A Phase 3 Open-Label Clinical Trial to Study the Immunogenicity, Safety and Tolerability of Recombinant Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine (V501) in Chinese Girls Aged 9-19 Years and Young Women Aged 20-26 Years
Phase: PHASE3
Conditions: Prevention of HPV Types 16- and 18-related Cervical Cancer, Cervical Intraepithelial Neoplasia (CIN) 1/2/3, and Cervical Adenocarcinoma in Situ
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03493542 
Document Date: 
13-Jan-2023
A Phase 3 Open-Label Clinical Trial to Study the  
Immunogenicity, Safety and Tolerability of Recombinant Human 
Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine 
(V501) in Chinese Girls Aged 9-19 Years and Young Women 
Aged 20-26 Years

Product:  V501
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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).
This protocol amendment is applicable only to China.
Protocol Title: A Phase 3 Open-Label Clinical Trial to Study the Immunogenicity, Safety 
and Tolerability of Recombinant Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) 
Vaccine (V501) in Chinese Girls Aged 9-19 Years and Young Women Aged 20-26 Years
Protocol Number: 213-03
Compound Number: V501
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER:   To Be Determined
EudraCT NUMBER: Not Applicable
Approval Date:  13 January 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
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
V501-213-03
13-JAN-2023
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.
V501-213-02
07-DEC-2018
The primary reason for this amendment is to extend the duration of immunogenicity follow-
up from 7 months to 60 months in participants aged 9 to 19 years.
V501-213-01
13-FEB-2018
Current literatures present the updated study procedures and methods of data analysis and 
ensure the consistency in the safety data collection throughout the protocol of this study.
V501-213-00
28-NOV-2017
Original protocol
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment [03]
Overall Rationale for the Amendment:
Sponsor underwent an entity name change and update the address.
Summary of Changes Table:
Section # and 
Name
Description of Change
Brief Rationale
Title Page
Section 12.1 Code 
of Conduct for 
Clinical Trials
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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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
Synopsis.......................................................................................................................12
2
Schedule of Activities (SoA)......................................................................................16
3
Introduction................................................................................................................22
3.1
Study Rationale .......................................................................................................22
3.2
Background..............................................................................................................22
3.2.1
Pharmaceutical and Therapeutic Background .....................................................23
3.3
Benefit/Risk Assessment.........................................................................................23
4
Objectives/Hypotheses and Endpoints.....................................................................24
5
Study Design...............................................................................................................27
5.1
Overall Design .........................................................................................................27
5.1.1
Study Diagram .....................................................................................................28
5.2
Number of Participants ..........................................................................................28
5.3
Beginning and End of Study Definition ................................................................28
5.3.1
Clinical Criteria for Early Study Termination .....................................................28
5.4
Scientific Rationale for Study Design....................................................................28
5.4.1
Rationale for Endpoints .......................................................................................29
5.4.1.1
Immunogenicity Endpoints...........................................................................29
5.4.1.2
Safety Endpoints...........................................................................................29
5.5
Justification for Dose ..............................................................................................29
6
Study Population........................................................................................................29
6.1
Inclusion Criteria....................................................................................................30
6.1.1
Inclusion Criteria for Base Stage .........................................................................30
6.1.2
Inclusion Criteria for Extension Stage.................................................................30
6.2
Exclusion Criteria ...................................................................................................31
6.3
Lifestyle Restrictions...............................................................................................32
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6.4
Screen Failures ........................................................................................................33
6.5
Participant Replacement Strategy.........................................................................33
7
Treatments..................................................................................................................33
7.1
Treatments Administered.......................................................................................33
7.2
Dose Modification ...................................................................................................33
7.3
Method of Treatment Assignment.........................................................................34
7.3.1
Stratification.........................................................................................................34
7.4
Blinding....................................................................................................................34
7.5
Preparation/Handling/Storage/Accountability ....................................................34
7.5.1
Dose Preparation..................................................................................................34
7.5.2
Handling, Storage and Accountability.................................................................34
7.6
Treatment Compliance...........................................................................................35
7.7
Concomitant Therapy.............................................................................................35
7.7.1
Rescue Medications and Supportive Care ...........................................................35
7.8
Treatment After the End of the Study ..................................................................35
7.9
Clinical Supplies Disclosure...................................................................................35
8
Discontinuation/Withdrawal Criteria......................................................................36
8.1
Discontinuation of Study Treatment.....................................................................36
8.2
Withdrawal from the Study ...................................................................................36
8.3
Lost to Follow Up....................................................................................................37
9
Study Assessments and Procedures..........................................................................37
9.1
Administrative and General Procedures ..............................................................38
9.1.1
Informed Consent/Assent.....................................................................................38
9.1.1.1
General Informed Consent/Assent................................................................38
9.1.2
Inclusion/Exclusion Criteria ................................................................................38
9.1.3
Participant Identification Card.............................................................................38
9.1.4
Medical History ...................................................................................................39
9.1.5
Prior and Concomitant Medications Review .......................................................39
9.1.5.1
Prior Medications..........................................................................................39
9.1.5.2
Concomitant Medications.............................................................................39
9.1.6
Assignment of Screening Number.......................................................................40
9.1.7
Assignment of Treatment/Randomization Number.............................................40
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9.1.8
Treatment Administration....................................................................................40
9.1.8.1
Preparation of Study Vaccine for Administration ........................................40
9.1.8.2
Study Vaccine Administration......................................................................41
9.1.8.3
Timing of Dose Administration....................................................................41
9.1.9
Discontinuation and Withdrawal .........................................................................41
9.1.10 Participant Blinding/Unblinding..........................................................................42
9.1.11 Calibration of Critical Equipment........................................................................42
9.1.12 Other Assessments...............................................................................................42
9.1.12.1 Physical Examinations and Vital Signs Prior to Study Vaccination.............42
9.2
Efficacy Assessments...............................................................................................43
9.2.1
Serum for Anti-HPV Antibody Testing...............................................................43
9.2.2
Immunogenicity Measurements...........................................................................43
9.3
Adverse Events (AE), Serious Adverse Events (SAE) and Other 
Reportable Safety Events .......................................................................................44
9.3.1
Time Period and Frequency for Collecting AE, SAE and Other 
Reportable Safety Event Information ..................................................................44
9.3.2
Method of Detecting AE, SAE and Other Reportable Safety Events..................46
9.3.3
Follow-up of AE, SAE and Other Reportable Safety Event Information............46
9.3.4
Regulatory Reporting Requirements for SAE .....................................................46
9.3.5
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..................................................................................46
9.3.6
Pregnancy and Exposure During Breastfeeding ..................................................46
9.3.7
Events of Clinical Interest (ECI)..........................................................................47
9.4
Treatment of Overdose...........................................................................................47
9.5
Safety........................................................................................................................47
9.5.1
Patient Reported Outcome ...................................................................................47
9.5.2
Pregnancy Testing................................................................................................48
9.5.3
Post-vaccination Observation Period (30 minutes)..............................................49
9.5.4
Clinical Laboratory Assessments.........................................................................49
9.6
Pharmacokinetics....................................................................................................50
9.7
Pharmacodynamics.................................................................................................50
9.8
Biomarkers ..............................................................................................................50
9.9
Future Biomedical Research Sample Collection..................................................50
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9.10
Visit Requirements..................................................................................................50
9.10.1 Prerequisites for Vaccination Visits.....................................................................50
9.10.2 Discontinued Participants Continuing to be Monitored in the Study ..................51
10
Statistical Analysis Plan ............................................................................................51
10.1
Statistical Analysis Plan Summary........................................................................51
10.2
Responsibility for Analyses/In-House Blinding....................................................53
10.3
Hypotheses/Estimation ...........................................................................................53
10.4
Analysis Endpoints..................................................................................................53
10.4.1 Immunogenicity Endpoints..................................................................................53
10.4.2 Safety Endpoints ..................................................................................................54
10.5
Analysis Populations...............................................................................................54
10.5.1 Immunogenicity Analysis Populations ................................................................54
10.5.2 Safety Analysis Populations ................................................................................55
10.6
Statistical Methods..................................................................................................55
10.6.1 Statistical Methods for Immunogenicity Analyses..............................................55
10.6.2 Statistical Methods for Safety Analyses ..............................................................58
10.6.3 Summaries of Baseline Characteristics, Demographics, and other 
Analyses...............................................................................................................59
10.7
Interim Analyses .....................................................................................................59
10.8
Multiplicity ..............................................................................................................59
10.9
Sample Size and Power Calculations ....................................................................60
10.9.1 Sample Size and Power for Immunogenicity Analyses.......................................60
10.9.2 Sample Size and Power for Safety Analyses .......................................................62
10.10 Subgroup Analyses..................................................................................................62
10.11 Compliance (Medication Adherence)....................................................................62
10.12 Extent of Exposure..................................................................................................62
11
References...................................................................................................................63
12
Appendices..................................................................................................................65
12.1
Appendix 1: Study Governance Considerations ..................................................65
Code of Conduct for Clinical Trials.................................................................................65
Financial Disclosure.........................................................................................................67
Data Protection.................................................................................................................67
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Confidentiality of Data ....................................................................................................67
Confidentiality of Participant Records.............................................................................68
Confidentiality of IRB/IEC Information..........................................................................68
Publication Policy............................................................................................................68
Compliance with Study Registration and Results Posting Requirements .......................68
Compliance with Law, Audit and Debarment .................................................................69
Data Quality Assurance ...................................................................................................69
Source Documents ...........................................................................................................70
Study and Site Closure.....................................................................................................70
12.2
Appendix 2: Contraceptive Guidance and Pregnancy Testing...........................71
Definitions........................................................................................................................71
Contraception Requirements............................................................................................71
Pregnancy Testing............................................................................................................73
12.3
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting..............................................74
Definition of AE ..............................................................................................................74
Definition of SAE ............................................................................................................75
Additional Events Reported.............................................................................................76
Recording AE and SAE ...................................................................................................76
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor..................79
12.4
Appendix 4: Clinical Laboratory Tests.................................................................81
12.5
Appendix 5: Country-specific Requirements .......................................................82
12.6
Appendix 6: Abbreviations and Trademarks.......................................................89
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LIST OF TABLES
  
Table 1
Study Treatment....................................................................................................33
Table 2
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................45
Table 3
Guidelines for Pregnant Participants: Managing Study Visits and Study 
Vaccinations .........................................................................................................49
Table 4
Analysis Strategy for Immunogenicity Variables– Base Stage............................56
Table 5
Analysis Strategy for Immunogenicity Variables – Extension Stage...................58
Table 6
Power for cLIA GMT ratio based on 766 enrolled participants 
calculated from the secondary endpoint seroconversion rate...............................60
Table 7
Sample size and power calculated based on cLIA seroconversion 
difference in proportion testing ............................................................................61
Table 8
Contraceptive Methods.........................................................................................72
Table 9
Protocol-Required Clinical Laboratory Assessments...........................................81
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LIST OF FIGURES
          
Figure 1
Study Diagram......................................................................................................28
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1
Synopsis
Protocol Title:  
A Phase 3 Open-Label Clinical Trial to Study the Immunogenicity, Safety and 
Tolerability of Recombinant Human Papillomavirus Quadrivalent (Types 6, 11, 16, 
18) Vaccine (V501) in Chinese Girls Aged 9-19 Years and Young Women Aged 20-26 
Years
Short Title: 
Immunobridging study of V501 in Chinese girls and young women
Objectives/Hypotheses and Endpoints:
In Chinese girls aged 9-19 years and young women aged 20-26 years (Base Stage):
Objective/Hypothesis
Endpoint
Primary

Objective: To demonstrate that 
administration of a 3-dose regimen of 
V501 induces non-inferior geometric 
mean titers (GMTs) for serum anti-HPV 
6, anti-HPV 11, anti-HPV 16, anti-HPV 
18 in girls aged 9-19 years compared to 
young women aged 20-26 years.

Hypothesis (H1): 3-dose regimen of 
V501 induces non-inferior immune 
responses in girls aged 9-19 years 
who are seronegative at Day 1 to the 
relevant HPV type compared to 
young women aged 20-26 years who 
are seronegative at Day 1 to the 
relevant HPV type, as measured by 
anti-HPV 6, 11, 16, and 18 GMTs at 
1 month post dose 3. (Each vaccine 
component will be analyzed 
separately. The statistical criterion 
for non-inferiority requires that the 
lower bound of two-sided 95% 
confidence interval of GMT ratio 
(girls vs. young women) be greater 
than 0.67 for each HPV type.)

Competitive Luminex immunoassay 
(cLIA) GMTs to each of HPV 6, 11, 
16, and 18 at 1 month post dose 3
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Secondary

Key objective: To demonstrate that a 3-
dose regimen of V501 induces non-
inferior immune responses with respect 
to seroconversion percentages to HPV 
types 6, 11, 16, and 18 in girls aged 9-19 
years compared to young women 20-26 
years.

Hypothesis (H2): 3-dose regimen of 
V501 induces non-inferior immune 
responses in girls aged 9-19 years 
who are seronegative at Day 1 to the 
relevant HPV type compared to 
young women aged 20-26 years who 
are seronegative at Day 1 to the 
relevant HPV type, as measured by 
the percentage of participants who 
seroconvert to each of HPV types 6, 
11, 16, and 18 by 1 month post dose 
3. (Each vaccine component will be 
analyzed separately. The statistical 
criterion for non-inferiority requires 
that the lower bound of two-sided 
95% confidence interval for the 
difference (girls minus young 
women) in seroconversion 
percentages be greater than -5 
percentage points for each HPV 
type.)

Objective: To summarize immune 
responses (including GMTs and 
seroconversion percentages) to HPV 
types 6, 11, 16, and 18 assessed using 
HPV total IgG Luminex immunoassay 
(IgG LIA).

Objective: To evaluate the safety and 
tolerability of V501 in girls aged 9-19 
years and young women aged 20-26 
years.

cLIA seroconversion percentages to 
each of HPV 6, 11, 16, and 18 at 1 
month post dose 3

IgG LIA GMTs and seroconversion 
percentages to each of HPV 6, 11, 
16, and 18 at 1 month post dose 3

Proportion of participants 
experiencing solicited injection-site 
adverse events (AEs)

Proportion of participants 
experiencing solicited systemic AEs

Proportion of participants 
experiencing serious adverse events 
(SAEs)
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In Chinese girls 9 to 19 years of age (Extension Stage):
Objective/Hypothesis
Endpoint 
Primary 

Objective: To evaluate persistence of 
immune responses induced by V501 in 
girls 9 to 19 years of age.

cLIA GMTs and seropositivity
percentages to each of HPV 6, 11, 
16, and 18 at Month 12, Month 24, 
Month 36, Month 48, and Month 60.

IgG LIA GMTs and seropositivity
percentages to each of HPV 6, 11, 
16, and 18 at Month 12, Month 24, 
Month 36, Month 48, and Month 60.
Secondary 

Objective: To evaluate the safety of 
V501 in girls 9 to 19 years of age.

Proportion of participants 
experiencing SAEs.
Overall Design:
Study Phase
Phase 3
Clinical Indication
Prevention of HPV types 16- and 18-related cervical cancer,
cervical intraepithelial neoplasia (CIN) 1/2/3, and cervical 
adenocarcinoma in situ among Chinese women.
Population
Healthy Chinese women
Study Type
Interventional
Type of Design
Single-arm, Single-site
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 62 months from the time the first participant 
signs the informed consent/assent until the last participant’s 
last study-related phone call or visit.  
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Number of Participants:
Approximately 766 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
All enrolled participants will intramuscularly receive a 3-
dose regimen of V501 at Day 1, Month 2, and Month 6. 
Duration of 
Participation
Each participant will participate in the study for 
approximately 7 months from the time the participant signs 
the informed consent/assent through the final contact in the 
base stage. Each participant will be receiving 3 doses of 
V501 and will be followed up to Month 7 in the base stage.
Participants 9 to 19 years of age who have received 3 doses 
of V501 during the base stage will be eligible to participate 
in the extension stage and will be followed up to Month 60.
Study governance considerations are outlined in Appendix 1. A list of abbreviations used in 
this document can be found in Appendix 6.
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2
Schedule of Activities (SoA)
Study Stage
Base Stage
(Participants 9-26 years of age)
Extension Stage
(Participants 9-19 years of age)
Notes
Study Visit 
Number/
Title
Visit 1
Day 1
Vacci-
nation 
1
Visit 2
Month 
1
Visit 3
Month 
2
Vacci-
nation 
2
Visit 4
Month 3
Visit 5
Month 
6
Vacci-
nation
3
Visit 6
Month 
7
Visit 7
Month 
12
Visit 8
Month 
24
Visit 9
Month 
36
Visit 
10
Month 
48
Visit 
11
Month 
60
Scheduled 
Day
1
32
62
93
184
215
366
732
1097
1462
1827
Scheduling 
Window:
± 0 
days
31 to 38 
days 
after 
Vacci-
nation 
1
± 21 
days
31 to 52
days 
after 
Vacci-
nation 2
± 28 
days
31 to 
49 days 
after 
Vacci-
nation 
3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Administrative Procedures
Informed 
Consent/
Assent
(Base Stage)
X
Written consent is obtained from 
participants aged 18-26 years. 
For participants aged 9-17 years, 
written consent is obtained from 
their parents(s) or legal 
guardian(s), and written assent 
will be obtained from the 
participant. Consent/assent must 
be obtained before any study 
procedures.
Informed 
Consent/
Assent 
(Extension 
Stage)
X
Written consent/assent is to be 
obtained at the Month 7 visit (if 
possible), or can be obtained at 
the Month 12 visit for 
participants eligible for the 
extension stage prior to any study 
procedure pertaining to the 
extension stage.
Assign 
Screening 
Number
X
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Study Stage
Base Stage
(Participants 9-26 years of age)
Extension Stage
(Participants 9-19 years of age)
Notes
Study Visit 
Number/
Title
Visit 1
Day 1
Vacci-
nation 
1
Visit 2
Month 
1
Visit 3
Month 
2
Vacci-
nation 
2
Visit 4
Month 3
Visit 5
Month 
6
Vacci-
nation
3
Visit 6
Month 
7
Visit 7
Month 
12
Visit 8
Month 
24
Visit 9
Month 
36
Visit 
10
Month 
48
Visit 
11
Month 
60
Scheduled 
Day
1
32
62
93
184
215
366
732
1097
1462
1827
Scheduling 
Window:
± 0 
days
31 to 38 
days 
after 
Vacci-
nation 
1
± 21 
days
31 to 52
days 
after 
Vacci-
nation 2
± 28 
days
31 to 
49 days 
after 
Vacci-
nation 
3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Review 
Inclusion/
Exclusion 
Criteria
(Base stage)
X
Review 
Inclusion/
Exclusion 
Criteria 
(Extension 
stage)
X
Eligibility for participation into 
extension stage will be reviewed 
on the same day of written 
consent/assent for Study 
Extension.
Participant 
Identification 
Card
X
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Study Stage
Base Stage
(Participants 9-26 years of age)
Extension Stage
(Participants 9-19 years of age)
Notes
Study Visit 
Number/
Title
Visit 1
Day 1
Vacci-
nation 
1
Visit 2
Month 
1
Visit 3
Month 
2
Vacci-
nation 
2
Visit 4
Month 3
Visit 5
Month 
6
Vacci-
nation
3
Visit 6
Month 
7
Visit 7
Month 
12
Visit 8
Month 
24
Visit 9
Month 
36
Visit 
10
Month 
48
Visit 
11
Month 
60
Scheduled 
Day
1
32
62
93
184
215
366
732
1097
1462
1827
Scheduling 
Window:
± 0 
days
31 to 38 
days 
after 
Vacci-
nation 
1
± 21 
days
31 to 52
days 
after 
Vacci-
nation 2
± 28 
days
31 to 
49 days 
after 
Vacci-
nation 
3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Medical 
History/ New 
Medical 
Condition
X
X
X
X
X
X
X
X
X
X
X
Base stage: At Day 1, medical 
history for 1 year prior to Day 1 
is collected. After Day 1, new 
conditions not already recorded 
as medical history or adverse 
events are collected.
For the participants who have had 
sexual intercourse, sexual history, 
lifetime gynecologic history,
pregnancy history, and method of 
contraception are also collected 
at Day 1. After Day 1, sexual 
activity/current method of 
contraception is collected at 
Month 2, Month 6, and Month 7.
Extension stage: Only new 
medical conditions not already 
recorded as medical history or 
adverse events are to be 
collected.
Review 
Medications 
and Non-Study 
Vaccination
X
X
X
X
X
X
X
X
X
X
X
Base stage: See Section 9.1.5.
Extension stage: Only non-study 
HPV vaccine mistakenly 
administered during the extension 
stage will be collected.
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Study Stage
Base Stage
(Participants 9-26 years of age)
Extension Stage
(Participants 9-19 years of age)
Notes
Study Visit 
Number/
Title
Visit 1
Day 1
Vacci-
nation 
1
Visit 2
Month 
1
Visit 3
Month 
2
Vacci-
nation 
2
Visit 4
Month 3
Visit 5
Month 
6
Vacci-
nation
3
Visit 6
Month 
7
Visit 7
Month 
12
Visit 8
Month 
24
Visit 9
Month 
36
Visit 
10
Month 
48
Visit 
11
Month 
60
Scheduled 
Day
1
32
62
93
184
215
366
732
1097
1462
1827
Scheduling 
Window:
± 0 
days
31 to 38 
days 
after 
Vacci-
nation 
1
± 21 
days
31 to 52
days 
after 
Vacci-
nation 2
± 28 
days
31 to 
49 days 
after 
Vacci-
nation 
3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Perform 
Physical 
Examination 
(Optional)
X
Optional, per investigator’s 
discretion; perform if needed to 
assess inclusion/exclusion criteria
Pregnancy 
Testing (Urine 
or Serum)
X
X
X
Pregnancy testing must be 
performed prior to each study 
vaccination in woman participant 
of childbearing potential 
according to the manufacturer’s 
instructions. The pregnancy test 
must be sensitive to 25 mIU/mL 
β-hCG. Results should be 
negative prior to vaccination.
Vital Signs 
Prior to 
Vaccination
X
X
X
Height and weight are to be 
measured at Day 1 only. Axillary 
temperature, pulse rate, 
respiratory rate, and blood 
pressure are to be taken prior to 
each vaccination. If the 
participant has a fever (defined as 
an axillary temperature of 
≥37.1°C) within the 24-hour 
period prior to vaccination, the 
vaccination should be 
rescheduled after the fever has 
resolved. 
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Study Stage
Base Stage
(Participants 9-26 years of age)
Extension Stage
(Participants 9-19 years of age)
Notes
Study Visit 
Number/
Title
Visit 1
Day 1
Vacci-
nation 
1
Visit 2
Month 
1
Visit 3
Month 
2
Vacci-
nation 
2
Visit 4
Month 3
Visit 5
Month 
6
Vacci-
nation
3
Visit 6
Month 
7
Visit 7
Month 
12
Visit 8
Month 
24
Visit 9
Month 
36
Visit 
10
Month 
48
Visit 
11
Month 
60
Scheduled 
Day
1
32
62
93
184
215
366
732
1097
1462
1827
Scheduling 
Window:
± 0 
days
31 to 38 
days 
after 
Vacci-
nation 
1
± 21 
days
31 to 52
days 
after 
Vacci-
nation 2
± 28 
days
31 to 
49 days 
after 
Vacci-
nation 
3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Assign 
Treatment/
Randomization 
Number
X
Study Vaccine 
Administration
X
X
X
The interval between the date of 
consent and the date of the Day 1 
visit should be no more than 14 
days apart. If the interval is 15 
days or longer, then the 
participant must be re-consented. 
All the study-related procedures 
for Day 1 visit except informed
consent/assent, baseline number 
assignment, participant 
identification card, should be 
performed on the same day of 
Day 1 vaccination. 
Efficacy procedures
Serum for 
Anti-HPV 
Antibody 
Testing
X
X
X
X
X
X
X
The serum collected at Day 1 for 
anti-HPV measurements must be 
collected before vaccination. 
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Study Stage
Base Stage
(Participants 9-26 years of age)
Extension Stage
(Participants 9-19 years of age)
Notes
Study Visit 
Number/
Title
Visit 1
Day 1
Vacci-
nation 
1
Visit 2
Month 
1
Visit 3
Month 
2
Vacci-
nation 
2
Visit 4
Month 3
Visit 5
Month 
6
Vacci-
nation
3
Visit 6
Month 
7
Visit 7
Month 
12
Visit 8
Month 
24
Visit 9
Month 
36
Visit 
10
Month 
48
Visit 
11
Month 
60
Scheduled 
Day
1
32
62
93
184
215
366
732
1097
1462
1827
Scheduling 
Window:
± 0 
days
31 to 38 
days 
after 
Vacci-
nation 
1
± 21 
days
31 to 52
days 
after 
Vacci-
nation 2
± 28 
days
31 to 
49 days 
after 
Vacci-
nation 
3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Safety procedures
30-minute 
Post-
Vaccination 
Observation 
Period
X
X
X
Provide 
Vaccination 
Report Card 
(VRC) to 
Participant 
X
X
X
Review and 
Collect VRC 
data
X
X
X
Phone call contacts are to be 
conducted every week for each 
participant by study site 
personnel before the VRCs are 
returned. The main purpose of 
phone call visit is to remind the 
participant to record the VRC and 
answer any questions related to 
VRC from participants.
Clinical 
Follow-up for 
Safety
X
X
X
X
X
X
X
X
X
X
X
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3
Introduction
3.1
Study Rationale 
Human papillomavirus (HPV) infection is a sexually transmitted disease. The incidence of 
HPV infection peaks soon after the onset of sexual activity. Therefore, an effective program 
to prevent HPV infection and disease through prophylactic immunization would ideally 
target individuals immediately prior to sexual contact. Preadolescents and adolescents 
represent an attractive target age group to implement HPV vaccination programs. However, 
direct efficacy evaluation of prophylactic HPV vaccines in preadolescents and adolescents 
aged 9-15 years is not feasible due to social, cultural, and legal constraints surrounding the 
notion of sexual activity among younger adolescents. In the MSD’s HPV vaccine program, 
efficacy claims for the recombinant human papillomavirus quadrivalent (Types 6, 11, 16, 18) 
vaccine (V501) in young women aged 16-26 years were extended to preadolescents and 
adolescents based on the demonstration of similar safety and immunogenicity in the two 
populations. 
For registration of V501 in China, two Phase 3 clinical trials were conducted, an 
immunogenicity study among Chinese girls and women aged 9-45 years and boys aged 9-15 
years (PN030) and an efficacy study among Chinese women aged 20-45 years (PN041). 
These studies have demonstrated that V501 is highly effective and safe in Chinese women 
aged 20-45 years and is highly immunogenic and generally well tolerated in Chinese girls 
and women aged 9-45 years and boys aged 9-15 years. Although an ad-hoc analysis on the 
immunogenicity data of PN030 was performed which demonstrated the non-inferior immune 
responses in girls aged 9-19 years compared with 20-26 years old and 27-45 years old, the 
PN030 study was not originally designed to prove non-inferiority of immune responses in 
girls aged 9-19 years compared with women aged 20-45 years with limited sample size. 
Therefore, V501 was approved in China only for women aged 20-45 years. And Chinese 
regulatory authority requires a local clinical study to demonstrate the immunogenicity of 
V501 in girls aged 9-19 years is non-inferior to that of women aged 20-26 years. This is a 
mandatory post-marketing requirement from the local regulatory authority.
Thus, an immunobridging study is required to demonstrate that at 1 month post-vaccination, 
HPV 6, 11, 16 and 18 antibody responses induced by V501 in girls aged 9-19 years are non-
inferior to those in women aged 20-26 years.
The main purpose of the Study Extension is to evaluate persistence of immune responses to 
V501 in Chinese girls aged 9 to 19 years. The global long-term follow-up study has 
demonstrated that administration of V501 to the younger age group induced durable immune 
responses and protection through 10 years post-vaccination. Durable immune responses to 
V501 up to 3.5 years post-vaccination was also demonstrated among Chinese women aged 9-
45 years in an extension study of PN030, but the sample size was very limited for the 
younger age group, therefore it is important to generate more comprehensive long-term 
immunogenicity data of V501 in Chinese girls.
3.2
Background
Refer to the Investigator’s Brochure (IB)/ approved labeling for detailed background 
information on V501.
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3.2.1
Pharmaceutical and Therapeutic Background
V501 consists of highly purified virus-like particles (VLPs) of the L1 capsid polypeptide for 
the HPV 6, 11, 16, and 18 virus types.
Over 50% of sexually active adults become infected with HPV during their lifetime [Kotloff, 
K. L., et al 1998] [Koutsky, L. 1997]. HPV infection causes benign and malignant dysplastic 
disease, localized primarily in the anogenital area and aerodigestive tract, in both men and 
women [Paavonen, J. 2007] [Madkan, V. K., et al 2007] [Stamataki, S., et al 2007]. 
Persistent HPV infection significantly increases the risk of cervical and other anogenital 
cancers, and oropharyngeal cancers [Forman, D., et al 2012]. HPV disease is frequently 
multicentric (i.e., affecting more than one anatomic site). For instance, strong positive 
associations have been reported between vulvar and vaginal cancers and histories of 
anogenital warts and cervical neoplasia [Madsen, B. S., et al 2008]. Also, individuals with 
genital warts have an elevated long-term risk of anogenital cancers and head and neck 
cancers [Blomberg, M., et al 2012]. Similarly, high prevalence of anal and oropharyngeal 
HPV infection has been reported in women with abnormal cervical cytology [Crawford, R., 
et al 2011]. Overall, HPV is responsible for approximately 5% of the global cancer disease 
burden [Parkin, D. M. and Bray, F. 2006].
Over 90 HPV types have been identified [Alani, R. M. and Münger, K. 1998]. HPV 16 and 
18 cause ~70% of high-grade cervical dysplasia (cervical intraepithelial neoplasia 2/3) cases 
and cervical and anal cancers, whereas HPV 6 and 11 cause >90% of genital warts [Koutsky, 
L. 1997]. HPV 6, 11, 16, or 18 are present in ~50% of low-grade cervical dysplasia (CIN 1) 
cases [Koutsky, L. 1997]. Therefore, a prophylactic vaccine that reduces infection with these 
4 HPV types will greatly reduce the burden of HPV disease in men and women.
3.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
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.
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4
Objectives/Hypotheses and Endpoints
In Chinese girls aged 9-19 years and young women aged 20-26 years (Base Stage):
Objective/Hypothesis
Endpoint
Primary

Objective: To demonstrate that 
administration of a 3-dose regimen of 
V501 induces non-inferior geometric 
mean titers (GMTs) for serum anti-HPV 
6, anti-HPV 11, anti-HPV 16, anti-HPV 
18 in girls aged 9-19 years compared to 
young women aged 20-26 years.

Hypothesis (H1): 3-dose regimen of 
V501 induces non-inferior immune 
responses in girls aged 9-19 years 
who are seronegative at Day 1 to the 
relevant HPV type compared to 
young women aged 20-26 years who 
are seronegative at Day 1 to the 
relevant HPV type, as measured by 
anti-HPV 6, 11, 16, and 18 GMTs at 
1 month post dose 3. (Each vaccine 
component will be analyzed 
separately. The statistical criterion for 
non-inferiority requires that the lower 
bound of two-sided 95% confidence 
interval of GMT ratio (girls vs. young 
women) be greater than 0.67 for each 
HPV type.)

Competitive Luminex immunoassay 
(cLIA) GMTs to each of HPV 6, 11, 
16, and 18 at 1 month post dose 3
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Objective/Hypothesis
Endpoint
Secondary

Key objective: To demonstrate that a 3-
dose regimen of V501 induces non-
inferior immune responses with respect 
to seroconversion percentages to HPV 
types 6, 11, 16, and 18 in girls aged 9-19 
years compared to young women 20-26 
years. 

Hypothesis (H2): 3-dose regimen of 
V501 induces non-inferior immune 
responses in girls aged 9-19 years 
who are seronegative at Day 1 to the 
relevant HPV type compared to 
young women aged 20-26 years who 
are seronegative at Day 1 to the 
relevant HPV type, as measured by 
the percentage of participants who 
seroconvert to each of HPV types 6, 
11, 16, and 18 by 1 month post dose 
3. (Each vaccine component will be 
analyzed separately. The statistical 
criterion for non-inferiority requires 
that the lower bound of two-sided 
95% confidence interval for the 
difference (girls minus young 
women) in seroconversion 
percentages be greater than -5
percentage points for each HPV 
type.)

cLIA seroconversion percentages to 
each of HPV 6, 11, 16, and 18 at 1 
month post dose 3

Objective: To summarize immune 
responses (including GMTs and 
seroconversion percentages) to HPV 
types 6, 11, 16, and 18 assessed using 
HPV total IgG Luminex immunoassay 
(IgG LIA).

IgG LIA GMTs and seroconversion 
percentages to each of HPV 6, 11, 16, 
and 18 at 1 month post dose 3
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Objective/Hypothesis
Endpoint

Objective: To evaluate the safety and 
tolerability of V501 in girls aged 9-19 
years and young women aged 20-26 
years.

Proportion of participants experiencing 
solicited injection-site adverse events 
(AEs)

Proportion of participants experiencing 
solicited systemic AEs

Proportion of participants experiencing 
serious adverse events (SAEs)
Exploratory

Objective: To summarize immune 
responses (including GMTs and 
seroconversion percentages) to HPV 
types 6, 11, 16, and 18 assessed using 
pseudovirion-based neutralization assay 
(PBNA).

PBNA GMTs and seroconversion 
percentages to each of HPV 6, 11, 16, 
and 18 at 1 month post dose 3
In Chinese girls 9 to 19 years of age (Extension Stage):
Objective/Hypothesis
Endpoint 
Primary 

Objective: To evaluate persistence of 
immune responses induced by V501 in 
girls 9 to 19 years of age.

cLIA GMTs and seropositivity 
percentages to each of HPV 6, 11, 16, 
and 18 at Month 12, Month 24, Month 
36, Month 48, and Month 60

IgG LIA GMTs and seropositivity 
percentages to each of HPV 6, 11, 16, 
and 18 at Month 12, Month 24, Month 
36, Month 48, and Month 60
Secondary 

Objective: To evaluate the safety of V501 
in girls 9 to 19 years of age.

Proportion of participants experiencing 
SAEs
Exploratory 

Objective: To summarize persistence of
immune responses to HPV types 6, 11, 
16, and 18 assessed using PBNA in girls 
9 to 19 years of age.

PBNA GMTs and seropositivity 
percentages to each of HPV 6, 11, 16, 
and 18 at Month 12, Month 24, Month 
36, Month 48, and Month 60
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5
Study Design 
5.1
Overall Design 
This is a single-arm, multi-site, open-label, immunogenicity, safety and tolerability study of 
V501 in Chinese girls aged 9-19 years and young women aged 20-26 years at the time of 
Day 1 vaccination. The study will evaluate whether V501 administered in girls aged 9-19 
years has a non-inferior immunogenicity compared with V501 in young women aged 20-26 
years as a comparative control for all the 4 vaccine HPV types. 
A total of approximately 766 participants who meet eligibility will be enrolled. All enrolled 
participants will receive one dose of V501 under open-label conditions at the Day 1, Month 
2, and Month 6 visits.
Collection of medical history will be conducted at Day 1 for all participants. Physical 
examination at Day 1 is optional and will be conducted, per investigator’s discretion, if 
needed to assess inclusion/exclusion criteria. Vital signs will be taken prior to each study 
vaccination.
Serum samples will be obtained from each participant at Day 1 prior to vaccination and 
Month 7 (1 month post dose 3) for measurement of anti-HPV antibodies for HPV 6, 11, 16, 
and 18 in the base stage. For participants who will enter the extension stage, serum samples 
will be obtained at the time points of Month 12, Month 24, Month 36, Month 48, and Month 
60 for measurement of anti-HPV antibodies.
A Vaccination Report Card (VRC) will be provided to each participant for recording all 
adverse events (AEs) within 30 days following each study vaccination. SAEs, cancers, 
overdoses, pregnancy events, lactation events, and infant SAEs will be collected during the 
entire period of study.
A pregnancy test will be performed prior to each study vaccination on all female participants
of childbearing potential. Any participant with a positive pregnancy test at Day 1 will not be 
vaccinated and will not be allowed to participate in the study. Any Participant with a positive 
pregnancy test after Day 1 will not be vaccinated until pregnancy outcome. Pregnant 
participants who receive less than 3 study vaccinations during the study will be offered the 
possibility to complete the vaccination course. Pregnancies and any associated AEs will be 
followed to outcome.
The estimated duration of base stage will be approximately 9 months from the time the first 
participant signs the informed consent/assent until the last participant’s last study-related 
phone call or visit. The final study visit of base stage will be Month 7. 
Participants in the 9-19 years old group who have received 3 doses of V501 in the base stage 
will be eligible to participant in the extension stage. Participants who continue in the 
extension stage will be followed up to Month 60, which is the final visit for Study Extension.
For the purposes of analysis and results reporting, the primary outcome of each stage will be 
defined as the Sponsor’s receipt of the last serology assay result in each stage.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Study SoA - Section 2. Details of each 
procedure are provided in Section 9 – Study Assessments and Procedures.
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5.1.1
Study Diagram
The study design is depicted in Figure 1.
Figure 1
Study Diagram
5.2
Number of Participants
Approximately 766 participants will be enrolled as described in Section 10.9. Enrollment will 
be stratified in a 1:1 ratio between two age strata: 9-19 years and 20-26 years (see Section 
7.3.1). Enrollment will be managed by investigator by limiting the total number of 
participants per each age group at each study site.
Participants 9 to 19 years of age who have received 3 doses of V501 in the base stage will be 
eligible to participate into the extension stage.
5.3
Beginning and End of Study Definition
The overall study begins when the first participant signs the informed consent/assent form.  
The overall study ends when the last participant completes the last study-related phone-call 
or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to be 
contacted by the investigator).  
5.3.1
Clinical Criteria for Early Study Termination
There are no pre-specified criteria for terminating the study early.
5.4
Scientific Rationale for Study Design 
The purpose of this trial is to fulfill the post-approval requirement in China to conduct an 
immunobridging study in girls aged 9-19 years and young women aged 20-26 years. Study 
Extension is to generate more comprehensive long-term immunogenicity data of V501 in 
Chinese girls aged 9-19 years.
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5.4.1
Rationale for Endpoints
5.4.1.1
Immunogenicity Endpoints
Anti-HPV 6, 11, 16, and 18 measured by competitive Luminex immunoassay (cLIA) will be 
analyzed as the primary indicator of immune responses post dose 3 to each vaccine 
component. cLIA is a standard assay to evaluate the immune responses to vaccination in 
HPV clinical programs.
Serum will be collected from all participants at Day 1 prior to study vaccination and Month 
7. Serum samples collected at Day 1 will be used to determine participant who had an HPV 
infection prior to enrollment. 
HPV total IgG Luminex immunoassay (IgG LIA) will be used as a secondary measurement, 
complementary to cLIA. IgG LIA GMTs and seroconversion percentages to the 4 vaccine 
HPV types will be summarized.
Pseudovirion-based neutralization assay (PBNA) developed by National Institutes for Food 
and Drug Control (NIFDC), will be used as an exploratory method to characterize the 
immune responses to the 4 vaccine HPV types. This method was required by the local 
authority which is the method recommended by WHO for anti-HPV measurement.
In the extension stage, serum samples will be obtained at Month 12, Month 24, Month 36, 
Month 48, and Month 60 for measurement of antibodies for HPV 6, 11, 16, and 18. The 
GMTs and seropositivity percentages measured by cLIA and IgG LIA methods will be used 
as primary immunogenicity endpoints, which is consistent with prior HPV studies. PBNA 
GMTs and seropositivity percentages to HPV 6, 11, 16, 18 will be the exploratory endpoints.
5.4.1.2
Safety Endpoints
The safety endpoints in this study were selected based on the product’s safety profile 
demonstrated in prior clinical studies. A list of the safety endpoints to evaluate safety and 
tolerability in the study population is provided in Section 9.5.1 and 10.4.2.
5.5
Justification for Dose 
The formulation and regimen of V501 are identical with prior global and local studies.
6
Study Population
Healthy girls between the ages of 9 and 19 years (inclusive) and healthy young women 
between the ages of 20 and 26 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.
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6.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
6.1.1
Inclusion Criteria for Base Stage
Type of Participant and Disease Characteristics
1. Only healthy participants are to be enrolled. A participant is judged to be in good 
physical health on the basis of medical history and physical examination.
Demographics
2. Participant is female between the ages of 9 years and 0 days and 26 years and 364 
days on the day of Day 1 vaccination.
3. A female participant is eligible to participate if she is not pregnant (see Appendix 2),
and at least one of the following conditions applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 2
OR 
b.) A WOCBP has not had sex with males or has had sex with males and used 
effective contraception as defined in Appendix 2 since the first day of participant’s 
last menstrual period through Day 1. And the participant understands and agrees that 
during the Day 1 through Month 7 period, she should not have sexual intercourse 
with males without effective contraception, and that the use of the rhythm method, 
withdrawal, and emergency contraception are not acceptable methods per the 
protocol.
Informed Consent/Assent
4. (Participants aged 9-17 years only) Participant’s parent or legal guardian provides 
written informed consent for the study. The participant provides written informed 
assent for the study. 
5. (Participants aged 18-26 years only) Participant provides written informed consent for 
the study. 
General
6. Participant agrees to provide study personnel with a primary telephone number as 
well as an alternate telephone number for follow-up purposes.
6.1.2
Inclusion Criteria for Extension Stage
1. Participant was enrolled in the 9-19 years old group in the base stage. 
2. Participant has received 3 doses of V501 during the base stage.
3. Participant and participant’s legally acceptable representative (if applicable) provides
written informed consent/assent for Study Extension.
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6.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
The following exclusion criteria are only applicable for the base stage. 
Participants enrolled in the 20-26 years old group will not participate in the extension stage, 
and participants enrolled in the 9-19 years old group who reported overdose or received non-
study HPV vaccine during the base stage will be excluded from the extension stage.
Medical Conditions†
1. Participant has a fever (defined as axillary temperature ≥37.1°C) within 24 hours 
prior to the Day 1 vaccination (if the participant meets this exclusion criterion, the 
Day 1 visit may be rescheduled for a time when this criterion is not met).
2. Participant 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. Participant is allergic to any vaccine component, including aluminum, yeast, or 
BENZONASETM (nuclease, Nycomed [used to remove residual nucleic acids from 
this and other vaccines]).
4. Participant with known thrombocytopenia or any coagulation disorder that would 
contraindicate intramuscular injections.
5. Participant is currently immunocompromised or has been diagnosed as having 
congenital or acquired immunodeficiency, human immunodeficiency virus (HIV)
infection, lymphoma, leukemia, systemic lupus erythematosus (SLE), rheumatoid 
arthritis, juvenile reheumatoid arthritis (JRA), inflammatory bowel disease, or other 
autoimmune condition.
6. Participant has a history of splenectomy.
7. Participant has any condition which in the opinion of the investigator might interfere 
with the evaluation of the study objectives.
8. Participant has a history of recent or ongoing alcohol or other drug abuse. Alcohol 
abusers are defined as those who drink despite recurrent social, interpersonal, and 
legal problems as a result of alcohol use.
9. Participant has a history of a positive test for HPV.
10. Participant has any history of abnormal Pap test showing squamous intraepithelial 
lesion (SIL) or ASC-US, ASC-H, or biopsy showing cervical intraepithelial neoplasia 
(CIN), adenocarcinoma in situ or cervical cancer.
11. Participant has a history of external genital wart, vulvar intraepithelial neoplasia 
(VIN), vaginal intraepithelial neoplasia (VaIN), vulvar cancer or vaginal cancer.
12. Participant has undergone hysterectomy (either vaginal or total abdominal 
hysterectomy).
† The history of medical conditions will be based on the self-report or medical chart provided 
by participant.
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Prior/Concomitant Therapy
13. Participant is receiving or has received in the year prior to Day 1 vaccination the 
following immunosuppressive therapies: radiation therapy, cyclophosphamide, 
azathioprine, methotrexate, any chemotherapy, cyclosporin, leflunomide (AravaTM),
TNF-α antagonists, monoclonal antibody therapies (including rituximab [Rituxan
TM]), intravenous gamma globulin (IVIG), antilymphocyte sera, or other therapy 
known to interfere with the immune response. With regard to systemic 
corticosteroids, a participant will be excluded if she 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.
14. Participant who has received immune globulin product (including RhoGAMTM
[Ortho-clinical Diagnostics]) or blood-derived product within 6 months prior to Day 1 
vaccination, or plan to receive any such product during Day 1 through Month 7 of the 
study.
15. Participant has received a marketed HPV vaccine, or has participated in an HPV 
vaccine clinical trial and has received either active agent or placebo.
16. Participant who has received inactivated or recombinant vaccines within 14 days 
prior to Day 1 vaccination or receipt of live vaccines within 21 days prior to Day 1 
vaccination.
Prior/Concurrent Clinical Study Experience
17. Participant is concurrently enrolled in clinical studies of investigational agents.
Diagnostic Assessments
Not Applicable.
Other Exclusions
18. Participant with >4 lifetime sexual partners.
19. Participant 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 of time when study visits would need to be scheduled.
20. 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.
6.3
Lifestyle Restrictions
No lifestyle restrictions are required.
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6.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study but are not subsequently entered in the study.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the data entry guidelines.
6.5
Participant Replacement Strategy
A participant who discontinues from vaccination or withdraws from the study will not be 
replaced.
7
Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
7.1
Treatments Administered
The study treatment to be used in this study is outlined below in Table 1 Study Treatment.
Table 1
Study Treatment
Study Treatment Name:
Recombinant Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) 
Vaccine (Gardasil® [V501])
Dosage Formulation:
A single-dose prefilled syringe
Unit Dose Strength(s):
Each 0.5-mL dose contains approximately 20 mcg of HPV 6 L1 protein, 
40 mcg HPV 11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg 
of HPV 18 L1 protein
Dosage Level(s):
0.5-mL per dose administered at Day 1, Month 2, and Month 6
Route of Administration:
Intramuscular injection
Sourcing:
Provided locally by the Sponsor
All supplies indicated in Table 1 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The study site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to Section 9.1.8 for details regarding administration of the study treatment.
7.2
Dose Modification 
Not Applicable.
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7.3
Method of Treatment Assignment 
Participants participating in this study will be allocated by non-random assignment.
7.3.1
Stratification
A total of approximately 766 participants will be enrolled in a 1:1 ratio between two age 
strata: 9-19 years and 20-26 years. All enrolled participants will receive a 3-dose regimen of 
V501.
7.4
Blinding 
This study is an open-label study; therefore, the Sponsor, investigator and participant will 
know the vaccine administered.
7.5
Preparation/Handling/Storage/Accountability
7.5.1
Dose Preparation
Processes for preparation and administration of the study vaccine are described in Section 
9.1.8. There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. 
7.5.2
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments 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 treatment 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 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 
treatments in accordance with the protocol and any applicable laws and regulations.
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7.6
Treatment Compliance
Interruptions from the protocol specified vaccination schedule (i.e. administration of 3 doses 
at scheduled time points) for reasons not defined per protocol require consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
7.7
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. If there is a 
clinical indication for any medication or vaccination specifically prohibited, discontinuation 
from study therapy or vaccination 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 primary 
physician. However, the decision to continue the participant on study treatment requires the 
mutual agreement of the investigator, the Sponsor and the participant.
See the exclusion criteria for specific restriction for prior and concomitant medications at 
Day 1 (Section 6.2) and prerequisites for other vaccination visits (Section 9.10.1).
If possible, the participant should not receive systemic corticosteroids, immunosuppressive
therapies, immune globulin or blood-derived products during Day 1 through Month 7 of the 
study, non-study inactivated or recombinant vaccines within 14 days prior to or 14 days after 
any dose of study vaccination, non-study live vaccines within 21 days prior to or 14 days
after any dose of study vaccination.
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 9.1.5.
7.7.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study.
7.8
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
7.9
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor 
and/or designee are not blinded. Study treatment (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
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8
Discontinuation/Withdrawal Criteria 
8.1
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment 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 treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of vaccination regimen will still continue to 
participate in the study as specified in Section 2 and Section 9.10.2.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the study plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9.
A participant must be discontinued from study treatment 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 treatment.
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at an unnecessary risk from 
continued administration of study treatment.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, see Section 2 and Section 9.10.2 for those procedures to be completed at each 
specified visit
Participants may be allowed to begin study treatment again if deemed medically appropriate
with consultation from the Clinical Director.
8.2
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 treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study are outlined in Section 9.1.9. 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 8.3.
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8.3
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, phone 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 pre-specified statistical data handling and analysis guidelines.
9
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 assuring that procedures are conducted by 
appropriately qualified or trained staff.  Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
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, etc.), 
and thus local regulations may require that additional informed consent, and assent if 
applicable, be obtained from the participant.  In these cases, such evaluations/testing 
will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant for the immunogenicity 
objectives over the duration of the base stage, including any extra assessments that may be 
required, will not exceed 20 mL.
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The maximum amount of blood collected from each participant who will continue in the 
extension stage for the immunogenicity objectives over the duration of the extension stage, 
including any extra assessments that may be required, will not exceed 50 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
9.1
Administrative and General Procedures
9.1.1
Informed Consent/Assent
The investigator or qualified designee must obtain documented consent, and assent if 
applicable, from each potential participant or each participant’s legally acceptable 
representative prior to participating in a clinical study. If there are changes to the 
participant’s status during the study (eg, health or age of majority requirements), the 
investigator or qualified designee must ensure the appropriate consent/assent is in place. 
9.1.1.1
General Informed Consent/Assent
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the study.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form and any written information provided to the participant must receive the 
IRB/IEC’s approval/favorable opinion in advance of use.  The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available 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/assent form or addendum to the original consent/assent form that captures the 
participant’s dated signature or by the participant’s legally acceptable representative’s dated 
signature.
Specifics about a study and the study population will be added to the consent/assent form 
template at the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
9.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
9.1.3
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 
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(including direct telephone numbers) to be utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a Participant Identification 
Card immediately after the participant provides written informed consent/assent. At the time 
of treatment 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 health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
9.1.4
Medical History
At the Day 1 visit, the participant’s medical history for 1 year prior to Day 1 will be 
collected. For the participants who have had sexual intercourse, sexual history, lifetime 
gynecologic history, pregnancy history, and method of contraception will also be collected at 
the Day 1 visit. After the Day 1 visit, sexual activity and current method of contraception will 
be collected at the Month 2, Month 6, and Month 7 visits.
After the Day 1 visit, any new medical condition that has not been previously documented 
(either as adverse events or as medical history conditions) will be collected.
9.1.5
Prior and Concomitant Medications Review
9.1.5.1
Prior Medications
Prior and concomitant use of medicines and non-study vaccines should be documented in the 
data collection system in the following manner:

“Special medications” (corticosteroids, immunosuppressive therapies, immune 
globulins, and blood-derived products) from the year 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” for 14 days prior to each study 
vaccination through 14 days after each study vaccination.

“Non-study live vaccines” for 21 days prior to each study vaccination through 14 
days after each study vaccination.
9.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study as outlined above.
For the specific case where a participant mistakenly receives a non-study HPV vaccine at any 
time during the study, the non-study HPV vaccine should be documented in the data 
collection system.
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9.1.6
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 treatment allocation.  Each 
participant will be assigned only one screening number.  Screening numbers must not be re-
used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
9.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Although 
treatment is allocated by non-random assignment, the numbers assigned are called 
“treatment/randomization numbers”. Treatment allocation will be managed by investigator.
Once a treatment/randomization number is assigned to a participant, it can never be re-
assigned to another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
9.1.8
Treatment Administration
Study vaccine will be administered at the study sites by the investigator and/or study staff.
The first dose of study vaccine will be administered at Day 1, which should be the day of 
allocation. The second and third (final) doses of study vaccine will be administered 
subsequently, at time points 2 and 6 months, respectively, after the first dose. 
The interval between the date of consent and the date of the Day 1 visit should be no more 
than 14 days apart. If the interval is 15 days or longer, then the participant must be re-
consented. 
All the study-related procedures for Day 1 visit except informed consent/assent, baseline 
number assignment, participant identification card, should be performed on the same day of 
Day 1 vaccination.
Participants should not be enrolled or vaccinated if protocol requirements are not met. At 
Day 1, study vaccine should be administered after the blood draw for anti-HPV testing (see 
Section 9.2.1). Pregnant participants should not be vaccinated (see Section 9.5.2 for 
management of study visits and study vaccinations for pregnant participants). 
Section 9.10.1 provides additional information on other prerequisites for vaccination visits.
9.1.8.1
Preparation of Study Vaccine for Administration
Study vaccine is provided by the Sponsor in single-dose syringes containing sufficient 
volume to administer a 0.5-mL dose. 
Study vaccine must be stored between 2°C to 8°C. Freezing destroys the study vaccine. If 
study vaccine freezes or is subjected to freezing temperature, or goes outside of the 
temperature ranges (2°C to 8°C), it should not be used. Refrigerator temperature logs should 
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be maintained at each vaccine storage site and storage temperatures should be monitored 
daily.
The study vaccine may be removed from the refrigerator and allowed to sit at room 
temperature for no longer than 15 minutes prior to administration. No dilution is required 
before administration. The vaccine syringe should be thoroughly mixed before administration 
by gently rolling the syringe between the palms of both hands for 30 seconds. After mixing, 
the study vaccine will appear as a whitish, semi-translucent suspension. If the appearance is 
otherwise, do not administer and contact the Sponsor immediately.
9.1.8.2
Study Vaccine Administration
At each vaccination visit, participants will receive study vaccine as a 0.5-mL intramuscular 
injection. The deltoid muscle of the nondominant arm is the preferred site of vaccination. 
Injections should be administered at a 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 with the following needle length and gauge specifications:
1-inch needle, 22 to 25 gauge, for participants weighing < 90 kg; 1½-inch needle, 22 to 25
gauge, for participants weighing ≥90 kg. If the injection is given in the thigh, a 1½ -inch 
needle, 22 to 25 gauge should be used.
Study vaccination should not be administered in the buttocks area. Injections should not be 
given within 2 cm of a tattoo, scar, or skin deformation.
All participants will be observed for at least 30 minutes after each vaccination. This 
observation period will be documented for any immediate reaction with particular attention 
to any evidence of allergic phenomena.
9.1.8.3
Timing of Dose Administration
Study vaccine will be administered at the following time points: Day 1, Month 2 (Day 62), 
and Month 6 (Day 184) (See Section 2 - SoA).
Acceptable day ranges for vaccination visits are as follows: 

Dose 1: Day 1 (±0 days)

Dose 2: Day 62 (± 21 days)

Dose 3: Day 184 (± 28 days)
The Day 1 visit is defined as the day that the first study vaccination is given (i.e., the date 
when Dose 1 of V501 is injected). 
9.1.9
Discontinuation and Withdrawal
Participants who discontinue study treatment prior to completion of the vaccination regimen
should be encouraged to continue to be followed for all remaining study visits.
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When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal).  Any 
adverse events which are present at the time of withdrawal should be followed in accordance 
with the safety requirements outlined in Section 9.3.

Month 7 is the final visit for Base Stage (exception: serum collection at Month 7 
should not be done if the participant has not received all 3 scheduled doses of study 
vaccine and only safety information will be collected).

Month 60 is the final visit for Extension Stage. 
The final visit assessment for participant withdraws from the study can be done via a phone 
call.
9.1.10
Participant Blinding/Unblinding
This is an open label study; there is no blinding for this study.
9.1.11
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical study that provides 
important information about inclusion/exclusion criteria and/or safety or efficacy parameters 
shall be suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the study site.
Critical Equipment for this study includes:

Refrigerator equipped with an appropriate temperature monitoring device to ensure 
the temperature is maintained at 2°C to 8°C for storage of study vaccines

Non frost-free freezer with an appropriate temperature monitoring device to ensure 
serum samples are stored at -20°C or colder until shipped to the Sponsor-designated 
Central Laboratory

Centrifuge for processing of blood samples
9.1.12
Other Assessments
9.1.12.1 Physical Examinations and Vital Signs Prior to Study Vaccination
A physical examination at Day 1 is optional. It will be conducted, per investigator’s 
discretion, if needed to determine whether the participant meets enrollment criteria for the 
study. Physical examination details will be documented in the participant’s chart and any 
medical condition will be documented in the data collection system. 
Height, weight, axillary temperature, pulse rate, respiratory rate, and blood pressure will be 
taken before study vaccination at Day 1.
Axillary temperature, pulse rate, respiratory rate, and blood pressure will also be taken before 
study vaccination at Month 2 and Month 6.
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If the participant has a fever (defined as an axillary temperature of ≥37.1°C) within the 24-
hour period prior to vaccination, the vaccination should be rescheduled after the fever has 
resolved.
Height, weight and axillary temperature will be documented in the data collection system and 
the other vital signs will be documented in the participant’s chart.
9.2
Efficacy Assessments 
9.2.1
Serum for Anti-HPV Antibody Testing
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Laboratory Manual. For collection of the serum samples, the study sites must follow 
instructions provided by the Sponsor-designated Central Laboratory and must use the
materials provided by the Sponsor-designated Central Laboratory. Samples should be 
shipped, labeled, and handled as instructed by the Sponsor/Central Laboratory. Specimen 
collection supplies provided by the Sponsor/Central Laboratory must be used by the site 
without substitution.
A 10-mL blood sample will be collected from each participant at each scheduled time point 
(Section 2- SoA) and serum will be separated for anti-HPV measurements. 
9.2.2
Immunogenicity Measurements
The 9-valent HPV competitive Luminex immunoassay (cLIA) will be used for the primary 
and key secondary objectives of the study. 
The 9-valent cLIA assay is used to measure antibodies to HPV VLPs, serotypes 6, 11, 16, 18, 
31, 33, 45, 52, and 58 before and after vaccination with the 9-valent HPV vaccine (V503) in 
V503 clinical program. The quadrivalent HPV (qHPV) cLIA was developed and used in 
prior clinical trials of V501. However, it has been replaced with 9-valent HPV cLIA, which 
is now used in V501 program. Therefore 9-valent HPV cLIA will be used in this study and 
only results of the 4 vaccine types (HPV 6, 11, 16, and 18) will be reported for the 
immunogenicity objective of the study.
Yeast-derived VLPs are coupled to a set of 9 distinct fluorescent Luminex microspheres. 
Antibody titers are determined in a multiplexed, competitive format in which known, type-
specific phycoerythrin (PE)-labeled, neutralizing monoclonal antibodies (mAbs) compete 
with the participant’s serum antibodies for binding to type-specific, conformationally 
sensitive, neutralizing epitopes on the VLPs. The fluorescent signals from the bound HPV-
specific detection mAbs are inversely proportional to the participant’s neutralizing antibody 
titers. Results for the assay are reported as concentration of antibody in arbitrary milli-Merck 
Units per milliliter (mMU/mL).
A fixed type-specific cutoff for serostatus will be used in the assay. The cutoffs were derived 
by repeatedly testing a panel of positive and negative samples against the standard curve. 
Any sample with a value less than the cutoff will be considered seronegative. Sample with a 
value equal to or greater than the cutoff will be considered seropositive. Samples are read 
from a standard curve, corrected for dilution as needed, and reported in mMU/mL. 
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In this study, 9-valent HPV total IgG Luminex immunoassay (IgG LIA) will be used as a 
secondary measurement, complementary to cLIA. 
9-valent IgG LIA was designed to measure a broader subset of the total antibody 
concentrations to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, determined in a 
multiplexed, direct binding format by measuring the amount of VLP-specific IgG bound to 
VLP-microspheres on the Luminex platform. Yeast-derived VLPs are coupled to a set of 9 
distinct fluorescent Luminex microspheres. Following incubation with human serum, 
fluorescent signal from an anti-human IgG detection antibody that binds directly to serum 
IgG and equally to each IgG subclass (1-4) is directly proportional to the individual’s HPV 
type-specific anti-VLP IgG antibody levels. Results for the assay are reported as 
concentration of antibody in mMU/mL. However, only results of anti-HPV 6, 11, 16, and 18 
will be reported for the immunogenicity objective of this study.
PBNA developed by NIFDC will be used in the exploratory analysis to characterize the 
immune responses to the 4 vaccine HPV types following study vaccination.
All the immunoassays listed above will also be used to evaluate the persistence of immune 
responses in the extension stage.
9.3
Adverse Events (AE), Serious Adverse Events (SAE) and Other Reportable 
Safety Events 
The definitions of an adverse event (AE) or serious adverse event (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 (Section 12.3).
AE, 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, who is a qualified physician, and any designees are responsible for 
detecting, assessing, 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 AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
9.3.1
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 consent form is signed 
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 treatment or a procedure. 
From the time of allocation/randomization through 30 days following the first vaccination(s) 
and from the time of any subsequent vaccination(s) through 30 days thereafter, all AEs, 
SAEs and other reportable safety events must be reported by the investigator. 
SAEs (regardless of causality) at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor. Other reportable safety events 
(cancer, pregnancy, breastfeeding exposure, and overdose) at any time outside of the time 
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period specified in the previous paragraph should also be reported to the Sponsor. In 
addition, SAEs of infants born to participants who received the study vaccine or who were 
breastfed during the study are reportable for the entire study period.
Investigators are not obligated to actively seek AE or SAE 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 treatment 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 timeframes as indicated in Table 2.
Table 2
Reporting Time Periods and Timeframes 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
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious 
Adverse Event 
(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
Serious 
Adverse Event 
(SAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report all
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Report all
Within 24 
hours of 
learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Report all
Within 5 
calendar 
days of 
learning of 
event
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Report all
Within 5 
calendar 
days of 
learning of 
event
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9.3.2
Method of Detecting AE, SAE and Other Reportable Safety Events
A VRC will be used by the participant to document any AEs within 30 days following each 
study vaccination.
9.3.3
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 AE, SAE and other reportable safety events 
including pregnancy (if the participant received at least 1 vaccine dose) and exposure during 
breastfeeding, ECI, 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 
8.3). In addition, the investigator will make every attempt to follow all non-serious AEs that 
occur in randomized participants for outcome.  Further information on follow-up procedures 
is given in Appendix 3. The investigator will make an assessment of intensity for each AE 
and SAE reported during the study based on Sponsor’s criteria (See “Assessment of 
Intensity” in Appendix 3, Section 12.3) and CFDA’s criteria (See Appendix 5 – Country-
specific Requirements, Section 12.5).
9.3.4
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 treatment 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 treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) 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 Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
9.3.5
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable to this study.
9.3.6
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, 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.
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All reported pregnancies (in participants who received at least 1 vaccine dose) must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
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.
All female participants of childbearing potential will undergo urine or serum pregnancy 
testing prior to each study vaccination (See Section 2 - SoA). Participants found to be 
pregnant at Day 1 are not eligible to participate in the study (Section 6.1 - Inclusion Criteria). 
Participants of childbearing potential are instructed to use effective contraception through 
Month 7 (See Appendix 2). Participants who inadvertently become pregnant before receiving 
all 3 doses of vaccine do not receive additional doses until ≥4 weeks after resolution of 
pregnancy and normalization of β-hCG levels as described in Table 3 (Section 9.5.2 -
Pregnancy Testing). Breastfeeding is not a contraindication to enrollment or to receiving 
study vaccinations. Pregnancy and breastfeeding in study participants and SAEs of infants 
born to participants who received the study vaccine or who were breastfed during the study 
must be reported as described in Section 9.3.1.
9.3.7
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor. There are no ECIs for this study.
9.4
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.
9.5
Safety 
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
9.5.1
Patient Reported Outcome
All participants will receive a VRC at the Day 1, Month 2, and Month 6 study vaccination 
visits. Using the VRC, the participant or the parent/legal guardian of the participant will be 
asked to record the following safety information: axillary temperature in the evening after 
each study vaccination and daily, at the same time of day, for 14 days after each study 
vaccination; solicited injection-site AEs (injection-site redness, swelling, induration, pain, 
and pruritus), solicited systemic AEs (hypersensitivity, headache, fatigue, vomiting, nausea, 
diarrhea, myalgia, pyrexia, and cough), and all other AEs within 14 days (Day 1 to Day 15) 
after each study vaccination; all AEs from Day 16 to Day 31 after each study vaccination. 
The participant or the parent/legal guardian of the participant will also be asked to record 
concomitant medications and concomitant vaccinations within 14 days following each study 
vaccination on VRC.
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The Day 1 VRC will be returned at the Month 1 visit. The Month 2 VRC will be returned at 
the Month 3 visit, and the Month 6 VRC will be returned at the Month 7 visit. However, 
phone call contacts will be conducted every week for each participant by study site personnel 
before the VRCs are returned. The main purpose of phone call contact is to remind the 
participant to record the VRC and answer any questions related to VRC from participants.
SAEs, cancer, overdose, pregnancy events (including non-randomized subjects with a 
positive Day 1 pregnancy test), lactation events and infant SAEs will be collected for the 
entire duration of study as instructed in the Section 9.3. In addition, new medical conditions 
not present at baseline and not reported as an adverse event will be collected throughout the 
study.
9.5.2
Pregnancy Testing
All women participants of childbearing potential will have a urine or serum pregnancy test 
(sensitive to 25 mIU/mL beta human chorionic gonadotropin [β-hCG]) performed at each 
vaccination visit (i.e. Day 1, Month 2, Month 6) per the manufacturer’s instructions. 
The pregnancy test results must be obtained prior to each study vaccination (on the day the 
participant is vaccinated). Any participant found to be pregnant at the Day 1 visit will not be 
allocated and will not participate in the study. 
For enrolled participants who become pregnant after receiving one or two 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 treatment in pregnant 
participants will be handled as described in Table 3.
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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 participant.
Between Day 1 and Month 2

No scheduled visits (excluding Month 1 visit) until 
resolution of the pregnancy (e.g., term, elective 
termination, spontaneous abortion).

The Month 2 study vaccination should be administered 
at least 4 weeks following resolution of pregnancy and 
after normalization of β-hCG levels.

The Month 6 study vaccination should be administered 
4 months after the Month 2 study vaccination.

The Month 7 visit should be conducted 1 month after 
the Month 6 study vaccination.
Between Month 2 and 
Month 6

No scheduled visits (excluding Month 3 visit) until 
resolution of the pregnancy (e.g., term, elective 
termination, spontaneous abortion).

The Month 6 study vaccination should be administered 
at least 4 weeks following resolution of pregnancy and 
after normalization of β-hCG levels.

The Month 7 visit should be conducted 1 month after 
the Month 6 study vaccination.
After Month 6

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).
9.5.3
Post-vaccination Observation Period (30 minutes)
All participants will be observed for at least 30 minutes after each study vaccination for any 
immediate reaction with particular attention to any evidence of allergic phenomena. This 
observation period will be documented in the participant’s study chart.
9.5.4
Clinical Laboratory Assessments
Refer to Section 12.4, Appendix 4 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency.
●
All protocol-required laboratory assessments, as defined in Appendix 4, must be 
conducted in accordance with the manufacturer’s instructions.
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●
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 dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
●
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
treatment, repeat assessments may be performed as determined by the investigator. 
9.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
9.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
9.8
Biomarkers
Biomarkers are not evaluated in this study.
9.9
Future Biomedical Research Sample Collection 
Future biomedical research samples will not be collected in this study.
9.10
Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
9.10.1
Prerequisites for Vaccination Visits
This section summarizes prerequisites for visits with study vaccinations and specimen 
collection. Deviations from these prerequisites require consultation between the investigator 
and the Sponsor and written documentation of the collaborative decision. See the 
Administrative Binder for a summary of deviations that require documentation in this study.
See the inclusion/exclusion criteria for specific restrictions at Day 1 (see Section 6.1 and
6.2). At the Month 2 and Month 6 study vaccination visits, study personnel should verify by 
questioning the participant and/or by examination that: 
1. The participant has not had a fever, i.e. axillary temperature <37.1°C, within the 24-
hour period prior to the Month 2 and Month 6 study vaccination visits.
2. The participant has not received any systemic (oral or parenteral) corticosteroids 
within 2 weeks prior to the Month 2 and Month 6 study vaccination visits.
3. The participant has not received a non-study inactivated or recombinant vaccine 
within 14 days prior to the Month 2 and Month 6 study vaccination visits or a non-
study live vaccine within 21 days prior to the Month 2 and Month 6 study vaccination 
visits.
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4. The participant is not pregnant as confirmed by a urine or serum pregnancy test.
If the participant does not meet the requirements listed above, the study visit (including 
specimen collection and study vaccination) should be rescheduled.
9.10.2
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study vaccinations but continue in the study may attend study 
visits per the SoA (Section 2). However, serum will not be collected at the Month 7 study 
visit from participants who did not complete the 3-dose regimen of study vaccination.
10
Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any final database lock, changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other non-confirmatory 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. A full CSR will be generated for Base Stage and a 
supplemental statistical report will be generated for Extension Stage.
10.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 10.2-10.12.  
Study Design Overview
A Phase 3 Open-Label Clinical Trial to Study the 
Immunogenicity, Safety and Tolerability of Recombinant 
Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) 
Vaccine (V501) in Chinese Girls Aged 9-19 Years and 
Young Women Aged 20-26 Years.
Treatment Assignment
It is a single-arm, open-label study. All enrolled participants 
will receive a 3-dose regimen of V501. Stratification factors 
are provided in Section 7.3.1.
Analysis Populations
Immunogenicity: Per protocol immunogenicity (PPI) 
population
Safety: All Participants as Treated (APaT) population
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Primary Endpoint(s)
Base stage:
The primary endpoints are cLIA GMTs to each of HPV 6, 
11, 16, and 18 at 1 month post dose 3.
Extension stage:

cLIA GMTs and seropositivity percentages to each of 
HPV 6, 11, 16, and 18 at Month 12, Month 24, Month 36, 
Month 48, and Month 60.

IgG LIA GMTs and seropositivity percentages to each of 
HPV 6, 11, 16, and 18 at Month 12, Month 24, Month 36, 
Month 48, and Month 60.
Secondary Endpoints
Base stage:
The key secondary endpoints are cLIA seroconversion 
percentages to each of HPV 6, 11, 16, and 18 at 1 month
post dose 3.
Extension stage:
Proportion of participants experiencing SAEs.
Statistical Methods for 
Key Immunogenicity 
Analyses
Base stage:
The primary hypotheses (H1) of non-inferiority of GMTs for 
each of HPV types 6, 11, 16, and 18 will be addressed by 4 
one-sided tests of non-inferiority, with H0: GMT1/GMT2 ≤ 
0.67 and Ha: GMT1/GMT2 > 0.67, at α=0.025. GMT1 and 
GMT2 represent the GMTs at 1 month post dose 3 in girls 
aged 9-19 years and young women aged 20-26 years, 
respectively.
Extension stage:
GMTs and seropositivity percentages to the each of HPV 
types 6, 11, 16, 18 will be summarized and plotted.
Statistical Methods for 
Key Safety Analyses
All safety data will be summarized as frequencies and 
percentages for the two age groups in the base stage and for 
the 9-19 years old group in the extension stage.
Interim Analyses
No interim analysis is planned. 
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Multiplicity
Since success is required on all 4 vaccine HPV types for each 
of the primary (H1) and secondary (H2) hypotheses, no 
multiplicity adjustment will be made for the multiple tests 
within each hypothesis. In addition, no adjustments will be 
made between primary and secondary hypotheses. 
No multiplicity will be adjusted for the extension stage.
Sample Size and Power 
The planned sample size is 766 participants. Success 
criterion of the study is the success on the primary hypothesis 
(H1) of the base stage; the overall power to claim the study 
success based on H1 is approximately 92% to demonstrate 
that girls aged 9-19 years is non-inferior to young women 
aged 20-26 years at an overall one-sided 2.5% alpha-level
under the assumptions listed in Section 10.9.1. 
The sample size of the extension stage is based on the 
number of participants eligible for entering the extension 
stage.
10.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This trial is being conducted as a single-arm, open-label study, i.e., all participants in this 
trial will receive V501; participants, investigators, and Sponsor personnel will be aware of 
participant treatment after each participant is enrolled.
10.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4.
10.4
Analysis Endpoints
10.4.1
Immunogenicity Endpoints
Base stage:
The primary immunogenicity endpoints are cLIA GMTs to HPV 6, 11, 16 and 18 at 1 month
post dose 3. The cLIA GMTs to HPV 6, 11, 16 and 18 at Day 1 will also be summarized.
The key secondary immunogenicity endpoints are the cLIA seroconversion percentages to
each of HPV 6, 11, 16 and 18 at 1 month post dose 3. Seroconversion is defined as changing 
serostatus from seronegative at Day 1 to seropositive at 1 month post dose 3. A participant 
with a cLIA titer at or above the serostatus cutoff value for a given HPV type is considered 
seropositive for that type. 
Anti-HPV 6, 11, 16, and 18 GMTs and seroconversion percentages measured by IgG LIA 
will be summarized as secondary objective of immunogenicity. 
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The exploratory endpoints for immunogenicity include GMTs and seroconversion 
percentages to each of HPV 6, 11, 16, and 18 measured by PBNA, which was developed by 
NIFDC.
Extension stage:
Anti-HPV GMTs and seropositivity percentages to HPV 6, 11, 16, and 18 at Month 12, 
Month 24, Month 36, Month 48, and Month 60 measured by cLIA and IgG LIA will be 
summarized to describe persistence of serum antibody responses to the 4 vaccine HPV types. 
The exploratory endpoints for immunogenicity include PBNA GMTs and seropositivity 
percentages to the 4 vaccine HPV types.
10.4.2
Safety Endpoints
Base stage:
Safety endpoints that will be used to evaluate the safety and tolerability of V501 will include 
proportions of participants who reported solicited injection-site AEs and solicited systemic 
AEs within Day 1 to Day 15 after study vaccination, and all AEs within Day 1 to Day 31 
after study vaccination. In addition, SAEs occurring at any time during the base stage and 
maximum axillary temperatures reported from Day 1 to Day 5 after study vaccination will be 
summarized. Pregnancy outcomes and infants SAEs during the base stage will also be 
summarized.
Extension stage:
SAEs, pregnancy outcomes, and infants SAEs during the extension stage will be 
summarized.
10.5
Analysis Populations
10.5.1
Immunogenicity Analysis Populations
Per-Protocol Immunogenicity Population
The per-protocol immunogenicity (PPI) population will serve as the primary population for 
the analysis of immune response to each of the 4 HPV types (6, 11, 16, and 18). To be 
included in this population, participants must:
(1) Have received all 3 study vaccinations with the correct dose of the correct clinical
material, and each vaccination visit must occur within the vaccination visit window 
specified in Section 2 – SoA.
(2) Be seronegative at Day 1 for the HPV type being analyzed. In the analysis of HPV 
types 6 and 11, a participant must be seronegative for both HPV types 6 and 11.
(3) Have provided Month 7 serum sample within the visit window specified in Section 2 –
SoA.
(4) At any time from Day 1 through Month 7, not meet any exclusion criteria that are 
deemed to potentially interfere with the evaluation of immune response to injections of 
V501.
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All Type-Specific 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 all 3 study vaccinations.
(2) Be seronegative at Day 1 for the HPV type being analyzed. In the analysis of HPV 
types 6 and 11, a participant must be seronegative for both HPV types 6 and 11.
(3) Have provided Month 7 serum sample.
Unlike the PPI population, this population will include participants who meet any exclusion 
criteria that were deemed to potentially interfere with the evaluation of immune responses to 
injections of V501. In addition, no day ranges on the timing of the vaccination and the 
collection of Month 7 serum sample will be applied. 
10.5.2
Safety Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all participants who received at least 1 dose of 
study vaccination and had clinical follow-up for safety.
10.6
Statistical Methods
10.6.1
Statistical Methods for Immunogenicity Analyses
Base stage:
V501 induced immune responses, as measured by cLIA anti-HPV 6, 11, 16 and 18 GMTs at 
1 month post dose 3, will be analyzed separately. The statistical criterion for non-inferiority 
requires that the lower bound of two-sided 95% confidence interval of GMT ratio (girls vs. 
young women) being greater than 0.67 for each HPV type. The study will be considered a 
success for immunobridging if the non-inferiority criteria for GMTs are met for all 4 HPV
types for the comparisons between girls aged 9-19 years vs. young women aged 20-26 years. 
Success on the seroconversion endpoints will provide further supporting evidence but is not 
required to declare study success. Anti-HPV 6, 11, 16, and 18 GMTs and seroconversion 
percentages measured by IgG LIA will be summarized as secondary objective of 
immunogenicity.
Immunobridging analysis
The primary hypotheses (H1) of non-inferiority of GMTs for each of HPV types 6, 11, 16
and 18 will be addressed by 4 one-sided tests of non-inferiority (one corresponding to each 
HPV type) conducted at the α=0.025 level (1-sided). For each HPV type, the hypotheses to 
be tested are
H0: GMT1/GMT2 ≤0.67
Ha: GMT1/GMT2 > 0.67
where GMT1 and GMT2 represent the GMTs at 1 month post dose 3, in the 9-19 years old 
group and in the 20-26 years old group, respectively. The point estimate of GMTs will be 
calculated by taking the anti-natural-logarithm of the arithmetic mean of the natural-
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logarithm-transformed anti-HPV titers. The test above will be conducted using an ANOVA 
model with a response of log individual titers and a fixed effect for comparison group. The 
statistical criterion for non-inferiority requires that the lower bound of two-sided 95% 
confidence interval of GMT ratio (9-19 years old vs. 20-26 years old) being greater than 
0.67.
The secondary hypothesis (H2) of non-inferiority of seroconversion percentages for each of
the vaccine HPV types (6, 11, 16 and 18) will be addressed by 4 one-sided tests of non-
inferiority (one corresponding to each HPV type) conducted at the α=0.025 level (1-sided).
The point estimate of seroconversion percentage for a particular HPV type is the ratio of the 
number of PPI-eligible participants for that particular HPV type who seroconverted to the 
relevant HPV type over the total number PPI-eligible participants for that particular HPV 
type who had evaluable Month 7 serology result based on serum sample collected within 31 
to 49 days post dose 3.
For each HPV type, the hypotheses to be tested are
H0: p1-p2 ≤-0.05
Ha: p1-p2 > -0.05
where p1 is the proportion of participants who seroconvert by 1 month post dose 3 in the 9-19
years old group and p2 is the proportion of participants who seroconvert by 1 month post 
dose 3 in the 20-26 years old group. 
The tests above will be conducted using the method of Miettinen and Nurminen [Miettinen, 
O. and Nurminen, M. 1985]. The statistical criterion for non-inferiority requires that the 
lower bound of two-sided 95% confidence interval for the difference (9-19 years old minus
20-26 years old) in seroconversion percentages being greater than -5 percentage points for 
each HPV type.
Table 4 summarizes the immunogenicity analyses for the base stage.
Table 4
Analysis Strategy for Immunogenicity Variables– Base Stage
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Objective
Anti-HPV 6, 11, 16 and 18 
cLIA GMTs at Month 7 (each 
type will be tested separately)
P
Point and 95% CI
estimation as well as 
statistical testing will 
be performed by using 
an ANOVA model.
PPI
Observed data 
only
Anti-HPV 6, 11, 16 and 18 
cLIA GMTs at Day 1 and 
Month 7
S
Point and 95% CI
estimation will be 
provided by using an 
ANOVA model.
ANPS
Observed data 
only
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Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Secondary Objective
cLIA % seroconversion to HPV 
6, 11, 16, 18 by Month 7 (each 
type will be tested separately).
P
Point and 95% CI 
estimation as well as 
statistical testing of 
binomial proportion 
based on Miettinen 
&Nurminen method
PPI
Observed data 
only
Anti-HPV 6, 11, 16 and 18 IgG 
LIA GMTs at Day 1 and 
Month 7
S
Point and 95% CI
estimation will be 
performed by using an 
ANOVA model.
PPI
Observed data 
only
IgG LIA % seroconversion to 
HPV 6, 11, 16, 18 by Month 7
S
Point and 95% CI 
estimation based on 
exact method
PPI
Observed data 
only
  † P=Primary approach; S=Supportive approach.
  ‡ Statistical models are described in further detail below:
ANPS = all type-specific naïve participants with serology; CI = confidence interval; GMT = geometric mean 
titer; PPI = per-protocol immunogenicity.
PBNA results (GMTs and seroconversion percentages) will be summarized as exploratory 
objective. The PBNA results of the base stage may be summarized in a supplemental report 
after the data are available.
Extension stage:
Participants in the 9-19 years old group who have completed 3 doses of study vaccination 
will be followed up to Month 60 to evaluate the persistence of the serum antibody titers for 
each of HPV 6, 11, 16 and 18 at Month 12, Month 24, Month 36, Month 48, and Month 60. 
Both cLIA and IgG LIA will be used to measure GMTs and seropositivity percentages.
Table 5 summarizes the immunogenicity persistence analyses for the extension stage.
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Table 5
Analysis Strategy for Immunogenicity Variables – Extension Stage
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
cLIA GMTs to HPV 6, 11, 16
and 18 at Month 12, Month 
24, Month 36, Month 48, and 
Month 60
P
Point and 95% CI 
estimation will be 
performed by using an 
ANOVA model; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
cLIA % seropositivity to HPV 
6, 11, 16 and 18 at Month 12, 
Month 24, Month 36, Month
48, and Month 60
P
Point and 95% CI 
estimation based on 
exact method; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
IgG LIA GMTs to HPV 6, 11, 
16 and 18 at Month 12, Month 
24, Month 36, Month 48, and 
Month 60
P
Point and 95% CI 
estimation will be 
performed by using an 
ANOVA model; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
IgG LIA % seropositivity to 
HPV 6, 11, 16 and 18 at 
Month 12, Month 24, Month 
36, Month 48, and Month 60
P
Point and 95% CI 
estimation based on 
exact method; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
cLIA GMTs to HPV 6, 11, 16
and 18 at Month 12, Month 
24, Month 36, Month 48, and 
Month 60
S
Reverse cumulative 
distribution curve
(RCD) at Month 12, 
Month 24, Month 36, 
Month 48, and Month 
60
PPI
Observed data 
only
  † P=Primary approach; S=Supportive approach.
CI = confidence interval; GMT = geometric mean titer; PPI = per-protocol immunogenicity.
PBNA results (GMTs and seropositivity percentages) will be summarized as exploratory 
objective. The results of PBNA may be summarized in a supplemental report upon its 
availability.
10.6.2
Statistical Methods for Safety Analyses
Base stage:
Safety and tolerability will be assessed by clinical review of all safety data collected after 
each study vaccination.
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Summary statistics, counts and percentage without confidence interval, will be provided by 
age group. Proportions of participants with solicited injection-site AEs, solicited systemic 
AEs within 14 days following study vaccination will be given. Maximum axillary 
temperatures recorded on the VRC from Day 1 to Day 5 post-vaccination will be 
summarized.
In addition, proportions of participants with all injection-site and systemic AEs (including 
solicited and non-solicited AEs) within 30 days following study vaccination, and proportions
of participants with SAEs through to Month 7 will also be summarized.
Both Sponsor’s criteria (See “Assessment of Intensity” in Section 12.3 Appendix 3) and 
CFDA’s criteria (See Section 12.5 Appendix 5 – Country-specific Requirements) will be 
applied to assess the intensity of adverse events. The incidence of greatest adverse event 
intensity reported by a participant based on both the two criteria will be tabulated for: all 
injection-site AEs and all systemic AEs within 30 days following any study vaccination.
All pregnancy outcomes and infant SAEs will be summarized.
Extension stage:
Summary statistics, including counts and proportion of participants with SAEs during the 
extension stage will be summarized for 9-19 years old participants.
In addition, pregnancy outcomes and infants SAEs during the extension stage will be 
summarized.
10.6.3
Summaries of Baseline Characteristics, Demographics, and other Analyses
Baseline characteristics, demographic variables, medical history, prior and concomitant 
therapies of the two age groups (9-19 years old vs. 20-26 years old) will be summarized 
using descriptive statistics or categorical tables. No statistical hypothesis tests will be 
performed on these characteristics.
The number and percentage of participants screened, allocated, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed.
New medical conditions will be collected during the entire period of the study. The data of 
new medical conditions will be separately summarized for each base and extension stage.
10.7
Interim Analyses
No interim analyses are planned for this study.
10.8
Multiplicity
Base stage:
For immunobridging primary (H1) and secondary (H2) hypotheses, success is claimed if 
hypotheses for all 4 HPV types are met. Therefore, no multiplicity adjustment will be made 
to account for the multiple HPV types. In addition, no multiplicity adjustment will be made 
between primary and key secondary hypotheses.
Extension stage: 
There is no multiplicity adjustment as there is no hypothesis for the extension stage.
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10.9 Sample Size and Power Calculations
The sample size of the study is driven by the hypothesis for the base stage. The sample size 
in the extension stage is based on the number of eligible participants for entering the 
extension stage.
10.9.1
Sample Size and Power for Immunogenicity Analyses
Approximately 766 participants will be enrolled. Table 6 summarizes the power calculation 
for the primary endpoint of cLIA GMT ratio under each HPV type. Success criterion of the 
study is the success on the primary hypothesis (H1) of the base stage. The overall power of 
study success based on H1 is 91.6% to establish that the non-inferiority of the primary 
endpoint cLIA GMT in girls aged 9-19 years vs. in young women aged 20-26 years at an 
overall one-sided, 2.5% alpha-level, if the underlying GMT ratio is greater than 0.67 for each 
HPV type.
The calculations are based on the following assumptions:
1.
The participants allocation ratio of 9-19 years old group vs. 20-26 years old group is 1:1;
2.
The true GMT ratio between the two age groups is 1 for HPV types 6, 11, 16 and 18;
3.
The standard deviation of the natural-log-transformed Month 7 titers is 1.2;
4.
Non-inferiority margin for GMT ratio is 0.67;
5.
The overall percentages of unevaluable participants are 27.3%, 23.1%, 27.3% and 23.1% 
for HPV Types 6, 11, 16, and 18, respectively. More specifically, 15%, 10%, 15% and 
10% of the participants are initially seropositive to HPV Types 6, 11, 16, and 18, 
respectively; the expected attrition rate through the Month 7 time point is 10%; the 
expected percentage of participants excluded due to vaccinations or serology samples out 
of range is no more than 5%. Take HPV 6 as an example, 27.3% is calculated as (1-(1-
0.15)*(1-0.1)*(1-0.05))*100%. 
The estimates of exclusion rates and standard deviation are based on data from previous 
V501 studies.
Table 6
Power for cLIA GMT ratio based on 766 enrolled participants calculated from the 
secondary endpoint seroconversion rate
Antigen
Assumed SD
Enrolled 
participants
Effective sample 
size
Power
HPV 6
1.2
383
278
0.975
HPV 11
1.2
383
294
0.981
HPV 16
1.2
383
278
0.975
HPV 18
1.2
383
294
0.981
Overall power
0.916
†
†Overall power is calculated by multiplying the power for each HPV type.  
The original GMT values are log transformed before analysis. As such, the CI for the means 
and the non-inferiority margin will be constructed on the natural log scale. The calculation is 
based on the two-sample t-test in 9-19 years old group and 20-26 years old group and carried 
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out using PASS 2008. The minimum criterion for success is that the lower bound of two-
sided 95% CI of difference between natural-log-transformed GMTs > log(0.67). Given the 
assumed SD of the natural-log-transformed Month 7 titers, this may occur when the observed 
difference between treatment groups is approximately log(0.82) or larger.
For the key secondary endpoint, cLIA seroconversion rate, there is an overall 84.2% power 
to establish that girls aged 9-19 years is non-inferior to young women aged 20-26 years at an 
overall one-sided, 2.5% alpha-level, if the difference (girls minus young women) in 
seroconversion rates is greater than -5 percentage points for each HPV type. Table 7 shows 
the sample size and power calculations for different HPV type under various assumed 
seroconversion rates for the reference group (young women aged 20-26 years). 
The calculations are based on the following assumptions: 
1. The participants allocation ratio of 9-19 years old group vs. 20-26 years old group is 1:1;
2. The true seroconversion rates are the same between the two age groups for HPV types 6, 
11, 16, and 18;
3. Non-inferiority margin for seroconversion rate is -5%;
4. The cLIA seroconversion rates for young women aged 20-26 years are 98.08%, 98.15%, 
98.08% and 98.11% corresponding to HPV 6, 11, 16 and 18 respectively, using the 
results of China V501-PN030 study; 
5. The overall percentages of unevaluable participants are 27.3%, 23.1%, 27.3% and 23.1% 
for HPV Types 6, 11, 16, and 18, respectively. More specifically, 15%, 10%, 15% and 
10% of the participants are initially seropositive to HPV Types 6, 11, 16, and 18, 
respectively; the expected attrition rate through the Month 7 time point is 10%; the 
expected percentage of participants excluded due to vaccinations or serology samples out 
of range is no more than 5%.
Table 7
Sample size and power calculated based on cLIA seroconversion difference in 
proportion testing
Antigen
Seroconversion rates 
for young women aged 
20-26 years
Enrolled 
subjects
Effective sample 
size
Power
HPV 6
98.08%
383
278
0.951
HPV 11
98.15%
383
294
0.966
HPV 16
98.08%
383
278
0.951
HPV 18
98.11%
383
294
0.964
Overall power
0.842†
†Overall power is calculated by multiplying the power for each HPV type.  
The estimates of exclusion rates are based on data from previous V501 studies. The 
calculation is based on an asymptotic method proposed by Miettinen and Nurminen (1985) 
[Miettinen, O. and Nurminen, M. 1985] and is carried out using PASS 2008. The minimum 
criterion for success is that the lower bound of two-sided 95% CI of difference > -5%. Given 
the assumed seroconversion rate of 98% in the 20-26 years old group, this may occur when 
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the observed difference in response rates is approximately -3% or larger.
10.9.2
Sample Size and Power for Safety Analyses
The probability of observing a specific AE in this study depends on the number of vaccinated 
participants with safety follow-up and the underlying incidence of that specific AE in the 
study population. 
Across six clinical studies, 19 participants out of 3,420 (0.56%) 9-17-year old girls who 
received V501 reported serious AEs; 0.058% (2 out of 3,420) participants reported serious 
vaccine-related AEs (MSD data on file). 
Assuming that all 383 participants aged 9-19 years enrolled in this study will have safety 
follow-up, then there is a 88.2% chance of observing at least one serious AE; and 20.1% 
chance of observing at least one serious vaccine-related AE, on at least one of the 383
participants in the 9-19 years old group. If no serious vaccine-related AEs are observed 
among the 383 participants in the 9-19 years old group, this study will provide 95%
confidence that the underlying percentage of participants with vaccine-related serious 
systemic AEs is <0.78% (one in every 128 participants) in the 9-19 years old group. This is 
based on calculation of a 1-sided 95% upper confidence limit of a binomial proportion using 
exact binomial method of Clopper and Pearson [Clopper, C. J. 1934]. 
10.10 Subgroup Analyses
Age group (9-19 years old and 20-26 years old) will be a natural subgroup factor for the base 
stage. No subgroup analysis will be conducted for the extension stage.
10.11 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 (Day 1, Month 2 and Month 6) 
will be described by histograms of actual intervals between vaccinations relative to the 
expected interval.
10.12 Extent of Exposure
As indicated in Section 9.1.8, each study participant is planned to be administered 0.5 mL of 
V501 at each vaccination visit (Day 1, Month 2, and Month 6). Thus, each participant is 
expected to be administered a total of 1.5 mL of V501 over a 6-month duration.
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11
References
[Alani, R. M. and Münger, 
K. 1998]
Alani RM, Münger K. Human 
papillomaviruses and associated 
malignancies. J Clin Oncol 1998;16:330-7.
[03Q42K]
[Blomberg, M., et al 
2012]
Blomberg M, Friis S, Munk C, Bautz A, 
Kjaer SK. Genital warts and risk of cancer:  a 
Danish study of nearly 50 000 patients with 
genital warts. J Infect Dis 2012;205:1544-53.
[03RR5X]
[Clopper, C. J. 1934]
Clopper CJ, Pearson ES. The use of 
confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 
1934;26(4):404-13.
[03Q0LW]
[Crawford, R., et al 2011]
Crawford R, Grignon A-L, Kitson S, Winder 
DM, Ball SLR, Vaughn K, et al. High 
prevalence of HPV in non-cervical sites of 
women with abnormal cervical cytology. 
Cancer 2011;11:1-6.
[03RR62]
[Forman, D., et al 2012]
Forman D, de Martel C, Lacey CJ, 
Soerjomataram I, Lortet-Tieulent J, Bruni L, 
et al. Global burden of human 
papillomavirus and related diseases. Vaccine 
2012;305:F12-F23.
[03RRYJ]
[Kotloff, K. L., et al 1998]
Kotloff KL, Wasserman SS, Russ K, Shapiro 
S, Daniel R, Brown W, et al. Detection of 
genital human papillomavirus and associated 
cytological abnormalities among college 
women. Sex Transm Dis 1998;25(5):243-50.
[03Q427]
[Koutsky, L. 1997]
Koutsky L. Epidemiology of genital human 
papillomavirus infection. Am J Med 
1997;102(5A):3-8.
[03Q47Y]
[Madkan, V. K., et al 
2007]
Madkan VK, Cook-Norris RH, Steadman 
MC, Arora A, Mendoza N, Tyring SK. The 
oncogenic potential of human 
papillomaviruses: a review on the role of 
host genetics and environmental cofactors. 
Br J Dermatol 2007;157:228-41.
[03QPM2]
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[Madsen, B. S., et al 
2008]
Madsen BS, Jensen HL, van den Brule AJC, 
Wohlfahrt J, Frish M. Risk factors for 
invasive squamous cell carcinoma of the 
vulva and vagina-Population-based case-
control study in Denmark. Int J Cancer 
2008;122:2827-34.
[03RR6L]
[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O, Nurminen M. Comparative 
analysis of two rates. Statistics in Medicine 
1985;4:213-26.
[03NTPN]
[Paavonen, J. 2007]
Paavonen J. Human papillomavirus infection 
and the development of cervical cancer and 
related genital neoplasias. Int J Infect Dis 
2007;11(Suppl 2):S3-S9.
[03QPLT]
[Parkin, D. M. and Bray, 
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Parkin DM, Bray F. Chapter 2: The burden 
of HPV-related cancers. Vaccine 
2006;24S3:S3-11-S3/25.
[04BBP9]
[Stamataki, S., et al 2007]
Stamataki S, Nikolopoulos TP, Korres S, 
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12
Appendices
12.1
Appendix 1: Study Governance Considerations
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.
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 
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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.
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 
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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.
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 
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.
Data Protection
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 which 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.
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 institutional review board, ethics review committee (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.
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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 in 
order to verify worksheet/case report form data.  By signing the consent form, the participant 
agrees to this process.  If study documents will be photocopied during the process of 
verifying worksheet/case report form 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.
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 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (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 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 
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Sponsor and agrees not to submit any information about this study or its results to those 
registries.
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 Good 
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); 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 Merck Code of Conduct for Clinical Trials.
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.
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,
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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 regulatory authority as a result of an audit or inspection to cure 
deficiencies in the study documentation and worksheets/case report forms.
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 
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 signed ICF, 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. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 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 may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
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 will 
promptly notify that study site’s IRB/IEC.
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12.2
Appendix 2: Contraceptive Guidance and Pregnancy Testing
Definitions 
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in Table 8 consistently and correctly during Day 
1 through Month 7.
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Table 8
Contraceptive Methods
Acceptable Contraceptive Methods  
Failure rate of >1% per year when used consistently and correctly. 
●
Male or female condom with or without spermicide
●
Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing) hormonal contraception b
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b 
●
Intrauterine hormone-releasing system (IUS)  
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for participants of 
clinical studies.
a) Typical use failure rates are higher than perfect-use failure rates (i.e., when used consistently and 
correctly). 
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
hormonal contraceptives are limited to those which inhibit ovulation. 
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Pregnancy Testing
WOCBP will have a urine or serum pregnancy test (sensitive to 25 mIU/mL β-hCG) prior to 
each study vaccination. Any participant found to be pregnant at the Day 1 visit will not be 
allocated and will not participate in the study (See Section 9.5.2).
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12.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
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 treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, 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 treatment 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 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose of study treatment 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 9.3.5 for protocol specific exceptions
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 
A 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 a serious adverse event.  A pre-existing condition is a clinical condition 
that is diagnosed prior to the use of an MSD product and is documented in the patient’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, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
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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 one 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.
Additional Events Reported
Additional Events which require reporting 
●
In addition to the above criteria, adverse events 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.
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 Adverse Event 
case report forms/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 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.
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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 sufficiently discomfort and interferes 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 redness or swelling from the day of vaccination through Day 15 
post-vaccination will be evaluated by maximum size.
Assessment of Causality
●
Did the Sponsor's product cause the adverse event?
●
The determination of the likelihood that the Sponsor's product caused the adverse 
event 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 initialed 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 adverse event 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 adverse event:
●
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?
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●
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 this 
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 one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH 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 INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.  
●
Consistency with Study treatment 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 case report forms /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. 
●
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 
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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 one 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.
Reporting of AE, SAE, 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 electronic data 
collection (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.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information 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 electronic data collection 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 electronic data collection 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 Trial File Binder (or 
equivalent).
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SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection 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 Trial File Binder (or equivalent).
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12.4
Appendix 4: Clinical Laboratory Tests 

The tests detailed in Table 9 will be performed by the local laboratory according to 
the manufacturer’s instructions. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6.1 and 6.2 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 9
Protocol-Required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Screening 
Tests

Urine or serum β human chorionic gonadotropin (β-hCG) pregnancy 
test (for all women participants of childbearing potential at all study 
vaccination visits)
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12.5
Appendix 5: Country-specific Requirements
CFDA’s Criteria on Assessment of Intensity of Adverse Events
Guideline of the Grading Standards for Adverse Events Intensity in Clinical Trials on 
Prophylactic Vaccines
Foreword
Vaccines are a class of special drugs usually used in healthy population to prevent diseases. 
Healthy subjects are selected for the clinical trials at different stages on the majority of 
prophylactic vaccines, and most prophylactic vaccines are used in healthy children. 
Therefore, safety concerns in the process of clinical studies of prophylactic vaccines are 
particularly important, and the requirements should be higher than those for general 
therapeutic drugs. 
Standardized standards for the evaluation and grading of adverse events have been gradually 
widely used in the evaluation of safety of therapeutic drugs in patients with specific diseases, 
but these grading standards apply to patients who may experience adverse events mild, 
moderate or severe clinical or laboratory abnormalities in the disease process, so the 
parameters may not be suitable for healthy volunteers. The aim of this guideline in 
formulating grading standards for the adverse events of prophylactic vaccines is to minimize 
the risks for healthy subjects in clinical trials. The defined values of parameters adopted in 
such adverse events grading standards are based on experience obtained from clinical trials 
on already marketed vaccines and information that has been made public in combination with 
consideration of the current reality of China.  
1. Overview
This Guideline applies to innovative prophylactic vaccines, and is applicable to the 
evaluation of severity of clinical and laboratory abnormalities (i.e. strength of adverse 
reactions) occurring in clinical trials in which the subjects are healthy adults and adolescents. 
Meanwhile, it can serve as the unblinding standards stipulated in the design of clinical trials 
on general prophylactic vaccine, as well as the reference for whether to terminate clinical
studies. In addition, the uniform adverse events grading standards provided by this guideline 
are conducive for comparison of safety data of prophylactic vaccines between different 
treatment groups in the same clinical trial or between different clinical trials. 
Clinical trials on prophylactic vaccines should strictly comply with the Good Clinical 
Practices (GCP) and meet relevant regulatory requirements. Management regulations require 
that adverse events occurring in clinical studies of vaccines should be inspected by related 
regulatory authorities and monitored by related main bodies (registration applicant, ethics 
committee and investigators), and appropriately reported for filing. 
Investigators of clinical trials on prophylactic vaccines must timely, comprehensively, 
objectively and accurately record all safety observation values and related data for evaluation 
of adverse events or adverse reactions; registration applicants must monitor the entire process 
of clinical studies. These adverse reaction grading standards are conducive for safety 
monitoring, timely judgment and appropriate reporting as required.
The aim of this Guideline and guidelines related to clinical trials on vaccines that have been 
issued are to provide references for the evaluation of safety of prophylactic vaccines for 
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clinical trials, and the classification and grading standards for adverse reactions here provide 
supplements to the integrity of safety data in clinical studies.
2. Basic Contents
The grading indicators for adverse reactions in clinical trials on prophylactic vaccines
provided by this Guideline include two parts (see details in the toxicity grading table). One 
part is clinical indicators (local reactions, systemic reactions, vital sign measurements), and 
the other part is laboratory indicators (blood chemistry, hematology and urinalysis), but not 
all safety indicators to be observed in clinical trials on prophylactic vaccines have been 
covered herein. For some special vaccines in the process of development, additional 
monitoring indicators may need to be added, or the specific defined values of parameters in 
the tables should be modified. For example, extra parameters are based on safety suggestions 
in pre-clinical toxicological studies or experience from previously marketed similar products.
Appropriate observation indicators may be selected from the adverse reactions grading tables 
herein according to the characteristics of different vaccines for clinical trials, and reasonable
safety monitoring and evaluation should be performed according to the respective 
characteristics of vaccines and disease prevalence.
(1) Adverse reactions grading tables
a. Clinical observation indicators (Appendix Table 1~3)
Appendix Table 1 Local Reactions Grading Table
Local reactions
Mild 
(Grade I)
Moderate 
(Grade II)
Severe 
(Grade III)
Potentially life-threatening
(Grade IV)
Pain
Does not affect 
activities
Affects activities or 
requires repeated 
use of non-narcotic 
analgesics
Affects activities 
or requires 
repeated use of 
narcotic analgesics
Emergency treatment or 
hospitalization
Skin and 
mucosa
Redness and 
itching
Diffuse, 
maculopapular rash, 
dryness, 
desquamation
Blisters, 
dampness, 
desquamation or 
ulceration
Peeling dermatitis, mucosal 
involvement, or erythema 
multiforme, or suspected 
Stevens-Johnsons syndrome
Induration *
<15 mm
15~30 mm
>30 mm
Gangrene or exfoliative 
dermatitis
Redness*
<15 mm
15~30 mm
>30 mm
Gangrene or exfoliative 
dermatitis
Swelling**
<15 mm and 
does not affect 
activities
15~30 mm or 
affects activities
>30 mm or 
restrains daily 
activities 
Gangrene
Rash (injection 
site)
<15 mm
15~30 mm
>30 mm
Pruritus
Mild pruritus at 
the injection site
Moderate pruritus
of the injection limb
Systemic pruritus
* In addition to the grading and evaluation of local reactions by most directly measuring the 
diameter, the development of and changes in the measurements should also be recorded. 
** The evaluation and grading of swelling should be based on the functional grades and 
actual measurements.
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Appendix Table 2 Vital Signs Grading Table
Vital signs*
Mild 
(Grade I)
Moderate 
(Grade II)
Severe 
(Grade III)
Potentially life-threatening 
(Grade IV)
Fever, axillary 
temperature*
37.1~37.5℃
37.6~39.0℃
>39.0℃
Oral temperature
**
37.7~38.5℃
38.6~39.5℃
39.6~40.5℃
>40℃
Tachycardia 
(beats/min)
101~115
116~130
>130
Emergency treatment or 
hospitalization due to 
arrhythmia
Bradycardia 
(beats/min)
50~54
45~49
<45
Emergency treatment or 
hospitalization due to 
arrhythmia
Hypertension 
(systolic blood 
pressure 
mmHg)***
141~150
151~155
>155
Emergency treatment or 
hospitalization due to severe 
hypertension
Hypertension 
(diastolic blood 
pressure 
mmHg)***
91~95
96~100
>100
Emergency treatment or 
hospitalization due to severe 
hypertension
Hypotension 
(systolic blood 
pressure mmHg) 
***
85~89
80~84
<80
Emergency treatment or 
hospitalization due to 
hypotensive shock  
Respiratory 
frequency 
(times/min)
17~20
21~25
>25
Requires intubation
* It is cited from China’s Prophylactic Vaccination Manual. The subjects should be tested in 
a stationary state. 
** Oral temperature; the subjects should not drink cold or hot beverage or smoke before the 
detection. 
*** It is necessary to compare with baseline blood pressure value before the use of vaccines 
in order to determine blood pressure abnormalities for specific analysis.
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Appendix Table 3 Systemic Reactions Grading Table 
Systemic 
reactions
Mild (Grade I)
Moderate 
(Grade II)
Severe (Grade III)
Potentially life-
threatening (Grade IV)
Hypersensitivity
Itching without 
rash
Local urticaria
Extensive urticaria, 
angioedema
Severe
hypersensitivity
Headache
Does not affect 
activities and
require no 
treatment
Transient, slightly 
affects activities 
and requires 
treatment 
(repeated use of 
non-narcotic 
analgesics)
Significantly
affects daily 
activities, with 
response to initial 
anesthetic 
treatment
Refractory, requires 
repeated anesthetic 
treatment. Emergency 
treatment or 
hospitalization
Fatigue, weakness
Normal activities 
were weakened 
for<48, and it 
does not affect 
activities
Normal activities 
were weakened by 
20%~50% for >48 
hours, and it 
slightly affects 
activities
Normal activities 
were weakened 
by>50%, and it 
significantly
affects daily 
activities, making 
the subject unable
to work
The subject cannot 
take care of 
himself/herself. 
Emergency treatment 
or hospitalization
Nausea, vomiting
Once to twice per 
24 hours, normal 
intake, does not 
affect activities
2~5 times/24 
hours, 
significantly 
decreased intake 
or restrained 
activities
> 6 times within 24 
hours, no significant 
intake, requires 
intravenous infusion 
Requires 
hospitalization due to 
hypotensive shock or 
nutrition through other 
means 
Diarrhea
Mild or transient, 
loose stool 2~3 
times/day, or 
mild diarrhea 
lasting < 1 week 
Moderate or 
continuous, 
4~5 times/day, or 
diarrhea lasting > 
1 week 
Watery stool > 6 
times/day, or 
bloody diarrhea, 
orthostatic 
hypotension, 
electrolyte 
imbalance, requires 
intravenous 
infusion > 2L
Hypotensive shock, 
requires 
hospitalization for 
treatment 
Myalgia
Does not affect 
daily activities
Muscle tenderness 
not at the injection 
site, slightly 
affects daily 
activities
Severe muscle 
tenderness, 
significantly
affects daily 
activities
Significant symptoms, 
muscle necrosis, 
requires emergency 
treatment or 
hospitalization
Cough
Transient, does 
not require 
treatment
Persistent cough, 
and treatment is 
effective
Paroxysmal cough 
which cannot be 
controlled by 
treatment
Emergency treatment 
or hospitalization
Other discomfort 
or clinical adverse 
reactions 
(according to the 
corresponding 
determination 
standards) 
Does not affect 
activities
Slightly affects 
activities and does 
not require  drug 
treatment 
Significantly
affects daily 
activities and 
requires  drug 
treatment
b. Laboratory indicators (Appendix Table 4~6) 
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Since all laboratory indicators as reference standards must be determined according to the 
stipulated normal values, the range of stipulated normal values should be provided to prove 
their reasonableness and feasibility. The following indicators are for reference only. 
Appendix Table 4 Blood Chemistry Measurements Grading Table
Serum
Mild (Grade I)
Moderate (Grade 
II)
Severe (Grade III)
Potentially life-
threatening 
(Grade IV)
Liver function—
elevated ALT 
and AST caused 
by influencing 
factors
1.25~2.5 ×ULN*
2.6~5 
×ULN
5.1~10
×ULN
>10×ULN
Creatinine
1.1~1.5×ULN
1.6~3.0×ULN
3.1~6×ULN
>6×ULN
BUN
1.25~2.5×ULN
2.6~5×ULN
5.1~10×ULN
>10×ULN
Bilirubin: 
elevated due to 
influencing 
factors, but 
functional  test 
proves normal 
1.1~1.5×ULN
1.6~2.0×ULN
2.0~3.0×ULN
>3.0×ULN
Bilirubin: 
elevated due to 
influencing 
factors 
accompanied by 
elevated 
indicators for 
liver function test
1.1~1.25×ULN
1.26~1.5×ULN
1.51~1.75×ULN
>1.75×ULN
Pancreatic 
enzymes—
amylase, lipase
1.1~1.5×ULN
1.6~2.0×ULN
2.1~5.0×ULN
>5.0×ULN
CPK-mg/dL
1.25~1.5×ULN
1.6~3.0×ULN
3.1~10×ULN
>10×ULN
*“ULN”: Refers to the upper limit of normal
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Appendix Table 5 Hematology Measurements Grading Table
Blood
Mild (Grade I)
Moderate 
(Grade II)
Severe 
(Grade III)
Potentially life-
threatening (Grade IV)
Hemoglobin (female) 
(g/dL)
12.0~13.0
10.0~11.9
8.0~9.9
<8.0
Hemoglobin (female) 
and changes (gm/dL) 
compared to before 
trial
Growth~1.5
1.6~2.0
2.1~5.0
>5.0
Hemoglobin (male) 
(g/dL)
12.5~14.5
10.5~12.4
8.5~10.4
<8.5
Hemoglobin (male) 
and changes (gm/dL) 
compared to before 
trial
Growth~1.5
1.6~2.0
2.1~5.0
>5.0
Leukocytosis 
(number/mm3)
>13,000/mm3
13,000~
15,000/mm3
15,000~
30,000/mm3
>30,000 
Leukopenia
(number/mm3)
2500～3500
1500~2499
1000~1499
<1000
Clotting time—
prolongation caused 
by influencing 
factors
1.0~1.10×ULN
1.11~1.20×ULN
1.21~1.25×ULN
>1.25×ULN
Partial 
thromboplastin 
time—prolongation 
caused by 
influencing factors
1.0~1.2×ULN
1.21~1.4×ULN
1.41~1.5×ULN
>1.5×ULN
“ULN”: Refers to the upper limit of normal 
Appendix Table 6 Urinalysis Measurements Grading Table
Urine
Mild 
(Grade I)
Moderate 
(Grade II)
Severe
(Grade III)
Potentially life-threatening 
(Grade IV)
Protein
Trace
1+
2+
>2+
Urine glucose
Trace
1+
2+
>2+
Blood cells 
(microscopy)
number of red blood 
cells under each high-
power field (rbc/hpf)
1~10
11~50
>50 or/and 
densely 
distributed red 
blood cells
Hospitalization for 
treatment or requires 
infusion of blood cell 
concentrates
Grading indicators in the tables above are not recommended for safety monitoring of healthy 
volunteers in clinical trials on all vaccines, and do not include all safety monitoring 
indicators. It is recommended to select monitoring indicators to be used in subjects in clinical 
trials on the corresponding prophylactic vaccines.
Whereas some physiological indicators for healthy infants and young children are 
significantly different from those for adults, it is recommended to make appropriate
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adjustments to such indicators combined with the specific conditions of clinical trials for 
specific applications. 
(2) General evaluation principles for the grading of adverse reactions 
For clinical abnormalities not involved in the above grading tables, adverse reactions should 
be graded and evaluated according to the following standards: 
Grade I, mild, short-term discomfort (<48 hours), requiring no medical treatment;
Grade II, moderate, mildly to moderately restrain daily activities, requiring no or only a little 
medical intervention; 
Grade III, severe, significantly restrains daily activities, requiring care of daily life and 
medical treatment, or maybe hospitalization;
Grade IV, life-threatening, extremely restrains daily activities, significantly requiring care of 
daily life, medical treatment and hospitalization;
(3) Severe or life-threatening adverse reactions
In clinical studies of prophylactic vaccines, the strength of any clinical events identified by 
clinical physicians as severe or life-threatening should be considered as Grade IV, including 
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, diffuse 
bruising, numbness or paralysis, acute psychosis, severe depression, etc.
The discovery of severe or rare adverse reactions usually requires clinical studies with large 
sample sizes, and sometimes such reactions need to be further evaluated after marketing. 
However, in pre-marketing clinical studies, the sample size should be enlarged as much as 
possible in order to find uncommon or rare severe adverse reactions. For vaccines whose 
primary applicable population is healthy individuals including infants and young children, 
their safety requirements are stricter than those for other drugs, and more cautious 
considerations should be taken into account. If necessary, clinical studies with safety 
observation indicators as the clinical evaluation endpoints may be carried out, and the 
minimal sample size should meet the statistical requirements. 
The China Food and Drug Administration will make timely modifications and improvements 
to this Guideline according to the status of clinical studies of prophylactic vaccines. 
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12.6
Appendix 6: Abbreviations and Trademarks
Abbreviation/Term
Definition
AE
adverse event
ANPS
all type-specific naïve participants with serology
APaT
all participants as treated
ASC-H
atypical squamous cells, cannot exclude HSIL
ASC-US
atypical squamous cells of undetermined significance
CFDA
China Food and Drug Administration
CI
confidence interval
CIN
cervical intraepithelial neoplasia
cLIA
competitive Luminex immunoassay
CONSORT
Consolidated Standards of Reporting Trials
CSR
clinical study report
ECI
events of clinical interest
eCRF
electronic case report form
GMTs
geometric mean titers
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HPV
human papillomavirus
HSIL
high-grade squamous intraepithelial lesion
IB
Investigators Brochure
ICF
informed consent form
IAF
informed assent form
IgG LIA
total IgG Luminex immunoassay
IVIG
intravenous gamma globulin
JRA
juvenile reheumatoid arthritis
mAbs
monoclonal antibodies
mMU
milli-Merck Unites
NIFDC
National Institutes for Food and Drug Control
NSAE
non-serious adverse event 
PBNA
pseudovirion-based neutralization assay
PE
phycoerythrin
PPI
per-protocol immunogenicity
qHPV
quadrivalent human papillomavirus
SAE
serious adverse event
SAP
statistical analysis plan
SIL
squamous intraepithelial lesion
SLE
systemic lupus erythematosus
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reactions
VaIN
vaginal intraepithelial neoplasia
VIN
vulvar intraepithelial neoplasia
VLP
virus-like particle
VRC
vaccination report card
WOCBP
woman participant of childbearing potential
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