AN OBSERVATIONAL SAFETY STUDY FOR PREVENAR 13 AMONG CHINESE CHILDREN
Conditions: Seizures, Urticaria and Angioedema, Apnea, Fever
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study Information
Title
An observational safety study for Prevenar 
13 among Chinese children 
Protocol Number
B1851193
Protocol Version Identifier
1.2
Date of Last Version of Protocol
30 January 2019
Active Substance
PF-06414256/13-valent pneumococcal 
vaccine
Medicinal Product
Prevenar 13®
Research Question and Objectives
The objective of this study is to expand the 
understanding of the safety profile of 
Prevenar 13 in Chinese pediatric 
populations.  
Author
, PhD, MPH
, Epidemiology 
Worldwide Safety & Regulatory
Pfizer Inc
235 East 42nd Street 
New York, NY 10017 
United States
PPD
PPD

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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
1. LIST OF ABBREVIATIONS................................................................................................4
2. RESPONSIBLE PARTIES....................................................................................................6
3. AMENDMENTS AND UPDATES.......................................................................................7
4. MILESTONES.......................................................................................................................8
5. RATIONALE AND BACKGROUND..................................................................................9
6. RESEARCH QUESTION AND OBJECTIVES .................................................................10
7. RESEARCH METHODS ....................................................................................................11
7.1. Study Design ...........................................................................................................11
7.2. Study Population .....................................................................................................11
7.2.1. Inclusion Criteria ........................................................................................11
7.2.2. Exclusion Criteria.......................................................................................11
7.3. Variables..................................................................................................................12
7.4. Data Sources............................................................................................................13
7.4.1. Yinzhou EHR Database..............................................................................14
7.4.2. Evaluation of Yinzhou EHR Database .......................................................15
7.5. Validation Study......................................................................................................15
7.5.1. Validation of ICD Codes ............................................................................15
7.5.2. A Prospective Cohort Study in a Sub-Population.......................................16
7.6. Study Size................................................................................................................17
7.7. Data Management ...................................................................................................17
7.8. Data Analysis ..........................................................................................................18
7.9. Quality Control........................................................................................................19
7.10. Adjudication Committee .......................................................................................19
7.11. Strengths and Limitations of the Research Methods.............................................20
8. PROTECTION OF HUMAN SUBJECTS ..........................................................................21
8.1. Patient Information and Consent.............................................................................21
8.2. Patient Withdrawal..................................................................................................21
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............22

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8.4. Ethical Conduct of the Study ..................................................................................22
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................22
9.1. Main Study Using Yinzhou EHR Database ............................................................22
9.2. Validation Study to Validate ICD Codes through Medical Chart Abstraction.......22
9.3. Validation Study to Interview Parents/Legal Guardians by HCPs at CDC 
Immunization Clinics Using Questionnaires.............................................................23
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........24
11. REFERENCES ..................................................................................................................25
LIST OF TABLES
Table 1.
Variables and Roles..................................................................................13
LIST OF FIGURES
Figure 1.
Flow Chart for Study Populations ............................................................12
Figure 2.
Components of Yinzhou EHR Database ..................................................14
Figure 3.
Procedures for the Validation Study.........................................................17

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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
13vPnC
13-valent pneumococcal conjugate vaccines
7vPnC
7-valent pneumococcal conjugate vaccine
AE
Adverse Event
AEFIS
Adverse event following immunization information 
system 
AEM
Adverse event monitoring 
CDC
Centers for disease control and prevention
EHR
Electronic health record 
EMR
Electronic medical record 
HCP
Healthcare Professional
HGRAC
Human Genetic Resources Administration of China 
Hib
Haemophilus influenzae type b 
ICD-10
International classification of diseases, tenth revision 
IEC
Independent ethics committee 
IPD
Invasive pneumococcal disease
IPV
Inactivated polio 
IRB
Institutional review board 
NID
National identification 
NIS
Non-interventional study
NMPA
National Medical Products Administration
PAC
Post authorization commitment
PPV
Positive predictive value 

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Abbreviation
Definition
RV 
Rotavirus 
SAP
Statistical analysis plan 
SOI
Safety outcome of interest
SOP
Standard operating procedure

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2. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Title
Affiliation
Address
, MD, PhD
 
 
 
China
, PhD, 
MPH
 
Epidemiology 
Worldwide Safety & 
Regulatory
Pfizer Inc
235 East 42nd Street 
New York, NY 10017 
United States
Investigators
Name, degree(s)
Title
Affiliation
Address
, PhD, MS
 
 
 
 
, China
, BS
 
 
 
 
, China
, BS
 
 
 
, China
, PhD, 
MS
, 
Epidemiology 
Worldwide Safety & 
Regulatory
Pfizer Inc
235 East 42nd Street 
New York, NY 10017
United States
, MS
Medical advisor 
Vaccine Medical Affair
Pfizer Inc
 
 
 
 China
, BS
 
 
 
, China
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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3. AMENDMENTS AND UPDATES
Amendment 
number
Date
Substantial or 
administrative 
amendment
Protocol 
section(s) 
changed
Summary of 
amendment(s)
Reason
1
12 December
2018
Substantial 

Section 1, 5, 
6, 8, and 9.

Section 2.

Section 7.

Editorial changes by 
abbreviating some 
terms such as safety 
outcomes of
interest, changing 
CFDA to NMPA.

Changed names of 
three investigators.

Re-estimated the 
study size based on 
the new data.

To update the 
protocol and make it 
concise.

To reflect on the 
change in study 
personnel.

The original study 
size was estimated 
based on the annual 
birth rate and the 
coverage for 
Prevenar 7.  The 
new exposure data 
showed the 
coverage for 
Prevenar 13 is much 
higher than 
Prevenar 7.  In order 
to renew the 
HGRAC 
application, it is 
necessary to 
re-estimate the 
study size.   
2
30 January 
2019
Administrative 

Section 7

Re-estimated the 
study size based on 
the more current 
data.

In order to renew 
the HGRAC 
application, it is 
necessary to re 
estimate the study 
size.   

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4. MILESTONES
Milestone
Planned date
Start of data collection (first data cut)*
15 December 2018
End of data collection (last data cut)*
30 September 2020
Study progress report 1
15 April 2018
Study progress report 2
15 April 2019
Study progress report 3
15 April 2020
Final study report
15 April 2021
*For the main study.

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5. RATIONALE AND BACKGROUND
Pneumococcal disease is a leading cause of serious illness throughout the world.1  It is an 
infection caused by Streptococcus pneumoniae bacteria (“pneumococcus”).  These bacteria 
can result in both invasive diseases such as bacteremic pneumonia, septicemia, and 
meningitis, and non-invasive diseases, such as pneumonia, otitis media, and sinus infections.  
One of the key risk factors of pneumococcal diseases is age, with children younger than 
2 years of age and the elderly being at the highest risk of developing pneumococcal-related 
infection.1  Pneumococcal disease is estimated to be the leading cause of vaccine-preventable 
morbidity and mortality among children younger than 5 years both globally and in China.1  
At least 1 million children die of pneumococcal disease every year, most of these being 
young children in developing countries.2 In China alone, approximately 30 thousand 
children in this age group die due to pneumococcal disease every year.3  
Currently, several approved vaccines to prevent S. pneumoniae infections are available on the 
market, including the 10-, and 13-valent pneumococcal conjugate vaccines (10vPnC; 
Synflorix, GlaxoSmithKline and 13vPnC; Prevnar 13, Pfizer, respectively), and the 23-valent 
pneumococcal polysaccharide vaccine (PPSV23; Pneumovax, SanofiPasteurMSD [in the US, 
Merck]). 13vPnC was approved in the European Union in December 2009 for the prevention 
of Invasive Pneumococcal Disease (IPD), pneumonia and acute otitis media caused by 
S. pneumoniae in infants, children and adolescents from 6 weeks to 17 years of age, and in 
the United States in February 2010 for the prevention of IPD and otitis media caused by 
S. pneumoniae in children 6 weeks through 5 years of age. 
13vPnC is in use in the national childhood immunization programs in many countries and 
contains polysaccharides from the 7 serotypes included in the original 7vPnC (4, 6B, 9V, 14, 
18C, 19F, and 23F) and an additional 6 serotypes (1, 3, 5, 6A, 7F, and 19A), all conjugated to 
cross-reactive material 197. It has been shown that the 6 additional serotypes in 13vPnC
increase coverage for IPD prevention in children <5 years of age from 74% to 88% globally.4
Importantly, the additional serotypes in 13vPnC are associated with a high percentage of 
pneumococcal disease in the developing world.5,6
In October 2016, 13vPnC was approved in China for the prevention of invasive disease
(including bacteremic pneumonia, meningitis, septicemia, and bacteremia) caused by 
Streptococcus pneumoniae for infants and children aged 6 weeks to 15 months.  13vPnC is 
recommended as a series of four doses, one dose at each of these ages: 2 months; 4 months; 
6 months; 12 through 15 months. Vaccines in China are classified into two categories. 
Type I vaccines are mandatory and provided for citizens by the government free of charge, 
and infants and children should get immunized according to the government’s regulations. 
These vaccines include tuberculosis (Bacillus Calmette–Guérin), diphtheria/tetanus/ 
pertussis, oral polio, measles/mumps/rubella, hepatitis B, hepatitis A, meningococcal, and 
Japanese encephalitis.  Type II vaccines are ones available on the private market for use on a 
voluntary base at the purchaser’s expense.  They consist of Haemophilus influenzae type b 
(Hib), pneumococcal conjugate, rotavirus (RV), inactivated polio (IPV), varicella, human 
papillomavirus, and influenza vaccines.  In China, all type I and type II vaccines are 

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administrated at China Centers for Disease Control and Prevention (CDC) immunization 
clinics.
13vPnC has a favorable benefit-risk profile.  Based on data from clinical trials and the 
worldwide safety experiences after authorization, convulsions/seizures, fever, apnea, and 
anaphylaxis/hypersensitivity are identified as known or potential risks associated with 
13vPnC among young children.7,8
To monitor these known and potential risks for 13vPnC among Chinese children receiving 
13vPnC in China, an observational study using a population-based electronic health record 
(EHR) database from 1 May 2017 to 31 July 2020 in Yinzhou district of Ningbo city in 
China is conducted in a real world setting. Yinzhou is one of the largest districts in 
economically developed Ningbo city.  Children exposed to 13vPnC in Yinzhou district are 
representative of those children likely receiving 13vPnC in China given that only families 
with sufficient financial resources can afford 13vPnC. In addition, the coverage for 7-valent 
pneumococcal conjugate vaccine (7vPnC) in Yinzhou district was similar to that in the 
published literature in China.9  As a population-based database, Yinzhou EHR database 
consists of complete immunization records and healthcare data of all children in the district.  
This allows for the possibility of monitoring the safety of 13vPnC in the context of routine 
medical care from outpatient visits to inpatient care and provides greater generalizable 
findings.
This observational safety study is a post authorization commitment (PAC) to fulfill the key 
monitoring activity requirement of the China National Medical Products Administration 
(NMPA).
6. RESEARCH QUESTION AND OBJECTIVES
This observational study using a population-based EHR database in Yinzhou district of 
Ningbo city is to expand the understanding of the safety profile of 13vPnC in Chinese 
pediatric populations. 
Objectives of the study are to:

Estimate incidence rates (per 1,000 person-days at risk and per 1,000 doses) of safety 
outcomes of interest (SOIs) including seizures (including febrile seizures), urticaria
and angioedema, apnea, and fever for the periods of 0 through 3 days (with 
0 indicating the day of vaccination), 4 through 7 days, and 0 through 7 days after the 
13vPnC vaccination by all doses and by each dose in the main study based on 
Yinzhou EHR database between 1 May 2017 and 31 July 2020.

Estimate the incidence rates (per 1,000 person-days at risk and per 1,000 doses) of 
SOIs mentioned above for the same periods after the 13vPnC vaccination by all doses
and by each dose in a sub-population of the main study through a prospective cohort 
study between 1 August 2018 and 31 July 2020.

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All SOIs are acute events and are likely to occur within 7 days post-vaccination based on the 
known safety profile of 13vPnC as well as biologic plausibility of these events occurring 
after vaccination.7,8
7. RESEARCH METHODS 
7.1. Study Design
This is an observational study based on a population-based EHR database.  In addition, a
validation study including validation of International classification of diseases, tenth revision 
(ICD-10) codes or ICD-10 code based algorithm for identifying all SOIs and a prospective 
cohort study in a sub-population of the main study will be conducted in order to offset the 
potential biased results from the main study because of potential misclassification of the 
SOIs due to miscoding and/or undercoding of ICD-10 codes used to identify the SOIs in the 
EHR database. 
7.2. Study Population
The main study population consists of eligible children aged 1-24 months receiving at least 
one dose of 13vPnC recorded in Yinzhou EHR database between 1 May 2017 and
24 July 2020 (ie, one week prior to the end of the study) (Figure 1).
7.2.1. Inclusion Criteria
To be eligible for the main study, children in Yinzhou population-based EHR database must 
be aged 1 to 24 months and receive at least one dose of 13vPnC between 1 May 2017 and 
24 July 2020 where the first dose is received before or on 24July 2020 since a 7-day 
post-vaccination follow-up for each dose in each child receiving 13vPnC is needed. For the 
prospective cohort in a sub-population of the main study, eligible children for the main study 
must receive the first dose of 13vPnC between 1 August 2018 and 24 July 2020 and an 
informed consent must be obtained from parents/legal guardians (Figure 1).
7.2.2. Exclusion Criteria
There are no exclusion criteria for this study.

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Figure 1.
Flow Chart for Study Populations
7.3. Variables
The exposure of interest is 13vPnC vaccine administered in CDC immunization clinics in 
Yinzhou district.  SOIs are seizures, urticaria and angioedema, apnea and fever.  Dates and 
doses of 13vPnC vaccination are recorded in Yinzhou CDC Immunization Administration 
Registry which is integrated into Yinzhou EHR database at an individual level. SOIs are 
documented in Yinzhou EHR database according to ICD coding in the database except ones 
in the CDC Adverse Event Following Immunization Information System (AEFIS).  The
events in AEFIS are recorded in text format based on a diagnosis. Variables and their 
descriptions are shown on Table 1. ICD codes or algorithm of ICD codes and diagnoses used 
to identify the SOIs in the study will be developed and documented in the statistical analysis 
plan (SAP).

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Table 1.
Variables and Roles
Variable
Role
Age at each dose of 13vPnC vaccination
Demographic
Gender
Demographic
Residency Status 
Demographic
Smoking in the family (only the prospective cohort in a sub-population)
Covariate 
Known allergies (only the prospective cohort in a sub-population)
Medical history
Preterm
Medical history
Low birth weight
Medical history
Sickle cell disease
Medical history
History of febrile seizure
Medical history
History of other seizures 
Medical history
History of urticaria
Medical history
History of angioedema 
Medical history
History of apnea
Medical history
Fever at the date prior to 13vPnC vaccination
Medical history
Other vaccines administrated the same date with 13vPnC
Co-administration 
Season of diagnosis for each safety outcome of interest
Covariate
Hospitalization for each safety outcome of interest 
Covariate 
Date of each dose of 13vPnC vaccination (based on barcode scanning)
Exposure 
Seizures (including febrile seizures)
Outcome
Urticaria and angioedema
Outcome
Apnea
Outcome
Fever
Outcome
Highest temperature for each day fever is reported (only the prospective 
cohort in a sub-population)
Outcome
Use of antipyretics post-vaccination (only the prospective cohort in a 
sub-population)
Covariate 
7.4. Data Sources
EHRs provide real-world clinical data with broad patient populations and have been 
increasingly used for post-approval drug safety studies over the past two decades in Europe 
and North America. In China, there are three major types of electronic healthcare databases 
including population-based EHR, electronic medical records (EMRs), and national claims.  
Since 2014, via collaboration with academic institutions in China, Pfizer has been evaluating 
these data sources and has determined that they provide potential value to post-marketing 
drug safety studies, particularly population-based EHRs.10 Yinzhou EHR database is 
selected for this study because this population-based EHR database consists of complete 
immunization records and healthcare data of all children in the district.

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7.4.1. Yinzhou EHR Database 
Yinzhou is one of the largest districts of economically developed Ningbo city in Zhejiang 
province, China and consists of approximately 1.6 million populations (740,000 permanent 
residents and 860,000 temporary residents).  The Yinzhou EHRs include data from three 
main sources (Figure 2): 

Yinzhou CDC databases;

Healthcare data including EMRs, claims and e-prescriptions from hospitals and 
community health centers within the district;

Healthcare data including EMRs, claims and e-prescriptions from the Women and 
Children’s hospital of Ningbo city.
Figure 2.
Components of Yinzhou EHR Database
Data from these data sources are entered into Yinzhou EHR database in real time. These 
data sources are linked via each individual’s unique personal identification number (termed 
the national identification (NID) number) used by each resident throughout life in China. In 
a situation where children do not yet have a NID number, data of those children are matched 
by names of children, dates of birth, names of parents/legal guardians, or home addresses.
Yinzhou CDC database: There are two CDC databases (ie, Immunization Administration 
Registry and CDC AEFIS) in the district. The Immunization Administration Registry 
includes immunization data at CDC immunization clinics for both type I and type II vaccines 
for all children aged <7 years.  The AEFIS is a passive surveillance system and collects 
AEFIs reports. All cases reported to AEFIS are to be investigated, with the exception of 
common adverse reactions that have a clear diagnosis (eg, fever, redness, and swelling on the 
injection site; induration). 

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Healthcare data from hospitals and community health centers within the district: 
Yinzhou district collect healthcare data of its residents from hospitals (3 tertiary general 
hospitals and 1 specialized hospital) and community health centers (20) within the district
including inpatient and outpatient visits from all hospitals and outpatient visits from all 
community health centers within the district.
Healthcare data from the Women and Children’s Hospital of Ningbo city: The Women 
and Children’s Hospital of Ningbo city is the only children hospital in the city. It is essential 
to have data from this hospital being part of Yinzhou EHR database because this hospital is
very likely to be the hospital of choice if families would seek medical care for their children 
outside hospitals of Yinzhou district.
7.4.2. Evaluation of Yinzhou EHR Database 
Yang et al conducted a detailed assessment of characteristics of Yinzhou EHR database in 
2016 and concluded that Yinzhou database has the necessary attributes for post-marketing 
drug safety surveillance and pharmacoepidemiologic studies,10 however, the data quality and 
its suitability for a post-approval vaccine safety study among pediatric populations was not 
assessed previously. It was therefore essential to conduct a pilot study before moving 
forward with a full-scale study using Yinzhou EHR database.  Therefore, Pfizer, 
collaborating with Fudan University and Yinzhou CDC, performed a pilot study to further 
evaluate the Yinzhou EHR database from September to December 2017.  Preliminary results 
of the pilot study indicated that the Yinzhou EHR database can be used to fulfill the 
requirement of this PAC, despite some limitations identified at the pilot study such as
sub-classifications of some ICD codes used in the database are either omitted and/or
combined with a few related or unelated diagnoses and a large number of children from 
transient families (temporary residents) move in or out of the district within a short period of 
time. To address these limitations, a validation study will be conducted.
7.5. Validation Study 
To minimize potential biased estimates in the main study, a validation study will be
conducted.  This validation study consists of two parts: validation of ICD codes used to 
identify all SOIs in the main study and a prospective cohort study in a sub-population of the 
main study. 
7.5.1. Validation of ICD Codes
To evaluate the accuracy of the ICD-10 codes or ICD-10 codes based algorithm for 
identifying all SOIs in the main study, relevant medical records of children having the ICD
codes for these events are going to be obtained from hospitals within Yinzhou district and 
Women and Children’s hospital of Ningbo city and outpatient medical records from 
community health centers within the district by Yinzhou CDC. A data abstraction form will 
be used to abstract data from the medical records.  The abstracted data will be sent to an
adjudication committee to determine whether the identified case is a true case. Then the 
adjudicated outcomes will be entered to the validation study database for analyses.  The 
Positive Predicted Value (PPV) of the ICD code or ICD code algorithms will be calculated
for the SOIs, using an adjudicated safety outcome based on the medical record as the gold 

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standard.  Although this study will attempt to obtain all relevant medical records of all 
children having the ICD codes from these hospitals and community health centers, it is 
possible that some medical records of these children may not be available for various 
reasons.  Procedures for this component are shown on Figure 3.
7.5.2. A Prospective Cohort Study in a Sub-Population
A prospective cohort study in a sub-population of the main study was initiated on 1 August
2018 after obtaining the approval of Human Genetic Resources Administration of China
(HGRAC) application.  The prospective cohort study will end on 31 July 2020.  Potential 
participants are enrolled at the time of a visit to CDC immunization clinics after the informed 
consent is obtained.  An initial questionnaire for the first dose is administered to parents/legal 
guardians of children in the office by healthcare professionals (HCPs) at the immunization 
clinics when a child receives the 13vPnC vaccination. A follow-up questionnaire at 7 days 
post-vaccination is administered by the HCPs either via a telephone or face-to-face interview
to parents/legal guardians of the children. The initial questionnaires and follow-up 
questionnaire are completed for each dose of the 13vPnC vaccination. It should be noted that 
responsibilities of HCPs at the CDC immunization clinics are to administer vaccines to 
children and they are not children’s treating HCPs.
Both a web-based questionnaire and a paper-based questionnaire are made available to the 
HCPs for their preference. The HCPs at CDC immunization clinics have access to the 
web-based questionnaire via their work computers. Based on the feedback from Yinzhou 
CDC, the HCPs would be likely to use the web-based questionnaire for a face-to-face 
interview and a paper-based questionnaire for a phone interview.  However, if a paper 
questionnaire is used at an interview, the HCP will be instructed to transfer the data from the 
completed paper questionnaire by completing a web-based questionnaire. A copy of the 
completed paper questionnaire will be uploaded to the validation study database. It is 
expected that completion of the initial questionnaire and the follow-up questionnaire will 
take approximately 20 minutes and 15 minutes respectively.
The questionnaires are pretested on a sample of HCPs and parents/legal guardians and 
revised to ensure clarity. Data elements on the questionnaire are similar to that in the main
study based on Yinzhou EHR database including: demographic information; household 
characteristics; medical history; and occurrences of the SOIs. Questions on the 
questionnaires consist of both yes/no and multiple-choice answers.  For questions related to 
SOIs, information on the date of onset, visits to a healthcare facility, the doctor’s diagnosis, 
etc. is collected.  The questionnaires do not solicit adverse events (AEs) other than the SOIs.  
There are no open-ended questions. Any product safety information that is otherwise 
volunteered will be handled in the manner described in the Section 9.3. 
In addition, a child’s medical records will be abstracted by Yinzhou CDC and reviewed by 
the adjudication committee if the parent/guardian indicates that the child visits a healthcare 
facility for one of the SOIs. The adjudicated outcomes will be subsequently entered and 
stored in the validation study database that is housed by Wanda Inc, the database builder and 
manager of Yinzhou EHR database. Although this study will attempt to obtain all relevant 
medical records of all children indicated a visit to a healthcare facility for the SOIs, it is 

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possible that some medical records of these children may not be available for various 
reasons. Procedures for this prospective cohort study are shown on Figure 3.
Figure 3.
Procedures for the Validation Study
7.6. Study Size 
This study includes all children 1 to 24 months of age who have received at least one dose of 
13vPnC in the Yinzhou EHR database.  Although the number of children in the Yinzhou 
EHR database varies from year to year, the birth rate in Yinzhou district has been steady with 
approximately 8,000 live-births each year. The coverage for the 7vPnC dose 1 vaccine in 
China was approximately 10% for children under 24 months.9  Assuming the same coverage 
for the 13vPnC dose 1 in Yinzhou district, the study size was originally estimated to be 
3,200 children exposed to at least one dose of 13vPnC during the approximately three-year 
study period. However, as of 30 January 2019, approximately 10,000 children 1 to 
24 months of age in the Yinzhou EHR database have already received at least one dose of 
13vPnC since the start of the main study (ie, 1 May 2017).  Based on the newly available
data, the study size is now re-estimated to be approximately 22,000 for the approximately 
three-year study period. 
7.7. Data Management 
All data for the main study are collected through the routine data collection practices of the 
Yinzhou EHR database.  The data in the Yinzhou EHR database are updated continually.  
The principal investigator or his delegates at Fudan University will have access to 
de-identified study specific data generated by the data builder and manager of the Yinzhou 
EHR database (Wanda Inc) via a secure server. Data for the main study will be stored in the 
form of SAS® datasets at the secure server. 

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Data obtained from the validation study will also be housed and managed by Wanda Inc.
Fudan University and Pfizer have full access to the de-identified study database.  Although 
identifiable data such as children’s NID numbers, their dates of birth, their names, etc. will 
be collected in one part of the validation study (ie, the prospective cohort study in a 
sub-population of the main study), these identifiable data will only be used by Wanda Inc to 
link children who participate in both the main study and the validation study for the purpose 
of analyses. The identifiable data will not be shared with Fudan University, Pfizer, or other 
third parties. 
The first annual progress report to NMPA presented the study status since the HGRAC 
application for the study was pending.  To prepare the subsequent annual progress reports to 
NMPA, the main study database is to be queried to identify the number of eligible children 
who have received a 13vPnC vaccination. For these children, routinely collected data are 
abstracted for the study variables: demographics; medical history; coadministration of other 
type I and type II vaccines if any, and the SOIs. Counts of the study variables in the main 
study will be included in the 2019 progress report and descriptive analyses will be conducted 
for the 2020 progress report.
Eligible children are followed in the Yinzhou EHR from the date of the first dose of the 
13vPnC vaccination until 7 days after the last dose of the 13vPnC vaccination, moving out of 
the district, death, loss to follow-up, or the end of the study (whichever occurs first) for the 
occurrence of the SOIs.
All data will be maintained by a trained group of data managers from Wanda Inc ensuring 
compliance with national regulations in China.  SAS® will be used for the statistical analyses. 
7.8. Data Analysis 
All analyses for the study will be descriptive.  The descriptive analyses will include 
frequency distributions of age at the time receiving each dose of 13vPnC, gender, residential 
status, year of 13vPnC vaccinations, co-administration of other vaccines at the same date, 
and medical history.  In addition, frequency distributions of the number of SOIs by age, 
gender, residential status, season of diagnosis, hospitalization, and year of 13vPnC 
vaccinations will also be described.  The frequency distributions mentioned above will be 
tabulated for both the main study and the prospective cohort study in the sub-population of 
the main study. 
Incidence rates per 1,000 person-days at risk and per 1,000 doses and its 95% CIs of the SOIs
will be calculated in three different time periods (ie, 0-3 days, 4-7 days, and 0-7 days 
post-vaccination) by all doses and by each dose. Additional analyses (eg, stratification by 
gender, residency, and co-administration of other vaccines) will be performed. The incident 
rates will be estimated for both the main study and the prospective cohort study in the 
sub-population of the main study. 

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The percentage of children’s medical charts that are available for the validation study will be 
described. The PPV of an ICD-10 code or ICD-10 code based algorithm used to identify the 
SOIs against adjudicated SOIs based on the information from medical records of children as 
a gold standard will be calculated for the validation of these codes in the main study. 
Additionally, the PPV of a reported SOI by parents/legal guardians that requires medical 
attentions against the adjudicated SOI based on the information from medical records of 
children as a gold standard will be also calculated in the prospective cohort study in the 
sub-population of the main study. Finally, among children who participate in both the main 
study and the prospective cohort study, sensitivity and specificity of an ICD code or 
ICD-10 code based algorithm identifying seizures or apnea in the main study will be 
calculated using the adjudicated seizures or apnea in the prospective cohort as a reference 
standard (ie, a gold standard). A positive percent of agreement and a negative percent of 
agreement will be estimated between an ICD code or ICD-10 code based algorithm 
identifying fever or urticaria and angioedema in the main study and the reported fever or 
urticaria and angioedema by parents/legal guardians in the prospective cohort as a 
non-reference standard (ie, a non-gold standard). 
Additional exploratory analyses and sensitivity analyses may be conducted. Detailed
methodology for summary and statistical analyses of data collected in this study will be 
documented in a SAP, which will be dated, filed and maintained by the sponsor. The SAP 
may modify the plans outlined in the protocol; any major modifications of endpoint 
definitions or their analyses would be reflected in a protocol amendment.
7.9. Quality Control
Fudan University and the database builder for the Yinzhou EHR database are responsible for 
following Pfizer’s standard operating procedures (SOPs) as well as any of their own SOPs 
whenever appropriate to ensure data quality and integrity, including archiving of statistical 
programs, appropriate documentation of data cleaning and validity for created variables, 
description of available data, and extent of validation of endpoints.
7.10. Adjudication Committee 
An adjudication committee consisting of three physicians will be set-up for the duration of 
the study. The primary role of the adjudication committee will be to:

Review and endorse the adjudication charter.

Agree case criteria for the SOIs.

Adjudicate cases of the SOIs against the case criteria.
The detailed role and responsibility of the adjudication committee as well as the adjudication 
process will be documented in the adjudication committee charter. 

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7.11. Strengths and Limitations of the Research Methods 
As one of the first of its kind to utilize a population-based EHR database in China for the 
purpose of post-approval safety studies, one of the key strengths of this study is completeness 
of vaccination record which is linked to healthcare data at hospitals and community health 
centers.  It allows for the possibility of monitoring the safety of 13vPnC in the context of 
routine medical care from outpatient visits to inpatient care. In addition, observational data 
using real-world data (like the data in the Yinzhou EHR database) may provide insight 
regarding safety outcomes in children who are underrepresented in clinical trials. 
Furthermore, results based on this population-based study would be more generalizable than 
those obtained from clinical trials.
Nevertheless, there are several limitations to this study. First, one main potential source of 
confounding is co-administration of multiple vaccines. Although co-administration of type I 
and type II vaccines is not recommended by China CDC, it exists in practice.  Additionally, it 
is possible that other type II vaccines may be administrated simultaneously with 13vPnC.  
For example, Hib, Pentaxim, RV1, and IPV vaccines can be given at the same time as 
13vPnC in Children aged 2 months and 4 months based on China CDC recommended 
vaccine schedule. It may not be possible to differentiate safety outcomes of these vaccines 
although there is a plan to conduct analyses to estimate the incidence rates of the safety 
outcomes for those receiving 13vPnC only and for those receiving 13vPnC plus 
co-administration of other vaccines (Section 7.8). Second, it is possible that some children 
may receive medical care from hospitals outside of the catchment area.  This information will 
not be captured by Yinzhou EHR except the care under Women and Children’s hospital of 
Ningbo city. However, it is reasonable to assume that the vast majority of families are likely 
to go to the Women and Children’s hospital of Ningbo city for the care since the next nearest 
Children’s hospital is about two hour away while the Women and Children’s hospital of 
Ningbo is less than a half hour away.  Third, similar to any studies using secondary data 
sources, misclassification of SOIs may exist, since Yinzhou EHR is not designed for the 
research purpose. SOIs not requiring medical attentions tend to be systematically 
undercoded (eg, low fever and mild urticaria and angioedema) in these data sources.
Although the prospective cohort study in a sub-population of the main study will be able to 
ascertain some of these events not requiring medical attention, it is possible that a small 
percentage of the events may be still under-reported. Fourth, like the rest of China, it is 
expected that a small percentage (approximately 10%) of children from families with 
sufficient financial resources may receive 13vPnC in Yinzhou district, It is possible that 
children receiving 13vPnC may be from tails of the target children population on either ends
that may not be the same as the rest of the target population in terms of health status. As a 
result, the incidence of safety outcomes of interest in the study may be either substantially 
lower or higher than that in countries that 13vPnC is included in the national childhood 
immunization programs or covered by private insurance.  Furthermore, SOIs requiring 
treatment may be miscoded.  But, the validation study will allow evaluation of the magnitude 
of misclassification as well as provide more accurate estimation of the incidence rates of 
SOIs. Last, some children in Yinzhou EHR don’t have a NID number during the study 
period. Healthcare data of these children will be mapped based on a combination of dates of 
birth, names of children, names of parents/legal guardians, or home addresses in the EHR 

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database. There is a chance of mismatching among the children although the likelihood is 
low.
8. PROTECTION OF HUMAN SUBJECTS
8.1. Patient Information and Consent
The informed consent is not applicable for the main study based on Yinzhou EHR database.
All parties will ensure protection of child personal data and will not include a child’s names
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.  The principal investigator or his delegates at Fudan University will not 
have access to the personal identification numbers since all data for the study are 
de-identified prior to being uploaded to the server that is created by the database builder. 
The informed consent is required for one part under the validation study (ie, a prospective 
cohort).  The informed consent form must be in compliance with local regulatory 
requirements and legal requirements.
The informed consent form used in the prospective cohort study in sub-population of the 
main study, and any changes made during the course of the study, must be prospectively 
approved by both the IRB/IEC and Pfizer before use.
HCPs at local immunization clinics in Yinzhou district who recruit parents/legal guardians
for the prospective cohort study in a sub-population must ensure that each study child, or 
his/her legally acceptable representative, is fully informed about the nature and objectives of 
the study and possible risks associated with participation.  HCPs will obtain written informed 
consent from the child’s legally acceptable representative before any study-specific activity 
is performed for the prospective cohort study in a sub-population.  Fudan University will 
retain the original of each child’s signed consent form.
8.2. Patient Withdrawal
Patient withdrawal is not applicable to the main study based on Yinzhou EHR database. 
For one component of the validation study (ie, a prospective cohort study), parents/legal 
guardians may withdraw children from the prospective cohort study in a sub-population at 
any time at their own request, or they may be withdrawn at any time at the discretion of the 
HCPs at CDC immunization clinics or sponsor for safety, behavioral, or administrative 
reasons. In any circumstance, every effort should be made to document subject outcome, if 
possible. The HCP should inquire about the reason for withdrawal and follow-up with the 
subject regarding any unresolved AEs. 
If the parent withdraws from the validation study, and also withdraws consent for disclosure 
of future information, no further evaluations should be performed, and no additional data 
should be collected. The sponsor may retain and continue to use any data collected before 
such withdrawal of consent.

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8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of Fudan University and Yinzhou CDC to have prospective approval 
of the study protocol, protocol amendments, and other relevant documents, if applicable, 
from the IRB/IEC.  All correspondence with the IRB/IEC should be retained in the 
Investigator File.  Copies of IRB/IEC approvals should be forwarded to Pfizer.
8.4. Ethical Conduct of the Study
The study will be conducted in accordance with the NMPA Draft Guidance on the Key 
Monitoring Activities of Drug Products by Manufacturing Enterprises, as well as with 
scientific purpose, value and rigor and follow generally accepted research practices described 
in Guidelines for Good Pharmacoepidemiology Practices issued by the International Society
for Pharmacoepidemiology, Good Epidemiological Practice guidelines issued by the 
International Epidemiological Association (IEA), International Ethical Guidelines for 
Epidemiological Research issued by the Council for International Organizations of Medical 
Sciences. 
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
9.1. Main Study Using Yinzhou EHR Database
This study includes data that already exist as structured data in an electronic database.  In 
these data sources, it is not possible to link (ie, identify a potential association between) a 
particular product and medical event for any individual.  Thus, the minimum criteria for 
reporting an AE (ie, identifiable patient, identifiable reporter, a suspect product, and event) 
are not available and AEs are not reportable as individual AE reports.
9.2. Validation Study to Validate ICD Codes through Medical Chart Abstraction
In addition, this study protocol requires human review of patient-level unstructured data; 
unstructured data refer to verbatim medical data, including text-based descriptions and visual 
depictions of medical information, such as medical records, images of physician notes, 
neurological scans, X-rays, or narrative fields in a database.  The reviewer is obligated to 
report AEs with explicit attribution to any Pfizer drug that appear in the reviewed 
information (defined per the patient population and study period specified in the protocol).  
Explicit attribution is not inferred by a temporal relationship between drug administration 
and an AE, but must be based on a definite statement of causality by a healthcare provider 
linking drug administration to the AE.
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows:

All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the data abstraction form and 
reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report 
Form.

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
Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form.
For these safety events with an explicit attribution to or associated with use of, respectively, a 
Pfizer product, the data captured in the medical record will constitute all clinical information 
known regarding these AEs.  No follow-up on related AEs will be conducted.
All research staff members will complete the Pfizer requirements regarding training on the 
following: “Your Reporting Responsibilities: Monitoring the Safety, Performance and 
Quality of Pfizer Products (Multiple Languages)” and any relevant Your Reporting 
Responsibilities supplemental training.  This training must be completed by research staff 
members prior to the start of data collection.  All trainings include a “Confirmation of 
Training Certificate” (for signature by the trainee) as a record of completion of the training, 
which must be kept in a retrievable format.  Copies of all signed training certificates must be 
provided to Pfizer. Re-training must be completed on an annual basis using the most current 
Your Reporting Responsibilities training materials.
9.3. Validation Study to Interview Parents/Legal Guardians by HCPs at CDC 
Immunization Clinics Using Questionnaires 
This protocol will use an external adjudication committee wherein, to maintain scientific 
integrity, adjudication of clinical endpoints defined in the study objectives will be performed.  
The committee is responsible for ongoing analysis of SOIs and of their adjudication as the 
SOIs (Section 7.5.2 Figure 3).  Events that are adjudicated not to be the SOIs will be handled 
as described at Section 9.2. 
Product safety information unrelated to the SOIs in the study that are volunteered by 
parents/legal guardians will be handled as described below. 
Any safety information for an individual child that is volunteered by a parent/legal guardian 
of the child during the course of this research must be reported as described below. 
The following safety events must be reported on the NISAEM Report Form: serious and 
non-serious AEs when associated with the use of the Pfizer product, and scenarios involving 
exposure during pregnancy, exposure during breast feeding, medication error, overdose, 
misuse, extravasation, lack of efficacy and occupational exposure (all reportable,
regardless of whether associated with an AE), when associated with the use of a Pfizer 
product. 
All HCPs at Yinzhou CDC immunization clinics who will administer the interview to the 
parent/legal guardian and complete the questionnaire tool will complete the Pfizer 
requirements regarding training on the following: “Your Reporting Responsibilities: 
Monitoring the Safety, Performance and Quality of Pfizer Products (Multiple Languages)”
and any relevant Your Reporting Responsibilities supplemental training.  This training must 

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be completed by the HCPs at CDC immunization clinics prior to the start of data collection.  
All trainings include a “Confirmation of Training Certificate” (for signature by the trainee) as 
a record of completion of the training, which must be kept in a retrievable format.  The study 
vendor will also provide copies of all signed training certificates to Pfizer.  Re-training must 
be completed on an annual basis using the most current Your Reporting Responsibilities 
training materials.
The HCPs at CDC immunization clinics will be trained to identify safety event information.  
In the event that a parent/legal guardian reports a safety event associated with a Pfizer 
product, the HCP will complete the NIS AEM Report Form and submit to Pfizer within 
24 hours of becoming aware of the safety event.  Included in the completion of the NIS AEM 
Report Form is the parent’s/legal guardian’s contact information; complete contact 
information should be obtained so that, once the NIS AEM Report Form is transferred to 
Pfizer, the NIS AEM Report Form can be assessed and processed according to Pfizer’s 
standard operating procedures, including requests for follow-up to the parent/legal guardian. 
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
Three study progress reports and the final study report will be submitted to the NMPA in 
2018, 2019, 2020, and 2021 respectively. Information from the study will be communicated 
to the scientific and medical community through relevant professional association meetings 
and/or a journal submission. 
COMMUNICATION OF ISSUES
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NIS protocol that the investigator becomes aware of.

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WHO Centers for Disease Control and Prevention. Pneumococcal disease. In: Atkinson 
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Pneumococcal vaccines: WHO position paper. Weekly Epidemiological Record, 
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3.
O'Brien KL, et al. Burden of disease caused by Streptococcus pneumoniae in children 
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Johnson HL, Deloria-Knoll M, et al. Systematic evaluation of serotypes causing 
invasive pneumococcal disease among children under five: the pneumococcal global 
serotype project.  PLoS Medicine/Public Library of Science 2010;7(10).
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Dinleyici EC, Yargic ZA. Current knowledge regarding the investigational 13-valent 
pneumococcal conjugate vaccine. Expert Rev Vaccines. 2009;8:977-986.
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Hausdorff WP. The roles of pneumococcal serotypes 1 and 5 in paediatric invasive 
disease. Vaccine. 2007;25:2406-2412.
7.
13vPnC Risk Management Plan dated December 11th, 2017.
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Rowhani-Rahbar A, Klein NP, Dekker CL, et al. Biologically plausible and 
evidence-based risk intervals in immunization safety research. Vaccine 2012;31:271-7.
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Wagner AL, Sun X, Montgomery JP, Huang Z, Boulton ML. The impact of residency 
and urbanicity on Haemophilus influenzae Type b and pneumococcal immunization in 
Shanghai Children: a Retrospective Cohort Study. PLoS One. 2014 May 14;9(5).
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Yang Y, Zhou X, Gao S, et al. Evaluation of Electronic Healthcare Databases for 
Post-Marketing Drug Safety Surveillance and Pharmacoepidemiology in China. Drug 
Safety. 2017 Aug 16.