Post-marketing Surveillance of GlaxoSmithKline (GSK) Biologicals' Human Papillomavirus (HPV)-16/18 Vaccine, Cervarix When Administered According to the Approved Prescribing Information in Korea
Conditions: Neoplasms, Rectal
Sponsor: GlaxoSmithKline

CONFIDENTIAL
14-MAY-2018
1
Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
9th Floor LS Yongsan Tower building,
92 Hangangdaero, Yongsan-gu,
Seoul, 04386, Korea
Marketed Product Name
GlaxoSmithKline (GSK) Biologicals’ Human 
papillomavirus (HPV) vaccine containing HPV-16/18 L1 
virus-like particles (VLPs) and AS04 adjuvant
eTrack study number 
and Abbreviated Title
208710 (EPI-HPV-077 VS KR PMS)
Date of protocol
Final: 07 November 2017
Amendment 1 Final: 14 May 2018
Title
Post-marketing surveillance of GlaxoSmithKline (GSK) 
Biologicals’ human papillomavirus (HPV)-16/18 vaccine, 
Cervarix when administered according to the approved 
Prescribing Information in Korea.
Detailed Title
A prospective, observational, multi-centre, post-marketing 
surveillance (PMS) to monitor the safety of 
GlaxoSmithKline (GSK) Biologicals’ human 
papillomavirus (HPV)-16/18 vaccine, Cervarix when 
administered to 9-25 years old subjects according to the 
approved Prescribing Information in Korea.
Co-ordinating author
Vaccine Medical Director Korea
Contributing authors
(Amended: 14 May 2018)
!
and 
, Clinical and 
Epidemiology R&D Project Leads
!
, Study Delivery Lead
!
, Safety Physician
!
, Lead Scientific Writer
!
and 
, Oversight 
Data Managers
!
, Statistician
!
, Regional VP Medical/Clinical GSK 
Vaccines
!
, Regional Epidemiologist
!
and 
, Local Medical 
Leads
!
and 
, Country 
Clinical Operations Heads
!
 Vaccines Medical Director
!
, Named Safety Contact
!
, Local Delivery Lead
GSK Biologicals’ protocol template for observational studies and interventional studies 
without administration of medicinal products as described in a research protocol based 
on the Protocol Document Standard version 15.0
© [2017-2018] GSK group of companies or its licensor.
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CONFIDENTIAL
208710 (EPI-HPV-077 VS KR PMS)
Protocol Amendment 1 Final
14-MAY-2018
2
Protocol Amendment 1 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
208710 (EPI-HPV-077 VS KR PMS)
Date of protocol
Amendment 1 Final: 14 May 2018
Detailed Title 
A prospective, observational, multi-centre, post-
marketing surveillance (PMS) to monitor the safety 
of GlaxoSmithKline (GSK) Biologicals’ human 
papillomavirus (HPV)-16/18 vaccine, Cervarix when 
administered to 9-25 years old subjects according to 
the approved Prescribing Information in Korea
Sponsor signatory
(Amended: 14 May 2018)
Dorota Borys,
Director, Clinical and Epidemiology R&D Project 
Lead, HPV and Hepatitis vaccines, 
RDC Belgium, GlaxoSmithKline Biologicals, SA.
Signature
Date
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Protocol Amendment 1 Final
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Protocol Amendment 1 Rationale
Amendment number: Amendment 1 
Rationale/background for changes: The protocol has been amended to address Ministry 
of Food and Drug Safety (MFDS) request for adding detailed description of enrolment 
plan, departments that will participate, method of PMS, collection of information 
regarding medical history, physical examination, and concomitant medication. In 
addition, collection of potential immune medicated diseases (pIMD) has been removed as 
it has not been considered mandatory for PMS, combined with results from other research 
studies to learn more about the vaccine and related diseases has been added in 
confidentiality section by referring to current Informed consents form (ICF), changed 
MFDS reporting method of personally identifiable information and added GSK reporting 
method of AEs/SAEs has been changed as it has been considered current PMS 
procedures, clarified vaccination schedule has been changed as it has been based on 
current prescribing information, and schedule period (such as Day 1 to Day 30) has been 
changed according to current writing process.
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208710 (EPI-HPV-077 VS KR PMS)
Protocol Amendment 1 Final
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Protocol Amendment 1 Physician Agreement
I agree:

To conduct the PMS in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, and with the terms of the 
PMS agreement and with any other PMS conduct procedures and/or PMS conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the PMS at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) or ‘Good 
Epidemiological Practice’ (GEP) or other applicable guidelines and all applicable 
regulatory requirements.

To ensure that all persons assisting me with the PMS are adequately informed about 
the GSK Biologicals PMS vaccine(s)/Product(s) and other PMS-related duties and 
functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative. 

To perform no other biological assays on the samples except those described in the 
protocol or its amendment(s).

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the PMS 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 
Biologicals will use and disclose the information solely for the purpose of complying 
with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the PMS and for one year following completion of the PMS.

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this PMS.
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208710 (EPI-HPV-077 VS KR PMS)
Protocol Amendment 1 Final
14-MAY-2018
5
eTrack study number and 
Abbreviated Title
208710 (EPI-HPV-077 VS KR PMS)
Date of protocol
Amendment 1 Final: 14 May 2018
Detailed Title
A prospective, observational, multi-centre, post-
marketing surveillance (PMS) to monitor the 
safety of GlaxoSmithKline (GSK) Biologicals’ 
human papillomavirus (HPV)-16/18 vaccine, 
Cervarix when administered to 9-25 years old 
subjects according to the approved Prescribing 
Information in Korea
Physician name
Signature
Date
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Sponsor Information
Sponsor
GlaxoSmithKline Biologicals
9th Floor, LS Yong-san Tower, 92 Hangangdae-ro, Yongsan-gu, Seoul, 04386, Korea
Sponsor Medical Expert for the PMS
Refer to the local PMS contact information document.
Sponsor PMS Monitor
Refer to the local PMS contact information document.
Sponsor PMS Contact for Reporting of a Serious Adverse Event (SAE)
GSK Biologicals Central Back-up PMS Contact for Reporting SAEs: refer to protocol 
8.4.1.
PMS Contact for Reporting SAEs: refer to the local study contact information 
document.
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Protocol Amendment 1 Final
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SYNOPSIS
Detailed Title
A prospective, observational, multi-centre, post-marketing 
surveillance (PMS) to monitor the safety of 
GlaxoSmithKline (GSK) Biologicals’ human papillomavirus 
(HPV)-16/18 vaccine, Cervarix when administered to 9-25 
years old subjects according to the approved Prescribing 
Information in Korea
Indication
(Amended: 14 May 
2018)
Cervarix is a vaccine indicated for active immunisation 
against HPV infection in males and females 9-25 years old as 
3 doses, 0, 1 and 6 months schedule. Children and 
adolescents 9-14 years old can be vaccinated with 2 doses, 0
and 6-12 months schedule. 
Objective 
To assess the safety of GSK Biologicals’ human 
papillomavirus (HPV)-16/18 vaccine, Cervarix, in terms of 
frequency and intensity of AEs and SAEs when administered 
according to the local Prescribing Information.
Rationale for the PMS
In Korea, GSK Biologicals’ human papillomavirus (HPV)-
16/18 vaccine, Cervarix was approved in July 2008. As per 
Ministry of Food and Drug Safety (MFDS) (Korea) 
requirements, this post-marketing surveillance (PMS) is 
being conducted to collect safety information on the use of 
Cervarix, in at least 600 Korean subjects within 30 days after 
the vaccination when administered according to the approved 
PI in Korea in a real health care setting over a 4 year period.
PMS design
(Amended: 14 May 
2018)

PMS design: A prospective, observational, non-
comparative, multi-centre PMS in Korea.

Study population: 9-25 years old males and females.

Vaccination schedule: Three doses of Cervarix will be 
administered as per the local Prescribing Information in 
Korea. Subjects aged 9-14 years old can be vaccinated 
with two dose schedule.
The recommended schedule is as follows:

Vaccination: The 9-25 years old subjects should be 
administered Cervarix with 3 doses (0.5mL each), 0, 1, 
and 6 months schedule. The 9-14 years old subjects can 
be vaccinated with 2 doses, 0 and 6-12 months schedule. 
In the 2-doses schedule, if the second dose is 
administered before 5 months after the first dose, the 
third dose vaccination is required. In the 3 doses 
schedule, if the vaccination schedule requires 
flexibility, the second dose can be administered 
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between 1 and 2.5 months and the third dose can be 
administered between 5 and 12 months after the first 
dose.
Note: The subject/subject’s parent’s/ Legally acceptable 
representative’s (LAR) signature in the ICF/IAF signifies 
enrolment of the subject into the PMS. The ICF/IAF is for 
the collection and handling of safety information and not for 
the vaccination procedure.

Safety monitoring: 

Recording of all AEs during the 30 day period (Day 
1 to Day 30) using diary cards after each dose of 
Cervarix is administered. 

Recording of SAEs reported throughout the PMS 
period up to 30 days (Day 1 to Day 30) after the last 
dose of Cervarix is administered during the subject’s 
participation in the PMS.

Blood Samples: No blood samples will be collected in 
this PMS.

Primary completion Date: last visit of Epoch 1
Refer to GLOSSARY OF TERMS for the definition of 
PCD.

End of Study (EoS): Last subject’s last visit. (Follow up 
after the last dose) 
Refer to GLOSSARY OF TERMS for the definition of 
EoS.

Duration of the PMS: The intended duration of this 
study is approximately 4 years.

Epoch 001: Prospective data collection starting at 
vaccination dose 1 and ending at follow up after
last dose. 
The below table presents the study group and the epoch 
foreseen in the PMS study.
Synopsis table 1 Study group and epoch foreseen in the 
study
Study group
Number of 
subjects
Age (Min/Max)
Epoch 001
HPV Group
Approx 600
9/25 years
X

Pregnant subjects: Pregnant subjects who receive 
Cervarix inadvertently or subjects who become pregnant 
within 30 days after any vaccination dose will be 
followed up to determine the pregnancy outcome. 
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Pregnancy outcome including the status of the mother 
and child will be forwarded to GSK. Generally, follow-
up should be no longer than 6 to 8 weeks following the 
estimated delivery date, if possible.

Type of PMS: Self-contained. 

Data collection: Standardised hard copy Case Report 
Form (CRF). SAEs, ADRs and pregnancy information 
will be collected by using the SAE, ADR and Pregnancy 
Reporting Form.
Discussion of PMS 
design
(Amended: 14 May 
2018)

All adverse events reported during the 30-day post-
vaccination follow-up period and all SAEs reported up 
to 30 days (Day 1 to Day 30) after the last dose
administered during the PMS will be collected as part of 
safety data in this PMS. These adverse events will be 
further classified by GSK at the time of statistical 
analyses as expected/unexpected based on the current 
Prescribing Information.
Number of subjects

As per the MFDS (Korea) requirements, safety 
information from a total of at least 600 evaluable 
subjects is needed for this PMS. Therefore, a total of at 
least 600 evaluable subjects will be enrolled over a 
period of 4 consecutive years. 
Endpoints
(Amended: 14 May 
2018)

Occurrence of AEs during the 30-day (Day 1 to Day 30)
follow-up period after each vaccine dose.

Occurrence of any SAE reported throughout the PMS 
period up to 30 days (Day 1 to Day 30) after the last 
dose of Cervarix administered during subject’s 
participation in the PMS.
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................6
SYNOPSIS......................................................................................................................7
LIST OF ABBREVIATIONS...........................................................................................15
GLOSSARY OF TERMS ...............................................................................................16
TRADEMARKS .............................................................................................................20
1.
INTRODUCTION....................................................................................................21
1.1.
Background ................................................................................................21
1.2.
Rationale for the PMS.................................................................................21
2.
OBJECTIVE (AMENDED: 14 MAY 2018)...............................................................22
3.
PMS DESIGN OVERVIEW (AMENDED: 14 MAY 2018) ........................................22
3.1.
Discussion of PMS design (Amended: 14 May 2018)..................................23
4.
STUDY POPULATION...........................................................................................24
4.1.
Number of subjects/centres (Amended: 14 May 2018)................................24
4.1.1.
Recruitment of PMS centres ........................................................24
4.2.
Inclusion criteria for enrolment....................................................................25
4.3.
Exclusion criteria for enrolment...................................................................25
5.
CONDUCT OF THE PMS.......................................................................................25
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................25
6.
DETAILED PMS PROCEDURES...........................................................................27
6.1.
Subject identification...................................................................................27
6.2.
General PMS aspects.................................................................................27
6.3.
Outline of PMS procedures (Amended: 14 May 2018) ................................27
6.4.
Detailed description of PMS procedures (Amended: 14 May 2018) ............28
6.4.1.
Check inclusion and exclusion criteria .........................................28
6.4.2.
Informed consent.........................................................................29
6.4.3.
Collect demographic data ............................................................29
6.4.4.
Record medical history ................................................................29
6.4.5.
Physical examination ...................................................................29
6.4.6.
Medication/Vaccination History....................................................29
6.4.7.
Check and record medication/vaccination....................................29
6.4.8.
Check contraindications, warnings and precautions to 
vaccination...................................................................................30
6.4.9.
Assess body temperature as pre-vaccination...............................30
6.4.9.1.
Vaccination.................................................................30
6.4.10.
Distribution, return and transcription of diary cards ......................30
6.4.11.
Recording of AEs, ADRs and SAEs.............................................31
6.4.12.
Procedures during follow-up visits/contacts .................................31
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6.4.13.
PMS conclusion...........................................................................31
7.
DESCRIPTION OF CERVARIX..............................................................................31
7.1.
Dosage and administration of Cervarix .......................................................31
7.2.
Contraindications to subsequent vaccination ..............................................31
7.3.
Warnings and precautions ..........................................................................31
7.4.
Concomitant medication/vaccination (Amended: 14 May 2018)..................32
7.4.1.
Recording of concomitant medications/products and 
concomitant vaccination...............................................................32
7.4.2.
Time window for recording concomitant 
medication/vaccination in the CRF...............................................32
8.
SAFETY.................................................................................................................33
8.1.
Safety definitions ........................................................................................33
8.1.1.
Definition of an adverse event......................................................33
8.1.2.
Definition of adverse drug reaction ..............................................34
8.1.3.
Definition of a serious adverse event ...........................................34
8.2.
Events or outcomes not qualifying as AEs or SAEs (Amended: 14 
May 2018)...................................................................................................35
8.2.1.
Pregnancy ...................................................................................35
8.2.2.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................36
8.3.
Detecting and recording AEs, ADRs and SAEs (Amended: 14 May 
2018) ..........................................................................................................36
8.3.1.
Time period for detecting and recording AEs, ADRs and 
SAEs ...........................................................................................36
8.3.2.
Evaluation of AEs, ADRs and SAEs.............................................38
8.3.2.1.
Active questioning to detect AEs, ADRs and 
SAEs ..........................................................................38
8.3.2.2.
Assessment of severity...............................................38
8.3.2.3.
Assessment of causality .............................................39
8.3.2.4.
Assessment of the outcomes......................................41
8.3.2.5.
Medically attended visits.............................................41
8.4.
Reporting of SAEs, Pregnancies and other events related to 
Cervarix (Amended: 14 May 2018) .............................................................41
8.4.1.
Prompt reporting of SAEs related to PMS participation/ 
related to Cervarix, pregnancies and other events to GSK...........41
8.4.2.
PMS Contact for Reporting SAEs, ADRs and pregnancies: 
Please refer to local PMS contact information..............................42
8.4.3.
Regulatory reporting requirements for SAEs................................42
8.4.4.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................43
8.4.5.
Completion and transmission of non-serious AEs related 
to Cervarix reports to GSK...........................................................43
8.4.6.
Completion and transmission of pregnancy reports to GSK 
Biologicals ...................................................................................44
8.5.
Follow-up of AEs and SAEs (Amended: 14 May 2018) ...............................44
8.5.1.
Follow-up of pregnancies.............................................................45
8.6.
Treatment of AEs........................................................................................45
9.
EFFICACY ASSESSMENT ....................................................................................45
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10. SUBJECT COMPLETION AND WITHDRAWAL.....................................................45
10.1.
Subject completion .....................................................................................45
10.2.
Subject withdrawal (Amended: 14 May 2018).............................................45
10.2.1.
Subject withdrawal from PMS ......................................................46
11. STATISTICAL METHODS......................................................................................46
11.1.
Endpoints (Amended: 14 May 2018)...........................................................46
11.2.
Determination of sample size......................................................................47
11.3.
Study cohorts to be evaluated.....................................................................47
11.3.1.
Total Vaccinated cohort ...............................................................47
11.3.2.
Total Safety cohort.......................................................................47
11.4.
Conduct of analyses ...................................................................................47
11.4.1.
Sequence of analyses..................................................................48
11.4.2.
Statistical considerations for interim analyses..............................48
11.5.
Statistical methods (Amended: 14 May 2018).............................................48
11.5.1.
Analysis of demographics/baseline characteristics ......................48
11.5.2.
Analysis of safety.........................................................................48
11.5.2.1.
Within group assessment ...........................................49
12. ADMINISTRATIVE MATTERS (AMENDED: 14 MAY 2018)...................................49
12.1.
Case Report Form ......................................................................................49
12.2.
Monitoring by GSK Biologicals....................................................................50
12.3.
Archiving of data at PMS sites ....................................................................51
12.4.
Audits .........................................................................................................52
12.5.
Posting of information on public registers....................................................52
12.6.
Ownership, confidentiality and publication (Amended: 14 May 2018)..........52
12.6.1.
Ownership ...................................................................................52
12.6.2.
Confidentiality ..............................................................................52
12.6.3.
Publication...................................................................................53
12.6.4.
Provision of PMS results to physicians, posting to the 
clinical trials registers and publication..........................................53
13. COUNTRY SPECIFIC REQUIREMENTS...............................................................54
14. REFERENCES.......................................................................................................55
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LIST OF TABLES
PAGE
Table 1
Study group and epoch foreseen in the study ........................................23
Table 2
Expected enrolment plan of subject........................................................24
Table 3
List of PMS procedures..........................................................................28
Table 4
Reporting periods for AEs, ADRs and SAEs ..........................................37
Table 5
Time frames for submitting SAEs and other events reports to 
GSK Biologicals .....................................................................................42
Table 6
Exact two-sided 95% CI for the percentage of subjects reporting 
at least one symptom with a sample size of 600 subjects.......................47
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LIST OF APPENDICES
PAGE
APPENDIX A AMENDMENTS ADMINISTRATIVE CHANGES TO THE 
PROTOCOL...........................................................................................56
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LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
CP
Concept Protocol
CRF
Case Report Form
EoS
End of Study
EPI
Expanded Program on Immunization
GEP
Good Epidemiological Practice
GSK
GlaxoSmithKline
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LAR
Legally Acceptable Representative
LSOP
Local Standard Operating Procedure
MFDS
Ministry of Food and Drug Safety
PCD
Primary Completion Date
PI
Prescribing Information
PII
Personally Identifiable Information
PMS
Post-Marketing Surveillance
SAE
Serious Adverse Event
SDV
Source Document Verification
SOP
Standard Operating Procedure
SPM
Study Procedure Manual
VCSP
GSK Biologicals’ Central Safety and Pharmacovigilance
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GLOSSARY OF TERMS
Adequate contraception:
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example: 

abstinence from penile-vaginal intercourse, when this 
is their preferred and usual lifestyle,

Combined estrogen and progesterone oral 
contraceptives, either combined or progestogen 
alone,

injectable progestogen,

implants of etenogestrel or levonorgestrel,

Contraceptive oestrogenic vaginal ring,

percutaneous contraceptive patches,

intrauterine device or intrauterine system,

male partner sterilisation prior to the female subject’s 
entry into the PMS, and this male is the sole partner 
for that subject,
The information on the male sterility can come from the 
site personnel’s review of the subject’s medical records; 
or interview with the subject on her medical history.

male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), and/or 
progesterone alone oral contraceptive.,

male condom combined with a female diaphragm, 
either with or without a vaginal spermicide (foam, 
gel, film, cream, or suppository). 
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, or for 
subjects who are and will continue to be abstinent from 
penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle.
Adverse drug reaction:
An adverse drug reaction is any adverse event whose 
causality to the drug cannot be ruled out and is assessed 
as “certain” or “probably/likely” or “possible” or 
“conditional/unclassified” or “unassessible
/unclassifiable”.
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Child in care:
A child who has been placed under the control or 
protection of an agency, organisation, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian.
Eligible:
Qualified for enrolment into the PMS based upon strict 
adherence to inclusion/exclusion criteria.
End of Study (EoS):
(Synonym of End of 
Trial)
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV). 
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of the 
last testing/reading released of the Human Biological 
Samples or imaging data, related to primary and 
secondary endpoints. EoS must be achieved no later than 
8 months after LSLV.
Epoch:
An epoch is a set of consecutive time points or a single 
time point from a single protocol. Epochs are defined to 
support a main purpose which is either to draw 
conclusions on subject participation or to draw a 
complete conclusion to define or precise the targeted 
label of the product. Supporting means that data collected 
at the time points included in an epoch must be sufficient 
to fulfil the purpose of the epoch.
Typical examples of epochs are screening, primary 
vaccinations, boosters, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety.
eTrack:
GSK’s tracking tool for clinical/epidemiology trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the per protocol analysis.
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Expected adverse event:
The presence/occurrence/intensity of an AE that is 
expected from the subjects during the post-vaccination 
follow-up period as described in the locally approved 
Prescribing Information
Legally acceptable 
representative
(The terms legal 
representative or legally 
authorized 
representative are used 
in some settings.)
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the PMS.
Menarche:
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development and 
pubic hair growth. Menarche usually occurs within 1-2 
years of breast development, thelarche. However, a young 
female can become pregnant before her first menses. 
Thus, a conservative definition of non-childbearing 
potential in a pre-menarcheal female is a young female 
who has not yet entered puberty as evidenced by lack of 
breast development (palpable glandular breast tissue).
Post-marketing 
surveillance:
Routine country-specific post vaccine/drug approval 
surveillance PMS mandated by regulatory authorities that 
applies an observational approach for the collection of 
safety information from subjects in a normal healthcare 
setting.
Primary completion 
date:
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for all primary outcomes, whether the clinical trial was 
concluded according to the pre-specified protocol or was 
terminated.
Prospective study:
A study in which the subjects/cases are identified and 
then followed forward in time in order to address one or 
more study endpoints.
Protocol amendment:
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, PMS design, or scientific
integrity of the PMS.
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Protocol administrative 
change:
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the PMS. 
Self-contained study:
Study with objectives not linked to the data of another 
study.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the PMS.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the PMS.
Surveillance:
Surveillance is defined as the ongoing systematic 
collection, collation, analysis, and interpretation of 
descriptive epidemiological health data on a specific 
disease. Surveillance can monitor incidence and/or 
prevalence, and/or inform about when and where health 
problems are occurring and who is affected.
Unexpected adverse 
event:
Any AE that is not described in the approved Prescribing 
Information. Unexpected AEs are therefore not expected 
to occur during the post-vaccination follow-up period.
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TRADEMARKS
The following trademarks are used in the present protocol.
Note: In the body of the protocol, the names of the vaccines will be written without 
the superscript symbol ™ or ® and in italics.
Trademarks of the GSK group of 
companies
Generic description
Cervarix
GlaxoSmithKline (GSK) Biologicals’ Human 
papillomavirus (HPV) vaccine containing 
HPV-16/18 L1 virus-like particles (VLPs) and 
AS04 adjuvant
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1.
INTRODUCTION
1.1.
Background
Anal cancer is rare in the general population with an average worldwide incidence of 1 
per 100,000, but is reported to be increasing in more developed regions. Globally, there 
are an estimated 27,000 new cases every year [de Martel C, 2012]. Women have higher 
incidences of anal cancer than men. Incidence is particularly high among populations of 
men who have sex with men (MSM), women with history of cervical or vulvar cancer, 
and immunosuppressed populations, including those who are HIV-infected and patients 
with a history of organ transplantation. 
In South Korea, the incidence of anal cancer by sex is 0.4 ASR (Age-standardized rates 
per 100,000 men per year) for men and 0.3 ASR (Age-standardized rates per 100,000 
women per year) for women [WHO/ICO HPV information center].
Data on the role of Human papillomavirus (HPV) in anogenital cancers other than the 
cervix is limited, but there is an increasing body of evidence strongly linking HPV DNA 
with cancers of the anus, vulva, vagina, and penis. Although these cancers are much less 
frequent compared to cervical cancer, their association with HPV make them potentially 
preventable and subject to similar preventative strategies as those for cervical cancer. 
[WHO/ICO HPV information center].
HPV related anal cancer is predominantly associated with infection with HPV types 16 
and 18 [Chaturvedi, 2010], that are included in Cervarix. This infers the possibility of 
using similar preventive strategies for both cancer types. 
Based on two studies comparing the immunogenicity of Cervarix and Gardasil in 
females (HPV-010 and HPV-071) with two other studies (HPV-011 and HPV-040) 
providing immunogenicity and safety data for Cervarix vaccination in males, the 
indication of Cervarix was updated to include anal cancer caused by HPV types 16, 18 
for both women and men by Ministry of Food and Drug Safety (MFDS) (Korea).
1.2.
Rationale for the PMS
In Korea, GSK Biologicals’ HPV vaccine containing HPV-16/18 L1 virus-like particles 
(VLPs) and AS04 adjuvant (Cervarix) was approved in July 2008. The indication was 
updated to include anal cancer caused by HPV types 16, 18 for both women and men. As 
per MFDS (Korea) requirements, this post-marketing surveillance (PMS) is being 
conducted to collect safety information on the use of Cervarix upon the expanded 
indication to anal cancer in both women and men, in at least 600 Korean women and men
within 30 days after the vaccination when administered according to the approved 
Prescribing Information (PI) in Korea in a real health care setting over a 4-year period. 
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2.
OBJECTIVE (AMENDED: 14 MAY 2018)
To assess the safety of GSK Biologicals’ HPV vaccine containing HPV-16/18 L1 virus-
like particles (VLPs) and AS04 adjuvant, in terms of frequency and intensity of adverse 
events (AEs) and serious adverse events (SAEs) when administered according to the local 
PI.
Refer to Section 11.1 for the definition of the endpoint.
3.
PMS DESIGN OVERVIEW (AMENDED: 14 MAY 2018)
Sequential Allocation of Subject 
Numbers
Cervarix (N ~ 600)
Vaccination
Dose 1
Follow-up
30-day follow-up 
after Dose 1
Vaccination 
Dose 2
Follow-up
30-day follow-up 
after Dose 2
Vaccination 
Dose 3
Follow-up
30-day follow-up 
after Dose 3
N: Number of subjects planned to be enrolled
PMS conclusion will depend on the concluding visit of the subject in the PMS.
Definition of Conclusion of PMS for a subject: Subjects who have completed 30-day follow-up after at least one dose, 
regardless of the number of doses, are considered to have completed the PMS.
Note: Eligible subjects can be enrolled at any stage in the PMS regardless of Cervarix dose(s) received previously. 
Follow-up for AEs will continue for 30 days after receiving each vaccine dose(s) in the PMS. Follow-up of SAEs will 
continue from the date of Visit 1 until 30 days after the last dose received in the PMS. Cervarix will be vaccinated 
according to local practice
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 8), are essential and 
required for study conduct. This PMS will be conducted by a continuous surveillance 
method.

PMS design: A prospective, observational, non-comparative, multi-centre PMS in 
Korea.

Study population: 9-25 years old males and females.

Vaccination schedule: Cervarix will be administered as per the local PI in Korea.
The recommended schedule is as follows:

Vaccination: The 9-25 years old subjects should be administered Cervarix with 3 
doses (0.5mL each), 0, 1, and 6 months schedule. The 9-14 years old subjects 
can be vaccinated with 2 doses, 0 and 6-12 months schedule. In the 2-dose
schedule, if the second dose is administered before 5 months after the first 
dose, the third dose vaccination is required. In the 3 doses schedule, if the 
vaccination schedule requires flexibility, the second dose can be administered 
between 1 and 2.5 months and the third dose can be administered between 5 
and 12 months after the first dose.
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Note: The subject/subject’s parent’s/LAR’s signature in the Informed Consent Form
(ICF)/Informed Assent Form (IAF) signifies enrolment of the subject into the PMS. 
The ICF/IAF is for the collection and handling of safety information and not for the 
vaccination procedure.

Safety monitoring: 

Recording of all AEs during the 30 day period (Day 1 to Day 30) using diary 
cards after each dose of Cervarix is administered. 

Recording of SAEs, adverse drug reactions (ADRs) and Pregnancy from the date 
of Visit 1 until 30 days (Day 1 to Day 30) after the last dose of Cervarix
administered during the subject’s participation in the PMS.

Blood Samples: No blood samples will be collected in this PMS.

Primary completion Date: last visit of Epoch 1.
Refer to GLOSSARY OF TERMS for the definition of PCD.

End of Study (EoS): Last subject last visit (Follow up after the last dose)
Refer to GLOSSARY OF TERMS for the definition of EoS.

Duration of the PMS: The intended duration of this study is approximately 4 years.

Epoch 001: Prospective data collection starting at vaccination dose 1 and ending 
at follow up after last dose.
The below table presents the study group and the epoch foreseen in the PMS study.

Study groups: The study groups and epoch foreseen in the study are provided in
Table 1.
Table 1
Study group and epoch foreseen in the study
Study groups
Number of subjects
Age at Dose 1 (Min/Max)
Epoch 001
HPV Group
Approx. 600
9/25 years
X

Type of PMS: Self-contained.

Data collection: Standardised hard copy Case Report Form (CRF). SAEs, ADRs and
pregnancy information will be collected by using the SAE, ADR and Pregnancy 
Reporting Form. 
3.1.
Discussion of PMS design (Amended: 14 May 2018)
All adverse events reported during the 30-day post-vaccination follow-up period and all 
SAEs reported throughout the PMS period up to 30 days (Day 1 to Day 30) after the last 
dose of Cervarix administered during the subject’s participation in the PMS, will be 
collected as part of safety data in this PMS. These adverse events will be further 
classified by GSK at the time of statistical analyses as expected/unexpected based on the 
locally approved Prescribing Information.
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4.
STUDY POPULATION
4.1.
Number of subjects/centres (Amended: 14 May 2018)
As per the MFDS (Korea) requirements, safety information from a total of at least 600 
evaluable subjects is needed for this PMS. Therefore, a total of at least 600 evaluable 
subjects will be enrolled over a period of 4 consecutive years.
4.1.1.
Recruitment of PMS centres
Overview of the recruitment plan:

This prospective, observational PMS will be conducted at multiple centres in private 
clinics and hospitals (department of pediatrics and obstetrics & gynecology, etc.) in 
Korea for a period of 4 years.

PMS population: Subjects who receive at least one dose of Cervarix as a part of 
routine practice at a clinic or hospital. Only subjects to whom Cervarix will be 
prescribed in routine clinical practice will be invited to participate in the 
surveillance. 

Eligible subjects may join the PMS after the ICF/IAF has been signed by the 
subject/subject’s parent/LAR. 

The PMS is required to be conducted in at least one hospital [with Institutional 
Review Board (IRB) oversight] in order for the PMS to be conducted in private 
clinics (without IRB). 

Target enrolment: A total of at least 600 subjects will be enrolled over a period of 4
years

The vaccine will be purchased by the subject/subject’s parents/LAR.

The recruitment will be monitored by the PMS monitor.
Table 2
Expected enrolment plan of subject
Period
Tentative calendar dates
Planned No. of enrolled subject*
1st Year
2017.07.28 ~ 2018.07.27
0
2ndYear
2018.07.28 ~ 2019.07.27
280
3rd Year
2019.07.28 ~ 2020.07.27
300
4thYear
2020.07.28 ~ 2021.07.27
20
Total
600**
* Approximate number
** At least 600 evaluable subjects will be recruited for the PMS.
Note: The above plan may be modified depending on conditions such as progress
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4.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity and regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at PMS entry:

Subject or/and subjects whose parent(s)/Legally Acceptable Representative(s) 
[LAR(s)], in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g., complete the diary cards, return for follow-up 
visits).

Korean male or female subjects aged 9-25 years who are eligible for the series of 
Cervarix according to the locally approved PI.

Written informed consent obtained from the subject/from the parent(s)/LAR of the 
subject.
4.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity and regulatory acceptability of the study or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of PMS entry. If ANY exclusion 
criterion applies, the subject must not be included in the PMS:

At the time of PMS entry, the contraindications and precautions of use indicated in 
the locally approved PI. PI should be checked and the subject must not be included 
in the PMS if there is any contraindication. Any changes in the locally approved PI 
must be implemented immediately.

Subjects who had previous administration of a HPV vaccine other than Cervarix will 
not be enrolled into the study

Subjects who are not eligible for vaccination with Cervarix according to the medical 
judgement of physician.

Child in care. Please refer to the GLOSSARY OF TERMS for the definition of child 
in care. 
5.
CONDUCT OF THE PMS
5.1.
Regulatory and ethical considerations, including the 
informed consent process
The PMS will be conducted in accordance with the ICH Guideline for GCP or other 
applicable guidelines (local rules and regulations of the country (MFDS) (Korea) and 
relevant GSK SOPs/Policies and Guidance), all applicable subject privacy requirements 
and the guiding principles of the Declaration of Helsinki. 
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The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favourable opinion/approval to conduct the PMS from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the PMS in that country.
Conduct of the PMS includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of PMS protocol and any subsequent amendments.

Subject/ subject’s parent(s)/LAR(s) informed consent and subject informed assent, as 
appropriate

Physician reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the physician, either verbally, in 
writing, or both.
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject or subject’s parent(s)/LAR(s) and subject informed assent prior to 
participation in the PMS. 
GSK Biologicals will prepare a model ICF which will embody the ICH GCP or other 
applicable guidelines and GSK Biologicals required elements. While it is strongly 
recommended that this model ICF is to be followed as closely as possible, the informed 
consent requirements given in this document are not intended to pre-empt any local 
regulations which require additional information to be disclosed for informed consent to 
be legally effective. Clinical judgement, local regulations and requirements should guide 
the final structure and content of the local version of the ICF.
In accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, 
a subject who can only be enrolled in the study with the consent of her parent(s) or 
legally acceptable representative (e.g., minors), should be informed about the study to the 
extent compatible with the subject’s understanding and, if capable, the subject should 
sign and personally date a written IAF. It is required that the assent be signed by each 
subject, if capable, in addition to the informed consent that is to be signed by her parent 
or legal representative. It should be assessed whether an assent is required depending on 
the age of the study population and the local requirements.
The physician has the final responsibility for the final presentation of the ICF and IAF, 
respecting the mandatory requirements of local regulations. The ICF and IAF generated 
by the physician with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
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6.
DETAILED PMS PROCEDURES
6.1.
Subject identification 
Subject numbers will be assigned sequentially to subjects who participate/whose 
parents/LARs consent to allow their children to participate in the PMS, according to the 
range of subject numbers allocated to each PMS centre.
6.2.
General PMS aspects
Supplementary PMS conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedure Manual (SPM). The SPM provides the 
physician and the site personnel with administrative and detailed technical information 
that does not impact the safety of the subjects.
6.3.
Outline of PMS procedures (Amended: 14 May 2018)
Table 3 presents the list of PMS procedures.
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Table 3
List of PMS procedures
Epoch
Epoch 001
Type of contact
Visit 1
Visit 2
Visit 3 c
Informed consent *
●
Check inclusion/exclusion criteria *
●
Check contraindications
●
●
●
Check warnings and precautions
●
●
●
Collect demographic data
●
Medical history *
●
Medication/Vaccination history **
●
Physical examination
●
O
O
Pre-vaccination body temperature
●
●
●
Record vaccination information
●
●
●
Distribution of diary cards
O
O
O
Recording of adverse events within 30 days post-vaccination, by physician
●
●
●
Return of diary cards a
O
O
Diary card transcription by physician
●
●
Record any concomitant medication/vaccination
●
●
●
Record any intercurrent medical conditions
●
●
Reporting of serious adverse events / ADRs/Pregnancy Information
●
●
●
PMS Conclusion b
●
●
●
●is used to indicate a PMS procedure or a vaccination-related non-PMS procedure that requires documentation in the 
individual CRF.
○is used to indicate a PMS procedure that does not require documentation in the individual CRF.
* For the subjects who have received Cervarix previously and are enrolled in the PMS, procedures for Informed 
Consent/Check inclusion/exclusion criteria/Medical history/Vaccination history can be conducted at the first PMS-
related visit.
** Medication/Vaccination history (within 30-days prior to the Cervarix vaccination)
For subjects who have received one or two dose/s of Cervarix before the PMS enrolment, previous Cervarix
vaccination history will be reported starting at the first PMS-related visit onwards irrespective of the number of dose 
subject received during the PMS. 
a – The subjects will be instructed to return the completed diary card to the physician on their next PMS visit or phone 
or mail, to report any AEs/SAEs/ADRs/Pregnancy during the 30 day period (Day 1 to Day 30) using diary cards after 
each dose of Cervarix is administered.
b –PMS CRF Conclusion section to be completed depending on the available concluding visit of the subject in the PMS. 
The CRF conclusion will be 30 days after the last dose.
C–The visit 3 can be omitted as 9-14 years old can be vaccinated with two dose schedule.
It is the physician’s responsibility to ensure that the dosing intervals are followed as 
described in the locally approved PI. However, if circumstances dictate other intervals, 
this will not lead to the exclusion of the subject from the analysis.
6.4.
Detailed description of PMS procedures (Amended: 14 May 
2018)
6.4.1.
Check inclusion and exclusion criteria
Check all applicable inclusion and exclusion criteria as described in Sections 4.2 and 4.3
before enrolment. 
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6.4.2.
Informed consent
The ICF/IAF for this PMS is for the collection and handling of personal and safety 
information after vaccination with Cervarix. Diary card(s) will be used to collect safety 
information and for source document verification. The ICF/IAF for this PMS will not 
include consent for vaccination as vaccination is at the discretion of subject/ 
parent(s)/LAR and the physician.
The signed/witnessed/thumb printed informed consent of the subject or subject’s 
parent(s)/LAR(s) must be obtained before study participation. The signed informed 
assent of a subject below the age of consent (i.e., minor) should be obtained in addition to 
the signed informed consent by her parent(s)/LAR(s) according to local rules and 
regulations. Refer to Section 5.1 for the requirements on how to obtain informed consent 
and assent, as appropriate.
6.4.3.
Collect demographic data
Record demographic data such as age, gender and ethnicity in the subject’s CRF.
6.4.4.
Record medical history
Obtain the subject’s medical history such as status (past/current), diagnosis, classify
(renal/liver disease/other) by interview and/or review of the subject’s medical records 
and record any pre-existing conditions or signs and/or symptoms present in a subject 
prior to the start of the PMS in the CRF.
6.4.5.
Physical examination
Perform a physical examination of the subject. Collected information (weight, height)
needs to be recorded in the CRF. 
At each study visit subsequent to the first visit, a physical examination will only be 
performed if the subject indicates during questioning that there may be some underlying 
pathology(ies) or if deemed necessary by the investigator or delegate.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this PMS or by referral to an appropriate 
health care provider. 
6.4.6.
Medication/Vaccination History
Collect information regarding all medicines/vaccines administered to the subject 30 days 
prior to vaccination with Cervarix during the PMS.
6.4.7.
Check and record medication/vaccination
Concomitant medication/vaccination must be recorded in the CRF (see Section 7.4).
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6.4.8.
Check contraindications, warnings and precautions to 
vaccination 
Contraindications, warnings and precautions to vaccination are to be checked at the
beginning of each vaccination visit (see Section 7.2) 
6.4.9.
Assess body temperature as pre-vaccination
The axillary, rectal, oral or tympanic body temperature of all subjects needs to be
measured prior to Cervarix administration as routine practice. The preferred route for 
recording temperature in this PMS will be axillary/tympanic. If the subject has fever 
[fever is defined as temperature 37.5°C on oral, axillary or tympanic setting, or 38.0°C on 
rectal setting] on the day of vaccination, the vaccination visit will be rescheduled.
6.4.9.1.
Vaccination
After completing the prerequisite procedures prior to vaccination, one dose of Cervarix
will be administered according to the PI (refer to Section 7.1). 
The vaccines will be observed closely for at least 30 minutes, with appropriate medical 
treatment readily available in case of anaphylaxis following the administration of 
Cervarix.
6.4.10.
Distribution, return and transcription of diary cards
The physician will provide the diary card to the subjects or subject’s parent(s)/LAR(s) to 
record e. g. Medication taken, AE, SAE, and pregnancy until next visit/contact. The 
subjects or subject’s 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 subjects or subject’s parent(s)/LAR(s) at the subsequent visit/contact. Any 
unreturned diary cards will be sought from the subjects or subject’s parent(s)/LAR(s) 
through telephone call(s) or any other convenient procedure. The Physician will 
transcribe the collected information into the CRF in English
After each vaccination, diary cards will be provided to the subjects or subject’s 
parent(s)/LAR(s) to record any AEs (i.e. on the day of vaccination and during the next 29 
days) occurring after vaccination. The subjects or subjects’ parent(s)/LAR(s) will be 
instructed to return the completed diary card to the physician on their next PMS visit or 
provide details during the telephonic interview from physicians or by postal mail. Site 
staff will try to contact subject or subject’s parent(s)/LAR(s) through telephone call(s) (at 
least 3 attempts) for any unreturned diary for follow up. Information collected will be 
treated confidentially and for the purpose of reporting SAE(s) to MFDS (Korea), and for 
publication, if required.
Collection of pregnancy outcome information from pregnant subjects who received 
Cervarix, at 6-8 weeks after the Estimated Date of Delivery, if possible.
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6.4.11.
Recording of AEs, ADRs and SAEs
Refer to Section 8.3 for procedures for the Physician to record AEs, ADRs and SAEs and
to Section 8.3 for guidelines on how to report these AEs /ADRs /SAEs to GSK 
Biologicals. 
The subjects or 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.
6.4.12.
Procedures during follow-up visits/contacts
Note that some of the procedures to be performed during the follow-up visits/contacts 
(recording of AEs/SAEs) and are described in Section 6.4.7 up to Section 6.4.11.
Following-up to return and transcription of diary cards (refer to Section 6.4.7).
Checking for pregnancy within 30 days after Cervarix vaccination as applicable.
6.4.13.
PMS conclusion
The physician will review safety data collected to ensure accuracy and completeness and 
will complete the PMS Conclusion page in the CRF.
7.
DESCRIPTION OF CERVARIX
All marketed vaccines to be used have been developed and manufactured by GSK 
Biologicals.
Refer to the locally approved PI for information on the formulation and presentation of 
the Cervarix vaccine to be used in this PMS.
7.1.
Dosage and administration of Cervarix
The vaccine should be administered as an intramuscular injection. The preferred sites are 
deltoid muscle in upper arms. Refer to the locally approved PI for more detailed 
information.
7.2.
Contraindications to subsequent vaccination 
The events that constitute absolute contraindications to further administration of Cervarix
are listed in the locally approved PI. If any of these events occur during the surveillance, 
the subject must not receive additional doses of vaccine but may continue other PMS 
procedures at the discretion of the physician and any applicable local recommendations.
7.3.
Warnings and precautions
Refer to the approved product label/package insert.
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7.4.
Concomitant medication/vaccination (Amended: 14 May 
2018)
All concomitant vaccinations according to local practice are allowed during the PMS. 
Collected information for concomitant medication/vaccination such as trade/generic 
name, route, frequency, total daily dose (dose, unit), start date, end date, indication etc. 
needs to be recorded in the CRF. The medication/vaccination history (within 30-days 
prior to the Cervarix vaccination) should be documented in the CRF. For subjects who 
have received any of their dose/s of Cervarix outside the PMS and appear for the 
subsequent dose/s in this PMS, previous Cervarix vaccination history will be reported 
starting at first visit onwards irrespective of the dose subject has appeared for in the PMS. 
(Refer to the Table 1).
At each PMS visit/contact, the physician should question the subjects or subject’s 
parent(s)/LAR(s) about any medication taken and vaccination received by the subject.
7.4.1.
Recording of concomitant medications/products and 
concomitant vaccination
The following concomitant medications/products/vaccines must be recorded in the 
eCRF/CRF or the SAE/ADR Report if administered during the indicated recording 
period: 

All concomitant medication/vaccination, 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, or 38.0°C (100.4°F) on rectal 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 PMS 
SAE report form, as applicable. Refer to Section 8.1.3 for the definition of a SAE.
7.4.2.
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 each dose of Cervarix and ending 30 days (Day 1 to Day 30) after 
each dose of Cervarix must be recorded in the CRF.

Any vaccine not foreseen in the PMS protocol administered in the period beginning 
30 days (Day – 29 to Day 1) preceding each dose of Cervarix and ending 30 (Day 1 
to Day 30) days after each dose of Cervarix must be recorded in the CRF.
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
Any investigational medication or vaccine administered throughout the PMS (i.e. 
from 30 days before the first dose of the vaccine and 30 days after the last dose of 
the vaccine) must be recorded in the CRF.
8.
SAFETY
The physician or site staff is/are responsible during the PMS for the detection and 
documentation of events meeting the criteria and definition of an adverse event (AE) or a 
serious adverse event (SAE) as provided in this protocol.
Each subject/subject’s parent(s)/LAR(s) will be instructed to contact the physician
immediately should they manifest any signs or symptoms they perceive as serious/of 
concern or indicating a change in subject’s health status.
8.1.
Safety definitions
8.1.1.
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 an AE include

Significant or unexpected worsening or exacerbation of the condition/indication 
under PMS.

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 Cervarix administration.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms temporally associated with vaccine administration.

Significant failure of expected pharmacological or biological action.
Examples of an AE DO NOT include:

Medical or surgical procedures (e.g. endoscopy, appendectomy) the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).
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
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the PMS that do not worsen.

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
PMS. These events will be recorded in the medical history section of the CRF (i.e. 
prior to the first PMS vaccination).
An Expected/Unexpected AE defined as below; 

Expected AE: The presence/occurrence/intensity of an AE that is expected from the 
subjects during the post-vaccination follow-up period as described in the locally 
approved Prescribing Information.

Unexpected AE: Any AE that is not described in the approved Prescribing 
Information. Unexpected AEs are therefore not expected to occur during the post-
vaccination follow-up period.
8.1.2.
Definition of adverse drug reaction
Adverse drug reaction (ADR) represents adverse, unintended reactions from normal 
administration/use of the pharmaceuticalscannot be excluded. Of the voluntarily reported 
adverse events, those with no known causal relationship with the pharmaceutical are 
deemed to be adverse drug reactions.
8.1.3.
Definition of a serious adverse event
A serious adverse event (SAE) is any untoward medical occurrence 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 AE.
d.
Results in disability/incapacity, 
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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.
or
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 room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalisation.
8.2.
Events or outcomes not qualifying as AEs or SAEs
(Amended: 14 May 2018)
8.2.1.
Pregnancy
Female subjects who are either pregnant or lactating and who inadvertently received 
Cervarix may continue other PMS procedures according to the locally approved 
Prescribing Information.
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or an SAE.
Note: The pregnancy itself should always be recorded on a paper pregnancy report
The following should always be considered as an SAE and will be reported as described 
in Sections 8.4.1.

Spontaneous pregnancy loss, including:

spontaneous abortion, (spontaneous pregnancy loss before/ at 22 weeks of 
gestation)

ectopic and molar pregnancy

stillbirth (intrauterine death of foetus after 22 weeks of gestation).
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the EMA 
Guideline on pregnancy exposure [EMA, 2006]. It is recognised that national regulations 
may be different.
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
Any early neonatal death (i.e., death of a live born infant occurring within the first 
seven days of life). 

Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a PMS subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion
8.2.2.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments (e.g. hepatomegaly, jaundice, 
pallor, edema, bradycardia, facial edema, loss of hearing, tachycardia, increased 
intracranial pressure, lymphadenopathy, etc.) 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 8.1.1, or of an SAE, as defined in Section 8.1.3. Clinically 
significant abnormal laboratory findings or other abnormal assessments that are detected 
during the PMS or are present at baseline and significantly worsen following the start of 
the PMS 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 PMS 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.
8.3.
Detecting and recording AEs, ADRs and SAEs (Amended: 
14 May 2018)
8.3.1.
Time period for detecting and recording AEs, ADRs and SAEs
All AEs and SAEs starting immediately following administration of each dose of 
Cervarix must be recorded onto the CRF and all SAEs must be reported using the PMS 
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.
The standard time period for collecting and recording SAEs will begin at the first receipt 
of Cervarix in the PMS and will end 30 days (Day 1 to Day 30) after the last dose of 
Cervarix administered during the subject’s participation in PMS. See Section 8.4 for 
instructions on reporting and recording SAEs.
An overview of the protocol-required reporting periods for AEs, ADRs and SAEs is 
given in Table 4.
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Table 4
Reporting periods for AEs, ADRs and SAEs
PMS activity
V1
29 days 
post-V1
V2
29 days 
post-V2
V3
29 days post-V3
Reporting of AEs 
(expected & unexpected)
Reporting of SAEs/ADRs and 
Pregnancy*
V: vaccination; Post-V: post-vaccination 
* For subjects who become pregnant after receiving Cervarix during PMS, the pregnancy outcome (whether full-term 
or premature, information on the status of the mother and child) of these subjects will be followed-up for 6-8 
weeks after delivery, if possible.
Note: Post-vaccination adverse events will be collected and reported only for Cervarix doses received within the PMS 
(after signing the ICF). Any adverse events collected after Cervarix doses received outside of this PMS shall be 
reported as a spontaneous report and shall follow guidance for reporting of spontaneous report.
All AEs reported within 30 days of each dose of the vaccine administered within the 
PMS and all SAEs reported throughout the PMS period up to 30 days (Day 1 to Day 30) 
after the last dose of Cervarix administered during the subject’s participation in the PMS
need to be recorded in the CRF. These AEs/ SAEs will be classified as 
expected/unexpected at the time of statistical analyses (refer to GLOSSARY OF TERMS
for definitions of expected/unexpected adverse events).
All AEs reported during the 30 day (Day 1 to Day 30) follow-up period after each 
vaccine dose will be recorded using diary cards provided to the subjects or parent/LAR(s) 
of the subject. The AEs/SAEs will be analysed in the PMS report according to the 
expectedness and unexpectedness criteria as defined in the locally approved Prescribing 
Information (also refer to GLOSSARY OF TERMS).
Note: Assessment of causality and outcome will be done as defined in the MFDS (Korea)
guidelines. According to the current version of MFDS (Korea) guidelines, causality will 
be assessed as: Certain; Probable/Likely; Possible; Unlikely; Conditional/Unclassified; 
Unassessible/Unclassifiable. Outcome will be assessed as recovered; not recovered; 
recovering; resolved with sequelae; fatal; unknown.
A post-surveillance AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 3. Physicians are not obligated to actively seek 
AEs/SAEs in former PMS participants. However, if the physician learns of any SAE, 
including a death, at any time after a subject has been discharged from the PMS, and 
he/she considers the event reasonably related to the Cervarix, the physician will promptly 
notify the Contact for Reporting SAEs.
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8.3.2.
Evaluation of AEs, ADRs and SAEs
8.3.2.1.
Active questioning to detect AEs, ADRs and SAEs
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 subjects or subject’s 
parent(s)/LAR(s) should be asked a non-leading question such as:
‘Have you/has your child acted differently or felt different in any way since receiving the 
vaccine or since the last visit’
When an AE/ADR/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 the
AE/SAE on the CRF or ADR Report Form, SAE Report Form as applicable. The 
physician is not allowed to send photocopies of the subject’s medical records to GSK 
Biologicals instead of appropriately completing the CRF. However, there may be 
instances when copies of medical records for certain cases are requested by GSK 
Biologicals. 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/SAE and not the individual signs/symptoms.
8.3.2.2.
Assessment of severity
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 AEs (SAEs) recorded during the PMS. The assessment will be based on the 
physician’s clinical judgement.
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The intensity of each AE and SAE recorded in the CRF or SAE Report Form, as 
applicable, should be assigned to one of the following categories:
1 (mild)
= An AE/SAE which is easily tolerated by the subject, causing 
minimal discomfort and not interfering with everyday activities.
For fever: ≥37.5°C to ≤38.0°C (Oral/Axillary/ Tympanic 
temperature).
2 (moderate)
= An AE/SAE which is sufficiently discomforting to interfere with 
normal everyday activities.
For fever: >38°C to ≤39.0°C (Oral/Axillary/ Tympanic 
temperature).
3 (severe)
= An AE/SAE which prevents normal, everyday activities (in a young 
child, such an AE would, for example, prevent attendance at 
school/kindergarten/a day-care centre and would cause the 
parent(s)/LAR(s) to seek medical advice).
For fever: >39.0°C (Oral/Axillary/ Tympanic temperature).
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category utilised for rating the intensity of an event; and both AEs and SAEs can 
be assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 8.1.3.
8.3.2.3.
Assessment of causality
The Physician is obligated to assess the relationship between Cervarix and the occurrence 
of each AE/SAE. The Physician will use clinical judgement to determine the relationship. 
Alternative plausible causes, based on natural history of the underlying diseases, 
concomitant therapy, other risk factors and the temporal relationship of the event to the 
administration of Cervarix will be considered and investigated. The Physician will also 
consult the local Prescribing Information (Summary of Product Characteristics, SPC) to
ensure an accurate assessment.
There may be situations when a SAE has occurred and the Physician has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the Physician always makes an assessment of causality for every event 
prior to submission of the SAE to GSK Biologicals. The Physician may change his/her 
opinion of causality in light of follow-up information, and update the SAE information 
accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
In case of concomitant administration of multiple vaccines, it may not be possible to 
determine the causal relationship of general AEs to the individual vaccines administered. 
The Physician should, therefore, assess whether the AE could be causally related to 
vaccination rather than to the individual vaccines.
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Causality of AEs should be assessed by the Physician using the following question:
Is there a reasonable possibility that the AE may have been caused by Cervarix?
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.3), 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

Other procedure not required by the protocol

Lack of efficacy of the vaccine(s), if applicable.

Erroneous administration

Other cause (specify).
Assessment of causality of these AEs will be done to reflect the requirement of MFDS 
(Korea) to assess the relationship of the AEs.
NOTE: The use of the term “drug” here refers to Cervarix.
As per MFDS (Korea) requirements, causality will be assessed as:
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.
Unlikely:
It is a transitory case which may not have causality with the administration and use 
of the drug, it is also able to be explained reasonably by other medications, chemical 
substances or latent disease.
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5.
Conditional/Unclassified:
In the case that more information is needed for a proper evaluation or additional 
information is under review.
6.
Unassessible/Unclassifiable:
In the case that could not be judged due to insufficient or conflicting information and 
no way to complement or validate.
If the physician judges that the causal relationship is 1. Certain, 2. Probable/Likely, 3.
Possible, 5. Conditional/Unclassified, or 6. Unassessible/Unclassifiable, they should 
classify the relevant event as an ADR according to the GSK Reporting Procedure and 
prepare an ADR Report.
8.3.2.4.
Assessment of the outcomes
Outcome of any non-serious AE occurring within 30 days post-vaccination or any SAE 
reported during the entire PMS will be assessed as:

Recovered/resolved.

Not recovered/not resolved.

Recovering/resolving.

Recovered with sequelae/resolved with sequelae.

Fatal.

Unknown.
8.3.2.5.
Medically attended visits
For each adverse event the subject experiences, subject’s parent(s)/LAR(s) will be asked 
if the subject received medical attention defined as hospitalisation or an otherwise 
unscheduled visit to or from medical personnel for any reason, including emergency 
room visits. This information will be recorded in the CRF.
8.4.
Reporting of SAEs, Pregnancies and other events related to
Cervarix (Amended: 14 May 2018)
8.4.1.
Prompt reporting of SAEs related to PMS participation/ related to
Cervarix, pregnancies and other events to GSK
SAEs that occur in the time period defined in Section 8.3.1 will be reported promptly to 
GSK within the timeframes described in Table 5 once the physician determines that the 
event meets the protocol definition of an SAE.
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Non-serious AEs related to the vaccine that occur in the time period defined in Section 
8.3.1 will be reported promptly to GSK Biologicals within the timeframes described in 
Table 5 once the physician determines that the event meets the protocol definition for that 
event.
Pregnancies that occur in the time period defined in Section 8.3.1 will be reported 
promptly to GSK within the timeframes described in Table 5 once the physician becomes 
aware of the pregnancy. The subject will be followed to determine the outcome of the 
pregnancy.
Table 5
Time frames for submitting SAEs and other events reports to GSK 
Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a Previous 
Report
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours*
SAE report
24 hours*
SAE report
All ADRs
5 days **
ADR Report 
Form
5 days **
ADR Report Form
Pregnancies
2 weeks *
Pregnancy 
Report Form
2 weeks *
Pregnancy Report Form
* Time frame is allowed after receipt or awareness of the information.
** Recommended Time frame for ADR reporting for the physicians after the awareness of the information.
8.4.2.
PMS Contact for Reporting SAEs, ADRs and pregnancies: Please 
refer to local PMS contact information
Back-up PMS Contact for Reporting SAEs, ADRs and Pregnancies
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Outside US & Canada sites:
Fax: 
 or 
Email address: 
8.4.3.
Regulatory reporting requirements for SAEs
The physician will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.4.1. 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 under surveillance. Prompt notification of SAEs by the physician to 
the PMS Contact for Reporting SAEs is essential so that legal obligations and ethical 
responsibilities towards the safety of other subjects are met.
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8.4.4.
Completion and transmission of SAE reports to GSK Biologicals
Once a physician becomes aware that an SAE has occurred in a PMS subject, she/he will 
report the information to GSK within 24 hours. The SAE Report Form will always be 
completed as thoroughly as possible with all available details of the event, signed by the 
physician (or designee), and forwarded to GSK within the designated time frames. If the 
physician does not have all information regarding an SAE, he/she will not wait to receive 
additional information before notifying GSK of the event and completing the form. The 
form will be updated when additional relevant information is received and forwarded to 
GSK WITHIN 24 HOURS.
The physician will always provide an assessment of causality at the time of the initial 
report. The causality assessment may change depending on the availability of 
additional/follow-up information.
Facsimile (Fax) transmission or e-mail delivery of the SAE Report Form is the preferred 
method to transmit this information to the Contact for Reporting SAEs. In rare 
circumstances and due to failure of facsimile or electronic 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 or e-mail must be accompanied by telephone call to the PMS Contact for 
Reporting SAEs.
8.4.5.
Completion and transmission of non-serious AEs related to 
Cervarix reports to GSK
Once a physician becomes aware that a non-serious AE related to vaccine has occurred in 
a PMS subject, the physician (or designee) must complete an ADR Report and forward it 
to GSK within 5 calendar days. The report will always be completed as thoroughly as 
possible with all available details of the event and then dated and signed by the physician
(or designee). Even if the physician does not have all information regarding an AE, the 
report should still be completed and forwarded to GSK within 5 calendar days. Once 
additional relevant information is received, the report should be updated and forwarded to 
GSK within two weeks.
The physician will always provide an assessment of causality at the time of the initial 
report.
Fax transmission or e-mail delivery is the preferred method to forward the paper ADR 
Report to the PMS Contact for Reporting SAEs. In absence/ dysfunction of fax 
equipment or electronic, the PMS Contact for Reporting SAEs must be notified by 
telephone within 5 calendar days. As soon as the fax equipment or electronic is working 
again, the physician (or designee) must fax or e-mail the report to the PMS Contact for 
Reporting SAEs within 5 calendar days.
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8.4.6.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the physician becomes aware that a subject is pregnant, the physician (or designee) 
must complete, date and sign a paper pregnancy notification report and fax or e-mail it to 
the PMS Contact for Reporting SAEs (refer to the local PMS contact information 
document) WITHIN 2 WEEKS.
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report.
8.5.
Follow-up of AEs and SAEs (Amended: 14 May 2018)
After the initial AE/SAE report, the physician is required to proactively follow each 
subject and provide further information to GSK Biologicals 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 PMS.
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 up to 30 
days (Day 1 to Day 30) after the last dose of Cervarix administered during the subject’s 
participation in the PMS.
Physicians will follow-up subjects:

With SAEs or subjects withdrawn from the PMS 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 PMS 
Monitor.
GSK Biologicals 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 PMS or during a recognised follow-up period, 
GSK Biologicals will be provided with a copy of any available post-mortem findings, 
including histopathology.
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8.5.1.
Follow-up of pregnancies
Pregnant subjects will be followed to determine the outcome of the pregnancy. 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 Biologicals using the paper pregnancy follow-up 
report and the SAE Report if applicable. Generally, the follow-up period does not need to 
be longer than six to eight weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this PMS, if the pregnancy outcome is an 
SAE, it should always be reported as an SAE.
8.6.
Treatment of AEs
Treatment of any adverse event 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.
9.
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 PMS 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 Cervarix would likely be omitted in this drug use investigation.
10.
SUBJECT COMPLETION AND WITHDRAWAL
10.1.
Subject completion
Subjects who have completed 30-day follow-up after at least one dose, regardless of the 
number of doses are considered to have completed the PMS.
10.2.
Subject withdrawal (Amended: 14 May 2018)
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 8.5).
Withdrawals will not be replaced.
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10.2.1.
Subject withdrawal from PMS
From an analysis perspective, a ‘withdrawal’ from the PMS refers to any subject who did 
not come back for the concluding visit/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 PMS when no PMS 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 attempts 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 PMS was made by the 
subject’s parent(s) or LAR(s), or by the physician, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event.

Lost to follow-up.

Death.

Other (specify).
11.
STATISTICAL METHODS
11.1.
Endpoints (Amended: 14 May 2018)

Occurrence of AEs during the 30-day (Day 1 to Day 30) follow-up period after each 
vaccine dose.

Occurrence of SAEs reported throughout the PMS period up to 30 days (Day 1 to 
Day 30) after the last dose administered during the subject’s participation in the
PMS.
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11.2.
Determination of sample size
According to MFDS (Korea) regulation requirement, at least 600 evaluable subjects will 
be recruited for the PMS. Therefore, 660 subjects are expected to be enrolled through the 
PMS period considering the dropout rate of 10% (out of 600 subjects). Depending on the 
status, the enrolment plan can be adjusted.
Table 6 presents the exact two-sided 95% confidence interval for a sample size of 600 
subjects.
Table 6
Exact two-sided 95% CI for the percentage of subjects reporting at 
least one symptom with a sample size of 600 subjects
Observed rate expressed as a 
percentage (number of subjects 
reporting at least one 
symptom*)
Exact two-sided 95% CI for this observed rate for a sample size of 600 
subjects
Lower limit (LL)
Upper limit (UL)
1%
0.4
2.2
2%
1.0
3.5
3%
1.8
4.7
4%
2.6
5.9
5%
3.4
7.1
10%
7.7
12.7
15%
12.2
18.1
20%
16.9
23.4
*: The symptom could be any one of expected AE, unexpected AE or SAE.
11.3.
Study cohorts to be evaluated
11.3.1.
Total Vaccinated cohort
The total vaccinated cohort will include all subjects who receive at least one dose of 
Cervarix in the PMS:
11.3.2.
Total Safety cohort
Safety analysis based on all vaccination groups will include all subjects who were
vaccinated per product information and have completed 30-day follow-up after at least 
one dose, regardless of the number of dose.
11.4.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final PMS report.
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11.4.1.
Sequence of analyses
Analysis will be performed bi-annually for the first two years and annually for the 
remaining follow-up years (based on pre-defined cut-off date for enrolment). A 
comprehensive analysis will be performed at the end of the PMS. The analysis, including 
individual data listings, will be based on the cohort for vaccinated subjects for whom the 
PMS conclusion page has been received at GSK before the pre-defined cut-off date.
Bi-annual PMS reports will be written for the first two years and annual PMS reports will 
be written for the remaining years. A comprehensive PMS report will be written at the 
end of the PMS. All analyses described will be performed on cleaned data for each bi-
annual/annual report. All reports will be sent to the GSK Biologicals’ Central Safety and 
Pharmacovigilance (VCSP) and to MFDS (Korea).
11.4.2.
Statistical considerations for interim analyses
As this is a descriptive PMS there will be no statistical adjustments required for the each 
bi-annual/ annual analysis. The results of these analyses will not have an impact on the 
future PMS conduct.
11.5.
Statistical methods (Amended: 14 May 2018)
11.5.1.
Analysis of demographics/baseline characteristics
Demographic characteristics (age, gender, and ethnicity) and weight, height of the PMS
cohort will be tabulated using descriptive statistics. Mean, standard deviation, median, 
minimum and maximum will be calculated for continuous variables, and frequency and 
percentage will be calculated for categorical variables.
The medical history by disease classification and per past/current status and vaccination 
history of the vaccinated subjects will also be presented.
The distribution of subjects vaccinated among the PMS centres by years will be 
tabulated.
11.5.2.
Analysis of safety
Safety analysis based on total vaccinated cohort, will include all subjects who were 
vaccinated per product information and have completed 30-day follow-up after at least 
one dose, regardless of the number of dose. Analysis of AE/SAE data reported after each 
dose will be performed separately.
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11.5.2.1.
Within group assessment
The AEs/ SAEs will be analysed in the PMS 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% confidence interval (CI), of any AEs
occurring within 30 days (Day 1 to Day 30) will be tabulated, for each dose, for overall 
doses and by number of subjects. The same calculations will be done for any adverse 
events according to the severity and for those assessed as causally related to vaccination.
The verbatim reports of signs and symptoms will be matched and coded according to the 
appropriate WHO-ART Preferred Term. The PMS physician will review and confirm the 
appropriate WHO-ART Preferred Term by responding to data queries if any 
discrepancies are reported while coding. The percentage of subjects with AEs occurring 
within 30 days (Day 1 to Day 30) with its exact 95% CI will be tabulated by preferred 
term. Similar tabulation will be done for AEs with relationship to vaccination and for 
AEs rated as grade 3.
The number and percentage of subjects who received concomitant medication/ 
vaccination at least once during the 30-day (Day 1 to Day 30) follow-up period will be 
tabulated after each vaccine dose and overall, with exact 95% CI. Similar tabulations will 
be done for the number of subjects by types of medication/ vaccination during the entire 
PMS period.
The outcome of pregnancy (reported in the pregnancy report form) for subjects who 
become pregnant subjects during PMS will be presented, If possible.
Serious adverse events and withdrawals due to adverse events reported during the PMS
period (each subject receiving the vaccine up to 30 days after the last dose) will be 
described in detail.
12.
ADMINISTRATIVE MATTERS (AMENDED: 14 MAY 2018)
To comply with GEP, acceptable ethical principles, applicable local regulatory 
requirements, LSOP and administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
Safety data is used for analysis and GSK does not forward personally identifiable 
information. In the PMS report, subject number which is a number identifying a 
subject will be reported to MFDS (Korea).
12.1.
Case Report Form
CRFs (and subject diary cards, if applicable), will be supplied by GSK Biologicals for 
recording all data.
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In all cases, 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 GSK standards and data cleaning procedures.
While completed CRFs are reviewed by a GSK Biologicals’ PMS Monitor at the PMS 
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 PMS data collected.
Any questions or comments related to the CRF should be directed to the assigned PMS 
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 investigational site.
12.2.
Monitoring by GSK Biologicals
Monitoring visits by a GSK PMS Monitor are for the purpose of confirming that GSK 
Biologicals’ sponsored PMS are being conducted in accordance with the acceptable 
ethical principles and the applicable 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 PMS).
The physician must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all PMS-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a CRF review and a Source Document 
Verification (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 PMS monitor and 
physician and should be filed in the monitor’s and physician’s PMS 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, and GSK procedures, GSK monitors will 
contact the site prior to the start of the PMS to review with the site staff the protocol, 
PMS requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
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.
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GSK will monitor the PMS to verify that, amongst others, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

PMS is conducted in accordance with the currently approved protocol and any 
amendments, any other PMS agreements, GSK POL/SOP/Bio Guidance Document, 
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 PMS, the monitor will conduct site 
closure activities with the physician or site staff, as appropriate, in accordance with 
applicable regulations, and GSK procedures.
12.3.
Archiving of data at PMS sites
Following closure of the PMS, the physician must maintain all site PMS 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.
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 PMS, any institutional requirements or applicable laws or regulations, or 
GSK standards/procedures; 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.
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12.4.
Audits
To ensure compliance with GSK Vaccines’ procedures and 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 PMS. Such 
audits/inspections can occur at any time during or after completion of the PMS. 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.
12.5.
Posting of information on public registers
PMS information from this protocol will be posted on www.clinicaltrials.gov before 
enrolment of subjects begins.
12.6.
Ownership, confidentiality and publication (Amended: 14 
May 2018)
12.6.1.
Ownership
All information provided by GSK and all data and information generated by the site as 
part of the PMS (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 PMS are the sole property of GSK, and are hereby 
assigned to GSK.
If a written contract for the conduct of the PMS which includes ownership provisions 
inconsistent with this statement is executed between GSK and the PMS site, that 
contract’s ownership provisions shall apply rather than this statement.
12.6.2.
Confidentiality
Documented evidence that a potential physician is aware and agrees to the confidential 
nature of the information related to the PMS 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 PMS (other than a subject’s medical records) will be kept confidential by the 
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 PMS. 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 IEC or IRB solely for the evaluation of the PMS; (iii) information which it is 
necessary to disclose in order to provide appropriate medical care to a PMS subject; (iv) 
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information from this PMS may also be combined with results from other research 
studies to learn more about the vaccine and related diseases; or (v) PMS results which 
may be published as described in the next paragraph. If a written contract for the conduct 
of the PMS which includes confidentiality provisions inconsistent with this statement is 
executed, that contract’s confidentiality provisions shall apply rather than this statement.
12.6.3.
Publication
For multicentre studies, the first publication or disclosure of PMS results shall be a 
complete, joint multicentre 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 PMS 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 twenty-one working days, or at least 
fifteen working days for abstracts/posters/presentations). Proposed Publications shall not 
include either GSK confidential information other than the PMS 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 PMS, which includes publication provisions 
inconsistent with this statement is executed, that contract’s publication provisions shall 
apply rather than this statement.
12.6.4.
Provision of PMS results to physicians, posting to the clinical 
trials registers and publication 
Where required by applicable regulatory requirements, a physician signatory will be 
identified for the approval of the PMS report. The physician will be provided reasonable 
access to statistical tables, figures, and relevant reports and will have the opportunity to 
review the complete PMS results at a GSK site or other mutually-agreeable location.
The results summary will be posted to the GSK Clinical PMS Register no later than 12 
months after the last subject’s last visit (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 PMS information will be posted to the GSK 
Clinical PMS Register to supplement the results summary.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
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13.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
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14.
REFERENCES
Centers for Disease Control and Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf
Chaturvedi AK. Beyond cervical cancer: burden of other HPV-related cancers among 
men and women. J Adolesc Health. 2010;46(4 Suppl):S20-6.
de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, Plummer M. Global 
burden of cancers attributable to infections in 2008. Lancet Oncol. 2012 Jun;13(6):607-
15.
EMA Guideline on the exposure to medicinal products during pregnancy: need for post-
authorization data (Doc. Ref. EMEA/CHMP/313666/2005) ‘adopted at Community level 
in May 2006); 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/11/WC500011303.pdf
WHO/ICO HPV information center, 
http://www.hpvcentre.net/statistics/reports/XWX.pdf 
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APPENDIX A
AMENDMENTS ADMINISTRATIVE CHANGES TO 
THE PROTOCOL
GlaxoSmithKline Biologicals
Vaccines R & D
Protocol Amendment 1
eTrack study number and 
Abbreviated Title 
208710 (EPI-HPV-077 VS KR PMS)
Administrative change 
number:
Amendment 1
Administrative change 
date:
14 May 2018
Co-ordinating author:
 Medical Writer from DreamCIS, contractor 
for GSK Biologicals
Rationale/background for changes:
The protocol has been amended to address Ministry of Food and Drug Safety (MFDS) 
request for adding detailed description of enrolment plan, departments that will 
participate, method of PMS, collection of information regarding medical history, physical 
examination, and concomitant medication. In addition, collection of potential immune 
medicated diseases (pIMD) has been removed as it has not been considered mandatory 
for PMS, combined with results from other research studies to learn more about the 
vaccine and related diseases has been added in confidentiality section by referring to 
current Informed consents form (ICF), changed MFDS reporting method of personally 
identifiable information and added GSK reporting method of AEs/SAEs has been 
changed as it has been considered current PMS procedures, clarified vaccination schedule 
has been changed as it has been based on current prescribing information, and schedule 
period (such as Day 1 to Day 30) has been changed according to current writing process.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
The list of contributing authors has been updated.
Contributing authors
!
and 
, Clinical and 
Epidemiology R&D Project Lead
!
, Study Delivery Lead
!
, Safety Physician
!
, Lead Scientific Writer
!
and 
, 
Oversight Data Manager
!
, Statistician
!
, Regional VP Medical/Clinical 
GSK Vaccines
!
, Regional Epidemiologist
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!
and 
, Local 
Medical Lead,
!
and 
, Country 
Clinical Operations Head
!
, Vaccines Medical Director
!
, Named Safety Contact
!
, Local Delivery Lead
Sponsor signatory has been updated.
Sponsor signatory
Frank Struyf Dorota Borys,
Director, Clinical and Epidemiology R&D Project 
Lead, HPV and Hepatitis vaccines, 
RDC Belgium, GlaxoSmithKline Biologicals, SA.
Synopsis has been updated as it has been based on current prescribing information as 
shown below:
Indication
Cervarix is a vaccine indicated for active 
immunisation against HPV infection in males and 
females 9-25 years old as 3 doses, 0-1-60, 1 and 6
months schedule. Children and adolescents 9-14 
years old can be vaccinated with 2 doses, 0-60 and 
6-12 months schedule.
Section 2. OBJECTIVES has been updated.
2.
OBJECTIVES
2.1.
Primary objective
Section 3. PMS DESIGN OVERVIEW has been updated to address MFDS request for 
method of PMS as shown below:
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 8), are essential and 
required for study conduct. This PMS will be conducted by a continuous surveillance 
method.
Section 3. PMS DESIGN OVERVIEW has been updated as it has been based on 
current prescribing information shown below:
The recommended schedule is as follows:
∀
Vaccination: The 9-25 years old subjects should be administered 0.5 mL dose of 
Cervarix with 3 doses (0.5mL each), 0, 1, and 6 months schedule. The 9-14 
years old subjects can be vaccinated with 2 doses, 0 and 6-12 months schedule. 
In the 2 doses schedule, if the second dose is administered before 5 months 
after the first dose, the third dose vaccination is required. In the 3 doses 
schedule, if the vaccination schedule requires flexibility, the second dose can 
be administered between 1 and 2.5 months and the third dose can be 
administered between 5 and 12 months after the first dose.
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Section 3. PMS DESIGN OVERVIEW has been updated according to current PMS 
procedures and writing process as shown below:
Sequential Allocation of Subject 
Numbers
Cervarix (N = ~ 600)
Vaccination
Dose 1
Follow-up
30-day follow-up 
after Dose 1
Vaccination 
Dose 2
Follow-up
30-day follow-up 
after Dose 2
Vaccination 
Dose 3
Follow-up
30-day follow-up 
after Dose 3
N: Number of subjects planned to be enrolled
PMS conclusion will depend on the concluding visit of the subject in the PMS.
Definition of Conclusion of PMS for a subject: Subjects who have completed 30-day follow-up after at least one dose, 
regardless of the number of doses, are considered to have completed the PMS.
Note: Eligible subjects can be enrolled at any stage in the PMS regardless of Cervarix dose(s) received previously. 
Follow-up for AEs will continue for 30 days after receiving each vaccine dose(s) in the PMS. Follow-up of SAEs will 
continue from the date of Visit 1 until 30 days after the last dose (dose 1, 2 or 3) received in the PMS. Cervarix will be 
vaccinated according to local practice

Safety monitoring: 

Recording of all AEs during the 30 day period (Day 0 to Day 29) (Day 1 to Day 
30) using diary cards after each dose of Cervarix is administered. 

Recording of SAEs, adverse drug reactions (ADRs) and Pregnancy from the date 
of Visit 1 until 30 days (Day 0 to Day 29) (Day 1 to Day 30) after the last dose
(dose 1, 2 and 3) of Cervarix administered during the subject’s participation in 
the PMS.

Duration of the PMS: The intended duration of this study is approximately 4 
years.

Epoch 001: Prospective data collection starting at vaccination dose 1 and ending 
at follow up after dose 3last dose.
Table 1
Study group and epoch foreseen in the study
Study groups
Number of subjects
Age at Dose 1 (Min/Max)
Epoch 001
prospectiveHPV Group
Approx 600
9/25 years
X
3.1.
Discussion of PMS design
All adverse events reported during the 30-day post-vaccination follow-up period and all SAEs 
reported throughout the PMS period up to 30 days (Day 0 to Day 29) (Day 1 to Day 30) after the 
last dose (dose 1, 2 or 3) of Cervarix administered during the subject’s participation in the PMS, will 
be collected as part of safety data in this PMS. These adverse events will be further classified by 
GSK at the time of statistical analyses as expected/unexpected based on the locally approved 
Prescribing Information.
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Section 4.1 Number of subjects/centres has been updated to address MFDS request for 
adding detailed description of enrolment plan and departments that will participate as 
shown below:
Overview of the recruitment plan:

This prospective, observational PMS will be conducted at multiple centres in private 
clinics and hospitals (department of pediatrics and obstetrics & gynecology, etc.) in 
Korea for a period of 4 years.

PMS population: Subjects who receive at least one dose of Cervarix as a part of 
routine practice at a clinic or hospital. Only subjects to whom Cervarix will be 
prescribed in routine clinical practice will be invited to participate in the 
surveillance. 

Eligible subjects may join the PMS after the ICF/IAF has been signed by the 
subject/subject’s parent/LAR. 

The PMS is required to be conducted in at least one hospital [with Institutional 
Review Board (IRB) oversight] in order for the PMS to be conducted in private 
clinics (without IRB). 

Target enrolment: A total of at least 600 subjects will be enrolled over a period of 4
years.

The vaccine will be purchased by the subject/subject’s parents/LAR.

The recruitment will be monitored by the PMS monitor.
Table 2
Expected enrolment plan of subject
Period
Tentative calendar dates
Planned No. of enrolled subject*
1st Year
2017.07.28 ~ 2018.07.27
0
2ndYear
2018.07.28 ~ 2019.07.27
280
3rd Year
2019.07.28 ~ 2020.07.27
300
4thYear
2020.07.28 ~ 2021.07.27
20
Total
600**
* Approximate number
** At least 600 evaluable subjects will be recruited for the PMS.
Note: The above plan may be modified depending on conditions such as progress
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Section 6.3. Outline of PMS procedures has been updated as it has been considered 
current PMS procedures as shown below:
Table 2Table 3 presents the list of PMS procedures.
Table 2Table3 List of PMS procedures
Epoch
Epoch 001
Type of contact
Visit 1
Visit 2
Visit 3 c
Informed consent *
●
Check inclusion/exclusion criteria *
●
Check contraindications
●
●
●
Check warnings and precautions
●
●
●
Collect demographic data
●
Medical history*
●
Medication/Vaccination history **
●
Physical examination
●
O
O
Pre-vaccination body temperature
●
●
●
Record vaccination information
●
●
●
Distribution of diary cards
O
O
O
Recording of adverse events within 30 days post-vaccination, by physician
●
●
●
Return of diary cards a
O
O
Diary card transcription by physician
●
●
Record any concomitant medication/vaccination
●
●
●
Record any intercurrent medical conditions
●
●
Reporting of serious adverse events / ADRs/Pregnancy Information
●
●
●
PMS Conclusion b
●
●
●
● is used to indicate a PMS procedure or a vaccination-related non-PMS procedure that requires documentation in the 
individual CRF.
○ is used to indicate a PMS procedure that does not require documentation in the individual CRF.
* For the subjects who have received Cervarix previously and are enrolled in the PMS, procedures for Informed 
Consent/Check inclusion/exclusion criteria/Medical history/Vaccination history can be conducted at the first PMS-
related visit.
** Medication/Vaccination history (within 30-days prior to the Cervarix vaccination)
For subjects who have received one or two dose/s of Cervarix before the PMS enrolment, previous Cervarix
vaccination history will be reported starting at the first PMS-related visit onwards irrespective of the number of dose 
subject received during the PMS. 
a – The subjects will be instructed to return the completed diary card to the physician on their next PMS visit or phone 
or mail, to report any AEs/SAEs/ADRs/Pregnancy during the 30 day period (Day 0 to Day 29) (Day 1 to Day 30) using 
diary cards after each dose of Cervarix is administered.
b –PMS CRF Conclusion section to be completed depending on the available concluding visit of the subject in the PMS. 
The CRF conclusion will be 30 days after the last dose. (dose 1, 2, 3).
C–The visit 3 can be omitted as 9-14 years old can be vaccinated with two dose schedule.
Section 6.4. Detailed description of PMS procedures has been updated to address 
MFDS request for collection of information regarding medical history, physical 
examination, and concomitant medication as shown below:
6.4.3.
Collect demographic data
Record demographic data such as age, weight, gender and ethnicity in the subject’s CRF.
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6.4.4.
Record medical history
Obtain the subject’s medical history such as status (past/current), diagnosis, classify 
(renal/liver disease/other) by interview and/or review of the subject’s medical records 
and record any pre-existing conditions or signs and/or symptoms present in a subject 
prior to the start of the PMS in the CRF.
6.4.5.
Physical examination
Perform a physical examination of the subject. Collected information (weight, height)
needs to be recorded in the CRF.
6.4.6.
Medication/Vaccination History
Collect information regarding all medicines/vaccines administered to the subject 30 days 
prior to vaccination with Cervarix during the PMS.
Section 6.4. Detailed description of PMS procedures has been updated as it has been 
considered current PMS procedures as shown below:
6.4.5.
Physical examination
At each study visit subsequent to the first visit, a physical examination will only be 
performed if the subject indicates during questioning that there may be some underlying 
pathology(ies) or if deemed necessary by the investigator or delegate.
6.4.10. Distribution, return and transcription of diary cards
After each vaccination, diary cards will be provided to the subjects or subject’s 
parent(s)/LAR(s) to record any AEs (i.e. on the day of vaccination and during the next 29 
days) occurring after vaccination. The subjects or subject's parent(s)/LAR(s) will be 
instructed to return the completed diary card to the physician on their next PMS visit or 
provide details during the telephonic interview from physicians or by postal mail. Site 
staff will try to contact subject or subject’s parent(s)/LAR(s) at least 3 attempts through 
telephone call(s) (at least 3 attempts) for any unreturned diary for follow up. Information 
collected will be treated confidentially and for the purpose of reporting SAE(s) to MFDS 
(Korea), and for publication, if required.
6.4.12. Procedures during follow-up visits/contacts
Following-up to return and transcription of diary cards (refer to Section 6.4.7).
Collection and verification of completed diary card during discussion with the subjects or 
subject’s parent(s)/LAR(s) at the subsequent visit/contact. Any unreturned diary cards 
will be sought from the subjects or subject’s parent(s)/LAR(s) 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 30 days after Cervarix vaccination, if possible as 
applicable.
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Section 7.4. Concomitant medication/vaccination has been updated as it has been 
considered current PMS procedures and current writing process as shown below:
All concomitant vaccinations according to local practice are allowed during the PMS and 
administration of these should be documented in the CRF. Collected information for 
concomitant medication/vaccination such as trade/generic name, route, frequency, 
total daily dose (dose, unit), start date, end date, indication etc. needs to be recorded in 
the CRF. The medication/vaccination history (within 30-days prior to the Cervarix
vaccination) should be documented in the CRF. For subjects who have received any of 
their dose/s of Cervarix outside the PMS and appear for the subsequent dose/s in this 
PMS, previous Cervarix vaccination history will be reported starting at first visit onwards 
irrespective of the dose subject has appeared for in the PMS. (Refer to the Table 1).
7.4.1.
Recording of concomitant medications/products and concomitant 
vaccination
The following concomitant medications/products/vaccines must be recorded in the 
eCRF/CRF or the Expedited Adverse EventSAE/ADR Report if administered during the 
indicated recording period: 
7.4.2.
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 each dose of Cervarix and ending 30 days (Day 0 to Day 29) (Day 
1 to Day 30) after each dose of Cervarix must be recorded in the CRF.

Any vaccine not foreseen in the PMS protocol administered in the period beginning 
30 days (Day-29 to Day 0) (Day –29 to Day 1) preceding each dose of Cervarix and 
ending 30 (Day 0 to Day 29) (Day 1 to Day 30) days after each dose of Cervarix
must be recorded in the CRF.
Section 8.2.3. Reporting adverse events of specific interest to GSK has been removed 
as it has not been considered mandatory for PMS
Section 8.2.3. Reporting adverse events of specific interest to GSK
Several adverse events of specific interest including but not limited to potential immune 
medicated diseases (pIMD) and postural orthostatic tachycardia Syndrome (POTS), 
chronic regional pain syndrome (CRPS) following the Cervarix vaccination require close 
monitoring and further assessment. pIMD list is provided in .
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Table 8
List of pIMDs
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve neuropathy, 
including paralysis and paresis 
(e.g. Bell’s palsy).

Optic neuritis.

Multiple sclerosis.

Transverse myelitis.

Guillain-Barré syndrome, including 
Miller Fisher syndrome and other 
variants.

Acute disseminated 
encephalomyelitis, including site 
specific variants e.g.: non-
infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis.

Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome.

Demyelinating peripheral 
neuropathies including:
-
Chronic inflammatory 
demyelinating 
polyneuropathy, 
-
Multifocal motor neuropathy 
-
Polyneuropathies associated 
with monoclonal 
gammopathy.

Narcolepsy.

Systemic lupus 
erythematosus and 
associated conditions

Systemic scleroderma 
(Systemic sclerosis), 
including:
-
Diffuse Scleroderma
-
CREST syndrome

Idiopathic inflammatory 
myopathies, including:
-
Dermatomyositis 
-
Polymyositis 

Anti-synthetase 
syndrome.

Rheumatoid Arthritis and 
associated conditions 
including: 
-
Juvenile Idiopathic 
Arthritis
-
Still’s disease.

Polymyalgia rheumatica.

Spondyloarthropathies, 
including: 
-
Ankylosing 
Spondylitis, 
-
Reactive Arthritis 
(Reiter's Syndrome),
-
Undifferentiated 
Spondyloarthritis,
-
Psoriatic Arthritis,
-
Enteropathic 
arthritis.

Relapsing Polychondritis.

Mixed Connective Tissue 
disorder.

Gout

Psoriasis.

Vitiligo.

Erythema nodosum.

Autoimmune bullous skin 
diseases (including pemphigus, 
pemphigoid and dermatitis 
herpetiformis).

Lichen planus.

Sweet’s syndrome.

Localised Scleroderma 
(Morphoea).
Vasculitis
Blood disorders
Others

Large vessels vasculitis including: 
-
Giant Cell Arteritis (Temporal 
Arteritis),
-
Takayasu's Arteritis. 

Medium sized and/or small vessels 
vasculitis including: 
-
Polyarteritis nodosa,
-
Kawasaki's disease, 
-
Microscopic Polyangiitis, 
-
Wegener's Granulomatosis 
(granulomatosis with 
polyangiitis), 

Autoimmune hemolytic 
anemia.

Autoimmune 
thrombocytopenia.

Antiphospholipid 
syndrome.

Pernicious anemia.

Autoimmune aplastic 
anemia.

Autoimmune 
neutropenia.

Autoimmune 
pancytopenia.

Autoimmune glomerulonephritis 
including:
-
IgA nephropathy, 
-
Glomerulonephritis rapidly 
progressive, 
-
Membranous 
glomerulonephritis, 
-
Membranoproliferative 
glomerulonephritis, 
-
Mesangioproliferative 
glomerulonephritis. 
-
Tubulointerstitial nephritis 
and uveitis syndrome.
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Vasculitis
Blood disorders
Others
-
Churg–Strauss syndrome 
(allergic granulomatous 
angiitis or eosinophilic 
granulomatosis with 
polyangiitis),
-
Buerger’s disease 
(thromboangiitis obliterans), 
-
Necrotizing vasculitis 
(cutaneous or systemic), 
-
anti-neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified),
-
Henoch-Schonlein purpura 
(IgA vasculitis), 
-
Behcet's syndrome,
-
Leukocytoclastic vasculitis.

Ocular autoimmune diseases 
including:
-
Autoimmune uveitis 
-
Autoimmune retinitis.

Autoimmune myocarditis.

Sarcoidosis.

Stevens-Johnson syndrome.

Sjögren’s syndrome.

Alopecia areata.

Idiopathic pulmonary fibrosis.

Goodpasture syndrome.

Raynaud’s phenomenon.
Liver disorders
Gastrointestinal disorders
Endocrine disorders

Autoimmune hepatitis.

Primary biliary cirrhosis.

Primary sclerosing cholangitis.

Autoimmune cholangitis.

Inflammatory Bowel 
disease, including:
-
Crohn’s disease, 
-
Ulcerative colitis, 
-
Microscopic colitis, 
-
Ulcerative proctitis.

Celiac disease.

Autoimmune pancreatitis.

Autoimmune thyroiditis 
(Hashimoto thyroiditis).

Grave's or Basedow’s disease.

Diabetes mellitus type I.

Addison’s disease.

Polyglandular autoimmune 
syndrome.

Autoimmune hypophysitis.
If the subject develops adverse event of specific interest during the surveillance period, 
the physician shall report it as an AE and follow up the subject to collect information 
using Targeted Follow-Up Questionnaires (TFUQ) provided by GSK. GSK may request 
additional information in such cases.
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Section 8. SAFETY has been updated as it has been considered current PMS procedures 
and writing process as shown below:
8.3. Detecting and recording AEs, ADRs and
8.3.1.
Time period for detecting and recording AEs, ADRs and SAEs
The standard time period for collecting and recording SAEs will begin at the first receipt 
of Cervarix in the PMS and will end 30 days (Day 0 to Day 29)(Day 1 to Day 30) after 
the last dose (dose 1, 2 or 3) of Cervarix administered during the subject’s participation in 
PMS. See Section 8.4 for instructions on reporting and recording SAEs.
An overview of the protocol-required reporting periods for AEs, ADRs and SAEs is 
given in Table 4.
All AEs reported within 30 days of each dose of the vaccine administered within the 
PMS and all SAEs reported throughout the PMS PMS period up to 30 days (Day 0 to 
Day 29)(Day 1 to Day 30) after the last dose (dose 1, 2, 3) of Cervarix administered 
during the subject’s participation in the PMS, and received within the PMS need to be 
recorded in the CRF. These AEs/ SAEs will be classified as expected/unexpected at the 
time of statistical analyses (refer to GLOSSARY OF TERMS for definitions of 
expected/unexpected adverse events).
All AEs reported during the 30 day (Day 0 to Day 29)(Day 1 to Day 30) follow-up period 
after each vaccine dose will be recorded using diary cards provided to the subjects or 
parent/LAR(s) of the subject. The AEs/SAEs will be analysed in the PMS report 
according to the expectedness and unexpectedness criteria as defined in the locally 
approved Prescribing Information (also refer to GLOSSARY OF TERMS).
8.4.
Reporting of SAEs, Pregnancies and other events related to Cervarix
8.4.2.
PMS Contact for Reporting SAEs, ADRs and pregnancies: Please refer to 
local PMS contact information
Back-up PMS Contact for Reporting SAEs, ADRs and Pregnancies
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Outside US & Canada sites:
Fax: 
 or 
Email address: 
8.4.4.
Completion and transmission of SAE reports to GSK Biologicals
Facsimile (Fax) transmission or e-mail delivery of the SAE Report Form is the preferred 
method to transmit this information to the Contact for Reporting SAEs. In rare 
circumstances and due to failure of facsimile or electronic 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.
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In the event of a death determined by the physician to be related to vaccination, sending 
of the fax or e-mail must be accompanied by telephone call to the PMS Contact for 
Reporting SAEs.
8.4.5.
Completion and transmission of non-serious AEs related to Cervarix reports 
to GSK
Once a physician becomes aware that a non-serious AE related to vaccine has occurred in 
a PMS subject, the physician (or designee) must complete an Expedited Adverse 
EventADR Report and forward it to GSK within 5 calendar days. The report will always 
be completed as thoroughly as possible with all available details of the event and then 
dated and signed by the physician (or designee). Even if the physician does not have all 
information regarding an AE, the report should still be completed and forwarded to GSK 
within 5 calendar days. Once additional relevant information is received, the report 
should be updated and forwarded to GSK within two weeks.
The physician will always provide an assessment of causality at the time of the initial 
report.
Fax transmission or e-mail delivery is the preferred method to forward the paper 
Expedited Adverse Event ADR Report to the PMS Contact for Reporting SAEs. In 
absence/ dysfunction of fax equipment or electronic, the PMS Contact for Reporting 
SAEs must be notified by telephone within 5 calendar days. As soon as the fax equipment 
or electronic is working again, the physician (or designee) must fax or e-mail the report 
to the PMS Contact for Reporting SAEs within 5 calendar days.
8.4.6.
Completion and transmission of pregnancy reports to GSK Biologicals
Once the physician becomes aware that a subject is pregnant, the physician (or designee) 
must complete, date and sign a paper pregnancy notification report and fax or e-mail it to 
the PMS Contact for Reporting SAEs (refer to the local PMS contact information 
document) WITHIN 2 WEEKS.
8.5.
Follow-up of AEs and SAEs
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 up to 30 
days (Day 0 to Day 29) (Day 1 to Day 30) after the last dose (dose 1, 2 or 3) of Cervarix
administered during the subject’s participation in the PMS.
8.5.1.
Follow-up of pregnancies
Pregnant subjects will be followed to determine the outcome of the pregnancy. 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 Biologicals using the paper pregnancy follow-up 
report and the Expedited Adverse EventSAE Report if applicable. Generally, the follow-
up period does not need to be longer than six to eight weeks after the estimated date of 
delivery.
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Section 10.2. Subject withdrawal has been updated as it has been considered current 
PMS procedures as shown below:
10.2.1. Subject withdrawal from PMS
From an analysis perspective, a ‘withdrawal’ from the PMS refers to any subject who did 
not come back for the concluding visit/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 PMS when no PMS 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 attemptattempts 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 PMS was made by the 
subject’s parent(s) or LAR(s), or by the physician, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event.

Moved from the PMS area.

Lost to follow-up.

Death.

Other (specify).
Section 11. STATISTICAL METHODS has been updated as it has been considered 
current PMS procedures as shown below:
11.1.
Endpoints

Occurrence of AEs during the 30-day (Day 0 to Day 29) (Day 1 to Day 30) follow-
up period after each vaccine dose.

Occurrence of SAEs reported throughout the PMS period up to 30 days (Day 0 to 
Day 29) (Day 1 to Day 30) after the last dose (dose 1, 2 or 3) administered during the 
subject’s participation in the PMS.
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11.5.
Statistical methods
11.5.2.1.
Within group assessment
The number and percentage, with exact 95% confidence interval (CI), of any AEs
occurring within 30 days (Day 0 to Day 29) (Day 1 to Day 30) will be tabulated, for each 
dose, for overall doses and by number of subjects. The same calculations will be done for 
any adverse events according to the severity and for those assessed as causally related to 
vaccination.
The verbatim reports of signs and symptoms will be matched and coded according to the 
appropriate WHO-ART Preferred Term. The PMS physician will review and confirm the 
appropriate WHO-ART Preferred Term by responding to data queries if any 
discrepancies are reported while coding. The percentage of subjects with AEs occurring 
within 30 days (Day 0 to Day 29) (Day 1 to Day 30) with its exact 95% CI will be 
tabulated by preferred term. Similar tabulation will be done for AEs with relationship to 
vaccination and for AEs rated as grade 3.
The number and percentage of subjects who received concomitant medication/ 
vaccination at least once during the 30-day (Day 0 to Day 29) (Day 1 to Day 30) follow-
up period will be tabulated after each vaccine dose and overall, with exact 95% CI. 
Similar tabulations will be done for the number of subjects by types of medication/ 
vaccination during the entire PMS period.
11.5.1. Analysis of demographics/baseline characteristics has been updated to address 
MFDS request for collection of information regarding medical history, physical 
examination, and concomitant medication as shown below:
Demographic characteristics (age, weight, gender, and ethnicity) and weight, height of 
the PMS cohort will be tabulated using descriptive statistics. Mean, standard deviation, 
median, minimum and maximum will be calculated for continuous variables, and 
frequency and percentage will be calculated for categorical variables.
The medical history by disease classification and per past/current status and vaccination 
history of the vaccinated subjects will also be presented. 
The distribution of subjects vaccinated among the PMS centres by years will be 
tabulated.
Section 12. ADMINISTRATIVE MATTERS has been updated as it has been 
considered current PMS procedures as shown below:
To comply with GEP, acceptable ethical principles, applicable local regulatory 
requirements, LSOP and administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
Blinding of subject initials when safetySafety data is used for analysis and for GSK LOC 
to accurately provide the subject initials on the PMS report before submission to MFDS 
(Korea).(GSK does not forward personally identifiable information. In the PMS report, 
subject number which is a number identifying a subject will be reported to MFDS 
(Korea). requires reporting of PMS subject’s initials in the PMS report).
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12.6.
Ownership, confidentiality and publication has been updated in confidentiality 
section by referring to current Informed consents form (ICF).
12.6.2. Confidentiality
All information provided by GSK and all data and information generated by the site as 
part of the PMS (other than a subject’s medical records) will be kept confidential by the 
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 PMS. 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 IEC or IRB solely for the evaluation of the PMS; (iii) information which it is 
necessary to disclose in order to provide appropriate medical care to a PMS subject; (iv) 
information from this PMS may also be combined with results from other research 
studies to learn more about the vaccine and related diseases; or (v) PMS results which 
may be published as described in the next paragraph. If a written contract for the conduct 
of the PMS which includes confidentiality provisions inconsistent with this statement is 
executed, that contract’s confidentiality provisions shall apply rather than this statement.
208710 | Protocol Amendment 1 14 May 2018 | TMF-515675 | 4.0