1 Gardasil TM : Quadrivalent Human Papillomavirus 6, 11, 16, 18 L1 VLP Vaccine Applicant: Merck &...

11

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

22

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

33

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

44

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

55

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.

66

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..

77

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

88

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.

99

Phase I/II Safety and Immunogenicity Phase I/II Safety and Immunogenicity StudiesStudies

001:001: HPV 11 L1 VLP VaccineHPV 11 L1 VLP Vaccine



006:006: HPV 18 L1 VLP Vaccine HPV 18 L1 VLP Vaccine

1010

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

1212

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

1313

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



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)

1414

Comparison of Study Design:Comparison of Study Design:Baseline Characteristics of SubjectsBaseline Characteristics of Subjects

SubjectsSubjects Protocol Protocol 005005




Inclusion CriteriaInclusion Criteria

AgeAge

GenderGender

16-23 years16-23 years

femalefemale


femalefemale


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)

1515

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


ASC-USASC-US


Screening Screening TriageTriage VoluntaryVoluntary VoluntaryVoluntary MandatoryMandatory MandatoryMandatory

Exit Exit ColposcopyColposcopy YesYes YesYes NoNo NoNo

Source: Interim Analysis, Table 1

1616

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

1717

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





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


paraffinparaffin


paraffinparaffin


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

1818

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




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

1919

Number of Subjects Enrolled:Number of Subjects Enrolled:Distribution by Protocol and RegionDistribution by Protocol and Region

(Efficacy Population)(Efficacy Population)




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

2121

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 16-HPV 16-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

2222

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 16-HPV 16-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.

2323

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.

2424


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


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.

2626

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%

2727

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]

2828

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


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


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



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

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


No. of No. of


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


GardasilGardasil

N=9075N=9075

PlaceboPlacebo

N= 9075N= 9075

NNNo. of No. of casescases IncidenceIncidence NN

No. of No. of


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



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


GardasilGardasil

N=9075N=9075

PlaceboPlacebo

N= 9075N= 9075


No. of No. of


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


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


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


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


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


No. of No. of


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



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%)


(96.8, 98.3%)(96.8, 98.3%)


(99.2, 99.9%)(99.2, 99.9%)


(71.8, 75.9%)(71.8, 75.9%)

Source: Table 5.3.5.3.3:14, p. 55, Integrated Summary of Immunogenicity

7878

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

7979

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

8282

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.

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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%)].

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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?

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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?

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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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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)?

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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?

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6.6. Please comment on post-marketing Please comment on post-marketing commitments.commitments.

1 Gardasil TM : Quadrivalent Human Papillomavirus 6, 11, 16, 18 L1 VLP Vaccine Applicant: Merck &...

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