FDA Advisory Committee Recommends
Approval for Use of GARDASIL(R) in Boys and Men
Committee Agrees that Clinical Data Support the Efficacy and Safety of Merck's GARDASIL in 9- to 26-Year-Old Boys and Men |
Sept. 9, 2009, 5:37 p.m. EDT
WHITEHOUSE STATION, N.J., Sep 09, 2009-- Merck & Co., Inc. announced today that the U.S. Food and Drug Administration's (FDA) Vaccines and Related Biological Products Advisory Committee agreed that efficacy, immunogenicity and safety data from clinical trials in males support the use of GARDASIL(R) [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant] in boys and men 9 through 26 years of age for the prevention of genital warts caused by human papillomavirus (HPV) types 6 and 11.
"Merck has been committed to pursuing the use of GARDASIL in both males and females since the vaccine was discovered over a decade ago," said Peter S. Kim, Ph.D., executive vice president, and president of Merck Research Laboratories. "We are pleased that the Advisory Committee agrees that the data support the use of GARDASIL in boys and men."
The committee's recommendation will be considered by the FDA in its review of the supplemental Biologics License Application (sBLA) that Merck submitted for GARDASIL in December 2008. The FDA is not bound by the committee's guidance, but takes its advice into consideration when reviewing vaccines. Merck expects a decision from the FDA in the fourth quarter of 2009 after the agency has completed its review of Merck's application.
"Today's discussion with the Advisory Committee brings the public health community closer to being able to provide GARDASIL to both men and women," said Anna R. Giuliano, Ph.D., Moffitt Cancer Center.
GARDASIL has been approved for use in the U.S. since June 2006 and is currently indicated for use in girls and young women 9 through 26 years of age for the prevention of cervical, vulvar and vaginal cancers caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18. More than 50 million doses have been distributed worldwide through June 2009, although the number of doses administered is not known.
Data for use of GARDASIL in boys and men presented
Clinical trials presented to the Advisory Committee evaluated the efficacy, immunogenicity and safety of GARDASIL in boys and men 9 to 26 years of age. Vaccine efficacy in males was evaluated in a randomized, double-blind, placebo-controlled trial. A total of 4,055 men were enrolled and received at least one dose of GARDASIL or placebo. Of these, 3,457 were heterosexual men aged 16 to 23 years and 598 were men who have sex with men aged 16 to 26 years.
The per-protocol efficacy (PPE) population was the predefined primary population for the demonstration of efficacy in 16- to 26-year-old men. As defined, this population included subjects who were not infected with HPV vaccine types at the start of the study, nor did they become infected with HPV vaccine types during the course of the vaccination series. These subjects were seronegative and HPV DNA negative to HPV vaccine types at day one, and HPV DNA negative through the vaccination series to month seven. This population also received the three shot series within a one-year time period and generally did not deviate from the protocol. The cases of the primary endpoint of external genital lesions (EGL) were counted starting after month seven.
Analyses were also conducted in the Full Analysis Set (FAS) population. The FAS population included all participants who received at least one dose of vaccine or placebo and endpoint cases were counted after day one, the day after the first dose of vaccine was given. The key difference from the PPE population was that the FAS also included participants who had been previously exposed, were already infected with HPV types, or became infected before the completion of the three-dose vaccine series (not specific to 6, 11, 16 and 18).
Per protocol efficacy
In the PPE analysis, GARDASIL was 90.4 percent efficacious (95 percent CI: 69.2, 98.1) against HPV 6, 11, 16 and 18-related EGL. Of 34 cases of EGL, 31 were genital warts. All cases of genital warts were positive for HPV 6 and/or 11 (three cases in the vaccine group and 28 in the placebo group). GARDASIL was 89.3 percent efficacious (95 percent CI: 65.5, 97.9) against HPV 6/11-related external genital warts.
There were three cases of HPV 6/11/16/18-related penile/perianal/perineal intraepithelial neoplasia (PIN) in the PPE analysis and all were in the placebo group. No cases of penile/perianal/perineal cancers were observed in the vaccine or placebo groups during the study. Although vaccine efficacy against HPV 6/11/16/18-related PIN 1 or worse was 100 percent (95 percent CI: <0, 100), there was no statistical significance due to the small number of cases seen in the study.
Full analysis set
In the FAS analysis, GARDASIL was 65.5 percent efficacious (95 percent CI: 45.8, 78.6) against HPV 6, 11, 16 and 18 EGL. Of 104 cases of EGL, 95 were genital warts positive for HPV 6 and/or 11 (24 cases in the vaccine group and 71 in the placebo group). GARDASIL was 66.8 percent efficacious (95 percent CI: 46.5, 80.0) against HPV 6/11-related external genital warts in this analysis.
In immunogenicity studies, GARDASIL generated robust immune responses to HPV types 6, 11, 16 and 18 in 9- to 15-year old boys and 16- to 26-year old men.
Immunobridging studies in 9- to 15-year old boys demonstrated that boys had approximately two to three fold higher HPV type-specific antibody levels at month seven compared to 16- to 26-year old men. These data established the non-inferiority of the peak immune response as measured at month seven for all four HPV-types in boys as compared to men.
Safety data for GARDASIL
Compared with placebo recipients, a slightly higher proportion of vaccinees reported injection site (64.1 percent GARDASIL; 53.6 percent placebo) and systemic adverse experiences (37.2 percent GARDASIL; 32.6 percent placebo), the majority of which were reported as mild to moderate intensity. Subjects who reported a severe intensity systemic adverse experience and/or an injection-site adverse experience were comparable between the two groups (systemic adverse experiences reported: 4.3 percent in the GARDASIL group versus 3.0 percent in the placebo group; injection-site adverse experiences reported: 2.0 percent in the GARDASIL group versus 1.0 percent in the placebo group). Overall, the safety profile observed in boys and men 9 to 26 years of age in clinical studies was consistent with the safety profile observed in clinical studies in girls and women 9 to 26 years of age.
Important information about GARDASIL
GARDASIL does not substitute for routine cervical cancer screening, and women who receive GARDASIL should continue to undergo screening.
GARDASIL has not been demonstrated to provide protection against diseases from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity. GARDASIL is not intended to be used for treatment of active genital warts; cervical, vulvar, and vaginal cancers; cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VaIN).
GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. Not all vulvar and vaginal cancers are caused by HPV, and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV Types 16 and 18.
Select safety information
GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL.
Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with GARDASIL. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion.
GARDASIL is not recommended for use in pregnant women.
The most common adverse reaction was headache. Common adverse reactions that were observed among recipients of GARDASIL at a frequency of at least 1.0 percent and greater than placebo were: fever, nausea, dizziness; and injection-site pain, swelling, erythema, pruritus and bruising.
Dosage and administration for GARDASIL
GARDASIL is a ready-to-use, three-dose, intramuscular vaccine. GARDASIL should be administered in three separate intramuscular injections in the deltoid region of the upper arm or in the higher anterolateral area of the thigh. The following dosage schedule is recommended: first dose at elected date, second dose two months after the first dose and the third dose six months after the first dose.
There are more than 100 types of HPV, of which about 30 to 40 types can infect the genital areas of women and men. HPV types 6 and 11 cause approximately 90 percent of genital warts cases. About one million people (both males and females) have visible genital warts at any point in time. There are currently no routine HPV screening methods in place for men.
GARDASIL is approved in 112 countries
GARDASIL (sold in some countries as SILGARD(R)) has been approved in 112 countries, and additional applications are currently under review with regulatory agencies in many more countries around the world.
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
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Prescribing information and patient product information for GARDASIL(R) is attached.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use GARDASIL safely and effectively. See full prescribing information for GARDASIL.
[Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant]
Suspension for intramuscular injection
Initial U.S. Approval: 2006
RECENT MAJOR CHANGES
Indications and Usage (1)
Indications (1.1) 09/2008
Limitations of GARDASIL Use and Effectiveness (1.2) 05/2009
Contraindications (4) 09/2008
Warnings and Precautions (5)
Syncope (5.1) 06/2009
INDICATIONS AND USAGE
GARDASIL is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine:
-- Cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18
-- Genital warts (condyloma acuminata) caused by HPV types 6 and 11
And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:
-- Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS)
-- Cervical intraepithelial neoplasia (CIN) grade 1
-- Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
-- Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
Limitations of GARDASIL Use and Effectiveness
-- Women who receive GARDASIL should continue to undergo cervical cancer screening. (1.2) (17.1)
-- GARDASIL has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity. (1.2) (14.2)
-- GARDASIL is not intended to be used for treatment of active genital warts; cervical, vulvar, and vaginal cancers; CIN; VIN; or VaIN. (1.2)
-- GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. (1.2) (14.3)
-- Not all vulvar and vaginal cancers are caused by HPV, and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV 16 and 18. (1.2)
-- GARDASIL does not protect against genital diseases not caused by HPV. (1.2)
-- Vaccination with GARDASIL may not result in protection in all vaccine recipients. (1.2)
DOSAGE AND ADMINISTRATION
0.5-mL suspension for intramuscular injection at the following schedule: 0, 2 months, 6 months. (2.1)
DOSAGE FORMS AND STRENGTHS
-- 0.5-mL suspension for injection as a single-dose vial and prefilled syringe (3) (11)
Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of GARDASIL. (11)
WARNINGS AND PRECAUTIONS
-- Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with GARDASIL. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position.
The most common adverse reaction was headache. Common adverse reactions (frequency of at least 1.0% and greater than AAHS control or saline placebo) are fever, nausea, dizziness; and injection-site pain, swelling, erythema, pruritus, and bruising. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc. at 1-877-888-4231 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.
GARDASIL may be administered concomitantly with RECOMBIVAX HB. (7.1)
USE IN SPECIFIC POPULATIONS
Safety and effectiveness of GARDASIL have not been established in the following populations:
-- Pregnant women. Physicians are encouraged to register pregnant women exposed to GARDASIL by calling 1-800-986-8999 so that Merck can monitor maternal and fetal outcomes (8.1).
-- Children below the age of 9 years and pediatric males of any age. (8.4)
-- Immunocompromised individuals. Response to GARDASIL may be diminished. (8.6)
-- Women 27 years of age and older. (14.4).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.