1、1,GardasilTM : Quadrivalent Human Papillomavirus 6, 11, 16, 18 L1 VLP VaccineApplicant: Merck & Co., Inc.,Vaccines and Related Biological Products Advisory Committee MeetingMay 18, 2006Nancy B. Miller, M.D.CBER, FDA,2,Review Team,Chairperson:Gopa Raychaudhuri, Ph.D.Regulatory Coordinator:Julienne Va
2、illancourt, R.Ph., M.P.H.Clinical:Nancy Miller, M.D. Joseph Toerner, M.D., M.P.H. Karen Goldenthal, M.D. Antonia Geber, M.D. Douglas Pratt, M.D., M.P.HStatistical:Henry Hsu, Ph.D., M.P.H. Lev Sirota, Ph.D. A. Dale Horne, Dr.Ph.Product:Robin Levis, Ph.D. Rolf Taffs, Ph.D. Gennady Rezapkin, Ph.D. Lori
3、s McVittie, Ph.D. Jerry Weir, Ph.D.Non-Clinical:Sally Hargus, Ph.D. Marion Gruber, Ph.D.Pharmacovigilance: Hector Izurieta, M.D.Robert Ball, M.D., M.P.H.Bioresearch Monitoring:Robert WesleyFacility: Susan Yu, Ph.D. Laurie Norwood, Ph.D.Advertising/Promotional Labeling: Maryann Gallagher,3,Gardasil:
4、Description,Each 0.5 mL dose contains 20 mcg HPV 6 L1 VLP40 mcg HPV 11 L1 VLP40 mcg HPV 16 L1 VLP20 mcg HPV 18 L1 VLPAdjuvant: 225 mcg aluminumAdministered 0, 2, and 6 months IM,4,Gardasil:Applicants Proposed Indications (1),Prevention of HPV 16/18 related:Cervical cancerCervical AISCIN 2 and CIN 3V
5、ulvar and vaginal cancerVIN 2 and VIN 3VaIN 2 and VaIN 3 Prevention of HPV 6/11/16/18 related:CIN grade 1Genital warts (condyloma acuminata)VIN grade 1 and VaIN grade 1HPV infection,AIS = Adenocarcinoma in situ; CIN = Cervical Intraepithelial Neoplasia; VIN = Vulvar Intraepthelial Neoplasia; VaIN =
6、Vaginal Intraepithelial Neoplasia,5,Gardasil:Applicants Proposed Indications (2),Children and adolescents 9 through 17 years of age and women 18 through 26 years of age.,6,Gardasil:FDA Proposed Indications,FDA considers the data submitted in the BLA to be supportive of use of Gardasil in preadolesce
7、nt and adolescent females 9-17 years of age and females 18-26 years of age.,7,Regulatory History,1997: Submission of IND for monovalent HPV 11 L1 VLP vaccine (Other INDs for monovalent HPV 16 and 18)2000: Submission of IND for quadrivalent HPV 6, 11, 16, 18 L1 VLP vaccine2001 (November): VRBPAC disc
8、ussion 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
9、BLA received including Phase 3 study data; 6 month priority review,8,Efficacy Endpoint for Preventive HPV Vaccines (Cervical Cancer),November 2001 VRBPAC: CIN 2/3 histology, AIS, or worse with virology.,9,Phase I/II Safety and Immunogenicity Studies,001: HPV 11 L1 VLP Vaccine002: HPV 16 L1 VLP Vacci
10、ne004: HPV 16 L1 VLP Vaccine006: HPV 18 L1 VLP Vaccine,10,Gardasil BLA: Protocols Contributing to Combined Efficacy Analysis,005: “Proof of Concept” Phase II Efficacy Trial (HPV 16)007: Quadrivalent Dose-Ranging and Efficacy Study013: CIN/Warts Efficacy Study015: CIN 2/3 Efficacy Study,11,Gardasil:P
11、rotocol 013 Substudies,011: Hepatitis B Concomitant Use Substudy012: HPV 16 Bridging Substudy,12,Immunogenicity and Safety Studies in Adolescents,016: Adolescent/Adult Bridging and End-Expiry Study018: Adolescent Immunogenicity and Safety Study,13,Comparison of Study Design:Protocols That Contribute
12、 to Combined Analysis,*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),14,Comparison of Study Design:Baseline Characteristics of Subjects,*23 years except for 26 years
13、in SingaporeSource: Table 1, HPV L1 VLP Vaccine Combined Efficacy (Interim Analysis Report),15,Comparison of Study Design:Pap Tests and Referral for Colposcopy,Source: Interim Analysis, Table 1,16,Comparison of Study Design:Triage Abnormal Pap Tests for Colposcopy,Source: Table 2.7.3-cervix cancer:
14、5,17,Comparison of Study Design:Laboratory Tests, Pathology Panel,*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 t
15、o group, HPV testing, dx at DCL.Until 10/2000, pathologists were Kurman/Sherman/Stoler/FerenczySource: Interim Analysis, Table 1,18,Comparison of Study Design: Number of Subjects, Median Age, and Duration of Follow-up In Efficacy Population,Total number of subjects with data for cervical disease eff
16、icacy = 20541Sources: CSR 007, Table 7-2 and 2.7.3cervix cancer Table 2.7.3:8,19,Number of Subjects Enrolled:Distribution by Protocol and Region(Efficacy Population),Source: Table 2.7.3-cervix cancer: 9,20,Subjects Excluded from Efficacy AnalysisBecause of Baseline HPV Status,*Day 1 includes Sero+ a
17、nd/or PCR+. Post Day 1 includes PCR+ only.Source: Interim Analysis Report, Table 2,21,Role of Baseline HPV Status and Endpoint Counting for Prophylactic Vaccine Efficacy Analyses,Nave: Subjects seronegative Day 1 and PCR negative Day 1 through Month 7.Source: Merck Briefing Document,22,Role of Basel
18、ine HPV Status and Endpoint Counting for Prophylactic Vaccine Efficacy Analyses,Source: Merck Briefing DocumentNote: Non-HPV 6, 11, 16, 18 related disease not included in analyses.,23,Efficacy Analysis Populations (1),Per Protocol Population for Efficacy (PPE): Received all 3 vaccinations, nave to r
19、elevant vaccine HPV type through Month 7, did not deviate from protocol; cases counted after Month 7.Modified Intent to Treat -1 Population (MITT-1): Same as PPE, but included protocol violatorsModified Intent to Treat-2 Population (MITT-2): Received at least 1 vaccination, nave to relevant vaccine
20、HPV type at Day 1, and had any follow-up visit after the first vaccination; cases counted from 30 days after dose 1.,24,Efficacy Analysis Populations (2),Restricted MITT-2 Population (RMITT-2): Seronegative and PCR negative to all four vaccine HPV types at Day 1 and a normal Pap test at Day 1; cases
21、 counted 30 days after dose 1.All MITT-1 Population: Nave to all four vaccine HPV types through Month 7, and cases counted starting after Month 7.,25,Efficacy Analysis Populations (3),Modified Intent to Treat-3 Population (MITT-3): Received at least one vaccination and had any follow-up visit one mo
22、nth after dose 1. Cases were counted from 30 days after dose 1. Subjects were included regardless of baseline HPV status.,26,Baseline Characteristicsof Subjects in Efficacy Population (Protocols 005, 007, 013, and 015),Squamous intraepithelial lesion (SIL) present at baseline: 12% PCR positive and/o
23、r seropositive to a vaccine HPV type: 27%,27,Endpoints from Efficacy Protocols(Protocols 005, 007, 013, and 015),Primary Endpoints:HPV 16/18 related CIN 2/3 or worse 015, combined analysisHPV 6/11/16/18 related CIN 013HPV 6/11/16/18 related External Genital Lesions (EGLs) 013,28,Other Endpoints,Othe
24、r Endpoints of Interest:HPV 16/18 related EGLsCIN 2/3 due to any HPV type and non-vaccine HPV typesEGL due to any HPV type and non-vaccine HPV types,29,Efficacy Against HPV 16/18 CIN 2/3 or Worse,30,Analysis of Efficacy AgainstHPV 16/18 Related CIN 2/3 or Worse (Protocol 015),Incidence Rate: Calcula
25、ted per 100 person years at risk.PPE: Nave 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, C
26、SR 015v2,31,Analysis of Efficacy AgainstHPV 16/18 Related CIN 2/3 or Worse (Protocols 005, 007, 013, 015),Source: Table 2.7.3-cervixcancer: 29, p. 127-8,32,Analysis of Efficacy of Against HPV 16/18 RelatedCIN 2/3 or Worse by HPV Type MITT 3 Analysis (Protocols 005, 007, 013, 015),Source: Table 2.7.3
27、-cervixcancer:31, p. 131,33,Efficacy AgainstHPV 6/11/16/18 CIN,34,Analysis of Efficacy AgainstHPV 6/11/16/18 Related CIN (Protocol 013),Source: Table 7-3, CSR 013v1, p. 240, Table 7-8. p 250.,35,Analysis of Efficacy AgainstHPV 6/11/16/18 Related CIN (Protocols 007, 013, 015),Source: Table2.7.3-cervi
28、xcancer: 26, p. 121-2,36,Cases of HPV 6/11/16/18Related CIN in PPE Population,Four cases occurred in the Gardasil group for the PP analysis (Protocol 015). All four cases had HPV 16 related CIN 1 at Month 12-13. One subject had anti-HPV 16 level just below level of detection and LSIL at Day 1 and HS
29、IL at Mo 7, and possibly had prior exposure to HPV 16; also non-nave 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
30、had anti-HPV 16 level at Mo 7 higher than GMT seen in Per Protocol Immunogenicity (PPI) population.,37,Analysis of Efficacy Against HPV 6/11/16/18Related CIN by HPV Type MITT-3(Protocols 005, 007, 013, 015),Source: Table 2.7.3-cervixcancer:28, p. 126,38,Efficacy Against HPV 6/11/16/18 Related CIN 2/
31、3 or Worse and AIS (Protocols 005, 007, 013, and 015),* Total number of cases in subjects who were sero+ and/or PCR+ at baseline for the relevant HPV type which was associated with disease.Source: Table 1-1, Additional efficacy analysis requested by CBER,39,Selected Characteristics for Subgroup of V
32、accine Related HPV PCR Positive and Seropositive Subjects at Day 1(Protocol 013),Source: Table 2a-2, Response to CBER questions from 3/1/06.,40,Efficacy Against Any HPV Type and Non-Vaccine HPV Type Related CIN,41,Overall Impact on CIN 2/3 or WorseDue to Any HPV Type (Protocols 007, 013, and 015),So
33、urce: Table 5.3.5.3.2:17, p. 78-9, Integrated Summary of Efficacy,42,Analysis of Efficacy Against Non-HPV 6/11/16/18 Related CIN 2 or CIN 3 Among Subjects in All MITT-1 Population (Protocols 007, 013, 015),All MITT-1 Population: Nave to all four vaccine HPV types through Month 7, received three dose
34、s of vaccine.Source: Table 3-4, Additional Efficacy Analyses Requested by CBER,43,Efficacy Against HPV 6/11/16/18Related External Genital Lesions (EGLs),44,Analysis of Efficacy AgainstHPV 6/11/16/18 EGL (Protocol 013),Source: Table 7-3, CSR 013v1, p. 240 and Table 7-18, p. 271,45,Analysis of Efficac
35、y AgainstHPV 6/11/16/18 Related EGLs(Protocols 007, 013, 015),Source: Table2.7.3-exgenlesions: 6, p. 39-40Table 4-1, Additional Efficacy Analyses Requested by CBER,46,Analysis of Efficacy Against HPV 6/11/16/18Related EGLs by HPV Type (Protocols 007, 013, 015),Source: Appendix 2.7.3-exgenlesions:9,
36、p. 64,47,Analysis of Efficacy Against HPV 16/18 Related EGLs (Protocols 007, 013, 015),Source: Table 2.7.3-exgenlesions:7, p. 41,48,Analysis of Efficacy Against HPV 6/11/16/18 Related EGL by Severity of Disease PPE Population (Protocols 007, 013, 015),Source: Table 1-1, Response to CBER request 5/1/
37、06.,49,Analysis of Efficacy Against HPV 6/11/16/18 Related EGL by Severity of Disease MITT-3 population (Protocols 007, 013, 015),Source: Table 1-3, CBER Additional Request for analyses, 5/1/06,50,Efficacy Against HPV 6/11/16/18 Related EGLs (Protocols 007, 013, and 015),* Total number of cases in s
38、ubjects 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,51,Impact of Gardasil on Incidence of EGLs Dueto Any HPV Type by Severity of Disease (Pr
39、otocols 007, 013, 015),Source: Table 2.7.3-exgenlesions: 9, p. 46,52,Efficacy Against Non-HPV 6/11/16/18Related EGL in All MITT-1 Population (Protocols 007, 013, 015),Source: Table 6-2, Additional Efficacy Analyses Requested by CBER,53,Safety,Safety PopulationSafety SurveillanceDeathsSAEsPregnancies
40、/Lactation,54,Safety Population:Detailed and General,Source: Tables 2.7.4: 4 and 5, p. 29-30, Summary of Clinical Safety 3/8/06,55,Vaccine Exposure in 9-15 Year OldFemale Subjects (Protocols 016 and 018),Source: Applicants response to additional CBER questions,56,Safety Surveillance(Detailed Safety
41、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 vaccinationTemperatures for 5 days after vaccination 100 F oralSolicited and unsolicited systemic AEs: Sore muscle, sore joints, headach
42、e, rash, diarrhea for 14 days after vaccination,57,Serious Adverse Event Reporting,Any SAE for day of consent to 14 days postdose 1, and 14 days postdose 2 and 3 regardless of attributionAny death or SAE which resulted in study discontinuationAny SAE throughout study which was possibly vaccine or pr
43、ocedure related or whose relationship was unclearPregnancy related SAEs throughout study,Source: Applicants Response to CBER question,58,Reporting New MedicalConditions,Pre-vaccinationStudy period through Month 7Study period after Month 7,59,Pregnancy and Lactation Reporting,All pregnancies were to
44、be followed to outcomeSAEs were reported for mothers and infants Lactation outcomes were followed,60,Safety Results,61,Deaths(Protocols 007, 013, 015, 016, 018),Source: Summary of Clinical Safety (3/8/06), Table 2.7.4:20, p. 56-61.,62,Serious Adverse Events (Protocols 007, 013, 015, 016, 018),Source
45、: Summary of Clinical Efficacy (3/8/06) Table 2.7.4:21, p. 63-102.,63,New Medical Conditions (Number and Percent) During Vaccination Period (through Month 7) and after Month 7 for Selected Organ Systems(Protocols 007, 013, 015, 016, 018),Source: Summary of Clinical Efficacy (3/8/06): Appendices 2.7.
46、4: 31, 33, 34, 36,64,Pregnancy Outcome Summary (Protocols 013, 015, 016, 018),*Percentage calculated with number of known outcomesSource: Summary of Clinical Safety (3/8/06), Table 2.7.4:24, p. 126-8.,65,Distribution of Congenital Anomalies by Estimated Dates of Conception (EDCn) Timing in Relation
47、to Vaccination (Protocols 013, 015, 016, 018),*Diagnoses included hip dysplasia, ankyloglossia and pyloric stenosis, congenitalhydronephrosis, club foot, and congenital megacolonSource: Table 2.7.4:26, p. 135, safety update 3/8/06,66,Adverse Events in Pregnancy/Lactation (1)(Protocols 013, 015, 016, 018),A similar pattern and occurrence of SAEs and AEs in pregnancy were reported in women who were vaccinated with Gardasil (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.,
