Gardasil (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine)

Gardasil is a non-infectious quadrivalent recombinant vaccine, which delivers the major capsid (L1) protein of human papillomavirus (HPV) types 6, 11, 16 and 18 in highly purified virus-like particles, in combination wth an aluminum-containing vaccine adjuvant.

Gardasil is specifically indicated for the prevention of conditions caused by HPV types 6, 11, 16 and 18 infections. These include cervical cancer, genital warts (condyloma acuminata), and precancerous or dysplastic lesions (including cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grades 1 and 2/3, vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3, and vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3).

Gardasil is supplies as a white, cloudy liquid for intramuscular injection. The recommended dosing regimen is 3 single injections of 0.5 ml of the vaccine, at day 0, 2 months after the first dose, and 6 months after the first dose.

FDA Approval
Approval of Gardasil for the prevention of cervical cancer, AIS, and CIN 2/3 related to HPV-6, -11, -16 and -18 infections was based on 4 placebo-controlled, double-blind, randomized trials, including two phase II trials (Protocol 005, n=2391; and Protocol 007, n=551) and two phase III trials, Protocols 013 and 015, also dubbed FUTURE (Females United To Unilaterally Reduce Endo/Ectocervical Disease) I & II (n=5442, n=12157, respectively); these studies treated a total of 20,541 women ages 16-26 at the time of enrollment. In all 4 trials, subjects received treatment on day 0, and 2 and 6 months thereafter. Protocol 005 investigated only the HPV-16 portion of the vaccine, while Protocol 007 and FUTURE I&II evaluated the full quadrivalent vaccine. Subjects were not prescreened for HPV status. All four trials were designed to investigate the prophylactic efficacy of the vaccine in preventing cervical cancer, cervical dysplasias, vulvar or vaginal dysplasias, or genital warts. Among subjects receiving the full treatment regimen, combined data from the four trials indicated 0 new cases of HPV-16 or -18 related CIN 2/3 or AIS, vs. 53 cases for placebo (100% efficacy); 4 new cases of HPV-6, -11, -16, or -18 related CIN (CIN 1, CIN 2/3) or AIS, vs. 83 for placebo (95.2% efficacy); and 1 case of HPV-6, -11, -16, or -18 related genital warts, vs. 91 for placebo (98.9% efficacy). The vaccine is designed as a prophylactic vaccine, and efficacy was not established in protecting subjects from disease caused by pre-existing HPV infection. The vaccine was efficacious in protecting subjects who were previously infected with 1 or more vaccine-related strains from disease associated with remaining strains (those for which they were negative at outset).

Predicted General Population Impact
In addition to the prophylactic efficacy established in the four trials, data were analyzed for the vaccine's predicted impact on the rates of HPV-related diseases in the general patient population, based on current infection rates, predicted treatment-regimen compliance, and population demographics. Gardasil was predicted to produce a 39.0% reduction in HPV-16 or -18 related CIN 2/3 or AIS (98.8% prophylactic efficacy); a 69.1% reduction in HPV-16 or -18 related VIN 2/3 and VaIN 2/3 (100.0% prophylactic efficacy); a 46.4% reduction in HPV-6, -11, -16, -18 related CIN (CIN 1, CIN 2/3) or AIS (93.7% prophylactic efficacy); and a 68.5% reduction in HPV-6, -11, -16, -18 related genital warts (93.4% prophylactic efficacy).

Ongoing Study Commitments

• Merck commits to conduct a short-term safety surveillance study in a U.S. Managed Care Organization (MCO). The study will include approximately 44,000 vaccinated subjects who will be followed for 60 days for assessment of general short-term safety (i.e., emergency room visits, hospitalizations, and deaths). The subjects will also be followed for 6 months subsequent to vaccination for new autoimmune disorders, rheumatologic conditions, or thyroiditis. Also, a sufficient number of children 11-12 years of age will be studied to permit an analysis of safety outcomes.
  Final Study Protocol Submission: December 31, 2006
  Enrollment Completion: December 31, 2008
  Study Completion: June 30, 2009
  Final Study Report: September 30, 2009
• Merck commits to collaborate with the cancer registries in four countries in the Nordic Region (Sweden, Norway, Iceland, and Denmark) to assess long-term outcomes following administration of Gardasil. In this study, approximately 5,500 subjects enrolled in Protocol 015 (one half from the placebo group that will have been vaccinated shortly after approval) will be followed for a total of 14 years. Two major goals of this study are: 1) to assess the long-term effectiveness of Gardasil by evaluating biopsy specimens for presence of HPV 6/11/16/18-related incident breakthrough cases of CIN 2/3, AIS and cervical cancer, VIN 2/3 and vulvar cancer, and VaIN 2/3 and vaginal cancer; and 2) to assess whether administration of Gardasil will result in replacement of these diseases due to vaccine HPV types with diseases due to non-vaccine HPV types. This study is designed to accomplish these goals as discussed in the June 6, 2006, submission to Merck’s BLA.
  Final Study Protocol Submission: December 8, 2006
  Enrollment Completion: Completed
  Study Completion: December 31, 2017
  Final Study Report: December 31, 2018
• Merck commits to conduct a study in collaboration with the Norwegian Government, if Gardasil is approved in the European Union and the Government of Norway incorporates HPV vaccination into its national guidelines, to assess the impact of HPV vaccination on the following in Norway:

  1. The long-term burden of HPV disease including the incidence of HPV 6/11/16/18-related cervical disease;
  2. The long-term burden of HPV disease caused by types other than HPV 6/11/16/18;
  3. The overall incidence of cervical HPV disease;
  4. The incidence of HPV-related cancers and pre-cancers (CIN 2/3, AIS and cervical cancer; VIN 2/3 and vulvar cancer; and VaIN 2/3 and vaginal cancer);
  5. The interaction between administration of Gardasil and pregnancy outcomes, especially congenital anomalies, by linking the vaccination registry with the Medical Birth Registry.

  The size and age range of the population studied will depend on the final vaccination guidelines implemented by the Norwegian Government. Although at this time no other governments in the Nordic region have committed to similar population studies, Merck will notify CBER of any other collaborations if they occur.
  Final Study Protocol Submission: Contingent on Norwegian Government’s response
  Enrollment Completion: 6 years after study initiation
  Study Completion: 7 years after study initiation
  Final Study Report: 8 years after study initiation

• Merck commits to submit final Clinical Study Reports (CSRs) for Protocols 013 and 015 when completed. As discussed, for these studies, an "all CIN 2/3, AIS or cervical cancer" analysis will evaluate the evidence for replacement of disease due to HPV types 16 and 18 with non-vaccine HPV types. Similar analyses will be done for VIN 2/3, VaIN 2/3, vulvar cancer and vaginal cancer.
  Final Study Protocol Submission: Completed
  Enrollment Completion: Completed
  Study Completion: April 30, 2007
  Final Study Report: June 30, 2007
• Merck commits to provide data concerning duration of immunity following administration of Gardasil as follows from the studies noted:

  1. The Nordic Long-Term Follow-up Study:
  Interim reports of effectiveness (i.e., incident breakthrough cases of CIN 2/3, AIS and cervical cancer; VIN 2/3 and vulvar cancer; and VaIN 2/3 and vaginal cancer) and immunogenicity results will be submitted in 2009, 2011, 2013, and 2015. Final Study Report: December 31, 2018
  2. Protocol 018 (Adolescent Sentinel Cohort):
  - Periodic reports beginning with Month 24 immunogenicity and long-term safety data: starting no later than March 30, 2007.
  - Publication of one year Post-dose 3 data: January 30, 2007.
  - A Biologics License Supplement (BLS) for 1.5 year Post-dose 3 data: June 30, 2007.
  - A Biologics License Supplement (BLS) for 2.5 year Post-dose 3 data: December 31, 2007.
  - A Biologics License Supplement (BLS) for 5.5 year Post-dose 3 data: December 31, 2010.
  3. Protocol 007:
  Publication of five-year immunogenicity data submitted: December 31, 2006.
  4. Protocol 005:
  Publication of seven and one half year immunogenicity data submitted: December 31, 2007.

• Merck agrees to establish a pregnancy registry in the U.S. to prospectively collect data on spontaneously-reported exposures to Gardasil during pregnancy. Merck commits to submit a protocol for the U.S. pregnancy registry by July 20, 2006. Merck agrees to address elements found in FDA's Guidance for Industry on Establishing Pregnancy Exposure Registries (9/2/2002) (http://www.fda.gov/cber/gdlns/pregexp.htm), as well as relevant Company Standard Operating Procedures. Furthermore, Merck will notify CBER of significant deviations from this guidance and/or specify the deviations in the protocol. Patient accrual/data collection will begin at time of CBER's approval of the protocol and end five years later. Merck will submit annual reports and a final summary report of the U.S. pregnancy registry's findings five years after initiation of patient accrual/data collection. The U.S. pregnancy database will be considered completed one month after discontinuation of patient accrual for the purpose of preparing a five-year final summary report. The five-year final summary report will be submitted to CBER five years and six months after initiation of patient accrual/data collection. After reviewing the five-year data, Merck and CBER will meet to discuss the need to continue further data collection in the U.S. pregnancy registry. CBER will have final approval regarding any decision to discontinue the U.S. pregnancy registry.
• Merck commits to provide CBER and simultaneously the FDA contractor for the Vaccine Adverse Events Reporting System (VAERS) all initial postmarketing "periodic" adverse experience reports received that are subject to periodic reporting (i.e., not covered under the "15-day Alert report" requirement under 21 CFR 600.80) on a monthly basis. Initial reports received by Merck in a given month will be submitted on VAERS forms to CBER and to the VAERS contractor by Working Day 10 of the following month. Merck also agrees to provide, in accordance with 21 CFR 600.80, the Quarterly Periodic Adverse Experience Report to the VAERS contractor. The Quarterly Adverse Experience Report will contain a recapitulation of all initial reports submitted for the current reporting period and will include all follow up information on VAERS forms collected during that three-month period. Merck commits to providing CBER this information using the aforementioned process, for the first three years after the date of licensure.

Adverse events associated with the use of Gardasil may include, but are not limited to, the following:

• Injection Site Pain
• Injection Site Swelling
• Injection Site Erythema
• Pyrexia
• Fever
• Nausea
• Nasopharyngitis

In addition, a small portion of patients (0.475%; n=102/21464) experienced all-cause serious adverse experiences, which included headache, gastroenteritis, appendicitis, and pelvic inflammatory disease.

Gardasil delivers HPV-6, -11, -16 and -18 L1 protein, conferring protection against these HPV strains, presumably through induction of humoral immune response. These strains are responsible for the majority of cases of cervical cancer, AIS, CIN and VIN, and for a number of cases of VaIN and genital warts.

Villa LL, Ault KA, Giuliano AR, Costa RL, Petta CA, Andrade RP, Brown DR, Ferenczy A, Harper DM, Koutsky LA, Kurman RJ, Lehtinen M, Malm C, Olsson SE, Ronnett BM, Skjeldestad FE, Steinwall M, Stoler MH, Wheeler CM, Taddeo FJ, Yu J, Lupinacci L, Railkar R, Marchese R, Esser MT, Bryan J, Jansen KU, Sings HL, Tamms GM, Saah AJ, Barr E. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006 Jul 7;24(27-28):5571-83. Epub 2006 May 15

Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. Journal of Clinical Investigation 2006 May;116(5):1167-73

Stanley M. Immune responses to human papillomavirus. Vaccine 2005 Sep 19; Epud ahead of print

Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, Wheeler CM, Koutsky LA, Malm C, Lehtinen M, Skjeldestad FE, Olsson SE, Steinwall M, Brown DR, Kurman RJ, Ronnett BM, Stoler MH, Ferenczy A, Harper DM, Tamms GM, Yu J, Lupinacci L, Railkar R, Taddeo FJ, Jansen KU, Esser MT, Sings HL, Saah AJ, Barr E. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncology 2005 May;6(5):271-8

For additional information regarding Gardasil or cervical cancer and precancerous lesions caused by HPV infections, please visit the Gardasil web page.