A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Children and Adolescents With Increased Risk of Pneumococcal Disease
Phase: PHASE3
Conditions: Pneumococcal Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT06177912 
Document Date: 
20-Feb-2024
A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety,
Tolerability, and Immunogenicity of V116 in Children and 
Adolescents With Increased Risk of Pneumococcal Disease

PRODUCT: V116
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20-FEB-2024
TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety, 
Tolerability, and Immunogenicity of V116 in Children and Adolescents With Increased Risk 
of Pneumococcal Disease
Protocol Number: 013-01
Compound Number: V116
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
Pending
EU CT
2023-506236-32
EudraCT
Not applicable
jRCT
Pending
WHO
Not applicable
UTN
U1111-1293-4944
IND
19316
Approval Date: 20 February 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 1
20-FEB-2024
The reason for this amendment is to 
address health authority feedback.
Original Protocol
18-SEP-2023
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendment:
The reason for this amendment is to address health authority feedback.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 10.7.2, EEA-specific 
Requirements
Added new section providing EEA-specific 
requirements for:
•
Exclusion Criteria 17 and 18,
•
maximum blood volumes, and
•
contraceptive requirements.
This change was made to address 
health authority feedback to align the 
protocol with requirements for EEA 
countries.
Section Number and Name
Description of Change
Brief Rationale
Additional Changes
Section 10.2, Appendix 2: 
Clinical Laboratory Tests
Added a footnote to Table 8 to specify that 
maximum blood volumes should follow local 
guidelines/recommendations, if specified.
Refer to Section 10.7.2 rationale.
Added a reference to Appendix 7 for EEA-
specific requirements.
Refer to Section 10.7.2 rationale.
Section 10.5.2, Contraceptive 
Requirements
Added a reference to Appendix 7 for EEA-
specific requirements.
Refer to Section 10.7.2 rationale.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................11
1.1
Synopsis.................................................................................................................11
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
2
INTRODUCTION..........................................................................................................18
2.1
Study Rationale....................................................................................................18
2.2
Background ..........................................................................................................19
2.2.1
Pharmaceutical and Therapeutic Background .............................................20
2.2.2
Information on Other Study-related Therapy ..............................................20
2.2.2.1
PPSV23..............................................................................................20
2.2.2.2
Pneumococcal Vaccination Guidelines..............................................21
2.3
Benefit/Risk Assessment......................................................................................22
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................23
4
STUDY DESIGN............................................................................................................25
4.1
Overall Design......................................................................................................25
4.2
Scientific Rationale for Study Design.................................................................26
4.2.1
Rationale for Endpoints ...............................................................................27
4.2.1.1
Safety Endpoints................................................................................27
4.2.1.2
Immunogenicity Endpoints................................................................27
4.2.1.3
Future Biomedical Research..............................................................28
4.2.2
Rationale for the Use of Comparator...........................................................28
4.3
Justification for Dose...........................................................................................28
4.4
Beginning and End-of-Study Definition ............................................................29
4.4.1
Clinical Criteria for Early Study Termination .............................................29
5
STUDY POPULATION ................................................................................................30
5.1
Inclusion Criteria.................................................................................................30
5.2
Exclusion Criteria................................................................................................32
5.3
Lifestyle Considerations......................................................................................34
5.4
Screen Failures.....................................................................................................34
5.5
Participant Replacement Strategy......................................................................34
6
STUDY INTERVENTION............................................................................................35
6.1
Study Intervention(s) Administered...................................................................35
6.1.1
Drug-Device Combination Products/Combination Medicinal Products......37
6.2
Preparation/Handling/Storage/Accountability .................................................37
6.2.1
Dose Preparation..........................................................................................37
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6.2.2
Handling, Storage, and Accountability........................................................37
6.3
Measures to Minimize Bias: Randomization and Blinding..............................38
6.3.1
Intervention Assignment..............................................................................38
6.3.2
Stratification.................................................................................................38
6.3.3
Blinding........................................................................................................39
6.4
Study Intervention Compliance..........................................................................39
6.5
Concomitant Therapy..........................................................................................39
6.5.1
Rescue Medications and Supportive Care ...................................................40
6.6
Dose Modification ................................................................................................40
6.6.1
Stopping Rules.............................................................................................40
6.7
Intervention After the End of the Study............................................................40
6.8
Clinical Supplies Disclosure................................................................................40
6.9
Standard Policies..................................................................................................41
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................42
7.1
Discontinuation of Study Intervention...............................................................42
7.2
Participant Withdrawal From the Study...........................................................42
7.3
Lost to Follow-up .................................................................................................42
8
STUDY ASSESSMENTS AND PROCEDURES........................................................43
8.1
Administrative and General Procedures ...........................................................43
8.1.1
Informed Consent.........................................................................................43
8.1.1.1
General Informed Consent.................................................................43
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................44
8.1.2
Inclusion/Exclusion Criteria ........................................................................44
8.1.3
Participant Identification Card.....................................................................44
8.1.4
Medical History ...........................................................................................45
8.1.5
Prior and Concomitant Medications Review...............................................45
8.1.5.1
Prior Medications...............................................................................45
8.1.5.2
Concomitant Medications..................................................................45
8.1.6
Assignment of Screening Number...............................................................45
8.1.7
Assignment of Randomization Number.......................................................46
8.1.8
Study Intervention Administration ..............................................................46
8.1.8.1
Timing of Dose Administration.........................................................46
8.1.9
Telephone Contact Questionnaire................................................................47
8.1.10
Electronic Vaccination Report Card ............................................................47
8.1.11
Discontinuation and Withdrawal .................................................................47
8.1.11.1
Withdrawal From Future Biomedical Research ................................47
8.1.12
Participant Blinding/Unblinding..................................................................48
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8.1.13
Calibration of Equipment.............................................................................49
8.2
Immunogenicity Assessments .............................................................................49
8.2.1
Multiplex Opsonophagocytic Assay............................................................49
8.2.2
Pneumococcal Electrochemiluminescence Assay .......................................50
8.3
Safety Assessments...............................................................................................50
8.3.1
Physical Examinations.................................................................................50
8.3.2
Clinical Safety Laboratory Assessments .....................................................51
8.3.3
Pregnancy Testing........................................................................................51
8.3.4
Body Temperature Measurement.................................................................51
8.3.5
Postvaccination Observation Period ............................................................52
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................52
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................52
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......54
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...55
8.4.4
Regulatory Reporting Requirements for SAE .............................................55
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................55
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................56
8.4.7
Events of Clinical Interest............................................................................56
8.4.8
Drug-device Combination Products/Combination Medicinal Products –
Complaints, PQCs, and Malfunctions..........................................................56
8.4.9
Adverse Events on the VRC ........................................................................56
8.4.9.1
Solicited Adverse Event.....................................................................56
8.4.9.2
Unsolicited Adverse Events...............................................................57
8.5
Treatment of Overdose........................................................................................57
8.6
Pharmacokinetics.................................................................................................57
8.7
Pharmacodynamics..............................................................................................57
8.8
Biomarkers ...........................................................................................................57
8.9
Future Biomedical Research Sample Collection...............................................57
8.10
Medical Resource Utilization and Health Economics.......................................58
8.11
Visit Requirements...............................................................................................58
8.11.1
Screening......................................................................................................58
8.11.2
Treatment Period/Vaccination Visit ............................................................58
9
KEY STATISTICAL CONSIDERATIONS ...............................................................59
9.1
Responsibility for Analyses/In-house Blinding .................................................59
9.2
Hypotheses/Estimation ........................................................................................59
9.3
Analysis Endpoints...............................................................................................59
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9.3.1
Immunogenicity Endpoints..........................................................................59
9.3.2
Safety Endpoints..........................................................................................60
9.4
Analysis Populations............................................................................................60
9.4.1
Immunogenicity Analysis Populations ........................................................60
9.4.2
Safety Analysis Populations ........................................................................61
9.5
Statistical Methods...............................................................................................61
9.5.1
Statistical Methods for Immunogenicity Analyses......................................61
9.5.2
Statistical Methods for Safety Analyses ......................................................64
9.5.2.1
Overall Safety Assessment ................................................................64
9.6
Interim Analyses ..................................................................................................65
9.7
Multiplicity ...........................................................................................................66
9.8
Sample Size and Power Calculations .................................................................66
9.8.1
Sample Size and Power for Immunogenicity Analyses...............................66
9.8.2
Sample Size and Power for Safety Analyses ...............................................67
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................69
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........69
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................69
10.1.2
Financial Disclosure.....................................................................................72
10.1.3
Data Protection.............................................................................................73
10.1.3.1
Confidentiality of Data ......................................................................73
10.1.3.2
Confidentiality of Participant Records...............................................73
10.1.3.3
Confidentiality of IRB/IEC Information............................................74
10.1.4
Committees Structure...................................................................................74
10.1.4.1
Executive Oversight Committee........................................................74
10.1.4.2
External Data Monitoring Committee ...............................................74
10.1.4.3
Scientific Advisory Committee (SAC)..............................................74
10.1.5
Publication Policy........................................................................................75
10.1.6
Compliance with Study Registration and Results Posting Requirements ...75
10.1.7
Compliance with Law, Audit, and Debarment ............................................75
10.1.8
Data Quality Assurance ...............................................................................76
10.1.9
Source Documents .......................................................................................77
10.1.10
Study and Site Closure.................................................................................77
10.2
Appendix 2: Clinical Laboratory Tests..............................................................78
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................79
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................79
10.3.2
Definition of AE ..........................................................................................79
10.3.3
Definition of SAE ........................................................................................80
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10.3.4
Additional Events Reported.........................................................................81
10.3.5
Recording AE and SAE ...............................................................................81
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................86
10.4
Appendix 4: Drug-Device Combination Products/ Combination 
Medicinal Products: Complaints, Product Quality 
Complaints/Malfunctions: Definitions, Recording, and Follow-up ................88
10.4.1
Definitions....................................................................................................88
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ....89
10.5
Appendix 5: Contraceptive Guidance................................................................91
10.5.1
Definitions....................................................................................................91
10.5.2
Contraceptive Requirements........................................................................92
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................93
10.7
Appendix 7: Country-specific Requirements....................................................97
10.7.1
Country-specific Requirements for Japan....................................................97
10.7.2
EEA-specific Requirements.........................................................................98
10.8
Appendix 8: Abbreviations ...............................................................................100
11
REFERENCES.............................................................................................................103
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LIST OF TABLES
Table 1
Study Interventions......................................................................................36
Table 2
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................................53
Table 3
Solicited Adverse Events for V116-013 ......................................................57
Table 4
Analysis Strategy for Immunogenicity Variables........................................63
Table 5
Analysis Strategy for Safety Parameters......................................................65
Table 6
Differences in Incidence of Adverse Event Rates Between the 2 
Vaccination Groups That Can be Detected With an Approximately 80% 
Probability....................................................................................................................68
Table 7
Protocol-required Safety Laboratory Assessments......................................78
Table 8
Blood Volumes Collected by Visit for Immunogenicity Assessments........78
Table 9
Injection-site AE Overall Intensity Grading Scale ......................................82
Table 10
Specific Systemic AE Overall Intensity Grading Scale...............................83
Table 11
Other Systemic AE Overall Intensity Grading Scale...................................84
Table 12
Vital Sign (Temperature) Overall Intensity Grading Scale .........................84
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LIST OF FIGURES
Figure 1
Schema.........................................................................................................15
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety, 
Tolerability, and Immunogenicity of V116 in Children and Adolescents With Increased Risk 
of Pneumococcal Disease
Short Title: Safety and Immunogenicity of V116 in Children and Adolescents With 
Increased Risk for Pneumococcal Disease
Acronym: STRIDE-13
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of V116 
with respect to the proportion of participants 
with adverse events (AEs).

Solicited injection-site AEs Day 1 
through Day 5 postvaccination

Solicited systemic AEs Day 1 
through Day 5 postvaccination

Vaccine-related serious AEs (SAEs) 
Day 1 through the duration of 
participation in the study
To compare the serotype-specific 
opsonophagocytic (OPA) geometric mean titers 
(GMTs) at 30 days postvaccination with V116 
versus PPSV23.
Hypothesis (H1): V116 is noninferior to 
PPSV23 as assessed by serotype-specific OPA 
GMTs at 30 days postvaccination for the 12 
common serotypes in V116 and PPSV23.
(The statistical criterion for noninferiority 
requires the lower bound of the 2-sided 95% 
confidence interval [CI] of the OPA GMT ratio 
[V116/PPSV23] to be >0.5.)
Hypothesis (H2): V116 is superior to PPSV23 
as assessed by serotype-specific OPA GMTs at 
30 days postvaccination for the 9 unique 
serotypes in V116.
(The statistical criterion for superiority requires 
the lower bound of the 2-sided 95% CI of the 
OPA GMT ratio [V116/PPSV23] to be >2.0.)
Serotype-specific OPA responses
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Secondary Objectives
Secondary Endpoints
To evaluate the serotype-specific 
immunoglobulin G (IgG) geometric mean 
concentrations (GMCs) at 30 days 
postvaccination with V116 compared with 
PPSV23.
Serotype-specific IgG responses
To evaluate the serotype-specific geometric 
mean fold rises (GMFRs) and proportions of 
participants with a ≥4-fold rise in serotype-
specific OPA responses and IgG responses from 
baseline to 30 days postvaccination within each 
vaccination group.
Serotype-specific OPA and IgG 
responses
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal infection
Population
Children and adolescents ≥2 to <18 years of age with 
increased risk for pneumococcal disease.
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active Control Without Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects
Care Provider
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 13 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related contact.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory result 
or at the time of final contact with the last participant, 
whichever comes last.
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Number of Participants:
Approximately 820 participants will be randomized, with approximately 492 participants in 
the V116 intervention group and 328 participants in the PPSV23 intervention group.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
V116
Pneumococcal 
21-valent 
conjugate 
vaccine
4 µg of each 
PnPs antigen 
(3, 6A, 7F, 8, 
9N, 10A, 
11A, 12F, 
15A, 15C, 
16F, 17F, 
19A, 20A, 
22F, 23A, 
23B, 24F, 31, 
33F, and 
35B)
0.5 mL
IM
Single dose at 
Visit 1 (Day 
1)
Test Product
PPSV23
Pneumococcal 
Vaccine, 
Polyvalent (23-
valent)
25 μg of each 
PnPs antigen 
(1, 2, 3, 4, 5, 
6B, 7F, 8, 
9N, 9V, 10A, 
11A, 12F, 14, 
15B, 17F, 
18C, 19A, 
19F, 20, 22F, 
23F, and 33F)
0.5 mL
IM
Single dose at 
Visit 1 (Day 
1)
Comparator
EEA=European Economic Area; IM=intramuscular; IMP=investigational medicinal product; 
NIMP/AxMP=noninvestigational/auxiliary medicinal product; PnPs=pneumococcal polysaccharide; 
PPSV23=pneumococcal vaccine, polyvalent (23-valent) (PNEUMOVAX™23); V116=pneumococcal 21-valent conjugate 
vaccine.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and 
applies to countries in the EEA. Country differences with respect to the definition/classification of IMP and NIMP/AxMP 
may exist. In these circumstances, local legislation is followed.
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Other current or former name(s) or alias(es) for study intervention(s) are as follows: V116: 
polyvalent pneumococcal conjugate vaccine (pPCV).
Total Number of 
Intervention 
Groups/Arms
2
Duration of 
Participation
Each participant will participate in the study for at least 6 months
from the time the participant or participant’s legally acceptable 
representative provides documented informed consent/assent through 
the final contact or discontinuation from the study.
Study Governance Committees:
Executive Oversight Committee
Yes
External Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Schema
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1.3
Schedule of Activities
Study Period:
Intervention and Follow-up
Notes
Visit Number:
1
2
3
4
5
Visit Type:
Visit
TC
Visit
TC
TC
Study Day:
Day 1
Day 7
Day 30
Day 90
Day 180
Visit Window:
-
Day 7 to 
Day 10
Day 30 
to Day 
44
Day 76 
to Day 
104
Day 166 
to Day 
194
Administrative Procedures
Screening Procedures
Informed Consent/Assent
X
Must be obtained before any study procedures are 
conducted. 
Informed Consent/Assent for Optional FBR
X
Must be obtained before FBR sample collection.
Assignment of Screening Number
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Medical History
X
Postrandomization Procedures
Assignment of Randomization Number
X
Prior/Concomitant Medication and Nonstudy 
Vaccination Review
X
X
X
X
X
V116/PPSV23 Administration (blinded)
X
Provide Electronic Device (if needed) or Configure 
Device (Personal or Provisioned) for eVRC Data 
Collection
X
Instructions for using the eVRC will be reviewed with 
the participant or participant’s legally acceptable 
representative.
Review eVRC Data With Participant or 
Participant’s LAR
X
X
Collect Electronic Device From Participant or 
Participant’s Legally Acceptable Representatives
Who Received an Electronic Device or Deactivate 
Personal Devices
X
Complete Telephone Contact Questionnaire
X
X
Safety Procedures
Complete Physical Examination
X
Performed by investigator or medically qualified 
designee before vaccination.
Pregnancy Test (if applicable)
X
Participants of childbearing potential must have a 
negative urine or serum test (consistent with local 
requirements and sensitive to ≤25 IU hCG) result before 
vaccination.
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Study Period:
Intervention and Follow-up
Notes
Visit Number:
1
2
3
4
5
Visit Type:
Visit
TC
Visit
TC
TC
Study Day:
Day 1
Day 7
Day 30
Day 90
Day 180
Visit Window:
-
Day 7 to 
Day 10
Day 30 
to Day 
44
Day 76 
to Day 
104
Day 166 
to Day 
194
Body Temperature Measurement
X
Measured before vaccination. Participants with febrile 
illness (temperature ≥100.4°F [≥38.0°C]) within 72 hours 
before vaccination must be rescheduled.
Postvaccination Observation Period
X
Observed by blinded study-site personnel for at least 
30 minutes postvaccination.
AE Monitoring
X
X
X
X
X
Nonserious AEs collected through Day 30 
postvaccination; all SAEs and deaths collected through 
Day 180.
Immunogenicity Assessments
Serum for Immunogenicity Assays
X
X
Visit 1 sample should be collected before vaccination.
Future Biomedical Research
Collect Buccal Swab for FBR
X
Buccal swab DNA samples for analysis should be 
obtained prior to the vaccination on Visit 1, on 
randomized and FBR consented/assented participants 
only, or at a later date as soon as the informed 
consent/assent is obtained.
AE=adverse event; DNA=deoxyribonucleic acid; eVRC=electronic vaccination report card; FBR=future biomedical research; hCG=human chorionic gonadotropin; 
IU=international units; LAR=legally acceptable representative; PPSV23=pneumococcal vaccine, polyvalent (23-valent) (PNEUMOVAX™23); SAE=serious adverse event; 
TC=telephone contact; V116=pneumococcal 21-valent conjugate vaccine.
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2
INTRODUCTION
The Sponsor is developing an investigational polyvalent pneumococcal 21-valent conjugate 
vaccine (V116) for the prevention of pneumococcal disease caused by the serotypes in the 
vaccine.
2.1
Study Rationale
Streptococcus pneumoniae is a major cause of vaccine-preventable disease worldwide. It is 
associated with considerable morbidity and mortality, with the highest burden in children 
<5 years and adults ≥70 years of age [Troeger, C., et al 2018]. Vaccines directed against 
S pneumoniae have reduced the incidence of disease caused by vaccine serotypes in the age 
groups being vaccinated (primarily children <5 years of age in most countries) and have 
reduced vaccine type disease in other age groups (indirect effect).
Both adults and children with certain underlying medical conditions are at higher risk for
pneumococcal disease compared to their healthy counterparts, even with widespread use of 
PCVs (Section 2.2.1). Populations at higher risk for pneumococcal disease can be further 
classified as immunocompetent at increased risk (individuals with chronic comorbid
conditions such as chronic heart disease, chronic lung disease, and diabetes mellitus); and
high-risk (individuals with immunocompromising conditions such as nephrotic syndrome or 
on immunosuppressive therapy) [Pelton, S. I., et al 2015]. Patients with chronic kidney
failure, cerebrospinal fluid leaks, or cochlear transplants are often classified as high-risk. A
retrospective cohort analysis of children <18 years of age during 2007–2010 found that the 
incidence rate ratios for IPD of at-increased-risk children and high-risk children compared to 
children without risk factors were 1.8 to 3.3 (<5 years of age) and 11.2 to 40.1 (5 to 17 years 
of age), respectively [Pelton, S. I., et al 2014].
Children with chronic comorbid conditions remain at increased risk due to non-vaccine 
serotypes and/or limited vaccine efficacy. During the post-PCV13 era, IPD cases among 
children with comorbidities (mainly immunosuppression due to primary immunodeficiency,
immunosuppressive, or radiation therapies and chronic respiratory diseases, including
asthma) caused by non-PCV13 serotypes accounted for the majority of cases. PPSV23-only 
serotypes were responsible for 50% of cases, and non-vaccine serotypes were responsible for 
the remaining 50%, with serotypes 11A and 15B (PPSV23 serotypes) and 6C, 23A, and 35B 
(non-vaccine serotypes) predominating [Lagousi, T., et al 2021].
Children and adolescents at increased risk for pneumococcal disease may benefit from 
receiving V116, as V116 has the potential to provide broader protection against 
pneumococcal disease compared with currently licensed pneumococcal vaccines, and
complement the protection afforded by primary pneumococcal vaccination regimens (Section 
2.2.2.2). V116 offers additional advantages due to being a conjugate vaccine, which includes
improved immune and memory response, longer lasting protection, potential for herd 
immunity, and improved immunogenicity in children [World Health Organization 2021] 
[Goldblatt, D. 2000].
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This clinical study is designed to evaluate the safety, tolerability, and immunogenicity of a 
single dose of V116 in children and adolescents at increased risk for pneumococcal disease.
This study will be conducted in children and adolescents ≥2 to <18 years of age who have 
completed a primary pneumococcal vaccination regimen and who are at increased risk of 
pneumococcal disease due to chronic medical conditions, including: chronic heart disease, 
chronic lung disease, diabetes mellitus, chronic liver disease, and chronic kidney disease. 
These chronic medical conditions were selected for inclusion based on their overall 
prevalence in a significant proportion of the overall pediatric population in the EU and US
compared to other increased-risk or high-risk conditions [Sahota, A. K., et al 2020] [Bell, R. 
A., et al 2009] [Schwimmer, J. B., et al 2006] [Chen, M. Y., et al 2018] [Temple, J. L., et al 
2016] [Zahran, H. S., et al 2018] [Mayer-Davis, E. J., et al 2018] [Lascar, N., et al 2018] 
[Bloom, C. I., et al 2019] [Viasus, D., et al 2011]. Vaccination recommendations for 
individuals with these conditions are generally aligned in the guidelines in the US, EU, and 
many other countries globally. While guidelines typically also include children with 
cerebrospinal fluid leaks and cochlear implants as being immunocompetent but with 
increased risk, these conditions are not included in this study due to their low prevalence in 
the population.
Additionally, individuals considered to be immunocompromised will not be included in this 
study. Data generated from V116 in the increased-risk children without 
immunocompromising conditions are anticipated to be applicable to the 
immunocompromised risk groups of children. Based on prior experience with PCVs and 
current pneumococcal vaccination guidelines for at-risk children, which recommend 
vaccination of some risk groups based on data from studies of other risk conditions, it is 
expected that V116 data may be generalizable to other at-risk populations, including 
immunocompromised children. Both PCV7 and PCV13 were evaluated in children with HIV 
and nephrotic syndrome, and were found to be generally safe and well tolerated [Liakou, C. 
D., et al 2011] [Nunes, M. C. 2012]. Randomized, controlled studies evaluated the 
immunogenicity and safety of PCV15 compared with PCV13 in persons aged 5–17 years 
with sickle cell disease [Quinn, C. T., et al 2023], and persons aged 6–17 years living with 
HIV infection [Wilck, M., et al 2023] and was found to be safe and immunogenic in both 
populations. PCV20 was recently approved in all children including at-risk and 
immunocompromised children based on data from healthy children and prior experience 
from PCV13 [Kobayashi, M. 2023].
2.2
Background
To date, the following studies have been completed with V116 in adults:
•
Phase 1/2 study (V116-001)
•
Phase 1 study in Japan (V116-002)
•
4 Phase 3 studies (V116-003, V116-004, V116-005, V116-006)
Results from Phase 1, 2, and 3 studies showed that V116 is immunogenic and has acceptable 
safety and tolerability in adults. Refer to the IB for detailed background information on 
V116.
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2.2.1
Pharmaceutical and Therapeutic Background
Pneumococcal disease (disease caused by S pneumoniae) continues to be a major cause of 
vaccine-preventable disease worldwide, resulting in considerable morbidity and mortality in 
both children and adults. Humans are the sole reservoir of S pneumoniae and the bacteria 
reside in the nasopharynx. It is estimated that in the year 2000, there were 14.5 million cases 
of pneumococcal disease worldwide and approximately 800,000 children <5 years of age 
died of the disease [O'Brien, K., et al 2009]. In particular, older adults (≥65 years of age), 
infants (<1 year of age) and individuals, including children, with certain medical conditions 
(eg, chronic lung disease, chronic liver disease, chronic heart disease, diabetes mellitus, 
chronic kidney disease), and immunocompromised individuals (eg, HIV, hematopoietic stem 
cell transplantation patients) are at increased risk of developing pneumococcal disease
[Pelton, S. I., et al 2014] [Viasus, D., et al 2011].
The introduction of infant vaccination with PCV7, PCV10, and PCV13 has significantly 
reduced the overall incidence of IPD in adults through indirect protection. However, despite 
reductions in IPD, there is still a burden of residual pneumococcal disease in older adults in 
countries which have broadly implemented pneumococcal vaccination in the pediatric 
population which is largely accounted for by non-vaccine serotypes[Lynch, J. P., III and 
Zhanel, G. G. 2010] [European Centre for Disease Prevention and Control 2020]. S 
pneumoniae serotypes were selected for inclusion in V116 based, in part, on available global 
epidemiology data with a primary focus on older adults (≥65 years of age) in the US and EU 
countries with an established pediatric vaccination program. V116 includes select serotypes 
from PPSV23, PCV13, PCV15, and PCV20, as well as unique serotypes not included in any 
licensed pneumococcal vaccine, thereby addressing the unmet medical need of preventing 
residual pneumococcal disease. V116 is being developed to prevent invasive disease and 
pneumonia caused by S pneumoniae serotypes 3, 6A, 6C, 7F, 8, 9N, 10A, 11A, 12F, 15A, 
15B, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, and 35B in children aged ≥2 to 
<18 years with underlying conditions and adults ≥18 years of age. 
Note that in the formulation of V116, serotype 15C is represented by deOAc15B as the 
molecular structures for deOAc15B and 15C are similar. V116 and PPSV23 contain 12 
common serotypes. Advances in serotyping methods led to reclassification of serotype 20 as 
serotype 20A [Calix, J. J., et al 2012]. The serotype is represented as 20 in PPSV23 product 
labeling, and as 20A in V116; immune responses to serotype 20A are assessed in this study.
2.2.2
Information on Other Study-related Therapy
2.2.2.1
PPSV23
Refer to the approved labeling for detailed background information on PPSV23.
PPSV23 is comprised of the polysaccharides from 23 of the serotypes causing disease in 
adults (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 
22F, 23F, and 33F). The formulation is not adjuvanted and no carrier protein is used.
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PPSV23 was first approved in the US in 1983 and is now licensed in >90 countries 
worldwide. PPSV23 is indicated for the prevention of pneumococcal disease in adults ≥50 
years of age and in individuals ≥2 years of age at increased risk for pneumococcal disease.
2.2.2.2
Pneumococcal Vaccination Guidelines
PCV7 was introduced in 2000 in the US and 2001 in the EU and widely adopted in NIPs for 
children worldwide. PCV10 and PCV13 were licensed in 2009-2010, replacing PCV7 in 
NIPs [Pilishvili, Tamara, et al 2010]. In June 2022 and April 2023, respectively, PCV15 and 
PCV20 were licensed for use in children in the US with worldwide licensing expected
[European Medicines Agency 2023] [Fink, D. L. 2022] [European Medicines Agency 2023a] 
[Toerner, J. G. 2023].
PCVs are commonly used in a 3-dose schedule or 4-dose schedule, where 2 or 3 doses are 
administered starting as early as 2 months of age, and the last dose administered at 12 to 15 
months of age [World Health Organization 2019] [U.S. Prescribing Information 2023] [U.S. 
Prescribing Information 2023a]. The choice of vaccine and schedule is based on several 
factors, including baseline incidence of disease, prior use of PCV7, and programmatic factors 
such as timeliness of vaccination and expected coverage. In addition to routine childhood 
immunization with PCV, there are recommendations to vaccinate children ≥2 years at 
increased risk for pneumococcal disease due to underlying disease, occupation, or 
institutionalization as individuals with conditions at increased risk for IPD might have 
infections caused by a broader range of serotypes than healthy children.

In the US, ACIP recommendations were recently updated to include PCV20 [Centers for 
Disease Control and Prevention 2023]. For children aged 2–18 years with any risk 
condition who have received all recommended doses of PCV before age 6 years, a dose 
of PCV20 or PPSV23 administered at least 8 weeks after the most recent dose of PCV is 
recommended if PCV13 or PCV15 were received in the primary schedule. An additional 
dose of PPSV23 5 years after the first dose is recommended in children with altered 
immunocompetence. If PCV20 was received in the primary schedule, no additional doses 
of any pneumococcal vaccine are indicated.

European national guidelines vary by country in recommendations for at-risk children as 
well as by age, risk condition, vaccine type and revaccination. In the EU, vaccination 
guidelines recommend mostly PCV13 (or PCV15 in countries that have updated their 
recommendations [ie, Greece]) and PPSV23 or PPSV23 only in at-risk children after 
completing a primary PCV regimen [European Centre for Disease Prevention and 
Control 2023]. Fewer countries recommend the sequential vaccination regimen of PCV13 
(or PCV15) followed by PPSV23 regardless of whether the primary PCV regimen was 
completed or not [Castiglia P. 2014]. A single dose of PPSV23 (with or without 
revaccination, ≥5 years after the first dose) is the most widely recommended regimen in 
children ≥2 years of age with increased risk of pneumococcal disease in most EU 
countries, as well as in Australia, New Zealand, and several South American countries. 
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2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
V116 includes the most prevalent serotypes that cause IPD in adults ≥65 years. With the 
broadest potential for protection against pneumococcal disease compared to any other adult 
licensed pneumococcal vaccine, V116 has been primarily developed to address the unmet 
medical need in adults. However, in most high income countries and several middle income
countries with pneumococcal vaccination guidelines, children ≥2 to <18 years of age with an 
increased risk of pneumococcal disease are currently recommended to receive an additional 
pneumococcal vaccination(s) to broaden the serotype coverage afforded by their routine 
primary vaccination course. Therefore, V116 has the potential to also provide this broader
protection against pneumococcal disease in children and complement the protection afforded 
by primary vaccination regimens.
The benefit-risk profile for V116 supports continued evaluation.
In this study, approximately 40% of participants will receive PPSV23, a vaccine indicated in 
the majority of guidelines globally in pediatric at-risk population. PPSV23 is currently 
registered and approved in >90 countries worldwide. V116 is expected to provide 
comparable immune responses to PPSV23 for the common serotypes while providing 
additional coverage for the serotypes unique to V116. It is unknown if the investigational 
V116 will have the same clinical benefit as PPSV23.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent/assent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Primary Objectives
Primary Endpoints
To evaluate the safety and tolerability of 
V116 with respect to the proportion of 
participants with adverse events (AEs).

Solicited injection-site AEs Day 1 
through Day 5 postvaccination

Solicited systemic AEs Day 1 through 
Day 5 postvaccination

Vaccine-related serious AEs (SAEs) 
Day 1 through the duration of 
participation in the study
To compare the serotype-specific 
opsonophagocytic (OPA) geometric mean 
titers (GMTs) at 30 days postvaccination
with V116 versus PPSV23.
Hypothesis (H1): V116 is noninferior to 
PPSV23 as assessed by serotype-specific 
OPA GMTs at 30 days postvaccination for 
the 12 common serotypes in V116 and 
PPSV23.
(The statistical criterion for noninferiority 
requires the lower bound of the 2-sided 95% 
confidence interval [CI] of the OPA GMT 
ratio [V116/PPSV23] to be >0.5.)
Hypothesis (H2): V116 is superior to 
PPSV23 as assessed by serotype-specific 
OPA GMTs at 30 days postvaccination for 
the 9 unique serotypes in V116.
(The statistical criterion for superiority 
requires the lower bound of the 2-sided 95% 
CI of the OPA GMT ratio [V116/PPSV23] 
to be >2.0.)
Serotype-specific OPA responses
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Secondary Objectives
Secondary Endpoints
To evaluate the serotype-specific 
immunoglobulin G (IgG) geometric mean 
concentrations (GMCs) at 30 days 
postvaccination with V116 compared with 
PPSV23.
Serotype-specific IgG responses
To evaluate the serotype-specific geometric 
mean fold rises (GMFRs) and proportions 
of participants with a ≥4-fold rise in
serotype-specific OPA responses and IgG
responses from baseline to 30 days 
postvaccination within each vaccination 
group.
Serotype-specific OPA and IgG responses
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To evaluate the cross-reactive immune 
responses to serotypes within a serogroup at 
30 days postvaccination.
Serotype-specific OPA and IgG responses
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, double-blind, active comparator-controlled clinical study to 
evaluate the safety, tolerability, and immunogenicity of V116 in children and adolescents
aged ≥2 to <18 years who have completed a primary pneumococcal vaccination regimen and 
who are at increased risk of pneumococcal disease (ie, chronic heart disease, chronic lung 
disease, diabetes mellitus, chronic liver disease, or chronic kidney disease).
Approximately 820 participants will be randomized in a 3:2 ratio to receive a single dose of 
either V116 or PPSV23 on Day 1. Randomization will be stratified by the number of 
increased-risk conditions for pneumococcal disease (1 increased-risk condition, or ≥2 
increased-risk conditions) and by prior pneumococcal vaccination and age:
•
Prior PCV7 alone
•
Prior PCV7 and one prior PPSV23 dose
•
Prior PCV10 alone and ≥2 to <6 years old
•
Prior PCV10 alone and ≥6 to <18 years old
•
Prior PCV10 and one prior PPSV23 dose
•
Prior PCV13 alone and ≥2 to <6 years old
•
Prior PCV13 alone and ≥6 to <18 years old
•
Prior PCV13 and one prior PPSV23 dose 
Note: Participants who previously received a combination of PCV7, PCV10, and/or PCV13 
or any doses of PCV15 or PCV20 will be excluded from this study.
Participants are to have ≥1 increased-risk condition listed in Inclusion Criteria #1
(Section 5.1). It is expected that ≥25 participants per risk condition will be enrolled. In 
participants with ≥2 increased-risk conditions, each condition will count towards the total per 
condition.
Participants risk condition(s) must be considered stable for ≥3 months with no anticipated 
major change in treatment expected for the duration of the study and with ≤1 hospitalization 
directly related to the risk condition within 3 months before study vaccination.
An eVRC will be used by the participant/participant’s legally authorized representative to 
record solicited injection-site AEs, solicited systemic AEs, and daily body temperatures from 
Day 1 through Day 5 after vaccination. Unsolicited AEs will also be recorded from Day 1 
through Day 30 after vaccination. The participant/participant’s legally authorized 
representative will be provided an electronic device or have their own electronic device 
configured, if compatible, to complete the eVRC.
Blood samples for immunogenicity assays will be drawn on Day 1 (Visit 1) and Day 30 
(Visit 3).
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Information for SAEs and deaths, regardless of whether the events are considered to be 
vaccine-related by the investigator, will be collected through completion of participation in 
the study.
An external DMC will conduct a periodic review of safety and tolerability data for the V116 
Phase 3 program. A description of the structure and function of the DMC, along with the 
timing and content of the safety reviews, will be outlined in the DMC charter. Information 
regarding the composition of the DMC is provided in Appendix 1.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study will evaluate the safety, tolerability, and immunogenicity of V116 in children and 
adolescents ≥2 to <18 years of age who have completed a primary pneumococcal vaccination 
regimen and who are at increased risk for pneumococcal disease.
Children and adolescents with one or more stable chronic medical conditions, including 
chronic heart disease, chronic lung disease, diabetes mellitus, chronic liver disease, and 
chronic kidney disease will be included in this study. The population of children and 
adolescents with these chronic medical conditions are at increased risk for IPD and were
selected for inclusion based on their overall prevalence in the pediatric population
(Section 2.1).
The randomization ratio of 3:2 was chosen to increase the number of participants exposed to 
V116 to expand the V116 safety and immunogenicity data in a population at increased risk 
for pneumococcal disease.
Participants will be stratified by prior PCV regimen received in infancy and prior PPSV23 
vaccination, as prior pneumococcal vaccination may impact immune responses to V116 and 
PPSV23 for the shared serotypes. Participants will also be stratified by the number of risk 
conditions (1 increased-risk condition only or ≥2 increased-risk conditions) as it is expected 
that the number of participants enrolled with 1 or more conditions will vary and to ensure 
balance between the intervention groups. Participants will also be stratified by age (≥2 to <6
and ≥6 to <18 years of age) for those who received PCV10 and PCV13 alone to ensure 
balance between the intervention groups.
Individuals with severe heart, liver, lung, or kidney disease, and those with uncontrolled 
diabetes will be excluded from this study to allow them to prioritize their medical care over 
participation in this study and to avoid associating the effects of medical treatment with the 
safety and immunogenicity of the vaccine.
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4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
Safety information will be collected from all participants (or participant's legally acceptable 
representative) on an eVRC. The eVRC used to record AEs during the postvaccination 
period(s) (Section 8.1.10) is structured as recommended in the final US FDA Patient-reported 
Outcome Guidance [U.S. Food and Drug Administration 2009].
The safety endpoints (ie, AEs and temperature) evaluated in this study are consistent with
previous studies of V116 and published data from marketed PCVs. Detailed information for
the safety endpoints evaluated in this study can be found in Section 9.3.2.
Definitions and reporting requirements for AEs are provided in Appendix 3.
4.2.1.2
Immunogenicity Endpoints
The immunogenicity endpoints are consistent with previous studies evaluating PCVs.
According to the CHMP and WHO guidance documents, immunogenicity studies can be 
conducted to support the licensing of new pneumococcal vaccines [European Medicines 
Agency 2006] [World Health Organization 2016] [World Health Organization 2013]. The 
OPA GMT, IgG GMC, GMFR, and proportion of participants with a 4-fold rise in OPA and 
IgG responses are acceptable assessments used to evaluate novel PCVs. Several studies have 
shown a positive correlation between serotype-specific OPA titers and IgG antibody 
concentrations in children and adults [Centers for Disease Control and Prevention 2010] 
[Anttila, M., et al 1999] [Romero-Steiner, S., et al 1997].
Thresholds of protection have been established in children <2 years of age, where 
serotype-specific IgG of ≥0.35 μg/mL measured by ELISA one month after primary 
immunization was used for the licensing of PCV based on analyses of pooled 
immunogenicity and efficacy data from randomized controlled studies of the initial 7-valent 
and investigational 9-valent PCVs [World Health Organization 2013]. However, this 
threshold is not as relevant for older children, especially those who have already completed a 
primary pneumococcal vaccination regimen. OPA titers provide an assessment of functional
immune responses as a surrogate marker for vaccine efficacy against pneumococcal disease 
and have been shown to correlate with vaccine-induced protection. Based on this, OPA titers 
will be used as the primary immunogenicity endpoint in this study. It is noted that OPA titer 
threshold values that correlate with protection in any age group have not been defined.
Sera from participants will be used to assess vaccine-induced, anti-PnPs, serotype-specific 
OPA and IgG responses using the validated MOPA and Pn ECL assay, respectively. 
Immunogenicity endpoints will be evaluated for all serotypes included in V116 and for 
cross-reactive serotypes within a serogroup.
Details on the immunogenicity endpoints evaluated in this study can be found in 
Section 9.3.1.
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4.2.1.3
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent/assent was provided 
during this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere
in the protocol and will only be conducted on specimens from appropriately 
consented/assented participants. The objective of collecting/retaining specimens for FBR is 
to explore and identify biomarkers that inform the scientific understanding of diseases and/or 
their therapeutic treatments. The overarching goal is to use such information to develop safer,
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator
Placebo-controlled clinical studies for new PCVs are no longer practical given the proven
clinical efficacy and widespread use of licensed pneumococcal vaccines worldwide.
PPSV23 is chosen as the comparator as it is the vaccine included in the majority of 
guidelines globally in this pediatric increased-risk population. Of the currently licensed 
pneumococcal vaccines, PPSV23 affords the broadest serotype protection and has the most 
serotypes in common with V116 (12 serotypes). PPSV23 is indicated for use in persons 
≥2 years of age for whom there is an increased risk of morbidity and mortality from 
pneumococcal disease due to aging and/or underlying medical conditions. As children with 
conditions at increased risk for IPD might have infections caused by a broader range of 
serotypes than healthy children, an additional dose of PPSV23 is recommended in children 
with altered immunocompetence as described in (Section 2.2.2).
Additionally, there is evidence to support effectiveness of PPSV23 against IPD in the 
pediatric population at increased risk of pneumococcal disease [Lagousi, T., et al 2021] 
[Fiore, A. E, et al 1999].
The use of PPSV23 in this study is consistent with the product labeling.
4.3
Justification for Dose
The single dose of V116 in the proposed pediatric study is the same regimen, formulation, 
and dose of V116 used in the adult Phase 3 studies. The V116 dose of 4 µg/each PnPs was 
selected based on review of safety and immunogenicity data from the Phase 1 and Phase 2 
studies in adults. In Phase 1, 2 doses of V116 were evaluated: a single dose containing 
2 µg/each PnPs and a single dose of 4 µg/each PnPs. Based on the data from Phase 1, the 
V116 dose of 4 µg/each PnPs was selected for further evaluation in Phase 2. Results from 
Phase 2 showed that the V116 dose of 4 µg/each PnPs is well tolerated and generates 
serotype-specific immune responses. These data supported the selection of the V116 dose of 
4 µg/each PnPs for further development in Phase 3.
The overall V116 Phase 3 program includes over 8,000 adults aged ≥18 years, of whom over
5,000 received V116. The safety profile of V116 in pediatric participants is expected to be 
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consistent with the safety profile established in the Phase 3 adult populations and based on 
prior experience with PCVs. Refer to the IB for detailed background information on V116.
The dose of PPSV23 selected for use in this study is the approved dose for both adults and 
children that is consistent with the approved US and EU dosing and product labeling of 
PNEUMOVAX™23.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects is such that the risk/benefit ratio to the study population as a whole is 
unacceptable. In addition, further recruitment in the study or at (a) particular study site(s) 
may be stopped as described in Appendix 1.10.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Documented diagnosis of ≥1 of the following risk conditions for pneumococcal disease 
as determined by the investigator, according to local clinical standards, which includes 
history and physical examination in combination with diagnostic tests and procedures and 
managed per local guidelines:
•
Diabetes mellitus receiving treatment with antidiabetic medication
•
Chronic compensated liver disease
•
Chronic lung disease, including but not limited to asthma (a diagnosis of asthma 
requires current medical therapy)
•
Chronic heart disease due to heart failure, congenital heart disease, cardiomyopathy, 
and/or valvular heart disease
•
Chronic kidney disease, with chronic kidney insufficiency/impairment
2. Receiving stable medical management for the risk conditions listed in Inclusion Criterion 
#1 for ≥3 months with no anticipated major change in treatment expected for the duration 
of the study and with ≤1 hospitalization directly related to the risk condition within 
3 months before study vaccination.
3. At least 8 weeks prior to enrollment, completed primary PCV regimen with PCV7, 
PCV10, or PCV13 with either a 2+1 or 3+1 regimen according to local 
recommendations; all doses of the primary regimen must be of the same vaccine.
a.
2+1: 2 priming doses followed by 1 booster dose administered prior to 2 years of age
or
b. 3+1: 3 priming doses followed by 1 booster dose administered prior to 2 years of age
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4. Is PPSV23 vaccine-naïve (participant who has never received PPSV23), or PPSV23
vaccine-experienced (participant who has received not more than 1 dose of PPSV23) ≥5 
years before study vaccination.
Demographics
5. Is an individual of any sex/gender, from ≥2 years to <18 years of age, at the time of 
providing the informed consent/assent.
Assigned Female Sex at Birth
6. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
•
Is not a POCBP
OR
•
Is a POCBP and:
-
Uses an acceptable contraceptive method, or is abstinent from penile-vaginal 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 6 weeks after the last dose of study intervention. The investigator should 
evaluate the potential for contraceptive method failure (ie, noncompliance, recently 
initiated) in relationship to the first dose of study intervention. Contraceptive use by 
POCBPs should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions are more stringent 
than the requirements above, the local label requirements are to be followed.
-
Has a negative highly sensitive pregnancy test (urine or serum) as required by local 
regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the 
first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is positive.
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.3.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant (or participant's legally acceptable 
representative) may also provide consent/assent for FBR. However, the participant may 
participate in the study without participating in FBR.
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5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Had a curative procedure/surgery for chronic heart disease and does not require
medication, follow-up, additional interventions, or further management per local 
guidelines.
2. Has a history of active hepatitis within 3 months before study vaccination (Day 1).
3. Has a history of diabetic ketoacidosis or 2 or more episodes of severe, symptomatic 
hypoglycemia within 3 months before study vaccination (Day 1).
4. Has a history of severely decreased kidney function (outlined in the Investigator Trial 
File Binder for this study), dialysis, autoimmune related chronic kidney disease, 
nephrotic syndrome of any cause, or an acute/reversible cause of kidney disease.
5. Has a history of severe pulmonary hypertension or history of Eisenmenger syndrome.
6. Has a history of IPD (positive blood culture, positive cerebrospinal fluid culture, or 
positive culture at another sterile site) or known history of other culture-positive 
pneumococcal disease within 3 years before study vaccination (Day 1).
7. Has a known hypersensitivity to any component of PPSV23 or V116 (including
diphtheria toxoid).
8. Has a known or suspected impairment of immunological function including, but not 
limited to, congenital or acquired immunodeficiency, documented HIV infection, 
functional or anatomic asplenia, or autoimmune disease (including, but not limited to, the
autoimmune conditions outlined in the Investigator Trial File Binder for this study).
9. Has a coagulation disorder contraindicating intramuscular vaccination.
10. *Had a recent febrile illness (defined as temperature ≥100.4°F [≥38.0°C]) or received 
antibiotic therapy for any illness occurring within 72 hours before receipt of study 
vaccine.
11. Has a known malignancy that is progressing or has required active treatment <3 years 
before randomization. Note: Participants with basal cell and/or squamous cell carcinoma 
of the skin, or carcinoma in situ that have undergone potentially curative therapy, are not 
excluded.
12. Planned organ transplantation (heart, liver, lung, kidney, or pancreas) or other planned 
major surgical procedure during the duration of this study.
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13. Expected survival for <1 year according to the investigator’s judgment.
Prior/Concomitant Therapy
14. Received ≥1 dose of PCV15 or PCV20.
15. Is expected to receive any pneumococcal vaccine during the study outside of the protocol.
16. *Received or is scheduled to receive systemic corticosteroids (total daily dose prednisone 
equivalent of ≥2 mg/kg or ≥20 mg/day for children >10 kg) for ≥14 consecutive days and 
has not completed intervention ≥14 days before receipt of study vaccine (Day 1) and 
through 30 days following vaccination. Note: Physiologic replacement doses (prednisone 
equivalent of approximately 5 mg/day), topical, ophthalmic, intraarticular or soft-tissue 
(eg, bursa, tendon steroid injections), and inhaled/nebulized steroids are permitted.
17. Is currently receiving systemic immunosuppressive therapy, including chemotherapeutic 
agents or other immunotherapies/immunomodulators used to treat cancer or other 
conditions, and interventions associated with organ or bone marrow transplantation, or 
autoimmune disease.
18. *Received any nonlive vaccine ≤14 days before receipt of study vaccine or is scheduled 
to receive any nonlive vaccine ≤30 days after receipt of study vaccine. Exception: 
Inactivated influenza vaccine and SARS-CoV-2 mRNA or SARS-CoV-2 protein subunit 
vaccine may be administered but must be given ≥7 days before or ≥15 days after receipt 
of study vaccine.
19. *Received any live virus vaccine (including SARS-CoV-2 live virus vaccines) ≤30 days 
before receipt of study vaccine or is scheduled to receive any live virus vaccine ≤30 days 
after receipt of study vaccine.
20. Received a blood transfusion or blood products, including immunoglobulin ≤6 months 
before receipt of study vaccine or is scheduled to receive a blood transfusion or blood 
product ≤30 days after receipt of study vaccine. Autologous blood transfusions are not 
considered an exclusion criterion.
21. Receiving chronic home oxygen therapy.
Prior/Concurrent Clinical Study Experience
22. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 2 months of participating in this current study.
Diagnostic Assessments
Not Applicable.
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Other Exclusions
23. In the opinion of the investigator, has a history of clinically relevant drug or alcohol use
that may interfere with participation in protocol-specified activities.
24. Has history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that might expose the participant to risk by participating in the study, 
confound the results of the study, or interfere with the participant’s participation for the 
full duration of the study.
25. Has a parent/legal guardian/legally acceptable representative who is unlikely to adhere to 
study procedures, keep appointments, or is planning to relocate during the study.
26. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For Exclusion Criteria with an asterisk (*), if the participant meets these exclusion 
criteria, Visit 1 may be rescheduled for a time when these criteria are not met.
Country-specific criteria are included in Appendix 7.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants with documented consent/assent to participate in 
the clinical study, but are not subsequently randomized in the study. A minimal set of screen-
failure information is required to ensure transparent reporting of screen-failure participants to 
meet the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen-failure details, eligibility 
criteria, and any AEs or SAEs meeting reporting requirements as outlined in the data entry 
guidelines.
5.5
Participant Replacement Strategy
A participant who withdraws from the study will not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (V116 and PPSV23) will be packaged to support enrollment. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
Country-specific requirements are noted in Appendix 7.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulatio
n
Unit Dose 
Strength(s
)
Dosage 
Level(s
)
Route of 
Administratio
n
Regimen/
Treatment 
Period/
Vaccinatio
n Regimen
Use
IMP 
or 
NIMP
/
AxMP
Sourcin
g
V116
Experimenta
l
Pneumococca
l 21-valent 
conjugate 
vaccine
Biological/Vaccin
e
Injection, 
Solution
4 µg of 
each PnPs 
antigen (3, 
6A, 7F, 8, 
9N, 10A, 
11A, 12F, 
15A, 15C, 
16F, 17F, 
19A, 20A, 
22F, 23A, 
23B, 24F, 
31, 33F, 
and 35B)
0.5 mL
IM
Single dose 
at Visit 1
(Day 1)
Test 
Product
IMP
Central
PPSV2
3
Active 
Comparator
Pneumococca
l Vaccine, 
Polyvalent 
(23-valent)
Biological/Vaccin
e
Injection, 
Solution
25 μg of 
each PnPs 
antigen (1, 
2, 3, 4, 5, 
6B, 7F, 8, 
9N, 9V, 
10A, 11A, 
12F, 14, 
15B, 17F, 
18C, 19A, 
19F, 20, 
22F, 23F, 
and 33F)
0.5 mL
IM
Single dose 
at Visit 1
(Day 1)
Comparato
r
IMP
Central 
or local
EEA=European Economic Area; IM=intramuscular; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; PnPs=pneumococcal 
polysaccharide; PPSV23=pneumococcal vaccine, polyvalent (23-valent) (PNEUMOVAX™23); V116=pneumococcal 21-valent conjugate vaccine.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Drug-Device Combination Products/Combination Medicinal Products
The drug-device product(s)/combination medicinal product(s), which are marketed and
provided for use in this study is PNEUMOVAX™23 (PPSV23). Refer to Section 8.4.8 and 
Appendix 4 for reporting events associated with these devices.
The investigational drug-device combination product(s)/investigational combination 
medicinal product(s) provided for use in this study are V116 pre-filled syringes. Refer to 
Section 8.4.8 and Appendix 4 for reporting events associated with these devices.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
Specific procedures that are required for dose preparation are outlined in the Investigator 
Trial File Binder.
As detailed in Section 6.3.3, study vaccines will be prepared by an unblinded pharmacist or 
qualified study-site personnel.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
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For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 3:2 ratio to receive either 
V116 or PPSV23, respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
•
Prior pneumococcal vaccination and age:
-
Prior PCV7 alone
-
Prior PCV7 and one prior PPSV23 dose
-
Prior PCV10 alone and ≥2 to <6 years old
-
Prior PCV10 alone and ≥6 to <18 years old
-
Prior PCV10 and one prior PPSV23 dose
-
Prior PCV13 alone and ≥2 to <6 years old
-
Prior PCV13 alone and ≥6 to <18 years old
-
Prior PCV13 and one prior PPSV23 dose
•
Number of increased-risk conditions for pneumococcal disease (including chronic heart 
disease or chronic lung disease or diabetes mellitus or chronic liver disease, and/or 
chronic kidney disease):
-
1 increased-risk condition 
-
≥2 increased-risk conditions*
*Note: The participant must meet the inclusion/exclusion criteria for each of the 
increased-risk conditions in order to be included in this stratum.
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It is expected that ≥25 participants per risk condition listed in Inclusion Criteria #1 
(Section 5.1) will be enrolled. In participants with ≥2 increased-risk conditions, each 
condition will count towards the 25 total per condition.
6.3.3
Blinding
A double-blinding technique will be used. Study intervention will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified study-site personnel. 
The participant, participant’s legally acceptable representative, the investigator, and Sponsor 
personnel or delegate(s) who are involved in the study intervention administration or clinical 
evaluation of the participants are unaware of the intervention assignments.
Because V116 and PPSV23 have a different appearance, the unblinded pharmacist (or 
qualified study-site personnel) will be responsible for receiving, maintaining, preparing 
and/or dispensing, and administering these study vaccines (Section 8.1.8).
To avoid bias, contact between the unblinded study-site personnel and study participants and 
their legally acceptable representatives is strictly prohibited for any study-related 
procedures/assessments other than administration of study vaccines. Blinded site personnel 
will be responsible for all other study procedures/assessments specified in Section 1.3.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) directly involved with the conduct of this 
study will remain blinded to the participant-level intervention assignment.
See Section 8.1.12 for the description of unblinding if a medical emergency occurs during the 
study.
6.4
Study Intervention Compliance
Given that a single dose of V116 or PPSV23 will be administered in this study, intervention 
compliance will not be assessed.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study (Section 5.2). 
If there is a clinical indication for any medications or vaccinations specifically prohibited, the 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant/participant’s legally acceptable representative.
It is important to record the use of any analgesic or antipyretic medication that occurs on the 
day of vaccination on the eVRC and appropriate eCRF.
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Listed below are specific restrictions for concomitant therapy or vaccination:
•
Administration of a nonstudy pneumococcal vaccine is prohibited during the study.
•
Nonstudy vaccines may only be administered before or after the receipt of study vaccine 
according to the time frames specified in the Exclusion Criteria (Section 5.2).
•
Receipt of systemic corticosteroids (total daily dose prednisone equivalent of ≥2 mg/kg 
or ≥20 mg/day for children >10 kg) for ≥14 consecutive days is prohibited from 14 days 
before vaccination through 30 days following vaccination. Note: Physiologic 
replacement doses (prednisone equivalent of approximately 5 mg/day), topical, 
ophthalmic, intraarticular or soft-tissue (eg, bursa, tendon steroid injections), and 
inhaled/nebulized steroids are permitted.
Any deviation from the above requires consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on participant management.
Use of prior and concomitant medications/vaccinations should be recorded as described in 
Section 8.1.5.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
No dose modification is allowed in this study.
6.6.1
Stopping Rules
There are no prespecified stopping rules for this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study-site personnel will be used to blind supplies. Study intervention 
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.12). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
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See Section 8.1.12 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur before the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent/assent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.11. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant/participant's 
legally acceptable representative are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant/participant’s legally acceptable representative, the following 
procedures are to be performed:
•
The site must attempt to contact the participant/participant’s legally acceptable 
representative and reschedule the missed visit. If contacted, the participant/participant’s 
legally acceptable representative should be counseled on the importance of maintaining 
the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the 
participant/participant’s legally acceptable representative at each missed visit (eg, 
telephone calls and/or a certified letter to the participant’s last known mailing address or 
locally equivalent methods). These contact attempts should be documented in the 
participant’s medical record.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent/assent may be used 
for screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent/assent be obtained from the participant (or 
participant's legally acceptable representative). In these cases, such evaluations/testing 
will be performed in accordance with those regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study will not exceed the volume mentioned in Appendix 2.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent, or assent if applicable, from each potential participant 
(or their legally acceptable representative) prior to participating in this clinical study or FBR. 
If there are changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent/assent is in place.
8.1.1.1
General Informed Consent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on an ICF. The form must include the study protocol number, study 
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protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent/assent discussion.
A copy of the signed and dated ICF should be given to the participant (or their legally 
acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant or their legally acceptable representative must receive the IRB/IEC’s 
approval/favorable opinion in advance of use. The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the willingness of the participant or their legally acceptable 
representative to continue participation in the study. The communication of this information 
will be provided and documented via a revised ICF or addendum to the original ICF that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study ICF.
Informed consent/assent will adhere to IRB/IEC requirements, applicable laws and 
regulations, and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent/assent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent/assent before performing any procedure 
related to FBR. A copy of the informed consent/assent will be given to the participant (or 
participant’s legally acceptable representative) before performing any procedure related to 
FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants (or participant's legally acceptable representative) will be given a participant 
identification card identifying them as participants in a research study. The card will contain 
study-site contact information (including direct telephone numbers) to be used in the event of 
an emergency. The investigator or qualified designee will provide the participant (or 
participant's legally acceptable representative) with a participant identification card 
immediately after documented informed consent/assent is provided. At the time of 
intervention randomization, site personnel will add the treatment/randomization number to 
the participant identification card.
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The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The participant’s 
relevant medical history for the 5 years before Visit 1 will be obtained to ensure that the 
participant satisfies the inclusion and exclusion criteria of the study.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The following must be documented by the investigator or qualified designee before 
vaccination at Visit 1 and recorded on the appropriate eCRF:
•
Prior vaccinations and medication taken by the participant within 30 days before study 
vaccination at Visit 1.
•
Any prior pneumococcal vaccination regardless of timing prior to Visit 1.
•
Any analgesic or antipyretic medication taken on the day of vaccination before 
vaccination.
8.1.5.2
Concomitant Medications
The participant/participant’s legally acceptable representative will use the eVRC
(Section 8.1.10) to record concomitant medications (including the use of any analgesic or 
antipyretic medication) and nonstudy vaccinations received from the day of vaccination
through 30 days postvaccination.
The investigator or qualified designee must record concomitant medications and nonstudy 
vaccinations on the appropriate eCRF through Day 30 after vaccination. Outside this period, 
report only concomitant medications related to an SAE.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the Screening Visit. Specific details on the Screening Visit requirements are in 
Section 8.11.1. Pre-trial screening logs may be collected for review by the Sponsor. If 
applicable, any information that would make the participant identifiable will be removed.
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8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
Unblinded study personnel will prepare and administer all study vaccines (Section 6.3.3). 
The unblinded study personnel who administer study vaccines should not have contact with 
participants/participant’s legally acceptable representative for any other study-related 
procedures/assessments.
Blinded site personnel will not be present in the examination room when study vaccines are 
administered.
Study vaccines should be prepared and administered by appropriately qualified members of 
the study personnel (eg, physician, nurse, physician’s assistant, nurse practitioner, 
pharmacist, or medical assistant) as allowed by local/state, country, and institutional 
guidance.
Procedures for handling, preparing, and administering the unblinded vaccines are provided in 
the Investigator Trial File Binder.
Study vaccine will be administered as a single IM injection, preferably in the deltoid region 
of the participant’s arm, according to the schedule specified in Section 1.3. Adequate 
treatment provision, including epinephrine and equipment for maintaining an airway, should 
be available for immediate use should an anaphylactic or anaphylactoid reaction occur 
[Centers for Disease Control and Prevention 2015].
8.1.8.1
Timing of Dose Administration
Study intervention will be administered as indicated in Section 1.3. Vaccinations may be 
administered at any time of day and without regard to timing of meals.
All participants will be observed for at least 30 minutes after vaccination for any immediate
reactions (Section 8.3.5). This observation must be performed by blinded site personnel
(Section 6.3.3).
Participants must not have a fever reported within 72 hours before each vaccination (Section 
1.3 and Section 8.3.4).
Administration of pregnancy tests (if applicable) must be performed before vaccine
administration.
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The collection of blood samples should be performed before vaccine administration.
8.1.9
Telephone Contact Questionnaire
Site personnel will contact the participant (or the participant’s legally acceptable 
representative, as applicable) as indicated in Section 1.3 to collect additional information 
based on a Telephone Contact Questionnaire provided by the Sponsor. Data to be reported 
from this discussion will include SAEs and/or any updates to previously reported safety 
information.
8.1.10
Electronic Vaccination Report Card
The eVRC is structured as recommended in the final US FDA Patient-reported Outcome 
Guidance [U.S. Food and Drug Administration 2009].
The participant/participant’s legally acceptable representative will use the eVRC to record 
body temperature (Section 8.3.4), solicited injection-site AEs, and solicited systemic AEs 
(Section 8.4.9.1). Unsolicited AEs (Section 8.4.9.2), concomitant medications, and nonstudy 
vaccinations (Section 8.1.5.2) will also be reported. The participant/participant’s legally 
acceptable representative will be provided an electronic device or have their own electronic 
device configured, if compatible, to complete the eVRC. If the participant receives assistance 
completing the eVRC, all data reported on the eVRC must be entered as reported by the 
participant.
The investigator or qualified delegate will review the data captured on the eVRC with the 
participant/participant’s legally acceptable representative as indicated in Section 1.3. Any 
changes to the data reported by the participant on the eVRC must be clearly explained in the 
participant’s source documents.
8.1.11
Discontinuation and Withdrawal
Participants who receive a single-dose intervention cannot discontinue study intervention 
(see Section 7.1).
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.11.1
Withdrawal From Future Biomedical Research
Participants or participant's legally acceptable representative may withdraw their 
consent/assent for FBR. Participants/Participant's legally acceptable representative may 
withdraw consent or assent at any time by contacting the study investigator. If medical 
records for the study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant’s consent or assent for FBR will be withdrawn. A letter will be sent from the 
Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
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investigator to inform the participant or participant's legally acceptable representative of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.12
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity grade of the AEs observed, the relation to study intervention, the reason thereof, etc, 
in the medical record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
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8.1.13
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure vaccine-induced OPA and IgG responses. 
These endpoints will be tested for all immunogenicity blood draws specified in Section 1.3.
Blood collection, storage, and shipment instructions for serum samples will be provided in 
the operations/laboratory manual. 
After completion of immunogenicity testing to evaluate the study objectives and hypotheses, 
serum samples will be stored to conduct any additional study-related testing as requested by 
regulatory agencies or the Sponsor. Leftover sera from the study may be used for other 
purposes, such as the development and/or validation of pneumococcal assays after 
completion of all study-related immunogenicity testing. These samples may be stored and 
further analysis may be performed, if required.
8.2.1
Multiplex Opsonophagocytic Assay
The MOPA will be used for measuring OPA responses. Opsonization of pneumococci for 
phagocytosis is an important mechanism by which antibodies to polysaccharides protect 
against disease in vivo. The OPA assay is a useful tool for assessing the protective function 
of serotype-specific antibodies and, therefore, the immunogenicity of pneumococcal vaccine 
formulations.
The MOPA is an antibody-mediated killing assay that measures the ability of human serum 
to kill S pneumoniae serotypes with the help of complement and phagocytic effector cells 
[Burton, Robert L. and Nahm, Moon H. 2006]. The ability of the assay to simultaneously test 
4 serotypes at a time reduces the amount of serum needed for testing. The assay readout is 
the opsonization index, which is the reciprocal of the highest dilution that gives ≥50% 
bacterial killing, as determined by comparison to assay background controls. The Sponsor 
has developed and optimized the MOPA in a high throughput microcolony platform, which 
not only covers all 21 serotypes in V116, but also includes serotypes 6C and 15B so that 
antibodies induced by vaccine serotypes 6A and 15C but cross-reactive to serotypes 6C and 
15B, respectively, can be measured. The assay has been validated for various performance 
parameters of the assay including precision, ruggedness, relative accuracy/dilutional 
linearity, and the limit of detection of the assay.
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8.2.2
Pneumococcal Electrochemiluminescence Assay
Serotype-specific IgG will be measured using the Pn ECL assay to assess the concentration 
of binding antibodies to capsular polysaccharide of S pneumoniae.
The Sponsor has developed, optimized, and validated a multiplex, ECL-based detection 
method for the quantitation of IgG serotype-specific antibodies. This multiplexed ECL assay 
not only detects all 21 serotypes contained in V116 but also detects serotypes 6C and 15B so 
that antibodies induced by vaccine serotypes 6A and 15C but cross-reactive to serotypes 6C 
and 15B, respectively, can be measured. The ECL assay is based on the Meso-Scale 
Discovery technology, which employs disposable multispot microtiter plates. Briefly, PnPs 
are bound to the surface of 96-well 10 plex carbon microplates, and serum containing 
purported anti-PnPs antibodies is added. The anti-PnPs antibodies bind to the coated plates 
and form an antibody-antigen complex. The bound antibody-antigen complex can be detected 
using a ruthenium labeled anti-human IgG. Plates are read by measure of the 
chemiluminescent signal emitted from the ruthenium tag upon electrochemical stimulation 
initiated at the electrode surfaces of the microplates. To improve the specificity to the 
pneumococcal serotypes in the vaccine, capsular polysaccharide, PnPs 25, and PnPs 72 are 
used for preadsorption of samples, standard, and controls. Assay validation studies showed 
excellent performance operating characteristics for precision (intraassay and interassay),
dilutability, ruggedness (to different plate lots and analysts), relative accuracy, and 
specificity.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard before vaccination at
Visit 1. The directed physical examination should focus on examining systems related to any 
ongoing conditions and/or follow-up on previously reported AEs.
Findings related to the physical examinations should be documented in the source 
documents. Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
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8.3.2
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 to 44 days after the last dose of study intervention, 
every attempt should be made to perform repeat assessments until the values return to 
normal or baseline or if a new baseline is established as determined by the investigator.
8.3.3
Pregnancy Testing
A pregnancy test consistent with local requirements (sensitive to at least 25 IU hCG) must be 
performed before study vaccination at Visit 1 (Day 1) in POCBP as described in Section 1.3.
Urine or serum tests can be used, and results must be negative before study vaccination can 
occur. A detailed definition of POCBP is provided in Appendix 5.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
8.3.4
Body Temperature Measurement
Each participant’s body temperature must be taken by study-site staff before vaccination as 
described in Section 1.3. The prevaccination temperature should be documented in the 
participant’s source documents. Participants who have febrile illness (defined as ≥100.4°F 
[≥38.0°C]) <72 hours before vaccination must be rescheduled.
The participant/participant’s legally acceptable representative will record oral (preferred in 
participants ≥3 years of age) or axillary (underarm) body temperature measurements on the 
eVRC (Section 8.1.10) from Day 1 to Day 5 after vaccination. Elevated temperatures 
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(≥100.4°F [≥38.0°C]) reported by the participant/participant’s legally acceptable 
representative Day 1 through Day 5 postvaccination will be reported as a solicited systemic 
event of pyrexia.
8.3.5
Postvaccination Observation Period
All participants will be observed for at least 30 minutes after vaccination for any immediate 
reactions. If any immediate AEs are observed during this period, the time at which the event 
occurred within this timeframe, as well as the event itself, any concomitant medications that 
were administered, and resolution of the event must be recorded on the appropriate eCRF.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant (or their 
legally acceptable representative) provides documented informed consent/assent, but before 
randomization, must be reported by the investigator if they cause the participant to be 
excluded from the study, or are the result of a protocol-specified intervention, including, but 
not limited to washout or discontinuation of usual therapy, diet, placebo, or a procedure.
All nonserious AEs and other reportable safety events (excluding pregnancy and lactation 
exposure) must be reported by the investigator from the day of randomization through 30 
days postvaccination.
All pregnancies and lactation exposure during breastfeeding must be reported by the 
investigator from the day of randomization through 6 weeks postvaccination.
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All SAEs must be reported by the investigator through 6 months postvaccination, regardless 
of whether related to the study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 2.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 2
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent/Assent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
– any death until 
participant 
completion of 
study
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
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Type of Event
Reporting Period:
Consent/Assent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (requiring
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (does not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant (or 
participant’s legally acceptable representative) is the preferred method to inquire about AE 
occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable for this study.
8.4.7
Events of Clinical Interest
There are no ECIs for this study.
8.4.8
Drug-device Combination Products/Combination Medicinal Products –
Complaints, PQCs, and Malfunctions
The method of documenting and reporting complaints, PQCs, and malfunctions will occur as 
below and in Appendix 4. Refer to Appendix 7 for country-specific information and 
definitions.
To fulfill regulatory reporting obligations worldwide, medical device information associated 
with AEs will be collected and reported to the Sponsor in the same time frame as AEs per
Section 8.4.1 via CRF (paper or electronic) and as per data entry guidelines.
PQCs/malfunctions, including those that involve a participant or any user/associated person, 
must be reported to the Sponsor. Sponsor shall review reported events by the investigator to 
fulfill the legal responsibility of notifying appropriate regulatory authorities and other entities 
about certain safety information relating to drug-device combination products/combination 
medicinal products being used in clinical studies.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality between the AE and the 
medical device or device constituent of combination product.
8.4.9
Adverse Events on the VRC
Participants/participant’s legally acceptable representative will use an eVRC to report 
solicited and unsolicited AEs.
The definitions of solicited and unsolicited AEs can be found in Appendix 3.
8.4.9.1
Solicited Adverse Event
Solicited AEs for this study are summarized in Table 3.
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Table 3
Solicited Adverse Events for V116-013
Type of Solicited 
Adverse Event
Predefined Solicited Adverse Events 
(Preferred Term)
Solicited Period
Injection-site Adverse 
Event

Injection-site pain or tenderness 
(injection-site pain)

Injection-site redness (injection-site 
erythema)

Injection-site swelling (injection-site 
swelling)
Day 1 to Day 5 postvaccination
Systemic Adverse Event

Muscle aches all over body (myalgia)

Headache (headache)

Tiredness (fatigue)

Hives or Welts (urticaria)

Irritability (irritability)

Joint pain (arthralgia)

Drowsiness (somnolence)

Feeling sick (malaise)
Day 1 to Day 5 postvaccination
Note: Daily temperatures will be solicited Day 1 through Day 5 postvaccination. Elevated temperatures of 
≥100.4°F (≥38.0°C) from Day 1 through Day 5 postvaccination will be categorized as solicited events of 
pyrexia.
8.4.9.2
Unsolicited Adverse Events
Unsolicited AEs for this study are events that are 1) not predefined in Table 3 or 
2) predefined in Table 3 but reported at any time outside the solicited period.
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than 1 dose of study vaccine in any 24-hour 
period.
No specific information is available on the treatment of overdose.
8.6
Pharmacokinetics
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Future Biomedical Research Sample Collection
All sample collections for study-specific assessments shown in the SoA are described within
the main Informed Consent.
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If the participant or participant's legally acceptable representative has provided documented 
informed consent/assent for FBR, leftover samples will be used for FBR. The following 
specimens will be included for FBR:
•
Buccal swab DNA for future research
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Screening procedures will be conducted at Visit 1 as outlined in Section 1.3. Potential 
participants will be evaluated to determine that they fulfill the entry requirements as set forth 
in Section 5.
If Visit 1 is rescheduled (see Section 5.2), a pregnancy test (if applicable); a body 
temperature measurement; and a review of inclusion/exclusion criteria, prior 
medications/vaccinations, and medical history must be repeated before vaccination.
8.11.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3. Participants are to be 
followed for at least 6 months after vaccination or until discontinuation from the study.
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9
KEY STATISTICAL CONSIDERATIONS
This section outlines the statistical analysis strategy and procedures for the study; further 
details will be provided in the SAP. If, after the study has begun, but prior to any 
unblinding/final database lock, changes are made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses, then the protocol will be 
amended (consistent with ICH Guideline E9). Changes to exploratory or other 
nonconfirmatory analyses made after the protocol has been finalized, but prior to any 
unblinding/final database lock, will be documented in the SAP and referenced in the CSR for 
the study. Post hoc exploratory analyses will be clearly identified in the CSR. 
9.1
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The study will be conducted as a double-blind study under in-house blinding procedures. The 
official final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department of the Sponsor will generate the randomized allocation 
schedule(s) for study intervention assignment. Randomization will be implemented in an IRT 
system. 
Blinding issues related to the planned IAs are described in Section 9.6.
9.2
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3 of the protocol.
9.3
Analysis Endpoints
Immunogenicity and safety endpoints will be evaluated for within- and/or between-
intervention.
9.3.1
Immunogenicity Endpoints
Immune responses will be measured for all 21 serotypes contained in V116: 12 serotypes 
common to V116 and PPSV23 (3, 7F, 8, 9N, 10A, 11A, 12F, 17F, 19A, 20A, 22F, and 33F) 
and 9 serotypes unique to V116 (6A, 15A, 15C, 16F, 23A, 23B, 24F, 31, and 35B), and 2 
cross-reactive serotypes (6C and 15B).
The primary immunogenicity endpoint includes:
•
Serotype-specific OPA GMTs at 30 days postvaccination
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The secondary immunogenicity endpoints include:
•
Serotype-specific IgG GMCs at 30 days postvaccination
•
Serotype-specific GMFR and proportion of participants with a ≥4-fold rise from baseline
(Day 1) to 30 days postvaccination for both OPA and IgG responses
The exploratory immunogenicity endpoints include the summaries of the cross-reactive 
immune responses to serotypes within a serogroup using serotype-specific OPA and IgG
responses at 30 days postvaccination.
9.3.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs and vital signs.
The safety endpoints for overall safety assessment that address the primary objectives 
include:
•
Proportion of participants with solicited injection-site AEs [redness (erythema), swelling 
(swelling), and pain or tenderness (pain)] from Day 1 through Day 5 postvaccination
•
Proportion of participants with solicited systemic AEs [(muscle aches all over body  
(myalgia), headache (headache), tiredness (fatigue), hives or welts (urticaria), irritability 
(irritability), join pain (arthralgia), drowsiness (somnolence), feeling sick (malaise), fever 
(pyrexia)] from Day 1 through Day 5 postvaccination. Note:  Daily temperatures will be 
solicited Day 1 through Day 5 postvaccination. Elevated temperatures of ≥100.4°F 
(≥38.0°C) will be categorized as solicited events of pyrexia.
•
Proportion of participants with vaccine-related SAEs from Day 1 through the duration of 
participation in the study
Additional safety endpoints for overall safety assessment include:
•
Proportion of participants with the broad AE categories consisting of any AE, any 
unsolicited AEs, and any vaccine-related AE from Day 1 through Day 30 postvaccination
•
Proportion of participants with the broad AE categories consisting of any SAE, any 
vaccine-related SAEs, and death from Day 1 through the duration of participation in the 
study. As this is a single-dose study, the broad AE category of discontinuation of study 
intervention due to an AE is not applicable
•
Proportion of participants with maximum temperature measurements meeting the 
Brighton Collaboration cut points from Day 1 through Day 5 postvaccination
9.4
Analysis Populations
9.4.1
Immunogenicity Analysis Populations
The PP population will serve as the primary population for the immunogenicity endpoint(s). 
The PP population excludes participants due to important deviations from the protocol that 
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may substantially affect the results of the primary immunogenicity endpoint(s). Potential 
deviations that may result in the exclusion of a participant from the PP population include:
•
Failure to receive study vaccine at Visit 1 (Day 1)
•
Failure to receive correct clinical material as per randomization schedule
•
Receipt of a prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion of a participant from the PP 
population for specific immunogenicity analyses (depending on the time point) include:
•
Receipt of a prohibited medication or prohibited vaccine prior to a blood sample 
collection
•
Collection of a blood sample outside the prespecified window
The final determination on important protocol deviations, and thereby the composition of the 
PP population, will be made prior to the final unblinding of the database and will be 
documented in a separate memo. 
A supportive analysis using the FAS population will also be performed for the primary 
immunogenicity endpoint. The FAS population consists of all randomized participants who 
received at least 1 study vaccination and have at least 1 serology result. Participants will be 
included in the vaccination group to which they are randomized for the analysis of the 
immunogenicity data using the FAS population.
9.4.2
Safety Analysis Populations
Safety Analyses will be conducted in the APaT population, which consists of all randomized 
participants who received one dose of study intervention. Participants will be included in the 
vaccination group corresponding to the study vaccination they actually received for the 
analysis of safety data using the APaT population. This will be the group to which they are 
randomized except for participants who take incorrect study vaccination; such participants 
will be included in the group corresponding to the study vaccination actually received.
At least 1 temperature measurement obtained subsequent to study intervention is required for
inclusion in the analysis of temperature.
9.5
Statistical Methods
9.5.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary and secondary 
immunogenicity objectives.
Immunogenicity analyses will be conducted for each serotype separately. 
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Primary Endpoints/Hypotheses (H1 and H2)
The first primary objective (to compare the serotype-specific OPA GMTs at 30 days
postvaccination with V116 versus PPSV23) will be assessed via the 2 hypotheses.
For the 12 common serotypes, the primary noninferiority hypothesis (H1) regarding OPA
GMT levels between recipients of V116 and PPSV23 is:
H0: GMT1/GMT2 ≤0.50 versus
H1: GMT1/GMT2 >0.50
where GMT1 is the serotype-specific OPA GMT for the V116 group and GMT2 is the
serotype-specific OPA GMT for the PPSV23 group. A ratio of 0.50 corresponds to an OPA
GMT that is 2.0-fold lower in the V116 group compared with the PPSV23 group. Rejecting
the null hypothesis (H0) at the 1-sided α=0.025 level corresponds to the lower bound of the
2-sided 95% CI on the GMT ratio (V116/PPSV23) being >0.50 and would lead to the
conclusion that the OPA response to V116 for the common serotype is noninferior to that of
PPSV23.
For the 9 serotypes that are unique to V116, the primary superiority hypothesis (H2)
regarding OPA GMT levels between recipients of V116 and PPSV23 is:
H0: GMT1/GMT2 ≤2.0 versus
H1: GMT1/GMT2 >2.0
where GMT1 is the serotype-specific OPA GMT for the V116 group, and GMT2 is the
serotype-specific OPA GMT for the PPSV23 group. A ratio of 2.0 corresponds to an OPA
GMT that is 2.0-fold higher in the V116 group compared with the PPSV23 group. Rejecting
the null hypothesis (H0) at the 1-sided α=0.025 level corresponds to the lower bound of the
2-sided 95% CI on the GMT ratio (V116/PPSV23) being >2.0 and would lead to the
conclusion that the OPA response to V116 for the unique serotype is superior to that of
PPSV23.
To address the first primary immunogenicity objective, the serotype-specific OPA GMTs at
30 days postvaccination will be compared between vaccination groups. The GMT ratio
estimation, 95% CI, and the hypothesis test (ie, 1-sided p-value) will be calculated using a
cLDA method proposed by Liang and Zeger [Liang, K-Y and Zeger, S. L. 2000] using data 
from both vaccination groups. In this model, the response vector consists of the log-
transformed antibody titers at baseline and 30 days postvaccination. This model allows the 
inclusion of participants who are missing either the baseline or postbaseline measurements, 
thereby increasing efficiency.
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Secondary Endpoints
A similar statistical model as used for the first primary objective will be used to address the
secondary objective that compares the serotype-specific IgG GMCs at 30 days
postvaccination with V116 compared with PPSV23.
Descriptive statistics with point estimates and within-group 95% CIs will be provided for all
other immunogenicity endpoints. For the continuous endpoints, the point estimates will be
calculated by exponentiating the estimates of the mean of the natural log values and the
within-group CIs will be derived by exponentiating the bounds of the CIs of the mean of the
natural log values based on the t-distribution. For the dichotomous endpoints, the within-
group CIs will be calculated based on the exact method proposed by Clopper and Pearson 
[Clopper, C. J. and Pearson, E. S. 1934].
Reverse Cumulative Distribution Curves for both OPA titers and IgG concentrations at 30 
days postvaccination will be graphically displayed by serotype.
A detailed analysis strategy for immunogenicity endpoints is listed in Table 4.
Table 4
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs 
Supportive 
Approacha
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoints
OPA GMTs at 30 days 
postvaccination for the 12
common serotypes in V116 and
PPSV23
P
cLDA
(estimate, 95% CI,
p-values)
PP
Model-based
S
FAS
OPA GMTs at 30 days 
postvaccination for the 9
unique serotypes in V116
P
cLDA
(estimate, 95% CI,
p-values)
PP
Model-based
S
FAS
Secondary Endpoints
IgG GMCs at 30 days post 
vaccination for the 1) 12 
common serotypes between 
V116 and PPSV23 2) 9 unique 
serotypes in V116
P
cLDA
(estimate, 95% CI)
PP
Model-based
GMFRs and proportions of 
participants with a ≥4-fold rise 
from baseline to 30 days 
postvaccination for 1) serotype-
specific OPA responses and 2) 
serotype-specific IgG responses 
within each vaccination group
P
Descriptive Statistics 
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
CI=confidence interval; cLDA=constrained longitudinal data analysis; FAS=full analysis set; GMC=geometric mean
concentration; GMFR=geometric mean fold rise; GMT=geometric mean titer; IgG=immunoglobulin G;
OPA=opsonophagocytic activity; PP=per-protocol.
a
P=Primary approach; S=Supportive approach.
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9.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs and postvaccination temperature measurements. 
9.5.2.1
Overall Safety Assessment
The overall safety evaluation will include a summary by vaccination group (V116 group and 
PPSV23 group) of the number and percentage of participants with any AEs, any unsolicited 
AEs, any vaccine-related AEs, any SAEs, any vaccine-related SAEs, and any AEs resulting 
in death after vaccination. Point estimates and 95% CIs for the between-group differences 
(V116 compared with PPSV23) in the percentages of participants with the event will be 
provided for these events.
The number and percentage of participants with specific AEs will also be provided. Point 
estimates and 95% CIs for the differences between vaccination groups in the percentages of 
participants with specific AEs will be provided for solicited AEs and AEs that occur in ≥2% 
of participants in the V116 group or PPSV23 group.
The number and percentage of participants with maximum temperature measurements 
meeting the Brighton Collaboration cut points [Marcy, S. M., et al 2004] will be provided 
along with point estimates and 95% CIs of between-group differences. 
CIs for between-group differences will be provided using the M&N method [Miettinen, O. 
and Nurminen, M. 1985]. Rainfall plots with point estimates and 95% CIs will be displayed 
for AEs that occur in ≥5% of participants in the V116 group or PPSV23 group.
A detailed analysis strategy for safety endpoints is listed in Table 5.
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Table 5
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
Between-
group 
95% CI
Graphical 
Display
Overall 
Safety 
Assessment
Solicited injection-site AE (Day 1 through Day 5 
postvaccination)a
X
X
Solicited systemic AE (Day 1 through Day 5 
postvaccination)a
X
X
Any AEb
X
X
Any unsolicited AEb
X
X
Any vaccine-related AEb
X
X
Any SAEb
X
X
Any vaccine-related SAEb
X
X
Deathb
X
X
Specific AEs by SOC and PTc
X
X
X
Maximum temperatures (Day 1 through Day 5 
postvaccination)d
X
X
AE=adverse event; CI=confidence interval; PT=preferred term; SAE=serious adverse event; SOC=system 
organ class.
a
Solicited injection-site AEs include redness (erythema), swelling (swelling), and pain and tenderness
(pain); solicited systemic AEs include muscle aches all over body (myalgia), headache (headache), 
tiredness (fatigue), hives or welts (urticaria), irritability (irritability), join pain (arthralgia), drowsiness 
(somnolence), feeling sick (malaise), fever (pyrexia). Note: Daily temperatures will be solicited Day 1 
through Day 5 postvaccination. Elevated temperatures of ≥100.4°F (≥38.0°C) will be categorized as 
solicited events of pyrexia.
b
These endpoints are broad AE categories. For example, descriptive statistics for the safety endpoint of 
“Any AE” will provide the number and percentage of participants with at least 1 AE.
c
Descriptive statistics, 95% Between-group CI, and Graphical Display will be provided for specific AEs 
with an incidence >0%, ≥2%, and ≥5% of participants, respectively, in each vaccination group.
d
Maximum temperature measurements are categorized by Brighton Collaboration cut points.
9.6
Interim Analyses
A periodic review of safety and tolerability data across the V116 pediatric study will be 
conducted by an independent, unblinded, external DMC. A description of the structure and 
function of the DMC, along with the timing and content of the safety review, will be outlined 
in the DMC charter. Information regarding the composition of the DMC is provided in 
Appendix 1. Unblinded immunogenicity data will be made available to the DMC upon
request to enable a benefit-risk assessment.
The DMC will serve as the primary reviewer of the results of the ongoing safety reviews and
will make recommendations for discontinuation of the study or protocol modifications to an
EOC of the Sponsor (see Appendix 1 for details on the Committees Structure for this study).
If the DMC recommends modifications to the design of the protocol or discontinuation of the
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study, the EOC of the Sponsor (and potentially other limited Sponsor personnel) may be
unblinded to results at the intervention level to act on these recommendations. The extent to
which individuals are unblinded with respect to ongoing safety reviews will be documented.
Additional logistical details will be provided in the DMC charter.
Study enrollment may be ongoing at the time of external DMC review. Blinding to
intervention assignment will be maintained at all investigational sites. Participant-level
unblinding will be restricted to an external unblinded statistician performing ongoing safety
reviews. Intervention-level ongoing safety reviews will be provided by the external
unblinded statistician to the DMC. Prior to final study unblinding, the external unblinded
statistician will not be involved in any discussions regarding modifications to the protocol,
statistical methods, identification of protocol deviations, or data validation efforts after the
safety reviews.
9.7
Multiplicity
The study will have met its primary immunogenicity objectives if noninferiority is 
demonstrated with respect to the OPA GMTs for the 12 common serotypes (via H1), and 
superiority is demonstrated with respect to OPA GMTs for the 9 unique serotypes (via H2). 
All hypotheses will be tested individually for each serotype at a 1-sided 0.025 alpha-level. 
This approach controls the 1-sided type 1 error rate at 0.025, and no multiplicity adjustment 
will be required.
9.8
Sample Size and Power Calculations
9.8.1
Sample Size and Power for Immunogenicity Analyses
The study will randomize approximately 820 participants, allocated in a 3:2 ratio to receive 
either V116 or PPSV23 (492 participants in the V116 group and 328 participants in the 
PPSV23 group). 
Primary Immunogenicity Endpoints/Hypotheses (H1 and H2)
For the primary hypotheses, this study has >90% power to declare noninferiority of V116 to 
PPSV23 for the 12 common serotypes (H1) and superiority of V116 to PPSV23 for the 9 
unique serotypes (H2) at an overall 1-sided 2.5% alpha-level.
The sample size and power calculations are based on the following assumptions:
•
For the 12 common serotypes, the underlying serotype-specific OPA GMT ratios 
(V116/PPSV23) and the standard deviation of natural log-transformed OPA results are 
assumed to be the same as that observed in the V116-004 Phase 3 study. The OPA GMT 
ratios range from 0.84 to 1.74. The standard deviations range from 0.93 to 1.43 for V116 
and range from 0.96 to 1.43 for PPSV23.
•
For the 9 unique serotypes, the underlying serotype-specific OPA GMT ratios 
(V116/PPSV23) and the standard deviation of natural log-transformed OPA results are 
assumed to be the same as that observed in the V116-004 Phase 3 study. The OPA GMT 
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ratios range from 2.90 to 23.72. The standard deviations range from 1.03 to 1.52 for 
V116 and range from 1.05 to 2.54 for PPSV23.
•
90% evaluability (443 participants in the V116 group and 295 participants in the PPSV23 
group).
Based on the assumptions above, the power for the primary hypotheses is calculated using a 
simulation-based approach. This approach uses the cLDA model for comparing OPA GMTs
between the 2 vaccination groups. The power is estimated as the number of successful 
iterations out of the total iterations in the simulation. The success within each iteration is 
defined as meeting both primary hypotheses for each serotype (ie, noninferiority for the 12 
common serotypes [H1] and superiority for the 9 unique serotypes [H2]).
9.8.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying incidence of participants with an SAE in the study 
population. The sample size was selected to achieve a reasonably sized safety database 
exposed to V116. Calculations below assume that 100% of randomized participants will be 
evaluable for safety analyses.
There is 80% probability of observing at least 1 SAE among 492 participants in the V116 
group if the true incidence rate is 0.33% (1 of every 306 participants receiving the vaccine).
There is a 50% probability of observing at least 1 SAE among 492 participants in the V116 
group if the true incidence rate is 0.14% (1 of every 710 participants receiving the vaccine). 
If no SAEs were observed among 492 participants, this study will provide 97.5% confidence 
that the underlying percentage of participants with an SAE is <0.75% (1 out of every 133 
participants) in the V116 group.
The percentage point differences between the 2 vaccination groups that could be detected 
with 80% probability are summarized in Table 6 for a variety of hypothetical underlying 
incidences of an AE.
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Table 6
Differences in Incidence of Adverse Event Rates Between the 2 Vaccination 
Groups That Can be Detected With an Approximately 80% Probability 
Incidence of an Adverse Event
Risk Difference
V116 (%)
N=492
PPSV23 (%)
N=328
Percentage Points
2.4
0.1
2.3
6.0
2.0
4.0
10.4
5.0
5.4
16.9
10.0
6.9
22.9
15.0
7.9
28.6
20.0
8.6
39.5
30.0
9.5
Incidences presented here are hypothetical and do not represent actual adverse experiences in 
either group. The incidences assume a 2-sided 5% alpha-level with 492 participants in the V116 
group and 328 participants in the PPSV23 group. No multiplicity adjustments were made.
Based on an asymptotic method proposed by Farrington and Manning (1990) [Farrington, C. P. 
and Manning, G. 1990]
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. Participants may 
withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
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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, frequently 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.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.6) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.3
Scientific Advisory Committee (SAC)
This study was developed in collaboration with an SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
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10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
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Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 7 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 7
Protocol-required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Pregnancy Testing
Highly sensitive serum or urine hCG pregnancy test (as needed for POCBP)
hCG=human chorionic gonadotropin; POCBP=participant/participants of childbearing potential
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Blood volumes collected from each participant over the duration of the study are detailed in 
Table 8.
Country-specific criteria are included in Appendix 7.
Table 8
Blood Volumes Collected by Visit for Immunogenicity Assessments
Visit 1
Visit 3
Total
Parameter
Approximate Blood Volume
Immunogenicity assessment
10 mL
10 mL
20 mL
Note: The maximum blood volume to be collected for each visit in this population should follow local 
guidelines/recommendations, if specified.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
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•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
Definition of Unsolicited and Solicited AE
•
An unsolicited AE is an AE that was not solicited using a VRC and that is communicated 
by a participant/participant’s legally authorized representative who has signed the 
informed consent. Unsolicited AEs include serious and nonserious AEs.
•
Solicited AEs are predefined local (at the injection/administration site) and systemic 
events for which the participant/participant’s legally authorized representative is 
specifically questioned, and which are noted by the participant/participant’s legally 
authorized representative in their VRC.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
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•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will assess the overall intensity of each AE and SAE (and other 
reportable event) reported during the study. An overall intensity grade will be assigned to 
injection-site AEs, specific systemic AEs, other systemic AEs, and vital sign 
(temperature) AEs as shown in the following tables. The overall intensity grading scales 
used in this study are adapted from the “FDA Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials, September 2007” [Food and Drug Administration 2007].
Table 9
Injection-site AE Overall Intensity Grading Scale
Injection-site 
Reaction to Study 
Vaccine/Placebo
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Injection-site AEs occurring Day 1 through Day 5 following receipt of study vaccine
Pain/Tenderness
Does not interfere 
with activity
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ED visit or 
hospitalization
Erythema/Redness
Size measured as
≤5 cm
Size measured as
5.1 to 10 cm
Size measured as
>10 cm
Necrosis or 
exfoliative 
dermatitis or 
results in ED visit 
or hospitalization
Swelling
Size measured as 
≤5 cm
Size measured as
5.1 to 10 cm
Size measured as
>10 cm
Necrosis or ED 
visit or 
hospitalization
Other
Does not interfere 
with activity
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ED visit or 
hospitalization
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Injection-site 
Reaction to Study 
Vaccine/Placebo
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Any injection-site reaction that begins ≥6 days after receipt of study vaccine
Pain/Tenderness
Erythema/Redness
Swelling
Other
Does not interfere 
with activity
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ED visit or 
hospitalization
AE=adverse event; ED=emergency department
The overall intensity grading scales used in this study are adapted from the “FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
Table 10
Specific Systemic AE Overall Intensity Grading Scale
Systemic (General)
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Headache
No interference 
with activity
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
or some interference 
with activity
Significant; any use 
of narcotic pain 
reliever or prevents 
daily activity
ED visit or 
hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
Arthralgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
Urticaria
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
Somnolence
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
Irritability
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
Malaise
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
AE=adverse event; ED=emergency department
The overall intensity grading scales used in this study are adapted from the “FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
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Table 11
Other Systemic AE Overall Intensity Grading Scale
Systemic Illnessa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)b
Illness or clinical 
AE (as defined 
according to 
applicable 
regulations)
No interference 
with activity
Some interference 
with activity not 
requiring medical 
intervention
Prevents daily 
activity and 
required medical 
intervention
ED visit or 
hospitalization
AE=adverse event; ED=emergency department; eVRC=electronic vaccination report card; SAE=serious adverse event
The overall intensity grading scales used in this study are adapted from the “FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
a
Based on information provided by the participant on the eVRC and verbally during the eVRC review during the 
primary safety follow-up period. For SAEs reported beyond the primary safety follow-up period, grading will be 
based on the initial report and/or follow-up of the event.
b
AEs resulting in death will be assessed as Grade 4.
Table 12
Vital Sign (Temperature) Overall Intensity Grading Scale
Vital Signsa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Fever/Pyrexia
(°C)b
(°F)b
38.0 to 38.4
100.4 to 101.1
38.5 to 38.9
101.2 to 102.0
39.0 to 40.0
102.1 to 104.0
>40.0
>104.0
The overall intensity grading scales used in this study are adapted from the “FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
a
Participant should be at rest for all vital sign requirements.
b
Body temperature; no recent hot or cold beverages or smoking.
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based on the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (diary, etc.), 
seroconversion or identification of vaccine virus in bodily specimen?
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-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant reexposed to the study intervention in the study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose vaccine study; or (3) study 
intervention(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
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•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
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•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Drug-Device Combination Products/ Combination Medicinal 
Products: Complaints, Product Quality Complaints/Malfunctions: Definitions, 
Recording, and Follow-up
The recording and follow-up procedures described in this protocol apply to drug-device 
combination products/combination medicinal products. For purposes of this section, devices 
in scope for device information collection include drug-device combination 
products/combination medicinal products as listed in Section 6.1.1. Product Quality 
Complaints/Malfunctions must be reported to the Sponsor.
10.4.1
Definitions
Combination Product – A product composed of any combination of a drug, a device, and a 
biological product. Each drug, device, and biological product included in a combination 
product is referred to as a “constituent part” of the combination product.
Complaint – Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
product after it is released for distribution.
A complaint does not necessarily need to involve a user or any other person. 
Constituent Part – A drug, device, or biological product that is part of a combination 
product.
Malfunction – The failure of a device including the device component of a combination 
product to meet its performance specifications or otherwise perform as intended. 
Performance specifications include all claims made in the labeling for the medical 
device/device constituent part. The intended performance of a device refers to the intended 
use for which the device is labeled or marketed.
Medical Device – Any instrument, apparatus, appliance, implement, machine, contrivance, 
implant, in-vitro reagent or other similar or related article, including a component part, or 
accessory which is intended for use in the diagnosis of disease or other conditions, or in the 
cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to 
affect the structure or any function of the body of man or other animals and which does not 
achieve its primary intended  purposes through chemical action within or on the body of man 
or other animals and which is not dependent upon being metabolized for the achievement of 
any of its primary intended purposes.
PQC – Any communication (written or oral) that describes a potential defect related to the 
identity, strength, quality, purity, or performance of a product identified by external 
customers. This includes potential device or device component malfunctions. 
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Serious deterioration of Health/Serious Injury/Serious Illness- This includes:
1. Life-threatening illness, even if temporary in nature ,
2. Results in permanent impairment of a body function or permanent damage to a body 
structure, 
3. A condition necessitating medical or surgical intervention, including hospitalization or 
prolonged hospitalization to preclude permanent impairment of a body function or 
permanent damage to a body structure, 
4. Cases that are considered medically significant, 
5. Fetal distress, fetal death or any congenital abnormality or birth defects.
Permanent means irreversible impairment or damage to a body structure or function, 
excluding trivial impairment or damage.
Japan specific definitions and documenting/reporting requirements can be found in 
Section 10.7.
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions
Recording
When a complaint, PQC/malfunction occurs it is the responsibility of the investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.
Adverse Events occurring during the study will be recorded in the participant’s medical 
records (or equivalent), in accordance with the investigator’s normal clinical practice, and on 
the appropriate CRF (paper or electronic) as per instructions provided in the data entry 
guidelines (or equivalent). Device constituent part of drug-device combination 
product/combination medicinal product information (regardless of participant or associated 
person) will be collected and reported to the Sponsor in the same time frame as SAEs as per
Section 8.4.1 via CRF (paper or electronic). PQCs/malfunctions must be reported to the 
Sponsor.
Assessing Causality
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
The investigator will use clinical judgment to determine the relationship.
Alternative causes such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration should 
be considered and investigated.
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Follow-up
The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant until becoming postmenopausal unless permanently sterile 
(see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one of the nonhormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only contraceptive implant b,c
IUS b,d
Nonhormonal IUD
Bilateral tubal occlusion (Tubal occlusion includes tubal ligation)
Azoospermic partner (vasectomized or secondary to medical cause, confirmed by medical history) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception b,c
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraception b,c
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner capable of producing sperm, during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
Penile/external or vaginal/internal condom with or without spermicidee
Cervical cap, diaphragm, or sponge with spermicide
A combination of penile/external condom with either cervical cap, diaphragm, or sponge with spermicide 
(double barrier methods)
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly)
b
Penile/external condoms must be used in addition to the POCBP’s hormonal contraception
c
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation
d
IUS is a progestin releasing IUD
e
Vaginal/internal condom used for contraceptive purposes
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM
Penile/external and vaginal/internal condom should not be used together (due to risk of failure with friction) e  
Country-specific criteria are included in Appendix 7.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
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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 Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant 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 before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study 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 Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
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9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Country-specific Requirements for Japan
Section 5.2 Exclusion Criteria
For study sites in Japan, to comply with current Japan national guidance, the following 
criterion replaces Exclusion Criterion 18 in Section 5.2:
18. *Received any nonlive vaccine ≤14 days before receipt of study vaccine or is scheduled 
to receive any nonlive vaccine ≤30 days after receipt of study vaccine. Exception: 
inactivated influenza vaccine may be administered but must be given ≥7 days before or 
≥15 days after receipt of study vaccine. SARS-CoV-2 mRNA or protein subunit vaccines 
may be administered but must be given ≥14 days before or ≥15 days after receipt of study 
vaccine. SARS-CoV-2 vaccines other than mRNA and protein subunit vaccines are not 
eligible for this exception and are subject to requirements of exclusion criteria 18 and 19.
Section 6.1.1 Drug-Device Combination Products/Combination Medicinal Products
The investigational drug-device combination product(s)/investigational combination 
medicinal product(s) provided for use in this study are V116 pre-filled syringes and 
PNEUMOVAX™23 (PPSV23) pre-filled syringes. Refer to Section 8.4.8 and Appendix 4
for reporting events associated with these devices.
Section 10.4 Appendix 4: Drug-Device Combination Products/Combination Medicinal 
Products: Complaints, Product Quality Complaints/Malfunctions: Definitions, 
Recording, and Follow-up
10.4.1 Definitions
Medical Device - Devices, etc. (other than regenerative medicine products) intended for use 
in the diagnosis, treatment, or prevention of disease in humans or animals, or intended to 
affect the structure or functions of the body of humans or animals.
Combination Medicinal Product - The products to be manufactured and marketed as a 
single drug, medical device, or regenerative medical product by combining 2 or more 
different type of drugs, medical devices or processed cells that are presumed to fall under the 
category of drugs, medical devices, or regenerative medical products if it is distributed alone.
Malfunction - The condition of the device constituent of product specified as combination 
product/medical device in this protocol is not good in terms of wide range of quality, safety, 
or performance, such as damage or failure in operation. Regardless of whether it occurs at 
any stage of design, delivery, storage, or use.
Serious Adverse Event due to Malfunction - Any SAE occurred in participant and/or the 
associated person in clinical trial, which caused by or suspected effects of the use of the 
device constituent of product specified as combination product/medical device in this 
protocol or the device recognized to have the same structure and principle as the device.
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Malfunction Which may Lead to Serious Adverse Events - Any malfunction of a device 
constituent of product specified as combination product in this protocol which might have led 
to the death of a participant and/or the associated person or to a serious deterioration in their 
state of health. “Which might have led to” means that there is the possibility that death or a 
serious deterioration might have occurred in a participant and/or the associated person, 
although these cases have not actually occurred.
10.4.2 Recording, Assessing Causality, and Follow-up of Complaints, 
PQCs/Malfunctions
Malfunction which may lead to SAEs will be reported to the Sponsor within 5 calendar days 
of the information via a paper reporting form.
10.7.2
EEA-specific Requirements
Section 5.2 Exclusion Criteria
For study sites in EEA countries, Exclusion Criteria 17 and 18 are as follows:
17. Received immunosuppressive therapy within 6 months before vaccination, including 
chemotherapeutic agents or other immunotherapies/immunomodulators used to treat cancer 
or other conditions, and interventions associated with organ or bone marrow transplantation, 
or autoimmune disease.
18. *Received any nonlive vaccine ≤15 days before receipt of study vaccine or is scheduled 
to receive any nonlive vaccine ≤30 days after receipt of any study vaccine. Exception: 
inactivated influenza vaccine and SARS-CoV-2 mRNA or protein subunit vaccine may be 
administered but must be given ≥15 days before or after receipt of study vaccine.
Section 10.2 Clinical Laboratory Tests
For study sites in EEA countries, the following note applies to Table 8 (Blood Volumes 
Collected by Visit for Immunogenicity Assessments):
NOTE: This table specifies the maximum blood volume to be collected for each visit. The 
blood draw limit should not exceed the EMA recommendation of 0.9 mL/kg body weight, 
which corresponds to 1% of total blood volume at a single time point. Additionally, during a 
period of 4 weeks, the blood draw limit should not exceed 2.4 mL/kg body weight, which is 
equivalent to 3% of the total blood volume.
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Section 10.5.2 Contraceptive Requirements
For study sites in EEA countries, the contraceptive methods allowed during the study include 
only those methods considered to be highly effective, as specified below:
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only contraceptive implant b,c
IUS b,d
Nonhormonal IUD
Bilateral tubal occlusion (Tubal occlusion includes tubal ligation)
Azoospermic partner (vasectomized or secondary to medical cause, confirmed by medical history) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception b,c
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraception b,c
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner capable of producing sperm, during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly)
b
Penile/external condoms must be used in addition to the POCBP’s hormonal contraception
c
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation
d
IUS is a progestin releasing IUD
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM
Penile/external and vaginal/internal condom should not be used together (due to risk of failure with friction)
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ACIP
Advisory Committee on Immunization Practices
AE
Adverse event
APaT
All-Participants-as-Treated
CFR
Code of Federal Regulations
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval
cLDA
Constrained longitudinal data analysis
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
CSR
Clinical study report
CTFG
Clinical Trial Facilitation Group
deOAc
De-O-acetylated
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECI
Event of clinical interest
ECL
Electrochemiluminescence
eCRF
Electronic case report form
EDC
Electronic data collection
EEA
European Economic Area
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EU
European Union
eVRC
Electronic vaccination report card
FAS
Full Analysis Set
FBR
Future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
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Abbreviation
Expanded Term
FSH
Follicle-stimulating hormone
FSR
First site ready
GCP
Good Clinical Practice
GMC
Geometric mean concentration
GMFR
Geometric mean fold rise
GMT
Geometric mean titer
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HRT
Hormone-replacement therapy
IA
Interim analysis(ses)
IB
Investigator’s Brochure
ICF
Informed Consent/Assent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IM
Intramuscular(ly)
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IPD
Invasive pneumococcal disease
IRB
Institutional Review Board
IRT
Interactive response technology
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LAM
Lactational amenorrhea method
M&N
Miettinen and Nurminen
MOPA
Multiplexed Opsonophagocytic Assay
mRNA
Messenger RNA
NIP
National immunization program
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Abbreviation
Expanded Term
OPA
Opsonophagocytic activity
PCV
Pneumococcal conjugate vaccine
Pn ECL
Pneumococcal electrochemiluminescence
PnPs
Pneumococcal polysaccharide
POCBP
Participant/participants of childbearing potential
PP
Per-protocol
PPSV23
Pneumococcal vaccine, polyvalent (23-valent) (PNEUMOVAX™23)
(Serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 
17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F)
PQC
Product quality complaint
RNA
Ribonucleic acid
SAC
Scientific Advisory Committee
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SLAB
Supplemental laboratory test(s)
SoA
Schedule of activities
SOC
System organ class
SUSAR
Suspected unexpected serious adverse reaction
US
United States
V116
Pneumococcal 21-valent conjugate vaccine
VRC
Vaccination report card
WHO
World Health Organization
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11
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