1 gardasil tm : quadrivalent human papillomavirus 6, 11, 16, 18 l1 vlp vaccine applicant: merck...
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GardasilGardasilTMTM : Quadrivalent : Quadrivalent Human Papillomavirus 6, 11, 16, 18 L1 VLP VaccineHuman Papillomavirus 6, 11, 16, 18 L1 VLP Vaccine
Applicant: Merck & Co., Inc.Applicant: Merck & Co., Inc.
Vaccines and Related Biological Products Vaccines and Related Biological Products Advisory Committee MeetingAdvisory Committee Meeting
May 18, 2006May 18, 2006
Nancy B. Miller, M.D.Nancy B. Miller, M.D.
CBER, FDACBER, FDA
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Review TeamReview TeamChairperson:Chairperson: Gopa Raychaudhuri, Ph.D.Gopa Raychaudhuri, Ph.D.Regulatory Coordinator:Regulatory Coordinator: Julienne Vaillancourt, R.Ph., M.P.H.Julienne Vaillancourt, R.Ph., M.P.H.Clinical:Clinical: Nancy Miller, M.D.Nancy Miller, M.D. Joseph Toerner, M.D., M.P.H.Joseph Toerner, M.D., M.P.H. Karen Goldenthal, M.D.Karen Goldenthal, M.D. Antonia Geber, M.D.Antonia Geber, M.D. Douglas Pratt, M.D., M.P.HDouglas Pratt, M.D., M.P.HStatistical:Statistical: Henry Hsu, Ph.D., M.P.H.Henry Hsu, Ph.D., M.P.H. Lev Sirota, Ph.D.Lev Sirota, Ph.D. A. Dale Horne, Dr.Ph.A. Dale Horne, Dr.Ph.Product:Product: Robin Levis, Ph.D.Robin Levis, Ph.D. Rolf Taffs, Ph.D.Rolf Taffs, Ph.D.
Gennady Rezapkin, Ph.D.Gennady Rezapkin, Ph.D. Loris McVittie, Ph.D.Loris McVittie, Ph.D.
Jerry Weir, Ph.D.Jerry Weir, Ph.D.Non-Clinical:Non-Clinical: Sally Hargus, Ph.D.Sally Hargus, Ph.D. Marion Gruber, Ph.D.Marion Gruber, Ph.D.Pharmacovigilance: Pharmacovigilance: Hector Izurieta, M.D.Hector Izurieta, M.D.
Robert Ball, M.D., M.P.H.Robert Ball, M.D., M.P.H.Bioresearch Monitoring:Bioresearch Monitoring: Robert WesleyRobert WesleyFacility: Facility: Susan Yu, Ph.D.Susan Yu, Ph.D.
Laurie Norwood, Ph.D.Laurie Norwood, Ph.D.Advertising/Promotional Labeling: Maryann GallagherAdvertising/Promotional Labeling: Maryann Gallagher
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Gardasil: DescriptionGardasil: Description
Each 0.5 mL dose contains Each 0.5 mL dose contains – 20 mcg HPV 6 L1 VLP20 mcg HPV 6 L1 VLP– 40 mcg HPV 11 L1 VLP40 mcg HPV 11 L1 VLP– 40 mcg HPV 16 L1 VLP40 mcg HPV 16 L1 VLP– 20 mcg HPV 18 L1 VLP20 mcg HPV 18 L1 VLP– Adjuvant: 225 mcg aluminumAdjuvant: 225 mcg aluminum
Administered 0, 2, and 6 months IMAdministered 0, 2, and 6 months IM
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Gardasil:Gardasil:Applicant’s Proposed Indications (1)Applicant’s Proposed Indications (1)
Prevention of HPV 16/18 related:Prevention of HPV 16/18 related:– Cervical cancerCervical cancer– Cervical AISCervical AIS– CIN 2 and CIN 3CIN 2 and CIN 3– Vulvar and vaginal cancerVulvar and vaginal cancer– VIN 2 and VIN 3VIN 2 and VIN 3– VaIN 2 and VaIN 3VaIN 2 and VaIN 3
Prevention of HPV 6/11/16/18 related:Prevention of HPV 6/11/16/18 related:– CIN grade 1CIN grade 1– Genital warts (condyloma acuminata)Genital warts (condyloma acuminata)– VIN grade 1 and VaIN grade 1VIN grade 1 and VaIN grade 1– HPV infectionHPV infection
AIS = Adenocarcinoma in situ; CIN = Cervical Intraepithelial Neoplasia; VIN = Vulvar Intraepthelial Neoplasia; VaIN = Vaginal Intraepithelial Neoplasia
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Gardasil:Gardasil:Applicant’s Proposed Indications (2)Applicant’s Proposed Indications (2)
Children and adolescents 9 through 17 Children and adolescents 9 through 17 years of age and women 18 through 26 years of age and women 18 through 26 years of age.years of age.
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Gardasil:Gardasil:FDA Proposed IndicationsFDA Proposed Indications
FDA considers the data submitted in FDA considers the data submitted in the BLA to be supportive of use of the BLA to be supportive of use of Gardasil in preadolescent and Gardasil in preadolescent and adolescent adolescent females 9-17 years of age and females and females 18-26 years of age18-26 years of age..
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Regulatory HistoryRegulatory 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 vaccine2001 (November): VRBPAC discussion of endpoints for Phase 3 development2002: Product development program granted fast track status; Initiation of Phase 3 trials2005 (May): Pre-BLA meeting, agreement to allow rolling BLA and Priority Review 2005 (August): Start of rolling BLA submisssion2005 (December): Last section of rolling BLA received including Phase 3 study data; 6 month priority review
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Efficacy Endpoint for Preventive Efficacy Endpoint for Preventive HPV Vaccines (Cervical Cancer)HPV Vaccines (Cervical Cancer)
November 2001 VRBPAC:November 2001 VRBPAC: CIN 2/3 histology, AIS, or worse with CIN 2/3 histology, AIS, or worse with
virology.virology.
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Phase I/II Safety and Immunogenicity Phase I/II Safety and Immunogenicity StudiesStudies
001:001: HPV 11 L1 VLP VaccineHPV 11 L1 VLP Vaccine
002:002: HPV 16 L1 VLP VaccineHPV 16 L1 VLP Vaccine
004:004: HPV 16 L1 VLP VaccineHPV 16 L1 VLP Vaccine
006:006: HPV 18 L1 VLP Vaccine HPV 18 L1 VLP Vaccine
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Gardasil BLA: Protocols Gardasil BLA: Protocols Contributing to Combined Efficacy Contributing to Combined Efficacy
AnalysisAnalysis
005: “Proof of Concept” Phase II Efficacy “Proof of Concept” Phase II Efficacy Trial (HPV 16) Trial (HPV 16)
007: Quadrivalent Dose-Ranging and Quadrivalent Dose-Ranging and Efficacy Study Efficacy Study
013: CIN/Warts Efficacy Study CIN/Warts Efficacy Study
015: CIN 2/3 Efficacy Study CIN 2/3 Efficacy Study
1111
GardasilGardasil:Protocol 013 SubstudiesProtocol 013 Substudies
011: Hepatitis B Concomitant Hepatitis B Concomitant Use SubstudyUse Substudy
012: HPV 16 Bridging Substudy HPV 16 Bridging Substudy
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Immunogenicity and Safety Immunogenicity and Safety Studies in AdolescentsStudies in Adolescents
016: Adolescent/Adult Bridging and Adolescent/Adult Bridging and End-Expiry Study End-Expiry Study
018: Adolescent Immunogenicity and Adolescent Immunogenicity and Safety Study Safety Study
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Comparison of Study Design:Comparison of Study Design:Protocols That Contribute to Combined AnalysisProtocols That Contribute to Combined Analysis
FeaturesFeatures Protocol Protocol 005005
Protocol Protocol 007007
Protocol Protocol 013013
Protocol Protocol 015015
SitesSites USUS US, US, InternationalInternational
US, US, InternationalInternational
US, US, InternationalInternational
DesignDesign DB, R, PCDB, R, PC DB, R, PCDB, R, PC DB, R, PCDB, R, PC DB, R, PCDB, R, PC
Vaccine Vaccine HPV 16HPV 16 GardasilGardasil Gardasil*Gardasil* GardasilGardasil
*384 subjects received HPV 16 to bridge to Protocol 005DB = Double blind; R=Randomized; PC = Placebo controlledFrom Table 1, HPV L1 VLP Vaccine Combined Efficacy (Interim Analysis)
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Comparison of Study Design:Comparison of Study Design:Baseline Characteristics of SubjectsBaseline Characteristics of Subjects
SubjectsSubjects Protocol Protocol 005005
Protocol Protocol 007007
Protocol Protocol 013013
Protocol Protocol 015015
Inclusion CriteriaInclusion Criteria
AgeAge
GenderGender
16-23 years16-23 years
femalefemale
16-23 years16-23 years
femalefemale
16-23 years16-23 years
femalefemale
16-26 years*16-26 years*
femalefemale
Lifetime Lifetime PartnersPartners 0-50-5 0-40-4 0-40-4 0-40-4
Exclusion CriteriaExclusion Criteria
Previous Previous abnormal abnormal PapPap
Not allowedNot allowed Not allowed Not allowed Not allowedNot allowed Not allowedNot allowed
*23 years except for 26 years in SingaporeSource: Table 1, HPV L1 VLP Vaccine Combined Efficacy (Interim Analysis Report)
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Comparison of Study Design:Comparison of Study Design:Pap Tests and Referral for ColposcopyPap Tests and Referral for Colposcopy
FeaturesFeatures Protocol 005Protocol 005 Protocol 007Protocol 007 Protocol 013Protocol 013 Protocol 015Protocol 015
Pap intervalPap interval 6 months6 months 6 months6 months 6 months 6 months 12 months12 months
Pap testPap test ThinPrepThinPrepTMTM ThinPrepThinPrepTMTM ThinPrepThinPrepTMTM ThinPrepThinPrepTMTM
Pap readingPap reading 5 regional 5 regional labslabs
DCL Lab, DCL Lab, IndianapolisIndianapolis
DCL Lab,DCL Lab,
IndianapolisIndianapolisDCL Lab, DCL Lab,
IndianapolisIndianapolis
Minimal Pap Minimal Pap ReferralReferral ASC-USASC-US
ASC-USASC-US
HPV (+) HC-IIHPV (+) HC-II
ASC-USASC-US
HPV (+) HC-IIHPV (+) HC-II
ASC-USASC-US
HPV (+) HC-IIHPV (+) HC-II
Screening Screening TriageTriage VoluntaryVoluntary VoluntaryVoluntary MandatoryMandatory MandatoryMandatory
Exit Exit ColposcopyColposcopy YesYes YesYes NoNo NoNo
Source: Interim Analysis, Table 1
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Comparison of Study Design:Comparison of Study Design:Triage Abnormal Pap Tests for ColposcopyTriage Abnormal Pap Tests for Colposcopy
ThinPrepThinPrepTMTM Pap ResultPap Result Protocol 005Protocol 005
Protocols 007Protocols 007
and 013and 013Protocol 015Protocol 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
LSILReferred for colposcopy
Referred for colposcopy
Repeat ThinPrepTM Pap in 6 months
Source: Table 2.7.3-cervix cancer: 5
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Comparison of Study Design:Comparison of Study Design:Laboratory Tests, Pathology PanelLaboratory Tests, Pathology Panel
FeaturesFeatures Protocol 005Protocol 005 Protocol 007Protocol 007 Protocol 013Protocol 013 Protocol 015Protocol 015
Laboratory Laboratory ProcessingProcessing
DCL Lab, DCL Lab, IndianapolisIndianapolis
DCL Lab, DCL Lab, IndianapolisIndianapolis
DCL Lab, DCL Lab, IndianapolisIndianapolis
DCL Lab, DCL Lab, IndianapolisIndianapolis
Pathology Pathology Panel Panel
Reading Reading (Endpoints)*(Endpoints)*
KurmanKurman
RonetteRonette
StolerStoler
Ferenczy^Ferenczy^
KurmanKurman
RonetteRonette
StolerStoler
FerenczyFerenczy
KurmanKurman
RonetteRonette
StolerStoler
FerenczyFerenczy
KurmanKurman
RonetteRonette
StolerStoler
FerenczyFerenczy
HPV HPV Causality Causality
AssessmentAssessment
Merck HPV Merck HPV PCR assay PCR assay
frozen frozen biopsybiopsy
Merck HPV Merck HPV PCR assay PCR assay
paraffinparaffin
Merck HPV Merck HPV PCR assay PCR assay
paraffinparaffin
Merck HPV Merck HPV PCR assay PCR assay
paraffinparaffin
*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/FerenczySource: Interim Analysis, Table 1
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Comparison of Study Design:Comparison of Study Design: Number of Subjects, Median Age, and Duration of Number of Subjects, Median Age, and Duration of
Follow-up In Efficacy PopulationFollow-up In Efficacy Population
SubjectsSubjects Protocol Protocol 005005
Protocol Protocol 007007
Protocol Protocol 013013
ProtocolProtocol
015015
NN
# Vaccine# Vaccine
# Placebo# Placebo
23912391
11931193
11981198
551551
276276
275275
54425442
27172717
27252725
1215712157
60826082
60756075
Median AgeMedian Age
(Range)(Range)
20 yr.20 yr.
(16-25)(16-25)
20 yr.20 yr.
(13-24)(13-24)
20 yr.20 yr.
(16-24)(16-24)
20 yr.20 yr.
(15-26)(15-26)
Mean duration Mean duration of follow-upof follow-up 3.1 years3.1 years 2.4 years2.4 years 1.7 years1.7 years 1.4 years1.4 years
Total number of subjects with data for cervical disease efficacy = 20541Sources: CSR 007, Table 7-2 and 2.7.3–cervix cancer Table 2.7.3:8
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Number of Subjects Enrolled:Number of Subjects Enrolled:Distribution by Protocol and RegionDistribution by Protocol and Region
(Efficacy Population)(Efficacy Population)
SubjectsSubjects Protocol Protocol 005005
Protocol Protocol 007007
Protocol Protocol 013013
Protocol Protocol 015015 TotalTotal
North North AmericaAmerica
23912391
(100%)(100%)
251251
(45.6%)(45.6%)
17131713
(29.8%)(29.8%)
913913
(7.5%)(7.5%)52685268
Latin Latin AmericaAmerica 00
187 187
(33.9%)(33.9%)
22782278
(39.8%)(39.8%)
31913191
(26.2%)(26.2%)56065606
EuropeEurope 00113113
(20.5%)(20.5%)
11891189
(20.7%)(20.7%)
7872 7872
(64.8%)(64.8%)91749174
Asia-PacificAsia-Pacific 00 00566566
(9.9%)(9.9%)
181181
(1.5%)(1.5%)747747
Source: Table 2.7.3-cervix cancer: 9
2020
Subjects Excluded from Efficacy AnalysisSubjects Excluded from Efficacy AnalysisBecause of Baseline HPV StatusBecause of Baseline HPV Status
GardasilGardasil PlaceboPlacebo TotalTotal
Number of Subjects EnrolledNumber of Subjects Enrolled 1029110291 1029210292 2058320583
Received Received >> 1 injection 1 injection 1026810268 1027310273 2054120541
Excluded from PPE analysisExcluded from PPE analysis
HPV 16HPV 16
HPV 18HPV 18
28182818
16261626
30083008
16921692
58265826
33183318
Sero and/or PCR+ HPV 16Sero and/or PCR+ HPV 16**
At Day 1At Day 1
At/before Month 7At/before Month 7
16541654
17701770
16791679
20292029
33333333
37993799
Sero and/or PCR+ HPV 18Sero and/or PCR+ HPV 18**
At Day 1At Day 1
At/before Month 7 At/before Month 7
574574
656656
572572
773773
11461146
14281428
*Day 1 includes Sero+ and/or PCR+. Post Day 1 includes PCR+ only.Source: Interim Analysis Report, Table 2
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Role of Baseline HPV Status and Endpoint Counting Role of Baseline HPV Status and Endpoint Counting for Prophylactic Vaccine Efficacy Analysesfor Prophylactic Vaccine Efficacy Analyses
Baseline Baseline HPV StatusHPV Status
HPV 6- HPV 6- relatedrelated
HPV 11- HPV 11- relatedrelated
HPV 16-HPV 16-relatedrelated
HPV 18- HPV 18- relatedrelated
Naïve to all 4 Naïve to all 4 vaccine HPV vaccine HPV typestypes
YesYes YesYes YesYes YesYes
Positive HPV Positive HPV 6 or 11, 6 or 11, Naïve 16/18Naïve 16/18
NoNo NoNo YesYes YesYes
Positive HPV Positive HPV 16, Naïve for 16, Naïve for 6/11/186/11/18
YesYes YesYes NoNo YesYes
Positive HPV Positive HPV 18, Naïve 18, Naïve 6/11/166/11/16
YesYes YesYes YesYes NoNo
Naïve: Subjects seronegative Day 1 and PCR negative Day 1 through Month 7.Source: Merck Briefing Document
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Role of Baseline HPV Status and Endpoint Counting Role of Baseline HPV Status and Endpoint Counting for Prophylactic Vaccine Efficacy Analysesfor Prophylactic Vaccine Efficacy Analyses
Baseline Baseline HPV StatusHPV Status
HPV 6- HPV 6- relatedrelated
HPV 11- HPV 11- relatedrelated
HPV 16-HPV 16-relatedrelated
HPV 18- HPV 18- relatedrelated
Naïve to all 4 Naïve to all 4 vaccine HPV vaccine HPV typestypes
YesYes YesYes YesYes YesYes
Positive HPV Positive HPV 6 or 11, 6 or 11, Naïve 16/18Naïve 16/18
NoNo NoNo YesYes YesYes
Positive HPV Positive HPV 16, Naïve for 16, Naïve for 6/11/186/11/18
YesYes YesYes NoNo YesYes
Positive HPV Positive HPV 18, Naïve 18, Naïve 6/11/166/11/16
YesYes YesYes YesYes NoNo
Source: Merck Briefing DocumentNote: Non-HPV 6, 11, 16, 18 related disease not included in analyses.
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Efficacy Analysis Populations (1)Efficacy Analysis Populations (1)
Per Protocol Population for Efficacy (PPE):Per Protocol Population for Efficacy (PPE): Received all 3 vaccinations, naïve to relevant Received all 3 vaccinations, naïve to relevant vaccine HPV type through Month 7, did not deviate vaccine HPV type through Month 7, did not deviate from protocol; cases counted after Month 7.from protocol; cases counted after Month 7.
Modified Intent to Treat -1 Population (MITT-1):Modified Intent to Treat -1 Population (MITT-1): Same as PPE, but included protocol violatorsSame as PPE, but included protocol violators
Modified Intent to Treat-2 Population (MITT-2):Modified Intent to Treat-2 Population (MITT-2): Received at least 1 vaccination, naïve to relevant Received at least 1 vaccination, naïve to relevant vaccine HPV type at Day 1, and had any follow-up vaccine HPV type at Day 1, and had any follow-up visit after the first vaccination; cases counted from visit after the first vaccination; cases counted from 30 days after dose 1.30 days after dose 1.
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Efficacy Analysis Populations (2)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.
2525
Efficacy Analysis Populations (3)Efficacy Analysis Populations (3)
Modified Intent to Treat-3 Population Modified Intent to Treat-3 Population (MITT-3):(MITT-3): Received at least one Received at least one vaccination and had any follow-up visit one vaccination and had any follow-up visit one month after dose 1. Cases were counted month after dose 1. Cases were counted from 30 days after dose 1. Subjects were from 30 days after dose 1. Subjects were included regardless of baseline HPV status.included regardless of baseline HPV status.
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Baseline CharacteristicsBaseline Characteristicsof Subjects in Efficacy Population of Subjects in Efficacy Population (Protocols 005, 007, 013, and 015)(Protocols 005, 007, 013, and 015)
Squamous intraepithelial lesion (SIL) Squamous intraepithelial lesion (SIL) present at baseline: present at baseline: 12%12%
PCR positive and/or PCR positive and/or seropositive to seropositive to a vaccine HPV type: a vaccine HPV type: 27%27%
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Endpoints from Efficacy ProtocolsEndpoints from Efficacy Protocols(Protocols 005, 007, 013, and 015)(Protocols 005, 007, 013, and 015)
Primary Endpoints:Primary Endpoints:
HPV 16/18 related CIN 2/3 or worse [015, HPV 16/18 related CIN 2/3 or worse [015, combined analysis]combined analysis]
HPV 6/11/16/18 related CIN HPV 6/11/16/18 related CIN [013][013]HPV 6/11/16/18 related External Genital HPV 6/11/16/18 related External Genital Lesions (EGLs) [013]Lesions (EGLs) [013]
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Other EndpointsOther Endpoints
Other Endpoints of Interest:Other Endpoints of Interest:
HPV 16/18 related EGLsHPV 16/18 related EGLsCIN 2/3 due to any HPV type and CIN 2/3 due to any HPV type and non-vaccine HPV typesnon-vaccine HPV typesEGL due to any HPV type and non-EGL due to any HPV type and non-vaccine HPV typesvaccine HPV types
2929
Efficacy Against HPV 16/18 Efficacy Against HPV 16/18 CIN 2/3 or WorseCIN 2/3 or Worse
3030
Analysis of Efficacy AgainstAnalysis of Efficacy AgainstHPV 16/18 Related CIN 2/3 or Worse HPV 16/18 Related CIN 2/3 or Worse
(Protocol 015)(Protocol 015)
GardasilGardasil
N=6082N=6082
PlaceboPlacebo
N=6075N=6075
PopulationPopulation NNNo. of No. of casescases IncidenceIncidence NN
No. of No. of casescases IncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
PPEPPE 53015301 00 0.00.0 52585258 2121 0.30.3100%100%(75.8, (75.8, 100%)100%)
MITT-3MITT-3 59475947 6767 0.60.6 59735973 111111 1.01.039.2%39.2%
(16.9, (16.9, 55.8%)55.8%)
Incidence Rate: Calculated per 100 person years at risk.PPE: Naïve to relevant HPV type, received three doses of vaccine, cases countedafter 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
3131
Analysis of Efficacy AgainstAnalysis of Efficacy AgainstHPV 16/18 Related CIN 2/3 or Worse HPV 16/18 Related CIN 2/3 or Worse
(Protocols 005, 007, 013, 015)(Protocols 005, 007, 013, 015)
HPV L1 VLP VaccineHPV L1 VLP Vaccine
N=10268N=10268
PlaceboPlacebo
N=10273N=10273
PopulationPopulation NNNo. of No. of CasesCases IncidenceIncidence NN
No. of No. of CasesCases IncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
PPEPPE 84878487 00 00 84608460 5353 0.40.4100%100%(92.9, (92.9, 100%)100%)
MITT-3MITT-3 98319831 122122 0.60.6 98969896 201201 0.90.939.0%39.0%
(23.3, (23.3, 51.7%)51.7%)
Source: Table 2.7.3-cervixcancer: 29, p. 127-8
3232
Analysis of Efficacy of Against HPV 16/18 RelatedAnalysis of Efficacy of Against HPV 16/18 RelatedCIN 2/3 or Worse by HPV Type – MITT 3 Analysis CIN 2/3 or Worse by HPV Type – MITT 3 Analysis
(Protocols 005, 007, 013, 015)(Protocols 005, 007, 013, 015)
GardasilGardasil
N=10268N=10268
PlaceboPlacebo
N=10273N=10273
HPV TypeHPV Type NNNo. of No. of casescases IncidenceIncidence NN
No. of No. of casescases IncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
HPV-16HPV-16 98319831 115115 0.50.5 98969896 184184 0.90.9 37.2%37.2%
(20.3, 50.7%)(20.3, 50.7%)
HPV-18HPV-18 88148814 77 0.040.04 88468846 3333 0.20.2 78.7%78.7%(51.0, 92.0%)(51.0, 92.0%)
Source: Table 2.7.3-cervixcancer:31, p. 131
3333
Efficacy AgainstEfficacy Against
HPV 6/11/16/18 CINHPV 6/11/16/18 CIN
3434
Analysis of Efficacy AgainstAnalysis of Efficacy AgainstHPV 6/11/16/18 Related CIN HPV 6/11/16/18 Related CIN
(Protocol 013)(Protocol 013)
Gardasil Gardasil
N=2717N=2717
PlaceboPlacebo
N=2725N=2725
PopulationPopulationNN
No. of No. of casescases IncidenceIncidence NN
No. of No. of casescases IncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
PPEPPE 22402240 00 00 22582258 3737 1.01.0100%100%(87.4, (87.4, 100%)100%)
MITT-3MITT-3 26072607 6565 1.21.2 26112611 113113 2.02.042.9%42.9%(21.9, (21.9,
58.6%)58.6%)
Source: Table 7-3, CSR 013v1, p. 240, Table 7-8. p 250.
3535
Analysis of Efficacy AgainstAnalysis of Efficacy AgainstHPV 6/11/16/18 Related CIN HPV 6/11/16/18 Related CIN
(Protocols 007, 013, 015)(Protocols 007, 013, 015)
GardasilGardasil
N=9075N=9075
PlaceboPlacebo
N=9075N=9075
PopulationPopulation NNNo. of No. of casescases IncidenceIncidence NN
No. of No. of casescases IncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
PPEPPE
CombinedCombined78587858 44 0.030.03 78617861 8383 0.70.7
95.2%95.2%
(87.2, (87.2, 98.7%)98.7%)
MITT-3 MITT-3 CombinedCombined
88148814 170170 1.01.0 88468846 317317 1.81.846.4%46.4%
(35.2, (35.2, 55.7%)55.7%)
Source: Table2.7.3-cervixcancer: 26, p. 121-2
3636
Cases of HPV 6/11/16/18Cases of HPV 6/11/16/18Related CIN in PPE PopulationRelated 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.
3737
Analysis of Efficacy Against HPV 6/11/16/18Related CIN by HPV Type – MITT-3
(Protocols 005, 007, 013, 015)
GardasilGardasil
N=10572N=10572
PlaceboPlacebo
N= 10273N= 10273
HPV HPV TypeType NN
No. of No. of casescases IncidenceIncidence NN
No. of No. of
casescasesIncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
HPV HPV 6/116/11
88148814 1616 0.10.1 88468846 6161 0.30.3 73.7%73.7%(53.8, 85.8%)(53.8, 85.8%)
HPV 16HPV 16 1012110121 155155 0.70.7 98969896 278278 1.31.3 45.6%45.6%(33.6, 55.6%)(33.6, 55.6%)
HPV 18HPV 18 88148814 1919 0.10.1 88468846 6363 0.40.469.7%
(48.8, 82.9%)(48.8, 82.9%)
Source: Table 2.7.3-cervixcancer:28, p. 126
3838
Efficacy Against HPV 6/11/16/18 Related CIN 2/3 or Worse and AIS (Protocols 005, 007, 013, and 015)
Gardasil Placebo
Day 1 Status
NNo.
casesIncidence N
No. of cases
IncidenceEfficacy
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
3939
Selected Characteristics for Subgroup of Vaccine Related HPV PCR Positive and
Seropositive Subjects at Day 1(Protocol 013)
GardasilGardasil PlaceboPlacebo
Subgroup Subgroup PopulationPopulation 156156 137137
History of History of cervicovaginal cervicovaginal
infection or STDinfection or STD35.9%35.9% 32.1%32.1%
Pap test with Pap test with HSILHSIL 6.5%6.5% 3.7%3.7%
Source: Table 2a-2, Response to CBER questions from 3/1/06.
4040
Efficacy Against Any HPV Type Efficacy Against Any HPV Type and Non-Vaccine HPV Type and Non-Vaccine HPV Type
Related CINRelated CIN
4141
Overall Impact on CIN 2/3 or WorseOverall Impact on CIN 2/3 or WorseDue to Any HPV Type Due to Any HPV Type
(Protocols 007, 013, and 015)(Protocols 007, 013, and 015)
GardasilGardasil
N=9075N=9075
PlaceboPlacebo
N= 9075N= 9075
PopulationPopulation NNNo. of No. of casescases IncidenceIncidence NN
No. of No. of
casescasesIncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
MITT-3MITT-3 88148814 287287 1.61.6 88468846 328328 1.91.912.2%12.2%(-3.2, (-3.2,
25.3%)25.3%)
Source: Table 5.3.5.3.2:17, p. 78-9, Integrated Summary of Efficacy
4242
Analysis of Efficacy Against Analysis of Efficacy Against Non-HPV 6/11/16/18Non-HPV 6/11/16/18 Related Related CIN 2 or CIN 3 Among Subjects in All MITT-1 Population CIN 2 or CIN 3 Among Subjects in All MITT-1 Population
(Protocols 007, 013, 015)(Protocols 007, 013, 015)
GardasilGardasil
N=9075N=9075
PlaceboPlacebo
N= 9075N= 9075
NNNo. of No. of casescases IncidenceIncidence NN
No. of No. of
casescasesIncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
CIN 2CIN 2 59935993 5959 0.70.7 57665766 4949 0.60.6-16.1%-16.1%(-73.2, (-73.2, 21.8%)21.8%)
CIN 3CIN 3 59935993 3636 0.40.4 57665766 2727 0.30.3-28.5%-28.5%(-120.1, (-120.1, 24.1%)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
4343
Efficacy Against HPV 6/11/16/18Efficacy Against HPV 6/11/16/18Related External Genital Lesions Related External Genital Lesions
(EGLs)(EGLs)
4444
Analysis of Efficacy AgainstAnalysis of Efficacy AgainstHPV 6/11/16/18 EGL (Protocol 013)HPV 6/11/16/18 EGL (Protocol 013)
Gardasil Gardasil
N=2717N=2717
PlaceboPlacebo
N=2725N=2725
PopulationPopulation NNNo. of No. of casescases IncidenceIncidence NN
No. of No. of casescases IncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
PPEPPE 22612261 00 0.00.0 22792279 4040 1.01.0100%100%(88.4, (88.4, 100%)100%)
MITT-3MITT-3 26712671 2626 0.50.5 26682668 8080 1.41.467.8%67.8%(49.3, (49.3,
80.1%)80.1%)
Source: Table 7-3, CSR 013v1, p. 240 and Table 7-18, p. 271
4545
Analysis of Efficacy AgainstAnalysis of Efficacy AgainstHPV 6/11/16/18 Related EGLsHPV 6/11/16/18 Related EGLs
(Protocols 007, 013, 015)(Protocols 007, 013, 015)
GardasilGardasil
N=9075N=9075
PlaceboPlacebo
N= 9075N= 9075
PopulationPopulation NNNo. of No. of casescases IncidenceIncidence NN
No. of No. of
casescasesIncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
PPE PPE 79877987 11 0.010.01 78997899 113113 0.90.999.1%99.1%(95.0, (95.0,
100.0%)100.0%)
RMITT-2RMITT-2 57425742 66 0.10.1 57755775 127127 1.11.195.3%95.3%(89.4, (89.4,
98.3%)98.3%)
MITT-3MITT-3 89548954 6868 0.40.4 89628962 229229 1.31.370.4%70.4%
(61.0, (61.0, 77.7%)77.7%)
Source: Table2.7.3-exgenlesions: 6, p. 39-40Table 4-1, Additional Efficacy Analyses Requested by CBER
4646
Analysis of Efficacy Against HPV 6/11/16/18Analysis of Efficacy Against HPV 6/11/16/18Related EGLs by HPV Type (Protocols 007, 013, 015)Related EGLs by HPV Type (Protocols 007, 013, 015)
Gardasil
N=9075
Placebo
N= 9075
NNo. of cases
Incidence NNo. of
casesIncidence
Efficacy
(95% CI)
MITT-3
HPV 6/118954 59 0.3 8962 194 1.1
69.6%(59.2,
77.7%)
MITT-3 HPV 16
8954 11 0.1 8962 55 1.180.0%
(61.3, 90.5%)
MITT-3 HPV 18
8954 2 0.01 8962 20 0.190.0%
(58.7, 98.9%)
Source: Appendix 2.7.3-exgenlesions:9, p. 64
4747
Analysis of Efficacy Against HPV 16/18 Related EGLs Analysis of Efficacy Against HPV 16/18 Related EGLs (Protocols 007, 013, 015)(Protocols 007, 013, 015)
GardasilGardasil
N=9075N=9075
PlaceboPlacebo
N= 9075N= 9075
Population - EGL Population - EGL typetype NN
No. of No. of casescases IncidenceIncidence NN
No. of No. of
casescasesIncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
PPE - PPE - Condyloma, VIN Condyloma, VIN 1 or VaIN 1)1 or VaIN 1)
77697769 00 0.00.0 77417741 2424 0.20.2 100.0%100.0%(83.4, 100.0%)(83.4, 100.0%)
PPE - VIN 2/3 or PPE - VIN 2/3 or VaIN 2/3 or VaIN 2/3 or worse)worse)
77697769 00 0.00.0 77417741 1010 0.10.1 100.0%100.0%(55.5, 100.0%)(55.5, 100.0%)
MITT-3 - MITT-3 - Condyloma, VIN Condyloma, VIN 1 or VaIN 1)1 or VaIN 1)
89548954 77 0.040.04 89628962 5151 0.30.3 86.2%86.2%(69.6, 94.7%)(69.6, 94.7%)
MITT-3 – MITT-3 –
VIN 2/3 or VaIN VIN 2/3 or VaIN 2/3 or worse)2/3 or worse)
89548954 88 0.050.05 89628962 2626 0.10.1 69.1%69.1%(29.8, 87.9%)(29.8, 87.9%)
Source: Table 2.7.3-exgenlesions:7, p. 41
4848
Analysis of Efficacy Against HPV 6/11/16/18 Analysis of Efficacy Against HPV 6/11/16/18 Related EGL by Severity of Disease –Related EGL by Severity of Disease –
PPE Population (Protocols 007, 013, 015)PPE Population (Protocols 007, 013, 015)
GardasilGardasil
N=9075N=9075
PlaceboPlacebo
N= 9075N= 9075
Population - Population - EGL typeEGL type NN
No. of No. of casescases IncidenceIncidence NN
No. of No. of
casescasesIncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
PPE - PPE - CondylomaCondyloma 78977897 11 0.00.0 78997899 9191 0.80.8 98.9%98.9%
(93.7, 100.0%)(93.7, 100.0%)
PPE – VIN 1PPE – VIN 1 78977897 00 0.00.0 78997899 1010 0.10.1 100.0%100.0%(55.4, 100.0%)(55.4, 100.0%)
PPE-VIN 2/3PPE-VIN 2/3 78977897 00 0.00.0 78997899 88 0.10.1 100.0%100.0%(41.4, 100.0%)(41.4, 100.0%)
PPE-VaIN 2/3PPE-VaIN 2/3 78977897 00 0.00.0 78997899 55 0.040.04 100.0%100.0%(<0.0, 100.0%)(<0.0, 100.0%)
Source: Table 1-1, Response to CBER request 5/1/06.
4949
Analysis of Efficacy Against HPV 6/11/16/18 Analysis of Efficacy Against HPV 6/11/16/18 Related EGL by Severity of Disease –Related EGL by Severity of Disease –
MITT-3 population (Protocols 007, 013, 015)MITT-3 population (Protocols 007, 013, 015)
GardasilGardasil
N=9075N=9075
PlaceboPlacebo
N= 9075N= 9075
Population - Population - EGL typeEGL type NN
No. of No. of casescases IncidenceIncidence NN
No. of No. of
casescasesIncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
MITT-3 MITT-3 CondylomaCondyloma 89548954 5858 0.30.3 89628962 184184 1.01.0 68.5%68.5%
(57.5, 77.0%)(57.5, 77.0%)
MITT-3MITT-3
VIN 1VIN 189548954 88 0.050.05 89628962 1919 0.10.1 57.8%57.8%
(<0.0, 84.0%)(<0.0, 84.0%)
MITT-3MITT-3
VIN 2/3VIN 2/389548954 77 0.040.04 89628962 2222 0.10.1 68.1%68.1%
(22.7, 88.5%)(22.7, 88.5%)
MITT-3MITT-3
VaIN 2/3VaIN 2/389548954 22 0.010.01 89628962 99 0.10.1 77.7%77.7%
(<0.0, 97.7%)(<0.0, 97.7%)
Source: Table 1-3, CBER Additional Request for analyses, 5/1/06
5050
Efficacy Against HPV 6/11/16/18 Related EGLs (Protocols 007, 013, and 015)
GardasilGardasil
N=9075N=9075
PlaceboPlacebo
N= 9075N= 9075
Day 1 Day 1 StatusStatus NN
No. of No. of casescases IncidenceIncidence NN
No. of No. of
casescasesIncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
Sero (-) Sero (-) PCR (+)PCR (+) 810810 4444 2.92.9 782782 4141 2.82.8 -4.0%-4.0%
(-63.2, 33.6%)(-63.2, 33.6%)
Sero (+) Sero (+) PCR (-)PCR (-) 12701270 00 0.00.0 13011301 44 0.20.2 100.0%100.0%
(-56.2, 100.0%)(-56.2, 100.0%)
Sero (+) Sero (+) PCR (+) PCR (+) 336336
55
[49]*[49]*1.01.0 331331
55
[50]*[50]*1.01.0 2.4%2.4%
(-324.3, 77.5%)(-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-exgenlesions:8, p. 43 and Table 7-1, Additional Efficacy Analyses Requested by CBER
5151
Impact of Gardasil on Incidence of EGLs Dueto Any HPV Type by Severity of Disease
(Protocols 007, 013, 015)
GardasilGardasil
N=9075N=9075
PlaceboPlacebo
N= 9075N= 9075
NNNo. of No. of casescases IncidenceIncidence NN
No. of No. of
casescasesIncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
RMITT 2 RMITT 2 condylomata, condylomata, VIN 1 or VaIN 1VIN 1 or VaIN 1
57345734 5252 0.50.5 57695769 151151 1.31.365.4%65.4%
(52.3, 75.3%)(52.3, 75.3%)
RMITT 2- VIN RMITT 2- VIN 2/3 or VaIN 2/3 2/3 or VaIN 2/3 or worseor worse
57345734 55 0.040.04 57695769 2727 0.20.281.3%81.3%
(50.8, 94.4%)(50.8, 94.4%)
MITT-3 – MITT-3 – condylomata, condylomata, VIN 1 or VaIN 1VIN 1 or VaIN 1
89548954 169169 1.01.0 89628962 284284 1.61.640.5%40.5%
(27.8, 51.1%)(27.8, 51.1%)
MITT-3 – VIN MITT-3 – VIN 2/3 or VaIN 2/3 2/3 or VaIN 2/3 or worseor worse
89548954 2222 0.10.1 89628962 4343 0.20.248.7%48.7%
(12.3, 70.8%)(12.3, 70.8%)
Source: Table 2.7.3-exgenlesions: 9, p. 46
5252
Efficacy Against Non-HPV 6/11/16/18Related EGL in All MITT-1 Population
(Protocols 007, 013, 015)
GardasilGardasil
N=9075N=9075
PlaceboPlacebo
N=9075N=9075
NNNo. of No. of casescases IncidenceIncidence NN
No. of No. of casescases IncidenceIncidence
EfficacyEfficacy
(95% CI)(95% CI)
EGL not EGL not related to related to HPV HPV 6/11/16/186/11/16/18
59995999 5252 0.60.6 57735773 4949 0.60.6 -2.1%-2.1%(-54.1, 32.2%)(-54.1, 32.2%)
Condyloma, Condyloma, VIN 1, VaIN 1VIN 1, VaIN 1 59995999 4646 0.50.5 57735773 4949 0.60.6 9.7%9.7%
(-37.9, 40.9%)(-37.9, 40.9%)
VIN 2/3 or VIN 2/3 or VaIN 2/3VaIN 2/3 59995999 55 0.10.1 57735773 66 0.10.1 19.8%19.8%
(-215.3, 80.6%)(-215.3, 80.6%)
Vulvar or Vulvar or vaginal vaginal cancercancer
59995999 11 0.010.01 57735773 00 0.00.0 NANA
Source: Table 6-2, Additional Efficacy Analyses Requested by CBER
5353
Safety
Safety PopulationSafety Population
Safety SurveillanceSafety Surveillance
DeathsDeaths
SAEsSAEs
Pregnancies/LactationPregnancies/Lactation
5454
Safety Population:Safety Population:Detailed and GeneralDetailed and General
Safety Safety PopulationPopulation GardasilGardasil PlaceboPlacebo
Detailed Safety Detailed Safety PopulationPopulation 61606160 40644064
General Safety General Safety PopulationPopulation 1177811778 96869686
Source: Tables 2.7.4: 4 and 5, p. 29-30, Summary of Clinical Safety 3/8/06
5555
Vaccine Exposure in 9-15 Year OldFemale Subjects
(Protocols 016 and 018)
AgeFemales
Gardasil
9 85
10 158
11 196
12 165
13 190
14 192
15 137
Total 1123
Source: Applicant’s response to additional CBER questions
5656
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
> 100° F oral– Solicited and unsolicited systemic AEs: Sore
muscle, sore joints, headache, rash, diarrhea for 14 days after vaccination
5757
Serious Adverse Event Reporting
Any SAE for day of consent to 14 days Any SAE for day of consent to 14 days postdose 1, and 14 days postdose 2 and 3 postdose 1, and 14 days postdose 2 and 3 regardless of attributionregardless of attributionAny death or SAE which resulted in study Any death or SAE which resulted in study discontinuationdiscontinuationAny SAE throughout study which was Any SAE throughout study which was possibly vaccine or procedure related or possibly vaccine or procedure related or whose relationship was unclearwhose relationship was unclearPregnancy related SAEs throughout studyPregnancy related SAEs throughout study
Source: Applicant’s Response to CBER question
5858
Reporting New MedicalConditions
Pre-vaccinationPre-vaccination
Study period through Month 7Study period through Month 7
Study period after Month 7Study period after Month 7
5959
Pregnancy and Lactation Reporting
All pregnancies were to be followed to All pregnancies were to be followed to outcomeoutcome
SAEs were reported for mothers and SAEs were reported for mothers and infants infants
Lactation outcomes were followedLactation outcomes were followed
6060
Safety Results
6161
Deaths(Protocols 007, 013, 015, 016, 018)
Gardasil (N=11, 0.9%) Placebo (N=7, 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-section1
Source: Summary of Clinical Safety (3/8/06), Table 2.7.4:20, p. 56-61.
6262
Serious Adverse Events (Protocols 007, 013, 015, 016, 018)
SAE (Organ system) Gardasil N=11778 Placebo N=9680
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 2.7.4:21, p. 63-102.
6363
New Medical Conditions (Number and Percent) During Vaccination Period New Medical Conditions (Number and Percent) During Vaccination Period (through Month 7) and after Month 7 for Selected Organ Systems(through Month 7) and after Month 7 for Selected Organ Systems
(Protocols 007, 013, 015, 016, 018)(Protocols 007, 013, 015, 016, 018)
Organ System During Vaccination Period Post Month 7
Gardasil
N=11778
Placebo
N=9868
Gardasil
N=10452
Placebo
N=9385
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 (<0.1%) 17 (0.2%) 26 (0.3%)
Source: Summary of Clinical Efficacy (3/8/06): Appendices 2.7.4: 31, 33, 34, 36
6464
Pregnancy Outcome Summary (Protocols 013, 015, 016, 018)
Gardasil (N=10418)Gardasil (N=10418) Placebo (N=9120)Placebo (N=9120)
Subjects with pregnanciesSubjects with pregnancies 1115 (10.7%)1115 (10.7%) 1151 (12.6%)1151 (12.6%)
Number of pregnanciesNumber of pregnancies 12441244 12721272
Number of fetuses/infants Number of fetuses/infants with known outcomeswith known outcomes 996996 10181018
Number of pregnancies with Number of pregnancies with unknown outcomesunknown outcomes 258258 263263
Live BirthsLive Births 621 (62.3%)621 (62.3%) 611 (60.0%)611 (60.0%)
Spontaneous miscarriageSpontaneous miscarriage 249 (25%)*249 (25%)* 257 (25.2%)*257 (25.2%)*
Late fetal deathsLate fetal deaths 11 (1.2%)11 (1.2%) 8 (0.9%)8 (0.9%)
*Percentage calculated with number of known outcomesSource: Summary of Clinical Safety (3/8/06), Table 2.7.4:24, p. 126-8.
6565
Distribution of Congenital Anomalies by Estimated Dates of Conception (EDCn) Timing in Relation to Vaccination (Protocols 013, 015, 016, 018)
GardasilGardasil PlaceboPlacebo
Congenital AnomaliesCongenital Anomalies 1515 1616
EDCn within 30 days of EDCn within 30 days of study vaccinestudy vaccine 5**5** 00
Live birth reported in Live birth reported in neonatal periodneonatal period 55 00
EDCn beyond 30 days of EDCn beyond 30 days of study vaccinestudy vaccine 1010 1616
Live birth reported in Live birth reported in neonatal periodneonatal period 88 1212
Live birth reported Live birth reported beyond neonatal periodbeyond neonatal period 11 11
Fetal LossFetal Loss 00 22
Intra-uterine diagnosisIntra-uterine diagnosis 11 11
**Diagnoses included hip dysplasia, ankyloglossia and pyloric stenosis, congenitalhydronephrosis, club foot, and congenital megacolonSource: Table 2.7.4:26, p. 135, safety update 3/8/06
6666
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 (N=40, 4.2%) or placebo (N=41, 4.3%).– These events included conditions leading
to C-section, premature labor, and conditions associated with pregnancy.
6767
Adverse Events in Pregnancy/Lactation (2)(Protocols 013, 015, 016)
Higher proportion of children with SAEs in Higher proportion of children with SAEs in women who received Gardasil while women who received Gardasil while breastfeeding in the vaccination period breastfeeding in the vaccination period (Gardasil N=17, 3.4%; placebo N=9, (Gardasil N=17, 3.4%; placebo N=9, 1.8%); the events were of similar nature in 1.8%); the events were of similar nature in both groups.both groups.– In both the vaccine and placebo groups, In both the vaccine and placebo groups,
these included respiratory infections, these included respiratory infections, gastroenteritis, and asthma.gastroenteritis, and asthma.
6868
Adverse Events in Infants/Lactation(3)Adverse Events in Infants/Lactation(3)(Protocols 013, 015, 016)(Protocols 013, 015, 016)
EventEventGardasilGardasil
N=500N=500
PlaceboPlacebo
N=495N=495
Respiratory Infections 12 4
Gastroenteritis/Diarrhea 5 2
Asthma 1 1
Bronchial ObstructionBronchial Obstruction 11 00
CellulitisCellulitis 11 00
DehydrationDehydration 11 00
Head InjuryHead Injury 11 00
Anomalous pulmonary Anomalous pulmonary venous returnvenous return
11 00
Unspecified Viral InfectionUnspecified Viral Infection 00 11
Febrile ConvulsionFebrile Convulsion 00 11
Source: Summary of Clinical Safety, Page 181-182 and Appendix 2.7.4:195, Pages 1076-1079
6969
FDA Safety Conclusion (1)FDA Safety Conclusion (1)
Although no obvious safety signal Although no obvious safety signal was identified, post-marketing was identified, post-marketing pharmacovigilance activities will pharmacovigilance activities will continue to collect AEs that occur continue to collect AEs that occur post-vaccination in a larger post-vaccination in a larger population.population.
7070
FDA Safety Conclusion (2)FDA Safety Conclusion (2)
An imbalance was noted regarding An imbalance was noted regarding the EDCn of infants who had the EDCn of infants who had congenital anomalies (five cases for congenital anomalies (five cases for mothers who received Gardasil vs. mothers who received Gardasil vs. none for mothers who received none for mothers who received placebo). However, there did not placebo). However, there did not appear to be a pattern among the appear to be a pattern among the congenital anomalies.congenital anomalies.
7171
Immunogenicity
Bridging immune response in Bridging immune response in adolescent girls to adult womenadolescent girls to adult women
Duration of immune responseDuration of immune response
Co-administration with Hepatitis B Co-administration with Hepatitis B vaccinevaccine
7272
Bridging Immune Response from Females 16-26 Years to
Females 9-15 Years of Age
Females naïve to the four vaccine Females naïve to the four vaccine HPV types are expected to benefit HPV types are expected to benefit most from the vaccine.most from the vaccine.
Efficacy studies cannot be conducted Efficacy studies cannot be conducted in preadolescent girls.in preadolescent girls.
7373
Month 7 HPV 6 GMTs and 95% CI by Age at Enrollment - 9 to 26 Year Old Female Recipients of
Gardasil (PPI)
Source: Figure 5.3.5.3.3:3, Integrated Summary of Immunogenicity
7474
Immunogenicity Bridging Between 9-15 Year Old Immunogenicity Bridging Between 9-15 Year Old Females in the Immunogenicity Studies to 16-26 Year Females in the Immunogenicity Studies to 16-26 Year
Old Females in the Efficacy Studies (PPI)Old Females in the Efficacy Studies (PPI)
9-15 Year Old Females in 9-15 Year Old Females in Protocols 016 and 018Protocols 016 and 018
16-23 Year Old subjects in 16-23 Year Old subjects in Protocols 013 and 015Protocols 013 and 015
Assay Assay (cLIA)(cLIA) nn
GMTGMT
mMU/mLmMU/mL95% CI95% CI nn
GMTGMT
mMU/mLmMU/mL95% CI95% CI
Anti-HPV Anti-HPV 66
927927 931.3931.3 876.9, 876.9, 989.2989.2 28272827 542.4542.4 526.6, 526.6,
558.7558.7
Anti-HPV Anti-HPV 1111 927927 1305.71305.7 1226.2, 1226.2,
1390.41390.4 28272827 766.1766.1 740.5, 740.5, 792.6792.6
Anti-HPV Anti-HPV 1616 929929 4944.94944.9 4538.5, 4538.5,
5334.85334.8 27072707 2313.82313.8 2206.2, 2206.2, 2426.72426.7
Anti-HPV Anti-HPV 1818 932932 1046.01046.0 971.2, 971.2,
1126.51126.5 30403040 460.7460.7 443.8, 443.8, 478.3478.3
Source: Table 5.3.5.3.3:29, p. 85, Integrated Summary of Immunogenicity
7575
Duration of Immune Response
7676
Persistence of Anti-HPV 18 Immune Responses in 18 to 26 Year Persistence of Anti-HPV 18 Immune Responses in 18 to 26 Year Old Female Recipients of GardasilOld Female Recipients of Gardasil (Seronegative at Day 1 and PCR (Seronegative at Day 1 and PCR
Negative Through Month 7) Versus Placebo Recipients Negative Through Month 7) Versus Placebo Recipients (Seropositive and PCR Negative at Day 1)(Seropositive and PCR Negative at Day 1)
Source: Figure 5.3.5.3.3:16, p. 69, Integrated Summary of Immunogenicity
7777
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 (N=2818)
HPV typeHPV type Seropositivity rate at Month 24 Seropositivity rate at Month 24 (95% CI)(95% CI)
Anti-HPV 6Anti-HPV 695.7%95.7%
(94.5, 96.6%) (94.5, 96.6%)
Anti-HPV 11Anti-HPV 1197.6%97.6%
(96.8, 98.3%)(96.8, 98.3%)
Anti-HPV 16Anti-HPV 1699.6%99.6%
(99.2, 99.9%)(99.2, 99.9%)
Anti-HPV 18Anti-HPV 1873.9%73.9%
(71.8, 75.9%)(71.8, 75.9%)
Source: Table 5.3.5.3.3:14, p. 55, Integrated Summary of Immunogenicity
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Co-administration of Gardasil with Hepatitis B Vaccine
Anti-HPV 6, 11, 16, and 18 immune Anti-HPV 6, 11, 16, and 18 immune responses were non-inferior when responses were non-inferior when Gardasil was given with or without Gardasil was given with or without Recombivax (SC rates, GMT ratios)Recombivax (SC rates, GMT ratios)Anti-Hepatitis B immune response was Anti-Hepatitis B immune response was similar when Recombivax was given with similar when Recombivax was given with or without Gardasil (SC rates)or without Gardasil (SC rates)– Anti-Hep B GMTs lower in coadministration Anti-Hep B GMTs lower in coadministration
groupgroup
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Applicant’s Proposed Post-marketing Commitments
Routine pharmacovigilanceRoutine pharmacovigilance
Phase 4 studiesPhase 4 studies
Other studiesOther studies
8080
Routine PharmacovigilanceRoutine Pharmacovigilance
Passive reporting of adverse events Passive reporting of adverse events (AEs) including:(AEs) including: Monthly submission of non-serious Monthly submission of non-serious
AE reportsAE reports Regular FDA-CDC-Sponsor Regular FDA-CDC-Sponsor
conference calls conference calls
Pregnancy registryPregnancy registry
8181
Phase 4 StudiesPhase 4 StudiesObservational safety surveillance study in Observational safety surveillance study in large U.S. MCO large U.S. MCO Investigation of serious AEs that Investigation of serious AEs that
occur in close temporal association occur in close temporal association with vaccination (60 days follow-up)with vaccination (60 days follow-up)
Nordic Long Term Follow-up StudyNordic Long Term Follow-up Study Longitudinal evaluation of subjects in Longitudinal evaluation of subjects in
Protocol 015 enrolled in Nordic Protocol 015 enrolled in Nordic countries using national registriescountries using national registries
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Nordic Long Term Follow-up Nordic Long Term Follow-up Study: OutcomesStudy: Outcomes
HPV-related diseasesHPV-related diseases
Long term effectiveness and duration of Long term effectiveness and duration of immune responseimmune response
Potential safety signalsPotential safety signals
Pregnancy outcomesPregnancy outcomes
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Other StudiesOther Studies
Evaluation of long term effectivenesss Evaluation of long term effectivenesss and duration of immune response:and duration of immune response: Extension of protocol 007Extension of protocol 007 Extension of protocol 018 Extension of protocol 018
Detection of unanticipated safety signals Detection of unanticipated safety signals through active surveillance in all studies.through active surveillance in all studies.
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Gardasil:FDA Review Conclusions
The efficacy, safety, and “bridging” immune The efficacy, safety, and “bridging” immune response data submitted to the BLA support response data submitted to the BLA support licensure of Gardasil in females 9-26 years of licensure of Gardasil in females 9-26 years of age age naïve to the relevant vaccine HPV typenaïve to the relevant vaccine HPV type for for prevention of the following diseases/events:prevention of the following diseases/events:– HPV 16/18 related cervical cancer, CIN 2/3 and AIS.HPV 16/18 related cervical cancer, CIN 2/3 and AIS.– HPV 6/11/16/18 related VIN 2, VIN 3, VaIN 2, VaIN 3HPV 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 HPV 6/11/16/18 related CIN 1, genital warts, VIN 1
and VaIN 1and VaIN 1
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Gardasil:FDA Review Concerns (1)
Applicant’s 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.
8686
Gardasil:FDA 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 due to HPV6/11/16/18 [ [39.0%39.0% (23.5, 51.7%)](23.5, 51.7%)]
– MITT-3: Overall efficacy CIN 2/3 or MITT-3: Overall efficacy CIN 2/3 or worse due to any HPV type [worse due to any HPV type [12.2%
(-3.2%, 25.3%)].(-3.2%, 25.3%)].
8787
Gardasil:FDA Review Concerns (3)
Longer-term efficacyLonger-term efficacy
–Study 005 results suggest favorable Study 005 results suggest favorable longer term efficacylonger term efficacy
Duration of immune responseDuration of immune response–Post-licensure commitmentsPost-licensure commitments
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Questions for the Committee
1.1. Do the data from studies 005, 007, 013, Do the data from studies 005, 007, 013, and 015 support the efficacy of Gardasil and 015 support the efficacy of Gardasil for the prevention of HPV 16/18 related for the prevention of HPV 16/18 related cervical cancer, cervical AIS, and cervical cancer, cervical AIS, and CIN 2/3 or worse in females 16-26 years CIN 2/3 or worse in females 16-26 years of age? of age?
8989
Questions for the Committee
2.2. Do the data from studies 007, 013, and Do the data from studies 007, 013, and 015 support the efficacy of Gardasil for 015 support the efficacy of Gardasil for the prevention of HPV 6/11/16/18 related the prevention of HPV 6/11/16/18 related VIN 2/3 and VaIN 2/3 in females 16-26 VIN 2/3 and VaIN 2/3 in females 16-26 years of age? years of age?
9090
Questions for the Committee
3.3. Do the data from studies 007, 013, and Do the data from studies 007, 013, and 015 support the efficacy of Gardasil for 015 support the efficacy of Gardasil for the prevention of HPV 6/11/16/18 related the prevention of HPV 6/11/16/18 related condyloma acuminata, VIN 1 andcondyloma acuminata, VIN 1 and
VaIN 1?VaIN 1?
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Questions for the Committee
4.4. Do the immunogenicity data support Do the immunogenicity data support bridging of the younger female bridging of the younger female population (9-15 years of age) to the population (9-15 years of age) to the efficacy population (females 16-26 years efficacy population (females 16-26 years of age)?of age)?
9292
Questions for the Committee
5.5. Do the safety data from studies 007, 013, Do the safety data from studies 007, 013, 015, 016 and 018 support the safety of 015, 016 and 018 support the safety of Gardasil for use in females 9-26 years of Gardasil for use in females 9-26 years of age?age?
9393
Questions for the Committee
6.6. Please comment on post-marketing Please comment on post-marketing commitments.commitments.