 
professional, or as part of a healthcare practice, managed care or health 
insurance company, trained or worked as a healthcare professional or market 
research professional (eliminated for reasons of confidentiality and increased 
awareness of medicines and their labels) 
6. Has not participated in any research studies about health-related products in the 
past 12 months 
7. Has not participated in a clinical trial in the past 12 months 
8. Has never participated in a study about over-the-counter birth control medicines 
 Use Phase Exclusion Criteria 
All subjects who agree to participate in the study and attend the initial enrollment visit at 
the site will be asked to make a self-selection and purchase (or use) decision.  Subjects 
presenting with any of the following will not be included in the use phase of the study 
(i.e., will not be allowed to purchase and use study medication though their self-selection 
decision and desire to purchase will be recorded): 
1. Unwilling to purchase study medication (pharmacy sites) 
2. Unwilling to be dispensed study product for use (clinic sites) 
3. Unwilling to provide informed consent 
4. Unwilling or unable to provide contact information 
5. Unwilling to state that the product is for their own use and no one else’s 
6. Premenarchal females 
7. Pregnant 
8. Male 
9. Known allergy to norgestrel or inactive ingredients. 
10. History of any cancer 


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Additionally, subjects must meet all of the following study inclusion criteria to be 
eligible for enrollment into the use phase of the study: 
• 
Evidence of a personally signed and dated informed consent form indicating that 
the subject (or a legal guardian) has been informed of all pertinent aspects of the 
study. 
• 
Willing and able to comply with the initial enrollment visit, planned phone calls 
and other study procedures, and the end of study visit. 
Subject eligibility will be reviewed and documented by the Investigator or his/her 
designee before subjects are allowed to be dispensed the study medication and begin 
the use phase of the study. 
 Recruitment Methods 
The recruitment methods discussed above and described below in more detail are 
designed to recruit a study population that will represent the likely OTC consumer 
population.  The characteristics of the eventual OTC oral contraceptive user population 
are not known.  In order to best simulate conditions of real OTC medicine use, every 
effort will be made to recruit subjects passively.  In contrast to intercept recruitment and 
other direct contact methods (e.g., recruiting from databases), passive advertising 
requires consumers who are interested enough on their own to respond to advertising.  
The characteristics of the study sample will then be the best estimate of those 
characteristics among the eventual user population. 
The content of the recruitment materials will be directed towards those who are 
interested in using an OTC birth control medicine.  Recruitment methods will include 
some or all of the following: newspaper advertisements, direct mail postcards, in-store 
signs, posters, internet and other digital media, and handouts/flyers.  Specific efforts will 
be made to make advertisements accessible to adolescents. 
As described above, due to the importance of including a sufficient number of 
adolescents in the study, and the challenging targets set at FDA’s request, active 
recruitment methods in clinic study sites will be implemented if passive recruitment of 
adolescents to study pharmacies is not robust enough to meet sample size goals. 
3.4 
Randomization 
There is no randomization in this study. 
3.5 
Data Collection 
Data will be collected in structured one-on-one interviews using a standardized 
questionnaire either in person (at the initial enrollment visit) or by telephone (in four 
follow-up interviews).  The interviews will be administered by a trained interviewer using 
an internet-based EDC application in which the interviewer will read the introductory 
scripts and the questions from the screen and will enter the responses directly into the 
study database.  The questionnaires will include primarily open-ended questions.  
Question types will include direct questions and follow-up questions for clarification.  No 
multiple-choice questions will be used.  To facilitate the accurate capture of responses, 
open-ended questions will have pre-coded answer alternatives.  It is important to note 
that these response alternatives will not be read to the participants, nor will participants 


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be able to see them on the screen.  Where close-ended questions are used (e.g., 
yes/no, or ok/not ok), participants will be asked to explain their answers so behavior can 
be adequately assessed.  When interviewers must type in open-ended question 
responses, they will capture short responses verbatim, and will accurately summarize 
longer responses.  
During the self-selection interview at the initial visit, the Opill® outer package including 
DFL will remain in front of the participant and the participant will be informed they can 
refer to the outer package at any time.  However, the participant will neither be 
encouraged nor discouraged from referring to the package in response to any specific 
question. 
Subjects who enter the use phase of the study will be asked to use an online diary to 
record their use of the study product daily.  Of note, a device will be provided for 
subjects who do not have easy access to a device with internet access. 
3.6 
Test Materials 
At the enrollment visit, participants will be provided with an empty Opill® package (box) 
that will display the proposed DFL (Appendix 18.1); they will review that package/box 
when making a self-selection and purchase/use decision.  
The product dispensed and taken home for use will include the exact same outer 
package, but will also have the study medication.  A reminder card (Appendix 18.3) and a 
CIL (Appendix 18.2) will also be in the package, and will be available to the subject when 
she purchases the product and opens the box in order to mimic the experience of an 
OTC consumer. 
Subjects who enter the use phase will be provided with a study information card (to 
include subject number and the central telephone number for any inquiries), the online 
medication use diary, as well the self-administered pregnancy test to use at the end of 
the study. 
3.7 
Study Administrative Structure 
Laboratoire HRA Pharma is the Sponsor for this study.  PEGUS Research is the contract 
research organization (CRO) responsible for the development of the study materials, 
training interviewers, fielding of the study, coding of open-ended responses, analysis of 
the data, and preparation of the study report. 
4 
STUDY TREATMENTS 
4.1 
Allocation to Treatment 
All subjects qualified to enroll in the use phase of this open-label study will be given the 
opportunity to purchase (or be dispensed, in the case of adolescent subjects enrolled at 
clinic sites) and use Opill® (norgestrel 0.075 mg).  Those that are dispensed study 
product will be included in the use phase of the study. 


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4.2 
Breaking the Blind 
Not applicable 
4.3 
Drug Supplies 
 Formulation and Packaging 
Opill® tablets for oral administration contain 0.075 mg norgestrel and the following 
inactive ingredients: cellulose, Food Drug and Cosmetics (US Federal Act) (FD&C) 
yellow No. 5, lactose, magnesium stearate, and polacrilin potassium. 
Opill® is packaged in a box containing a blister card with 28 tablets, constituting a four-
week supply. 
 Preparation and Dispensing 
All subjects who are dispensed study medication will receive norgestrel 0.075 mg 
tablets.  Subjects are to use the investigational product (IP) based on their 
understanding of the directions available on the outer packaging (on the DFL) and inside 
the product packaging (in the CIL and on the reminder card). 
Subjects will be allowed to resupply with the study product at the study site during the 
study enrollment visit and if they choose to return to the site at any point.  Subjects will 
not be allowed to receive more than 8 packages during the entire 16-week study period.  
This limit will not be disclosed to subjects unless they try to obtain more than a total of 8 
packages over the course of the study.  Any such requests that exceed the limit and the 
reason for that request will be recorded. 
Please note that 8 packages constitute twice the product that would be needed for once 
daily use during the study period.  It is typical in an AUT to allow subjects to obtain 
product in excess of the amount they would need, because without that allowance, no 
judgement can be made about whether subjects would take more than the instructed 
doses. Additionally, many women are accustomed (and advised) to obtaining several 
months of oral contraceptive supply at a time. 
 Drug Storage and Accountability 
The Investigator will ensure that the IP is stored under recommended storage conditions 
at the site and in accordance with the drug label (store at controlled room temperature 
20°C to 25°C [68°F to 77°F]). 
The IP must be stored as indicated on the package.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the 
monitor by the sites.  Deviations outside of the range of 20°C to 25°C [68°F to 77°F], but 
between 15°C and 30°C [59°F and 86°F], will be documented and reported to the 
Sponsor by the monitors and IP will continue to be used.  If a deviation is identified 
outside the range of 15°C to 30°C [59°F to 86°F], the deviation must be reported upon 
discovery and the IP must be quarantined and not used until the Sponsor provides 
documentation of permission to use the IP.  The Investigator must maintain adequate 
records documenting the receipt, use, loss, or other disposition of the IP. 


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At the end of the trial, subjects will be asked to return, any unused study medication, 
empty packaging, and e-diary device (if applicable) to the study site.  If the study site or 
PEGUS Research has not received the unused medication or empty packaging within 10 
days after the subject exits the study, follow-up telephone calls will be placed requesting 
that the subject return all study materials to the site.  Subjects may also be provided with 
a pre-paid, pre-addressed United States Postal Service (USPS) envelope to send any 
materials directly to PEGUS Research.   
The Sponsor will provide instructions as to disposition of any unused and returned IP.   
4.4 
Drug Administration 
Subjects who use the IP are to use it based on their understanding of the Opill® labeling. 
Because use of the IP is not driven by protocol, there are no medication errors involving 
subject exposure to the IP, though there may be potential medication errors or uses 
outside of what is foreseen in the protocol that do or do not involve the participating 
subject.  Any such medication error will be reported to the HRA pharmacovigilance (PV) 
department.  If applicable, any associated adverse event(s) (AE(s)) will be documented 
via the mechanism for spontaneous AE reports. 
 Compliance 
There is no protocol-directed use of the IP and subjects will use the product at their own 
discretion based on their understanding of the DFL and other material on or in the 
package.  The subjects will report on their use of the product in the online diary and four 
follow-up telephone interviews. 
4.5 
Concomitant Medication(s) 
The IP packaging will contain information about the use of certain other medications 
when taking Opill® (the DFL includes the direction to ask a doctor or pharmacist before 
use if you are taking or have recently taken certain medications).  Subjects will be queried 
at enrollment about medications that they are currently taking.  During the four study 
telephone interviews, subjects will be queried about any changes to their enrollment 
medications and any new medications that they have begun taking since the start of the 
study. 
4.6 
Rescue/Escape/Salvage Therapy 
Not applicable. 
4.7 
Batch recall 
In case a batch recall is required during the course of this protocol, site monitors will be 
responsible for communicating with research sites and for organizing and following-up on 
the logistics of the recall, in collaboration with the Sponsor and research sites.   


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At the end of the process, the site monitors will ensure that the total number of IPs 
returned to PEGUS Research matches the total number of IPs delivered to all sites. Any 
discrepancy must be explained. 
5 
STUDY PROCEDURES 
5.1 
Telephone Screening of Passively Recruited Potential Subjects 
Potential subjects who respond to passive advertising will call a toll-free phone number or 
visit a study website.  Telephone calls will be answered at a centralized unit and initial 
study inclusion and exclusion questions will be asked by screening interviewers trained 
on study-specific screening.  The website will similarly check study inclusion/exclusion, 
and allow those qualified to make an appointment for the in-person enrollment visit.  
Subjects who meet the study inclusion criteria and remain interested will be assigned an 
appointment date and time for a face-to-face interview at the pharmacy site closest to 
their location (residence or place of work).  The potential subjects will be provided the 
name and location of the pharmacy site.   
5.2 
Active Recruitment of Potential Subjects 
As discussed above, potential adolescent subjects presenting to clinic sites seeking oral 
contraception will be informed of the study and invited to participate.  If they choose to 
participate, they will be routed to study staff who will perform the initial screening in 
person, and conduct the remainder of the enrollment process as described below. 
5.3 
Study Period 
 Enrollment Visit, Self-Selection/Purchase Decision 
At the enrollment visit, which takes place at the retail pharmacy or health clinic study site 
and is conducted by trained site staff, initial study inclusion criteria will be reviewed and 
potential subjects will be shown the Opill® outer package.  Subjects will be given as much 
time as needed to review the information on the outer package.  After reviewing the outer 
package, they will be asked if the product is right for them to use and for those that say 
the product is right for them, whether they want to purchase/obtain the product for their 
own use.  Reasons for selection/non-selection and purchase/non-purchase will be 
collected. 
 Mock Purchase 
In many AUTs, subjects are asked to “purchase” the study product, typically for a 
nominal fee.  This purchase transaction is intended to make the study process more 
OTC-like, and helps minimize the likelihood of subjects enrolling who are not truly 
interested in the study medication. Subjects do not know at the time of the purchase 
decision or for the remainder of their study participation that any money that they pay for 
study product will be reimbursed to them at the end of the study. 
In some AUTs, however, the “purchase” is not feasible for one reason or another.  In this 
study, targets for adolescent participation are challenging, requiring the addition of active 
recruitment in a clinical environment for adolescent subjects only.  Barriers to 


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participation are already quite high for adolescents.  Because adolescents seeking care 
in the clinical environment are typically able to receive their care and medications 
without any cost to them, subjects enrolled in the clinical environment will not be asked a 
purchase question.  Rather, they will be asked whether they want to receive study 
product for their own use.  There will be no mock purchase transaction.  This will 
eliminate that potential barrier to participation. 
Adolescent subjects who respond to study advertising in the traditional way will all be 
enrolled at pharmacy sites, as will all adult subjects.  The mock purchase procedures will 
be in place for all subjects who enroll at pharmacy sites. 
Throughout this document, “purchase” and “purchasers” refers to any subject who either 
agrees to purchase and conducts a purchase transaction (as will be the case for all 
adults and any adolescents who enroll at pharmacy sites) or who agrees to be 
dispensed the study product for their own use (in the case of adolescent subjects 
enrolled at clinic sites). 
 After Purchase Decision and Before Study Entry 
The purpose of this study is to see how the subject complies with the labeled directions; 
therefore, the date of the first use of study medication is determined by the subject.  
Study Day 1 will be defined as the day the product is dispensed to the participant.   
On Study Day 1, at the site, subjects will complete the enrollment interview, providing 
information on any associated medications, associated medical conditions and selected 
demographic information.  Subjects will then be asked to complete the REALM1 or 
REALM-Teen2 test to establish reading ability. 
Next, use phase exclusion criteria will be assessed, and qualified subjects who decide to 
purchase/obtain the product will provide informed consent.  Please note that in this study, 
as is typical in actual use trials, a waiver of consent will be sought for the prior elements 
of the enrollment interview, so as to avoid the potential bias to self-selection that the 
details necessary for informed consent may introduce. The informed consent document 
will be presented electronically, and signatures will be collected electronically.  However, 
all consent procedures will be conducted face-to-face.  There will be no consent 
administered remotely to subjects (or with parents or legal guardians, if applicable). 
Subjects that provide consent will be provided with a self-administered pregnancy test 
and asked to use it there at the site.  Results will be recorded, and any subjects who are 
found to be pregnant will be excluded from use, and the event documented.  Adolescent 
subjects recruited from the clinical environment whose pregnancy test is positive because 
of a recent abortion will not be excluded. Subjects who are found to be pregnant based 
on their initial positive pregnancy test will be asked the self-selection question again to 
determine if they make a correct non-selection decision once they have the confirmation 
that they are likely pregnant. 
Qualified subjects will be required to provide contact information (for the purposes of 
conducting telephone follow-up interviews and providing compensation).  Subjects who 


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chose to will then purchase the IP and site study staff will complete the IP accountability 
form in the EDC system.  Subjects will be told they are allowed to return to the study site 
at any time to purchase/obtain additional study medication.  Subjects will subsequently be 
reimbursed for all purchases, but are not informed of this until the study is completed.  
Subjects will not be allowed to purchase/obtain more than 8 four-week supply packages 
during the study period, although this limit will not be communicated to the subjects 
unless they attempt to purchase/obtain more than that.  Any requests for 
purchase/dispensing of more than the limit will be recorded, as will the reason for such 
requests. 
Subjects will also be informed that interim and end-of-study phone interviews will be 
conducted at weeks 4, 8, 12, and 16 (with an allowable window of +/- 4 days for 
interviews at weeks 4 and 8, and +/-5 days for interviews at weeks 12 and 16).  Subjects 
are not required or directed to continue taking the medication for this period.  Subjects 
who have decided to proceed to the use phase of the study will be dispensed the product 
to use how and when they see fit based only on guidance from labeling. 
Subjects will be introduced to and trained to use the online medication use diary.  
Subjects will also be provided with a subject information card and a self-administered 
pregnancy test and given instructions to use the test at the end of the study period.  
Subjects will record the results of the home pregnancy test in the online medication use 
diary. 
5.4 
Use Phase 
Subjects who enter the use phase of the study take home the IP to use how and when 
they see fit based only on guidance from the labeling.  Contact with subjects during the 
use phase is limited and targeted toward collecting data necessary to evaluate study 
endpoints. 
 Unscheduled Study Site Visits 
During any unscheduled visit to a study site for purposes of subjects obtaining additional 
IP, the study staff contact with the subjects will be limited to: 
1. Dispensing additional IP with no questions asked, answered, or directions given 
about the use of the IP by the study staff (except for questions that are explicitly 
directed to study staff in their capacity as a pharmacist as described above in 
Section 3.1 above). 
2. Appropriately documenting the IP dispensed. 
3. Assisting any subject presenting self-reported AEs by immediately having the 
subject contact PEGUS Research or by collecting the relevant details and 
reporting that to PEGUS Research staff. 
 Online Medication Use Diary 
Subjects will be asked to record their use of the IP in an online, web browser-based 
medication use diary.  If a subject does not have easy access to a device with internet 
connectivity, a device will be provided to them. The diary will record use of the product, 


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including time of day.  Additionally, subjects will be asked to record each instance of 
heterosexual vaginal intercourse, along with any contraceptive method used. 
 Telephone Interviews 
The four scheduled phone interviews at weeks 4, 8, 12 and 16 will be conducted by 
PEGUS Research clinical staff (trained nurse interviewers) to collect information such as 
specific subject behaviors, AEs and concomitant medications. 
5.4.3.1 Week 4/8/12/16 Telephone Interview  
Trained nurse interviewers will conduct the interim and end of study (EOS) interviews.  
Interim interviews will be conducted at week 4 (day 28 +/- 4), week 8 (day 56 +/- 4), week 
12 (day 84 +/- 5), and week 16 (day 112 +/- 5).  The intent of the monthly telephone 
interview is to collect information about use of the product, AEs and concomitant 
medications.  Each interview will assess whether the subject has started taking the IP, and 
if so, collect information about how they have taken it.  Questions will be designed to 
collect information about behaviors related to the use of the IP in a non-biasing and 
masked manner to avoid influencing future behavior (e.g. “Besides taking the medication, 
is there anything else you have done to prevent pregnancy since we last spoke?”). 
5.4.3.2 End-of-Study Interview / Early Termination Interview 
In most cases, the EOS interview will take place during the week 16 telephone contact, 
after the week 16 interim interview is complete.  However, it is conceptualized as a 
separate interview in order to allow for collection of key end of study measures in cases 
where subjects elect to withdraw before the 16-week telephone call.  The EOS interview 
will collect information from the subject regarding the use of other forms of 
contraception, and the timing of such use.  This interview allows for direct questions 
about the rationale behind any behaviors that are not consistent with the DFL and CIL 
instructions, without concern about biasing the subject's subsequent behavior.  
Additional questions will be asked to include subject’s experience with the study product, 
future contraceptive plans, and history and plans for interactions with a healthcare 
provider. Subjects will also be asked about possible pregnancy and will be asked to take 
the EOS self-administered pregnancy test, conducted at home, and record the results in 
their online medication use diary. Electronic reminders to complete and record the 
results of the self-administered home pregnancy test as well as schedule the EOS visit 
(described in Section 5.4.4 below) will be delivered every other day beginning at the day 
following completion of the use phase.  Any subjects who do not report the results of 
their self-administered pregnancy test and also have not completed the end of study visit 
by 5 days after completion of the use phase will be contacted via telephone and asked to 
take the provided home pregnancy test and report those results by telephone, and to 
schedule an EOS visit. 
 End of Study Visit 
After completion of the EOS interview, subjects will be asked to return to the study site to 
return any study materials.  At that visit, subjects will again conduct a self-administered 


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pregnancy test, with pregnancy test results confirmed and recorded by site staff. Any 
subjects that fail to return for an EOS visit will be contacted via telephone and asked to 
schedule an EOS visit.  For subjects who complete the EOS visit (and its associated 
pregnancy test) but have not reported the at-home pregnancy test will not require 
additional follow up.  While the intent is for the EOS visit to be conducted within 10 days 
of the subject’s completion of the use phase, if a subject presents for the EOS visit 
outside of that window, EOS visit procedures will still be conducted until the study has 
ended. 
5.5 
Subject Withdrawal (Early Termination) 
If a subject notifies study staff of their intention to withdraw from the study early, the 
clinical interviewer will attempt to complete the next scheduled interim interview (unless 
the subject withdraws consent for disclosure of future information).  An EOS interview will 
also be conducted with any subject who discontinues or withdraws consent prior to Week 
16.  This interview will attempt to collect the EOS information and the reasons for the 
subject’s early termination.  These subjects will also be asked to perform and report the 
results of the EOS self-administered pregnancy test, and to return materials to the site 
where an additional self-administered pregnancy test will be performed. 
Subject participation may be terminated by an investigator during the study for any of the 
following reasons: 
• 
Significant protocol violation 
• 
AEs, including serious adverse events (SAEs) 
• 
Pregnancy 
• 
Physician decision 
• 
Subject’s request 
• 
At the discretion of the Investigator or designee if s/he feels that study 
discontinuation is necessary to protect the subject, or that there are 
unmanageable factors that will interfere significantly with the study procedures 
and/or the interpretation of results. 
Any such subjects will be asked to return any unused study medication (and empty 
packaging), e-diary devices where applicable, and will be precluded from purchasing 
additional study medication.  Data collected up to the point of withdrawal will be retained 
and used as appropriate in the data analysis.  Ongoing data collection will be allowed if 
applicable (such as for AE follow-up), unless the subject requests otherwise. 
Subjects may withdraw from the trial at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor (or Sponsor 
designee) for safety or behavioral reasons, or the inability of the subject to comply with 
the protocol required schedule of study visits or procedures at a given study site. 
If a subject refuses contact for scheduled follow-up calls, any effort made to contact the 
subject will be documented.  In any circumstance, every effort will be made to determine 
and document subject outcome, if possible.  The investigator will inquire about the reason 
for withdrawal, request the subject to return all unused IP and empty packaging, request 


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the subject to participate in a final telephone interview, if applicable, and follow up with 
the subject regarding any unresolved AEs. 
A subject may be declared lost to follow-up if, during the study, the available contact 
information is determined to be incorrect and no other information is available.  Every 
attempt will be made to contact lost to follow-up subjects, including three phone call 
attempts and a letter sent via USPS.  Subjects whose status is withdrawn, lost to follow-
up, withdrawal due to an AE or withdrawal from the study for other reasons will be 
recorded in the study database. 
If a subject wishes to stop participation in the study, the Investigator/interviewer will 
document the reason for withdrawal, ask the end of treatment questions where possible 
and follow up with the subject regarding any new or unresolved AEs, request that the 
subject conduct the at home EOS pregnancy test and instruct the subject to return all 
unused IP and any empty packaging. Data collected up to the point of withdrawal will be 
retained and used as appropriate in the data analysis. 
 
 


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5.6 
Study Flow 
Study procedures are represented in a flow chart in Figure 1 below. 
Figure 1  Study Procedures Flowchart 


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6 
ASSESSMENTS 
Every effort will be made to ensure that the protocol-required procedures are completed 
as described.  However, it is anticipated that from time to time, there may be 
circumstances outside of the control of the Investigator that may make it unfeasible to 
perform the procedure.  In these cases, the Investigator will take all steps necessary to 
ensure the safety and well-being of the subject.  When a protocol-required procedure 
cannot be performed, the Investigator will document the reason for this and any 
corrective and preventive actions which he/she has taken to ensure that normal 
processes are adhered to as soon as possible. 
The study team will be informed of these incidents in a timely fashion.  All data will be 
collected using an EDC Data Collection Instrument (DCI). 
6.1 
Screening Assessment 
Subjects will be screened both over the telephone and during the initial visit to determine 
those individuals who will be included or excluded from the trial.  
6.2 
Enrollment Interview 
Subjects will be shown the Opill® outer package and allowed to make a decision about 
whether the product is appropriate for them to use and whether to purchase/obtain Opill® 
for their own use.  Subsequent questions will be asked to gather limited medical and 
medication history as it pertains to use of the IP, as well as subject demographics.  
6.3 
Reading Level Assessment 
The REALM1 (for adults) or the REALM-Teen2 (for adolescents age 12 to 17) test will be 
used to measure reading grade level and will be the measure of literacy used for this 
study.  The REALM score corresponds to four grade-equivalent reading levels as shown 
in Table 2 below, while the REALM-Teen score corresponds to five grade-equivalent 
reading levels as shown in Table 3 below.  A REALM score of 60 or less (a reading level 
of 8th grade or lower) defines the low literacy subgroup among adult participants. 
The REALM-Teen test does not have a 9th grade reading level cutoff, so a cutoff score of 
60 or lower will be used to define the low literacy cohort for the adolescent group as well 
(which is the midpoint of the 8th-9th grade-equivalent reading level).  This allows for a 
somewhat more conservative requirement to be classified as low literacy among the 
adolescent cohort in comparison to a cutoff for 10th grade-equivalent reading level. 
The REALM-Teen will be used to demonstrate (along with demographics) that adolescent 
participants represent a diversity of age, race, educational attainment, and reading ability.  
However, given the relatively small absolute number of low literacy adolescents expected 
(if 25% of the goal sample of 175 adolescents meet the criteria, this would yield 
approximately 44 low literacy adolescents), low literacy adolescents will be included with 
low literacy adult participants to comprise the overall low literacy subgroup for analysis. 
 
 


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Table 2 REALM Test Grade-equivalent Reading Levels 
 
REALM1 Score 
Grade-equivalent 
Reading Level 
Included as 
Low-literacy 
Included as 
Normal-literacy 
0-18 
3rd 
X 
 
19-44 
4th to 6th 
X 
 
45-60 
7th to 8th 
X 
 
61-66 
9th and above 
 
X 
Table 3 REALM-Teen Test Grade-equivalent Reading Levels 
REALM-Teen2 
Score 
Grade-equivalent 
Reading Level 
Included as  
Low-literacy 
Included as  
Normal-literacy 
0-37 
3rd 
X 
 
38-47 
4th - 5th 
X 
 
48-58 
6th - 7th 
X 
 
59-62 
8th - 9th 
≤ 60 
≥ 61 
63-66 
10th and above 
 
X 
 
Given that literacy (as measured by the REALM or REALM-Teen) is not known in 
advance and cannot be directly used in screening in an AUT, targets for low literacy are 
not set.  In self-selection and actual use studies that recruit in the typical manner, the 
proportion of low literacy participants typically ranges from 12-18%.  Every effort will be 
made to make the advertising accessible to those with lower literacy; however, in an AUT 
literacy cannot be controlled for without biasing the representativeness of the sample.  It 
is not realistic or possible to control for who responds to the advertising or self-selects to 
use the product. 
In contrast with label comprehension studies, whose samples are meant to be 
approximately representative of the general population and therefore controlling for 
factors of interest like literacy is potentially justified, one of the overarching goals of an 
AUT is to enroll a sample that is representative of the likely OTC user population.  In this 
setting, controlling for literacy would compromise the representativeness of the sample in 
a manner that is inappropriate.  The number of responders that would need to be 
excluded in order to supplement the low literacy proportion of the sample would likely be 
as large as the target sample.  With that degree of exclusion, the risk of introducing bias 
would be significant, and would run counter to the principal of enrolling a sample as 
representative of the likely OTC population as possible. 
While it is inappropriate to control for literacy to force a specified proportion of low literacy 
participants in an AUT, it is still important to have a sample of low literacy participants of 
sufficient size to allow for conclusions to be drawn as to performance of study endpoints 
among subjects of low literacy.  The total sample size was selected to ensure that the 
absolute size of the subgroup of low literacy participants will be large enough to evaluate 
the endpoints in that subgroup.  If 15% of 900 subjects are classified as low literacy by 
the REALM or REALM-Teen, the cohort of low literacy subjects will be approximately 135 


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subjects, representing a subgroup of sufficient size.  As an illustration, the 95% 
confidence interval (calculated using the Exact method) around a point estimate of 85% 
for 135 subjects is +/-7.2%. 
6.4 
Pregnancy Testing 
During the enrollment interview, after answering the self-selection question, all subjects 
will be asked if they are currently pregnant, and after informed consent is obtained, 
subjects will perform a self-administered pregnancy test at the site.  Subjects with a 
positive result will be asked the selection question again, and then excluded from 
participating in the use phase of the study.  Additionally, at the end of the enrollment 
interview, subjects who are proceeding into the use phase will be provided with a home 
pregnancy test with the instructions to use it at home at the end of the study and record 
the results in the online diary.  Nurse interviewers will inquire about the results of the 
home pregnancy test during the EOS interview.  After completion of the EOS interview, 
subjects will be asked to return to the study site to return all unused study medication 
and packaging.  During that visit, an additional pregnancy test will be administered and 
results entered by site staff.  If subjects have not completed the home pregnancy test at 
the EOS interview, and if they have not returned to the study site for the site-recorded 
pregnancy test, an additional call will be placed at 5 (+3) days following the EOS 
interview to collect home pregnancy test results.  This will allow for shipping time if the 
subject requires an additional at home pregnancy test to be sent to them.  In addition, at 
the time a subject withdraws or is withdrawn from the study early, nurse interviewers will 
inquire if the subject would be willing to take the pregnancy test and report the results in 
their electronic diary and return to the site for the EOS visit. 
6.5 
Medication Use Diary 
Subjects will be asked to report their use of the study product daily using a web-based 
electronic diary.  Date and time of each dose taken will be recorded, as well as instances 
of heterosexual vaginal intercourse and any additional contraceptive methods used in 
each instance. Subjects will also record the results of the EOS home pregnancy test in 
the electronic diary. An internet-connected device will be provided to subjects who do not 
have easy access to the internet. 
6.6 
Interim Follow-up Telephone Interviews  
During the course of the study, all participants will be contacted four times via telephone 
by a trained nurse interviewer who will ask a series of scripted questions related to the 
use of the IP, as well as collect information related to concomitant medications and 
adverse events. 
The answers to these questions will be part of the study database and used to determine 
the performance of the endpoints.  There will be a total of 4 phone interviews, at weeks 4, 
8, 12, and 16 during which the nurses will limit the dialogue with the subjects to the 
interview script. 


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6.7 
End-of-Study/Early Termination Telephone Interview  
At the end of the study (typically this will be in conjunction with the 16-week call), or upon 
early termination from the study, all participants will be contacted via telephone by a 
trained nurse interviewer who will ask a series of questions related to the use of the study 
medication and the at-home, self-administered end of study pregnancy test results, as 
well as collect information related to concomitant medications and AEs. 
As participation for that subject will then be complete, and therefore the risk of biasing 
future behavior irrelevant, this EOS interview will include direct questions about how the 
product was used.  The answers to these questions will be part of the study database and 
used to determine the performance of some of the endpoints. 
Typically, the EOS interview will be conducted during the 16-week telephone call 
immediately following the 16-week interim follow-up interview.  However, in cases where 
subjects may withdraw or be withdrawn earlier for any reason, the EOS interview will be 
conducted by telephone at that time.  
6.8 
End-of-Study Visit  
After the end-of-study interview is completed, subjects will be asked to return to the local 
study site within 10 days to return any unused medication and packaging, as well as any 
other study materials.  Additionally, subjects will be asked to conduct an additional self-
administered pregnancy test, with results confirmed and recorded by site staff. While the 
intent is for the EOS visit to be conducted within 10 days of the subject’s completion of 
the use phase, if a subject presents for the EOS visit outside of that window, EOS visit 
procedures will still be conducted until the study has ended. 
7 
ADVERSE EVENT REPORTING 
7.1 
Adverse Events 
All observed or volunteered AEs regardless of suspected causal relationship to the IP will 
be reported as described in the following sections.  This study includes only one 
treatment group. 
While responsibility for collection, recording, and reporting of all AEs will be assumed by 
PEGUS Research, study staff at the study sites will identify any spontaneous reporting of 
AEs to the site staff and facilitate the reporting to the centralized clinical nurse 
interviewers.  For this section “Investigator” refers to the central principal investigator at 
PEGUS Research who oversees this process. 
For all AEs, the Investigator must pursue and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for 
classification as an SAE requiring immediate notification to the Sponsor or its designated 
representative.  For all AEs, sufficient information should be obtained by the Investigator 
to determine the causality of the AE.  The Investigator is required to assess causality.  
Follow-up by the Investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the Investigator, and the Sponsor concurs with that 
assessment. 


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As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness further information may be requested 
from the Investigator to provide clarity and understanding of the event in the context of 
the clinical trial. 
7.2 
Reporting Period 
SAEs will be recorded on the specific case report form (CRF).  For SAEs, the active 
reporting period to the Sponsor or its designated representative begins from the time that 
the subject provides informed consent, which is obtained prior to the subject’s 
participation in the use phase of the study, i.e., prior to undergoing any study-related 
procedure and/or receiving investigational product, through and including 28 calendar 
days after the last administration of the IP.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the Sponsor if the Investigator becomes 
aware of them; at a minimum, all SAEs that the Investigator believes have at least a 
reasonable possibility of being related to the IP are to be reported to the Sponsor. 
Non-serious AEs will be collected and recorded in the study database from the time the 
subject has taken at least 1 dose of study treatment through last subject visit. 
7.3 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation wherein subjects are 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of AEs include but are not limited to: 
• 
Abnormal test findings 
• 
Clinically significant symptoms and signs 
• 
Changes in physical examination findings 
• 
Hypersensitivity 
• 
Progression/worsening of underlying disease 
• 
Drug abuse 
• 
Drug dependency. 
Additionally, they may include the signs or symptoms resulting from: 
• 
Drug overdose 
• 
Drug withdrawal 
• 
Drug misuse 
• 
Drug interactions 
• 
Extravasation 
• 
Exposure during pregnancy 
• 
Exposure via breastfeeding 


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• 
Medication error 
• 
Occupational exposure. 
7.4 
Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported 
as an AE are as follows: 
• 
Test result is associated with accompanying symptoms, and/or, 
• 
Test result requires additional diagnostic testing or medical/surgical 
intervention, and/or, 
• 
Test result leads to a change in study dosing or discontinuation from the 
study, significant additional concomitant drug treatment, or other 
therapy, and/or, 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does 
not constitute an AE. Any abnormal test result that is determined to be an error does not 
require reporting as an AE. 
7.5 
Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose that: 
• 
Results in death 
• 
Is life threatening (immediate risk of death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity (substantial 
disruption of the ability to conduct normal life functions) 
• 
Results in congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an event is an 
important medical event.  An important medical event may not be immediately life 
threatening and/or result in death or hospitalization.  However, if it is determined that the 
event may jeopardize the subject or may require intervention to prevent one of the other 
AE outcomes, the important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
 Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
Investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section 7.12). 


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7.6 
Hospitalization 
AEs reported from studies associated with hospitalization or prolongations of 
hospitalization are considered serious.  Any initial admission (even if less than 24 hours) 
to a healthcare facility meets these criteria.  Admission also includes transfer within the 
hospital to an acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, 
medical floor to a coronary care unit, neurological floor to a tuberculosis unit). 
Hospitalization does not include the following: 
• 
Rehabilitation facilities 
• 
Hospice facilities 
• 
Respite care (e.g., caregiver relief) 
• 
Skilled nursing facilities 
• 
Nursing homes 
• 
Routine emergency room admissions 
• 
Same day surgeries (as outpatient/same day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 
• 
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting 
condition (e.g., for work-up of persistent pre-treatment lab abnormality) 
• 
Social admission (e.g., subject has no place to sleep) 
• 
Administrative admission (e.g., for yearly physical exam) 
• 
Protocol specified admission during a study (e.g., for a procedure 
required by the study protocol) 
• 
Optional admission not associated with a precipitating clinical AE 
(e.g., for elective cosmetic surgery) 
• 
Hospitalization for observation without a medical AE 
• 
Pre-planned treatments or surgical procedures. These should be noted 
in the baseline documentation for the entire protocol and/or for the 
individual subject. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the procedure 
was performed should be reported if it meets the definition of an AE.  For example, an 
acute appendicitis that begins during the AE reporting period should be reported as the 
AE and the resulting appendectomy should be recorded as treatment of the AE. 


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7.7 
Severity Assessment 
If required on the AE CRFs, the Investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, 
these intensity grades are defined as follows: 
MILD 
Does not interfere with subject's usual function. 
MODERATE 
Interferes to some extent with subject's usual function. 
SEVERE 
Interferes significantly with subject's usual function. 
 
Note the distinction between the severity and the seriousness of an AE.  A severe event 
is not necessarily an SAE.  For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it 
met one of the criteria for SAEs, listed above. 
7.8 
Causality Assessment 
The Investigator’s assessment of causality must be provided for all AEs (serious and non- 
serious); the Investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting 
requirements if applicable.   The Investigator’s causality assessment is the determination 
of whether there exists a reasonable possibility that the IP caused or contributed to an 
AE; generally, the facts (evidence) or arguments to suggest a causal relationship should 
be provided.  If the Investigator does not know whether or not the IP caused the event, 
then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor.  If the Investigator's causality assessment is 
"unknown but not related to investigational product", this should be clearly documented 
on study records. 
In addition, if the Investigator determines an SAE is associated with study procedures, 
the Investigator must record this causal relationship in the source documents and CRF, 
as appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. 
7.9 
Exposure During Pregnancy 
For investigational products and for marketed products, an exposure during pregnancy 
(EDP) occurs if: 
• 
A female becomes, or is found to be, pregnant either while receiving or being 
exposed (e.g., due to treatment or environmental exposure) or after discontinuing 
or having been directly exposed to the investigational product; 
• 
A male has been exposed (e.g., due to treatment or environmental exposure) to 
the investigational product prior to or around the time of conception or is exposed 
during his partner’s pregnancy. 
If a study subject becomes or is found to be pregnant during the study subject’s treatment 
with the IP, the Investigator must submit this information to the Sponsor as a SAE and 


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EDP report, regardless of whether an SAE has occurred.  The information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
Follow-up is conducted to obtain pregnancy outcome information for all EDP reports with 
an unknown outcome.  The Investigator will follow the pregnancy until completion (or until 
pregnancy termination) and notify the Sponsor of the outcome as a follow up to the initial 
EDP report.  In the case of a live birth, the health of the neonate can be assessed at the 
time of birth.  In the event of a termination, the reason(s) for termination should be 
specified and, if clinically possible, the structural integrity of the terminated fetus should 
be assessed by gross visual inspection (unless pre-procedure test findings are conclusive 
for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly 
[in a live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows: 
• 
Spontaneous abortion includes miscarriage and missed abortion. 
Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as SAEs 
when the Investigator assesses the infant death as related or possibly related to 
exposure to the IP. 
Additional information regarding the EDP may be requested by the Investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow up on 
preterm infants to identify developmental delays).   
7.10 Withdrawal Due to Adverse Events 
Withdrawal due to AE should be distinguished from withdrawal due to insufficient 
response, according to the definition of AE noted earlier, and recorded on the appropriate 
AE CRF page. 
When a subject withdraws due to an SAE, the SAE must be reported in accordance with 
the reporting requirements defined herein. 
7.11 Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported 
by the study subject.  In addition, each study subject will be questioned about AEs during 
all phone interviews. 
7.12 Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE 
occurs, expedited reporting will follow local and international regulations, as appropriate. 


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 Serious Adverse Event Reporting Requirements 
If an SAE occurs, the Sponsor is to be notified within 24 hours of study staff or 
Investigator awareness of the event.  In case of SAE, the Investigator must immediately 
complete the SAE data collection form and send it by fax or by email within 24 hours to 
the Sponsor’s PV Department: 
Fax: +33 1 42 77 03 52 
Email: pharmacovigilance@hra-pharma.com 
 
In particular, if the SAE is fatal or life-threatening, notification to the Sponsor must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE 
reports as well as to the initial and follow-up reporting of EDP cases. 
In the rare event that the Investigator does not become aware of the occurrence of an 
SAE immediately (e.g., if an outpatient study subject initially seeks treatment elsewhere), 
the Investigator is to report the event within 24 hours after learning of it and document the 
time of his/her first awareness of the AE. 
For all SAEs, the Investigator is obligated to pursue and provide information to the 
Sponsor in accordance with the time frames for reporting specified above.  In addition, an 
Investigator may be requested by the Sponsor to obtain specific additional follow-up 
information in an expedited fashion.  This information collected for SAEs is more detailed 
than that captured for a non-serious AE.  In general, this will include a description of the 
AE in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality.  Information on other possible causes of 
the event, such as concomitant medications and illnesses must be provided.  In the case 
of a subject death, a summary of available autopsy findings must be submitted as soon 
as possible to the Sponsor or its designated representative. 
 Non-Serious Adverse Event Reporting Requirements 
All AEs will be reported in the AE portion of the study database.  It should be noted that 
the form for collection of SAE information is not the same as the form for collection of 
other AEs.  Where the same data are collected, the forms must be completed in a 
consistent manner.  For example, the same event term should be used on both forms.  
AEs should be reported using concise medical terminology on the CRFs as well as on the 
form for collection of SAE information. 
 Sponsor Reporting Requirements to Regulatory Authorities 
Adverse event reporting to regulatory authorities, including suspected unexpected serious 
adverse reactions (SUSAR) is the responsibility of the Sponsor PV department and will 
be carried out in accordance with applicable local regulations by the Sponsor. 


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8 
DATA MANAGEMENT 
8.1 
EDC System 
Information collected during the participant interviews will be entered directly into an 
EDC application (DATATRAK ONE, DATATRAK International, Inc.).  Automatic data 
checks will alert users of discrepancies and inconsistencies, where applicable.  In the 
event of a data entry error, users will have the ability to correct information previously 
entered.  Data Management will review the information entered as defined in this 
protocol.  
All users will have a unique login user name and password, and system access 
privileges will be strictly controlled and documented.  Whenever data is modified after 
the initial data entry process, a computer-generated audit trail entry will be created.  The 
audit trail, user access privilege processes, and electronic signatures collected by the 
system will be compliant with 21 Code of Federal Regulations (CFR) Part 11 
requirements.  
8.2 
Electronic Diary System 
A web-based electronic diary will be provided to all subjects with a reliable internet 
connection.  The e-diary will be programmed and hosted by a qualified vendor 
(eClinicalHealth Ltd, Stirling, United Kingdom), and will be compliant with 21 Code of 
Federal Regulations Part-11 requirements.  Subjects will be instructed to record 
information regarding their use of the study product every day.  Subjects will also be 
asked to enter additional data regarding sexual behaviors (heterosexual vaginal 
intercourse) and additional contraception methods to fully evaluate adherence to label 
directions.  The electronic diary will also serve as the primary means of reporting the 
results of the EOS at-home self-administered pregnancy test. Diary data will be imported 
into the EDC system to be included in the study database. 
8.3 
Data Management Plan 
A detailed Data Management Plan (DMP) will describe procedures to ensure the proper 
management and quality of study data and additional PEGUS Standard Operating 
Procedures (SOPs) specify the activities performed to ensure the quality, accuracy and 
reliability of the statistical analysis and the final study report.  
8.4 
Conceptual Approach to Self-Selection 
While this is not a dedicated self-selection study, one of the primary endpoints in this 
study is the proportion of the self-selection population that make a correct selection 
decision. 
Conceptually, the self-selection decision can be characterized as a 2x2 table (Table 4 
below) where the participant's decision to select or not select the study product for use is 
crossed with whether or not it is appropriate for participant to use, based on participant's 
self-reported health status and clinical characteristics. 


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Table 4 Self-Selection Decision Outcomes 
Participant’s 
Selection Decision 
Appropriate to Use 
YES 
NO 
YES (selectors) 
Cell A 
Correct Decision 
Cell B 
Incorrect Decision 
NO (non-selectors) 
Cell C 
Incorrect Decision 
Cell D 
Correct Decision 
The four cells in the self-selection matrix can be characterized as follows.  
Cell A: Participants who say the study product is right for them to use and based 
on their self-reported medical and demographic information, the study product is 
right for them to use.  
Cell B: Participants who say the study product is right for them to use and based 
on their self-reported medical and demographic information, the study product is 
not right for them to use.  
Cell C: Participants who say the study product is not right for them to use and 
based on their self-reported medical and demographic information, the study 
product is right for them to use.  
Cell D: Participants who say the study product is not right for them to use and 
based on their self-reported medical and demographic information, the study 
product is not right for them to use. 
8.5 
Classification Activities 
To evaluate participants for the self-selection endpoint, each participant will be classified 
on two key variables: (1) the selection decision and (2) the appropriateness of use given 
the selection decision, in order to populate the typical 2x2 self-selection table (Table 4 
above).  Participants will be classified on these two variables as described in Sections 
8.5.1 and 8.5.2 below. 
 Selection Decision 
The selection phase of the interview consists of the self-selection question and the 
purchase (or equivalent) question, with accompanying neutral follow-up questions.  All 
subjects who go on to purchase/obtain the study product will be categorized as 
selectors.  Subjects who do not eventually complete the purchase/dispensing of the 
product will be classified as a selector or a non-selector primarily based on their 
responses to the initial self-selection and purchase questions.  However, all information 
recorded during the selection phase of the interview will be considered in the 
classification of participants as selectors or non-selectors.  Participants who offer 
modifying information in open-ended responses to neutral probing will be re-categorized 
accordingly.   


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A participant who initially indicates that the product is OK for their use, but who 
independently and unprompted changes their decision during the selection phase of the 
interview would be categorized as a non-selector.  However, any information offered 
once the interview proceeds beyond the selection phase of the interview will not be 
considered during selection classification.  Financial and cost-related reasons for saying 
no to the purchase question will not be used as rationale for re-classifying participants 
who would otherwise be selectors. 
One exception to this will be for the subset of subjects that select the product, report not 
being pregnant, sign consent, and then receive a positive result from the subsequent 
enrollment pregnancy test.  These subjects will be re-asked the selection question and 
their classification as a selector or non-selector will take into account this second 
selection decision made in light of new health status information.   
The selection decision for each participant will be examined on a case-by-case basis, 
taking into account all the information gathered during the selection phase of the 
interview.  Two independent coders will evaluate the available data and indicate whether 
the participant is a selector or a non-selector.  Discrepancies will be resolved by a third 
coder (as described in Section 8.5.4). 
 Appropriate to Use 
Non-selectors will be classified on the variable Appropriate for Use as follows: 
Yes: meets the label criteria for use, representing those who could have 
selected appropriately, but did not (Cell C). 
No: does not meet the label requirements for use, and appropriately did not 
select (Cell D).  This includes those participants who otherwise might have 
met the strict criteria for appropriate use according to the DFL, but who give a 
medically appropriate rationale for their non-selection decision.  For example, 
if a participant who otherwise meets the labeled criteria for use does not 
select the product and cites the fact that they have unexplained vaginal 
bleeding between their menstrual periods as their reason for not selecting 
(which otherwise does not disqualify a subject from using, but rather suggests 
that they talk to a doctor), that participant will be re-classified from Cell C to 
Cell D.  A physician will review the casebook for each participant who falls 
into Cell C to determine if any participants meet that criterion. 
Selectors will be classified on the variable Appropriate for Use as follows: 
Yes: either meets the strict DFL criteria for use (1-Correct Selectors) or 
reported and measured characteristics justify the selection decision (2-
Acceptable Selectors), representing those who chose to use the product who 
made a clinically acceptable decision despite not meeting the strict label 
criteria for use (Cell A). 
No: does not meet strict label criteria and reported and measured 
characteristics do not justify the selection decision (3-Incorrect Selectors), 
representing those who chose to use the product, but should not have (Cell 
B). 
Further definitions of Correct, Acceptable, and Incorrect Selectors follow: 


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1) Correct Selectors.  Participant meets the strict criteria of the DFL, 
including: 
a) No absolute contraindications (not male, no history of cancer, not 
pregnant, does not have a known allergy to one of the ingredients) 
b) Is a woman of childbearing potential?  This would include all women 
who do not report any of the following:  surgical sterilization (tubal 
ligation, hysterectomy, or bilateral oophorectomy) or postmenopausal 
for at least one year. 
2) Acceptable Selectors.  Participant does not meet the strict criteria of the 
DFL, but selection is classified as appropriate because they are judged 
clinically (see Section 8.5.3) to be an appropriate selector.  This group is 
expected to be quite small and might include for example:  a woman who 
has a history of breast cancer, but who reports that she knows that her 
cancer is not hormone sensitive or has been told by a healthcare provider 
she can use hormonal contraception. 
3) Incorrect Selectors.  This group includes selectors who are not correct or 
acceptable, including having any of the following: 
a) An absolute contraindication to the product (has a history of any 
cancer, is pregnant and intends to use while pregnant, and/or has a 
known allergy to an ingredient) 
b) Is a man 
c) Is a woman without childbearing potential?  This would include all 
women who report any of the following:  surgical sterilization (tubal 
ligation, hysterectomy, or bilateral oophorectomy) or postmenopausal 
for at least one year. 
Please note that the criteria upon which initial selection is judged include the absolute 
contraindications, as translated from the prescription labeling contraindications section to 
the proposed DFL. In addition, in the selection classification, the second self-selection 
decision made by those subjects with a positive pregnancy test result during the 
enrollment visit will trump the initial decision those women made, although data 
regarding the initial decision will also be presented.  
Two conditional contraindications from the prescription labeling are presented in other 
sections of the DFL (i.e., not in the “do not use” section) to reflect their conditional 
nature, namely, unexplained intermenstrual bleeding and liver problems. The fact that 
these two warnings are conditional rather than absolute (i.e. they are “ask a doctor 
before use” warnings rather than “do not use” warnings) means that consumer behavior 
relative to these warnings cannot be evaluated as part of the initial self-selection 
decision, because correct behavior depends on subsequent actions (asking a doctor), 
and initial selection is not necessarily inappropriate if the subject does select to use and 
then indeed follows those instructions to talk to a doctor about using the medicine.. 
Evaluation of the instructions regarding those two messages will be evaluated 
individually based on the complete subject behavior in discrete endpoints.   


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 Physician Mitigation 
Participants occasionally decide to select a product for use that according to the strict 
DFL-defined algorithm appears to be an incorrect decision, but when evaluated from a 
clinical perspective is acceptable.  Examples might include a woman who has a history 
of breast cancer (which makes her algorithmically incorrect) but who clarifies that she 
knows that her cancer is not hormone sensitive, or that she has been told by a 
healthcare provider that she can use hormonal contraception.  Note, however, that in 
this example she would still be excluded from the use phase of the study.  This review 
and clinical judgement will be done by three physicians working independently, 
evaluating the entire casebook for each Incorrect Selector (as defined above in Section 
8.5.2) for evidence that the participant made a clinically justifiable selection decision.  
Their assessments are then compared, and any discrepancies resolved by a majority 
rule. In cases where a physician reviewer reclassifies a subject in this way, their 
justification for the reclassification will be recorded. 
 Coding of Open-ended Responses 
The responses to open-ended questions will be coded to make them amenable to 
numeric analysis and display.  Coding procedures will follow PEGUS Research SOP 
DAT:008.  After completion of the study, listings of individual responses for each 
question will be created.  The listings will be reviewed to discover the underlying 
conceptual structure suggested by the data, and a coding frame (a list of categories, 
each of which is assigned a one or two-digit number) will be created for each question.  
The coding frames will be reviewed and revised as necessary when 100% of the data is 
collected and cleaned.  When the coding frame is finalized, reviewed and approved, 
coding may be performed.   
Coding will be done using data from the final, clean data set.  Two coders working 
independently will code each question with a significant number of responses.  Their 
code assignments will then be compared and the Coding Supervisor will resolve any 
discrepancies.  Multiple codes (typically no more than seven) may be assigned to 
elements of one response.  Once coded, these data will be displayed in standard 
frequency tables.  For these tables, the unit of analysis, and thus the denominator, 
changes to become the number of responses rather than the number of participants. 
9 
DATA ANALYSIS/STATISTICAL METHODS 
This is a naturalistic, observational trial to assess selection and use patterns from the 
prospective OTC population in a simulated OTC setting.  The analyses will largely employ 
descriptive statistics including frequencies, percentages and appropriate summary 
statistics. 
A detailed methodology for the statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be finalized prior to 
database lock.  The SAP may modify the plans outlined in the protocol; however, any 
major modifications to the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. 


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9.1 
Sample Size Determination 
For the purposes of this AUT, sample size has been set at approximately 900 
purchasers (use phase participants).  Given that subjects are responding to recruitment 
aimed at those interested in an OTC birth control medicine, most subjects who choose to 
purchase the study product are expected to actually use the product during the study. 
Assuming approximately 900 purchasers, if 80% of those purchasers use the product 
within the study period, that would yield an actual user population of approximately 720.  
Allowing for a further 20% loss to follow-up would yield a measurable user population of 
approximately 576. 
Because AUTs are not hypothesis-testing comparative trials, study sample size is 
designed to allow for adequate evaluation of key endpoints across all participants and 
among several subgroups.  As the analysis of AUTs typically focuses on estimating the 
proportion (and associated 95% confidence intervals) of individual endpoints, sample 
size is most often based on the number of participants needed to constrain the 
confidence interval (CI) to a limited range.  As an illustration, for this study, assuming an 
85% correct behavior to any single endpoint (of course, the CI depends on the actual 
point estimate and will be calculated based on the data), a sample of 720 participants 
would constrain the CI to ±2.8%.  Table 5 provides the 2-sided 95% CI for various 
sample sizes around a point estimate of 85%. 
Table 5  Two-sided 95% CIs for Various Sample Sizes Around 85% Point Estimate 
N=900a 
N=720b 
N=576c 
N=135d 
95% CI around a point estimate of 85% 
+/-2.5% 
+/-2.8% 
+/-3.2% 
+/-7.2% 
a Purchasers 
b User population (allowing for 20% non-users) 
c User population (allowing for 20% loss-to-follow up) 
d Low literacy subjects 
 
9.2 
Analysis Populations 
The populations of interest are defined as follows: 
• 
Screening Population: All those who respond to study advertisements and 
complete initial screening questions. 
• 
Self-Selection Population: Participants who accept the invitation to 
participate and meet study inclusion criteria, participate in a face-to-face 
interview at the study site, make a self-selection decision, and provide 
responses to all relevant medical history questions. 
• 
Purchasers: Responders who meet study enrollment criteria and 
purchase/obtain the study medication. 
• 
User Population: Subjects who take at least one dose of study medication 
during the study.  
9.3 
Endpoint Analysis 
A summary of the disposition of subjects (including those who respond to 
advertisements, the screening and self-selection populations, purchasers, and users) 


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and reasons for exclusion from these populations will be provided.  Demographic 
characteristics, medical history and other background information will be summarized 
for the self-selection, purchaser, and user populations. 
Frequencies and percentages will be presented for categorical data, mean, standard 
deviation (SD); median, and range will be presented for numerical data. 
Frequencies, percentages and 2-sided 95% CI will be calculated for the primary and 
secondary endpoints using the exact method, without using assumptions or 
approximations based on distributions.  For the primary endpoints, it will be 
concluded that the established target threshold is reached if the lower limit of the CI of 
the point estimate is equal to or exceeds the value of the pre-determined threshold. 
Endpoints and demographics will be presented for subgroups of interest, with 
participants dichotomized on the corresponding variables, which include (but are not 
necessarily limited to) literacy, gender, age (adolescent vs. adult women), and history of 
previous hormonal birth control use. 
A more detailed description of planned data analysis procedures will be found in the 
Statistical Analysis Plan (SAP) which will be approved and signed before the database 
is locked. 
 Primary Endpoint Analysis 
Frequencies, percentages and two-sided 95% CIs will be calculated for the primary 
endpoints for the entire study population and for selected subgroups. 
9.3.1.1 Self-Selection:  Proportion of self-selection population who make a correct 
selection decision regarding use of the product. 
The first primary endpoint is the proportion of those subjects making the self-selection 
decision who make a correct decision about whether the product is right for them to use. 
9.3.1.1.1 Populating the Self-Selection Table 
Each participant will be classified on two key variables: (1) whether they are a selector 
and (2) whether their use of the product would be appropriate, in order to populate the 
typical 2x2 self-selection table. 
Selection Decision:  The selection phase of the interview consists of the self-selection 
question and purchase (or equivalent) question, with accompanying neutral follow-up 
questions.  All subjects who go on to purchase/obtain the study product will be 
categorized as selectors.  Subjects who do not eventually complete the 
purchase/dispensing of the product will be classified as a selector or a non-selector 
primarily on the basis of the initial self-selection and purchase questions (the second 
selection decision will be included for those with a positive enrollment pregnancy test).  
However, all information recorded during the selection phase of the interview, including 
verbatim responses to open-ended follow-up questions, will be considered in the 
classification of participants as selectors or non-selectors.  Participants who offer 


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modifying information in open-ended responses to neutral probing will be re-categorized 
accordingly. For the subset of subjects that select the product, report not being pregnant, 
sign consent, and then receive a positive result from the subsequent enrollment 
pregnancy test, a second selection question will be asked.  Their classification as a 
selector or non-selector will take into account this second selection decision made in 
light of new health status information. 
Appropriate to Use:   
Non-selectors will be classified on the variable Appropriate for Use as follows: 
Yes: meets the label criteria for use, representing those who could have 
selected appropriately, but did not (Cell C). 
No: does not meet the label requirements for use, and appropriately did not 
select (Cell D).  This includes those participants who otherwise might have 
met the strict criteria for appropriate use according to the DFL, but who give a 
medically appropriate rationale for their non-selection decision.  For example, 
if a participant who otherwise meets the labeled criteria for use does not 
select the product and cites the fact that they have unexplained vaginal 
bleeding between their menstrual periods as their reason for not selecting 
(which otherwise does not disqualify a subject from using, but rather suggests 
that they talk to a doctor), that participant will be re-classified from Cell C to 
Cell D.  A physician will review the casebook for each participant who falls 
into Cell C to determine if any participants meet that criterion. 
Selectors will be classified on the variable Appropriate for Use as follows: 
Yes: either meets the strict label criteria for use (1-Correct Selectors) or 
reported and measured characteristics justify the selection decision (2-
Acceptable Selectors), representing those who chose to use the product who 
made a clinically acceptable decision despite not meeting the strict label 
criteria for use (Cell A). 
No: does not meet strict label criteria and reported and measured 
characteristics do not justify the selection decision (3-Incorrect Selectors), 
representing those who chose to use the product, but should not have (Cell 
B). 
Further definitions of Correct, Acceptable, and Incorrect Selectors follow: 
1) Correct Selectors.  Participant meets the strict criteria of the DFL, 
including: 
a) No absolute contraindications (not male, no history of any cancer, not 
pregnant, does not have a known allergy to one of the ingredients) 
b) Is a woman of childbearing potential?  This would include all women 
who do not report any of the following:  surgical sterilization (tubal 
ligation, hysterectomy, or bilateral oophorectomy) or postmenopausal 
for at least one year. 
2) Acceptable Selectors.  Participant does not meet the strict criteria of the 
DFL, but selection is classified as appropriate because they are judged 
clinically (see Section 8.5.3) to be an appropriate selector.  This group is 


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expected to be quite small and might include for example:  a woman who 
has a history of breast cancer, but who reports that she has been told by 
a healthcare provider that her cancer is not hormone sensitive and she 
can use oral contraceptives. 
3) Incorrect Selectors.  This group includes selectors who are not correct or 
acceptable, including having any of the following: 
a) An absolute contraindication to the product (has a history of any 
cancer, is pregnant and intends to use while pregnant, and/or has a 
known allergy to one of the ingredients) 
b) Is a man 
c) Is a woman without childbearing potential?  This would include all 
women who report any of the following:  surgical sterilization (tubal 
ligation, hysterectomy, or bilateral oophorectomy) or postmenopausal 
for at least one year. 
Please note that the criteria upon which initial selection is judged include the absolute 
contraindications.  Two conditional contraindications from the prescription labeling are 
presented in other sections of the DFL to reflect their conditional nature, namely, 
unexplained intermenstrual bleeding and liver problems.  The fact that these two 
warnings are conditional rather than absolute (i.e. they are “ask a doctor before use” 
warnings rather than “do not use” warnings) means that consumer behavior relative to 
these warnings cannot be evaluated as part of the initial self-selection decision, because 
correct behavior depends on subsequent actions (asking a doctor), and initial selection 
is not necessarily inappropriate if the subject does select to use the product but indeed 
follows those instructions to talk to a doctor about use of the medicine. Evaluation of the 
instructions regarding those two messages will be done individually based on the 
complete subject behavior in discrete endpoints. 
9.3.1.1.2 Analyzing the Self-Selection Table 
Cell A represents a correct decision, namely consumers for whom the study product is 
right to use who choose to use it, and therefore presents very little potential adverse 
clinical consequences.   
Cell C, while not technically correct, is a decision that accrues no health risk, but rather 
is a missed opportunity to use the drug.  Thus, these participants are considered neither 
correct nor incorrect and are usually left out of the primary self-selection analysis. 
The most critical self-selection decision is made by participants who, based on their 
health status, should not use the study medication (cells B and D).  Unlike an incorrect 
decision by consumers for whom this product is appropriate (cell C), an incorrect 
decision (cell B) by these consumers who should not use the medicine has potential 
efficacy or safety implications. Because it is expected that very few subjects will be 
inappropriate for use, this endpoint will be measured by the following proportion, taken 
from the self-selection table [(cell A + cell D)/(all subjects)].   
Other proportions will also be presented, including the total correct selectors as 
described by the equation [(cell A + cell D)/(cell A + cell B + cell D)] (excluding cell C) 


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and the typical self-selection metric, namely the proportion described by the equation 
[cell D/(cell B + cell D)].  This proportion represents a correct non-selection decision.  In 
other words, this is the proportion of those who should not select the product who 
correctly do not select. 
9.3.1.2 Actual Use:  Use of the study medication every day 
This is adherence to the instruction to take one tablet every day, and is measured as the 
proportion of active dosing days among the user population (all subjects who take at 
least one dose of the IP) where a dose was taken (excluding days after a subject 
discontinues use of the IP—defined as the point at which no additional doses are taken).  
Specifically, to be included in the numerator (representing appropriate adherent use), a 
dosing day must meet one or more of the following criteria: 
1. A tablet must be taken at some time during the dosing day. 
2. Subject reports using a condom (or another barrier method) for any act of 
intercourse or abstaining from intercourse. 
Regarding #2 above, the DFL provides explicit instructions for consumers when they 
miss pills which mitigate any risk of pregnancy related to that missed pill.  So, while 
overall adherence to the daily dosing schedule will be presented as well (without 
accounting for secondary barrier method use for acts of intercourse or for abstinence), 
the overall measure of adherence will allow for those label-directed or appropriate 
consumer behaviors. Please note that for the purposes of this endpoint, diary data will 
serve as the primary source of data, with interview data collected by telephone used to 
supplement only in cases where diary data may be missing. 
9.3.1.3 Actual Use:  Use of the study medication at the same time of day 
This endpoint is the proportion of active dosing days among the user population (all 
subjects who take at least one dose of the IP) which demonstrate adherence to the 
labeled directions for use related to the time of day the study medication is taken 
(excluding days after a subject discontinues use of the IP).  Specifically, to be included in 
the numerator (representing appropriate adherent use), a dosing day must meet one or 
more of the following criteria: 
1. For all dosing days where a tablet was taken the preceding day, the tablet is 
taken no later than 27 hours after the previous tablet (representing 24 hours from 
last dose plus three hours, consistent with the DFL instructions). 
2. Subject reports using a condom (or another barrier method) for any act of 
intercourse or abstaining from intercourse. 
Again, regarding #2 above, the DFL provides explicit instructions for consumers when 
they are late taking their pill which mitigates any risk of pregnancy related to that late 
dose.  So, while overall adherence to taking the product at the same time every day will 
be presented as well (without accounting for secondary barrier method use for acts of 
intercourse or for abstinence), the overall measure of adherence to dose timing will allow 
for those label-directed or appropriate consumer behaviors. Please note that for the 


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purposes of this endpoint, diary data will serve as the primary source of data, with 
interview data collected by telephone used to supplement in cases where diary data may 
be missing. 
9.3.1.4 Actual Use:  Use of the study medication without an extended break or any 
break between packs 
While another endpoint measures all instances of any missed pills, this endpoint is 
intended to capture the special cases in which any subjects take an extended break from 
daily pill taking for any reason at any time, including. subjects who miss any pills 
between packs.  For example, there may be subjects who do not appreciate the 
difference between a COC (where a medication break during menstruation is common) 
and the IP instructions which call for use daily without any breaks.  This concept is 
measured as the proportion of the user population who do not take an extended break or 
a break between packs (where a single pack is defined as 28 tablets).  A "break" is 
distinguished from discontinuation (defined above), which is a consumer choice not 
proscribed by the label. 
The numerator will comprise the total user population minus those subjects who miss 
taking the IP for seven consecutive days on at least one occasion OR for four 
consecutive days or more on at least two occasions during active use of the product OR 
who take any break between packs (including missing one pill between packs), as 
recorded in their medication use diary.  Subjects with a qualifying use pattern will be 
asked directly about that use during the next scheduled follow-up telephone interview.  
Please note that missed pills that are not included this endpoint are accounted for in 
another primary endpoint.  Also note that for the purposes of this endpoint, diary data will 
serve as the primary source of data, with interview data collected by telephone used only 
to supplement in cases where diary data may be missing. 
 Target Thresholds 
Objective target thresholds will be set for all the primary endpoints.  The objective will be 
considered met for these endpoints if the lower bound of the 2-sided 95% CI for each 
endpoint meets or exceeds the established threshold.  Target thresholds and a summary 
of the associated rationale follow. 
9.3.2.1 Self-Selection:  Proportion of self-selection population who make a correct 
selection decision regarding use of the product. 
HRA proposes to test this message as a primary endpoint because it is the self-selection 
phase of the study that will determine appropriate use of the product based on the DFL.  
This endpoint measures several relevant messages in the label:  
Use: 
For daily use by women to prevent pregnancy 
Allergy alert: Do not use if you are allergic to this product or any of its ingredients. 
Do not use: 
● if you are male 


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● if you have ever had any cancer 
● if you are already pregnant or think you may be pregnant 
This endpoint addresses both correct selection to use in order to prevent unintended 
pregnancy but also measures appropriate de-selection among individuals who should 
not use this product.   
Do not use if you are male.  This contraceptive pill is not intended for use by men.  Use 
by a man would represent a fundamental misunderstanding of the product and its 
indication.  Use by men is very unlikely:  National Health and Nutrition Examination 
Survey (NHANES; 2011-2012) data showed no evidence of men of any age taking oral 
contraceptive pills3.  However, if a man were to take a POP, it is unlikely to have serious 
clinical consequences.  A variety of different progestogens, in a variety of doses and 
routes of administration, have been tested as hormonal contraceptives for men.  
Testosterone alone is effective but adding progestin results in an increased rate and 
extent of suppression4.  High doses of progestins suppress endogenous production of 
gonadotrophins and testosterone thereby inhibiting spermatogenesis.  Common side 
effects include acne and changes in mood and libido which are rarely severe enough to 
lead to discontinuation.  Suppression of spermatogenesis is reversed when the 
treatment is stopped5.   
In theory, use of the POP could suppress spermatogenesis rendering a man less fertile.  
However, it is unlikely that 0.075 mg/day would have much of an effect on 
spermatogenesis and would be unlikely to render a man infertile unless he already had a 
very low sperm count.  In any case, the effect is reversed when the treatment is stopped. 
Other potential consequences would include the theoretical exacerbation of any pre-
existing medical condition which is adversely affected by a progestin in the same way, 
and to the same extent as it would for a woman.  Such conditions would include the 
United States Medical Eligibility Criteria (USMEC) Category 3 conditions6, i.e.  ischemic 
heart disease, stroke, Systemic Lupus Erythematosus (SLE) with anti-phospholipid 
antibodies, breast cancer with no evidence of current disease for five years, 
hepatocellular adenoma and malignant hepatoma and just one USMEC Category 4 
condition, current breast cancer.  The likely effect of progestin on these pre-existing 
conditions is discussed with respect to their occurrence in women later in this document. 
In summary, use of the POP by a man would be inappropriate, but is not likely to expose 
the male user to significant or lasting harm. 
Do not use if you have ever had any cancer.  The warning against use of the product by 
women with a history of cancer arises from a concern that reproductive hormones may 
increase the likelihood of, or accelerate, recurrence of certain cancers, most prominently 
breast cancer.  While the DFL warning is intended to protect women with any history of 
progestin-sensitive cancers, consumers may not know whether their specific cancer is 


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progestin-sensitive.  Other non-breast cancers which are progestin-sensitive are 
exceedingly rare in this target population. 
In the USMEC, breast cancer is a ‘category 4 condition’ for all hormonal contraceptives 
including the POP.  Note, however, that history of breast cancer is a ‘category 3 
condition’ for all hormonal contraceptives including the POP, when five disease-free 
years have passed.  The USMEC recommendations are based on expert opinion 
relating to a theoretical risk based on the knowledge that some breast cancers have 
progesterone receptors7.  In fact, there is no specific data on the risk of use of a POP in 
a woman with breast cancer that would allow this risk to be quantified. 
There are no direct data on the effect of hormonal contraceptives on the progress or 
outcome of breast cancer if a POP is taken since use of hormonal contraceptives in 
those with breast cancer is generally avoided.  While there are no data on hormonal 
contraceptives in those with breast cancer, there are limited data from trials of hormone 
replacement therapy (HRT) use among menopausal women with breast cancer and this 
is the closest to relevant evidence.  Unlike POPs, HRT contains estrogen in combination 
with progestins.  In the 1990s, two randomized clinical trials started in Scandinavia 
addressing whether HRT is safe for women with previous breast cancer.  The HABITS 
(hormonal replacement therapy after breast cancer—is it safe?) study, an open 
randomized controlled trial (RCT) with allocation to either HRT or ‘best treatment without 
hormones’ randomized 434 women8.  After a median follow-up of 2.1 years, 26 women 
in the HRT group and seven in the non-HRT group had a new breast-cancer event and 
the trial was terminated.  The Stockholm trial was started in 1997 and designed to 
minimize the dose of progestogen in the HRT arm.  Disease-free women with a history 
of breast cancer were randomized to HRT (n=188) or no HRT (n=190).  The trial was 
stopped in 2003 when the HABITS trial reported increased recurrence of breast cancer.  
However, the Stockholm data showed no excess risk after 4 years of follow-up9.  A long-
term follow-up published in 2013 after 10.8 years of follow-up reported no difference in 
new breast cancer events: 60 in the HRT group versus 48 among controls (hazard ratio 
(HR)=1.3; 95% confidence interval (CI) = 0.9-1.9).  No differences in mortality or new 
primary malignancies were found9. 
So, should a woman with a history of breast cancer take norgestrel 0.075 mg tablets for 
a prolonged period of time, it is possible that her prognosis would be worse.  It should be 
remembered that the limited data on HRT involves the use of estrogen in combination 
with progestins and that the dose of progestin in the POP is low.  In the study by Trinh et 
al10, there was no increased risk of breast cancer recurrence associated with use of the 
levonorgestrel-releasing intrauterine system (LNG-IUS).  However, in a subgroup 
analysis of women who developed breast cancer while using an LNG-IUS and who 
continued to use the LNG IUS, there was a higher risk of recurrence of borderline 
statistical significance10.  Thus, use of any hormonal contraceptive should be avoided in 
women with breast cancer unless otherwise directed by a doctor. 
With respect to a comparison of risks, it should be noted that pregnancy itself (which 
Opill® use is aimed to prevent) worsens the prognosis for women with breast cancer11.   


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It is, however, unlikely that women with a history of breast cancer would use norgestrel 
0.075 mg tablets.  The DFL clearly directs women with a history of breast cancer not to 
use the product and women with breast cancers are very likely to be well informed about 
the need to avoid ‘hormones’.  They are also highly likely to be under the care of a 
physician who, since pregnancy is a major risk during breast cancer, is likely to 
encourage and monitor their use of contraception.  Further, breast cancer is relatively 
rare among women of reproductive age.  According to the 2011-2012 NHANES, among 
women 15-44 years of age, only 0.21% reported having ever been diagnosed with 
breast cancer.  Among these women in the NHANES sample who had been diagnosed 
with breast cancer at some point in their lifetime, none reported currently taking birth 
control pills3.  Several other studies also found that the prevalence of breast cancer was 
less than 1% among women seeking reproductive health services12-14. 
In summary, although the concern about the use of hormonal contraceptives among 
women with breast cancer arose primarily from COCs containing estrogen, there is also 
some concern about women with breast cancer being exposed to progesterone.  Breast 
cancer is very rare in women of reproductive age, and women with breast cancer are 
very aware of their condition and unlikely to ignore a clear warning on the DFL, making 
the likelihood of such exposure due to use of a POP very low. 
Do not use if you are already pregnant or think you may be pregnant.  The OTC label 
warns against use of norgestrel 0.075 mg tablets in pregnancy, because a pregnant 
woman clearly has no need for contraception.  The inadvertent use of hormonal birth 
control (HBC) in pregnancy is bound to occur occasionally, whether in the prescription or 
OTC setting, because some women may start HBC not knowing they are already 
pregnant or become pregnant while using HBC.  There are no reports of adverse 
consequences of use of HBC in pregnancy.    
There are two possible scenarios under which a pregnant woman might be exposed to a 
POP, whether in the prescription or OTC setting.  Firstly, a woman might start taking 
norgestrel 0.075 mg tablets without realizing that she is already pregnant in which case 
the fetus would be exposed to norgestrel 0.075 mg/day from the day she started taking 
the pill until she stopped taking it.  Second, a woman might become pregnant while 
taking norgestrel 0.075 mg tablets and not realize it immediately and continue taking the 
tablets for a period during that pregnancy in which case the fetus would be exposed to 
the product from the moment of conception until the woman stopped taking the pill. 
There are two possible consequences of a pregnant woman taking a POP for some 
period: 
A. Teratogenesis.  Taking norgestrel 0.075 mg tablets during pregnancy appears to 
pose little risk, although it is not recommended, and confers no benefit.  The 2016 
USMEC states that ‘there is no known harm to the woman, the course of her 
pregnancy, or the fetus if progestin only contraceptives (POC) are inadvertently used 
during pregnancy’6.  In an American Society for Reproductive Medicine (ASRM) 
educational bulletin recommending luteal phase supplementation with progesterone 
in IVF cycles (which of course exposes the embryo and fetus to high doses of 


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progesterone), the authors state ‘there is no evidence to indicate that maternal 
exposure to progesterone or 17-hydroxyprogesterone during pregnancy increases 
risk for birth defects’15.  The concern regarding exposure to synthetic progestins 
relates to a possible risk of virilization of female fetuses and hypospadias in male 
offspring.  The same ASRM educational bulletin, however, concludes that analysis of 
the published literature relating to maternal progestogen exposure during pregnancy 
and virilization of the genitalia in female infants indicates that most reported cases 
involved high doses of progestins derived from androgens, particularly ethisterone 
and norethindrone15.  Most reported cases of masculinized female infants are 
associated with maternal exposure to methyltestosterone, methandriol and 
danazol16.  In a report of an investigation into the association between progestin 
intake and hypospadias using national US databases, the authors reviewed the 
literature16.  They concluded that most of the studies did not report a significant 
increase in genital defects and that much of the data came from studies involving 
exposure to higher dose androgenic progestins no longer used in contraceptives.  
Moreover, these studies had many methodologic limitations, e.g. analysis of all 
exposures as a single entity regardless of indication; type of progestin, timing, or 
duration of exposure; small sample sizes; potentially differential ascertainment of 
outcomes between cases and controls; and inability to examine potential covariates.  
The Carmichael study included infants exposed to progestin contraceptives and 
examined bivariate risks associated with any intake during the month before 
pregnancy or the first three months of pregnancy, intake during each month 
separately, and intake by medication content16.  They reported that progestin intake 
for the purpose of contraception was not associated with increased risk of 
hypospadias.  In a recently published prospective observational cohort study on oral 
contraceptive use and birth defects, data were collected among 880,694 live births 
from Danish registries between 1997 and 201117.  The study did not distinguish 
between POPs and COCs.  The main outcome measure was the number of major 
birth defects throughout one year of follow-up.  No increase in prevalence of major 
birth defects was seen with oral contraceptive exposure among women with recent 
use before pregnancy.  
In summary, taking norgestrel 0.075 mg tablets during pregnancy appears to pose 
little risk, although it is not recommended, and confers no benefit. 
B. Delay in the diagnosis of pregnancy.  In either scenario described above in which 
a pregnant woman takes norgestrel 0.075 mg tablets during pregnancy, there may 
be a delay in the diagnosis of pregnancy, thus delaying the provision of antenatal 
care if pregnancy is continued or limiting the woman’s options for choosing 
pregnancy termination if desired.  Most women experience a number of symptoms 
during early pregnancy (such as nausea) which alert them to the possibility they are 
pregnant.  Moreover, the DFL advises women using the OTC POP to consult a 
health professional if they have not had a period for 8 weeks.  It seems unlikely that 
the diagnosis of pregnancy would be delayed by more than 8 weeks, a delay which 
should not interfere critically with delivery of antenatal care.  


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In summary, inadvertent use of norgestrel 0.075 mg tablets in pregnancy is expected 
to be rare and the available data on the intake of low dose progestins for a limited 
period in pregnancy suggest that there are no significant clinical consequences. 
Please note that the criteria upon which initial selection is judged include the absolute 
contraindications, as translated from the prescription labeling contraindications section to 
the proposed DFL.  Two conditional contraindications from the prescription labeling are 
presented in the “ask a doctor before use” instead of the “do not use” section of the DFL 
to reflect their conditional nature, namely, unexplained intermenstrual bleeding and liver 
problems.  Evaluation of the instructions regarding those two messages will not be 
included in this self-selection measure, but will instead be evaluated based on 
subsequent subject behavior in discrete endpoints. 
Based on the rationale given above, HRA has designated a target threshold of 85% for 
overall self-selection, reflecting the relative safety of this product and the likely modest 
clinical consequences for failure to select appropriately. 
9.3.2.2 Actual Use:  Use of the study medication every day 
This is designated a primary endpoint, due to the relevance of the instruction to efficacy. 
The relevant message in the DFL:  
Directions: 
● Take 1 tablet … every day 
■ This product will work best to prevent pregnancy when taken exactly as directed  
● if you are more than 3 hours late taking your tablet or miss taking your tablet on 1 or 
more days: 
■ take 1 tablet immediately, as soon as you remember that you missed it 
■ then go back to taking your daily tablet at your usual time 
■ use a condom (or another barrier method) every time you have sex during the next 2 
days (48 hours), because it takes 2 days for Opill® to start working again 
POPs contain a relatively low dose of progestogen.  Distribution and elimination of 
progestogen are fairly rapid such that by 24 hours after administration, serum steroid 
concentrations are near baseline18.  Thus, it is important for a POP user to take a pill 
every day in order to maintain the contraceptive effect of the progestin on the genital 
tract.  The main mechanism of action of the POP is to thicken cervical-vaginal mucus, 
rendering it less permeable to sperm transport18.  There are also effects on tubal motility, 
on the endometrium, and on ovulation - which contribute to contraceptive efficacy.  Since 
ovulation is inhibited or impaired in around 50% of cycles among women taking the 
POP18, strict adherence to daily pill taking may be more crucial to efficacy than it is with 
the COC, which inhibits ovulation in 99% of the cycles.  Thus, failure to take a pill every 
day will reduce the contraceptive efficacy of the POP.  While no contraceptive method is 


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100% effective, there are significant differences between POP failure rates during 
perfect use (when a pill is taken every day) and typical use when mistakes are made, 
primarily missing pills.  The perfect-use failure rate of the POP is around 1%.  During 
typical use, when POPs have been prescribed by a health professional, the failure rate is 
9%20, demonstrating the effect on effectiveness of diminished compliance.  
In setting a threshold for this primary endpoint, it is important to look into the observed 
daily compliance with contraceptive pill taking in the Rx environment.  It is known that 
compliance with all types of daily medication is far from perfect and that many women 
find it hard to comply with daily contraceptive pill taking.  A number of published studies 
are available that provide insight into women’s use of oral contraceptive pills, including 
the extent to which women adhere to the requirement to take the medication every day.  
A wide variety of methods, ranging from retrospective self-report surveys to electronic 
monitoring have been used to measure contraceptive pill use.  Two studies whose 
methods most closely align to the proposed methods for measuring compliance in the 
actual use study (i.e., data collected via subject diaries and outcome expressed as 
average number of missed pills) suggest that women report missing between 1.0 -1.2 
pills per cycle21, 22.  Both of these studies utilized instrumented pill dispensers which 
allowed for electronic monitoring of pill use in addition to subject diary reports; results 
based on electronic monitoring indicated that women actually missed on average 
between 2.621 to 4.722 active pills per cycle.  While these studies were conducted among 
women using a combined oral contraceptive (COC) pill, there is no reason to think that 
behavior may be different among women using a POP.  These data were collected in a 
formal study in which women were highly likely to perform better than average (since 
they had received uniform instructions and knew that they were being monitored).  
Based on these data, typical use of oral contraceptive pills is likely to be characterized 
by women missing on average between 1 to 4.7 pills per month21, 22.  As compliance is 
imperfect in the prescription environment, one should expect similarly limited compliance 
in an OTC setting.  HRA may seek to identify or collect additional data to characterize 
compliance with oral contraceptives in the prescription environment, to provide 
perspective for evaluating compliance in this actual use study. 
 
The potential outcome if women fail to follow the label instruction to take a POP pill 
every day is a risk of pregnancy, assuming they are sexually active.  There are no data 
which directly quantify the risk of pregnancy after missed POPs.  In contrast to COCs, 
there are also no data on the effect on the hypothalamo-pituitary-ovarian axis (HPO axis) 
of missing POPs (i.e., there is no indirect measure of the likelihood of conception after 
missed pills).  In the recently updated US Selected Practice Recommendations for 
Contraceptive Use (US SPR)23, ‘no evidence was found on the effects of missed POPs 
available in the United States of America (US/USA) on measures of contraceptive 
effectiveness including pregnancy, follicular development, hormone levels or cervical 
mucus quality.’  Therefore, the likelihood of the occurrence of pregnancy if a woman 
does not adhere to the instruction to take a POP every day can only be hypothesized.  It 
is not known how many POP pills need to be missed before contraceptive efficacy 
returns to zero.  


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The risk of pregnancy also depends crucially on when contraceptive pills are missed and 
when sexual intercourse occurs relative to the menstrual cycle.  The risk of conception 
will be low among women who, for example, have intercourse less often than once a 
week or whose failure to take the pill in a timely way occurs eight days before ovulation.  
Thus, individual episodes of missed pills will not typically result in pregnancy.  Despite 
the relatively poor pattern of pill-taking during typical (vs. perfect) use, over the course of 
one year, the failure rate of the POP in the Rx environment is <10%24.  In contrast, a 
sexually active woman who uses no method of contraception has a risk of pregnancy of 
at least 80% over the course of one year24.  It follows then that failure to take a pill every 
day in a manner which is typical of average contraceptive pill taking behavior as 
described above probably does not incur a very high risk of pregnancy.    
As intermittent non-compliance with daily pill-taking is common even in the prescription 
environment, and has modest effects on pregnancy risk, as guided by FDA, HRA will 
evaluate this endpoint at a target threshold of 85%. 
9.3.2.3 Actual Use:  Use of the study medication at the same time of day. 
HRA proposes to test this label message as the third primary endpoint as this message 
pertains to an important difference between POPs and COCs.  
The relevant message in the DFL:  
Directions: 
● Take 1 tablet at the same time … 
■ this product will work best to prevent pregnancy when taken exactly as directed 
● if you are more than 3 hours late taking your tablet 
or miss taking your tablet on 1 or more days: 
■ take 1 tablet immediately, as soon as you remember that you missed it 
■ then go back to taking your daily tablet at your usual time 
■ use a condom (or another barrier method) every time you have sex during the next 2 
days (48 hours), because it takes 2 days for Opill® to start working again 
According to prescribing information, POPs are meant to be taken at the same time each 
day, within a 3-hour window.  The OTC norgestrel 0.075 mg tablets DFL instructs users 
to take the pill at the same time every day, because doing so is important to product 
effectiveness.  While there are no data specific to norgestrel, data from other POPs 
suggest that peak serum concentrations are reached around 2 hours after 
administration18.  Distribution and elimination are fairly rapid such that by 24 hours after 
administration serum steroid concentrations are near baseline18.  Thus, it is important to 
take a pill every day, and close to the same time each day, in order to maintain the 
contraceptive effect of the progestin on the reproductive tract.  Instructions for use of 
POPs direct women to take the pill at the same time every day and regard failure to take 


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the pill during the three-hour period after this time as an indication for using back-up 
contraception if the woman has sex during the relevant time period. However, White et 
al25 note that the recommendation that back-up contraception be used if a POP is taken 
more than three hours later than the scheduled time is not based on firm evidence. 
Moreover, no clinical data are available that correlate pregnancy rates with timeliness in 
taking POPs26. 
In the prescription environment, data suggest many people are poor at complying with 
daily pill taking, as discussed above.  The Rx labeling for both COCs and POPs include 
directions that the pill be taken at the same time each day.  There are data on the timing 
of oral contraceptive ingestion, collected via retrospective survey.  One retrospective 
study of 1,311 women making initial family planning visits to metropolitan health 
department clinics found that only 20% of users said they took a pill every day, within 
two hours of the same time every day23.  One study was identified that provides 
quantitative information on timing of pill use in the context of a randomized study 
evaluating the impact of an adherence aid among users of a particular COC 
(ethinylestradiol 20 µg/drospirenone 3 mg) over the course of one year24.  All medication 
for this study was provided by a digital pill dispenser that had various capabilities for 
reminding women to take the pill at the appropriate time.  The time at which the 
dispenser reminded the woman to take a pill each day (reference time) was set by the 
first pill release but could be changed.  It is important to note that for the purposes of this 
study, pills that were dispensed early were considered to be dispensed at the reference 
time.  Among women whose pill dispensers issued an audible alarm, the mean (SD) 
daily delay in pill release was 88 minutes (SD=126 minutes).  It was 178 minutes 
(SD=140 minutes) among women whose dispenser only gave a visual prompt.  These 
values indicate that a large proportion of women took the pill more than 2 hours late, 
despite being actively prompted.  Failing to take a POP within the three-hour time 
window is likely to be quite common in both the Rx and OTC environments.  Among 
women prescribed a POP in the Rx environment, the typical use failure rate is 3% to 
10%, and this likely includes the contribution of women who take their pills late.  One 
would not expect late pill taking to be any less common in the OTC situation.  
Failure to follow the instruction to take a pill at the same time every day (failure to take 
the daily pill within the three-hour window) may diminish contraceptive efficacy.  
Although serum steroid concentrations will have returned to almost baseline 24 hours 
after POP administration, any effect on the HPO axis is likely to be sustained beyond 24 
hours.  This means the POP’s action on cervical-vaginal mucus, tubal motility, 
endometrium, and ovulation – are still in effect, so taking a pill later than 27 hours after 
the previous pill is unlikely to be nearly as risky as having intercourse without any 
contraception.  That is, some efficacy is likely to be retained even if the pill were taken 
late.  Moreover, the chance of pregnancy in the event of late pill taking will depend on 
the time in the menstrual cycle when pills are taken late and on the occurrence of 
intercourse during the narrow window of vulnerability to conception.   


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HRA believes achieving good compliance is important, and accordingly has proposed 
this be a primary endpoint.  However, it is apparent that a delay in taking the daily pill will 
have less potential consequence than taking a break for a number of consecutive days 
or missing a pill entirely (the other compliance-related primary endpoints assessing 
optimal use for efficacy).  Considering the limited effect of delaying the daily pill, and the 
data that suggest that compliance is low in the prescription environment, and the fact 
that that low compliance is already accounted for by the known failure rate in typical Rx 
use of POPs, with guidance from FDA, HRA will evaluate this primary endpoint at a 
target threshold of 80%. 
9.3.2.4 Actual Use:  Use of the study medication without an extended break or any 
break between packs 
This is designated a primary endpoint, due to the relevance of the instruction to efficacy.  
The relevant message in the DFL are:  
Directions: 
● Take 1 tablet at the same time every day 
● Never skip your daily tablet 
● to prevent pregnancy, take this product every day, even when you bleed or have 
spotting 
● When you finish this pack, start the next one the following day without a break  
POPs including norgestrel 0.075 mg tablets are to be taken every day without any 
breaks at all, and it is particularly important that POP users do not take breaks of several 
consecutive days.  In contrast to POPs, COC was developed to include a 7-day pill-free 
interval which induced a regular monthly ‘withdrawal’ bleed, with some brands 
recommending shorter breaks.  COCs are the more commonly used "birth control pill."  
This raises the potential that women who have taken a COC in the past, or who are 
familiar with COC dosing, may think that the same regimen is required for a POP and so 
may deliberately take a break from pill taking for some days at the end of their pill 
packet.   
There are no data to suggest whether and how frequently this type of misunderstanding 
occurs in the prescription environment.  The consequences of deliberately taking an 
extended (4-7 day) break from taking OTC norgestrel 0.075 mg tablets at the end of a 
pack or packs due to misunderstanding the OTC directions for use would be a potential 
risk of pregnancy.  Missing a POP for a number of consecutive days impairs 
contraceptive efficacy and if this is repeated monthly and the norgestrel 0.075 mg tablets 
user is having sex, the risk of pregnancy is increased.  
There are data to show that contraceptive efficacy is achieved after just two consecutive 
days of taking a POP18, which mitigates the risk due to occasionally missing single pills 
intermittently.  It follows, in contrast, that missing pills on consecutive days is riskier than 


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missing just one pill, and that the more pills that are missed consecutively, the more 
likely contraceptive failure becomes.  In a randomized controlled trial (RCT) comparing 
two POPs, one containing 30 mcg LNG/day, the other 75 mcg desogestrel/day19, two of 
the three in-treatment pregnancies that occurred during use of the desogestrel POP 
were attributed to gross non-compliance (missing 12 tablets; stopping the POP for ‘some 
weeks’).  In the LNG-POP group, one of four pregnancies that occurred was attributed to 
missing 12 pills.  So, missing one pill on three consecutive days is riskier than missing 
one pill three times over the course of a packet of pills but on non-consecutive days.  
Compliance with daily pill-taking (which is also assessed as a separate primary 
endpoint) is known to be challenging whether the pills are obtained by prescription or 
OTC, making assessment of this behavior an important endpoint.   
Given the potential clinical significance of missing pills over several consecutive days, 
whether due to misunderstanding proper dosing of a POP or for any other reason, and 
based on FDA’s feedback, HRA will evaluate this endpoint at a target threshold of 90%. 
 Secondary Endpoint Analysis 
9.3.3.1 Actual Use:  Proportion of user population who do not use together with another 
form of hormone-containing birth control 
This secondary endpoint is the proportion in which the denominator is all users (the user 
population) and the numerator is all women who appropriately do not use the product 
together with another form of hormone-containing birth control. 
9.3.3.2 Actual Use:  Proportion of user population who report using a condom or other 
barrier method (or abstaining from intercourse) for the first 48 hours after 
starting to use the study medication 
This secondary endpoint is defined as the proportion in which the denominator is all 
users of the product and the numerator is all subjects who either report using a condom 
(or another barrier method of birth control) if they had intercourse or who abstained from 
intercourse for the first 48 hours after starting the study medication. 
9.3.3.3 Self-Selection/Actual Use:  Proportion of self-selection population taking one of 
the “ask a doctor or pharmacist before use” products who do not select (and 
cite that as the reason for not selecting), who select but do not use (and cite 
that as the reason for not using), or who report contacting a healthcare provider 
or pharmacist 
This secondary endpoint is the proportion defined by the denominator including all 
subjects who participate in the self-selection interview who report taking one of the “ask 
a doctor or pharmacists before use” compounds (including, phenytoin, carbamazepine, 
barbiturates, primidone, topiramate, oxcarbazepine, rifampin, rifabutin, bosentan, a 
prescription drug to treat HIV/AIDS, a supplement containing St. John’s Wort, or use of 
an emergency contraceptive containing ulipristal acetate in the past 5 days) and the 


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numerator is all such subjects who either do not select or use (and cite this warning as 
the reason for not selecting or using), or who report talking with a doctor or pharmacist 
about use during the course of the study. 
9.3.3.4 Self-Selection/Actual Use:  Proportion of self-selection population who report 
having liver problems who either do not select (and cite that as the reason for 
not selecting), who select but do not use (and cite that as the reason for not 
using), or who report contacting a healthcare provider about use of the product 
This secondary endpoint is the proportion defined by the denominator including all 
subjects who participate in the self-selection interview who report having liver problems 
and the numerator is all such subjects who either do not select or use (and cite this 
warning as the reason for not selecting or using), or who report talking with a healthcare 
provider about use during the course of the study. 
9.3.3.5 Actual Use:  Proportion of user population who experience one of the “Talk to a 
doctor” conditions listed within the “When using this product” or “Stop use and 
ask a doctor” sections who report contacting a healthcare provider and/or stop 
use as directed by the label 
This secondary endpoint is the proportion defined by the denominator including all users 
who report experiencing one of the “Talk to a doctor” conditions within the “When using 
this product” section (including unexplained vaginal bleeding between periods before 
starting Opill®, vaginal bleeding that is repeatedly brought on by sex, menstrual periods 
lasting more than 8 days or unusually heavy, no periods for two months, sudden or 
severe pain in lower belly, migraines with aura/worsening migraines, pregnancy, or 
symptoms of jaundice) and the numerator is all such subjects who report talking with a 
doctor about use during the course of the study or stopping use. 
Please note that this endpoint comprises measurement of behaviors related to a number 
of conditions that are expected to occur with relatively low frequency.  The proportions 
related to each individual message/behavior will be presented individually, as well as 
being aggregated in the formal endpoint analysis. 
9.3.3.6 Actual Use:  Number of pregnancies reported during the course of the study 
This endpoint is intended to characterize the pregnancies that may occur during the 
course of the study.  While it does not directly measure behavior related to messages on 
the DFL, it is of interest. For the purposes of this endpoint, pregnancies will be defined 
as any reported pregnancy during the use phase of the study, or any confirmed positive 
pregnancy test (at home or at EOS visit) that is conducted within 12 days of the end of 
the subject’s use phase. 


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 Other Measures Analysis 
The other measures are as follows: 
A. Actual Use:  Character and frequency of adverse events as reported by the user 
population. 
B. Actual Use:  Patterns of use in the user population, including discontinuation 
rates and reasons for discontinuation. 
C. Actual Use:  Proportion of user population who experience severe vomiting or 
diarrhea within 4 hours of taking their daily pill who report using a condom or 
other barrier method of contraception every time they have sex (or abstain from 
intercourse) for the next 48 hours. 
D. Actual Use:  Characterize healthcare seeking behavior among subjects. 
9.4 
Safety Analysis 
Adverse event (AE) analyses will include all events which initially occurred, or worsened 
following treatment. Adverse events will be summarized by the Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT) 
and classified according to their severity (mild, moderate, or severe) and relationship 
(related or not related) to study product. For the summary by severity, subjects who have 
multiple occurrences of the same AE will be classified according to the worst reported 
severity of the AE.  Similarly, for the summary by relationship to the study product, the 
AE will be classified according to the worst relationship. 
9.5 
Interim Analysis 
There will be no interim analysis for this study 
9.6 
Missing Data 
All missing data will be considered missing and no statistical procedures will be 
employed to estimate or impute missing data. 
9.7 
Open-ended Data 
Verbatim responses will be coded as described in Section 8.5.4 above, with coded 
responses presented within individual question tables.  For all verbatim responses 
(including those which were coded), listings will be generated and presented. 
10 DATA HANDLING AND RECORD KEEPING 
10.1 Data Collection Instruments / Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to a paper data 
record, an electronic data record or both, depending on the data collection method used 
in this study. 
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of the Sponsor and should not be made available in 
any form to third parties, except for authorized representatives of the Sponsor or 
appropriate regulatory authorities, without written permission from the Sponsor. 


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The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms 
(source documents) and ensuring that they are accurate, authentic/original, attributable, 
complete, consistent, legible, timely (contemporaneous), enduring, and available when 
required.  The CRFs must be signed by the Investigator or by an authorized staff 
member to attest that the data contained on the CRFs are true.   
In most cases, the CRF, or part of the CRF, will also serve as source documents.  In 
these cases, a document should be available at the Investigator’s site as well as at the 
Sponsor and clearly identify those data that will be recorded in the CRF, and for which 
the CRF will stand as the source document. 
Data for this study will be entered directly into a validated EDC system.  This system will 
provide a complete audit trail, which includes information about the initial data entry and 
all changes and deletions.  When the data collection form is saved, data edits will check 
entries in each field and provide immediate notification to the interviewer of data that is 
unacceptable (a different value must be entered) or questionable (the data field must be 
checked and if left intact, an explanation must be given).  Using this system, the 
interviewer will be able to correct entries or make clarifications while the participant is 
still being interviewed. 
All users will have a unique login user name and password, and system access 
privileges will be strictly controlled and documented.  The audit trail, user access 
privilege processes, and electronic signatures collected by the system will be compliant 
with 21 CFR Part 11 requirements. 
If an internet connection is not available at the time of enrollment, subjects will be 
rescheduled for another time.  If internet connection is interrupted during the course of 
an enrollment interview, the remainder of the interview will be completed when the 
internet connection is restored. Due to the complexity of the branching logic in the data 
collection instruments, use of electronic informed consent, and the requirement of 
creating a subject account for use in consenting and the electronic diary application, 
data will not be gathered on any paper copies of electronic case report forms in this 
study.  In the event the interview is interrupted due to loss of internet connectivity, the 
interview must be continued within a 3-day period to ensure data consistency and 
quality. 
 
10.2 Study Documentation 
PEGUS Research will maintain accurate and complete records of the study.  Study files 
and critical documents will be maintained at PEGUS Research throughout the study 
period, and will be retained or transferred to the Sponsor at its direction. 
10.3 Confidentiality of Study Documents and Electronic Records 
PEGUS Research holds all study-related documents and communications in the strictest 
confidence.  PEGUS Research will ensure that the participant’s anonymity is maintained.  
On documents submitted to the Sponsor, participants will not be identified by name or 


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other personally identifiable information, but by numerical identification code generated 
by the EDC system. 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
The procedures described herein pertaining to the conduct, evaluation and 
documentation of this study are designed to ensure that the sponsor and study 
personnel abide by Good Clinical Practice (GCP) guidelines.  The study will also be 
carried out in keeping with applicable local law(s) and regulation(s).    
SOPs from PEGUS Research will be followed to ensure quality.  PEGUS Research is 
responsible for selecting sites and training study personnel.  Training will consist of an 
overview of the protocol as well as detailed instructions on the methods, including 
participant recruitment, proper administration of the questionnaire, use of the EDC 
application and guidelines for correctly capturing and entering responses.  Study-specific 
interview completion guidelines will be developed to serve as the basis for training.  All 
training will be documented. 
Regulatory authorities, the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), and / or the sponsor’s or CRO’s clinical quality assurance group may 
request access to all source documents, CRFs, and other study documentation for on-
site audit or inspection.  Direct access to these documents must be guaranteed by the 
investigator, who must provide support at all times for these activities. 
12 ETHICS 
The study will be carried out in keeping with applicable local law(s) and regulation(s).    
12.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study 
protocol, protocol amendments, informed consent documents, and other relevant 
documents, e.g., recruitment posters, if applicable, from the IRB/IEC.  All 
correspondence with the IRB/IEC will be retained in the investigator file.  Copies of 
IRB/IEC approvals will be forwarded to the Sponsor. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC 
approval is where the change is necessary to eliminate apparent immediate hazards to 
the subjects.  In that event, the investigator must notify the IRB/IEC and the Sponsor in 
writing immediately after the implementation. 
12.2 Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as 
well as the general principles set forth in the International Ethical Guidelines for Health-
related Research Involving Humans (Prepared by the Council for International 
Organizations of Medical Sciences (CIOMS) in collaboration with the World Health 
Organization (WHO) 2016), International Council on Harmonization (ICH) Tripartite 
Guidelines for Good Clinical Practice (E6 (R1) Current Step 4 version dated 10 June 


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1996), and the Declaration of Helsinki – Ethical Principles for Medical Research 
Involving Human Subjects (World Medical Association, 2013).  
In addition, the study will be conducted in accordance with the protocol, the ICH 
guideline on GCP, and applicable local regulatory requirements and laws. 
PEGUS Research will oversee the process for the approval of all Investigators, trial 
protocol, informed consent forms and other relevant trial documents.  All 
correspondence with the IRB will be retained in the trial files for each site.  All records 
identifying participants will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.  Participant 
names will be collected for compensation purposes only and will not be linked to any 
study data.  This information will not be supplied to the sponsor or any other entity.  No 
personal identifiable information will be captured in the study database.  In accordance 
with the Federal Privacy Standard, a Notice of Information Practices, which describes 
how participants’ health information will be used and disclosed and how they can obtain 
access to this information, will be made available, if applicable. 
12.3 Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject 
names or other identifiable data in any reports, publications, or other disclosures, except 
where required by law. Explicit permission to gather sensitive data will be sought and 
documented prior to any data collection.  No personally identifiable information (PII) will 
be retained following the study for subjects that either did not pass the screening phase 
or who do not qualify for the use phase of the study, or choose not to sign consent.  Any 
data collected after explicit permission is granted will be retained as anonymous study 
data for use by the sponsor. 
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws. 
The informed consent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC before use, and available for 
inspection.   
The investigator, or a person designated by the investigator, will obtain informed consent 
from each subject before dispensing of study medication.  Informed consent documents 
will be presented electronically, and signatures gathered digitally, however, all consent 
procedures (including obtaining informed consent from a parent or legal guardian, if 
necessary) will be conducted in person.  An archived copy of the signed informed 
consent document will be made available to subjects digitally. 
All subjects who are classified as children according to local laws and regulations will be 
required to have parental consent for participation in the study as is dictated in 21 CFR 
50 subpart D. However, please note the definition of a child, according to 21 CFR 
50.3(o) is as follows: “Children means persons who have not attained the legal age for 
consent to treatments or procedures involved in clinical investigations, under the 
applicable law of the jurisdiction in which the clinical investigation will be conducted.” In 
many states, adolescents seeking contraception do not need parental consent for 


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treatment, and therefore do not meet the definition of “children” in § 50.3(o).  These 
adolescents are not subject to the requirements of 21 CFR 50 subpart D and may 
consent for research related to that treatment. Please note that states define the age or 
conditions upon which an adolescent can consent to contraceptive services differently, 
and local laws and regulations will be adhered to based on the state of each research 
site. 
In addition to being explicitly allowed for by regulation, there are compelling scientific 
reasons for not imposing a higher bar for entry into this study for adolescents who are 
not defined as children according to local laws. Adolescents are of special public health 
concern when it comes to access to contraception because of the implications of 
unintended pregnancy among that age group. Barriers to access to contraception are 
often higher for adolescents. Numerous professional organizations (AAFP, ACOG, AMA, 
APHA, ACCP) have called for the availability of oral contraceptive over-the-counter, to 
include access for all ages. Indeed, FDA has specifically requested a challenging quota 
of adolescent participants for this study, and has expressed specific concern about the 
bias that may be introduced by only including adolescents who have the degree of 
parental involvement required for parental consent.   
No additional waiver of the need for parental consent will be sought (above and beyond 
the appropriate classification of those adolescents who have attained the legal age for 
consent to contraceptive services as not children, and therefore not needing parental 
consent).  Where state and local laws define an adolescent as a child for the purposes of 
consenting to contraceptive services, parental consent and adolescent subject assent 
will be required for participation in this study and will be documented. 
In the case of all subjects (but perhaps most notably for adolescents), the investigator 
must ensure that the subject understands the research procedures and is able to give 
truly informed consent.  If a subject meets the regulatory requirements for signing 
informed consent, but in the judgement of the investigator is either inadequately 
informed or incapable of providing consent, that subject will not be allowed to proceed. 
All records identifying participants will be kept confidential, and to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.  Participant 
names will be collected for scheduling and compensation only.  No PII will be stored in 
the study database.  This information will not be supplied to the sponsor or any other 
entity.  In accordance with the Federal Privacy Standard, a Notice of Information 
Practices, which describes how participants’ health information will be used and 
disclosed and how they can obtain access to this information, will be made available, if 
applicable. 
Participants’ implicit consent will be obtained prior to collecting any personally-
identifiable contact information.  Explicit verbal consent to gather sensitive data will be 
requested and documented prior to collecting any health or other sensitive information. 
Participant names, contact information, and other identifiable data will be maintained 
entirely separate from the study database.  All parties will ensure protection of 
participant personal data and will not include participant names on any data forms, 
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Personally-identifiable data will be replaced by a numerical code consisting of a 
numbering system generated by the EDC system in order to de-identify the study 
participant.  In case of data transfer, PEGUS will maintain high standards of 
confidentiality and protection of participant personal data. 
12.4 Opt in for Future Research Contact 
During the informed consent process, subjects will be given the opportunity to opt in to 
allow the use of their contact information for the purpose of inviting them to participate in 
potential future research in topics related to their participation in this study.  Subjects will 
be informed that their decision about whether or not to opt in for any potential future 
contact will in no way impact their participation in the current study. 
While the purpose and procedures for any such hypothetical future study are unknown, 
and therefore cannot be described here or in the informed consent document associated 
with this study, any materials used to contact or invite those subjects who opt in to future 
studies would be submitted for IRB review, as would the associated protocol and data 
collection tools, in order to ensure subject safety. 
Please note that under no circumstances will subjects’ contact information collected as 
part of this study be disclosed to any other parties, including the study sponsor or other 
commercial or research entities. 
12.5 Liability and Insurance 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, 
its legal liability for injuries caused to participating persons and arising out of this 
research performed strictly in accordance with the scientific protocol as well as with 
applicable law and professional standards. 
12.6 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
competent authority in any area of the world, or if the Investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the 
investigational product, the Sponsor should be informed immediately.  
In addition, the investigator will inform the Sponsor immediately of any urgent safety 
measures taken by the investigator to protect the study subjects against any immediate 
hazard, and of any serious breaches of this protocol or of ICH GCP that the Investigator 
becomes aware of. 
12.7 Mandatory Reporting 
There will not be questions in the interview addressing personal sexual experience and it 
is not expected that participants will spontaneously disclose information that would 
trigger mandatory reporting requirements.  However, interviewers will be trained in the 
mandatory reporting conditions in each state where the interviews are conducted and to 
identify such conditions if they are reported by participants.  Participants will be informed 
in the introduction to the study that confidentiality will be strictly guarded, except for 
circumstances requiring reporting to authorities. 


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13 SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority 
decision, change in opinion of the IRB/IEC, drug safety problems, or at the discretion of 
the Sponsor.  In addition, the Sponsor retains the right to discontinue development of 
Opill® at any time. 
If a study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the participating pharmacy study sites.  As directed by the Sponsor, all study materials 
must be collected and all CRFs completed to the greatest extent possible. 
14 PUBLICATION OF STUDY RESULTS 
14.1 Communication of Results by the Sponsor 
The Sponsor fulfills its commitment to publicly disclose clinical trial results through 
posting the results of studies on www.clinicaltrials.gov (ClinicalTrials.gov) and other 
public registries in accordance with applicable local laws/regulations. 
15 EMERGENCY CONTACTS 
In emergency situations, the investigator should contact PEGUS Research Inc. by 
telephone on the number listed on the title page of the protocol. 
16 STUDY DURATION AND DATES 
The duration of this study is expected to be around 8 months (from first subject enrolled 
in the study until last subject last visit), with subject recruitment proposed to start Q4 
2017 and end in Q2 2018. The actual overall study duration or subject recruitment period 
may vary. 
 


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17 REFERENCES 
1. Murphy, Peggy W.; Davis, Terry C.; Long, Sandra W.; Jackson, Robert H.; 
Decker, Barbara C.  Rapid Estimate of Adult Literacy in Medicine (REALM): a 
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2. Davis TC, Wolf MS, Arnold CL, Byrd RS, Long SW, Springer T, Kennen E, 
Bocchini JA. Development and validation of the Rapid Estimate of Adolescent 
Literacy in Medicine (REALM-Teen): a tool to screen adolescents for below-
grade reading in health care settings. Pediatrics. 2006 Dec 1;118(6):e1707-14. 
3. Centers for Disease Control and Prevention (CDC). National Center for Health 
Statistics (NCHS). National Health and Nutrition Examination Survey Data. 
Hyattsville, MD: U.S. Department of Health and Human Services, Centers for 
Disease Control and Prevention, 2011-2012. 
https://wwwn.cdc.gov/nchs/nhanes/search/nhanes11_12.aspx  
4. Wang, C., Festin, M. P., & Swerdloff, R. S. (2016). Male Hormonal 
Contraception: Where Are We Now? Current Obstetrics and Gynecology 
Reports, 5(1), 38-47. 
5. Grimes, D. A., Lopez, L. M., Gallo, M. F., Halpern, V., Nanda, K., & Schulz, K. F. 
(2012). Steroid hormones for contraception in men. The Cochrane Library. 
6. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for 
Contraceptive Use, 2016. MMWR Recomm Rep 2016;65(No. RR-3):1-104.  DOI: 
http://dx.doi.org/10.15585/mmwr.rr6503a1 
7. Yip, C. H., & Rhodes, A. (2014). Estrogen and progesterone receptors in breast 
cancer. Future Oncology, 10(14) 2293-2301. 
8. Holmberg, L., & Anderson, H. (2004). HABITS (hormonal replacement therapy 
after breast cancer—is it safe?), a randomised comparison: trial stopped. The 
Lancet, 363(9407), 453-455. 
9. Fahlén, M., Fornander, T., Johansson, H., Johansson, U., Rutqvist, L. E., 
Wilking, N., & von Schoultz, E. (2013). Hormone replacement therapy after 
breast cancer: 10 year follow up of the Stockholm randomised trial. European 
Journal of Cancer, 49(1), 52-59. 
10. Trinh, X. B., Tjalma, W. A., Makar, A. P., Buytaert, G., Weyler, J., & van Dam, P. 
A. (2008). Use of the levonorgestrel-releasing intrauterine system in breast 
cancer patients. Fertility and Sterility, 90(1), 17-22. 
11. Raphael, J., Trudeau, M. E., & Chan, K. (2014). Outcome of patients with 
pregnancy during or after breast cancer: a review of the recent literature. Current 
Oncology, 22, S8-18. 
12. Grossman, D., Fernandez, L., Hopkins, K., Amastae, J., Garcia, S. G., & Potter, 
J. E. (2008). Accuracy of self-screening for contraindications to combined oral 
contraceptive use. Obstetrics and Gynecology, 112(3), 572-578. 
13. Grossman, D., White, K., Hopkins, K., Amastae, J., Shedlin, M., & Potter, J. E. 
(2011). Contraindications to combined oral contraceptives among over-the-
counter compared with prescription users. Obstetrics and Gynecology, 117(3), 
558-565. 
14. Shotorbani, S., Miller, L., Blough, D. K., & Gardner, J. (2006). Agreement 
between women's and providers' assessment of hormonal contraceptive risk 
factors. Contraception, 73(5), 501-506. 
15. Practice Committee of the American Society for Reproductive Medicine. (2008). 
Progesterone supplementation during the luteal phase and in early pregnancy in 
the treatment of infertility: an educational bulletin. Fertility and Sterility, 89(4), 
789-792. 


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16. Carmichael, S. L., Shaw, G. M., Laurent, C., Croughan, M. S., Olney, R. S., & 
Lammer, E. J. (2005). Maternal progestin intake and risk of hypospadias. 
Archives of Pediatrics & Adolescent Medicine, 159(10), 957-962. 
17. Charlton, B. M., Mølgaard-Nielsen, D., Svanström, H., Wohlfahrt, J., Pasternak, 
B., & Melbye, M. (2016). Maternal use of oral contraceptives and risk of birth 
defects in Denmark: prospective, nationwide cohort study. BMJ, 352, h6712. 
18. McCann, M. F., & Potter, L. S. (1994). Progestin-only oral contraception: a 
comprehensive review: II. Mode of action. Contraception, 50(6), (Suppl 1) S13-
21. 
19. Korver, T. (1998). A double-blind study comparing the contraceptive efficacy, 
acceptability and safety of two progestogen-only pills containing desogestrel 75 
μg/day or levonorgestrel 30 μg/day: collaborative study group on the desogestrel-
containing progestogen-only pill. The European Journal of Contraception & 
Reproductive Health Care, 3(4), 169-178. 
20. Raymond EG. (2007). Progestin-only pills. In: Hatcher RA, Trussell J, Nelson AL, 
et al, editors. Contraceptive technology. 19th ed. New York:Ardent Media, Inc.; 
2007, pp. 181–191. 
21. Potter, L., Oakley, D., de Leon-Wong, E., & Cañamar, R. (1996). Measuring 
compliance among oral contraceptive users. Family planning perspectives. 28(4) 
154-158. 
22. Hou, M. Y., Hurwitz, S., Kavanagh, E., Fortin, J., & Goldberg, A. B. (2010). Using 
daily text-message reminders to improve adherence with oral contraceptives: a 
randomized controlled trial. Obstetrics & Gynecology, 116(3), 633-640. 
23. Curtis KM, Jatlaoui TC, Tepper NK, et al. U.S. Selected Practice 
Recommendations for Contraceptive Use, 2016. MMWR Recomm Rep 
2016;65(No. RR-4):1–66. DOI: http://dx.doi.org/10.15585/mmwr.rr6504a1. 
Accessed on December 16, 2016. Oakley, D., Sereika, S., & Bogue, E. L. (1991). 
Oral contraceptive pill use after an initial visit to a family planning clinic. Family 
planning perspectives. 23(4) 150-154. 
24. Wiegratz, I., Elliesen, J., Paoletti, A. M., Walzer, A., & Kirsch, B. (2015). 
Adherence with ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended 
regimen supported by the use of a digital tablet dispenser with or without 
acoustic alarm: an open-label, randomized, multicenter study. International 
journal of women's health. 7, 19-29. 
25. White, K., Potter, J. E., Hopkins, K., Fernández, L., Amastae, J., & Grossman, D. 
(2012). Contraindications to progestin-only oral contraceptive pills among 
reproductive-aged women. Contraception, 86(3), 199-203. 
26. Raymond EG. Progestin-only pills. In: Hatcher RA, Trussell J, Nelson, AL, et al, 
editors. Contraceptive technology. 20th ed. Ardent Media, Inc.; 2011, pp. 237–
47. 
 


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18 APPENDICES 
18.1 Mock Package and Drug Facts Label 
 
DFL Panel 1 
 
 
 


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DFL Panel 2 
 
 
 
 
 


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DFL Panel 3 
 


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Carton including DFL 
 
 
 
 
 


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18.2 Consumer Information Leaflet 
 
CIL Table of Contents – Page 2 
 
 
 
 
 
 


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CIL Pages 3-5 
 
 
 
 
 
 
 


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CIL Pages 6-8 
 
 
 
 
 
 
 
 


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CIL Pages 9-10 and Cover Page 
 
 
 
 
 
 
 


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CIL (Five Panel, Foldable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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18.3 Reminder Card 
 
 
 
 
 

SAP_001.pdf: 
Proprietary Material of PEGUS Research, Inc. 
Do Not Copy or Distribute Without Permission 
 
 
 
 
 
CLINICAL STATISTICAL ANALYSIS PLAN 
 
A Multi-Center Oral Contraceptive Pill Use Trial Conducted In an OTC 
Naturalistic Environment (OPTION) 
151042-001 
 
Final v1.0 
Date: 20 MAR 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEGUS Research, Inc. 
 
 
CONFIDENTIAL


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Clinical Statistical Analysis Plan, 151042-001, Final v1.0 
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Page 2 of 11 
Signatures 
 
Authors: 
 
Russell D. Bradford 
 
 
_______________________    ____________________ 
V.P., Medical Affairs  
 
Signature 
 
                Date  
 
 
 
Approvals: 
 
Sarah Farnsworth                              _______________________    ____________________ 
V.P, Scientific Affairs  
 
Signature 
 
                Date  
 
 
 
 
Irene Laurora                                     _______________________    ___________________ 
V.P., US Medical Affairs 
 
Signature 
 
                Date 
 
 
 
 
 
 
 
 
 
 
Sarah Farnsworth
Digitally signed by Sarah Farnsworth 
DN: cn=Sarah Farnsworth, o=PEGUS Research, Inc., ou=VP, 
Scientific Affairs, email=FarnsworthS@pegus.com, c=US 
Reason: I am approving this document 
Location: PEGUS Research, Inc. 
Date: 2020.03.20 18:58:25 -06'00'
Digitally signed by Russell D. Bradford, MD, MSPH 
DN: cn=Russell D. Bradford, MD, MSPH, o=PEGUS 
Research, Inc., ou=Vice President, Medical Affairs, 
email=bradfordr@pegus.com, c=US 
Reason: I am the author of this document 
Date: 2020.03.20 19:00:34 -06'00'
Irene Laurora
Digitally signed by Irene Laurora 
Date: 2020.03.23 12:18:39 -04'00'


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Clinical Statistical Analysis Plan, 151042-001, Final v1.0 
STA:001:TMP:01:03 (effective 02 January 2019) 
 
Page 3 of 11 
TABLE OF CONTENTS 
1. 
INTRODUCTION .............................................................................................................................................. 4 
2. 
TRIAL OBJECTIVES........................................................................................................................................ 4 
3. 
TRIAL DESIGN ................................................................................................................................................. 4 
3.1 
Naturalistic Design ....................................................................................................... 4 
3.2 
Eligibility Criteria .......................................................................................................... 5 
3.2.1 
Self-Selection Phase / Initial Enrollment Visit ........................................................ 5 
3.2.2 
Use Phase Exclusion Criteria ................................................................................ 5 
3.3 
Sample Size Determination .......................................................................................... 6 
3.4 
Randomization ............................................................................................................. 7 
4. 
GENERAL STATISTICAL CONSIDERATIONS .......................................................................................... 7 
4.1 
General Principles........................................................................................................ 7 
4.2 
Handling of Withdrawn Subjects .................................................................................. 7 
4.3 
Handling of Missing Data ............................................................................................. 7 
4.4 
Handling Protocol Violations ........................................................................................ 7 
4.5 
Interim Analyses and Data Monitoring.......................................................................... 8 
4.6 
Data Capture and Processing ...................................................................................... 8 
4.7 
Data Review ................................................................................................................ 9 
5. 
ANALYSIS SETS ............................................................................................................................................... 9 
6. 
STATISTICAL METHODOLOGY .................................................................................................................. 9 
6.1 
Efficacy ........................................................................................................................ 9 
6.2 
Pharmacokinetics / Pharmacodynamics ......................................................................10 
6.2.1 
Primary Endpoint Analysis ...................................................................................10 
6.2.2 
Secondary Endpoint Analysis ..............................................................................10 
6.2.3 
Other Analyses ....................................................................................................10 
6.2.4 
Safety and Compliance ........................................................................................10 
6.2.4.1 
Adverse Events and Serious Adverse Events ...................................................10 
6.2.4.2 
Pregnancies .....................................................................................................10 
6.2.4.3 
Protocol Deviations ..........................................................................................10 
7. 
DATASETS AND SUPPORTING DOCUMENTATION ............................................................................. 10 
7.1 
Datasets .....................................................................................................................10 
7.2 
Supporting Documentation ..........................................................................................10 
8. 
DOCUMENT HISTORY AND CHANGES IN THE PLANNED STATISTICAL ANALYSIS ............... 11 
9. 
REFERENCES .................................................................................................................................................. 11 
 


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Clinical Statistical Analysis Plan, 151042-001, Final v1.0 
STA:001:TMP:01:03 (effective 02 January 2019) 
 
Page 4 of 11 
1. 
Introduction 
Opill® (norgestrel 0.075 mg) is proposed for an Rx-to-OTC (over-the-counter) switch.  
This combined Self-Selection (SS) / Actual Use Trial (AUT) was intended to be 
conducted to demonstrate appropriate consumer selection and use behavior as guided 
by OTC labeling when using the product in the absence of a physician or other learned 
intermediary.   
 
Due to technical issues with the e-diary application, the study was terminated shortly 
after the study was initiated, resulting in a sample size that is statistically insufficient to 
analyze the Primary and Secondary Endpoints as well as the Other Analyses described 
in Section 9.3 of the protocol.  As such, only analyses relating to subject safety, including 
the number of pregnancies observed over the course of the study, will be completed for 
this study.  
2. 
Trial Objectives 
The objective of this study was to evaluate the adequacy of the proposed OTC labeling 
to guide the behavior of subjects in an OTC-like setting when selecting and using Opill®; 
however, only the safety outcomes will be reported on for this study due to the early 
termination of the study.   
3. 
Trial Design 
This was an observational, open-label, multi-center, 16-week study designed to create 
as much as possible an OTC-like environment in which participants made an initial self-
selection and purchase decision about Opill® based only on their reading of the outside 
of the package including the DFL. Qualified participants who chose to do so purchased 
the study medication, left the study site and used the product on their own, guided by the 
OTC labeling. The study was designed to assess if, when and how subjects use the 
medication in an OTC-like environment.  
 
It is important to note that none of the information gathered at screening, enrollment, or 
during the 16-week study period was only discussed with subjects at the End-of-Study 
interview. 
3.1 
Naturalistic Design 
This was a multi-center trial conducted in a simulated OTC environment. Study 
characteristics and procedures were designed to make it as naturalistic as possible. 
Some of the key naturalistic elements included the following: 
• 
There were minimal exclusionary criteria imposed on participants, making this 
trial nearly an all-comers study to mimic the likely OTC population. 
• 
The study was conducted in retail pharmacies, representing typical locations 
where consumers now commonly purchase OTC medicines (adult and 
adolescent subjects) and women’s health clinics (adolescent subjects). 
• 
The proposed OTC packaging and labeling was the only product information 
provided to participants during the study. Participants only reviewed the outer 
packaging including DFL at the initial visit. Study staff did not provide any 


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Page 5 of 11 
additional information or encouragement regarding product selection at that visit. 
Staff did not answer participant questions about the study medication and instead 
referred subjects to the labeling. However, any questions related to the “Ask a 
doctor or pharmacist before use” section of the DFL that were asked of study 
staff in their capacity as healthcare provider or pharmacist were recorded. 
After purchasing the study product, participants took the package with them when they 
left the site. The package included the outer packaging, and, inside the package, the 
consumer information leaflet (CIL), a reminder card (which highlights the key messages 
about directions for use from the DFL) and study medication. 
3.2 
Eligibility Criteria 
3.2.1 Self-Selection Phase / Initial Enrollment Visit 
In order to enroll a sample as representative as possible of the likely OTC consumer 
population, the study inclusion criteria were defined as broadly as it is feasible. Subjects 
were required to meet the following initial screening study inclusion criteria: 
1. Able to read, speak and understand English  
2. 12 years of age or older 
3. Can see well enough to read information on the label  
4. Another member of the respondent’s household has not participated in this study 
5. Consumer or someone else in the household does not work for a market 
research or advertising company, public relations firm, news organization, 
pharmacy or pharmaceutical company, medicine manufacturer, as a healthcare 
professional, or as part of a healthcare practice, managed care or health 
insurance company, trained or worked as a healthcare professional or market 
research professional (eliminated for reasons of confidentiality and increased 
awareness of medicines and their labels) 
6. Has not participated in any research studies about health-related products in the 
past 12 months 
7. Has not participated in a clinical trial in the past 12 months 
8. Has never participated in a study about over-the-counter birth control medicines 
3.2.2 Use Phase Exclusion Criteria 
All subjects who agreed to participate in the study and attended the initial enrollment visit 
at the site were asked to make a self-selection and purchase (or use) decision.  Subjects 
presenting with any of the following were not included in the use phase of the study (i.e., 
were not allowed to purchase and use study medication though their self-selection 
decision and desire to purchase was recorded): 
1. Unwilling to purchase study medication (pharmacy sites) 
2. Unwilling to be dispensed study product for use (clinic sites) 
3. Unwilling to provide informed consent 
4. Unwilling or unable to provide contact information 


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Page 6 of 11 
5. Unwilling to state that the product is for their own use and no one else’s 
6. Premenarchal females 
7. Pregnant 
8. Male 
9. Known allergy to norgestrel or inactive ingredients. 
10. History of any cancer 
Additionally, subjects must have met all of the following study inclusion criteria to be 
eligible for enrollment into the use phase of the study: 
• 
Evidence of a personally signed and dated informed consent form indicating that 
the subject (or a legal guardian) has been informed of all pertinent aspects of the 
study. 
• 
Willing and able to comply with the initial enrollment visit, planned phone calls 
and other study procedures, and the end of study visit. 
Subject eligibility was reviewed and documented by the Investigator or his/her designee 
before subjects were allowed to be dispensed the study medication and begin the use 
phase of the study. 
3.3 
Sample Size Determination 
For the purposes of this AUT, sample size was set at approximately 900 purchasers 
(use phase participants).  Given that subjects were responding to recruitment aimed at 
those interested in an OTC birth control medicine, most subjects who chose to purchase 
the study product were expected to actually use the product during the study. 
 
Assuming approximately 900 purchasers, if 80% of those purchasers used the product 
within the study period, that would yield an actual user population of approximately 720. 
Allowing for a further 20% loss to follow-up would yield a measurable user population of 
approximately 576. 
 
Because AUTs are not hypothesis-testing comparative trials, study sample size was 
designed to allow for adequate evaluation of key endpoints across all participants and 
among several subgroups. As the analysis of AUTs typically focuses on estimating the 
proportion (and associated 95% confidence intervals) of correct behavior for individual 
endpoints, sample size is most often based on the number of participants needed to 
constrain the confidence interval (CI) to a limited range.  As an illustration, for this study, 
assuming an 85% correct behavior to any single endpoint (of course, the CI depends on 
the actual point estimate and is calculated based on the data), a sample of 720 
participants would constrain the CI to ±2.8%. Table 1 provides the 2-sided 95% CI for 
various sample sizes around a point estimate of 85%. 
 
Table 1 Two-sided 95% CIs for Various Sample Sizes Around 85% Point Estimate 
N=900a 
N=720b 
N=576c 
N=135d 
95% CI around a point estimate of 85% 
+/-2.5% 
+/-2.8% 
+/-3.2% 
+/-7.2% 


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Page 7 of 11 
a Purchasers 
b User population (allowing for 20% non-users) 
c User population (allowing for 20% loss-to-follow up) 
d Low literacy subjects 
 
3.4 
Randomization 
There was no randomization in this study. 
4. 
General Statistical Considerations 
4.1 
General Principles 
Statistical analyses of the data will be performed by PEGUS Research using the SAS 
System for Windows v 9.4 (SAS Institute, Cary, NC). All analyses performed in this study 
will be descriptive. 
Frequencies and percentages will be presented for categorical data, mean, standard 
deviation (SD); median, and range will be presented for numerical data. Percentages will 
be rounded to one decimal place. The category of missing data will be displayed only if 
there are actually missing values. Frequencies, percentages and 2-sided 95% CIs will be 
calculated using the exact method.  
4.2 
Handling of Withdrawn Subjects 
For subjects that chose to withdraw at any point during the study, an attempt was made 
to collect End-of-Study (EOS) information and the reasons for the subject’s early 
termination. Data gathered prior to subject withdrawal and any ongoing data collection 
will be included in the analysis for completed questions, unless the subject withdrew 
consent or requested otherwise. Subjects who did not complete the study will be 
described in a disposition table. Any subjects who withdrew their consent or were 
determined to be lost to follow-up will be described in the disposition table as well. 
Withdrawn subjects were not replaced. 
4.3 
Handling of Missing Data 
Missing data will not be imputed; the statistical analyses will be based on cases with 
relevant data available. For endpoint calculations, if missing data makes it so a case 
(subject or a dosing instance) cannot be classified as to whether or not it belongs in the 
numerator, that case will also be excluded from the denominator. All missing data will be 
flagged, and a reason for why the data are missing will be described in a footnote in 
each applicable statistical table. 
4.4 
Handling Protocol Violations 
All deviations from the protocol will be reviewed and any decision regarding inclusion or 
exclusion of subjects in study analyses due to the presence of a deviation will be made 
and documented before database lock. 
 
Events that qualify as protocol deviations will be identified in a separate document.  All 
protocol deviations will be categorized and assessed to determine the severity of the 
deviation and reviewed before database lock. 
 


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A full list of protocol deviations will be included in the final Clinical Study Report (CSR). 
4.5 
Interim Analyses and Data Monitoring 
No interim analyses are planned for this study. Final data analyses will be performed 
upon database lock. Data were monitored by site monitors and PEGUS data 
management staff on an ongoing basis to ensure protocol procedures were being 
followed. While a formal Independent Data Monitoring Committee was not established 
for this study, the sponsor was informed of study progress, amount and nature of data 
queries, and protocol violations. 
4.6 
Data Capture and Processing 
Data were collected in structured one-on-one interviews using a standardized 
questionnaire either in person (at the initial enrollment visit), by telephone (in four follow-
up interviews), and in an electronic diary. The interviews were administered by a trained 
interviewer using an internet-based EDC application in which the interviewer read the 
introductory scripts and the questions from the screen and entered the responses 
directly into the study database. The questionnaires included primarily open-ended 
questions. Question types included direct questions and follow-up questions for 
clarification. To facilitate the accurate capture of responses, open-ended questions had 
pre-coded answer alternatives. It is important to note that these response alternatives 
were not read to the participants, nor were participants able to see them on the screen. 
Where close-ended questions were used (e.g., yes/no, or ok/not ok), participants were 
asked to explain their answers so behavior could be adequately assessed. When 
interviewers recorded open-ended responses, they captured short responses verbatim, 
and accurately summarized longer responses. 
 
During the self-selection interview at the initial visit, the Opill® outer package including 
DFL remained in front of the participant and the participant was informed that they could 
refer to the outer package at any time. However, the participant was neither encouraged 
nor discouraged from referring to the package in response to any specific question. 
 
Subjects who entered the use phase of the study were asked to use an online diary to 
record their use of the study product daily. Of note, a device was provided for subjects 
who did not have easy access to a device with internet access. 
 
Information collected during the participant interviews was entered directly into an EDC 
application (DATATRAK ONE, DATATRAK International, Inc.). Automatic data checks 
alerted users of discrepancies and inconsistencies, where applicable. In the event of a 
data entry error, users had the ability to correct information previously entered. Data 
Management staff reviewed the information entered as defined in this protocol. 
 
All users had a unique login user name and password, and system access privileges 
were strictly controlled and documented. Whenever data was modified after the initial 
data entry process, a computer-generated audit trail entry was created. The audit trail, 
user access privilege processes, and electronic signatures collected by the system were 
compliant with 21 CFR Part 11 requirements. 
 
A web-based electronic diary was provided to all subjects with a reliable internet 
connection.  The e-diary was programmed and hosted by a qualified vendor 


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(eClinicalHealth Ltd, Stirling, United Kingdom). Subjects were instructed to record 
information regarding their use of the study product every day. Subjects were also asked 
to enter additional data regarding sexual behaviors (heterosexual vaginal intercourse) 
and additional contraception methods to fully evaluate adherence to label directions.  
The electronic diary was intended to serve as the primary means of reporting the results 
of the EOS at-home self-administered pregnancy test. Diary data were imported into the 
EDC system to be included in the study database. 
 
However, as noted previously, problems with the usability and reliability of the e-diary 
system led to the premature termination of this study. 
4.7 
Data Review 
Data review were ongoing during the course of this study. Data were reviewed by 
PEGUS Research for accuracy, and all validation and documentation will be completed 
before database lock.  
5. 
Analysis Sets 
The populations of interest are defined as follows: 
• 
Screening Population: All those who respond to study advertisements and begin 
initial screening questions. 
• 
Self-Selection Population: Participants who accept the invitation to participate and 
meet study inclusion criteria, participate in a face-to-face interview at the study site, 
make a self-selection decision, and provide responses to all relevant medical history 
questions. 
• 
Safety Population: Subjects who signed the informed consent document.  
• 
Purchasers: Responders who meet study enrollment criteria and purchase/obtain 
the study medication. 
• 
User Population: Subjects who take at least one dose of study medication during 
the study. 
6. 
Statistical Methodology 
This is a naturalistic, observational trial to assess selection and use patterns from the 
prospective OTC population in a simulated OTC setting. The analyses will largely employ 
descriptive statistics including frequencies, percentages and appropriate summary statistics. 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to 
the respective subject set. Percentages will be rounded to one decimal place. The category 
of missing data will be displayed only if there are actually missing values.  
Each of the categorical endpoints will be evaluated by computing point estimates and their 
binomial two-sided 95% confidence intervals (CIs) (calculated using the exact Clopper-
Pearson method). 
6.1 
Efficacy 
Not applicable for this study. 


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6.2 
Pharmacokinetics / Pharmacodynamics 
Not applicable for this study. 
6.2.1 Primary Endpoint Analysis 
As discussed in Section 2, only endpoints related to safety outcomes will be analyzed and 
reported on for this study. 
6.2.2 Secondary Endpoint Analysis 
Only Secondary Endpoint F will be analyzed and reported on for this study: 
Actual Use:  Number of pregnancies reported during the course of the study 
6.2.3 Other Analyses 
Only Other Measure A will be analyzed and reported on for this study: 
Actual Use:  Character and frequency of adverse events as reported by the user 
population 
6.2.4 Safety and Compliance 
6.2.4.1 Adverse Events and Serious Adverse Events 
Adverse event (AE) and Serious Adverse Event (SAE) analyses will include all events which 
initially occurred or worsened following treatment. Adverse events will be summarized by 
the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and 
Preferred Term (PT) and classified according to their severity (mild, moderate, or severe) 
and relationship (related or not related) to study product. For the summary by severity, 
subjects who have multiple occurrences of the same AE/SAE will be classified according to 
the worst reported severity of the AE/SAE.  Similarly, for the summary by relationship to the 
study product, the AE/SAE will be classified according to the worst relationship. 
6.2.4.2 Pregnancies 
All pregnancies that were reported during the study will be described including an 
assessment of whether they occurred on or off the study drug.  
6.2.4.3 Protocol Deviations 
A listing of all protocol deviations reported during the study will be created and included in 
the final clinical study report.  
7. 
Datasets and Supporting Documentation 
7.1 
Datasets 
All table analyses data points will come from the locked study datasets. 
7.2 
Supporting Documentation 
PEGUS Research will maintain accurate and complete records of the study. Study files and 
critical documents were maintained at PEGUS Research throughout the study period, and 


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will be retained or transferred to the Sponsor at its direction. PEGUS Research holds all 
study-related documents and communications in the strictest confidence. PEGUS Research 
will ensure that the participant’s anonymity is maintained. On documents submitted to the 
Sponsor, participants will not be identified by name or other personally identifiable 
information, but by numerical identification code generated by the EDC system. 
8. 
Document History and Changes in the Planned Statistical Analysis 
Document 
Version / Date 
Summary of Changes 
Final SAP 
Final v1.0_20MAR2020 
N/A 
9. 
References 
Not applicable for this study.