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Summary Basis for Regulatory Action - Gardasil, December 3, 2010

Date: December 3, 2010

From: Jeff Roberts, M.D., Chair of the Review Committee

BLA/ STN#: 125126/1895

Applicant Name: Merck & Co.

Date of Submission: February 26, 2010

PDUFA Goal Date: December 27, 2010

Proprietary Name/ Established Name: GARDASIL®/Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine

Additional Indication Sought Under This BLA Supplement: prevention of anal cancer and the associated precancerous lesions (anal intraepithelial neoplasia (AIN) grades 1, 2, and 3) caused by HPV types 6, 11, 16, and 18 in males and females 9 through 26 years of age.

Recommended Action: Approval

Signatory Authorities Action: Approval

Offices Signatory Authority: Wellington Sun, M.D., Director Division of Vaccines and Related Products Applications, Office of Vaccine Research and Review 

X - I concur with the summary review.
I concur with the summary review and include a separate review to add further analysis. 
I do not concur with the summary review and include a separate review.

Table 1: Review documents used in compiling this SBRA:
 

Review Category

Reviewer

Clinical Review

Jeff Roberts, M.D.

Nancy Miller, M.D.

Statistical Review

Martha Lee, Ph.D.

Pharmacovigilance Review

Michael Nguyen, M.D.

Labeling Review

Lisa Stockbridge, Ph.D.

Dana Jones

Advisory Committee Transcript

November 17, 2010

  1. Introduction

    GARDASIL® is a non-infectious recombinant quadrivalent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. It was licensed in the U.S. in June of 2006. At the time of submission of the Biologics License Application supplement (sBLA), the vaccine was indicated for prevention of the following the following: cervical, vulvar and vaginal cancer and the associated precancerous lesions caused by HPV types 6, 11, 16, and 18 in girls and women ages 9 through 26; and genital warts caused by types 6 and 11 in both males and females ages 9 through 26.

    On February 26, 2010, Merck submitted sBLA 125126/1895, in support of the additional indication for Gardasil of prevention of anal cancer and the associated precancerous lesions (anal intraepithelial neoplasia (AIN) grades 1, 2, and 3) caused by HPV types 6, 11, 16, and 18 in males and females 9 through 26 years of age.

    It is important to note that this application requests approval for an additional indication, but it would not effect a change in the population for whom Gardasil is indicated. Immunogenicity and safety data in this population were evaluated in previous applications (both internally by CBER and in consultation with a series of advisory committees), and those data are described in the package insert. Therefore, CBER’s review of this application focused on the efficacy data.

  2. Background

    Human papillomavirus (HPV) infects the epithelium at multiple anatomic sites, resulting in a variety of distinct clinical entities. Anal infection with oncogenic, high risk HPV types (hrHPV) is associated with the development of anal dysplastic lesions and ultimately anal cancer.

    To study the potential of Gardasil to prevent HPV-associated anal dysplastic disease, the applicant conducted a randomized, placebo-controlled, double-blinded trial in ~600 men having sex with men (MSM) at risk for anal HPV infection and disease.

    The two most notable issues that arose in the review of the application were:

    • use of AIN as the clinical endpoint to assess efficacy in the prevention of anal cancer, and
    • the scientific rationale for extrapolating efficacy in the prevention of AIN and anal cancer to females based on data in males
  3. Chemistry Manufacturing and Controls (CMC)
  4. Full CMC review of the product was completed at the time Gardasil was originally licensed in June 2006. All lots of vaccine used in the submitted study were reviewed and released for distribution by CBER.

    In addition, the laboratory assays to document HPV infection by PCR and to measure immune response to vaccination (competitive Luminex Immunoassay (cLIA)) have been reviewed by CBER. Therefore, no new CMC review was performed in the context of this submission.

  5. Nonclinical Pharmacology/Toxicology
  6. No new pharmacology/toxicology data were requested or submitted in the context of this submission.

  7. Clinical
  8. The pivotal Phase 3 trial submitted to the sBLA was a double-blind, placebo-controlled, study in which male subjects were randomized 1:1 to receive Gardasil or aluminum adjuvant-containing saline (herein referred to as AAHS control). Subjects were followed for a number of clinical endpoints associated with genital HPV infection. Of the 4065 males recruited and randomized, 602 were men who have sex with men (MSM) who underwent more extensive surveillance for anal pathology, including rectal exam, anal cytology, anal HPV PCR, and anoscopy with anal biopsy if indicated. The MSM subjects were then evaluated in a separate analysis referred to as the MSM Substudy, which comprises the pivotal data evaluated for this application.

    Efficacy

    The primary pre-specified efficacy endpoint was a composite of HPV 6, 11, 16, and 18-related AIN grades 1, 2, and 3, and anal cancer in the per protocol efficacy (PPE) population (seronegative and PCR negative for vaccine HPV types (6, 11, 16, and 18)). Vaccine efficacy (VE) in the prevention of this composite endpoint was 78% (95%CI: 40, 93). All of the cases in the analysis were AIN (no cases of anal cancer were diagnosed). VE for prevention of advanced anal dysplasia, AIN2 or worse, was 75% (95%CI: 8, 95).

    To evaluate the effect of current HPV infection and/or previous HPV exposure among vaccinees, a series of analyses were conducted to examine prevention of vaccine HPV type-associated AIN and anal cancer in the full analysis set (FAS), a population that included all randomized subjects, regardless HPV status at screening. VE for prevention of HPV 6, 11, 16, and 18-related AIN1+ and AIN2+ in the FAS population was 50% (95%CI: 26, 67) and 54% (95%CI: 18, 75), respectively.

    To evaluate the potential population impact, a series of analyses were conducted to examine prevention of all dysplastic anal disease, regardless of its association with HPV. VE for prevention of AIN1+ and AIN2+, regardless of HPV detection, in the FAS population was 26% (95%CI: -1, 46) and 24% (95%CI:-14, 50), respectively. Identical analyses in the generally HPV naïve (GHN) population (at screening, seronegative for vaccine HPV types (6, 11, 16, and 18) and PCR negative for all 14 HPV types tested for?) generated the following VE estimates for prevention of AIN1+ and AIN2+: 55% (95%CI: 8, 79) and 53% (95%CI: -15, 82), respectively. With regard to these analyses of efficacy regardless of HPV detection, the clinical reviewer noted that:
    “The GHN analysis models the potential vaccine efficacy among sexually naïve (and therefore, HPV naïve) individuals. In other words, the GHN analysis estimates how effective the vaccine may be for individuals 9 to 15 years of age. In clinical practice, individuals are not likely to be screened for HPV infection prior to receipt of the vaccine. Therefore, the FAS analysis represents the best estimate of efficacy among individuals 16 to 26 years of age.”

    Safety

    The safety data presented in the original Study 020 CSR (finalized 05-Dec-2008) were assessed in the review of the original application for an indication of prevention of genital warts in males. In this dataset, there were no new reported serious adverse events, deaths, or new subject discontinuations due to adverse experiences.

    In addition, because study subjects were well beyond the vaccination phase (Day 1 to Month 7), there were very minor changes to the data overall. These included revisions due to such things as data entry errors and changes to encoding of terms. Thus, the safety data submitted to this sBLA are nearly identical to the original males sBLA submission. For details of the CBER assessment, please refer to the clinical review of the males sBLA published on the FDA website under the October 19, 2009 approval package, here: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm094042.htm.

    CBER’s overall assessment of the safety data has not changed. Gardasil appears to have an acceptable safety profile. No safety signals were identified.

    Pediatrics

    Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), this application for a new indication is required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric age groups. The applicant requested a waiver from the requirements of PREA for children 0-8 years of age. The review team agreed to grant the waiver request because the product does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients in this age group and is not likely to be used in a substantial number of pediatric patients in this group. The reason for the review team’s conclusion was that evidence indicates that the rare cases of HPV-related disease that occur in this age group (0 to 8 years) are not vaccine-preventable.

    The Pediatric Review Committee (PeRC) concurred with this decision. Effective upon approval of the supplement, the product will be labeled for use in children 9 years of age and older.

    Clinical Reviewer Overall Conclusions

    Data submitted to the sBLA demonstrate that Gardasil is efficacious in the prevention of AIN caused by HPV 6/11/16/18 in males 16-26 years of age.

    The data linking anal hrHPV infection to AIN and subsequent anal cancer are persuasive. AIN (particularly AIN2+) is a reasonable correlate endpoint for evaluating an intervention for the prevention of anal cancer.

    Based on the available epidemiological, histological, and pathophysiological data, it is reasonable to extrapolate from the efficacy data in males in order to grant the indication of prevention of AIN and anal cancer in females.

    Immunogenicity bridging data provides a basis for inferring protection of 9 to 15 year old individuals against AIN and anal cancer.

    In the pre-licensure safety database, which includes approximately 5400 males, no safety signals have been identified. The applicant has committed to a Phase IV safety surveillance study in males. No revisions to the pharmacovigilance program are recommended at this time.

    During the review of the applicant’s previous sBLA for prevention of genital warts in males, the applicant agreed to extend Study 020 to 10 years of follow-up. The study extension will provide data on long term safety, immunogenicity, and efficacy on the endpoints of persistent infection, external genital lesions, AIN and anal cancer. The proposed protocol revision is adequate to evaluate long term follow-up on these outcomes.

    The available data support the approval of Gardasil for use in males and females 9 through 26 years of age for the prevention of AIN and anal cancer caused by HPV types 6, 11, 16, and 18.

  9. Statistical

    The CBER statistical reviewer concluded that the data presented in the application support that:

    • Gardasil is indicated in males 9 through 26 years of age for the prevention of AIN grades 1, 2, and 3 caused by HPV types 6, 11, 16 and 18; and
    • Gardasil is indicated in males 9 through 26 years of age for the prevention of anal cancer caused by HPV types 16 and 18.

    The reviewer noted that the MSM substudy data support the proposed indications for the prevention of AIN 1+ and anal cancer in men, but no data were submitted to support extension of these indications to women. The reviewer deferred to the judgment of the clinical reviewer, acknowledging that the decision about whether to extend the indications to women will be made based on evaluation of a broader set of data, e.g., histology, pathophysiology, and epidemiology.

  10. Advisory Committee Meeting

    During the review process CBER determined that a Vaccine and Related Biological Products Advisory Committee (VRBPAC) should be convened to discuss effectiveness of vaccinating males and females with Gardasil for prevention of anal dysplasia and anal cancer. The VRBPAC was held on Novermber 17, 2010. The review team asked the Committee to 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.
  11. As a whole, the judgment of the Committee was that the data support an indication for the prevention of AIN and anal cancer in males and that the rationale for extrapolating efficacy to females is appropriate and scientifically sound. Several members expressed a desire to engage in more discussion regarding safety of the product, but it was recognized that the population for whom Gardasil is indicated would not change should the additional indication for prevention of AIN and anal cancer be approved.

  12. Labeling
  13. The package insert (PI) and the patient package insert (PPI) were submitted by the applicant with proposed changes to reflect the additional indication in males and females. Both documents were evaluated by a reviewer in the Advertising and Promotional Labeling Branch (APLB). In addition, each review team member contributed to internal discussions. The most substantial labeling issue involved the consideration of the indication in females based on efficacy data in males. In consultation with the VRBPAC, the review team concluded that it is reasonable to bridge the efficacy data in males to females.

    After several minor revisions to the PI and PPI were agreed to in a series of discussions with the applicant, the review committee determined that the prescribing information as it pertains to the new indication is acceptable.

  14. Postmarketing
  15. CBER review of the pharmacovigilance plan noted the status of three major postmarketing regulatory commitments: an active surveillance study in 189,000 female Gardasil recipients (complete), a pregnancy registry (ongoing), and an active surveillance study in 135,000 male Gardasil recipients (planning phase). The reviewer assessed the identified risks and the potential risks and commented on the proposed and ongoing actions.

    The reviewer noted that since the vaccine is currently indicated in both males and females 9 through 26 years of age, the new indication is not expected to fundamentally change the target population. The reviewer concluded that the pharmacovigilance plan is adequate. No further regulatory action for postmarketing safety surveillance was recommended.

  16. Recommendation
  17. The review committee recommended approval of the BLA supplement.