Assessment of Safety of GlaxoSmithKline (GSK) Vaccines' Quadrivalent Seasonal Influenza Vaccine, Fluarix Tetra When Administered According to the Approved Prescribing Information in Korea.
Conditions: Influenza, Human
Sponsor: GlaxoSmithKline

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CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
3 
GSK Vaccines’ protocol template for observational studies and interventional studies without 
administration of medicinal products as described in a research protocol based on Protocol 
Document Standard version 13.2 
 
Copyright 2015-2019 of the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited. 
 
 
 
 
 
 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
4 
Protocol Amendment 3 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
204687 [EPI FLU-050 VS KR PMS] 
Date of protocol amendment 
Amendment 3 Final: 08 Mar 2019 
Detailed Title 
A prospective, observational, multi-center, drug use 
investigation to monitor the safety of 
GlaxoSmithKline (GSK) Vaccines’ quadrivalent 
seasonal influenza vaccine, Fluarix Tetra when 
administered according to the approved Prescribing 
Information in Korea. 
Sponsor signatory 
(Amendment 3: 08 Mar 2019) 
Bach-Yen Nguyen 
Clinical and Epidemiology Project Lead, Flu and 
Preparedness Activities 
Clinical R & D 
U.S. Vaccine Research and Development Center 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
5 
Protocol Amendment 3 Rationale 
Amendment number: 
Amendment 3 
Rationale/background for changes: 
 
Editorial changes  
 
Changes as per MFDS Request 
─ Describe statistical processing method in “10.5.2. Safety Analysis” 
─ Correct typo errors on Research Subject Inclusion Criteria Table in “4.2. 
Inclusion Criteria” (ONLY applicable in Korean protocol) 
 
Clarification of ADR analysis to be consistent with planned AEs and SAEs 
analysis 
 
 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
6 
Protocol Amendment 3 Physician Agreement 
I agree: 
 
To conduct the Drug Use Investigation in compliance with this protocol, any mutually 
agreed future protocol amendments or protocol administrative changes, and with any 
other Drug Use Investigation conduct procedures and/or Drug Use Investigation 
conduct documents provided by GlaxoSmithKline Vaccines (GSK Vaccines). 
 
To assume responsibility for the proper conduct of the Drug Use Investigation at this 
site. 
 
That I am aware of, and will comply with applicable ethical practices and regulatory 
requirements. 
 
To ensure that all persons assisting me with the Drug Use Investigation are adequately 
informed about Fluarix Tetra and Drug Use Investigation-related duties and functions 
as described in the protocol. 
 
Not to implement any changes to the protocol without agreement from the sponsor and 
prior review and written approval from the Institutional Review Board (IRB) (at sites 
that do not have IRB oversight, before they can implement changes to the protocol, 
they need prior agreement of the sponsor), except where necessary to eliminate an 
immediate hazard to the subjects, or where permitted by all applicable regulatory 
requirements (for example, for administrative aspects of the Drug Use Investigation). 
 
To co-operate with a representative of GSK Vaccines in the monitoring process of the 
Drug Use Investigation and in resolution of queries about the data. 
 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the physician’s ownership interest in the 
sponsor, and more generally about his/her financial ties with the sponsor. GSK 
Vaccines will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I: 
 
Agree to supply GSK Vaccines 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 Drug Use Investigation and for one year following completion of the 
Drug Use Investigation. 
 
Agree that GSK Vaccines may disclose any information it has about such ownership 
interests and financial ties to regulatory authorities. 
 
Agree to provide GSK Vaccines with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this Drug Use Investigation. 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
7 
eTrack study number and 
Abbreviated Title 
204687 [EPI FLU-050 VS KR PMS] 
Date of protocol amendment 
Amendment 3 Final: 08 Mar 2019 
Detailed Title 
A prospective, observational, multi-center, drug use 
investigation to monitor the safety of 
GlaxoSmithKline (GSK) Vaccines’ quadrivalent 
seasonal influenza vaccine, Fluarix Tetra when 
administered according to the approved Prescribing 
Information in Korea. 
Physician name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
8 
SYNOPSIS 
Detailed Title 
A prospective, observational, multi-center, drug use 
investigation to monitor the safety of GlaxoSmithKline (GSK) 
Vaccines’ quadrivalent seasonal influenza vaccine, Fluarix 
Tetra when administered according to the approved 
Prescribing Information in Korea. 
Rationale for the 
Drug Use 
Investigation 
GSK Vaccines’ quadrivalent seasonal influenza vaccine D-
QIV, Fluarix Tetra was registered in Korea in December 2014 
indicated for 3 years and above. As per MFDS requirements, 
this drug use investigation (as a part of PMS) is being 
conducted to collect safety information on the use of Fluarix 
Tetra over a 6 years period. In order to meet the MFDS’s 
requirement requesting that at least 600 subjects are followed 
after Fluarix Tetra administration, according to the approved 
PI in Korea, around 720 adults and children from three years 
of age are intended to be enrolled in order to collect safety 
information within 21 days (Day 0 to Day 20) post 
vaccination. 
In addition to the extension of an age indication to include 6 
to 35 months of age for Fluarix Tetra, additional drug use 
investigation for new age group is being conducted to collect 
safety information on the use of Fluarix Tetra for  4 years 
according to the MFDS requirement. Almost  720 children 
aged  6 to 35 months  will be  enrolled in order to collect 
safety information within 21 days (Day 0 to Day 20) post 
vaccination. 
Objective 
To assess the safety of GSK Vaccines’ quadrivalent seasonal 
influenza vaccine D-QIV, Fluarix Tetra, in terms of 
frequency and intensity of AEs and SAEs when administered 
according to the local PI in adults and children from 6 months  
of age in Korea. 
Study design 
(Amendment 3: 08 
Mar 2019) 
Drug use investigation design: A prospective, observational, 
non-comparative, multi-center study in Korea. 
Vaccination schedule: Vaccination as per locally approved PI 
(which is not part of the drug use investigation): to adults and 
previously vaccinated children aged ≥6 months, a single 0.5 
ml dose of Fluarix Tetra will be administered. To previously 
unvaccinated children aged 6 months to <9 years, two doses 
will be administered with a second 0.5 ml dose at least 4 
weeks apart from the first one as per the local PI in Korea. 
Safety monitoring: 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
9 
- 
Recording of all AEs during the 21 days (Day 0 to 
Day 20) using diary cards after Fluarix Tetra is 
administered. 
- 
Recording of all ADRs reported during the 21 
days (Day 0 to Day 20) follow-up period after 
administration of Fluarix Tetra 
- 
Recording of SAEs from the date of vaccination 
until 21 days (Day 0 to Day 20) after Fluarix Tetra 
is administered during the subject’s participation in 
the study. 
Blood Samples: No blood samples will be collected in this 
drug use investigation. 
All subjects who receive at least one dose of the Fluarix Tetra 
and can be evaluated for whether the subject experienced an 
AE will be included in the safety population. For each 
subject, this drug use investigation will include a single or two 
visits and a follow-up contact 21 days (Day 0 to Day 20) after 
each vaccination with Fluarix Tetra. 
Pregnant subjects who receive Fluarix Tetra or subjects who 
become pregnant within 21 days after vaccination with 
Fluarix Tetra will be followed to determine the outcome of 
the pregnancy, if possible. At the end of the pregnancy, 
whether that be full-term or premature, information on the 
status of the mother and child will be forwarded to GSK, if 
possible. Generally, follow-up should be no longer than 6 to 8 
weeks following the estimated delivery date, if possible. 
Duration of the drug use investigation:  
- 6 years (for children 36 months and above and adults). 
- 4 years (for children from 6 to 35 months of age)  
Type of drug use investigation: Self-contained. 
Data collection: Standardised hard copy CRF (SAEs, ADRs, 
Pregnancy information will be collected by using the SAE, 
ADR, Pregnancy Reporting Form). 
Discussion of study 
design 
(Amendment 3: 08 
Mar 2019) 
All AEs including ADRs and SAEs reported during the 21 
days (Day 0 to Day 20) post-vaccination follow-up period of 
Fluarix Tetra in the drug use investigation will be collected as 
part of safety data in this drug use investigation. These AEs 
will be further classified by GSK at the time of statistical 
analyses as expected/unexpected based on the current PI. 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
10 
Number of subjects 
According to MFDS requirement, at least 600 evaluable 
subjects should be recruited for each drug use investigation. 
Therefore, max 1440 subjects (720 vaccinees ≥ 3 years old 
and above and 720 vaccinees between 6-35 months old) will 
be enrolled through the drug use investigation period. We 
assume that 20% of enrolled participants might drop out 
(depending on the status of actual enrolment), then the plan 
can be adjusted accordingly 
Endpoints  
Occurrence of AEs during the 21 days (Day 0 to Day 20) 
follow-up period after vaccination. 
Occurrence of SAEs starting from the date of vaccination in 
the drug use investigation up to 21 days (Day 0 to Day 20) 
after vaccination of the subject in the drug use investigation. 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
11 
TABLE OF CONTENTS 
PAGE 
SYNOPSIS ......................................................................................................................8 
TABLE OF CONTENTS ................................................................................................ 11 
LIST OF TABLES ......................................................................................................... 14 
LIST OF ABBREVIATIONS ........................................................................................... 16 
GLOSSARY OF TERMS ............................................................................................... 18 
TRADEMARKS ............................................................................................................. 19 
1. 
INTRODUCTION .................................................................................................... 20 
1.1. 
Background ................................................................................................. 20 
1.2. 
Rationale for the study ................................................................................ 20 
2. 
OBJECTIVE ........................................................................................................... 21 
3. 
STUDY DESIGN OVERVIEW ................................................................................. 21 
3.1. 
Discussion of study design .......................................................................... 23 
4. 
DRUG USE INVESTIGATION COHORT ................................................................ 23 
4.1. 
Number of subjects/centers ......................................................................... 23 
4.1.1. 
Recruitment at study centers ........................................................ 23 
4.2. 
Inclusion criteria for enrolment .................................................................... 23 
4.3. 
Exclusion criteria for enrolment ................................................................... 24 
5. 
SELECTION OF STUDY CENTERS AND PHYSICIANS ........................................ 24 
5.1. 
Selection of study centers ........................................................................... 24 
5.2. 
Selection of physicians ................................................................................ 25 
6. 
CONDUCT OF THE STUDY ................................................................................... 25 
6.1. 
Regulatory and ethical considerations, including the informed consent 
process ....................................................................................................... 25 
6.2. 
Subject identification ................................................................................... 25 
6.3. 
General study aspects ................................................................................ 26 
6.3.1. 
Description, dosage/administration of Fluarix Tetra ...................... 26 
6.3.2. 
Contraindications to subsequent vaccination................................ 26 
6.3.3. 
Warnings and precautions ............................................................ 26 
6.3.4. 
Concomitant medication/vaccination ............................................ 26 
6.4. 
Outline of study procedures ........................................................................ 27 
6.5.  
Detailed description of study procedures ..................................................... 28 
6.5.1. 
Procedures prior to study participation ......................................... 28 
6.5.2. 
Procedures related to vaccination and outside the drug use 
investigation ................................................................................. 28 
6.5.3. 
Procedures during the study ........................................................ 29 
7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................... 30 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
12 
7.1. 
Safety definitions ......................................................................................... 31 
7.1.1. 
Definition of an adverse event ...................................................... 31 
7.1.2.  
Definition of adverse drug reaction ............................................... 32 
7.1.3. 
Definition of a serious adverse event ........................................... 32 
7.1.4. 
Pregnancy .................................................................................... 33 
7.1.5. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................. 33 
7.2. 
Detecting and recording adverse events, adverse drug reactions, 
serious adverse events, and pregnancies ................................................... 33 
7.2.1. 
Time period for detecting and recording adverse events, 
adverse drug reactions serious adverse events, and 
pregnancies ................................................................................. 33 
7.2.2. 
Evaluation of adverse events, adverse drug reactions and 
serious adverse events ................................................................ 34 
7.3. 
Reporting of serious adverse events, adverse drug reactions                                          
and pregnancies ......................................................................................... 38 
7.3.1.  
Prompt reporting of serious adverse events and other 
events to GSK Vaccines .............................................................. 38 
7.3.2. 
Contact information for reporting serious adverse events 
and other events to GSK Vaccines ............................................... 39 
7.3.3.  
Completion and transmission of SAE to GSK Vaccines ............... 39 
7.3.4.  
Completion and transmission of ADR report to GSK 
Vaccines ...................................................................................... 40 
7.3.5. 
Completion and transmission of pregnancy reports to GSK 
Vaccines ...................................................................................... 40 
7.3.6. 
Regulatory reporting requirements for serious adverse 
events .......................................................................................... 40 
7.4. 
Follow-up of adverse events, serious adverse events, and 
pregnancies ................................................................................................ 41 
7.4.1. 
Follow-up of adverse events and serious adverse events ............ 41 
7.4.2. 
Follow-up of pregnancies ............................................................. 41 
7.5.  
Treatment of adverse events ....................................................................... 42 
8. 
EFFICACY ASSESSMENT ..................................................................................... 42 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ..................................................... 42 
9.1. 
Subject completion ...................................................................................... 42 
9.2. 
Subject withdrawal ...................................................................................... 42 
10. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES ............... 43 
10.1. 
Endpoints .................................................................................................... 43 
10.2. 
Sample size consideration .......................................................................... 43 
10.3. 
Drug use investigation cohort to be evaluated ............................................. 44 
10.3.1.  Total vaccinated cohort ................................................................ 44 
10.3.2.  Total Safety cohort ....................................................................... 44 
10.4.  Conduct of analyses .................................................................................... 44 
10.4.1.  Sequence of analyses .................................................................. 44 
10.4.2.  Statistical considerations for interim analyses .............................. 44 
10.5.  Statistical methods ...................................................................................... 45 
10.5.1.  Analysis of demographics/baseline characteristics ....................... 45 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
13 
10.5.2.  Analysis of safety ......................................................................... 45 
11. ADMINISTRATIVE MATTERS ................................................................................ 46 
11.1. 
Case Report Form....................................................................................... 46 
11.2. 
Monitoring by GSK Vaccines ....................................................................... 46 
11.3. 
Archiving of data at study sites .................................................................... 47 
11.4. 
Audits .......................................................................................................... 48 
11.5. 
Posting of information on public registers .................................................... 48 
11.6. 
Ownership, confidentiality, and publication .................................................. 48 
11.6.1. 
Ownership .................................................................................... 48 
11.6.2. 
Confidentiality .............................................................................. 48 
11.6.3. 
Publication ................................................................................... 49 
11.6.4. 
Provision of study results to physicians, posting to the 
clinical  trials registers, and publication ........................................ 49 
12. COUNTRY SPECIFIC REQUIREMENTS ............................................................... 50 
13. REFERENCES ....................................................................................................... 50 
 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
14 
LIST OF TABLES 
PAGE 
Table 1 
List of study procedures ......................................................................... 27 
Table 2 
Reporting periods for adverse events, adverse drug reaction, 
serious adverse events, and pregnancies ............................................... 34 
Table 3 
Time frames for submitting SAEs and other event reports related 
to GSK Vaccines .................................................................................... 39 
Table 4 
Exact two-sided 95% CI for the percentage of subjects reporting at 
least one symptom with a sample size of 600 subjects ........................... 43 
 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
15 
LIST OF APPENDICES 
PAGE 
APPENDIX A AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL ........................................................................................... 50 
 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
16 
LIST OF ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
CI 
Confidence Interval 
CP 
Concept Protocol 
CRF 
Case Report Form 
EDD 
Estimated Delivery Date 
EPI 
Expanded Program on Immunization 
GEP 
Good Epidemiological Practice 
GSK 
GlaxoSmithKline 
IAF 
Informed Assent Form 
ICF 
Informed Consent Form 
IM 
Intramuscular 
IRB 
Institutional Review Board 
IU 
International Units 
KIDS 
Korean Institute of Drug Safety & Risk Management 
LAR 
Legally Acceptable Representative 
LOC 
Local Operating Company 
LSC 
Local Study Contact 
LSLV 
Last Subject’s Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFDS 
Ministry of Food and Drug Safety 
PI 
Prescribing Information 
PMS 
Post Marketing Surveillance 
PT 
Preferred Term 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
17 
QIV 
Quadrivalent Influenza Vaccine 
SAE 
Serious adverse event 
SDV 
Source Document Verification 
VCSP 
Vaccines’ Central Safety and Pharmacovigilance 
 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
18 
GLOSSARY OF TERMS 
Adverse drug reaction: 
Adverse drug reaction represents adverse, unintended 
reactions from normal administration/use of the 
pharmaceuticals, etc. for which the causal relationship 
with the particular pharmaceutical cannot be excluded. Of 
the voluntarily reported adverse events, those with no 
known causal relationship with the pharmaceutical are 
deemed to be adverse drug reactions.  
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product. 
Drug use investigation 
(study): 
Company sponsored pharmaco-epidemiological studies or 
surveys carried out in accordance with the terms of the 
marketing authorization and conducted with the aim of 
identifying or quantifying a safety hazard relating to an 
authorized medicinal product. 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
eTrack: 
GSK’s tracking tool for clinical trials. 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol. 
Expected adverse event: 
An adverse event that is expected from the subject during 
the post-vaccination follow-up period as described in the 
locally approved Prescribing Information. 
Subject: 
An individual who has been contacted in order to 
participate or participates in the drug use investigation. 
Unexpected adverse 
event: 
Any adverse event reported in addition to those expected 
during the drug use investigation. Adverse events that are 
not reflected in the approved Prescribing Information. 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
19 
TRADEMARKS 
The following trademarks are used in the present protocol. 
Note: In the body of the Protocol (including the synopsis), the names of the 
vaccines/products and/or medications will be written without the superscript symbol ™ or 
®. 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Generic description 
Fluarix Tetra 
 
GlaxoSmithKline (GSK) Vaccines’ 
quadrivalent seasonal influenza vaccine, 
Fluarix Tetra. 
 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
20 
1. 
INTRODUCTION 
1.1. 
Background 
Vaccination is currently the most effective means of controlling the impact of influenza in 
populations at risk (elderly and children). Influenza viruses circulate in humans virtually 
every winter in temperate regions of both hemispheres and throughout the year in tropical 
regions. 
Currently, the strategy is to use a trivalent influenza vaccine which contains two A strains 
(H1N1 and H3N2) and one B strain. Since 1983, two evolutionarily distinct strains of 
influenza B virus coexist in the human population and since 1988 both strains are 
circulating in various countries worldwide [Barr, 2006]. In five of the last eight years, 
more influenza cases were due to the mismatched B virus than to H1N1 virus [CDC, 
2010]. 
Data in literature suggest that children, without appropriate immunologic priming, 
vaccinated with a vaccine containing the recommended B-strain might not be protected 
against an infection with the co-circulating strain from the other B-lineage. Indeed, in a 
study on non-immunized (unprimed) infants, no cross-reactive antibodies were found in 
the sera [Levandowski, 1991]. 
As the two evolutionarily distinct strains of influenza B virus co-circulate and as cross-
reactivity between those two lineages is low and even almost non-existing in an unprimed 
population, an additional B-strain antigen in the seasonal vaccine may offer a better 
protection [Englund, 2006; Levandowski, 1991]. 
GSK Vaccines has developed a QIV which contains two A-strains and two B-strains. The 
drug use investigation was designed to evaluate the safety of the QIV in adults and 
children from 6 months of age in Korea. 
1.2. 
Rationale for the study 
GSK Vaccines’ quadrivalent seasonal influenza vaccine D-QIV, Fluarix Tetra was 
registered in Korea in December 2014. As per MFDS requirements, this drug use 
investigation (as part of PMS) is being conducted to collect safety information on the use 
of Fluarix Tetra over a 6 years period. In order to meet the MFDS’s requirement 
requesting that at least 600 subjects to be followed after Fluarix Tetra administration, 
according to the approved PI in Korea, around 720 adults and children from three years of 
age are intended to be enrolled in order to collect safety information within 21 days (Day 0 
to Day 20) post vaccination. 
In addition to the extension of an age indication to include 6 to 35 months of age for 
Fluarix Tetra, additional drug use investigation for new age group is being conducted to 
collect safety information on the use of Fluarix Tetra for 4 years according to the MFDS 
requirement. Almost  720 children aged 6 to 35 months will be enrolled in order to collect 
safety information within 21 days (Day 0 to Day 20) post vaccination. 

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2. 
OBJECTIVE 
 
To assess the safety of GSK Vaccines’ quadrivalent seasonal influenza vaccine D-
QIV, Fluarix Tetra, in terms of frequency and intensity of AEs and SAEs when 
administered according to the local PI in adults and children from six months of age 
in Korea. 
Refer to Section 10.1 for the definition of the endpoints (AE and SAE). 
3. 
STUDY DESIGN OVERVIEW 
Sequential Allocation of Subject Numbers 
 
 
Fluarix Tetra (N=max 1,440 (720 
vaccinees ≥ 3 years old, 720 
vaccinees between 6-35 months 
old)) 
 
 
 
 
 
           Vaccination 
           (Fluarix Tetra) 
 
Drug Use Investigation 
Conclusion 
21 days (Day 0 to Day 20) 
follow-up after vaccination 
with Fluarix Tetra 
 
N: Number of subjects planned to be enrolled 
Drug use investigation conclusion will depend on the 21 days contact of the subject in the drug use investigation. 
Definition of Conclusion of drug use investigation for a subject: A subject who is available for the concluding follow-up 
contact 21 days (Day 0 to Day 20) after receiving Fluarix Tetra is considered to have completed the drug use 
investigation. 
 
 
Drug use investigation design: A prospective, observational, non-comparative, multi-
center study in Korea. 
 
Vaccination schedule: Vaccination as per locally approved PI (which is not part of the 
drug use investigation): to adults and previously vaccinated children aged ≥6 months, 
a single 0.5 ml dose of Fluarix Tetra will be administered. To previously unvaccinated 
children aged 6 months to <9 years, two doses will be administered with a second 0.5 
ml dose at least 4 weeks apart from the first one as per the local PI in Korea. 
Fluarix Tetra may be administered to pregnant women/lactating women as per PI, if there 
is a clear need. Pregnancy outcome (whether full-term or premature, information on the 
status of the mother and child) in vaccinated pregnant subjects will be followed-up at 6-8 
weeks after delivery, if possible. 
Note: 
 
Vaccination with Fluarix Tetra is not part of the drug use investigation. 
 
Signature of the subject/subject’s parent(s)/LAR(s) on the ICF/IAF signify 
enrolment of the subject into the drug use investigation. The ICF/IAF is for the 
collection and handling of safety information and not for the vaccination 
procedure. 

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 
Administration of vaccines included in the EPI and other licensed vaccines are 
allowed in this drug use investigation regardless of the time of administration. 
 
Safety monitoring: 
 
Recording of all AEs during the 21 days (Day 0 to Day 20) using diary cards after 
Fluarix Tetra is administered. 
 
The participating physician will transcribe the collected information into the CRF 
in English. 
 
Recording of all ADRs reported during the 21 days (Day 0 to Day 20) follow-up 
period after administration of Fluarix Tetra 
 
Recording of SAEs from the date of vaccination until 21 days (Day 0 to Day 20) 
after Fluarix Tetra is administered during the subject’s participation in the study. 
 
All AEs , ADRs and SAEs starting immediately following administration of 
Fluarix Tetra must be recorded onto the CRF and all ADRs and SAEs must be 
reported using the ADR reporting form and SAE reporting form, the latter to be 
sent to GSK according to the required timelines, irrespective of intensity or 
whether or not they are considered vaccination-related. 
 
Parents of children aged 6 months to <12 years wil be contacted  to provide 
details of any AEs experienced by the children 21 days after the children receives 
the vaccination.  
 
Subjects for whom diary card transcription into CRF will be done through phone 
contact are considered to have completed the drug use investigation. 
 
Blood Samples: No blood samples will be collected in this drug use investigation. 
 
All subjects who receive at least one dose of the Fluarix Tetra and can be evaluated 
for whether the subject experienced an AE will be included in the safety population. 
For each subject, this drug use investigation will include a single or two visits and a 
follow-up contact 21 days (Day 0 to Day 20) after each vaccination with Fluarix 
Tetra. 
 
Pregnant subjects who receive Fluarix Tetra or subjects who become pregnant 
within 21 days after vaccination with Fluarix Tetra will be followed to determine 
the outcome of the pregnancy, if possible. At the end of the pregnancy, whether that 
be full-term or premature, information on the status of the mother and child will be 
forwarded to GSK, if possible. Generally, follow-up should be no longer than 6 to 8 
weeks following the EDD, if possible. 
 
Duration of the drug use investigation:  
- 6 years (for children 36 months and above and adults). 
- 4 years (for children from 6 to 35 months of age)  
 
Type of drug use investigation: Self-contained. 

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 
Data collection: Standardised hard copy CRF (SAEs, ADRs, Pregnancy information 
will be collected by using the SAE, ADR, Pregnancy Reporting Form). 
3.1. 
Discussion of study design 
All AEs including SAEs reported during the 21 days (Day 0 to Day 20) post-vaccination 
follow-up period of Fluarix Tetra in the drug use investigation will be collected as part of 
safety data in this drug use investigation. These AEs will be further classified by GSK at 
the time of statistical analyses as expected/unexpected based on the current PI. 
4. 
DRUG USE INVESTIGATION COHORT 
4.1. 
Number of subjects/centers 
According to MFDS requirement, at least 600 evaluable  subjects should be recruited for 
each drug use investigation. Therefore, max 1440 subjects (720 vaccinees ≥ 3 years old 
and above and 720 vaccinees between 6-35 months old)  will be enrolled through the drug 
use investigation period. We assume that 20% of enrolled participants might drop out 
(depending on the status of actual enrolment), then the plan can be adjusted accordingly. 
4.1.1. 
Recruitment at study centers 
 
This prospective, observational drug use investigation will be conducted at multiple 
centers (mainly in hospitals and private clinics) in Korea. 
 
Study population: Subjects aged ≥6 months who receive Fluarix Tetra as a part of 
routine practice at a private clinic or hospital. Only subjects to whom Fluarix Tetra 
is administered in routine clinical practice will be invited to participate in the drug 
use investigation. 
 
Eligible subjects will join the drug use investigation after the ICF/IAF has been 
signed by the subject/subject’s parent(s)/LAR(s). 
 
The drug use investigation is required to be conducted in at least one hospital with 
IRB oversight in order for the drug use investigation to be conducted in private 
clinics with no IRB. 
 
The vaccine will be purchased by the subject/subject’s parent(s)/LAR(s). 
 
The recruitment will be monitored by the study monitor. 
4.2. 
Inclusion criteria for enrolment 
All subjects must satisfy the following criteria at drug use investigation entry: 
 
Male or female subjects who were vaccinated with Fluarix Tetra or eligible to receive 
Fluarix Tetra according to the locally approved PI. 
Note: According to current approved PI, the subjects below are included. 

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 
Centers that are securing physicians who have expertise in the Fluarix Tetra and 
influenza, have received training necessary for performance of the study, or have 
practical experience 
 
Centers that can handle subject's personal information to keep them confidential 
 
Centers that can give support to enable the physician to be familiar with the 
notification and protocol 
5.2. 
Selection of physicians 
Physicians will be selected, who can fully achieve the following conditions: 
 
Physicians who have expertise in the Fluarix Tetra and influenza, have received 
training necessary for performance of the study, or have practical experience 
 
Physicians who can be familiar with and follow the notification and protocol 
6. 
CONDUCT OF THE STUDY 
6.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The drug use investigation will be conducted according to the local rules and regulations of 
the country (MFDS). 
Submission of the protocol and any protocol amendments to regulatory agencies will occur 
in accordance with local regulatory requirements. When submission to the local regulatory 
authority is required, the timing of the submission relative to IRB submission or approval 
and whether or not the authority will provide their approval of or favourable opinion on the 
protocol or amendment before it can be implemented will depend on local regulatory 
requirements. 
IRB approval has to be obtained prior to drug use investigation start. If the regulatory 
authority and/or IRB advise that drug use investigation studies do not need ethical review 
this must be documented. In any event, submission to an IRB in all institutions where IRB 
are available must be carried out and documented. 
6.2. 
Subject identification 
Subject numbers will be assigned sequentially to subjects who consent/whose 
parent(s)/LAR(s) consent to allow their children to participate in the drug use 
investigation, according to the range of subject numbers allocated to each study center. 

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6.3. 
General study aspects 
6.3.1. 
Description, dosage/administration of Fluarix Tetra 
6.3.1.1. 
Description of Fluarix Tetra 
Refer to the locally approved PI for information on the formulation and presentation of the 
Fluarix Tetra vaccine to be used in this drug use investigation. 
6.3.1.2. 
Dosage and administration of Fluarix Tetra 
The vaccine should be administered as an intramuscular injection (0.5 mL). 
6.3.2. 
Contraindications to subsequent vaccination 
Refer to the approved product label/package insert. 
6.3.3. 
Warnings and precautions 
Refer to the approved product label/package insert. 
6.3.4. 
Concomitant medication/vaccination 
All concomitant medications/vaccinations according to local practice are allowed during 
the drug use investigation and administration of these should be documented in the CRF. 
At each drug use investigation visit/contact, the physician should question the subject/ 
subject’s parent(s)/LAR(s) about any medication taken and vaccination received by the 
subject. 
All concomitant medications/vaccinations, with the exception of vitamins and/or dietary 
supplements, are to be recorded in the CRF. This also applies to concomitant medication 
administered prophylactically in anticipation of reaction to the vaccination and any 
medication intended to treat an AE. 
A prophylactic medication is a medication administered in the absence of any symptom 
and in anticipation of a reaction to the vaccination (e.g. an anti-pyretic is considered to be 
prophylactic when it is given in the absence of fever and any other symptom, to prevent 
fever from occurring [fever is defined as temperature 37.5 °C (99.5 °F) on oral/axillary/ 
tympanic setting]. 
Similarly, concomitant medication administered for the treatment of an SAE, at any time, 
must be recorded on the CRF concomitant medication section and in the SAE report form, 
as applicable. Refer to Section 7.1.3 for the definition of a SAE. 

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* Vaccination history is influenza vaccine history within the three previous seasons. 
a The subject/subject’s parent(s)/LAR(s) will be instructed to return the completed diary card to the physician or phone or 
mail, to report any AEs/ADRs/SAEs during the 21 days (Day 0 to Day 20) using diary cards after Fluarix Tetra is 
administered. 
** Subjects who are pregnant and receive Fluarix Tetra or subjects who become pregnant within 21 days after receiving 
Fluarix Tetra should report to/notify GSK, if possible. Pregnancy outcome in vaccinated pregnant subjects will be 
followed-up at 6-8 weeks after delivery, if possible. 
6.5.          Detailed description of study procedures 
6.5.1.         Procedures prior to study participation 
6.5.1.1.        Informed consent 
The ICF/IAF for this drug use investigation is for the collection and handling of personal 
and safety information after vaccination with Fluarix Tetra. Diary cards will be used to 
collect safety information and for SDV. The ICF/IAF for this drug use investigation will 
not include consent for vaccination as vaccination is at the discretion of the 
subject/subject’s parent(s)/LAR(s) and the physician. Informed consent may be taken after 
the vaccination. Parent(s)/LAR(s) who agree to have their eligible children participate in 
this drug use investigation will return the diary card to physician and accept a telephone 
interview from physicians for collection of safety information. Information collected will 
be treated confidentially and for the purpose of reporting SAE(s) to KIDS, and for public 
disclosure, if required. 
Before performing any other study procedure, the signed informed consent as ICF/IAF of 
the subject/subject’s parent(s)/LAR(s) must be obtained. 
6.5.2. 
Procedures related to vaccination and outside the drug use 
investigation 
6.5.2.1. 
Contraindications, warnings, and precautions to vaccination 
Contraindications, warnings, and precautions to vaccination are to be checked at the 
beginning of each vaccination visit (see Sections 6.3.2 and 6.3.3). 
6.5.2.2. 
Pre-vaccination body temperature 
The body (oral, axillary or tympanic) temperature of all subjects needs to be measured 
prior to Fluarix Tetra administration. The preferred route for recording temperature in this 
drug use investigation will be oral/axillary/tympanic depending on the age of enrolled 
vaccinees. . If the subject has fever [fever is defined as temperature 37.5 °C (99.5 °F) on 
oral, axillary or tympanic setting on the day of vaccination, the vaccination visit will be 
rescheduled. 
6.5.2.3. 
Vaccination 
 
After completing the prerequisite procedures prior to vaccination, Fluarix Tetra will 
be administered according to the PI (refer to Section 6.3.1.2 for description of the 
vaccine administration procedure). If the physician or delegate determines that the 

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subject’s health on the day of vaccination temporarily precludes vaccination, the visit 
will be rescheduled. 
 
The vaccinees will be observed closely for at least 30 minutes, with appropriate 
medical treatment readily available in case of anaphylaxis following the administration 
of Fluarix Tetra. 
6.5.3. 
Procedures during the study 
6.5.3.1. 
Check inclusion and exclusion criteria 
Check all applicable inclusion and exclusion criteria as described in Sections 4.2 and 4.3 
before enrolment. 
6.5.3.2. 
Demographic data 
Record demographic data such as age, height, weight, gender, and ethnicity in the subject’s 
CRF. 
6.5.3.3. 
Medical history 
Perform a history-directed medical examination and record any significant pre-existing 
conditions or signs and/or symptoms present judged by physicians in a subject prior to the 
start of the drug use investigation in the CRF. Treatment of any abnormality observed 
during this examination has to be performed according to local medical practice outside 
this drug use investigation or by referral to an appropriate health care provider. 
6.5.3.4. 
Vaccination history 
Influenza vaccine history within the three previous seasons must be recorded in the CRF. 
And collect information regarding all vaccines not foreseen in the protocol administered to 
the subject 21 days (Day -20 to Day 0) prior to vaccination with Fluarix Tetra. 
6.5.3.5. 
Physical examination 
Perform a physical examination of the subject. Collected information needs to be recorded 
in the CRF. 
6.5.3.6. 
Reproductive history (Only for Pregnant Subjects) 
Once the physician becomes aware of a pregnancy, the reproductive history of the pregnant 
subject will be collected and recorded in the CRF. 
6.5.3.7. 
Record concomitant medication/vaccination 
Concomitant medication/vaccination must be recorded in the CRF (see Section 6.3.4 ). 
6.5.3.8. 
Distribution, return, and transcription of diary cards 
The physician will provide the diary card to the subject/subject’s parent(s)/LAR(s) to 
record e.g. medication taken until the next visit/contact. The subject/subject’s 

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parent(s)/LAR(s) will be instructed to return the completed diary card to the physician at 
the next visit/contact. 
 
Collection and verification of the completed diary card will take place during 
discussion with the subject/subject’s parent(s)/LAR(s) at the subsequent visit/contact. 
Any unreturned diary cards will be sought from the subjects through telephone call(s) 
or any other convenient procedure. The physician will transcribe the collected 
information into the CRF in English. 
 
Collection of pregnancy outcome information from pregnant subjects who received 
Fluarix Tetra, at 6-8 weeks after the EDD, if possible. 
6.5.3.9. 
Record AEs, ADRs and SAEs 
 
The subject/subjects’ parent(s)/LAR(s) will be instructed to contact the physician 
immediately should the subjects manifest any signs or symptoms they perceive as 
serious. 
 
Refer to Section 7.2 for procedures for the physician to record AEs, ADRs and SAEs 
and to Section 7.3 for guidelines on how to report these ADRs/SAEs to GSK 
Vaccines. 
 
After vaccination, diary cards will be provided to the subjects to record body (oral/ 
axillary/tympanic) temperature and any AEs (i.e. on the day of vaccination and during 
the next 20 days) occurring after vaccination. The subject/subject’s parent(s)/LAR(s) 
will be instructed to return the completed diary card to the physician on their next drug 
use investigation visit or provide details during the phone or by postal mail. 
6.5.3.10. 
Procedures during follow-up visits/contacts for AEs/ ADRs /SAEs 
Note that some of the procedures to be performed during the follow-up visits/contacts 
(record AEs) are described in Section 6.5.3.6 up to Section 6.5.3.9. 
 
Collection and verification of completed diary card during discussion with the 
subject/subject’s parent(s)/LAR(s) at the subsequent visit/contact. Any unreturned 
diary cards will be sought from the subjects through telephone call(s) or any other 
convenient procedure. The physician will transcribe the collected information into the 
CRF in English. 
 
Checking for pregnancy within 21 days after Fluarix Tetra vaccination, if possible. 
6.5.3.11. 
Study conclusion 
The physician will review safety data collected to ensure accuracy and completeness and 
will complete the drug use investigation conclusion page in the CRF. 
7. 
       ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The physician or site staff is/are responsible during the drug use investigation for the 
detection and documentation of events meeting the criteria and definition of an AE, ADR 
and a SAE as provided in this protocol. 

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Each subject/subject’s parent(s)/LAR(s) will be instructed to contact the physician 
immediately should the subject manifests any signs or symptoms they perceive as serious. 
7.1. 
Safety definitions 
7.1.1. 
Definition of an adverse event 
An AE is any untoward medical occurrence in a subject, temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes failure 
to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
Examples of included AE: 
 
Significant or unexpected worsening or exacerbation of the condition. 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after Fluarix Tetra administration even though 
they may have been present prior to the start of the drug use investigation. 
 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of a concurrent 
medication (overdose per se should not be reported as an AE/SAE). 
 
Signs, symptoms temporally associated with vaccine administration. 
 
Significant failure of expected pharmacological or biological action. 
Examples of AE (DO NOT include): 
 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the drug use investigation that do not worsen. 
NB. AEs to be recorded as expected AEs are described in Section Error! Reference 
source not found.. All other AEs will be recorded as unexpected AEs. 
Example of events to be recorded in the medical history section of the CRF: 
 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the start 
of the drug use investigation (i.e. prior to the first study vaccination). 

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7.1.2.         Definition of adverse drug reaction 
Adverse drug reaction (ADR) represents adverse, unintended reactions from normal 
administration/use of the pharmaceuticals, etc. for which the causal relationship with the 
particular pharmaceutical cannot be excluded. Of the voluntarily reported adverse events, 
those with no known causal relationship with the pharmaceutical are deemed to be adverse 
drug reactions. 
7.1.3. 
 Definition of a serious adverse event 
A SAE is any AE that: 
a. 
Results in death. 
b. Is life-threatening. 
NB: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
c. 
Requires hospitalisation or prolongation of existing hospitalisation. 
NB: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or out-patient setting. 
Complications that occur during hospitalisation are also considered AEs. If a 
complication prolongs hospitalisation or fulfils any other serious criteria, the event 
will also be considered serious. When in doubt as to whether ‘hospitalisation’ occurred 
or was necessary, the AE should be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition (known/diagnosed 
prior to informed consent signature) that did not worsen from baseline is not 
considered an SAE. 
d. Results in disability/incapacity, or 
NB: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained ankle) 
which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study subject. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. Examples 
of such events are invasive or malignant cancers, intensive treatment in an emergency 

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room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not 
result in hospitalisation. 
7.1.4. 
Pregnancy 
Any eligible pregnant female for whom the participating physician has decided to 
administer Fluarix Tetra vaccine may be enrolled in the drug use investigation after the 
subject has signed the ICF/IAF. If the participating physician becomes aware of a 
pregnancy during the course of the 21 days follow-up of his/her female subjects, he/she has 
to notify GSK using the Pregnancy Notification form within 2 weeks, if possible. 
All pregnant subjects in the drug use investigation will be followed up to 6-8 weeks after 
delivery for outcome of pregnancy, if possible. 
While pregnancy itself is not considered an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded and reported as an 
AE or a SAE, as described in Section 7.1.1 and 7.1.3, and will be followed, if possible, as 
described in Section 7.4.1. 
7.1.5. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
Abnormal laboratory findings (e.g. clinical chemistry, haematology, urinalysis) or other 
abnormal assessments that are judged by the physician to be clinically significant will be 
recorded as AEs or SAEs if they meet the definition of an AE, as defined in section 7.1.1, 
or of an SAE, as defined in Section 7.1.3. Clinically significant abnormal laboratory 
findings or other abnormal assessments that are detected during the drug use investigation 
or are present at baseline and significantly worsen following the start of the study will be 
reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or 
other abnormal assessments that are associated with the disease being studied, unless 
judged by the physician as more severe than expected for the subject’s condition, or that 
are present or detected at the start of the drug use investigation and do not worsen, will not 
be reported as AEs or SAEs. 
The physician will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
7.2. 
Detecting and recording adverse events, adverse drug 
reactions, serious adverse events, and pregnancies 
7.2.1. 
Time period for detecting and recording adverse events, adverse 
drug reactions serious adverse events, and pregnancies 
All AEs, ADRs and SAEs starting immediately following administration of Fluarix Tetra 
must be recorded onto the CRF and all ADRs and SAEs must be reported using the ADR 
reporting form and SAE reporting form, the latter to be sent to GSK according to the 

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As a consistent method of collecting safety information, the subject/subject’s 
parent(s)/LAR(s) should be asked a non-leading question such as: 
 ‘Have you acted differently or felt different/has your child acted differently or felt different 
in any way since receiving the vaccine or since the last visit?’ 
When an AE/SAE occurs, it is the responsibility of the physician to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) relative to 
the event. The physician will then record all relevant information regarding an 
AE/ADR/SAE on the CRF, ADR Report Form or SAE Report Form as applicable. It is not 
acceptable for the physician to send photocopies of the subject’s medical records to GSK 
Vaccines instead of the appropriate completed AE/SAE pages on the CRF. However, there 
may be instances when copies of medical records for certain cases are requested by GSK 
Vaccines. In this instance, all subject identifiers will be blinded on the copies of the 
medical records prior to submission to GSK Vaccines. 
The physician will attempt to establish a diagnosis pertaining to the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/ADR/SAE and not the individual signs/symptoms. 
7.2.2.2.        Assessment of intensity 
Intensity of the following AEs will be assessed as described: 
The physician will assess the maximum intensity that occurred over the duration of the 
event for all other AEs, including ADR and SAEs reported during the drug use 
investigation. The assessment will be based on the physician’s clinical judgement. 
The intensity of each AE, ADR and SAE recorded in the CRF, ADR Report form or SAE 
Report Form, as applicable, should be assigned to one of the following categories: 

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CCI
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.

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Is there a reasonable possibility that the AE may have been caused by Fluarix Tetra? 
Non-serious and serious AEs will be evaluated as two distinct events. If an event meets 
criteria to be determined ‘serious’ (see Section 7.1.3), additional examinations/tests will be 
performed by the physician in order to determine ALL possible contributing factors 
applicable to each SAE. 
Possible contributing factors include: 
 
Medical history 
 
Other medication 
 
Protocol required procedure 
 
Other procedure not required by the protocol 
 
Lack of efficacy of the vaccine(s), if applicable 
 
Erroneous administration 
 
Other cause (specify) 
NOTE: The use of the term “drug” here refers to Fluarix Tetra. 
The relationship of the drug to an AE will be determined by the physician based on the 
following definitions: 
1. Certain: 
 
The relationship of the administration and use of the drug is reasonable and it is 
not able to be explained by other medication, chemical substances or concomitant 
disease, it shows clinically reasonable response on withdrawal of the drug, the 
decisive case in the pharmacological or phenomenological aspect on re-challenge 
of the drugs if needed. 
2. Probable/Likely: 
 
The temporal sequence of the administration and use of the drug is appropriate 
and it does not seem that it is accompanied by other medications, chemical 
substances or concomitant disease, in the case that shows clinically appropriate 
response on withdrawal of the drug (no information for re-challenge). 
3. Possible: 
 
The temporal sequence of the administration and use of the drug is appropriate but 
it is also able to be explained by other medications, chemical substances or 
concomitant disease, and information related to withdrawal of the drug is 
insufficient or vague. 
4. Not-Related: 

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Amendment 3 
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 
The AE is not related to the drug if there is evidence that clearly indicates an 
alternative explanation. If the subject has not received the drug, the timing of the 
exposure to the drug and the onset of the AE are not reasonably related in time, or 
other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
5. Conditional/Unclassified: 
 
In the case that more information is needed for a proper evaluation or additional 
information is under review. 
6. Unassessable/Unclassifiable: 
 
In the case that could not be judged due to insufficient or conflicting information 
and no way to complement or validate. 
7.2.2.4.    Assessment of the outcomes 
Outcome of any non-serious AE occurring within 21 days post-vaccination or any SAE 
reported during the entire drug use investigation will be assessed as: 
 
Recovered/resolved. 
 
Not recovered/not resolved. 
 
Recovering/resolving. 
 
Recovered with sequelae/resolved with sequelae. 
 
Fatal (SAEs only). 
 
Unknown. 
7.2.2.5.     Medically attended visits 
For each AE the subject experiences, subject/subject’s parent(s)/LAR(s) will be asked if 
the subject received medical attention defined as hospitalisation, an emergency room visit 
or a visit to or from medical personnel (medical doctor) for any reason and this information 
will be recorded in the CRF. 
7.3. 
Reporting of serious adverse events, adverse drug reactions                          
and pregnancies 
7.3.1.       Prompt reporting of serious adverse events and other events to                      
GSK Vaccines 
SAEs will be reported promptly to GSK as described in Table 3 once the physician 
determines that the event meets the protocol definition of an SAE. 
ADRs will be reported promptly to GSK as described in Table 3, if possible, once the 
physician becomes aware of an ADR. 

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Amendment 3 
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via the telephone does not replace the need for the physician to complete and sign the SAE 
Report Form within 24 hours. 
In the event of a death determined by the physician to be related to vaccination, sending of 
the fax must be accompanied by telephone call to the Contact for Reporting SAEs, ADRs 
and Pregnancies. 
7.3.4.    Completion and transmission of ADR report to GSK Vaccines   
Once the physician is aware of an adverse drug reaction that the subject experienced, 
he/she should report to GSK. 
The physician (or his/her designee) should record as all detailed information obtained 
about the adverse drug reaction as possible in the section for ADR Report Form completely 
and send to GSK. If the physician does not have all information about the adverse drug 
reaction, he/she does not wait for additional information before completing the form and 
notifies to GSK. When obtaining additional information, the report form should be 
updated. 
The physician sends ADR Report Form to the Contact for Reporting SAEs, ADRs and 
Pregnancies that collects an adverse drug reaction by fax or e-mail.  
7.3.5. 
Completion and transmission of pregnancy reports to GSK 
Vaccines 
Once the physician becomes aware that a subject is pregnant, the physician (or designee) 
must complete a Pregnancy Report Form and fax or e-mail it to the Contact for Reporting 
SAEs, ADRs and Pregnancies (refer to the Sponsor Information Sheet) within 2 weeks, if 
possible. 
The Pregnancy Report Form will always be completed as thoroughly as possible with all 
available details and then dated and signed by the physician (or designee), if possible. Even 
if the physician does not have all information regarding the pregnancy, the form should 
still be completed and forwarded to GSK within 2 weeks, if possible. Once additional 
relevant information is received, the form will be updated and forwarded to GSK within 2 
weeks, if possible. 
In absence/dysfunction of facsimile equipment, the Contact for Reporting SAEs, ADRs 
and Pregnancies should be notified by telephone within 2 weeks, if possible. As soon as 
the facsimile equipment is working again, the physician (or designee) must fax the 
Pregnancy Report Form to the Contact for Reporting SAEs, ADRs and Pregnancies (refer 
to the Sponsor Information Sheet) within 2 weeks, if possible. 
7.3.6.       Regulatory reporting requirements for serious adverse events 
The physician will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 0. GSK Vaccines has a legal responsibility to promptly notify, as 
appropriate, both the local regulatory authority and other regulatory agencies about the 

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safety of a product surveillance. Prompt notification of SAEs by the physician to the 
Contact for Reporting SAEs, ADRs and Pregnancies is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met. 
7.4. 
Follow-up of adverse events, serious adverse events, and 
pregnancies 
7.4.1. 
Follow-up of adverse events and serious adverse events 
After the initial AE/SAE report, the physician is required to proactively follow each 
subject and provide further information to GSK Vaccines on the subject’s condition. 
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the drug use investigation. 
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 21 
days after vaccination. 
Physicians will follow-up subjects: 
 
With SAEs or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up. 
 
Or in the case of other non-serious AEs, until or they are lost to follow-up. 
Clinically significant laboratory abnormalities will be followed-up until they have returned 
to normal or a satisfactory explanation has been provided. Additional information 
(including but not limited to laboratory results) relative to the subsequent course of such 
abnormalities noted for any subject must be made available to the study monitor. 
GSK Vaccines may request that the physician perform or arrange for the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The physician is obliged to assist. If a 
subject dies during participation in the drug use investigation or during a recognised 
follow-up period, GSK Vaccines will be provided with a copy of any available post-
mortem findings, including histopathology. 
7.4.2. 
Follow-up of pregnancies 
Pregnant subjects will be followed to determine the outcome of the pregnancy, if possible. 
At the end of the pregnancy, whether full-term or premature, information on the status of 
the mother and child will be forwarded to GSK, if possible. Generally, the follow-up 
period does not need to be longer than 6 to 8 weeks after the EDD, if possible. 

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7.5.          Treatment of adverse events 
Treatment of any AE is at the sole discretion of the physician and according to current 
good medical practice. Any medication administered for the treatment of an AE should be 
recorded in the subject’s CRF. 
8. 
         EFFICACY ASSESSMENT 
Efficacy of a vaccine is assessed by the reduction in the occurrence of the disease targeted 
by the vaccine in people immunized with the vaccine comparing to those not vaccinated. A 
drug use investigation will be implemented within the routine clinical setting to collect 
unspecified safety and efficacy data of the drug through the study period. It will be difficult 
for the physicians to request the subject after vaccination to revisit for assessment and/or 
laboratory testing not deemed necessary in normal clinical practice due to the physical, 
logistic, and economic burden to the subject. Therefore, the efficacy assessment of Fluarix 
Tetra would likely be omitted in this drug use investigation. 
9. 
       SUBJECT COMPLETION AND WITHDRAWAL 
9.1. 
Subject completion 
A subject who is available for the concluding follow-up contact 21 days after receiving 
Fluarix Tetra is considered to have completed the drug use investigation. 
9.2. 
Subject withdrawal 
Subjects who are withdrawn because of SAEs/AEs must be clearly distinguished from 
subjects who are withdrawn for other reasons. Physicians will follow subjects who are 
withdrawn as result of a SAE/AE until resolution of the event (see Section 7.3). 
Withdrawals will not be replaced. 
From an analysis perspective, a ‘withdrawal’ from the drug use investigation refers to any 
subject who was not available for the concluding contact foreseen in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
A subject is considered a ‘withdrawal’ from the drug use investigation when no study 
procedure has occurred, no follow-up has been performed and no further information has 
been collected for this subject from the date of withdrawal/last contact. 
Physicians will make an attempt to contact those subjects who do not return for scheduled 
visits or follow-up. 
Information relative to the withdrawal will be documented in the CRF. The physician will 
document whether the decision to withdraw a subject from the study was made by the 

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10.5.         Statistical methods 
10.5.1.       Analysis of demographics/baseline characteristics 
Descriptive demographic characteristics (age, height, weight, gender, and ethnicity) of the 
study cohort will be tabulated. 
In the descriptive summary, mean, standard deviation, median, minimum, and maximum 
will be computed for continuous variables such as age. Frequencies and percentages will 
be calculated for categorical variables such as gender. 
The pre-existing medical history, vaccination history within the three previous seasons 
(yes/no), concomitant medication/vaccination at least once during the 21 days (Day 0 to 
Day 20) follow up period and record years will also be presented. 
The distribution of subjects vaccinated among the drug use investigation centers by years 
will be tabulated. 
10.5.2.       Analysis of safety 
A safety analysis based on the total safety cohort will include all subjects who were 
vaccinated as per Korean PI and have completed 21-days follow-up after at least one dose, 
regardless of the number of dose. 
10.5.2.1.      Within group assessment 
The AEs/ADRs/SAEs will be analysed in the drug use investigation report according to the 
expectedness and unexpectedness criteria (Refer to GLOSSARY OF TERMS for the 
definitions of expected AEs and unexpected AEs). 
The number and percentage, with exact 95% CI, of any AEs, ADRs and SAEs occurring 
within 21 days (Day 0 to Day 20) will be tabulated for the number of subjects receiving 
Fluarix Tetra. 
The verbatim reports of signs and symptoms will be matched and coded according to the 
appropriate WHOART PT. The drug use investigation physician will review and confirm 
the appropriate WHOART PT by responding to data queries if any discrepancies are 
reported while coding. The percentage of subjects with AEs, ADRs, and SAEs occurring 
within 21 days (Day 0 to Day 20) with its exact 95% CI will be tabulated by PT. 
The outcome of pregnancy (reported in the pregnancy report form) for subjects who were 
pregnant at the time of vaccination and those who become pregnant within 21 days after 
vaccination will be presented, if possible. 
SAEs reported during the drug use investigation period [each subject receiving the vaccine 
up to 21 days (Day 0 to Day 20) after vaccination and for pregnant subjects until 6-8 weeks 
after delivery] will be described in detail, if possible. 

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The incidence proportion of AEs as overall and by age group and gender will be 
measured with the exact 95% CI. An exploratory comparison between these groups will 
be performed using Chi-square exact test with the statistical significance level 0.05. 
11. ADMINISTRATIVE MATTERS 
To comply with acceptable ethical principles, local regulatory requirements, and 
administrative obligations relating to data collection, monitoring, archiving data, audits, 
confidentiality, and public disclosure must be fulfilled. Blinding of subjects initials when 
safety data is used for analysis and for GSK LOC provides the subject’s No. on the PMS 
report before submission to MFDS. (GSK does not forward personally identifiable 
information and MFDS requires reporting of drug use investigation subject’s No. in the 
PMS report). 
11.1. 
Case Report Form 
CRFs (and subject diary cards, if applicable), will be supplied by GSK Vaccines for 
recording all data. 
Unless specifically required by MFDS, subject initials will not be collected nor transmitted 
to GSK. Subject data necessary for analysis and reporting will be entered/transmitted into a 
validated database or data system. Clinical data management will be performed in 
accordance with applicable data cleaning procedures. 
While completed CRFs are reviewed by a GSK Vaccines’ designated study monitor at the 
study site, omissions or inconsistencies detected by subsequent in-house CRF review may 
necessitate clarification or correction of data or omissions or inconsistencies with 
documentation and approval by the physician or appropriately qualified designee. In all 
cases the physician remains accountable for the study data collected. 
Any questions or comments related to the CRF should be directed to the assigned study 
monitor. 
The physician will keep a paper copy of each CRF and any data query forms of the final 
version of the data generated at the site. 
11.2. 
Monitoring by GSK Vaccines 
Monitoring visits by a GSK Vaccines’ designated study monitor are for the purpose of 
confirming that GSK Vaccines’ sponsored study are being conducted in accordance with 
the acceptable ethical principles and the regulatory requirement(s) (verifying continuing 
compliance with the protocol, amendment(s), verifying that the site staff and facilities 
continue to be adequate to conduct the study). 
The physician must ensure provision of reasonable time, space, and qualified personnel for 
monitoring visits. 

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Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a CRF review and a SDV. By SDV we 
understand verifying CRF by comparing them with the source data that will be made 
available by the physician for this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the CRF. This document should be completed and signed by the study monitor and 
physician and should be filed in the monitor’s and physician’s study file. Any data item for 
which the CRF will serve as the source must be identified, agreed, and documented in the 
source documentation agreement form. 
In accordance with applicable regulations, GSK monitors will contact the site prior to the 
start of the study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory and ethical requirements. When reviewing data 
collection procedures, the discussion will also include identification, agreement, and 
documentation of data items for which the CRF entries will serve as the source document. 
GSK will monitor the study to verify that, amongst others, the: 
 
Data are authentic, accurate, and complete. 
 
Safety and rights of subjects are being protected. 
 
Study is conducted in accordance with the currently approved protocol and any 
amendments, any other study agreements, acceptable ethical principles, applicable 
local regulatory requirements, and all applicable regulatory requirements. 
The physician and the head of the medical institution (where applicable) agrees to allow 
the monitor direct access to all relevant documents. 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the physician or site staff, as appropriate, in accordance with 
applicable regulations. 
11.3. 
Archiving of data at study sites 
Following closure of the study, the physician must maintain all site study records in a safe 
and secure location. The records must be maintained to allow easy and timely retrieval, 
when needed (e.g. audit or inspection), and whenever feasible, to allow any subsequent 
review of data in conjunction with assessment of the facility, supporting systems, and staff. 
Where permitted by applicable laws/regulations or institutional policy, some or all of these 
records can be maintained in a validated format other than hard copy (e.g. microfiche, 
scanned, electronic for studies with an eCRF); however, caution needs to be exercised 
before such action is taken. The physician must assure that all reproductions are legible 
and are a true and accurate copy of the original and meet accessibility and retrieval 
standards, including re-generating a hard copy, if required. Furthermore, the physician 
must ensure there is an acceptable back-up of these reproductions and that an acceptable 
quality control process exists for making these reproductions. 

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GSK will inform the physician/institution of the time period for retaining these records to 
comply with all applicable regulatory requirements. However, the physician/institution 
should seek the written approval of the sponsor before proceeding with the disposal of 
these records. The minimum retention time will meet the strictest standard applicable to 
that site for the study, any institutional requirements or applicable laws or regulations; 
otherwise, the minimum retention period will default to 3 years. 
The physician/institution must notify GSK of any changes in the archival arrangements, 
including, but not limited to, the following: archival at an off-site facility, transfer of 
ownership of the records in the event the physician leaves the site. 
11.4. 
Audits 
To ensure compliance with acceptable ethical principles 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 can occur at any time 
during or after completion of the study. If an audit or inspection occurs, the physician 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. 
11.5. 
Posting of information on public registers 
Study information from this protocol will be posted on www.clinicaltrials.gov before 
enrolment of subjects begins. 
11.6. 
Ownership, confidentiality, and publication 
11.6.1. 
Ownership 
All information provided by GSK and all data and information generated by the site as part 
of the study (other than a subject’s medical records) are the sole property of GSK. 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights which are conceived or reduced to practice by site staff during the course of 
or as a result of the study are the sole property of GSK, and are hereby assigned to GSK. 
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between GSK and the study site, that contract’s 
ownership provisions shall apply rather than this statement. 
11.6.2. 
Confidentiality 
Documented evidence that a potential physician is aware and agrees to the confidential 
nature of the information related to the study must be obtained by means of a 
confidentiality agreement. 
All information provided by GSK and all data and information generated by the site as part 
of the study (other than a subject’s medical records) will be kept confidential by the 

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physician and other site staff. This information and data will not be used by the physician 
or other site personnel for any purpose other than conducting the study. These restrictions 
do not apply to: (i) information which becomes publicly available through no fault of the 
physician or site staff; (ii) information which it is necessary to disclose in confidence to an 
IRB solely for the evaluation of the study; (iii) information which it is necessary to 
disclose in order to provide appropriate medical care to a study subject; or (iv) study 
results which may be published as described in the next paragraph. If a written contract for 
the conduct of the study which includes confidentiality provisions inconsistent with this 
statement is executed, that contract’s confidentiality provisions shall apply rather than this 
statement. 
11.6.3. 
Publication 
For multi-centers studies, the first publication or disclosure of study results shall be a 
complete, joint multi-centers publication or disclosure coordinated by GSK. Thereafter, 
any secondary publications will reference the original publication(s). 
Prior to submitting for publication, presentation, use for instructional purposes, or 
otherwise disclosing the study results generated by the site (collectively, a ‘Publication’), 
the physician shall provide GSK with a copy of the proposed Publication and allow GSK a 
period to review the proposed Publication (at least 21 working days, or at least 15 working 
days for abstracts/posters/presentations). Proposed Publications shall not include either 
GSK confidential information other than the study results or personal data on any subject, 
such as name or initials. 
At GSK’s request, the submission or other disclosure of a proposed Publication will be 
delayed a sufficient time to allow GSK to seek patent or similar protection of any 
inventions, know-how or other intellectual or industrial property rights disclosed in the 
proposed Publication. 
If a written contract for the conduct of the study, which includes publication provisions 
inconsistent with this statement is executed, that contract’s publication provisions shall 
apply rather than this statement. 
11.6.4. 
  Provision of study results to physicians, posting to the clinical  
trials registers, and publication 
Where required by applicable regulatory requirements, an physician signatory will be 
identified for the approval of the study report. The physician 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. 
The results summary will be posted to the GSK Clinical Study Register no later than 12 
months after the LSLV or sooner if required by legal agreement, local law or regulation. In 
addition, a manuscript will be submitted to a peer-reviewed journal for publication within 
18 months of LSLV. When manuscript publication in a peer-reviewed journal is not 
feasible, further study information will be posted to the GSK Clinical Study Register to 
supplement the results summary. 

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Amendment 3 
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A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge. 
 
12. 
COUNTRY SPECIFIC REQUIREMENTS 
Not applicable 
13. 
REFERENCES 
1) 시판 후 약물감시 업무 가이드라인 
https://www.drugsafe.or.kr/iwt/ds/ko/bbs/EgovBbs.do?bbsId=BBSMSTR_000000
000041&nttId=536 
2) Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of binomial. Biometrika. 1934;26:404-413. 
3) Barr IG, Komadina N, Durrant C, Sjogren H, Hurt AL, Shaw RP. Circulation and 
antigenic drift in human influenza B-viruses in SE Asia and Oceania since 2000 et 
al. Commun Dis Intell. 2006;30:350-357. 
4) Beyer WEP, Palache AM., Baljet M et al. Antibody induction by influenza 
vaccines in elderly: a review of the literature. Vaccine. 1989;7:385-394. 
5) Brydak L, Machala M. Humoral immune response to influenza vaccination in 
patients from high risk groups. Drugs. 2000;60:35-53. 
6) CDC. http://www.cdc.gov/flu/weekly/fluactivity.htm 
7) Englund JA, Walter EB, Gbadebo A, Monto AS, Zhu Y, Neuzil KM. 
Immunization with trivalent inactivated influenza vaccine in partially immunized 
toddlers. Pediatrics. 2006;118:e579-e585. 
8) Hannoun C, Megas F, and Piercy J. “Immunogenicity and protective efficacy of 
influenza vaccination”. Virus Res. 2004;103:133-138. 
9) Heckler R, Baillot A, Engelmann H, Neumeier E, Windorfer A. Cross-protection 
against homologous drift variants of influenza A and B after vaccination with split 
vaccine. Intervirology. 2007;50:58-62. 
10) Levandowski RA, Regnery HL, Staton E, Burgess BG, Williams MS, Groothuis 
IR. Antibody responses to influenza B viruses in immunologically unprimed 
children. Pediatrics. 1991;88:1031-1036. 

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CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
53 
Protocol Administrative Change Amendment 3 Rationale 
Amendment number: 
Administrative Change 1 Amendment 3 
Rationale/background for changes: 
• 
Administrative changes (change of contact details of safety reporting (e mail 
address), corrections to names of study personnel, correction of typographical 
error) 
 
Editorial changes  
 
Changes as per MFDS Request 
─ Describe statistical processing method in “10.5.2. Safety Analysis” 
─ Correct typo errors on Research Subject Inclusion Criteria Table in “4.2. 
Inclusion Criteria” (ONLY applicable in Korean protocol) 
 
Clarification of ADR analysis to be consistent with planned AEs and SAEs 
analysis 
 
Protocol Administrative Change 1 Amendment 3 Physician 
Agreement 
 
SYNOPSIS 
Study design 
(Amendment 3: 08 
Mar 2019) 
Drug use investigation design: A prospective, observational, 
non-comparative, multi-center study in Korea. 
Vaccination schedule: Vaccination as per locally approved PI 
(which is not part of the drug use investigation): to adults and 
previously vaccinated children aged ≥6 months, a single 0.5 
ml dose of Fluarix Tetra will be administered. To previously 
unvaccinated children aged 6 months to <9 years, two doses 
will be administered with a second 0.5 ml dose at least 4 
weeks apart from the first one as per the local PI in Korea. 
Safety monitoring: 
- 
Recording of all AEs during the 21 days (Day 0 to 
Day 20) using diary cards after Fluarix Tetra is 
administered. 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
54 
- 
Recording of all ADRs reported during the 21 
days (Day 0 to Day 20) follow-up period after 
administration of Fluarix Tetra 
- 
Recording of SAEs from the date of vaccination 
until 21 days (Day 0 to Day 20) after Fluarix Tetra 
is administered during the subject’s participation in 
the study. 
…… 
Duration of the drug use investigation:  
- 6 years (for children 36 months and above and adults). 
- 4 years (for children from 6 to 35 months of age)  
Type of drug use investigation: Self-contained. 
Data collection: Standardised hard copy CRF (SAEs, ADRs, 
Pregnancy information will be collected by using the SAE, 
ADR, Pregnancy Reporting Form). 
Discussion of study 
design 
(Amendment 3: 08 
Mar 2019) 
All AEs including ADRs and SAEs reported during the 21 
days (Day 0 to Day 20) post-vaccination follow-up period of 
Fluarix Tetra in the drug use investigation will be collected as 
part of safety data in this drug use investigation. These AEs 
will be further classified by GSK at the time of statistical 
analyses as expected/unexpected based on the current PI. 
 
3. 
 
STUDY DESIGN OVERVIEW 
Sequential Allocation of Subject Numbers 
 
 
Fluarix Tetra (N=max 1,440 (720 
vaccinees ≥ 3 years old, 720 
vaccinees between 6-35 months 
old)) 
 
 
 
 
 
           Vaccination 
           (Fluarix Tetra) 
 
Drug Use Investigation 
Conclusion 
21 days (Day 0 to Day 20) 
follow-up after vaccination 
with Fluarix Tetra 
 
N: Number of subjects planned to be enrolled 
Drug use investigation conclusion will depend on the 21 days contact of the subject in the drug use investigation. 
Definition of Conclusion of drug use investigation for a subject: A subject who is available for the concluding follow-up 
contact 21 days (Day 0 to Day 20) after receiving Fluarix Tetra is considered to have completed the drug use 
investigation. 
…… 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
55 
 
Safety monitoring: 
 
Recording of all AEs during the 21 days (Day 0 to Day 20) using diary cards after 
Fluarix Tetra is administered. 
 
The participating physician will transcribe the collected information into the CRF 
in English. 
 
Recording of all ADRs reported during the 21 days (Day 0 to Day 20) follow-up 
period after administration of Fluarix Tetra 
 
Recording of SAEs from the date of vaccination until 21 days (Day 0 to Day 20) 
after Fluarix Tetra is administered during the subject’s participation in the study. 
 
All AEs , ADRs and SAEs starting immediately following administration of 
Fluarix Tetra must be recorded onto the CRF and all ADRs and SAEs must be 
reported using the ADR reporting form and SAE reporting form, the latter to be 
sent to GSK according to the required timelines, irrespective of intensity or 
whether or not they are considered vaccination-related. 
 
Parents of children aged 6 months to <12 years wil be contacted  to provide 
details of any AEs experienced by the children 21 days after the children receives 
the vaccination.  
 
Subjects for whom diary card transcription into CRF will be done through phone 
contact are considered to have completed the drug use investigation. 
…… 
 
Duration of the drug use investigation:  
- 6 years (for children 36 months and above and adults). 
- 4 years (for children from 6 to 35 months of age)  
 
Type of drug use investigation: Self-contained. 
 
Data collection: Standardised hard copy CRF (SAEs, ADRs, Pregnancy information 
will be collected by using the SAE, ADR, Pregnancy Reporting Form). 
 
6.3.4.1.    Time window for recording concomitant medication/vaccination in the 
CRF 
All concomitant medications, with the exception of vitamins and/or dietary supplements, 
administered at any time during the period starting with the administration of Fluarix Tetra 
and ending 21 days (Day 0 to Day 20) after vaccination must be recorded in the CRF. 
Any vaccine not foreseen in the drug use investigation protocol administered in the period 
beginning 21 days (Day -20 to Day 0) preceding the dose of Fluarix Tetra and ending 21 
days (Day 0 to Day 20) after the dose of Fluarix Tetra must be recorded in the CRF. 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
56 
Any investigational medication or vaccine administered throughout the drug use 
investigation (i.e. from 21 days before the first dose of the vaccine and 21 days after 
administration of the dose of the vaccine) must be recorded in the CRF. 
 
6.5.3.9.   
Record AEs, ADRs and SAEs 
 
The subject/subjects’ parent(s)/LAR(s) will be instructed to contact the physician 
immediately should the subjects manifest any signs or symptoms they perceive as 
serious. 
 
Refer to Section 7.2 for procedures for the physician to record AEs, ADRs and SAEs 
and to Section 7.3 for guidelines on how to report these AEs /ADRs/SAEs to GSK 
Vaccines. 
 
After vaccination, diary cards will be provided to the subjects to record body (oral/ 
axillary/tympanic) temperature and any AEs (i.e. on the day of vaccination and during 
the next 20 days) occurring after vaccination. The subject/subject’s parent(s)/LAR(s) 
will be instructed to return the completed diary card to the physician on their next drug 
use investigation visit or provide details during the phone or by postal mail. 
 
6.5.3.10.   Procedures during follow-up visits/contacts for AEs/ ADRs /SAEs 
Note that some of the procedures to be performed during the follow-up visits/contacts 
(record AEs) and are described in Section 6.3.4 6.5.3.6 up to Section 6.5.3.9. 
 
7.    
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The physician or site staff is/are responsible during the drug use investigation for the 
detection and documentation of events meeting the criteria and definition of an AE or , 
ADR and a SAE as provided in this protocol. 
Each subject/subject’s parent(s)/LAR(s) will be instructed to contact the physician 
immediately should the subject manifest any signs or symptoms they perceive as serious. 
 
7.1.4.   
 Adverse events Pregnancy  
All AEs reported during the 21 days (Day 0 to Day 20) follow up period after 
administration of the vaccine dose will be recorded using diary card provided to the 
subject/subject’s parent(s)/LAR(s). The AEs/SAEs will be analysed in the drug use 
investigation report according to the expectedness and unexpectedness criteria as defined 
in the locally approved PI (also refer to GLOSSARY OF TERMS). 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
58 
All AEs/ADRs/SAEs reported within 21 days (Day 0 to Day 20) of administration of 
Fluarix Tetra within the drug use investigation and all SAEs reported from the date of 
vaccination up to 21 days (Day 0 to Day 20) after administration of Fluarix Tetra within 
the study need to be recorded in the CRF. These AEs/ADRs/SAEs will be classified as 
expected/unexpected at the time of statistical analyses (refer to GLOSSARY OF TERMS 
for definitions of expected/unexpected AEs). 
Note: Assessment of causality and outcome will be performed by the physician according 
to the following classification. Causality will be assessed as: Certain; Probable/Likely; 
Possible; Not-Related; Conditional/ Unclassified; Unassessable/Unclassifiable. Outcome 
will be assessed as recovered; not recovered; recovering; resolved with sequelae; fatal; 
unknown. 
 
7.2.2.1.   
Active questioning to detect adverse events, adverse drug 
reactions and serious adverse events 
The physician needs to collect information on any AE in the subject. At the time of 
analysis, an assessment on whether the AE is expected (contained in the local PI) or 
unexpected (not contained in the local PI) will be done by GSK. 
As a consistent method of collecting safety information, the subject/subject’s 
parent(s)/LAR(s) should be asked a non-leading question such as: 
 ‘Have you acted differently or felt different/has your child acted differently or felt different 
in any way since receiving the vaccine or since the last visit?’ 
When an AE/SAE occurs, it is the responsibility of the physician to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) relative to 
the event. The physician will then record all relevant information regarding an 
AE/ADR/SAE on the CRF, ADR Report Form or SAE Report Form as applicable. It is not 
acceptable for the physician to send photocopies of the subject’s medical records to GSK 
Vaccines instead of the appropriate completed AE/SAE pages on the CRF. However, there 
may be instances when copies of medical records for certain cases are requested by GSK 
Vaccines. In this instance, all subject identifiers will be blinded on the copies of the 
medical records prior to submission to GSK Vaccines. 
The physician will attempt to establish a diagnosis pertaining to the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/ADR/SAE and not the individual signs/symptoms. 
 
7.2.2.2.        Assessment of intensity 
Intensity of the following AEs will be assessed as described: 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
59 
The physician will assess the maximum intensity that occurred over the duration of the 
event for all other AEs, including ADR and SAEs reported during the drug use 
investigation. The assessment will be based on the physician’s clinical judgement. 
The intensity of each AE, ADR and SAE recorded in the CRF, ADR Report form or SAE 
Report Form, as applicable, should be assigned to one of the following categories: 
 
10.5.1.       Analysis of demographics/baseline characteristics 
Descriptive demographic characteristics (age, height, weight, gender, and ethnicity) of the 
study cohort will be tabulated. 
In the descriptive summary, mean, standard deviation, median, minimum, and maximum 
will be computed for continuous variables such as age. Frequencies and percentages will 
be calculated for categorical variables such as gender. 
The pre-existing medical history, vaccination history within the three previous seasons 
(yes/no), concomitant medication/vaccination at least once during the 21 days (Day 0 to 
Day 20) follow up period and record years will also be presented. 
The distribution of subjects vaccinated among the drug use investigation centers by years 
will be tabulated. 
 
10.5.2.1.      Within group assessment 
The AEs/ADRs/SAEs will be analysed in the drug use investigation report according to the 
expectedness and unexpectedness criteria (Refer to GLOSSARY OF TERMS for the 
definitions of expected AEs and unexpected AEs). 
The number and percentage, with exact 95% CI, of any AEs and ADRs, ADRs and SAEs 
occurring within 21 days (Day 0 to Day 20) will be tabulated for the number of subjects 
receiving Fluarix Tetra. 
The verbatim reports of signs and symptoms will be matched and coded according to the 
appropriate WHOART PT. The drug use investigation physician will review and confirm 
the appropriate WHOART PT by responding to data queries if any discrepancies are 
reported while coding. The percentage of subjects with AEs, ADRs, and AEs rated as 
grade 3 SAEs occurring within 21 days (Day 0 to Day 20) with its exact 95% CI will be 
tabulated by PT. 
The number and percentage of subjects who received concomitant medication/ vaccination 
at least once during the 21 days (Day 0 to Day 20) follow up period will be tabulated, with 
exact 95% CI. The number and percentage of doses for which the subjects received 
concomitant medication/vaccination at least once during the 21 days (Day 0 to Day 20) 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
60 
follow up period will be tabulated over the entire drug use investigation period, with exact 
95% CI. Similar tabulations will be done for the number of subjects by types of 
medication/vaccination during the entire drug use investigation period. 
The outcome of pregnancy (reported in the pregnancy report form) for subjects who were 
pregnant at the time of vaccination and those who become pregnant within 21 days after 
vaccination will be presented, if possible. 
SAEs reported during the drug use investigation period [each subject receiving the vaccine 
up to 21 days (Day 0 to Day 20) after vaccination and for pregnant subjects until 6-8 weeks 
after delivery] will be described in detail, if possible. 
The incidence proportion of AEs as overall and by age group and gender will be 
measured with the exact 95% CI. An exploratory comparison between these groups will 
be performed using Chi-square exact test with the statistical significance level 0.05. 
11.6.3.    Publication 
For multi centermulti-centers studies, the first publication or disclosure of study results 
shall be a complete, joint multi centermulti-centers publication or disclosure coordinated 
by GSK. Thereafter, any secondary publications will reference the original publication(s). 
 
 
 

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CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
63 
be enrolled through the drug use investigation period in 
anticipation of a dropout rate of 20% but depending on the 
status of actual enrolment, the plan can be adjusted. 
1. 
 INTRODUCTION 
1.1 
Background 
GSK Vaccines has developed a QIV which contains two A-strains and two B-strains. The 
drug use investigation was designed to evaluate the safety of the QIV in adults and 
children from three years 6 months of age in Korea 
1.2 
 Rationale for the study 
In addition to the extension of an age indication to include 6 to 35 months of age for 
Fluarix Tetra, additional drug use investigation for new age group is being conducted 
to collect safety information on the use of Fluarix Tetra for  4 years according to the 
MFDS requirement. Almost  720 children aged  6 to 35 months  will be  enrolled in 
order to collect safety information within 21 days (Day 0 to Day 20) post vaccination. 
2. 
OBJECTIVE 
 
To assess the safety of GSK Vaccines’ quadrivalent seasonal influenza vaccine D-
QIV, Fluarix Tetra, in terms of frequency and intensity of AEs and SAEs when 
administered according to the local PI in adults and children from three years six 
months of age in Korea. 
 
3. 
STUDY DESGIN OVERVIEW 
 
 Sequential Allocation of Subject Numbers 
 
 
Fluarix Tetra (N= 720 1,440) 
 
 
 
 
 
           Vaccination 
           (Fluarix Tetra) 
 
Drug Use 
Investigation 
Conclusion 
21 days (Day 0 to 
Day 20) follow-up 
after vaccination 
with Fluarix Tetra 
 
N: Number of subjects planned to be enrolled 
 
 
Vaccination schedule: Vaccination as per locally approved PI (which is not part of 
the drug use investigation): to adults and previously vaccinated children aged ≥36 
months, a single 0.5 ml dose of Fluarix Tetra will be administered. To previously 
unvaccinated children aged 36 months to <9 years, two doses will be administered 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
64 
with a second 0.5 ml dose at least 4 weeks apart from the first one as per the local 
PI in Korea. 
 
 
Safety monitoring::  
- In previously unvaccinated children aged 36 months to <9 years,Parents of 
Children aged 6 months to < 12 years will be contacted to provide details of any 
AEs experienced by the children 21 days after the children receives the 
vaccination.  
- Children Subjects for whom diary card transcription into CRF will be done 
through phone contact are considered to have completed the drug use 
investigation. 
 
Duration of the drug use investigation: 6 years. 
- 6 years (for children 36 months and above and adults). 
- 4 years (for children from 6 to 35 months of age)  
 
4. 
DRUG USE INVESTIGATION COHORT 
4.1 
   Number of subjects/centers 
As per the MFDS requirements, safety information from a total of at least 600 evaluable 
subjects is needed for this drug use investigation. In consideration of a dropout rate of 
20%, 
about 720 subjects in total will be enrolled over a period of 6 consecutive years. 
According to MFDS requirement, at least 600 evaluated subjects should be recruited 
for each drug use investigation. Therefore, about 1440 subjects (720 for 3 years old 
and above and 720 between 6-35 months old) will be enrolled through the drug use 
investigation period in anticipation of a dropout rate of 20% but depending on the 
status of actual enrolment, the plan can be adjusted. 
4.1.1 
Recruitment at study centers 
This prospective, observational drug use investigation will be conducted at multiple centers 
(mainly in hospitals and private clinics) in Korea for a period of 6 consecutive years. 
 
 
Study population: Subjects aged ≥36 months who receive Fluarix Tetra as a part of 
routine practice at a private clinic or hospital. Only subjects to whom Fluarix Tetra 
will be prescribed  is administered in routine clinical practice will be invited to participate in 
the drug use investigation. 
 
Target enrolment: Around 720 subjects in total will be enrolled over a period of 6 
consecutive years to meet the requirement of 600 evaluable subjects. 
 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
66 
participants might drop out (depending on the status of actual enrolment), then the 
plan can be adjusted accordingly 
According to MFDS requirement, at least 600 evaluable subjects should be recruited for 
the drug use investigation. Therefore, about 720 subjects will be enrolled through the drug 
use investigation period in anticipation of a dropout rate of 20%. Depending on the status 
of actual enrolment, the plan can be adjusted. 
 
Table 4 presents the exact two-sided 95% CI for a sample size of 600 subjects for each 
group 2). 
10.4.1.     Sequence of analyses 
Analysis will be performed bi-annually for the first two years and annually for the 
remaining follow-up years for each study group (3 years old and above, and 6-35 
months old children). (based on pre defined cut-off date for enrolment). A comprehensive 
analysis, pooling all years will be performed at the end of the drug use investigation. The 
analysis, including individual data listings, will be based on the cohort for vaccinated 
subjects for whom the drug use investigation conclusion page has been received at GSK 
before the pre-defined cut-off date. All periodic and final statistical analysis reports will be 
sent to the GSK VCSP and to MFDS. 
11.1 
Case Report Form 
While completed CRFs are reviewed by a GSK Vaccines’ designated study monitor at the 
study site, omissions or inconsistencies detected by subsequent in-house CRF review may 
necessitate clarification or correction of data or omissions or inconsistencies with 
documentation and approval by the physician or appropriately qualified designee. In all 
cases the physician remains accountable for the study data collected. 
11.2 
Monitoring by GSK Vaccines 
Monitoring visits by a GSK Vaccines’ designated study monitor are for the purpose of 
confirming that GSK Vaccines’ sponsored study are being conducted in accordance with 
the acceptable ethical principles and the regulatory requirement(s) (verifying continuing 
compliance with the protocol, amendment(s), verifying that the site staff and facilities 
continue to be adequate to conduct the study). 
 
 
 

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CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
70 
7.3.3     Completion and transmission of SAE to GSK Vaccines 
Facsimile (Fax) or E-mail transmission of the SAE Report Form is the preferred method to 
transmit this information to the Contact for Reporting SAEs the Contact for Reporting 
SAEs, ADRs and Pregnancies. In rare circumstances and due to failure of facsimile 
equipment, notification by telephone is acceptable, with a copy of the SAE Report Form 
sent by overnight mail. Initial notification via the telephone does not replace the need for 
the physician to complete and sign the SAE Report Form within 24 hours. 
In the event of a death determined by the physician to be related to vaccination, sending of 
the fax must be accompanied by telephone call to the Contact for Reporting SAEs the 
Contact for Reporting SAEs, ADRs and Pregnancies. 
7.3.4     Completion and transmission of SAE to GSK Vaccines 
The physician sends ADR Report Form to the GSK staff (or designee) the Contact for 
Reporting SAEs, ADRs and Pregnancies that collects an adverse drug reaction by fax or 
e-mail. Below are the fax number, telephone number and address of the GSK staff (or 
designee) collecting an adverse drug reaction. 
7.3.5     Completion and transmission of pregnancy reports to GSK Vaccines 
Once the physician becomes aware that a subject is pregnant, the physician (or designee) 
must complete a Pregnancy Report Form and fax or e-mail it to the Contact for Reporting 
SAEs the Contact for Reporting SAEs, ADRs and Pregnancies (refer to the Sponsor 
Information Sheet) within 2 weeks, if possible. 
The Pregnancy Report Form will always be completed as thoroughly as possible with all 
available details and then dated and signed by the physician (or designee), if possible. Even 
if the physician does not have all information regarding the pregnancy, the form should 
still be completed and forwarded to GSK within 2 weeks, if possible. Once additional 
relevant information is received, the form will be updated and forwarded to GSK within 2 
weeks, if possible. 
In absence/dysfunction of facsimile equipment, the Contact for Reporting SAEs the 
Contact for Reporting SAEs, ADRs and Pregnancies should be notified by telephone 
within 2 weeks, if possible. As soon as the facsimile equipment is working again, the 
physician (or designee) must fax the Pregnancy Report Form to the Contact for Reporting 
SAEs the Contact for Reporting SAEs, ADRs and Pregnancies (refer to the Sponsor 
Information Sheet) within 2 weeks, if possible. 

CONFIDENTIAL 
                                                                          204687 [EPI FLU-050 VS KR PMS] 
 
 
Amendment 3 
08-MAR-2019 
71 
7.3.6     Regulatory reporting requirements for serious adverse events 
The physician will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 0. GSK Vaccines has a legal responsibility to promptly notify, as 
appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product surveillance. Prompt notification of SAEs by the physician to the 
Contact for Reporting SAEs the Contact for Reporting SAEs, ADRs and Pregnancies is 
essential so that legal obligations and ethical responsibilities towards the safety of other 
subjects are met. 
10.2.     Sample size consideration 
According to MFDS requirement, at least 600 evaluable  subjects should be recruited for 
each drug use investigation. Therefore, aboutmax 1440 subjects (720 vaccinees ≥ 3 years 
old and above and 720 vaccinees between 6-35 months old)  will be enrolled through the 
drug use investigation period. We assume that 20% of enrolled participants might drop out 
(depending on the status of actual enrolment), then the plan can be adjusted accordingly