Merck conducted six phase 1 and phase 2 clinical studies between 1997 and 2004

VRBPAC Background Document

Gardasil™ HPV Quadrivalent Vaccine

May 18, 2006 VRBPAC Meeting

Introduction and Background:

Cervical cancer is an important public health problem in the United States, with 9,710
new cervical cancer cases and 3,700 deaths due to cervical cancer projected for 2006.

Cervical cancer has been associated with human papilloma virus (HPV) infection. The
applicant, Merck, Inc., began a clinical development program in 1997 with a recombinant
HPV virus-like particle (VLP) vaccine for the prevention of cervical cancer. The
applicant’s clinical development program proceeded using a quadrivalent VLP vaccine,
Gardasil™ that contains the major capsid protein (L1 protein) from four types of HPV:
types 6, 11, 16, and 18. HPV types 16 and 18 are thought to be responsible for more than
50% of cervical cancer, but more than 15 different types of HPV are considered to be
“oncogenic” and are associated with development of cervical cancer. Cervical
intraepithelial neoplasia grade 2/3 (CIN 2/3) and adenocarcinoma in situ (AIS) are
considered to be precursors to cervical cancer. Condyloma acuminata results from
infection with many different types of HPV, but HPV 6 and 11 are thought to be
responsible for a majority of these cases. Therefore, a vaccine that is highly efficacious
in providing protection against HPV types 6, 11, 16, and 18, based on available
epidemiological data, might be capable having a significant impact in preventing cervical
cancer and condyloma acuminata. The Vaccine and Related Biological Products
Advisory Committee (VRBPAC) discussion will focus on the results submitted to the
biologics license application (BLA) from the clinical development program of Gardasil™
for prevention of HPV disease in females.

Regulatory Milestones:

1997 Submission of the original investigational new drug application (IND) for

monovalent VLP vaccine containing the L1 protein from HPV 11. Subsequent
INDs were submitted for monovalent VLP vaccines containing L1 proteins from
HPV 16 and 18, respectively. Phase 1 and phase 2 evaluations were conducted
under these INDs.

2000 Submission of the original IND for the quadrivalent VLP vaccine containing the

L1 protein from HPV types 6, 11, 16, and 18. Additional phase 1, phase 2, and
phase 3 studies were conducted under this IND.

2001 November: VRBPAC discussion of the endpoints to be used in the phase III

development program for vaccines for prevention of cervical cancer. The
VRBPAC committee members discussed different endpoints and ultimately
concurred with the use of CIN 2/3, AIS, or cervical cancer (i.e. CIN 2/3 or worse)

Jemal A, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106-130.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

by histology (with virology to determine the associated HPV type) as the primary
endpoint in the evaluation of a vaccine to prevent cervical cancer.

2002 CBER granted fast track designation to Merck’s development program for the

HPV quadrivalent vaccine for prevention of cervical cancer. Merck initiated
phase 3 clinical trials of the HPV quadrivalent vaccine.

2005 May: Pre-BLA meeting. CBER agreed that the efficacy data limited to the first

24 weeks of the phase 3 studies could be submitted to the BLA in order to support
efficacy. CBER encouraged early (rolling) submission of CMC, pre-clinical and
phase 1 and 2 clinical data. CBER agreed to grant a priority review of the BLA.

November: CBER determined that clinical efficacy, immune response, and safety
data from studies conducted in females would be considered for licensure for use
in females. Immune response studies conducted in males might contribute
important safety data but would not provide data to be considered for licensure in
males. (A separate clinical development program is ongoing for men and boys.)

December: Completion of the “rolling” BLA submission with receipt of the
efficacy data from the phase 3 studies.

Summary of Clinical Data:

Table 1: Clinical studies
Study
Number

Vaccine
HPV type

Phase Total sample size

(Gardasil™ plus
placebo)

Geographic
Distribution of Study
Populations

001 11

140

North

America

002 16

109

North

America

004 16

480

North

America

005 16

2409

North

America

006 18

North

America

007

6/11/16/18

1106^

North America, Latin
America, Europe

013
(011 + 012)

(FUTURE I)

6/11/16/18 3*

5455

North America, Latin
America, South America,
Europe, Asia, Australia

015

(FUTURE II)

6/11/16/18

12167

North America, South
America, Europe, Asia

016

6/11/16/18

1529^

North America, Latin
America, South America,
Europe, Asia, Australia

018

6/11/16/18

939

North America, Latin
America, Europe, Asia

* Double-blind, randomized, placebo-controlled studies
^ Includes subjects randomized to different doses of HPV quadrivalent VLP

Does not include 304 subjects who received HPV monovalent VLP vaccine in a

bridging substudy.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Phase 1 and Phase 2 Studies

Merck conducted six phase 1 and phase 2 clinical studies between 1997 and 2004. Four
smaller phase 1 or early phase 2 studies evaluated monovalent HPV VLP vaccines,
serotypes 11, 16, or 18, in order to characterize safety and immune responses among
different doses. Two larger phase 2 studies were conducted between 2000 and 2004 that
included clinical endpoints in addition to the safety and immune response endpoints. The
results of these studies were used to identify appropriate dose and endpoints to be used in
the phase 3 pivotal studies. The studies suggested an acceptable safety profile for further
clinical development. The larger phase 2 studies provided supportive evidence of
vaccine activity. The applicant’s clinical development program focused on a three-dose
regimen at months 0, 2, and 6 based on previous clinical and immunological experiences
with their hepatitis B vaccine product.

Studies 001, 002, and 006 were small phase 1 safety studies that evaluated the
monovalent HPV VLP serotypes 11, 16, and 18, respectively. Studies 001 and 002
enrolled 249 subjects, and approximately 200 received the vaccine. The results
demonstrated a “dose response”, where higher doses generally resulted in larger post-
vaccination geometric mean titers. Overall, the immune responses in subjects who
received the 20 µg, 40 µg, or 50µg dose were better than the immune responses in
subjects who received the 10 µg dose. There appeared to be no advantage in immune
responses to an 80 µg dose, or to the administration of a fourth dose.

Study 005 began to demonstrate initial evidence of activity of a 40 µg monovalent HPV
16 VLP vaccine against HPV disease due to HPV type 16. For subjects in study 005
without evidence of infection with HPV 16 at baseline, the applicant reported no cases of
CIN due to HPV 16 out of of 753 subjects in the vaccine group and nine cases of CIN
due to HPV 16 out of 750 subjects in the placebo group.

Study 007 evaluated different doses of each antigen, characterized by “low, medium, and
high” dose groups. The study also incorporated clinical HPV endpoints. The study
enrolled just over 1,000 women. Of note, the secondary efficacy analysis included only
women who were seronegative for HPV at baseline with a secondary endpoint of
detection of HPV 6/11/16/18 DNA on two or more consecutive cervicovaginal samples
by PCR (“persistent HPV cases”). In this analysis, the following number of persistent
HPV cases were recorded: 4 out of 235 subjects randomized to receive the “low” dose, 7
out of 232 randomized to receive the “medium” dose, 3 out of 234 randomized to receive
the “high” dose, and 35 out of 233 randomized to receive placebo. In general, subjects
randomized to receive the higher doses had greater proportions of adverse events.
Therefore, the lower dose group (20/40/40/20 µg for HPV types 6, 11, 16, and 18,
respectively) appeared to have comparable activity to the higher dose groups and had a
better safety profile. The 20/40/40/20 µg dose was brought forward for clinical
development in the phase 3 studies.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Phase 3 Studies

Two randomized, double-blinded, placebo-controlled phase III studies evaluated the
clinical efficacy and safety of Gardasil™. The two studies, the FUTURE I and FUTURE
II studies, evaluated the clinical endpoints of CIN 2/3 or worse and external genital
lesions due to HPV. The Future II study, which was the larger of the two studies and had
a straightforward design, will be presented first.

Study 015: The FUTURE II Study

The sponsor provided the results from the phase 3 study, “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 16-23 year old women
– The FUTURE II Study.” The study’s primary objective was the determination of safety
and efficacy in the prevention of cervical carcinoma due to HPV type 16 or 18 following
administration of a three-dose regimen among women who had no evidence of previous
infection with HPV.

Female subjects 16-23 years of age who had normal baseline pelvic examinations were
eligible for enrollment and were not prescreened for HPV prior to randomization.
Subjects were randomized 1:1 to receive Gardasil™ or placebo intramuscularly, at
months 0, 2, and 6. Subjects returned on study at months 7, 12, 24, 36, and 48 for review
of serious adverse events, complete physical examination including examination of
external genitalia, and Pap test for cytology. Cytology specimens were evaluated using
the Bethesda System-2001.

Subjects were referred to colposcopy based on a mandatory

Pap test triage algorithm (see appendix A for colposcopy algorithm). An expert
pathology panel, consisting of four pathologists, reviewed the slides prepared from
cervical biopsy/definitive therapy specimens (see Appendix B for Pathology Panel). The
consensus diagnosis of this panel represented the final diagnosis for purposes of the
study’s efficacy endpoints. A lot consistency substudy and an enhanced safety substudy
were incorporated into the study design.

The study began enrollment on June 24, 2002 and ultimately screened approximately
12,700 subjects. In total, 12,167 subjects were enrolled in the study. Of the 540 subjects
who were screened but not enrolled, most were found to have met exclusion criteria
before study entry, for example, reporting greater than 4 lifetime sexual partners or
having a condition that in the opinion of the investigator would interfere with study
participation. The study’s database in preparation for BLA submission was locked on
June 10, 2005. The study is still ongoing. Overall 228 subjects discontinued
participation during the vaccination period, which represented approximately 2% of the
overall study population. The mean duration of clinical endpoint follow-up for this study
after the month 7 study visit was approximately 1.4 years.

Wright TC, et al. Am J Obstet Gynecol, 2003 Jul;189(1):295-304.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

A total of 10,585 subjects, or 87% of all enrolled subjects, met the criteria for the per
protocol population for the primary HPV 16/18 efficacy analysis. (See appendix C for
definitions of the populations for the analyses) The results of the study demonstrated a
vaccine efficacy of 100% for the per protocol primary analysis of efficacy for HPV
16/18, as shown in the table below:

Table 2. Study 015: Analysis of efficacy, per protocol population, against vaccine-
relevant HPV types 16 and 18 CIN 2/3 or worse, and against HPV types 6, 11, 16,
and 18 CIN 2/3 or worse.

[From original BLA, Tables 7-2 and 7-9, complete study report (CSR) for study 015,
pp. 229 and 246, respectively.]

Gardasil™

N=6082

Placebo
N=6075

Endpoint

N
(subgroup)

Number
of cases

PY at
risk

Incidence
Rate per
100 years
at risk

N
(subgroup)

Number
of cases

PY at
risk

Incidence
Rate per
100 years
at risk

Observed
Efficacy

95%
CI

HPV
16/18 CIN
2/3 or
Worse

5301

7435.1 0 5258

7385.5 0.3

100%

75.8,
100%

HPV
6/11/16/18
CIN 2/3 or
Worse*

5383

7545.7 0 5370

7541.5 0.3

100%

81.1,
100%

*Secondary endpoint

It is important to note here that

the applicant’s analyses were specific to the HPV type.

For example, from the efficacy datasets submitted with the BLA subject number
AN47906 is a 21 year old subject randomized to receive Gardasil™. She had evidence of
HPV infection type 16 by PCR detection of HPV 16 DNA at the baseline visit and was
excluded from the efficacy analysis for HPV type 16. She met the colposcopy algorithm
during the study and received a panel diagnosis of CIN 3 disease with virologic evidence
of HPV 16 from her biopsy. However, she was included in the per protocol efficacy
analysis for HPV 18 because she did not meet exclusion criteria for the per protocol
population for HPV 18. Therefore, because she contributed favorable efficacy data for
HPV 18 “incidence rate per 100 years at risk”, she ultimately contributed favorable
primary endpoint efficacy data for the overall per protocol population for HPV 16/18.
The applicant’s modified intent to treat population 2 (MITT-2) included subjects who
were negative at baseline for the vaccine-relevant HPV types 6, 11, 16, or 18 and
received at least one vaccine.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 3. Study 015:

Analysis of efficacy, MITT-2 population, against vaccine-

relevant HPV types 16 and 18 CIN 2/3 or worse.

[From original BLA, Table 7-4, CSR for study 015, p. 235.]

Gardasil™

N=6082

Placebo
N=6075

Endpoint N

(subgroup)

Number
of cases

PY at
risk

Incidence
Rate per
100 years
at risk

N
(subgroup)

Number
of cases

PY at
risk

Incidence
Rate per
100 years
at risk

Observed
Efficacy

95%
CI

HPV
16/18
CIN 2/3
or
Worse

5736

10797.2 <0.001 5766

10881.5 0.3

97.2%

83.4,
99.9%

Table 4 presents the analysis of all subjects who received at least one vaccine regardless
of baseline HPV serostatus or PCR results and had documentation of follow up at least
once after the one month study visit (MITT-3 population):

Table 4. Study 015:

Analysis of efficacy, MITT-3 population, against vaccine-

relevant HPV 16 and 18 CIN 2/3 or worse

[From original BLA, Table 11-86, CSR for study 015, p. 657.]

Gardasil™

N=6082

Placebo
N=6075

Endpoint N

(subgroup)

Number
of cases

PY at
risk

Incidence
Rate per
100 years
at risk

N
(subgroup)

Number
of cases

PY at
risk

Incidence
Rate per
100 years
at risk

Observed
Efficacy

95%
CI

HPV
16/18
CIN 2/3
or
Worse

5947

11159.5 0.6 5973

116

11242.9 1.0

40.9%

19.7,
56.9%

Secondary endpoints of study 015 included the presence of external genital lesions. The
following tables demonstrate the observations of genital lesions (EGL) due to vaccine-
associated HPV types in the per protocol population and the observations of genital
lesions due to any type of HPV in the MITT-3 population.

Table 5. Study 015:

Analysis of efficacy, per protocol population, against EGL due

to HPV type 6, 11, 16, or 18. [

From original BLA, Table 7-11, CSR for study 015, p.

251.]

Gardasil™

N=6082

Placebo
N=6075

Endpoint

Number
of cases

PY at
risk

Incidence
Rate per
100 years at
risk

N Number

of Cases

PY at
risk

Incidence
Rate per
100 years at
risk

Observed
Efficacy

95%
CI

HPV
6/11/16/18
EGL

5401

7545.8

<0.001 5387

7513.7 0.9

98.6%

91.8,
100%

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 6. Study 015: Analysis of efficacy, MITT-3 population, against EGL due to
any type HPV.
[

From original BLA, CSR for study 015, Table 11-99, p. 673.]

Gardasil™

N=6082

Placebo
N=6075

Endpoint

Number
of cases

PY at
risk

Incidence
Rate per
100 years at
risk

N Number

of Cases

PY at
risk

Incidence
Rate per
100 years at
risk

Observed
Efficacy

95%
CI

HPV any
type EGL

6016

11,116.4 0.9 6027

177

11,153.6 1.6

45.6%

29.8,
58.0%

Study 013: The FUTURE I Study

The BLA contained results from the phase 3 study, “A study to evaluate the efficacy of
the quadrivalent HPV (types 6, 11, 16, 18) L1 virus like particle (VLP) vaccine in
reducing the incidence of HPV 6, 11, 16, and 18 related external genital warts, VIN,
VaIN, Vulvar Cancer, and Vaginal Cancer in 16-23 year old women.” The study’s co-
primary objectives included the determination of vaccine efficacy based on incidence of
CIN, adenocarcinoma in situ, or cervical cancer due to all four HPV types (6, 11, 16, and
18) following administration of a three-dose regimen among women who had no
evidence of previous infection with HPV. The study was designed to provide evidence of
safety and efficacy for the prevention of cervical cancer in a population of adolescent and
young adult females.

This multi-center and multinational study enrolled healthy female subjects 16-23 years of
age who had normal baseline pelvic examinations. Subjects were not prescreened for
HPV prior to randomization. Subjects received vaccine formulation or placebo
intramuscularly at months 0, 2, and 6. Subjects returned on study at months 3, 7, 12, 18,
24, 30, 36, and 48 for review of safety and complete physical examination including
examination of external genitalia. Pap tests were performed at day 1 and months 7, 12,
18, 24, 30, and 36. Sera for immunogenicity were obtained at day 1 and at months 7, 12,
24 and 48. Subjects were first evaluated in one of two embedded substudies: either
concomitant administration with hepatitis B vaccine (study 011) or a comparative arm
with a monovalent HPV 16 (study 012). Therefore, randomization schemes differed as to
whether subjects were first enrolled in study 011 or study 012. After administration of
three doses of study vaccines or placebo, subjects were followed for the primary clinical
outcomes (study 013). For study 013, approximately the same proportions were
randomly assigned to Gardasil™ or placebo. Cytology specimens were evaluated using
the Bethesda System-2001.

The study included an algorithm for referral to colposcopy,

which differed slightly from that used in study 015 (see Appendix A). Subjects in study
015 who had atypical squamous cells of undetermined significance (ASC-US) were not
referred to colposcopy, but had a Pap test repeated sooner at 6 months instead of
scheduled 12 months. In this study, subjects with ASC-US received an HPV probe, and
if positive were referred to colposcopy. An expert pathology panel, consisting of four

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

pathologists, reviewed the slides prepared from cervical biopsy/definitive therapy
specimens (see Appendix B). The consensus diagnosis of this panel represented the final
diagnosis for purposes of the study’s primary efficacy endpoint. This study’s co-primary
endpoint was CIN 1 or worse.

The study began enrollment on December 28, 2001 and ultimately screened 6767
subjects. In total, 5759 subjects were enrolled in the study and had a mean duration of
follow-up of 1.7 years. For the 1008 subjects who screened for the study but did not
enroll, most were found to have met exclusion criteria before study entry, for example,
reporting greater than 4 lifetime sexual partners or having a condition that in the opinion
of the investigator would interfere with study participation. The study database was
locked on November 4, 2005 for evaluation of the efficacy endpoints. The study is still
ongoing. Overall 274 subjects discontinued participation during the vaccination period,
which represented approximately 5% of the overall study population. The 304 subjects
randomized to receive monovalent HPV 16 VLP vaccine in the substudy 012 were not
evaluated for the longer term efficacy and safety follow up in study 013. An additional
246 (4.5%) of subjects did not complete the longer term follow up after the vaccination.
The demographic characteristics between the Gardasil™ vaccine group and the placebo
group were well balanced. Approximately 78% of subjects were included in the per
protocol efficacy population for HPV 6/11/16/18; 22% were excluded from per protocol
population. About 27% of subjects were either seropositive to a vaccine-relevant HPV
type or had positive PCR at baseline. This difference in proportions reflects the HPV
type-specific analyses of the data, where a subject could be excluded from one HPV type-
specific per protocol efficacy population but be included in other HPV type-specific
efficacy populations as illustrated above by the subject in study 015. The following
tables outline the applicant’s analyses similar to the above descriptions for study 015,
although for study 013 the primary endpoint was CIN 1 or worse:

Table 7. Study 013:

Analysis of efficacy, per protocol population, against vaccine-

relevant HPV 6, 11, 16 or 18 CIN 1 or worse.

[From original BLA, Table 7-4, CSR for study 013, p. 242.]

Gardasil™

N=2717

Placebo
N=2725

Endpoint

N
(subgroup)

Number
of cases

PY at
risk

Incidence
Rate per
100
person
years at
risk

N
(subgroup)

Number
of cases

PY at
risk

Incidence
Rate per
100
person
years at
risk

Observed
Efficacy

95% CI

HPV
6/11/16/18
CIN 1 or
worse

2240

3779.8 0 2258

3787.4 1.0

100%

87.4,
100.0%

The applicant’s analysis of the subjects who were negative at baseline for all four HPV
types and received at least one vaccine (MITT-2 population) was an approach to evaluate
vaccine efficacy on a modified intent-to-treat basis.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 8. Study 013:

Analysis of efficacy, MITT-2 population, against vaccine-

relevant HPV 6, 11, 16 or 18 CIN 1 or worse

[From original BLA, Table 7-7, CSR for study 013, p. 249.]

Gardasil™

N=2717

Placebo
N=2725

Endpoint

N
(subgroup)

Number
of cases

PY at
risk

Incidence
Rate per
100
person
years at
risk

N
(subgroup)

Number
of cases

PY at
risk

Incidence
Rate per
100
person
years at
risk

Observed
Efficacy

95%
CI

HPV
6/11/16/18
CIN 1 or
worse

2557

(both
CIN 1)

5490.1 <0.001 2573

5489.0 1.0

96.5%

86.7,
99.6%

Similar to study 015, the applicant provided an analysis of all study subjects who
received at least one vaccine and had follow up data collected at least one month after
receipt of vaccine in the study (MITT-3 population). Table 9 presents data for the
endpoint CIN 2/3 or worse, which was not the primary endpoint for study 013; however,
these data are provided for comparison to study 015.

Table 9. Study 013:

Analysis of efficacy, MITT-3 population, against vaccine-

relevant HPV types 6, 11, 16 or 18 CIN 1 or worse, and CIN 2/3 or worse.

[From original BLA, Table 7-8, CSR for study 013, p. 250.]

Gardasil™

N=2717

Placebo
N=2725

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

Efficacy

95%

HPV
6/11/16/18
CIN 1 or
worse

2607

5566.5

1.2 2611

113

5525.4 2.0 42.9%

21.9,

58.6%

HPV
6/11/16/18
CIN 2/3 or
worse

2607

5585.0

0.9 2611

5570.4 1.1 22.8%

<0,

48.2%

The study’s co-primary endpoint was the presence of external genital lesions (EGL). The
results of the per protocol population for vaccine-relevant EGL and the MITT-3
population for EGL due to any type of HPV are presented below.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 10. Study 013:

Analysis of efficacy, per protocol population, against external

genital lesions EGL due to HPV types 6, 11, 16, and 18.
[

From original BLA, Table 7-14, CSR for study 013, p. 264.]

Gardasil™

N=2717

Placebo
N=2725

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

Efficacy

95% CI

HPV
6/11/16/18
Related
EGL

2261

3865.2

<0.001 2279

3868.4 1.0 100.0%

88.4,

100.0%

Table 11. Study 013:

Analysis of efficacy, MITT-3 population, against EGL due to

any type HPV.

[From original BLA, Table 11-82, CSR for study 013, p. 626.]

Gardasil™
N=2717

Placebo
N=2725

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100 person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100 person

years at

risk

Observed

Efficacy

95%

EGL due
to any
HPV type

2671

5641.9

1.5 2668

126

5598.5 2.3 31.5%

9.2,

48.5%

Combined Efficacy Analyses

The following tables demonstrate efficacy analyses that were provided by the applicant.
Efficacy data from studies 007, 013, and 015 where subjects were randomized to receive
either Gardasil™ or placebo were included. Please refer to Appendix C for definitions of
the efficacy analysis populations.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 12. Studies 007, 013 and 015:

Combined analysis of efficacy against the

incidence of CIN 2/3 or worse due to vaccine-relevant HPV 6, 11, 16, or 18.

[From original BLA, Summary of Clinical Efficacy, Table 2.7.3-cervixcancer: 27].

Gardasil™

N=9075

Placebo
N=9075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

Efficacy

95%

HPV
6/11/16/18
CIN 2/3 or
worse

MITT-2

8625

17139.1

<0.001 MITT-2

8673

17231.2 0.4 98.5%

91.6,

100%

HPV
6/11/16/18
CIN 2/3 or
worse

MITT-3

8814

118

17467.0

0.7 MITT-3

8846

186

17527.5 1.1 36.3%

19.4,

49.9%

* There were no cases of CIN 2/3 or worse in this analysis among Gardasil™ recipients
in study 013

Table 13. Studies 007, 013 and 015:

Combined analysis of efficacy against incidence

of CIN 2/3 or worse due to any type HPV.

[From additional efficacy analyses requested by CBER and submitted March 15, 2006,
Table 2-2 p. 21.]

Gardasil™

N=9075

Placebo
N=9075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

Efficacy

95%

HPV any
type CIN
2/3 or
worse

RMITT-2*

5638

11333.4

0.5 RMITT-2

5701

11454.4 0.8 37.9%

13.2,

55.9%

HPV any
type CIN
2/3 or
worse

MITT-3

8814

287

17409.5

1.6 MITT-3

8846

328

17469.4 1.9 12.2%

<0.0,

25.3%

Here the applicant provided integrated efficacy analyses due to any type HPV for the

RMITT-2 population and did not submit integrated efficacy analyses for the MITT-2
population.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 14. Studies 007, 013 and 015:

Combined analysis of efficacy against EGL due

to vaccine-relevant HPV 6, 11, 16, 18 in MITT-2 and MITT-3 populations.

[From original BLA, Summary of Clinical Efficacy, Appendix 2.7.3 exgenlesions-8,
p.63.]

Gardasil™

N=9075

Placebo
N=9075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

Efficacy

95%

EGL due
to HPV
6/11/16/18

MITT-2

8760

17300.4

0.1 MITT-2

8786

174

17297.5 1.0 94.8%

90.0,

97.7%

EGL due
to HPV
6/11/16/18

MITT-3

8954

17595.0

0.4 MITT-3

8962

229

17560.1 1.3 70.4%

61.0,

77.7%

Table 15. Studies 007, 013 and 015: Combined analysis of efficacy against EGL due
to any type HPV among RMITT-2 and MITT-3 populations.

[From original BLA, Summary of Clinical Efficacy, Appendix 2.7.3 exgenlesions-9, p.
46.]

Gardasil™

N=9075

Placebo
N=9075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

Efficacy

95%

EGL due
to any
HPV
type

RMITT-2*

5734

11298.0

0.5 RMITT-2

5769

167

11345.6 1.5 65.7%

53.4,

75.1%

EGL due
to any
HPV
type

MITT-3

8954

185

17487.4

1.1 MITT-3

8962

307

17480.0 1.8 39.8%

27.5,

50.1%

As with the integrated analyses for CIN 2/3 or worse, the applicant provided integrated

efficacy analyses due to any type HPV for the RMITT-2 population and did not submit
integrated efficacy analyses for the MITT-2 population.

In addition, the applicant provided the results of study 005, in which subjects were
clinically evaluated for a mean duration of 3.1 years following the administration of a
monovalent HPV 16 VLP or placebo. The results from this study were based on longer-
term follow up compared to the results from the other studies that provided efficacy data.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 16. Study 005: Analysis of efficacy, MITT-3 population, against the incidence
of CIN 2/3 or worse due to any HPV type.

[From original BLA, CSR for study 005, Table 11-33.]

Monovalent HPV 16 VLP

N=1193

Placebo
N=1198

Endpoint

(subgroup)

Number

of cases

risk

Incidence

Rate per

100 person

years at risk

(subgroup)

Number

of cases

risk

Incidence

Rate per

100 person

years at risk

Observed

Efficacy

95%

HPV any
type CIN
2/3 or
worse

MITT-3

1017

3635

0.7 MITT-3

1050

3683 1.4 45.3%

10.9,

67.1%

HPV any
type CIN
3

MITT-3

1017

3638

0.2 MITT-3

1050

3700 0.6 70.9%

25.6,

90.4%

Concerns Regarding Primary Endpoint Analyses among Subgroups

There were two important concerns that were identified during the course of the efficacy
review of this BLA. One was the potential for Gardasil™ to enhance disease among a
subgroup of subjects who had evidence of persistent infection with vaccine-relevant HPV
types at baseline. The other concern was the observations of CIN 2/3 or worse cases due
to HPV types not contained in the vaccine. These cases of disease due to other HPV
types have the potential to counter the efficacy results of Gardasil™ for the HPV types
contained in the vaccine.

Evaluation of the potential of Gardasil™ to enhance cervical disease in
subjects who had evidence of persistent infection with vaccine-relevant HPV
types prior to vaccination.

The results of exploratory subgroup analyses for study 013 suggested a concern that
subjects who were seropositive and PCR-positive for the vaccine-relevant HPV types had
a greater number of CIN 2/3 or worse cases as demonstrated in the following table:

Table 17. Study 013: Applicant’s analysis of efficacy against vaccine-relevant HPV
types CIN 2/3 or worse among subjects who were PCR positive and seropositive for
relevant HPV types at day 1

. [From original BLA, study 013 CSR, Table 11-88, p. 636]

Gardasil™

N=2717

Placebo
N=2725

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

Efficacy

95% CI

HPV
6/11/16/18
CIN 2/3
or worse

156

278.9

11.1 137

247.1 7.7 -44.6%

<0.0,
8.5%

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

CBER further evaluated this subgroup by looking at potential imbalances in the baseline
demographic characteristics:

Table 18; Study 013: Selected characteristics for subgroup of PCR positive and
seropositive for vaccine-relevant HPV types at day 1.

[From additional efficacy analyses requested by CBER and submitted March 15, 2006,
table 1e-2, p. 13.]

Study 013

subgroup

Gardasil™ Placebo

Subgroup population

156 137

Current smoker

34.6% 31.4%

History of cervicovaginal
infection or STD

35.9% 32.1%

Pap test with HSIL

6.5% 3.7%

The applicant also provided an analysis of the subgroup of subjects who were PCR
positive and/or seropositive for the relevant vaccine HPV type at day 1. In this subgroup,
subjects were included if they were PCR positive and seropositive, PCR positive and
seronegative, or PCR negative and seropositive at the day 1 evaluation.

Table 19. Study 013: Analysis of efficacy against vaccine-relevant HPV types CIN
2/3 or worse among subjects who were PCR positive and/or seropositive for the
relevant HPV type at day 1.

[From additional efficacy analyses requested by CBER and submitted March 15, 2006,
table 1e-2, p. 13.]

Gardasil™

N=2717

Placebo
N=2725

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

Efficacy

95%

HPV
6/11/16/18
CIN 2/3
or worse

685

1385.6

3.5 664

1350.3 2.6 -33.7%

<0.0,

15.3%

This demonstrated a limitation of the evaluation of small subgroups, where subgroups
might have imbalances in baseline demographic characteristics. In this case, it appeared
that subjects in this subgroup of study 013 who received Gardasil™ might have had
enhanced risk factors for development of CIN 2/3 or worse compared to placebo
recipients. In study 015, the applicant conducted a subgroup primary efficacy analyses
for HPV 16/18. Here, the evaluation of this subgroup did not raise a concern about
enhancement of cervical disease due to HPV:

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 20. Study 015: Analysis of efficacy against vaccine-relevant HPV types CIN
2/3 or worse among subjects who were PCR positive and seropositive for the
relevant HPV type at day 1

[From additional efficacy analyses requested by CBER and submitted March 15, 2006,
Table 1a-1, p. 2.]

Gardasil™

N=6082

Placebo
N=6075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

risk

Incidence

Rate per

100

person

years at

risk

Observed

reduction

95% CI

HPV
6/11/16/18
CIN 2/3
or worse

398

703.0

6.0 430

760 6.3

5.4

<0.0,

39.0%

The baseline demographic data appeared to be more balanced in this subgroup in study
015. Furthermore, evaluation of the subgroups of subjects who were PCR positive and
seropositive for relevant HPV type at day 1 across studies and for HPV 6, 11, 16 and 18
types tempered evidence of disease enhancement.

Table 21. Combined analysis studies 007, 013 and 015: Analysis of efficacy against
vaccine HPV related CIN among subjects who were PCR positive and seropositive
for the relevant HPV type at day 1.

[From additional efficacy analyses requested by CBER and submitted March 15, 2006,
Table 1b-1, p. 4.]

Gardasil™

N=9075

Placebo
N=9075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed
reduction

95%

HPV
6/11/16/18
CIN 2/3
or worse

568

1016.2

7.4 580

1044.0 6.6 -11.7

<0.0,

20.6%

Therefore, while the subgroup from study 013 remains a concern of the clinical review
team, there is some evidence that this represented an unbalanced subgroup where
Gardasil™ recipients at baseline had more risk factors for development of CIN 2/3 or
worse. Furthermore, when the subgroups from three studies are combined, these groups
appear to be more similar. Finally, there is compelling evidence that the vaccine lacks
therapeutic efficacy among women who have had prior exposure to HPV and have not
cleared previous infection (PCR positive and seropositive), which represented
approximately 6% of the overall study populations.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Cases of CIN 2/3 or worse due to HPV types not associated with Gardasil™

The second concern was the observations of CIN 2/3 or worse cases due to HPV types
not associated with Gardasil™.

Table 22. Study 015: Analysis of efficacy against CIN 2/3 or worse due to any HPV
type, restricted MITT-2 population.

[From original BLA, CSR for study 015, Table 7-12, p. 256.]

Gardasil™

N=6082

Placebo
N=6075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

efficacy

95%

HPV
any type
CIN 2/3
or worse

3789

7,186.6

0.4 3826

7272.7 0.7 36.5%

<0.0,

60.5%

The applicant’s analyses primarily focused on vaccine-relevant HPV analyses.
Therefore, at CBER’s request the applicant provided an additional analysis of the
subgroup of subjects who met the “per protocol” definition for all four vaccine-relevant
HPV types:

Table 23. Study 015:

Analysis of efficacy against CIN 2/3 or worse due to any type

HPV, subgroup of subjects meeting the “per protocol” population for all four
vaccine-relevant HPV types.

[From the applicant’s response to CBER questions to MRL sent via secure email on
March 1, 2006, Table 1-2, p. 17.]

Gardasil™

N=6082

Placebo
N=6075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

Cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed
reduction

95%

HPV any
type CIN
2/3 or
worse

3899

5470.2

0.8 3703

5214.4 0.9 14.4%

<0.0,

44.3%

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 24. Study 013:

Analysis of efficacy against CIN 2/3 or worse due to any HPV

type, restricted MITT-2 population

[From original BLA, CSR for study 013, Table 7-24, p. 290.]

Gardasil™

N=2717

Placebo
N=2725

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed
reduction

95%

HPV any
type CIN
1 or worse

1683

102

3635.8

2.8 1697

135

3613.1 3.7 24.9%

2.2,

42.5%

HPV type
6/11/16/18
CIN 1 or
worse

1683

3685.7

0 1697

3689.9 1.1 100%

90.1,

100%

HPV not
related to
6/11/16/18
CIN 1 or
worse

1683

102

3635.8

2.8 1697

107

3627.2 2.9 4.9%

<0,

28.2%

*The applicant did not provide an analysis for this study of CIN 2/3 or worse.

Finally, the applicant provided analyses across all studies using Gardasil™.

Table 25. Studies 007, 013, and 015: Analysis of efficacy against CIN 2/3 or worse
due to any HPV type among subgroup of subjects meeting the “per protocol”
population for all four vaccine-relevant HPV types

[From the applicant’s response to CBER questions to MRL sent via secure email on
March 1, 2006, Table 1-2 p. 19.]

Gardasil™

N=9075

Placebo
N=9075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

Cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

reduction

95%

HPV any
type CIN
2/3 or
worse

5685

8631.5

0.9 5457

8315.7 1.0 16.9%

<0,

39.8%

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 26. Studies 007, 013, and 015

Analysis of efficacy against CIN 2/3 or worse

due to any HPV type among subgroup of subjects meeting the “per protocol”
population for all four vaccine-relevant HPV types, and who had normal Pap
smears at day 1

[From the applicant’s response to CBER questions to MRL sent via secure email on
March 1, 2006, Table 1-2 p. 20.]

Gardasil™

N=9075

Placebo
N=9075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

Cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed

reduction

95%

HPV any
type CIN
2/3 or
worse

5051

7680.9

0.7 4887

7465.8 0.9 20.5%

<0,

45.5%

The applicant also provided an analysis of efficacy against CIN 2/3 due to any type HPV
in the population that is considered to cover nearly all subjects enrolled in studies 007,
013, and 015, the MITT-3 population.

Table 27. Studies 007, 013, and 015

Analysis of efficacy against CIN 2/3 or worse

due to any HPV type, MITT-3 population

[From the applicant’s responses to CBER questions submitted March 15, 2006, Table on
p. 17.]

Gardasil™

N=9075

Placebo
N=9075

Endpoint

(subgroup)

Number

of cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

(subgroup)

Number

Cases

PY at

risk

Incidence

Rate per

100

person

years at

risk

Observed
reduction

95%

HPV any
type CIN
2/3 or
worse

8814

287

17409.5

1.6 8846

328

17469 1.9 12.2%

<0,

25.3%

HPV not
6/11/16/18
CIN 2/3 or
worse

8814

169

-- 8846

142

-- -- --

Therefore, CIN 2/3 or worse due to HPV types not contained in Gardasil™ were
identified among subjects randomized to receive Gardasil™ as well as in subjects
randomized to receive placebo. In the subgroup of subjects that did not have prior
exposure to vaccine-relevant HPV and had normal baseline Pap tests, there appeared to
be a modest efficacy of approximately 20% against CIN 2/3 or worse due to any type
HPV. We again note the important limitations of a subgroup analysis where imbalances

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

in baseline demographics could account for differences in the subgroup efficacy
determinations. The degree to which cases of CIN 2/3 or worse due to HPV types not
associated with Gardasil™ might offset its efficacy against vaccine-relevant HPV types
has not been fully elucidated in these studies. The BLA contained virologic
characterization of disease due to HPV types 6, 11, 16 or 18 and did not characterize
other HPV types. The applicant proposed a plan to identify the HPV types other than 6,
11, 16, or 18 from the studies’ clinical specimens.

Studies in Younger Age Groups

Study 016: “Bridging” immune response study and “End-expiry” study

Study 016, “A study to demonstrate immunogenicity and tolerability of the quadrivalent
HPB (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine in preadolescents and
adolescents, and to demonstrate end-expiry specifications for the vaccine”, was a phase 2
study of the safety and immunogenicity of Gardasil™ when administered to
approximately 2,500 healthy children 10 to 15 years of age and healthy adolescent and
adult females 16 to 23 years of age. In addition to the primary objective of safety, the
study contained two “substudies” that were designed to evaluate immune responses
following partial doses and to compare immune responses in children 10 to 15 years of
age to the immune responses in adolescent and young adult females 16 to 23 years of age.
Therefore, the study was intended to serve as an immune response “bridging study” to
support the use of Gardasil™ in girls ages 10 to 15 years. The table below illustrates the
immune response analyses by comparison of GMT between 10-15 year old females and
16-23 year old females.

Table 28. Protocol 016: Statistical Analysis of Non-Inferiority of Month 7 HPV
cLIA GMTs Comparing 10-15 year old females to 16-23 year old females.

[From original BLA, CSR synopsis, protocol 016, p. 127.]

10-15 year old females

N=506

16-23 year old females

N=511

Assay

N Estimated

GMT

(mmU/mL)

N Estimated

GMT

(mmU/mL)

Estimated

Fold

Difference

Group

A/Group B

(95% CI)

p-value for

non-

inferiority

Anti-
HPV 6

426

960.0

320

574.9 1.67

(1.46, 1.91)

< 0.001

Anti-
HPV 11

426

1224.8

320

705.9 1.74

(1.50, 2.00)

< 0.001

Anti-
HPV 16

427

4713.3

306

2548.0 1.85

(1.55, 2.21)

< 0.001

Anti-
HPV 18

429

918.4

340

452.9 2.03

(1.72, 2.39)

< 0.001

The end expiry substudy enrolled approximately 500 subjects to receive a 20%
formulation (2/8/8/4), approximately 500 subjects to receive a 40% formulation

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

(8/16/16/8), approximately 500 subjects to receive a 60% formulation (12/24/24/12), and
approximately 1500 subjects to receive the full dose formulation. The subjects receiving
different dose formulations were from one of each of the three age/gender groups. There
appeared to be a dose response with increasing dose formulations in this study.

Study 018: Safety and immune response younger children

Study 018, “A safety and immunogenicity study of quadrivalent HPV (types 6, 11, 16,
18) L1 virus-like particle (VLP) in preadolescents and adolescents”, was designed to
demonstrate non-inferiority of immune responses between males and females 9 to 15
years of age. Over 1700 children, one-half boys and one-half girls were randomized in a
2:1 fashion to receive Gardasil™ or placebo. The primary objective was the collection of
safety data, which contributed to the overall safety database discussed below. The
following figure represents an immune response analysis across all studies and all age
groups of female subjects for HPV 16. In general, immune responses to HPV types 6, 11,
and 18 appeared to be similar to this figure:

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Safety

The safety data from all clinical studies were reviewed. These data across all protocols,
in which subjects received Gardasil™ (studies 007, 013, 015, 016 and 018), are
summarized here. Serious adverse events (SAEs) or deaths appeared to be reported with
equal frequencies between Gardasil™ groups and placebo groups and are outlined in the
tables below.

Table 29. Number (%) of SAEs and deaths combined from studies 007, 013, 015,
016, and 018.

[From March 8, 2006 safety update tables 2.7.4: 20 and 2.7.4: 21.]
Serious adverse event

Gardasil™ N=11778

Placebo N=9680

SAE over study period

101 (0.9%)

97 (1.0%)

SAE reported 1-15 days

53 (0.5%)

42 (0.4%)

Deaths [Table 2.7.4:20]

11 7

There were eleven deaths in subjects who received Gardasil™: six were attributed to
traumatic injuries or drug overdose, one death attributed to pancreatic cancer, one death
attributed to cardiac arrhythmia, one death attributed to DVT/PE, one death attributed to
DIC with possible sepsis, and one death attributed to pneumonia and sepsis. Of the seven
deaths in subjects who received placebo, five were attributed to traumatic injuries or
suicide, one death attributed to complications of labor and delivery, and one death
attributed to pulmonary embolism. Most deaths occurred months or years after the third
vaccination and thus there were no obvious temporal associations between deaths and
administration of study vaccine. A review of the serious adverse events that were
observed in subjects randomized to receive Gardasil™ did not demonstrate a safety
signal of concern.

Table 30. Review of SAEs by organ system in studies 007, 013, 015, 016 and 018.

[From March 8, 2006 safety update submitted to BLA, Table 2.7.4:21]

Serious adverse event

Gardasil™ N=11778

Placebo N=9680

Gynecological or obstetrical

42 41

Gastrointestinal

11 6

*Appendicitis

4 1

Injury

6 6

Neurological

4 7

Immune mediated

2 4

Coagulation/DVT

2 1

Pulmonary

2 5

Genitourinary

6 3

Endocrine

1 0

Injection site reaction

1 0

Psychiatric

5 2

Cardiovascular

1 1

Musculoskeletal

1 1

ENT

1 0

Administration of excess study vaccine

16 20

Total

101 97

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Local and systemic reactogenicity data from the subjects who kept more intensive diary
cards (Detailed Safety Population) in the several days following vaccination
demonstrated that subjects randomized to receive Gardasil™ had a greater proportion
with mild to moderate injection site reactions. Severe injection site reactions were very
infrequently reported but higher in the subjects randomized to receive Gardasil™.

Table 31. Detailed Safety Population: Number (%) of subjects who reported
injection site adverse event experiences by maximum intensity rating following any
vaccination in studies 007, 013, 015, 016 and 018.

[From original BLA, safety summary, Table 2.7.4:45.]

Injection site adverse
reactions

Gardasil™ N=6160

Placebo N=4064

Subjects with injection site
experiences

5030 (82.9%)

2927 (73.3%)

Mild

3162 (52.1%)

2125 (53.2%)

Moderate

1586 (26.1%)

724 (18.1%)

Severe

271 (4.5%)

76 (1.9%)

Table 32. Detailed Safety Population: Number (%) of subjects who reported
systemic adverse reactions of 2% or greater in the 15 days following receipt of study
vaccine.

[From original BLA, safety summary, Table 2.7.4:14.]

Systemic adverse reaction

Gardasil™ N=6160

Placebo N=4064

Subjects reporting systemic
adverse reaction

3591 (59.2%)

2414 (60.4%)

Headache

1602 (26.4%)

1101 (27.6%)

Pyrexia

782 (12.9%)

440 (11.0%)

Nausea

370 (6.1%)

251 (6.3%)

Diarrhea

224 (3.7%)

144 (3.6%)

Nasopharyngitis

353 (5.8%)

245 (6.1%)

Pharyngolaryngeal pain

266 (4.4%)

190 (4.8%)

Dizziness

214 (3.5%)

142 (3.6%)

Skin disorder

210 (3.5%)

143 (3.6%)

Abdominal pain upper

193 (3.2%)

136 3.4%)

Influenza

192 (3.2%)

154 (3.9%)

Dysmenorrheal

178 (2/9%)

152 (3.8%)

Abdominal pain

157 (2.6%)

82 (3.2%)

Fatigue

156 (2.6%)

85 (2.1%)

Vomiting

147 (2.4%)

81 (2.0%)

Injury, poisoning,
procedural complications

143 (2.4%)

85 (2.1%)

Myalgias

119 (2.0%)

81 (2.0%)

Pain in extremity

118 (1.9%)

95 (2.4%)

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

The following table outlines the reports of new medical problems that were collected
during the vaccination schedule and following the vaccination schedule. The organ
systems that are bolded indicate differences between the Gardasil™ and placebo groups.

Table 33. New Medical Conditions (number and percent) during the vaccination
period (day 0 through month 7) and after month 7, selected organ system
evaluations where proportions differed between Gardasil™ and placebo groups

[From March 8, 2006 safety update submitted to BLA, Appendix 2.4.7:31.]

During vaccination period

Post month 7

Organ System

Gardasil™

N= 11778

(%)

Placebo

N= 9868

(%)

Gardasil™

N= 10452

(%)

Placebo

N= 9385

(%)

Eye disorders

118 (1.0)

72 (0.7)

82 (0.8)

78 (0.8)

Conjunctivitis

61 (0.5)

36 (0.4)

45 (0.4)

54 (0.6)

Respiratory, thoracic,
mediastinal disorders

379 (3.2)

234 (2.4)

172 (1.6)

154 (1.6)

Cough

104 (0.9)

70 (0.7)

42 (0.4)

41 (0.4)

Nasal congestion

31 (0.3)

21 (0.2)

3 (<0.1)

Pharyngeolaryngeal pain

119 (1.0)

64 (0.7)

30 (0.3)

36 (0.4)

Allergic rhinitis

46 (0.4)

18 (0.2)

15 (0.1)

12 (0.1)

Surgical or medical procedures

384 (3.3)

296 (3.1)

477 (4.6)

495 (5.3)

Appendectomy

19 (0.2)

4 (<0.1)

17 (0.2)

26 (0.3)

One potential safety signal in the BLA was reports of congenital anomalies among
women who became pregnant and gave birth during the study period. When limited to
receipt of vaccine within 30 days of becoming pregnant, there were five reports of
congenital anomalies among women who received Gardasil™ and no reports of
congenital anomalies among women who received placebo. However, the five congenital
anomalies were widely varied and did not fit a particular pattern. The following table
outlined pregnancies and pregnancy outcomes that were observed in all clinical studies of
Gardasil™.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Table 34. Pregnancy outcomes from studies 013, 105, 016 and 018.

[From March 8, 2006 safety update submitted to BLA, table 2.7.4:24.]

Gardasil™ N=10418

Placebo N=9120

Number of pregnancies

1115 (10.7%)

1151 (12.6%)

Live births

621 (62.3%)*

611 (60%)*

Vaginal delivery

467 (75.2%)

462 (75.6%)

Infant outcome = normal

570 (91.8%)

569 (93.1%)

Infant outcome = abnormal

49 (7.9%)

40 (6.5%)

Congenital anomaly: live births

14 (2.3%)

12 (2.0%)

Other medical condition

39 (6.3%)

28 (4.6%)

Congenital anomaly infant or
fetus

15 16

Abdominal wall defect

0 5

Cardiac

8 5

Chromosomal abnormality

2 0

Craniofacial/ENT

4 2

Gastrointestinal

3 0

Hematological

0 1

Orthopedic/musculoskeletal 3 5
Renal

0 1

* Percent based on known pregnancy outcome

Some infants had more than one reported congenital anomaly

The applicant further evaluated congenital anomalies by the timing of the administration
of study vaccine. Here, infant/fetus congenital anomalies are summarized by the
estimated date of conception within or beyond 30 days of receipt of study vaccine.

Table 35. Distribution of congenital anomaly cases

. [From March 8, 2006 safety

update submitted to BLA, table 2.7.4:26.]

Gardasil™ Placebo

Congenital anomaly infant
or fetus

15 16

EDC within 30 days

EDC beyond 30 days

10 16

Summary of the five cases of congenital anomalies in the Gardasil™ group:

Hip dysplasia

Pyloric stenosis, ankyloglossia

Congenital hydronephrosis

Congenital megacolon

Left talipes equinovarus

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Appendix B

For all studies included in the efficacy composite (Studies 005, 007, 013, and 015), these
procedures were used for cervical biopsy/definitive therapy specimens, from original
BLA Summary of Clinical Efficacy – cervixcancer section 2.7.3, p. 42:

Slides of tissue specimens were prepared by the program central laboratory. The
laboratory reviewed the slides and provided a diagnosis for the purpose of
management of the subject. The diagnosis from the laboratory was not included
in the endpoint definition because studies have shown that pathologists who read
histologic slides for the purpose of medical management tend to over-diagnosis
CIN 1 lesions due to medicolegal pressure. The slides prepared by the central
laboratory from the cervical biopsy/definitive therapy specimens were submitted
to an expert Pathology Panel. This panel, consisting of four pathologists,
reviewed these slides for the purpose of providing the official diagnosis for the
primary analysis of vaccine efficacy. The Pathology Panel was blinded to the
results of the PCR analysis of the cervical biopsy/definitive therapy specimen and
HPV PCR swabs obtained during routine visits. The consensus diagnosis of the
panel represented the final diagnosis for study purposes.

VRBPAC Background Document
Gardasil™ HPV Quadrivalent Vaccine

Appendix C:

Applicant’s definitions of the populations used in efficacy analyses.

Per Protocol:

•

Received all three vaccinations

•

Seronegative at day 1 and PCR-negative at day 1 and at month 7 to the appropriate
HPV types

•

Did not deviate from the protocol

•

Clinical endpoints were counted beginning one month after the third dose (month 7)

Modified Intent-to-treat population 1 (MITT-1):

•

Received all three vaccinations

•

Seronegative at day 1 and PCR-negative at day 1 and at month 7 to the appropriate
HPV types

•

Clinical endpoints were counted beginning one month after the third dose (month 7)

Modified Intent-to-treat population 2 (MITT-2):

•

Received at least one vaccine

•

Seronegative at day 1 and PCR-negative at day 1 to the appropriate HPV types

•

Had any follow-up visit after one month following the first injection

•

Clinical endpoints were counted beginning one month after the first dose (month 1)

Modified Intent-to-treat population 2, restricted (RMITT-2):

•

Received at least one vaccine

•

Seronegative at day 1 and PCR-negative at day 1 to the appropriate HPV types

•

Had any follow-up visit after one month following the first injection

•

Pap test results normal at day 1

•

Clinical endpoints were counted beginning one month after the first dose (month 1)

Modified Intent-to-treat population 3 (MITT-3)

•

Received at least one vaccine

•

Had any follow-up visit after one month following the first injection

•

Clinical endpoints were counted beginning one month after the first dose (month 1)