An Open-Label Phase III Clinical Trial to Study the Immunogenicity and Tolerability of GARDASIL®9 (A Multivalent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in Adult Women (27- to 45-Year-Olds) Compared to Young Adult Women (16 to 26 Year Olds)
Phase: PHASE3
Conditions: Cervical Cancer, Vulvar Cancer, Vaginal Cancer, Genital Warts, Human Papillomavirus Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03158220 
Document Date: 
15-Mar-2017
An Open-Label Phase III Clinical Trial to Study the Immunogenicity 
and Tolerability of GARDASIL®9 (A Multivalent Human 
Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in 
Adult Women (27- to 45-Year-Olds) Compared to Young Adult 
Women (16 to 26 Year Olds)

Product:  V503
1
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF THE MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (hereafter referred to as the 
Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A. Protocol-specific Sponsor Contact 
information can be found in the Investigator Trial File Binder (or equivalent).
TITLE:
An Open-Label Phase III Clinical Trial to Study the Immunogenicity and Tolerability of 
GARDASIL®9 (A Multivalent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] 
Vaccine) in Adult Women (27- to 45-Year-Olds) Compared to Young Adult Women (16 to 
26 Year Olds)
EudraCT NUMBER:  2015-005093-38
 
 
04M9HD
 
 
059WG4

Product:  V503
2
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Table of Contents
Table of Contents...............................................................................................................2
LIST OF TABLES .............................................................................................................7
SUMMARY OF CHANGES.............................................................................................8
1.0
SUMMARY ..........................................................................................................10
1.1
Title ...................................................................................................................10
1.2
Indication..........................................................................................................10
1.3
Summary of Rationale.....................................................................................10
1.4
Summary of Study Design...............................................................................11
1.5
Sample...............................................................................................................12
1.6
Dosage/Dosage Form, Route, and Dose Regimen .........................................12
Table 2
Vaccine Formulation (0.5-mL Dose) ..........................................................12
1.7
Study Flow Chart.............................................................................................13
2.0
CORE PROTOCOL ............................................................................................15
2.1
Objectives and Hypotheses .............................................................................15
2.1.1
Primary Objective ..........................................................................................15
2.1.2
Secondary Objectives.....................................................................................15
2.2
Subject Inclusion Criteria...............................................................................15
2.3
Subject Exclusion Criteria..............................................................................16
2.4
Study Design and Duration.............................................................................18
2.4.1
Summary of Study Design.............................................................................18
2.4.2
Treatment Plan...............................................................................................19
2.5
List of Immunogenicity Measurements .........................................................19
2.6
List of Safety Measurements...........................................................................19
2.7
Data Analysis Summary..................................................................................20
2.7.1
Immunogenicity Analyses .............................................................................20
2.7.2
Safety Analyses..............................................................................................21
2.8
DATA MONITORING COMMITTEE.........................................................22
3.0
PROTOCOL DETAILS ......................................................................................22
 
 
04M9HD
 
 
059WG4

Product:  V503
3
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
3.1
Rationale...........................................................................................................22
3.1.1
9-Valent HPV Vaccine ..................................................................................22
3.1.2
Rationale for this Study .................................................................................23
Potential Benefits of Prophylactic HPV Vaccination in Adult Women .23
3.1.2.1
Rationale for the Study Design ...............................................................24
3.1.2.2
Rationale for Future Biomedical Research .............................................25
3.1.2.3
3.2
Study Procedures .............................................................................................25
3.2.1
Identifying Study Subjects.............................................................................25
3.2.2
Informed Consent...........................................................................................25
General Informed Consent......................................................................26
3.2.2.1
Consent and Collection of Specimens for Future Biomedical Research 26
3.2.2.2
3.2.3
Subject Identification Card ............................................................................26
3.2.4
Concomitant Medication(s)/Treatment(s)......................................................27
3.2.5
Assignment of Screening Number.................................................................27
3.2.6
Assignment of Allocation Number ................................................................27
3.2.7
Dispense Electronic Vaccination Report Cards.............................................28
3.2.8
Vaccination and Evaluation ...........................................................................28
3.2.9
Management of Pregnant Subjects.................................................................28
Table 3
Guidelines for Pregnant Subjects: Managing Study Visits and Study 
Vaccinations..........................................................................................................29
3.2.10 Dosage and Administration............................................................................29
3.2.11 Future Biomedical Research Samples ...........................................................30
3.2.12 Blinding/Unblinding ......................................................................................30
3.2.13 General Precautions for Administration of Study Vaccines..........................30
3.2.14 Discontinuation/Withdrawal Criteria.............................................................30
Discontinuation of Vaccination ..............................................................30
3.2.14.1
Withdrawal from the Study.....................................................................31
3.2.14.2
Withdrawal from Future Biomedical Research ......................................31
3.2.14.3
Lost to Follow-up....................................................................................31
3.2.14.4
3.3
Immunogenicity Measurements .....................................................................32
3.4
Safety Measurements.......................................................................................32
 
 
04M9HD
 
 
059WG4

Product:  V503
4
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
3.4.1
Clinical Measurements for Safety..................................................................32
3.4.2
Assessing and Recording Adverse Events.....................................................33
Definition of an Overdose for This Protocol and Reporting of Overdose 
3.4.2.1
to the Sponsor .........................................................................................34
Reporting of Pregnancy and Lactation to the Sponsor ...........................34
3.4.2.2
Immediate Reporting of Adverse Events to the Sponsor........................35
3.4.2.3
3.4.2.3.1
Serious Adverse Events ...................................................................35
3.4.2.3.2
Events of Clinical Interest................................................................36
Evaluating Adverse Events.....................................................................36
3.4.2.4
Table 4
Evaluating Adverse Events .........................................................................37
Sponsor 
Responsibility 
for 
Reporting 
Adverse 
Events 
and 
3.4.2.5
Patient/Device Events and Incidents.......................................................39
3.5
Statistical analysis plan ...................................................................................39
3.5.1
In-house Blinding...........................................................................................39
3.5.2
Hypothesis/Estimation ...................................................................................39
3.5.3
Analysis Endpoints ........................................................................................39
Immunogenicity ......................................................................................39
3.5.3.1
Safety ......................................................................................................40
3.5.3.2
3.5.4
Analysis Populations......................................................................................40
Immunogenicity Analysis Populations ...................................................40
3.5.4.1
Table 5
Acceptable Day Ranges for Vaccination Visits .........................................41
Table 6
Acceptable Day Ranges for Collection of Serum Samples .......................41
Safety Analysis Population.....................................................................42
3.5.4.2
3.5.5
Statistical Methods.........................................................................................42
Immunogenicity Analyses ......................................................................42
3.5.5.1
Statistical Methods for Safety Analyses .................................................43
3.5.5.2
Table 7
Analysis Strategy for Safety Parameters ...................................................44
Summaries of Baseline Characteristics, Demographics, and Other 
3.5.5.3
Analyses..................................................................................................45
3.5.6
Multiplicity ....................................................................................................46
3.5.7
Sample Size and Power Calculations.............................................................46
 
 
04M9HD
 
 
059WG4

Product:  V503
5
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Sample Size and Power for Immunogenicity Analyses ..........................46
3.5.7.1
Table 8
Study Power Depending on Exclusion Rates.............................................47
3.5.7.1.1
Sample Size and Power for Safety Analyses ...................................47
Table 9
Probability of Observing At Least One Vaccine Related Serious Adverse 
Event for Various Theoretical Incidence Rates ................................................48
3.5.8
Interim Analysis.............................................................................................48
3.6
DEFINITION OF COMPLIANCE MEASURE...........................................48
3.7
Labeling, Packaging, Storage, Dispensing, and Return of Clinical 
Supplies.............................................................................................................48
3.7.1
Product Description .......................................................................................48
Table 10
Investigational Medicinal Product .............................................................49
3.7.2
Packaging Information...................................................................................49
3.7.3
Clinical Supplies Disclosure..........................................................................49
3.7.4
Shipment of Investigational Medicinal Product ............................................49
3.7.5
Storage and Handling Requirements..............................................................50
3.7.6
Accountability of Investigational Medicinal Product....................................51
3.7.7
Return of Investigational Medicinal Product.................................................51
3.8
Data Management............................................................................................51
3.9
Biological Specimens........................................................................................52
4.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................52
4.1
Confidentiality..................................................................................................52
4.1.1
Confidentiality of Data ..................................................................................52
4.1.2
Confidentiality of Subject Records................................................................52
4.1.3
Confidentiality of Investigator Information...................................................52
4.1.4
Confidentiality of IRB/IEC Information........................................................53
4.2
Compliance with Financial Disclosure Requirements..................................53
4.3
Compliance with Law, Audit and Debarment ..............................................53
4.4
Compliance with Trial Registration and Results Posting Requirements...55
4.5
Quality Management System..........................................................................56
4.6
Data Management............................................................................................56
4.7
Publications ......................................................................................................56
 
 
04M9HD
 
 
059WG4

Product:  V503
6
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
5.0
LIST OF REFERENCES....................................................................................58
6.0
Appendices............................................................................................................60
6.1
Merck Code of Conduct for Clinical Trials...................................................60
6.2
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................62
6.3
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit 
and by Sample Types.......................................................................................66
7.0
Signatures .............................................................................................................67
7.1
Sponsor's Representative ................................................................................67
7.2
Investigator.......................................................................................................67
 
 
04M9HD
 
 
059WG4

Product:  V503
7
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
LIST OF TABLES
Table 1
Protocol Amendment 2 - Summary of Changes ................................................8
Table 2
Vaccine Formulation (0.5-mL Dose)...............................................................12
Table 3
Guidelines for Pregnant Subjects: Managing Study Visits and Study 
Vaccinations.....................................................................................................29
Table 4
Evaluating Adverse Events..............................................................................37
Table 5
Acceptable Day Ranges for Vaccination Visits...............................................41
Table 6
Acceptable Day Ranges for Collection of Serum Samples .............................41
Table 7
Analysis Strategy for Safety Parameters..........................................................44
Table 8
Study Power Depending on Exclusion Rates...................................................47
Table 9
Probability of Observing At Least One Vaccine Related Serious Adverse 
Event for Various Theoretical Incidence Rates ...............................................48
Table 10
Investigational Medicinal Product...................................................................49
 
 
04M9HD
 
 
059WG4

Product:  V503
8
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
SUMMARY OF CHANGES
Primary Reason for this amendment
The primary reason for V503-004-02 protocol amendment is change in sponsor of this study
from MSD Vaccins, a French société par actions simplifiée to Merck Sharp & Dohme Corp., 
Table 1
Protocol Amendment 2 - Summary of Changes
Section 
Number(s)
Section Title(s)
Description of Change(s)
NA
Title Page 
Updated name and contact of the 
sponsor
2.2
Subject Inclusion Criteria
Updated inclusion criteria 5 to reflect 
standard text for the V503 program. 
Added instructions for contraceptive 
use for women with no childbearing 
potential. 
 
 
04M9HD
 
 
059WG4

Product:  V503
9
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
ABBREVIATIONS AND DEFINITIONS
AE
adverse event 
ANSS 
all type-specific naïve subjects with serology 
AW
adult women
cLIA 
competitive Luminex® immunoassay 
CRA 
clinical research associate 
e-CRF 
electronic case report form 
CSP 
clinical study protocol 
CSR 
clinical study report 
EDC
electronic data capture
EU
European Union 
GMT 
geometric mean titre 
HPV 
human papillomavirus 
ICF 
informed consent form 
IEC 
independent ethics committee 
IMP
IRT
investigational medicinal product
Interactive response technology
mAbs
monoclonal antibodies
mMU/mL 
milli merck units per millilitre
PPI
per protocol immunogenicity
qHPV
quadrivalent human papillomavirus vaccine
SAE 
serious adverse event
VLP 
virus-like particles 
eVRC 
Electronic vaccination report card 
YAW
9vHPV
young adult women
9-valent (6/11/16/18/31/33/45/52/58) human 
papillomavirus vaccine
 
 
04M9HD
 
 
059WG4

Product:  V503
10
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
1.0 SUMMARY
Title
1.1
An Open-Label Phase III Clinical Trial to Study the Immunogenicity and Tolerability of 
GARDASIL®9 (A Multivalent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] 
Vaccine) in Adult Women (27- to 45-Year-Olds) compared to Young Adult Women (16- to 
26-Year-Olds)
Indication
1.2
Prevention of cervical, vulvar, vaginal, and anal cancers and related precancers, external genital 
lesions, Pap test abnormalities, and persistent infection caused by HPV Types 6, 11, 16, 18, 31, 
33, 45, 52, and 58.
Summary of Rationale
1.3
GARDASIL®91 is a prophylactic 9-valent human papillomavirus (9vHPV) (Types 6, 11, 16, 18, 
31, 33, 45, 52, and 58) L1 virus-like particle (VLP) vaccine that is comprised of VLPs of the 4 
human papillomavirus (HPV) types (Types 6, 11, 16, and 18) contained in GARDASIL®,2 plus 
the VLPs of 5 additional oncogenic HPV types (Types 31, 33, 45, 52, and 58). This vaccine 
offers the potential of significant prophylactic cancer coverage in addition to that already 
provided by GARDASIL®, with an increase in overall cervical cancer coverage from 
approximately 70% to 90%. 
GARDASIL®9 received marketing authorization in the European Union (EU) in June 2015 for 
active immunization of individuals from the age of 9 years against premalignant lesions and 
cervical, vulvar, vaginal and anal cancers caused by vaccine HPV types and genital warts 
(Condyloma acuminata) caused by specific HPV types. 
The efficacy of GARDASIL® is relevant to GARDASIL®9 since the vaccines are manufactured 
by a similar process and contain 4 of the same HPV L1 VLPs. 
As summarized in the GARDASIL®9 Summary of Product Characteristics, the efficacy of 
GARDASIL®9 was compared with that of the quadrivalent HPV (qHPV) vaccine with respect to 
HPV types 6, 11, 16, and 18. The population included girls and women between 16 to 26 years
(Protocol 001) and girls between 9 to 15 years (Protocol 009). Immune responses for 
                                                
1 GARDASIL®9 (Human Papillomavirus 9-valent Vaccine, Recombinant) is a registered trademark of Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.
2 GARDASIL [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] is a registered 
trademark of Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A. GARDASIL is also known as SILGARD 
in some countries. SILGARD is a trademark of Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.
 
 
04M9HD
 
 
059WG4

Product:  V503
11
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
GARDASIL®9 were found to be non-inferior to immune responses for GARDASIL®. Of the 
subjects receiving GARDASIL®9, 99.6% to 100% became seropositive for antibodies against all 
9 vaccine types by Month 7 across all groups tested. GARDASIL®9 was also found to be 
efficacious in preventing HPV 31-, 33-, 45-, 52-, and 58-related persistent infection and disease 
in girls and women between 16 to 26 years (Protocol 001).
Clinical study results suggest that women older than 26 years of age without evidence of prior 
exposure to the vaccine types can benefit from GARDASIL®.3,4 The long-term effectiveness and 
safety of the GARDASIL® vaccine in older women have also been found to be high5. Studies 
also suggest that subjects who have been previously exposed to HPV might benefit from HPV 
vaccination.6,7 In several EU countries such as Austria, Italy, Ireland, and Germany, there is 
acknowledgement of HPV vaccine benefit after HPV exposure and/or treatment. Canada and 
Australia have recommended the qHPV vaccine for women between 27 to 45 years of age. 
Studies with GARDASIL®9 in women older than 26 years of age have not been conducted. 
This study is designed to assess the safety and immunogenicity of GARDASIL®9 in 27- to 45-
year-old women, to complete the evaluation of GARDASIL®9 in the extended age range of 
female subjects for whom GARDASIL® was proven to be effective. This study is primarily 
powered to demonstrate the non-inferior immunogenicity of GARDASIL®9 in 27- to 45-year-old 
women, compared with 16- to 26-year-old women, the population in which GARDASIL®9 has 
been demonstrated to be effective, with respect to the 7 oncogenic HPV types (Types 16, 18, 31, 
33, 45, 52, and 58).
Summary of Study Design
1.4
This study will enrol a total of approximately 1,200 subjects, i.e., 600 women 16- to 26-years-old
and 600 women 27- to 45-years-old, all of whom have not yet received a prophylactic HPV 
                                                
3 Muñoz N, Manalastas R Jr, Pitisuttithum P, Tresukosol D, Monsonego J, Ault K, et al. Safety, immunogenicity, 
and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24–45 
years: a randomised, double-blind trial. Lancet. 2009 Jun 6;373:1949-57.
4 Castellsagué X, Muñoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K, et al. End-of-study safety, 
immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24–45 
years of age. Br J Cancer. 2011;105(1):28-37.
5 Luna J, Plata M, Gonzalez M, Correa A, Maldonado I, Nossa C, et al. Long-term follow-up observation of the 
safety, immunogenicity, and effectiveness of GardasilTM in adult women. PLoS ONE. 2013;8(12):e83431.
6 Joura EA, Garland SM, Paavonen J, Ferris DG, Perez G, Ault KA, et al. Effect of the human papillomavirus 
(HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis 
of trial data. BMJ. 2012 Mar 27;344:e1401.
7 Kang WD, Choi HS, Kim SM. Is vaccination with quadrivalent HPV vaccine after loop electrosurgical excision 
procedure effective in preventing recurrence in patients with high-grade cervical intraepithelial neoplasia (CIN2-3)? 
Gynecol Oncol. 2013 Aug;130(2):264-8.
 
 
04M9HD
 
 
059WG4

Product:  V503
12
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
vaccine. The study will provide a comparison of immunogenicity of GARDASIL®9 in 27- to 
45-year-old women, with 16- to 26-year-old women, with respect to the 7 oncogenic HPV types 
(Types 16, 18, 31, 33, 45, 52, and 58). The responses to the two non-oncogenic HPV types 
included in the vaccine (Types 6 and 11) will be presented using descriptive statistics. The 
number of subjects to be enrolled in the study was determined based on the primary 
immunogenicity objective.
All subjects will be administered a standard 3-dose regimen (Day 1, Month 2, Month 6) of 
GARDASIL®9. Serum samples will be collected on Day 1 and Month 7 for anti-HPV 6, 11, 16, 
18, 31, 33, 45, 52, and 58 antibody assays. The time point for comparison of immune responses 
will be Month 7, or approximately 4 weeks after the administration of the third dose. The 
safety/tolerability profile of the vaccine will be evaluated in all subjects in the study. Safety 
information will be collected on Day 1 through 1 month following the third vaccination or for a 
total of approximately 7 months for each subject. 
The end of the study will be defined as when final report of study results is available. 
Sample
1.5
This study will enrol healthy women in 2 age groups: 16- to 26-year-olds and 27- to 
45-year-olds. Each age group will be further stratified into subgroups of 16- to 20-year-olds and 
21- to 26-year-olds for young adult women (YAW) and 27- to 36-year-olds and 37- to 
45-year-olds for adult women (AW). Enrolment will be monitored to make sure that no single 
age stratum (i.e., subgroup) exceeds 55% of the total sample of a given age group (i.e., enrolment 
in an age stratum will be stopped when around 330 subjects in that age stratum have been 
vaccinated).  
Dosage/Dosage Form, Route, and Dose Regimen
1.6
Subjects will receive GARDASIL®9
(HPV
9-valent vaccine [recombinant, adsorbed]) 
administered as a 0.5-mL intramuscular injection on Day 1, Month 2 and Month 6. The vaccine 
formulation is summarized in Table 2.
GARDASIL®9 is available as a suspension for injection. It appears as a clear liquid with white 
precipitate.
Table 2
Vaccine Formulation (0.5-mL Dose) 
HPV 6 
(mcg)
HPV 
11 
(mcg)
HPV 
16 
(mcg)
HPV 
18 
(mcg)
HPV 
31 
(mcg)
HPV 
33 
(mcg)
HPV 
45 
(mcg)
HPV 
52 
(mcg)
HPV 
58 
(mcg)
Total 
VLP 
(mcg)
AAHS†
(mcg)
30
40
60
40
20
20
20
20
20
270
500
† AAHS, Merck Aluminum Adjuvant (amorphous aluminum hydroxyphosphate sulfate)
HPV, human papillomavirus; VLP, virus-like particle.
 
 
04M9HD
 
 
059WG4

Product:  V503
13
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Study Flow Chart
1.7
Visit Windows (a):
Consent 
Visit
2 months 
after 
Day 1, 
±3 weeks
6 months 
after 
Day 1, 
±4 weeks
3 to 
7 weeks 
after 
Month 6
Event/Test
Day 1
(Visit 1)
Month 2 
(Visit 2)
Month 6 
(Visit 3)
Month 7 
(Visit 4)
(b)
Obtain informed consent form / assent
+
Informed Consent for Future Biomedical Research
+
Assign screening number 
+
Review inclusion/Exclusion criteria (c)
+
Collect medical history (past year)
+
Collect demographics
+
Collect height and weight
+
Update Medical History (new conditions not already 
recorded as medical history or adverse events (AEs)
+
+
+
Review medications and non-study vaccines (d)
+
+
+
+
Pregnancy test (serum or urine) (e)
+
+
+
+
Blood sample for anti-HPV antibody testing (including 
retention serum) (10 ml of blood each time) (f) 
+
+
Blood (DNA) for Future Biomedical Research (j)
+
Collect oral temperature (g) 
+
+
+
 
 
04M9HD
 
 
059WG4

Product:  V503
14
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Visit Windows (a):
Consent 
Visit
2 months 
after 
Day 1, 
±3 weeks
6 months 
after 
Day 1, 
±4 weeks
3 to 
7 weeks 
after 
Month 6
Event/Test
Day 1
(Visit 1)
Month 2 
(Visit 2)
Month 6 
(Visit 3)
Month 7 
(Visit 4)
(b)
Assign allocation number 
+
Perform vaccination (Intramuscular; prefer deltoid 
muscle of non-dominant arm; do not give in buttocks) 
+
+
+
Provide electronic vaccination report card (eVRC)
+
Review and collect eVRC data (h) 
+
+
+
Review AEs, clinical follow-up for safety (i) 
+
+
+
+
(a) To calculate visit windows, assume 1 month equals 30 days and 1 week equals 7 days.  
(b)  Whenever possible, when a subject discontinues/withdraws prior to study completion, all applicable activities scheduled for 
the final study visit should be performed at the time of discontinuation except for serum collection for HPV testing. 
(c) A physical examination may be performed during Visit 1 if deemed necessary by the investigator to assess eligibility criteria. 
(d) See Section 3.2.2.2 for details of documentation times and time period restrictions for medications and non-study vaccines. If 
other non-study vaccines are administered at any time during the study, they should not be administered in the same limb as the 
study vaccine and must be appropriately documented.
(e) The serum or urine pregnancy test will be performed per the manufacturer’s instructions. A pregnancy test will be performed 
before administration of each dose of the study vaccine and at the final Month 7 visit on all subjects. The pregnancy test must be 
performed prior to serum collection for HPV testing at Day 1.
(f) Blood sample for anti-HPV measurements must be collected prior to the first study vaccination. Serum must be shipped as 
specified by the Sponsor. The retention serum vial must remain at the study site until the Sponsor notifies the study site to ship 
the samples. Leftover main study serum sample will be stored for future biomedical research if the subject consents to the Future 
Biomedical Research.
(g) If the subject has a fever (defined as an oral temperature of ≥37.8°C or 100.0°F) within the 24-hour period prior to receiving 
a study vaccination, the subject should not receive study vaccine, and the vaccination visit should be rescheduled until after the 
fever has resolved. Oral temperature will be measured prior to each vaccination
(h) The investigator should instruct the subject to use the eVRC to document oral temperature in the evening after each study 
vaccination and daily, at the same time of day, for 4 days after each study vaccination. Additionally, injection-site and systemic 
adverse event(s) (AEs), concomitant medications, and concomitant vaccinations are to be documented in the eVRC starting after 
each study vaccination for a total of 15 days, including the day of vaccination (Day 1 to Day 15). 
(i)
Observe subjects for at least 15 minutes after each vaccination for immediate untoward effects. Serious adverse events 
(SAEs), pregnancy events, and lactation events should be reported to the Sponsor’s , within 24 hours. Adverse events and SAEs 
will be followed for 15 days and 30 days, respectively, after the last dose (i.e., after the third dose for subjects completing the 
vaccination schedule or after the last received dose in the event of the subject withdrawing).
(j) Informed consent for future biomedical research samples must be obtained to collect the DNA sample.
 
 
04M9HD
 
 
059WG4

Product:  V503
15
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
2.0 CORE PROTOCOL
Objectives and Hypotheses
2.1
Primary Objective
2.1.1
To demonstrate that the administration of GARDASIL®9 in 27- to 45-year-old women induces 
non-inferior geometric mean titres (GMTs) for serum anti-HPV 16, 18, 31, 33, 45, 52, and 58 
compared with 16- to 26-year-old women.
Hypothesis: GARDASIL®9 induces in 27- to 45-year-old women anti-HPV 16, 18, 31, 33, 45, 
52, and 58 GMTs at 4 weeks after Dose 3 that are non-inferior to those induced in 16- to 
26-year-old women who are seronegative at Day 1 to the relevant HPV types. (The GMT ratios 
for HPV 16, 18, 31, 33, 45, 52, and 58 will be analysed separately. The statistical criterion for 
non-inferiority requires the lower bound of the two-sided 95% confidence interval (CI) of the 
GMT ratio [27- to 45-year-old women versus 16- to 26-year-old women] to be greater than 0.50 
for each HPV type).
Secondary Objectives
2.1.2
The secondary objectives are:
To evaluate the safety/tolerability of GARDASIL®9 in 27- to 45-year-old women compared with
16- to 26-year-old women;
To demonstrate that GARDASIL®9 is immunogenic with respect to HPV types 16, 18, 31, 33, 
45, 52, and 58 in 27- to 45-year-old women;
To summarize humoral immune responses (including anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 
58 GMTs and seroconversion rates at Day 1 and 4 weeks after Dose 3) in 16- to 26-year-old and 
27- to 45-year-old women who received GARDASIL®9.
Hypothesis: GARDASIL®9 generates anti-HPV 16, 18, 31, 33, 45, 52 and 58 seroconversion 
rates 4 weeks after Dose 3 that are acceptable in 27- to 45-year-old women who are seronegative 
at Day 1 to the relevant HPV type(s). (Seroconversion is defined as changing serostatus from 
seronegative at Day 1 to seropositive by 4 weeks after Dose 3) (The seroconversion rate for each 
of the HPV types 16, 18, 31, 33, 45, 52, and 58 will be tested separately. Acceptability is defined 
as the lower bound of the two-sided 95% CI for the seroconversion rate being greater than 90%).
Subject Inclusion Criteria
2.2
To be included in the study and to receive the first study vaccination, subjects must meet all 
inclusion criteria. For items with an asterisk (*), if the subject does not meet these inclusion 
criteria, the Day 1 visit may be rescheduled for a time when these criteria can be met.
1. Independent Ethics Committee (IEC)-approved written informed consent form (ICF) and 
privacy language as per national regulations must be obtained from the subject and/or 
 
 
04M9HD
 
 
059WG4

Product:  V503
16
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
from the subject’s parent(s) or legal guardian(s) prior to any study-related procedures 
(including discontinuation of prohibited medication, if applicable); assent (for minor 
subjects) by the subject is given as required by local law. The subject may also provide 
consent/assent for Future Biomedical Research. However, the subject may participate in 
the main trial without participating in Future Biomedical Research.
2. Subject is a woman between the ages 16 years and 0 days and 45 years and 364 days as 
of first vaccination.
3. Subject is judged to be in good physical health on the basis of medical history, physical 
examination (if deemed necessary), and laboratory testing. 
4. Subject, or subject's parent or guardian, is able to understand and adhere to the study 
procedures (e.g., is not planning to relocate far from the investigational centre during the 
study period); is able to read, understand, and complete the electronic vaccination report 
card (eVRC); is able to understand the risks involved with the study; and voluntarily 
agrees to participate in the study by giving written informed consent.
5. *Since the first day of the subject’s last menstrual period through Day 1, the subject has 
not had sex with males or has had sex with males and used effective contraception with 
no failures (an example of a failure is a male condom that ruptures during sexual 
intercourse). Effective contraception is defined as a marketed, approved contraceptive 
product that the subject has used per the manufacturer’s instructions with every act of 
sexual intercourse. The subject understands and agrees that during the Day 1 through 
Month 7 period, she should not have sexual intercourse with males without effective 
contraception, and the uses of the rhythm method alone, withdrawal alone, and 
emergency contraception, are not acceptable methods per the protocol. Subjects who 
have reached menopause, undergone hysterectomy, bilateral oophorectomy, or bilateral 
tubal ligation are eligible without the use of contraceptives. Postmenopausal status is 
defined as: (1) No menses for >1 year but <3 years and confirmed by follicle stimulating 
hormone (FSH) levels elevated into the postmenopausal range, or (2) no menses for at 
least 3 years.
6. * Subject has had no temperature ≥37.8°C or 100.0°F (oral) within 24 hours prior to the 
first injection.
7. Subject agrees to provide study personnel with a primary telephone number as well as an 
alternate telephone number for follow-up purposes.
Subject Exclusion Criteria
2.3
To be included and receive the first study vaccination, subjects should not have any exclusion 
criteria. For items with an asterisk (*), if the subject meets these exclusion criteria, the Day 1 
visit may be rescheduled for a time when these criteria are not met. 
1. Subject has a history of an abnormal Pap test or abnormal cervical biopsy results 
(showing cervical intraepithelial neoplasia or worse) or cervical disease (i.e., surgical 
treatment for cervical lesions).
 
 
04M9HD
 
 
059WG4

Product:  V503
17
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
2. Subject has history of genital warts, Vulvar Intraepithelial Neoplasia or Vaginal 
Intraepithelial Neoplasia.
3. Subject has a history of a positive test for HPV.
4. Subject has a history of known prior vaccination with an HPV vaccine, i.e., received a 
marketed HPV vaccine, or has participated in an HPV vaccine clinical study and has 
received either active agent or placebo.
5. Subject is pregnant (as determined by serum or urine pregnancy test).
6. Subject is, at the time of signing ICF, a user of recreational or illicit drugs or has had a 
recent history (within the last year) of drug or alcohol abuse or dependence. Alcohol 
abusers are defined as those who drink despite recurrent social, interpersonal, and/or legal 
problems as a result of alcohol use.
7. Subject has a history of severe allergic reaction, including known allergy to any vaccine 
component, including aluminum, yeast, or BENZONASE® (nuclease, Nycomed [used to 
remove residual nucleic acids from this and other vaccines]) (e.g., swelling of the mouth 
and throat, difficulty breathing, hypotension or shock) that met the criteria for serious 
adverse experiences defined in this protocol.
8. Subject has had a splenectomy, or is currently immunocompromised or has been 
diagnosed as having a congenital or acquired immunodeficiency, HIV infection, 
lymphoma, leukaemia, systemic lupus erythematosus, rheumatoid arthritis, juvenile 
rheumatoid arthritis, inflammatory 
bowel disease, or other autoimmune or 
immunosuppressive condition, or has a history of any disease, which, in the investigator’s 
opinion, may confound the results of the study or pose an additional risk to the subject.
9. Subject is receiving or has received in the year prior to enrolment the following 
immunosuppressive therapies: radiation therapy, cyclophosphamide, azathioprine, 
methotrexate, any chemotherapy, cyclosporin, leflunomide (tumour necrosis factor-α 
antagonists, monoclonal antibody therapies (including rituximab [Rituxan]), intravenous 
gamma globulin, antilymphocyte sera, or other therapy known to interfere with the 
immune response. With regard to systemic corticosteroids, a subject will be excluded if 
she is currently receiving steroid therapy, has recently (defined as within 2 weeks of 
enrolment) received such therapy, or has received 2 or more courses of high dose 
corticosteroids (≥20mg/day of prednisone [or equivalent] orally or parenterally) lasting at 
least 1 week in duration in the year prior to enrolment. Subjects using inhaled, nasal, or 
topical corticosteroids are considered eligible for the study.
10. Subject has received any immune globulin or blood-derived product within the 3 months 
prior to the Day 1 vaccination, or plans to receive any such product during Day 1 through 
Month 7 of the study.
11. * Subject has received non-replicating (inactivated) vaccines within 14 days prior to the 
Day 1 vaccination or has received replicating (live) vaccines within 21 days prior to the 
Day 1 vaccination.
 
 
04M9HD
 
 
059WG4

Product:  V503
18
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
12. Subject has thrombocytopenia or other coagulation disorder that would contraindicate 
intramuscular injections.
13. Subject is concurrently enrolled in a clinical study of investigational agent.
14. Subject has a history or current evidence of any condition, therapy, lab abnormality or 
other circumstance that might confound the results of the study, or interfere with the 
subject’s participation for the full duration of the study, such that it is not in the best 
interest of the subject to participate.
15. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or Sponsor staff directly involved with this trial.
Study Design and Duration
2.4
Summary of Study Design
2.4.1
This is an international, multicentre; open-label, immunogenicity and tolerability study of 
GARDASIL®9 in 16- to 45-year-old women. 
Approximately 1,200 healthy women, all of whom have not yet received a prophylactic HPV 
vaccine, will be enrolled in the study (i.e., 600 YAW between 16 to 26 years of age and 600 AW
between 27 to 45 years of age). Each age group will be divided in 2 strata defined as 16- to 
20-year-olds and 21- to 26-year-olds for YAW and 27- to 36-year-olds and 37- to 45-year-olds
for AW. The immunogenicity data will be summarized by strata and age group, and the safety 
data will be summarized for 16- to 26-year-old women and 27- to 45-year-old women. All 
enrolled subjects will receive a 3-dose regimen (Day 1, Month 2, and Month 6) of 
GARDASIL®9. Serum samples will be obtained on Day 1 and Month 7 for anti-HPV 6, 11, 16, 
18, 31, 33, 45, 52, and 58 testing. Immunogenicity analyses will be performed after all subjects 
have completed the Month 7 visit. 
Medical history (past year) will be collected on Day 1 for all subjects. Oral temperature will be 
measured prior to each vaccination. Vital signs (height, weight, and oral temperature) will be 
collected on Day 1. Physical examination will be conducted on Day 1 if deemed necessary by the 
investigator. 
Subjects will be monitored for safety and tolerability from Day 1 through 1 month following the 
third vaccination or for a total of approximately 7 months for each subject. A pregnancy test will 
be performed before administration of each dose of the study vaccine and at the final Month 7 
visit on all subjects. The pregnancy test must be performed prior to serum collection for HPV 
testing at Day 1. Any subject with a positive pregnancy test at Day 1 will not be vaccinated and 
will not be allowed to participate in the study.  Subjects with a positive pregnancy test after Day 
1 will not be vaccinated with subsequent doses until resolution of the pregnancy as outlined in
Table 3. Pregnant subjects who receive less than 3 vaccinations during the study will be offered 
the possibility to complete the vaccination course. Pregnancies and associated adverse 
experiences will be followed to outcome. 
 
 
04M9HD
 
 
059WG4

Product:  V503
19
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Treatment Plan
2.4.2
Approximately 1,200 healthy women will receive GARDASIL®9 as a 3-dose regimen of 0.5-mL 
intramuscular injections administered on Day 1, Month 2, and Month 6.
Study vaccine must be stored in a refrigerator that has a temperature between 2°C and 8°C
(35.6°F and 46.4°F). If the refrigerator in which the study vaccine is stored deviates from the 2°C 
to 8°C (35.6°F and 46.4°F) range, study vaccinations should be suspended and the Sponsor or 
designee should be contacted immediately so that an investigation can be conducted.
List of Immunogenicity Measurements
2.5
Serum will be collected for analysis of anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 responses 
by competitive Luminex® immunoassay (cLIA). Serum will be analysed to support the primary
and secondary objectives. 
At Day 1, blood samples will be collected prior to the first study vaccination to identify subjects 
who have been exposed to study vaccine HPV types prior to enrolment. Serology results at Day 
1 are not part of the inclusion/exclusion criteria; thus, no subject will be excluded from the study 
based on these results. After Day 1, serum specimens will be collected at the Month 7 study visit 
as specified in the Study Flow Chart (Section 1.7).
List of Safety Measurements
2.6
Each subject will receive an electronic VRC at the Day 1, Month 2, and Month 6 study 
vaccination visits. On the eVRC, the subject or the subject's parent or guardian will be asked to 
record oral temperature in the evening after each study vaccination and daily, at the same time of 
the day, for 4 days after each vaccination for the purpose of identifying febrile events. In 
addition, beginning after each study vaccination and for a total of 15 days including the day of 
vaccination (Day 1 to Day 15), the subject will be asked to record injection-site and systemic 
adverse events (AEs), concomitant medications, and concomitant vaccinations on the eVRC. 
Serious adverse events (SAEs), pregnancy information, and lactation information will also be 
collected as described in Section 3.4. In addition, new medical conditions not present at baseline 
and not reported as an AE (i.e., incident medical conditions occurring outside of a Day 1 to 
Day 15 period post-vaccination and not considered SAEs) will be collected throughout the study. 
In case of pregnancy, the pregnancy and any serious adverse experiences in study subjects and 
their infants must be followed to outcome. In addition, if subjects receive study vaccine while 
breastfeeding during the Day 1 through Month 7 period, any serious adverse experiences in the 
study subjects and their infants must be followed to outcome.
 
 
04M9HD
 
 
059WG4

Product:  V503
20
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Data Analysis Summary
2.7
Immunogenicity Analyses
2.7.1
The primary analyses of immunogenicity will be conducted in the Per Protocol Immunogenicity 
(PPI) population as defined in Section 3.5.4.1.
The primary hypotheses of non-inferiority of GMTs for HPV oncogenic types 16, 18, 31, 33, 45, 
52, and 58 will be based on one-sided tests of non-inferiority comparing Month 7 GMTs for each 
component. Analysis of variance (ANOVA) models (one per HPV oncogenic type) with a 
response of log individual titres and a fixed effect for age group will be used. The hypotheses to 
be tested are: H0: GMTAW/GMTYAW ≤0.50 versus H1: GMTAW/GMTYAW >0.50, where GMTAW
represents the GMTs in 27- to 45-year-old subjects and GMTYAW represents the GMTs in 16- to 
26-year-old subjects. Each hypothesis will be tested at α=0.025 level (one-sided). The statistical 
criterion for non-inferiority in these tests corresponds to the lower bound of the two-sided 95% 
CI for the geometrical mean ratio of 27- to 45-year-old subjects versus 16- to 26-year-old 
subjects being greater than 0.50. Success of the study will be declared if non-inferiority can be 
confirmed for all HPV oncogenic types. Therefore, no adjustment for multiplicity is required.
For this study on women 16- to 45-years of age, the rate of exclusion from the PPI analysis 
populations is expected to range from 25% to 35% of enrolled subjects mainly due to HPV 
seropositivity at baseline and possibly protocol deviations that could potentially interfere with 
immune response to vaccination of GARDASIL®9. The expected GMT ratio AW/YAW is 0.7, 
reflecting the fact that the immunogenicity of any HPV vaccine decreases with the increasing age 
of the subjects, and the variability (standard deviation) of each serotype on the natural log scale 
is estimated to be 1.2. If 1,200 subjects are enrolled in the study in a 1:1 fashion with regards to 
the 2 age groups, the evaluable population will range from 780 to 900 subjects. If the exclusion 
rate from PPI analysis population is 35% for 1 HPV type and 25% for the 6 others, this study 
will have over 90% power to rule out a 2-fold decrease in GMT for the 7 oncogenic HPV types 
(Types 16, 18, 31, 33, 45, 52, and 58). 
The secondary hypotheses of acceptability of the anti-HPV 16, 18, 31, 33, 45, 52 and 58 
seroconversion rates in the 27- to 45-year-old women group will be tested based on the 95% CIs 
for the single group proportion calculated using the exact binomial method (Clopper-Pearson 
method) for single proportions. For each HPV type, the statistical criterion for acceptability 
requires that the lower bound of the 95% CIs of the seroconversion rate for each of the antigens 
is greater than 90%. 
Assuming a true seroconversion rate to each HPV type >98% and a percentage of subjects 
excluded from the PPI analysis population <35% for HPV 16 and <25% for HPV 18, 31, 33, 45, 
52 and 58, the power of the secondary hypothesis testing is >99% using aType I error α=0.025 
(one-sided).
Another secondary objective is to summarize HPV antibody responses (including anti-HPV 6, 
11, 16, 18, 31, 33, 45, 52, and 58 GMTs and seroconversion rates at Day 1 and 4 weeks after 
Dose 3) in 16- to 26-year-old and 27- to 45-year-old women who received GARDASIL®9. In 
 
 
04M9HD
 
 
059WG4

Product:  V503
21
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
addition, exploratory analyses will be conducted to provide HPV antibody responses by age 
strata (i.e., 16- to 20-year-olds and 21- to 26-year-olds for YAW and 27- to 36-year-olds and 37-
to 45-year-olds for AW).
Safety Analyses
2.7.2
All subjects who received at least 1 dose of GARDASIL®9 and have safety follow-up data will 
be included in the analysis of safety. Statistical analyses of AEs will follow the 3-tiered analysis 
approach commonly used by the Sponsor/Vaccine Manufacturer when conducting safety 
assessments. 
Tier 1 analysis compares between group difference by providing incidence summaries by each 
group, computing (incidence) risk differences and 95% CIs of risk differences between groups 
and computing p-values corresponding to tests of significance of the risk differences. P-values 
and 95% CIs for between-age-group differences in the percentage of subjects with events will be 
calculated using the Miettinen and Nurminen [20] method.
Tier-1 AEs in this study include:

injection-site adverse reactions prompted for on the eVRC occurring Day 1 to Day 5 
following any vaccination, and 

elevated temperatures (≥37.8°C or 100.0°F) from Day 1 to Day 5 following any 
vaccination. 
Tier 2 analysis follows the Tier 1 analysis approach, except p-values are not computed. 
Tier-2 AE summaries include:

systemic AEs within 14 days following any vaccination occurring in 1% of subjects in 
any group, 

injection-site adverse reactions not prompted for on the eVRC occurring Day 1 to Day 5 
following any vaccination in 1% of subjects in any group, 

SAEs occurring within 14 days (Day 1 to Day 15) following any vaccination,

serious vaccine-related AEs observed at any time during the study, and 

severe injection-site adverse reactions Day 1 to Day 5 following any vaccination visit.
Tier-3 AEs include summaries (counts and percentages) by each age-group for any other AEs, 
including all injection-site adverse reactions occurring from Day 1 to Day 5 following each 
vaccination visit, all systemic AEs occurring within 14 days (Day 1 to Day 15) of each 
vaccination visit, and all SAEs occurring during the study and not included in the Tier-2 
analysis.
 
 
04M9HD
 
 
059WG4

Product:  V503
22
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
DATA MONITORING COMMITTEE
2.8
Since its market introduction in 2006, over 183 million doses of GARDASIL® have been 
distributed (as of April 2015). The safety profile is well characterized and continuously 
monitored by routine post-marketing surveillance activities. Based on the continued medical 
monitoring performed by the 9vHPV vaccine (V503) clinical team, its overall safety profile 
appears to be similar to that of GARDASIL® [22]. 
In June 2015, GARDASIL®9 (V503) was granted marketing authorization in Europe. Since this 
is an open-label Phase 3 study, a Data Monitoring Committee was not deemed necessary in this 
context.
3.0 PROTOCOL DETAILS
Rationale
3.1
9-Valent HPV Vaccine
3.1.1
A 9-valent (Types 6/11/16/18/31/33/45/52/58) human papillomavirus (9vHPV) vaccine was 
developed to cover 7 cancer-causing HPV types (HPV 16, 18, 31, 33, 45, 52, and 58) which are 
together responsible for approximately 90% of cervical cancers and HPV-related vulvar, vaginal, 
and anal cancers, and 2 HPV types (HPV 6 and 11) which are responsible for 90% of genital 
warts [1, 2, 3, 4, and 5]. In clinical studies, the 9vHPV vaccine prevented infection and disease 
due to the HPV vaccine types in females 16 to 26 years of age [6]. Key aspects of the 9vHPV 
vaccine development program are summarized in published literature [7]. The 9vHPV vaccine 
was licensed in the U.S.A in December 2014, in Canada in February 2015, and in the EU and 
Australia in June 2015 under the name GARDASIL™9 (Merck & Co., Inc., Kenilworth, New 
Jersey, U.S.A.). As of December 2016, the 9-valent (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) 
HPV L1 VLP vaccine (9vHPV vaccine) was approved under the name GARDASIL ®9 in over 
40 countries.
The 9vHPVvaccine formulated with Merck Aluminum Adjuvant (amorphous aluminum
hydroxyphosphate sulfate) consists of highly purified VLPs of the L1 capsid proteins from HPV 
6, 11, 16, 18, 31, 33, 45, 52, and 58. Like for GARDASIL®, the L1 capsid proteins in the vaccine 
are individually expressed in Saccharomyces cerevisiae yeast. The HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58 L1 VLPs final aqueous products are comprised of recombinant L1 polypeptides for 
their respective viral types that have self-assembled into VLPs. Following fermentation, the 
VLPs are isolated from lysed yeast cells by standard techniques, highly purified, and then 
adsorbed onto Merck Aluminum Adjuvant (amorphous aluminum hydroxyphosphate sulfate)
without the addition of preservative. After preparation of the Monovalent Bulk Adsorbed 
Products, the bulks are mixed to create the 9vHPVvaccine with the desired concentrations of 
each monovalent L1 VLP. The 9vHPVvaccine is not a live virus vaccine. It is not capable of 
causing viral infection.
 
 
04M9HD
 
 
059WG4

Product:  V503
23
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Rationale for this Study
3.1.2
Potential Benefits of Prophylactic HPV Vaccination in Adult Women
3.1.2.1
Changes in sexual behaviour in the past 30 years characterized by rising age at first marriage and 
an increase in divorce rates have meant more widespread premarital sexual intercourse and 
acquisition of new sexual partners around middle age. The potential for HPV infection and 
disease exists in women in their third, fourth, and fifth decades of life [8]. Studies suggest that 
the curve of incident high-risk HPV infections is bimodal with a first peak in women under 
25 years of age and a second peak after menopause [9]. Older women still experience a 
substantial burden of HPV-related diseases and are frequently naïve to at least one strain covered 
by the HPV vaccine. A recent study indicated high acceptance of the vaccine in older women 
(>26 years) even if the cost of the vaccine had to be self-borne [10].
Clinical studies provide evidence for a potential benefit from the qHPV vaccine GARDASIL®
for women older than 26 years of age [8]. The efficacy of GARDASIL® is relevant to 
GARDASIL®9 since the vaccines are manufactured by a similar process and contain 4 of the 
same HPV L1 VLPs. The efficacy of GARDASIL®9 was compared with that of the qHPV 
vaccine with respect to HPV types 6, 11, 16, and 18 in a population of 16- through 26-year-old 
women (Protocol 001) and in 9- through 15-year-old girls (Protocol 009) [6, 11]. Immune 
responses for GARDASIL®9 were non-inferior to immune responses for the qHPV vaccine. Of 
the subjects receiving GARDASIL®9, 99.6% to 100% became seropositive for antibodies against 
all 9 vaccine types by Month 7 across all groups tested. GARDASIL®9 was also found to be 
efficacious in preventing HPV 31-, 33-, 45-, 52-, and 58-related persistent infection and disease 
in girls and women between 16 to 26 years (Protocol 001) [12].
The end-of-study results from a multicentric GARDASIL® study with a median follow-up of 
4 years in 3,819 adult women, ages 24 to 45 [13], confirm and extend an interim analysis of this 
study in establishing that older women without evidence of prior exposure to the vaccine types 
can benefit from the vaccine [8]. The safety profile in adult women was similar to that seen in 
younger women, with a somewhat greater number of subjects administered the GARDASIL®
vaccine having adverse injection-site experiences versus controls (76.7% versus 64.2%) [13].
The long-term effectiveness and safety (through 6 years) of the GARDASIL® vaccine in older 
women has also been found to be high [14]. Studies with GARDASIL®9 in women older than 26 
years of age have not been conducted.
In several EU countries such as Austria, Italy, Ireland, and Germany, there is acknowledgement 
of HPV vaccine benefit after HPV exposure and/or treatment. Studies also suggest that subjects 
who have been previously exposed to HPV might benefit from HPV vaccination [15, 16, 17]. No 
negative impact was seen in women between 16 and 26 years of age who were seropositive
(HPV 16/18) and deoxyribonucleic acid (DNA) positive [18] at the time of vaccination, and 
vaccine efficacy was seen in women between 16 and 26 years of age who were seropositive 
(HPV 6/11/16/18) and DNA negative [19]. Results suggest that antibodies elicited by natural 
infection may not provide complete protection from subsequent HPV reinfection/reactivation and 
related disease over time in women aged 16 to 26 years, and that the robust immune response to 
the HPV vaccine may prevent recurrence or reactivation of disease with vaccine HPV types [19].
 
 
04M9HD
 
 
059WG4

Product:  V503
24
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Rationale for the Study Design
3.1.2.2
An important objective of the GARDASIL®9 (V503) clinical development program is to 
demonstrate that V503 and GARDASIL® exhibit similar performance with respect to oncogenic 
HPV types 16 and 18. In the V503 program, the efficacy findings with GARDASIL® will be 
bridged to V503 based on the demonstration of non-inferior immunogenicity. A primary 
objective of Protocol V503-001 was to demonstrate that anti-HPV 16 and 18 responses in young 
women 16 to 26 years of age administered V503 are non-inferior to responses in young women 
administered GARDASIL®.
Similarly, Protocol GDS01C/V503-009 was designed to 
demonstrate that anti-HPV 16 and 18 responses in subjects 9 to 15 years of age administered 
V503 are non-inferior to responses in subjects administered GARDASIL®. Protocol 
GDS07C/V503-020 was designed to accomplish the same objective in young men, 16 to 26 
years of age. 
Clinical studies provide evidence for a potential benefit from the qHPV vaccine GARDASIL ®
for women older than 26 years of age [8]. GARDASIL®9 received marketing authorization in the 
EU in June 2015 for active immunization of females and males from the age of 9 years. This 
study is designed to assess the safety and immunogenicity of GARDASIL®9 in 27- to 45-year-
old women, to complete the evaluation of GARDASIL®9 in the extended age range of female 
subjects for whom GARDASIL® was proven to be effective. This study is primarily powered to 
demonstrate the non-inferior immunogenicity of GARDASIL®9 in 27- to 45-year-old women, 
compared with 16- to 26-year-old women, the population in which GARDASIL®9 has been 
demonstrated to be effective, with respect to the 7 oncogenic HPV types (Types 16, 18, 31, 33, 
45, 52, and 58). The antibody response to the non-oncogenic types HPV 6/11, which are 
responsible for genital warts, will also be assessed as a secondary objective. The peak of genital 
warts in females is at 20-24 years. Consequently, although the benefit of vaccinating 
27-45 year-old women with a HPV 6/11 vaccine is not negligible, the more clinically relevant 
part of the vaccine efficacy of GARDASIL®9 in that age range is related to the 7 oncogenic 
types HPV 16/18/31/33/45/52/58, as reflected in the primary objective.
The choice of the non-inferiority margin is driven by the clinical relevance and the expected 
variability of the endpoints, and the desired accuracy of the conclusions of the study. A 2-fold 
non-inferiority margin is considered as appropriate to assess any negative trend in 
immunogenicity with GARDASIL®9 in 27-45 year-olds women compared with 16-26 year-olds 
women. Specifically, it is reflecting the fact that the immunogenicity of any HVP vaccines 
decreases with the increasing age of the subjects making impossible the use of a more stringent 
non-inferior margin (e.g., 1.5). In addition a more stringent margin is considered to be of limited 
interest as there is currently no known minimum immunologic correlate for HPV vaccine 
efficacy, due to high efficacy of the vaccine; such  margin would not be expected to add further 
clinical significance to the results.
This study will include approximately 1,200 women into each of the 2 age groups (27- to 
45-year-old subjects and 16- to 26-year-old subjects). Each age group will be further stratified 
into subgroups of 16- to 20-year-olds and 21- to 26-year-olds for YAW and 27- to 36-year-olds 
and 37- to 45-year-olds for AW. Enrolment will be monitored to make sure that no single age 
 
 
04M9HD
 
 
059WG4

Product:  V503
25
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
stratum (i.e., subgroup) exceeds 55% of the total sample of a given age group (i.e., enrolment in 
an age stratum will be stopped when around 330 subjects in that age stratum have been 
vaccinated).
Rationale for Future Biomedical Research
3.1.2.3
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial. 
This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere in 
the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future Biomedical 
Research is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. The overarching goal is to use such information to 
develop safer, more effective vaccines, and/or to ensure that subjects receive the correct dose of 
the correct vaccine at the correct time. The details of this Future Biomedical Research sub-trial
are presented in Appendix 6.2: Collection and Management of Specimens for Future Biomedical 
Research. 
Study Procedures
3.2
Identifying Study Subjects
3.2.1
Potential study subjects and/or the parent(s)/legal guardian(s) of potential study subjects (for 
subjects less than 18 years of age, according to specific local regulations [see Section 3.2.2]) will 
be informed by the investigator about the possibility of their participation in the study. They will 
be contacted through a telephone call, an invitation letter, an information meeting and/or during a 
medical visit with the investigator. The study objectives, obligations, benefits and risks will be 
discussed with potential subjects. The investigator will mention that the participation is voluntary 
and that withdrawal from the study or non-participation in the study will have no effect on the 
care to which the subject is otherwise entitled.
Informed Consent 
3.2.2
The investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial or Future Biomedical Research. If there are changes to the 
subject’s status during the trial (e.g., health or age of majority requirements), the investigator or 
qualified designee must ensure the appropriate consent is in place.
 
 
04M9HD
 
 
059WG4

Product:  V503
26
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
General Informed Consent
3.2.2.1
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations and 
Sponsor requirements.
Additional ICFs will be obtained in case of a pregnancy occurring during the study to collect 
data on pregnancy, general data on the baby’s health at delivery and complications, if any. The 
subject or their legal representative must receive a copy of the signed and dated ICF.
Consent and Collection of Specimens for Future Biomedical Research
3.2.2.2
The investigator or qualified designee will explain the Future Biomedical Research consent to 
the subject, answer all of her questions, and obtain written informed consent before performing 
any procedure related to the Future Biomedical Research sub-trial.  A copy of the informed 
consent will be given to the subject.
Subject Identification Card
3.2.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee will 
provide the subject with a Subject Identification Card immediately after the subject provides 
written informed consent. At the time of treatment allocation, site personnel will add the 
allocation number to the Subject Identification Card.
 
 
04M9HD
 
 
059WG4

Product:  V503
27
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
The subject identification card also contains contact information for the emergency unblinding 
call center so that a health care provider can obtain information about trial vaccination in 
emergency situations where the investigator is not available.
Concomitant Medication(s)/Treatment(s)
3.2.4
See the exclusion criteria for specific restrictions for prior and concomitant medications at Day 
1. Use of medicines and non-study vaccines will be reviewed at each visit and should be 
documented in the data collection system in the following manner: 

“Special Medications” (corticosteroids, immunosuppressives, immune globulins, and 
blood products) from 3 days prior to Day 1 through Month 7;

“Other Medications” from 3 days prior to each study vaccination through 15 days (Day 1 
to Day 15) after each study vaccination; 

“Non-Study Non-Replicating (Inactive) Vaccines” for 14 days prior to each study 
vaccination through 15 days (Day 1 to Day 15) after each study vaccination; and

“Non-Study Replicating (Live) Vaccines” for 21 days prior to each study vaccination 
through 15 days (Day 1 to Day 15) after each study vaccination.
If possible, the subject should not receive special medications or non-study vaccines within the 
time periods given above. Subjects may receive allergen desensitization therapy and tuberculin 
skin testing while participating in the study.  
Assignment of Screening Number
3.2.5
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur prior to vaccine allocation.  Each subject will be assigned 
only one screening number.  Screening numbers must not be re-used for different subjects.
Any subject who is screened multiple times will retain the original screening number assigned at 
the initial screening visit.
Assignment of Allocation Number
3.2.6
A subject who passes screening will be assigned an allocation number from the allocation 
schedule corresponding to the subject’s age group.  The allocation number identifies the subject 
for all procedures occurring afterscreening.  Once an allocation number is assigned to a subject, 
it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 allocation number.
 
 
04M9HD
 
 
059WG4

Product:  V503
28
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
The allocation number to be obtained from the interactive response technology (IRT) system is a 
6 digit number within a pre-specified range of values. The allocation number is assigned just 
before vaccination and will also be transferred in EDC.
During the Day 1 visit, one may discover a condition that will make the subject ineligible for the 
study.  For example, exclusionary medical conditions mentioned in the inclusion/exclusion 
questions may be found during limited medical history review.  Thus, all pre-vaccination data 
must be collected and all study procedures must be completed before the subject is assigned an
allocation number.
Dispense Electronic Vaccination Report Cards
3.2.7
The vaccination report card was developed to be administered electronically via a hand –held 
device. This item was structured as recommended in the final FDA Patient Reported Outcome 
(PRO) Guidance. The investigator or delegate will train the subject or subject’s parent/legal 
guardian in the use of the electronic vaccination report card prior to dispensing it at Visit 1. Oral
temperatures, injection-site AEs, eVRC-prompted systemic complaints, other complaints or 
illnesses, and medications will be recorded on the eVRC throughout the study. The study site 
personnel will review the data captured on the eVRC with the subject or subject’s parent/legal 
guardian at Visit 2 through Visit 4.
Vaccination and Evaluation
3.2.8
Please review the study flow chart (Section 1.7) for time frames within which to schedule study 
visits.
Management of Pregnant Subjects
3.2.9
All subjects will have a serum or urine pregnancy test performed before administration of each 
dose of the study vaccine and at the final Month 7 visit per the manufacturer’s instructions.
Any subject with a positive pregnancy test at Day 1 will not be vaccinated and will not be 
allowed to participate in the study.
For subjects who become pregnant after receiving one or two study vaccinations, study visits and 
vaccinations will be paused until resolution of the pregnancy (e.g. term, elective termination, 
spontaneous abortion). Study visits and study vaccination in pregnancy subjects will be handled 
as described in Table 3.  Breastfeeding is not a contraindication to receiving study vaccinations. 
Pregnancy and breast-feeding in study subjects and infant serious adverse experiences (SAEs) 
must be reported as described in Section 3.4.
 
 
04M9HD
 
 
059WG4

Product:  V503
29
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Table 3
Guidelines for Pregnant Subjects: Managing Study Visits and Study Vaccinations
Time When Pregnancy is 
Detected
Action
Day 1 (before first vaccination)
Do not vaccinate subject
Between Day 1 and Month 2
(After study vaccine dose 1 and 
before study vaccine dose 2 
was administered)
No scheduled visits 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
(After study vaccine dose 2 and 
before study vaccine dose 3 
was administered)
No scheduled visits 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
(After study vaccine dose 3 was 
administered)
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).
Dosage and Administration
3.2.10
Study vaccine will be administered at Day 1, Month 2, and Month 6. At each visit, subjects will 
receive GARDASIL®9 as a 0.5-mL intramuscular injection using a syringe. Injections should be 
administered at a 90° angle into the muscle tissue using a needle long enough to ensure 
intramuscular deposition of vaccine. The deltoid muscle of the non-dominant arm is the preferred 
site of vaccination. Study vaccines should not be administered into the buttocks area. Injections 
should not be given within 2 cm of a tattoo, scar, or skin deformity.  
The subject should be afebrile (oral temperature <37.8ºC or 100.0°F) for 24 hours prior to each 
vaccination. If the subject reports having been febrile within this 24-hour pre-vaccination period, 
no vaccination will be administered to her. The subject should be rescheduled to return for the 
vaccination visit once the fever has been resolved for at least 24 hours.
If other non-study vaccinations are administered at any time during the study, they should not be 
administered in the same limb as the study vaccine and must be appropriately documented. The 
injection site for these non-study vaccines must also be documented.  
 
 
04M9HD
 
 
059WG4

Product:  V503
30
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Future Biomedical Research Samples
3.2.11
The following specimens are to be obtained and stored as part of Future Biomedical Research:

DNA for future research

Leftover main study serum from anti-HPV antibody testing stored for future research
Blinding/Unblinding 
3.2.12
Not applicable. This is an open-label study.
General Precautions for Administration of Study Vaccines
3.2.13
Adequate treatment provisions, including epinephrine, should be available for immediate use 
should any anaphylactic or anaphylactoid reactions occur. The subject should stay at least 
15 minutes at the investigator's office to detect any immediate AE.
A sterile syringe and needle should be used for the vaccination injection for each subject. 
Needles should not be recapped. Safe disposal procedures should be followed.
Discontinuation/Withdrawal Criteria
3.2.14
Discontinuation of Vaccination
3.2.14.1
Discontinuation of study vaccination does not represent withdrawal from the study.
As certain data on clinical events beyond study vaccination 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 vaccination. Therefore, all participants who discontinue study 
vaccination prior to completion of the vaccination period, will still continue to participate in the 
trial.
Participants may discontinue study vaccination at any time for any reason or be dropped from the 
study vaccination at the discretion of the investigator should any untoward effect occur.
In 
addition, a participant may be discontinued from study vaccination by the investigator or the 
Sponsor if study vaccination is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.
A participant must be discontinued from study vaccination 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 
vaccination.
For participants who are discontinued from study vaccination but continue to be monitored in the 
trial, all visits and procedures, as outlined in the trial flowchart, should be completed, except for 
serum collection for HPV testing at the final visit.
 
 
04M9HD
 
 
059WG4

Product:  V503
31
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Participants may be allowed to begin study vaccination again if deemed medically appropriate.
Withdrawal from the Study
3.2.14.2
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 vaccination or be 
followed at scheduled protocol visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed except for serum collection for HPV 
testing at the time of discontinuation.  Any adverse events which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 3.4.2 - Assessing and Recording Adverse Events.
Withdrawal from Future Biomedical Research
3.2.14.3
Subjects may withdraw their consent for Future Biomedical Research.  Subjects may withdraw 
consent at any time by contacting the principal investigator for the main trial.  If medical records 
for the main trial are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@merck.com).  Subsequently, the subject's consent for 
Future Biomedical Research will be withdrawn.  A letter will be sent from the Sponsor to the 
investigator confirming the withdrawal. It is the responsibility of the investigator to inform the 
subject of completion of withdrawal.  Any analyses in progress at the time of request for 
withdrawal or already performed prior to the request being received by the Sponsor will continue 
to be used as part of the overall research trial data and results.  No new analyses would be 
generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or the 
specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for specimen 
withdrawal cannot be processed.
Lost to Follow-up
3.2.14.4
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject 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 subject 
at each missed visit (e.g. phone calls and/or a certified letter to the subject’s last 
 
 
04M9HD
 
 
059WG4

Product:  V503
32
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
known mailing address or locally equivalent methods). These contact attempts should 
be documented in the subject’s medical record.

Note:  A subject is not considered lost to follow up until the last scheduled visit for 
the individual subject.  The amount of missing data for the subject will be managed 
via the pre-specified data handling and analysis guidelines
Immunogenicity Measurements
3.3
The assay used in this study is the 9-valent HPV cLIA. The purpose of the assay is to detect 
antibodies to HPV VLPs types 6, 11, 16, 18, 31, 33, 45, 52, and 58, before and after vaccination 
with GARDASIL®9. Tests will be performed by Focus Diagnostics, Inc. (California, U.S.A) to
measure HPV antibodies at baseline and evaluate the serological response after vaccination.  
Yeast-derived VLPs are coupled to a set of 9 distinct fluorescent Luminex microspheres. 
Antibody titres are determined in a multiplexed, competitive format in which known HPV 
type-specific, phycoerythrin-labelled, neutralising monoclonal antibodies (mAbs) compete with 
the subject’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 subject’s neutralizing antibody titres. Results 
for the assay are reported as a concentration of antibody in arbitrary milli-Merck Units per 
millilitre (mMU/mL). 
The HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 cLIA is performed in a 96-well microtitre plate. A 
12-point standard curve using reference serum pool from adult females immunized with 9-v 
HPV vaccine, 4 controls, and 16 samples are added to the plate in duplicate. Samples are tested 
at a 1:4 and a 1:40 dilution. The detection antibodies followed by the VLP-microspheres for 
types 6, 11, 16, 18, 31, 33, 45, 52, and 58 are added to each well. The plates are sealed with foil 
covers and incubated for 15 to 25 hours. Following incubation, the plates are washed and then 
analysed on a BioPlex (Luminex) instrument.
The seropositivity cutoffs for HPV types are assessed using a panel of sera from subjects that are 
highly likely to be HPV naïve (children), and from subjects who are likely to be seropositive.   
Any sample being tested for a specific HPV type with a cLIA titre lower than the cutoff 
corresponding to that HPV type is considered seronegative for that HPV type.
Safety Measurements
3.4
Clinical Measurements for Safety
3.4.1
All subjects will be observed for at least 15 minutes after each study vaccination for any 
untoward effects, including allergic reactions. This observation period will be documented in the 
subject’s study chart.  
Each subject will receive an electronic VRC at the Day 1, Month 2, and Month 6 study 
vaccination visits. On the eVRC, the subject or the subject's parent or guardian will be asked to 
 
 
04M9HD
 
 
059WG4

Product:  V503
33
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
record oral temperature in the evening after each study vaccination and daily, at the same time of 
day, for 4 days after each study vaccination for the purpose of identifying febrile events. They 
will also be asked to record any injection-site reactions prompted in the eVRC, i.e., injection-site 
tenderness, swelling, or redness occurring after each study vaccination and daily for 4 days after 
each study vaccination (solicited injection-site reactions). In addition to injection-site reactions 
prompted in the eVRC, the subject or the subject's parent or guardian will be asked to assess the 
presence of other injection-site reactions and systemic AEs starting after each study vaccination 
for a total of 15 days. The subject or the subject's parent or guardian will be asked to record 
injection-site and systemic AEs, concomitant medications, and concomitant vaccinations on the 
eVRC. 
The information on the eVRC should be generated only by the subject or the subject's parent or 
legal guardian.. The subject will be expected to bring the eVRC to the study site at the next 
scheduled visit. In case of hospitalization or visit to another physician, the subject or the subject's 
parent or legal guardian should be informed to contact the investigator immediately.
The study site personnel will review the data captured on the eVRC with the subject or subject’s 
parent/legal guardian at Visit 2 through Visit 4.
All eVRC information will be recorded in the EDC system. The investigator/sub-investigator 
will determine causality of systemic AEs recorded on the eVRC using the guidelines given in 
Section 3.4.2.4 and will classify each event as an SAE or non-serious AE. If an oral temperature 
indicates a fever (defined as an oral temperature of ≥37.8°C or 100.0°F), the AE of “fever” must 
be documented in the electronic case report forms (e-CRFs).
At the time of eVRC review at the next scheduled visit, subjects will be questioned regarding 
any new medical conditions that occurred beyond Day 15
(after
dosing).
The 
investigator/sub-investigator will determine if the medical condition is to be reported as an SAE 
using the reporting guidelines provided below. 
Assessing and Recording Adverse Events
3.4.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol -
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time.
 
 
04M9HD
 
 
059WG4

Product:  V503
34
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Sponsor's product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by the Sponsor for human use.
Adverse events may occur during the course of the use of the Sponsor's product in clinical trials 
or within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation baseline period as 
a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
All adverse events will be collected from the time the consent form is signed through 14 days 
following the first vaccination(s) and from the time of any subsequent vaccination(s) through 14 
days thereafter, and such events will be recorded at each examination on the Adverse Event case 
report forms/worksheets.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
3.4.2.1
Sponsor
In this trial, an overdose is any dose higher than 0.75 mL of vaccine in any one dose or receiving 
>4 doses (0.5mL each dose).
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor either by electronic media or paper.  Sponsor Contact information can be found in 
the Investigator Trial File Binder.
Reporting of Pregnancy and Lactation to the Sponsor
3.4.2.2
Although not considered an adverse event, it is the responsibility of the investigators or their 
designees to report any pregnancy in a subject (spontaneously reported to them or detected by 
urine or serum pregnancy test per protocol) that occurs during the trial through 1 month
following the last vaccination.  If a subject becomes pregnant during the trial, including subjects 
who never received vaccine allocation and had a positive pregnancy test at Day 1, all related 
information must be reported to the SPONSOR. For subjects who become pregnant with LMP 
prior or equal to Day 30 following the final vaccination, the pregnancy will be collected in the 
SPONSOR'S global safety database. Furthermore, all fetal loss pregnancy outcomes (ectopic 
pregnancy, elective termination, spontaneous abortion, late fetal death) must be reported as a 
 
 
04M9HD
 
 
059WG4

Product:  V503
35
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Serious Adverse Experience (Other Important Medical Event). All subjects who receive study 
vaccine, including discontinued subjects who agree to provide further information, must be 
followed to the completion/termination of the pregnancy. In addition, if the pregnancy continues 
to term, the outcome (health of the infant) must be reported.
If a subject receives study vaccine while breastfeeding all related information, including 
outcome, must be reported to the SPONSOR. Infant serious adverse experiences (SAEs) for all 
infants born to subjects who received study vaccine must be reported to the SPONSOR.
All pregnancy, lactation, and infant SAE events must be reported within 24 hours to the 
SPONSOR either by electronic media or paper. SPONSOR contact information can be found in 
the Investigator Trial File Binder. Refer to Data Entry Guidelines (DEGs) for instructions for 
reporting these events.
Immediate Reporting of Adverse Events to the Sponsor
3.4.2.3
3.4.2.3.1 Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is a cancer;

Is associated with an overdose;

Is another important medical event 
Refer to Table 4 for additional details regarding each of the above criteria.  
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause, that occurs to any subject from the time the consent is signed through 1 month following 
the last vaccination, whether or not related to the Sponsor's product, must be reported within 24 
hours to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder.
Additionally, any serious adverse event brought to the attention of an investigator who is a 
qualified physician at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor if the event is either:

A death that resulted in the subject discontinuing the trial 
or

A serious adverse event that is considered by an investigator who is a qualified physician to 
be vaccine related.
 
 
04M9HD
 
 
059WG4

Product:  V503
36
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
All subjects with serious adverse events must be followed up for outcome.
3.4.2.3.2 Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor either by electronic media or paper.  Sponsor Contact 
information can be found in the Investigator Trial File Binder.
Events of clinical interest for this trial include:

An overdose of Sponsor's product, as defined in Section 3.4.2.1- Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
Evaluating Adverse Events
3.4.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to the 
elements outlined in Table 4.The investigator’s assessment of causality is required for each 
adverse event.  Refer to Table 4 for instructions in evaluating adverse events.
 
 
04M9HD
 
 
059WG4

Product:  V503
37
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Table 4
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities) 
Injection site redness or swelling from the day of vaccination through Day 4 post-vaccination will be evaluated by maximum size.
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer; or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose 
that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the test vaccine to be discontinued?
Relationship 
to test vaccine 
Did the test vaccine cause the adverse event?   The determination of the likelihood that the test vaccine 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 vaccine and the adverse event based upon the 
available information.  
The following components are to be used to assess the relationship between the test vaccine and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the test vaccine caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the test vaccine such as:  reliable history, acceptable compliance assessment 
(e.g., diary), seroconversion or identification of vaccine virus in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the test vaccine? 
Is the time of onset of the AE compatible with a vaccine-induced effect?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or
environmental factors
 
 
04M9HD
 
 
059WG4

Product:  V503
38
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Relationship
The following components are to be used to assess the relationship between the test vaccine and the AE:  (continued)
to test vaccine 
Dechallenge
(not applicable for vaccines)
(continued) 
Rechallenge
Was the subject reexposed to the test vaccine in this trial?
      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 trial is a single-dose 
vaccine trial.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE 
BEEN CAUSED BY THE TEST VACCINE, OR IF REEXPOSURE TO THE TEST VACCINE POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. 
CLINICAL MONITOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency with Trial 
Vaccine Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test vaccine or vaccine 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.  
Record one of the following:
Use the following criteria as guidance (not all criteria must be present to be indicative of a vaccine relationship).
Yes, there is a reasonable possibility of 
vaccine relationship.
There is evidence of exposure to the test vaccine.  The temporal sequence of the AE onset relative to the administration of the test vaccine 
is reasonable.  The AE is more likely explained by the test vaccine than by another cause.
No, there is not a reasonable possibility of 
vaccine relationship
Subject did not receive the test vaccine OR temporal sequence of the AE onset relative to administration of the test vaccine is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
 
 
04M9HD
 
 
059WG4

Product:  V503
39
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Sponsor Responsibility for Reporting Adverse Events and Patient/Device 
3.4.2.5
Events and Incidents
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
Statistical analysis plan
3.5
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to database lock, changes are made to primary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with International Conference on Harmonisation [ICH] Guideline E-9). Changes to 
exploratory or other non-confirmatory analyses made after the protocol has been finalized, 
along with an explanation as to when and why they occurred, will be listed in the clinical 
study report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in 
the CSR.. All statistical analyses specified in this protocol will be conducted using SAS ®
Version 9.3 or higher.
In-house Blinding
3.5.1
All subjects in this study will receive GARDASIL®9; the study is thus open-label. However, 
laboratory personnel conducting HPV assays will be blinded to all subjects' age. 
Hypothesis/Estimation
3.5.2
Objectives and hypotheses of the study are stated in Section 2.1.
The study will be considered a success if the non-inferiority criteria for GMTs are met for 
HPV types 16, 18, 31, 33, 45, 52, and 58 for the comparisons between 27- to 45-year-old 
women versus 16- to 26-year-old women that received GARDASIL®9.
Analysis Endpoints
3.5.3
Immunogenicity
3.5.3.1
The primary immunogenicity endpoints are the cLIA GMTs to HPV 16, 18, 31, 33, 45, 52 
and 58 at 4 weeks after Dose 3.
The secondary immunogenicity endpoints are:
the cLIA seroconversion percentages to HPV 16, 18, 31, 33, 45, 52 and 58 by 4 weeks after
Dose 3 in 27- to 45-year-old women.
the cLIA GMTs and the cLIA seroconversion percentages to each of HPV 6, 11, 16, 18, 31, 
33, 45, 52, and 58 by 4 weeks after Dose 3 in 16- to 26-year-old women and 27- to 45-year-
old women.
 
 
04M9HD
 
 
059WG4

Product:  V503
40
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
A subject with a cLIA titre at or above the serostatus cutoff for a given HPV type (see 
Section 3.3) is considered seropositive for that type. Seroconversion is defined as changing 
serostatus from seronegative at Day 1 to seropositive, by 4 weeks after Dose 3.
Safety
3.5.3.2
Safety assessment will focus on injection-site adverse reactions and elevated temperatures 
Day 1 to Day 5 post-vaccination and systemic AEs Day 1 to Day 15 post-vaccination, 
reported on the electronic VRC. In addition, SAEs and pregnancy will be collected from the 
time the ICF is signed through 1 month following the last vaccination.
Analysis Populations
3.5.4
Immunogenicity Analysis Populations
3.5.4.1
Per Protocol Immunogenicity Population
The per-protocol immunogenicity (PPI) analysis populations will serve as the primary
populations of subjects for the analysis of immune responses to each of the 9 HPV types (6, 
11, 16, 18, 31, 33, 45, 52, and 58). The PPI analysis populations are HPV type-specific, i.e., 
each HPV type has its own PPI analysis population. To be included in a particular HPV type-
specific PPI analysis population, subjects must:

Have received all 3 vaccinations of the correct dose of GARDASIL®9 within 
acceptable day ranges (See Table 5).

Have evaluable serology results at Day 1 and Month 7 based on serum samples 
collected within acceptable day ranges (See Table 6).

Be seronegative to the appropriate HPV type at Day 1.

Have no protocol deviations that could interfere with the evaluation of subject's 
immune response to GARDASIL®9.
To be included in the PPI analysis population for HPV 6 and 11, subjects must be 
seronegative to both HPV 6 and 11 at Day 1. To be included in the PPI analysis population 
for any other vaccine HPV type, subjects need to be seronegative to that specific type at Day 
1. The final determination of protocol deviation categories deemed as having potential to 
interfere with evaluation of immune response to GARDASIL®9 will be made prior to 
database lock and will be recorded in a separate study document.
 
 
04M9HD
 
 
059WG4

Product:  V503
41
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Table 5
Acceptable Day Ranges for Vaccination Visits
Dose of 9vHPV Vaccine 
Scheduled for Injection
Protocol Specified
Visit Window
Day Range for Inclusion 
in Statistical Analysis 
(Relative to Day 1†)
Dose 1
Day 1†
0
Dose 2
Month 2 ± 3 weeks
36 to 84
Dose 3
Month 6 ± 4 weeks
148 to 218
†  Day 1 refers to the date when Dose 1 of the study vaccine is injected. For vaccinations after Day 1, the 
day ranges for inclusion in the statistical analysis are wider than the protocol-specified visit windows 
primarily to account for differences at the study sites in counting months (e.g., 1 calendar month versus 
30 days versus 4 weeks).
9vHPV, 9-valent human papillomavirus.
Table 6
Acceptable Day Ranges for Collection of Serum Samples
Study Visit
Target Collection Day
(Relative to Day 1†)
Day Range for Inclusion in 
Statistical Analysis†
Day 1
0
–14 to 0 (Relative to Day 1)‡
Month 7
30 days after Dose 3
21 to 49 after Dose 3§
† Day 1 refers to the date when dose 1 of study vaccine is injected. For Month 7, indicated target 
collection/day range is relative to date of injection of Dose 3 of study vaccine.
‡ Applies to both the PPI and ANSS analysis populations.
§ Applies to the PPI analysis lation only. The day range for the ANSS analysis population is 21 to 105 days 
after dose 3.
ANSS = All type-specific naïve subjects with serology; PPI = Per-protocol immunogenicity.
All Type-Specific Naïve Subjects with Serology Population
A supportive immunogenicity analysis will be carried out on the all type-specific naïve 
subjects with serology (ANSS) analysis population. The ANSS analysis populations are HPV 
type-specific similar to the PPI analysis populations. To be included in these sets of subjects, 
subjects must: 

Have received all 3 vaccinations of GARDASIL®9;

Have evaluable serology results at Day 1 and Month 7 based on serum samples 
collected within acceptable day ranges (See Table 6);

Be seronegative to the appropriate HPV type at Day 1.
To be included in the ANSS analysis population for HPV 6 and 11, subjects must be 
seronegative to both HPV 6 and 11 at Day 1. To be included in the ANSS analysis population
for any other vaccine HPV type, subjects need to be seronegative to that specific type at Day 
1.
Unlike the PPI analysis populations, ANSS analysis populations will not exclude subjects 
who had protocol deviations deemed as having potential to interfere with evaluation of 
 
 
04M9HD
 
 
059WG4

Product:  V503
42
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
immune response to GARDASIL®9. In addition, no day ranges on the timing of the 
vaccination will be applied. 
Safety Analysis Population
3.5.4.2
The all subjects as-treated (ASaT) analysis population, comprised of subjects who received at 
least 1 dose of GARDASIL®9 and had at least 1 study visit with safety follow-up, will be the 
primary population for safety analyses.
Statistical Methods
3.5.5
Immunogenicity Analyses
3.5.5.1
The primary hypotheses of non-inferiority of GMTs for the oncogenic HPV types 16, 18, 31, 
33, 45, 52, and 58 will be addressed by 7 one-sided tests of non-inferiority (one 
corresponding to each HPV type) conducted at Type I error α=0.025 (1-sided). For each HPV 
type, the hypotheses to be tested are:
H0: GMTAW/GMTYAW ≤0.50
VersusH1: GMTAW/GMTYAW >0.50
where GMTAW represents the GMTs at Month 7 in 27- to 45-year-old subjects and GMTYAW
represents the GMTs at Month 7 in 16- to 26-year-old subjects. The hypothesis testing will 
be conducted using an ANOVA model with a response of log individual titres and a fixed 
effect for age group. The statistical criterion for non-inferiority requires that the lower bound 
of two-sided 95% confidence interval (CI) of GMT ratio (27- to 45-year-old subjects versus 
16- to 26-year-old subjects) being greater than 0.50.
It is assumed that the true GMT ratio AW/YAW is 0.7 which is based on the results from 
V501 Protocol 019 where GMTs were observed to decrease with age at vaccination. The 
proposed approach (using a non-inferiority margin of 2.0) is appropriate to estimate the GMT 
ratio and corresponding 95% CIs, and assess any negative trend in immunogenicity with 
GARDASIL®9 in AW compared to YAW. Moreover, the scientific merit of a non-inferior 
margin of 1.5 would be limited as there is currently no known minimum immunologic 
correlate for HPV vaccine efficacy, due to high efficacy of GARDASIL®9; it is not expected 
to add further clinical significance to the results. A study powered for a more stringent non-
inferiority margin would require a substantial increase in sample size which was not deemed 
necessary for the purpose of this study, based on the immunogenicity data available when 
this study was designed. 
The secondary hypotheses of acceptability of the anti-HPV 16, 18, 31, 33, 45, 52 and 58 
seroconversion rates in the 27- to 45-year-old women group will be tested based on the 95% 
CIs for the single group proportion calculated using the exact binomial method (Clopper-
Pearson method) for single proportions. For each HPV type, the statistical criterion for 
acceptability requires that the lower bound of the 95% CIs of the seroconversion rate for each 
of the antigens is greater than 90%.
 
 
04M9HD
 
 
059WG4

Product:  V503
43
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Primary and secondary endpoints (including anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 
GMTs and seroconversion rates at 4 weeks after Dose 3) will be summarized within each age 
group and enrolment strata (16- to 20-year-olds and 21- to 26-year-olds for YAW and 27- to 
36-year-olds and 37- to 45-year-olds for AW [Section 2.4.1]) for all subjects in the PPI
analysis populations. Furthermore, in order to assess the sensitivity of the results, these 
analyses will be repeated on the ANSS analysis populations. 
In calculations of GMTs by HPV type, cLIA titres reported as less than the Lower Limit of 
Quantification (LLOQ) of the relevant HPV type will be replaced by the half of the LLOQ in 
the numerical computation of GMT. No search for outliers will be performed. 
In addition, reverse cumulative distribution curves will be provided for graphical 
comparisons of distributions of HPV titres by age groups.
Statistical Methods for Safety Analyses
3.5.5.2
Safety and tolerability will be assessed by statistical and clinical review of all safety data 
collected throughout the study. Summaries will be provided for each age group. Statistical 
analyses of AEs will follow the 3-tiered analysis approach commonly used by the Sponsor 
when conducting safety assessments, as outlined in Section 2.7.2. 
Regardless of incidence, all AEs will be summarized as frequencies and percentages by each 
age group, by vaccination visit, and across all vaccination visits. 
Specific AEs for which summaries will be provided are identified in Table 7.
Incidence is defined as (number of subjects with the indicated endpoint divided by the total 
number of subjects with follow-up over the relevant period) × 100%.
Confidence intervals (95%) and 2-sided p-values will be provided without adjusting for 
multiplicity.
The method of Miettinen and Nurminen [20] will be used for all comparisons of groups.
Risk differences, CIs, and p-values will be computed across all sites combined (i.e., no 
stratification by study sites will be performed).
Treatment administration data will be summarized for each age group including number of 
vaccine injections received. Imputation methods will not be used to replace missing safety 
data.
 
 
04M9HD
 
 
059WG4

Product:  V503
44
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Table 7
Analysis Strategy for Safety Parameters
Follow-Up Period
Summaries/Analyses
After Any 
Vaccination 
Visit
Any 
Time 
During 
Study
Incidence
Risk 
Difference 
and 95% 
CI (b)
p-Value
Adverse Event Endpoint
Day 1
to Day 
5 (a)
Day 1
to Day 
15 (a)
Clinical AEs
Any AE
●
●
Deaths
●
●
Injection-site adverse reactions (c)
Injection-site pain/tenderness, 
swelling, and redness 
Other injection-site adverse 
reactions
●
●
●
●
●
     ● (d)
●
Severe injection-site adverse 
reactions
●
●
●
Number (%) of subjects by 
maximum intensity rating, over all 
injection-site adverse reactions
●
●
Number (%) of subjects by 
maximum intensity rating, within 
each of the categories of 
injection-site adverse reactions
●
●
Systemic AEs
Systemic AEs
●
●
   ● (e)
Number (%) of subjects by 
maximum intensity rating, over all 
systemic AEs
●
●
Temperatures
Elevated temperatures (f)
●
●
●
●
Maximum temperatures (g)
●
●
AEs of Special Interest
Serious AEs
●
●
●
Serious VR AEs
●
●
●
New medical conditions
●
●
(a) The day of vaccination is counted as Day 1.
(b) Defined as the difference in incidence between the comparison groups.
(c) For the injection-site redness and swelling 0 to 2.5 cm (0 to 1 inch) will be categorized as mild, >2.5 to 5 
cm (>1 inch to 2 inches) will be categorized as moderate, and >5 cm (>2 inches) will be categorized as 
severe.
(d) Only for injection-site adverse reactions occurring in ≥1% of subjects in either group.
(e) Only for systemic AEs occurring in ≥1% of subjects in either group.
(f)
Defined as maximum (over the follow-up period) temperature ≥37.8°C (≥100°F, oral equivalent).
(g) Distribution of maximum temperatures over the relevant follow-up period. 
AEs, adverse events; VR, vaccine-related.
 
 
04M9HD
 
 
059WG4

Product:  V503
45
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Summaries of Baseline Characteristics, Demographics, and Other Analyses
3.5.5.3
Baseline characteristics and demographic variables will be summarized by age groups using 
descriptive statistics or categorical tables on all subjects enrolled in the study and on all PPI-
eligible subjects (i.e., subjects belonging to at least one PPI analysis populations). No formal 
statistical testing of differences between age groups with respect to these characteristics will 
be performed.
Quantitative variables (except antibody titres) will be displayed using descriptive statistics by 
way of sample size, mean, standard deviation, median, minimum, and maximum. Antibody 
titres will be displayed using descriptive statistics by way of sample size, GMTs, and two-
sided 95% CIs.
Categorical variables will be displayed using descriptive statistics by way of sample size, 
count by category, and proportion by category. Missing data will be counted but not included 
in the calculation of proportions.
Subject Accounting
The number and percentage of subjects screened (ICF signed), enrolled (allocation number 
assigned), vaccinated (at least once and at each vaccination time point), discontinued, and the 
primary reason for discontinuation will be displayed by age group. Reasons for subjects 
excluded from the PPI analysis populations will be summarized and displayed in subject 
accounting tables. A summary of subjects screened/vaccinated by country/site will be 
provided.
Subject Characteristics
Demographic variables and other baseline characteristics such as age, vital signs (height, 
weight, and oral temperature), and country will be summarized by strata and age group.  
Baseline HPV Status
A serum sample will be collected from all subjects at the Day 1 visit for the purpose of 
assessing baseline HPV serostatus to the 9vHPVvaccine HPV types (HPV 6, 11, 16, 18, 31, 
33, 45, 52, and 58). A subject will be considered seropositive to a given HPV type at Day 1 if 
the subject’s anti-HPV titre is greater than or equal to the corresponding serostatus cutoff for 
that HPV type or seronegative to a given HPV type at Day 1 if the subject’s anti-HPV titre is 
less than the corresponding serostatus cutoff for that HPV type. For each HPV type, the 
proportions of subjects who are seronegative or seropositive will be summarized by strata 
and age group.
Prior and Concomitant Medications
The number and percentage of subjects with prior medications or vaccinations prior to each 
study vaccination will be summarized for each age group. The relevant pre-injection day 
 
 
04M9HD
 
 
059WG4

Product:  V503
46
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
ranges for summarization will be 3 days for medications, 14 days for non-live virus vaccines,
and 21 days for live virus vaccines. 
Similarly, the number and percentage of subjects with concomitant medications or 
vaccinations within 15 days (Day 1 to Day 15) following any study vaccination will be 
summarized for each age group. The number of subjects with “Special Medications” 
(corticosteroids, immunosuppressives, immune globulins, and blood products [Section3.2.4]) 
will be summarized for each age group throughout the study period. 
New Medical Conditions: New medical conditions occurring during the study (i.e., incident 
medical conditions occurring outside of a Day 1 to Day 15 period post-vaccination and not 
considered SAEs) will be summarized for each age group.
Multiplicity
3.5.6
For the primary hypotheses, success requires that non-inferiority be established for all 
oncogenic HPV types (i.e., 16, 18, 31, 33, 45, 52, and 58); thus, no multiplicity adjustment is 
necessary for this study.
Sample Size and Power Calculations
3.5.7
Sample Size and Power for Immunogenicity Analyses
3.5.7.1
This study will include approximately 1,200 women into each of the 2 age groups (27- to 
45-year-old subjects and 16- to 26-year-old subjects).
The power of the study was calculated using SAS Version 9.3 based on the assumption of 
log-normality of the post-vaccination titres.
The analysis of the immunogenicity endpoints will follow a Per Protocol approach. In the 
scope of the study, i.e., an immunogenicity study with a 3-dose HPV vaccination schedule on 
women 16- to 45-years of age, the rate of dropout and general protocol deviations deemed as 
having potential to interfere with evaluation of immune response to GARDASIL®9 leading to 
exclusion from the per protocol analysis is expected to be less than 15%. Based on a previous 
study conducted with GARDASIL® in 24- to 45-year-old women (Study V501 Protocol 019), 
it is assumed that 10 to 20% of enrolled subjects would be seropositive at baseline for a given 
HPV type. This would lead to an overall rate of exclusion from the PPI analysis populations
ranging from 25% to 35% of enrolled subjects. Given these exclusion rates, starting with 
1,200 enrolled subjects (600 per age group), Table 8 shows the number of evaluable subjects 
and the corresponding power for one single comparison depending on the percentage of 
subjects excluded from the PPI analysis populations.
 
 
04M9HD
 
 
059WG4

Product:  V503
47
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Table 8
Study Power Depending on Exclusion Rates
Number of 
enrolled 
subjects per 
group
Estimated 
percentage of 
subjects 
excluded from 
the PPI Sets
Number of 
evaluable 
subjects 
per group 
Standard 
deviation 
(natural 
log scale)
Expected 
GMT 
ratio 
AW/YAW
Power for 
one single 
comparison
600
35%
390
1.2
0.7
0.97
600
25%
450
1.2
0.7
0.99
AW, adult women; GMT, geometric mean titre; PPI, per protocol immunogenicity; YAW, young adult 
women.
The expected GMT ratio AW/YAW is 0.7, reflecting the fact that the immunogenicity of any 
HVP vaccines decreases with the increasing age of the subjects. It is to be noted that the 
study may result in an upper bound of the two-sided 95% CI around the GMT ratio 
AW/YAW being lower than 1, although the non-inferiority would be demonstrated if the 
lower bound is greater than 0.5 (i.e., the non-inferiority margin). If 1,200 subjects are 
enrolled in the study in a 1:1 fashion with regards to the 2 age groups, the evaluable 
population will range from 780 to 900 subjects. If the exclusion rate from the Per Protocol 
analysis is 35% for 1 HPV type and 25% for the 6 others, this study will have over 90% 
power to rule out a 2-fold decrease in GMT for the 7 oncogenic HPV types (Types 16, 18, 
31, 33, 45, 52, and 58). The power calculation is based on an estimate of 1.2 for the 
variability of each serotype on the natural log scale and assumes that the true GMT ratio
AW/YAW is 0.7 which is based on the results from Study V501 Protocol 019 where GMTs
were observed to decrease with age at vaccination.
Assuming a true seroconversion rate to each HPV type >98% and a percentage of subjects 
excluded from the PPI analysis populations <35% for HPV 16 and <25% for HPV 18, 31, 33, 
45, 52, and 58, the power of the secondary hypothesis testing is >99% using Type I error 
α=0.025 (one-sided).
3.5.7.1.1 Sample Size and Power for Safety Analyses
The probability of observing at least 1 vaccine-related SAE in this study depends on the 
number of subjects vaccinated and the underlying incidence rate in the study population. 
Table 9 shows the probability of observing at least one vaccine-related SAE within the 1,200 
subjects who will receive GARDASIL®9 for various theoretical incidence rates.
 
 
04M9HD
 
 
059WG4

Product:  V503
48
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Table 9
Probability of Observing At Least One Vaccine Related Serious Adverse 
Event for Various Theoretical Incidence Rates
Incidence Rates
Probability of at Least 1 Serious 
Adverse Event
1.0%
99%
0.5%
99%
0.1%
70%
0.05%
45%
0.01%
11%
If no vaccine related SAE is observed in the 1,200 subjects who will receive GARDASIL®9 
in this study, there is a 99% probability that the true incidence rate is <0.39%. 
Interim Analysis
3.5.8
No interim analysis is planned.
DEFINITION OF COMPLIANCE MEASURE
3.6
Compliance is defined in this study as receipt of all scheduled study vaccinations. To 
summarise compliance, the numbers of subjects 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 in the CSR.
Labeling, Packaging, Storage, Dispensing, and Return of Clinical Supplies
3.7
Product Description
3.7.1
Investigational Medicinal Product (IMP) will be provided by the Sponsor as summarized in 
Table 10. 
 
 
04M9HD
 
 
059WG4

Product:  V503
49
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Table 10
Investigational Medicinal Product
Product Name
Potency
Dosage Form/
Contents/Route of
Administration
Storage 
Conditions
GARDASIL®9
V503 (9-Valent 
HPV L1 VLP)
Vaccine
(Recombinant, 
adsorbed)
HPV Types (L1 protein)
6/11/16/18/31/33/45/52/58
30/40/60/40/20/20/20/20/20 
mcg
Adsorbed on AAHS 500 mcg
Sterile suspension 
for intramuscular
injection
1 dose (0.5 mL)
Shake well before 
use.
Store at 2.0 to 
8.0°C (35.6°F 
and 46.4°F).
Do not freeze.
Protect from 
light.
AAHS, Merck Aluminum Adjuvant (amorphous aluminum hydroxyphosphate sulfate); HPV, human 
papillomavirus; VLP, virus-like particle.
GARDASIL®9 is available as a suspension for injection. It appears as a clear liquid with 
white precipitate.
Packaging Information
3.7.2
Supplies will be labelled in accordance with local regulatory requirements.
Clinical Supplies Disclosure
3.7.3
Not applicable. This study is open-label.
Shipment of Investigational Medicinal Product
3.7.4
The IMP will be shipped to the study sites, refrigerated and stored at 2.0°C to 8.0°C (35.6°F 
to 46.4°F). Upon receipt at the study site, the vaccine should be removed from the outer 
secondary shipping box and placed immediately into the refrigerator.
Each shipment will include an electronic temperature-monitoring device to verify 
maintenance of the cold chain during transport, as well as an Acknowledgement of Receipt 
form.
Upon arrival of the shipment at the study site, the person responsible will verify that the 
content of the shipment corresponds to the order and that the products arrived in good 
condition. He/she will acknowledge receipt in IRT, For temperature excursions noted via the 
device, the temperature data recorded during shipment will be downloaded the current 
customer complaint process should be followed to acknowledge the excursions 
 
 
04M9HD
 
 
059WG4

Product:  V503
50
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Storage and Handling Requirements
3.7.5
For details on storage and handling requirements, please see Section 3.7.5.. The storage 
conditions will be indicated on the product label.  
The clinical supplies storage area at the study site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range specified in this 
protocol or in the product label attached to the protocol. Documentation of temperature 
monitoring should be maintained. Supplies should be stored in the original nested box with 
the lid closed to minimize exposure to light. If the refrigerator in which the study vaccine is 
stored deviates from the 2.0°C to 8.0°C range (35.6°F to 46.4°F), study vaccinations should 
be suspended and the Sponsor (or designee) should be contacted immediately. Vaccine must 
NOT be frozen.  
A daily refrigerator temperature log must be maintained at the study site. The refrigerator 
must be equipped with an appropriately calibrated min/max thermometer and/or circular 
chart temperature recorder. The temperature log will be reviewed by the Clinical Research 
Associate (CRA) throughout the study. An appropriate back up system (i.e., alarm or
generator) and study site personnel telephone numbers should be in place in the event of a 
refrigerator failure.
In case of a cold chain break (i.e., if the temperature of the refrigerator is lower than 2.0°C or 
exceeds 8.0°C [lower than 35.6°F or exceeds 46.4°F]):
The investigator (or designee) at the site should follow the current clinical complaint process 
to file an excursion
The investigator (or designee) must wait for further instructions from the Sponsor or from the 
CRA, as to whether or not the study vaccines can be used. The investigator is not allowed to 
use the study vaccines before getting the Sponsor (or designee) approval to do so.
The cold chain break must be documented in the Investigator Site File and in the Trial Master 
File.
The IMP must be received by a designated person at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designated 
assistants have access. IMP is to be administered only in accordance with the protocol.
Any concerns raised about the manufacturing, packaging, labelling, or distribution of IMP 
supply which could potentially impact its suitability for use should be immediately reported 
to the Sponsor. The IMP must be quarantined until the Sponsor feed-back is received as to 
whether or not the vaccine can be used.
Unused study vaccines taken out from the stock at study site are considered to be unusable 
and cannot be returned to the stock. They must be quarantined and returned back to the 
Sponsor (or designee) as soon as possible.
 
 
04M9HD
 
 
059WG4

Product:  V503
51
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Accountability of Investigational Medicinal Product
3.7.6
For the accountability procedure, please refer to Guidelines for IMP Management on site.
Return of Investigational Medicinal Product
3.7.7
All empty primary containers will be destroyed at the study site according to local 
regulations. Supplies will need to be returned to the depot of origin if destruction is not 
possible locally.
Empty boxes of study vaccines must be kept at study site to enable verification of the vaccine 
accountability by the CRA (or designee) and can afterwards be destroyed on site.
The following should be returned to the distributor according to the procedures detailed in 
the Investigator Site File:
Study vaccines unusable following a cold chain deviation, as soon as possible;
Study vaccines expiring within the current month, immediately; 
Unused study vaccines which remain in stock at study site after the last administration to the 
last subject of the corresponding study site, after verification of vaccine accountability;
Study vaccines concerned by a batch recall, immediately.
The CRA (or designee) will organise the return of unusable and unused study vaccines, 
which should be returned by ambient transport. The list of the returned study vaccines should 
be enclosed in the returned package. For the return procedure, please refer to Guidelines for 
IMP Management on site. The distributor will confirm the receipt of each study vaccine 
returned (at unit level).
Data Management
3.8
Study data will be acquired via electronic format. As part of their responsibilities, the 
principal investigator or sub-investigator agree to maintain adequate case histories for the 
subjects treated as part of the research under this protocol. The principal investigator or sub-
investigator agree to maintain source documentation (e.g., laboratory reports), to enter 
subject data into the e-CRF as accurately as possible, and to respond to any reported 
discrepancies rapidly.
Each e-CRF will allow data entry by study site staff that can add and edit data, identify and 
resolve discrepancies, and view records. This system provides immediate direct data transfer 
to the database, as well as immediate detection of discrepancies, enabling study site 
coordinators to resolve and manage discrepancies in a timely manner. 
Each person involved with the study will have an individual user name and password that 
allows for record traceability. Thus, the system, and subsequently any investigative reviews, 
can identify coordinators, investigators, and individuals who have entered or modified 
records, as well as the time and date of any modifications. A quality review of the data will 
 
 
04M9HD
 
 
059WG4

Product:  V503
52
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
be performed by the study site with additional reviews by the clinical monitor through source 
data verification.
Biological Specimens
3.9
Information regarding biological specimens for this protocol will be provided by the 
Sponsor. Please see the Investigator Site File for further details.
4.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
4.1
Confidentiality of Data
4.1.1
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/ERC) 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 trial 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.
Confidentiality of Subject Records
4.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject 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 subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
4.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1.
name, address, telephone number and e-mail address;
2.
hospital or clinic address and telephone number;
3.
curriculum vitae or other summary of qualifications and credentials; and
4.
other professional documentation.
 
 
04M9HD
 
 
059WG4

Product:  V503
53
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
4.1.4
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  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.
Compliance with Financial Disclosure Requirements
4.2
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.
Compliance with Law, Audit and Debarment
4.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., 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 trial.
 
 
04M9HD
 
 
059WG4

Product:  V503
54
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by sponsor, is provided in Section 6.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/IEC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The Sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
 
 
04M9HD
 
 
059WG4

Product:  V503
55
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, the Sponsor, will designate, per country, a national principal 
coordinator (Protocol CI), responsible for coordinating the work of the principal investigators 
at the different trial sites in that Member State, according to national regulations.  For a 
single-center trial, the Protocol CI is the principal investigator.  In addition, the Sponsor must 
designate a principal or coordinating investigator to review the trial report that summarizes 
the trial results and confirm that, to the best of his/her knowledge, the report accurately 
describes the conduct and results of the trial [Clinical Study Report (CSR) CI].  The Sponsor 
may consider one or more factors in the selection of the individual to serve as the Protocol CI 
and or CSR CI (e.g., availability of the Protocol/CSR CI during the anticipated review 
process, thorough understanding of clinical trial methods, appropriate enrollment of subject 
cohort, timely achievement of trial milestones).  The Protocol CI must be a participating trial 
investigator.
Compliance with Trial Registration and Results Posting Requirements
4.4
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 trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. The Sponsor of this trial, will review 
this protocol and submit the information necessary to fulfill these requirements. Sponsor
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial 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 
 
 
04M9HD
 
 
059WG4

Product:  V503
56
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
4.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
4.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
4.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. The Sponsor will post a synopsis of trial results for 
approved products on www.clinicaltrials.gov by 12 months after the last subject's last visit 
for the primary outcome, 12 months after the decision to discontinue development, or 
product marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
 
 
04M9HD
 
 
059WG4

Product:  V503
57
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
04M9HD
 
 
059WG4

Product:  V503
58
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
5.0 LIST OF REFERENCES
1. Serrano B, Alemany L, Tous S, Bruni L, Clifford GM, Weiss T, et al. Potential impact 
of a nine-valent vaccine in human papillomavirus related cervical disease. Infect Agent 
Cancer. 2012 Dec 29;7(1):38.
2. de Sanjosé S, Alemany L, Ordi J, Tous S, Alejo M, Bigby SM, et al. Worldwide human 
papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive 
lesions of the vulva. Eur J Cancer. 2013 Nov;49(16):3450-61.
3. Alemany L, Saunier M, Alvarado-Cabrero I, Quirós B, Salmeron J, Shin HR et al.
Human papillomavirus DNA prevalence and type distribution in anal carcinomas 
worldwide. Int J Cancer. 2015 Jan 1;136(1):98-107.
4. Alemany L, Saunier M, Tinoco L, Quirós B, Alvarado-Cabrero I, Alejo M, et al. Large 
contribution of human papillomavirus in vaginal neoplastic lesions: A worldwide study 
in 597 samples. Eur J Cancer. 2014 Nov;50(16):2846-54. 
5. Lacey CJ, Lowndes CM, Shah KV. Chapter 4: Burden and management of non-
cancerous HPV-related conditions: HPV-6/11 disease. Vaccine. 2006 Aug 31;24(Suppl 
3):S35-S41.
6. Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C, Mehlsen J, et al. A 9-valent 
HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med.
2015 Feb 19;372(8):711-23.
7. Pitisuttithum P, Velicer C and Luxembourg A. 9-valent HPV vaccine for cancers, pre-
cancers and genital warts related to HPV. Expert Rev Vaccines. 2015 Nov 
14;14(11):1405-19.
8. Muñoz N, Manalastas R Jr, Pitisuttithum P, Tresukosol D, Monsonego J, Ault K, et al. 
Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 
11, 16, 18) recombinant vaccine in women aged 24–45 years: a randomised, double-
blind trial. Lancet. 2009 Jun 6;373:1949-57.
9. Molano M, Posso H, Weiderpass E, van den Brule AJ, Ronderos M, Franceschi S, et al. 
Prevalence and determinants of HPV infection among Colombian women with normal 
cytology. Br J Cancer. 2002 Jul 29;87(3):324-33.
10. Dempsey AF, Brewer SE, Pyrzanowski J, Sevick C, O’Leary ST. Acceptability of 
human papillomavirus vaccines among women older than 26 years. Vaccine. 2015 Mar 
24;33(13):1556-61.
11. Vesikari T, Brodszki N, van Damme P, Diez-Domingo J, Icardi G, Petersen LK, et al. A 
randomized, double-blind, phase III study of the immunogenicity and safety of a 9-
valent human papillomavirus L1 virus-like particle vaccine (V503) versus Gardasil® in 
9-15-year-old girls. Pediatr Infect Dis J. 2015 Sep;34(9):992-8.
12. GARDASIL®9 [Summary of Product Characteristics]. Sanofi Pasteur MSD SNC. Lyon, 
France.
Available 
from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
Product_Information/human/003852/WC500189111.pdf.
 
 
04M9HD
 
 
059WG4

Product:  V503
59
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
13. Castellsagué X, Muñoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K, et al. 
End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 
16, 18) recombinant vaccine in adult women 24–45 years of age. Br J Cancer.
2011;105(1):28-37.
14. Luna J, Plata M, Gonzalez M, Correa A, Maldonado I, Nossa C, et al. Long-Term 
follow-up observation of the safety, immunogenicity, and effectiveness of GardasilTM 
in adult women. PLoS ONE. 2013;8(12):e83431.
15. Kang WD, Choi HS, Kim SM. Is vaccination with quadrivalent HPV vaccine after loop 
electrosurgical excision procedure effective in preventing recurrence in patients with 
high-grade cervical intraepithelial neoplasia (CIN2-3)? Gynecol Oncol.
2013
Aug;130(2):264-8.
16. Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E, Salmerón J, 
et al, for the VIVIANE Study Group. Efficacy, safety, and immunogenicity of the 
human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-
year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE 
study. Lancet. 2014 Dec 20;384(9961):2213-27.
17. Joura EA, Garland SM, Paavonen J, Ferris DG, Perez G, Ault KA, et al. Effect of the 
human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with 
cervical and vulvar disease: retrospective pooled analysis of trial data. BMJ. 2012 Mar 
27;344:e1401.
18. Haupt RM, Wheeler CM, Brown DR, Garland SM, Ferris DG, Paavonen JA, et al. 
Impact of an HPV6/11/16/18 L1 virus-like particle vaccine on progression to cervical 
intraepithelial neoplasia in seropositive women with HPV16/18 infection. Int J Cancer.
2011;129(11):2632-42.
19. Olsson SE, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez-Avila M, Wheeler CM, et 
al. Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and 
anogenital disease in subjects with serological evidence of prior vaccine type HPV 
infection. Hum Vaccin. 2009 Oct;5(10):694-704.
20. Miettinen O and Nurminen M. Comparative analysis of two rates. Stat Med.
1985 Apr-Jun;4(2):213-26.
21. International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals [updated 
2015 Dec]. Available from: http://www.icmje.org/recommendations/archives/
22. Moreira ED Jr, Block SL, Ferris D, Giuliano AR, Iversen OE, Joura EA, et al. Safety 
Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical 
Trials. Pediatrics. 2016 Aug;138(2). pii: e20154387.
 
 
04M9HD
 
 
059WG4

Product:  V503
60
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
6.0 APPENDICES
Merck Code of Conduct for Clinical Trials
6.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck 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 which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
 
 
04M9HD
 
 
059WG4

Product:  V503
61
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck 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
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, Sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck 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 including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
04M9HD
 
 
059WG4

Product:  V503
62
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Collection and Management of Specimens for Future Biomedical Research
6.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2.   Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 3.2.11 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how vaccines work
o
Biomarkers responsible for how a vaccine enters and is removed by the body
o
Other pathways vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and vaccine development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to vaccines, enhance our understanding of human disease and ultimately improve 
public health through development of novel treatments targeted to populations with the 
greatest need.  All specimens will be used by the Sponsor or those working for or with 
the Sponsor.
3.   Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
 
 
04M9HD
 
 
059WG4

Product:  V503
63
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4.  Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between subject identifiers 
and this unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5.   Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6.   Withdrawal from Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Subjects may withdraw 
 
 
04M9HD
 
 
059WG4

Product:  V503
64
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
consent at any time by contacting the principal investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@merck.com). 
Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for withdrawal of consent and/or destruction cannot be processed. 
7.   Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
 
 
04M9HD
 
 
059WG4

Product:  V503
65
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial.
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
04M9HD
 
 
059WG4

Product:  V503
66
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
6.3
Sample Types
Trial Visit
Day1
Visits 1
Month 2 
Visit 2
Month 6 
Visit 3
Month 7 
Visits 4
Blood Parameter 
Approximate Blood Volume (mL)
Serum β-Human Chorionic 
Gonadotropin (β-hCG)a
1ml
1ml
1ml
1ml
Serum for Anti-HPV 
antibody testing
10ml
NA
NA
10ml
Blood (DNA) for Future 
Biomedical Research
8.5ml
NA
NA
NA
Expected Total (mL)
19.5ml
1ml
1ml
11ml
a. Serum collection for β-hCG is only for subjects who get serum pregnancy test
 
 
04M9HD
 
 
059WG4

Product:  V503
67
Protocol/Amendment No.: 004-02
V503-004-02
15-Mar-2017
7.0
SIGNATURES
Sponsor's Representative
7.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
7.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 3.4.2 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
04M9HD
 
 
059WG4