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GARDASIL

Vaccines and Related Biological Products Advisory Committee Meeting Gardasil For Prevention of Anal Dysplasia and Anal Cancer Jeff Roberts, M.D. FDA/CBER/OVRR/DVRPA November 17, 2010. GARDASIL.

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GARDASIL

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  1. Vaccines and Related Biological Products Advisory Committee MeetingGardasil For Prevention of Anal Dysplasia and Anal CancerJeff Roberts, M.D.FDA/CBER/OVRR/DVRPANovember 17, 2010

  2. GARDASIL Gardasil is a noninfectious recombinant vaccine containing virus-like particles (VLPs) from HPV types 6, 11, 16, and 18 Current Indications: • females 9 through 26 years of age: • prevention of HPV 6, 11, 16, 18-related cervical, vulvar, and vaginal cancer and the related precancerous lesions • prevention of HPV 6 and 11-related genital warts • males 9 through 26 years of age: • prevention of HPV 6 and 11-related genital warts

  3. Gardasil for Prevention of Anal Cancer and AIN Requested additional indication: • males and females 9 through 26 years of age • prevention of HPV 6, 11, 16, and 18-related anal cancer and AIN grades 1, 2, and 3* Submitted study: • randomized controlled trial in ~600 MSMs, with AIN1+ as the primary endpoint *Approval for this indication would not change the population for whom Gardasil is already indicated

  4. Discussion Topics for the Committee Please comment on the following: • the strength of the data to support an indication for the prevention of AIN and anal cancer in males, and • the scientific rationale for extrapolating efficacy in the prevention of AIN and anal cancer to females.

  5. Agenda FDA Introduction Jeff Roberts, M.D., CBER Overview of Anal HPV, AIN, and Anal Cancer Joel Palefsky, M.D., UCSF Gardasil in the Prevention of Anal Cancer; Patrick Brill-Edwards, M.D., Merck MSM Substudy Results Elizabeth Garner, M.D., M.P.H., Merck Clinical Review of Data Supporting the Efficacy of Gardasil in the Prevention of AIN and Anal Cancer Jeff Roberts, M.D., CBER Open Public Hearing Committee Discussion and Recommendations Adjourn

  6. Vaccines and Related Biological Products Advisory Committee MeetingClinical Review of Data Supporting the Efficacy of Gardasil in the Prevention of Anal Dysplasia and Anal CancerJeff Roberts, M.D.FDA/CBER/OVRR/DVRPANovember 17, 2010

  7. Outline • Background • AIN as a surrogate clinical endpoint • Bridging efficacy to females • Pivotal Phase 3 study of Gardasil • Trial design – MSM substudy • Results • Efficacy • Immunogenicity • Discussion topics for the committee

  8. Cervical Disease Endpoints Fall Along a Spectrum … persistent infection incident infection Virology Toward the right on the spectrum: Validity Reproducibility Relevance Certainty Size Complexity Expense Ethical concerns Adapted from Lowy DR, Schiller JT. J Clin Invest. 2006 May;116(5):1167-73.

  9. 2001 VRBPAC on Cervical Cancer Surrogate Endpoint • Some advocated for a virological endpoint, because HPV infection is a “necessary and sufficient” cause of cervical cancer • Ultimately, the committee recommended a CIN2+ endpoint • Uncertainty about hypothetical efficacy concerns was prominent, for example: • Would prevention of HPV 16 and 18 provide a more favorable niche for other oncogenic HPV types? • Subsequently, HPV vaccine studies produced data that are fairly definitive in rejecting hypothetical efficacy concerns

  10. Pre-specified Endpoint in MSM Substudy Represents a Shift to the Left on This Spectrum AIN 1+ … CIN 2+ … Histology AIN 1 AIN 2 AIN 3 Adapted from Lowy DR, Schiller JT. J Clin Invest. 2006 May;116(5):1167-73.

  11. Observations Regarding AIN1+ as a Surrogate Clinical Endpoint • Histopathology provides sound theoretical support • Strong association between anal HPV and AIN/anal cancer • Epidemiology of anal HPV, AIN, and progression of disease less well-established than for cervical disease • ~10% of anal cancers are HPV(-), so HPV is not “necessary and sufficient” • Hypothetical efficacy concerns, e.g., type replacement, largely rejected

  12. Observations Regarding Extrapolating Efficacy to Females • Anal anatomy, histology, and pathophysiology similar in males and females • Strong associations with behavioral (e.g., receptive anal intercourse) and immune (e.g., HIV status) risk factors do not appear to be different across gender • Efficacy is established at another site (cervical) in females • Immune response to Gardasil is similar in males and females • Anal HPV-related disease in women, particularly progression of AIN, is less well characterized in females than in males

  13. V501-020 MSM Substudy Design • 3463 HM males, 16-23 years old, and 602 MSM, 16-26 years old from 18 different countries, randomized 1:1 to: • Gardasil 0.5mL IM, at 0, 2 and 6 months • Placebo control (AAHS in saline) 0.5mL IM, at 0, 2 and 6 months • Primary Efficacy Objective: HPV 6, 11, 16, or 18-related external genital warts, penile/perianal/perineal intraepithelial neoplasia (PIN) • Men having Sex with Men (MSM) SubstudyEfficacy Objective: HPV 6, 11, 16, or 18-related anal intraepithelial neoplasia (AIN) and Anal Cancer in MSM subjects

  14. Study V501-020 MSM Substudy Design (cont) Key Exclusion Criteria: • No history of, or current clinical evidence of, genital warts • No gross genital lesion suggesting sexually transmitted disease • No autoimmune disorders or other conditions leading to immunocompromise, including a diagnosis of HIV infection • Lifetime number of sexual partners >0 and ≤5* *MSMs who reported 0 lifetime sexual partners could be enrolled, as long as they self-identified as MSM or reported engaging in oral sex with another man within the past year.

  15. Surveillance for Efficacy Endpoints • Both HM and MSM • external genital inspection • routine collection of external genital (i.e., penile, scrotal, perianal/perineal) swabs for HPV PCR • biopsy of external genital lesions if indicated (unless not related to HPV) • MSM only: • anal swab for HPV PCR • anal pap testing • if abnormal pap, or if anal lesion noted on visual exam, referral for high resolution anoscopy Day 1 and every 6mo Day 1 and every 6mo

  16. Efficacy Analysis Populations Per-protocol efficacy (PPE) - subjects who: • received all 3 doses • had Month 7 PCR results • were HPV-naïve (i.e., seronegative at Day 1 and PCR negative from Day 1 through Month 7) to the vaccine HPV type being analyzed • did not violate protocol • cases for the PPE analysis were counted starting after Month 7 Generally HPV Naïve (GHN) • seronegative to vaccine types and PCR negative to all 14 HPV* types tested • if MSM, anal pap at Day 1 negative for SIL • received at least 1 dose of vaccine or placebo • cases counted starting at Day 1 Full analysis set (FAS) - subjects who: • received at least 1 dose of vaccine or placebo • cases counted starting at Day 1 *HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59

  17. MSM Substudy Demographics

  18. MSM Substudy Subject Characteristics, HPV Status at Enrollment

  19. Efficacy Against HPV 6/11/16/18-Related AIN and Anal Cancer in the MSM PPE Population N = Number of subjects randomized to the respective vaccination group. n = Number of subjects in the PPE population eligible for the respective analysis AIN = Anal Intraepithelial Neoplasia

  20. Efficacy Against HPV 6/11/16/18-Related AIN and Anal Cancer in the MSM FAS Population * *For comparison, the following are comparable analyses (FAS) for CIN2+ in: “young adult women” (YAW, 16-26yo) 146 v 303 cases; 52% (41, 61) “mid-adult women” (MAW, 27-45yo) 21 v 27 cases; 22% (-43, 58)

  21. Efficacy Against AIN and Anal Cancer in the MSM Population – Regardless of HPV Type * *For comparison, the following are comparable analyses (GHN) for CIN2+ in: “young adult women” (YAW, 16-26yo) 77 v 136 cases; 43% (24, 57) ** **For comparison, the following are comparable analyses (FAS) for CIN2+ in: “young adult women” (YAW, 16-26yo) 421 v 516 cases; 18% (7, 28) “mid-adult women” (MAW, 27-45yo) 49 v 43 cases; -14% (-76, 26)

  22. Efficacy Against HPV 6/11/16/18-Related AIN and Anal Cancer in the MSM PPE Population

  23. Immunogenicity Stratified by Age and Gender: Month 7 anti-HPV GMTs(in mMU) †9-15 year-old subjects from Protocols 018. ‡ 16-26 year-old female subjects from Protocols 007, 013, 015 (consistency lot substudy), 016 and 019. ║16-26 year-old male subjects from Protocol 020 N = Number of subjects randomized in the respective group who received at least 1 injection. n = Number of subjects contributing to the analysis. CI = Confidence interval; GMT = Geometric mean titer

  24. Discussion Topics for the Committee Please comment on the following: • the strength of the data to support an indication for the prevention of AIN and anal cancer in males, and • the scientific rationale for extrapolating efficacy in the prevention of AIN and anal cancer to females.

  25. Abbreviations AAHS amorphous aluminum hydroxyphosphate sulfate AC anal cancer AIN anal intraepithelial neoplasia ASC-US atypical squamous cells of undetermined significance CIN cervical intraepithelial neoplasia cLIA competitive luminex immunoassay EGL external genital lesions FAS full analysis set analysis population GHN generally HPV naïve analysis population HSIL high-grade squamous intraepithelial lesion HM heterosexual males hrHPV high risk human papillomavirus (oncogenic HPV types) LSIL low-grade squamous intraepithelial lesion MSM men having sex with men PI persistent infection PPE per protocol efficacy analysis population qHPV quadrivalent HPV vaccine (Gardasil) sBLA biologics license application supplement VaIN vaginal intraepithelial neoplasia VIN vulvar intraepithelial neoplasia VLP virus-like particles VRBPAC Vaccines and Related Biological Products Advisory Committee

  26. Anal Cancer Indication: Review Team Chairperson Jeff Roberts, M.D. Regulatory Project Managers Laura Montague Valerie Marshall Clinical Jeff Roberts, M.D. Nancy Miller, M.D. Statistical Martha B. Lee, Ph.D. Pharmacovigilance Michael D. Nguyen, M.D. Advertising/Promotional Labeling: Lisa L. Stockbridge, Ph.D. Dana Jones

  27. Extra Slides

  28. Safety: Close-out Data from Study 020 • Since original clinical study report (CSR) for 020 (12/5/08): • No new SAEs • No deaths • No new discontinuations due to AEs • With the exception of New Medical History, which contains data that extend beyond the vaccination phase, data is nearly identical • New Medical History numbers still comparable, both by SOC and by diagnoses consistent with autoimmune phenomena

  29. Summary of AEs, Days 1-15 Following Any Vaccination, V501-020 N = number of subjects in the ASaT analysis set in the respective vaccination group who had follow-up data n = number of cases *Causality determined by clinical investigator **Deaths in the entire study period: Gardasil: 3 (2 MVAs and 1 gunshot wound); Control: 10

  30. Systemic AEs* Days 1-15 Following Vaccination, V501-020 N = number of subjects in the ASaT analysis set in the respective vaccination group who had follow-up data n = number of cases *Incidence ≥2% in one or more vaccination groups **Pyrexia defined as maximum oral temperature ≥38.5°C • Analysis of AEs by System Organ Class was similarly unremarkable

  31. Injection Site AEs, Days 1-5 Following Vaccination, V501-020 N = number of subjects in the ASaT analysis set in the respective vaccination group who had follow-up data n = number of subjects with the indicated characteristic

  32. Postmarketing • Postmarketing commitments for original males efficacy supplement: • 44,000 males in a U.S. MCO followed for: • ER visits and hospitalizations up to 60 days post-vaccination • New onset autoimmune conditions up to 6 months post-vaccination • Study 020 extension: • 10 years of follow-up to evaluate efficacy in the prevention of external genital lesions (EGL)

  33. Anal Cancer Epidemiology • Anal cancer represents ~4% of all lower GI tract cancers in U.S.* • ~5000 new cases per year; 40%/60% male to female** • Compared to: Colon cancer: ~100,000 new cases per year; very slight male predominance *Partridge and Koutsky. Lancet Infect Dis. 2006 Jan;6(1):21-31. **Jemal et al. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49.

  34. Incidence of Anal Cancer is Increasing National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program (http://www.seer.cancer.gov).

  35. Incidence of Colon Cancer is Decreasing National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program (http://www.seer.cancer.gov).

  36. Screening and treatment for anal precancer • In contrast to cervical cytology, the efficacy and cost-effectiveness of anal cytology screening has not been established, especially in a broad population. • Even if precancerous lesions can be identified for treatment, patients face a difficult clinical course, frequently complicated by pain, bleeding, anal stenosis. • Unlike treatment for cervical dysplastic lesions, the entire transformation zone of the anal canal cannot be safely removed; therefore, recurrences are more frequent and pervasive.

  37. Cervical Transformation Zone SCJ = squamocolumnar junction

  38. The Cervical Transformation Zone is Vulnerable to HPV-mediated Neoplastic Progression Tzone columnar epithelium stratified squamous epithelium squamous metaplasia Department of Pathology; University of Cambridge

  39. Anal T-zone • Transition from stratified squamous to columnar epithelium similar to cervical t-zone

  40. Anal Cancer and HPV - Pathophysiology • Approximately 90% of cancers involving the anal canal are oncogenic, “high risk” (hrHPV) positive • Compare to: ~25% of perianal skin cancers are hrHPV positive* • Basaloid features and adjacent AIN are strongly positively associated with hrHPV status, suggesting that, • “…like cancer of the uterine cervix, the development of cancer of the anal canal may require infection with hrHPV, whereas a dual etiology of perianal skin cancers bears parallels to vulvar and penile cancers.” *Frisch et al. Cancer Res. 1999 Feb 1;59(3):753-7.

  41. AIN, Anal Cancer and HPV • Rate of hrHPV positivity increases with increasing severity of dyplasia* *Wong et al. Mod Pathol. 2010 Jan;23(1):144-50.

  42. Anal HPV and Disease:Gender and Behavioral Differences • Receptive anal intercourse is strongly associated with HPV infection and disease. • Relative proportion of anal cancers in HM versus MSM is not well established • In one 18-70yo HM cohort, 7.0% had anal hrHPV by PCR* • By comparison: • In HIV+ MSMs, 88% positive for anal hrHPV** • In U.S. females 14-59yo, overall prevalence of cervical hrHPV = 15.2%*** • Anal HPV infection in women and MSM results to some degree from transmission thru anal sex. The mode of acquisition in HM is less well understood, but the prevalence of anal hrHPV is nonetheless substantial. *Nyitray et al. J Infect Dis. 2010 May 15;201(10):1498-508. **Salit et al. AIDS. 2010 May 1. [Epub ahead of print] ***Dunne et al. JAMA. 2007 Feb 28;297(8):813-9.

  43. Anal HPV and Disease:Gender and Behavioral Differences • Overall, 90%-93% of anal cancers are associated with HPV* (in men, 80-90%)** • In one study, the following percentages of anal cancer specimens were positive for hrHPV:*** • 90% of anal cancers among women • 58% among heterosexual men (HM) • 100% among men who have sex with men (MSM) • HPV 16, 18, 31, and 33 are the predominant types *Chaturvedi AK. J Adolesc Health. 2010 Apr;46(4 Suppl):S20-6. **Giuliano et al. Vaccine. 2008 Aug 19;26 Suppl 10:K17-28. ***Frisch M. Dan Med Bull. 2002 Aug;49(3):194-209.

  44. Study Procedures for MSM Study 020, Final Study Report – p.74

  45. Study Procedures for MSM (cont) Study 020, Final Study Report – p.74

  46. Regulatory Background • Overall: Clinical development program for Gardasil for males includes • 020: ~4000 16-26yo males to evaluate prevention of EGL and AIN* • 016: safety and immunogenicity bridging that included 9-15yo males • 018: safety and immunogenicity bridging that included 9-15yo males • Dec 2008 – pre-sBLA meeting with Merck to discuss males indication submission • AIN endpoint case splits presented; CBER considered this an interim analysis and recommended adjustment for Type 1 error in the final analysis • Dec 2008 - submission of supplement requesting indication in males for prevention of external genital lesions (EGL) • Men having sex with men (MSM) substudy (AIN) data not submitted at this time • Oct 2009 – CBER approves indication in males for prevention of genital warts • Feb 2010 – current sBLA submitted • December 27, 2010 – PDUFA date for this submission *EGL = external genital lesions (penile, perineal, perianal neoplasia (PIN) and anogenital warts) AIN = anal intraepithelial neoplasia; analogous to cervical intraepithelial neoplasia (CIN)

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