Beruflich Dokumente
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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:
TABLE OF CONTENTS
PAGE
PROTOCOL SYNOPSIS.................................................................................................... 7
B. INVESTIGATOR(S).................................................................................. 114
APPENDICES................................................................................................................. 127
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.
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
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
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.
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.
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
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.
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
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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.
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.
See Protocol Section I.G., Safety Measurements, for definitions of serious adverse experiences.
See Protocol Section I.G., Safety Measurements, for definitions of serious adverse experiences.
I. CLINICAL SECTIONS
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
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
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
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
c. Immunogenicity
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
B. OBJECTIVES (CONT.)
2. Secondary
Efficacy Study
3. Exploratory
Efficacy Study
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
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
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.
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:
e. History of severe allergic reaction (e.g., swelling of the mouth and throat,
difficulty breathing, hypotension or shock) that required medical intervention.
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.
E. STUDY DESIGN
1. Summary of Study Design
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).
Table 4
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
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
2) Placebo
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.
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
e. Diet/Activity/Other
No special restrictions will apply except for those noted under the
inclusion/exclusion criteria.
a. Consent
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.
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
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)).
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.
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.
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.
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.
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.
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.
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.
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.
All Subjects
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.
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.
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.
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.
d) Remove the spatula and the cytobrush from the PreservCyt liquid
and twist the cap on the vial securely.
Randomization
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.
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.
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 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
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.
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:
Table 7
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 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.
b) Inspect the vulvar, perineal, and perianal areas for abnormal lesions.
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.
k) Assess the severity of each cervical lesion using green filter as needed
to examine the vascular patterns.
d) Place biopsy forceps over the abnormal lesion (usually near the
squamocolumnar junction).
f) Check to make sure the forceps are properly aligned (fixed end of
forceps jaw towards cervical os).
i) Squeeze handles together quickly and firmly to close forceps jaws and
excise lesion.
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.
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
b) Place dispersive pad near operative site (thigh) and plug into
Electrosurgical Unit (ESU).
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.
Laser Conization
c) Set laser unit parameters (power, optical focusing of the laser beam)
and test safety systems.
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.)
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.
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.
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.
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.
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:
AND
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.
3. Immunogenicity
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.
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.
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.
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:
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.
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.
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.
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
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.
Maximum intensity:
Results in death; or
Is a cancer; or
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
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.
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?
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.)
OR
OR
OR
OR
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.
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.
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.
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
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.)
Safety/Tolerability
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:
AND
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.
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 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.
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.
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.
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.
Efficacy Study
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.
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%
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%.
8. Interim Analyses
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.
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.
Table 9
For reference, in past HPV vaccine studies, adverse experiences that have occurred at
a rate of 20 to 30% are erythema and swelling.
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
Product Description
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.
5. Study Disclosure
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.
7. Distribution
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.
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
2. Shipment of Specimens
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.
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
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.
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
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.
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.
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.
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.
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
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.
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
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.
G. CONFIDENTIALITY (CONT.)
For All Studies
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.
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.
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.
In the event the SPONSOR prematurely terminates a particular trial site, the
SPONSOR will promptly notify that sites IRB/IEC.
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.
A. SPONSORS REPRESENTATIVE
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.
Primary Investigator(s)
Secondary/Subinvestigator(s)
Secondary/Subinvestigator(s)
Secondary/Subinvestigator(s)
Secondary/Subinvestigator(s)
A. SPONSORS REPRESENTATIVE
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.
Primary Investigator(s)
Secondary/Subinvestigator(s)
Secondary/Subinvestigator(s)
Secondary/Subinvestigator(s)
Secondary/Subinvestigator(s)
LIST OF REFERENCES
1. Wang SK, Tsiatis AA. Approximately optimal one-parameter boundaries for group
sequential trials. Biometrics 1987;43:193-99.
4. Murakami M, Gurski KJ, Stellar MA. Human Papillomavirus vaccines for cervical
cancer. J Immunother 1999;22(3):212-8.
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.
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.
ATTACHMENTS
Date:_________________________
_________________________________
_________________________________
_________________________________
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.
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.
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.
APPENDICES
1. Pregnancy Reporting and Follow-Up HPV Vaccine Clinical Program
APPENDIX 1
SOP_revision 2
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