MENVEO Pregnancy Registry: an Observational Study on the Safety of MENVEO Exposure in Pregnant Women and Their Offspring
Conditions: Meningococcal Disease, Pregnancy, Infections, Meningococcal
Sponsor: GlaxoSmithKline

Doc Number: 66333097
 Novartis Vaccines and Diagnostics
Observational Study Protocol V59_72OB
01 SEP 14 Final Version 2.0
Confidential
Page 1 of 54
OBS-01 TEMP 01 / Atlas No. 295927
Version No. 1 / Version Date: November 27, 2012
Title
Menveo® pregnancy registry: an observational study 
on the safety of Menveo exposure in pregnant women 
and their offspring
Protocol version identifier
V2.0
Date of last version protocol
01 SEP 14
BB-BLA No
Not applicable.
Active substance
Oligosaccharides derived from capsular
polysaccharides of Neisseria meningitidis serogroups 
A, C, W and Y, each conjugated to the CRM197 carrier 
protein.
Medicinal product
Meningococcal quadrivalent CRM-197 conjugate 
vaccine (Menveo®)
Product reference
Not applicable.
Procedure number
Not applicable.
Marketing authorisation 
holder(s)
Novartis Vaccines and Diagnostics 
Joint PASS study
No
Research question and 
objectives
The objective of the Menveo Pregnancy Registry is to 
evaluate pregnancy outcomes among women 
immunized with the Menveo vaccine within 28 days 
prior to conception or at any time during pregnancy. 
The primary outcomes of interest include major 
congenital malformation, preterm birth, and low birth 
weight.
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Doc Number: 66333097
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Observational Study Protocol V59_72OB
01 SEP 14 Final Version 2.0
Confidential
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OBS-01 TEMP 01 / Atlas No. 295927
Version No. 1 / Version Date: November 27, 2012
1.0
TABLE OF CONTENTS
1.0 
TABLE OF CONTENTS..................................................................................... 3
2.0 
LIST OF ABBREVIATIONS .............................................................................. 5
3.0 
RESPONSIBLE PARTIES.................................................................................. 6
3.1 
Main Author(s) of the Protocol ........................................................................ 6
3.2 
Principal Investigator....................................................................................... 6
3.3 
Coordinating Investigator(s)............................................................................. 6
3.4 
CRO or Other Service Provider........................................................................ 6
3.5 
Advisory Committee........................................................................................ 6
4.0 
ABSTRACT........................................................................................................ 7
5.0 
AMENDMENTS AND UPDATES ................................................................... 15
6.0 
MILESTONES .................................................................................................. 16
7.0 
RATIONALE AND BACKGROUND............................................................... 17
8.0 
RESEARCH QUESTION AND OBJECTIVES................................................. 20
9.0 
RESEARCH METHODS................................................................................... 21
9.1 
Study Design ................................................................................................. 21
9.2 
Setting ........................................................................................................... 21
9.2.1 
Study Period........................................................................................... 21
9.2.2 
Study Subjects........................................................................................ 21
9.2.3 
Study Population Selection..................................................................... 21
9.2.3.1 
Reference Groups............................................................................... 23
9.3 
Variables ....................................................................................................... 24
9.3.1 
Exposure of Interest ............................................................................... 24
9.3.2 
Outcome(s) of Interest............................................................................ 24
9.3.3 
Other Variables ...................................................................................... 25
9.4 
Data Sources.................................................................................................. 26
9.4.1 
Operational Exposure Definition ............................................................ 30
9.4.2 
Operational Outcome Definition and Identification Process.................... 31
9.4.3 
Operational Variable(s) Definition ......................................................... 31
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01 SEP 14 Final Version 2.0
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9.4.4 
Advisory Committee(s) .......................................................................... 32
9.5 
Study Size...................................................................................................... 32
9.6 
Data Management.......................................................................................... 33
9.6.1 
Data Processing...................................................................................... 33
9.6.2 
Software and Hardware.......................................................................... 34
9.7 
Data Analysis................................................................................................. 34
9.7.1 
Statistical Hypotheses............................................................................. 37
9.7.2 
Analysis of Demographics and Baseline Characteristics......................... 37
9.7.3 
Statistical Methods................................................................................. 37
9.7.4 
Statistical Considerations ....................................................................... 38
9.8 
Quality Control.............................................................................................. 39
9.8.1 
Validation .............................................................................................. 39
9.8.2 
Record Retention.................................................................................... 40
9.9 
Limitations of the Research Methods ............................................................. 40
9.10 
Other Aspects ................................................................................................ 40
10.0 
PROTECTION OF HUMAN SUBJECTS.......................................................... 41
10.1 
Regulatory and Ethical Compliance ............................................................... 42
10.2 
Informed Consent .......................................................................................... 42
10.3 
Responsibilities of the Investigator and IRB................................................... 45
10.4 
Protocol Adherence........................................................................................ 46
11.0 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ ADVERSE 
REACTIONS ................................................................................................................ 47
12.0 
PLANS FOR DISSEMINATING AND COMMUNICATING RESULTS......... 49
12.1 
Registration in Public Database(s).................................................................. 49
12.2 
Publications ................................................................................................... 49
13.0 
REFERENCES.................................................................................................. 51
APPENDIX 1: LIST OF STAND-ALONE DOCUMENTS........................................... 53
APPENDIX 2: ENCEPP CHECKLIST FOR STUDY PROTOCOLS............................ 54
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Doc Number: 66333097
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Version No. 1 / Version Date: November 27, 2012
2.0
LIST OF ABBREVIATIONS
ACIP
Advisory Committee on Immunization Practices
AEs 
Adverse Events
BRFSS
Behavioral Risk Factor Surveillance System
CBER
Center for Biologics Evaluation, Research 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
GLP
Good Laboratory Practice
GPP 
Good Pharmacoepidemiological Practice
HCP
Health care provider
HIPAA
Health Insurance Portability and Accountability Act
HMO
Health maintenance organization
IAB
Induced abortion
ICSR
Individual Case Safety Reports
IM
Intramuscular
IRB
Institutional review board
LMP
Last menstrual period
LBW
Low birth weight
MACDP
Metropolitan Atlanta Congenital Defects Program
MCM
Major congenital malformation
MSL
Medical science liaison
NVD
Novartis Vaccines and Diagnostics
NVSS
National Vital Statistics System
PMC
Post marketing commitment
PRAMS
Pregnancy Risk Assessment Monitoring System
PSUR
Periodic Safety Update Report
RCC
Registry Coordination Center
SAB
Spontaneous abortion
SAC
Scientific Advisory Committee
SAEs
Serious Adverse Events
SAP
Statistical analysis plan
SOP
Standard operating procedure
STROBE
STrengthening the Reporting of OBservational studies in Epidemiology
US
United States
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4.0 
ABSTRACT
Name of Sponsor
Novartis Vaccines 
and Diagnostics
Protocol number:
V59_72OB
Health authority 
study registration 
number(s): N/A
Date of Protocol 
Abstract:
16 AUG 13
Title of Study: Menveo® pregnancy registry: an observational study on the safety of 
Menveo exposure in pregnant women and their offspring
Study Period: The pregnancy registry will 
be implemented after approval by 
applicable regulatory authority and central 
institutional review board (IRB) with the 
goal of enrolling 100 exposed pregnancies 
over a 3-year period. The data collection 
process for each participant will begin at 
enrollment (during 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 established to 
meet a post marketing commitment 
(PMC) agreed upon with CBER to 
establish a pregnancy registry to 
prospectively collect data on pregnancy
exposures to Menveo.
Rationale and Background: The Menveo® Pregnancy Registry is established to meet a 
CBER PMC and is designed to collect prospective data on pregnancy outcomes among 
pregnant women vaccinated with Menveo within 28 days prior to conception or at any 
time during pregnancy. The 28-day window prior to conception corresponds with the 
time to immunologic response as indicated in the Menveo product label (Menveo 
package insert, 2012). The Advisory Committee on Immunization Practices (ACIP) 
recommends routine administration of a MenACWY vaccine for all persons aged 11 
through 18 years. Thus, the registry population will primarily consist of adolescents. 
Menveo is not indicated in pregnancy. However, inadvertent pregnancy exposures are 
anticipated because the targeted age group for the vaccine includes young women of 
reproductive potential. The registry will add to the current clinical experience with 
Menveo by 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. Novartis 
Vaccines and Diagnostics (NVD) 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 
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Doc Number: 66333097
 Novartis Vaccines and Diagnostics
Observational Study Protocol V59_72OB
01 SEP 14 Final Version 2.0
Confidential
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OBS-01 TEMP 01 / Atlas No. 295927
Version No. 1 / Version Date: November 27, 2012
Name of Sponsor
Novartis Vaccines 
and Diagnostics
Protocol number:
V59_72OB
Health authority 
study registration 
number(s): N/A
Date of Protocol 
Abstract:
16 AUG 13
(SAC) and will provide an independent review of registry data.
Research Question and Objectives: The objective of the Menveo Pregnancy Registry 
is to evaluate pregnancy outcomes among women immunized with the Menveo vaccine 
within 28 days prior to conception 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 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 Menveo Pregnancy Registry is a prospective, observational study of 
women inadvertently immunized with the Menveo vaccine within 28 days prior to 
conception 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 Food and Drug Administration (FDA) guidance for designing and 
implementing pregnancy exposure registries (FDA, 2002).
Population: The study population will include pregnant women within the United 
States (US) who were immunized with the Menveo vaccine within 28 days prior to 
conception or at any time during pregnancy. Because the vaccine is not indicated in 
pregnancy, the majority of exposures will be inadvertently administered in the first 
trimester of pregnancy. 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 data on pregnancy exposures and outcomes. An evaluable subject is 
a pregnant woman 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. The minimum criteria 
required for enrollment into the registry are as follows:
▫
Sufficient evidence to confirm that Menveo exposure occurred within 28 days prior 
to conception or at any time during pregnancy
▫
Sufficient information to determine whether the pregnancy is prospectively or 
retrospectively registered (ie, whether the outcome of pregnancy was known at the 
time of first contact with the registry)
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Doc Number: 66333097
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Observational Study Protocol V59_72OB
01 SEP 14 Final Version 2.0
Confidential
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OBS-01 TEMP 01 / Atlas No. 295927
Version No. 1 / Version Date: November 27, 2012
Name of Sponsor
Novartis Vaccines 
and Diagnostics
Protocol number:
V59_72OB
Health authority 
study registration 
number(s): N/A
Date of Protocol 
Abstract:
16 AUG 13
▫
Date the pregnancy exposure is registered
▫
Full reporter (ie, HCP) contact information to allow for follow-up (name, address, 
etc.)
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 Menveo vaccine. These providers will be 
identified through NVD Menveo distribution data and medical science liaisons (MSLs), 
as well as HCP provider networks and HMOs.
The primary population for analysis will include prospectively enrolled pregnant 
women exposed to Menveo who are not lost to follow-up (ie, with outcome information 
that meet the minimum criteria for evaluation). Retrospective reports will also include 
exposed pregnant women for which the pregnancy outcome is known (ie, an 
abnormality has been identified on a diagnostic 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 
cases reported prior to knowledge of outcome. Therefore, retrospective reports will not 
be included in the primary analysis and statistical calculation of risk. Retrospective 
reports with reported MCMs 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 provider 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 rates from external surveillance sources and rates from published literature
will be the primary comparators. Background rates in the general population on 
pregnancy outcomes, such as preterm birth and LBW, are readily available from 
national vital statistics (Martin, 2012). Published rates of MCMs are available from the 
Centers for Disease Control and Prevention (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 rates will be 
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Doc Number: 66333097
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Observational Study Protocol V59_72OB
01 SEP 14 Final Version 2.0
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OBS-01 TEMP 01 / Atlas No. 295927
Version No. 1 / Version Date: November 27, 2012
Name of Sponsor
Novartis Vaccines 
and Diagnostics
Protocol number:
V59_72OB
Health authority 
study registration 
number(s): N/A
Date of Protocol 
Abstract:
16 AUG 13
age-adjusted to reflect the age distribution of the Menveo Pregnancy Registry 
population.
Variables: 
Exposure(s) of interest
This pregnancy registry is strictly observational. Menveo vaccination is not indicated in 
pregnancy. Therefore, Menveo vaccination exposure in pregnancy is expected to be 
inadvertent and to occur in early pregnancy. When a pregnant woman self-enrolls in the 
registry, she will be asked when and where she was immunized with the Menveo
vaccine. She will then be asked to provide a medical release that allows the registry to 
confirm Menveo vaccination with the appropriate source. The registry will contact the 
Menveo vaccination 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 Menveo
vaccination and date of vaccination.
Outcome(s) of Interest
MCM: 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 
weighing <500 g). This definition is consistent with, but not restricted to, the CDC 
MACDP definition. 
Preterm birth: An infant born at gestational age <37 weeks.
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 Menveo exposure to the 
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Version No. 1 / Version Date: November 27, 2012
Name of Sponsor
Novartis Vaccines 
and Diagnostics
Protocol number:
V59_72OB
Health authority 
study registration 
number(s): N/A
Date of Protocol 
Abstract:
16 AUG 13
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: Last menstrual period (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
Concomitant medical conditions
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
▫
SAB: fetal death or expulsion of products of conception prior to 20 weeks’ 
gestation. Terminology may include missed abortion, incomplete abortion, and 
inevitable 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
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OBS-01 TEMP 01 / Atlas No. 295927
Version No. 1 / Version Date: November 27, 2012
Name of Sponsor
Novartis Vaccines 
and Diagnostics
Protocol number:
V59_72OB
Health authority 
study registration 
number(s): N/A
Date of Protocol 
Abstract:
16 AUG 13
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. 
Study Size: The registry seeks to enroll 100 exposed pregnancies. Approximately 58% 
of these pregnancies can be expected to result in a live birth ( Ventura, 2012). Given the 
patient population will primarily be adolescents, a high percentage of these pregnancies 
can be expected to be unintended, unwanted, and likely to result in IAB. It is expected 
that the vast majority (99%) of prenatal exposures will occur during the first trimester 
(before pregnancy status is known).
According to the CDC MACDP, the prevalence rate of MCMs for mothers <25 years of 
age in the US is 2.54% (Correa, 2007). With a sample size of 58 first-trimester exposed 
pregnancies resulting in a live birth, the study will have 80% power to detect a 4.46-fold 
increase in the prevalence rate of MCMs as compared with the CDC MACDP rate. 
According to the CDC National Vital Statistics System (NVSS), the prevalence rates of 
preterm birth and LBW for mothers <25 years of age are 12.37% and 8.70%, 
respectively (Martin, 2012). With a sample size of approximately 58 exposed live births, 
the study will provide 80% power to detect a statistically significant 1.99-fold increase 
in the prevalence rate of preterm birth and 2.40-fold increase in the prevalence rate of 
LBW, as compared with the CDC NVSS rates. 
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 rates with 
that of comparators. 
Overall and stratum-specific point estimates and 1-sided 95% confidence intervals will 
be calculated using the exact binomial distribution for prevalence rates of MCMs, 
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Version No. 1 / Version Date: November 27, 2012
Name of Sponsor
Novartis Vaccines 
and Diagnostics
Protocol number:
V59_72OB
Health authority 
study registration 
number(s): N/A
Date of Protocol 
Abstract:
16 AUG 13
preterm birth, and LBW among pregnant women exposed to Menveo and their live 
births.
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 rate 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 with the CDC MACDP following the outcome, which calculates rates 
by this convention. A secondary analysis will be conducted including pregnancy losses 
with reported MCMs occurring at less than 20 weeks’ gestation in the calculation of 
risk. The prevalence rate of combined MCMs in exposed subjects will be compared 
with that of the CDC MACDP (Correa, 2007). The prevalence rates of preterm births 
and LBW will be calculated as proportions, with the number of live births as the 
denominator. These prevalence rates in exposed subjects will be compared with those of 
the CDC NVSS (Martin, 2012). 
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 
IRB for approval prior to registry implementation. 
Milestones: 
Start of data collection: The registry will be implemented after approval by applicable 
regulatory authority and central IRB. Data collection will commence after a start-up 
period of approximately 4 months.
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Version No. 1 / Version Date: November 27, 2012
Name of Sponsor
Novartis Vaccines 
and Diagnostics
Protocol number:
V59_72OB
Health authority 
study registration 
number(s): N/A
Date of Protocol 
Abstract:
16 AUG 13
End of data collection: The registry seeks to enroll 100 participants, and enrollment is 
expected to take approximately 3 years. After all available follow-up data are collected 
on participants, the data will be cleaned. This follow-up and cleaning process may take 
approximately 10 months.
Annual updates will be provided in the Annual CBER PMC updates and in the Periodic 
Safety Update Reports (PSURs) and Development Safety Update Reports (DSUR).
Final report of study results: A final report will be produced approximately 6 months 
after all data have been collected and cleaned. 
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5.0 
AMENDMENTS AND UPDATES
Number
Date
Section of the 
study protocol
Amendment or 
update
Reason
1
4 AUG 14
Title page, 2.0,  
synopsis, 9.5, 10.2, 
11.0, 12.2, 13.0
Amendment
Main reasons:
FDA’s suggestion 
and align safety data 
collection and 
reporting activities 
with Novartis SOP 
and GVP module VI.
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6.0 
MILESTONES
Milestone
Planned date
Start of data collection
The registry will be implemented after 
approval by applicable regulatory authority 
and central IRB. Data collection will 
commence after a start-up period of 
approximately 4 months.
End of data collection
The registry seeks to enroll 100 
participants, and enrollment is expected to 
take approximately 3 years. After all 
available follow-up data are collected on 
participants, the data will be cleaned. This 
follow-up and cleaning process may take 
approximately 10 months.
Annual updates
Annual updates will be provided in the
Annual CBER PMC updates and in the 
PSURs and DSUR.
Final report of study results
A final report will be produced 
approximately 6 months after all data have 
been collected and cleaned. 
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7.0 
RATIONALE AND BACKGROUND
Invasive meningococcal disease is a severe infection caused by the bacteria Neisseria 
meningitidis, and usually results in bacteremia and/or meningitis. The signs of 
meningococcal meningitis in adults include headache, stiff neck, fever, chills, malaise, 
and prostration. Asymptomatic colonization of the upper respiratory tract by encapsulated 
N meningitidis is common, yet only a small percentage of colonized persons develop 
disease.
The 5 major meningococcal serogroups associated with disease are A, B, C, Y, and W-
135. Serogroup prevalence varies with geography, time of year, and age group. Currently, 
serogroup B and C strains are most prevalent in Europe, and serogroup B, C and Y strains 
are most prevalent in North America (ECDC, 2011; Stephens, 2007). N meningitidis
serogroup A strains are responsible for large epidemics of bacteremia and meningitis in 
sub-Saharan Africa (Rosenstein, 2001). Outbreaks due to serogroup W have also recently 
been reported in the same geographic location and among Hajj pilgrims (Taha, 2002).
The case-fatality rate for meningococcal disease generally ranges from 9% to 12% but 
can be as high as 40% among patients with meningococcemia (Rosenstein, 2001). The 
overall incidence of meningococcal disease in the United States (US) during recent 
decades has been approximately 0.9 to 1.5 cases per 100,000 population, but attack rates 
in outbreaks in sub-Saharan Africa, mainly due to meningococcal serogroup A, have been 
more dramatic (approximately 500 to 1000 cases per 100,000) (Rosenstein, 2001). Risk 
factors for disease include overcrowded housing conditions, active and passive smoking, 
complement deficiency, and functional or anatomic asplenia (Goldschneider, 1969).
Novartis Vaccines and Diagnostics (NVD) has developed a quadrivalent conjugate 
vaccine (Menveo®) aimed at preventing disease in infants and older age groups due to N
meningitidis serogroups A, C, W, and Y. The Advisory Committee on Immunization 
Practices (ACIP) recommends routine administration of a MenACWY vaccine for all 
persons aged 11 through 18 years. A single dose of vaccine should be administered at age 
11 or 12 years, and a booster dose should be administered at age 16 years. As of May 
2013, MenACWY is approved for adolescents and adults in more than 60 countries. More 
than 10 million persons worldwide have received doses of MenACWY that were 
distributed commercially.
The immunogenicity assessments of MenACWY were conducted in rabbits (single- and 
repeat-dose toxicity and reproductive and developmental toxicity studies). A pilot 
reproductive and developmental toxicity study (embryofetal development) was conducted 
to assess the maternal toxicity and teratogenic potential of 5 doses of AlPO4 adjuvanted 
and non-adjuvanted MenACWY. A definitive reproductive and developmental toxicity 
study, including postnatal evaluation, was also performed with non-adjuvanted 
MenACWY to evaluate any effect of 5 MenACWY doses on maternal toxicity, female 
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reproduction, embryofetal toxicity, and offspring development. The results of these 
studies are summarized below.
In the Good Laboratory Practice (GLP) range-finding (pilot) reproductive and 
developmental toxicity study, 40 female rabbits received a total of 5 intramuscular (IM)
MenACWY doses, with or without alum. Three 25 μg/0.5 mL doses were injected prior to 
mating and two 25 or 50 μg/0.5 mL doses were injected during gestation. The vaccine 
was not maternally toxic or teratogenic, and no embryofetal alterations related to 
treatment with the test article or to the elicited antibodies were identified. Circulating 
antibodies were detected in maternal animals throughout the study and in fetuses at the 
end of gestation.
In the definitive reproductive and developmental toxicity study, 128 female rabbits 
received a total of 5 IM MenACWY doses; three 25 μg/0.5 mL doses were injected prior 
to mating and two 25 μg/0.5 mL doses during gestation. Two groups of animals 
underwent cesarean section, and embryos were subjected to external and visceral 
examination, while remaining rabbits delivered naturally and were observed for 4 weeks 
for effects on F1 offspring. The phases covered in this definitive study include effects on 
cohabitation through mating, tubal transport, implantation, gestation, early organogenesis 
and embryofetal development, parturition, lactation, maternal behavior, and development 
of offspring. The vaccine was not maternally toxic or teratogenic and had no effects on 
postnatal development at the clinical dose administered 5 times during the course of the 
study. Antibody titers (by enzyme-linked immunosorbent assay [ELISA]) and serum 
bactericidal activity (SBA) were maximal in the maternal animals after 2 and 3 doses.
Antibodies (ELISA and SBA) were also detected in fetuses at the end of gestation and in 
kits 4 weeks after birth.
NVD did not study vaccination in pregnancy as one of the objectives of clinical studies 
before licensure. Pregnant women were excluded from enrollment, and the use of birth 
control, where appropriate, was an entry criterion. Despite this requirement, 43 women in 
studies V59P13, V59P17, and V59P18 were found to be pregnant during the 6-month 
follow-up period. Of these women, 37 were administered MenACWY. All 7 spontaneous 
abortions occurred among women vaccinated with MenACWY.
In addition to reports in clinical trials, NVD received reports of 10 additional instances of 
MenACWY exposure during pregnancy via passive post marketing safety surveillance. 
One pregnancy ended in spontaneous abortion (SAB) 52 days after vaccination with both 
MenACWY and a rabies vaccine. Two pregnancies ended in normal deliveries of healthy 
infants, and the outcomes of the remaining 7 pregnancies are unknown.
The Menveo Pregnancy Registry is established to meet a CBER post marketing 
commitment (PMC) and is designed to collect prospective data on pregnancy outcomes 
among women immunized with the Menveo vaccine within 28 days prior to conception or 
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at any time during pregnancy. The 28-day window prior to conception was established 
based on data from the Menveo product label (Menveo package insert, 2012). 
Effectiveness of the Menveo vaccine in subjects 11 through 55 years of age was evaluated 
in a randomized, controlled clinical study comparing the hSBA responses following 1
dose of Menveo, showing that 68%-75% subjects have seroresponse 28 days after 
vaccination with Menveo.
Menveo is not indicated in pregnancy. However, inadvertent pregnancy exposures are 
anticipated because the targeted age group for the vaccine includes young women of 
reproductive potential. The registry will add to the current clinical experience with 
Menveo by 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. NVD 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.
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8.0 
RESEARCH QUESTION AND OBJECTIVES
The objective of the Menveo Pregnancy Registry is to evaluate pregnancy outcomes 
among women immunized with the Menveo vaccine within 28 days prior to conception or 
at any time during pregnancy. The primary outcomes of interest include major congenital 
malformations (MCM), preterm birth, and low birth weight (LBW). 
Other pregnancy outcomes will be collected, including stillbirths and 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 rate 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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9.0 
RESEARCH METHODS
9.1 
Study Design
The Menveo Pregnancy Registry is a prospective, observational study of pregnant women
immunized with the Menveo vaccine within 28 days prior to conception 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 Food and Drug Administration 
(FDA) guidance for designing and implementing pregnancy exposure registries (FDA, 
2002).
9.2 
Setting
9.2.1 Study Period
The pregnancy registry will be implemented after approval by applicable regulatory 
authority and central institutional review board (IRB). The target enrollment goal of the 
registry is 100 prospectively enrolled pregnant women. The data collection process for 
each participant will begin at enrollment (during 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).
9.2.2 Study Subjects
The study population will include pregnant women within the US who were immunized 
with the Menveo vaccine within 28 days prior to conception or at any time during 
pregnancy. Because the vaccine is not indicated in pregnancy, the majority of exposures 
will likely be inadvertently administered in the first trimester of pregnancy. Enrollment 
and data collection will be coordinated through a registry coordination center (RCC). 
Eligible pregnant women may self-enroll in this pregnancy registry, and HCPs may also 
report de-identified data on pregnancy exposures and outcomes.
9.2.3 Study Population Selection
The minimum criteria required for enrollment into the registry are as follows:
▫
Sufficient evidence to confirm that Menveo exposure occurred within 28 days prior to 
conception or at any time during pregnancy
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▫
Sufficient information to determine whether the pregnancy is prospectively or 
retrospectively registered (ie, whether the outcome of pregnancy was known at the 
time of first contact with the registry)
▫
Date the pregnancy exposure is registered
▫
Full reporter (ie, HCP) contact information to allow for follow-up (name, address, 
etc.)
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 Menveo vaccine. These providers will be identified through NVD 
Menveo distribution data and medical science liaisons (MSLs), as well as HCP provider 
networks and health maintenance organizations (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, and messaging by MSLs 
may also be used, including the following:
▫
Internet:
-
FDA listing of pregnancy registries on www.fda.gov
-
www.clinicaltrials.gov
-
Society for Maternal-Fetal Medicine listing of registries
-
PPD website
-
NVD website
▫
Print:
-
Menveo prescribing information
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Menveo medication guide
-
Medical journal advertising and/or direct to physician advertising
-
Registry contact information in report(s)
▫
Education:
-
MSL outreach to treating HCPs
-
Scientific presentations and publications
-
Distribution of report(s) to HCPs
9.2.3.1
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 rates from external surveillance sources and rates from published 
literature will be the primary comparators. To the extent possible, comparator rates will 
be age-adjusted to reflect the age distribution of the Menveo Pregnancy Registry 
population.
Background Rates on Pregnancy Outcomes
Background rates in the general population on pregnancy outcomes, such as premature 
birth and LBW, are readily available from national vital statistics or publications in the 
scientific literature (Martin, 2012).
Background Rates on Congenital Anomalies
Published rates of MCMs are available from the Centers for Disease Control and 
Prevention (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 rates from the general 
population, this is not an unrealistic comparison (Honein, 1999), and background rates 
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). When an 
analysis includes data from an external comparator, it is important to thoroughly 
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understand the methodology of the external comparator, and to take this into 
consideration when designing the analysis plan (Kennedy, 2004).
Background Rates 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 rates.
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 prior Menveo vaccination is a 
condition of enrollment. Menveo vaccination is not indicated in pregnancy. Therefore, 
Menveo vaccination exposure in pregnancy is expected to be inadvertent and to occur 
within 28 days of conception or in early pregnancy. 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.
9.3.2 Outcome(s) of Interest
MCM: The registry defines and codes MCMs with criteria specified by CDC MACDP 
(CDC, 2007). 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 these defects are not likely to contribute to a risk for a vaccine exposure, the 
registry includes these defects to maintain this consistency with the CDC MACDP. 
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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
LBW: An infant whose birth weight is <2500 g
9.3.3 Other Variables
Maternal characteristics: Age, ethnicity, race
Prenatal data: Last menstrual period (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
Concomitant medical conditions
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
▫
SAB: fetal death or expulsion of products of conception prior to 20 weeks’ gestation. 
Terminology may include missed abortion, incomplete abortion, and inevitable 
abortion.
▫
IAB: voluntary interruption of pregnancy, including pregnancy termination that 
occurs electively, to preserve maternal health, or due to fetal abnormalities
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▫
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. 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.
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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
Provided 
by 
relevant 
HCP
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 & 
timing)
X
X a
X a
Obstetrical history
X
X a
X b
Family history of MCMs 
X
X a
X b
Menveo exposure information
X
X a
X a
Concurrent conditions, concomitant 
medications, alcohol & tobacco use 
during pregnancy
X
X a
X a
Pregnancy status
X
Xa
Outcome information (live birth, still 
birth, SAB, gestational age, birth 
weight, infant/fetus sex)
X
MCM noted & description
X
Contributing factors
X
Xb
a Obtain updated information since the previous contact.
b Collect information not previously obtained, 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. After applicable subject informed consent is obtained 
from eligible women, the reporter will 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 Menveo Exposure (may be provided initially by the pregnant woman at registry 
enrollment and confirmed by the vaccinating HCP)
▫
Menveo administration, including dose, timing, and lot number
Other Conditions and Exposures
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▫
Concurrent maternal conditions
▫
Concomitant medications taken 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
Follow-up at End of Second Trimester
Pregnancy Status
▫
Updates to EDD (ie, 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
▫
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
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Targeted Follow-up Process
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 NVD 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
Menveo administered 28 days prior to conception or at any time during pregnancy (from 
conception until pregnancy outcome) will constitute exposure. The 28-day window prior 
to conception corresponds with the time to immunologic response as indicated in the 
Menveo product label (Menveo package insert, 2012). Menveo exposure will be further 
categorized by earliest trimester of exposure. Menveo is not indicated in pregnancy and is 
typically given to adolescents and young adults. Thus, the vast majority of pregnancy 
exposures will be inadvertent first trimester exposures, most likely prior to recognition of 
the pregnancy. For this registry, gestational weeks will be estimated from the most 
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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 Menveo vaccine. She will then be asked to provide a medical 
release that allows the registry to confirm Menveo vaccination with the appropriate 
source. The registry will contact the Menveo vaccination 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 Menveo vaccination and date of vaccination.
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 Menveo 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 
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), concomitant medical conditions, concomitant medications and vaccines, 
and alcohol, tobacco, and illicit drug use. At pregnancy outcome, the obstetric HCP will 
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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 NVD. 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.
9.5 
Study Size
Currently the market share of Menveo is approximately 20%, with an annual absolute 
dose distribution of 1.8 million in 2012. It can be assumed that market shares will remain 
stable over the course of the 3-year duration of the study. The Advisory Committee on 
Immunization Practices (ACIP) recommends routine administration of a MenACWY 
vaccine for all persons aged 11 through 18 years. A single dose of vaccine should be 
administered at age 11 or 12 years, and a booster dose should be administered at age 16 
years. It is roughly estimated that of all Menveo vaccinations, approximately 76% are 
provided to individuals less than 18 years of age (Novartis Vaccines and Diagnostics, 
2012). Given the low rate of pregnancy in this age group, exposure during pregnancy at 
the recommended ages can be expected to occur infrequently. Likewise, vaccination 
among women of peak reproductive age (25-29 years) can also be expected to be rare 
(Ventura, 2012). In addition, willingness to participate and completion of follow-up in the 
pregnant adolescent population are expected to be very low. It is therefore anticipated 
that, per year, approximately 15 exposed women will be enrolled through the registry 
system and that approximately 60 supplemental identified exposures of Menveo in 
pregnancy can be expected from external sources.
The registry is expected to prospectively enroll approximately 100 women with exposure 
to Menveo 28 days prior to conception or during pregnancy over a 3-year period.
Approximately 58% of these pregnancies can be expected to result in a live birth (
Ventura, 2012). Given the patient population will be mainly adolescents, a high 
percentage of these pregnancies can be expected to be unintended, unwanted, and likely 
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to result in IAB. Therefore, it is anticipated that the registry will yield approximately 58
live births. It is expected that the vast majority (99%) of pregnancy exposures will occur 
within 28 days prior to conception 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 Menveo exposure in pregnancy will limit the statistical 
power of this study. As noted below, there should be sufficient power to identify risks for 
relatively common outcomes such as preterm birth and LBW. However, there is less 
power to identify risks of rarer outcomes such as MCM.
According to the CDC MACDP, the prevalence rate of MCMs for mothers <25 years of 
age in the US is 2.54% (Correa, 2007). With a sample size of 58 first trimester exposed 
pregnancies resulting in a live birth, the study will have 80% power to detect a 4.46-fold 
increase in the prevalence rate of MCMs as compared with the CDC MACDP rate.
According to the CDC National Vital Statistics System (NVSS), the prevalence rate of 
preterm birth for mothers <25 years of age is 12.37% (Martin, 2012). With a sample size 
of approximately 58 exposed live births, the study will provide 80% power to detect a 
statistically significant 1.99-fold increase in the prevalence rate of preterm birth as 
compared with the CDC NVSS rate. 
According to the CDC NVSS, the prevalence rate of LBW for mothers <25 years of age 
is 8.70% (Martin, 2012). With a sample size of 58 exposed live births, the study will 
provide 80% power to detect a statistically significant 2.40-fold increase in the prevalence 
rate of LBW as compared with the CDC NVSS rate. 
The registry acknowledges the challenges of enrolling this number of 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.
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 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. 
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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
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 provider 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 
calculation of risk. 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.
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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 health care providers, health care provider 
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 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 “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. 
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Analysis Population
The primary population for analysis will include prospective evaluable subjects exposed 
to Menveo that are not lost to follow-up (ie, subjects with appropriate outcome 
information that meet the minimum criteria for evaluation). 
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 
cases with MCMs will be reviewed and reported separately for signal detection purposes.
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, n’s, and percentages. Adjustment for confounders of 
potential associations will be made with multivariate regression methods if appropriate 
and will be described in detail in the SAP.
The registry will identify the number of cases for the primary outcomes of MCM, preterm 
birth, LBW, and in addition for second trimester SABs; proportions of these outcomes 
will be calculated with 1-sided 95% confidence intervals 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. 
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9.7.1 Statistical Hypotheses
This registry is primarily descriptive and designed to detect potential safety signals, rather 
than test hypotheses.
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 rates with that of 
comparators. Further details will be provided in the SAP.
9.7.3 Statistical Methods
Overall and stratum-specific point estimates and 1-sided 95% confidence intervals will be 
calculated using the exact binomial distribution for prevalence rates of MCMs, preterm 
birth, and LBW among pregnant women exposed to Menveo and their live births. Most 
structural defects have their origins in the first trimester of pregnancy, the period of 
organogenesis. In addition to overall prevalence of MCM, the analysis of MCMs will be 
stratified by trimester of exposure to Menveo. The prevalence rate 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, among women with first 
trimester exposure. 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 rates by this convention. A secondary analysis will be conducted including 
pregnancy losses with reported MCMs occurring at less than 20 weeks’ gestation in the 
calculation of risk. The prevalence rate 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. 
The prevalence rate of preterm births and LBW will be calculated as proportions, with the 
number of live births as the denominator. These prevalence rates in exposed cases will be 
compared with those of the CDC NVSS (Martin, 2012). Because MCMs are often 
associated with preterm birth and LBW, infants with MCMs will be excluded from 
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analyses of these outcomes and will not be counted in the numerator or denominator 
when prevalence rates are determined.
The outcome data will be stratified by the earliest trimester of exposure to Menveo. 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 LMP and 
reported gestational age, the HCP will be asked to verify the data.
If it is feasible, comparisons between the registry and an appropriate internal and/or 
external comparison group will be examined (see Section 9.2.3.1 for a description of 
potential comparators).
Methods to Control for Confounding and Effect Modification
For analyses of associations between pregnancy outcomes and Menveo exposure, 
confounding and effect modification will be evaluated. 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)
▫
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 potential subgroups of 
interest, potentially including 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 prevalent, it may be difficult to achieve adequate 
numbers of prospectively identified pregnant women if all pregnancies with prior prenatal 
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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 address 
bias introduced by this practice.
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, rates 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 
each group may be conducted in an attempt to address this potential source of bias.
Following the MACDP convention, calculation of MCM risk will exclude fetal losses 
(SABs, IABs, stillbirths, etc.) for which no MCMs have been detected as they may 
introduce a 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.
9.8 
Quality Control
9.8.1 Validation
Ensuring that the data obtained and delivered to NVD 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.
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9.8.2 Record Retention
Investigators must retain all study records required by NVD and by the applicable 
regulations in a secure and safe facility. The investigator must consult a NVD 
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. 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 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 voluntary, the included subjects may not be 
representative of the overall US pregnant women population. 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 rates of pregnancy 
outcomes will be observed due to random variability (NBDPN, 2004). With the outcomes 
of interest occurring at relatively low prevalence rates, cases of a particular condition 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 
rates 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 rates 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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10.0
PROTECTION OF HUMAN SUBJECTS
NVD 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 HIPAA Authorization
As a post marketing safety reporting activity, this registry meets the criteria outlined 
below and is therefore exempt from the US HIPAA Authorization.
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:
a.
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;
b.
To track FDA-regulated products;
c.
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
d.
To conduct post marketing surveillance;”
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To further clarify this issue, an article published by the Pregnancy Labeling Task Force, 
US FDA, states:
-
“the HIPPA 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 et al, 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.
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 Menveo 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 the parent or guardian. Written consent from both parents or 
guardians 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 Code of Federal Regulations (CFR) 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:
a.
An adequate plan is provided to protect the identifiers from improper use and 
disclosure (see Section 10.0).
b. An adequate plan is provided to remove the identifiers at the earliest opportunity.
c.
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-
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marketing surveillance for the initial enrollment and follow-up through outcome of 
pregnancy.
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.
Figure 10.2-1 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 10.2-1: Consent and data collection process
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 NVD 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 
Subject Contact
HCP Data Collection
Eligible pregnant woman contacts 
registry  PI/RCC completes/signs form 
indicating they obtained subject’s 
informed consent (verbal or written) and 
medical releases for HCPs to provide data 
to registry
HCP of eligible pregnant woman 
completes/signs form indicating they 
obtained participant’s informed consent 
(verbal or written) and medical releases 
for HCPs to provide data to registry
RCC interviews subject
HCP interviews subject and sends 
copies of 1) form indicating consent 
was obtained, 2) medical releases, and 
3) subject interview form to PI/RCC 
for follow-up with HCPs
Informed Consent/Assent
(May include waiver of 
Documentation)
of Informed Consent)
Waiver of Informed 
Consent
RCC contacts vaccinating 
HCP to confirm/ provide 
vaccine data
RCC contacts obstetric HCP 
to obtain maternal and 
obstetric data
RCC contacts obstetric HCP 
to obtain pregnancy/ infant
outcome
Enrolling HCP provides de-
identified vaccine data
Enrolling HCP provides de-
identified maternal and 
obstetric data
Enrolling HCP provides de-
identified pregnancy/infant
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an inspection of the site is requested by a regulatory authority, the investigator must 
inform NVD 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 NVD and the SAC for ongoing consultations regarding the review, analysis, 
and conduct of the registry.
The RCC is responsible for assisting the PI in all aspects of patient recruitment, informed 
consent, data collection and management. As is noted in Section 10.0, the RCC staff is 
fully trained and compliant in SOPs on the protection of human subjects and data privacy.
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 NVD and approved by the IRB before it can be implemented.
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11.0 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ ADVERSE 
REACTIONS
The registry will follow industry guidance (FDA, 2002) for regulatory reporting of 
adverse events, 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, PSURs, and 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 marketing authorization 
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 adverse events to specific pregnancy 
outcomes and they will be classified as Serious Adverse Events.  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.
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The following reports are considered as special scenarios, irrespective if a clinical event 
has also occurred.
!
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 not actively sought AEs reported for the vaccine of interest 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 adverse events and vaccine exposure in pregnancy data to the appropriate 
regulatory authorities within the required timeframe, as required by regulations.
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12.0 
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 updates will be provided in the Annual FDA PMC updates and in the Periodic 
Safety Update Reports (PSURs) and Development Safety Update Reports (DSUR). These 
updates will include the following information, presented separately for prospective and 
retrospective reports.
1.
Basic Information:
!
number of pregnant women enrolled to date
!
number of pregnancies with outcome known (stratified by live birth, 
spontaneous abortions, elective terminations, fetal deaths/stillbirths)
!
number of pregnancies with outcome pending
!
number of pregnancies lost to follow-up
2. For pregnancies with known outcome, line listings and summaries of:
!
demographics, obstetrical, and medical history of mothers
!
weeks of gestational age at exposure
!
number of vaccine doses received
!
weeks of gestational age at completion or termination of pregnancy
!
for live births and deaths/stillbirths, whether multiple birth, small for 
gestational age, preterm delivery, and congenital anomalies or other fetal 
abnormalities
!
for spontaneous abortions and elective terminations, abnormalities in products 
of conception if available.
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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 of STrengthening the Reporting of 
OBservational studies in Epidemiology (STROBE). NVD 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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13.0 
REFERENCES
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.
Correa A, Cragan J, Kucik J, et al. Metropolitan Atlanta Congenital Defects Program 40th 
anniversary edition surveillance report: reporting birth defects surveillance data 1968-
2003. Birth Defects Res A. 2007;79:65-93.
Correa-Villasenor A, Cragan J, Kucik J, O’Leary L, Siffel C, Williams L. The 
Metropolitan Atlanta Congenital Defects Program: 35 years of birth defects surveillance 
at the Centers for Disease Control and Prevention. Birth Defects Res A. 2003:67:617-624.
Covington DL, Roberts SS, Albano J, McKain LF. Pregnancy exposure registries: 
challenges in identifying comparison groups. Pharmacoepidemiol Drug Saf. 2009;18
(Suppl1):S11.
European Centre for Disease Prevention and Control. Surveillance of invasive bacterial 
diseases in Europe 2008/2009. Stockholm: ECDC; 2011.
http://www.ecdc.europa.eu/en/publications/Publications/1107_SUR_IBD_2008-09.pdf.
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.
Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. 
I. The role of humoral antibodies. J Exp Med. 1969;129:1307-1326.
Good pharmacoepidemiological practice (GPP), International Society for 
Pharmacoepidemiology. http://www.pharmacoepi.org/resources/guidelines_08027.cfm.
Honein MA, Paulozzi LJ, Cragan JD, Correa A. Evaluation of selected characteristics of 
pregnancy drug registries. Teratology. 1999;60:356-64.
Kennedy DL, Uhl K, Kweder SL. Pregnancy exposure registries. Drug Saf. 
2004;27(4):215-28.
Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2010. Natl Vital Stat 
Rep. 2012;51(1):1-72.
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National Birth Defects Prevention Network (NBDPN). Guidelines for conducting birth 
defects surveillance. Sever, LE, ed. Atlanta, GA: National Birth Defects Prevention 
Network, Inc., June 2004. http://www.nbdpn.org/birth defects surveillance gui.php. 
Novartis Vaccines and Diagnostics, Inc. A Phase IV study to assess the safety of Menveo 
vaccine being used by HMO subjects aged 11-21 years of age. Observational Study 
Interim Report V59_34OB. September 18, 2012.
Rosenstein N, Perkins B, Stephens DS, Popovic T, Hughes J. Meningococcal disease. N 
Engl J Med 2001;344(18):1378-1388.
Savitz DA, Hertz-Picciotto I, Poole C, Olshan AF. Epidemiologic measures of the course 
and outcome of pregnancy. Epidemiol Rev. 2002;24:91-101.
Stephens DS. Conquering the meningococcus. FEMS Microbiol Rev. 2007;31:3-14.
STrengthening the Reporting of OBservational studies in Epidemiology statement.
http://www.strobe-statement.org/
Taha MK, Parent Du Chatelet I, Schlumberger M, Sanou I, Djibo S, de Chabalier F, et al. 
Neisseria meningitidis serogroups W135 and A were equally prevalent among meningitis 
cases occurring at the end of the 2001 epidemics in Burkina Faso and Niger. J Clin 
Microbiol. 2002;40(3):1083-1084.
Ventura SJ, Curtin SC, Abma JC, Henshaw SK. Estimated pregnancy rates and rates of 
pregnancy outcomes for the United States, 1990-2008. Natl Vital Stat Rep. 2012;60(7):1-
21.
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APPENDIX 1: LIST OF STAND-ALONE DOCUMENTS
Not applicable.
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APPENDIX 2: ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.
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