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Product: V501

Protocol/Amendment No.: 015-00

THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE


CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK & CO., INC.,
WHITEHOUSE STATION, NJ, U.S.A.

THIS PROTOCOL IS FOR WORLDWIDE USE. BOTH U.S. AND NON-U.S.


SITES ARE TO FOLLOW THE INSTRUCTIONS IN THIS DOCUMENT AS
DIRECTED.

SPONSOR:
Merck & Co., Inc. (hereafter referred to as the SPONSOR)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ, 08889-0100, U.S.A.

TITLE:
A Randomized, Worldwide, Placebo-Controlled, Double-Blind Study to Investigate the
Safety, Immunogenicity, and Efficacy on the Incidence of HPV 16/18-Related CIN 2/3 or
Worse of the Quadrivalent HPV (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP)
Vaccine in 16- to 23-Year-Old WomenThe FUTURE II Study (Females United to
Unilaterally Reduce Endo/Ectocervical Disease)

INVESTIGATOR(S):
PRIMARY:
SECONDARY/SUBINVESTIGATOR:

SITE:

INSTITUTIONAL REVIEW BOARD/ETHICS REVIEW COMMITTEE:

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CIN 2/3 Efficacy Trial in Women

TABLE OF CONTENTS
PAGE

PROTOCOL SYNOPSIS.................................................................................................... 7

STUDY FLOW CHART................................................................................................... 17

SPONSOR CONTACT INFORMATIONU.S. SITE(S)............................................... 18

SPONSOR CONTACT INFORMATIONNON-U.S. SITE(S)..................................... 20

I. CLINICAL SECTIONS ..................................................................................... 22


A. BACKGROUND AND RATIONALE ........................................................ 22
1. Epidemiology ......................................................................................... 22
2. Mercks Ongoing HPV Vaccine Clinical Program................................ 22
a. Demographic and Behavioral Characteristics of the
Study Population .............................................................................. 22
b. Tolerability of HPV Vaccines (Preliminary Data)........................... 23
c. Determination of the Target Immune Responses............................. 24
d. Immunogenicity of the Quadrivalent HPV Vaccine ........................ 25
3. Rationale for the Current Study ............................................................. 26
a. Efficacy ............................................................................................ 26
b. Safety................................................................................................ 27
c. Immunogenicity ............................................................................... 28
B. OBJECTIVES .............................................................................................. 28
1. Primary................................................................................................... 28
2. Secondary............................................................................................... 29
3. Exploratory............................................................................................. 29
C. HYPOTHESES ............................................................................................ 29
1. Primary................................................................................................... 29
D. SUBJECT DEFINITION ............................................................................. 30
1. Inclusion Criteria.................................................................................... 30
2. Exclusion Criteria .................................................................................. 31
E. STUDY DESIGN......................................................................................... 33
1. Summary of Study Design ..................................................................... 33
2. Treatment ............................................................................................... 36
a. Treatment Plan ................................................................................. 36
b. Clinical Material............................................................................... 37
1) Quadrivalent HPV Vaccine........................................................ 37
2) Placebo ....................................................................................... 38

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CIN 2/3 Efficacy Trial in Women

TABLE OF CONTENTS (CONT.)


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3) Labeling of Material for Injection.............................................. 38


4) Subject Unblinding..................................................................... 39
c. Special Handling Requirements....................................................... 40
d. Prior and Concomitant Medication(s)/Treatment(s) ........................ 40
e. Diet/Activity/Other .......................................................................... 40
3. Study Procedures.................................................................................... 41
a. Consent............................................................................................. 41
b. Study Visit Schedule ........................................................................ 41
c. Full Evaluation Visit (Day 1, Month 7, 12, 24, 36,
and 48)Study Procedures (Including Prevaccination
Procedures on Day 1) ....................................................................... 44
d. Vaccination Visit (Day 1, Month 2, and Month 6) .......................... 46
e. Unscheduled Visit ............................................................................ 47
f. Status/Retention Visit ...................................................................... 48
g. Study Visit Requirements ................................................................ 50
h. Collection and Handling of Specimens............................................ 50
1) Serum or Urine Specimen for Pregnancy Test........................... 51
2) Urine Specimen for Gonorrhea and Chlamydia
LCR or PCR or SDA.................................................................. 51
3) Serum for Antibody Measurements ........................................... 51
4) Labial/Vulvar/Perineal and Perianal Swabs for
HPV PCR ................................................................................... 52
5) HSV Culture (If Indicated)......................................................... 53
6) pH, Wet Mount, Whiff Test, KOH (Performed at
the Investigators Discretion)..................................................... 54
7) Endo/Ectocervical Swab for HPV PCR ..................................... 54
8) Pap Test for Liquid Cytology (ThinPrep) .............................. 55
i. Assignment of Allocation Number and Vaccine ............................. 56
j. Vaccine/Placebo Administration...................................................... 57
1) Preparation for Administration .................................................. 57
2) Guidelines for Vaccinations....................................................... 57
k. Clinical Follow-Up........................................................................... 58
l. Biopsy/Colposcopy/Definitive Procedures ...................................... 59
1) Procedure for External Genital Lesion Biopsy .......................... 59
2) Guidelines for Colposcopy......................................................... 60
3) Procedures for Colposcopy ........................................................ 63
4) Procedures for Cervical Biopsy ................................................. 64
5) Procedures for Endocervical Curettage (ECC)
(Optional) ................................................................................... 66

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CIN 2/3 Efficacy Trial in Women

TABLE OF CONTENTS (CONT.)


PAGE

6) Procedures for Definitive Therapy............................................. 66


m. Laboratory Measurements................................................................ 73
F. EFFICACY AND IMMUNOGENICITY
MEASUREMENTS ..................................................................................... 74
1. Primary Endpoint ................................................................................... 74
2. Other Efficacy Measurements................................................................ 74
3. Immunogenicity ..................................................................................... 75
4. PCR Assays to Detect HPV in Clinical Specimens ............................... 75
a. Multiplex PCR Assays ..................................................................... 75
b. Quantitative PCR Assays ................................................................. 76
c. Type-Specific PCR to Detect High-Risk HPV Types
Other Than Vaccine Types............................................................... 76
5. Preparation and Disposition of Thinsections of Biopsy
Tissue ..................................................................................................... 77
6. Blinding of HPV PCR Results ............................................................... 78
7. Unblinding Treatment AssignmentInterim Analysis ......................... 79
G. SAFETY MEASUREMENTS ..................................................................... 80
1. All Subjects ............................................................................................ 80
2. For Subjects Participating in the NSAE Substudy................................. 80
3. Evaluating and Recording Adverse Experiences ................................... 81
4. Immediate Reporting of Adverse Experiences to the
SPONSOR.............................................................................................. 85
a. Serious Adverse Experiences........................................................... 85
b. Selected Nonserious Adverse Experiences ...................................... 86
5. Development of a Serious Medical Condition of Special
Interest.................................................................................................... 86
H. STUDY DURATION AND SUBMISSION OF DATA ............................. 86
I. DATA ANALYSIS...................................................................................... 88
1. Responsibility for Analyses/In-House Blinding .................................... 88
2. Hypotheses ............................................................................................. 89
3. Variables and Time Points ..................................................................... 90
4. Approach to Analyses ............................................................................ 91
5. Statistical Methods ................................................................................. 92
6. Multiplicity Considerations.................................................................... 94
7. Sample Sizes and Power Calculations ................................................... 95
8. Interim Analyses .................................................................................... 97
9. Safety Analyses...................................................................................... 98

II. ADMINISTRATIVE AND REGULATORY SECTIONS.............................. 100

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CIN 2/3 Efficacy Trial in Women

TABLE OF CONTENTS (CONT.)


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A. LABELING, PACKAGING, STORAGE, AND RETURN


OF CLINICAL SUPPLIES ........................................................................ 100
1. Standard Policies/Drug Accountability................................................ 100
2. Subject and Replacement Supplies Information .................................. 100
3. Product Descriptions ............................................................................ 100
4. Primary Packaging and Labeling Information ..................................... 101
5. Study Disclosure .................................................................................. 101
6. Storage Requirements .......................................................................... 102
7. Distribution .......................................................................................... 102
8. Site Retention Samples ........................................................................ 102
B. BIOLOGICAL SPECIMENS .................................................................... 102
1. Labeling of Specimens......................................................................... 102
2. Shipment of Specimens........................................................................ 103
C. CLINICAL AND LABORATORY DATA COLLECTION..................... 103
1. Method of Data Collection................................................................... 103
2. Laboratory Results ............................................................................... 104
3. Vaccination Report Cards .................................................................... 104
D. STUDY DOCUMENTATION AND RECORDS
RETENTION ............................................................................................. 105
1. Steering Committee.............................................................................. 106
2. Executive/Advisory Committee ........................................................... 107
3. Pathology Panel.................................................................................... 107
4. Data and Safety Monitoring Board ...................................................... 108
E. INFORMED CONSENT ........................................................................... 108
F. INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT
ETHICS COMMITTEE (IEC) ..................................................................... 109
G. CONFIDENTIALITY................................................................................ 110
1. Confidentiality of Data......................................................................... 110
2. Confidentiality of Subject Records ...................................................... 111
3. Confidentiality of Investigator Information ......................................... 111
H. COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT ................. 111
I. COMPLIANCE WITH FINANCIAL DISCLOSURE
REQUIREMENTS....................................................................................... 113
J. QUALITY CONTROL AND QUALITY ASSURANCE......................... 113
K. PUBLICATIONS....................................................................................... 113

III. SIGNATURESU.S. SITE(S) ....................................................................... 114


A. SPONSORS REPRESENTATIVE........................................................... 114

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CIN 2/3 Efficacy Trial in Women

TABLE OF CONTENTS (CONT.)


PAGE

B. INVESTIGATOR(S).................................................................................. 114

IV. SIGNATURESNON-U.S. SITE(S) ............................................................. 115


A. SPONSORS REPRESENTATIVE........................................................... 115
B. INVESTIGATOR(S).................................................................................. 115

LIST OF REFERENCES ................................................................................................ 116

ATTACHMENTS ........................................................................................................... 117

APPENDICES................................................................................................................. 127

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PROTOCOL SYNOPSIS

PRODUCT: V501
PROTOCOL TITLE: A Randomized, Worldwide, Placebo-Controlled, Double-Blind Study to
Investigate the Safety, Immunogenicity, and Efficacy on the Incidence of HPV 16/18-Related
CIN 2/3 or Worse of the Quadrivalent HPV (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP)
Vaccine in 16- to 23-Year-Old WomenThe FUTURE II Study (Females United to Unilaterally
Reduce Endo/Ectocervical Disease)
PROTOCOL/AMENDMENT NO.: 015-00 / Multicenter
U.S. IND NO.: 9030 CLINICAL PHASE: III
OBJECTIVES:
1. Primary
Safety
To demonstrate that a 3-dose regimen of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP
vaccine is generally well tolerated.
Efficacy Study
To demonstrate that intramuscular administration of a 3-dose regimen of quadrivalent HPV
(Types 6, 11, 16, 18) L1 VLP vaccine reduces the incidence of the composite endpoint of
HPV 16- and 18-related high-grade cervical abnormalities (CIN 2/3) or HPV 16- and
18-related invasive cervical carcinoma in subjects who are PCR negative and seronegative at
baseline and PCR negative 1 month after completion of the vaccination series for the relevant
HPV type.
Consistency Lot Substudy
To demonstrate that the Final Manufacturing Process (FMP) results in quadrivalent HPV
(Types 6, 11, 16, 18) L1 VLP vaccine that, when given in a 3-dose regimen, induces
consistent serum anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 responses 4 weeks
Postdose 3.
2. Secondary
Efficacy Study
To estimate the impact of the administration of the quadrivalent HPV (Types 6, 11, 16, 18)
L1 VLP vaccine on the rates of colposcopic biopsy and definitive excisional cervical
procedures (LEEP, laser conization, cold-knife conization) performed due to HPV 16- and
HPV 18-related disease.
Consistency Lot Substudy
To evaluate the persistence of vaccine-induced serum anti-HPV 6, anti-HPV 11, anti-HPV 16
and anti-HPV 18 responses in subjects who are PCR negative and seronegative at baseline
and PCR negative 1 month after completion of the vaccination series for the relevant HPV
type.

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3. Exploratory
Efficacy Study
To estimate the impact of the administration of the quadrivalent HPV (Types 6, 11, 16, 18)
L1 VLP vaccine on the incidence of the composite endpoint of ALL CIN 2/3 or invasive
cervical carcinoma (caused by any vaccine or non-vaccine HPV type) in subjects who are
PCR negative and seronegative at baseline and PCR negative 1 month after completion of the
vaccination series for high risk HPV types.
HYPOTHESES:
1. Primary
Safety
The quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine is generally well tolerated in
16- to 23-year-old females.
Efficacy Study
Administration of a 3-dose regimen of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP
vaccine reduces the incidence of the composite endpoint of HPV 16- or HPV 18-related
CIN 2/3 or invasive cervical carcinoma compared with placebo in subjects who are PCR
negative and seronegative at baseline and PCR negative 1 month after completion of the
vaccination series for the relevant HPV type. (The statistical criterion for success requires
that the lower bound of the confidence interval for the vaccine efficacy exclude 0%.)
Consistency Lot Substudy
a) Three separate lots of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine induce
similar immune responses, as measured by the percentage of subjects who achieve serum
anti-HPV 6 200 mMU/mL, anti-HPV 11 200 mMU/mL, anti-HPV 16 200 mMU/mL,
and anti-HPV 18 200 mMU/mL, at Week 4 Postdose 3. (Each vaccine component will
be analyzed separately. The statistical criterion for similarity requires that the upper
bound of the confidence interval for the maximum absolute difference in proportions
between any 2 of the 3 lots exclude 10 percentage points or more for each HPV type.)
b) Three separate lots of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine induce
similar immune responses, as measured by the serum geometric mean titers (GMTs) to
HPV 6, 11, 16, and 18, at Week 4 Postdose 3. (Each vaccine component will be analyzed
separately. The statistical criterion for consistency requires that the upper bound of the
confidence interval for the fold-difference in GMTs between any 2 lots exclude a fold-
difference of 2 or greater for each HPV type.)
STUDY DESIGN AND DURATION: This is a randomized, placebo-controlled, multicenter,
multinational, double-blind, efficacy endpoint study operating under in-house blinding
procedures. Approximately 11,500 subjects will be randomized in a 1:1 ratio to receive either
quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine or Merck aluminum adjuvant placebo.
The study will employ a fixed event design, whereby the interim and final analyses of the primary
efficacy hypotheses are scheduled to be conducted at the time that specific target numbers of
cases of the primary endpoint have been observed. The primary endpoint is the combined
incidence of HPV 16-related CIN 2/3 or worse and HPV 18-related CIN 2/3 or worse. For each
subject enrolled, the duration of the study is expected to be ~4 years. Enrollment is expected to
be completed within 12 months after the first subject is enrolled at the first site. An attrition rate

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of 15% is expected through Month 7 of the study, and an attrition rate of no more than 5% per
year is expected thereafter. Retention efforts will be maximized to ensure compliance with the
protocol and optimal data collection. These efforts will include frequent contacts with subjects
and other efforts as authorized by local Institutional Review Boards/Independent Ethics
Committees. In countries where the infrastructure permits, subjects enrolled in this study will
also be enrolled in a separate long-term follow-up protocol that will assess the long-term duration
of vaccine efficacy. Participation in this long-term follow-up protocol will be voluntary and
subject to a separate protocol and informed consent.
There will be 2 substudies within the main study. Subjects enrolled in these substudies will
undergo all procedures described in the main study protocol. They will undergo additional
procedures as part of the substudies. The first study is a tolerability assessment substudy, which
will enroll 1150 subjects (10% of the overall sample) in the United States. In addition to a
rigorous protocol-mandated assessment of SAEs, subjects in this substudy will undergo full
assessment of nonserious adverse experiences (NSAE) using vaccine report cards (see
Section I.G.2. and II.C.3.). The second substudy is a consistency lot substudy in 3000 subjects.
Subjects in this substudy will undergo serum sampling at Day 1 and Months 7, 12, 24, 36, and 48.
For the purposes of subject accounting for the primary analyses, subjects will be regarded as
having completed the consistency lot substudy if they have completed the full vaccination
regimen (3 doses) and they have completed the follow-up visit at Month 7. Subjects will be
regarded as having completed the NSAE substudy if they have received the full vaccination
regimen (3 doses) and returned its corresponding vaccination report card. Subjects will be
regarded as having completed the efficacy study if they have completed the full vaccination
regimen (3 doses) and they have completed follow-up visits through the time at which the
required numbers of cases of the primary efficacy endpoints are observed, or when the 48-month
visit is completed, which ever comes first (unless an abnormal ThinPrep Pap test at 48 months
requires additional visits).
For the purpose of endpoint collection for the efficacy phase of the study, laboratory personnel,
the pathology panel, and the investigators, site personnel and subjects will remain blinded to
whether subjects received the quadrivalent HPV vaccine or the quadrivalent vaccine-matched
placebo throughout the entire study period (~4 years). Thus, all investigators and technicians
who have the entire responsibility for the ascertainment and confirmation of efficacy endpoints
will be blinded for the duration of the entire study.
Once the final efficacy data are unblinded (i.e., all subjects have completed Month 48), subjects
randomized to receive the quadrivalent HPV vaccine-matched placebo will be eligible to receive
active quadrivalent HPV vaccine under a separate protocol if vaccine efficacy is demonstrated.
Participation is this protocol will be voluntary and subject to a separate informed consent. The
decision to vaccinate placebo subjects after the final analysis of the protocol will be made in
conjunction with the recommendation of the Data Safety Monitoring Board.
At the time of enrollment, subjects must meet all inclusion criteria and have none of the exclusion
criteria. Written consent will be obtained from each subject prior to the subject being entered into
the study. In the case of a minor, assent must be obtained along with the written consent of a
parent/guardian.
1. Vaccination
Subjects will receive vaccine or placebo at Day 1, Month 2, and Month 6. A urine pregnancy
test will be performed for all subjects prior to the administration of each vaccination dose.
The urine pregnancy test must be sensitive to 25 IU hCG. Any subject with a positive

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pregnancy test will not be vaccinated. However, these women will undergo all other
protocol-specific procedures (excluding those that are contraindicated during pregnancy) and
will continue to be followed in the study. In the event of a loss of pregnancy status within
protocol-prescribed windows, subjects may continue to receive vaccine, starting at least
2 weeks after termination of the pregnancy or normalization of the urine hCG levels.
Pregnancy does not represent an exclusion from the primary efficacy analysis.
2. Gynecologic Evaluation
Full Evaluation Visits
A complete gynecological physical examination will be conducted on Day 1 and at Months 7,
12, 24, 36, and 48 on all subjects, with a medical/gynecological history obtained at these time
points. A general physical exam to include oral temperature, sitting pulse and blood pressure,
and respirations will be conducted on Day 1 on all subjects and thoroughly documented in the
subjects chart. Laboratory measurements will include those routinely performed at the
yearly gynecologic exam and protocol-specific exams as follows:
Mandatory tests: ThinPrep Pap test (Day 1 and Months 7, 12, 24, 36, 48),
endo/ectocervical swab for HPV (Day 1 and Months 7, 24, 36, 48), labial/vulvar/
perineal/perianal swab (Day 1 and Month 7 only), urine (Polymerase Chain Reaction
[PCR] or Ligase Chain Reaction [LCR] or Strand Displacement Amplification [SDA])
for chlamydia and gonorrhea (Day 1 and Months 24 and 48), and serum sample for anti-
HPV levels (Day 1 only).
Optional tests: These tests will be performed if clinically indicated at the investigators
discretion: test for gonorrhea, chlamydia, herpes (viral culture), pH of vaginal fluid,
saline wet mount preparation for trichomonas and bacterial vaginosis, whiff test for
bacterial vaginosis, and KOH testing for yeast. At any time during the study, a
nontreponemal test for syphilis, hepatitis B serology, hepatitis C serology, and/or HIV
test may be obtained if risk factors or clinical exams warrant such testing. Subjects who
test positive for any of these pathogens should be referred for proper counseling and
treatment. These subjects will continue to participate in the study.
The subjects participating in the consistency lot substudy will continue to require serum
specimen collection at Months 7, 24, and 48.
Status/Retention Visits
Subjects will be contacted by phone or invited to the clinic every 3 months to ascertain
pregnancy status, obtain gynecologic history, inquire for serious adverse experiences (SAEs),
and to ensure that the study site has updated addresses for the subjects.

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3. Cervical Cancer Screening


Cytology
All cytological evaluation for the subjects will be performed within the context of the study.
All cytologic examinations will utilize the ThinPrep Pap Test. Cytology specimens will be
evaluated using The Bethesda System2001. All ThinPrep Pap Tests will be read by a
central laboratory selected by the SPONSOR. The diagnoses generated by the central
laboratory will be used for management of subjects in the study according to study-mandated
guidelines. All Pap reports should be reviewed and signed by an M.D./D.O. investigator/sub-
investigator.
Colposcopy
The study has a mandatory, protocol-prescribed strategy for referral of subjects with Pap test
abnormalities to colposcopy and biopsy during the study. Any deviation from this mandatory
strategy will require prior approval by the medical monitor. Subjects with ThinPrep Pap
Tests obtained during the study showing any of the following should be treated according to
the algorithm described in Table 1.
Table 1

Mandatory Regimen for Triage of Abnormal Pap Tests for Colposcopy


ThinPrep Pap Result Action
Negative for intraepithelial lesion or Routine visit interval as specified by the protocol.
malignancy (includes reactive,
reparative, inflammatory, etc.)
Atypical Squamous Cells of Repeat ThinPrep Pap Test 6 months later
Undetermined Significance (ASC-US)
Atypical Squamous Cells, cannot rule Referral to colposcopy.
out HSIL (ASC-H)
Low-grade Squamous Intraepithelial Repeat ThinPrep Pap Test 6 months later
Lesions (LSIL)
High-grade Squamous Intraepithelial Referral to colposcopy.
Lesions (HSIL)
Atypical Glandular Cells (to include Referral to colposcopy.
atypical endocervical, endometrial,
NOS, adenocarcinoma in situ,
adenocarcinoma)
Inadequate Specimen Repeat Pap Test as soon as possible
Colposcopy should only be performed according to the guidelines in this table.

For the ASC-US and LSIL Repeat Paps: If the repeat ThinPrep Pap Test reveals ASC-H, LSIL,
HSIL or Atypical Glandular Cells, then the subject will be referred to colposcopy. If the repeat test
is negative for squamous intraepithelial lesion, then the subject will return to routine ThinPrep
Pap Testing schedule. If the repeat Pap reveals ASC-US, then the central lab performs reflex HPV
testing on residual ThinPrep material (High Risk Probe, Hybrid Capture II, DIGENE). If
positive, the subject is referred for colposcopy. If negative, then the subject returns for Pap
screening at the routine visit interval. Subjects with a diagnosis of LSIL at Month 48 will be
referred immediately for colposcopy. Subjects with a diagnosis of ASC-US at Month 48 will have
reflex HPV testing on residual ThinPrep material (High Risk Probe, Hybrid Capture II,
DIGENE) completed. If positive, the subject is referred for immediate colposcopy. This
colposcopy must be performed within 2 months of the Month 48 visit. All specimens collected
during this colposcopy will be handled through the study central lab.

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Subjects who undergo colposcopy may undergo biopsy if clinically indicated. The most
severe area of abnormality observed on colposcopy should be biopsied. Separate biopsy
forceps must be used for each of the distinct lesions that are biopsied.
Cervical biopsy specimens will be sent for analysis to a single central laboratory selected by
the SPONSOR. The diagnoses provided by this laboratory will be used for routine
management of subjects. However, the diagnoses provided by the central laboratory will not
represent the official diagnoses for study purposes. Rather, all routine slides generated by the
central laboratory will be sent to an adjudication panel of up to 5 pathologists with expertise
in gynecologic pathology, particularly cervical pathology (Pathology Panel). The consensus
diagnosis of this panel will represent the final diagnosis for study purposes. If the diagnosis
of the pathology panel is CIN 2/3 or worse, and the diagnosis of the local laboratory is of a
lower grade abnormality, then the investigator will be notified of the discrepancy in
diagnoses.
Cervical biopsy specimens will be sent to the SPONSOR or a designee for HPV analysis.
HPV analysis will be performed on Thinsection microtomy specimens. Each biopsy
specimen will be analyzed by HPV PCR, regardless of whether an HPV-related histologic
diagnosis is made, for the purpose of determining the causal HPV type in the lesion. HPV
typing will be performed using the Multiplex PCR Assay to detect vaccine HPV types on all
samples. Samples that test negative for HPV vaccine types will be analyzed for non-vaccine
HPV types using type-specific HPV PCR assays to detect non-vaccine HPV types in the
biopsy lesion.
Definitive Therapy
The study has mandatory protocol-prescribed guidelines for referral to definitive therapy.
Definitive therapy is mandated only in the following circumstances:
biopsy-confirmed CIN 2/3 or cervical cancer
2 repeated HSIL diagnoses on ThinPrep Pap Test without confirmed CIN 2/3 or
cervical cancer on biopsy.
An ECC demonstrating CIN 2/3, AIS, or cervical cancer;
1 HSIL Pap with an unsatisfactory colposcopic examination including a negative
examination of the vagina
Atypical Glandular Cells or AIS on Pap result with unsatisfactory colposcopy or negative
biopsy
CIN 1 on at least 2 consecutive biopsies obtained over a period of at least 1 year.
Loop Electrosurgical Excision Procedure (LEEP) or laser conization are the preferred
methods for definitive therapy. LEEP and laser excision are study procedures. Cold-knife
conization should be reserved for rare instances where definitive therapy is required and
LEEP or laser conization is not indicated. Cold-knife conization will also be a study
procedure. Ablative therapy (e.g., cryotherapy) should be strongly avoided. Such ablative
therapy will not be a study procedure. If ablative therapy is performed, biopsy specimens
should be obtained from areas of highest abnormalities prior to the surgery and sent to the
central laboratory and the SPONSOR for histopathologic review and HPV analysis. Subjects
who undergo definitive therapy (LEEP, laser excision, cold-knife conization, cryotherapy or
other ablative therapy) will continue to be followed through completion of scheduled visits.

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However, their follow-up for the purpose of the primary efficacy analysis will end on the date
of the procedure.
LEEP, laser conization, or cold-knife conization will be performed by a study physician
experienced in the procedure (>20 of the relevant procedures/year for at least 2 years). The
LEEP, laser conization, or cold-knife conization procedure will be performed according to a
study mandated protocol. LEEP, laser conization, or cold-knife conization specimens will be
submitted in their entirety to the study central laboratory for processing and diagnosis using
study-specific guidelines. The central laboratory diagnosis will be used for management of
subjects. However, this diagnosis will not be the diagnosis of record. Rather, all H&E slides
generated by the central laboratory will be sent to the Pathology Panel. The consensus
diagnosis of this panel will represent the final diagnosis for study purposes. If the diagnosis
of the Pathology Panel is CIN 2/3 or worse, and the diagnosis of the local laboratory is of a
lower grade abnormality, then the investigator will be notified of the discrepancy in
diagnoses.
SUBJECT SAMPLE: Approximately 11,500 subjects will be enrolled. Subjects in the study will
be between the age of 16 and 23 years, with 0 to 4 lifetime sexual partners. Subjects with
0 lifetime sexual partners must be at least 18 years olds and seeking contraception at the time of
enrollment. This study targets women with a maximum of 4 lifetime male or female sexual
partners in order to minimize the proportion of enrolled subjects who are HPV positive at
baseline. In addition, in order to retain a cohort with a reasonable risk of becoming infected after
the vaccination series has been completed, virgins will be excluded from the study, with the
exception of those women at least 18 years of age who are seeking contraception at the time of
enrollment or have recently obtained contraception.
The study will not have a screening phase. It is expected that ~18% of the subjects enrolled will
be HPV 16 seropositive at Day 1 or PCR positive at Day 1 or Month 7 and that ~18% of the
subjects enrolled will be HPV 18 seropositive at Day 1 or PCR positive at Day 1 or Month 7. It
is also expected that the attrition rate will be ~15% through Month 7 of the study and no more
than 5% per year thereafter. Assuming that all subjects followed beyond Month 7 are eligible to
be endpoints, a sample size of 11,500 will provide ~8000 subjects who are eligible to be cases
according to the HPV 16-related disease definition and ~8000 subjects who are eligible to be
cases according to the HPV 18-related disease definition. Since the primary endpoint is a
composite endpoint, any subject who is eligible to be an endpoint according to the HPV 16-
related disease definition, the HPV 18-related disease definition or both will be included in the
population at risk for the primary analysis. Assuming an ~8% overlap in the number of subjects
who are HPV 16 or 18 seropositive at Day 1 or PCR positive Day 1 through Month 7, the
population at risk for the primary analysis will include ~9000 subjects. Enrollment will continue
until the target enrollment of 11,500 subjects has been reached. All subjects who are enrolled,
who receive at least 1 dose of vaccine and who have safety data will be included in the primary
safety analysis.
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN: Subjects will be randomized
1:1 to receive quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine or alum-placebo at Day 1,
Month 2, and Month 6. Each dose of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine
will contain 20 g HPV 6 L1 VLP, 40 g HPV 11 L1 VLP, 40 g HPV 16 L1 VLP, and 20 g
HPV 18 L1 VLP, along with 225 g of alum. Each dose of alum-placebo will contain 225 g of
Merck Aluminum Adjuvant.
In addition, 1500 subjects who are randomized to received the quadrivalent HPV vaccine as part
of the study will be randomized to 1 of 3 quadrivalent HPV vaccine consistency lots (500 subjects

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per lot), as part of a consistency lot substudy across a subset of domestic and international study
centers. Within the consistency lot substudy, there will also be 1500 subjects randomized to
receive placebo in order to keep the efficacy study double-blinded and to maintain a 1:1 ratio of
subjects in the quadrivalent HPV vaccine and placebo groups at each study site for the larger
efficacy evaluation. The 3000 subjects in this substudy will be enrolled towards the end of the
study. At the time that ~8500 subjects have been enrolled in the efficacy study, a second
allocation schedule will be generated which will randomize the 3000 subjects in the substudy in a
1:1:1:3 ratio to receive 1 of 3 consistency lots of quadrivalent HPV vaccine or placebo.
Vaccine or placebo will be given as a 0.5-mL intramuscular injection in the deltoid muscle of the
nondominant arm, or in the thigh if this is the subjects preference or if she has received an
injectable or implantable contraceptive medication in the nondominant arm.
EFFICACY MEASUREMENTS:
1. Primary Endpoint
The primary endpoint of the study is the combined incidence of HPV 16-related CIN 2/3 or
worse and HPV 18-related CIN 2/3 or worse. This endpoint will occur if on any single
biopsy, ECC, or LEEP/conization tissue block, the following occur:
Pathology panel consensus diagnosis of: CIN 2, CIN 3 (including squamous carcinoma in
situ), adenocarcinoma in situ, invasive squamous cervical carcinoma, or invasive
adenocarcinoma of the cervix
AND
Detection of HPV 16 and/or HPV 18 by biopsy Thinsection PCR in an adjacent section from
the same biopsy block.
2. Other Efficacy Measurements
In addition to the primary endpoint definition, the incidence of all CIN 2/3 or worse
(regardless of causal HPV type) will be measured for the purpose of a separate combined
analysis of clinical studies. For biopsies in which HPV 16 or HPV 18 are not detected by
Thinsection PCR, type-specific HPV PCR assays will be used to evaluate non-vaccine HPV
types in the biopsy lesion.
Serum will be collected for analysis of anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV
18 levels at Day 1. In subjects enrolled in the consistency lot substudy, anti-HPV responses
will be assessed at Months 7, 24, and 48. Cervical and external genital swabs will be
collected at Day 1 and Month 7 for HPV 16 and HPV 18 PCR analysis. Cervical samples
will also be collected for HPV 16 and HPV 18 PCR analysis at Months 24, 36, and 48 in all
subjects.

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SAFETY MEASUREMENTS:
1. All Subjects
All subjects will be observed for at least 30 minutes following each vaccination for any
immediate reaction, with particular attention to any evidence of allergic phenomena.
Serious adverse experiences will be recorded for all subjects from Day 1 through Day 14 after
each dose of vaccine/placebo.
At Months 2, 6, and 7, subjects will be solicited for any gynecologic health concerns and any
serious AEs that may have occurred.
All pregnancies in which the date of conception is estimated to be between Day 1 and
Month 7 will be recorded and followed for outcome.
2. Safety Substudy (NSAE)
At preselected sites, a subset of subjects (n=1150) will be followed for all adverse
experiences from Day 1 to Day 14 after each dose of vaccine/placebo. Temperature will be
recorded for 5 days following each injection (4 hours after injection, and daily for the next
4 days). All adverse experiences (AEs) will be collected on the subjects Vaccination Report
Card daily for 14 days after each vaccination.
DATA ANALYSIS:
Efficacy Study
The primary efficacy analysis will be per-protocol. The primary efficacy hypothesis will be
addressed by constructing a two-sided exact confidence interval for the vaccine efficacy to ensure
that the lower bound of the confidence interval exceeds 0%. The study employs a fixed event
design. An interim analysis of the primary endpoint will be conducted when at least 19 cases of
the primary endpoint have been observed, and the final analysis will be conducted when at least
29 cases of the primary endpoint have been observed. Assuming a true vaccine efficacy of 80%,
there will be 95% power for the test of the primary hypothesis at the final analysis. The primary
K\SRWKHVLV ZLOO EH WHVWHG DW WKH  OHYHO WZRVLGHG  DW WKH LQWHULP DQDO\VLV DQG WKH
OHYHO WZRVLGHG DWWKHILQDODQDO\VLV7KHPXOWLSOLFLW\DGMXVWPHQWZDVFRPSXWHGXVLQJ
the power boundaries of Wang and Tsiatis [1]. The sample size calculation was based on an HPV
16-related CIN 2/3 or worse incidence rate of 0.76% and an HPV 18-related CIN 2/3 or worse
incidence rate of 0.15% over the 3 years of postdose 3 follow-up.
Consistency Lot Substudy
The primary immunogenicity analysis will be per-protocol. The first primary immunogenicity
hypothesis, regarding consistency of the 3 lots of quadrivalent HPV vaccine with respect to the
percentage of subjects who achieve anti-HPV 6 200 mMU/mL, anti-HPV 11 200 mMU/mL,
anti-HPV 16 200 mMU/mL, and anti-HPV 18 200 mMU/mL at Week 4 Postdose 3, will be
addressed by 3 pairwise comparisons for each HPV type (12 comparisons in total). Within each
HPV type, each pairwise comparison will test the equivalence of the 2 lots (within 10 percentage
points) using 2 one-sided tests at the 0.05 level. This criterion requires that the two-sided
90% confidence interval for the difference in rates be entirely contained within the interval
(-10%, 10%). This criterion will ensure that the upper bound of the confidence interval for the
maximum absolute difference in rates between any 2 of the 3 lots is <10 percentage points. The
assumed response rate to each HPV type in the vaccine is 90% for each lot.

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The second primary immunogenicity hypothesis, regarding consistency of the 3 lots of


quadrivalent HPV vaccine with respect to the GMTs to HPV 6, 11, 16, and 18 at Week 4
Postdose 3, will also be addressed by 3 pairwise comparisons for each HPV type (12 comparisons
total). Each pairwise comparison will test the equivalence of the 2 lots (within 2-fold) using
2 one-sided tests at the 0.05 level. This criterion requires that the two-sided 90% confidence
interval for the ratio of GMTs be entirely contained within the interval (0.5, 2.0). An ANOVA
model will be used with a response of natural log individual titers and fixed effects for study
center and quadrivalent HPV lot. The assumed standard deviation of the natural log titers is 1.2.
If equivalence can be established in all 3 pairwise comparisons for each HPV type and endpoint,
then the 3 lots will be considered consistent for that HPV type and endpoint. Equivalence must
be established for both endpoints (rates and GMTs) and for all 4 HPV types for the 3 quadrivalent
HPV lots to be considered consistent. The overall type I error rate for this consistency testing
will be controlled at the 0.05 level. The overall power for the consistency lot substudy is 93%.
Success or failure in the consistency lot substudy and in the main CIN 2/3 efficacy study are
independent. That is, if the consistency lot substudy fails to meet its primary endpoint, the main
CIN 2/3 efficacy study may still be declared a success.

ANY SERIOUS ADVERSE EXPERIENCE, INCLUDING DEATH DUE TO ANY CAUSE, WHICH
OCCURS TO ANY SUBJECT FROM THE TIME THE CONSENT IS SIGNED THROUGH
14 DAYS FOLLOWING THE FIRST VACCINATION(S) AND FROM THE TIME OF ANY
SUBSEQUENT VACCINATION(S) THROUGH 14 DAYS THEREAFTER, WHETHER OR NOT
RELATED TO THE INVESTIGATIONAL PRODUCT, MUST BE REPORTED WITHIN
24 HOURS TO ONE OF THE INDIVIDUAL(S) LISTED ON THE SPONSOR CONTACT
INFORMATION PAGE.

ADDITIONALLY, ANY SERIOUS ADVERSE EXPERIENCE BROUGHT TO THE ATTENTION


OF THE INVESTIGATOR AT ANY TIME OUTSIDE OF THE TIME PERIOD SPECIFIED IN
THE PREVIOUS PARAGRAPH ALSO MUST BE REPORTED IMMEDIATELY TO ONE OF
THE INDIVIDUALS LISTED ON THE SPONSOR CONTACT INFORMATION PAGE IF THE
EVENT IS EITHER:

1. A DEATH WHICH RESULTED IN THE SUBJECT DISCONTINUING THE STUDY


OR
2. A SERIOUS ADVERSE EXPERIENCE THAT IS CONSIDERED BY THE INVESTIGATOR TO
BE POSSIBLY, PROBABLY, OR DEFINITELY VACCINE RELATED.
OR
3. A SERIOUS ADVERSE EXPERIENCE THAT IS CONSIDERED BY THE INVESTIGATOR TO
BE POSSIBLY, PROBABLY, OR DEFINITELY RELATED TO A STUDY PROCEDURE.
ALL SUBJECTS WITH SERIOUS ADVERSE EXPERIENCES MUST BE FOLLOWED UP FOR
OUTCOME

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STUDY FLOW CHART


Random
ization Months
Event/Test Day 1 2 6 7 12 24 36 48
Obtain informed consent +
Complete gynecologic history + + + + + +
Gynecologic physical examination + + + + + +
Physical examination +
Specimen collection/laboratory measurements (in serial order):
Pregnancy test a + + +
Urine for gonorrhea PCR or LCR or SDA + + +
Urine for chlamydia PCR or LCR or SDA + + +
Serum for HPV RIA antibody measurements (Types 6, 11, 16, + + + +
18) b
Labial/vulvar/perineal/and perianal swabs for HPV PCR c + +
Endo/ectocervical swab for HPV 16 and 18 PCR c, d + + (+) (+) (+)
Pap test (ThinPrep) for cytology e + + + + + +
If clinically indicated:
Colposcopy and cervical biopsy for histology and HPV detection
LEEP procedure
Vaccination f + + +
Clinical follow-up for safety g + + +
Clinical contact visit documentation h + + + + + + + +
Note: Any test may be repeated if medically indicated.
The Month 2 visit can be performed with 3 weeks. The Month 6 visit and all scheduled visits from Month 12 through
Month 48 can be performed within 4 weeks. The interval between the Month 6 and Month 7 visits should be a
minimum of 3 weeks and a maximum of 7 weeks from the Month 6 vaccination. Any visit for pelvic specimen
collection should be performed at least 2 days after menses is completed. An attempt should be made not to collect
pelvic specimens within 2 days prior to menses. If despite the above, visible blood is noted in the vagina, the specimen
may be collected. The presence of visible blood in the vagina should be noted on the Specimen Collection workbook
form.
a
By a serum or urine test. The urine pregnancy test must be sensitive to 25 IU hCG.
b
Serum specimens will be collected in all subjects at Day 1 (N=11,500). In addition, serum specimens will be
collected in the subjects participating in the consistency lot substudy (n=3000) on Months 7, 12, 24, 36, and 48.
Serum for antibody measurements may be collected after the pelvic exam, but before vaccination.
c
Specimens will be tested by type-specific HPV PCR at a central laboratory selected by SPONSOR.
d
PCR testing for Types 6, 11, 16, and 18 will be mandatory for subjects at enrolled in the consistency lot substudy at
Day 1 and Month 7, but for the subjects not participating in the consistency lot substudy Types 6 and 11 testing will
be optional at Day 1 and Month 7. The Month 24, 36, and 48 collection will be mandatory; however, PCR testing for
Types 6, 11, 16, and 18 will be optional.
e
Pap test to be performed by central laboratory selected by SPONSOR.
f
Temperature and weight will be measured prior to each injection.
g
Serious adverse experiences will be collected for all subjects. All reports of pregnancy will be collected and
forwarded to the SPONSOR. In addition, a subjects participating in the NSAE substudy (n=1150) will complete
Vaccination Report Cards after each vaccination study visit for the reporting of nonserious adverse experiences.
h
Contact visit documentation will be required every 3 months between study visits after Month 6 (Month 9, 15, 18, 21,
27, 30, 33, 39, 42, and 45). This information can be obtained via a telephone or electronic mail contact.
( ) Specimens must be obtained for SPONSOR optional testing.

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SPONSOR CONTACT INFORMATIONU.S. SITE(S)


REPORTING OF SERIOUS ADVERSE EXPERIENCES

ANY SERIOUS ADVERSE EXPERIENCE, INCLUDING DEATH DUE TO ANY CAUSE, WHICH
OCCURS TO ANY SUBJECT FROM THE TIME THE CONSENT IS SIGNED THROUGH 14 DAYS
FOLLOWING THE FIRST VACCINATION(S) AND FROM THE TIME OF ANY SUBSEQUENT
VACCINATION(S) THROUGH 14 DAYS THEREAFTER, WHETHER OR NOT RELATED TO THE
INVESTIGATIONAL PRODUCT, MUST BE REPORTED WITHIN 24 HOURS TO ONE OF THE
INDIVIDUAL(S) LISTED ON THE SPONSOR CONTACT INFORMATION PAGE.
ADDITIONALLY, ANY SERIOUS ADVERSE EXPERIENCE BROUGHT TO THE ATTENTION OF THE
INVESTIGATOR AT ANY TIME OUTSIDE OF THE TIME PERIOD SPECIFIED IN THE PREVIOUS
PARAGRAPH ALSO MUST BE REPORTED IMMEDIATELY TO ONE OF THE INDIVIDUALS LISTED
ON THE SPONSOR CONTACT INFORMATION PAGE IF THE EVENT IS EITHER:
1. A DEATH WHICH RESULTED IN THE SUBJECT DISCONTINUING THE STUDY
OR
2. A SERIOUS ADVERSE EXPERIENCE THAT IS CONSIDERED BY THE INVESTIGATOR TO BE
POSSIBLY, PROBABLY, OR DEFINITELY VACCINE RELATED.
OR
3. A SERIOUS ADVERSE EXPERIENCE THAT IS CONSIDERED BY THE INVESTIGATOR TO BE
POSSIBLY, PROBABLY, OR DEFINITELY RELATED TO A STUDY PROCEDURE.
ALL SUBJECTS WITH SERIOUS ADVERSE EXPERIENCES MUST BE FOLLOWED UP FOR
OUTCOME.

See Protocol Section I.G., Safety Measurements, for definitions of serious adverse experiences.

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SPONSOR CONTACT INFORMATIONU.S. SITE(S) (CONT.)


RETURN ALL CLINICAL SUPPLIES WITH INVENTORY DOCUMENTATION TO:
See Protocol Section II.A., Labeling, Packaging, Storage, and Return of Clinical Supplies.

SHIP BIOLOGICAL SPECIMENS TO:


See Protocol Section II.B., Biological Specimens.

THE INVESTIGATOR WILL FORWARD THE ORIGINAL SIGNED SIGNATURE FORM(S)


AND LABEL PAGES TO:
See Protocol Section II.C., Clinical and Laboratory Data Collection.

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SPONSOR CONTACT INFORMATIONNON-U.S. SITE(S)


REPORTING OF SERIOUS ADVERSE EXPERIENCES

ANY SERIOUS ADVERSE EXPERIENCE, INCLUDING DEATH DUE TO ANY CAUSE, WHICH
OCCURS TO ANY SUBJECT FROM THE TIME THE CONSENT IS SIGNED THROUGH 14 DAYS
FOLLOWING THE FIRST VACCINATION(S) AND FROM THE TIME OF ANY SUBSEQUENT
VACCINATION(S) THROUGH 14 DAYS THEREAFTER, WHETHER OR NOT RELATED TO THE
INVESTIGATIONAL PRODUCT, MUST BE REPORTED WITHIN 24 HOURS TO ONE OF THE
INDIVIDUAL(S) LISTED ON THE SPONSOR CONTACT INFORMATION PAGE.
ADDITIONALLY, ANY SERIOUS ADVERSE EXPERIENCE BROUGHT TO THE ATTENTION OF THE
INVESTIGATOR AT ANY TIME OUTSIDE OF THE TIME PERIOD SPECIFIED IN THE PREVIOUS
PARAGRAPH ALSO MUST BE REPORTED IMMEDIATELY TO ONE OF THE INDIVIDUALS LISTED
ON THE SPONSOR CONTACT INFORMATION PAGE IF THE EVENT IS EITHER:
1. A DEATH WHICH RESULTED IN THE SUBJECT DISCONTINUING THE STUDY
OR
2. A SERIOUS ADVERSE EXPERIENCE THAT IS CONSIDERED BY THE INVESTIGATOR TO BE
POSSIBLY, PROBABLY, OR DEFINITELY VACCINE RELATED.
OR
3. A SERIOUS ADVERSE EXPERIENCE THAT IS CONSIDERED BY THE INVESTIGATOR TO BE
POSSIBLY, PROBABLY, OR DEFINITELY RELATED TO A STUDY PROCEDURE.
ALL SUBJECTS WITH SERIOUS ADVERSE EXPERIENCES MUST BE FOLLOWED UP FOR
OUTCOME.

Telephone Office: Telephone Office:


FAX No.: FAX No.:
Telephone Home: Telephone Home:
Or

Telephone Office: Telephone Office:


FAX No.: FAX No.:
Telephone Home: Telephone Home:

See Protocol Section I.G., Safety Measurements, for definitions of serious adverse experiences.

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SPONSOR CONTACT INFORMATIONNON-U.S. SITE(S) (CONT.)


RETURN ALL CLINICAL SUPPLIES WITH INVENTORY DOCUMENTATION TO:
See Protocol Section II.A., Labeling, Packaging, Storage, and Return of Clinical Supplies.

SHIP BIOLOGICAL SPECIMENS TO:


See Protocol Section II.B., Biological Specimens.

Telephone Office: Telephone Office:


FAX No.: FAX No.:

THE INVESTIGATOR WILL FORWARD THE ORIGINAL SIGNED SIGNATURE FORM(S)


AND LABEL PAGES TO:
See Protocol Section II.C., Clinical and Laboratory Data Collection.

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CIN 2/3 Efficacy Trial in Women

I. CLINICAL SECTIONS

A. BACKGROUND AND RATIONALE


1. Epidemiology
Over 50% of sexually active adults will become infected with human
papillomavirus (HPV) during their lifetime [2]. HPV infection can result in
2 related anogenital diseases: dysplasia that may result in cancer and genital
warts. These diseases are associated with substantial morbidity and mortality [2].
Every year, 471,000 cases of cervical cancer are diagnosed worldwide [3]. The
5-year survival for this disease is ~70% [4]. In the developed world, routine Pap
screening has reduced the incidence of cervical cancer by 75% [5]. However,
sporadic Pap screening in the developing world and among the disadvantaged in
the United States has failed to reduce the incidence of cervical cancer [3; 4; 6; 7].
The incidence of HPV-related anal cancer has doubled in the last 25 years [8].
Screening programs to detect early disease are not available. Genital warts cause
significant morbidity [9 to 11]. The HPV types associated with genital warts also
cause recurrent respiratory papillomatosis, a devastating pediatric disease that
occurs by transmission of HPV from an infected mother to her child [12].
Over 90 HPV types have been identified [13]. HPV 16 and 18 cause ~70% of
high-grade cervical dysplasia (cervical intraepithelial neoplasia 2/3 or CIN 2/3)
cases and cervical and anal cancers, whereas HPV 6 and 11 cause >90% of genital
warts [2]. HPV 6, 11, 16, or 18 are present in ~50% of low-grade cervical
dysplasia (CIN 1) cases [2]. Therefore, a prophylactic vaccine that reduces
infection with these 4 HPV types will greatly reduce the burden of HPV disease in
men and women.
2. Mercks Ongoing HPV Vaccine Clinical Program
A total of 4316 women have been enrolled in 6 HPV vaccine clinical studies.
Approximately 2700 received 1 dose of an HPV vaccine. In all studies, study
vaccine was administered at a 0-, 2-, 6-month schedule. In Protocol 001, ~50% of
subjects received a fourth dose of vaccine/placebo.
a. Demographic and Behavioral Characteristics of the Study Population

The studies have enrolled young women with 5 lifetime male sexual partners
to reduce the enrollment of those who had already acquired a vaccine-type
HPV infection. However, some study subjects were seropositive for
1 vaccine-type HPV or had PCR evidence of infection with 1 vaccine-type

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A. BACKGROUND AND RATIONALE (CONT.)


HPV at enrollment. For analysis of immunogenicity to each vaccine type,
only subjects who were PCR- and seronegative to the vaccine HPV type being
analyzed were included (for example, for analysis of HPV 16 vaccine
immunogenicity, only baseline HPV 16 negative subjects were included). All
enrolled subjects have been included in analyses of vaccine safety.
Protocol 007, the first international quadrivalent HPV vaccine dose-ranging
study, has enrolled 1155 subjects. Approximately 45, 30, and 25% of the
subjects were enrolled in the United States, Latin America, and Europe,
respectively. The mean age of the subjects was 20 years. The median number
of lifetime male sexual partners was 2, and 21.7% of the subjects had had
1 pregnancy.
b. Tolerability of HPV Vaccines (Preliminary Data)

Monovalent HPV Vaccines


In monovalent HPV vaccine studies that are not in-house blinded, the
incidences of systemic and injection site adverse experiences (AEs) were
comparable between vaccinees (n=643) and placebo recipients (n=120).
There have been no serious AEs (SAEs) attributed to the vaccines to date.
Pooled AE data from Protocol 005 (N=2392) are available. In the study, 0.3%
of the cohort experienced an SAE (none vaccine related); 0.4% discontinued
due to a nonserious AE (mostly due to a vaccine/placebo-related AE).
Quadrivalent HPV Vaccine
An interim analysis of Protocol 007 based on partially screened, partially
audited data was conducted to select the formulation of HPV vaccine for use
in this study. Based on safety and immunogenicity data, the formulation
chosen includes 20, 40, 40, and 20 g of HPV 6, 11, 16, and 18 L1 VLPs,
respectively, along with 225 g of Merck Aluminum Adjuvant. Table 2
presents the preliminary overall AE rates for this formulation and for alum
(225 g/dose) placebo. In the study, 286 subjects received 1 dose of
quadrivalent HPV vaccine 20/40/40/20 g formulation, and 145 subjects
received alum (225 g/dose) placebo. There was a slight increase in injection
site AE rates in vaccine-recipients compared with placebo-recipients. The
incidences of systemic AEs were comparable between treatment groups. The
most common local adverse experience was pain/tenderness at the injection
site. The most common systemic adverse experience was headache.

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A. BACKGROUND AND RATIONALE (CONT.)


Table 2

Quadrivalent HPV Vaccine


Clinical Adverse Experience Summary
(Days 0 to 14 Following Any Vaccination Visit)
(Incidence 2% Per Treatment Arm to Preserve Blinding)
(Preliminary Data, Partially Audited)

20/40/40/20 Placebo 225


(N=286) (N=145)
n (%) n (%)

Number of subjects 286 145


Subjects without follow-up 4 1
Subjects with follow-up 282 144
Number (%) of subjects:
with no adverse experience 31 (11.0) 22 (15.3)
with one or more adverse experience 251 (89.0) 122 (84.7)
injection-site adverse experiences 232 (82.3) 103 (71.5)
systemic adverse experiences 183 (64.9) 92 (63.9)

with vaccine-related adverse experiences 242 (85.8) 110 (76.4)


injection-site adverse experiences 232 (82.3) 103 (71.5)
systemic adverse experiences 97 (34.4) 48 (33.3)
Percentages are calculated based on the number of subjects with follow-up after each visit.

Determined by the investigator to be possibly, probably, or definitely related to vaccine.

Further information can be obtained in the Quadrivalent HPV Vaccine


Confidential Investigator Brochure.

c. Determination of the Target Immune Responses

The minimal anti-HPV responses associated with protection against HPV


infection have not been established. Criteria for acceptable doses were
developed based on serum anti-HPV responses associated with neutralization
in preclinical models. Anti-HPV levels >20 milli-Merck units/mL (mMU/mL,
arbitrary units) neutralized a large input load of HPV 11 virions or HPV 6, 16,
or 18 pseudovirions in vitro. These results were confirmed for HPV 11
vaccine in Protocol 001. It was hypothesized that by achieving anti-HPV
200 mMU/mL at Week 4 Postdose 3, subjects would maintain an anti-HPV
>20 mMU/mL in the persistence phase. Thus, subjects were judged to have
had an acceptable response to the quadrivalent HPV vaccine if they achieved
serum anti-HPV 6, 11, 16, or 18 200 mMU/mL 4 weeks Postdose 3.

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A. BACKGROUND AND RATIONALE (CONT.)


d. Immunogenicity of the Quadrivalent HPV Vaccine

The interim analysis of Protocol 007 based on preliminary data showed that
all formulations of quadrivalent HPV vaccine induced high anti-HPV 6, 11,
16, and 18 geometric mean titers (GMTs) Postdose 3. A dose-response
relationship for anti-HPV responses was not seen. Protocol 007 enrolled some
subjects who were seropositive for HPV 6, 11, 16, and/or 18 at baseline.
These subjects had been infected with HPV prior to enrollment and had
mounted an anti-HPV response to this infection. Such subjects provide a
reference against which to examine vaccine-induced anti-HPV responses. All
vaccine formulations achieved anti-HPV 6, 11, 16, 18 GMTs that were
substantially higher than those associated with an ongoing or previous
infection with vaccine-HPV types (see Figure 1).
Figure 1

Protocol 007 Phase IIb Quadrivalent HPV Vaccine Dose-Ranging Study


Postdose 3 Anti-HPV GMTs in Subjects Who Were Seronegative and
PCR-Negative for the Relevant HPV Type at Baseline Compared With
Seronegative Placebo Recipients and With Day 0 anti-HPV GMTs in Subjects
Who Were Seropositive at Baseline (Interim AnalysisPreliminary Data)
Geometric Mean Titer (mMU/mL)

1000

100

10

1
HPV 6 HPV 11 HPV 16 HPV 18
Placebo Day 0 Seropositive subjects Quad Vaccine 40/40/40/40 g
Quad Vaccine 20/40/40/20 g Quad Vaccine 80/80/40/80 g

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A. BACKGROUND AND RATIONALE (CONT.)


3. Rationale for the Current Study
a. Efficacy

CIN 2/3 or Cervical Intraepithelial Neoplasia Grades 2 and 3 represents


replacement of normal cervical epithelium with dysplastic cells. CIN 2 is
defined as moderate to high-grade dyplasia encompassing between 1/3 and 2/3
of the thickness of the cervical epithelium. CIN 3 represents 2/3 to full
thickness high-grade dyplasia or carcinoma in situ. Both CIN 2 and CIN 3 are
considered high-grade cervical lesions and are indications for wide excision
worldwide. In women with CIN 2/3, excision prevents the development of
cervical cancer.
CIN 2/3 lesions are the immediate and obligate clinical and pathologic
precursors to cervical cancer. An assessment of efficacy with regards to HPV
16- and 18-related CIN 2/3 lesions is the most clinically relevant and accurate
way of determining whether administration of the prophylactic quadrivalent
HPV vaccine will reduce the incidence of cervical cancer related to HPV 16
and 18. Thus the primary objective of the study is to demonstrate that the
quadrivalent HPV vaccine reduces the incidence of HPV 16/18-related
CIN 2/3.
The effect of the quadrivalent HPV vaccine on the overall incidence of CIN
2/3 represents an important public health question. Since the protective
response generated by L1 VLP vaccines is thought to be type-specific, it is
anticipated that the vaccine will not prevent infection with non-vaccine HPV
types. Nevertheless, since HPV 16 and 18 cause ~50% of CIN 2 lesions and
70% of CIN 3 lesions [2], it is anticipated that administration of the
quadrivalent HPV vaccine will reduce the overall incidence of CIN 2/3. The
impact that marked reductions in the incidence of HPV types 16 and 18 may
have on HPV infection and disease related to non-vaccine HPV types remains
to be determined. To address this question, all CIN 2/3 lesions will be
analyzed for the presence of vaccine and non-vaccine HPV types. The
incidence of CIN 2/3 related to any HPV vaccine type will be summarized in
HPV nave subjects by treatment group. However, the definitive analysis of
this issue will be performed through a combined analysis of all Phase II/III
studies in the clinical program to obtain sufficient cases of CIN 2/3 to address
this question accurately.
For each subject, the efficacy of the quadrivalent HPV vaccine will be
evaluated over a 3.5 year period following vaccination. An interim analysis
may reveal vaccine efficacy while the study is ongoing. However,
vaccination of subjects in the placebo arm will not be offered until the
mandated protocol follow-up has been completed and the final efficacy

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A. BACKGROUND AND RATIONALE (CONT.)


analysis is fully accomplished. This measure will allow for a better
assessment of the duration of the vaccine efficacy. In addition, the protocols
full duration of follow-up will allow for an assessment of the vaccine impact
on the overall incidence of CIN 2/3 and for a more reliable distinction
between a delay on the establishment of high grade lesions and the actual
prevention of their occurrence. Subject safety will not be jeopardized by
delaying vaccination because the protocol screening procedures and the
referral to colposcopy follow the highest standards of clinical practice.
CIN 2/3 ascertainment will be performed using a protocol-mandated strategy.
Subjects will undergo Pap testing at Day 1 and Months 7, 12, 24, 36, and 48.
A mandatory colposcopy triage strategy will be in place for the study (see
Section I.E.3.l.2)). Subjects meeting protocol criteria will be sent to
colposcopy. Colposcopy will be performed by an experienced colposcopist
who has been trained in protocol-specific colposcopy procedures. If a lesion
is seen on colposcopy, it should be biopsied. If more than 1 area is to be
biopsied, then the lowermost (most dorsal) lesion should be biopsied first.
Each lesion should be biopsied using separate forceps. Each biopsy should be
placed in a separate container. All biopsies will be sent to the SPONSORs
central laboratory for processing and analysis. An independent Panel of
Pathologists will provide the final pathologic diagnoses for study purposes.
Eligibility for Analysis
Subjects will be enrolled into the study regardless of vaccine-type HPV
serologic and PCR status. However, because the vaccine under evaluation is a
prophylactic vaccine, only subjects who are negative for relevant vaccine
types through the completion of the vaccination regimen will be eligible for
the primary efficacy analysis. Thus, for the HPV 16-related endpoint, subjects
must be (1) PCR negative for HPV 16 DNA at Day 1 and Month 7 and
(2) anti-HPV 16 seronegative at Day 1. For the HPV 18-related endpoint,
subjects must be (1) PCR negative for HPV 18 DNA at Day 1 and Month 7
and (2) anti-HPV 18 seronegative at Day 1. Subjects who are excluded from
the primary efficacy evaluation will be followed for evaluation of vaccine
tolerability and for secondary efficacy analyses. To limit the number of
subjects who will not be evaluable for the primary efficacy hypotheses, only
females with a history of 0 to 4 lifetime male or female sexual partners will be
enrolled.
b. Safety

All subjects who enroll in the study and who receive at least 1 dose of vaccine
will be evaluated and followed to assess vaccine tolerability. In 100% of the
enrolled subjects, serious adverse experiences (SAE) will be collected and

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A. BACKGROUND AND RATIONALE (CONT.)


reported. In a 10% subset of the population (N=1150), both nonserious and
serious adverse events will be collected and reported (nonserious AE
substudy). All subjects enrolled in the United States will participate in the
nonserious AE substudy.

c. Immunogenicity

Immunogenicity will be evaluated in 3000 subjects (1500 vaccinees and


1500 placebo-recipients). The immunogenicity evaluation will have
2 components. First, the 1500 vaccinees will be randomized into a formal
consistency lot substudy. This substudy will evaluate the consistency with
respect to postdose 3 immunogenicity of 3 separate lots of Final
Manufacturing Process (FMP) quadrivalent HPV vaccine.

In addition to the formal consistency lot evaluation, subjects will be followed


for an evaluation of persistence of antibody responses through the end of the
study.

B. OBJECTIVES
1. Primary

Safety

To demonstrate that a 3-dose regimen of quadrivalent HPV (Types 6, 11, 16, 18)
L1 VLP vaccine is generally well tolerated.

Efficacy Study

To demonstrate that intramuscular administration of a 3-dose regimen of


quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine reduces the incidence of
the composite endpoint of HPV 16- and 18-related high-grade cervical
abnormalities (CIN 2/3) or HPV 16- and 18-related invasive cervical carcinoma in
subjects who are PCR negative and seronegative at baseline and PCR negative
1 month after completion of the vaccination series for the relevant HPV type.

Consistency Lot Substudy

To demonstrate that the Final Manufacturing Process (FMP) results in


quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine that, when given in a
3-dose regimen, induces consistent serum anti-HPV 6, anti-HPV 11, anti-HPV 16,
and anti-HPV 18 responses 4 weeks Postdose 3.

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B. OBJECTIVES (CONT.)
2. Secondary

Efficacy Study

To estimate the impact of the administration of the quadrivalent HPV (Types 6,


11, 16, 18) L1 VLP vaccine on the rates of colposcopic biopsy and definitive
excisional cervical procedures (LEEP, laser conization, cold-knife conization)
performed due to HPV 16- and HPV 18-related disease.

Consistency Lot Substudy

To evaluate the persistence of vaccine-induced serum anti-HPV 6, anti-HPV 11,


anti-HPV 16 and anti-HPV 18 responses in subjects who are PCR negative and
seronegative at baseline and PCR negative 1 month after completion of the
vaccination series for the relevant HPV type.

3. Exploratory

Efficacy Study

To estimate the impact of the administration of the quadrivalent HPV (Types 6,


11, 16, 18) L1 VLP vaccine on the incidence of the composite endpoint of ALL
CIN 2/3 or invasive cervical carcinoma (caused by any vaccine or non-vaccine
HPV type) in subjects who are PCR negative and seronegative at baseline and
PCR negative 1 month after completion of the vaccination series for high risk
HPV types.

C. HYPOTHESES
1. Primary

Safety

The quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine is generally well
tolerated in 16- to 23-year-old females.

Efficacy Study

Administration of a 3-dose regimen of quadrivalent HPV (Types 6, 11, 16, 18) L1


VLP vaccine reduces the incidence of the composite endpoint of HPV 16- or HPV
18-related CIN 2/3 or invasive cervical carcinoma compared with placebo in
subjects who are PCR negative and seronegative at baseline and PCR negative
1 month after completion of the vaccination series for the relevant HPV type.
(The statistical criterion for success requires that the lower bound of the
confidence interval for the vaccine efficacy exclude 0%.)

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C. HYPOTHESES (CONT.)
Consistency Lot Substudy

a) Three separate lots of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP
vaccine induce similar immune responses, as measured by the percentage of
subjects who achieve serum anti-HPV 6 200 mMU/mL, anti-HPV 11
200 mMU/mL, anti-HPV 16 200 mMU/mL, and anti-HPV 18
200 mMU/mL, at Week 4 Postdose 3. (Each vaccine component will be
analyzed separately. The statistical criterion for similarity requires that the
upper bound of the confidence interval for the maximum absolute difference in
proportions between any 2 of the 3 lots exclude 10 percentage points or more
for each HPV type.)

b) Three separate lots of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP
vaccine induce similar immune responses, as measured by the serum
geometric mean titers (GMTs) to HPV 6, 11, 16, and 18, at Week 4
Postdose 3. (Each vaccine component will be analyzed separately. The
statistical criterion for consistency requires that the upper bound of the
confidence interval for the fold-difference in GMTs between any 2 lots exclude
a fold-difference of 2 or greater for each HPV type.)

D. SUBJECT DEFINITION
1. Inclusion Criteria

Candidate subjects must meet ALL of the following:

a. Healthy, females age 16 to 23 years with intact uteri.

b. No clinical evidence of gross purulent cervicitis (otherwise postpone until


after treatment or lack of laboratory confirmation of treatable cause).

c. Must agree to refrain from douching/vaginal cleansing or using vaginal


medication or preparation for 48 hours prior to any scheduled visit that
includes a pelvic examination.

d. Must agree to refrain from sexual activity (including vaginal and anal
penetration and any genital contact) for 48 hours prior to any scheduled visit
that includes a pelvic exam, in an attempt to avoid detection of viral DNA
which has been deposited in the vagina or on the perineal/perianal area during
sexual intercourse and is not the result of ongoing infection.

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D. SUBJECT DEFINITION (CONT.)


e. Not pregnant now (as determined by a serum pregnancy test or urine
pregnancy test sensitive to 25 IU -hCG), and must agree to use effective
contraception through Month 7 of the study. Effective contraception will be
considered: oral contraceptives, injection or implant contraception such as
DEPO-PROVERA (sterile medroxyprogesterone acetate suspension, USP,
Pharmacia and Upjohn), NORPLANT (levonorgestrel implants, Wyeth-
Ayerst), IUD, sterilization, abstinence, condom (male), diaphragm, cervical
cap.

f. Individuals who have had sexual intercourse in the 2 weeks prior to


enrollment must have been using effective contraception as defined above.
(Emergency contraception is not considered effective contraception for
enrollment into the study.)

g. Individuals with a lifetime history of 0 to 4 male or female sexual partners.


Women with 0 lifetime male or female sexual partners must be at least
18 years of age and seeking contraception at the time of enrollment or have
recently obtained contraception to be permitted to enter the study.

h. Must agree to provide study personnel with a primary telephone number as


well as an alternate telephone number for follow-up purposes.

i. No temperature 100F or 37.8C (oral) within 24 hours prior to the first


injection.

2. Exclusion Criteria

Candidate subjects who manifest any of the following exclusion criteria at the
time of randomization will not be eligible for the study:

a. Individuals concurrently enrolled in clinical studies of investigational agents


or studies involving collection of cervical specimens.

b. History of known prior vaccination with an HPV vaccine.

c. Receipt of inactivated vaccines within 14 days prior to enrollment or receipt


of live virus vaccines within 21 days prior to enrollment.

d. Individuals with any prior abnormal Pap test showing squamous


intraepithelial lesion (SIL), ASC-US, ASC-H, or biopsy showing cervical
intraepithelial neoplasia (CIN).

e. History of severe allergic reaction (e.g., swelling of the mouth and throat,
difficulty breathing, hypotension or shock) that required medical intervention.

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D. SUBJECT DEFINITION (CONT.)


f. Individuals allergic to any vaccine component, including aluminum, yeast, or
BENZONASE (nuclease, Nycomed [used to remove residual nucleic acids
from this and other vaccines]).

g. Individuals who have received any immune globulin (including RhoGAM


[Ortho-Clinical Diagnostics]) or blood derived products within the 6 months
prior to the first injection, or plan to receive any through Month 7 of the study.

h. Individuals with history of splenectomy, known immune disorders


(e.g., systemic lupus erythematosus, rheumatoid arthritis), or receiving
immunosuppressives (e.g., substances or treatments known to diminish the
immune response such as radiation therapy, administration of antimetabolites,
antilymphocytic sera, systemic corticosteroids). Individuals who have
received periodic treatments with immunosuppressives, defined as at least
3 courses of oral corticosteroids each lasting at least 1 week in duration for the
year prior to enrollment, will be excluded. Subjects using topical steroids
(i.e., inhaled or nasal) will be eligible for vaccination.

i. Individuals who are immunocompromised or have been diagnosed as having


HIV infection.

j. Individuals with known thrombocytopenia or any coagulation disorder that


would contraindicate intramuscular injections.

k. History of recent or ongoing alcohol abuse or other drug abuse.

l. Any condition which in the opinion of the investigator might interfere with the
evaluation of the study objectives.

m. Any plans to permanently relocate from the area prior to the completion of the
study or to leave for an extended period of time when study visits would need
to be scheduled.

n. Individuals with >4 lifetime male or female sexual partners.

o. Inability to give informed consent/assent.

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E. STUDY DESIGN
1. Summary of Study Design

This is a randomized, placebo-controlled, multicenter, multinational, double-blind


efficacy endpoint study operating under in-house blinding procedures.
Approximately, 11,500 healthy 16- to 23-year-old females who meet the
eligibility criteria will be enrolled worldwide in the study. Subjects will be
randomized in a 1:1 ratio to receive either the quadrivalent HPV vaccine (225 g
of Merck aluminum adjuvant with 20 g HPV 6 VLP, 40 g HPV 11 VLP, 40 g
HPV 16 VLP, and 20 g HPV 18 VLP per injection) or placebo containing
225 g of aluminum adjuvant per injection.

All subjects in the study will be followed for serious adverse experiences as
described in Section I.G.. In a 10% subset of the study population from any of the
U.S. sites only, both nonserious and serious adverse events will be collected and
reported (nonserious AE [NSAE] substudy). All subjects enrolled in the United
States will participate in this substudy (~1150 subjects).
In addition, 1500 subjects who are randomized to receive the quadrivalent HPV
vaccine as part of the study will be randomized to 1 of 3 quadrivalent HPV
vaccine consistency lots (500 subjects per lot), as part of a consistency lot
substudy across a subset of domestic and international study centers. Within the
consistency lot substudy, there will also be 1500 subjects randomized to receive
placebo in order to keep the efficacy study double-blinded and to maintain a
1:1 ratio of subjects in the quadrivalent HPV vaccine and placebo groups at each
study site for the larger efficacy evaluation. The 3000 subjects in this substudy
will be enrolled towards the end of the study. At the time that ~8500 subjects
have been enrolled in the efficacy study, a second allocation schedule will be
generated which will randomize the 3000 subjects in the substudy in a 1:1:1:3
ratio to receive 1 of 3 consistency lots of quadrivalent HPV vaccine or placebo.
Subjects in the United States may be dually enrolled in both the consistency lot
and NSAE substudies (see Table 3). The number of subjects dually enrolled will
vary according to pace of enrollment of the U.S. sites. It is also possible that
subjects in the United States will not participate in the consistency lot substudy if
the U.S. enrollment target is met before the consistency lots are available.
Subjects in the substudy will receive all 3 doses of vaccine from the consistency
lot to which they were randomized (see Table 4).

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E. STUDY DESIGN (CONT.)


Table 3

Subject Substudy Participation


Approximate Number
Substudy Category Region Timing of Enrollment Enrolled

NSAE U.S. Immediately/linked to initial 850


enrollment
NSAE and U.S. Last third of enrollment/ 300
consistency lot dependent on consistency
lot availability
Consistency lot International Last third of enrollment/ 2700
dependent on consistency
lot availability
Total 3850

Table 4

Efficacy Study with Consistency Lot Substudy


All Vaccines Administered in a 0-, 2-, 6-Month Schedule
Approximate
Studies in Which Group Will Number
Group Treatment Regimen Participate Enrolled

A Quadrivalent HPV Vaccine Efficacy study 4250


B Placebo Efficacy study 5750
C Lot 1 FMP Quad HPV Efficacy study 500
Consistency lot substudy
D Lot 2 FMP Quad HPV Efficacy study 500
Consistency lot substudy
E Lot 3 FMP Quad HPV Efficacy study 500
Consistency lot substudy
Total 11,500

May include quadrivalent HPV vaccine Consistency Lot 1, 2, or 3, or other lots of FMP quadrivalent HPV
vaccine material

All subjects will sign an informed consent/assent prior to initiation of study


procedures and vaccine injection. The subject, investigator (and his/her staff) and
the SPONSOR are blinded to who receives the vaccine and who receives placebo.
Each dose of the vaccine or placebo will be administered intramuscularly at Day 1
and Months 2 and 6.

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E. STUDY DESIGN (CONT.)


The efficacy study will employ a fixed event design, whereby the interim and
final analyses of the primary efficacy hypothesis are scheduled to be conducted at
the time that specific target numbers of cases of the primary endpoint have been
observed. The primary endpoint is the combined incidence of HPV 16-related
CIN 2/3 or worse and HPV 18-related CIN 2/3 or worse. This endpoint will occur
if on any single biopsy, ECC, or LEEP/conization tissue block, the Pathology
panel provides 1 of the following consensus diagnosis: CIN 2, CIN 3 (including
squamous carcinoma in situ) adenocarcinoma in situ (AIS), invasive squamous
cervical carcinoma, or invasive adenocarcinoma of the cervix and HPV 16 and/or
HPV 18 detected in an adjacent section, defined as positive HPV 16 or HPV 18
Thin-section PCR assay. For each subject enrolled, the duration of the study is
expected to be ~4 years. Enrollment is expected to be completed within
12 months after the first subject is enrolled at the first site. The attrition rate is
expected to be ~15% through Month 7 of the study and no more than 5% per year
thereafter. However, retention efforts will be maximized to ensure compliance
with the protocol and optimal data collection. These efforts will include frequent
contacts with subjects and other efforts as authorized by local Institutional
Review Boards/Independent Ethics Committees. In countries where the
infrastructure permits, subjects enrolled in this study will also be enrolled in a
separate long-term follow-up protocol that will assess the long-term duration of
vaccine efficacy. Participation in this long-term follow-up protocol will be
voluntary and subject to a separate informed consent.

The study is operating under in-house blinding procedures. However, an interim


analysis will be conducted when at least 19 cases of the primary endpoint have
been observed, and if the study meets its primary criterion for success at the
interim time point, a regulatory package for the Quadrivalent HPV (Types 6, 11,
16, and 18) L1 VLP vaccine will be submitted to regulatory authorities for
review. At this time, the clinical, statistical and data management personnel
assigned to the HPV vaccine project at the SPONSOR will most likely have
access to the individual treatment assignments of the subjects in the study. The
remainder of the study will be considered an extension, the purpose of which will
be to collect data on the longer-term efficacy of the vaccine with respect to the
primary endpoint and to allow a sufficient number of cases to accrue across all of
the Phase III studies for a combined analysis of these studies addressing the
efficacy of the vaccine in reducing all CIN 2/3 or cervical cancer. It is important
to note that for the efficacy phase and the extension phase of the study, laboratory
personnel, the pathology panel, and the investigators, site personnel and subjects
will remain blinded to whether subjects received the quadrivalent HPV vaccine or
the quadrivalent vaccine-matched placebo throughout the entire study period
(~4 years). The data collected which impact ascertainment of efficacy endpoints
are the following: (1) Pap tests, which are read by a central laboratory; (2) the

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E. STUDY DESIGN (CONT.)


biopsy samples, which are read by the pathology panel; and (3) the PCR test
results, which are provided by a blinded laboratory. Therefore, all investigators
and technicians who have the entire responsibility for the ascertainment and
confirmation of efficacy endpoints will be blinded for the duration of the entire
study. If the interim analysis results do not meet the primary statistical criterion
for success, the submission of the regulatory package for review will be delayed
until the final results from this study are available, and the study will remain in-
house blinded at the SPONSOR for its duration.

This trial will be conducted under the supervision of the following committees:
Steering Committee, Executive/Advisory Committee, Pathology Panel, and Data
Safety Monitoring Board. Detailed descriptions of each committees roles and
responsibilities are provided in Section II.D.

2. Treatment

a. Treatment Plan

Subjects will be randomized in a 1:1 ratio to receive quadrivalent HPV


vaccine or placebo. Each participant will receive 1 injection at Day 1, Month
2 (3 weeks), and Month 6 (4 weeks). In total, 4250 subjects will receive an
available clinical lot of quadrivalent HPV vaccine (HPV 6 20 g, HPV 11
40 g, HPV 16 40 g and HPV 18 20 g), 1500 subjects will receive FMP
quadrivalent HPV vaccine from 1 of 3 consistency lots (HPV 6 20 g, HPV
11 40 g, HPV 16 40 g and HPV 18 20 g), and 5750 subjects will
receive placebo. The quadrivalent HPV vaccine and the placebo contain
225 g of aluminum adjuvant per dose. Vaccine or placebo should be given
as a 0.5-mL intramuscular injection in the nondominant arm (preferred). The
deltoid muscle is the preferred site for intramuscular injection in adults. If the
subject has received injection or implant contraception such as DEPO-
PROVERATM (sterile medroxyprogesterone acetate suspension, USP.
Pharmacia) in both arms in the past 9 months, or if it is her preference, the
injection may be given in the thigh, rather than use the arm that received the
injectable contraception (e.g., DEPO-PROVERATM). Data suggest that
injections given in the buttocks frequently are given in fatty tissue instead of
into the muscle. Such injections have resulted in a lower seroconversion rate
in studies evaluating certain vaccines (no such study has been conducted for
the HPV vaccine). Thus, the vaccine/placebo should not be administered in
the buttocks area. A needle long enough to ensure intramuscular deposition of
vaccine should be used for the injections. Vaccine or placebo should be
administered using a 1.0-mL syringe with the following needle length and

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E. STUDY DESIGN (CONT.)


gauge specifications: 1-inch needle, 22 to 23 gauge, for women weighing
<200 pounds (90.9 kg.), 1-inch needle, 22 to 23 gauge for women weighing
200 pounds (90.9 kg). If the injection is given in the thigh, a 1-inch
needle, 22 to 23 gauge, should be used.

Distribution of clinical supplies will be managed through the Interactive Voice


Response System (IVRS). At Day 1, study personnel will access the IVRS
after a subject has signed the consent form and the subject has met
inclusion/exclusion criteria. The IVRS will assign the subject an allocation
number and then subsequently assign a unique vial identification number for
the vial of clinical material the subject should receive at that visit. The IVRS
will automatically assign the appropriate clinical material based on the
subjects treatment allocation. The study personnel will access IVRS at each
subsequent visit when administration of vaccine is to occur for assignment of
a unique vial identification number for the clinical material to be administered
to the subject.

At the time of vaccine administration, the tear-off portion of the label will be
removed from each vial and placed on the L-page of the workbooklet. The
following information should be recorded on the tear off portion of the label:
dose number and the subjects allocation number.

Used and unused vaccine/placebo vials are to be retained at the site until the
SPONSOR representative is able to verify the sites accounting for all of the
vials originally shipped to the sites. After all of the vials have been accounted
for (using vaccine administration/accountability guidelines), the used vials
may be discarded according to the procedures of the site for handling
hazardous waste. This destruction should be documented. The unused vials
should be returned to the SPONSOR by the SPONSOR representative at the
completion of the study. All vaccine/placebo should be appropriately
accounted for on the vaccine accountability log sheet contained within the
Administrative Binder.

b. Clinical Material

1) Quadrivalent HPV Vaccine

The vaccine is provided by the SPONSOR in single-dose vials containing


a volume of 0.75 mL. The vaccine will be administered as a 0.5-mL dose.
Each 0.5-mL dose contains 225 g of aluminum as amorphous aluminum
hydroxyphosphate sulfate (Merck Aluminum Adjuvant).

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E. STUDY DESIGN (CONT.)


The vaccine must be stored between 2 to 8C (36 to 47F). Freezing
destroys the vaccine. If vaccine freezes or is subjected to freezing
temperatures, it should not be used. Refrigerator temperature logs should
be maintained at each vaccine storage site and storage temperatures should
be monitored daily. Should the refrigerator go out of the 2 to 8C (36 to
47F) range, IVRS technical support and the SPONSOR should be
notified immediately. The vaccine must not be used if it has been frozen,
as freezing destroys the potency.

2) Placebo

To provide an appropriate control for the Quadrivalent HPV (Types 6, 11,


16, 18) L1 VLP Vaccine, the placebo used in this study will be Merck
standard aluminum diluent (225 g alum) in normal saline, USP (NaCl
0.9%). Placebo will be provided by the SPONSOR in single-dose vials
containing a volume of 0.75 mL. The placebo dose will be administered
as a 0.5-mL dose. Storage conditions should be identical to those for the
vaccine. Should the refrigerator go out of the 2 to 8C (36 to 47F) range,
IVRS technical support and the SPONSOR should be notified
immediately.

3) Labeling of Material for Injection

The quadrivalent HPV vaccine and matching placebo for the study are
supplied in identical vials. A double-panel, blinded label will be affixed to
each vial. The appearance of all quadrivalent HPV vaccine and placebo
vials will be indistinguishable.

Each vial of vaccine/placebo will bear a unique component identification


number. This number is not the subject's allocation number.

A label similar to the following will be used on all clinical material


(vaccine or placebo):

MERCK RESEARCH LABORATORIES


Component ID# WP-XXXX
Quadrivalent HPV Vaccine / Placebo
0.5-mL Dose for IM Injection
Administer Per Protocol No. 015 Store Refrigerated at 2-8C DO NOT FREEZE

Caution: New Drug Limited by Federal (U.S.A.) Law to Investigational Use

"WP" numbers are an internal packaging control number.

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E. STUDY DESIGN (CONT.)


Each container will be labeled with double-panel tear-off labels containing
information similar to the following: unique vial identification number,
packaging control number, quadrivalent HPV vaccine or placebo, protocol
(015), dose volume, dosing instructions (follow protocol for dosing
instructions), and storage conditions. The tear-off portion of the label will
also contain the unique vial identification number and space for
transcribing the dose number and the allocation number assigned to the
subject by the IVRS system described below. This tear-off label will be
affixed to the L-page in the subject workbooklet.

The clinical supplies will be managed by an Interactive Voice Response


System (IVRS). The initial vaccine supplies, as directed by the IVRS, are
shipped to the investigator site in advance of the projected enrollment date
(usually 2 weeks prior to scheduled visit), along with some contingency
inventory to meet unanticipated needs. Upon meeting inclusion
requirements, the subject is randomized through the IVRS. The IVRS will
assign an allocation number and appropriate component identification
number for the vaccination. Upon subsequent visits, the site coordinator
will enter the IVRS (using a password) and provide the subjects allocation
number and visit number. The IVRS then assigns the appropriate
component identification number to be used for subject vaccination. The
IVRS verbally confirms each transaction and faxes a confirmation sheet,
detailing the IVRS transaction, to the investigator site. This
documentation is to be retained in the subjects files. Site inventory and
enrollment are monitored daily by the IVRS to facilitate resupply.

All clinical material (i.e., vaccine and placebo) must be accounted for by
appropriately documenting the administration (or wasting) of each vial.
Upon receipt at the site, any empty or partially empty vials must be
disposed of according to standard methods for handling medical infectious
hazardous waste after the SPONSOR is able to verify the sites accounting
for all of the vials originally shipped to the site. IVRS is to be notified
immediately of the condition of damaged vials at the time of shipment
receipt at the site.

4) Subject Unblinding

The subject's treatment group should only be unblinded in the case of a


medical emergency. Every effort should be made to contact the
SPONSOR. If the SPONSOR cannot be reached prior to unblinding, the
subjects treatment group can be unblinded by calling the IVRS technical
support and entering the unblinding password in the unblinding option.

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E. STUDY DESIGN (CONT.)


This menu option is available to the investigator only. Any unblinding
that occurs at the site must be documented. A blinded confirmation fax
will be sent to the investigator site and SPONSOR if a subject is unblinded
through the IVRS. This documentation is to be retained in the subjects
files.

c. Special Handling Requirements

The vaccine must be stored between 2 to 8C (36 to 47F). Freezing


destroys the vaccine. If vaccine freezes or is subjected to freezing
temperatures, it should not be used. Any deviation from this temperature
range must be reported immediately to SPONSOR. Storage conditions for
placebo should be identical to those for the vaccine. Further details regarding
the quadrivalent HPV vaccine are found in the II. Administrative and
Regulatory Section.

d. Prior and Concomitant Medication(s)/Treatment(s)

To reduce their potential interference with the evaluation of the immunologic


response and reactogenicity of the study vaccine or placebo, nonstudy
inactivated vaccines must not be administered within the 14 days before or
14 days after any dose of study vaccine. Nonstudy live virus vaccines must
not be administered within the 21 days prior to or 14 days after any dose of
study vaccine. Immune globulin (including Rho-GAM) or blood derived
products must not be administered within 6 months prior to vaccination and
should not be administered during the vaccination series or at any other time
during the study, if at all possible. Any such treatment should be discussed
with the clinical monitor. If the subject receives any oral or parenteral
corticosteroids, then the interval between the end of the course of
corticosteroid and vaccination must be at least 2 weeks.

Subjects may receive allergen desensitization therapy and tuberculin skin


testing while participating in this study.

e. Diet/Activity/Other

No special restrictions will apply except for those noted under the
inclusion/exclusion criteria.

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E. STUDY DESIGN (CONT.)


3. Study Procedures

a. Consent

Written consent must be obtained from each subject or if the subject is a


minor, from the subjects legal guardian, prior to the subject being entered
into the study. Assent must also be obtained from minors. A copy of the
signed consent form will be given to each subject for her records. Verification
of the subjects identity and age is to be determined prior to obtaining written
consent. Any government issued photo identification will suffice for
verification purposes and should be documented in the subjects file.

Nonrandomized Subjects

If a subject has signed an informed consent form but is not randomized, the
investigator must submit a STATUS form to the SPONSOR for the subject.
This form reports basic demographics and the reason(s) for exclusion. The
investigator shall also submit an AE form if applicable. Unless otherwise
directed, no other data need be submitted for these subjects.

Subject Discontinuation/Withdrawal

Subjects may withdraw at any time or be dropped from the study at the
discretion of the investigator should any untoward effects occur. In addition, a
subject may be withdrawn by the investigator or the SPONSOR if she violates
the study plan or for administrative and/or other safety reasons. The
investigator or study coordinator must notify the SPONSOR immediately
when a subject has been discontinued/withdrawn due to an adverse experience
(telephone or FAX). When a subject discontinues/withdraws prior to study
completion, all applicable activities scheduled for the final study visit should
be performed at the time of discontinuation. Any adverse experiences which
are present at the time of discontinuation/withdrawal should be followed in
accordance with the safety requirements outlined in Sections I.G.3.

A single subject cannot be assigned more than one allocation number.

b. Study Visit Schedule

During the course of this study subjects will be required to complete 4 types
of study visits: full evaluation, vaccination, unscheduled, and retention/status.
The full evaluation visit will include a complete gynecologic history and
gynecologic physical examination for all subjects. Swab specimens are
included in the Day 1 and Months 7, 24, 36, and 48 full evaluation visits. The

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E. STUDY DESIGN (CONT.)


endo/ectocervical and labial/vulvar/perineal/perianal swab specimens will be
used to establish baseline HPV status. The endo/ectocervical swab collected
after Month 7 will allow for an evaluation of the relationship between type-
specific HPV infection and the development of CIN 2/3 related to that type.
The vaccination visit includes pregnancy testing as well as the administration
of the study vaccine or placebo. The unscheduled visit includes all cytology
and colposcopy/biopsy strategy mandated visits. The criteria for an
unscheduled visit are based on the ThinPrep Pap test result. The final type
of visit will serve as a status/retention contact. Table 5 displays the 3 types of
scheduled visits along with the study visit timing.

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E. STUDY DESIGN (CONT.)


Table 5

Visit Type by Visit Interval

Month D1 M2 M6 M7 M9 M12 M15 M18 M21 M24 M27 M30 M33 M36 M39 M42 M45 M48
Visit Type
FULL X X X X X X
VAX X X X
RET X X X X X X X X X X X X X X X X X X
FULL = Full evaluation visit; VAX = Vaccination Visit; RET = Retention Contact.
The Month 2 visit can be performed with 3 weeks. The Month 6 visit and all scheduled Full visits from Month 12 through
Month 48 can be performed within 4 weeks. The interval between the Month 6 and Month 7 visits should be a minimum of
3 weeks and a maximum of 7 weeks from the Month 6 vaccination.
Unscheduled visits may occur under the following circumstances:
6 months after a full evaluation visit based on certain ThinPrep Pap test results (see Mandatory ThinPrep Triage
Algorithm, Table 7).
For colposcopy and biopsy based on certain ThinPrep Pap test (see Mandatory ThinPrep Triage Algorithm, Table 7).
For LEEP, laser conization, or cold-knife conization based on certain biopsy results (see Procedures for Definitive
Therapy, Section I.E.3.l.6)).

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E. STUDY DESIGN (CONT.)


c. Full Evaluation Visit (Day 1, Month 7, 12, 24, 36, and 48)Study
Procedures (Including Prevaccination Procedures on Day 1)

A gynecologic/medical history is to be obtained at Day 1 and Months 7, 12,


24, 36, and 48 for all subjects. On Day 1, prior to vaccination, participants
will be questioned about their lifetime number of male and/or female sexual
partners, age of first sexual intercourse, any history of genital warts, abnormal
Pap tests, gynecologic surgeries, cervical cancer in the family, any history of
sexually transmitted diseases, menstrual status, pregnancy history, method of
contraception, and tobacco consumption.

This study targets women with a maximum of 4 lifetime male or female


sexual partners in order to minimize the proportion of enrolled subjects who
are HPV positive at baseline. In addition, in order to retain a cohort with a
reasonable risk of becoming infected after the vaccination series has been
completed, virgins will be excluded from the study, with the exception of
those women at least 18 years of age who are seeking contraception at the
time of enrollment or have recently obtained contraception.

A complete gynecological exam will be performed at Day 1 and Months 7, 12,


24, 36, and 48 which includes speculum and bimanual exams. Additionally,
at Day 1 a general physical exam will be performed in conjunction with the
gynecological exam. The documented physical exam will include weight,
sitting blood pressure, sitting pulse, respirations, and an oral temperature. The
Day 1 physical exam will also include the subjects height measurement.
Laboratory measurements will include those routinely performed at the yearly
gynecological exam: the only mandatory protocol measurement for all
subjects is a urine (Polymerase Chain Reaction [PCR] or Ligase Chain
Reaction [LCR] or Strand Displacement Amplification [SDA]) test for
chlamydia and gonorrhea at Day 1 and Months 24 and 48. The following
optional tests may be performed at the investigator's discretion during the full
evaluation visit: test for herpes simplex (viral culture), vaginal fluid pH;
saline wet mount preparation for trichomonas and bacterial vaginosis; whiff
test for bacterial vaginosis; and KOH testing for yeast.

In this study, HPV analysis will include type-specific PCR assays to detect
HPV infection. The subjects participating in the consistency lot substudy will
have serologic assays performed to measure HPV 6, 11, 16, and 18 antibody
responses following vaccination or after natural infection with HPV 6, 11, 16,
and 18. While all subjects will require serum specimen collection at Day 1,
only subjects participating in the consistency lot substudy will continue to
require serum specimen collection at Months 7, 24, and 48.

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E. STUDY DESIGN (CONT.)


Cervicovaginal specimens for HPV PCR testing (labial/vulvar/perineal and
perianal swabs and an endo/ectocervical swab) will be obtained at Day 1 and
Month 7. The endo/ectocervical specimen continue to be collected at
Months 24, 36, and 48.

ThinPrep Pap tests for cytology will be performed at Day 1, Months 7, 12,
24, 36, and 48 and at any unscheduled visit that the investigator deems
necessary to obtain a sample (e.g., at time of colposcopy). All ThinPrep
Pap tests will be tested at a cytology laboratory selected by the SPONSOR.
Cytology specimens will be evaluated using The Bethesda System-2001. The
SPONSORs central laboratory will automatically perform reflex HPV testing
on residual ThinPrep material using the Digene Hybrid Capture II High-
Risk Probe on repeat ThinPrep Pap tests that reveal Atypical Squamous
Cells of Undetermined Significance (ASC-US). The diagnoses generated by
the central laboratory will be used for management of subjects in the study
according to study-mandated guidelines. All Pap reports must be reviewed
and signed by an M.D./D.O. investigator/subinvestigator.

Referral to colposcopy is based on a Mandatory ThinPrep Triage Algorithm


(see Section I.E.3.I.1)). Deviation from this algorithm is strongly
discouraged. It should occur only rarely. All deviations in colposcopy triage
requires previous authorization from the clinical monitor. Referral to
definitive therapy will also be based on a mandatory protocol-specified
algorithm (see Section I.E.3.I.5)). Subjects that require biopsy or definitive
therapy will continue to be followed through the completion of scheduled
visits.

Ongoing education is to be provided to the subjects which may include written


materials (e.g., IRB/ERCapproved pamphlets from the clinical site) to
increase the subjects knowledge base regarding HPV, sexually transmitted
diseases, pregnancy prevention, and other womens health related issues.

At any time during the study, a test for gonorrhea, chlamydia, syphilis,
hepatitis B serology, hepatitis C serology, and/or HIV test may be obtained if
risk factors or clinical exams warrant such testing. Subjects testing positive to
HIV testing should be referred for appropriate counseling and treatment but
may continue in the study. They will not be included in the primary efficacy
analysis. Subjects who test positive for gonorrhea, chlamydia, syphilis,
hepatitis B (hepatitis B serum antigen [HBsAg]), or hepatitis C (hepatitis C
antibody [HCAb]) may remain in the study. Subjects testing positive for these
diseases should be referred for appropriate counseling and treatment.

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E. STUDY DESIGN (CONT.)


Any gynecological abnormalities found at any time during the study will be
referred for appropriate care. Diagnoses of vaginitis or cervicitis may be
managed by the investigator. If vaginitis is diagnosed, the subject should be
treated according to the local standard of care. Treatment can be administered
following vaccination. If there is clinical evidence of gross purulent cervicitis
during a scheduled visit that involves a pelvic exam, the vaccination and
specimen collection should be postponed until after treatment or laboratory
confirmation of no treatable cause. Treatment for chlamydia or gonorrhea can
be administered during visits after specimen collection and vaccination have
been completed.

At each visit, participants should be asked about their interim gynecologic


history. Study retention activities will also be performed, including ensuring
that the study site has updated addresses, telephone numbers, or other contact
information for the subject.
d. Vaccination Visit (Day 1, Month 2, and Month 6)

At the study visits on Day 1, Month 2, and Month 6, all examinations and
specimen collections will take place prior to vaccination. Temperature (oral),
weight, sitting blood pressure, sitting pulse, respirations, and a serum or urine
pregnancy test will be checked prior to each injection at Day 1, Month 2, and
Month 6. If the subject has had a temperature of 100F or 37.8C (oral)
within 24 hours prior to an injection, the injection will be postponed. If the
subject has an elevated temperature at these visits, no procedures are to be
performed. The subject is to be rescheduled.

At Day 1, if the subject meets the inclusion/exclusion criteria, she will be


randomized and assigned an allocation number. A pregnancy test will be
performed at the investigative site. Pregnancy test results must be available
prior to vaccination. Pregnancy testing will be performed prior to each
injection for all subjects at Day 1, Months 2 and 6, prior to the administration
of each vaccination dose. The pregnancy test must be sensitive to 25 IU
-hCG. Any subject with a positive pregnancy test must not be vaccinated. If
the subject is found to be pregnant at the Day 1 visit, the subject will not be
randomized and hence will not receive vaccine and will not participate in the
study. The completion of the vaccination series after the first dose of vaccine
will depend on the number of doses administered at the time pregnancy is
detected. If pregnancy is detected after the Day 1 visit, but before the
Month 2 visit (after receiving the first vaccine dose), the subject will receive
no further vaccinations irrespective of pregnancy outcome. The subject will
remain in the study and complete all subsequent study visits and other study

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E. STUDY DESIGN (CONT.)


procedures as per protocol and at the investigators discretion. If pregnancy
develops after the Month 2 visit (after receiving the second vaccine dose), the
subject will not return for subsequent visits until the resolution of the
pregnancy (term, miscarriage, abortion, etc.). The investigator will maintain
regular contact with the subject for the purpose of pregnancy assessment.
Irrespective of pregnancy outcome, at the resolution of pregnancy the subject
will resume the study visits starting with the visit that was pending prior to
pregnancy. The subject is eligible to complete the vaccination series (receive
the last dose of vaccine) starting at least 2 weeks after resolution of pregnancy
and normalization of hCG levels. If pregnancy is detected after completion of
the vaccine series, the subject will complete the study visits as per protocol
and at the investigators discretion. Routine study procedures that are
contraindicated during pregnancy will not be performed at visits conducted
during the pregnancy. After randomization, all pregnancies through Study
Month 7 (including discontinued subjects) will be followed to the
completion/termination of the pregnancy. If the pregnancy continues to term,
the outcome (health of infant) must be reported to the SPONSOR.
(See Pregnancy Reporting and Follow-Up HPV Vaccine Clinical Program,
Appendix 1.) All pregnancies are to be reported to the SPONSOR.
Pregnancy does not represent an exclusion from the primary efficacy analysis.

e. Unscheduled Visit
An unscheduled visit will be required under the following circumstances:
A repeat ThinPrep Pap Test is needed, as per the Mandatory
Regimen for Triage of Abnormal Pap Tests to Colposcopy. For this
visit, mandatory study procedures will be limited to collection of a
ThinPrep Pap Test and completion of the relevant worksheet pages.
The subject requires colposcopy based on Mandatory Regimen for
Triage of Abnormal Pap Tests to Colposcopy. For this visit, mandatory
study procedures will include colposcopy and biopsy (see
Section I.E.3.l.2)) and completion of the requisite worksheet pages.
The subject requires a definitive cervical excisional procedure (LEEP,
laser conization, or, in rare instances, cold-knife conization) according
to the protocols mandatory definitive therapy algorithm. For this
visit, mandatory study procedures will include definitive therapy (see
Section I.E.3.l.6)) and completion of the requisite worksheet pages.

Tissue samples from subjects who undergo colposcopic biopsy or definitive


therapy will be evaluated for presence of HPV 16 and 18 (and other high-risk
HPV types) within the lesion.

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E. STUDY DESIGN (CONT.)


f. Status/Retention Visit
Subjects will also be contacted by phone or invited to the clinic every
3 months to ascertain pregnancy status, obtain gynecologic history, inquire for
SAE events, and ensure that the study site has updated addresses, telephone
numbers, or other contact information for each subject. Subject follow-up
may not be necessary every 3 months in countries where the investigator site
has access to registry databases. However, efforts should be maximized to
ensure compliance with the protocol and optimal data collection. These
efforts will include frequent contacts with subjects and other interventions
authorized by local Institutional Review Boards/Independent Ethics
Committees. All contacts should be documented in the subjects chart.

Table 6, Study Flow Chart, summarizes the specimen collection at each


scheduled visit in the order in which the specimens should be obtained.

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E. STUDY DESIGN (CONT.)


Table 6

Study Flow Chart


Random
ization Months
Event/Test Day 1 2 6 7 12 24 36 48
Obtain informed consent +
Complete gynecologic history + + + + + +
Gynecologic physical examination + + + + + +
Physical examination +
Specimen collection/laboratory measurements (in serial order):
Pregnancy test a + + +
Urine for gonorrhea PCR or LCR or SDA + + +
Urine for chlamydia PCR or LCR or SDA + + +
Serum for HPV RIA antibody measurements (Types 6, 11, 16, + + + +
18) b
Labial/vulvar/perineal/and perianal swabs for HPV PCR c + +
Endo/ectocervical swab for HPV 16 and 18 PCR c, d + + (+) (+) (+)
Pap test (ThinPrep) for cytology e + + + + + +
If clinically indicated:
Colposcopy and cervical biopsy for histology and HPV detection
LEEP procedure
Vaccination f + + +
Clinical follow-up for safety g + + +
h
Clinical contact visit documentation + + + + + + + +
Note: Any test may be repeated if medically indicated.
The Month 2 visit can be performed with 3 weeks. The Month 6 visit and all scheduled visits from Month 12 through
Month 48 can be performed within 4 weeks. The interval between the Month 6 and Month 7 visits should be a
minimum of 3 weeks and a maximum of 7 weeks from the Month 6 vaccination. Any visit for pelvic specimen
collection should be performed at least 2 days after menses is completed. An attempt should be made not to collect
pelvic specimens within 2 days prior to menses. If despite the above, visible blood is noted in the vagina, the
specimen may be collected. The presence of visible blood in the vagina should be noted on the Specimen Collection
workbook form.
a
By a serum or urine test. The urine pregnancy test must be sensitive to 25 IU hCG.
b
Serum specimens will be collected in all subjects at Day 1 (N=11,500). In addition, serum specimens will be
collected in the subjects participating in the consistency lot substudy (n=3000) on Months 7, 12, 24, 36, and 48.
Serum for antibody measurements may be collected after the pelvic exam, but before vaccination.
c
Specimens will be tested by type-specific HPV PCR at a central laboratory selected by SPONSOR.
d
PCR testing for Types 6, 11, 16, and 18 will be mandatory for subjects at enrolled in the consistency lot substudy at
Day 1 and Month 7, but for the subjects not participating in the consistency lot substudy Types 6 and 11 testing will
be optional at Day 1 and Month 7. The Month 24, 36, and 48 collection will be mandatory; however, PCR testing for
Types 6, 11, 16, and 18 will be optional.
e
Pap test to be performed by central laboratory selected by SPONSOR.
f
Temperature and weight will be measured prior to each injection.
g
Serious adverse experiences will be collected for all subjects. All reports of pregnancy will be collected and
forwarded to the SPONSOR. In addition, a subjects participating in the NSAE substudy (n=1150) will complete
Vaccination Report Cards after each vaccination study visit for the reporting of nonserious adverse experiences.
h
Contact visit documentation will be required every 3 months between study visits after Month 6 (Month 9, 15, 18,
21, 27, 30, 33, 39, 42, and 45). This information can be obtained via a telephone or electronic mail contact.
( ) Specimens must be obtained for SPONSOR optional testing.

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E. STUDY DESIGN (CONT.)

g. Study Visit Requirements

Subjects and study personnel should adhere to the following procedures: If


necessary, any scheduled visit may be rescheduled within the allowed time
range of 3 weeks (Months 2) or 4 weeks (Months 6 and Months 12 through
48). The interval between the Month 6 and Month 7 visits should be a
minimum of 3 weeks and a maximum of 7 weeks from the vaccination visit.
For study visits that include pelvic exams, study personnel should verify by
verbal history that:

1) Subjects have refrained from vaginal douching/vaginal cleansing or using


any vaginal medication or preparation for 48 hours prior to any scheduled
visit that includes a pelvic exam. If the subject has not refrained from
douching or using a vaginal medication or preparation during the 48 hours
prior to the scheduled visit, the exam and specimen collection will be
postponed until this criterion has been met.

2) Subjects have refrained from any sexual activity (including vaginal and
anal intercourse; manual/oral genital contact; or genital/genital contact,
whether same sex or opposite sex) for 48 hours prior to any scheduled
visit which includes a pelvic exam. If the subject has not refrained from
sexual activity for 48 hours prior to the scheduled visit, the exam and
specimen collection will be postponed until this criterion has been met.

3) Subjects have had no menses within 2 days of any scheduled visit


involving specimen collection. Any visit for specimen collection should
be done at least 2 days after menses is completed. If possible, no
specimen should be collected within 2 days prior to menses. If, despite
the above, visible blood is noted in the vagina, then the specimen may be
collected. The presence of visible blood in the vagina should be noted on
the Specimen Collection Worksheet.

4) Subjects have not had a temperature of 100F or 37.8C (oral) within


24 hours prior to each injection. If a subject has a temperature 100F or
37.8C oral within 24 hours prior to an injection, the injection will be
postponed. (Note: This requirement is for vaccination visits only.)

h. Collection and Handling of Specimens

Procedures should be conducted in the order listed in Table 6, the Study Flow
Chart. The following are the step-by-step procedures for collecting specimens
for the mandatory protocol-specified tests, the supplies needed to perform
these examinations, and the procedures for handling and transporting the
specimens for processing and/or testing.

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E. STUDY DESIGN (CONT.)


There is no need to change gloves during specimen collection unless
contamination occurs. Use a no-touch technique to keep all swab tips and
swab shafts (portion that will be placed in a collection/transport tube)
untouched. A plastic, nonlubricated, single-use, individually wrapped plastic
speculum will be used.

1) Serum or Urine Specimen for Pregnancy Test

Procedure should be performed for all subjects as per the manufacturers


instructions on the day of the study visit at the investigator site on Day 1,
Months 2 and 6 prior to vaccination.

2) Urine Specimen for Gonorrhea and Chlamydia LCR or PCR or SDA

This test will be performed for all subjects at Day 1 and Months 24 and
48. Collect urine into a 100-mL sterile, plastic cup. (Note: The subject
should not have urinated within the 1 hour prior to this urine collection. If
she has, have her wait at least 1 hour from her last urination before
collecting this urine specimen). Approximately 10 mL of urine will be
used for gonorrhea and chlamydia PCR or LCR analysis. Approximately
15 to 20 mL of urine (first voidedNOT midstream) will be used for
gonorrhea and chlamydia SDA analysis. The urine specimen should be
refrigerated at 2 to 8C (36 to 47F) until testing. Urine should be tested
within 4 days of collection. This test will be done at the investigative site
or at a laboratory selected by the site. The SDA analysis of urine for
gonorrhea and chlamydia should be performed in accordance with the
manufacturers instructions.

3) Serum for Antibody Measurements

All Subjects

HPV cRIA Analysis: Serum will be collected in all subjects at Day 1. A


15-mL (nonheparinized, red-top tubes) blood specimen will be collected
and serum separated avoiding any hemolysis. A minimum of 5.0 mL of
serum should be aliquoted to a labeled vial for testing of RIA or
neutralization antibodies by SPONSOR as visit specified.

All sera should be stored in the labeled vials provided by the SPONSORs
central laboratory in a freezer at -20C or below until shipped frozen on
dry ice to address noted on SPONSOR central laboratory Contact
Information page. The freezer must be a non-frost-free freezer.

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E. STUDY DESIGN (CONT.)


Retention Serum: An additional 1.5 mL of serum, from the Day 1
collection is to be stored at the investigative site. This retention serum
should be stored in a labeled vial provided by the SPONSORs central
laboratory in a freezer at -20C or below until shipped frozen on dry ice to
address of the SPONSOR upon request only. The SPONSOR will notify
the site when the retention samples can be destroyed or sent to MRL.

Consistency Lot Substudy Subjects

HPV cRIA Analysis: In addition to Day 1, serum will be collected in the


consistency lot substudy subjects (n=3000) at Months 7, 24, and 48. A
15-mL (nonheparinized, red-top tubes) blood specimen will be collected
and serum separated avoiding any hemolysis. A minimum of
5.0 mL of serum should be aliquoted to a labeled vial for testing for RIA
or neutralization antibodies by SPONSOR as visit specified.

All sera should be stored in the labeled vials provided by the SPONSORs
central laboratory in a freezer at -20C or below until shipped frozen on
dry ice to address noted on SPONSOR central laboratory Contact
Information page. The freezer must be a non-frost-free freezer.

Retention Serum: An additional 1.5 mL of serum, at all time points as


described above, is to be stored at the investigative site. This retention
serum should be stored in a labeled vial provided by the SPONSORs
central laboratory in a freezer at -20C or below until shipped frozen on
dry ice to address of the SPONSOR upon request only. The SPONSOR
will notify the site when the retention samples can be destroyed or sent to
MRL.

The following examinations should be conducted in a positive educational


manner by: (1) describing the procedures to the subject in advance,
(2) maintaining eye contact with the subject during periods of explanation and
whenever possible, (3) explaining all findings clearly to the subject. The
subject should be encouraged to give feedback to the examiner, especially
when the examination is painful. The examiner should forewarn the subject
that they may experience mild to moderate discomfort. All examinations and
biopsies should be assisted.

4) Labial/Vulvar/Perineal and Perianal Swabs for HPV PCR

Procedure should be performed for all subjects as per the protocol-


mandated instructions below on the Day 1 and Month 7 study visit.
a) Remove DACRON (supplied by SPONSOR) swab from its
packaging.

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b) When collecting the labial/vulvar/perineal specimen, swab back and
forth in a tight zigzag motion from the clitoral prepuce down to the
posterior fourchette on first 1 side and then the other, so 2 parallel
zigzag paths down the perineum will allow collection between the
folds of the labia minora and majora. With a separate swab, swab the
perianal area.

c) Place both swabs in the collection/transport tube containing the


specimen transport medium (STM). Break off the ends of the shafts
protruding from the tube by bending them sharply against the rim of
the tube. The shafts are prescored to facilitate breaking.

d) Securely cap the collection/transport tube containing the specimen.

e) Within 30 minutes of collection, place the specimen in a -20C freezer


or in a bucket containing dry ice until ready to ship.

f) Samples should be shipped according to instructions summarized in


the SPONSORs central laboratory manual to the address noted on
SPONSOR Contact Information page.
5) HSV Culture (If Indicated)

Unroof vesicles, if present. Vigorously rub lesions with a DACRON


swab and place swab in appropriate transport medium. Transport to
laboratory for viral culture. These procedures will be done at the
investigative site.

Now insert nonlubricated plastic speculum of the appropriate size


(individually wrapped). Metal speculums should be avoided. Painless
insertion may be achieved by asking the subject to relax the vaginal
muscles by breathing deeply in through her nose and then out through her
mouth. Upon exhalation, the examiner puts gentle downward pressure
with 1 or 2 fingers at the opening of the vagina. No lubrication is to be
used other than moistening with warm water prior to the insertion of the
speculum. The speculum blades should be inserted obliquely, not
vertically through the introitus, immediately rotating to a horizontal plane,
and then slowly opening after the vaginal apex is reached.

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6) pH, Wet Mount, Whiff Test, KOH (Performed at the Investigators
Discretion)

Vaginal pH should be checked by using a DACRON swab (supplied by


Investigator) to collect a sample from the posterior vaginal pool. The pH
paper should not be applied directly to the vaginal side wall. Dab the
swab onto the pH paper, remove and compare to the standard to determine
pH. Using the same DACRON swab, after touching the pH paper,
touch the swab to each of the 2 glass slides (separate portions of 1 slide
may be used if it is the standard procedure at the site). One slide should
be treated with normal saline, and the other diluted with 10% potassium
hydroxide. Alternatively, after touching the pH paper, touch the swab to a
glass slide for dilution with 10% potassium hydroxide. Then, rinse the
swab in ~2 mL normal saline and place a drop of the dilute sample on the
other slide. Place the cover slip over the slide with saline and examine for
motile trichomonads and clue cells. A transient fishy odor after
application of 10% potassium hydroxide is characteristic of bacterial
vaginosis; this is the so-called whiff test. If the subject has signs and
symptoms of a yeast infection, then place a cover slip over the slide with
10% potassium hydroxide, and examine microscopically for branched and
budding hyphae of Candida albicans.
7) Endo/Ectocervical Swab for HPV PCR

Procedure should be performed for all subjects as per the protocol-


mandated instructions below on the Day 1 and Months 7, 24, 36, and
48 study visit.

a) Remove DACRON swab (supplied by SPONSOR) from its


packaging.

b) Introduce the swab into the cervical os with enough pressure to


maintain contact with the epithelium but not to induce bleeding. Twirl
the swab only 1 to 2 times, and then use a back-and-forth swiping
motion across the ectocervix from anterior to posterior cervical lip (top
to bottom).

c) Place the swab in the collection tube containing the STM. Break off
the end of the shaft protruding from the tube by bending it sharply
against the rim of the tube. The shaft is prescored to facilitate
breaking.
d) Securely cap the transport tube containing the specimen.
e) Within 30 minutes of collection, place the specimen in a -20C freezer
or in a bucket containing dry ice until ready to ship.

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f) Samples should be shipped according to instructions summarized in
the SPONSORs central laboratory manual to the address noted on
SPONSOR Contact Information page.
8) Pap Test for Liquid Cytology (ThinPrep)

Procedure should be performed for all subjects as per the protocol-


mandated instructions below on the Day 1 and the Months 7, 12, 24, 36,
and 48 study visit.

a) Using a plastic spatula, scrape the ectocervix in a 360 arc for 2 full
rotations, being sure to include the squamocolumnar junction in the
portion sampled. Place the spatula into the open PreservCyt, using
vigorous shaking and swishing of the spatula to rinse all of the cellular
debris from the spatula. It is acceptable to leave the spatula in the
open PreservCyt until the cytobrush collection is completed.

b) Insert a cytobrush into the cervical os, and turn for 1 single 360 arc.
Place the cytobrush immediately into the ThinPrep liquid.

c) Use the spatula to rub against the cytobrush in order to dislodge as


much cellular debris as possible from the cytobrush and spatula.
Swish and rinse the cytobrush, and knock it against the side of the vial
at least 10 times to release enough epithelial cells for an adequate Pap
test sample. To minimize adherence of cellular debris to the collection
devices, the rinsing and swishing procedures should be performed
within 2 minutes of collection.

d) Remove the spatula and the cytobrush from the PreservCyt liquid
and twist the cap on the vial securely.

e) Store PreservCyt vials containing the specimens at room


temperature until they are sent to the cytology laboratory.

f) Liquid cytology Pap tests will be tested at a cytology laboratory


selected by the SPONSOR (see SPONSOR Contact Information page).
These specimens must be processed within 21 days of collection to
preserve sample integrity according to the manufacturers instructions.
To comply with this requirement specimens must be shipped
according to instructions summarized in the SPONSORs central
laboratory manual.

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i. Assignment of Allocation Number and Vaccine

Randomization

For study randomization, an allocation schedule will be generated by the


Clinical Biostatistics department of the SPONSOR. Throughout this study
and across all study sites, there will be no repetition of an allocation number.
Subjects will be assigned an allocation number at the time of randomization
on Day 1. This department will also generate a schedule for the component
identification numbers that will be used to identify the vaccine/placebo vials
that correspond to the subjects treatment group for the purpose described
below.

An Interactive Voice Response System (IVRS) will be used to allocate


subjects and assist with vaccine supplies management to the study sites. At
the first visit, study personnel will access the IVRS after a subject has signed
the consent form and the subject has met the inclusion/exclusion criteria. The
IVRS will assign the subject an allocation number and then assign a unique
vial identification number for the vial of clinical material the subject should
receive at that visit. The IVRS will assign the appropriate clinical material
based on the subjects treatment allocation. The study personnel will access
IVRS at each subsequent visit when administration of vaccine is to occur for
assignment of a unique vial identification number for the clinical material to
be administered to the subject.

The allocation number will never change and will always remain the number
that was assigned at the first vaccination visit. Once assigned, an allocation
number cannot be reused for any reason. Allocation numbers for subjects
who discontinue or withdraw may not be reassigned.

With the IVRS, allocation numbers will be predesignated to each site. All of
the clinical materials (vaccine/placebo) will be labeled with unique
identification numbers to be used in conjunction with the IVRS and the
allocation schedule for the site.

Nonrandomization Subjects

If a subject has signed an informed consent form but is not randomized, the
investigator must submit a STATUS form to the SPONSOR for the subject.
This form reports basic demographics and the reason(s) for exclusion. The
investigator shall also submit an AE form if applicable. Unless otherwise
directed, no other data need be submitted for these subjects.

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j. Vaccine/Placebo Administration

1) Preparation for Administration

The vaccine or placebo should be used as supplied. No dilution is


required before administration. Mix the contents of the vial thoroughly
before withdrawal and use by rolling the vial between the palms of both
hands for 30 seconds prior to administration. The 0.5-mL dose for the
quadrivalent HPV vaccine/placebo should be withdrawn from the vial
containing 0.75 mL of injectable material. The quadrivalent HPV vaccine
and the placebo are whitish, semi-translucent suspensions when
thoroughly mixed. If the appearance is otherwise, do not administer, and
call the SPONSOR (see SPONSOR Contact Information page) and the
IVRS.

The preferred site for the intramuscular injections is in the deltoid muscle.
A needle long enough to ensure intramuscular deposition of vaccine
should be used for the injections.

2) Guidelines for Vaccinations

The 0.5-mL injection of vaccine or placebo will be administered


intramuscularly at Day 1 and at Months 2 and 6. Injections should be
administered at a 90 angle into the deltoid muscle of the nondominant
arm using a 1.0-mL syringe with the following needle length and gauge
specifications: 1-inch needle, 22 to 23 gauge, for women weighing
<200 pounds (90.9 kg.), 1-inch needle, 22 to 23 gauge, for women
weighing 200 pounds (90.9 kg). If the injection is given in the thigh, a
1-inch, 22 to 23 gauge should be used.

The vaccination may be given in the thigh if this is the subjects


preference. If a subject has received injection or implant contraception
such as DEPO-PROVERATM (sterile medroxyprogesterone acetate
suspension, USP, Pharmacia) in both arms in the past 9 months, or if it is
her preference, the injection may be given in the thigh. If NORPLANT
is used, avoid arm with levonorgestrel implants. Injections should not be
given within 2 cm of a tattoo, scar, or skin deformity. Do not inject into
an arm in which injection or implant contraception such
DEPO-PROVERA was injected at any time in the past 9 months.

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k. Clinical Follow-Up

All subjects will be observed for at least 30 minutes. This period of


observation should be documented after each vaccination for any immediate
reaction with particular attention to any evidence of allergic phenomena.

All subjects will be followed for the reporting of serious adverse experiences
from the time the consent is signed through 14 days following the first
vaccination and from the time of any subsequent vaccination(s) through
14 days. Additionally, any serious adverse experience brought to the attention
of the investigator at any time outside the 14 day reporting period must be
reported if the event is either a death which resulted in the subject
discontinuing the study, a SAE that is considered to be vaccine related, or a
SAE that is considered to be related to a study procedure.

The subjects participating in the NSAE substudy (n=1150) will be followed


for the reporting of all nonserious adverse experiences using Vaccination
Report Cards (VRCs) for 14 days following each injection of vaccine/placebo
(day of vaccination plus 14 calendar days). These subjects are to record
injection-site reactions, systemic reactions, and temperature daily on the VRC
for Day 1 (beginning 4 hours postinjection and then daily thereafter) through
Day 5 following each vaccination. Temperatures should be taken
approximately the same time each day. The subject is also to record all
adverse experiences that occur during the 15-day period (day of vaccination
plus 14 calendar days) after each injection. All injection-site reactions and
systemic adverse experiences (AEs), regardless of severity, will be reported
on the appropriate worksheet forms, as well as reasons for premature
withdrawal from the study. Any elevated temperature (100F or 37.8C
oral) will be recorded as an adverse experience. If a subject does not record
an actual temperature, but reports a feverish feeling, this will be
documented as an adverse experience on the appropriate worksheet form.

The VRC should be reviewed for completeness by the study site personnel at
the Month 2 visit, Month 6 visit, and the Month 7 visit or by phone if the VRC
was mailed back to the site and no timely visit is scheduled. All comments
are to be reviewed by the study personnel and discussed with the participant
for clarification if necessary. The information on the VRC should be
generated only by the subject and is to be signed and dated by the subject to
confirm the accuracy of the recorded information. Original information
recorded by the participant should never be altered by study personnel. Any
information gained by phone contact with the subject should be clearly
documented, initialed, and dated on the subject workbooklet or source

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documentation, other than the VRC. Discrepancies between information
obtained during the telephone contact and the VRC need to be resolved;
however, information on the VRC will be accepted over the telephone contact
in the event that discrepancies cannot be resolved.

Subjects Discontinuing From Study: Those subjects who withdraw/discontinue


prior to completion of the study will be asked to return for a final, close-out
visit if it has been at least 4 months since the last visit that included a pelvic
exam. Procedures performed at this visit will be the same as those performed
at the final study visit (Month 48).
l. Biopsy/Colposcopy/Definitive Procedures

The study has mandatory guidelines for referral of subjects for colposcopy
and biopsy (see Section I.E.3.l.3)), Procedures for Colposcopy. Any
deviation from this mandatory guideline will require prior approval by the
medical monitor. The biopsies will be processed and read by a central
laboratory selected by the SPONSOR. Biopsy results as read by the central
pathology laboratory will be used for routine management of the subject.
Subjects who undergo cervical biopsy during the study will remain in the
study. The interval between the cervical biopsy and the next scheduled visit
that includes a pelvic exam must be at least 2 months, unless for definitive
therapy.

If no lesion is noted on colposcopy and/or the colposcopy exam is


unsatisfactory, and the subject was referred based on cytologic abnormality,
an endocervical cutterage (ECC) along with a careful inspection of the vagina
may be performed if it is deemed by the investigator to be medically
indicated. A curet may be used, but not a brush when obtaining the specimen.
Thinsection HPV PCR analysis will be done on all ECC specimens, along
with a histopathologic review.

The procedures for external genital biopsy, colposcopy, cervical biopsy, and
definitive therapy that may be performed during the study are provided in the
following sections:

1) Procedure for External Genital Lesion Biopsy


Visible external genital warts/lesions noted during the study period,
between Day 1 through Month 48, will be biopsied. Select 1 external wart
to biopsy. To perform the biopsy, use a 30-gauge needle and a syringe of
1 to 2 mL of either 1% lidocaine or bacteriostatic saline to infiltrate below
the epidermis of the wart. Elevate the wart and remove tangentially with

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fine scissors, then use silver nitrate as needed for hemostasis. Advise the
patient to keep the area clean and to expect spotting for 3 days with
healing by 1 week. Place the biopsy specimen in the external genital
lesion biopsy specimen kit container provided by the central laboratory for
routine histologic analysis to confirm HPV histology changes. (Sections
of the tissue blocks will be made available to the SPONSOR for HPV 6
and 11 for biopsy thin section PCR). For specimen handling and shipping
refer to the central laboratory manual. Specimens will be reviewed by a
pathologist for histopathology at a cytology laboratory designated by the
SPONSOR. In addition, cervical tissue specimens will be prepared by the
central laboratory for HPV analysis to be performed by the SPONSOR or
its designee.

Genital warts should be treated as per the local standard of care.

2) Guidelines for Colposcopy


The following are mandatory guidelines for referral to colposcopy. These
guidelines are generally consistent with international recommendations.
Subjects with ThinPrep Pap tests obtained during the study showing any
of the following should undergo colposcopy and biopsy according to the
ThinPrep triage algorithm in Table 7:

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Table 7

Mandatory Regimen for Triage of Abnormal Pap Tests to Colposcopy


ThinPrep Pap Result Action
Negative for intraepithelial lesion or Routine visit interval as specified by the protocol.
malignancy (includes reactive,
reparative, inflammatory, etc.)
Atypical Squamous Cells of Repeat ThinPrep Pap Test 6 months later
Undetermined Significance (ASC-US)
Atypical Squamous Cells, cannot rule Referral to colposcopy.
out HSIL (ASC-H)
Low-grade Squamous Intraepithelial Repeat ThinPrep Pap Test 6 months later
Lesions (LSIL)
High-grade Squamous Intraepithelial Referral to colposcopy.
Lesions (HSIL)
Atypical Glandular Cells (to include Referral to colposcopy.
atypical endocervical, endometrial,
NOS, adenocarcinoma in situ,
adenocarcinoma)
Inadequate Specimen Repeat Pap Test as soon as possible
Colposcopy should only be performed according to the guidelines in this table.

For the ASC-US and LSIL Repeat Paps: If the repeat ThinPrep Pap Test reveals ASC-H, LSIL,
HSIL or Atypical Glandular Cells, then the subject will be referred to colposcopy. If the repeat test
is negative for squamous intraepithelial lesion, then the subject will return to routine ThinPrep
Pap Testing schedule. If the repeat Pap reveals ASC-US, then the central lab performs reflex HPV
testing on residual ThinPrep material (High Risk Probe, Hybrid Capture II, DIGENE). If
positive, the subject is referred for colposcopy. If negative, then the subject returns for Pap
screening at the routine visit interval. Subjects with a diagnosis of LSIL at Month 48 will be
referred immediately for colposcopy. Subjects with a diagnosis of ASC-US at Month 48 will have
reflex HPV testing on residual ThinPrep material (High Risk Probe, Hybrid Capture II,
DIGENE) completed. If positive, the subject is referred for immediate colposcopy. This
colposcopy must be performed within 2 months of the Month 48 visit. All specimens collected
during this colposcopy will be handled through the study central lab.

Subjects who undergo colposcopy may undergo biopsy if clinically


indicated. The most severe area of abnormality observed on colposcopy
should be biopsied. Separate biopsy forceps must be used for each of
the distinct lesions that are biopsied.

Subjects who undergo cervical biopsy during the study will remain in the
study. The interval between the cervical biopsy and the next scheduled
visit that includes a pelvic exam must be at least 2 months, unless for
definitive therapy.

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Cervical and/or wart biopsy specimens will also be sent to the SPONSOR
or a designee for HPV analysis. HPV analysis will be performed on
Thinsection microtomy specimens. Each biopsy specimen will be
analyzed by HPV PCR, regardless of whether an HPV-related histologic
diagnosis is made, for the purpose of determining the causal HPV type in
the lesion. HPV typing will be performed using the Multiplex PCR Assay
to detect vaccine HPV types on all samples. Samples that test negative for
HPV vaccine types will be analyzed for non-vaccine HPV types using
type-specific HPV PCR assays to detect non-vaccine HPV types in the
biopsy lesion.

If a subject has a Pap test performed outside of the study, the investigator
should request the subject to sign a medical release to obtain the cytology
report. If the cytology results are borderline (any result that is not
normal or reactive /reparative changes or negative for squamous
intraepithelial lesion or malignancy), the investigator should arrange for
an unscheduled study visit for a ThinPrep Pap test. The ThinPrep test
result will be evaluated per the Mandatory Regimen for Triage of
Abnormal Pap Test to Colposcopy table. In addition, please inform the
Merck clinical monitor or medical program coordinator.

Colposcopy and biopsy outside of the study are to be strongly


discouraged. Subjects may be referred for colposcopy and biopsy outside
the study-mandated algorithm only if approved by the Merck medical
monitor. If a subject has a colposcopy/biopsy performed outside of the
study, the investigator should request the subject to sign a medical release
to obtain the following: (1) the operative report; (2) the results of the
biopsy; (3) the specimen H&E slides; and (4) the specimen block. Please
inform the Merck clinical monitor or medical program coordinator.

The cervical biopsy specimens will be processed and read by a single


central laboratory selected by the SPONSOR. Biopsy specimens will be
prepared at the central pathology laboratory and reviewed by a pathologist
for the purpose of management of the subject. However, the diagnoses
provided by the central laboratory will not represent the official diagnoses
for study purposes. Rather, all routine slides generated by the central
laboratory will be sent for review by an independent adjudication panel
(Pathology Panel), consisting of up to 5 pathologists, for the purpose of
providing the official diagnosis for the efficacy evaluation. The consensus
diagnosis of this panel will represent the final diagnosis for study
purposes. If the diagnosis of the pathology panel is CIN 2/3 or worse, and

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the diagnosis of the central laboratory is of a lower grade abnormality,
then the investigator will be notified of the discrepancy in diagnoses. The
slides will be returned to the originating central pathology laboratory at
the completion of review by the SPONSOR.

Colposcopy Quality Control (QC)

Colposcopy will be performed only by an experienced colposcopist


(>50 colposcopies per year for at least 2 years). To ensure that colposcopy
practices and skill levels are standardized across investigator sites, and
that colposcopists at all sites develop a uniform approach to all study
colposcopies, colposcopists will be required to participate in colposcopic
standardization training. The purpose of this training is to evaluate the
colposcopic practice at all investigator sites, to standardize colposcopy and
biopsy practices, and to provide a guide for all aspects of the protocol
related to colposcopy and histologic sampling of the cervix.

3) Procedures for Colposcopy


The following is the standard examination for a colposcopy. The Reid
Index for colposcopy ascertainment is to be followed and documented in
the workbooklet/case report form. All abnormal areas are to be biopsied
using separate forceps for each lesion.

a) Assist patient to dorsal lithotomy position.

b) Inspect the vulvar, perineal, and perianal areas for abnormal lesions.

c) Insert sterile saline- or sterile water-lubricated single-use, individually


wrapped plastic speculum.

d) Visualize the entire cervix through the colposcope at low power.

e) Repeat Pap test, based on the local standard of care.

f) Use optional visualization adjuncts (i.e., condom or rubber glove


finger tube over speculum, lateral side-wall retractor) if necessary to
enhance colposcopic visualization.

g) Remove mucus and debris by liberally applying 5% acetic acid to the


cervix using cotton balls and ring forceps, large cotton swabs or by
spray technique. Avoid use of 44 gauze pads.

h) Reapply acetic acid (or Lugols solution) to the cervix for a minimum
of 60 seconds. Thereafter, reapply acetic acid every 3 to 5 minutes or
when the columnar epithelium is no longer blanched.

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i) Identify the entire squamocolumnar junction (360), if able.

j) Identify acetowhite cervical lesions if present.

k) Assess the severity of each cervical lesion using green filter as needed
to examine the vascular patterns.

l) Obtain cervical biopsies and/or endocervical curettage per protocol, if


necessary (see next section).

m) Inspect the vagina by colposcopic examination, if appropriate


(discordance between cytology and colposcopic impression). Apply
5% acetic acid or Lugols solution to the entire epithelium and then
view by low power colposcopic magnification, noting acetowhite (or
yellowish if Lugols solution used) vaginal lesions, and if appropriate,
biopsy.

n) The Reid Colposcopic Index (RCI) is to be used to classify any


identified lesions.

o) Biopsy vulvar, vaginal, perineal, and perianal lesions when


appropriate.

4) Procedures for Cervical Biopsy

a) At a minimum, select the most abnormal lesion to biopsy, noting


location and quadrant.

b) Apply local anesthesia, if local standard of care.

c) Biopsy posterior lip lesions first if multiquadrant lesion is of same


estimated severity. Otherwise, always biopsy the most severe lesion
first.

d) Place biopsy forceps over the abnormal lesion (usually near the
squamocolumnar junction).

e) Open forceps jaws to sufficient extent.

f) Check to make sure the forceps are properly aligned (fixed end of
forceps jaw towards cervical os).

g) Rotate biopsy handles to place lesion in center of biopsy jaw angle if


necessary.

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h) Exert moderate pressure with biopsy forceps to push cervix backwards
until cervix is fixed in position.

i) Squeeze handles together quickly and firmly to close forceps jaws and
excise lesion.

j) Lock biopsy jaws to secure tissue (if locking mechanism available) or


just hold tightly, then pass the forceps to the assistant.

k) If another lesion in the cervix is identified for biopsy, use different


forceps in obtaining the specimen.

l) Confirm by colposcopic visualization that an appropriate and adequate


biopsy was collected. The biopsy should be perpendicular to the
epithelium and deep enough to sample the entire epithelium along with
a small amount of stroma (at least 2 mm) for histology.

m) Tamponade biopsy site with cotton swab.

n) Place biopsy specimen in the cervical biopsy specimen kit-specified


container. For specimen handling and shipping refer to the central
laboratory manual. Specimens will be reviewed by a pathologist for
histopathology at a cytology laboratory designated by the SPONSOR.
In addition, cervical tissue specimens will be prepared by the central
laboratory for HPV analysis to be performed by the SPONSOR or its
designee.

o) Repeat the biopsy procedure for each additional biopsy performed


using a different pair of forceps. Collect all biopsy specimens prior to
establishing hemostasis, if possible.

p) Obtain complete hemostasis with directed silver nitrate stick or


Monsels (ferric subsulfate) paste application.

q) Instruct patient to: (1) take nonsteroidal anti-inflammatory drugs for


uterine cramping (provided no allergy), (2) report significant bleeding
immediately, and (3) refrain from use of vaginal products, douching,
tampons, and sexual intercourse for 3 to 7 days.

r) Document abnormalities and biopsy site(s).

If no lesion is noted on colposcopy, and the subject was referred based on


cytologic abnormality, an endocervical curettage (ECC) may be performed
if it is deemed by the investigator to be medically indicated. A curet may
be used, but not a cytobrush, when obtaining the ECC specimen.

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E. STUDY DESIGN (CONT.)


5) Procedures for Endocervical Curettage (ECC) (Optional)

a) Obtain an endocervical curettage specimen either before or after


cervical biopsies (based on local standard of care), if indicated.

b) Insert open basket endocervical curette into cervical os.

c) Apply gentle pressure at the distal tip of curet against the endocervical
canal and pull the curet from inside to outside with pressure, while
simultaneously rotating the curet in a circular direction. The curet
should advance no more than 20 mm up the canal and should be
rotated completely 2 to 3 times. Avoid sampling ectocervical lesions
that extend proximally into the endocervical canal, if possible.

d) Spin the curet rapidly to trap epithelium in the basket and remove the
curet from the canal. Scraped material remaining in the canal can be
retrieved with small forceps.

e) Place the specimen on paper, telfa and/or submerge into a labeled


ECC specimen container of appropriate fixative. Obtain adequate
hemostasis.

f) Specimens will be submitted to the central laboratory selected by the


SPONSOR for histopathologic view. Results will be used to plan
treatment, if necessary. (Specimens from the ECC will be prepared by
the central lab for HPV PCR analysis by the SPONSOR or its designee
using Multiplex PCR Assay to detect vaccine HPV types on all
samples. Samples that test negative for HPV vaccine types will be
analyzed for non-vaccine HPV types using type-specific multiplex
PCR assays to detect non-vaccine HPV types in the biopsy lesion.

6) Procedures for Definitive Therapy

Definitive Therapy
Subjects who undergo cervical biopsy during the study will be referred for
definitive therapy according to mandatory protocol-prescribed guidelines
including:
Biopsy-confirmed CIN 2/3 or cervical cancer
2 repeated HSIL diagnoses on ThinPrep Pap Test without confirmed
CIN 2/3 or cervical cancer on biopsy.
an ECC demonstrating CIN 2/3, AIS, or cervical cancer

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1 HSIL Pap with an unsatisfactory colposcopic examination including
a negative examination of the vagina
Atypical Glandular Cells or AIS on Pap result with unsatisfactory
colposcopy or negative biopsy
CIN 1 on at least 2 consecutive biopsies obtained over a period of at
least 1 year.
Acceptable Study Procedure for Definitive Therapy

The LEEP (Loop Electrosurgical Excision Procedure) is the preferred


method for definitive therapy. LEEP is a study procedure.

The deeper top hat LEEP cone is also acceptable.

Laser conization is an acceptable study procedure if the LEEP is not


the standard practice of care.

Cold-knife conization should be reserved only for rare instances in


which definitive therapy is required and LEEP is not indicated. Cold-
knife conization is a study procedure. Biopsy specimens are to be
obtained from the areas of highest abnormalities at the time of the
conization procedure. This is to be sent to the SPONSOR for
histopathologic review and HPV analysis.

Nonstudy Procedure for Definitive Therapy

Ablative therapy (cryotherapy) is not a study procedure. If


performed, biopsy specimens are to be obtained from areas of highest
abnormalities prior to the ablative therapy and sent to the SPONSOR
for histopathologic review and HPV analysis.

Subjects who undergo definitive therapy (LEEP, laser conization, cold-


knife conization, cryotherapy, laser therapy or other ablative therapy) will
continue to be followed through completion of scheduled visits. However,
they will not be further eligible for the efficacy endpoint. Definitive
therapy outside the study should be strongly discouraged. If a subject
does undergo therapy outside of the study, all efforts will be made to
obtain the diagnostic slides, local pathology diagnosis, and tissue block for
HPV analysis. The interval between definitive therapy and the next
scheduled visit that includes a pelvic exam must be at least 2 months. If
the interval is <2 months, the next visit should be postponed.

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E. STUDY DESIGN (CONT.)


Cervical tissue specimens will be submitted to the central laboratory
selected by the SPONSOR for histopathologic review. In addition,
specimens will be prepared by the central lab for HPV PCR analysis by
the SPONSOR or its designee using the Multiplex PCR Assay to detect
vaccine HPV types on all samples. Samples that test negative for HPV
vaccine types will be analyzed for non-vaccine HPV types using type-
specific HPV PCR assays to detect non-vaccine HPV types in the biopsy
lesion.

Loop Electrosurgical Excision of High Grade Lesions

The LEEP provider should be an experienced physician (defined as


performing 20 LEEP procedures per year for at least 2 years) and must
have documented formal instruction, i.e., residency or postgraduate course
or American Society for Colposcopy and Cervical Pathology (ASCCP)
training course. Similar requirements for countries outside the United
States apply.

The LEEP procedure is a shallow pass to remove the cervical


transformation zone. It may be a single or multiple pass and is ~8 mm
deep. The top hat cone implies a deeper wedge resection, ~15 to 25 mm
deep. It is performed by the top-hat method of successively more
internal and smaller loops. LEEP is a study procedure.

LEEP excisional procedures are contraindicated in the following


conditions: allergy to all local anesthetics; pregnancy; severe acute
cervicitis (severe acute cervicitis should be diagnosed and treated, and
excision conducted after the infection has resolved); obvious invasive
cancer, significant glandular neoplasia (Atypical Glandular Cells favor
neoplasia, cervical adenocarcinoma in situ [AIS], Adenocarcinoma); and
microinvasive cancer.

A biopsy of each identified affected lesion is to be obtained prior to


performing the LEEP. LEEP/laser conization/cold-knife conization
specimens will be submitted in their entirety to the study central
laboratory for processing and diagnosis. These specimens will be
processed at the central laboratory using study-specific guidelines. The
central laboratory diagnosis will be used for management of subjects.
However, this diagnosis will not be the diagnosis of record in this study.
Rather, all routine slides generated by the central laboratory will be sent to
the Pathology Panel. The consensus diagnosis of this panel will represent

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E. STUDY DESIGN (CONT.)


the final diagnosis for study purposes. If the diagnosis of the Pathology
Panel is CIN 2/3 or worse, and the diagnosis of the central laboratory is of
a lower grade abnormality, then the investigator will be notified of the
discrepancy in diagnoses.

Note: All instruments used for this procedure must be nonconductive.

a) Assist subject into dorsal lithotomy position.

b) Place dispersive pad near operative site (thigh) and plug into
Electrosurgical Unit (ESU).

c) Place vaginal speculum and secure smoke evacuation tubing.

d) Set electrosurgical unit parameters (power, cut/blend) and test safety


systems.

e) Identify cervical pathology by colposcopic exam.

f) If appropriate, apply half-strength Lugols solution to cervix and


identify transformation zone limits.

g) Give local anesthesia if no allergy4 quadrant (3, 6, 9, 12)


intracervical injection of lidocaine with epinephrine.

h) Biopsy areas of the most severe abnormalities for histopathologic


review (see Section I.E.3.l.4)). If 2 or more different areas are
sampled, use a fresh biopsy forceps for each area. This will avoid
cross-contamination. The following specimens will be submitted to
the central laboratory: 2- to 3-mm size of tissue per location in
fixative for histopathologic review (tissue must be shipped at room
temperature on the day of collection).

i) Select appropriate loop electrode size to remove transformation zone


and lesion, insert into hand piece and plug hand piece into
electrosurgical unit.

j) Activate smoke evacuator.

k) Initiate excision by depressing cut switch if using handpiece, cut


down (perpendicular to tissue), across transformation zone and straight
out at opposite side of transformation zone (depth of 8 mm) and avoid
vaginal sidewall contact.

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l) Repeat cut procedure (reduced power) along endocervical canal with
smaller 10x10 loop electrode if top hat conization necessary.

m) Hand excised tissue to assistant and dictate its orientation. Orient the
tissue by placing a suture at the 12 oclock location. Place tissue into
labeled specimen container of fixative supplied by the central
laboratory. Tissue must be shipped at room temperature to the central
laboratory on the day of collection for histopathologic review. Note:
If the top hat procedure is performed, the tissue from each loop or
pass should be placed in a separate labeled container.

n) Inspect endocervical canal opening and perform ECC, if medically


indicated. Follow procedures for ECC (see Section I.E.3.l.5)
Procedures for Endocervical Curettage).

o) Fulgurate base of the excision with coagulation using the ball or


paddle electrode until adequate hemostasis and fulgurate 5 mm of the
endocervical margin. If lesion extended beyond the excision, ablate
the area and record on the LEEP Case Report Form and source
document.

p) If hemostasis is inadequate, pack base of excision with Monsels


(ferric subsulfate) paste or in rare event suture may be required.

q) Remove blood from posterior fornix.

r) Deactivate ESU and smoke evacuator.

s) Remove dispersive pad and vaginal speculum.

t) Assist subject up from table.

u) Instruct patient to: (1) take nonsteroidal anti-inflammatory drugs as


needed (provided no allergy), (2) refrain from use of vaginal products,
douching, tampons, and sexual intercourse for 2 to 4 weeks, and
(3) report significant bleeding and signs of infection (fever, pain)
immediately.

v) The specimen is to be transferred in the appropriately labeled vial


provided in the LEEP Specimen Kit. These samples are be sent to the
SPONSOR central laboratory for a histopathological review by the
pathologist. The specimen will be prepared by the SPONSOR central
laboratory for HPV PCR analysis to be performed by the SPONSOR
or its designee.

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E. STUDY DESIGN (CONT.)


w) Complete source documents and the LEEP case report form and
prepare Requisition forms for submission to the central laboratory.

Laser Conization

The laser conization provider should be an experienced physician (defined


as performing 20 laser conization procedures per year for at least 2 years)
and must have documented formal instruction, i.e., residency or
postgraduate course or American Society for Colposcopy and Cervical
Pathology (ASCCP) training course. Similar requirements for countries
outside the United States apply.

Procedure for Laser Conization

a) Assist subject into dorsal lithotomy position.

b) Place vaginal speculum and secure smoke evacuation tubing.

c) Set laser unit parameters (power, optical focusing of the laser beam)
and test safety systems.

d) Identify cervical pathology by colposcopic exam.

e) If appropriate, apply half-strength Lugols solution to cervix and


identify transformation zone limits.

f) Give local anesthesia if no allergy4 quadrant (3, 6, 9, 12)


intracervical injection of lidocaine with epinephrine. If needed
paracervical injection of the anesthetic may also be used. General
anesthesia may be provided if so preferred. If general anesthesia is
preferred, intracervical injection of lidocaine with epinephrine may
still be used if there is no allergy to the components of the injection.

g) Biopsy areas of the most severe abnormalities for histopathologic


review (2- to 3-mm size per location) (see Section I.E.3.l.4),
Procedures for Cervical Biopsy, d) to n)). If 2 or more different areas
are sampled, use a fresh biopsy forceps for each area. This will avoid
cross contamination. The specimens will be submitted to the central
laboratory.

h) Activate smoke evacuator.

i) Initiate excision by marking the border of the area to be excised with


the laser beam.

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E. STUDY DESIGN (CONT.)


j) Cut the cone by the laser beam, using small depressor instruments or
hooks to position the cone for optimal excision with the laser beam.

k) Hand excised tissue to assistant and dictate its orientation. Orient the
tissue by placing a suture at the 12 oclock location. Place tissue into
labeled specimen container of 10% buffered zinc formalin supplied by
the central laboratory. Tissue must be shipped at room temperature to
the central laboratory on the day of collection for histopathologic
review. (The specimen will be prepared by the SPONSOR central lab
for HPV PCR analysis to be performed by the SPONSOR or its
designee as for the LEEP.)

l) Inspect endocervical canal opening and perform ECC, if medically


indicated. Follow procedures for ECC (see Section I.E.3.l.5)
Procedures for Endocervical Curettage).

m) Use the defocused laser beam in the wound area until adequate
hemostasis, and evaporize 5 mm of the ectocervical margin. If lesion
extends beyond the excision, remove that lesion also and record on the
laser conization workbooklet/case report form and source document.

n) If hemostasis is inadequate, inject more lidocaine with adrenaline or in


rare event suture may be required.

o) Remove blood from posterior fornix.

p) Remove dispersive pad and vaginal speculum and deactivate smoke


evacuator.

q) Assist subject up from table.

r) Instruct patient to: (1) refrain from use of vaginal products, douching,
tampons, and sexual intercourse for 2 weeks, and (2) report significant
bleeding and signs of infection (fever, pain) immediately.

s) Complete source documents and the laser conization workbooklet/case


report form and prepare requisition forms for submission to the central
laboratory.

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E. STUDY DESIGN (CONT.)


Cold-Knife Conization

Cervical cold-knife conization is a study procedure but should be


performed only when the LEEP procedure is not indicated. A cervical
cold-knife conization specimen represents a conically shaped section of
the cervix that will vary in size according to the lesion. A broad, shallow
conization would be performed for a predominantly exocervical lesion and
a narrow, deep conization is appropriate for a predominantly endocervical
lesion. A biopsy of the affected tissue should be obtained prior to this
procedure and the specimen should be oriented and submitted to the
central laboratory as described in Section I.E.3.l.6) for the pre-LEEP
biopsy.

Ablative Therapy and Hysterectomy Are Not Study Procedures

If a subject undergoes ablative therapy (cryotherapy) or a hysterectomy


during the study, biopsy specimens obtained at the time of cryotherapy or
hysterectomy will be sent to the SPONSOR central laboratory for
histopathologic review and the HPV analysis. If a hysterectomy is
performed during the study, special arrangements will be made to secure
the specimens for submission to the central laboratory.

m. Laboratory Measurements

Urine specimens will be obtained at Day 1, Months 24 and 48 for all subjects,
to be tested for chlamydia and gonorrhea PCR or LCR or SDA. Urine or
blood specimens will be obtained at Day 1, Months 2 and 6 for pregnancy
testing.

A 15-mL blood specimen will be obtained from each study participant at


Day 1. Additional 15-mL blood specimens will be obtained from subjects
participating in the Consistency Lot substudy (n=3000) at Months 7, 24, and
48. All blood specimens will be collected in a red top collection tube
(nonheparinized but not a serum-separator tube). All samples may be tested
by cRIA for serum anti-HPV 6, 11, 16, and 18 (at MRLs discretion) at all
time points stated.

If a serum specimen is to be sent for optional testing during the study


(hepatitis B, hepatitis C, HIV, syphilis), then draw additional blood as per
requirements of investigative site.

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Swabs obtained from the labia/vulva/perineum and the perianal and
endo/ectocervical areas will be tested for HPV PCR by the SPONSOR or
SPONSOR designated laboratory. All subjects who are enrolled in the
consistency lot substudy will have these samples tested for HPV 6, HPV 11,
HPV 16, and HPV 18 by multiplex PCR at Day 1 and Month 7. For subjects
not participating in the consistency lot substudy Types 6 and 11 testing will be
optional at Day 1 and Month 7. Additional type-specific HPV PCR assays
may also be used to analyze these swab specimens at Day 1 and Month 7 to
detect non-vaccine HPV types. The Month 24, Month 36 and Month 48
endo/ectocervical specimens may be analyzed for presence of vaccine HPV
type DNA using multiplex PCR. This additional testing will be optional and
at the discretion of the SPONSOR.

All biopsy samples will be analyzed by Thinsection PCR for HPV 16/18. For
biopsies in which HPV 16 or HPV 18 are not detected by Thinsection PCR,
type-specific HPV PCR assays will be used to evaluate non-vaccine HPV
types in the biopsy lesion. Assay descriptions are provided in Protocol
Section I.F.4., Efficacy and Immunogenicity Measurements.

F. EFFICACY AND IMMUNOGENICITY MEASUREMENTS


1. Primary Endpoint

The primary endpoint of the study is the combined incidence of HPV 16-related
CIN 2/3 or worse and HPV 18-related CIN 2/3 or worse. This endpoint will occur
if on any single biopsy, ECC, or LEEP/conization tissue block, the following
occur:

Pathology panel consensus diagnosis of: CIN 2, CIN 3 (including squamous


carcinoma in situ), adenocarcinoma in situ, invasive squamous cervical
carcinoma, or invasive adenocarcinoma of the cervix,

AND

Detection of HPV 16 and/or HPV 18 by biopsy Thinsection PCR in an


adjacent section from the same biopsy block.

2. Other Efficacy Measurements

In addition to the primary endpoint definition, the incidence of all CIN 2/3
(regardless of causal HPV type) will be measured. For biopsies in which HPV 16
or HPV 18 are not detected by Thinsection PCR, type-specific HPV PCR assays
will be used to evaluate non-vaccine HPV types in the biopsy lesion.

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Serum will be collected for analysis of anti-HPV 6, anti-HPV 11, anti-HPV 16
and anti-HPV 18 levels at Day 1 in all samples. Thereafter, serum will be
collected only in subjects participating in the consistency lot substudy.
Cervicovaginal samples will be collected for HPV 16 and HPV 18 PCR analysis
at Day 1 and Months 7, 24, and 48 in all subjects. HPV 6 and 11 PCR analysis
will be mandated in subjects participating in the consistency lot substudy. For all
other subjects this testing will be optional.

3. Immunogenicity

cRIA for Serum Antibody Response to HPV

The HPV 16 and 18 antibody assays are competitive radioimmunoassays. Four


separate assays for each of the HPV types are performed. The following
procedures will be performed at Merck Research Laboratories (MRL),
West Point, PA or a central laboratory designated by the SPONSOR: Polystyrene
beads coated with a limiting amount of either HPV 16 or 18 antigen are incubated
with a mixture of a limiting amount of either HPV 16 or 18 specific monoclonal
antibodies (MAb) and a serum sample. HPV 16 or 18 VLP-specific antibodies in
the serum sample will compete with the HPV 16 or 18 MAb for a limited number
of binding sites on the antigen-coated bead. Goat anti-mouse 125I is used to detect
the amount of MAb bound to the beads. Quantitation is by standard curve.

A fixed cutoff will be used in the assays. The cutoff is derived by repeatedly
testing a panel of positive and negative samples against the standard curve. Any
sample with a value less than the cutoffs will be considered serostatus negative.
Samples with values equal to or greater than the cutoff will be considered
serostatus positive. Samples are read from a standard curve, corrected for dilution
as needed, and reported in mMU/mL. The cutoffs for the HPV 16 and 18
competitive radioimmunoassay are 6 mMU/mL and 13 mMU/mL, respectively.

4. PCR Assays to Detect HPV in Clinical Specimens

a. Multiplex PCR Assays

The following procedures will be done at MRL, West Point, PA or a central


laboratory designated by SPONSOR. For the detection of HPV types 6, 11,
16, 18, swab samples and Thinsection microtomy specimens are received and
then prepared for multiplex PCR using a DNA purification method (Qiagen

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Technology Kit). Multiplex PCR (based on real-time fluorescent PCR) allows
the simultaneous detection of 3 gene products (L1, E6, and E7) for a given
HPV type in 1 reaction. The HPV type-specific primer pairs based on the
published HPV L1, E6, and E7 sequences, are used to specifically amplify a
portion of each gene simultaneously. The specific amplicons are detected in
real-time by fluorescently-labeled oligonucleotide probes. The gene-specific
oligonucleotide probes are each labeled with a different fluorescent label
(FAM, JOE, or TET), and the fluorescent emission is captured during PCR
cycling by the 7700 instrument. After analysis of the raw fluorescent data by
the Sequence Detection Software, a threshold cycle (Ct), which represents the
PCR cycle at which an increase in reporter fluorescence above a baseline
signal can first be detected, is determined. Each gene-specific assay
(i.e., gene-specific dye layer) is considered positive if the Ct is <45 cycles. A
gene-specific assay is considered negative if the Ct = 45. A sample is called
positive when 2 or 3 genes are positive (Ct <45 cycles) or when the same
single gene scores positive (Ct<45 cycles) on consecutive tests.

b. Quantitative PCR Assays

The following procedures will be done at MRL, West Point, PA or a central


laboratory designated by the SPONSOR. Swabs are received and prepared for
PCR using a DNA purification method (Qiagen Technology Kit). Samples
previously determined to be positive by multiplex PCR (see above) may be
further analyzed using HPV type-specific primers based on the HPV E7 genes
only (see above) to determine the HPV genome copy number. Copy number
determination is by standard curve using qualified plasmid standards for the
HPV E7 genes.

c. Type-Specific PCR to Detect High-Risk HPV Types Other Than Vaccine


Types

PCR assays to determine HPV in biopsy Thinsections will be performed at a


central laboratory designated by the SPONSOR or at MRL, West Point, PA.
Thinsections are prepared for PCR using a DNA purification method (Qiagen
Technology Kit). HPV 16, 18 Multiplex PCR (see above) will then be
performed on a fraction of the DNA prepared from each Thinsection to
determine the HPV type in the Thinsection. Thinsections positive by HPV
multiplex PCR for HPV 16, 18 may be further analyzed by HPV type-specific
primers based on the HPV E7 genes only to quantify viral load (see above).
Thinsections negative by HPV multiplex PCR for HPV 16, 18 will be further
analyzed by type-specific multiplex PCR assays for HPV types 31, 45, 52, and
58. For description of multiplex assays see Section I.F.4.a. For samples

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negative for HPV 16, 18, 31, 45, 52, and 58 further analysis will be done
using biplex HPV PCR assays to detect additional high-risk HPV types,
namely HPV 33, 35, 59, 68. 56, 51, and 55. Biplex assays for the additional
types are essentially the same assays as multiplex PCR assays (see above
section a), but will only detect the HPV E6 and E7 genes.

5. Preparation and Disposition of Thinsections of Biopsy Tissue

The following procedures will be performed at a central laboratory designated by


the SPONSOR. The procedures will be performed by an experienced, qualified
histotechnologist according to the central laboratorys SOP. The histotechnologist
will assure that the microtome and work areas are clean and free of contaminants.
All Thinsection microtomy for PCR will be performed at a time when all other
routine work has been completed, so potential contaminations can be minimized.
Prior to sectioning each block, a new blade will be installed in the microtome.
The blade will only be positioned so that it is at the left margin of the block
surface. Technicians sectioning study blocks will utilize biologically clean
gloves while handling the blocks (new gloves for each block). First, the
histotechnologist will face the block by removing two 4-micron sections from the
face of the block. These sections will be discarded. Using sterile plastic forceps,
the next two 4-micron paraffin sections (proximal end) are collected and floated
in a water bath for the preparation of 1 H&E slide (Slide 1, with 2 sections).

The forceps are discarded and a new blade is inserted into the microtome. Nine
more 4-micron sections are cut and using the clean, central part of the microtome
blade. Each section is then placed with a new pair of sterile plastic forceps (new
forceps per tube) in an individual sterile labeled tube and the cap is replaced.

There will be 9 individual tubes (Tube 1, 2, 3, 4, 5, 6, 7, 8, 9), each containing one


4-micron section. The pair of sterile plastic forceps used each time is then
discarded after placing the cut section in each tube. Each tube is then place inside
a plastic sleeve and sealed.

Slides and tubes will be labeled with subjects allocation number. The specimen
tubes are collated with the appropriate specimen requisition and prepared for
shipping to Covance Central Laboratory and then in turn, shipped on to MRL.

Two additional 4-micron sections (distal end) are cut and placed on 1 slide
(Slide 2, with 2 sections) for H&E staining. Both H&E slides (Slides 1 and 2)
will have a histopathologic review by the central laboratory's pathologist.

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The microtome is cleaned in preparation for the next block and the process above
is repeated. The microtome blade is replaced with a new blade and adjusted for
each new biopsy block and the same procedure is to be followed. A new pair of
clean gloves and a new pair of clean, disposable forceps will be used for each
block being sectioned. The used blade may be retained for cutting non-PCR
blocks. The total number of sections to be cut from each block is 13. A total of
2 slides and 9 tubes:

Slides 1, 2 (H&E), with 2 sections each, stained.

Tubes 1, 2, 3, 4, 5, 6, 7, 8, 9 (HPV PCR Analysis), 1 section per tube.

6. Blinding of HPV PCR Results

The subjects and investigators will be blinded to individual results of Merck's


type specific HPV PCR assay (both on routine visits and on biopsy Thinsections)
until the end of the study (after study data are cleaned and audited for the final
analysis of the study). The clinical, statistical, and data management personnel at
the SPONSOR will be blinded to the PCR results until the study data are cleaned
and audited for the interim analysis if the interim analysis meets the primary
statistical criterion for success or until the study data are cleaned and audited for
the final analysis otherwise. The rationale for this blinding is as follows:

The primary analysis of a Phase II study has demonstrated that administration


of a 3-dose regimen of HPV 16 L1 VLP vaccine substantially reduced the
incidence of new HPV 16 infection (defined as detection of HPV 16 DNA in
cervicovaginal specimens obtained on at least 2 consecutive visits) during an
18-month period following the completion of the vaccination regimen.
Although quite encouraging, these results have some limitations (small
numbers, only 1 HPV type evaluated, short duration of follow-up, insufficient
sample size to evaluate whether reductions in infection were accompanied by
reductions in clinical HPV disease).

However, assuming the quadrivalent HPV (types 6, 11, 16, 18) L1 VLP
vaccine is similarly effective, and this efficacy persists for the duration of the
FUTURE II study, then notification of sites and subjects of development of
new HPV 6, 11, 16, or 18 infection will represent a de facto unblinding of
study subjects. Such an unblinding is incompatible with a Phase III study
design.

The safety of subjects or their sexual partners will not be compromised by the
delay in notification, as follows:

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F. EFFICACY AND IMMUNOGENICITY MEASUREMENTS (CONT.)


Subject Safety

Mercks type-specific HPV 6, 11, 16, and 18 PCR assays are experimental. The
prognostic significance of these assays with regards to cervical cancer has not
been defined. The assays have not been approved for use in triage of subjects
with normal, borderline, or abnormal Pap test to colposcopy.

Subjects are already receiving intensive, state of the art cervical cancer screening
using the most sensitive techniques currently available, including generic (non
type-specific) HPV testing using the DIGENE Hybrid Capture II Assay, which
is an FDA-approved assay for the risk stratification of ASC-US Pap tests. In
addition, the protocol has a low threshold for referral of subjects to colposcopy.

Notification of Partners

One potential use of HPV testing is to notify subjects of their HPV status so that
they can alert their sexual partners. The results of the Hybrid Capture II testing
will be given to subjects in HPV positive/negative format. Although the results of
the type-specific HPV test will not be shared with subjects, overall HPV status is
provided directly or indirectly by the results of cytologic testing through other
means. HPV is detected in nearly 100% of subjects with a Pap diagnosis of LSIL
and HSIL. Since a Pap diagnosis of ASC-US triggers reflex Hybrid Capture II
testing, HPV status will be provided even to subjects who are diagnosed with
ASC-US. Thus, women who develop lesions can notify their partners that they
have changes consistent with HPV infection.

7. Unblinding Treatment AssignmentInterim Analysis

Vaccination of subjects who were randomized to the placebo arm will not be
offered until the mandated protocol follow-up has been completed and the final
efficacy analysis is fully accomplished. While the interim analysis may reveal
vaccine efficacy, the continuation of the protocol will allow for a better
assessment of the duration of the vaccine efficacy. In addition, the protocols full
duration of follow-up will allow for an assessment of the vaccine impact on the
overall incidence of CIN 2/3 and for a more reliable distinction between a delay
on the establishment of high grade lesions and the actual prevention of their
occurrence. Subject safety will not be jeopardized by delaying vaccination
because the protocol screening procedures and the referral to colposcopy follow
the highest standards of clinical practice.

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G. SAFETY MEASUREMENTS
1. All Subjects

All subjects will be followed for the reporting of serious adverse experiences from
the time the consent is signed through 14 days following the first vaccination and
from the time of any subsequent vaccination(s) through 14 days thereafter, and
such events will be recorded at each examination on the Adverse Experience Case
Report Forms. Additionally, any serious adverse experience brought to the
attention of the investigator at any time outside the 14 day reporting period must
be reported if the event is either a death which resulted in the subject
discontinuing the study, a SAE that is considered to be vaccine related, or a SAE
that is considered to be related to a study procedure. Serious adverse experiences
will be collected as described in Section I.G.4.a.

All subjects will be observed for at least 30 minutes following each vaccination
for any immediate reaction, with particular attention to any evidence of allergic
phenomena.

At Months 2, 6, 7, and all subsequent visits, subjects will be questioned for any
gynecologic health concerns and any serious AEs that may have occurred.

2. For Subjects Participating in the NSAE Substudy

Subjects participating in the NSAE substudy (n=1150) will be evaluated for all
Adverse Experiences (AEs) during the 14-day period after each dose. At each
vaccination visit, the subject will receive a Vaccination Report Card (VRC).
They will receive instructions for recording any adverse events during the 14-day
postvaccination period of follow-up. All local (i.e., injection-site) and systemic
reactions will be recorded regardless of severity. They will also receive a digital
thermometer which is intended only for the subject in the study. After each
vaccination, the subject will be asked to take and record their temperature 4 to
6 hours later, and then daily at approximately the same time each day for 4 days.
The preferred method for taking temperatures will be oral. For the purposes of
this study, fever is considered an adverse experience if it is 37.8C (100F)
oral. If a subject does not record an actual temperature, but reports a feverish
feeling, this will be documented as an adverse experience on the appropriate case
report form.

The VRC should be reviewed for completeness by the study site personnel at the
Month 2 visit, and the Month 7 visit or by phone if the VRC was mailed back to
the site and no timely visit is scheduled. All comments are to be reviewed by the
study personnel and discussed with the participant for clarification if necessary.
The information on the VRC should be generated only by the subject and is to be

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G. SAFETY MEASUREMENTS (CONT.)


signed and dated by the subject to confirm the accuracy of the recorded
information. Original information recorded by the participant should never be
altered by study personnel. Any information gained by phone contact with the
subject should be clearly documented, initialed, and dated on the subject
workbooklet or source documentation, other than the VRC. Discrepancies
between information obtained during the telephone contact and the VRC need to
be resolved; however, information on the VRC will be accepted over the
telephone contact in the event that discrepancies cannot be resolved.

3. Evaluating and Recording Adverse Experiences

An adverse experience is defined as any unfavorable and unintended change in


the structure, function, or chemistry of the body temporally associated with the
use of the SPONSORS product, whether or not considered related to the use of
the product. Any worsening (i.e., any clinically significant adverse change in
frequency and/or intensity) of a preexisting condition which is temporally
associated with the use of the SPONSORS product, is also an adverse experience.

Changes resulting from normal growth and development which do not vary
significantly in frequency or severity from expected levels are not to be
considered adverse experiences. Examples of this may include, but are not
limited to, teething, typical crying in infants and children, and onset of menses or
menopause occurring at a physiologically appropriate time.

The investigator will evaluate all adverse experiences as to:

Maximum intensity:

For adult trials (13 years of age.)

Mild is awareness of sign or symptom, but easily tolerated;

Moderate is discomfort enough to cause interference with usual activity;

Severe is incapacitating with inability to work or do usual activity.

Injection site redness or swelling beginning from the day of vaccination


through Day 4 postvaccination will be evaluated by maximum size.

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G. SAFETY MEASUREMENTS (CONT.)


Seriousness:

A serious adverse experience is any adverse experience occurring at any dose


that:

Results in death; or

Is life threatening (places the subject, in the view of the investigator, at


immediate risk of death from the experience as it occurred [Note: This
does not include an adverse experience that, had it occurred in a more
severe form, might have caused death.]); or

Results in a persistent or significant disability/incapacity (substantial


disruption of ones ability to conduct normal life functions); or

Results in or prolongs an existing inpatient hospitalization (hospitalization


is defined as an inpatient admission, regardless of length of stay, even if
the hospitalization is a precautionary measure for continued observation)
(Note: Hospitalization [including hospitalization for an elective
procedure] for a preexisting condition which has not worsened does not
constitute a serious adverse experience.); or

Is a congenital anomaly/birth defect (in offspring of subject taking the


product regardless of time to diagnosis); or

Is a cancer; or

Is the result of an overdose (whether accidental or intentional).

ALSO:

Other important medical events that may not result in death, not be life
threatening, or not require hospitalization may be considered a serious adverse
experience when, based upon appropriate medical judgment, the event may
jeopardize the subject and may require medical or surgical intervention to
prevent one of the outcomes listed previously (designated above by a ).

Duration:

Record the start and stop dates of the adverse experience. If less than 1 day,
indicate the appropriate length of time and units.

Action taken (Did the adverse experience cause the test vaccine to be
discontinued?); and

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G. SAFETY MEASUREMENTS (CONT.)


Relationship to test vaccine (Did the test vaccine cause the adverse
experience?):

The determination of the likelihood that the test vaccine caused the adverse
experience will be provided by the investigator. The investigators
signed/dated initials and date on the source document or worksheet, that
supports the causality noted on the AE form, ensures that a medically
qualified assessment of causality was done. This initialed document must be
retained for the required regulatory time frame. The criteria below are
intended as reference guidelines to assist the investigator in assessing the
likelihood of a relationship between the test vaccine and the adverse
experience based upon the available information.

The following components are to be used to assess this relationship; the


greater the correlation with the components and their respective elements (in
number and/or intensity), the more likely the test vaccine caused the adverse
experience (AE):

Exposure:
Is there evidence that the subject was actually exposed to the test vaccine
such as: reliable history, acceptable compliance assessment (e.g., diary),
seroconversion or identification of vaccine virus in bodily specimen?

Time Course:
Did the AE follow in a reasonable temporal sequence from administration
of the test vaccine?

Is the time of onset of the AE compatible with a vaccine-induced effect?

Likely Cause:
Is the AE not reasonably explained by another etiology such as underlying
disease, other vaccine(s), or other host or environmental factors?

Rechallenge:
Was the subject re-exposed to the test vaccine in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge.
If no, this is a negative rechallenge.

(Note: This criterion is not applicable if: (1) the initial AE resulted in
death or permanent disability, or (2) the study is a single-dose drug study
or a single-dose vaccine study.)

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G. SAFETY MEASUREMENTS (CONT.)


NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE
EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN
CAUSED BY THE TEST VACCINE, OR IF REEXPOSURE TO THE
TEST VACCINE POSES ADDITIONAL POTENTIAL SIGNIFICANT
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE
APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AND
THE INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL
REVIEW BOARD.

Consistency With Test Study Vaccine Profile:


Is the clinical/pathological presentation of the AE consistent with previous
knowledge regarding the test vaccine or vaccine class pharmacology or
toxicology?

The assessment of relationship will be reported on the case report forms


by the investigator according to his/her best clinical judgment, including
consideration of the above elements. Use the following scale of criteria as
guidance (not all criteria must be present to be indicative of a vaccine
relationship):

Definitely related to test vaccine:


There is evidence of exposure to the test vaccine.
The temporal sequence of the AE onset relative to administration of the
test vaccine is reasonable.
The AE is more likely explained by the test vaccine than by another cause.
Rechallenge (if feasible) is positive.
The AE shows a pattern consistent with previous knowledge of the test
vaccine or test vaccine class.

Probably related to test vaccine:


There is evidence of exposure to the test vaccine.
The temporal sequence of the AE onset relative to administration of the
test vaccine is reasonable.
The AE is more likely explained by the test vaccine than by another cause.

Possibly related to test vaccine:


There is evidence of exposure to the test vaccine.
The temporal sequence of the AE onset relative to administration of the
test vaccine is reasonable.
The AE could have been due to another equally likely cause.

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G. SAFETY MEASUREMENTS (CONT.)


Probably not related to test vaccine:
There is evidence of exposure to the test vaccine.
There is another more likely cause of the AE.
Rechallenge (if performed) is negative or ambiguous.

Definitely not related to test vaccine:


The subject did not receive the test vaccine.

OR

Temporal sequence of the AE onset relative to administration of the test


vaccine is not reasonable.

OR

There is another obvious cause of the AE.

4. Immediate Reporting of Adverse Experiences to the SPONSOR

a. Serious Adverse Experiences

ANY SERIOUS ADVERSE EXPERIENCE, INCLUDING DEATH DUE TO


ANY CAUSE, WHICH OCCURS TO ANY SUBJECT FROM THE TIME
THE CONSENT IS SIGNED THROUGH 14 DAYS FOLLOWING THE
FIRST VACCINATION(S) AND FROM THE TIME OF ANY
SUBSEQUENT VACCINATION(S) THROUGH 14 DAYS
THEREAFTER, WHETHER OR NOT RELATED TO THE
INVESTIGATIONAL PRODUCT, MUST BE REPORTED WITHIN
24 HOURS TO ONE OF THE INDIVIDUAL(S) LISTED ON THE
SPONSOR CONTACT INFORMATION PAGE.

ADDITIONALLY, ANY SERIOUS ADVERSE EXPERIENCE BROUGHT


TO THE ATTENTION OF THE INVESTIGATOR AT ANY TIME
OUTSIDE OF THE TIME PERIOD SPECIFIED IN THE PREVIOUS
PARAGRAPH ALSO MUST BE REPORTED IMMEDIATELY TO ONE
OF THE INDIVIDUALS LISTED ON THE SPONSOR CONTACT
INFORMATION PAGE IF THE EVENT IS EITHER:

1. A DEATH WHICH RESULTED IN THE SUBJECT DISCONTINUING


THE STUDY

OR

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G. SAFETY MEASUREMENTS (CONT.)


2. A SERIOUS ADVERSE EXPERIENCE THAT IS CONSIDERED BY
THE INVESTIGATOR TO BE POSSIBLY, PROBABLY, OR
DEFINITELY VACCINE RELATED.

OR

3. A SERIOUS ADVERSE EXPERIENCE THAT IS CONSIDERED BY


THE INVESTIGATOR TO BE POSSIBLY, PROBABLY, OR
DEFINITELY RELATED TO A STUDY PROCEDURE.

ALL SUBJECTS WITH SERIOUS ADVERSE EXPERIENCES MUST BE


FOLLOWED UP FOR OUTCOME.

b. Selected Nonserious Adverse Experiences

Although not considered an adverse experience, it is the responsibility of


investigators or their designees to report any pregnancy in a subject
(spontaneously reported to them, or detected by urine or serum pregnancy test
per protocol) that occurs during the study to the SPONSOR. After
randomization, all pregnancies through Study Month 7 (including
discontinued subjects) will be followed to the completion/termination of the
pregnancy. If the pregnancy continues to term, the outcome (health of infant)
must be reported to one of the individuals listed on the SPONSOR Contact
Information page. (See Appendix 1, Pregnancy Reporting and Follow-up
HPV Vaccine Clinical Program.)

5. Development of a Serious Medical Condition of Special Interest

If at any time during the course of the study the subject should develop a serious
medical condition that meets the criteria for serious adverse experiences as
previously defined in Section I.G.3., the SPONSOR will be granted access to the
subject's medical records for a review of these, after a release of medical
information form is signed by the subject, or the subject's guardian in the case of a
minor. The decision to review the subject's medical record is left at the discretion
of the SPONSOR.

H. STUDY DURATION AND SUBMISSION OF DATA


For each subject enrolled, the duration of the study will be ~4 years. Enrollment is
expected to be completed within 1 year after the first subject is enrolled at the first
site. If a subject requests to discontinue/withdraw prior to the end of the study, the
subject should be asked to return for a final visit if it has been at least 4 months since
the last visit that included a pelvic exam. The visit should not be done

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H. STUDY DURATION AND SUBMISSION OF DATA (CONT.)


if it is medically contraindicated or if the subject refuses. This visit would consist of
the same exams, specimen collection, and tests conducted at the Month 48 visit. The
subject would be discontinued from the study at the end of this final visit. Results of
the study may become available while the study is ongoing. Even if the vaccine is
found to be effective, the study will continue to its conclusion (when all subjects have
completed 4 years of evaluation). At the time that these early results become
available, neither the subject nor the investigator will be unblinded to the subjects
treatment group.

For the purposes of subject accounting for the primary analyses, subjects will be
regarded as having completed the consistency lot substudy if they have completed the
full vaccination regimen (3 doses) and they have completed the follow-up visit at
Month 7. Subjects will be regarded as having completed the NSAE substudy if they
have received the full vaccination regimen (3 doses) and returned its corresponding
vaccination report card. Subjects will be regarded as having completed the efficacy
study if they have completed the full vaccination regimen (3 doses) and they have
completed follow-up visits through the time at which the required numbers of cases
of the primary efficacy endpoints are observed, or when the 48-month visit is
completed, which ever comes first (unless an abnormal ThinPrep Pap test at
48 months requires additional visits).

Once the final efficacy data are unblinded (i.e., all subjects have completed
Month 48), subjects randomized to receive the quadrivalent HPV vaccine-matched
placebo will be eligible to receive active quadrivalent HPV vaccine under a separate
protocol if vaccine efficacy is demonstrated. Participation is this protocol will be
voluntary and subject to a separate informed consent. The decision to vaccinate
placebo subjects after the final analysis of the protocol will be made in conjunction
with the recommendation of the Data Safety Monitoring Board.

Subjects enrolled at certain sites (in countries where appropriate infrastructure exists)
will also be offered enrollment in a separate study to determine the long-term efficacy
of the vaccine. Participation in this study will be voluntary.

Subject Relocation

Given the duration of the study and the age of the study population, it can be expected
that subjects may temporarily or permanently relocate during the study. The
SPONSOR must be contacted for each temporary (>4 months) and permanent
relocation as soon as the situation is known. Every effort should be made to adjust
study visits around a subjects temporary absence (college breaks, summer vacations).
Every effort should be made to have a permanently or temporarily relocated subject
seen at another site participating in this study so they can remain in the study.

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I. DATA ANALYSIS
1. Responsibility for Analyses/In-House Blinding

The data collected under this protocol will be analyzed by the Vaccine Clinical
Biostatistics Department of the SPONSOR. This study will be double-blinded
and will operate under in-house blinding procedures. There will be a data and
safety monitoring board (DSMB). An unblinded statistician at the SPONSOR
who is unrelated to this protocol will serve as a member of the DSMB and will be
responsible for conducting the interim analysis and for presenting the interim
results to the rest of the DSMB.

Although the study is operating under in-house blinding procedures, if the study
meets its criterion for success at the interim time point, a regulatory package for
the Quadrivalent HPV (Types 6, 11, 16 and 18) L1 VLP vaccine will be submitted
to regulatory authorities for review. At this time, the clinical, statistical and data
management personnel assigned to the HPV vaccine project at the SPONSOR
will most likely have access to the individual treatment assignments of the
subjects in the study. The remainder of the study will be considered an extension,
the purpose of which will be to collect data on the longer-term efficacy of the
vaccine with respect to the primary endpoint and to allow a sufficient number of
cases to accrue across all of the Phase III studies for a combined analysis of these
studies addressing the efficacy of the vaccine in reducing all CIN 2/3 or cervical
cancer.

It is important to note that for the efficacy phase and the extension phase of the
study, laboratory personnel, the pathology panel, and the investigators, site
personnel and subjects will remain blinded to whether subjects received the
quadrivalent HPV vaccine or the quadrivalent vaccine-matched placebo
throughout the entire study period (~4 years). The data collected which impact
ascertainment of efficacy endpoints are the following: (1) Pap tests, which are
read by a central laboratory; (2) the biopsy samples, which are read by the
pathology panel; and (3) the PCR test results, which are provided by a blinded
laboratory. Therefore, all investigators and technicians who have the entire
responsibility for the ascertainment and confirmation of efficacy endpoints will be
blinded for the duration of the entire study.

If the interim analysis results do not meet the primary statistical criterion for
success, the submission of a regulatory package will be delayed until the final
results for this study are available, and the study will remain in-house blinded at
the SPONSOR for its duration.

Regardless of the timing of the submission, the official clinical database will not
be unblinded for the submission until medical/scientific review has been
completed, protocol violators have been identified, and data have been declared
complete.

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I. DATA ANALYSIS (CONT.)


If, after the study has begun, changes are made to the statistical analysis plan
stated below, then these deviations to the plan will be listed, along with an
explanation as to why they occurred, in the Data Analysis Plan and/or the Clinical
Study Report for the study, as appropriate.

2. Hypotheses

Primary

Safety

The quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine is generally well
tolerated in 16- to 23-year-old females.

Efficacy Study

Administration of a 3-dose regimen of quadrivalent HPV (Types 6, 11, 16, 18) L1


VLP vaccine reduces the incidence of the composite endpoint of HPV 16- or HPV
18-related CIN 2/3 or invasive cervical carcinoma compared with placebo in
subjects who are PCR negative and seronegative at baseline and PCR negative
1 month after completion of the vaccination series for the relevant HPV type.
(The statistical criterion for success requires that the lower bound of the
confidence interval for the vaccine efficacy exclude 0%.)

Consistency Lot Substudy

a. Three separate lots of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP
vaccine induce similar immune responses, as measured by the percentage of
subjects who achieve serum anti-HPV 6 200 mMU/mL, anti-HPV 11
200 mMU/mL, anti-HPV 16 200 mMU/mL, and anti-HPV 18
200 mMU/mL, at Week 4 Postdose 3. (Each vaccine component will be
analyzed separately. The statistical criterion for similarity requires that the
upper bound of the confidence interval for the maximum absolute difference in
proportions between any 2 of the 3 lots exclude 10 percentage points or more
for each HPV type.)

b. Three separate lots of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP
vaccine induce similar immune responses, as measured by the serum
geometric mean titers (GMTs) to HPV 6, 11, 16, and 18, at Week 4
Postdose 3. (Each vaccine component will be analyzed separately. The
statistical criterion for consistency requires that the upper bound of the
confidence interval for the fold-difference in GMTs between any 2 lots exclude
a fold-difference of 2 or greater for each HPV type.)

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I. DATA ANALYSIS (CONT.)


3. Variables and Time Points

Safety/Tolerability

The primary variables of interest for safety/tolerability are serious vaccine-related


adverse experiences, if any occur, and severe, injection-site reactions. Unless
they are considered serious adverse events, reports of injection-site reactions will
only be collected from subjects participating in the nonserious adverse experience
substudy.

Efficacy

The primary variable of interest for efficacy is the combined incidence of HPV
16-related CIN 2/3 or worse and HPV 18-related CIN 2/3 or worse. This
endpoint will occur if on any single biopsy, ECC or LEEP/conization tissue
block, the following occur:

Pathology panel consensus diagnosis of: CIN 2, CIN 3 (including squamous


carcinoma in situ), adenocarcinoma in situ, invasive squamous cervical
carcinoma, or invasive adenocarcinoma of the cervix,

AND

Detection of HPV 16 and/or HPV 18 by biopsy Thinsection PCR in an


adjacent section from the same biopsy block.

Of secondary interest are the incidence of colposcopic biopsy and definitive


excisional cervical procedures (LEEP, laser conization, cold-knife conization)
performed due to HPV 16- and 18-related cervical disease and the overall
incidence of ALL CIN 2/3 and invasive cervical cancer (caused by any vaccine or
non-vaccine HPV type).

Immunogenicity (Consistency Lot Substudy)

For immunogenicity, the following endpoints are of primary interest: (1) the
percentage of subjects who achieve anti-HPV 6 200 mMU/mL, anti-HPV 11
200 mMU/mL, anti-HPV 16 200 mMU/mL, and anti-HPV 18 200 mMU/mL
at Week 4 Postdose 3, and (2) the GMTs to HPV 6, 11, 16 and 18 at Week 4
Postdose 3. Of secondary interest are the GMTs to HPV 6, 11, 16 and 18 at
Months 12, 24, 36, and 48. These variables will be measured only in the subjects
participating in the consistency lot substudy.

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I. DATA ANALYSIS (CONT.)


4. Approach to Analyses

The efficacy study employs a fixed event design, whereby the interim and final
analyses of the primary efficacy hypothesis are scheduled to be conducted at the
time that specific target numbers of cases of the primary endpoint have been
observed.

Primary Efficacy Hypothesis: The primary approach to the analysis of efficacy


will be per-protocol. To be included in the primary efficacy evaluation, subjects
must: (1) be seronegative to HPV 16 or 18 by RIA on Day 1 and PCR negative
for the same HPV type from Day 1 through Month 7, (2) complete the vaccination
regimen, (3) not fail on any of exclusion criteria (a)-(c) or (g)-(i) (Protocol
Section I.D.2.), and (4) not engage in sexual intercourse within 48 hours prior to
the Day 1 or Month 7 visit. A listing of the subjects excluded from the primary
efficacy analysis will be provided which will note subject demographics and the
reason excluded.

Several supporting modified intent-to-treat (MITT) analyses will also be


performed. The first MITT analysis will include all subjects who are seronegative
and PCR negative at baseline to the appropriate HPV types, who receive at least
1 dose of Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine or placebo,
and who have any follow-up visit after 1 month following the first injection. The
second MITT analysis will include all subjects who receive at least 1 dose of
Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine or placebo and who
have any follow-up visit following Month 7, regardless of initial serology and
PCR status. Finally, the third MITT analysis will include all subjects who are
seronegative at enrollment and PCR negative at enrollment through Month 7 to
the appropriate HPV types, who receive all 3 vaccinations, and who have any
follow-up visit following Month 7. The primary difference between this
population and the per-protocol population is the inclusion of general protocol
violators.

Primary Immunogenicity Hypotheses (Consistency Lot Substudy): The primary


approach to the analyses of immunogenicity will be per-protocol as well. For the
immunogenicity evaluation, each vaccine component will be analyzed separately.
To be included in the primary immunogenicity analysis for the HPV 6 and HPV
11 components, subjects must be seronegative by RIA to HPV 6 and 11 at Day 1
and must be PCR-negative to HPV 6 and 11 Day 1 through Month 7. To be
included in the primary immunogenicity analysis for the HPV 16 and HPV 18
components, subjects are only required to be seronegative by RIA at Day 1 and
PCR-negative Day 1 through Month 7 for the component being analyzed. In
addition, subjects must receive all 3 doses of the correct clinical material within

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I. DATA ANALYSIS (CONT.)


acceptable day ranges (to be defined in the Data Analysis Plan), must have at least
1 valid serology result Postdose 3 within acceptable day ranges, must not fail on
any of exclusion criteria (a)-(c) or (g)-(i) (Protocol Section I.D.2.), and must not
engage in sexual intercourse within 48 hours prior to the Day 1 or Month 7 visit.

Primary Safety Hypothesis: All subjects who received at least one injection and
have follow-up data will be included in the assessment of serious adverse events.
All subjects in the nonserious adverse event substudy who received at least one
injection and have follow-up data will be included in the more comprehensive
safety summary.

5. Statistical Methods

Primary Hypotheses

Safety: The incidence of adverse events (Days 1 to 14) and incidence of elevated
temperatures (Days 1 to 4) will be summarized by treatment group after each
injection and after any injection. The incidence of injection-site reactions and
systemic AEs will be summarized by treatment group (vaccine or placebo) as
well. Safety will also be summarized both separately and combined for subjects
who are baseline: (1) seronegative and PCR negative, (2) seropositive and PCR
negative, (3) seronegative and PCR positive, and (4) seropositive and PCR
positive.

Efficacy: Vaccine efficacy is defined as VE =1 - (rv/rp), where, rv = # of


cases/person-years of follow-up in the vaccine group, and rp = # of cases/person-
years of follow-up in the placebo group. The null hypothesis of the vaccine
efficacy = 0 will be tested by constructing a two-sided exact confidence interval
for the vaccine efficacy.

Under the assumption that rv and rp are independent Poisson means, the number of
cases in the vaccine group Cv, given the total number of cases observed Cv+p, is
binomially distributed with = rv/( rv + rp), where is the proportion of cases in
the vaccine group. The lower bound of the 100*(1-)% exact confidence interval
for can be calculated by searching for the L such that the probability of
observing Cv or more vaccine cases out of Cv+p total cases is /2. The upper
bound of the exact confidence interval for can be calculated by searching for U
such that the probability of observing Cv or less vaccine cases out of Cv+p total
cases is /2. The exact confidence interval for vaccine efficacy will then have
lower bound VEL = (1-2* U)/(1- U) and upper bound VEU = (1-2* L)/(1- L). In
the event that there is unequal follow-up between groups, the following formulas
will be used: lower bound VEL = (1- U/k)/(1- U) and upper bound VEU =
(1- L/k)/(1- L), where k= Follow-Up in Vaccine Group/Total Follow-Up.

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I. DATA ANALYSIS (CONT.)


Immunogenicity (Consistency Lot Substudy): The first primary immunogenicity
hypothesis, regarding consistency of the 3 lots of quadrivalent HPV vaccine with
respect to the percentage of subjects who achieve anti-HPV 6 200 mMU/mL,
anti-HPV 11 200 mMU/mL, anti-HPV 16 200 mMU/mL, and anti-HPV 18
200 mMU/mL at Week 4 Postdose 3, will be addressed by 3 pairwise
comparisons for each HPV type (12 comparisons in total). Within each HPV
type, each pairwise comparison will test the equivalence of the 2 lots (within
10 percentage points) using 2 one-sided tests at the 0.05 level. This criterion
requires that the two-sided 90% confidence interval for the difference in rates be
entirely contained within the interval (-10%, 10%). This criterion will ensure that
the upper bound of the confidence interval for the maximum absolute difference
in rates between any 2 of the 3 lots is <10 percentage points.

The second primary immunogenicity hypothesis, regarding consistency of the


3 lots of quadrivalent HPV vaccine with respect to the GMTs to HPV 6, 11, 16,
and 18 at Week 4 Postdose 3, will also be addressed by 3 pairwise comparisons
for each HPV type (12 comparisons total). Each pairwise comparison will test the
equivalence of the 2 lots (within 2-fold) using 2 one-sided tests at the 0.05 level.
This criterion requires that the two-sided 90% confidence interval for the ratio of
GMTs be entirely contained within the interval (0.5, 2.0). An ANOVA model
will be used with a response of log individual titers and fixed effects for study
center and quadrivalent HPV lot.

If equivalence can be established in all 3 pairwise comparisons for each HPV type
and endpoint, the 3 lots will be considered consistent for that HPV type and
endpoint. Equivalence must be established for both endpoints (rates and GMTs)
and for all 4 HPV types for the 3 quadrivalent HPV lots to be considered
consistent. The overall type I error rate for this consistency testing will be
controlled at the 0.05 level.

Additional Endpoints

GMTs and the proportion of subjects with anti-HPV 200 mMU/mL will be
summarized by time point and lot for each HPV type. Graphical displays of the
distribution of titers in each lot of the quadrivalent HPV vaccine will be provided
by HPV type.

The efficacy of the vaccine in reducing the incidence of colposcopic biopsy and
definitive excisional cervical procedures (LEEP, laser conization, cold-knife
conization) performed due to HPV 16- and 18-related disease will be estimated
using the same methodology as that which will be used for the primary efficacy
hypothesis. The efficacy of the vaccine in reducing the overall incidence of ALL
CIN 2/3 and invasive cervical cancer (caused by any vaccine or non-vaccine HPV
type) will also be estimated.

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I. DATA ANALYSIS (CONT.)


To explore the possibility of waning vaccine efficacy over time and/or changing
HPV epidemiology over time, an exploratory analysis to investigate a potentially
waning vaccine effect will be considered. However, with ~29 observed cases of
the primary endpoint at the final analysis, it will be difficult to draw any definitive
conclusions about the changes in vaccine efficacy over time even if a waning
vaccine effect is observed.

Combined Analysis

The data from this protocol will be combined in a prespecified analysis with
efficacy data from Protocols 005, 007, and 013 to obtain a more precise estimate
of the vaccine efficacy in reducing HPV 16- or 18-related CIN 2/3 or worse and
an estimate of the vaccine efficacy in reducing all CIN 2/3 or worse.

6. Multiplicity Considerations

There is only one primary efficacy hypothesis for the study. It will be tested with
an interim analysis at the time that at least 19 endpoint cases have been observed
and at a final analysis when at least 29 endpoint cases have been observed. In
order to control the overall type I error rate for the efficacy study at I=0.05 two-
sided, the I-levels used at the interim and final analyses must be adjusted to
account for the multiple, correlated analyses. The effective I-levels at the interim
and final analyses were computed using the power boundaries of Wang and
Tsiatis [1]. Using an alpha boundary shape of 0.2 (where 0.0 represents the
OBrien-Fleming boundary and 0.5 represents the Pocock boundary), a two-sided
alpha of 0.0204 will be spent at the interim analysis, and a two-sided alpha of
0.0411 will be spent at the final analysis.

There are 2 primary immunogenicity hypotheses for the consistency lot substudy.
However, the success of the substudy requires that consistency be established for
all 4 HPV types with respect to both rates and GMTs, so no multiplicity
adjustment is necessary for the substudy.

The goals of the efficacy study and consistency lot substudy are considered
independent. Therefore, no multiplicity adjustment will be made for the multiple
hypotheses.

Note that no multiplicity adjustments will be made for the treatment group
comparisons of multiple safety endpoints. Caution should be exercised when
interpreting results when the overall type I error is not controlled.

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I. DATA ANALYSIS (CONT.)


7. Sample Sizes and Power Calculations

Efficacy Study

It is expected that ~18% of the subjects enrolled will be HPV 16 seropositive at


Day 1 or PCR positive at Day 1 or Month 7 and that ~18% of the subjects
enrolled will be HPV 18 seropositive at Day 1 or PCR positive at Day 1 or
Month 7. It is also expected that the attrition rate will be ~15% through Month 7
of the study and no more than 5% per year thereafter. Assuming that all subjects
followed beyond Month 7 are eligible to be endpoints, a sample size of 11,500
will provide ~8000 subjects who are eligible to be cases according to the HPV 16-
related disease definition and ~8000 subjects who are eligible to be cases
according to the HPV 18-related disease definition. Since the primary endpoint is
a composite endpoint, any subject who is eligible to be an endpoint according to
the HPV 16-related disease definition, the HPV 18-related disease definition or
both will be included in the population at risk for the primary analysis. Assuming
an ~8% overlap in the number of subjects who are HPV 16 or 18 seropositive at
Day 1 or PCR positive Day 1 through Month 7, the population at risk for the
primary analysis will include ~9000 subjects.

The expected incidence of CIN 2/3 or worse related to HPV Type 16 is 0.76% in
the placebo group over the 41 months after Postdose 3, while the expected
incidence of CIN 2/3 or worse related to HPV Type 18 is 0.15% in the placebo
group over the 41 months after Postdose 3. Assuming that subjects who
discontinue the study are at risk for HPV 16- or 18-related CIN 2/3 or worse for
half of the study, the planned sample size would be expected to yield 29 cases of
HPV 16- or 18-related CIN 2/3 or worse during the study. In order to avoid
problems with imprecise incidence and efficacy estimates, this study will employ
a fixed event design with an interim analysis. The interim analysis will be
conducted at the time that at least 19 cases are observed. The power for the
interim analysis assuming varying true vaccine efficacies is given in Table 8. For
the purpose of the sample size calculations, the true efficacy is assumed to be
80%. This should be a conservative estimate based on Protocol 005 primary
analysis data. If the true vaccine efficacy is slightly higher, 85%, then there will
be 90% power to declare the vaccine efficacious at the interim analysis using a
two-sided =0.0204. If there is equal follow-up in the 2 treatment groups, a 15/4
(placebo/vaccine) case split (73% observed efficacy) will be statistically
significant. The final analysis will be conducted when at least 29 cases are
observed. Table 8 also shows the power for the final analysis assuming varying
true vaccine efficacies. Assuming that the true vaccine efficacy is 80%, there is
95% power to declare the vaccine efficacious at the final analysis with a two-
sided =0.0411. Assuming that there is equal follow-up in the 2 treatment
groups, a 21/8 split (~62% observed efficacy) will be statistically significant.

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I. DATA ANALYSIS (CONT.)


Table 8

Power Sensitivity Analysis

True Vaccine
Analysis -Level Number of Cases Efficacy Power
Interim 0.0204 19 80% 80%
85% 90%
90% 97%
Final 0.0411 29 80% 95%
85% 99%
90% >99%

Consistency Lot Substudy

It is expected that 15, 18, and 18% of the subjects enrolled in the consistency lot
substudy will be seropositive at Day 1 or PCR positive at Day 1 or Month 7 for
HPV Types 6/11, 16, and 18, respectively. In addition, the attrition rate through
Month 7 of the study is assumed to be 15%. Therefore, it is expected that 361
(500 x 0.85 x 0.85) of the 500 subjects randomized to receive each of the
consistency lots will be evaluable for the HPV 6 and 11 endpoints and 348 (500 x
0.82 x 0.85) of the 500 subjects will be evaluable for the HPV 16 and
18 endpoints.

For the first primary immunogenicity hypothesis involving the consistency of the
3 lots with respect to the percentage of subjects who achieve anti-HPV 6
200 mMU/mL, anti-HPV 11 200 mMU/mL, anti-HPV 16 200 mMU/mL, and
anti-HPV 18 200 mMU/mL at Week 4 Postdose 3, the assumed response rate for
each HPV type in each lot is 90%. (The assumed response rate is based on
Protocols 001, 002, 004, and 006). With 361 evaluable subjects for the HPV 6
and 11 endpoints and 348 evaluable subjects for the HPV 16 and 18 endpoints,
this study has 98.3% power to rule out a 10-percentage-point difference in rates
among the 3 lots (=0.05) for each HPV type. Assuming independence of the
4 HPV types, the overall power for the first primary immunogenicity hypothesis
is 93.4%.

For the second primary immunogenicity hypothesis involving the consistency of


the 3 lots of quadrivalent HPV vaccine with respect to GMTs for HPV 6, 11, 16
and 18, the standard deviations of the natural logarithm of Month 7 titers are
assumed to be no more than 1.2 for each HPV type. (The assumed standard

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I. DATA ANALYSIS (CONT.)


deviation is based on Protocols 001, 002, and 004). With 361 evaluable subjects
for the HPV 6 and 11 endpoints and 348 evaluable subjects for the HPV 16 and
18 endpoints, this study has 99.9% power to rule out a 2-fold difference in the
ratio of GMTs (=0.05) for each HPV type. Assuming independence of the
4 HPV types, the overall power for the second primary immunogenicity
hypothesis is 99.6%.

If the 2 primary immunogenicity hypotheses are assumed to be independent, the


overall power for the consistency lot substudy is 93%.

8. Interim Analyses

An interim analysis is planned to be conducted at the time that at least 19 cases of


the primary endpoint have been observed. The purpose of the interim analysis is
to provide an early assessment of the vaccine efficacy with respect to the HPV 16-
or 18-related CIN 2/3 or worse endpoint.

The critical database fields for identifying protocol violators, identifying cases,
and conducting the primary analysis will be identified, and all critical data that are
in-house will be screened prior to the interim analysis. A separate document
outlining the critical data fields and detailed screening plan will be written. The
analysis will be performed by an unblinded statistician unrelated to this study.
The unblinded statistician will provide the results of the analysis to a DSMB. The
DSMB will then communicate to the HPV vaccine project team at the SPONSOR
information regarding whether or not the study met the statistical criterion for
success prespecified in the protocol.

If the study meets the statistical criterion for success at the interim time point, a
regulatory package for the Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP
vaccine will be submitted to regulatory authorities for review at an earlier time
point. The interim data from this study will be the primary efficacy data included
in the submission. This data will also be combined with efficacy data from other
Phase IIb/III protocols to obtain a more precise estimate of the vaccine efficacy
with regard to HPV 16/18-related CIN 2/3 or worse. Should the interim results
from this study trigger a submission for regulatory review, the remainder of the
data in the official clinical database that were collected prior to the interim
analysis will be screened and cleaned. The database will be audited and a copy
will be unblinded and frozen.

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I. DATA ANALYSIS (CONT.)


If the study does not meet the statistical criterion for success at the interim time
point, the SPONSOR will not to proceed with an early submission to regulatory
authorities for review. The results from the interim analysis will remain blinded
to everyone except the designated unblinded statistician, the DSMB, and possibly
a small senior management committee until the end of the study (i.e., until the
complete data have been screened, cleaned and audited for the final analysis). It
may be necessary for the interim analysis results to be provided to a senior
management committee by the designated unblinded statistician to enable
decisions to be made regarding the overall HPV program. The senior
management committee would consist of 4 to 5 members representing Research,
Clinical, Regulatory and Biostatistics. This committee would not make decisions
which would impact the conduct of this study.

The study will continue until at least 29 cases of the primary endpoint are
observed regardless of the outcome of the interim analysis. This will allow for
the collection of longer-term efficacy data. It will also allow additional cases of
CIN 2/3 or worse due to any HPV type to accrue for use in a combined analysis of
Protocols 005, 007, 013 and this study, the purpose of which is to assess the
quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccines impact on all CIN 2/3.

9. Safety Analyses

Safety and tolerability will be assessed by statistical and clinical review of all
safety data collected throughout the study. All subjects who are vaccinated and
who have safety follow-up data will be included in an analysis of serious adverse
experiences. All subjects in the nonserious adverse experience substudy who are
vaccinated and who have safety follow-up data will be included in all of the other
safety analyses and summaries.

To provide an overall assessment of safety from the substudy, measures such as


the incidence of: (1) any adverse experiences, (2) any injection-site adverse
experiences, (3) any systemic adverse experiences, and (4) any vaccine-related
adverse experiences that occurred throughout the study will be summarized.
Adverse experiences will be summarized as frequencies and as percentages by
treatment group by vaccination visit and across all vaccination visits. Risk
differences between recipients of the quadrivalent HPV vaccine and recipients of
the placebo will be estimated for specific adverse experiences within 14 days
postvaccination occurring in at least 1% of the subjects in either treatment group.
Statistical testing will be performed for specific adverse experiences prompted for
on the vaccination report card (VRC). Temperatures Days 1 to 5 following
vaccination will also be summarized.

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I. DATA ANALYSIS (CONT.)


With 5750 subjects in each of the vaccine and placebo groups in this study,
Table 9 provides the differences in adverse experience incidence rates between
the 2 groups that there is an 80% probability of detecting with a two-sided
significance level of 0.05.

Table 9

Differences in Adverse Experience Incidence Rates Between


the Quadrivalent HPV (Types 6, 11, 16, and 18) L1 VLP Vaccine
and Placebo Groups That Can be Detected With ~80%
Probability Using a Two-Sided Significance Level of 0.05
True Incidence Rate of Adverse
Experience in Quadrivalent HPV True Incidence Rate Detectable Percentage
(Types 6, 11, 16 and 18) L1 VLP of Adverse Experience Point Difference in
Vaccine Group (%) in Placebo Group (%) Incidence Rates of
(N=5750) (N=5750) Adverse Experience
0.14 0.01 0.13
0.31 0.1 0.21
1.5 1 0.5
11.5 10 1.5
21.9 20 1.9
32.2 30 2.2

For reference, in past HPV vaccine studies, adverse experiences that have occurred at
a rate of 20 to 30% are erythema and swelling.

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II. ADMINISTRATIVE AND REGULATORY SECTIONS

A. LABELING, PACKAGING, STORAGE, AND RETURN OF


CLINICAL SUPPLIES
1. Standard Policies/Drug Accountability

Investigational clinical supplies must be received by a designated person at the


study site, handled and stored safely and properly, and kept in a secured location
to which only the investigator and designated assistants have access. Clinical
supplies are to be administered only in accordance with the protocol. The
investigator is responsible for keeping accurate records of the clinical supplies
received from the SPONSOR, the amount administered to the subjects, and the
amount remaining at the conclusion of the study. The Clinical Monitor should be
contacted with any questions concerning investigational products where special or
protective handling is indicated. At the end of the study, all unused clinical
supplies must be returned as indicated on the Contact Information page(s). U.S.
sites should follow instructions for the Clinical Supplies Return Form (V464) and
contact your SPONSOR representative for review of shipment and form before
shipping. Sites outside of the United States should check with local country
Merck personnel for appropriate documentation that needs to be completed for
vaccine accountability.

2. Subject and Replacement Supplies Information

Supplies will be packaged for ~11,500 subjects plus overage to account for
replacement supplies. All clinical supplies will be packaged according to a Merck
generated randomized component ID schedule. This study will be conducted
using an Interactive Voice Response System (IVRS) for subject allocation and
clinical supplies inventory management.

3. Product Descriptions

Investigational materials will be provided by MRL as summarized in Table 10.

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A. LABELING, PACKAGING, STORAGE, AND RETURN OF


CLINICAL SUPPLIES (CONT.)
Table 10

Product Description

Product Potency Dosage form Dose Storage


Quadrivalent 40/80/80/40 Sterile Solution 0.5 mL Store refrigerated at
HPV Vaccine mcg/mL for IM Injection 2 to 8C. DO NOT
FREEZE.
Placebo for Placebo Sterile Solution 0.5 mL Store refrigerated at
Quadrivalent for IM Injection 2 to 8C. DO NOT
HPV Vaccine FREEZE.

4. Primary Packaging and Labeling Information

Each vial of Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine or Placebo
will receive a double-panel blinded label containing information similar to the
following: component identification number, control number, storage conditions,
dosage instructions Administer as Per Protocol, cautionary statements as
applicable.

Labels will appear similar to the following:

MERCK RESEARCH LABORATORIES


Component ID# WP-XXXX
Quadrivalent HPV Vaccine / Placebo
0.5-mL Dose for IM Injection
Administer Per Protocol No. 015 Store Refrigerated at 2-8C Do Not Freeze
Caution: New Drug Limited by Federal (U.S.A.) Law to Investigational Use
"WP" numbers are an internal packaging control number.

5. Study Disclosure

The subjects treatment group should only be unblinded in the case of an


emergency. In case of medical emergency, every effort should be made to contact
the SPONSOR. If the SPONSOR cannot be reached, the subjects treatment
group can be unblinded by the investigator by calling the IVRS and entering the
unblinding password in the unblinding option. Any unblinding that occurs at the
site must be documented. A blinded confirmation fax will also be sent to the
SPONSOR if a subject is unblinded through the IVRS.

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A. LABELING, PACKAGING, STORAGE, AND RETURN OF


CLINICAL SUPPLIES (CONT.)
6. Storage Requirements

All vaccine and placebo supplies will be shipped to the sites as a refrigerated
solution to be stored at 2 to 8C (refer to Table 10). A temperature-monitoring
device will be sent with each shipment.

A refrigerator/freezer temperature log must be maintained at the site. The


temperature log will be reviewed by the appropriate SPONSOR representative
throughout the study. An appropriate back up system (i.e., alarm, generator, and
study site personnel telephone numbers) should be in place in the event of a
refrigerator/freezer failure.

7. Distribution

Distribution of clinical supplies will be managed through the IVRS.

Used and unused vaccine/placebo vials should be retained at the site until the
MRA is able to account for all of the vials originally shipped to the sites. After all
of the vials have been accounted for, the used vials may be discarded according to
the procedures of the site. The unused vials should be returned to the SPONSOR
by the MRA at the completion of the study.

8. Site Retention Samples

Retention vials will not be sent to the sites for this study.

B. BIOLOGICAL SPECIMENS
The laboratory that is analyzing any clinical samples should be blinded to the
subject's treatment.

It is the responsibility of the primary investigator to ensure that all staff personnel
who will be handling, packaging, and/or shipping clinical specimens act in
conformance with International Air Transport Association (IATA) regulations
relating to the handling and shipping of hazardous goods.

1. Labeling of Specimens

All specimens shipped to Merck Research Laboratories will be labeled with


preprinted computer-generated labels provided by SPONSOR and SPONSORs
central laboratory. Labels can only be affixed to dry surfaces. However, they can
be used on polypropylene or polyethylene and will survive freezing and thawing.
The labels will contain the following information:

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B. BIOLOGICAL SPECIMENS (CONT.)


a. Protocol and site number
b. Subject allocation number(to be completed by study personnel in waterproof
ink)
c. Subject initials (to be completed by study personnel in waterproof ink)
d. Study day or study month
e. Sample date (to be completed by study personnel in waterproof ink)
f. Sample I.D. (serum, ecto/endocervical swab, etc.)
g. Project number (V501)

Specimens will have allocation numbers on the label.

2. Shipment of Specimens

Properly labeled specimens will be shipped according to instructions summarized


in the SPONSORs central laboratory manual. Inventory forms, tubes for
freezing/shipping specimens, and shipping containers will be provided by the
SPONSORs central laboratory.

C. CLINICAL AND LABORATORY DATA COLLECTION


1. Method of Data Collection

Workbooklets/worksheets will be provided by the SPONSOR to record data in the


clinic. Data on workbooklets/worksheets may be handwritten. For all other
protocol required information that is originally recorded elsewhere (e.g., x-ray,
lab results, diary cards), either a copy will be sent to the SPONSOR directly, or
hand transcribed onto worksheets (as directed by the study procedures). In this
instance, the actual date of an examination (e.g., x-ray, phlebotomy) should be
reported on the worksheets; this may be different from that of the office or clinic
visit. Whenever possible, all information requested on a worksheet should be
completed. If information is not available, it should be documented as such
(e.g., temporarily or permanently missing).

Periodically, a representative of the SPONSOR will review study documents (see


Protocol Section II.D., Study Documentation and Records Retention) to verify
compliance with the protocol. The SPONSOR representative will also review the
accuracy of the data compared to source documents.

After preliminary review of these worksheets by the Investigator/study staff, the


worksheets are entered into a database by SPONSOR personnel. Original
worksheets will remain at the site as source/support documents.

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C. CLINICAL AND LABORATORY DATA COLLECTION (CONT.)


As a result of the SPONSOR data review process, corrections or changes to data
may be required. Discrepancies or questions concerning the data will be sent to
the Investigator. The discrepancy reports should be resolved by the
Investigator/study staff, signed and dated, and a copy returned to the SPONSOR.
The original discrepancy report must be retained in the subject binder as a record
of changes or acknowledgment of the receipt of queries on the data.

Shortly after the last patient visit has been completed and the data have been
entered into the SPONSOR database, the SPONSOR will send a Declaration by
Investigator form (Signature Page) identifying the patient allocation
numbers/visits for the study. The original signed and dated signature page and
label page (if applicable) must be sent to the SPONSOR at the specified address
on the SPONSOR Contact page of the Protocol. A photocopy of the signature
page and label page (if applicable) is retained at the site. After the study data
have been finalized, the SPONSOR will provide a SPONSORS Declaration
and will attach a final, complete copy of the data handling and entry guidelines
used in this study. The worksheets, final data handling and entry guidelines, and
discrepancy forms will serve as the sites record of the final study data and will be
retained at the site along with the source documents.

2. Laboratory Results

All assay results will be entered into the MRL clinical database.

3. Vaccination Report Cards

The subjects participating in the NSAE substudy will be given a vaccination


report card (VRC) on which to record all adverse experiences which occur during
the 14-day period (day of vaccination plus 14 calendar days) after each injection.
All local and systemic reactions will be reported, regardless of severity, as well as
reasons for premature withdrawal from the study, on the appropriate case report
forms. Any elevated temperature (100F or 37.8C oral) will be recorded as an
adverse experience. If a subject does not record an actual temperature, but reports
a feverish feeling, this will be documented as an adverse experience on the
appropriate case report form.

The VRC should be reviewed for completeness by the study site personnel at the
Month 2 visit, the Month 6 visit, and the Month 7 visit or by phone if the VRC
was mailed back to the site and no timely visit is scheduled. All comments are to
be reviewed by the study personnel and discussed with the participant for
clarification if necessary. The information on the VRC should be generated only
by the subject and is to be signed and dated by the subject to confirm the accuracy

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C. CLINICAL AND LABORATORY DATA COLLECTION (CONT.)


of the recorded information. Original information recorded by the participant
should never be altered by study personnel. Any information gained by phone
contact with the subject should be clearly documented, initialed, and dated on the
subject workbooklet or source documentation, other than the VRC. Discrepancies
between information obtained during the telephone contact and the VRC need to
be resolved; however, information on the VRC will be accepted over the
telephone contact in the event that discrepancies cannot be resolved.

D. STUDY DOCUMENTATION AND RECORDS RETENTION


Study documentation includes all case report forms, data correction forms,
workbooks, source documents, monitoring logs and appointment schedules,
SPONSOR-investigator correspondence and regulatory documents (e.g., signed
protocol and amendments, Independent Ethics or Institutional Review Committee
correspondence and approval, approved and signed subject consent forms, Statement
of Investigator form, clinical supplies receipts, and distribution records).

Source documents include all recordings of observations or notations of clinical


activities and all reports and records necessary for the evaluation and reconstruction
of the clinical research study. Accordingly, source documents include, but are not
limited to, laboratory reports, ECG tracings, x-rays, radiologist reports, subject
diaries, biopsy reports, ultrasound photographs, subject progress notes, hospital charts
or pharmacy records and any other similar reports or records of any procedure
performed in accordance with the protocol.

Source documents may also include SPONSOR workbooks, CRFs, or electronic


devices when information is recorded directly onto such forms or devices. The
investigator should identify to the SPONSOR which data will be directly recorded
onto workbooks, CRFs, or electronic devices. A form will be supplied by the
SPONSOR for this identification. This source document identification form should
be maintained in the sites Regulatory Binder. Any document which serves as a
source document (e.g., workbooklet, handwritten CRF, hospital chart, diary,
questionnaire) should be signed or initialled and dated by the individual making the
observation/recording. Counter signatures or initials may be appropriate in certain
cases where medical assessments/observations are made by one individual but
dictated to a third party for recording.

In the event that the workbook or CRF is used as a source document, the
workbook/CRF must be signed and dated by the individual making the entry. The
signature and date are also required if the entry is made by an individual not
identified as a primary investigator or secondary/subinvestigator in the protocol
(e.g., ophthalmologist) or not under the direct supervision of the primary investigator.

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D. STUDY DOCUMENTATION AND RECORDS RETENTION (CONT.)


Whenever possible, the original recording of an observation should be retained as the
source document; however, a photocopy is acceptable provided that it is a clear,
legible, and exact duplication of the original document.

Government agency regulations and directives require that all study documentation
pertaining to the conduct of a clinical trial must be retained by the investigator. They
shall be retained until at least 2 years after the last approval of a marketing
application in an International Conference on Harmonisation (ICH) region. The
SPONSOR will notify the investigator in writing when retention is no longer
necessary.

1. Steering Committee

Responsibility

The Steering Committee consists of specialists in the field of gynecology,


oncology, virology, pathology, epidemiology, and biostatistics. The Steering
Committee provides the overall scientific and operational direction for the trial
through consideration of recommendations from its working committees. The
Steering Committee is responsible for the conduct of the trial according to the
highest scientific and ethical standards, as well as approving revisions and
amendments to the protocol. In addition, the Steering Committee will receive and
decide on any recommendations made by the Data and Safety Monitoring Board
(DSMB) regarding early stopping of the study. The Steering Committee will
remain blinded to results during the course of the study. However, during the
course of the study, the DSMB may elect to unblind some members of the
Steering Committee to certain aspects of the data (see Section II.D.2.
Executive/Advisory Committee). The Steering Committee must approve all
scientific reports concerning the main findings of the trial. The Steering
Committee will meet at least once per year or more frequently if this is in the
interest of the study. Subcommittees of the Steering Committee will include:
Executive/Advisory and Publications.

Membership of the Steering Committee is composed of representatives from the


participating countries in the clinical trial, MRL Clinical Monitors, Lead Medical
Program Coordinator and the Blinded Program Statistician.

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D. STUDY DOCUMENTATION AND RECORDS RETENTION (CONT.)


2. Executive/Advisory Committee

Responsibility

The executive committee decides on practical issues during the conduct of the
trial and reports and advises the Steering Committee. Any action by the
Executive Committee that deviates from the intent of the protocol of the trial
needs approval by the Steering Committee. The Executive Committee will have
regular meetings at intervals of at least once per quarter. The committee
schedules periodic and ad hoc meetings of the Steering Committee.

Membership of the executive committee is composed of the Steering Committee


Chairperson and Co-Chairperson, 2 to 3 investigators, and MRL Clinical
Monitors, Lead Medical Program Coordinator and the Blinded Program
Statistician.

The executive committee meets with the DSMB to discuss any recommendation
for the discontinuation of the study or modification of the protocol, and reports
these recommendations to the Steering Committee. The executive committee
therefore avoids having the entire Steering Committee unblinded when the DSMB
needs to present unblinded information to justify their recommendation.

3. Pathology Panel

Responsibility

The Pathology Panel will be responsible for providing the definitive pathologic
diagnoses of cervical biopsy, endocervical curettage and definitive therapy
specimens for the purpose of determining the presence of endpoints in the study.
Cervical histology slides will be evaluated by this Panel. The committee will
prepare reports on each possible event without information on vaccine allocation
that might identify the subjects study treatment.

A separate Standard Operating Procedure will be written prior to reading of the


first pathology slide for the study. This SOP will be approved by the Panel as
well as the Executive Committee members.

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D. STUDY DOCUMENTATION AND RECORDS RETENTION (CONT.)


4. Data and Safety Monitoring Board

The Data and Safety Monitoring Board (DSMB) assesses the effects of the study
vaccine during the trial and may give advise to the Steering Committee. With the
exception of a non-voting Merck statistician, the members of the committee are
independent of Merck Research Laboratories and clinical investigators
participating in this trial, and will not have any other involvement in the study,
nor will they have any relation to study participants. The board monitors the trial
for evidence of beneficial or adverse effects of the study vaccine using the
guidelines proposed by the protocol. The board may recommend any steps to
ensure the safety and integrity of the trial. Furthermore, it may recommend that
the trial be terminated or that specific high-risk patient groups be withdrawn from
the study, if any subgroup manifests serious or widespread side effects. To
guarantee the unrestricted performance of its task, the board may receive the
individual study morbidity and mortality data from a designated MRL statistician.

Reports of all serious adverse experiences in this study from the MRL Worldwide
Adverse Experience database and the clinical database will be presented to the
committee.

The interim monitoring guidelines that the DSMB will follow will be described in
the Data Analysis Plan, which will be completed before the first interim analysis.
The DSMB minutes will summarize the actions and deliberations of the DSMB
and will be made available to Merck and the Steering Committee at the
conclusion of the trial.

E. INFORMED CONSENT
The investigator must obtain documented consent from each potential subject in
biomedical research or when an investigational vaccine is administered to subjects in
a clinical study. If a Patient Package Insert (PPI) exists for any product being used in
the study within the indication and dosage of the prescribing information, the consent
form will reference the PPI and the investigator shall provide a copy of it to the
subject for his/her review before the subject signs the Informed Consent Form. If the
study is outside of the indication or dosage, the consent form shall include all relevant
information from the PPI but the subject will not be given a copy of the PPI.

Consent must be documented by the subjects dated signature on a Consent Form


along with the dated signature of the person conducting the consent discussion. If
local law does not allow written consent, then oral consent, attested to by the dated
signature of an impartial witness (someone not involved with the conduct of the
study), is the required alternative.

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E. INFORMED CONSENT (CONT.)


If the subject is illiterate, an impartial witness should be present during the entire
informed consent reading and discussion. Afterward, the subject should sign and date
the informed consent, if capable. The impartial witness should also sign and date the
informed consent along with the individual who read and discussed the informed
consent (i.e., study staff personnel).

If the subject is legally incompetent (i.e., a minor or mentally incapacitated), the


written consent of a parent, legal guardian or legal representative must be obtained.
Assent must also be obtained from minors. Depending on local law or review
committee requirements such consent may also need to be signed by an impartial
witness.

The information from the consent form should be translated and communicated to the
subject in language understandable to the subject. When the study subject population
includes non-English speaking people, an accurately translated consent form should
be provided with a written statement by the translator (whether the translator is the
investigator, the Clinical Monitor, or a professional translator), indicating that the
consent form is an accurate translation of the accompanying English version.

A copy of the signed and dated consent form (along with the PPI if appropriate)
should be given to the subject before participation in the trial.

The initial informed consent form and any subsequent revised written informed
consent form, and written information must receive the IRB/IECs approval/favorable
opinion in advance of use. The subject or his/her legally acceptable representative
should be informed in a timely manner if new information becomes available that
may be relevant to the subjects willingness to continue participation in the trial. The
communication of this information should be documented.

A copy of the FDA Regulations Regarding Informed Consent, the World Medical
Association Declaration of Helsinki, and a sample consent form are attached to this
protocol.

F. INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT ETHICS


COMMITTEE (IEC)
For Studies Conducted Under the U.S. IND

The investigator is responsible for obtaining Review Board approval of the protocol,
as well as approval of all subsequent major changes, in compliance with local law.
Copies of these approvals must be forwarded to the SPONSOR. The IRB will
comply with all federal, state, and local laws. Particular attention is drawn to the

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F. INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT


ETHICS COMMITTEE (IEC) (CONT.)
Food and Drug Administration Regulations for Institutional Review Boards (21 CFR,
Part 56), and the International Conference on Harmonisation (ICH) Guidelines for
Good Clinical Practices for IRB/IEC Committees. Copies of relevant information
derived from these guidelines are attached to this protocol. The investigator is
responsible for obtaining initial and continuing review (at intervals not less than once
per year) of the study by an IRB. Written approval from the IRB must be forwarded
to the SPONSOR before clinical supplies will be shipped. For continuing studies,
written approval from the IRB must be sent to the SPONSOR at intervals not to
exceed 1 year.

The investigator shall also obtain from the IRB and submit to the SPONSOR, a
signed statement indicating that it complies with Good Clinical Practices. A sample
IRB Compliance letter is attached to this protocol.

The SPONSOR will promptly be advised of any regulatory inspection (relating to this
study), of either the institution or the IRB. The investigator will promptly provide the
SPONSOR with a copy of any inspection report.

For Studies Not Conducted Under the U.S. IND

The investigator is responsible for obtaining Review Board approval of the protocol,
as well as approval of all subsequent major changes, in compliance with local law.
Copies of these approvals must be forwarded to the SPONSOR. Particular attention
is drawn to the International Conference on Harmonisation (ICH) Guidelines for
Good Clinical Practices for Institutional Review Board/Independent Ethics
Committees, and a copy of the guidelines is attached to this protocol.

The investigator shall also obtain from the IEC and submit to the SPONSOR, a
signed statement indicating that it complies with Good Clinical Practices. A sample
IEC Compliance letter is attached to this protocol.

G. CONFIDENTIALITY
1. Confidentiality of Data

For Studies Conducted Under the U.S. IND

Particular attention is drawn to the regulations promulgated by the Food and Drug
Administration under the Freedom of Information Act providing, in part, that
information furnished to clinical investigators and Institutional Review Boards
will be kept confidential by the Food and Drug Administration only if maintained
in confidence by the clinical investigator and Institutional Review Board.

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G. CONFIDENTIALITY (CONT.)
For All Studies

By signing this protocol, the investigator affirms to the SPONSOR that


information furnished to the investigator by the SPONSOR will be maintained in
confidence and such information will be divulged to the Institutional Review
Board, Ethical Review Committee, 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 Section II.K.,
Publications.

2. Confidentiality of Subject Records

By signing this protocol, the investigator agrees that the SPONSOR (or
SPONSOR representative), Institutional Review Board/Independent Ethics
Committee (IRB/IEC) or Regulatory Agency representatives may consult and/or
copy study documents (see Protocol Section II.D., Study Documentation and
Records Retention) in order to verify case report form data. By signing the
consent form, the subject agrees to this process. If study documents will be
photocopied during the process of verifying case report form information, the
subject will be identified by unique code only; full names/initials will be masked.

3. Confidentiality of Investigator Information

By signing this protocol, the investigator recognizes that certain personal


identifying information (e.g., name, hospital or clinic address, curriculum vitae)
may be made part of a regulatory submission and may be transmitted (either in
hard copy or electronically) to all Merck subsidiaries/agents worldwide for
internal study management purposes or as required by individual regulatory
agencies. Additionally, the investigators name, hospital/clinic address/phone
number may be included when reporting certain serious adverse events to
regulatory agencies or to other investigators.

H. COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT


By signing this protocol, the investigator agrees to conduct the study in an efficient
and diligent manner and in conformance with this protocol; generally accepted
standards of Good Clinical Practice; 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 Merck & Co., Inc., is
attached.

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H. COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT


(CONT.)
The investigator also agrees to allow monitoring, audits, Institutional Review
Board/Independent Ethics Committee review and regulatory agency inspection of
trial-related documents and procedures and provide for direct access to all study-
related source data and documents.

The investigator agrees not to seek reimbursement from patients, their insurance
providers, or from government programs for procedures included as part of the study
reimbursed to the investigator by the SPONSOR.

The investigator shall prepare and maintain complete and accurate study
documentation in compliance with Good Clinical Practice standards and applicable
federal, state, and local laws, rules and regulations; and, for each subject participating
in the study, provide all data, and upon completion or termination of the clinical study
submit any other reports to the SPONSOR as required by this protocol or as otherwise
required pursuant to any agreement with the SPONSOR.

Study documentation (see Protocol Section II.D., Study Documentation and Records
Retention) will be promptly and fully disclosed to the SPONSOR by the investigator
upon request and also shall be made available at the investigators site upon request
for inspection, copying, review and audit at reasonable times by representatives of the
SPONSOR or any regulatory agencies. The investigator agrees to promptly take any
reasonable steps that are requested by the SPONSOR as a result of an audit to cure
deficiencies in the study documentation and case report forms.

International Conference of Harmonization Good Clinical Practice guidelines


(Section 4.3.3) recommend that the investigator inform the subjects primary
physician about the subjects participation in the trial if the subject has a primary
physician and if the subject agrees to the primary physician being informed.

Persons debarred from conducting or working on clinical studies by any court or


regulatory agency 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 investigators knowledge, threatened.

In the event the SPONSOR prematurely terminates a particular trial site, the
SPONSOR will promptly notify that sites IRB/IEC.

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I. COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS


By signing this protocol, the investigator agrees to provide to the SPONSOR accurate
financial information to allow the SPONSOR to submit complete and accurate
certification and disclosure statements as required by U.S. Food and Drug
Administration regulations (21 CFR Part 54). The investigator further agrees to
provide this information on a Financial Disclosure/Certification Form that is provided
by Merck & Co., Inc. This requirement also extends to subinvestigators.

J. QUALITY CONTROL AND QUALITY ASSURANCE


By signing this protocol, the SPONSOR agrees to be responsible for implementing
and maintaining quality control and quality assurance systems with written SOPs to
ensure that trials are conducted and data are generated, documented, and reported in
compliance with the protocol, accepted standards of Good Clinical Practice, and all
applicable federal, state, and local laws, rules and regulations relating to the conduct
of the clinical study.

K. PUBLICATIONS
As this study is part of a multicenter trial, publications derived from this study should
include input from the principal investigator, his/her colleagues, the other
investigators in this trial, and SPONSOR personnel. Such input should be reflected in
publication authorship, and whenever possible, preliminary agreement regarding the
strategy for order of authors names should be established before conducting the
study. Subsequent to the multicenter publication, or 24 months after completion of
the study, whichever comes first, an investigator and/or his/her colleagues may
publish the results for their study site independently.

The SPONSOR must have the opportunity to review all proposed abstracts,
manuscripts, or presentations regarding this study 60 days prior to submission for
publication/presentation. Any information identified by the SPONSOR as
confidential must be deleted prior to submission, it being understood that the results
of this study are not to be considered confidential. SPONSOR review can be
expedited to meet publication guidelines.

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III. SIGNATURESU.S. SITE(S)

A. SPONSORS REPRESENTATIVE

TYPED NAME SIGNATURE DATE

B. INVESTIGATOR(S)
I agree to conduct this clinical study in accordance with the design and specific
provisions of this protocol; deviations from the protocol are acceptable only with a
mutually agreed upon protocol amendment. I also agree to report all information or
data in accordance with the protocol and, in particular, I agree to report any serious
adverse experiences as defined in Section I.G. of this protocol. I also agree to handle
all clinical supplies provided by the SPONSOR and collect and handle all clinical
specimens in accordance with the protocol.

TYPED NAME(S) SIGNATURE DATE

Primary Investigator(s)

Secondary/Subinvestigator(s)

Secondary/Subinvestigator(s)

Secondary/Subinvestigator(s)

Secondary/Subinvestigator(s)

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IV. SIGNATURESNON-U.S. SITE(S)

A. SPONSORS REPRESENTATIVE

TYPED NAME SIGNATURE DATE

B. INVESTIGATOR(S)
I agree to conduct this clinical study in accordance with the design and specific
provisions of this protocol; deviations from the protocol are acceptable only with a
mutually agreed upon protocol amendment. I also agree to report all information or
data in accordance with the protocol and, in particular, I agree to report any serious
adverse experiences as defined in Section I.G. of this protocol. I also agree to handle
all clinical supplies provided by the SPONSOR and collect and handle all clinical
specimens in accordance with the protocol.

TYPED NAME(S) SIGNATURE DATE

Primary Investigator(s)

Secondary/Subinvestigator(s)

Secondary/Subinvestigator(s)

Secondary/Subinvestigator(s)

Secondary/Subinvestigator(s)

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LIST OF REFERENCES
1. Wang SK, Tsiatis AA. Approximately optimal one-parameter boundaries for group
sequential trials. Biometrics 1987;43:193-99.

2. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med


1997;102(5A);3-8.

3. Anonymous. Consensus statement: National Institutes of Health Consensus


Development Conference statement on cervical cancer. Gynecol Oncol 1997;66:351-
61.

4. Murakami M, Gurski KJ, Stellar MA. Human Papillomavirus vaccines for cervical
cancer. J Immunother 1999;22(3):212-8.

5. Sigurdsson K. Effect of organized screening on the risk of cervical cancer: evaluation


of screening activity in Iceland, 1964-1991. Int J Cancer 1993;54;563-70.

6. Cain JM, Howett MK. Preventing cervical cancer. Science 2000;288:1753-4.

7. Cox JT. Evaluation of abnormal cervical cytology. Clin Lab Med 2000;20(2):303-
43.

8. Palefsky JM, Holly EA, Ralston ML, Da Costa M, Greenblatt RM. Prevalence and
risk factors for anal human papillomavirus infection in human immunodeficiency
virus (HIV)-positive and high-risk HIV-negative women. J Infect Dis 2001;183:383-
91.

9. Handsfield HH. Clinical presentation and natural course of anogenital warts. Am J


Med 1997;102(5A):16-20.

10. Beutner KR, Reitano MV, Richwald GA, Wiley DJ, and the AMA Expert Panel on
External Genital Warts. External genital warts: report of the American Medical
Association consensus conference. Clin Infect Dis 1998;27:796-806.

11. Maw RD, Reitano M, Roy M. An international survey of patients with genital warts:
perceptions regarding treatment and impact on lifestyle. Int J STD AIDS 1998;9:571-
8.

12. Green GE, Bauman NM, Smith RJH. Pathogenesis and treatment of juvenile onset
recurrent respiratory papillomatosis. Otolaryngol Clin North Am
2000;33(1):187-207.

13. Alani RM, Munger K. Human papillomaviruses and associated malignancies. J Clin
Oncol 1998;16:330-7.

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ATTACHMENTS

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118

VACCINE CONSENT FORM


You (or your child) are invited to be in a research study. You need to decide whether you want (or, your child) to
participate or not. Please take your time to make your decision. Carefully read the following and ask the study doctor any
questions which you may have. The study is being conducted for Merck & Co., Inc., the Sponsor.
Why is the study being done?
The purpose of this study is to test the safety of the research study vaccine, [insert name of vaccine], Another purpose
is to see if [insert name of vaccine], prevents [insert the name of the disease or condition].
Who should not be in the study?
[Insert exclusion criteria that the subject/parent) can assess in simple language].
What will I (or my child) be asked to do? What are my (or my childs) requirements?
The study doctor or staff will ask you about your (or your childs) medical history and will examine you (or your child). You (or
your child) will be administered [insert name of vaccine] (or you may receive [insert name of active comparator, if any]).
You and the study doctor will not know whether you (or your child) are receiving the real vaccine. You (or your child) have a
____in ___ chance of receiving the active vaccine. You (or your child) will be required to visit the study doctor about [insert
number of times]. At each visit the study doctor or staff may do any or all of the following [insert a summary of study
procedures in simple language (e.g., a bulleted list, a simplified table, a check list of procedures)].
What is known about this (these) vaccine(s)?
This is the first time that the vaccine has been used in man. OR
The vaccine has been used in [insert approximate number of subjects (worldwide) who have received the vaccine].
How long will I (my child) be in the study?
You (your child) will be in the study about [insert number of weeks, months, or years].
How many other people (children) will be participating in the study?
About [insert number of participants at all sites] people will be participating in the study.
Will I be paid? [Include section only if applicable]
You will be paid as follows:[insert payment information]
What adverse (bad) effects can happen to me (my child) by participating in the study?
The following adverse effects have been reported by people taking [insert name of vaccine] in previous studies or seen
in animal experiments: [insert any foreseeable risks or discomforts as bullets or summary]. The study doctor or
staff will discuss these with you. There can be other adverse effects that are not presently known about [insert name of
vaccine]. It is not known how the study vaccine may affect an unborn baby. There may be some discomfort from the
procedures, including (e.g., slight pain or bruises from taking blood or from administering the vaccine).
If I (or my child) have an adverse effect, who will pay the doctor and hospital bills?
If you (your child) are injured or become sick directly from the Merck study vaccine, Merck & Co., Inc., the Sponsor of the
study, will provide reimbursement for the reasonable costs of medical treatment to the extent such costs are not covered
by your medical or hospital insurance or by third-party or governmental programs providing such coverage. No other
form of compensation is available.
What benefit can I (or my child) expect?
If the vaccine works, you (your child) may have some benefit. On the other hand, it may not work and there may
be no benefit.
Are there any other vaccines that I (or my child) may be able to take to prevent the disease or drugs that I (or my
child) can take if I (or my child) get the disease, if I (or my child) dont want to participate in the study?
The following other vaccines, drugs, or procedures are available as alternatives to [insert name of vaccine]:
[insert other vaccines, drugs, and/or procedures].
Who will be able to see my (my childs) records and know that I (my child is) am in the study?
If you agree to (have your child) become part of this study, your name will be held in confidence. Unless required
by law, only the study doctor and staff, sponsor representatives involved in this study, independent ethics
committees and inspectors from government regulatory agencies will have direct access to your (your childs)
medical records to check the study information.
Will I be told if new information about the vaccine is discovered during the study?
You will be told in a timely manner of any significant new information that may affect your willingness to (to have
your child) stay in this study.
Who do I call if I have questions?
For questions about the study or if you (your child) have a study-related injury, call the study doctor
__________________[insert name] at _________[insert telephone number].
For questions about your (childs) rights as a participant in the study, call __________________[insert name] at
________[insert telephone number].
Can I refuse to be part in the study and can I be asked to leave the study?
Your (your childs) participation in this study is voluntary. You can choose not to take part in the study, or you can quit at
any time. You (your child) will not lose any benefits to which you (your child) are otherwise entitled. If you (your child) quit
the study, you can receive the standard treatment for this condition. You (Your child) will not be prevented from
participating in future studies.
You (Your child) may be asked to leave the study by the study doctor or Merck & Co., Inc., without your consent if you need
other treatment, if you do not follow the study plan, if you (your child) have a study-related injury or for any other reason.
You will receive a signed copy of this consent form.
I have read and understand this consent form. All my questions have been answered. I volunteer (to have my child) to
take part in this study.
Print Childs Name___________________________________________ Date of Birth__________
or Signature of Volunteer (if adult)______________________________ Date_________________
Signature of Parent/Guardian (if child)___________________________ Date_________________
Signature of Person Conducting Review of Consent___________________ Date_________________

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119
Merck & Co., Inc
Code of Conduct for Clinical Trials
I. Introduction
A. Purpose
Merck & Co., Inc. (Merck) conducts clinical trials worldwide to evaluate the safety and effectiveness of our products. As
such, we are committed to designing, implementing, conducting, analyzing and reporting these studies in compliance with
the highest ethical and scientific standards. Protection of patient safety is the overriding concern in the design of clinical
trials. In all cases, Merck clinical studies will be consistent with standards established by the Declaration of Helsinki and in
compliance with all local and/or national regulations and directives.
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the party
(parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This Code is not
intended to apply to studies which are observational in nature, or which are retrospective. Further, this Code does not apply
to investigator-initiated studies (e.g., Medical School Grant Program), which are not under the control of Merck.
II. Scientific Issues
A. Study Conduct
1. Study Design
Except for pilot or estimation studies, clinical trial protocols will be hypothesis-driven to assess safety, efficacy and/or
pharmacokinetic or pharmacodynamic indices of Merck or comparator products. Alternatively, Merck may conduct outcomes
research trials, studies to assess or validate various endpoint measures, or studies to determine patient preferences, etc.
The design and conduct of a study (i.e., patient population, duration, statistical power) must be adequate to address the
specific purpose of the study. Research subjects must meet protocol entry criteria to be enrolled in the study, unless
specifically exempted by the Merck study monitor.
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate patients, adequacy of facilities and
staff, previous performance in Merck studies, as well as budgetary considerations. Prior to study initiation, sites are
evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Study sites are monitored to assess compliance with the study protocol and general principles of Good Clinical Practice.
Merck reviews clinical data for accuracy, completeness and consistency: data are verified versus source documentation
according to standard operating procedures. Per Merck policies and procedures, if fraud and/or misconduct are
suspected, the issue is investigated: when necessary, the clinical site will be closed and, if appropriate, the responsible
regulatory authorities and ethics review committees notified.
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of studies it conducts. Some early phase or pilot
studies are intended to be hypothesis-generating rather than hypothesis testing. In such cases, publication of results may not
be appropriate since the trial may be underpowered and the analyses complicated by statistical issues of multiplicity.
Mercks policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice guidelines. In
summary, authorship should reflect significant contribution to the design and conduct of the study, performance or
interpretation of the analysis, and/or writing of the manuscript. All named authors must be able to defend the study results
and conclusions. Merck funding of a study will be acknowledged in publications.
III. Patient Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site. Significant
changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that changes required
urgently to protect patient safety and well-being may be enacted in anticipation of IRB/ERC approval. For each site, the
IRB/ERC and Mercks Consent Form Review department (U.S. studies) or local medical director (non-U.S. studies) will
approve the patient informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that patient welfare is of primary importance. Potential patients
will be informed of the risks and benefits of, as well as alternatives to, study participation. At a minimum, study designs will
take into account the local standard of care. Patients are never denied access to appropriate medical care based on
participation in a Merck clinical study.
All participation in Merck clinical trials is voluntary. Patients are enrolled only after providing informed consent for
participation. Patients may withdraw from a Merck study at any time, without any influence on their access to, or receipt of,
medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding patient confidentiality, to the greatest extent possible. Unless required by law, only the
investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical records that
might identify the research subject by name.
D. DNA Research
DNA sequence analyses, including use of archival specimens collected as part of a clinical trial, will only be performed with
the specific informed consent of the subject. With IRB approval, an exception to this restriction on use of archival
specimens may be possible (for instance, if specimens are de-identified and are not referable to a specific subject).
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is Mercks policy to compensate investigators (or the sponsoring institution) in a fair manner for
the work performed in support of Merck studies. Merck does not pay incentives to enroll patients in its trials. However, when enrollment is
particularly challenging, additional payments may be made to compensate for the time spent in extra recruiting efforts.
Merck does not pay for patient referrals. However, Merck may compensate referring physicians for time spent on chart
review to identify potentially eligible patients.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring institution
is being paid or provided a grant for performing the study. However, the local IRB/ERC may wish to alter the wording of
the disclosure statement to be consistent with financial practices at that institution. As noted above, publications resulting
from Merck studies will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g. to scientific meetings, investigator meetings, etc.) will be consistent
with local guidelines and practices including, in the U.S., those established by the American Medical Association (AMA).
V. Investigator Commitment
Investigators will be expected to review Mercks Code of Conduct as an attachment to the study protocol, and in signing the
protocol, agree to support these ethical and scientific standards.

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Date:_________________________

(insert Primary Investigators name and address below)

_________________________________

_________________________________

_________________________________

RE: Insert title of protocol and protocol number

Dear Dr. _________________________(insert name of Primary Investigator):

My signature below verifies that the IRB/IEC listed below operates in accordance with
applicable national/local and institutional regulations and guidelines which govern
IRB/IEC operations.

_________________________________ _____________________________ _______


Printed Name, IRB/IEC Chairperson Signature, IRB/IEC Chairperson Date
(insert name and address of IRB/IEC here)

IRBs Federal Assurance number is:__________________________ (optional for U.S. IRBs)

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ICH HARMONISED TRIPARTITE GUIDELINE


GUIDELINE FOR GOOD CLINICAL PRACTICE
Section 3: INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
3.1 Responsibilities
3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be
paid to trials that may include vulnerable subjects.
3.1.2 The IRB/IEC should obtain the following documents:
trial protocol(s)/amendments(s), written informed consent form(s) and consent form updates that the
investigator proposes for use in the trial, subject recruitment procedures (e.g. advertisements), written
information to be provided to subjects, Investigators Brochure (IB), available safety information, information
about payments and compensation available to subjects, the investigators current curriculum vitae and/or other
documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfill its
responsibilities.
The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in writing,
clearly identifying the trial, the documents reviewed and the dates for the following:
-approval/favourable opinion;
-modifications required prior to its approval/favourable opinion;
-disapproval/negative opinion; and
-termination/suspension of any prior approval/favourable opinion.
3.1.3 The IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a
current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests.
3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk
to human subjects, but a least once per year.
3.1.5 The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in
the judgment of the IRB/IEC, the additional information would add meaningfully to the protection of the rights,
safety and/or well-being of the subjects.
3.1.6 When a non-therapeutic trail is to be carried out with the consent of the subjects legally acceptable
representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or other
document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for
such trials.
3.1.7 Where the protocol indicates that prior consent of the trial subject or the subjects legally acceptable
representative is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or
other documents) adequately addresses relevant ethical concerns and meets applicable regulatory
requirements for such trials (i.e. in emergency situations).
3.1.8 The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents
problems of coercion or undue influence on the trial subjects. Payments to a subject should be prorated and
not wholly contingent on completion of the trial by the subject.
3.1.9 The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts,
and schedule of payment to trial subjects, is set forth in the written informed consent form and any other written
information to be provided to subjects. The way payment will be prorated should be specified.
3.2 Composition, Functions and Operations
3.2.1 The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and
experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is
recommended that the IRB/IEC should include:
(a) At least five members.
(b) At least one member whose primary area of interest is in a nonscientific area.
(c) At least one member who is independent of the institution/trial site.
Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should
vote/provide opinion on a trial-related matter.
A list of IRB/IEC members and their qualifications should be maintained.
3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should maintain written
records of its activities and minutes of its meetings, and should comply with GCP and with the applicable
regulatory requirement(s).

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3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as stipulated in its
written operating procedures, is present.
3.2.4 Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or
advise.
3.2.5 The investigator may provide information on any aspect of the trial, but should not participate in the
deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
3.2.6 An IRB/IEC may invite non-members with expertise in special areas for assistance.
3.3 Procedures
The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
3.3.1 Determining its composition (names and qualifications of the members) and the authority under which it is
established.
3.3.2 Scheduling, notifying its members of, and conducting its meetings.
3.3.3 Conducting initial and continuing review of trials.
3.3.4 Determining the frequency of continuing review, as appropriate.
3.3.5 Providing, according to the applicable regulatory requirements, expedited review and approval/favourable
opinion of minor change(s) in ongoing trials that have the approval/favourable opinion of the IRB/IEC.
3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favourable
opinion of the trial.
3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC
approval/favourable opinion of an appropriate amendment, except when necessary to eliminate immediate
hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g.,
change of monitor(s), telephone number(s) (see 4.5.2).
3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
(a) Deviations from, or changes of the protocol to eliminate immediate hazards to the trial subjects (see
3.3.7, 4.5.2, 4.5.4).
(b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see
4.10.2)
(c) All adverse drug reactions (ADRs that are both serious and unexpected.)
(d) New information that may affect adversely the safety of the subjects of the conduct of the trial.
3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution concerning:
(a) Its trial-related decisions/opinions.
(b) The reasons for its decisions/opinions.
(c) Procedures for appeal of its decisions/opinions.
3.4 Records
The IRB/IEC should retain all relevant records (e.g., write procedures, membership lists, lists of
occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for a
period of at least 3 years after completion of the trial and make them available upon request from the regulatory
authority(ies).
The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written procedures
and membership lists.

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FDA REGULATIONS REGARDING INFORMED CONSENT


(CODE OF FEDERAL REGULATIONS, TITLE 21, PART 50)

50.20 General Requirements for Informed Consent


Except as provided in 50.23, no investigator may involve a human being as a subject in research covered by these
regulations unless the investigator has obtained the legally effective informed consent of the subject or the subjects
legally authorized representative. An investigator shall seek such consent only under circumstances that provide the
prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize
the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in
language understandable to the subject or the representative. No informed consent, whether oral or written, may include
any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the
subjects legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from
liability for negligence.
50.25 Elements of Informed Consent
(a) Basic elements of informed consent. In seeking informed consent, the following information shall be provided to each
subject:
(1) A statement that the study involves research, an explanation of the purposes of the research and the expected
duration of the subjects participation, a description of the procedures to be followed, and identification of any
procedures which are experimental.
(2) A description of any reasonably foreseeable risks or discomforts to the subject.
(3) A description of any benefits to the subject or to others which may reasonably be expected from the research.
(4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to
the subject.
(5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be
maintained and that notes the possibility that the Food and Drug Administration may inspect the records.
(6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation
as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further
information may be obtained.
(7) An explanation of whom to contact for answers to pertinent questions about the research and research subjects
rights, and whom to contact in the event of a research-related injury to the subject.
(8) A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to
which the subject is otherwise entitled, and that the subject may discontinue participation at any time without
penalty or loss of benefits to which the subject is otherwise entitled.
(b) Additional elements of informed consent. When appropriate, one or more of the following elements of information shall
also be provided to each subject:
(1) A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if
the subject is or may become pregnant) which are currently unforeseeable.
(2) Anticipated circumstances under which the subjects participation may be terminated by the investigator without
regard to the subjects consent.
(3) Any additional costs to the subject that may result from participation in the research.
(4) The consequences of a subjects decision to withdraw from the research and procedures for orderly termination of
participation by the subject.
(5) A statement that significant new findings developed during the course of the research which may relate to the
subjects willingness to continue participation will be provided to the subject.
(6) The approximate number of subjects involved in the study.
(c) The informed consent requirements in these regulations are not intended to preempt any applicable Federal, State, or
local laws which require additional information to be disclosed for informed consent to be legally effective.
(d) Nothing in these regulations is intended to limit the authority of a physician to provide emergency medical care to the
extent the physician is permitted to do so under applicable Federal, State, or local law.
50.27 Documentation of Informed Consent
(a) Except as provided in 56.109(c), informed consent shall be documented by the use of a written consent form
approved by the IRB and signed by the subject or the subjects legally authorized representative. A copy shall be
given to the person signing the form.
(b) Except as provided in 56.109(c), the consent form may be either of the following:
(1) A written consent document that embodies the elements of informed consent required by 50.25. This form may
be read to the subject or the subjects legally authorized representative but, in any event, the investigator shall
give either the subject or the representative adequate opportunity to read it before it is signed.
(2) A short form written consent document stating that the elements of informed consent required by 50.25 have
been presented orally to the subject or the subjects legally authorized representative. When this method is used,
there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be
said to the subject or the representative. Only the short form itself is to be signed by the subject or the
representative. However, the witness shall sign both the short form and a copy of the summary, and the person
actually obtaining the consent shall sign a copy of the summary. A copy of the summary shall be given to the
subject or the representative in addition to a copy of the short form.

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FOOD AND DRUG ADMINISTRATION REGULATIONS FOR INSTITUTIONAL REVIEW BOARDS (CODE OF FEDERAL
REGULATIONS, TITLE 21, PART 56)
Subpart B Organization and Personnel
56.107 IRB Membership
a. Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research
activities commonly conducted by the institution. The IRB shall be sufficiently qualified through the experience and expertise
of its members, and the diversity of the members, including consideration of race, gender, cultural backgrounds, and
sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and
welfare of human subjects. In addition to possessing the professional competence necessary to review the specific research
activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and
regulations, applicable law, and standards of professional conduct and practice. The IRB shall therefore include persons
knowledgeable in these areas. If an IRB regularly reviews research that involves a vulnerable category of subjects, such as
children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the
inclusion of one or more individuals who are knowledgeable about and experienced in working with those subjects.
b. Every nondiscriminatory effort will be made to ensure that no IRB consists entirely of men or entirely of women, including the
institutions consideration of qualified persons of both sexes, so long as no selection is made to the IRB on the basis of
gender. No IRB may consist entirely of members of one profession.
c. Each IRB shall include at least one member whose primary concerns are in the scientific area and at least one member
whose primary concerns are in nonscientific areas.
d. Each IRB shall include at least one member who is not otherwise affiliated with the institution and who is not part of the
immediate family of a person who is affiliated with the institution.
e. No IRB may have a member participate in the IRBs initial or continuing review of any project in which the member has a
conflicting interest, except to provide information requested by the IRB.
f. An IRB may, in its discretion, invite individuals with competence in special areas to assist in the review of complex issues
which require expertise beyond or in addition to that available on the IRB. These individuals may not vote with the IRB.
Subpart C IRB Functions and Operations
56.108 IRB Functions and Operations
In order to fulfill the requirements of these regulations, each IRB shall:
a. Follow written procedures: (1) For conducting its initial and continuing review of research and for reporting its findings and
actions to the investigator and the institution; (2) for determining which projects require review more often than annually and
which projects need verification from sources other than the investigator that no material changes have occurred since
previous IRB review; (3) for ensuring prompt reporting to the IRB of changes in research activity, and (4) for ensuring that
changes in approved research, during the period for which IRB approval has already been given, may not be initiated without
IRB review and approval except where necessary to eliminate apparent immediate hazards to the human subjects.
b. Follow written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug
Administration of: (1) Any unanticipated problems involving risks to human subjects or others; (2) any instance of serious or
continuing noncompliance with these regulations or the requirements or determinations of the IRB; or (3) any suspension or
termination of IRB approval.
c. Except when an expedited review procedure is used (see 56.110), review proposed research at convened meetings at
which a majority of the members of the IRB are present, including at least one member whose primary concerns are in
nonscientific areas. In order for the research to be approved, it shall receive the approval of a majority of those members
present at the meeting.
56.109 IRB Review of Research
a. An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research
activities covered by these regulations.
b. An IRB shall require that information given to subjects as part of informed consent is in accordance with 50.25. The IRB
may require that information, in addition to that specifically mentioned in 50.25, be given to the subjects when in the IRBs
judgment the information would meaningfully add to the protection of the rights and welfare of subjects.
c. An IRB shall require documentation of informed consent in accordance with 50.27, except that the IRB may, for some or all
subjects, waive the requirement that the subject or the subjects legally authorized representative sign a written consent form
if it finds that the research presents no more than minimal risk of harm to subjects and involves no procedures for which
written consent is normally required outside the research context. In cases where the documentation requirement is waived,
the IRB may require the investigator to provide subjects with a written statement regarding the research.
d. An IRB shall notify investigators and the institution in writing of its decision to approve or disapprove the proposed research
activity, or of modifications required to secure IRB approval of the research activity. If the IRB decides to disapprove a
research activity, it shall include in its written notification a statement of the reasons for its decision and give the investigator
an opportunity to respond in person or in writing.
e. An IRB shall conduct continuing review of research covered by these regulations at intervals appropriate to the degree of risk,
but not less than once per year, and shall have authority to observe or have a third party observe the consent process and
the research.

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WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI

Recommendations Guiding Medical Physicians in Biomedical


Research Involving Human Subjects
Adopted by the 18th World Medical Assembly Helsinki, Finland, June 1964 and amended by the 29th World Medical
Assembly Tokyo, Japan, October 1975, 35th World Medical Assembly Venice, Italy, October 1983, and the 41st World
Medical Assembly Hong Kong, September 1989 and the 48th General Assembly, Somerset West, Republic of South
Africa, October 1996.
INTRODUCTION
It is the mission of the physician to safeguard the health of the people. His or her knowledge and conscience are
dedicated to the fulfillment of this mission.
The Declaration of Geneva of the World Medical Association binds the physician with the words, The health of my patient
will be my first consideration, and the International Code of Medical Ethics declares that, A physician shall act only in the
patients interest when providing medical care which might have the effect of weakening the physical and mental condition
of the patient.
The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and
prophylactic procedures and the understanding of the etiology and pathogenesis of disease.
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies
especially to biomedical research.
Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects.
In the field of biomedical research a fundamental distinction must be recognized between medical research in which the
aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely
scientific and without implying direct diagnostic or therapeutic value to the person subjected to the research.
Special caution must be exercised in the conduct of research which may affect the environment, and the welfare of
animals used for research must be respected.
Because it is essential that the results of laboratory experiments be applied to human beings to further scientific
knowledge and to help suffering humanity, the World Medical Association has prepared the following recommendations as
a guide to every physician in biomedical research involving human subjects. They should be kept under review in the
future. It must be stressed that the standards as drafted are only a guide to physicians all over the world. Physicians are
not relieved from criminal, civil and ethical responsibilities under the laws of their own countries.
I. BASIC PRINCIPLES
1. Biomedical research involving human subjects must conform to generally accepted scientific principles and
should be based on adequately performed laboratory and animal experimentation and on a thorough
knowledge of the scientific literature.
2. The design and performance of each experimental procedure involving human subjects should be clearly
formulated in an experimental protocol which should be transmitted for consideration, comment and
guidance to a specially appointed committee independent of the investigator and the sponsor provided that
this independent committee is in conformity with the laws and regulations of the country in which the
research experiment is performed.
3. Biomedical research involving human subjects should be conducted only by scientifically qualified persons
and under the supervision of a clinically competent medical person. The responsibility for the human
subject must always rest with a medically qualified person and never rest on the subject of the research,
even though the subject has given his or her consent.
4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance of
the objective is in proportion to the inherent risk to the subject.
5. Every biomedical research project involving human subjects should be preceded by careful assessment of
predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the
interests of the subject must always prevail over the interests of science and society.
6. The right of the research subject to safeguard his or her integrity must always be respected. Every
precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on
the subjects physical and mental integrity and on the personality of the subject.

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I. BASIC PRINCIPLES (CONT.)


7. Physicians should abstain from engaging in research projects involving human subjects unless they are
satisfied that the hazards involved are believed to be predictable. Physicians should cease any
investigation if the hazards are found to outweigh the potential benefits.
8. In publication of the results of his or her research, the physician is obliged to preserve the accuracy of the
results. Reports of experimentation not in accordance with the principles laid down in this Declaration
should not be accepted for publication.
9. In any research on human beings, each potential subject must be adequately informed of the aims,
methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or
she should be informed that he or she is at liberty to abstain from participation in the study and that he or
she is free to withdraw his or her consent to participation at any time. The physician should then obtain the
subjects freely-given informed consent, preferably in writing.
10. When obtaining informed consent for the research project the physician should be particularly cautious if
the subject is in a dependent relationship to him or her or may consent under duress. In that case the
informed consent should be obtained by a physician who is not engaged in the investigation and who is
completely independent of this official relationship.
11. In case of legal incompetence, the informed consent should be obtained from the legal guardian in
accordance with the national legislation. Where physical or mental incapacity makes it impossible to
obtain informed consent, or when the subject is a minor, permission from the responsible relative replaces
that of the subject in accordance with national legislation.
Whenever the minor is in fact able to give a consent, the minors consent must be obtained in addition to
the consent of the minors legal guardian.
12. The research protocol should always contain a statement of the ethical considerations involved and should
indicate that the principals enunciated in the present Declaration are complied with.
II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE (CLINICAL RESEARCH)
1. In the treatment of the sick person, the physician must be free to use a new diagnostic and therapeutic
measure, if in his or her judgment it offers hope of saving life, reestablishing health or alleviating suffering.
2. The potential benefits, hazards and discomfort of a new method should be weighed against the
advantages of the best current diagnostic and therapeutic method.
3. In any medical study, every patient (including those of a control group, if any) should be assured of the
best proven diagnostic and therapeutic method. This does not exclude the use of inert placebo in studies
where no proven diagnostic or therapeutic method exists.
4. The refusal of the patient to participate in a study must never interfere with the physician-patient
relationship.
5. If the physician considers it essential not to obtain informed consent, the specific reasons for this proposal
should be stated in the experimental protocol for transmission to the independent committee (1,2).
6. The physician can combine medical research with professional care, the objective being the acquisition of
new medical knowledge, only to the extent that the medical research is justified by its potential diagnostic
or therapeutic value for the patient.
III. NONTHERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS (NONCLINICAL BIOMEDICAL
RESEARCH)
1. In the purely scientific application of medical research carried out on a human being, it is the duty of the
physician to remain the protector of the life and health of that person on whom biomedical research is
being carried out.
2. The subjects should be volunteers; either healthy persons or patients for whom the experimental design is
not related to the patients illness.
3. The investigator or the investigating team should discontinue the research if in his/her or their judgment it
may, if continued, be harmful to the individual.
4. The research on man, the interest of science and society should never take precedence over
considerations related to the well being of the subject.

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Protocol/Amendment No.: 015-00 127

APPENDICES
1. Pregnancy Reporting and Follow-Up HPV Vaccine Clinical Program

BP4651.DOC VERSION 8.0 APPROVED 11-Apr-2002


Worldwide Protocol U.S. IND/Non-U.S. IND Restricted Confidential Limited Access
Product: V501
Protocol/Amendment No.: 015-00
Appendix: 1

APPENDIX 1

Pregnancy Reporting and Follow-Up HPV Vaccine Clinical Program

BP4658.DOC VERSION 4.0 APPROVED 11-Apr-2002


Worldwide Protocol U.S. IND/Non-U.S. IND Restricted Confidential Limited Access
Subject: Pregnancy Reporting and Follow-up Dept.: 976
HPV Vaccine Clinical Program Rev.: 02
Effective Date: 22-Feb-OO

Name Signature Date


Written By:

SOP_revision 2
02/22/00