Quadrivalent Human Papillomavirus (HPV) Recombinant Vaccine Approved by FDA
Jun 9, 2006 - 12:36:37 AM
U.S. Food and Drug Administration (FDA) today approved a Quadrivalent Human Papillomavirus Recombinant Vaccine. It is the first and only vaccine to prevent cervical cancer and vulvar and vaginal pre-cancers caused by HPV types 16 and 18 and to prevent low-grade and pre-cancerous lesions and genital warts caused by HPV types 6, 11, 16 and 18 and is developed by Merck and will be marketed under trade name Gardasil.
The FDA approved Gardasil for the prevention of cervical cancer; cervical intraepithelial neoplasia (CIN) 2/3 and adenocarcinoma in situ (AIS), vulvar intraepithelial neoplasia (VIN) 2/3 and vaginal intraepithelial neoplasia (VaIN) 2/3 caused by HPV types 16 and 18. Gardasil is also approved for the prevention of genital warts and low-grade cervical lesions (CIN 1) caused by HPV types 6, 11, 16 and 18. Gardasil is approved for 9- to 26-year-old girls and women.
"Merck is proud to be the leader in cervical cancer vaccine research and development," said Richard T. Clark, chief executive officer and president, Merck & Co., Inc. "Bringing forward this life-saving scientific advance is yet another testament to Merck's long-standing mission to research and develop novel vaccines and medicines that can greatly improve public health."
Gardasil is designed to prevent the majority of HPV-related clinical diseases, those caused by HPV 6, 11, 16 and 18. HPV types 16 and 18 account for approximately 70 percent of cases of cervical cancer, AIS (non-invasive cervical cancer), CIN 3, VIN 2/3 and VaIN 2/3, and account for 50 percent of CIN 2 lesions. HPV 6 and 11 cause approximately 90 percent of genital wart cases. These four types of HPV also cause approximately 35 to 50 percent of all low-grade cervical, vaginal and vulvar lesions (CIN I, VIN I and VaIN I). There are an estimated 4.7 million abnormal Pap results that require follow-up each year in the United States. At least 3 million of these results are caused by some type of HPV. All four types cause abnormal Pap test results; the lesions caused by types 6 and 11 are clinically indistinguishable from pre-cancerous lesions caused by types 16 and 18.
"Gardasil is a major health breakthrough - the first vaccine specifically designed to prevent cancer - and is approved to prevent not only cervical cancer but also genital warts," said Kevin Ault, MD, associate professor, Department of Gynaecology and Obstetrics, Emory University School of Medicine, and clinical study investigator for Gardasil. "Use of Gardasil can help significantly reduce the human and economic burden of cervical cancer, pre-cancerous or low-grade lesions and genital warts caused by HPV 6, 11, 16 and 18 in the United States, and the rest of the world, in this generation and future generations."
In the United States, approximately 10,000 women are diagnosed with cervical cancer every year, and an average of 10 women die each day from the disease.
In clinical studies, Gardasil prevented 100 percent of HPV 16 and 18 related cervical cancer in women not previously exposed to the relevant HPV types. The efficacy of Gardasil, which includes results from an HPV-16 prototype of Gardasil, was evaluated in four placebo-controlled, double-blind, randomized Phase II and Phase III clinical studies. Together, the Phase II and III studies evaluated 20,541 women aged 16 to 26 years. Study participants were followed for up to five years after enrolment.
The studies' primary analyses were conducted in women who received all three vaccinations within one year of enrollment, did not have major deviations from the study protocol and were naïve to the relevant HPV type(s) prior to dose one and through one month post-dose three (Month 7). Efficacy was studied in the individual studies and in combined analyses and measured starting after the Month 7 visit. In the combined analyses Gardasil prevented 100 percent of HPV 16- and 18- related cervical pre-cancers and non-invasive cervical cancers (CIN 2/3, and AIS, or adenocarcinoma in situ). There were no cases in the 8,487 women who received Gardasil compared to 53 cases in the 8,460 women who received placebo. It also prevented 95 percent of low-grade cervical dysplasia (low grade lesions) and pre-cancers (CIN 2/3 or AIS) caused by HPV 6, 11, 16 or 18. There were 4 cases in the 7,858 women who received Gardasil compared to 83 cases in the 7,861 women who received placebo. It prevented 99 percent of cases of genital warts caused by HPV 6 or 11. There was one case in the 7,897 women who received Gardasil compared to 91 cases in the 7,899 women who received placebo.
Gardasil also prevented 100 percent of HPV 16- and 18-related vulvar and vaginal pre-cancers (VIN 2/3 or VaIN 2/3) in women not previously exposed to the relevant HPV types. There were no cases in the 8,641 women who received Gardasil compared to 24 cases in 8,667 women who received placebo. VIN 2/3 and VaIN 2/3 are the immediate precursors to vulvar and vaginal cancers.
These studies also showed that administration of Gardasil to women who are already infected with one or more vaccine related HPV types prior to vaccination protects them from clinical disease caused by the remaining vaccine types but may not alter the course of an infection that is already present.
In all studies, Gardasil was generally well tolerated and few subjects (0.1 percent) discontinued due to adverse events. Vaccine-related adverse experiences that were observed in clinical trials at a frequency of at least 1.0 percent among recipients of Gardasil and also greater than those observed among recipients of placebo, respectively, were pain (83.9 percent vs. 75.4 percent), swelling (25.4 percent vs. 15.8 percent), erythema (24.6 percent vs. 18.4 percent), fever (10.3 percent vs. 8.6 percent), and pruritis (3.1 percent vs. 2.8 percent). Most injection-site reactions were reported to be mild to moderate in intensity.
Prior vaccination strategies have shown that the ideal time to administer any vaccine is before exposure to the infection. Adolescents are an important group to vaccinate against HPV - one in four people ages 15 to 24 are infected with HPV. In addition, in a survey of 525 mothers with children as young as 11 years, up to 80 percent of mothers said they would allow their daughters to receive a vaccine that helps protect against cervical cancer.
Merck studied the anti-HPV 6, -11, -16 and -18 immune responses for Gardasil in 10-to 15-year-old girls compared to those in 16- to 23-year-old adolescent and young adult women. Among the study participants who received Gardasil, the immune responses (geometric mean titers, GMTs) in 10- to 15-year-old girls were similar to those in 16- to 23-year-old women. Similar outcomes were observed in a comparison of immune responses among 9- to 15-year-old girls to immune responses in 16- to 26-year-old adolescents and females. Based on these analyses, the FDA approved Gardasil for use in adolescent girls ages 9 to 15.
Studies examine impact of Gardasil in the general population
A secondary analysis to assess the potential impact of Gardasil on rates of cervical cancer and other HPV-related diseases on the general population was also conducted. This analysis included all women regardless of whether they were infected with HPV prior to vaccination, developed an infection after the start of vaccination and those who may not have completed the 3-dose vaccination. In this analysis, Gardasil reduced the risk for development of cervical pre-cancerous lesions and cervical cancer caused by HPV types 16 and 18 by approximately 40 percent in just two to four years. Genital warts (related to type 6, 11, 16 and 18), which develop more quickly than cervical cancer and pre-cancerous lesions, were reduced by almost 70 percent. Virtually all of the cases of CIN and genital warts seen in subjects who received Gardasil resulted from infections that were present when the women received their vaccination.
In the United States, approximately 20 million people are infected with HPV, and approximately 80 percent of females will have acquired HPV by age 50. For most people, HPV goes away on its own; however in some, certain high-risk types of HPV, if unrecognized and untreated, can lead to cervical cancer. In the United States, approximately 10,000 women are diagnosed with cervical cancer every year, and an average of 10 women die each day from the disease. Cervical cancer is the second most common cause of cancer death in women worldwide, resulting in nearly a half-million diagnoses and 240,000 deaths each year. In addition, certain low-risk types of HPV cause genital warts and can lead to abnormal Pap results. Approximately 1 million cases of genital warts occur each year in the United States and an estimated 32 million cases occur worldwide. Additionally, there are an estimated 4.7 million abnormal Pap results that require follow-up each year in the United States. At least 3 million of these results are caused by some type of HPV. HPV related disease, including screening, follow-up and treatment, costs about $5 billion per year in the U.S. Used in conjunction with screening, Gardasil can help significantly reduce the human and economic burden of cervical cancer and other HPV-related diseases in the United States.
In 1995, Merck entered into a license agreement and collaboration with CSL Limited relating to technology used in Gardasil. Gardasil is the third new Merck vaccine to be approved by the FDA in 2006. ROTATEQ® received FDA approval in February to prevent rotavirus gastroenteritis, a leading cause of severe infant diarrhea, and ZOSTAVAX® was approved by the FDA and in the European Union in May to prevent shingles in adults 60 and older. Other regulatory agencies around the world are reviewing applications for Gardasil, ROTATEQ and ZOSTAVAX.
On June 1, 2006, Gardasil was approved in Mexico. Applications for Gardasil are currently under review with regulatory agencies on five continents, including but not limited to agencies in Argentina, Australia, Brazil, the European Union, New Zealand, Singapore and Taiwan. Additionally, Merck is actively working to accelerate the availability of Gardasil in the developing world: in December, Merck announced a partnership with India's Council of Medical Research to study Gardasil. Merck is also working with PATH and the Gates Foundation to develop HPV vaccination programs that will facilitate introduction of Gardasil to the most impoverished nations.
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