A Phase 3, Open-label Clinical Study to Evaluate the Immunogenicity and Safety of 9vHPV Vaccine, in Japanese Boys and Girls, 9 to 15 Years of Age.
Phase: PHASE3
Conditions: Papillomavirus Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04772534 
Document Date: 
19-Sep-2022
A Phase 3, Open-label Clinical Study to Evaluate the 
Immunogenicity and Safety of 9vHPV Vaccine, in Japanese Boys 
and Girls, 9 to 15 Years of Age.

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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Open-label Clinical Study to Evaluate the Immunogenicity and 
Safety of 9vHPV Vaccine, in Japanese Boys and Girls, 9 to 15 Years of Age.
This protocol amendment is applicable only to Japan.
Protocol Number: 066-02
Compound Number: V503
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
EudraCT
2020-001170-29
Approval Date: 19 September 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 2 (066-02)
19-SEP-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA.
Amendment 1 (066-01)
15 MAR 2021
Enrollment of girls aged 9 to 14 years old will be initiated prior to that of boys aged 
9 to 15 years old to support earlier filing of the 2-dose girl arm data.
Original Protocol
23 NOV 2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
10.1
Appendix 1: 
Regulatory, Ethical, and 
Study Oversight 
Considerations
Throughout
Sponsor entity name and address change
Merck Sharp & Dohme Corp. underwent an entity 
name and address change to Merck Sharp & Dohme 
LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and update to the address.
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Section # and Name
Description of Change 
Brief Rationale 
10.1.1 Code of Conduct for 
Clinical Trials
II. Scientific Issues / A. Trial 
Conduct
Updated to include the following in each 
section:
1. Trial Design
All trial protocols are and will be assessed 
for the need and capability to enroll 
underrepresented groups.
2. Site Selection
MSD’s clinical trials are conducted 
globally in many different countries and in 
diverse populations, including people of 
varying age, race, ethnicity, gender, and 
accounting for other potential disease 
related factors.
Where appropriate, and in accordance with 
regulatory authority guidance, MSD will 
make concerted efforts to raise awareness 
of clinical trial opportunities in various 
communities. MSD will seek to engage 
underrepresented groups and those 
disproportionately impacted by the disease 
under study. MSD will support clinical 
trial investigators to enroll 
underrepresented groups and expand 
access to those who will ultimately use the 
products under investigation.
To align with updated Sponsor template text.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................19
2
INTRODUCTION..........................................................................................................23
2.1
Study Rationale....................................................................................................23
2.2
Background ..........................................................................................................25
2.2.1
Pharmaceutical and Therapeutic Background .............................................25
2.2.1.1
Disease Burden and Epidemiology for HPV-related Disease............26
2.2.2
Preclinical and Clinical Studies ...................................................................28
2.2.2.1
Completed Clinical Studies................................................................28
2.2.2.2
Ongoing Clinical Studies in Japan.....................................................28
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................29
4
STUDY DESIGN............................................................................................................30
4.1
Overall Design......................................................................................................30
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................32
4.2.1.1
Immunogenicity Endpoints................................................................32
4.2.1.2
Safety Endpoints................................................................................32
4.2.1.3
Future Biomedical Research..............................................................32
4.3
Justification for Dose...........................................................................................32
4.4
Beginning and End of Study Definition .............................................................33
4.4.1
Clinical Criteria for Early Study Termination .............................................33
5
STUDY POPULATION ................................................................................................33
5.1
Inclusion Criteria.................................................................................................33
5.2
Exclusion Criteria................................................................................................34
5.3
Lifestyle Considerations......................................................................................36
5.4
Screen Failures.....................................................................................................36
5.5
Participant Replacement Strategy......................................................................36
6
STUDY INTERVENTION............................................................................................36
6.1
Study Intervention(s) Administered...................................................................36
6.2
Preparation/Handling/Storage/Accountability .................................................38
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6.2.1
Dose Preparation..........................................................................................38
6.2.2
Handling, Storage, and Accountability........................................................38
6.3
Measures to Minimize Bias: Randomization and Blinding..............................39
6.3.1
Intervention Assignment..............................................................................39
6.3.2
Stratification.................................................................................................39
6.3.3
Blinding........................................................................................................39
6.4
Study Intervention Compliance..........................................................................39
6.5
Concomitant Therapy..........................................................................................39
6.5.1
Rescue Medications and Supportive Care ...................................................40
6.6
Dose Modification ................................................................................................40
6.7
Intervention After the End of the Study............................................................40
6.8
Clinical Supplies Disclosure................................................................................40
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................40
7.1
Discontinuation of Study Intervention...............................................................40
7.2
Participant Withdrawal From the Study...........................................................41
7.3
Lost to Follow-up .................................................................................................42
8
STUDY ASSESSMENTS AND PROCEDURES........................................................42
8.1
Administrative and General Procedures ...........................................................43
8.1.1
Informed Consent.........................................................................................43
8.1.1.1
General Informed Consent.................................................................43
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................44
8.1.2
Inclusion/Exclusion Criteria ........................................................................44
8.1.3
Participant Identification Card.....................................................................44
8.1.4
Medical History ...........................................................................................44
8.1.5
Demographics ..............................................................................................45
8.1.6
Prior and Concomitant Medications Review...............................................45
8.1.6.1
Prior Medications...............................................................................45
8.1.6.2
Concomitant Medications..................................................................45
8.1.7
Assignment of Screening Number...............................................................45
8.1.8
Assignment of Treatment/Randomization Number.....................................46
8.1.9
Study Intervention Administration ..............................................................46
8.1.9.1
Timing of Dose Administration.........................................................47
8.1.10
Discontinuation and Withdrawal .................................................................47
8.1.10.1
Withdrawal From Future Biomedical Research ................................47
8.1.11
Participant Blinding/Unblinding..................................................................48
8.1.12
Calibration of Equipment.............................................................................48
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8.2
Immunogenicity Assessments .............................................................................48
8.2.1
Blood Sample Collection for Serum Anti-HPV Antibody Testing .............48
8.2.2
Competitive Luminex Immunoassay...........................................................48
8.3
Safety Assessments...............................................................................................49
8.3.1
Physical Examinations.................................................................................49
8.3.2
Oral Temperature Measurements.................................................................49
8.3.3
Clinical Safety Laboratory Assessments .....................................................50
8.3.4
Vaccination Report Card..............................................................................50
8.3.5
Postvaccination Observation Period (30 Minutes) ......................................51
8.3.6
Pregnancy Testing........................................................................................51
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety
Events....................................................................................................................52
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................53
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......54
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...55
8.4.4
Regulatory Reporting Requirements for SAE .............................................55
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................55
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................56
8.4.7
Events of Clinical Interest............................................................................56
8.5
Treatment of Overdose........................................................................................56
8.6
Pharmacokinetics.................................................................................................56
8.7
Pharmacodynamics..............................................................................................56
8.8
Future Biomedical Research Sample Collection...............................................56
8.9
Visit Requirements...............................................................................................56
8.9.1
Screening......................................................................................................56
8.9.2
Prerequisites for Vaccination Visits (Day 1, Month 2, and Month 6).........57
8.9.3
Discontinued Participants Continuing to be Monitored in the Study ..........57
9
STATISTICAL ANALYSIS PLAN .............................................................................57
9.1
Statistical Analysis Plan Summary.....................................................................58
9.2
Responsibility for Analyses/In-house Blinding .................................................59
9.3
Hypotheses/Estimation ........................................................................................60
9.4
Analysis Endpoints...............................................................................................60
9.4.1
Immunogenicity Endpoints..........................................................................60
9.4.2
Safety Endpoints..........................................................................................60
9.5
Analysis Populations............................................................................................60
9.5.1
Immunogenicity Analysis Populations ........................................................60
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9.5.2
Safety Analysis Population..........................................................................62
9.6
Statistical Methods...............................................................................................62
9.6.1
Statistical Methods for Immunogenicity Analyses......................................62
9.6.2
Statistical Methods for Safety Analyses ......................................................63
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................65
9.7
Interim Analyses ..................................................................................................65
9.8
Multiplicity ...........................................................................................................65
9.9
Sample Size and Power Calculations .................................................................65
9.10
Subgroup Analyses...............................................................................................66
9.11
Compliance (Medication Adherence).................................................................66
9.12
Extent of Exposure...............................................................................................66
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................67
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........67
10.1.1
Code of Conduct for Clinical Trials.............................................................67
10.1.2
Financial Disclosure.....................................................................................69
10.1.3
Data Protection.............................................................................................70
10.1.3.1
Confidentiality of Data ......................................................................70
10.1.3.2
Confidentiality of Participant Records...............................................70
10.1.3.3
Confidentiality of IRB/IEC Information............................................70
10.1.4
Publication Policy........................................................................................71
10.1.5
Compliance with Study Registration and Results Posting Requirements ...71
10.1.6
Compliance with Law, Audit, and Debarment ............................................71
10.1.7
Data Quality Assurance ...............................................................................72
10.1.8
Source Documents .......................................................................................73
10.1.9
Study and Site Closure.................................................................................73
10.2
Appendix 2: Clinical Laboratory Tests..............................................................74
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................75
10.3.1
Definition of AE ..........................................................................................75
10.3.2
Definition of SAE ........................................................................................76
10.3.3
Additional Events Reported.........................................................................77
10.3.4
Recording AE and SAE ...............................................................................77
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................80
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................82
10.5
Appendix 5: Contraceptive Guidance................................................................83
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10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................84
10.7
Appendix 7: Country-specific Requirements....................................................89
10.8
Appendix 8: Abbreviations .................................................................................90
11
REFERENCES...............................................................................................................91
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................37
Table 2
Blood Collection Volumes...............................................................................43
Table 3
Guidelines for Pregnant Participants: Managing Study Visits and Study 
Vaccinations.....................................................................................................52
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................54
Table 5
Acceptable Day Ranges for Vaccination Visits...............................................61
Table 6
Acceptable Day Ranges for Collection of Serum Samples .............................61
Table 7
Analysis Strategy for Immunogenicity Variables............................................63
Table 8
Analysis Strategy for Safety Parameters..........................................................64
Table 9
Estimate of Incidence of Adverse Event and Half-width of 95% 
Confidence Interval Based on Hypothetical Number of Participants with 
Adverse Event among 100 Participants in the Study Arm ..............................66
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................18
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PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Open-label Clinical Study to Evaluate the Immunogenicity and 
Safety of 9vHPV Vaccine, in Japanese Boys and Girls, 9 to 15 Years of Age. 
Short Title: Phase 3 Study for Immunogenicity and Safety of the 9vHPV Vaccine in 
Japanese Boys and Girls
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
This study will evaluate 2 different dose regimens of the 9-valent human papillomavirus 
(9vHPV) vaccine: a 3-dose regimen in Japanese boys aged 9 to 15 years old and a 2-dose 
regimen in Japanese boys and girls aged 9-14 years old. The base phase of the study (Period 
I) will assess the immunogenicity and safety of the 9vHPV vaccine through 7 months 
following the first dose. The extension phase of the study (Period II) will assess the safety 
and the antibody persistence to the 9vHPV vaccine through 30 months following the first 
dose.
Primary Objectives
Primary Endpoints
- To estimate percent seroconversion for the 
vaccine HPV types (6, 11, 16, 18, 31, 33, 45, 
52 and 58) at Month 7 in Japanese boys aged 
9 to 15 years who received 3 doses of the 
9vHPV vaccine
- Serum antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52 and 58
- To estimate percent seroconversion for the 
vaccine HPV types (6, 11, 16, 18, 31, 33, 45, 
52 and 58) at Month 7 in Japanese boys aged 
9 to 14 years who received 2 doses of the 
9vHPV vaccine
- Serum antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52 and 58
- To estimate percent seroconversion for the 
vaccine HPV types (6, 11, 16, 18, 31, 33, 45, 
52 and 58) at Month 7 in Japanese girls aged 
9 to 14 years who received 2 doses of the 
9vHPV vaccine
- Serum antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52 and 58
- To evaluate the safety and tolerability of the 
9vHPV vaccine in Japanese boys aged 9 to 
15 years who received 3 doses and Japanese 
boys and girls aged 9 to 14 years who 
received 2 doses of the 9vHPV vaccine
- Solicited injection-site adverse events
- Systemic adverse events
- Serious adverse events
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Secondary Objectives
Secondary Endpoints
- To estimate the immune response for the 
vaccine HPV types (6, 11, 16, 18, 31, 33, 45, 
52 and 58) at Month 7 including geometric 
mean titers (GMTs) in Japanese boys aged 9 
to 15 years who received 3 doses of the 
9vHPV vaccine
- Serum antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52 and 58
- To estimate the immune response for the 
vaccine HPV types (6, 11, 16, 18, 31, 33, 45, 
52 and 58) at Month 7 including GMTs in 
Japanese boys aged 9 to 14 years who 
received 2 doses of the 9vHPV vaccine 
- Serum antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52 and 58
- To estimate the immune response for the 
vaccine HPV types (6, 11, 16, 18, 31, 33, 45, 
52 and 58) at Month 7 including GMTs in 
Japanese girls aged 9 to 14 years who 
received 2 doses of the 9vHPV vaccine
- Serum antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52 and 58
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
‒
Prevention of premalignant lesions and cancers affecting the 
cervix, vulva, vagina, anus and head and neck caused by vaccine 
HPV types
‒
Prevention of genital warts (Condyloma acuminata) caused by 
vaccine HPV types
‒
2-dose (0, 6-12 months) schedule in 9 through 14 years old
Population
Japanese boys and girls aged 9 to 15 years old
Study Type
Interventional
Intervention 
Model
Parallel
This is a multi-site study.
Type of Control
No control
Study Blinding
Unblinded Open-label
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Blinding Roles
No Blinding
Estimated 
Duration of Study
The Sponsor estimates that the study will require approximately 40
months from the time the first participant's legally acceptable 
representative provides documented informed consent until the last 
participant’s last study-related contact.
For purposes of analysis and reporting, the overall study ends when 
the Sponsor receives the last laboratory result or at the time of final 
contact with the last participant, whichever comes last.
Number of Participants:
Approximately 300 participants will be allocated in three arms (approximately
100 participants will be allocated for each arm).
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Intervention Groups and Duration:
Intervention 
Groups
The study will enroll participants in three groups:
1.
3-dose in 9 to 15 years old boys 
2.
2-dose in 9 to 14 years old boys
3.
2-dose in 9 to 14 years old girls 
Detailed explanation for the age group differences between 3-dose regimen 
(9 to 15 years old) and 2-dose regimen (9 to 14 years old) is shown in 
Section 4.2.
All participants will receive open-label 9vHPV vaccine (V503).
Arm Name
Drug
Dose Strength
Dose 
Frequency
Route of 
Admin.
Vaccination 
Regimen
Use
3-dose in 
9 to 15 
years old 
boys
V503
(9vHPV 
vaccine)
HPV
6/11/16/18/31/
33/45/52/58
L1 VLP:
30/40/60/40/
20/20/20/20/
20 mcg per 
dose
3 Doses
Intra-
muscular
Day 1,
Month 2
Month 6
Experi
mental
2-dose in 
9 to 14 
years old 
boys
V503
(9vHPV 
vaccine)
HPV
6/11/16/18/31/
33/45/52/58
L1 VLP:
30/40/60/40/
20/20/20/20/
20 mcg per 
dose
2 Doses
Intra-
muscular
Day 1,
Month 6
Experi
mental
2-dose in 
9 to 14 
years old 
girls
V503
(9vHPV 
vaccine)
HPV
6/11/16/18/31/
33/45/52/58
L1 VLP:
30/40/60/40/
20/20/20/20/
20 mcg per 
dose
2 Doses
Intra-
muscular
Day 1,
Month 6
Experi
mental
9vHPV=9-valent human papillomavirus, HPV=human papillomavirus, VLP=virus-like particle
Other current or former names or aliases for study intervention are as 
follows: the 9vHPV vaccine, SILGARD®9 and GARDASILTM9.
Total 
Number of 
Intervention 
Groups/ 
Arms
3 arms
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Duration of 
Participation
Each participant will participate in the study for approximately 30 months 
from the time the participant’s legally acceptable representative provides 
documented informed consent through the final contact. Each participant 
will be receiving total 3 doses at Day 1, Month 2 and Month 6, or total 2
doses at Day 1 and Month 6. After the completion of vaccination and 
Month 7 visit (Period I), each participant will be followed through Month 
30 (Period II).
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
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1.3
Schedule of Activities
Schedule of Activities for 3-dose in 9 to 15 years old boys (vaccination at Day 1, Month 2 and Month 6)
Study Period
Period I
Period II
Notes
Visit Number
1
2
3
4
5
6
Scheduled Day/Month
Day 1
Month 2
Month 6
Month 7
Month 18
Month 30
Visit Window*
±3 weeks
±4 weeks
3 to 7 
weeks after 
Month 6
±4 weeks
±4 weeks
To calculate visit windows, assume 
1 month=30 days and 
1 week=7 days
Administrative Procedures
Obtain Informed Consent/Assent
X
Obtain documented assent from 
the participant as far as possible
Obtain Informed Consent/Assent for Future 
Biomedical Research
X
Participation in future biomedical 
research is optional and consent 
must be obtained before collection 
of blood [deoxyribonucleic acid 
(DNA)] samples. Obtain 
documented assent from the 
participant as far as possible
Review Inclusion/Exclusion Criteria
X
Assign Participant Identification Card
X
Collect Medical History
X
Update Medical History
(new conditions not already recorded as 
medical history or adverse events)
X
X
X
X
X
Review Prior/Concomitant Medication and 
Non-study Vaccination
X
X
X
X
X
X
See Section 6.5 for prerequisites 
for medications and non-study 
vaccines and Section 8.1.6 for data 
collection timeframe.
Vaccine Allocation/Randomization
X
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Study Period
Period I
Period II
Notes
Visit Number
1
2
3
4
5
6
Scheduled Day/Month
Day 1
Month 2
Month 6
Month 7
Month 18
Month 30
Visit Window*
±3 weeks
±4 weeks
3 to 7 
weeks after 
Month 6
±4 weeks
±4 weeks
To calculate visit windows, assume 
1 month=30 days and 
1 week=7 days
Clinical and Laboratory Procedures
Measure Oral Temperature
X
X
X
Prior to each vaccination and Day 
1 blood sample collection. 
Participants who have a fever 
(defined as an oral temperature of 
≥37.5°C) within the 24-hour period 
prior to vaccination should not 
receive study vaccine and the 
vaccination visit must be 
rescheduled.
Record Height and Weight
X
Prior to vaccination
Physical Examination (optional, per 
investigator's discretion; perform if needed to 
assess inclusion/exclusion criteria)
X
Blood Sample Collection (Serum for anti-
HPV)
X
X
X
X
Serum for anti-HPV antibody 
testing must be collected before 
vaccination on Day 1
Blood Sample Collection (DNA) for Future 
Biomedical Research
X
Prior to vaccination from enrolled 
participants only (optional)
9vHPV Vaccine Administration
X
X
X
30-minute postvaccination observation period
X
X
X
Observe participants for 30 
minutes after each vaccination for 
immediate untoward effects
Provide Vaccination Report Card (VRC)
X
X
X
See Section 8.3.4 for data collected 
in VRC.
Review and Collect VRC data
X
X
X
Telephone contacts after 15 days 
from Day 1, Month 2 and Month 6, 
respectively to remind the 
participant’s legally acceptable 
representative of completing VRC
Adverse Events Monitoring
X
X
X
X
X
X
* Regarding protocol study visit windows, the following situations require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision: a participant needs to be scheduled earlier than the start of a visit window or the study site is considering skipping a visit.
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Schedule of Activities for 2-dose in 9 to 14 years old boys and girls (vaccination at Day 1 and Month 6)
Study Period
Period I
Period II
Notes
Visit Number
1
2
3
4
5
6
Scheduled Day/Month
Day 1
Month 2
Month 6
Month 7
Month 18
Month 30
Visit Window*
±3 weeks
±4 weeks
3 to 7 
weeks after 
Month 6
±4 weeks
±4 weeks
To calculate visit windows, assume 
1 month=30 days and 
1 week=7 days
Administrative Procedures
Obtain Informed Consent/Assent
X
Obtain documented assent from the 
participant as far as possible
Obtain Informed Consent/Assent for Future 
Biomedical Research
X
Participation in future biomedical 
research is optional and consent 
must be obtained before collection 
of blood (DNA) samples. Obtain 
documented assent from the 
participant as far as possible
Review Inclusion/Exclusion Criteria
X
Assign Participant Identification Card
X
Collect Medical History
X
Update Medical History
(new conditions not already recoded as 
medical history or adverse events)
X
X
X
X
X
Review Prior/Concomitant Medication and 
Non-study Vaccination
X
X
X
X
X
X
See Section 6.5 for prerequisites for 
medications and non-study vaccines
and Section 8.1.6 for data collection 
timeframe. 
Vaccine Allocation/Randomization
X
Clinical and Laboratory Procedures
Measure Oral Temperature
X
X
Prior to each vaccination and Day 1 
blood sample collection. 
Participants who have a fever 
(defined as an oral temperature of 
≥37.5°C) within the 24-hour period 
prior to vaccination should not 
receive study vaccine and the 
vaccination visit must be 
rescheduled.
Record Height and Weight
X
Prior to vaccination
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Study Period
Period I
Period II
Notes
Visit Number
1
2
3
4
5
6
Scheduled Day/Month
Day 1
Month 2
Month 6
Month 7
Month 18
Month 30
Visit Window*
±3 weeks
±4 weeks
3 to 7 
weeks after 
Month 6
±4 weeks
±4 weeks
To calculate visit windows, assume 
1 month=30 days and 
1 week=7 days
Physical Examination (optional, per 
investigator's discretion; perform if needed to 
assess inclusion/exclusion criteria)
X
Urine Pregnancy Testing (females)
X
X
Pregnancy testing results should be 
negative prior to vaccination
Blood Sample Collection (Serum for anti-
HPV)
X
X
X
X
Serum for anti-HPV antibody 
testing must be collected before 
vaccination on Day 1
Blood Sample Collection (DNA) for Future 
Biomedical Research
X
Prior to vaccination from enrolled 
participants only (optional)
9vHPV Vaccine Administration
X
X
30-minute postvaccination observation period
X
X
Observe participants for 30 minutes 
after each vaccination for 
immediate untoward effects
Provide VRC
X
X
See Section 8.3.4 for data collected 
in VRC.
Review and Collect VRC data
X
X
Telephone contacts after 15 days 
from Day 1 and Month 6, 
respectively to remind the 
participant’s legally acceptable 
representative of completing VRC
Adverse Events Monitoring
X
X
X
X
X
X
* Regarding protocol study visit windows, the following situations require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision: a participant needs to be scheduled earlier than the start of a visit window or the study site is considering skipping a visit.
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2
INTRODUCTION
2.1
Study Rationale
HPV infection causes benign and malignant dysplastic disease, localized primarily in the 
anogenital area and upper airway, in both males and females [Paavonen, J., 2007] [Madkan, 
V.K., et al 2007] [Stamataki, S., et al 2007]. Persistent HPV infection significantly increases 
the risk of developing cervical, anogenital, and oropharyngeal cancers [Forman, D., et al 
2012]. HPV disease is frequently multicentric (i.e., affecting more than one anatomic site). 
Individuals with genital warts due to HPV infection have an elevated long-term risk of 
developing anogenital and head and neck cancers [Blomberg, M., et al 2012].
Vaccination against HPV has been shown to aid in reducing the burden of HPV diseases in 
males and females. In contrast to cervical cancer in females, there is no widespread screening 
program for any HPV related cancers in males, making prophylactic vaccination a readily 
practical preventive measure for HPV diseases especially in males, in both developed and 
developing countries. An additional potential benefit of HPV vaccination in males is the 
generation of herd protection, which in turn could lead to a substantial reduction of HPV 
diseases in both males and females [Baseman, J.G., et al 2005]. Previous public health 
experience has shown that gender-restricted vaccination programs are substantially less 
effective than universal vaccination [WHO 2017]. Moreover, gender-neutral vaccination 
programs are expected to be more resilient to sudden drops in vaccine uptake [Elfström, K. 
M., et al 2016]. It is likely that the most effective means to reduce the burden of HPV disease 
using a safe and effective prophylactic vaccine is to vaccinate both males and females. In 
fact, gender neutral vaccination of HPV vaccine is increasing internationally, as over 40
countries or regions have adopted this approach as of March 2020.
HPV infection is transmitted via contact with an infected individual or a contaminated object 
and occurs most often during sexual activity. About sixty percent of sexual partners of 
infected individuals develop lesions a few weeks to 8 months after exposure [Oriel, J.D.,
1971]. HPV is often acquired immediately after sexual debut and the risk of HPV infection is 
strongly correlated with the number of lifetime sexual partners [Xi, L.F., et al 1997] 
[Koutsky, L. 1997]. Males and females in their late teens and early twenties are at the highest 
risk for HPV infection, as early sexual activity is accompanied with a higher likelihood of 
having multiple sexual partners, thus increasing the risk of exposure to the virus. The 
incidence of HPV infection increases with age during the teen years and peaks in the early 
twenties; The probability of acquiring a new genital HPV infection is similar for sexually 
active males and females [Partridge, J.M., et al 2007]. The prevalence of anogenital HPV 
infection in men remains relatively consistent throughout their lifespan while women 
generally exhibit decreased prevalence with age [Giuliano, A.R., et al 2011]-2 [Palefsky, 
J.M., et al 2010] [Castle, P.E. et al 2005] [Schiffman, M., et al 2007]. Men exhibit 
diminished immune response to natural HPV infection, which may contribute to their higher 
HPV prevalence across ages [Giuliano, A.R., et al 2015] [Lu, B., et al 2012]. Therefore, HPV 
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vaccination in younger individuals can play a key role in prevention of HPV-related diseases 
both in males and females.
On the other hand, direct efficacy evaluation of prophylactic HPV vaccine in 9 to 15 years 
old subjects is not feasible because younger adolescents are generally not exposed to HPV.
Thus, immunogenicity bridging by comparison of immunogenicity data between younger 
adolescents and adults is a reasonable means to extend the efficacy confirmed in adults to 
preadolescents and adolescents.
Global clinical studies have demonstrated that the quadrivalent HPV (qHPV) vaccine (V501) 
can prevent external genital and intra-anal persistent infection, anal precancers and 
anogenital warts caused by HPV 6, 11, 16 and 18 in males [Giuliano, A.R., et al 2011] 
[Palefsky, J.M., et al 2011] [Ferris, D.G., et al 2017]. A local clinical study conducted in 
Japanese males aged 16 to 26 years also demonstrated that qHPV vaccine prevents external 
genital and intra-anal persistent infection caused by HPV 6, 11, 16, and 18 [Mikamo, H., et al 
2019]. In addition, high immune responses in younger males have been demonstrated by 
another immunogenicity bridging study in Japanese boys aged 9 to 15 years [Murata, S., et al 
2019].
The 9vHPV vaccine (V503) was developed to cover the 4 HPV types addressed by qHPV 
vaccine and the addition 5 high-risk HPV serotypes (31, 33, 45, 52, and 58). HPV 6 and 11 
which are responsible for approximately 90% of genital wart cases [Pitisuttithum, P., et al 
2015] [Garland, S.M., et al 2009], and HPV types 16, 18, 31, 33, 45, 52, and 58 are 
responsible for approximately 90% globally of cervical cancers and HPV-related vulvar, 
vaginal, and anal cancers [Serrano, B., et al 2012] [de Sanjosé, S., et al 2013] [Alemany, L., 
et al 2015] [Alemany, L., et al 2014] [Lacey, C.J.N., et al 2006] [de Sanjosé, S., et al 2019]. 
The 9vHPV vaccine was initially licensed in the USA in December 2014 and has been 
licensed in many countries under the name GARDASILTM9. In Japan, the 9vHPV vaccine 
was approved for female as SILGARD®9 Aqueous Suspension for Intramuscular Injection 
Syringes in July 2020. The 9vHPV vaccine has demonstrated efficacy for the prevention of 
genital diseases caused by vaccine 9vHPV types in 16- to 26-year-old females and high 
immune responses in 9- to 15-year-old girls, including Japanese [Joura, E.A., et al 2015] 
[Huh, W.K., et al 2017] [Garland, S.M., et al 2018] [Iwata, S., et al 2017]. Efficacy of the 
9vHPV vaccine in boys 9-15 years of age was inferred based on an immunogenicity bridging 
study which demonstrated non-inferior HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 antibody 
responses in boys who received 3 doses of 9vHPVvaccine versus females 16-26 years who 
also received 3 doses [Van Damme, P., et al 2015]. In males 16-26 years of age, efficacy of 
the 9vHPV vaccine was inferred based on 2 immunogenicity bridging studies: one pivotal 
study which demonstrated non-inferior HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 antibody 
responses in males who received the 9vHPV vaccine versus females who received the 
9vHPV vaccine [Castellsagué, X., et al 2015]; and one supportive study which demonstrated 
non-inferior HPV 6, 11, 16, and 18 antibody responses in males who received the 9vHPV 
vaccine compared with males who received qHPV vaccine [Van Damme, P., et al 2016]. 
Thus, a study to confirm efficacy of the 9vHPV vaccine in Japanese males aged 16 to 26 
years (Protocol V503-064) is ongoing for the use of the 9vHPV vaccine for prevention of 
condyloma acuminata and anal cancers and related precancers caused by vaccine 9vHPV 
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types in Japanese males, and this immunogenicity study for boys aged 9 to 15 years (Protocol 
V503-066) will be conducted to bridge the 9vHPV vaccine efficacy findings in young 
Japanese males.
In addition, it is becoming increasingly important to study the immune response of young
adolescents using alternative vaccination regimens to the 3-dose regimen of HPV vaccine as 
a schedule with fewer doses may positively impact vaccination programs by increasing 
acceptability and compliance while reducing costs. Based on the result in Protocol V503-010 
that immune responses after 2-dose (at Day 1 and Month 6 or Day 1 and Month 12) regimen 
of the 9vHPV vaccine in girls and boys 9 to 14 years of age were non-inferior to those after 
3-dose in young females 16 to 26 years of age [Iversen, O.E., et al 2016], 2-dose (0 and 6 to 
12 months) regimen of the 9vHPV vaccine has been approved as an alternative regimen and 
included in the national immunization program in some foreign countries. In World Health 
Organization (WHO) position paper published in 2017, 2-dose schedule (0 and 5 to 13 
months) of the 9vHPV vaccine is recommended for girls and boys aged 9 to14 years [WHO 
2017]. In addition, recent research has demonstrated non-inferiority of immune responses up 
to 120 months postvaccination after 2-dose of qHPV vaccine in girls aged 9 to 13 years 
compared with that after 3-dose in adult females aged 16 to 26 years [Donken, R. et al 2019].
These have encouraged the interest in the 2-dose regimen. 
This study will evaluate the immunogenicity and safety of the 9vHPV vaccine following a 3-
dose regimen in Japanese boys aged 9 to 15 years as well as that following a 2-dose regimen 
in Japanese boys and girls aged 9 to 14 years. The scientific rationale for the study design is 
described in Section 4.2.
2.2
Background
Refer to the IB/approved labeling for detailed background information on the 9vHPV vaccine
(V503).
2.2.1
Pharmaceutical and Therapeutic Background
The 9vHPV vaccine is an aluminum-adjuvanted recombinant protein vaccine prepared from 
the highly purified virus-like particles (VLPs) of the recombinant major capsid (L1) protein 
of HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. 
The 9vHPV vaccine is currently indicated for the prevention of cervical, vulvar, vaginal, and 
anal cancers, and precancerous or dysplastic lesions, genital warts, and infection caused by 
the 9 HPV types targeted by the vaccine in many countries. In USA, the 9vHPV vaccine was 
conditionally approved for the prevention of oropharyngeal and other head and neck cancer.
In Japan, the 9vHPV vaccine was approved for the prevention of cervical cancer, cervical 
precancers, vulvar and vaginal precancers, and genital warts caused by 9vHPV types in 
females.
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2.2.1.1
Disease Burden and Epidemiology for HPV-related Disease
Anogenital Warts
Anogenital warts are generally benign, exophytic, hyperkeratotic lesions on the penile shaft 
(most common site of lesions), scrotum, perineum, and anus in males. In females, the lesions 
may appear over the vulva, urethra, vagina, perineum, and anus. In general, the lesions do not 
cause any physical discomfort [Chuang, T.Y., et al 1984]. Some patients experience itching, 
burning, bleeding, moisture, irritation or soreness, especially with lesions in the perianal 
region. Patients are often distressed by the lesions’ appearance. Genital warts (condyloma 
acuminata) are caused by HPV-6 or -11 account for approximately 75 to 90% of cases in 
both males and females [Aubin, F., et al 2008] [Garland, S.M., et al 2009] [Chan, P.K., et al 
2009] [Yanofsky, V.R., et al 2012]. The incubation period following exposures is 3 weeks to 
8 months [Yanofsky, V.R., et al 2012]. Treatment consists of chemical or physical ablation 
and is often unsuccessful. Recurrence rates are high [Stone, K.M., 1995]. In Japan, genital 
warts are categorized as one of the sentinel reporting diseases of Category V Infectious 
Diseases by The Law Concerning the Prevention of Infectious Diseases and Medical Care for 
Patients of Infections (Infectious Diseases Control Law). According to the Infectious 
Diseases Weekly Report based on Infectious Diseases Control Law, the total reported 
number of genital warts cases in 2019 was 6263 (males: 4113, females: 2150) [MHLW. 
2019]. The prevalence of genital warts in Japan peaks at ages 25 to 29 years in males and 20
to 24 years in females [NIID. 2018]. 
Anal Cancer
Triggered by HPV infection, anal cancer develops through persistent infections and precursor 
lesions [Valvo, F., et al 2019]. The association between anal cancer and HPV infection is 
strongly suggested by the results of clinical trials. In a report by de Martel et al., HPV-DNA 
was demonstrated in 35,000 of 40,000 worldwide cases of anal cancer [de Martel, C., et al 
2017]. Similarly, HPV-DNA was detected in 88.3% of anal cancers in a large-scale global 
study [Alemany, L., et al 2015]. Of the HPV types detected in invasive anal cancer in males, 
HPV type 16 (73.4%) was most common, followed by type 18 (5.2%), and type 6, 11, 31, 33 
and 45 were also detected [De Vuyst H., et al 2009]. HPV type 16 and 18 were also detected 
in anal adenocarcinoma [Herfs, M., et al 2018]. In Japan, though HPV type distribution data 
is limited, 1086 new anal cancer cases occurred in 2017 based on national cancer incidence 
data from the National Cancer Registration and Statistics Cancer Information Service of the 
National Cancer Research Center [Japan National Cancer Center 2017]. In addition, Daling 
et al. reported that HPVs were detected in 78.0% and 97.7% anal cancer of heterosexual 
males and males who have sex with males, respectively [Daling, J.R., et al 2004].
Cervical Cancer and Precancerous Dysplasia
Cervical cancer is the fourth most common cancer in females worldwide [de Martel, C., et al 
2017]. Approximately 570,000 new patients diagnosed and approximately 310,000 patients 
die each year worldwide [Bray, F., et al 2018]. Eighty percent (80%) of these cases of 
cervical cancers occur in developing countries. In Japan, the number of cervical cancer 
patients was reported to be around 11,000 in 2017 [Japan National Cancer Center 2017], and 
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the number of deaths due to cervical cancer was reported to be 2,871 in 2018 [Japan National 
Cancer Center 2018]. In developed countries, implementation of cervical cancer screening
programs using the Pap test has reduced the incidence of cervical cancer by 75%. 
Nonetheless, an estimated 13,800 new cervical cancers and 4,290 cervical cancer deaths will 
occur in the USA in 2020 [American Cancer Society 2020]. Moreover, the screening rate for 
cervical cancer in Japan is low (approximately 40%) [Japan National Cancer Center 2019].
Vulvar and Vaginal Cancer
About 50% of vulvar and vaginal cancers are caused by HPV. These cancers arise from pre-
malignant precursor lesions and rates of HPV-related vulvar and vaginal cancers have 
increased (these cancers share epidemiologic features with cervical cancer, and they are often 
found in females with cervical precancer and cancer) [Bosch, F.X., et al 2002] [Christensen, 
N.D. 2005]. 
Head and Neck Cancer
Head and neck cancers are a heterogeneous group of tumors at different anatomic sites with
various etiologies. The majority of head and neck tumors are squamous cell carcinomas
arising from mucosal surfaces of the oral cavity, pharynx, and larynx [Dufour, X., et al 2012]. 
Traditional risk factors for head and neck cancers predominantly included tobacco and
excessive alcohol use. However, in the recent years, HPV infection was found to be
associated with a substantial proportion of head and neck tumors, especially in the
oropharynx [Castellsagué, X., et al 2016] [de Martel, C., et al 2017]. Although oral HPV 
infection is an established independent risk factor for head and neck squamous cell 
carcinoma [Gillison, M. L., et al 2012] [Mork, J., et al 2001] [Tam, S., et al 2018] [Wood, Z. 
C., et al 2017], early detection of HPV-related head and neck cancers is difficult due to 
challenges in identification of precancerous lesions and the apparent rapid progression to 
invasive disease [Gillison, M. L., et al 2015].
In Japan, the number of head and neck cancer patients was reported to be over 27,000 in 
2017 [Japan National Cancer Center 2017], and the number of deaths due to head and neck 
cancer was reported to be around 8,400 in 2018 [Japan National Cancer Center 2018]. 
Globally, approximately 38,000 to 45,000 head and neck cancers are attributed to HPV each
year, and the incidence is increasing [de Martel, C., et al 2017]. In the USA, HPV causes 
approximately 15,700 new oropharyngeal cancers annually, of which approximately 10,400 
(66%) are attributed to the high-risk HPV types prevented by the 9vHPV vaccine [Viens, L. 
J., et al 2016]. In Europe, HPV causes approximately 13,800 cases each year [de Martel, C., 
et al 2017], and most of the HPV positive head and neck cancer cases are attributed to the 
high-risk HPV types in the 9vHPV vaccine [Hartwig, S., et al 2017] [de Martel, C., et al 
2017].
Recurrent Respiratory Papillomatosis (RRP)
This disease is manifested as rapidly-growing exophytic lesions in the upper airway, most 
often in the larynx, causing severe respiratory and speech impairment. Repeated surgical 
excision is often needed [Glikman, D., et al 2005] [Szeps, M., et al 2005].
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2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on completed preclinical and clinical studies conducted with 
the 9vHPV vaccine.
2.2.2.1
Completed Clinical Studies
A global phase 3 study (Protocol V503-001) was conducted to evaluate the efficacy, 
immunogenicity and safety in females aged 16 to 26 years including Japanese females [Joura, 
E.A., et al 2015] [Huh, W.K., et al 2017] [Garland, S.M., et al 2018]. The 9vHPV vaccine 
prevented infection and disease caused by the HPV vaccine types and was generally well-
tolerated. For younger adolescents, Protocol V503-002 was conducted and it has been 
demonstrated that competitive Luminex Immunoassay (cLIA) GMTs for the vaccine HPV 
types following 3 doses in both non-Japanese boys and girls aged 9 to 15 years were non-
inferior to those in females aged 16 to 26 years, thereby supporting the bridging of efficacy 
findings in 16- to 26-year-old females to 9- to 15-year-old preadolescent and adolescent girls 
[Van Damme, P., et al 2015]. A local study (Protocol V503-008) also showed that a 3-dose 
regimen of the 9vHPV vaccine induced high HPV antibody responses and was generally well 
tolerated in Japanese girls aged 9 to 15 years [Iwata, S., et al 2017].
To investigate 2-dose regimen, a phase 3 study (Protocol V503-010) was conducted in non-
Japanese boys and girls aged 9 to 14 years. The immune responses for girls and boys aged 9 
to 14 years who received a 2-dose series were non-inferior to immune responses for young 
females aged 16 to 26 years who received a 3-dose series [Iversen, O.E., et al 2016].
Details of completed clinical studies with the 9vHPV vaccine are shown in the IB.
2.2.2.2
Ongoing Clinical Studies in Japan
A global phase 3 study (Protocol V503-049) is currently being conducted to evaluate the 
efficacy, immunogenicity and safety of the 9vHPV vaccine in the prevention of oral 
persistent infection caused by any of the high-risk HPV types covered by the vaccine in adult 
males 20 to 45 years of age including Japanese males.
A local phase 3 study (Protocol V503-064) is currently being conducted to evaluate the 
efficacy, immunogenicity and safety of the 9vHPV vaccine in Japanese males 16 to 26 years 
of age, in order to pursue indications for anal cancer and its precancerous or dysplastic 
lesions caused by vaccine 9vHPV types in both males and females, and genital warts in 
males in Japan.
2.3
Benefit/Risk Assessment
The 9vHPV vaccine has been shown to be beneficial and efficacious in preventing persistent
genital HPV infection and disease associated with the 9 HPV types (6, 11, 16, 18, 31, 33, 45, 
52, and 58). The frequency, severity, and magnitude of adverse events (AEs) identified in 
previous studies [Moreira, E.D.J, et al 2016] [Moreira, E.D.J, et al 2018] and post marketing 
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surveillance [Shimabukuro, T.T., et al 2019] [Donahue, J.G., et al 2019] support a favorable 
benefit-risk for the 9vHPV vaccine in this study population.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
This study will evaluate 2 different dose regimens of the 9-valent human papillomavirus 
(9vHPV) vaccine: a 3-dose regimen in Japanese boys aged 9 to 15 years old and a 2-dose 
regimen in Japanese boys and girls aged 9-14 years old. The base phase of the study (Period 
I) will assess the immunogenicity and safety of the 9vHPV vaccine through 7 months 
following the first dose. The extension phase of the study (Period II) will assess the safety 
and the antibody persistence to the 9vHPV vaccine through 30 months following the first 
dose.
Objectives
Endpoints
Primary
‒
To estimate percent seroconversion for 
the vaccine HPV types (6, 11, 16, 18, 31, 
33, 45, 52 and 58) at Month 7 in 
Japanese boys aged 9 to 15 years who 
received 3 doses of the 9vHPV vaccine
‒
Serum antibody titer to each of HPV 
6, 11, 16, 18, 31, 33, 45, 52 and 58
‒
To estimate percent seroconversion for 
the vaccine HPV types (6, 11, 16, 18, 31, 
33, 45, 52 and 58) at Month 7 in 
Japanese boys aged 9 to 14 years who 
received 2 doses of the 9vHPV vaccine
‒
Serum antibody titer to each of HPV 
6, 11, 16, 18, 31, 33, 45, 52 and 58
‒
To estimate percent seroconversion for 
the vaccine HPV types (6, 11, 16, 18, 31, 
33, 45, 52 and 58) at Month 7 in 
Japanese girls aged 9 to 14 years who 
received 2 doses of the 9vHPV vaccine
‒
Serum antibody titer to each of HPV 
6, 11, 16, 18, 31, 33, 45, 52 and 58
‒
To evaluate the safety and tolerability of 
the 9vHPV vaccine in Japanese boys 
aged 9 to 15 years who received 3 doses 
and Japanese boys and girls aged 9 to 14 
years who received 2 doses of the 
9vHPV vaccine
‒
Solicited injection-site adverse events
‒
Systemic adverse events
‒
Serious adverse events
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Objectives
Endpoints
Secondary
‒
To estimate the immune response for the 
vaccine HPV types (6, 11, 16, 18, 31, 33, 
45, 52 and 58) at Month 7 including 
geometric mean titers (GMTs) in 
Japanese boys aged 9 to 15 years who 
received 3 doses of the 9vHPV vaccine
‒
Serum antibody titer to each of HPV 
6, 11, 16, 18, 31, 33, 45, 52 and 58
‒
To estimate the immune response for the 
vaccine HPV types (6, 11, 16, 18, 31, 33, 
45, 52 and 58) at Month 7 including 
GMTs in Japanese boys aged 9 to 14 
years who received 2 doses of the 
9vHPV vaccine
‒
Serum antibody titer to each of HPV 
6, 11, 16, 18, 31, 33, 45, 52 and 58
‒
To estimate the immune response for the 
vaccine HPV types (6, 11, 16, 18, 31, 33, 
45, 52 and 58) at Month 7 including 
GMTs in Japanese girls aged 9 to 14 
years who received 2 doses of the 
9vHPV vaccine
‒
Serum antibody titer to each of HPV 
6, 11, 16, 18, 31, 33, 45, 52 and 58
Tertiary/Exploratory
‒
To assess the persistence of anti-HPV 6, 
11, 16, 18, 31, 33, 45, 52 and 58 
antibody responses at Month 18 and 30
‒
Serum antibody titer to each of HPV 
6, 11, 16, 18, 31, 33, 45, 52 and 58
4
STUDY DESIGN
4.1
Overall Design
This is a phase 3 open-label study to evaluate the immunogenicity and safety of a 9vHPV 
(types 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine (V503) in Japanese boys and girls aged 9 
to 15 years. This study will consist of two periods. Period I of the study is to evaluate the 
immunogenicity and safety/tolerability of the 9vHPV vaccine up to the time point of Month 
7. Period II of the study is to evaluate the long-term immunogenicity and safety from Month 
7 to Month 30. Analysis of the base phase (Period I) for the 2-dose arm in girls aged 9 to 14 
years old is planned to be conducted when all girl participants have completed their Period I 
(Month 7 visit) or discontinued from study before that time. Analysis of the base phase 
(Period I) for the 2-dose and 3-dose arms in boys and extension phase (Period II) for all arms 
will be conducted at the end of study.
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This study will enroll approximately 300 Japanese boys and girls in total, and approximately 
100 participants will be allocated to each of the following three arms:

3-dose (Day 1, Month 2 and Month 6) in boys aged 9 to 15 years

2-dose (Day 1 and Month 6) in boys aged 9 to 14 years 

2-dose (Day 1 and Month 6) in girls aged 9 to 14 years
Enrollment of the girl cohort will be initiated first. Enrollment of the boy cohorts will be 
initiated at a later time to be determined by the Sponsor.
Blood samples will be collected on Day 1 immediately before vaccination, and subsequently 
Month 7, Month 18 and Month 30 to evaluate HPV antibody responses.
Participants will be followed for injection-site AEs and systemic AEs from Day 1 through 
Day 15 following each vaccination. SAEs will be recorded regardless of causality from the 
time of allocation/randomization through 6 months post last dose. Vaccine-related SAEs and 
deaths will be collected throughout the study. New medical conditions (defined as incident 
medical conditions occurring outside of a Days 1 to Days 15 period following each 
vaccination and not considered SAEs) will be recorded for all participants at each study visit 
throughout the study.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study is designed to evaluate immunogenicity against the vaccine HPV types (6, 11, 16, 
18, 31, 33, 45, 52 and 58) and safety of 3-dose of the 9vHPV vaccine in Japanese boys aged 
9 to 15 years as well as 2-dose of the 9vHPV vaccine in Japanese boys and girls aged 9 to 14 
years. Immunogenicity result (cLIA GMTs) in this study will be used for cross-study 
comparison.
Efficacy and safety of 3-dose regimen in Japanese males aged 16 to 26 years will be 
evaluated in Protocol V503-064. Efficacy in Japanese boys 9-15 years of age who received 3 
doses and in Japanese boys 9-14 years of age who received 2 doses will be inferred based on 
demonstration of non-inferior immunogenicity at Month 7 in the cohorts of Japanese boys in 
this study versus Japanese males 16-26 years of age who will have received 3 doses in V503-
064.
Efficacy and safety of 3-dose regimen in Japanese females aged 16 to 26 years was 
demonstrated in Protocol V503-001. Efficacy in Japanese girls 9-14 years of age who 
received 2 doses will be inferred based on demonstration of non-inferior immunogenicity at 
Month 7 in the cohort of Japanese girls in this study versus Japanese females 16-26 years of 
age who received 3 doses in V503-001.
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The age range in this study (9 to 15 years old for 3-dose regimen and 9 to 14 years old for 2-
dose regimen) is consistent with the indication for 9vHPV vaccine in foreign countries where 
2-dose regimen has been approved for boys and girls aged 9 to 14 years whereas 3-dose 
regimen has been approved for 9 years old or older.  
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
Serum antibody titer to each of HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58 will be analyzed as 
the indicator of immune responses using previously established methods including cLIA as 
the primary immunoassay [Roberts, C., et al 2014]. The assay has been used in previous 
clinical studies within the 9vHPV vaccine program. Details on the immunogenicity endpoints 
evaluated in this study can be found in Section 8.2.1 and Section 9.4.1.
4.2.1.2
Safety Endpoints
Safety assessments in this study are consistent with those used in previous studies of the
9vHPV vaccine and qHPV vaccine. Paper Vaccination Report Card (VRC) will be used to 
record AEs during the postvaccination periods. Details for the VRC are provided in Section 
8.3.4.
Details on the safety endpoints evaluated in this study can be found in Section 8.3 and
Section 9.4.2.
Details on AEs, including definitions and reporting requirements, can be found in
Appendix 3.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
4.3
Justification for Dose
The 0.5 mL dose administered as a 3-dose regimen (Day 1, Month 2, Month 6) is based on 
the global efficacy, immunogenicity, and safety clinical studies that supported the licensure 
of the 9vHPV vaccine and is consistent with the approved dosing and product labeling of the 
9vHPV vaccine (Japan, USA, EU, and other countries).
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The rationale for the selection of both the 2-dose regimen and the interval used in applying 
the 2 doses is based on the result from Protocol V503-010 that immune responses, measured 
by cLIA GMT, for girls and boys 9 to 14 years of age who received a 2-dose series at Day 1 
and Month 6 were non-inferior to immune responses for young female 16 to 26 years of age 
who received a 3-dose series at Day 1, Month 2 and Month 6 [Iversen, O.E., et al 2016]. The 
2-dose regimen has been approved in some foreign countries as an alternative regimen and 
WHO also recommended 2-dose schedule (0 and 5 to 13 months) of the 9vHPV vaccine for 
girls and boys aged 9 to14 years [WHO 2017]. Therefore, the 2-dose regimen is expected to 
demonstrate high immune responses also in Japanese boys and girls aged 9 to 14 years. 
4.4
Beginning and End of Study Definition
The overall study begins when the first participant's legally acceptable representative 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Healthy male and female participants between the ages of 9 and 15 years (inclusive) will be 
enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
The history of medical conditions will be based on the self-report or medical chart provided 
by participant’s legally acceptable representative. 
Type of Participant and Disease Characteristics
1. Is healthy and is judged to be in good physical health based on medical history and 
physical examination.
Demographics
2. Is Japanese male or female.
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3. Is aged at the time of providing the documented informed consent (inclusive).
(3-dose boy arm) male from 9 years to 15 years old
(2-dose boy arm) male from 9 years to 14 years old
(2-dose girl arm) female from 9 years to 14 years old
Informed Consent
4. The participant’s legally acceptable representative has provided documented informed 
consent for the study and when applicable, the participant has provided documented
informed assent. The participant/legally acceptable representative may also provide 
consent/assent for future biomedical research. However, the participant may participate in 
the main study without participating in future biomedical research.
Additional Categories
5. Agrees to provide study personnel at the study site with a primary telephone number as 
well as an alternate means of contact, if available (such as an alternate telephone number, 
SNS or e-mail) for follow-up purposes.
6. Has a legally acceptable representative who can read, understand and complete the VRC.
7. Must not yet have had coitarche and does not plan on becoming sexually active during 
the Day 1 through Month 7.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
The history of medical conditions will be based on the self-report or medical chart provided 
by participant’s legally acceptable representative. For items with an asterisk (*), if the 
exclusion criterion is met, then the Day 1 visit may be rescheduled for a time when the 
criterion is not met.
Medical Conditions
1. *Has a fever (defined as oral temperature≥37.5°C) within the 24-hour period prior to the 
Day 1 visit.
2. Has a history of severe allergic reaction (e.g, swelling of the mouth and throat, difficulty 
breathing, hypotension or shock) that required medical intervention. 
3. Is allergic to any vaccine component, including aluminum, yeast, or BENZONASETM
(nuclease, Nycomed [used to remove residual nucleic acids from this and other vaccines]). 
For this exclusion criterion, an allergy to vaccine components is defined as an allergic 
reaction that met the criteria for severe AEs or SAEs defined in Appendix 3.
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4. Has known thrombocytopenia or any coagulation disorder that would contraindicate 
intramuscular injections.
5. Is currently immunocompromised or has been diagnosed as having a congenital or 
acquired immunodeficiency, HIV infection, lymphoma, leukemia, systemic lupus 
erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel 
disease, or other auto immune condition.
6. Has a history of splenectomy.
7. Has a history of genital warts or positive test for HPV.
8. Has a history or current evidence of any condition, therapy, lab abnormality or other
circumstance that might confound the results of the study, or interfere with the
participant’s participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate by judgement of investigator.
9. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has 
had a recent history (within 12 months) of drug or alcohol abuse or dependence at the 
discretion of the investigator. Alcohol abusers are defined as those who drink despite 
recurrent social, interpersonal, and/or legal problems because of alcohol use.
10. (Female only) Is pregnant as determined by urine pregnancy test.
Prior/Concomitant Therapy
11. Has received within 12 months prior to enrollment, is receiving, or plans to receive 
during Day 1 through Month 7 of the study, the following immunosuppressive therapies: 
radiation therapy, cyclophosphamide, azathioprine, methotrexate, any chemotherapy, 
cyclosporin, leflunomide, TNF-α antagonists, monoclonal antibody therapies (including 
rituximab), intravenous gamma globulin (IVIG), antilymphocyte sera, or other therapy 
known to interfere with the immune response. Regarding systemic corticosteroids, a 
participant will be excluded if the participant is currently receiving steroid therapy, has 
recently (defined as within 2 weeks of Day 1 vaccination) received such therapy, or has 
received 2 or more courses of corticosteroids (orally or parenterally) lasting at least 1 
week in duration in the year prior to Day 1 vaccination. Participants using inhaled, nasal, 
or topical steroids are considered eligible for the study.
12. Has received within the 3 months prior to the Day 1 vaccination, is receiving, or plans to 
receive during Day 1 through Month 7 of the study, any immune globulin product
(including Rho(D) human immune globulin [Benesis™]) or blood-derived product other
than IVIG.
13. *Has received inactivated or recombinant vaccines within 14 days prior to Day 1
vaccination or receipt of live vaccines within 28 days prior to Day 1 vaccination.
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14. Has previously received a marketed HPV vaccine, or has participated in a clinical trial for 
any HPV vaccine (receiving either active agent or placebo).
Prior/Concurrent Clinical Study Experience
15. Is concurrently enrolled in other clinical studies of investigational agents.
Diagnostic Assessments
None.
Other Exclusions
16. Is unlikely to adhere to the study procedures, keep appointments, or is planning to 
permanently relocate from the area prior to the completion of the study or to leave for an 
extended period when study visits would need to be scheduled.
17. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
No lifecycle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently allocated/randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet
the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any AEs or SAEs meeting reporting requirements as outlined in the data entry 
guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study vaccination OR withdraws from the study will not 
be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm Name
Arm 
Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength
Dosage 
Level
Route 
of 
Admin.
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
3-dose in 
9 to 15 years 
old boys
Experi
mental
V503
(9vHPV 
vaccine)
Biological/
Vaccine
Sterile 
Suspension
HPV 
6/11/16/18/31/
33/45/52/58 L1 
VLP:
30/40/60/40/20/
20/20/20/20 mcg 
per dose
0.5 mL
IM
Day 1, 
Month 2, 
Month 6
Experi
mental
IMP
Provided 
centrally 
by 
Sponsor
2-dose in
9 to 14 years 
old boys
Experi
mental
V503
(9vHPV 
vaccine)
Biological/
Vaccine
Sterile 
Suspension
HPV
6/11/16/18/31/
33/45/52/58 L1 
VLP:
30/40/60/40/20/
20/20/20/20 mcg 
per dose
0.5 mL
IM
Day 1, 
Month 6
Experi
mental
IMP
Provided 
centrally 
by 
Sponsor
2-dose in
9 to 14 years 
old girls
Experi
mental
V503
(9vHPV 
vaccine)
Biological/
Vaccine
Sterile 
Suspension
HPV
6/11/16/18/31/
33/45/52/58 L1 
VLP:
30/40/60/40/20/
20/20/20/20 mcg 
per dose
0.5 mL
IM
Day 1, 
Month 6
Experi
mental
IMP
Provided 
centrally 
by 
Sponsor
9vHPV=9-valent human papillomavirus, HPV=human papillomavirus, VLP=virus-like particle, IM=Intramuscular
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.9 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3. Information on preparation and administration of 
study vaccine is provided in Section 6.3.1 and Section 8.1.9.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
IRT system will be used to allocate participants to either the 3-dose or 2-dose regimen arms
based on gender and age at the time of providing the informed consent. 
Fifteen-years-old boys will be assigned to the 3-dose regimen arm until the boys 3-dose 
regimen arms reaches 100 participants. Girls aged 9 to 14 years will be assigned to the 2-
dose regimen arm without randomization until the girls 2-dose regimen arm reaches 100 
participants. 
Boys aged 9 to 14 years will be randomized in a 1:1 ratio to either 3-dose or 2-dose regimen 
until 100 participants are enrolled in each of the 3-dose and 2-dose regimen arms. If the 
combined 9- to 14-year-old boys randomized to the 3-dose regimen and the 15-year-old boys 
assigned to the 3-dose regimen reach 100 participants before the 9- to 14-year-old boys 
randomized to the 2-dose regimen reaches 100 participants, randomization of 9 to 14 year-
old boys to the 3-dose regimen will be stopped, and subsequent 9- to 14-year-old boys 
enrolled will be allocated to the 2-dose regimen until the boys 2-dose regimen arm reaches 
100 participants. Similarly, if the boys 2-dose regimen arm reaches 100 participants before 
the boys 3-dose regimen arm reaches 100 participants, randomization of 9- to 14-year-old 
boys into the 2-dose regimen arm will be stopped and subsequent 9-to 14-year-old boys 
enrolled will be allocated to the 3-dose regimen until the boys 3-dose regimen arm reaches 
100 participants.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the vaccine administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified vaccination plan specified in Section 1.3 require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during time periods specified by this protocol for that medication or vaccination (Section 
5.2). If there is a clinical indication for any medications or vaccinations specifically 
prohibited, discontinuation from study intervention may be required. The investigator should 
discuss any questions regarding this with the Sponsor Clinical Director. The final decision on 
any supportive therapy or vaccination rests with the investigator and/or the participant’s 
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primary physician. However, the decision to continue the participant on study intervention
requires the mutual agreement of the investigator, the Sponsor, and the participant.
Listed below are specific restrictions for concomitant therapy or vaccination:

See the exclusion criteria for specific restriction for prior and concomitant medications at 
Day 1 (Section 5.2) and prerequisites for other vaccination visits (Section 8.9.2).

If possible, participants should not receive “Special medications” (corticosteroids,
immunosuppressive therapies, immune globulin products, and blood-derived products) 
from Day 1 through Month 7, non-study inactivated or recombinant vaccines from 14 
days prior to each study vaccination through 14 days after each study vaccination, or 
non-study live vaccines from 28 days prior to each study vaccination through 14 days 
after each study vaccination.

“Non-study HPV vaccine” must not be used at any time during the study.

Participants may receive allergen desensitization therapy and tuberculin skin testing
while participating in the study.
Use of prior and concomitant medications/vaccination should be recorded as described in 
Section 8.1.6.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
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As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified vaccination 
regimen will still continue to participate in the study as specified in Section 1.3 and Section
8.9.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.10 and Section 
8.9.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
‒
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
‒
The participant has a medical condition or personal circumstance which, in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study intervention.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, see Section 1.3 and Section 8.9.3 for those procedures to be completed at each 
specified visit.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.10. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
‒
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
‒
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These contact 
attempts should be documented in the participant’s medical record.
‒
Note: A participant is not considered lost to follow-up until the last scheduled visit for 
the individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
‒
Study procedures and their timing are summarized in the SoA.
‒
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
‒
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder 
(or equivalent).
‒
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
‒
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
‒
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
‒
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant's legally 
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acceptable representative. In these cases, such evaluations/testing will be performed in
accordance with those regulations.
The total volume of blood collected for immunogenicity testing and blood (DNA) for future 
biomedical research is outlined in Table 2. The maximum amount of blood collected from 
each participant over the duration of the study will not exceed approximately 48.5 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Table 2
Blood Collection Volumes
Visit 1
Visit 4
Visit 5
Visit 6
Anti-HPV Immunogenicity Testing
10 mL
10 mL
10 mL
10 mL
Blood (DNA) for Future Biomedical 
Research
8.5 mL
-
-
-
Total Volume
18.5 mL
10 mL
10 mL
10 mL
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant's legally acceptable 
representative prior to participating in this clinical study or future biomedical research. If 
there are changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate
documented informed consent is in place. The documented assent should be obtained as far 
as possible.
8.1.1.1
General Informed Consent
Informed consent given by the participant's legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant's legally acceptable 
representative and of the person conducting the consent discussion. Informed assent should 
be obtained from the participant as far as possible.
A copy of the signed and dated informed consent form should be given to the participant's 
their legally acceptable representative before participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant's legally acceptable representative must receive the IRB/IEC’s 
approval/favorable opinion in advance of use. The participant's legally acceptable 
representative should be informed in a timely manner if new information becomes available 
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that may be relevant to the participant’s willingness to continue participation in the study. 
The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s legally 
acceptable representative’s dated signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant’s legally acceptable representative, answer all of his/her questions, 
and obtain documented informed consent before performing any procedure related to future 
biomedical research. A copy of the informed consent will be given to the participant's legally 
acceptable representative before performing any procedure related to future biomedical 
research.  The documented assent should be obtained as far as possible.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant's legally acceptable representative provides documented informed consent. At 
the time of intervention allocation/randomization, site personnel will add the 
treatment/randomization number to the participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator. At Visit 1 (Day 1), the participant’s 
medical history for the year prior to Visit 1 will be collected.
After the Day 1 visit, any new medical history that has not been previously documented (ie, 
incident medical conditions occurring outside of Days 1 to Days 15 period following each 
vaccination and not considered SAEs) will be collected.
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8.1.5
Demographics
Demographics will be collected in the data collection system, as discussed in the electronic 
Case Report Form (eCRF) entry guidelines.
8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review prior medications or vaccinations on Day
1. A participant receiving any of the prior medications or vaccinations prohibited in the 
exclusion criteria (Section 5.2) should not be enrolled into the study. Prior and concomitant 
medications or vaccinations should be documented in the data collection system per the 
following timeframe.
‒
“Special medications” (corticosteroids, immunosuppressive therapies as defined in the 
exclusion criteria, immune globulin products, and blood-derived products) from 3 days 
prior to Day 1 through Month 7.
‒
“Other medications” from 3 days prior to each study vaccination through 14 days after 
each study vaccination.
‒
“Non-study inactivated or recombinant vaccines” from 14 days prior to each study 
vaccination through 14 days after each study vaccination.
‒
“Non-study live vaccines” from 28 days prior to each study vaccination through 14 
days after each study vaccination.
‒
“Non-study HPV vaccine” must not be used at any time during the study. However, for 
the specific case where a participant mistakenly receives any non-study HPV vaccines, 
the non-study HPV vaccine must be reported on the appropriate eCRF, regardless of 
when the non-study vaccine was received.
8.1.6.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study time frames specified in Section 8.1.6.1.
Participants may receive allergen desensitization therapy and tuberculin skin testing while 
participating in the study.
8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization/intervention
allocation. Each participant will be assigned only 1 screening number. Screening numbers 
must not be re-used for different participants.
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Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.9.1.
8.1.8
Assignment of Treatment/Randomization Number
All eligible fifteen-years-old boys and girls aged 9 to 14 years will be allocated by 
nonrandom assignment, and boys aged 9 to 14 years will be randomly allocated. They will 
receive a treatment/randomization number. The treatment/randomization number identifies 
the participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Study Intervention Administration
Preparation of Study Vaccine
The study vaccine must be stored at 2.0°C to 8.0°C. Do NOT freeze the study vaccine. 
Protect the study vaccine from light. The study vaccine must be used as supplied (no dilution 
before administration). The vaccine vial should be thoroughly mixed before administration 
by gently rolling vial between the palms of both hands for 30 seconds before withdrawing the 
0.5 mL dose of vaccine from single-dose vial using a sterile needle and syringe. The study 
vaccine should be a whitish, semi-translucent suspension when thoroughly mixed. If the 
appearance of vaccine is otherwise, do not administer, and contact the Sponsor immediately.
Adequate treatment provision, including epinephrine and equipment for maintaining an 
airway should be available for immediate use in case that an anaphylactic or anaphylactoid
reaction occur [Center for Disease Control and Prevention 2015].
Study Vaccine Administration
Study vaccine should be administered by the designated physician at Day 1, Month 2 (only 
for 3-dose boy arm), and Month 6. At each vaccination visit, participant will receive the 
9vHPV vaccine as a 0.5 mL intramuscular injection. The deltoid muscle of the nondominant 
arm is the preferred site of vaccination. Study vaccinations should not be administered in the 
buttocks area. Injections should not be given within 2 cm of a tattoo, scar, or skin 
deformation.
Injections should be administered at 90° angle into the muscle tissue using a needle long 
enough to ensure intramuscular deposition of study vaccine. The study vaccine should be 
administered in the deltoid muscle using preferably a 1.0 mL syringe (the largest allowable 
size is a 3.0 mL syringe).
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Observing Participants After Vaccination
All participants will be observed by study personnel for at least 30 minutes after each study 
vaccination for any untoward effects, including allergic reactions. This observation period 
will be documented in the participant’s study chart.
Vaccination information, such as Component Identification Number and time of vaccination, 
must be recorded on the appropriate eCRF as per the data entry guidelines.
8.1.9.1
Timing of Dose Administration
The first dose of study vaccine will be administered at Day 1, which should be the day of 
allocation/randomization. For 3-dose regimen arm, the second and third (final) doses of study 
vaccine will be administered at Month 2 (± 3 weeks) and Month 6 (± 4 weeks), respectively. 
For 2-dose regimen arms, the second (final) doses of study vaccine will be administered at 
Month 6 (± 4 weeks) (Section 1.3).
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the scheduled
vaccination regimen should be encouraged to continue to be followed for all remaining study 
visits as outlined in the SoA and Section 8.9.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the next study visit (exception: serum sample collection should not be 
performed unless the participant has received all scheduled doses of the study vaccine) at the 
time of withdrawal. Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
8.1.10.1
Withdrawal From Future Biomedical Research
Participants or participants' legally acceptable representatives may withdraw their consent for 
future biomedical research. Participants or participants' legally acceptable representatives 
may withdraw consent at any time by contacting the investigator. If medical records for the 
main study are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@MSD.com). Subsequently, the participant's 
consent for future biomedical research will be withdrawn. A letter will be sent from the 
Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant's legally acceptable representative of completion of 
withdrawal. Any analyses in progress at the time of request for withdrawal or already 
performed prior to the request being received by the Sponsor will continue to be used as part 
of the overall research study data and results. No new analyses would be generated after the 
request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
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the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
8.2.1
Blood Sample Collection for Serum Anti-HPV Antibody Testing
Blood samples will be collected for analysis of antibodies specific for HPV 6, 11, 16, 18, 31, 
33, 45, 52, and 58 titers in serum. On Day 1, blood samples will be collected prior to the first 
study vaccination to identify participants who have been exposed to study vaccine HPV types 
prior to enrollment. Serology results on Day 1 are not part of the inclusion/exclusion criteria; 
thus, no participant will be excluded from the study based on these results. After Day 1, 
serum specimens will be collected at Month 7, Month 18, and Month 30 to evaluate 
persistence of immune responses.
Blood sample collection, storage, and shipment instructions for serum samples will be 
provided in the Laboratory Manual. Blood samples will be collected for anti-HPV antibody 
testing per the schedule indicated in the SoA (Section 1.3).
After completion of immunogenicity testing to evaluate the study objectives, all leftover 
serum samples will be stored for up to 15 years. The samples may be used to conduct any 
additional study-related testing, biomarker testing, or to support HPV assay 
development/validation activities as required by regulatory agencies or the Sponsor.
8.2.2
Competitive Luminex Immunoassay
The 9vHPV cLIA will be used as a primary method to evaluate antibodies specific for HPV 
6, 11, 16, 18, 31, 33, 45, 52, and 58 in serum. The purpose of the assay is to detect these HPV 
antibodies before and after vaccination with the 9vHPV vaccine. The testing will be
performed by Q Squared Solutions (California, USA).
For the 9vHPV cLIA, HPV type-specific, yeast-derived VLPs are coupled to 9 distinct
Luminex magnetic microspheres. Each VLP-coupled microsphere has its own distinct
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fluorescent dye that can be recognized by excitation with an infrared laser, allowing for the
measurement of antibodies against multiple HPV types from a single test of an individual’s
serum. HPV type-specific monoclonal antibodies labeled with R-Phycoerythrin (PE) compete
with an individual’s serum antibodies for binding to the neutralizing epitopes of the VLPs.
The fluorescent signal from the PE-labeled, type-specific monoclonal antibodies is inversely
proportional to the anti-HPV antibody concentration of a sample. Antibody concentrations
are derived from a standard curve, which is generated using a reference standard made from a
pool of serum from individuals immunized against the nine HPV types. A standard curve for
each HPV type is calculated using a weighted 4 parameter logistic curve fit. Results are
expressed as milli-Merck Units per milliliter (mMU/mL).
The assay was validated at Q Squared Solutions. Validation evaluated precision, linearity,
lower limit of quantitation, upper limit of quantitation, and relative accuracy/dilutability for 
the quantitation of antibodies specific to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. 
Serostatus cutoffs for each HPV type will be predefined. A participant will be considered 
seropositive to a given HPV type at Day 1 if the participant’s anti-HPV titer, as assessed by 
cLIA, is greater than or equal to the corresponding serostatus cutoff for that HPV type. A 
participant will be considered seronegative to a given HPV type at Day 1 if the participant’s 
anti-HPV titer, as assessed by cLIA, is less than the corresponding serostatus cutoff for that 
HPV type.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A physical examination is optional and will be conducted by an investigator on Day 1 to 
determine whether the participant meets eligibility criteria for enrollment.
Height and weight will be recorded on Day 1 before administration of the study vaccine.
Physical examination details will be recorded in the participant’s study chart. Any medical 
condition identified during physical examination will be documented in the data collection 
system. Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Oral Temperature Measurements
Oral temperature will be assessed before study vaccine administration on Day 1, Month 2 
(only for 3-dose boy arm), and Month 6 as well as blood sample collection on Day 1. If the 
participant has a fever (defined as an oral temperature of ≥37.5°C) within the 24-hour period 
prior to receiving a study vaccination, the participant should not receive the study vaccine, 
and the vaccination visit should be rescheduled until after the fever has resolved.
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Postvaccination, if an oral temperature indicates a fever (defined as an oral temperature of 
≥37.5°C), then an AE of “fever” must be documented in the eCRF.
8.3.3
Clinical Safety Laboratory Assessments
There will be no protocol-specific clinical safety laboratory assessments for this study. If 
laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or discontinuation of the 
study vaccine), then the results must be recorded in the appropriate case report form (CRF)
(eg, SLAB).
8.3.4
Vaccination Report Card
The investigator or delegate will train the participant’s legally acceptable representative in 
the use of the VRC at Visit 1 (Day 1). Temperatures, injection-site reactions, other 
complaints or illnesses, and concomitant medications or vaccinations will be recorded on the 
VRC by the participant’s legally acceptable representative. The participant’s legally 
acceptable representative should be informed to contact the investigator immediately in the 
event of a hospitalization or visit to another physician.
The participant’s legally acceptable representative will use the VRC to document the 
following information:
‒
Oral temperatures measured from Day 1 (day of vaccination) through Day 5 
postvaccination.

Participant’s legally acceptable representative will record participant’s oral 
temperature in the evening after each study vaccination and daily, at the same time of 
day, for 4 days after each study vaccination for the purpose of identifying febrile 
events

Note: If an oral temperature indicates a fever (defined as an oral temperature of
≥37.5°C), the AE of “fever” must be documented in the appropriate eCRF
‒
Solicited injection-site AEs (redness/erythema, swelling, and tenderness/pain) from
Day 1 through Day 5 postvaccination
‒
Injection-site and systemic AEs from Day 1 through Day 15 postvaccination
‒
Concomitant medications and non-study vaccinations from Day 1 through Day 15
postvaccination
In order to ensure that the VRC is being filled out without delay, telephone contacts to
remind the participant’s legally acceptable representative will be conducted after 15 days 
postvaccination.
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All participant’s legally acceptable representative will be expected to bring the VRC to the 
study site at the next scheduled visit. The investigator or delegate will review the data 
captured on the VRC with the participant’s legally acceptable representative at Visit 2 
(Month 2), Visit 3 (Month 6, only for 3-dose boy arm), and Visit 4 (Month 7). For the AEs
outlined above, the investigator will use the information provided by the participant’s legally 
acceptable representative both on the VRC, and verbally at the time of VRC review, to apply 
the appropriate assessment of causality as described in Appendix 3. At the time of VRC 
review at the next scheduled visit, participant’s legally acceptable representative will be 
questioned regarding any new medical conditions that occurred beyond Day 15 
postvaccination. The investigator will determine if the medical condition is to be reported as 
an SAE using the reporting guidelines provided in Section 8.4.
8.3.5
Postvaccination Observation Period (30 Minutes)
All participants will be observed for at least 30 minutes after each vaccination for any 
immediate reactions. If any immediate AEs (including allergic reactions) are observed during 
this period, the time at which the event occurred within this timeframe, as well as the event 
itself, any concomitant medications that were administered, and resolution of the event, must
be recorded on the appropriate eCRF.
8.3.6
Pregnancy Testing

Pregnancy testing
‒
Pregnancy testing requirements for study exclusion are described in Section 5.2.
‒
Pregnancy testing (urine) should be conducted prior to vaccination at Visit 1 and 
Visit 3.
‒
For participants who become pregnant after receiving a study vaccination, study 
visits and vaccination will be paused until resolution of the pregnancy (e.g. term, 
elective termination, spontaneous abortion). Study visits and study vaccination in 
pregnancy participants will be handled as described in Table 3. Breastfeeding is not 
a contraindication to receiving study vaccinations. Pregnancy and exposure during 
breastfeeding must be reported as described in Section 8.4.5.
‒
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator to establish the absence of pregnancy at any time 
during the participant’s participation in the study.
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Table 3
Guidelines for Pregnant Participants: Managing Study Visits and Study 
Vaccinations
Visit Where Pregnancy is Detected
Action
Day 1
Do not enroll the participant
Between First and Second Vaccination 
Visits 

No scheduled visits until resolution of the 
pregnancy (e.g. term, elective termination, 
spontaneous abortion).

The second study vaccination visit should be 
administered at least 4 weeks following resolution 
of pregnancy, after normalization of β-human 
chorionic gonadotropin (β-hCG) , and in 
accordance to the intervention group assigned and 
visit windows in Section 1.3.
After Second Vaccination Visits

Continue with scheduled study visits during the 
pregnancy.

Safety follow-up will be conducted after resolution 
of the pregnancy (e.g. term, elective termination, 
spontaneous abortion).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, intensity 
and causality.
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant's legally 
acceptable representative provides documented informed consent but before
allocation/randomization must be reported by the investigator if they cause the participant to 
be excluded from the study, or are the result of a protocol-specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of allocation/randomization through 14 days following the first vaccination(s) 
and from the time of any subsequent vaccination(s) through 14 days thereafter, all AEs, 
SAEs, and other reportable safety events must be reported by the investigator. All SAEs and 
other reportable safety events that occur from the time of allocation/randomization through 6 
months following the last vaccination must be reported by the investigator, regardless of 
whether the events are considered to be vaccine-related by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:
‒
A death that occurs prior to the participant completing the study, but outside the time 
period specified in the previous paragraph.
OR
‒
An SAE that is considered by an investigator, who is a qualified physician, to be vaccine 
related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 4.
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Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of 
Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine 
related.
- any death until 
participant 
completion of study
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout or 
run-in treatment 
including placebo run-
in)
Report all
Previously reported 
– Follow to 
completion/
termination; report 
outcome
Within 24 hours 
of learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days of 
learning of event
(unless serious)
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 5 
calendar days of 
learning of event
NSAE=nonserious adverse event; SAE=serious adverse event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated/randomized
participants for outcome. Further information on follow-up procedures is given in Appendix 
3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
None.
8.4.7
Events of Clinical Interest
None.
8.5
Treatment of Overdose
In this study, an overdose is defined as a participant receiving >1 dose of study vaccine in a 
24-hour period, or >3 doses of study vaccine throughout the study.
Sponsor does not recommend specific treatment for an overdose.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
If the participant's legally acceptable representative provides documented informed consent 
for FBR, the following specimens will be obtained as part of FBR:
‒
DNA for future research
8.9
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.9.1
Screening
The screening visit or the last screening visit (for re-screening) should be on the same day of 
randomization and the first dose of vaccination. Potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5. Screening 
procedures may be repeated after consultation with the Sponsor.
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If possible, all Day 1 visit procedures should be performed on the day of consent. If date of 
Day 1 visit (and all procedures) is later than consent date, the interval between the date of 
consent and the date of the Day 1 visit should be no more than 14 days. If the interval is 15 
days or longer, then the participant’s legally acceptable representative must be reconsented.
8.9.2
Prerequisites for Vaccination Visits (Day 1, Month 2, and Month 6)
This section summarizes prerequisites for vaccination visits. See the inclusion/exclusion 
criteria for specific restrictions on Day 1 (see Section 5.1 and Section 5.2). At Month 2 (only 
for 3-dose boy arm) and Month 6 study vaccination visits, study personnel should verify by 
questioning the participant’s legally acceptable representative and/or by examination that:
1.
The participant has not had a fever (oral temperature ≥37.5°C) within the 24-hour period 
prior to the vaccination visit.
2.
The participant has not received any systemic (oral or parenteral) corticosteroids in 14 
days prior to any study vaccination visits.
3.
The participant has not received a non-study inactivated or recombinant vaccine within 
14 days prior to any study vaccination visit or a non-study live vaccine within 28 days 
prior to any study vaccination visit.
If the participant does not meet the requirements listed above, the study visit (including 
specimen collection and study vaccination) should be re-scheduled.
8.9.3
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study vaccinations but continue in the study will attend study 
visits per the SoA (Section 1.3). However, serum will not be collected at the Month 7 study 
visit or subsequent visits from participants who did not complete the specified study 
vaccination regimen.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a supplemental statistical analysis plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in 
the CSR.
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9.1
Statistical Analysis Plan Summary
Study Design Overview
A phase 3, open-label clinical study to evaluate the immunogenicity 
and safety of 9vHPV vaccine, in Japanese 9-15 boys and 9-14 girls 
of age
Treatment Assignment
Approximately 300 participants will be enrolled and allocated in a 
1:1:1 ratio based on gender and age into the 3-dose [0,2,6 regimen] 
in 9 to 15 years old boys, 2-dose [0,6 regimen] in 9 to 14 years old 
boys and 2-dose [0,6 regimen] in 9 to 14 years old girls arms. 
Details are provided in Section 6.3.1.
Analysis Populations
Immunogenicity: Per-Protocol Immunogenicity (PPI) population
Safety: All Participants as Treated (APaT) population
Primary Endpoint(s)

Seroconversion to each of HPV 6, 11, 16, 18, 31, 33, 45, 52 
and 58 at 1 month post last dose (Month 7) following 3 doses 
of the 9vHPV vaccine. 

Seroconversion to each of HPV 6, 11, 16, 18, 31, 33, 45, 52 
and 58 at 1 month post last dose (Month 7) following 2 doses 
of the 9vHPV vaccine.
Key Secondary Endpoints

Geometric mean titers (GMTs) to each of HPV 6, 11, 16, 18, 
31, 33, 45, 52 and 58 at 1 month post last dose (Month 7) 
following 3 doses of the 9vHPV vaccine.

GMTs to each of HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58 at 1 
month post last dose (Month 7) following 2 doses of the 
9vHPV vaccine.
Statistical Methods for 
Key Immunogenicity 
Analyses
The primary immunogenicity objective is estimation of the HPV 6, 
11, 16, 18, 31, 33, 45, 52 and 58 seroconversion at 1 month post last 
dose (Month 7) following 3 doses and 2 doses of the 9vHPV 
vaccine. Seroconversion to a specific HPV type is defined as 
changing serostatus from seronegative at Day 1 to seropositive at 1 
month post last dose (Month 7). Percent seroconversion will be 
evaluated by computing point estimates and constructing 95% 
confidence interval (CI) of the percent of participants who 
seroconvert at 1 month post last dose (Month 7). Calculation of the 
95% CI of percent seroconversion is based on the exact binomial 
method proposed by Clopper and Pearson [Clopper, C. J. and 
Pearson, E. S. 1934]. 
The secondary objective is to estimate GMTs at 1 month post last 
dose (Month 7) for each of HPV 6, 11, 16 ,18, 31, 33, 45, 52, and 
58 following 3 doses and 2 doses of the 9vHPV vaccine. GMTs and 
corresponding 95% CI will be derived by taking the anti-logarithm 
of the mean and corresponding 95% CI of the mean of the log-
transformed anti-HPV titers.
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Statistical Methods for 
Key Safety Analyses
Incidence of solicited injection-site AEs, systemic AEs, SAEs, and 
serious vaccine-related AEs will be summarized by study arm.
Interim Analyses
No interim analyses are planned in this study.
Multiplicity
Not applicable. The study is an estimation-only study.
Sample Size and Power 
The study will enroll 300 participants (100 participants for each 
study arm) to receive V503. At least 95 participants evaluable per 
study arm will allow estimation of percent seroconversion that has a 
corresponding 95% CI with a half-width of about 3 percentage 
points, assuming true percent seroconversion of 99% and the 
discontinuation rate and exclusion from the HPV type-specific PPI 
population of at most 5%. In addition, at least 95 participants 
evaluable per study arm provides at least 0.99 probability to 
demonstrate that the point estimate of the percent seroconversion 
exceeds 90% for all of the 9 HPV types when the true percent 
seroconversion is 99%. At least 95 participants evaluable per study 
arm provides at least 0.88 probability to attain a lower limit of 95% 
CI of percent seroconversion equal to or more than 90% when the 
true percent seroconversion is at least 99%.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
designee/Clinical Biostatistics department of the Sponsor. This trial is being conducted as an 
open-label study, i.e., participants, investigators, and Sponsor personnel will be aware of 
participant treatment assignments after each participant is enrolled and treatment is assigned. 
First database lock will be executed when all girls aged 9 to 14 years old in the 2-dose arm 
have either completed the Month 7 visit (1 month post last dose) or discontinued from the 
study before that time to report on base phase analysis for this arm. 
A second database lock will be executed at end-of-study to report on base phase analysis for
the 2-dose and 3-dose arms in boys and on extension phase analysis for all study arms for 
safety and persistence of immune response.
Summaries of the primary and secondary immunogenicity endpoints will be reported in 
Integrated Summary of Immunogenicity reports where in addition to reporting the 
immunogenicity results in this study, the study results will be compared with 
immunogenicity results in studies of 16 to 26 year-old Japanese males and females who 
received 3 doses of the 9vHPV vaccine for the purpose of immunobridging efficacy in 16 to 
26 year-old Japanese males and females to 9 to 15 year-old Japanese boys and girls. The 
results of the 2-dose arm in girls and the 2-dose and 3-dose arms in boys will be reported in 
two separate integrated Summary of Immunogenicity reports. The details about the analysis 
will be documented in a separate iSAP.
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9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. The study is an estimation-only study. No 
hypothesis will be tested. 
9.4
Analysis Endpoints
9.4.1
Immunogenicity Endpoints
The primary immunogenicity endpoints are seroconversion to HPV 6, 11, 16, 18, 31, 33, 45, 
52 and 58 at 1 month post last dose (Month 7) following 3 doses; and following 2 doses of 
the 9vHPV vaccine. Seroconversion is defined as changing serostatus from seronegative at 
Day 1 to seropositive at 1 month post last dose (Month 7). A participant with a cLIA titer at 
or above the serostatus cutoff for a given HPV type is considered seropositive for that HPV 
type.
The key secondary immunogenicity endpoints are cLIA geometric mean titers (GMTs) for
anti-HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58 at 1 month post last dose (Month 7) following 3 
doses; and following 2 doses of the 9vHPV vaccine. Exploratory endpoints include cLIA 
GMTs and seropositivity for each vaccine HPV type at Months 18 and 30 to assess 
persistence of immune responses.
9.4.2
Safety Endpoints
•
Solicited injection-site AEs and elevated temperatures Days 1 through 5 post vaccination 
•
Systemic AEs, SAEs and Serious vaccine-related AEs Days 1 through 15 post 
vaccination 
•
SAEs and Serious vaccine-related AEs observed any time during the study
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
Per-Protocol Immunogenicity (PPI) Population
The PPI population will serve as the primary population for the analysis of immune response 
to each HPV-types. To be included in this population, participants must:
(1) Have received all required vaccinations of 9vHPV vaccine with the correct dose within 
acceptable day ranges (see Table 5).
(2) Have provided blood samples for serology testing within 21 to 49 days post last dose.
(3) Be seronegative to the appropriate HPV type(s) at Day 1.
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(4) Have no other protocol violations that could interfere with the evaluation of participant’s 
immune response to the study vaccine.
The final determination on protocol violations, which will be used for determining the PPI
population, will be made prior to the database lock and will be documented in a separate 
memo.
Table 5
Acceptable Day Ranges for Vaccination Visits
Vaccination Dose
Protocol Specified
Visit Window
Day Range for Inclusion in Statistical Analysis 
(Relative to Day 1†)
3-Dose [0,2,6 regimen]
Dose 1
Day 1†
0
Dose 2
Month 2 ± 3 weeks
36 to 84
Dose 3
Month 6 ± 4 weeks
148 to 218
2-Dose [0,6 regimen]
Dose 1
Day 1†
0
Dose 2
Month 6 ± 4 weeks
148 to 218
† Day 1 refers to the date when vaccination dose 1 was administered. 
Table 6
Acceptable Day Ranges for Collection of Serum Samples
Study Visit
Sample Type
Target Collection Day
(Relative to Day 1)†
Day Range for Inclusion in Statistical Analysis
(Relative to Day 1†) 
Day 1
Serum
0
–14 to 0
Month 7
Serum
30 days post last dose
21 to 49 post last dose
Month 18
Serum
548
366 to 730
Month 30
Serum
913
731 to 1004
† Day 1 refers to the date when vaccination dose 1 was administered. For Month 7, indicated target collection/day range 
is relative to date of injection of last dose of 9vHPV vaccine.
All Naïve Participants with Serology (ANPS) Population
A supportive immunogenicity analysis will be carried out on the all type-specific naïve 
participants with serology population. To be included in this population, participants must:
(1) Have received at least 1 vaccination.
(2) Have provided serum samples with evaluable results.
(3) Be seronegative to the appropriate HPV types at Day 1.
For each of the PPI and ANPS analysis populations:
1) To be included in the analysis population for HPV 6 or 11, participants must be 
seronegative to both HPV 6 and 11 at Day 1;
2) To be included in the analysis population for any other vaccine HPV type, participants 
must be seronegative at Day 1 only for the HPV type being analyzed.
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9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all participants 
who received at least 1 dose of 9vHPV vaccine and have provided safety data at any time 
during the study. Participants will be included in the study arm corresponding to the study 
treatment they actually received for the analysis of safety data using the APaT population 
(i.e., 3 doses [0,2,6 regimen] or 2 doses [0,6 regimen] of 9vHPV vaccine). For participants 
who received only 1 dose of 9vHPV vaccine, or a participant allocated to the 3-dose regimen 
arm but received 2 doses that does not correspond to the [0,6 regimen], a safety profile listing 
will be created separately from the safety reports that will be provided for the 3-dose [0,2,6 
regimen] and 2-dose [0,6 regimen] arms.
9.6
Statistical Methods
9.6.1
Statistical Methods for Immunogenicity Analyses
Estimation of percent seroconversion
Within a study arm, the point estimate of percent seroconversion is calculated as the percent 
of participants with evaluable serology result at 1 month post last dose (Month 7) who 
seroconvert at 1 month post last dose (Month 7), where seroconversion is as defined in 
Section 9.4.1. Calculation of the corresponding 95% CI is based on the exact binomial 
method proposed by Clopper and Pearson (1934).
Estimation of percent seropositivity
For each of the Months 18 and 30 time points, within a study arm, the point estimate of 
percent seropositivity for a given HPV type is calculated as the percent of participants with 
evaluable serology result with cLIA titer at or above the serostatus cutoff for the given HPV 
type. Calculation of the corresponding 95% CI is based on the exact binomial method 
proposed by Clopper and Pearson (1934).
Estimation of GMTs
Within a study arm, GMTs and corresponding 95% CI will be derived by taking the anti-
logarithm of the mean and corresponding 95% CI (calculated based on the t-distribution) of 
the mean of the log-transformed anti-HPV titers. Anti-HPV titers reported as less than the 
LLOQ of the relevant anti-HPV type will be replaced by the half of the LLOQ in the log-
transformation of anti-HPV titers.
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Table 7
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoints
Seroconversion to each HPV 6, 11, 
16, 18, 31, 33, 45, 52 and 58 at 1 
month post last dose (Month 7) 
following 3 doses of 9vHPV 
vaccine
P
Point 
estimate, 95% 
CI by exact 
binomial 
method
PPI
Observed 
data only
S
ANPS
Seroconversion to each HPV 6, 11, 
16, 18, 31, 33, 45, 52 and 58 at 1 
month post last dose (Month 7) 
following 2 doses of 9vHPV 
vaccine
P
Point 
estimate, 95% 
CI by exact 
binomial 
method
PPI
Observed 
data only
S
ANPS
Secondary Endpoints
GMTs to each HPV 6, 11, 16, 18, 31, 
33, 45, 52 and 58 at 1 month post last 
dose (Month 7) following 3 doses of 
9vHPV vaccine
P
Point estimate
and 95% CI
PPI
Observed 
data only
S
ANPS
GMTs to each HPV 6, 11, 16, 18, 31, 
33, 45, 52 and 58 at 1 month post last 
dose (Month 7) following 2 doses of 
9vHPV vaccine
P
Point estimate
and 95% CI
PPI
Observed 
data only
S
ANPS
Abbreviations: P = Primary, PPI = Per-protocol immunogenicity, S = Supportive, ANPS = all naïve 
participants with serology
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs).
The analysis of safety results usually follows a tiered approach in the studies conducted by 
the Sponsor. However, this study has no comparison between study arms. Thus, the 
following summaries will be provided as described in Table 8.
–
Incidence is defined as (number of participants with the indicated endpoint divided by the 
total number of participants with follow-up over the relevant period)*100%.
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–
For the measured adverse events of redness and swelling, 0 to 1 inch will be categorized 
as mild intensity, >1 inch to 2 inches will be categorized as moderate intensity, and >2 inches 
will be categorized as severe intensity.
The specific events of interest in this study will be injection-site prompted adverse events on 
the VRC, such as pain/tenderness, swelling and redness/erythema occurring Day 1 through 5 
following any vaccination, and elevated temperature (≥37.5°C), from Day 1 through 5 
following any vaccination.
Table 8
Analysis Strategy for Safety Parameters
Follow-Up Period
After Any Vaccination Visit
Any Time 
During 
Study
Adverse Event Endpoint
Within 
study 
arm 
95%CI||
Day 1
to Day 5†
Day 1
to Day 15†
Clinical AEs/vaccine-related AEs
Any AEs/vaccine-related AEs
●
Deaths
●
Injection-site AEs/vaccine-related AEs
Injection-site 
AEs/vaccine-related 
AEs 
of 
pain/tenderness, 
swelling, and redness/erythema 
Other injection-site AEs/vaccine-related AEs
●
●
●
●
Severe injection-site AEs§/vaccine-related AEs
●
●
Number (%) of participants by maximum intensity rating, 
over all injection-site AEs§/vaccine-related AEs
●
Number (%) of participants by maximum intensity rating, 
within each of the categories of injection-site AEs§/vaccine-related 
AEs
●
Systemic AEs/vaccine-related AEs
Any systemic AEs/vaccine-related AEs
●
●
Number (%) of participants by maximum intensity rating, 
over all systemic AEs/vaccine-related AEs
●
Temperatures
Elevated temperatures#
●
●
Maximum temperatures††
●
AEs of Special Interest
Serious AEs
Serious vaccine-related AEs
●
●
●
●
●
●
New medical conditions‡‡
●
Pregnancy outcomes
●
†
The day of vaccination is counted as Day 1.  Day 1 to Day 5 refers to the period within 4 days of a vaccination.  Day 1 
to Day 15 refers to the period within 14 days of a vaccination.
§
For the measured adverse events of redness and swelling 0 to 1 inch will be categorized as mild, >1 inch to 2 inches 
will be categorized as moderate and >2 inches will be categorized as severe.
#
Defined as maximum (over the follow-up period) temperature ≥37.5°C.
†† Distribution of maximum temperatures over the relevant follow-up period. 
‡‡ Including new medical conditions considered potentially of an autoimmune nature.
||
The exact binomial method proposed by Clopper and Pearson (1934).
AEs = Adverse events; CI = Confidence interval
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9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Baseline characteristics and demographic variables
Baseline and demographic characteristics; prior and concomitant therapies; counts and 
percent of participants screened, enrolled, vaccinated and the primary reason for 
discontinuation; will be summarized in tabular format by study arm. No statistical hypothesis 
tests will be performed on these characteristics.  
9.7
Interim Analyses
No interim analyses are planned in this study.
9.8
Multiplicity
Not applicable.  The study is an estimation-only study.
9.9
Sample Size and Power Calculations
A total sample size of 300 participants will be enrolled. 100 participants will be enrolled in 
each study arm. When the discontinuation rate and exclusion from the HPV type-specific PPI 
population is at most 5%, at least 95 participants in each study arm will be evaluable for the 
analysis of immune response at 1 month post last dose (Month 7).  In each arm, at least 95 
participants evaluable per study arm will allow estimation of percent seroconversion that has 
a corresponding 95% CI with half-width of about 3 percentage points, assuming true percent 
seroconversion of 99%. In addition, at least 95 participants evaluable per study arm provides 
at least 0.99 probability to demonstrate that the point estimate of percent seroconversion 
exceeds 90% for all of 9 HPV types when the true percent seroconversion is 99%. At least 95 
participants evaluable per study arm provides at least 0.88 probability to attain a lower limit 
of 95% CI of percent seroconversion equal to or more than 90% when the true percent 
seroconversion is at least 99%.
For the safety analysis, all participants are expected to be evaluable. If no SAE are observed 
among the 100 participants per study arm, this study will provide 95% confidence that the 
underlying percentage of participants with an SAE is <3.0% in each study arm.
The estimate and the half-width of the 95% confidence interval for the underlying percentage 
of participants with the adverse event given various hypothetical observed number of 
participants with an adverse event within the study arm are provided in Table 9.  These 
calculations are based on the exact binomial method proposed by Clopper and Pearson 
(1934).
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Table 9
Estimate of Incidence of Adverse Event and Half-width of 95% Confidence 
Interval Based on Hypothetical Number of Participants with Adverse Event among 100 
Participants in the Study Arm
Hypothetical Number of Participants
with Adverse Event
Estimate of Incidence
Half-width of 95% Confidence Interval†
1
1%
2.7%
2
2%
3.4%
4
4%
4.4%
8
8%
5.8%
16
16%
7.6%
32
32%
9.5%
† Based on the exact binomial method (Clopper and Pearson, 1934).
9.10
Subgroup Analyses
No subgroup analyses are planned for this study.
9.11
Compliance (Medication Adherence)
Compliance is defined in this study as receipt of all scheduled study vaccinations. To 
summarize compliance, the numbers of participants who receive each vaccination will be 
tabulated.  Compliance with the planned vaccination schedule (3-dose: Day 1, Month 2, 
Month 6, 2-dose: Day 1, Month 6) will be described by histograms of actual intervals 
between vaccinations relative to the expected interval.
9.12
Extent of Exposure
As indicated in Section 6.1, each study participant is planned to be administered 0.5 mL of 
9vHPV vaccine at each vaccination visit (3-dose: Day 1, Month 2, Month 6, 2-dose: Day 1, 
Month 6). Thus, each participant is expected to be administered a total of 1.5 mL of 9vHPV 
vaccine over a 6-month duration for 3-dose 9 to 15 years old boys, 1.0 mL of 9vHPV vaccine
over a 6-month duration for 2-dose 9 to 14 years old boys and 2-dose 9 to 14 years old girls, 
respectively.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
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Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study.  MSD will 
support clinical trial investigators to enroll underrepresented groups and expand access to those who will 
ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
‒
There are no protocol-specific requirements for safety laboratory testing.
‒
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2.
‒
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

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 study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
‒
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
‒
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
‒
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, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
‒
In offspring of participant taking the product regardless of time to diagnosis.
f. Other important medical events
‒
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include 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 hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
‒
Is a cancer
‒
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
‒
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
‒
Injection site erythema/redness or swelling from the day of vaccination through Day 5 
postvaccination will be evaluated by maximum size.
Assessment of causality
‒
Did the Sponsor’s product cause the AE?
‒
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
‒
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
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-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(diary, etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose vaccine study; or (3) 
Sponsor’s product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
‒
Consistency with study intervention profile: Is the clinical/pathological presentation 
of the AE consistent with previous knowledge regarding the Sponsor’s product or drug 
class pharmacology or toxicology?
‒
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
‒
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
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-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
‒
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
‒
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
‒
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
‒
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
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◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
Not applicable.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e. RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants' legal guardians, at a study visit by 
the investigator or his or her designate. Informed consent for future biomedical research 
should be presented to the participants' legal guardians on the visit designated in the SoA. 
If delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant's legal guardians will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants or their legal guardians may withdraw their consent for future biomedical 
research and ask that their biospecimens not be used for future biomedical research. 
Participants or their legal guardians may withdraw consent at any time by contacting the 
investigator for the main study. If medical records for the main study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to main study use only. If specimens 
were collected from study participants specifically for future biomedical research, these
specimens will be removed from the biorepository and destroyed. Documentation will be 
sent to the investigator confirming withdrawal and/or destruction, if applicable. It is the 
responsibility of the investigator to inform the participant and participant's legal guardian 
of completion of the withdrawal and/or destruction, if applicable. Any analyses in 
progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research study data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
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specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
9vHPV
9-valent human papillomavirus
AE
adverse event 
ANPS
All Naïve Participants with Serology
APaT
All Participants as Treated
CI
confidence interval
β-hCG
β-human chorionic gonadotropin
cLIA
competitive Luminex Immunoassay
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CSR
Clinical Study Report
DNA
deoxyribonucleic acid 
eCRF
electronic Case Report Form
ECG
Electrocardiogram
EDC
electronic data collection 
EMA
European Medicines Agency
FBR
future biomedical research
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice 
GMT
Geometric mean titer
HIV
human immunodeficiency virus
HPV
human papillomavirus
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IM
Intramuscular
IRB
Institutional Review Board 
IRT
interactive response technology
iSAP
integrated statistical analysis plan
IVIG
intravenous gamma globulin
mMU/mL
milli-Merck Units per milliliter
NSAE
nonserious adverse event
PE
Phycoerythrin
PK
pharmacokinetic
PPI
Per-Protocol Immunogenicity
qHPV
quadrivalent HPV
RNA
ribonucleic acid
RRP
Recurrent Respiratory Papillomatosis
SAE
serious adverse event 
SoA
schedule of activities
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TNF-α
tumor necrosis factor-alpha
VLP
virus-like particle
VRC
vaccination report card
WHO
World Health Organaization
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11
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