Prevalence, Strain Circulation and Disease Burden of Seasonal Influenza A and B in Panama, Selected Countries of Central America and the Caribbean From the Year 2010 to 2015
Conditions: Influenza, Human
Sponsor: GlaxoSmithKline

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Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
GlaxoSmithKline Export Panamá, S. A.
Clayton City of Knowledge, Bldg 230
P.O. Box 0819-08530
Panama, Rep. Of Panama
eTrack study number and 
Abbreviated Title
205049 (EPI-FLU-052 BOD PA DB)
Date of protocol
Final Version 1: 29 March 2016
Title
Prevalence, strain circulation and disease burden of 
seasonal Influenza A and B in Panama, selected 
countries of Central America and the Caribbean from 
the Year 2010 to 2015.
Detailed Title
An observational, retrospective, database study of the 
burden of seasonal Influenza A and B in Panama, 
selected countries of Central America and the 
Caribbean from the Year 2010 to 2015.
Co-ordinating author
, Scientific Writer
Contributing authors

Regional Epidemiology Manager, 
LATAM

, Global Epidemiologist

, Director 
Epidemiology, LATAM

, Study Delivery Lead

, Lead Statistician

, Project Statistician

, Local Delivery Lead

, Study Data Manager

, Cluster Medical 
Lead Andina-Caricam

, Medical 
Affairs Manager, Caricam

, Senior Manager, Clinical Data 
Management
GSK Biologicals’ protocol template for database studies based on the Protocol 
Document Standard version 14.1.1
Copyright 2016 of the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited.
 
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PPD
PPD
PPD
PPD
PPD
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Protocol Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
205049 (EPI-FLU-052 BOD PA DB)
Date of protocol
Final Version 1: 29 March 2016
Detailed Title
An observational, retrospective, database study of the 
burden of seasonal Influenza A and B in Panama, 
selected countries of Central America and the 
Caribbean from the Year 2010 to 2015.
Sponsor signatory
Eduardo Ortega-Barria
Vice President and Head of Clinical R&D and 
Medical Affairs, Latin America
GlaxoSmithKline Biologicals
Signature
Date
 
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Protocol Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, with the terms of the study 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline Biologicals (GSK Biologicals).

To assume responsibility for the proper conduct of the study.

That I am aware of, and will comply with applicable guidelines and all applicable 
regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about 
study-related duties and functions as described in the protocol.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor, and more generally about his/her financial ties with the sponsor. GSK 
Biologicals will use and disclose the information solely for the purpose of complying 
with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
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eTrack study number and 
Abbreviated Title
205049 (EPI-FLU-052 BOD PA DB)
Date of protocol
Final Version 1: 29 March 2016
Detailed Title
An observational, retrospective, database study of the 
burden of seasonal Influenza A and B in Panama, 
selected countries of Central America and the 
Caribbean from the Year 2010 to 2015
Investigator name
Signature
Date
 
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
GlaxoSmithKline Export Panamá, S. A, Clayton City of Knowledge, Bldg 230
P.O. Box 0819-08530
Panama, Rep. Of Panama
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
 
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SYNOPSIS
Detailed Title
An observational, retrospective, database study of the burden 
of seasonal Influenza A and B in Panama, selected countries 
of Central America and the Caribbean from the Year 2010 to 
2015
Rationale for the 
study
Evidence is needed to assess prevalence and incidence of 
seasonal influenza A and B, assess the potential mismatch and 
identify clinical features of seasonal Influenza A and B by 
country. Thus, this study aims to raise awareness to the public 
health stakeholders the need for quadrivalent influenza 
vaccine (QIV) and support its recommendation by:

Generating burden of disease data that highlights the 
contribution of influenza to hospitalization, mortality, 
cardiovascular disease and other complications.

Providing evidence, documenting the mismatch between 
circulating B strains and those included in the 
recommended seasonal vaccine and co-circulation of 
influenza across different seasons.

Understanding the burden of disease of influenza B 
strains and the added value of a QIV.
The data from this study,

May support the implementation and expansion of 
existing universal mass vaccination (UMV) strategies for 
influenza.

the current recommendation is to vaccinate the 
elderly, health care workers, children (in some 
countries vaccination is limited to children with 
chronic diseases), adults with chronic diseases. Some 
countries in the study region also recommend 
influenza vaccination in pregnant women [TAG 
recommendations for influenza vaccination, 2014]

Can provide robust and reliable data  to develop future 
health economics (HE) model adaptations in the selected 
study regions.

May provide evidence of the added value of deploying 
QIVs and thus further support the need and 
recommendation for QIVs for different age groups.
Description of the 
The Gorgas Memorial Institute for Health Studies (ICGES) is 
a public health institution established in Panama dedicated to 
 
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database
health research and disease prevention. It has been performing
virological isolations of influenza and is a part of the World 
Health Organisation (WHO) Global Influenza Surveillance 
and Response System (GISRS) and a direct collaborator of the 
CDC.
From 2010 a sentinel surveillance program is being conducted 
in Panama within the ICGES to collect data on influenza and 
other respiratory viruses using CDC guidance for Respiratory 
Disease Surveillance.:
Respiratory samples from 18 sentinel sites scattered around 
the country are sent to ICGES and tested for 16 respiratory 
viruses, including influenza, using real-time PCR. 
In addition to ICGES role in Panama, the ICGES will serve as 
a coordinating center for compiling influenza surveillance 
data from National Influenza Surveillance Programs from 3 
other countries within the region as well as conducting strain 
typing of influenza B isolates, a procedure not routinely done 
in these countries
The seasonal influenza A and/or B cases reported in the study 
region are recorded in country specific national influenza 
surveillance program databases. The data recorded in these 
databases is individual level data and anonymised with unique 
ID and key.
Samples of seasonal influenza A and/or B positive cases 
identified in the country specific databases are transferred to 
ICGES with unique ID and key. At ICGES, the 
specimen/samples are processed and tested. The results are
cleaned and collated in the ICGES database.
This multi-country study aims to utilize this data recorded via 
National Influenza Surveillance Program at ICGES for 
analyzing the burden of influenza in Panama and selected 
countries of Central America and the Caribbean.
Objectives
Primary

To describe seasonal influenza A and/or B cases by age 
and virus subtype (AH1N1/A H3N2) and B-strain 
lineage (Victoria and Yamagata) using data reported via 
National Surveillance Program in Panama, selected 
countries of Central America and the Caribbean from 
January 2010 to December 2015. 
 
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Secondary
From the January 2010 to December 2015, in each selected 
country:

To describe clinical features and outcomes (clinical 
manifestations, duration of illness, complications) of 
seasonal Influenza A cases and B cases (overall and by 
subtypes or lineages) in different seasons.

To describe the temporal and geographical distribution of 
seasonal influenza A and/or B (overall and by subtypes or 
lineages) cases within different seasons.

To estimate the percentage of co-circulation of influenza 
B lineages (yamagata and Victoria lineages) among the 
study population, by age (<1, 1-4, 5-9, 10-14, 15-19, 20-
24, 25-44, 45-49, 50-59, 60-64 and 65 years) or age 
groups and by region.

To describe the mismatch between the B-strain included 
in the Trivalent Influenza Vaccines (TIV) and the 
circulating B strains in different seasons.
Study design

Type of study: Self contained.

Type of design: Epidemiological, non-interventional, 
observational, retrospective, database study.

Study population: All subjects who have laboratory 
confirmed diagnosis of influenza (laboratory confirmed 
case) and reported in the national influenza surveillance 
system in selected countries from the Year 2010-2015.

General study aspects: All seasonal influenza A and/or B
cases reported in the ICGES database will be screened. 
Demographic data, date of onset of the first symptom and 
data on A-virus subtype and B-strain lineage, geographic 
region where the virus was isolated, clinical features and 
outcomes (clinical symptoms, duration of illness, 
complications) experienced by all influenza positive 
subjects (subjects with a laboratory confirmed influenza 
diagnosis) will be validated, extracted and transferred 
from the ICGES database to the sponsor or to the site of 
analysis, as applicable.

Period of data collection: The study will include data on 
all the subjects with a laboratory confirmed influenza
diagnosis, reported in the ICGES database of Panama, 
from January 2010 to December 2015. For all eligible 
subjects, individual level anonymised and key coded data
 
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will be collected from the database.

Epoch 001: Retrospective data collection.
Synopsis Table 1
Study group and epoch foreseen in the study
Study Group
Epoch
Epoch 001
Retrospective
x
Number of subjects
The study will encompass all subjects reported in the ICGES
database of Panama from January 2010 to December 2015
who meet the inclusion criteria.
Endpoints
Primary

Occurrence of seasonal influenza A and/or B cases by 
age, virus subtype and strain lineage from January 2010 
to December 2015, in Panama, selected countries of
Central America and the Caribbean (using the data 
reported via National Influenza Surveillance Program).
Secondary

Occurrence of clinical features and outcomes (clinical 
symptoms, duration of illness, complications)
experienced by subjects who have laboratory confirmed 
diagnosis of seasonal influenza A and/or B, in different 
seasons from 2010 to 2015.

Frequency of seasonal influenza A and/or B cases 
reported in different temporal and geographical locations
within different seasons from 2010 to 2015.

Occurrence of influenza caused by B-strain and presented 
by B lineages among the study population, by age (<1, 1-
4, 5-9, 10-14, 15-19, 20-24, 25-44, 45-49, 50-59, 60-64 
and 65 years) and by region.

Compare the characteristics of the influenza B-infection
as observed in the database and the B-strain included in 
the trivalent influenza vaccine.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................5
SYNOPSIS......................................................................................................................6
LIST OF ABBREVIATIONS...........................................................................................14
GLOSSARY OF TERMS ...............................................................................................15
1.
INTRODUCTION....................................................................................................17
1.1.
Background ................................................................................................17
1.2.
Description of the database ........................................................................17
1.3.
Rationale for the study................................................................................18
2.
OBJECTIVES.........................................................................................................19
2.1.
Primary objective ........................................................................................19
2.2.
Secondary objectives..................................................................................19
3.
STUDY DESIGN ....................................................................................................20
3.1.
Feasibility assessment................................................................................20
3.2.
Study limitations..........................................................................................20
3.3.
Study design overview................................................................................20
4.
STUDY POPULATION ...........................................................................................21
4.1.
Number of subjects.....................................................................................21
4.2.
Inclusion criterion........................................................................................21
4.3.
Exclusion criteria.........................................................................................21
5.
STATISTICAL METHODS......................................................................................21
5.1.
Endpoints....................................................................................................21
5.1.1.
Primary endpoint..........................................................................21
5.1.2.
Secondary endpoints ...................................................................22
5.2.
Sample size consideration ..........................................................................22
5.3.
Study cohort/ data sets to be analysed .......................................................22
5.3.1.
Total cohort..................................................................................22
5.4.
Derived and transformed data.....................................................................22
5.5.
Statistical methods......................................................................................23
5.5.1.
Analysis of demographics/baseline characteristics ......................23
5.5.2.
Analysis of primary objective........................................................23
5.5.3.
Analysis of secondary objectives .................................................23
5.6.
Interpretation of analyses............................................................................23
5.7.
Conduct of analyses ...................................................................................23
5.7.1.
Sequence of analyses..................................................................24
5.7.2.
Statistical considerations for interim analyses..............................24
6.
CONDUCT OF THE STUDY ..................................................................................24
6.1.
Regulatory and ethical considerations ........................................................24
6.2.
Informed consent........................................................................................24
6.3.
Data privacy................................................................................................24
 
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6.4.
Outline of data extraction procedures .........................................................25
6.5.
Detailed description of data extraction and handling procedures ................25
6.5.1.
Identification of eligible study cases in ICGES influenza 
national surveillance program database.......................................25
6.5.2.
Identification and anonymisation of eligible subjects ....................25
6.5.3.
Extraction of individual data .........................................................25
6.5.4.
Database check and transfer from ICGES to GSK.......................25
6.5.4.1.
Check of data set content and format .........................26
6.5.4.2.
Check of data completeness and consistency ............26
6.5.5.
Handling of incomplete data, missing data and 
discrepancies...............................................................................26
7.
ADMINISTRATIVE MATTERS ...............................................................................26
7.1.
Record retention .........................................................................................26
7.2.
Quality assurance.......................................................................................27
7.3.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................27
7.4.
Provision of study results to investigators ...................................................27
8.
COUNTRY SPECIFIC REQUIREMENTS...............................................................27
9.
REFERENCES.......................................................................................................28
 
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LIST OF TABLES
PAGE
Table 1
Study group and epoch foreseen in the study ........................................21
Table 2
Number of specimen samples of influenza cases per year from 
January 2010 to December 2014 ...........................................................22
Table 3
List of data extraction procedures...........................................................25
 
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LIST OF APPENDICES
PAGE
APPENDIX A CURRENT DATABASE STATISTICS FOR PANAMA............................29
 
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LIST OF ABBREVIATIONS
CI:
Confidence Interval
DB:
Database
GSK:
GlaxoSmithKline
ICH:
International Conference on Harmonisation
ICGES:
Instituto Conmemorativo Gorgas de Estudios de la Salud
IEC:
Independent Ethics Committee
IRB:
Institutional Review Board
ISPE:
International Society for Pharmacoepidemiology
LL:
Lower Limit
UL:
Upper Limit
UMV:
Universal Mass Vaccination
 
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GLOSSARY OF TERMS
Anonymised data:
Information about an individual that GSK or a third party 
cannot reasonably attribute to the individual, or could 
only attribute to the individual by expending a 
disproportionate amount of time, effort or expense (e.g. 
de-identified or aggregated information). For the purpose 
of this template, Key-Coded personally identifiable 
information (PII) shall not be considered Anonymised 
Information.
Database:
A database is a set of pre-existing tables and views 
containing data. The term “pre-existing” implies that the 
analysis will be done on retrospective data and the term 
“views” implies that the data can be made readily 
available in an electronic format through a 
straightforward extract, without re-encoding and manual 
manipulation (like a transpose, a translation, split of a 
field into several fields, etc).
Database study:
A study involving the use of pre-existing data maintained 
in an electronic format; this will not include collection of 
new data that requires (re-) encoding via CRF/eCRF and 
retesting of human biological samples.
Eligible:
Qualified for enrolment into the study based upon the 
inclusion/exclusion criteria.
Epidemiology study:
An observational study or an interventional study without 
administration of medicinal product(s) as described in a 
research protocol.
Epoch:
An epoch is a self-contained set of consecutive 
timepoints or a single timepoint from a single protocol. 
Self-contained means that data collected for all subjects 
at all timepoints within that epoch allows to draw a 
complete conclusion. A typical example of epoch is 
retrospective data collection.
eTrack:
GSK’s tracking tool for clinical/epidemiology studies.
Evaluable:
Meeting all eligibility criteria, and, therefore, included in 
the analysis (see Section 5.3 for details on criteria for 
evaluability).
Key coded information:
Refers to encoded or otherwise pseudoanonymised PII 
from which direct identifiers have been removed and 
replace by a unique identifier or random code. Key coded 
 
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PII shall not be considered anonymised information.
Non-interventional 
(observational) Human 
Subject Research:
Studies where medicinal products, should they be 
administered, are prescribed in normal (routine) medical 
practice. No medical care or medical/scientific procedures 
as required in a research protocol are administered to 
participants except as part of routine medical care.
Personally Identifiable 
Information:
Refers to information, regardless of the medium in which 
such information is held or expressed, that identifies or 
that reasonably could be used to identify an individual.
Retrospective study:
A study that looks backward in time (e.g. at events that 
occurred in the past; outcomes and exposure can no 
longer be influenced), usually using medical records, 
databases or interviews in order to address one or more 
study endpoints. 
Self-contained study:
Study with objectives not linked to the data of another 
study.
Study population:
Sample of population of interest.
Subject:
Term used throughout the protocol to denote a person 
about whom some medical information has been recorded 
in a database.
 
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1.
INTRODUCTION
1.1.
Background
Influenza A and B viruses are important human respiratory pathogens which are 
transmitted mainly by droplets and aerosols originating from the respiratory secretions of 
infected people. Both influenza A and influenza B viruses cause seasonal influenza 
epidemics and out-of season sporadic cases and outbreaks. Influenza occurs globally with 
an annual attack rate estimated at 5%-10% in adults and 20%-30% in children [WHO, 
2012]. The annual mortality rate due to influenza is as high as 300,000–500,000 deaths 
worldwide [WHO, 2008].
In temperate climates, seasonal epidemics are experienced mainly during the winter while 
in tropical regions, influenza may occur throughout the year, causing outbreaks more 
irregularly [WHO, 2012]. In tropical areas, seasonal patterns appear to be less 
pronounced, with year-round isolation of virus [WHO, 2008].
Annual incidence and dominance of seasonal influenza A and/or B vary geographically. 
In addition environmental factors such as viral coexistence and Latitudinal Gradients
have at least some impact on the geographic spread of seasonal influenza A and/or B, 
either through effects on transmission or host susceptibility [Finkelman, 2007]. In 
addition, influenza pandemics occur due to the emergence of new influenza A virus 
subtype s. These pandemics spread globally due to lack of existing or limited immunity 
against these new subtypes [Hampson, 2006]. In the region of Latin America and the 
Caribbean (LA&C), due to underreporting, scarce information on influenza mortality and 
morbidity is available. It is therefore difficult to estimate the burden of disease due to 
poor quality and heterogeneity of the accessible data. The actual amplitude of influenza
infections in LA&C is often unclear by the lack of usage of specific diagnostic methods 
by physicians to confirm etiology, as most reported data come from clinical diagnoses of 
influenza-like illnesses (ILI) [Savy, 2012].
Most of the current seasonal influenza vaccines include two influenza A strains and one
influenza B strain and are registered as Trivalent Influenza Vaccines (TIVs) [WHO, 
2012]. The reported efficacy/effectiveness of influenza vaccines varies substantially with 
factors such as the case definition (e.g. laboratory-confirmed influenza disease or the less 
specific ILI), and with the level match/ mismatch between the vaccine strains and 
prevailing influenza strains. When the vaccine strains closely match the circulating 
influenza viruses, vaccine efficacy rates in individuals younger than 65 years of age 
typically range from 70% to 90% [WHO, 2012]. Hence, surveillance platforms for 
seasonal influenza are critical for monitoring and communicating the observed impact of 
introducing seasonal influenza vaccination in a given population [WHO, 2012].
1.2.
Description of the database
The Gorgas Memorial Institute for Health Studies (ICGES) is a public health institution 
established in Panama dedicated to health research and disease prevention. It has been 
performing virological isolations of influenza and is a part of the World Health 
 
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Organisation (WHO) Global Influenza Surveillance and Response System (GISRS) and a 
direct collaborator of the CDC.
From 2010 a sentinel surveillance program is being conducted in Panama within the 
ICGES to collect data on influenza and other respiratory viruses using CDC guidance for 
Respiratory Disease Surveillance.
Respiratory samples from 18 sentinel sites scattered around the country are sent to 
ICGES and tested for 16 respiratory viruses (such as Adenovirus, parainfluenza, 
RSV/VSR, Bocavirus, Coronavirus, Metapneumovirus, Rhinovirus, other viruses, etc), 
including influenza, using multiplex PCR. 
In addition to ICGES role in Panama, the ICGES will serve as a coordinating center for 
compiling influenza surveillance data from National Influenza Surveillance Programs 
from 3 other countries within the region as well as conducting strain typing of influenza 
B isolates, a procedure not routinely done in these countries
The seasonal influenza A and/or B cases reported in the study centers are recorded in 
country specific national influenza surveillance program databases. The data in these 
databases is individual level data and anonymised with unique ID and key.
Samples of seasonal influenza A and/or B positive cases identified in the country specific 
databases are transferred to ICGES with unique ID and key. At ICGES, the 
specimen/samples are processed. The results are cleaned and collated in the ICGES 
database.
This multi-country study aims to utilize this data recorded via National Influenza
Surveillance Program at ICGES for analyzing the burden of influenza in Panama and 
selected countries of Central America and the Caribbean (potential countries may include 
Guatemala, El Salvador and Jamaica).
1.3.
Rationale for the study
Evidence is needed to assess prevalence and incidence of seasonal influenza A & B, 
assess the potential mismatch and identify clinical features of seasonal Influenza A and B 
by country and in this region. Thus, this study aims to raise awareness to the public health 
stakeholders the need for quadrivalent influenza vaccine (QIV) and support its 
recommendation by:

Generating burden of disease data that highlights the contribution of influenza to 
hospitalization, mortality, cardiovascular disease and other complications.

Providing evidence and documenting the mismatch between circulating B strains and 
those included in the recommended trivalent seasonal vaccines and B-lineage co-
circulation of influenza across different seasons.

Understanding the burden of disease caused by influenza B strains and the added 
value of a QIV.
 
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The data from this study,

may support the implementation and expansion of existing universal mass 
vaccination (UMV) strategies for influenza.

the current recommendation is to vaccinate the elderly, health care workers, 
children (in some countries vaccination is limited to children with chronic 
diseases), adults with chronic diseases. Some countries in the study region also 
recommend influenza vaccination in pregnant women [TAG recommendations 
for influenza vaccination, 2014]

can provide robust and reliable data  to develop future HE model adaptations in the 
selected study regions.

may provide evidence of the added value of deploying QIVs and thus further support 
the need and recommendation for QIVs for different age groups.
2.
OBJECTIVES
2.1.
Primary objective

To describe seasonal influenza A and/or B cases by age and virus subtype 
(AH1N1/A H3N2) and B-strain lineage (Victoria and Yamagata) using data reported 
via National Surveillance Program in Panama, selected countries of Central America 
and the Caribbean from January 2010 to December 2015.
Refer to Section 5.1.1 for the definition of the primary endpoint.
2.2.
Secondary objectives
From January 2010 to December 2015, in each selected country:

To describe clinical features and outcomes (clinical manifestations, duration of 
illness, complications) of seasonal Influenza A and B cases in (overall and by 
subtypes or lineages) different seasons.

To describe the temporal and geographical distribution of seasonal influenza A 
and/or B (overall and by subtypes or lineages) cases within different seasons.

To estimate the percentage of co-circulation of influenza B lineages (yamagata and 
Victoria lineages) among the study population, by age (<1, 1-4, 5-9, 10-14, 15-19, 
20-24, 25-44, 45-49, 50-59, 60-64 and 65 years) or age group and by region.

To describe the mismatch between the B-strain included in the Trivalent Influenza 
Vaccines (TIV) and the circulating B strains in different seasons.
Refer to Section 5.1.2 for the definition of the secondary endpoints.
 
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3.
STUDY DESIGN
3.1.
Feasibility assessment
Since 2010, Panama has implemented a sentinel surveillance program to collect data on 
influenza and other respiratory viruses. This national passive surveillance program 
collects, integrates and analyzes epidemiological information from select hospitals and 
health centers across the country (10 hospitals and 12 health centers). The ICGES plays 
an integral part of this surveillance system by serving as the National Reference 
Laboratory. Its technical capacity and expertise includes immunofluorescence, multiplex 
reverse transcription polymerase chain reaction (RT-PCR) and viral isolation. The
average samples processed per year for this surveillance program is approximately 1,872
samples.
Due to the robust reputation of ICGES in influenza surveillance within the region for 
being excellent reference laboratory for influenza, collaboration with Influenza 
surveillance program in other countries will be possible for this study.
The ICGES laboratory works closely with CDC and is one of the National Influenza 
Center (NIC) laboratories as well as part of the WHO Influenza External Quality 
Assessment Project (EQAP) Working Team. Since 2008, the ICGES laboratory has 
obtained the highest score in quality control.
ICGES has also played a strong role in the region by serving as a sub-regional center of 
reference during the influenza pre-pandemic and pandemic period and got strong support 
of the US HHS (United States Health and Human Services).
3.2.
Study limitations
This study has a few limitations listed below:

Since ICGES is a secondary database underreporting may be expected.
3.3.
Study design overview

Type of study: Self contained.

Type of design: Epidemiological, non-interventional, observational, retrospective, 
database study.

General study aspects: All seasonal influenza A and/or B cases reported in the 
ICGES database will be screened. Demographic data, date of onset of the first 
symptom and data on A-virus subtype and B-strain lineage, geographic region where 
the virus was isolated, clinical features and outcomes (clinical symptoms, duration of 
illness, complications) experienced by all influenza positive subjects will be 
validated, extracted and transferred from the ICGES database to the sponsor or to the 
site of analysis, as applicable. The data will then be analysed and the results will be 
presented.
 
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
Period of data collection: The study will include data of all subjects with a laboratory 
confirmed influenza diagnosis, reported in the ICGES database of Panama, from 
January 2010 to December 2015. For all eligible subjects, individual level 
anonymised and key coded data will be collected from the database.

Epoch 001: Retrospective data collection.
Table 1
Study group and epoch foreseen in the study
Study Group
Epoch
Epoch 001
Retrospective
x
4.
STUDY POPULATION
4.1.
Number of subjects
The study will encompass all subjects reported in the ICGES database of Panama from 
the January 2010 to December 2015.
4.2.
Inclusion criterion
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study or regulatory acceptability. Therefore, adherence to 
the criteria as specified in the protocol is essential.
All subjects must satisfy the following criterion at study entry:

All subjects diagnosed with seasonal influenza A and/or B, reported in the ICGES
database of Panama, from January 2010 to December 2015.
4.3.
Exclusion criteria
Not applicable.
5.
STATISTICAL METHODS
5.1.
Endpoints
5.1.1.
Primary endpoint

Occurrence of seasonal influenza A and/or B cases by age, virus subtype and strain 
lineage from the January 2010 to December 2015, in Panama, selected countries of
Central America and the Caribbean (using the data reported via National Influenza 
Surveillance Program).
 
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5.1.2.
Secondary endpoints

Occurrence of clinical features and outcomes (clinical symptoms, duration of illness, 
complications) experienced by subjects who have laboratory confirmed diagnosis
seasonal influenza A and/or B, in different seasons from 2010 to 2015.

Frequency of seasonal influenza A and/or B cases reported in different temporal and 
geographical locations within different seasons from 2010 to 2015.

Occurrence of influenza caused by B-strain and presented by B lineages among the 
study population, by age (<1, 1-4, 5-9, 10-14, 15-19, 20-24, 25-44, 45-49, 50-59, 60-
64 and 65 years) and by region.

Compare the characteristics of the influenza B-infection as observed in the database 
and the B-strain included in the trivalent influenza vaccine.
5.2.
Sample size consideration
Since this is a retrospective database study, all cases of seasonal influenza A and/or B, 
reported in the ICGES database of Panama, from January 2010 to December 2015 will be 
included in the study. The total specimen samples of influenza cases per year ranged from 
47 to 276 (refer to Table 2).
Table 2
Number of specimen samples of influenza cases per year from 
January 2010 to December 2014
Year
Total specimen samples 
received (N)
Influenza (A+B) positive
Influenza B positive
N
N
2010
1665
207
14
2011
1413
47
0
2012
2236
276
178
2013
2115
190
0
2014
1725
140
55
5.3.
Study cohort/ data sets to be analysed
5.3.1.
Total cohort
The Total cohort will comprise of all eligible subjects included in the study.
5.4.
Derived and transformed data

Influenza is defined as any positive laboratory test from one or more of the clinical 
specimens [Guidelines for the epidemiological surveillance of influenza, 2012].
 
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5.5.
Statistical methods
5.5.1.
Analysis of demographics/baseline characteristics
Demographic characteristics (age and gender) will be summarised by group using 
descriptive statistics:

Frequency tables will be generated for categorical variable such as gender.

Mean, median and standard deviation will be provided for continuous data such as 
age.

The distribution of influenza cases by month and year will also be tabulated.
5.5.2.
Analysis of primary objective
The proportion of subjects with influenza caused by seasonal influenza A and/or B
among all influenza cases reported with exact 95% confidence interval (CI) by age, A-
virus subtype and B-strain lineage and overall will be calculated.
5.5.3.
Analysis of secondary objectives
Seasonal influenza A and/or B cases will be described using frequency and percentages 
by temporal (calendar weeks/months) and geographical distributions (by country and by 
region within the country [if data is available])within different influenza seasons (2010-
2011, 2011-2012, 2012-2013, 2013-2014 and 2014-2015).Frequency and percentage for 
clinical features and outcomes (clinical manifestations, duration of illness, complications) 
experienced by influenza positive subjects will be tabulated by type of influenza 
(seasonal influenza A and/or B) in different seasons from 2010-2015. Frequency and 
percentage for influenza B lineages by age (<1, 1-4, 5-9, 10-14, 15-19, 20-24, 25-44, 45-
49, 50-59, 60-64 and 65 years) and region will also be provided.
The characteristics of the influenza B-infection as observed in the database and the B 
strain included in the trivalent influenza vaccine will be assessed using frequency and 
percentage for each year. The proportion of matched B-strains and mis-matched B-strains 
will be estimated along with 95% CI.
5.6.
Interpretation of analyses
All the analyses with respect to the primary and secondary endpoints will be descriptive. 
These descriptive analyses will not be interpreted, except describing the study results.
5.7.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
 
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5.7.1.
Sequence of analyses
The final analysis will be performed when all required data for the study have been 
extracted from the ICGES database and transferred to the sponsor or to the site of 
analysis, as applicable.
5.7.2.
Statistical considerations for interim analyses
All analyses will be conducted using the final data and no statistical adjustment will be 
required as no interim analysis is planned for this study.
6.
CONDUCT OF THE STUDY
6.1.
Regulatory and ethical considerations
The study will be conducted in accordance with all applicable regulatory requirements, 
including all applicable subject privacy requirements and the guiding principles of the 
Declaration of Helsinki.
GlaxoSmithKline Biologicals (GSK Biologicals) will seek favourable opinion/approval 
to conduct the study prior to data extraction or will document that neither a favourable 
opinion nor an approval to conduct the study is needed.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both
6.2.
Informed consent
Prior to the data processing and analysis, all data will be anonymised. GSK Biologicals
personnel and delegates will not be able to make a link between the data and specific 
individuals. Therefore no patient consent is needed. For further details see Section 6.3.
6.3.
Data privacy
Data privacy is protected by using anonymised data (see glossary of terms).
The ICGES database is fully coded. No GSK Biologicals personnel will have the ability 
to link data to an identifiable individual.
 
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6.4.
Outline of data extraction procedures
Table 3 presents the list of data extraction procedures.
Table 3
List of data extraction procedures
Epoch: Retrospective data collection
Identification of eligible study cases in ICGES
influenza national surveillance program database
Identification and anonymisation of eligible subjects
Extraction of individual data
Dataset check and transfer from ICGES to GSK
Handling of incomplete data, missing data and 
discrepancies
6.5.
Detailed description of data extraction and handling
procedures
6.5.1.
Identification of eligible study cases in ICGES influenza national 
surveillance program database
The ICGES database of Panama will be checked for all seasonal influenza A and/or B 
positive cases reported via influenza surveillance programs from 2010 to 2015.
6.5.2.
Identification and anonymisation of eligible subjects
All subjects with a laboratory diagnosis of seasonal influenza A and/or B, will be 
identified from this database. The data present in ICGES database is already anonymised, 
therefore subject identification number allocation is not required.
6.5.3.
Extraction of individual data
All seasonal influenza A and/or B cases reported in the ICGES database will be validated 
and extracted in the required file format e.g. Statistical Analysis System (SAS) datasets. 
The following data will be collected for seasonal influenza A and/or B positive subjects:

Demographic data such as age and gender.

Data on A-virus subtype and B-strain lineage (when available), geographic region,
clinical features and outcomes (clinical manifestations, duration of illness, 
complications) etc.
6.5.4.
Database check and transfer from ICGES to GSK
ICGES will transfer the data files extracted for the study on GSK SAS Drug 
Development (SDD) secured web platform (SDD) as SAS data sets (if data cannot be 
provided by ICGES in SAS format, GSK can alternatively accept Excel spreadsheets).
 
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Additionally to the data sets, ICGES will provide a description of each data set, including 
a description of each column and its attributes (data type, length and as applicable, 
decodes if codes are used, and coding dictionary reference for codes and terms related to 
a specific coding and terminology system like ICD-10, SNOMED, WHOART, MedDRA, 
…). 
6.5.4.1.
Check of data set content and format
Prior to starting the programming of the analyses, the GSK person responsible for the 
analyses will check if the data files content and format meet the requirements for the 
statistical analyses. This will include (but will not be limited to) checks on the 
subject/case identifiers consistency, checks on the presence of the analyses variables, 
checks on list of values and/or codes and checks on the numeric and date formats. Any 
finding will be feedback to ICGES database owner and require a new transfer, until 
content and format are appropriate for the statistical analyses.
6.5.4.2.
Check of data completeness and consistency
Any data deficiency such as incomplete data, missing data and data discrepancies that 
would be detected by GSK statistician or epidemiologist and that are critical for the 
analyses will be feedback to ICGES database owner. Depending on the possibility of the 
database owner to correct data, corrected data will be retransferred or not to GSK. 
6.5.5.
Handling of incomplete data, missing data and discrepancies
As applicable, the rules taken for handling incomplete data, missing data and data 
discrepancies in statistical analyses will be documented in the SAP (e.g.: handling 
missing data and codes such as ‘UNK’, ‘N/A’, ‘ND’; calculation of a duration from 
partial dates; censoring of discrepant data …)
7.
ADMINISTRATIVE MATTERS
To comply with regulatory requirements and GSK standards, administrative obligations 
relating to protocol amendments, protocol administrative changes and termination of the 
study must be fulfilled.
7.1.
Record retention
The datasets sent by the database owner will be loaded and archived at GSK as per the 
applicable requirements and the retention policies.
The minimum retention time will meet the strictest standard applicable for the study, as 
dictated by the applicable guidelines or applicable laws or regulations, or GSK 
standards/procedures; otherwise, the minimum retention period will default to 30 years.
 
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7.2.
Quality assurance
To ensure compliance with Good Clinical Practice (GCP) or other applicable guidelines 
and all applicable regulatory requirements, GSK may conduct a quality assurance audit. 
Regulatory agencies may also conduct a regulatory inspection of this study. Such 
audits/inspections could occur at any time during or after completion of the study. If an 
audit or inspection occurs, the database owner and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and 
the time of his/her staff to the auditor/inspector to discuss findings and any relevant 
issues.
7.3.
Posting of information on publicly available clinical trial 
registers and publication policy
Database studies that do not evaluate vaccines/products are progressed for publication in 
the scientific literature when the results provide important scientific or medical 
knowledge.
7.4.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
8.
COUNTRY SPECIFIC REQUIREMENTS
IRB approval for epidemiological observational studies.
 
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9.
REFERENCES
Brian S. Finkelman, Ce´cile Viboud, Katia Koelle, Matthew J. Ferrari, Nita Bharti, Bryan 
T. Grenfell. Global Patterns in Seasonal Activity of Influenza A/H3N2, A/H1N1, and B 
from 1997 to 2005: Viral Coexistence and Latitudinal Gradients. PLoS ONE 2007; 2(12): 
e1296.
Hampson AW, Mackenzie JS. The influenza viruses. Med J Aust. 2006 Nov 20; 185(10 
Suppl):S39-43.
Lineamientos para la Vigilancia Epidemiológica de Influenza (Guidelines for the 
epidemiological surveillance of influenza). January 2012.
TAG recommendations for influenza vaccination. 
http://www.paho.org/hq/index.php?option=com_content&view=article&id=6202%3A20
11-tag-recommendations-influenza-vaccine&catid=4203%3Atag-recommendations-for-
influenza-vaccine&Itemid=4321&lang=en, 2014. Accessed on 29 March 2016
Vilma Savy, Agustin Ciapponi, Ariel Bardach, Demia´n Glujovsky, Patricia Aruj,
Agustina Mazzoni, Luz Gibbons, Eduardo Ortega-Barrı´, Romulo E. Colindres. Burden 
of influenza in Latin America and the Caribbean: a systematic review and meta-analysis. 
DOI:10.1111/irv.12036. 2012.
World Health Organisation (WHO). Influenza. 25 January 2008. 
http://www.who.int/immunisation/topics/influenza/en/index.html
World Health Organisation (WHO) - Weekly epidemiological record. 23 November 
2012, 87th year. No. 47, 2012, 87, 461–476. http://www.who.int/wer.
 
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APPENDIX A
CURRENT DATABASE STATISTICS FOR 
PANAMA
 
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