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Vaccines and Related Biological Products Advisory Committee Meeting Male Indication for GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] Jeff Roberts, M.D. FDA/CBER/OVRR/DVRPA September 9, 2009. GARDASIL® . Each 0.5 mL dose contains

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Vaccines and Related Biological Products Advisory Committee MeetingMale Indication for GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant]Jeff Roberts, M.D.FDA/CBER/OVRR/DVRPASeptember 9, 2009

gardasil
GARDASIL®
  • 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 amorphous aluminum hydroxyphosphate sulfate (AAHS)
  • Administered 0, 2, 6 months IM
  • Licensed June 2006
gardasil3
GARDASIL®
  • Current indications:
    • Girls and women 9 through 26 years of age for the prevention of:
      • Cervical, vulvar, and vaginal cancer caused by 16 and 18
      • Associated precursor dysplastic lesions (CIN, VIN, VaIN, AIS)
      • Genital warts caused by 6 and 11
  • Additional indication sought:
    • “Gardasil is indicated in boys and men 9 through 26 years of age for the prevention of genital warts (condyloma acuminata) caused by HPV types 6 and 11.”
agenda
Agenda

FDA Introduction Jeff Roberts, M.D., CBER

Sponsor Presentation Merck Representatives

FDA Presentation Jeff Roberts, M.D., CBER

Open Public Hearing

FDA Presentation of Questions Jeff Roberts, M.D., CBER

Committee Discussion and

Recommendations

Adjourn

condyloma acuminata genital warts in males
Condyloma Acuminata (Genital Warts) in Males
  • ~200 per 100,000 U.S. men per year are newly diagnosed with genital warts (Koshiol et al)
  • Among males visiting an STD clinic, genital warts is second to nonspecific urethritis as the most common new diagnosis (Dempsey et al)
  • Treatment is unpleasant, and recurrence is common; causes psychosocial distress
  • 70%-100% are HPV 6 and/or 11 positive (Partridge and Koutsky)
prevention of genital warts
Prevention of Genital Warts
  • Effectiveness of preventive measures is summarized in a recent WHO publication:
    • “Abstinence and condom use can reduce the risk of acquiring warts, but limited use of these methods reduces their impact at a population level. Condoms cannot prevent skin-to-skin HPV transmission in genital areas not covered by the condom or during non-penetrative intercourse” (WHO, 2008).
gardasil for males clinical development program
Gardasil for Males: Clinical Development Program

V501-020:Pivotal Phase III Efficacy and Safety

  • Randomized (1:1), double blind, placebo-controlled trial in males 16-26 years of age
  • Primary efficacy objective: prevention of external genital lesions

V501-016: Phase III Immunogenicity and Safety

  • Double blind trial in both genders 10-15 years of age and females 16-23 years of age
  • Immunogenicity objective: non-inferiority in adolescents compared with adults

V501-018: Phase III Immunogenicity and Safety

  • Randomized (2:1), double blind, placebo-controlled trial in both genders 9-15 years of age
  • Immunogenicity objective: non-inferiority in males compared with females
study v501 020 design
Study V501-020 Design
  • 4065 males, 16-26 years of age, randomized 1:1 to:
    • Gardasil0.5mL IM, at 0, 2 and 6 months
    • Control (AAHS adjuvant in saline) 0.5mL IM, at 0, 2 and 6 months
  • Subjects underwent genitourinary exam with HPV PCR (and biopsy if indicated after Day 1) on Day 1 and every 6 months from month 7-36
  • Primary Efficacy Objective: vaccine type-related “external genital lesions” (EGL): genital warts, penile/perianal/perineal intraepithelial neoplasia (PIN), and penile/perianal/perineal cancer
  • Men having Sex with Men (MSM) Substudy Efficacy Objective: vaccine type-related anal intraepithelial neoplasia (AIN) or Anal Cancer in MSM subjects
study v501 020 design cont
Study V501-020 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
subject characteristics hpv status at enrollment
Subject Characteristics, HPV Status at Enrollment

N = Number of subjects randomized.

m = Number of subjects in the respective category.

n = Number of subjects with non-missing data

*14 HPV types were tested for by PCR (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59)

analysis populations
Analysis Populations
  • Efficacy:
  • 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

  • Full analysis set (FAS) - subjects who:
  • received at least 1 dose of vaccine or placebo

Cases counted starting at Day 1

  • Safety:
  • All-Subjects-As-Treated (ASaT): all randomized subjects who received at least 1 injection and had follow-up data.
efficacy against hpv 6 11 16 18 related egl in the ppe population by hpv type
Efficacy Against HPV 6/11/16/18-Related EGL in the PPE Population, by HPV Type

N = Number of subjects randomized to the respective vaccination group.

n = Number of subjects in the PPE population eligible for the respective analysis

EGL = External genital lesions with a diagnosis of condyloma, PIN, or Penile/Perianal/Perineal Cancer; PIN = Penile/Perianal/Perineal intraepithelial neoplasia

efficacy against hpv 6 11 16 18 related egl in the ppe population by disease endpoint
Efficacy Against HPV 6/11/16/18-Related EGL in the PPE Population, by Disease Endpoint

N = Number of subjects randomized to the respective vaccination group.

n = Number of subjects in the PPE population eligible for the respective analysis

EGL = External genital lesions with a diagnosis of condyloma, PIN, or Penile/Perianal/Perineal Cancer; PIN = Penile/Perianal/Perineal intraepithelial neoplasia

efficacy against condyloma in different analysis populations
Efficacy Against Condyloma in Different Analysis Populations

n = Number of subjects in the relevant population eligible for the respective analysis

PPE = Per Protocol Efficacy population

GHN = Generally HPV Naïve (received at least 1 dose of vaccine or placebo; seronegative to 6, 11, 16, and 18 AND PCR negative to all 14 types tested (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59); cases counted starting at Day 1)

FAS = Full Analysis Set

CI = Confidence interval

slide16
Efficacy Against Any HPV Type Related Condyloma Stratified by Subject Characteristics (FAS Population)

N = Number of subjects randomized to the respective vaccination group.

n = Number of subjects in the FAS population eligible for the respective analysis

*Any HPV Type Tested = PCR (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59); serology (6, 11, 16, and 18)

immunogenicity bridging to males 9 15 years of age month 7 anti hpv gmts in mmu
Immunogenicity Bridging to Males 9-15 Years of Age: Month 7 anti-HPV GMTs (in mMU*)

†9-15 year-old male subjects from Protocols 016 and 018.

‡16-26 year-old male subjects from Protocol 020

χFor the null hypothesis that GMTBoys/GMTMen <=0.5 (2-fold decrease), a p-value <0.025 supports a conclusion that the specific type anti-HPV response in Boys is non-inferior to the response in Men.

N = Number of subjects randomized in the respective group who received at least 1 injection.

n = Number of subjects in the indicated immunogenicity population.

*mMu = Milli Merck units (units for reporting titer by Merck’s competitive luminex immunoassay (cLIA)

immunogenicity stratified by age and gender month 7 anti hpv gmts in mmu
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

duration of efficacy immunogenicity
Duration of Efficacy/Immunogenicity
  • As in females, correlate of protection is not established in males.
  • Reverse cumulative distribution curves of titers at 24 months indicate that the pattern of decline of titers is similar in males and females.
  • 10 year follow-up extension of efficacy and immunogenicity in the pivotal study, V501-020, has been proposed by the sponsor.
  • Protocol 018, which includes males and females 9-15 years of age, has immunogenicity and efficacy follow-up to 10 years.
safety v501 020
Safety – V501-020
  • Safety Assessments were done at each vaccination visit and every 3 months post-vaccination series
  • All subjects were given a Vaccine Report Card (VRC) to record:
    • Oral temperature out to 5 days
    • Injection-site AE’s out to 14 days
    • Systemic AE’s out to 14 days
summary of aes days 1 15 following any vaccination v501 020
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

systemic aes days 1 15 following vaccination v501 020
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
injection site aes days 1 5 following vaccination v501 020
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

pooled safety population studies v501 020 016 and 018
Pooled Safety Population – Studies V501-020, -016, and -018

*Placebo was saline alone in Protocol 018, the only study in the clinical development program in which placebo did not contain adjuvant.

  • Summary analyses of AEs in pooled safety dataset lead to conclusions similar to those from V501-020.
saes days 1 to 15 following vaccination pooled safety population
SAEs, Days 1 to 15 Following Vaccination, Pooled Safety Population

*There were a total of 7 subjects who received a mixed vaccine/placebo regimen that are not counted in the safety tables.

injection site reactions in boys compared with men
Injection Site Reactions in Boys Compared with Men

†9-15 year-old male subjects from Protocols 016 and 018.

‡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 in the indicated immunogenicity population.

postmarketing experience with gardasil in women
Postmarketing Experience with Gardasil in Women
  • Syncope, sometimes accompanied by traumatic injury, has been noted
  • Other AEs being monitored*, no evidence of causation
  • Current postmarketing commitment:
    • 44,000 females receiving all three doses: Powered to detect a 2 fold increase in a risk, with a background rate of 1/10,000, with alpha 0.05 and power of 80%.

*Guillan Barre, transverse myelitis, motor neuron disease, demyelinating disease, Bell’s palsy, Autoimmune diseases, DVTs, PEs (most on HCs, not an issue for boys), Pancreatitis, Unexplained death, Seizures

need for postmarketing studies
Need for Postmarketing Studies
  • Clinical trial safety database (Gardasil: 3097 subjects; Control: 2305 subjects) and worldwide post-marketing safety data are limited in males
  • Literature documents gender differences in vaccine reactogenicity and adverse events (Cook)
  • Different background rates for morbidity and mortality
postmarketing proposed by sponsor
Postmarketing Proposed by Sponsor
  • Phase IV Observational Study
  • 27,000 males (9-26 y/o) who receive at least one dose of Gardasil
  • General short-term safety, ER visits and hospitalizations
  • Self-comparison reference period, beginning 60 days after vaccination
  • Safety Review Committee (SRC) review safety signals and determine follow up
cber summary and conclusions
CBER Summary and Conclusions
  • Data submitted to the BLA supplement demonstrate that Gardasil is efficacious in the prevention of genital warts caused by HPV 6 and 11 in males 16-26 years of age.
  • Data from studies V501-016 and -018 demonstrate that anti-HPV GMT’s against each of the 4 VLP types in 9-15 year old males are non-inferior to those in 16-26 year old males.
    • Immunogenicity bridging provides a basis for inferring protection of 9-15 year old males against genital warts.
  • In the safety database, which includes ~5400 males, no safety signals have been identified. The details of the postmarketing plan are the subject of ongoing discussions with the sponsor.
gardasil for males review team
Gardasil for Males: Review Team
  • Chairperson Jeff Roberts, M.D.
  • Regulatory Project Managers Elizabeth Valenti

Laura C. Montague

  • Clinical Jeff Roberts, M.D.

Nancy Miller, M.D.

  • Statistical Martha B. Lee, Ph.D.
  • Bioresearch Monitoring Robert Wesley
  • Non-Clinical Ching-Long Joe Sun, Ph.D.
  • CMC Robin Levis, Ph.D.
  • Pharmacovigilance Andrea R. Sutherland, M.D., M.Sc., M.P.H.

Michael D. Nguyen, M.D.

  • Advertising/Promotional Labeling: Lisa L. Stockbridge, Ph.D.
references
References
  • Cook IF. Sex differences in injection site reactions with human vaccines. Hum Vaccin. 2009 Jul;5(7):441-9.
  • Dempsey AF, Koutsky LA, Golden M. Potential impact of human papillomavirus vaccines on public STD clinic workloads and on opportunities to diagnose and treat other sexually transmitted diseases. Sex Transm Dis. 2007 Jul;34(7):503-7.
  • Koshiol JE, Laurent SA, Pimenta JM. Rate and predictors of new genital warts claims and genital warts-related healthcare utilization among privately insured patients in the United States. Sex Transm Dis. 2004 Dec;31(12):748-52.
  • Partridge JM, Koutsky LA. Genital human papillomavirus infection in men. Lancet Infect Dis. 2006 Jan;6(1):21-31.
  • World Health Organization. Human Papillomavirus (HPV) Vaccine Background Paper. September 2008. http://www.who.int/immunization/documents/HPVBGpaper_final_03_04_2009.pdf
autoimmune associated events pooled safety dataset
Autoimmune-Associated Events, Pooled Safety Dataset

N = Number of individuals who received at least one dose of either vaccine or placebo

n = Number of individuals with specific new Medical Conditions

postmarketing considerations
Postmarketing Considerations
  • Standard 42 day window
  • Variable onset windows and analysis time-frames, in addition to temporal statistical scanning methods to look for clusters of onset intervals
  • Identify a pre-specified list of AEs of primary interest (clinical trials, Gardasil in females, adolescent vaccines); flexibility to add signals detected
  • Determine background rates and use reported rates vs. expected background rates (in addition to self-control) to identify signals
  • Analysis to assess safety in younger age groups (9-15)
  • All SAEs reported and included in analysis regardless of the assessment of possible causality
  • Date by which the sponsor anticipates the final report will be available, although feasibility of this study will be influenced by vaccine policies and uptake.