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

Gardasil TM : Quadrivalent Human Papillomavirus 6, 11, 16, 18 L1 VLP Vaccine Applicant: Merck & Co., Inc. Vaccines and Related Biological Products Advisory Committee Meeting May 18, 2006 Nancy B. Miller, M.D. CBER, FDA. Review Team. Chairperson: Gopa Raychaudhuri, Ph.D.

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

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  1. GardasilTM : Quadrivalent Human Papillomavirus 6, 11, 16, 18 L1 VLP VaccineApplicant: Merck & Co., Inc. Vaccines and Related Biological Products Advisory Committee Meeting May 18, 2006 Nancy B. Miller, M.D. CBER, FDA

  2. Review Team Chairperson: Gopa Raychaudhuri, Ph.D. Regulatory Coordinator: Julienne Vaillancourt, R.Ph., M.P.H. Clinical: Nancy Miller, M.D. Joseph Toerner, M.D., M.P.H. Karen Goldenthal, M.D. Antonia Geber, M.D. Douglas Pratt, M.D., M.P.H Statistical: Henry Hsu, Ph.D., M.P.H. Lev Sirota, Ph.D. A. Dale Horne, Dr.Ph. Product: Robin Levis, Ph.D. Rolf Taffs, Ph.D. Gennady Rezapkin, Ph.D. Loris McVittie, Ph.D. Jerry Weir, Ph.D. Non-Clinical: Sally Hargus, Ph.D. Marion Gruber, Ph.D. Pharmacovigilance: Hector Izurieta, M.D. Robert Ball, M.D., M.P.H. Bioresearch Monitoring: Robert Wesley Facility: Susan Yu, Ph.D. Laurie Norwood, Ph.D. Advertising/Promotional Labeling: Maryann Gallagher

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

  4. Gardasil:Applicant’s Proposed Indications (1) • Prevention of HPV 16/18 related: • Cervical cancer • Cervical AIS • CIN 2 and CIN 3 • Vulvar and vaginal cancer • VIN 2 and VIN 3 • VaIN 2 and VaIN 3 • Prevention of HPV 6/11/16/18 related: • CIN grade 1 • Genital warts (condyloma acuminata) • VIN grade 1 and VaIN grade 1 • HPV infection AIS = Adenocarcinoma in situ; CIN = Cervical Intraepithelial Neoplasia; VIN = Vulvar Intraepthelial Neoplasia; VaIN = Vaginal Intraepithelial Neoplasia

  5. Gardasil:Applicant’s 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 preadolescent and adolescent females 9-17 years of age and females 18-26 years of age.

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

  8. Efficacy Endpoint for Preventive HPV Vaccines (Cervical Cancer) November 2001 VRBPAC: CIN 2/3 histology, AIS, or worse with virology.

  9. Phase I/II Safety and Immunogenicity Studies • 001:HPV 11 L1 VLP Vaccine • 002:HPV 16 L1 VLP Vaccine • 004:HPV 16 L1 VLP Vaccine • 006:HPV 18 L1 VLP Vaccine

  10. Gardasil BLA: Protocols Contributing to Combined Efficacy Analysis • 005: “Proof of Concept” Phase II Efficacy Trial (HPV 16) • 007: Quadrivalent Dose-Ranging and Efficacy Study • 013: CIN/Warts Efficacy Study • 015: CIN 2/3 Efficacy Study

  11. Gardasil:Protocol 013 Substudies • 011: Hepatitis B Concomitant Use Substudy • 012: HPV 16 Bridging Substudy

  12. Immunogenicity and Safety Studies in Adolescents • 016: Adolescent/Adult Bridging and End-Expiry Study • 018: Adolescent Immunogenicity and Safety Study

  13. Comparison of Study Design:Protocols That Contribute to Combined Analysis *384 subjects received HPV 16 to bridge to Protocol 005 DB = Double blind; R=Randomized; PC = Placebo controlled From 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 in Singapore Source: 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: 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 to group, HPV testing, dx at DCL. ^Until 10/2000, pathologists were Kurman/Sherman/Stoler/Ferenczy Source: 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 efficacy = 20541 Sources: CSR 007, Table 7-2 and 2.7.3–cervix 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+ and/or PCR+. Post Day 1 includes PCR+ only. Source: Interim Analysis Report, Table 2

  21. Role of Baseline HPV Status and Endpoint Counting for Prophylactic Vaccine Efficacy Analyses Naïve: Subjects seronegative Day 1 and PCR negative Day 1 through Month 7. Source: Merck Briefing Document

  22. Role of Baseline HPV Status and Endpoint Counting for Prophylactic Vaccine Efficacy Analyses Source: Merck Briefing Document Note: Non-HPV 6, 11, 16, 18 related disease not included in analyses.

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

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

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

  26. Baseline Characteristicsof Subjects in Efficacy Population (Protocols 005, 007, 013, and 015) • Squamous intraepithelial lesion (SIL) present at baseline: 12% • PCR positive and/or seropositive to a vaccine HPV type: 27%

  27. Endpoints from Efficacy Protocols(Protocols 005, 007, 013, and 015) Primary Endpoints: • HPV 16/18 related CIN 2/3 or worse [015, combined analysis] • HPV 6/11/16/18 related CIN [013] • HPV 6/11/16/18 related External Genital Lesions (EGLs) [013]

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

  29. Efficacy Against HPV 16/18 CIN 2/3 or Worse

  30. Analysis of Efficacy AgainstHPV 16/18 Related CIN 2/3 or Worse (Protocol 015) Incidence Rate: Calculated per 100 person years at risk. PPE: Naïve to relevant HPV type, received three doses of vaccine, cases counted after Month 7. MITT-3: Included regardless of baseline HPV status; received at least one dose of vaccine, cases counted 30 days post-dose 1. Sources: Table 7-2, p. 229; Table 7-5, p. 236, CSR 015v2

  31. Analysis of Efficacy AgainstHPV 16/18 Related CIN 2/3 or Worse (Protocols 005, 007, 013, 015) 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-cervixcancer:31, p. 131

  33. Efficacy Against HPV 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-cervixcancer: 26, p. 121-2

  36. Cases of HPV 6/11/16/18Related CIN in PPE Population • Four cases occurred in the Gardasil group for the PP analysis (Protocol 015). • All four cases had HPV 16 related CIN 1 at Month 12-13. • One subject had anti-HPV 16 level just below level of detection and LSIL at Day 1 and HSIL at Mo 7, and possibly had prior exposure to HPV 16; also non-naïve to HPV 18 at Day 1 and colposcopy triggered by the HSIL at Mo 7, led to a diagnosis of HPV 18 related CIN 3 at Mo 9. • Three other subjects developed LSIL at Mo 7 and Mo 12, which led to colposcopies with the resulting diagnoses. One had anti-HPV 16 level at Mo 7 higher than GMT seen in Per Protocol Immunogenicity (PPI) population.

  37. Analysis of Efficacy Against HPV 6/11/16/18Related CIN by HPV Type – MITT-3(Protocols 005, 007, 013, 015) Source: Table 2.7.3-cervixcancer:28, p. 126

  38. Efficacy Against HPV 6/11/16/18 Related CIN 2/3 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 Vaccine 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) Source: 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: Naïve to all four vaccine HPV types through Month 7, received three doses of vaccine. Source: Table 3-4, Additional Efficacy Analyses Requested by CBER

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

  44. Analysis of Efficacy AgainstHPV 6/11/16/18 EGL (Protocol 013) Source: Table 7-3, CSR 013v1, p. 240 and Table 7-18, p. 271

  45. Analysis of Efficacy AgainstHPV 6/11/16/18 Related EGLs(Protocols 007, 013, 015) Source: Table2.7.3-exgenlesions: 6, p. 39-40 Table 4-1, Additional Efficacy Analyses Requested by CBER

  46. Analysis of Efficacy Against HPV 6/11/16/18Related EGLs by HPV Type (Protocols 007, 013, 015) Source: Appendix 2.7.3-exgenlesions:9, 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 5/1/06.

  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 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

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