4CMenB Pregnancy Registry: an Observational Study of the Safety of 4CMenB Exposure in Pregnant Women and Their Offspring.
Conditions: Infections, Meningococcal
Sponsor: GlaxoSmithKline

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Title
BEXSERO® pregnancy registry: an observational study
of the safety of BEXSERO exposure in pregnant women 
and their offspring.
Protocol version identifier
Version 2
Date of last version of 
protocol
12 AUG 2016
EU PAS Register No:
EUPAS 12183
Active substance
Recombinant Neisseria meningitidis group B 
NHBA/NadA/fHbp proteins (50/50/50 micrograms);
outer membrane vesicles (OMV) from Neisseria 
meningitidis group B strain NZ98/254 measured as 
amount of total protein containing the PorA P1.4 (25 
micrograms).
Medicinal product
BEXSERO suspension for injection in pre-filled syringe 
Meningococcal Group B Vaccine (rDNA, component, 
adsorbed).
Product reference
Not applicable.
Procedure number
Not applicable.
Marketing authorisation 
holder(s)
GlaxoSmithKline Biologicals S.A
Joint PASS study
No
Research question and 
objectives
The objective of the BEXSERO Pregnancy Registry is 
to evaluate pregnancy outcomes among women
immunized with the BEXSERO vaccine within 30 days 
prior to the last menstrual period or at any time during 
pregnancy. The primary outcomes of interest include 
major congenital malformation, preterm birth, and low 
birth weight.
Country(ies) of study
United States
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Authors
, DrPH
, PharmD, MPH
, MD, MPH, PhD
Marketing authorisation holder(s) 
Marketing authorisation 
holder(s) 
GlaxoSmithKline Biologicals S.A
Rue de l’Institut 89 
BE – 1330 Rixensart 
Belgium
MAH contact person
Clinical and Epidemiology R&D
GlaxoSmithKline,
Hullenbergweg 83/85, 
Amsterdam, 
The Netherlands 
Email: 
Property of GlaxoSmithKline Biologicals S.A. (hereafter referred to as GSK) 
Confidential
May not be used, divulged, published or otherwise disclosed without written
consent of GSK
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1.
TABLE OF CONTENTS
1.
TABLE OF CONTENTS ....................................................................................... 3
LIST OF TABLES .......................................................................................................... 6
LIST OF FIGURES......................................................................................................... 7
2.
LIST OF ABBREVIATIONS................................................................................. 8
3.
RESPONSIBLE PARTIES................................................................................... 10
3.1
Main Author(s) of the Protocol ........................................................................ 10
3.2
Principal Investigator....................................................................................... 10
3.3
Coordinating Investigator(s) ............................................................................ 10
3.4
Advisory Committee........................................................................................ 10
4.
ABSTRACT......................................................................................................... 11
5.
AMENDMENTS AND UPDATES...................................................................... 21
6.
MILESTONES..................................................................................................... 22
7.
RATIONALE AND BACKGROUND ................................................................. 23
8.
RESEARCH QUESTION AND OBJECTIVES ................................................... 26
9.
RESEARCH METHODS..................................................................................... 27
9.1
Study Design ................................................................................................... 27
9.2
Setting ............................................................................................................. 27
9.2.1
Study Period ............................................................................................. 27
9.2.2
Study Subjects .......................................................................................... 27
9.2.3
Study Population Selection ....................................................................... 27
9.3
Variables ......................................................................................................... 32
9.3.1
Exposure of Interest.................................................................................. 32
9.3.2
Outcome(s) of Interest .............................................................................. 32
9.3.3
Other Variables......................................................................................... 33
9.4
Data Sources.................................................................................................... 34
9.4.1
Operational Exposure Definition............................................................... 38
9.4.2
Operational Outcome Definition and Identification Process ...................... 39
9.4.3
Operational Variable(s) Definition............................................................ 39
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9.4.4
Advisory Committee(s)............................................................................. 40
9.4.5
MCM Monitoring and Signal Generation.................................................. 40
9.5
Study Size........................................................................................................ 41
9.6
Data Management............................................................................................ 42
9.6.1
Data Processing ........................................................................................ 42
9.6.2
Software and Hardware............................................................................. 42
9.7
Data Analysis .................................................................................................. 42
9.7.1
Statistical Hypotheses ............................................................................... 45
9.7.2
Analysis of Demographics and Baseline Characteristics............................ 46
9.7.3
Statistical Methods.................................................................................... 46
9.7.4
Statistical Considerations.......................................................................... 48
9.8
Quality Control................................................................................................ 49
9.8.1
Validation................................................................................................. 49
9.8.2
Record Retention ...................................................................................... 49
9.9
Limitations of the Research Methods............................................................... 50
9.10 Other Aspects .................................................................................................. 50
10.
PROTECTION OF HUMAN SUBJECTS............................................................ 51
10.1 Regulatory and Ethical Compliance ................................................................. 52
10.2 Informed Consent ............................................................................................ 52
10.3 Responsibilities of the Investigator and IRB .................................................... 54
10.4 Protocol Adherence ......................................................................................... 55
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ ADVERSE 
REACTIONS....................................................................................................... 56
12.
PLANS FOR DISSEMINATING AND COMMUNICATING RESULTS ........... 58
12.1 Registration in Public Database(s) ................................................................... 58
12.2 Publications..................................................................................................... 58
13.
CRITERIA FOR STUDY TERMINATION......................................................... 59
14.
REFERENCES .................................................................................................... 60
APPENDIX 1: LIST OF STAND-ALONE DOCUMENTS........................................... 63
APPENDIX 2: ENCEPP CHECKLIST FOR STUDY PROTOCOLS............................ 64
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APPENDIX 3: ADDITIONAL INFORMATION.......................................................... 74
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LIST OF TABLES
Table 4.1 
Detectable effect size assuming 80% power................................18
Table 6-1
Overview of study milestones. ....................................................22
Table 9.4-1 
Summary table of evaluations .....................................................35
Table 9.5-1 
Detectable effect size assuming 80% power................................42
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LIST OF FIGURES
Figure 9.2.3-1
Registry enrollment, informed consent and data collection process
...................................................................................................29
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2.
LIST OF ABBREVIATIONS
ACIP
Advisory Committee on Immunization Practices
AE
Adverse event
CBER
Center for Biologics Evaluation and Review
CEDD
Corrected estimated date of delivery
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CRF
Case report form
DSUR
Development Safety Update Report
EDC
Electronic data capture
EDD
Estimated date of delivery
ELISA
Enzyme-linked immunosorbent assay
FDA
Food and Drug Administration
GPP
Good Pharmacoepidemiological Practice
GSK                           GlaxoSmithKline Biologicals S.A.
HCP
Health care provider
HIPAA
Health Insurance Portability and Accountability Act
HMO
Health maintenance organization
IAB
Induced abortion
ICH
International Conference on Harmonisation
ICSR
Individual Case Safety Reports
IMD
Invasive meningococcal disease
IRB
Institutional review board
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LMP
Last menstrual period 
LBW
Low birth weight
MACDP
Metropolitan Atlanta Congenital Defects Program
MAH
Market Authorisation Holder
MCM
Major congenital malformation
MSL
Medical science liaison
NVSS
National Vital Statistics System 
PMC
Post-marketing commitment
PSUR
Periodic Safety Update Report
RCC
Registry Coordination Center
SAB
Spontaneous abortion
SAC
Scientific Advisory Committee
SAEs
Serious adverse events
SAP
Statistical analysis plan
SBA
Serum bactericidal assay
SOP
Standard operating procedure
STROBE
STrengthening the Reporting of OBservational studies in 
Epidemiology
US
United States
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3.
RESPONSIBLE PARTIES
3.1
Main Author(s) of the Protocol
, DrPH, PPD
, PharmD, MPH, PPD
, MD, MPH, PhD
3.2
Principal Investigator
, MD, PPD
3.3
Coordinating Investigator(s)
Not applicable.
3.4
Advisory Committee
The Scientific Advisory Committee will provide an independent review of registry data 
and will include specialists from appropriate fields such as obstetrics, pediatrics, clinical 
research, genetics, epidemiology, and teratology from academic institutions, private 
practice, and/or government agencies.
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4.
ABSTRACT
Name of MAH:
GlaxoSmithKline
Biologicals S.A.
Protocol number:
V72_82OB
Date of Protocol 
Abstract:
12 AUG 16
Title of Study: BEXSERO pregnancy registry: an observational study of the safety of
BEXSERO exposure in pregnant women and their offspring
Study Period: Enrollment in the 
pregnancy registry will commence on 
31 January 2016 and will continue for 
a period of 3 years or pending review 
by the Center for Biologics Evaluation 
and Research (CBER), and discussion
of results with GlaxoSmithKline S.A.
(GSK) will submit a full study report
to CBER by 31 May 2020. The data 
collection process for each participant 
will begin at enrollment (post
exposure to BEXSERO within 30 days 
of the last menstrual period or at any 
time during the pregnancy), and
follow-up will occur at the end of the 
second trimester (approximately
24 weeks’ gestation) and at pregnancy 
outcome (delivery or early
termination).
Study Type: This study is designed to meet a 
post-marketing commitment (PMC) agreed 
upon with CBER to establish a pregnancy 
registry to prospectively collect data on 
pregnancy exposures to BEXSERO.
Rationale and Background: The BEXSERO Pregnancy Registry is established to meet 
a CBER PMC and is designed to collect prospective data on pregnancy outcomes 
among pregnant women vaccinated with BEXSERO within 30 days prior to the last 
menstrual period (LMP) or at any time during pregnancy. BEXSERO was approved by 
the Food and Drug Administration (FDA) for use in individuals 10 through 25 years of 
age in January 2015. Subsequently, the Advisory Committee on Immunization Practices 
recommended that a serogroup B meningococcal vaccine should be administered to 
persons in the United States (US) aged ≥10 years who are at increased risk of 
meningococcal disease (those with persistent complement component deficiencies, 
anatomic or functional asplenia, microbiologists routinely exposed to isolates of 
Neisseria meningitidis and persons identified to be at increased risk because of a 
serogroup B meningococcal disease outbreak). BEXSERO is not contraindicated during 
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Biologicals S.A.
Protocol number:
V72_82OB
Date of Protocol 
Abstract:
12 AUG 16
pregnancy, but should be used during pregnancy only if clearly needed. Inadvertent 
exposure during pregnancy may also occur because the age group targeted for 
vaccination includes young women of reproductive potential. The registry will add to 
the current clinical experience with BEXSERO®, supplementing data from animal 
toxicology studies and human exposure data. Pregnancy data will be collected at 
registry enrollment, at the end of the second trimester of pregnancy, and at pregnancy 
outcome for both mother and infant. GSK sponsors the registry in consultation with 
specialists from appropriate fields such as obstetrics, pediatrics, clinical research, 
genetics, epidemiology, and teratology from academic institutions, private practice, 
and/or government agencies. These individuals constitute the Scientific Advisory 
Committee (SAC) and will provide an independent review of registry data.
Research Question and Objectives: The objective of the BEXSERO Pregnancy 
Registry is to evaluate pregnancy outcomes among women immunized with the
BEXSERO vaccine within 30 days prior to LMP or at any time during pregnancy. The 
primary outcomes of interest include major congenital malformation (MCM), preterm
birth, and low birth weight (LBW). Other pregnancy outcomes will also be collected,
including spontaneous abortions (SABs) and stillbirths.
This registry is primarily descriptive and designed to detect potential safety signals 
rather than test hypotheses.
Study Design: The BEXSERO Pregnancy Registry is a prospective, observational study
of women immunized with the BEXSERO vaccine within 30 days prior to LMP or at 
any time during pregnancy as part of routine care. It is strictly observational; the 
schedule of office visits and all treatment regimens will be determined by the treating 
health care provider (HCP). This phase 4 pregnancy registry follows current FDA 
guidance for designing and implementing pregnancy exposure registries (FDA, 2002).
Population: The study population will include pregnant women within the US who 
received at least 1 dose BEXSERO vaccine within 30 days prior to LMP or at any time
during pregnancy. BEXSERO is not contraindicated during pregnancy but should be 
used only if clearly needed and inadvertent exposure during pregnancy may occur,
particularly during the early stages of pregnancy before pregnancy status is known.
Enrollment and data collection will be coordinated through a registry coordination
center (RCC). The registry will allow eligible pregnant women to self-enroll and also
allow HCPs and/or health maintenance organizations (HMOs) to report de-identified 
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Name of MAH:
GlaxoSmithKline
Biologicals S.A.
Protocol number:
V72_82OB
Date of Protocol 
Abstract:
12 AUG 16
data on pregnancy exposures and outcomes. An evaluable subject is a pregnant woman
with data submitted and/or confirmed by an HCP that contains at least the minimum 
criteria for a report and is not lost to follow-up. The minimum criteria required for 
enrollment into the registry are as follows:
!
Sufficient evidence to confirm that exposure to a meningococcal B vaccine 
(confirmed or possible BEXSERO exposure) occurred within 30 days prior to LMP 
or at any time during pregnancy
!
Sufficient information to determine whether the pregnancy is prospectively or 
retrospectively registered (i.e., whether the outcome of pregnancy was known at the 
time of first contact with the registry)
!
Date the pregnancy exposure is registered
!
Full reporter (i.e., HCP) contact information to allow for follow-up (name, address, 
etc.)
In the event that it cannot be ascertained to which meningococcal B vaccine the woman 
was exposed, an unknown exposure cohort will be established and analyzed separately. 
Because registry enrollment is open to all eligible pregnant women, an active 
recruitment campaign will reach out to immunization providers and their patients in a 
broad variety of settings. The recruitment strategy will target HCPs who are known to 
immunize patients specifically with the BEXSERO vaccine. These providers could be 
identified through GSK BEXSERO distribution data and/or medical science liaisons, as 
well as HCP networks and HMOs. Recruitment strategies could include the distribution
of informational kits to HCPs and their patients and ongoing awareness and educational 
activities via the internet and/or through other media.
The primary population for analysis will include prospectively enrolled pregnant
women exposed to at least 1 dose of BEXSERO who are not lost to follow-up (i.e., with
outcome information that meet the minimum criteria for evaluation). In the event that a 
fetal abnormality is identified on a diagnostic prenatal test prior to enrollment (i.e., that 
the pregnancy outcome is presumed known at enrollment), this will be considered a 
retrospective report and will also be included in this study. Retrospective reports can be 
biased toward the reporting of more unusual and severe cases and are less likely to be 
representative of the general population experience than cases reported prior to 
knowledge of the outcome. Therefore, retrospective reports will not be included in the 
primary analysis and statistical calculations. Retrospective reports with reported MCMs 
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Name of MAH:
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Protocol number:
V72_82OB
Date of Protocol 
Abstract:
12 AUG 16
will be captured in the registry and reviewed to aid in detection of early signals and will 
be listed in registry reports.
Data from HCP networks and HMOs that provide de-identified data on all exposed 
pregnancies in their networks will fall into the category of prospective registry reports, 
as these networks/HMOs provide objective data on every pregnancy exposure in the 
network/HMO, both positive and negative outcomes. Thus, they avoid the reporting bias 
inherent in retrospective reporting only after a negative outcome has been noted.
Background prevalence estimates from external surveillance sources and estimates from
published literature will be the primary comparators. Background estimates in the 
general population on pregnancy outcomes, such as preterm birth and LBW, are readily
available from national vital statistics (Martin, 2015). Published prevalence estimates of
MCMs are available from the Centers for Disease Control and Prevention’s (CDC’s)
Metropolitan Atlanta Congenital Defects Program (MACDP), which is an ongoing 
population-based birth defects surveillance program (Correa, 2007). To the extent 
possible, comparator prevalence estimates will be age-adjusted to reflect the age 
distribution of the BEXSERO Pregnancy Registry population.
Variables: 
Exposure(s) of interest
This pregnancy registry is strictly observational. Although not contraindicated during 
pregnancy, BEXSERO should be used during pregnancy only if clearly needed. 
Inadvertent exposure during pregnancy may also occur, particularly during the early 
stages of pregnancy before pregnancy status is known. When a pregnant woman self-
enrolls in the registry, she will be asked when and where she was immunized with the
BEXSERO vaccine, or any meningococcal B vaccine if the brand is unknown. She will 
then be asked to provide a medical release that allows the registry to confirm with the 
appropriate source the exposure to a meningococcal B vaccine occurred. The registry 
will contact the vaccine provider to confirm the vaccination date, brand, and lot number.
If HCPs provide de-identified data to the registry, they must be able to verify the 
vaccination with BEXSERO and date of vaccination.
Outcome(s)
Major congenital malformation (MCM): The registry defines an MCM as any major
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Protocol number:
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Date of Protocol 
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structural or chromosomal defect or combination of 2 or more conditional defects in 
live-born infants, stillbirths, or fetal losses of any gestational age (including outcomes 
prior to 20 weeks’ gestation or weighing <500 g). This definition is consistent with, but 
not restricted to, the CDC MACDP definition (which includes conditional defects only
if they occur in the presence of a major defect) and thus increases the sensitivity of 
monitoring.
Preterm birth: An infant born at gestational age <37 weeks.
Low birth weight (LBW): An infant whose birth weight is <2500 g.
Outcome variables will be provided by the obstetric HCP and/or pediatrician attending 
the birth. The HCP will be asked to describe any congenital malformations observed in 
the infant or fetus and will also be asked to report the gestational age and birth weight. 
These 2 variables will be used to calculate preterm birth (gestational age <37 weeks at 
birth) and LBW (birth weight <2500 g).
A teratologist/geneticist will review all reported congenital anomalies and classify them 
using the CDC’s MACDP system. Additionally, the teratologist/geneticist will provide 
an opinion regarding the possible temporal association of the BEXSERO exposure to 
the development of observed defects. The SAC will meet periodically to review the data 
and reach consensus on the coding and classification of MCMs and other outcomes of 
interest.
Other Variables
Maternal characteristics: Age, ethnicity, race
Prenatal data: LMP, estimated date of delivery (EDD), corrected estimated date of 
delivery (CEDD)
Obstetrical history: Previous pregnancies, live births, stillbirths, SABs, induced 
abortions (IABs), births with congenital malformations, family history of congenital 
malformations.
Concurrent medical conditions 
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Protocol number:
V72_82OB
Date of Protocol 
Abstract:
12 AUG 16
Concomitant medications and vaccines 
Alcohol, tobacco, and illicit drug use 
Pregnancy outcomes
Each pregnancy outcome will be classified in 1 of the following mutually exclusive 
categories:
!
Live birth: an infant born alive
!
Stillbirth: fetal death occurring at or after 20 weeks’ gestation, or if gestational age
is unknown, a fetus weighing 500 g or more.
!
Spontaneous abortions (SABs): fetal death or expulsion of products of conception 
prior to 20 weeks’ gestation, or if gestational age is unknown, weighing less than 
500g. Terminology may include missed abortion, incomplete abortion, and 
inevitable abortion.
!
Induced abortions (IABs): voluntary interruption of pregnancy, including pregnancy
termination that occurs electively, to preserve maternal health, or due to fetal 
abnormalities
!
Ectopic pregnancy: implantation of a conception outside of the uterus
!
Molar pregnancy: a conception that results in a gestational trophoblastic tumor 
Data Sources: The pregnant woman and/or appropriate members of her health care
team will serve as data reporters to the registry. The registry is strictly observational; the 
schedule of office visits and all treatment regimens will be determined by the treating 
HCP. There are no additional laboratory tests or assessments required as part of this 
registry. Only data noted as part of routine care will be collected.
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Name of MAH:
GlaxoSmithKline
Biologicals S.A.
Protocol number:
V72_82OB
Date of Protocol 
Abstract:
12 AUG 16
Study Size: The pregnancy registry is a PMC agreed upon with the CBER to commence 
enrollment on 31 January 2016 and to continue for a period of 3 years or pending CBER
review and discussion of results with GSK. GSK will submit a full study report to
CBER by 31 May 2020.
The registry will prospectively enroll women with exposure to a meningococcal B 
vaccine 30 days prior to LMP or at any time during pregnancy. The primary population 
for analysis will be those vaccinated with BEXSERO only. In the event that it cannot be 
ascertained to which meningococcal B vaccine the woman was exposed, an unknown 
exposure cohort will be established and analyzed separately.
BEXSERO is not contraindicated during pregnancy, but should be used during 
pregnancy only if clearly needed. Under current ACIP recommendations, the CDC 
estimates that approximately 350,000 individuals will be advised to receive a 
meningococcal B vaccine (MacNeil, 2015), of whom it is likely that a small proportion 
will be exposed during pregnancy. There are uncertainties regarding the degree of 
market penetration and vaccine uptake that will be achieved in at-risk groups. A recent 
US study of the safety of Cervarix® in pregnancy was terminated due to low accrual of 
subjects attributed to low uptake of the vaccine in the US (GSK, 2015). To account for 
this, and that the proportion of clinically recognized pregnancies that can be expected to 
result in a live birth is approximately 62% (Martin, 2015), a range of sample size 
estimates was considered, from a minimum of 5 to 150 live births.
It is likely that the majority of exposures will occur inadvertently within 30 days prior to 
LMP or early in the first trimester before pregnancy status is known. If exposures occur 
later in pregnancy, results will be stratified by trimester of exposure, acknowledging 
that the power of stratified analyses to detect low prevalences will be limited by the 
sample size of each subgroup.
According to the CDC MACDP, the prevalence of MCMs for mothers <25 years of age
in the US is 2.54% (Correa, 2007). According to the CDC National Vital Statistics 
System (NVSS), the prevalence of preterm birth and LBW for mothers <25 years of age
are 11.71% and 8.50%, respectively (Martin, 2015).
The table below depicts sample sizes of 5, 20, 50, 100, and 150 live births and the 
associated effect sizes (i.e., the ratio of the registry-derived prevalence versus the 
reference prevalence) that would be detectable using a binomial distribution, a power of 
80%, and a 1-sided Type I (false positive) error rate of 5% (Altman, 1991). For 
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Protocol number:
V72_82OB
Date of Protocol 
Abstract:
12 AUG 16
example, with a sample size of 100 live births, the study will have 80% power to detect 
a 1.79-fold increase in the prevalence of preterm birth compared with the reference of 
11.71% (population prevalence). In other words, if the registry-derived prevalence 
estimate is at least 1.79 times higher than the reference prevalence of preterm birth, the 
1-sided 95% confidence interval for the estimate will exclude 11.71% (i.e., will lie 
above 11.71%), with a probability of 80%.
Table 4.1
Detectable effect size assuming 80% power
Sample Size
(N of live 
births)
Effect Size
(ratio of the registry-derived prevalence versus the reference prevalence for 
mothers <25 years of age)
MCM
[reference = 2.54%]
PTB
[reference = 11.71%]
LBW
[reference = 8.50%]
5
19.30
5.75
7.92
20
7.95
3.13
3.69
50
4.23
2.24
2.59
100
3.07
1.79
1.96
150
2.66
1.63
1.82
Abbreviations: LBW = low birth weight; MCM = major congenital malformation; PTB = preterm birth.
Data Analysis: This registry is primarily descriptive and designed to detect potential
safety signals, rather than test hypotheses.
Demographic and baseline characteristics will be summarized with simple descriptive 
statistics and data listings for the evaluable populations of pregnant women and live 
births. Demographic and baseline characteristics will also be summarized for the 
population that is lost to follow-up and compared with the evaluable populations to 
assess potential differences. These data will be reviewed for potential confounding 
factors that could affect the interpretation of comparisons of registry outcome
prevalence estimates with that of comparators.
Overall and stratum-specific point estimates and 95% confidence intervals will be 
calculated using the binomial distribution for prevalence estimates of MCMs, preterm
birth, and LBW among pregnant women exposed to at least 1 dose of BEXSEROand
their live births.  For each prevalence estimate, both 1-sided and 2-sided 
95% confidence intervals will be calculated and reported. One-sided confidence 
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Name of MAH:
GlaxoSmithKline
Biologicals S.A.
Protocol number:
V72_82OB
Date of Protocol 
Abstract:
12 AUG 16
intervals are appropriate, as we are specifically interested in detecting outcome 
prevalence estimates greater than the respective reference prevalences, and 2-sided 
confidence intervals will provide further description of the accuracy of the estimates.   
For MCM, the overall prevalence of MCM will be reported. Since most structural 
defects have their origins in the first trimester of pregnancy during the period of 
organogenesis, analyses of MCM will be stratified by trimester of exposure if 
applicable. It is expected that the vast majority (99%) of prenatal exposures will occur 
during the first trimester before the pregnancy is recognized. The prevalence of 
combined MCMs reported to the registry will be calculated as a proportion, with the 
number of MCMs as the numerator and the number of live births as the denominator. 
Fetal losses with reported MCMs occurring at or after 20 weeks’ gestation will be 
included in the numerator of the estimate of risk for MCMs to increase sensitivity and to 
allow comparison with the CDC MACDP, which calculates prevalence by this 
convention. A secondary analysis will be conducted including fetal losses with reported 
MCMs occurring at less than 20 weeks’ gestation in the calculation of prevalence. The 
prevalence of combined MCMs in exposed subjects will be compared with that of the 
CDC MACDP (Correa, 2007). The prevalence of preterm births and LBW will be 
calculated as proportions, with the number of live births as the denominator. These 
prevalence estimates in exposed subjects will be compared with those of the CDC 
NVSS (Martin, 2015).
Informed Consent and Ethical Approval: As a post-marketing safety reporting
activity, this registry qualifies for exemption of US Health Insurance Portability and
Accountability Act (HIPAA) authorization. It also qualifies for a waiver of 
documentation of informed consent (verbal consent) for adult women who self-enroll, 
and it qualifies for a waiver of informed consent for de-identified data reported to the 
registry. If a minor requests participation in the registry and all eligibility criteria are 
met, the registry will obtain assent from the minor and signed written consent from the 
parent or guardian. The protocol and informed consent waivers will be submitted to an 
institutional review board (IRB) for approval prior to registry implementation.
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Name of MAH:
GlaxoSmithKline
Biologicals S.A.
Protocol number:
V72_82OB
Date of Protocol 
Abstract:
12 AUG 16
Criteria for Study Termination
In accordance with FDA guidance (FDA, 2002), criteria for discontinuing the registry 
will include insufficient sample size recruitment, unacceptably low levels of exposure or 
enrollment, and/or the availability of more appropriate methods to gather relevant 
information. It is proposed that enrollment in the pregnancy registry will be reviewed by 
CBER on receipt of each annual report, and an appropriate course of action will be 
agreed upon after discussion with GSK. The registry acknowledges the challenges of 
enrolling exposed pregnancies in a young population of limited size in the US and will 
carefully monitor enrollment trends and outcomes. This is an open registry with 
initiation of patient recruitment from the time of launch.
Milestones: 
Start of data collection: 31 January 2016.
End of data collection: The pregnancy registry will continue enrolling exposed 
pregnancies for a period of 3 years or pending CBER review and discussion of results
with GSK.
Annual interim reports will be submitted to CBER per the PMC and GSK will submit a 
full study report to CBER by 31 May 2020.
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5.
AMENDMENTS AND UPDATES
Number
Date
Section of the 
study protocol
Amendment or 
update
Reason
1
12AUG16
Throughout the text 
of this protocol.
Amendment
To reflect the change 
of Sponsor from 
Novartis Vaccines 
and Diagnostics Inc. 
to GlaxoSmithKline 
Biologicals S.A.
1
12AUG16
page 1
Amendment
EU PAS register 
number has been 
added in the 
coversheet.
1
12AUG16
Throughout the text 
of this protocol.
Amendment
The name of the 
vaccine (BEXSERO) 
has been capitalized.
1
12AUG16
Annex 2 ENCEPP 
CHECKLIST 
Amendment
ENCePP Checklist 
updated and attached 
to this protocol.
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6.
MILESTONES
Table 6-1
Overview of study milestones. 
Milestone
Planned date 
Start of data collection
31 January 2016
End of data collection
The pregnancy registry will continue enrolling 
exposed pregnancies for a period of 3 years (final 
enrollment: 31 January 2019) and subsequent
follow-up of enrolled infants will continue until 
30 November 2019 (maximum 10 months follow-up 
post enrolment) or pending CBER review and 
discussion of results with GSK. 
Annual updates
Annual interim reports will be provided to CBER 
per the PMC.
Final report of study results
A final report will be produced approximately 
6 months after all data have been collected and 
cleaned and will be submitted to CBER by 
31 May 2020.
Abbreviations: CBER = Center for Biologics Evaluation and Review; IRB = institutional review board; 
GSK = GlaxoSmithKline Biologicals S.A.
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7.
RATIONALE AND BACKGROUND
The gram-negative bacterium Neisseria meningitidis is the most common cause of
bacterial meningitis in children and young adults in developed countries (Khatami, 2010). 
For the majority, exposure results in asymptomatic nasopharyngeal carriage. For those 
who develop invasive meningococcal disease (IMD), the disease spectrum ranges in 
severity from mild influenza-like illness to meningoencephalitis, prostration, and death in 
10% to 15% of patients. Long-term side effects including neurological deficit, limb 
amputation, hearing loss, blindness, and skin scarring can occur in up to 20% of cases 
(Edmond, 2010). 
Six major meningococcal serogroups are associated with invasive disease: A, B, C, W, X, 
and Y (Stephens 2007a). Serogroup prevalence varies with geography, time of year, and 
age group. Serogroups B, C, and Y strains are currently the most prevalent in North 
America (Stephens, 2007b), while serogroup B and C strains are the most prevalent in 
Europe (ECDC, 2015); serogroup A strains (which have largely disappeared from Europe 
and North America) are responsible for large annual epidemics of bacteremia and 
meningitis in sub-Saharan Africa (WHO, 2014). Serogroups W and X meningococci have 
been responsible for epidemics in sub-Saharan Africa since 2002 (Stephens, 2007).
The incidence of IMD in the United States (US) has fluctuated cyclically since the early 
1970s, ranging from 0.5 to 1.5 cases per 100,000 population. Since 1996, the incidence 
has declined sharply and in 2012 the incidence was 0.18/100,000, serogroup B accounting 
for 0.04/100,000 cases (Adams, 2014). The incidence is highest in infants aged <1 year, 
with a second peak occurring in adolescents and young adults (Cohn, 2013). Most IMD 
cases are sporadic, but between 2009 and 2015, there were 32 cases of serogroup B 
meningococcal disease associated with outbreaks at 5 US universities, including 1 fatality 
(MacNeil, 2015).
Since 2010, routine use of quadrivalent meningococcal conjugate vaccine covering 
serogroups A, C, W, and Y is recommended in the US for adolescents and others at 
increased risk for meningococcal disease (Cohn, 2013). More recently, vaccines against 
serogroup B disease have been approved by the Food and Drug Administration (FDA) for 
use in individuals 10 through 25 years of age (FDA, 2014; FDA, 2015). In February 
2015, the Advisory Committee on Immunization Practices (ACIP) recommended that a 
meningococcal group B vaccine should be administered to persons in the US aged 
≥10 years who are at increased risk for meningococcal disease. This includes persons 
with persistent complement component deficiencies (estimated at approximately
80,000 persons in the US), persons with anatomic or functional asplenia (approximately
100,000 persons), microbiologists routinely exposed to isolates of Neisseria meningitides 
(approximately 100,000 persons), and persons identified to be at increased risk because of 
a serogroup B meningococcal disease outbreak (approximately 60,000 between 2009 and 
2013) (MacNeil, 2015).
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BEXSERO was developed by to help confer protection against a broad range of 
meningococcal B strains causing disease. It is formulated with 3 major recombinant 
proteins (factor H binding protein, neisserial heparin binding antigen, and Neisseria
adhesin A) combined with bacterial outer membrane vesicles derived from the New 
Zealand outbreak strain NZ98/254, containing PorA type P1.4 as the main antigen 
(Giuliani, 2006) and aluminium hydroxide as an adsorbent. In those aged 10 to 25 years, 
it should be administered in a 2-dose schedule (0.5 mL each), each dose at least 1 month 
apart (Bexsero® prescribing information, 2015).
GSK did not study vaccination in pregnancy as one of the objectives of clinical studies 
pre-licensure; pregnant women were excluded from enrollment, and the use of birth 
control, where appropriate, was an entry criterion. Well-controlled studies in pregnant 
women are otherwise not available; however, during participation in 1 of 6 Legacy 
Novartis (GSK) sponsored studies (V72P10, V72_29, V72_41 V102_03) and supportive 
studies (V72P4 and V72P5), 32 subjects became pregnant (Rastogi, 2015). Of these, 25 
had received at least 1 dose of BEXSERO 20 gave birth to live-born infants with no 
abnormalities, 1 had a therapeutic abortion, and 1 had an ectopic pregnancy. Two women
gave birth to live-born infants with congenital abnormalities: Prader-Willi syndrome and 
absence of second toe of 1 foot. The latter infant died at 2 months after birth from sudden 
infant death syndrome. Independent review of each pregnancy outcome found no 
association with BEXSERO vaccination (Rastogi, 2015). For 1 participant, the outcome is
unknown because the subject was lost to follow-up. In response to outbreaks in 
universities in the US, the Centers for Disease Control and Prevention (CDC) sponsored 2
studies in which pregnant women were eligible to enroll. As of 27 June 2014, 5 
pregnancies were reported in the CDC-sponsored studies at Princeton University and the 
University of California, Santa Barbara. For all 5 women, therapeutic abortion was 
planned (Baumblatt, 2015).
Reproduction studies have been performed in female rabbits at BEXSERO doses up to 
15 times the human dose on a body weight basis and have revealed no evidence of 
impaired fertility or harm to the fetus due to BEXSERO. A summary of these studies is 
provided as follows:
The pilot embryofetal dose-range developmental toxicity study in rabbits (GLP Study No. 
UBA00041) tested 5 doses (3 prior to mating and 2 during gestation) at 1 to 2 times the 
highest anticipated human clinical dose of BEXSERO. No hazard of vaccination to 
maternal animals or the developing fetuses was identified. (Pilaro, 2004; cited by Ching-
Long, 2014).The vaccine was immunogenic in maternal animals, and fetuses had 
circulating antibodies (enzyme-linked immunosorbent assay [ELISA] and serum 
bactericidal assay [SBA] with rabbit complement).
The definitive fertility, developmental, and perinatal/postnatal reproduction toxicity study 
in rabbits (GLP Study No. UBA00044) tested 5 doses of BEXSERO(3 prior to mating 
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and 2 during gestation) at a dose equivalent to the absolute human dose or 15 times the 
human dose on a body weight basis (4 kg in rabbits and 60 kg in humans). This study was 
designed to comply with FDA guidance on the testing of the developmental toxicity of 
vaccines, and according to International Conference on Harmonisation (ICH) Harmonised
Tripartite Guideline (ICH, 1996) (stages A through E of the reproductive process, with 
the exception of determination of effects on estrous cycle). Evaluation of the maternal 
animals, their developing fetuses, and offspring for up to 4 weeks after birth demonstrated 
that BEXSERO was not a reproductive or developmental toxicant (Ching-Long, 2014).
The vaccine was immunogenic in the maternal animals; circulating antibodies were 
detected in their fetuses and persisted in offspring through day 29 of lactation (ELISA and 
SBA with rabbit complement).
BEXSERO is not contraindicated during pregnancy, but according to the vaccine label, 
BEXSERO should be used during pregnancy only if clearly needed. Inadvertent exposure 
within 30 days prior to last menstrual period (LMP) or early in the first trimester (before 
pregnancy status is known) might be expected to occur because the age group targeted for 
the vaccine includes young women of reproductive potential. The BEXSERO Pregnancy 
Registry is established to meet a Center for Biologics Evaluation and Research (CBER)
post-marketing commitment (PMC) and is designed to collect prospective data on 
pregnancy outcomes among women immunized with the BEXSERO vaccine within 30 
days prior to LMP or at any time during pregnancy. The registry will add to the current 
clinical experience with BEXSERO, supplementing existing data from animal toxicology 
studies and human exposure data. Pregnancy data will be collected at registry enrollment 
and, where accessible, at the end of the second trimester of pregnancy, and at pregnancy 
outcome for both mother and infant. GSK will sponsor the registry in consultation with 
specialists from appropriate fields such as obstetrics, pediatrics, clinical research, 
genetics, epidemiology, and teratology from academic institutions, private practice, 
and/or government agencies. These individuals constitute the Scientific Advisory 
Committee (SAC) and will provide an independent review of registry data.
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8.
RESEARCH QUESTION AND OBJECTIVES
The objective of the BEXSERO Pregnancy Registry is to evaluate pregnancy outcomes 
among women immunized with the BEXSERO vaccine within 30 days prior to the LMP
or at any time during pregnancy. The primary outcomes of interest include major 
congenital malformations (MCMs), preterm birth, and low birth weight (LBW).
Other pregnancy outcomes will be collected, including stillbirths and spontaneous 
abortions (SABs). The probability of SAB varies greatly as a function of when the 
pregnancy is enrolled in the registry (Savitz, 2002). Because pregnancies will be reported 
to the registry at different and imprecise times during gestation, calculation of the 
prevalence of SAB from the registry is deemed inappropriate and could lead to erroneous 
conclusions. For example, if a woman enrolls in the registry at 16 weeks of pregnancy, 
only an SAB after this time could be detected and included in prospective reports. 
Similarly, SABs occurring earlier in gestation may not have been recognized and/or 
reported.
This registry is primarily descriptive and designed to detect potential safety signals rather 
than test hypotheses.
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9.
RESEARCH METHODS
9.1
Study Design
The BEXSERO Pregnancy Registry is a prospective, observational study of pregnant
women immunized with the BEXSERO vaccine within 30 days prior to LMP or at any
time during pregnancy. It is strictly observational; the schedule of office visits and all
treatment regimens will be determined by the treating health care provider (HCP). The
registry will collect data that are routinely documented in the patient’s medical record in 
the course of usual care.
The design of this pregnancy registry follows current FDA guidance for designing and 
implementing pregnancy exposure registries (FDA, 2002).
9.2
Setting
Not applicable.
9.2.1
Study Period
The pregnancy registry will be implemented after approval by the applicable regulatory 
authority and central institutional review board (IRB). The data collection process for 
each participant will begin at enrollment (during pregnancy), follow-up will occur
(pending ongoing cooperation by the woman and her HCP) at the end of the second 
trimester (approximately 24 weeks’ gestation) and at pregnancy outcome (delivery or 
early termination).
9.2.2
Study Subjects
The study population will include pregnant women within the US who received at least 1 
dose of BEXSERO vaccine (confirmed or possible exposure) within 30 days prior to 
LMP or at any time during pregnancy. BEXSERO should be used during pregnancy only 
if clearly needed, but inadvertent exposure during pregnancy might be expected because
the age group targeted for the vaccine includes young women of reproductive potential. 
9.2.3
Study Population Selection
The minimum criteria required for enrollment into the registry are as follows:
!
Sufficient evidence to confirm that exposure to a serogroup B meningococcal vaccine
(confirmed or possible BEXSERO vaccination) occurred within 30 days prior to LMP 
or at any time during pregnancy
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!
Sufficient information to determine whether the pregnancy is prospectively or 
retrospectively registered (i.e., whether the outcome of pregnancy was known at the 
time of first contact with the registry)
!
Date the pregnancy exposure is registered
!
Full reporter (i.e., HCP) contact information to allow for follow-up (name, address, 
etc.)
In the event that it cannot be ascertained to which meningococcal B vaccine the woman 
was exposed, an unknown exposure cohort will be established and analyzed separately.
Enrollment in the Registry
Enrollment and data collection will be coordinated through a registry coordination center 
(RCC) staffed by trained registry coordinators located in the US. These registry 
coordinators will be the first line of communication with participants and their HCPs. The 
coordinators are experienced in working directly with both patients and HCPs to establish 
a rapport with them and assist them in fulfilling registry requirements. The team will be 
formally trained in the appropriate methods for handling registry calls with scripts and 
decision trees in place. Please also refer to Section 10.3 for additional details of the RCC.
Eligible pregnant women may be enrolled in various ways. They may self-enroll in the 
registry by calling the pregnancy registry telephone number directly or their HCP can, 
with their consent, enroll them on their behalf. Alternatively HCPs may report 
de-identified data on pregnancy exposures and outcomes occurring within their
network/health maintenance organization (HMO). 
Figure 9.2.3-1 outlines the process flow for enrolling registry participants under the
3 models:
1. Self-enrollment with signed informed consent or verbal consent (waiver of 
documentation of informed consent)
2. HCP enrollment with signed informed consent or verbal consent (waiver of 
documentation of informed consent)
3. De-identified data provided by HCPs under the waiver of informed consent provision.
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Figure 9.2.3-1
Registry enrollment, informed consent and data collection 
process
Participant self-enrollment
Eligible pregnant woman contacts 
registry to enroll. RCC describes 
registry objectives and 
requirements for participation.
Registry Initiation
Informed Consent
Data Collection (participant, obstetric, outcome data)
HCP enrollment 
HCP of eligible  pregnant woman 
describes registry and asks woman 
if she would like to enroll. HCP 
contacts registry.
De-identified data  from HCP
HCP of eligible pregnant woman 
contacts registry.
RCC reviews informed consent 
with the woman and answers 
questions.  RCC completes/signs 
ICF indicating the woman  
provided informed consent (verbal 
or written) and medical releases 
for HCPs to provide data to 
registry.
HCP of eligible pregnant woman 
completes/signs ICF indicating 
they obtained participant’s 
informed consent (verbal or 
written) and medical releases for 
HCPs to provide data to registry.
Waiver of Informed Consent
Participant Data
RCC interviews  Participant
Participant Data
HCP interviews  participant and 
sends copies of 1) form indicating 
consent was obtained, 2) medical 
releases, and 3) subject interview 
form to RCC for follow-up with 
HCPs.
Vaccine Data
RCC contacts vaccinating HCP 
to confirm/  provide vaccine 
data
Vaccine Data 
Enrolling HCP provides de-
identified vaccine data
Obstetric Data 
RCC contacts obstetric HCP to 
obtain maternal and obstetric 
data
Outcome Data 
RCC contacts obstetric HCP to 
obtain pregnancy/ infant 
outcome
Obstetric Data 
Enrolling HCP provides de-
identified maternal and 
obstetric data
Outcome Data 
Enrolling HCP provides de-
identified pregnancy/infant
Abbreviations: HCP = health care provider; ICF = informed consent form; PI = principal 
investigator; RCC = registry coordination center.
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Registry Awareness and Recruitment
Because registry enrollment is open to all eligible pregnant women, an active recruitment 
campaign will reach out to immunization providers and their patients in a broad variety of 
settings. The recruitment strategy will target HCPs who are known to immunize patients 
specifically with the BEXSERO vaccine. This might include OBGYN consultants and 
other specialists attending high-risk groups as defined by the ACIP recommendation 
(MacNeil, 2015). These providers could be identified through GSK BEXSERO
distribution data and/or medical science liaisons (MSLs), as well as HCP networks and 
HMOs.
This targeted awareness will include the distribution of a comprehensive informational kit 
designed to solicit interest among pregnant women in registry participation. All
messaging will be in line with product labeling.
The kit may include:
!
Branded registry information sheet and/or brochure that will briefly describe the 
registry purpose and procedures
!
Enrollment form and sample patient consent form
!
Prescribing information
!
Participant consent to contact card (this card enables the RCC to contact the potential 
patient and provide additional information about the registry)
Persistent awareness activities incorporating the above awareness materials as well as a 
variety of other approaches such as internet, product labeling, or messaging by MSLs 
may also be used, for example:
!
Internet:
-
FDA listing of pregnancy registries on www.fda.gov
-
www.clinicaltrials.gov
-
Society for Maternal-Fetal Medicine listing of registries
-
PPD website
-
GSK website )
!
Print:
-
BEXSERO prescribing information
-
BEXSERO medication guide
-
Medical journal advertising and/or direct to physician advertising
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-
Registry contact information in report(s)
!
Education:
-
MSL outreach to treating HCPs
-
Scientific presentations and publications
-
Distribution of report(s) to HCPs
Reference Groups
Given the inherent difficulties in identifying a comparison group (Covington, 2009), 
several different methods may be used to review the data for safety signals. As described 
below, background prevalence estimates from external surveillance sources and estimates
from published literature will be the primary comparators. To the extent possible, 
comparator prevalence estimates will be age-adjusted to reflect the age distribution of the 
BEXSERO Pregnancy Registry population.
Background Prevalence Estimates of Pregnancy Outcomes
Background prevalence estimates in the general population of pregnancy outcomes, such 
as premature birth and LBW, are readily available from national vital statistics or 
publications in the scientific literature (Martin, 2015).
Background Prevalence Estimates of Major Congenital Malformations (MCMs) 
Published prevalence estimates of MCMs are available from the CDC’s Metropolitan 
Atlanta Congenital Defects Program (MACDP), which is an ongoing population-based
birth defects surveillance program (Correa, 2007). The primary objectives of MACDP are 
to regularly and systematically monitor births of malformed infants for changes in 
incidence or other unusual patterns suggesting environmental influences, and to develop a
case registry for use in epidemiological studies. MACDP actively searches for MCMs
among the 50,000 annual births to residents of metropolitan Atlanta’s 5 counties and 
abstracts medical records at all Atlanta obstetric hospitals, Atlanta pediatric referral
hospitals, genetics labs, and vital records (Correa-Villasenor, 2003). While there are 
inherent problems with comparing data from women exposed to specific vaccines in 
pregnancy with background prevalence estimates from the general population, this is not 
an unrealistic comparison (Honein, 1999), and background estimates may be the only
practical comparator. MACDP has been used as a comparator by over 60% of pregnancy 
registries identified in a recent survey (Covington, 2009).
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Background Prevalence Estimates from Literature or Other Studies
The registry is committed to identifying other appropriate comparison groups, and 
research of the literature and other sources, such as other pregnancy registries or 
observational studies, will continue in order to obtain appropriate background prevalence 
estimates.
9.3
Variables
The sections below describe the theoretical aspects of relevant variables. Data sources 
and operational definitions are discussed in Section 9.4.
9.3.1
Exposure of Interest
This pregnancy registry is strictly observational and confirmed exposure to a 
meningococcal B vaccine within 30 days prior to LMP or at any time during pregnancy is 
a condition of enrollment. The exposure of interest is exposure to at least 1 dose of the 
BEXSERO vaccine. In the event that it cannot be ascertained to which meningococcal B 
vaccine the woman was exposed, an unknown exposure cohort will be established and 
analyzed separately.
BEXSERO is not contraindicated during pregnancy, but should be used during pregnancy 
only if clearly needed. Inadvertent exposure within 30 days prior to LMP or early in the 
first trimester (before pregnancy status is known) may be expected to occur because the 
age group targeted for the vaccine includes young women of reproductive potential. Data
to be collected include the date of vaccination, facility (e.g., HCP office, clinic, or
commercial facility such as a pharmacy or other retail outlet), dose, and lot number if 
available. In the event that it cannot be ascertained to which meningococcal B vaccine the 
woman was exposed, an unknown exposure cohort will be established and analyzed 
separately.
9.3.2
Outcome(s) of Interest
Major Congenital Malformation (MCM): The registry defines, classifies, and codes
MCMs with criteria specified by CDC MACDP (CDC, 2007). Newborn and infant 
conditions that are not necessarily considered MCMs appear in the Exclusion List for the 
MACDP. These conditions may be included under certain circumstances by CDC criteria 
and will be considered “conditional defects” in the registry (e.g., skin tags, webbed toes, 
etc.). Please see the following link for a listing of all MACDP MCMs and conditions on 
the Exclusion List:
http://www.cdc.gov/ncbddd/birthdefects/documents/macdpcode0807.pdf.
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The registry defines an MCM as any major structural or chromosomal defect or 
combination of 2 or more conditional defects in live-born infants, stillbirths, or fetal
losses of any gestational age (including outcomes prior to 20 weeks’ gestation or birth 
weight <500 g). This definition is consistent with, but not restricted to, the CDC MACDP
definition. Clusters of conditional abnormalities (as defined by CDC MACDP) and data 
from aborted fetuses of less than 20 weeks’ gestation, when available, will be included to 
increase sensitivity of monitoring. The MACDP includes conditional defects only if in the 
presence of a major defect. This registry will consider reports of 2 or more conditional
defects as a defect case, to increase signal sensitivity and to capture instances where a 
combination of conditional events might constitute a major defect or syndrome.
The registry conforms to the CDC MACDP guidelines in disqualifying as defects those 
findings that are present in infants born at less than 36 weeks of gestation, and are 
attributable to prematurity itself, such as patent ductus arteriosus, patent foramen ovale, 
or inguinal hernias. The CDC MACDP classification does include chromosomal defects. 
Though vaccine exposure is not likely to contribute to a risk for chromosomal defects, the 
registry includes these defects to maintain this consistency with the CDC MACDP.
Live-born infants with only transient or infectious conditions or with biochemical 
abnormalities will be classified as being without reported MCMs unless there is a 
possibility that the condition reflects an unrecognized MCM. Detected and reported 
transient or infectious conditions or biochemical abnormalities in infants without reported 
MCMs and defects that are excluded by the CDC guidelines will be noted in an appendix 
in the registry reports.
Preterm birth: An infant born at gestational age <37 weeks
Low Birth Weight: An infant whose birth weight is <2500 g
9.3.3
Other Variables
Maternal characteristics: Age, ethnicity, race
Prenatal data: LMP, estimated date of delivery (EDD), corrected estimated date of 
delivery (CEDD)
Prenatal tests: Name of test, date of test, result
Obstetrical history: Previous pregnancies, live births, stillbirths, SABs, induced 
abortions (IABs), births with congenital malformations, family history of congenital 
malformations
Concurrent medical conditions 
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Concomitant medications and vaccines 
Alcohol, tobacco, and illicit drug use 
Pregnancy outcomes
Each pregnancy outcome will be classified in 1 of the following mutually exclusive 
categories:
!
Live birth: an infant born alive
!
Stillbirth: a fetal death occurring at 20 weeks’ gestation or greater, or if gestational 
age is unknown, a fetus weighing 500 g or more
!
Spontaneous abortion (SAB): fetal death or expulsion of products of conception prior 
to 20 weeks’ gestation, or if gestational age is unknown, weighing less than 500g
-
Terminology may include missed abortion, incomplete abortion, and inevitable
abortion.
!
Induced Abortion (IAB): voluntary interruption of pregnancy, including pregnancy 
termination that occurs electively, to preserve maternal health, or due to fetal 
abnormalities
!
Ectopic pregnancy: implantation of a conception outside of the uterus
!
Molar pregnancy: a conception that results in a gestational trophoblastic tumor
Infant outcomes: Gestational age, birth weight, sex
9.4
Data Sources
The pregnant woman and appropriate members of her health care team will serve as data 
reporters to the registry. The registry is strictly observational; the schedule of office visits 
and all treatment regimens will be determined by the treating HCP. There will be no 
additional laboratory tests or assessments required as part of this registry. Only data noted 
as part of routine care will be collected. Data related to maternal characteristics will be 
provided by the pregnant woman or by her HCP (Section 9.4.3). Interim follow-up and 
outcome data will be provided by the obstetric HCP and/or pediatrician attending the 
birth, where accessible (Section 9.4 – Attempts to Obtain the Follow-up Information).
Additionally, the teratologist/geneticist on the SAC will provide an opinion regarding the 
possible temporal association of the BEXSERO exposure to the development of observed 
defects. If additional information is needed to aid in classification or temporality 
assessment, the teratologist will request additional information using the targeted follow-
up process outlined in Section 9.4.2. The SAC will meet periodically to review the data, 
discuss the MCM cases and their classification and temporality with the teratologist, and 
reach a consensus on the coding and classification of MCMs and other primary endpoints.
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HCPs may also report de-identified data to the registry. The following table provides a 
summary of data that will be collected at specific time points and the source of data. See 
Figure 9.2.3-1 for the various enrollment and data collection options used by the registry.
Table 9.4-1
Summary table of evaluations
Information requested
Registration 
provided by 
participant
and/or Ob
HCP
Interim 
prenatal
follow-up
(end of 2nd
trimester)
provided by 
Ob HCP
Pregnancy 
outcome 
provided by 
Ob HCP 
and/or 
pediatrician 
attending 
birth
Targeted follow-
up to collect 
information not 
previously 
obtained b, 
provided by the 
Ob HCP and/or 
pediatrician 
attending birth
Maternal contact information, 
alternate contact information, HCP
contact information
X
X a
X a
Maternal characteristics (age, 
ethnicity, race, etc.)
X
X a
Maternal prenatal information 
(LMP, EDD, CEDD, prenatal test
results and timing)
X
X a
X a
Obstetrical history
X
X a
X
Family history of MCMs
X
X a
X
BEXSERO exposure information
X
X a
X a
Concurrent conditions, 
concomitant medications, alcohol 
& tobacco use during pregnancy
X
X a
X a
Pregnancy status
X
X a
Outcome information (live birth, 
still birth, SAB, gestational age,
birth weight, infant/fetus sex)
X
MCM noted and description
X
Contributing factors
X
X
Abbreviations: CEDD = corrected estimated date of deliver; EDD = estimated date of delivery; HCP = 
health care provider; LMP = last menstrual period; MCM(s) = major congenital malformation(s); Ob = 
obstetric; SAB = spontaneous abortion.
a Obtain updated information since the previous contact.
b Targeted follow up is designed to collect addition information (if necessary) to facilitate characterization 
of the fetal loss and/or MCMs. 
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Registration Process
Registry enrollment may be initiated by pregnant women or by their HCPs, who will act 
as data reporters to the registry. HCPs may also submit de-identified data to the registry.
See Figure 9.2.3-1 for the various enrollment and data collection options used by the 
registry. After applicable subject informed consent is obtained from eligible women, the 
reporter will be asked to complete the Registration Form and submit it to the registry.
HCPs may also report de-identified pregnancy and outcome data to the registry. The
registry will provide a variety of convenient means for reporters to communicate with and 
submit data to the registry.
Information Collected at Registration
Reporter Information
!
Contact information for the patient (if the patient self-enrolls), as well as alternate 
contact information, such as a permanent address and/or next of kin.
!
HCP reporter contact information
Maternal Information
!
Maternal demographics (age, ethnicity, race)
!
LMP
!
EDD determined from LMP
!
CEDD (e.g., by ultrasound), if available
!
Prenatal tests (diagnostic or screening) performed, date of test, and findings including 
the identification of congenital anomalies
Maternal Obstetrical History
!
Number of previous pregnancies
!
Outcome of previous pregnancies: live births, stillbirths, SABs, IABs, ectopic 
pregnancies, molar pregnancies
!
History of offspring with congenital anomalies
!
Maternal and paternal history of congenital anomalies
Maternal BEXSERO Exposure (may be provided initially by the pregnant woman at 
registry enrollment and confirmed by the vaccinating HCP)
!
BEXSERO administration, including dose, timing, and lot number
!
Other Conditions and Exposures
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!
Concurrent maternal conditions
!
Concomitant medications or vaccinations during pregnancy
!
Tobacco, alcohol, and illicit drug use during pregnancy
Pregnancy Follow-up
Around the end of the second trimester and in the month of the EDD, the Interim 
Pregnancy Follow-up Form and Pregnancy Outcome Form, respectively, will be 
requested from the obstetric HCP.
Information Collected at Interim Pregnancy Follow-up and Pregnancy Outcome
Interim Pregnancy Follow-up at End of Second Trimester
Pregnancy Status
!
Updates to EDD (i.e., CEDD)
!
Subsequent prenatal tests (diagnostic or screening) performed and findings including 
the identification of congenital anomalies
!
Pregnancy complications (preterm labor, eclampsia, placental abruption)
!
Details of pregnancy outcome if pregnancy is not ongoing as described below
Other Exposures
!
Concomitant medications and vaccinations
!
Tobacco, alcohol, and illicit drug use during pregnancy
Additional Information Collected at Pregnancy Outcome
Fetal Outcome
!
Pregnancy outcome (live birth, stillbirth, SAB, IAB, ectopic pregnancy, molar 
pregnancy)
!
Date of outcome of pregnancy
!
Gestational age at outcome
!
Fetal/infant characteristics: sex, birth weight
-
MCM(s) and assessment of potential contributing factors
-
For a fetal loss (SAB, stillbirth), factors that may have had an impact on the fetal 
loss and attribution
Targeted Follow-up Process
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If there is an MCM or other event of interest noted, in order to properly characterize the 
event, additional information may be requested from the reporting HCP on the Targeted 
Follow-up Form:
!
Details of the MCM/condition
!
Etiology
!
Outcome attribution
!
Specific questions requested by GSK and/or the MCM evaluator
Attempts to Obtain the Follow-up Information
In the month that the follow-up is due, the HCP will be contacted and asked to provide 
follow-up information. Three subsequent attempts, as necessary, will be made every
2 weeks via various modes of communication. If there is still no response from the 
provider, a final communication will be sent indicating the case is lost to follow-up. If 
this communication prompts a response from the HCP or the requested data is later 
received, the case will be re-opened and assessed for evaluability. If, at any point in the 
follow-up process, the reporter indicates that the patient is lost to follow-up, no further 
attempts will be made.
Follow-up Process for Clarification of Information
For critical data points, if there are outstanding questions, discrepancies between forms, 
or missing data, the appropriate reporter will be contacted for clarification. Three 
subsequent attempts, as necessary, will be made every 2 weeks. If no further information 
is obtained on an otherwise evaluable case, the discrepant information in the data fields 
may be left blank, identified as “unspecified.” On a case-by-case basis, qualified registry 
staff or the principal investigator may make a determination on discrepant information 
(e.g., determination of partially illegible word or illogical year).
9.4.1
Operational Exposure Definition
At least 1 dose of BEXSERO administered 30 days prior to LMP or at any time during 
pregnancy (from conception until pregnancy outcome) will constitute exposure. In the 
event that it cannot be ascertained to which meningococcal B vaccine the woman was 
exposed, an unknown exposure cohort will be established and analyzed separately. The 
30-day window prior to conception corresponds with the time to immunologic response 
as indicated in the BEXSERO product label (Bexsero® prescribing information, 2015).
BEXSERO exposure will be further categorized by earliest trimester of exposure.
BEXSERO is not contraindicated in pregnancy, but should be used during pregnancy 
only if clearly needed (Bexsero® prescribing information, 2015). Inadvertent exposure 
within 30 days prior to LMP or early in the first trimester (before pregnancy status is 
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known) may also be expected to occur because the age group targeted for the vaccine 
includes young women of reproductive potential. For this registry, gestational weeks will
be estimated from the most reliable EDD as reported by the HCP. If a CEDD is provided 
by the HCP, it will be used instead. The date of conception will be calculated as the most 
reliable EDD minus 38 weeks. If the EDD is not available or never estimated, the first 
day of the LMP may be used to estimate gestational age. The second trimester will be 
considered to begin at week 14 after the date of conception or LMP, and the third 
trimester, at week 28. If there is a discrepancy between gestational age calculated from
LMP and reported gestational age, the HCP will be asked to verify the data.
When a pregnant woman enrolls in the registry, she will be asked when and where she 
was immunized with the BEXSERO vaccine, or any meningococcal B vaccine if the 
brand is unknown. She will then be asked to provide a medical release that allows the 
registry to confirm with the appropriate source the exposure to a meningococcal B 
vaccine occurred. The registry will contact the vaccine provider to confirm the 
vaccination date, brand, and lot number. If HCPs provide de-identified data to the 
registry, they must be able to verify the vaccination with BEXSERO and date of 
vaccination. In the event that it cannot be ascertained to which meningococcal B vaccine 
the woman was exposed, an unknown exposure cohort will be established and analyzed 
separately.
9.4.2
Operational Outcome Definition and Identification Process
All outcome variables will be provided by the obstetric HCP and/or pediatrician attending 
the birth. The HCP will be asked to describe any MCMs observed in the infant or fetus 
and will also be asked to report the gestational age and birth weight. These 2 variables 
will be used to calculate preterm birth (gestational age <37 weeks at birth) and LBW 
(birth weight <2500 g). A teratologist/geneticist will review all reported congenital 
anomalies and classify them using the CDC’s MACDP system as specified in Section 
9.3.2. Additionally, the teratologist/geneticist will provide an opinion regarding the 
possible temporal association of the BEXSERO exposure to the development of observed 
defects. If additional information is needed to aid in classification or temporality 
assessment, the teratologist will request additional information using the targeted 
follow-up process outlined in Section 9.4.
The SAC will meet periodically to review the data, discuss the MCM cases and their 
classification and temporality with the teratologist, and reach consensus on the coding 
and classification of MCMs and other primary endpoints.
9.4.3
Operational Variable(s) Definition
As is indicated in Section 9.4, for women who self-enroll in the registry, maternal 
characteristics will be provided by the pregnant woman at registry enrollment. After the 
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woman provides consent and medical release for her HCP(s) to provide data, the obstetric 
HCP will provide prenatal data (LMP, EDD, and CEDD), prenatal test data (test, date of 
test, and result), obstetrical history (previous pregnancies, live births, stillbirths, SABs, 
IABs, births with congenital malformations, and family history of congenital 
malformations), concurrent medical conditions, concomitant medications and vaccines, 
and alcohol, tobacco, and illicit drug use. At pregnancy outcome, the obstetric HCP will 
provide pregnancy outcomes data (live birth, stillbirth, SAB, IAB, or ectopic or molar 
pregnancy) and infant outcome (gestational age, birth weight, and sex).
If HCPs provide de-identified data to the registry, they will provide required data on 
maternal characteristics, prenatal data, obstetrical data, and pregnancy outcome data.
9.4.4
Advisory Committee(s)
An SAC will be established to oversee the scientific affairs of the registry, including its 
ongoing monitoring. The SAC will comprise recognized experts in the fields of 
teratology, epidemiology, maternal and fetal medicine, and therapeutic areas from 
government, academia, private practice, and GSK. The SAC will meet prior to each
registry report to review the accumulated body of data from the registry, including review 
and classification of reported MCMs, and to carry out any actions required, including 
review and interpretation of interim data analyses and reports and publications of registry 
data. The SAC may meet on ad hoc occasions if indicated. In addition to the above 
activities, the SAC will design and implement strategies to heighten awareness of the 
registry.
9.4.5
MCM Monitoring and Signal Generation
On an ongoing basis, the registry teratologist and SAC will review all reports of MCM 
individually and cumulatively for potential signals that are generated in the collection of 
this information. The registry will adopt a plan developed by the Antiretroviral Pregnancy
Registry to determine what constitutes a signal for a MCM, how it is reviewed, and what 
action might be taken should such a signal be seen (Covington, 2004). For example, the 
“Rule of Three” convention specifies that once 3 similar MCMs have accumulated with 
any specific exposure, these cases are flagged for immediate review. The likelihood of 
finding 3 of any specific MCM in a cohort of <600 by chance alone is less than 5% for all 
but the most common MCM classes (i.e., those occurring with the rate of <1/700). To 
enhance the insurance of prompt, responsible, and appropriate action in the event of a 
potential signal, the registry will employ the strategy of “threshold” based on the Council 
of International Organizations for the Medical Sciences (CIOMS, 1999). The threshold 
for action will be determined by the extent of certainty about the cases and tempered by 
the specifics of the cases.
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9.5
Study Size
The pregnancy registry is a PMC agreed upon with the CBER to commence enrolment on 
31 January 2016 and to continue for a period of 3 years or pending CBER review and 
discussion of results with GSK. will submit a full study report to CBER by 31 May 2020. 
The registry will prospectively enroll women with confirmed or possible (i.e. if the brand 
is unknown) exposure to BEXSERO 30 days prior to LMP or at any time during 
pregnancy. BEXSERO is not contraindicated during pregnancy, but should be used 
during pregnancy only if clearly needed. Under the current ACIP recommendations, the 
CDC estimates 350,000 individuals will be advised to receive a meningococcal B vaccine 
(MacNeil, 2015), of whom it is likely that a small proportion will be exposed during 
pregnancy. There are uncertainties regarding the degree of market penetration and 
vaccine uptake that will be achieved in at-risk groups. A recent US study of the safety of 
Cervarix® in pregnancy was terminated due to low accrual of subjects attributed to low 
uptake of the vaccine in the US (GSK, 2015). To account for this, and that the proportion 
of clinically recognized pregnancies that can be expected to result in a live birth is 
approximately 62% (Martin, 2015), a range of sample size estimates was considered, 
from a minimum of 5 to 150 live births.
It is likely that the majority of exposures (99%) will be the result of inadvertent exposure 
within 30 days prior to LMP or early in the first trimester before pregnancy status is 
known. If exposures occur later in pregnancy, results will be stratified by trimester of 
exposure, acknowledging that the power of stratified analyses to detect statistically 
significant differences will be limited by the sample size of each subgroup.
The expected low frequency of BEXSERO exposure in pregnancy will limit the statistical 
power of this study. As the sample size of the study increases, there will be a 
corresponding increase in the power of the study to detect increases in the prevalence of 
outcomes. The study will have greater power to detect prevalence increases for relatively 
common outcomes (with higher prevalence) but will have less power to for more 
uncommon outcomes, such as MCM.
According to the CDC MACDP, the prevalence of MCMs for mothers <25 years of age in 
the US is 2.54% (Correa, 2007). According to the CDC National Vital Statistics System 
(NVSS), the prevalence of preterm birth and LBW for mothers <25 years of age are
11.71% and 8.50%, respectively (Martin, 2015). 
The table below depicts sample sizes of 5, 20, 50, 100, and 150 live births and the 
associated effect sizes (i.e., the ratio of the registry-derived prevalence versus the 
reference prevalence) that would be detectable using a binomial distribution, a power of 
80%, and a 1-sided Type I (false positive) error rate of 5% (Altman, 1991). For example, 
with a sample size of 100 live births, the study will have 80% power to detect a 1.79-fold 
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increase in the prevalence of preterm birth compared with the reference of 11.71%
(population prevalence). In other words, if the registry-derived prevalence estimate is at 
least 1.79 times higher than the reference prevalence of preterm birth, the 1-sided 95% 
confidence interval for the estimate will exclude 11.71% (i.e., will lie above 11.71%),
with a probability of 80%.
Table 9.5-1
Detectable effect size assuming 80% power
Sample size
(N of live 
births)
Effect size
(ratio of the registry-derived prevalence versus the reference prevalence for mothers 
<25 years of age) 
MCM
[reference = 2.54%]
PTB
[reference = 11.71%]
LBW
[reference = 8.50%]
5
19.30
5.75
7.92
20
7.95
3.13
3.69
50
4.23
2.24
2.59
100
3.07
1.79
1.96
150
2.66
1.63
1.82
Abbreviations: LBW = low birth weight; MCM = major congenital malformations; PTB = preterm birth.
9.6
Data Management
9.6.1
Data Processing
Data for this prospective registry will be managed with an electronic data capture (EDC) 
platform, which is 21 Code of Federal Regulations (CFR) Part 11 compliant. Participants 
and their HCPs will provide data over the phone or by completing a paper case report 
form (CRF), which can be submitted to the registry via mail or fax. The data will be 
reviewed by a registry clinical research associate for correctness and completeness and 
entered into the database. 
9.6.2
Software and Hardware 
Power calculations presented in this protocol were conducted using SAS statistical 
software and a 1-sample binomial distribution with a 1-sided Type I error rate of 5%. 
Data analyses will be performed similarly using SAS (version 9.2 or higher; SAS 
Institute, Cary, NC).
9.7
Data Analysis
Registry Case Management and Disposition
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Prospective Registry Reports
The registry will encourage prospective registration, which is defined as registration of a 
pregnancy exposure prior to knowledge or perceived knowledge of the pregnancy 
outcome (e.g., structural defect or genetic abnormality noted on a prenatal test). Those 
with no abnormalities identified on a prenatal test prior to enrollment will be considered 
prospective and included in the analysis. The rationale, potential bias, and analytic 
techniques to address any bias that may be introduced by this practice are addressed in 
Section 9.7.4.
Data from HCP networks and HMOs that provide de-identified data on all exposed 
pregnancies in their network will fall into the category of prospective registry reports, as 
these networks/HMOs provide objective data on every pregnancy exposure in the 
network/HMO, both positive and negative outcomes. Thus, they avoid the reporting bias 
inherent in retrospective reporting only after a negative outcome has been noted.
Retrospective Registry Reports
Retrospective reports will also include subjects for whom the pregnancy outcome has 
already occurred or an abnormality has been identified on a diagnostic or screening 
prenatal test prior to enrollment. Retrospective reports can be biased toward the reporting 
of more unusual and severe cases and are less likely to be representative of the general 
population experience than reports reported prior to knowledge of outcome. Therefore, 
retrospective reports will not be included in the primary analysis and statistical 
calculations. Retrospective reports with reported MCMs and/or spontaneous fetal losses
will be reviewed to aid in detection of early signals and listed in registry reports. 
Retrospective reports will not be actively solicited by the registry and will not be captured 
in the registry database unless a congenital anomaly is reported.
Loss to Follow-up
For a prospective report or pregnancy where follow-up information on the pregnancy 
outcome (live birth, fetal loss, etc.) is never obtained or is unavailable, the pregnancy will 
be considered lost to follow-up. Subjects lost prior to pregnancy outcome will be tallied
in the registry reports but not included in the statistical analyses.
Duplicate Registry Reports
With registry reports coming from multiple HCPs, HCP networks, and HMOs, it is 
important to ensure that each case is counted only once (NBDPN, 2004). Identification of 
duplicate reports may be problematic for the anonymously reported de-identified cases 
where there is no specific identifying information. Reports received by the registry will be 
reviewed for possible duplicate reporting. On receipt of a registration form, the report will 
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be compared with other reports made by the same reporter or compared with other data 
(such as age, LMP, EDD, and exposure information) to determine if the same report was 
received previously. If no duplication is identified, the report will be entered into the 
database. If a duplicate report is later identified through recall or the systematic check for 
duplicates, the case reported earliest or the one with the most complete data will be
maintained as the valid case and updated with any data from the other report not already
captured. The duplicate report will be flagged and designated as “Invalid,” with the 
reason being noted as “duplicate report.”
Evaluable Registry Reports
An evaluable report is a subject with data submitted or confirmed by an HCP that 
contains at least the minimum criteria for a report and is not lost to follow-up. 
Prospectively reported evaluable subjects with known outcomes will be included in the 
primary analysis for the registry report. Evaluable retrospective reports will be 
summarized separately in the report. Patient-reported data without HCP confirmation will 
be summarized separately in the report.
Invalid Registry Reports
An invalid registry report is a report for which the minimum data elements are never 
obtained despite requests for the missing data. If the minimum data are not provided 
initially, the report will be considered to be pending until all attempts to resolve queries 
for missing data and requests for follow-up information are complete. If, after all attempts 
at follow-up are made, the minimum criteria are still not met, the report will be 
considered invalid due to insufficient information. Invalid reports will not be included in 
the registry analyses.
Analysis Population
The primary population for analysis will include prospective evaluable participants
exposed to BEXSERO that are not lost to follow-up (i.e., participants with appropriate 
outcome information that meet the minimum criteria for evaluation). Because early 
prenatal testing is so frequent, it may be difficult to achieve adequate numbers of 
prospectively identified pregnant women if all pregnancies with prior prenatal testing are 
excluded from the analysis. Therefore, the primary analysis will include pregnancies 
enrolled prior to outcome but after prenatal testing as long as the test does not indicate the 
presence of an abnormality.
Exclusions for Analysis Purposes
Invalid registry reports and pregnancies deemed lost to follow-up will be excluded from 
the primary analysis. Retrospective reports will not be included, although retrospective 
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cases with MCMs will be reviewed and reported separately for signal detection purposes.
In the event that it cannot be ascertained to which meningococcal B vaccine the woman 
was exposed, an unknown exposure cohort will be established and analyzed separately.
Sequential Pregnancies
The number and outcome of sequential pregnancies will be noted and presented. 
Sequential pregnancies will be included in the analytic dataset.
Multiple Gestation Pregnancies
The number, type (e.g., twin, triplet), and outcome of multiple gestation pregnancies will 
be noted and presented. Multiple gestation pregnancies will be included in the analytic 
dataset.
General Considerations for Data Analyses
This study is observational, and epidemiological methods will be employed for data 
collection and analyses.
Descriptive analysis will be performed for all prospective, evaluable data. The summary 
statistics for continuous and categorical variables to be used will be specified in the 
statistical analysis plan (SAP) but may include means, standard deviations, medians, 
minimums, maximums, percentiles, frequencies, and percentages. For analyses of 
associations between pregnancy outcomes and BEXSERO exposure, confounding and 
effect modification will be evaluated descriptively. 
The registry will identify the number of cases for the primary outcomes of MCM, preterm 
birth, LBW, and in addition for second trimester SABs; prevalence estimates will be 
calculated as proportions of these outcomes from the total number of pregnant women or 
live births, or in the case of second trimester SABs, the subset of women exposed prior to
the 20th week of gestation. For each prevalence estimate, both 1-sided and 2-sided 
95% confidence intervals will be calculated and reported.  One-sided confidence intervals 
are appropriate as we are specifically interested in detecting outcome prevalence 
estimates greater than their respective reference prevalence, and 2-sided confidence 
intervals will provide further description of the accuracy of the estimates.   
9.7.1
Statistical Hypotheses
This registry is primarily descriptive and designed to detect potential safety signals, rather 
than test hypotheses. We are specifically interested in detecting whether the prevalence 
estimates of MCM, preterm birth, and LBW among the live births of pregnant women 
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exposed to BEXSERO are greater than the prevalence of these outcomes among the 
general population. 
9.7.2
Analysis of Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized with simple descriptive 
statistics and data listings for the evaluable populations of pregnant women and live 
births. Demographic and baseline characteristics will also be summarized for the 
population that is lost to follow-up and compared with the evaluable populations to assess 
potential differences. These data will be reviewed for potential confounding factors that 
could affect the interpretation of comparisons of registry outcome prevalence estimates
with those of comparators. Further details will be provided in the SAP.
9.7.3
Statistical Methods
Overall and stratum-specific point estimates and 95% confidence intervals will be 
calculated using the binomial distribution for prevalence estimates of MCMs, preterm 
birth, and LBW among pregnant women exposed to BEXSEROand their live births. For 
each prevalence estimate, both 1-sided and 2-sided 95% confidence intervals will be 
calculated and reported. One-sided confidence intervals are appropriate as we are 
specifically interested in detecting outcome prevalence estimates greater than their 
respective reference prevalence, and 2-sided confidence intervals will provide further 
description of the accuracy of the estimates.   
Because most structural defects have their origins in the first trimester of pregnancy
during the period of organogenesis, analyses of MCM will be stratified by trimester of
exposure, if applicable. It is expected that the vast majority (99%) of prenatal exposures 
will occur during the first trimester before the pregnancy is recognized. The prevalence of 
combined MCMs reported to the registry will be calculated as a proportion with the 
number of MCMs as the numerator and the number of live births as the denominator.
Pregnancy losses with reported MCMs occurring at or after 20 weeks’ gestation will be 
included in the numerator of the estimate of risk for MCMs to increase sensitivity and to
allow comparison of outcomes with the CDC MACDP, which calculates prevalence by
this convention. A secondary analysis will be conducted including pregnancy losses with 
reported MCMs occurring at less than 20 weeks’ gestation. The prevalence of combined
MCMs in exposed cases will be compared with that of the CDC MACDP (Correa, 2007).
Only cases meeting the CDC MACDP criteria for a defect or with 2 or more conditional 
defects will be included in the primary analysis. Single minor defects do not constitute a 
MCM according to the CDC MACDP classification; therefore, they will be listed in the 
report, but not included in the primary analysis.
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The prevalence of preterm births and LBW will be calculated as proportions, with the 
number of live births as the denominator. These prevalence estimates in exposed cases 
will be compared with those of the CDC NVSS (Martin, 2015). Because MCMs are often 
associated with preterm birth and LBW, sensitivity analyses will be performed excluding 
infants with MCMs from the numerator and denominator when prevalence estimates are 
determined for these outcomes.
Formulas for the calculation of prevalence of the primary outcomes are presented below: 
MCM prevalence =
Number of live births and fetal losses occurring at 
≥20 weeks gestation with MCM
Number of live births (all fetal losses excluded from 
denominator per MACDP convention)
Preterm birth prevalence =
Number of preterm live births
Number of live births
LBW prevalence = 
Number of LBW live births
Number of live births 
The MCM outcome data will be stratified by the earliest trimester of exposure to
BEXSERO®. For this registry, gestational weeks are estimated from the most reliable
EDD as reported by the HCP. If a CEDD is provided by the HCP, it will be used instead. 
The date of conception will be calculated as the most reliable EDD minus 38 weeks. If
the EDD is not available or never estimated, the first day of the LMP may be used to 
estimate gestational age. The second trimester will be considered to begin at week 14, and 
the third trimester, at week 28. If there is a discrepancy between gestational age 
calculated from the LMP and reported gestational age, the HCP will be asked to verify the 
data.
If it is feasible, descriptive comparisons between the registry and an appropriate internal
and/or external comparison group will be examined (see Section 9.2.3 for a description of 
potential reference groups).
Methods to Control for Confounding and Effect Modification
For analyses of associations between pregnancy outcomes and BEXSERO exposure, 
confounding and effect modification will be evaluated descriptively. A detailed 
description of these analyses will be available in the SAP. Potential confounders/effect 
modifiers may include the following:
!
Maternal characteristics (e.g., age, ethnicity, race)
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Previous pregnancy outcomes (e.g., MCMs, stillbirth)
!
Pregnancy complications (e.g., preterm labor, eclampsia, placental abruption)
!
Comorbidities (e.g., diabetes, hypertension)
!
Concomitant exposures (e.g., medications, alcohol, tobacco)
!
Infant/fetus sex
Subgroup Analyses
Analyses will be stratified by trimester of exposure and other subgroups of interest,
potentially including number of doses of BEXSERO received, gestational age at 
enrollment and maternal age. Additional details on subgroup analyses will be described in 
the SAP. Comparisons may be made to external cohorts, if appropriate.
9.7.4
Statistical Considerations
Because early prenatal testing is so frequent, it may be difficult to achieve adequate 
numbers of prospectively identified pregnant women if all pregnancies with prior prenatal
testing are excluded from the analysis. Therefore, the primary analysis will include 
pregnancies enrolled prior to outcome but after prenatal test as long as the test does not 
indicate an abnormality. However, this practice could potentially bias the results by 
lowering the overall risk of MCMs (Honein, 1999). The analysis will attempt to 
determine bias introduced by this practice by examining the data with and without these 
cases.
While the registry analysis will be limited primarily to prospective reports, some 
pregnancy exposures will be reported only following pregnancy outcome (retrospective 
cases). Each retrospective report will be carefully reviewed. In general, retrospective 
reports of exposures to vaccines or medication following notification of outcome are 
biased toward reporting of the severe and unusual cases and are not reflective of the 
general experience with the vaccine or medication. Moreover, information about the total 
number of exposed persons is not known. Therefore, prevalence estimates of outcomes 
cannot be calculated from these data. However, a series of reported MCMs can be 
analyzed to detect patterns of specific MCMs and can identify early signals of vaccine or
medication risks.
Those pregnancies that have reached EDD, but for which outcome information was 
unobtainable after 4 attempts, will be considered lost to follow-up. It is possible that 
outcomes among pregnancies lost to follow-up could differ from those with documented 
outcomes. Because of differences in individual reporting patterns, it is currently not 
possible to assess with any certainty what impact the potential biases the losses to follow-
up may have on the analysis. However, efforts at comparing some of the characteristics of 
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each group may be conducted in an attempt to assess this potential source of bias (details 
to follow in the SAP).
When an analysis includes data from an external comparator, it is important to thoroughly 
understand the methodology of the external comparator and to take this into consideration 
when designing the analysis plan (Kennedy, 2004). As such, MACDP convention will be 
followed for the calculation of MCM prevalence: only live births of 20 weeks of gestation 
or greater will be included in the denominator. Fetal losses (SABs, IABs, stillbirths, etc.) 
with or without detected MCMs will be excluded from the denominator. The MACDP 
excludes fetal losses from the denominator to maintain consistency over time, as fetal 
death records were unavailable prior to 1994. In addition, the inclusion of fetal losses in 
the denominator may introduce classification bias. The percentage of these pregnancies 
consisting of potentially normal outcomes or MCMs is unknown. The data collection 
form attempts to obtain information on MCMs detected at the time of the outcome. 
However, the reporting physician may not know the condition of the aborted fetus. It is 
acknowledged that including only live births in the denominator is likely to overestimate 
the defect prevalence; however, there is only a small difference between prevalence 
estimates calculated using only live births versus live births plus fetal losses in the 
denominator given that the number of fetal deaths that are reported are a small proportion 
of the pregnancies 20 weeks or greater (Correa, 2007). 
9.8
Quality Control
9.8.1
Validation
Ensuring that the data obtained and delivered to GSK are of high quality will be an 
ongoing, multi-step process involving programming of edit checks for critical data 
variables in the EDC system and visual review for completeness, logic, consistency, and 
accuracy. As recommended in regulatory guidance documents, CRFs are carefully 
designed to ensure data quality and integrity. All subject-reported data will be verified by 
the appropriate HCP.
9.8.2
Record Retention
Investigators must retain all study records required by GSK and by the applicable 
regulations in a secure and safe facility. The investigator must consult a GSK
representative before disposal of any study records, and must notify the sponsor of any 
change in the location, disposition, or custody of the study files. Documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced will be retained for a period of 5 years in accordance with Good 
Pharmacoepidemiological Practice (GPP) guidelines (GPP, 2009). These documents 
should be retained for a longer period, however, if required by the applicable regulatory
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor 
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to inform the investigator/institution as to when these documents no longer need to be 
retained.
These principles of record retention will also be applied to the storage of laboratory 
samples, if applicable and provided that the integrity of the stored sample permits testing.
For observational studies, study records or documents may include the analyses files, 
syntaxes (usually stored at the site of the database), but also questionnaires.
9.9
Limitations of the Research Methods
Since participation in the registry will be accomplished in 3 ways (through voluntary self-
enrollment by the pregnant women, through HCP enrollment on behalf of the woman
with her consent, or finally, through the collection of de-identified data from HCPs within 
a network/HMO), the included subjects may not be representative of the overall 
population of US pregnant women. If possible, a sensitivity analysis will be conducted 
according to pregnant women’s method of enrollment: the data collected from pregnant 
women who provide consent and either self-enroll or authorize their HCPs to enroll them 
in the registry will be examined separately from the de-identified data collected from 
HCPs on pregnancy exposures and outcomes within a network/HMO.
Additionally, it is possible that even in prospectively reported cases, potential bias could 
exist. For example, high-risk pregnancies or low-risk pregnancies may be more likely to 
be reported. It is also possible, and entirely likely, that differences in the prevalence 
estimates of pregnancy outcomes will be observed due to random variability (NBDPN, 
2004). With the prevalence of the outcomes of interest being relatively low, cases of a 
particular outcome can be expected to be quite rare, and the coincidence of 2 or more 
cases in time may be just that: a coincidence. Confidence intervals will be carefully 
examined in order to assess the potential role of random variability.
Furthermore, it will be important to rule out other explanations for changing prevalence 
over time, including changes in medical diagnoses and technologies, changes in reporting 
and case ascertainment, and changes in the population at risk. In order to minimize the 
effect of these changes, the most current prevalence estimates available at the time of 
reporting for the population of interest will be used for analyses.
9.10
Other Aspects
Not applicable.
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10.
PROTECTION OF HUMAN SUBJECTS
GSK respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with applicable laws and regulations.
Each patient’s identity will be known only to the third-party contractor (PPD), the central 
registry site (principal investigator and RCC), and the enrolling individual (i.e., patient or 
HCP). The registry will assign patient and infant identification numbers, which will be 
used to identify registry participants and their infant offspring. The dataset used in each 
analysis of data from the registry will contain coded registry subject identifiers only for 
both the pregnant mothers and infants.
Each full-time and temporary employee in the RCC is fully trained in the protection of 
human subjects and data privacy and follows established standard operating procedures 
(SOPs) that outline specifically how to maintain confidentially and data protection of all 
registry participants. These SOPs also establish procedures to take should privacy be 
compromised in any way. The RCC staff must train and test on these privacy SOPs 
annually.
Exemption of Health Insurance Portability and Accountability Act Authorization
As a post-marketing safety reporting activity, this registry meets the criteria outlined 
below and is therefore exempt from the US Health Insurance Portability and 
Accountability Act (HIPAA) authorization.
The US CFR, 45 CFR 164.512, states:
“(iii) A person subject to the jurisdiction of the Food and Drug Administration (FDA) 
with respect to an FDA-regulated product or activity for which that person has 
responsibility, for the purpose of activities related to the quality, safety or effectiveness of 
such FDA-regulated product or activity. Such purposes include:
!
To collect or report adverse events (or similar activities with respect to food or dietary 
supplements), product defects or problems (including problems with the use or 
labeling of a product), or biological product deviations;
!
To track FDA-regulated products;
!
To enable product recalls, repairs, or replacement, or lookback (including locating and 
notifying individuals who have received products that have been recalled, withdrawn, 
or are the subject of lookback); or
!
To conduct post marketing surveillance”
To further clarify this issue, an article published by the Pregnancy Labeling Task Force, 
US FDA, states:
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“…the HIPAA Privacy Rule specifically permits the disclosure of protected health 
information by covered entities such as physicians or hospitals for public health 
purposes related to the quality, effectiveness and safety of FDA-regulated 
products to both the manufacturers and directly to the FDA. This includes 
collecting or reporting adverse events, tracking FDA-regulated products and 
conducting post-marketing surveillance to comply with requirements or at the 
direction of the FDA.” (Kennedy, 2004).
10.1
Regulatory and Ethical Compliance
This study was designed and shall be implemented and reported in accordance with GPP, 
with applicable local regulations and with the ethical principles laid down in the 
Declaration of Helsinki. The protocol will be submitted for approval to applicable 
regulatory authority and central IRB prior to registry implementation.
10.2
Informed Consent
Informed consent will be obtained for each registry participant who self-enrolls or is 
enrolled by her HCP. As is noted below, this registry qualifies for a waiver of 
documentation of informed consent. Adult participants will be given the option to provide 
verbal consent under the waiver of documentation of informed consent or signed
informed consent if they prefer where consent is obtained in person. If the participant 
chooses the verbal consent option, the RCC completes and signs and dates a form 
documenting that the RCC read the registry participant information sheet to the 
participant via telephone, answered all of the participant’s questions regarding the 
registry, and verbally consented to participate. A copy of this form is then mailed to the 
participant and the original is filed in the registry file. 
Minors are defined as individuals who have not attained the legal age for consenting to 
treatments, procedures, or clinical investigations under applicable law in various states 
within the US. The definition of a minor and an emancipated minor varies by state within 
the US. Given the patient population for BEXSERO vaccine, many of the potential
registry participants may be minors. This registry will follow applicable laws for the state 
in which the participant resides. If a minor requests participation in the registry and all 
eligibility criteria are met, the registry will obtain assent from the minor and signed 
written consent from a parent or guardian. Written consent from both parent(s) or both 
guardian(s) will be obtained in the US states in which this is required by local laws and 
regulations.
At the initial screening with potential participants, the registry associate will obtain 
consent to collect basic information about the individual, such as age and state of 
residence, to determine whether the individual is a minor and to ensure that applicable 
local laws and regulations are followed.
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Waiver of Documentation of Informed Consent
The following US regulations indicate that waiver of documentation of informed consent 
is appropriate for this registry.
As stated in the US 21 CFR 56.109 (and additionally in 45 CFR 46.117[c][2]):
!
“(c) An IRB shall require documentation of informed consent in accordance with
!
50.27 of this chapter, except as follows:
!
The IRB may, for some or all subjects, waive the requirement that the subject, or the 
subjects legally authorized representative, sign a written consent form if it finds that 
the research presents no more than minimal risk of harm to subjects and involves no 
procedures for which written consent is normally required outside the research 
context.
!
(d) In cases where the documentation requirement is waived under paragraph
!
(c)(1) of this section, the IRB may require the investigator to provide subjects with a 
written statement regarding the research.”
The research involves no more than minimal risk to the subjects. This is an 
observational study that involves no experimental intervention and poses no possibility of 
physical harm. The only potential risk is a breach of confidentiality, and the registry has 
well-established procedures in place to prevent any such breach of confidentiality. As 
described above, extensive safeguards are in place to ensure that patients’ privacy is 
protected:
!
An adequate plan is provided to protect the identifiers from improper use and 
disclosure (see Section 10).
!
An adequate plan is provided to remove the identifiers at the earliest opportunity.
!
Adequate assurances are provided that the protected health information will not be 
reused or disclosed to any other person or entity.
The research involves no procedures for which written consent is normally required 
outside the research context. Enrollment in this observational study will be strictly 
voluntary. The schedule of patient visits and all treatment regimens will be at the 
complete discretion of the treating HCP. Data submitted to the registry will be limited to 
data routinely collected and documented in the patient’s medical record.
For HCPs who report de-identified pregnancy exposure and outcome data to the registry, 
a waiver of informed consent is applicable as specified under CFR 46.116 (d) waiver of 
informed consent requirement and CFR 45, part 164.512 waiver criteria for 
post-marketing surveillance for the initial enrollment and follow-up through outcome of 
pregnancy.
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The research will involve no more than minimal risk to the subjects. This will be an 
observational registry that is a PMC with CBER. It involves no experimental intervention 
and poses no possibility of physical harm. The pregnant patient’s HCP, who is strictly 
obligated to maintain confidentiality, will submit routinely collected data to the registry. 
Patient confidentiality will be protected, as no identifying information will be sent to the 
registry. Only the HCP will know the identity of the patient. As described above, 
extensive safeguards will be in place to assure that patients’ privacy is protected.
The waiver will not adversely affect the rights and welfare of the subjects. The 
privacy risks to individuals whose protected health information will be used or disclosed 
are reasonable in relation to the anticipated benefits to future patients, and the importance 
of the knowledge that may reasonably be expected to result from the research.
The research could not practicably be conducted without the waiver. A critical 
component of a registry such as this is the need to enroll a substantial number of subjects 
to have the statistical power necessary to assess risk. In order to enroll as many patients as 
possible, this registry seeks to accept self-enrollments from patients as well as de-
identified data from HCPs under this waiver of informed consent.
10.3
Responsibilities of the Investigator and IRB
The protocol, waiver of documentation of informed consent, and waiver of informed 
consent will be reviewed and approved by an IRB before study implementation. A signed 
and dated statement that the protocol and waivers have been approved by the IRB will be 
given to GSK before study initiation. Prior to study start, the investigator will sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol. If 
an inspection of the site is requested by a regulatory authority, the investigator must 
inform GSK immediately that this request has been made.
The principal investigator is responsible for providing oversight of the registry and all 
submissions (protocol, amendments) to the IRB. The principal investigator will be 
available to GSK and the SAC for ongoing consultations regarding the review, analysis, 
and conduct of the registry.
The RCC is responsible for assisting the principal investigator in all aspects of patient 
recruitment, informed consent, data collection, and management. As is noted in Section 
10, the RCC staff is fully trained and compliant in SOPs on the protection of human 
subjects and data privacy.
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10.4
Protocol Adherence
The registry investigator will apply due diligence to protocol adherence. If a protocol 
amendment is necessary to improve the conduct of the study, such an amendment will be 
agreed upon by GSK and approved by the IRB before it can be implemented.
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11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ ADVERSE 
REACTIONS
The registry will follow industry guidance (FDA, 2002) for regulatory reporting of 
adverse events (AEs), as stated below:
“The Agency considers pregnancy exposure registry reports (both prospective and 
retrospective) as derived from active solicitation of patient information. Accordingly, a
sponsor holding marketing authorization for an approved drug or licensed biological
product must submit to the Agency, within 15 calendar days, reports of adverse events 
from the registry that are both serious and unexpected by regulatory definition and where 
a reasonable possibility exists that the drug or biological product caused the adverse event 
[see 21 CFR 310.305(c)(1), 314.80(c)(2)(iii) and (e), and 600.80(c)(1), (c)(2)(iii) and (e)].
Current reporting requirements in the regulations consider any congenital anomaly within
the definition of a serious adverse event [21 CFR 314.80(a) and 600.80(a)].” (FDA, 2002)
In addition to the above, because the registry is a study specifically to follow-up in 
pregnant women, exposure in pregnancy to the vaccine of interest itself will not be 
reported individually but will be reported by PPD to the sponsor’s Safety Department on 
a monthly basis as line listings. The registry final report will summarize the data on these 
exposures in pregnancy reported to the registry. Additionally, annual CBER PMC 
updates, periodic safety update reports (PSURs), and development safety update reports 
(DSURs) will provide data on exposure in pregnancy reported to the registry. For subjects 
enrolled in the registry, exposure in pregnancy to any other product (as well as the 
vaccine of interest) for which the sponsor is the market authorisation holder (MAH) will 
be collected and reported on the monthly line listing. For subjects not enrolled in the 
registry, exposure to any product for which the sponsor is the MAH will be reported
within 1 business day to the sponsor’s safety department as an individual report.
The registry will limit active solicitation of AEs to specific pregnancy outcomes and they
will be classified as serious adverse events (SAEs). These actively solicited SAEs include
MCM, LBW, preterm birth, SAB, still birth, IAB, molar pregnancy, and ectopic 
pregnancy. In addition to actively solicited SAEs, any maternal death will be reported as 
individual case safety reports (ICSRs) to the sponsor’s safety department.
For any product for which the sponsor is the MAH, all AEs and special scenarios, 
whether actively sought or not actively sought, which are reported to the study staff will 
be collected during the course of the registry and will be reported to the sponsor’s Safety 
Department within 1 business day of awareness by PPD. The sponsor’s Safety 
Department will be responsible for assessing the seriousness of these events.
The following reports are considered as special scenarios, irrespective if a clinical event 
has also occurred.
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!
Drug-drug or drug-food interaction
!
Drug use during lactation or breast-feeding
!
Lack of effectiveness
!
Overdose
!
Drug abuse and misuse
!
Drug maladministration or accidental exposure
!
Dispensing errors / medication errors
!
Withdrawal or rebound symptoms
All AEs reported for the vaccine of interest that were not actively sought will be
summarized in the interim and final study reports as line listings in the appendix.
Reports of AEs for all products for which the sponsor is the MAH from subjects who are 
not enrolled in the registry will also be reported to the sponsor’s Safety Department but 
will not be listed in the study report.
All AE reports will use the sponsor’s report forms.
The sponsor’s Safety Department will forward all applicable valid ICSRs of actively 
sought AEs and vaccine exposure in pregnancy data to the appropriate regulatory
authorities within the required timeframe, as required by regulations.
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12.
PLANS FOR DISSEMINATING AND COMMUNICATING RESULTS
12.1
Registration in Public Database(s)
Key design elements of this registry will be posted in publicly accessible databases 
including, but not limited to, the FDA pregnancy registry website and clinicaltrials.gov. 
Furthermore, key results of this registry will be posted in publicly accessible databases 
within the required time-frame from completion of the data collection where applicable 
and in compliance with current regulations.
12.2
Publications
Annual interim reports will be provided to CBER per the PMC.
Upon closure of the registry, a final report will be generated which will be submitted to 
the relevant regulatory authorities. The final report will also be available to HCPs.
The data may also be considered for reporting at scientific conferences or for publication 
in scientific journals. Preparation of such manuscripts will be prepared independently by 
the SAC and in accordance with the current guidelines for STrengthening the Reporting 
of OBservational studies in Epidemiology (STROBE, 2009). GSK will be entitled to view
the results and interpretations included in the manuscript and provide comments prior to 
submission of the manuscript for publication.
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13.
CRITERIA FOR STUDY TERMINATION
In accordance with FDA guidance (FDA, 2002), it is proposed that enrollment in the 
pregnancy registry will be reviewed by CBER on receipt of each annual report. In 
discussion with GSK, criteria for discontinuing the registry will include the following: 
!
The sample size recruited is insufficient to detect a minimum 2-fold increase in the 
prevalence of at least one of the major outcomes.
!
The feasibility of collecting sufficient information diminishes to unacceptable levels 
because of low exposure rates, poor enrollment, or loss to follow-up. The vaccine is 
currently recommended for those in the US who are at high risk of meningitis and are 
≥10 years of age. Given the limited size of the population for whom the vaccine is 
recommended and the young age of the population targeted, low levels of exposure 
are likely even in the event of high vaccine uptake in the target group.
!
More appropriate methods of gathering information for exposure during pregnancy 
are preferable or become available (e.g., if the vaccine is used in a sufficient quantity 
in the target population in another jurisdiction that is deemed acceptable to CBER). 
The registry acknowledges the challenges of enrolling exposed pregnancies and will 
carefully monitor enrollment trends and outcomes. This is an open registry with initiation 
of patient recruitment from the time of launch.
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14.
REFERENCES
Adams DA, Jajosky RA, Ajani U, et al; Centers for Disease Control and Prevention.
(2014) Summary of Notifiable Diseases—United States, 2012. MMWR Morb Mort Wkly 
Rep; 61(53):1-121.
Altman DG. (1991) Practical Statistics for Medical Research. London, UK; Chapman & 
Hall.
Baumblatt J. Department of Health and Human Services, Food and Drug Administration,
Center for Biologics Evaluation and Research MEMORANDUM. (2015). 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UC
M434722.pdf.
BEXSERO (Meningococcal Group B Vaccine) [prescribing information] (2015).
https://www.novartisvaccinesdirect.com/pdf/Bexsero®_PI.pdf.
Centers for Disease Control and Prevention (CDC), Division of Birth Defects and 
Developmental Disabilities. (2007) Birth defects and genetic diseases branch 6-digit 
codes for reportable congenital anomalies. 
http://www.cdc.gov/ncbddd/birthdefects/MACDP.html.
Ching-Long JS; Food and Drug Administration. (2014) Toxicology Review of MenB 
(BEXSERO) STN: 125546.0. 
http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm435045.htm
Cohn AC, MacNeil JR, Clark TA, et al; Centers for Disease Control and Prevention 
(CDC). (2013) Prevention and control of meningococcal disease: recommendations of the 
Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep;
22;62(RR-2):1-28.
Correa A, Cragan J, Kucik J, et al. (2007) Metropolitan Atlanta Congenital Defects 
Program 40th anniversary edition surveillance report: reporting birth defects surveillance
data 1968-2003. Birth Defects Res A; 79:65-93.
Correa-Villasenor A, Cragan J, Kucik J, O’Leary L, Siffel C, Williams L. (2003) The
Metropolitan Atlanta Congenital Defects Program: 35 years of birth defects surveillance
at the Centers for Disease Control and Prevention; Birth Defects Res A; 67:617-624.
Council for International Organizations of Medical Sciences (CIOMS) Working Groups 
II (revised) and V (new). (1999) Guidelines for Preparing Core Clinical-Safety 
Information on Drugs (2nd ed.). World Health Organization: Geneva, Switzerland.
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Covington DL, Roberts SS, Albano J, McKain LF. (2009) Pregnancy exposure registries: 
challenges in identifying comparison groups. Pharmacoepidemiol Drug Saf;
18(suppl 1):S11.
Covington DL, Tilson H, Elder J, Doi P. (2004) Assessing teratogenicity of antiretroviral 
drugs: monitoring and analysis plan of the Antiretroviral Pregnancy Registry. 
Pharmacoepidemiol Drug Saf; 13(8):537-545.
Edmond K, Clark A, Korczak VS, Sanderson C, Griffiths UK, Rudan I. (2010) Global 
and regional risk of disabling sequelae from bacterial meningitis: a systematic review and 
meta-analysis. Lancet Infect Dis; 10(5):317-328. 
European Centre for Disease Prevention and Control (ECDC). (2015) Surveillance of 
invasive bacterial diseases in Europe, 2012. Stockholm: ECDC.
Food and Drug Administration (FDA). (2002) Guidance for industry: establishing 
pregnancy exposure registries. Rockville, Md. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida 
nces/ucm071639.pdf
Food and Drug Administration (FDA). (2014) October 29, 2014 Approval - Trumenba
[press release].
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm420998.htm.
Food and Drug Administration (FDA). (2015) January 23, 2015 Approval -
BEXSERO[press release].
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm431370.htm.
Giuliani M, Adu-Bobie J, Comanducci M, et al. (2006) A universal vaccine for serogroup 
B meningococcus. Proc Natl Acad Sci U S A; 103(29):10834-10839.
Good Pharmacoepidemiological Practice (GPP), International Society for
Pharmacoepidemiology. (2007) 
http://www.pharmacoepi.org/resources/guidelines_08027.cfm.
GlaxoSmithKline; Organization of Teratology Specialists. Post-marketing safety study to 
assess the risk of spontaneous abortion following administration of CERVARIX in the 
United States and Canada. In: ClinicalTrials.gov. 
https://clinicaltrials.gov/ct2/show/NCT01290393?term=NCT01290393&rank=1. NLM 
identifier: NCT01290393. Accessed: May 13, 2015.
Honein MA, Paulozzi LJ, Cragan JD, Correa A. (1999) Evaluation of selected 
characteristics of pregnancy drug registries. Teratology; 60:356-364.
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ICH. (1996) ICH Harmonised Tripartite Guideline: Guideline for good clinical practice 
E6 (R1) International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
Kennedy DL, Uhl K, Kweder SL. (2004) Pregnancy exposure registries. Drug Saf;
27(4):215-228.
Khatami A, Pollard AJ. (2010) The epidemiology of meningococcal disease and the 
impact of vaccines. Expert Rev Vaccines; 9(3):285-298. Published erratum appears in
(2011) Expert Rev Vaccines; 10(3):398.
MacNeil J; Advisory Committee on Immunization Practices. (2015) Considerations for 
use of serogroup B meningococcal (MenB) vaccines in persons at increased risk. 
http://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2015-02/mening-
MacNeil.pdf
Martin JA, Hamilton BE, Osterman MJ, et al. (2015) Births: final data for 2013. Natl 
Vital Stat Rep; 64(1):1-68.
National Birth Defects Prevention Network (NBDPN). (2004) Guidelines for conducting 
birth defects surveillance. Sever, LE (ed). Atlanta, Ga: National Birth Defects Prevention 
Network, Inc http://www.nbdpn.org/docs/NBDPN_Guidelines2008.pdf
Rastogi A; Food and Drug Administration. (2015) Clinical Review: BEXSERO®. STN: 
125546/0. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UC
M434714.pdf
Savitz DA, Hertz-Picciotto I, Poole C, Olshan AF. (2002) Epidemiologic measures of the
course and outcome of pregnancy. Epidemiol Rev; 24:91-101.
Stephens DS. (2007) Conquering the meningococcus. FEMS Microbiol Rev; 31:3-14. 
Stephens DS, Greenwood B, Brandtzaeg P. (2007) Epidemic meningitis, 
meningococcaemia, and Neisseria meningitidis. Lancet; 369(9580):2196-2210. 
STrengthening the Reporting of OBservational studies in Epidemiology statement. (2009) 
http://www.strobe-statement.org/
World Health Organization (WHO). (2014) Meningitis outbreak response in sub-Saharan 
Africa. Geneva: World Health Organization.
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APPENDIX 1: LIST OF STAND-ALONE DOCUMENTS
Not applicable.
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APPENDIX 2: ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Doc.Ref. EMA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 3)
Adopted by the ENCePP Steering Group on 01/07/2016
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
welcomes innovative designs and new methods of research. This Checklist has been developed 
by ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to 
promote the quality of such studies, not their uniformity. The user is also referred to the 
ENCePP Guide on Methodological Standards in Pharmacoepidemiology, which reviews and 
gives direct electronic access to guidance for research in pharmacoepidemiology and 
pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the section number of the protocol 
where this issue has been discussed should be specified. It is possible that some questions do 
not apply to a particular study (for example, in the case of an innovative study design). In this 
case, the answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for 
each section should be used to explain why. The “Comments” field can also be used to 
elaborate on a “No” answer. 
This Checklist should be included as an Annex by marketing authorisation holders when 
submitting the protocol of a non-interventional post-authorisation safety study (PASS) to a 
regulatory authority (see the Guidance on the format and content of the protocol of non-
interventional post-authorisation safety studies). The Checklist is a supporting document and 
does not replace the format of the protocol for PASS as recommended in the Guidance and 
Module VIII of the Good pharmacovigilance practices (GVP).
Study title:
BEXSERO® pregnancy registry: an observational study of the safety of BEXSERO
exposure in pregnant women and their offspring.
Study reference number:
V72_82OB
European Network of Centres for 
Pharmacoepidemiology and 
Pharmacovigilance
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Section 1: Milestones
Yes
No
N/A
Section
Number
1.1 Does the protocol specify timelines for 
1.1.1 Start of data collection1
1.1.2 End of data collection2
1.1.3 Study progress report(s) 
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
1.1.6 Final report of study results.
6
6
6
6
6
Comments:
This is an FDA PMC. EMA has accepted this study in replacement of another study 
which was agreed with EMA and GSK. For this reason it was registered in EUPAS 
Register but this is not a milestone in the protocol
Section 2: Research question
Yes
No
N/A
Section
Number
2.1 Does the formulation of the research question 
and objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address 
an important public health concern, a risk identified in the 
risk management plan, an emerging safety issue)
2.1.2 The objective(s) of the study?
8
8
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
                                               
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.
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Section 2: Research question
Yes
No
N/A
Section
Number
generalised)
2.1.4 Which hypothesis(-es) is (are) to be 
tested? 
2.1.5 If applicable, that there is no a priori
hypothesis?
9.2.3
9.7.1
Comments:
This registry is primarily descriptive and designed to detect potential safety signals 
rather than test hypotheses.
Section 3: Study design
Yes
No
N/A
Section 
Number
3.1 Is the study design described? (e.g. cohort, case-
control, cross-sectional, new or alternative design) 
9.1
3.2 Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
9.1
3.3 Does the protocol specify measures of 
occurrence? (e.g. incidence rate, absolute risk)
11
3.4 Does the protocol specify measure(s) of 
association? (e.g. relative risk, odds ratio, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm 
(NNH) per year)
7
3.5 Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection)
11
Comments:
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Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1 Is the source population described?
9
4.2 Is the planned study population defined in terms 
of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication? 
4.2.5 Duration of follow-up?
9.2.1
9.2.2
9.2.2
9.2.2
9.2.1
4.3 Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)  
9.2.3
Comments:
Section 5: Exposure definition and 
measurement
Yes
No
N/A
Section
Number
5.1 Does the protocol describe how the study 
exposure is defined and measured? (e.g. 
operational details for defining and categorising exposure, 
measurement of dose and duration of drug exposure)
9.2.3
5.2 Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, 
use of validation sub-study)
9.2.3
5.3 Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
9.2.2
5.4 Is exposure classified based on biological 
mechanism of action and taking into account 
the pharmacokinetics and pharmacodynamics of 
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Section 5: Exposure definition and 
measurement
Yes
No
N/A
Section
Number
the drug?
Comments:
Exposure must occur within 30 days prior to last menstrual period or at any time 
during pregnancy
Section 6: Outcome definition and 
measurement
Yes
No
N/A
Section 
Number
6.1 Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
9.3.2
6.2 Does the protocol describe how the outcomes 
are defined and measured? 
9.3.2
6.3 Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, prospective 
or retrospective ascertainment, use of validation sub-study)
9.3.2
6.4 Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease, disease management)
Comments:
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Section 7: Bias
Yes
No
N/A
Section
Number
7.1 Does the protocol describe how confounding will 
be addressed in the study?
7.1.1. Does the protocol address confounding 
by indication if applicable?  
9.7.3, 
9.7.4
9.7.3
7.2 Does the protocol address:
7.2.1. Selection biases (e.g. healthy user bias)
7.2.2. Information biases (e.g. misclassification 
of exposure and endpoints, time-related 
bias) 
9.7.3
9.3, 9.4, 
9.7, 9,9 
7.3 Does the protocol address the validity of the 
study covariates?
9.3.3
Comments:
Section 8: Effect modification
Yes
No
N/A
Section 
Number
8.1 Does the protocol address effect modifiers? (e.g. 
collection of data on known effect modifiers, sub-group analyses, 
anticipated direction of effect)
9.7.3
Comments:
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Section 9: Data sources
Yes
No
N/A
Section
Number
9.1 Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.)
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient interview 
including scales and questionnaires, vital statistics, etc.)
9.1.3 Covariates?
9.4.1
9.4.2
4.9.3
9.2 Does the protocol describe the information 
available from the data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily dosage,  
prescriber)
8.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
8.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, life style, etc.)
9.4.1
9.4.2
9.4.3
9.3 Is a coding system described for:
9.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC)Classification System)
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
Activities (MedDRA)) 
9.3.3 Covariates?
9.3
9.3
9.3
9.4 Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)
Comments:
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The exposure (the vaccine) will be described by lot number where available.
Section 10: Analysis plan
Yes
No
N/A
Section 
Number
10.1 Is the choice of statistical techniques 
described? 
9.7.3
10.2 Are descriptive analyses included?
4.7.3
10.3 Are stratified analyses included?
9.7.3
10.4 Does the plan describe methods for adjusting 
for confounding?
9.7.3
10.5 Does the plan describe methods for handling 
missing data?
9.7
10.6 Is sample size and/or statistical power 
estimated?
9.5
Comments:
Section 11: Data management and quality 
control
Yes
No
N/A
Section
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
9.8.2
11.2 Are methods of quality assurance described?
9.8
11.3 Is there a system in place for independent 
review of study results? 
3.4
Comments:
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Section 12: Limitations
Yes
No
N/A
Section
Number
12.1
Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
12.1.2 Information bias?
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
9.9
9.9
9.9
12.2 Does the protocol discuss study feasibility? 
(e.g. study size, anticipated exposure, duration of follow-
up in a cohort study, patient recruitment)
9.5
Comments:
Section 13: Ethical issues
Yes
No
N/A
Section
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described?
10.2 10.3
13.2 Has any outcome of an ethical review 
procedure been addressed?
10.3
13.3 Have data protection requirements been 
described?
10
Comments:
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Section 14: Amendments and deviations
Yes
No
N/A
Section
Number
14.1 Does the protocol include a section to 
document amendments and deviations? 
5
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/A
Section
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)? 
12-12.2
15.2 Are plans described for disseminating study 
results externally, including publication?
12-12.2
Comments:
Name of the main author of the protocol: ___________________________
Date: 
/
/
Signature: ___________________________
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APPENDIX 3: ADDITIONAL INFORMATION
Not applicable.
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UserName: 
 
Title:  Cluster Head 
Date: Monday, 05 September 2016, 07:49   GMT 
Meaning: As an approver, I agree with the content and format of this document. 
================================================

Doc Number: 81195352
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Protocol V72_82OB
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Page 1 of 4
OBSERVATIONAL STUDY PROTOCOL V72_82OB
Amendment Number 1
Amendment Date: 12AUG16
BEXSERO® pregnancy registry: an observational study of the safety of 
BEXSERO® exposure in pregnant women and their offspring.
The present amendment introduces changes to the study protocol since the version 1
of the protocol. These changes are reflected into the revised protocol associated to 
this amendment.
Property of GlaxoSmithKline Biologicals S.A. (hereafter referred to as GSK)
Confidential
May not be used, divulged, published or otherwise disclosed without written
consent of GSK.
 
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RATIONALE AND DESCRIPTION OF CHANGE(S)
Rationale for major changes: 
As of March 2, 2015 GlaxoSmithKline Biologicals has acquired the non-influenza 
vaccines business from Novartis Vaccines and Diagnostics. 
The Marketing Authorization Holder (MAH) for BEXSERO® in the US market was 
Novartis Vaccines and Diagnostics Inc. until June 15th when CBER has officially
approved the transfer of MAH to GlaxoSmithKline Biologicals S.A.
This Protocol Amendment v.1. reflects the change of the Study Sponsor from Novartis 
Vaccines and Diagnostics Inc. to GlaxoSmithKline Biologicals S.A.
As a consequence of the acquisition also MAH contacts have been updated (both address 
and e-mail contacts).
Rationale for minor Change:
The EU PAS Register Number has been added to the coversheet of Study Protocol v. 2.
The name of the vaccine has been capitalized.
The ENCePP Checklist has been produced for this protocol and attached as a separate 
document
LIST OF CHANGE(S)
CHANGE 1 (throughout the text of the Protocol)
Previously read:
Novartis Vaccines and Diagnostics (or NVD)
Now reads:
GlaxoSmithKline Biologicals S.A. (or GSK)
Rationale for change: 
To reflect the change of Sponsor from Novartis Vaccines and Diagnostics to 
GlaxoSmithKline Biologicals.
CHANGE 2 (Coversheet of the Protocol)
Previously read:
 
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Page 3 of 4
EU PAS register number was not indicated
Now reads:
EU PAS Register number: EUPAS 12183
Rationale for change: 
EMA has accepted to replace commitment for study V72_39OB with study
V72_82OB and it has been included in the RMP as a Post Authorization Safety
Study (PASS) cat. 3. Therefore it has been registered in EU PAS Register and a 
registration number has been attributed.
CHANGE 3 (throughout the text of the Protocol)
Previously read:
Bexsero
Now reads:
BEXSERO
Rationale for change: 
The name of the vaccine “BEXSERO” has been capitalized according to GSK 
indications.
CHANGE 4 (APPENDIX 2 ENCEPP CHECKLIST FOR STUDY PROTOCOLS)
Previously read:
Not applicable
Now reads:
“See attached appendix 2”
Rationale for change: 
When the version 1 of the protocol was finalized, it was not supposed to be
registered to ENCePP and a ENCePP checklist was not applicable. After the 
approval from EMA to accept V72_82OB in place of another commitment with
EMA (V72_39OB), this Study Protocol was posted in ENCePP (EU PAS Register)
 
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and a ENCePP Checklist is now produced and attached to the Revised Study 
Protocol .
 
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UserName: 
 
Title:  Cluster Head 
Date: Monday, 05 September 2016, 07:48   GMT 
Meaning: As an approver, I agree with the content and format of this document. 
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