GardasilTM : Quadrivalent Human Papillomavirus 6, 11, 16, 18 L1 VLP Vaccine Applicant: Merck

1
GardasilTM Quadrivalent Human
Papillomavirus 6, 11, 16, 18 L1 VLP
VaccineApplicant Merck Co., Inc.

• Vaccines and Related Biological Products Advisory
  Committee Meeting
• May 18, 2006
• Nancy B. Miller, M.D.
• CBER, FDA

2
Review Team

• Chairperson Gopa Raychaudhuri, Ph.D.
• Regulatory Coordinator Julienne Vaillancourt,
  R.Ph., M.P.H.
• Clinical Nancy Miller, M.D.
• 
  Joseph Toerner, M.D., M.P.H.
• 
  Karen Goldenthal, M.D.
• 
  Antonia Geber, M.D.
• 
  Douglas Pratt, M.D., M.P.H
• Statistical Henry Hsu, Ph.D., M.P.H.
• 
  Lev Sirota, Ph.D.
• 
  A. Dale Horne, Dr.Ph.
• Product Robin Levis, Ph.D.
• 
  Rolf Taffs, Ph.D.
• Gennady Rezapkin, Ph.D.
• Loris McVittie, Ph.D.
• 
  Jerry Weir, Ph.D.
• Non-Clinical Sally Hargus, Ph.D.
• 
  Marion Gruber, Ph.D.
• Pharmacovigilance Hector Izurieta,
  M.D.
• Robert Ball, M.D., M.P.H.

3
Gardasil Description

• Each 0.5 mL dose contains
• 20 mcg HPV 6 L1 VLP
• 40 mcg HPV 11 L1 VLP
• 40 mcg HPV 16 L1 VLP
• 20 mcg HPV 18 L1 VLP
• Adjuvant 225 mcg aluminum
• Administered 0, 2, and 6 months IM

4
GardasilApplicants Proposed Indications (1)

• Prevention of HPV 16/18 related
• Cervical cancer
• Cervical AIS
• CIN 2 and CIN 3
• Vulvar and vaginal cancer
• VIN 2 and VIN 3
• VaIN 2 and VaIN 3
• Prevention of HPV 6/11/16/18 related
• CIN grade 1
• Genital warts (condyloma acuminata)
• VIN grade 1 and VaIN grade 1
• HPV infection

AIS Adenocarcinoma in situ CIN Cervical
Intraepithelial Neoplasia VIN Vulvar
Intraepthelial Neoplasia VaIN Vaginal
Intraepithelial Neoplasia
5
GardasilApplicants Proposed Indications (2)

• Children and adolescents 9 through 17 years of
  age and women 18 through 26 years of age.

6
GardasilFDA Proposed Indications

• FDA considers the data submitted in the BLA to be
  supportive of use of Gardasil in preadolescent
  and adolescent females 9-17 years of age and
  females 18-26 years of age.

7
Regulatory History

• 1997 Submission of IND for monovalent HPV 11 L1
  
• VLP vaccine (Other INDs for monovalent HPV 16 and
  18)
• 2000 Submission of IND for quadrivalent HPV 6,
  11, 16, 18 L1 VLP vaccine
• 2001 (November) VRBPAC discussion of endpoints
  for Phase 3 development
• 2002 Product development program granted fast
  track status Initiation of Phase 3 trials
• 2005 (May) Pre-BLA meeting, agreement to allow
  rolling BLA and Priority Review
• 2005 (August) Start of rolling BLA submisssion
• 2005 (December) Last section of rolling BLA
  received including Phase 3 study data 6 month
  priority review

8
Efficacy Endpoint for Preventive HPV Vaccines
(Cervical Cancer)

• November 2001 VRBPAC
• CIN 2/3 histology, AIS, or worse with virology.

9
Phase I/II Safety and Immunogenicity Studies

• 001 HPV 11 L1 VLP Vaccine
• 002 HPV 16 L1 VLP Vaccine
• 004 HPV 16 L1 VLP Vaccine
• 006 HPV 18 L1 VLP Vaccine

10
Gardasil BLA Protocols Contributing to Combined
Efficacy Analysis

• 005 Proof of Concept Phase II Efficacy
  Trial (HPV 16)
• 007 Quadrivalent Dose-Ranging and
  Efficacy Study
• 013 CIN/Warts Efficacy Study
• 015 CIN 2/3 Efficacy Study

11
GardasilProtocol 013 Substudies

• 011 Hepatitis B Concomitant Use Substudy
• 012 HPV 16 Bridging Substudy

12
Immunogenicity and Safety Studies in Adolescents

• 016 Adolescent/Adult Bridging and
  End-Expiry Study
• 018 Adolescent Immunogenicity and Safety
  Study

13
Comparison of Study DesignProtocols That
Contribute to Combined Analysis
Features Protocol 005 Protocol 007 Protocol 013 Protocol 015
Sites US US, International US, International US, International
Design DB, R, PC DB, R, PC DB, R, PC DB, R, PC
Vaccine HPV 16 Gardasil Gardasil Gardasil
384 subjects received HPV 16 to bridge to
Protocol 005 DB Double blind RRandomized PC
Placebo controlled From Table 1, HPV L1 VLP
Vaccine Combined Efficacy (Interim Analysis)
14
Comparison of Study DesignBaseline
Characteristics of Subjects
Subjects Protocol 005 Protocol 007 Protocol 013 Protocol 015
Inclusion Criteria Inclusion Criteria Inclusion Criteria Inclusion Criteria Inclusion Criteria
Age Gender 16-23 years female 16-23 years female 16-23 years female 16-26 years female
Lifetime Partners 0-5 0-4 0-4 0-4
Exclusion Criteria Exclusion Criteria Exclusion Criteria Exclusion Criteria Exclusion Criteria
Previous abnormal Pap Not allowed Not allowed Not allowed Not allowed
23 years except for 26 years in
Singapore Source Table 1, HPV L1 VLP Vaccine
Combined Efficacy (Interim Analysis Report)
15
Comparison of Study DesignPap Tests and
Referral for Colposcopy
Features Protocol 005 Protocol 007 Protocol 013 Protocol 015
Pap interval 6 months 6 months 6 months 12 months
Pap test ThinPrepTM ThinPrepTM ThinPrepTM ThinPrepTM
Pap reading 5 regional labs DCL Lab, Indianapolis DCL Lab, Indianapolis DCL Lab, Indianapolis
Minimal Pap Referral ASC-US ASC-US HPV () HC-II ASC-US HPV () HC-II ASC-US HPV () HC-II
Screening Triage Voluntary Voluntary Mandatory Mandatory
Exit Colposcopy Yes Yes No No
Source Interim Analysis, Table 1
16
Comparison of Study DesignTriage Abnormal Pap
Tests for Colposcopy
ThinPrepTM Pap Result Protocol 005 Protocols 007 and 013 Protocol 015
ASC-US Reflex HPV test on residual ThinPrepTM material if probe positive, referred for colposcopy if probe negative, Pap at routine interval Reflex HPV test on residual ThinPrepTM material if at least one probe positive, referred for colposcopy if both probes negative, Pap at routine interval Repeat ThinPrepTM Pap in 6 months
LSIL Referred for colposcopy Referred for colposcopy Repeat ThinPrepTM Pap in 6 months
Source Table 2.7.3-cervix cancer 5
17
Comparison of Study DesignLaboratory Tests,
Pathology Panel
Features Protocol 005 Protocol 007 Protocol 013 Protocol 015
Laboratory Processing DCL Lab, Indianapolis DCL Lab, Indianapolis DCL Lab, Indianapolis DCL Lab, Indianapolis
Pathology Panel Reading (Endpoints) Kurman Ronette Stoler Ferenczy Kurman Ronette Stoler Ferenczy Kurman Ronette Stoler Ferenczy Kurman Ronette Stoler Ferenczy
HPV Causality Assessment Merck HPV PCR assay frozen biopsy Merck HPV PCR assay paraffin Merck HPV PCR assay paraffin Merck HPV PCR assay paraffin
All biopsies in 4 studies read by one of several
pathologists in central Lab for patient
management. Biopsies also independently read by
panel of expert pathologists for final diagnosis
for study purposes (endpoints). Panel blinded to
group, HPV testing, dx at DCL. Until 10/2000,
pathologists were Kurman/Sherman/Stoler/Ferenczy S
ource Interim Analysis, Table 1
18
Comparison of Study Design Number of Subjects,
Median Age, and Duration of Follow-up In Efficacy
Population
Subjects Protocol 005 Protocol 007 Protocol 013 Protocol 015
N Vaccine Placebo 2391 1193 1198 551 276 275 5442 2717 2725 12157 6082 6075
Median Age (Range) 20 yr. (16-25) 20 yr. (13-24) 20 yr. (16-24) 20 yr. (15-26)
Mean duration of follow-up 3.1 years 2.4 years 1.7 years 1.4 years
Total number of subjects with data for cervical
disease efficacy 20541 Sources CSR 007, Table
7-2 and 2.7.3cervix cancer Table 2.7.38
19
Number of Subjects EnrolledDistribution by
Protocol and Region(Efficacy Population)
Subjects Protocol 005 Protocol 007 Protocol 013 Protocol 015 Total
North America 2391 (100) 251 (45.6) 1713 (29.8) 913 (7.5) 5268
Latin America 0 187 (33.9) 2278 (39.8) 3191 (26.2) 5606
Europe 0 113 (20.5) 1189 (20.7) 7872 (64.8) 9174
Asia-Pacific 0 0 566 (9.9) 181 (1.5) 747
Source Table 2.7.3-cervix cancer 9
20
Subjects Excluded from Efficacy AnalysisBecause
of Baseline HPV Status
Gardasil Placebo Total
Number of Subjects Enrolled 10291 10292 20583
Received gt 1 injection 10268 10273 20541
Excluded from PPE analysis HPV 16 HPV 18 2818 1626 3008 1692 5826 3318
Sero and/or PCR HPV 16 At Day 1 At/before Month 7 1654 1770 1679 2029 3333 3799
Sero and/or PCR HPV 18 At Day 1 At/before Month 7 574 656 572 773 1146 1428
Day 1 includes Sero and/or PCR. Post Day 1
includes PCR only. Source Interim Analysis
Report, Table 2
21
Role of Baseline HPV Status and Endpoint Counting
for Prophylactic Vaccine Efficacy Analyses
Baseline HPV Status HPV 6- related HPV 11- related HPV 16-related HPV 18- related
Naïve to all 4 vaccine HPV types Yes Yes Yes Yes
Positive HPV 6 or 11, Naïve 16/18 No No Yes Yes
Positive HPV 16, Naïve for 6/11/18 Yes Yes No Yes
Positive HPV 18, Naïve 6/11/16 Yes Yes Yes No
Naïve Subjects seronegative Day 1 and PCR
negative Day 1 through Month 7. Source Merck
Briefing Document
22
Role of Baseline HPV Status and Endpoint Counting
for Prophylactic Vaccine Efficacy Analyses
Baseline HPV Status HPV 6- related HPV 11- related HPV 16-related HPV 18- related
Naïve to all 4 vaccine HPV types Yes Yes Yes Yes
Positive HPV 6 or 11, Naïve 16/18 No No Yes Yes
Positive HPV 16, Naïve for 6/11/18 Yes Yes No Yes
Positive HPV 18, Naïve 6/11/16 Yes Yes Yes No
Source Merck Briefing Document Note Non-HPV 6,
11, 16, 18 related disease not included in
analyses.
23
Efficacy Analysis Populations (1)

• Per Protocol Population for Efficacy (PPE)
  Received all 3 vaccinations, naïve to relevant
  vaccine HPV type through Month 7, did not deviate
  from protocol cases counted after Month 7.
• Modified Intent to Treat -1 Population (MITT-1)
  Same as PPE, but included protocol violators
• Modified Intent to Treat-2 Population (MITT-2)
  Received at least 1 vaccination, naïve to
  relevant vaccine HPV type at Day 1, and had any
  follow-up visit after the first vaccination
  cases counted from 30 days after dose 1.

24
Efficacy Analysis Populations (2)

• Restricted MITT-2 Population (RMITT-2)
  Seronegative and PCR negative to all four vaccine
  HPV types at Day 1 and a normal Pap test at Day
  1 cases counted 30 days after dose 1.
• All MITT-1 Population Naïve to all four vaccine
  HPV types through Month 7, and cases counted
  starting after Month 7.

25
Efficacy Analysis Populations (3)

• Modified Intent to Treat-3 Population (MITT-3)
  Received at least one vaccination and had any
  follow-up visit one month after dose 1. Cases
  were counted from 30 days after dose 1. Subjects
  were included regardless of baseline HPV status.

26
Baseline Characteristicsof Subjects in Efficacy
Population (Protocols 005, 007, 013, and 015)

• Squamous intraepithelial lesion (SIL) present at
  baseline 12
• PCR positive and/or seropositive to a vaccine
  HPV type 27

27
Endpoints from Efficacy Protocols(Protocols 005,
007, 013, and 015)

• Primary Endpoints
• HPV 16/18 related CIN 2/3 or worse 015, combined
  analysis
• HPV 6/11/16/18 related CIN 013
• HPV 6/11/16/18 related External Genital Lesions
  (EGLs) 013

28
Other Endpoints

• Other Endpoints of Interest
• HPV 16/18 related EGLs
• CIN 2/3 due to any HPV type and non-vaccine HPV
  types
• EGL due to any HPV type and non-vaccine HPV types

29

• Efficacy Against HPV 16/18 CIN 2/3 or Worse

30
Analysis of Efficacy AgainstHPV 16/18 Related
CIN 2/3 or Worse (Protocol 015)
Gardasil N6082 Gardasil N6082 Gardasil N6082 Placebo N6075 Placebo N6075 Placebo N6075
Population N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
PPE 5301 0 0.0 5258 21 0.3 100 (75.8, 100)
MITT-3 5947 67 0.6 5973 111 1.0 39.2 (16.9, 55.8)
Incidence Rate Calculated per 100 person years
at risk. PPE Naïve to relevant HPV type,
received three doses of vaccine, cases
counted after Month 7. MITT-3 Included
regardless of baseline HPV status received at
least one dose of vaccine, cases counted 30
days post-dose 1. Sources Table 7-2, p. 229
Table 7-5, p. 236, CSR 015v2
31
Analysis of Efficacy AgainstHPV 16/18 Related
CIN 2/3 or Worse (Protocols 005, 007, 013, 015)
HPV L1 VLP Vaccine N10268 HPV L1 VLP Vaccine N10268 HPV L1 VLP Vaccine N10268 Placebo N10273 Placebo N10273 Placebo N10273
Population N No. of Cases Incidence N No. of Cases Incidence Efficacy (95 CI)
PPE 8487 0 0 8460 53 0.4 100 (92.9, 100)
MITT-3 9831 122 0.6 9896 201 0.9 39.0 (23.3, 51.7)
Source Table 2.7.3-cervixcancer 29, p. 127-8
32
Analysis of Efficacy of Against HPV 16/18
RelatedCIN 2/3 or Worse by HPV Type MITT 3
Analysis (Protocols 005, 007, 013, 015)
Gardasil N10268 Gardasil N10268 Gardasil N10268 Placebo N10273 Placebo N10273 Placebo N10273
HPV Type N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
HPV-16 9831 115 0.5 9896 184 0.9 37.2 (20.3, 50.7)
HPV-18 8814 7 0.04 8846 33 0.2 78.7 (51.0, 92.0)
Source Table 2.7.3-cervixcancer31, p. 131
33

• Efficacy Against
• HPV 6/11/16/18 CIN

34
Analysis of Efficacy AgainstHPV 6/11/16/18
Related CIN (Protocol 013)
Gardasil N2717 Gardasil N2717 Gardasil N2717 Placebo N2725 Placebo N2725 Placebo N2725
Population N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
PPE 2240 0 0 2258 37 1.0 100 (87.4, 100)
MITT-3 2607 65 1.2 2611 113 2.0 42.9 (21.9, 58.6)
Source Table 7-3, CSR 013v1, p. 240, Table 7-8.
p 250.
35
Analysis of Efficacy AgainstHPV 6/11/16/18
Related CIN (Protocols 007, 013, 015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N9075 Placebo N9075 Placebo N9075
Population N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
PPE Combined 7858 4 0.03 7861 83 0.7 95.2 (87.2, 98.7)
MITT-3 Combined 8814 170 1.0 8846 317 1.8 46.4 (35.2, 55.7)
Source Table2.7.3-cervixcancer 26, p. 121-2
36
Cases of HPV 6/11/16/18Related CIN in PPE
Population

• Four cases occurred in the Gardasil group for the
  PP analysis (Protocol 015).
• All four cases had HPV 16 related CIN 1 at Month
  12-13.
• One subject had anti-HPV 16 level just below
  level of detection and LSIL at Day 1 and HSIL at
  Mo 7, and possibly had prior exposure to HPV 16
  also non-naïve to HPV 18 at Day 1 and colposcopy
  triggered by the HSIL at Mo 7, led to a diagnosis
  of HPV 18 related CIN 3 at Mo 9.
• Three other subjects developed LSIL at Mo 7 and
• Mo 12, which led to colposcopies with the
  resulting diagnoses. One had anti-HPV 16 level
  at Mo 7 higher than GMT seen in Per Protocol
  Immunogenicity (PPI) population.

37
Analysis of Efficacy Against HPV
6/11/16/18Related CIN by HPV Type
MITT-3(Protocols 005, 007, 013, 015)
Gardasil N10572 Gardasil N10572 Gardasil N10572 Placebo N 10273 Placebo N 10273 Placebo N 10273
HPV Type N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
HPV 6/11 8814 16 0.1 8846 61 0.3 73.7 (53.8, 85.8)
HPV 16 10121 155 0.7 9896 278 1.3 45.6 (33.6, 55.6)
HPV 18 8814 19 0.1 8846 63 0.4 69.7 (48.8, 82.9)
Source Table 2.7.3-cervixcancer28, p. 126
38
Efficacy Against HPV 6/11/16/18 Related CIN 2/3
or Worse and AIS (Protocols 005, 007, 013, and
015)
Gardasil Gardasil Gardasil Placebo Placebo Placebo
Day 1 Status N No. cases Incidence N No. of cases Incidence Efficacy 95 CI
MITT-3 9831 122 0.7 9896 201 0.9 39.0 (23.3, 51.7)
PCR (-) Sero (-) 9342 1 0.6 9400 81 0.4 98.8 (92.9, 100.0)
PCR (-) Sero () 853 0 0.0 910 4 0.2 100 (-63.6, 100.0)
PCR () Sero (-) 661 42 3.2 626 57 4.6 31.2 (-4.5, 54.9)
PCR () Sero () 473 79 121 9.1 499 69 130 7.3 -25.8 (-76.4, 10.1)
Total number of cases in subjects who were
sero and/or PCR at baseline for the relevant
HPV type which was associated with
disease. Source Table 1-1, Additional efficacy
analysis requested by CBER
39
Selected Characteristics for Subgroup of Vaccine
Related HPV PCR Positive and Seropositive
Subjects at Day 1(Protocol 013)
Gardasil Placebo
Subgroup Population 156 137
History of cervicovaginal infection or STD 35.9 32.1
Pap test with HSIL 6.5 3.7
Source Table 2a-2, Response to CBER questions
from 3/1/06.
40

• Efficacy Against Any HPV Type and Non-Vaccine HPV
  Type Related CIN

41
Overall Impact on CIN 2/3 or WorseDue to Any HPV
Type (Protocols 007, 013, and 015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N 9075 Placebo N 9075 Placebo N 9075
Population N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
MITT-3 8814 287 1.6 8846 328 1.9 12.2 (-3.2, 25.3)
Source Table 5.3.5.3.217, p. 78-9, Integrated
Summary of Efficacy
42
Analysis of Efficacy Against Non-HPV 6/11/16/18
Related CIN 2 or CIN 3 Among Subjects in All
MITT-1 Population (Protocols 007, 013, 015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N 9075 Placebo N 9075 Placebo N 9075
N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
CIN 2 5993 59 0.7 5766 49 0.6 -16.1 (-73.2, 21.8)
CIN 3 5993 36 0.4 5766 27 0.3 -28.5 (-120.1, 24.1)
All MITT-1 Population Naïve to all four vaccine
HPV types through Month 7, received three doses
of vaccine. Source Table 3-4, Additional
Efficacy Analyses Requested by CBER
43

• Efficacy Against HPV 6/11/16/18
• Related External Genital Lesions (EGLs)

44
Analysis of Efficacy AgainstHPV 6/11/16/18 EGL
(Protocol 013)
Gardasil N2717 Gardasil N2717 Gardasil N2717 Placebo N2725 Placebo N2725 Placebo N2725
Population N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
PPE 2261 0 0.0 2279 40 1.0 100 (88.4, 100)
MITT-3 2671 26 0.5 2668 80 1.4 67.8 (49.3, 80.1)
Source Table 7-3, CSR 013v1, p. 240 and Table
7-18, p. 271
45
Analysis of Efficacy AgainstHPV 6/11/16/18
Related EGLs(Protocols 007, 013, 015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N 9075 Placebo N 9075 Placebo N 9075
Population N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
PPE 7987 1 0.01 7899 113 0.9 99.1 (95.0, 100.0)
RMITT-2 5742 6 0.1 5775 127 1.1 95.3 (89.4, 98.3)
MITT-3 8954 68 0.4 8962 229 1.3 70.4 (61.0, 77.7)
Source Table2.7.3-exgenlesions 6, p.
39-40 Table 4-1, Additional Efficacy Analyses
Requested by CBER
46
Analysis of Efficacy Against HPV
6/11/16/18Related EGLs by HPV Type (Protocols
007, 013, 015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N 9075 Placebo N 9075 Placebo N 9075
N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
MITT-3 HPV 6/11 8954 59 0.3 8962 194 1.1 69.6 (59.2, 77.7)
MITT-3 HPV 16 8954 11 0.1 8962 55 1.1 80.0 (61.3, 90.5)
MITT-3 HPV 18 8954 2 0.01 8962 20 0.1 90.0 (58.7, 98.9)
Source Appendix 2.7.3-exgenlesions9, p. 64
47
Analysis of Efficacy Against HPV 16/18 Related
EGLs (Protocols 007, 013, 015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N 9075 Placebo N 9075 Placebo N 9075
Population - EGL type N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
PPE - Condyloma, VIN 1 or VaIN 1) 7769 0 0.0 7741 24 0.2 100.0 (83.4, 100.0)
PPE - VIN 2/3 or VaIN 2/3 or worse) 7769 0 0.0 7741 10 0.1 100.0 (55.5, 100.0)
MITT-3 - Condyloma, VIN 1 or VaIN 1) 8954 7 0.04 8962 51 0.3 86.2 (69.6, 94.7)
MITT-3 VIN 2/3 or VaIN 2/3 or worse) 8954 8 0.05 8962 26 0.1 69.1 (29.8, 87.9)
Source Table 2.7.3-exgenlesions7, p. 41
48
Analysis of Efficacy Against HPV 6/11/16/18
Related EGL by Severity of Disease PPE
Population (Protocols 007, 013, 015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N 9075 Placebo N 9075 Placebo N 9075
Population - EGL type N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
PPE - Condyloma 7897 1 0.0 7899 91 0.8 98.9 (93.7, 100.0)
PPE VIN 1 7897 0 0.0 7899 10 0.1 100.0 (55.4, 100.0)
PPE-VIN 2/3 7897 0 0.0 7899 8 0.1 100.0 (41.4, 100.0)
PPE-VaIN 2/3 7897 0 0.0 7899 5 0.04 100.0 (lt0.0, 100.0)
Source Table 1-1, Response to CBER request
5/1/06.
49
Analysis of Efficacy Against HPV 6/11/16/18
Related EGL by Severity of Disease MITT-3
population (Protocols 007, 013, 015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N 9075 Placebo N 9075 Placebo N 9075
Population - EGL type N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
MITT-3 Condyloma 8954 58 0.3 8962 184 1.0 68.5 (57.5, 77.0)
MITT-3 VIN 1 8954 8 0.05 8962 19 0.1 57.8 (lt0.0, 84.0)
MITT-3 VIN 2/3 8954 7 0.04 8962 22 0.1 68.1 (22.7, 88.5)
MITT-3 VaIN 2/3 8954 2 0.01 8962 9 0.1 77.7 (lt0.0, 97.7)
Source Table 1-3, CBER Additional Request for
analyses, 5/1/06
50
Efficacy Against HPV 6/11/16/18 Related EGLs
(Protocols 007, 013, and 015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N 9075 Placebo N 9075 Placebo N 9075
Day 1 Status N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
Sero (-) PCR () 810 44 2.9 782 41 2.8 -4.0 (-63.2, 33.6)
Sero () PCR (-) 1270 0 0.0 1301 4 0.2 100.0 (-56.2, 100.0)
Sero () PCR () 336 5 49 1.0 331 5 50 1.0 2.4 (-324.3, 77.5)
Total number of cases in subjects who were
sero and/or PCR at baseline for the relevant
HPV type which was associated with
disease. Source Table 2.7.3-exgenlesions8, p.
43 and Table 7-1, Additional Efficacy Analyses
Requested by CBER
51
Impact of Gardasil on Incidence of EGLs Dueto
Any HPV Type by Severity of Disease (Protocols
007, 013, 015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N 9075 Placebo N 9075 Placebo N 9075
N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
RMITT 2 condylomata, VIN 1 or VaIN 1 5734 52 0.5 5769 151 1.3 65.4 (52.3, 75.3)
RMITT 2- VIN 2/3 or VaIN 2/3 or worse 5734 5 0.04 5769 27 0.2 81.3 (50.8, 94.4)
MITT-3 condylomata, VIN 1 or VaIN 1 8954 169 1.0 8962 284 1.6 40.5 (27.8, 51.1)
MITT-3 VIN 2/3 or VaIN 2/3 or worse 8954 22 0.1 8962 43 0.2 48.7 (12.3, 70.8)
Source Table 2.7.3-exgenlesions 9, p. 46
52
Efficacy Against Non-HPV 6/11/16/18Related EGL
in All MITT-1 Population (Protocols 007, 013,
015)
Gardasil N9075 Gardasil N9075 Gardasil N9075 Placebo N9075 Placebo N9075 Placebo N9075
N No. of cases Incidence N No. of cases Incidence Efficacy (95 CI)
EGL not related to HPV 6/11/16/18 5999 52 0.6 5773 49 0.6 -2.1 (-54.1, 32.2)
Condyloma, VIN 1, VaIN 1 5999 46 0.5 5773 49 0.6 9.7 (-37.9, 40.9)
VIN 2/3 or VaIN 2/3 5999 5 0.1 5773 6 0.1 19.8 (-215.3, 80.6)
Vulvar or vaginal cancer 5999 1 0.01 5773 0 0.0 NA
Source Table 6-2, Additional Efficacy Analyses
Requested by CBER
53
Safety

• Safety Population
• Safety Surveillance
• Deaths
• SAEs
• Pregnancies/Lactation

54
Safety PopulationDetailed and General
Safety Population Gardasil Placebo
Detailed Safety Population 6160 4064
General Safety Population 11778 9686
Source Tables 2.7.4 4 and 5, p. 29-30, Summary
of Clinical Safety 3/8/06
55
Vaccine Exposure in 9-15 Year OldFemale Subjects
(Protocols 016 and 018)
Age Females Gardasil
9 85
10 158
11 196
12 165
13 190
14 192
15 137
Total 1123
Source Applicants response to additional CBER
questions
56
Safety Surveillance(Detailed Safety Cohort)

• Vaccine Report Cards for 14 days after each
  vaccination (Protocols 005, 007, 013 NSAE 015)
• Solicited local AEs Pain, tenderness, redness
  for 5 days after vaccination
• Temperatures for 5 days after vaccination
• gt 100 F oral
• Solicited and unsolicited systemic AEs Sore
  muscle, sore joints, headache, rash, diarrhea for
  14 days after vaccination

57
Serious Adverse Event Reporting

• Any SAE for day of consent to 14 days postdose 1,
  and 14 days postdose 2 and 3 regardless of
  attribution
• Any death or SAE which resulted in study
  discontinuation
• Any SAE throughout study which was possibly
  vaccine or procedure related or whose
  relationship was unclear
• Pregnancy related SAEs throughout study

Source Applicants Response to CBER question
58
Reporting New MedicalConditions

• Pre-vaccination
• Study period through Month 7
• Study period after Month 7

59
Pregnancy and Lactation Reporting

• All pregnancies were to be followed to outcome
• SAEs were reported for mothers and infants
• Lactation outcomes were followed

60

• Safety Results

61
Deaths(Protocols 007, 013, 015, 016, 018)
Gardasil (N11, 0.9) Placebo (N7, 0.7)
Trauma 5 3
DVT/PE 1 1
Sepsis, DIC 1
Sepsis, pneumonia 1
Arrythmia 1
Pancreatic Cancer 1
Convulsion, drug use 1
Suicide 2
Asphyxiation post-C-section 1
Source Summary of Clinical Safety (3/8/06),
Table 2.7.420, p. 56-61.
62
Serious Adverse Events (Protocols 007, 013, 015,
016, 018)
SAE (Organ system) Gardasil N11778 Placebo N9680
Gyn or Obstetrical 42 41
GI 11 6
Appendicitis 4 1
Injury 6 6
Neurological 4 7
Immune mediated 2 4
Coagulation/DVT 2 1
Pulmonary 2 5
GU 6 5
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 (0.9) 97 (1.0)
Source Summary of Clinical Efficacy (3/8/06)
Table 2.7.421, p. 63-102.
63
New Medical Conditions (Number and Percent)
During Vaccination Period (through Month 7) and
after Month 7 for Selected Organ
Systems(Protocols 007, 013, 015, 016, 018)
Organ System During Vaccination Period During Vaccination Period Post Month 7 Post Month 7
Gardasil N11778 Placebo N9868 Gardasil N10452 Placebo N9385
Cardiac 11 (0.1) 12 (0.1) 21 (0.2) 13 (0.1)
Endocrine 20 (0.2) 17 (0.2) 40 (0.4) 33 (0.4)
GI 711 (6.0) 638 (6.6) 7272 (7.0) 595 (6.3)
Immune 150 (1.3) 112 (1.2) 105 (1.0) 88 (0.9)
Musculoskeletal 387 (3.3) 256 (2.6) 320 (3.1) 242 (2.6)
Neoplasms 68 (0.6) 50 (0.5) 105 (1.0) 67 (0.7)
Nervous system 684 (5.8) 495 (5.1) 333 (3.2) 217 (2.3)
Psychiatric 168 (1.4) 162 (1.7) 212 (2.2) 203 (2.2)
Surgical 384 (3.3) 296 (3.1) 477 (4.6) 495 (5.3)
Appendectomy 19 (0.2) 4 (lt0.1) 17 (0.2) 26 (0.3)
Source Summary of Clinical Efficacy (3/8/06)
Appendices 2.7.4 31, 33, 34, 36
64
Pregnancy Outcome Summary (Protocols 013, 015,
016, 018)
Gardasil (N10418) Placebo (N9120)
Subjects with pregnancies 1115 (10.7) 1151 (12.6)
Number of pregnancies 1244 1272
Number of fetuses/infants with known outcomes 996 1018
Number of pregnancies with unknown outcomes 258 263
Live Births 621 (62.3) 611 (60.0)
Spontaneous miscarriage 249 (25) 257 (25.2)
Late fetal deaths 11 (1.2) 8 (0.9)
Percentage calculated with number of known
outcomes Source Summary of Clinical Safety
(3/8/06), Table 2.7.424, p. 126-8.
65
Distribution of Congenital Anomalies by Estimated
Dates of Conception (EDCn) Timing in Relation to
Vaccination (Protocols 013, 015, 016, 018)
Gardasil Placebo
Congenital Anomalies 15 16
EDCn within 30 days of study vaccine 5 0
Live birth reported in neonatal period 5 0
EDCn beyond 30 days of study vaccine 10 16
Live birth reported in neonatal period 8 12
Live birth reported beyond neonatal period 1 1
Fetal Loss 0 2
Intra-uterine diagnosis 1 1
Diagnoses included hip dysplasia, ankyloglossia
and pyloric stenosis, congenital hydronephrosis,
club foot, and congenital megacolon Source Table
2.7.426, p. 135, safety update 3/8/06
66
Adverse Events in Pregnancy/Lactation
(1)(Protocols 013, 015, 016, 018)

• A similar pattern and occurrence of SAEs and AEs
  in pregnancy were reported in women who were
  vaccinated with Gardasil (N40, 4.2) or placebo
  (N41, 4.3).
• These events included conditions leading to
  C-section, premature labor, and conditions
  associated with pregnancy.

67
Adverse Events in Pregnancy/Lactation
(2)(Protocols 013, 015, 016)

• Higher proportion of children with SAEs in women
  who received Gardasil while breastfeeding in the
  vaccination period (Gardasil N17, 3.4 placebo
  N9, 1.8) the events were of similar nature in
  both groups.
• In both the vaccine and placebo groups, these
  included respiratory infections, gastroenteritis,
  and asthma.

68
Adverse Events in Infants/Lactation(3)(Protocols
013, 015, 016)
Event Gardasil N500 Placebo N495
Respiratory Infections 12 4
Gastroenteritis/Diarrhea 5 2
Asthma 1 1
Bronchial Obstruction 1 0
Cellulitis 1 0
Dehydration 1 0
Head Injury 1 0
Anomalous pulmonary venous return 1 0
Unspecified Viral Infection 0 1
Febrile Convulsion 0 1
Source Summary of Clinical Safety, Page 181-182
and Appendix 2.7.4195, Pages 1076-1079
69
FDA Safety Conclusion (1)

• Although no obvious safety signal was identified,
  post-marketing pharmacovigilance activities will
  continue to collect AEs that occur
  post-vaccination in a larger population.

70
FDA Safety Conclusion (2)

• An imbalance was noted regarding the EDCn of
  infants who had congenital anomalies (five cases
  for mothers who received Gardasil vs. none for
  mothers who received placebo). However, there
  did not appear to be a pattern among the
  congenital anomalies.

71
Immunogenicity

• Bridging immune response in adolescent girls to
  adult women
• Duration of immune response
• Co-administration with Hepatitis B vaccine

72
Bridging Immune Response from Females 16-26 Years
toFemales 9-15 Years of Age

• Females naïve to the four vaccine HPV types are
  expected to benefit most from the vaccine.
• Efficacy studies cannot be conducted in
  preadolescent girls.

73
Month 7 HPV 6 GMTs and 95 CI by Age at
Enrollment - 9 to 26 Year Old Female Recipients
of Gardasil (PPI)
Source Figure 5.3.5.3.33, Integrated Summary of
Immunogenicity
74
Immunogenicity Bridging Between 9-15 Year Old
Females in the Immunogenicity Studies to 16-26
Year Old Females in the Efficacy Studies (PPI)
9-15 Year Old Females in Protocols 016 and 018 9-15 Year Old Females in Protocols 016 and 018 9-15 Year Old Females in Protocols 016 and 018 16-23 Year Old subjects in Protocols 013 and 015 16-23 Year Old subjects in Protocols 013 and 015 16-23 Year Old subjects in Protocols 013 and 015
Assay (cLIA) n GMT mMU/mL 95 CI n GMT mMU/mL 95 CI
Anti-HPV 6 927 931.3 876.9, 989.2 2827 542.4 526.6, 558.7
Anti-HPV 11 927 1305.7 1226.2, 1390.4 2827 766.1 740.5, 792.6
Anti-HPV 16 929 4944.9 4538.5, 5334.8 2707 2313.8 2206.2, 2426.7
Anti-HPV 18 932 1046.0 971.2, 1126.5 3040 460.7 443.8, 478.3
Source Table 5.3.5.3.329, p. 85, Integrated
Summary of Immunogenicity
75

• Duration of Immune Response

76
Persistence of Anti-HPV 18 Immune Responses in 18
to 26 Year Old Female Recipients of Gardasil
(Seronegative at Day 1 and PCR Negative Through
Month 7) Versus Placebo Recipients (Seropositive
and PCR Negative at Day 1)
Source Figure 5.3.5.3.316, p. 69, Integrated
Summary of Immunogenicity
77
Seropositivity Rates for Anti-HPV 6, 11, 16, and
18 at Month 24 (Vaccinated Women 18-26 years)
with Serology Data at All Time Points (N2818)
HPV type Seropositivity rate at Month 24 (95 CI)
Anti-HPV 6 95.7 (94.5, 96.6)
Anti-HPV 11 97.6 (96.8, 98.3)
Anti-HPV 16 99.6 (99.2, 99.9)
Anti-HPV 18 73.9 (71.8, 75.9)
Source Table 5.3.5.3.314, p. 55, Integrated
Summary of Immunogenicity
78
Co-administration of Gardasil with Hepatitis B
Vaccine

• Anti-HPV 6, 11, 16, and 18 immune responses were
  non-inferior when Gardasil was given with or
  without Recombivax (SC rates, GMT ratios)
• Anti-Hepatitis B immune response was similar when
  Recombivax was given with or without Gardasil (SC
  rates)
• Anti-Hep B GMTs lower in coadministration group

79
Applicants Proposed Post-marketing Commitments

• Routine pharmacovigilance
• Phase 4 studies
• Other studies

80
Routine Pharmacovigilance

• Passive reporting of adverse events (AEs)
  including
• Monthly submission of non-serious AE reports
• Regular FDA-CDC-Sponsor conference calls
• Pregnancy registry

81
Phase 4 Studies

• Observational safety surveillance study in large
  U.S. MCO
• Investigation of serious AEs that occur in close
  temporal association with vaccination (60 days
  follow-up)
• Nordic Long Term Follow-up Study
• Longitudinal evaluation of subjects in Protocol
  015 enrolled in Nordic countries using national
  registries

82
Nordic Long Term Follow-up Study Outcomes

• HPV-related diseases
• Long term effectiveness and duration of immune
  response
• Potential safety signals
• Pregnancy outcomes

83
Other Studies

• Evaluation of long term effectivenesss and
  duration of immune response
• Extension of protocol 007
• Extension of protocol 018
• Detection of unanticipated safety signals through
  active surveillance in all studies.

84
GardasilFDA Review Conclusions

• The efficacy, safety, and bridging immune
  response data submitted to the BLA support
  licensure of Gardasil in females 9-26 years of
  age naïve to the relevant vaccine HPV type for
  prevention of the following diseases/events
• HPV 16/18 related cervical cancer, CIN 2/3 and
  AIS.
• HPV 6/11/16/18 related VIN 2, VIN 3, VaIN 2, VaIN
  3
• HPV 6/11/16/18 related CIN 1, genital warts, VIN
  1 and VaIN 1

85
GardasilFDA Review Concerns (1)

• Applicants Per Protocol HPV type-specific
  analyses that indicated a very high level of
  efficacy in naïve subjects may not reflect the
  efficacy of Gardasil for all HPV related disease
  on a population basis.
• HPV related disease occurred in Gardasil
  recipients.
• Some vaccine recipients were non-naïve at
  baseline for one or more vaccine HPV type(s), and
  some of these subjects developed HPV disease
  related to that HPV type(s).
• Subjects who were naïve to all four vaccine HPV
  types could still develop disease related to an
  HPV type not included in the vaccine.

86
GardasilFDA Review Concerns (2)

• Modified Intent to Treat analysis (MITT-3) of all
  vaccinated females across studies 005, 007, 013,
  and 015 demonstrate modest efficacy against CIN
  2/3
• MITT-3 Overall efficacy CIN 2/3 or worse due to
  HPV6/11/16/18 39.0 (23.5, 51.7)
• MITT-3 Overall efficacy CIN 2/3 or worse due to
  any HPV type 12.2
• (-3.2, 25.3).

87
GardasilFDA Review Concerns (3)

• Longer-term efficacy
• Study 005 results suggest favorable longer term
  efficacy
• Duration of immune response
• Post-licensure commitments

88
Questions for the Committee

• Do the data from studies 005, 007, 013, and 015
  support the efficacy of Gardasil for the
  prevention of HPV 16/18 related cervical cancer,
  cervical AIS, and CIN 2/3 or worse in females
  16-26 years of age?

89
Questions for the Committee

• Do the data from studies 007, 013, and 015
  support the efficacy of Gardasil for the
  prevention of HPV 6/11/16/18 related VIN 2/3 and
  VaIN 2/3 in females 16-26 years of age?

90
Questions for the Committee

• Do the data from studies 007, 013, and 015
  support the efficacy of Gardasil for the
  prevention of HPV 6/11/16/18 related condyloma
  acuminata, VIN 1 and
• VaIN 1?

91
Questions for the Committee

• Do the immunogenicity data support bridging of
  the younger female population (9-15 years of age)
  to the efficacy population (females 16-26 years
  of age)?

92
Questions for the Committee

1. Do the safety data from studies 007, 013, 015,
   016 and 018 support the safety of Gardasil for
   use in females 9-26 years of age?

93
Questions for the Committee

1. Please comment on post-marketing commitments.