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FDA Approval for a Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine

 Brand name(s): Gardasil®

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interaction, and contraindications.

 Anal Cancer
 

On December 23, 2010, the Food and Drug Administration (FDA) approved the vaccine Gardasil for the prevention of anal cancer and associated precancerous lesions due to human papillomavirus (HPV) types 6, 11, 16, and 18 in people ages 9 through 26 years.

Gardasil is already approved for the same age population for the prevention of cervical, vulvar, and vaginal cancer and the associated precancerous lesions caused by HPV types 6, 11, 16, and 18 in females.  It is also approved for the prevention of genital warts caused by types 6 and 11 in both males and females.

“Treatment for anal cancer is challenging; the use of Gardasil as a method of prevention is important as it may result in fewer diagnoses and the subsequent surgery, radiation or chemotherapy that individuals need to endure,” said Karen Midthun, M.D., director of the FDA’s Center for Biologics Evaluation and Research.

Although anal cancer is uncommon in the general population, the incidence is increasing. HPV is associated with approximately 90 percent of anal cancer. The American Cancer Society estimates that about 5,300 people are diagnosed with anal cancer each year in the United States, with more women diagnosed than men.

Gardasil’s ability to prevent anal cancer and the associated precancerous lesions [anal intraepithelial neoplasia (AIN) grades 1, 2, and 3] caused by anal HPV-16/18 infection was studied in a randomized, controlled trial of men who self-identified as having sex with men (MSM). This population was studied because it has the highest incidence of anal cancer. At the end of the study period, Gardasil was shown to be 78 percent effective in the prevention of HPV 16- and 18-related AIN.  Because anal cancer is the same disease in both males and females, the effectiveness data was used to support the indication in females as well. 

Gardasil will not prevent the development of anal precancerous lesions associated with HPV infections already present at the time of vaccination. For all of the indications for use approved by the FDA, Gardasil's full potential for benefit is obtained by those who are vaccinated prior to becoming infected with the HPV strains contained in the vaccine.

Individuals recommended for anal cancer screening by their health care provider should not discontinue screening after receiving Gardasil.

As of May 31, 2010, more than 65 million doses of Gardasil had been distributed worldwide, since its approval in 2006 according to the manufacturer, Merck & Co. Inc. The most commonly reported adverse events include fainting, pain at the injection site, headache, nausea, and fever. Fainting is common after injections and vaccinations, especially in adolescents. Falls after fainting may sometimes cause serious injuries, such as head injuries. Fainting can be prevented by keeping the vaccinated person seated for up to 15 minutes after vaccination. This observation period is also recommended to watch for severe allergic reactions, which can occur after any immunization.

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 Genital Warts
 

On October 16, 2009, the FDA approved use of the recombinant quadrivalent human papillomavirus vaccine (Gardasil®, made by Merck & Co., Inc.) for the prevention of genital warts (condyloma acuminata) due to human papillomavirus (HPV) types 6 and 11 in boys and men ages 9 years through 26 years.

Each year, about two out of every 1,000 men in the United States are newly diagnosed with genital warts.

Gardasil is currently approved for use in girls and women ages 9 years through 26 years for the prevention of cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18; precancerous lesions caused by HPV types 6, 11, 16, and 18; and genital warts caused by HPV types 6 and 11.

HPV is the most common sexually transmitted infection in the United States, and most genital warts are caused by HPV infection.

"This vaccine is the first preventive therapy against genital warts in boys and men ages 9 years through 26 years, and, as a result, fewer men will need to undergo treatment for genital warts," said Karen Midthun, M.D., acting director of the FDA's Center for Biologics Evaluation and Research.

Gardasil's effectiveness was studied in a randomized trial of 4,055 males ages 16 years through 26 years. The results showed that in men who were not infected by HPV types 6 and 11 at the start of the study, Gardasil was nearly 90 percent effective in preventing genital warts caused by infection with HPV types 6 and 11.

Studies were conducted to measure the immune response to the vaccine in boys ages 9 years through 15 years. The results showed that the immune response was as good as that found in the 16 years through 26 years age group, indicating that the vaccine should have similar effectiveness.

The manufacturer will conduct postmarketing studies to obtain additional information on the safety and effectiveness of Gardasil in boys and men.

Gardasil is given as three injections over a 6-month period. Headache, fever, and pain at the injection site, itching, redness, swelling, and bruising were the most common side effects observed.

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 Vaginal and Vulvar Cancer
 

On September 8, 2008, the FDA announced the approval of the vaccine Gardasil for the prevention of vaginal and vulvar cancer caused by human papillomavirus (HPV) types 16 and 18 in girls and women ages 9 to 26. These two HPV types cause 70 percent of cervical cancers, and are known to also cause some vulvar and vaginal cancers.

"There is now strong evidence showing that this vaccine can help prevent vulvar and vaginal cancers due to the same viruses for which it also helps protect against cervical cancer," said Jesse L. Goodman, M.D., M.P.H., director of the FDA's Center for Biologics Evaluation and Research. "While vulvar and vaginal cancers are rare, the opportunity to help prevent them is potentially an important additional benefit from immunization against HPV."

The FDA originally approved Gardasil in 2006 for girls and women ages 9 to 26 for the prevention of cervical cancer caused by HPV types 16 and 18, precancerous genital lesions caused by HPV types 6, 11, 16, and 18 and genital warts caused by HPV types 6 and 11.

HPV includes more than 100 related viruses and more than 30 types can be transmitted via sexual contact. According to the U.S. Centers for Disease Control and Prevention (CDC), HPV is the most common sexually transmitted infection in the United States with 6.2 million Americans becoming infected with genital HPV each year.

For most women, the body's own defense system will clear HPV, thereby preventing serious health problems. However, some HPV types can cause abnormal cell growth in areas of the cervix, vagina, vulva, and other organs that years later may turn into cancer.

Regarding the prevention of vulvar and vaginal cancer, Gardasil's manufacturer, Merck & Co. Inc., followed more than 15,000 participants from the original studies for about two additional years. Approximately half had received Gardasil as part of the original study; the other half did not receive Gardasil and served as a control group.

Among females who tested negative for HPV types 16 or 18 at the start of the study, Gardasil was highly effective in preventing  HPV-related precancerous vulvar and vaginal lesions, which are considered to be the precursors for cancer. In the control group, 10 individuals developed precancerous vulvar lesions and nine developed precancerous vaginal lesions, all related to HPV types 16 or 18. No individuals in the Gardasil group developed either kind of precancerous lesion due to HPV types 16 or 18.

There was no evidence for benefit among women found to have been previously infected, prior to immunization, with the HPV types included in the vaccine. Therefore, to receive Gardasil's full potential for benefit, it is important to be vaccinated prior to becoming infected with the HPV strains contained in the vaccine. 

Gardasil's label has been revised to note that the presently available information is insufficient to support use beyond age 26, the current FDA-approved age. Also, new information has been added showing that Gardasil does not protect against diseases caused by HPV types not contained in the vaccine.

No vaccine is 100 percent effective, and Gardasil does not protect against HPV infections that a woman may already have at the time of vaccination. Therefore, all women should get regular Pap tests, even after they have been vaccinated. Routine Pap screening remains critically important to detect precancerous changes, which would allow treatment before cancer develops.

Since the FDA approved Gardasil in 2006, the majority of reported adverse events have not been serious. The most commonly reported adverse events have included syncope (fainting), pain at the injection site, headache, nausea, and fever. Fainting is common after injections and vaccinations, especially in adolescents. Falls after fainting may sometimes cause serious injuries, such as head injuries, which can be prevented with simple steps, such as keeping the vaccinated person seated for up to 15 minutes after vaccination. This observation period is also recommended to watch for severe allergic reactions, which can occur after any immunization.

As part of the original approval, Merck committed to a safety surveillance study of 44,000 individuals in a managed care organization. The study is assessing short- and long-term safety for all of Gardasil's approved uses.As with all vaccines, FDA and CDC continue to closely monitor Gardasil's safety.

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 Cervical Cancer
 

On June 8, 2006, the FDA announced the approval of Gardasil, the first vaccine developed to prevent cervical cancer, precancerous genital lesions and genital warts due to human papillomavirus (HPV) types 6, 11, 16 and 18 in girls and women ages 9 through 26 years. Gardasil was evaluated and approved in 6 months under FDA's priority review process--a process for products with potential to provide significant health benefits.

"Today is an important day for public health and for women's health, and for our continued fight against serious life-threatening diseases like cervical cancer," said Alex Azar, Deputy Secretary, U.S. Department of Health and Human Services (HHS). "HHS is committed to advancing critical health measures such as the development of new and promising vaccines to protect and advance the health of all Americans."

HPV is the most common sexually-transmitted infection in the United States. The CDC estimates that about 6.2 million Americans become infected with genital HPV each year and that over half of all sexually active men and women become infected at some time in their lives.  On average, there are 9,710 new cases of cervical cancer and 3,700 deaths attributed to it in the United States each year. Worldwide, cervical cancer is the second most common cancer in women with more than 470,000 new cases and 233,000 deaths each year.

For most women, the body's own defense system will clear the virus and most infected women do not develop related health problems.  However, some HPV types can cause abnormal cells on the lining of the cervix that years later can turn into cancer.  Other HPV types can cause genital warts.  The vaccine is effective against HPV types 16 and 18, which cause approximately 70 percent of cervical cancers and against HPV types 6 and 11, which cause approximately 90 percent of genital warts. 

"This vaccine is a significant advance in the protection of women's health in that it strikes at the infections that are the root cause of many cervical cancers," said Andrew C. von Eschenbach, MD, Acting Commissioner of FDA.  "The development of this vaccine is a product of extraordinary work by scientists as well as by FDA's review teams to help facilitate the development of very novel vaccines to address unmet medical needs.  This work has resulted in the approval of a number of new products recently, including Gardasil, which address significant public health needs."

Gardasil is a recombinant vaccine (contains no live virus) that is given as three injections over a six-month period.  Immunization with Gardasil is expected to prevent most cases of cervical cancer due to HPV types included in the vaccine.  However, females are not protected if they have been infected with that HPV type(s) prior to vaccination, indicating the importance of immunization before potential exposure to the virus.  Also, Gardasil does not protect against less common HPV types not included in the vaccine, thus routine and regular Pap screening remain critically important to detect precancerous changes in the cervix to allow treatment before cervical cancer develops.

"This is the first vaccine licensed specifically to prevent cervical cancer. Its rapid approval underscores FDA's commitment to help make safe and effective vaccines available as quickly as possible. Not only have vaccines dramatically reduced the toll of diseases in infants and children, like polio and measles, but they are playing an increasing role protecting and improving the lives of adolescents and adults," said Jesse Goodman, MD, MPH, Director of FDA's Center for Biologics Evaluation and Research.

Four studies, one in the United States and three multinational, were conducted in 21,000 women to show how well Gardasil worked in women between the ages of 16 and 26 by giving them either the vaccine or placebo.  The results showed that in women who had not already been infected, Gardasil was nearly 100 percent effective in preventing precancerous cervical lesions, precancerous vaginal and vulvar lesions, and genital warts caused by infection with the HPV types against which the vaccine is directed.  While the study period was not long enough for cervical cancer to develop, the prevention of these cervical precancerous lesions is believed highly likely to result in the prevention of those cancers.

The studies also evaluated whether the vaccine can protect women already infected with some HPV types included in the vaccine from developing diseases related to those viruses.  The results show that the vaccine is only effective when given prior to infection.

Two studies were also performed to measure the immune response to the vaccine among younger females aged 9-15 years.  Their immune response was as good as that found in 16-26 year olds, indicating that the vaccine should have similar effectiveness when used in the 9-15 year age group.

The safety of the vaccine was evaluated in approximately 11,000 individuals.  Most adverse experiences in study participants who received Gardasil included mild or moderate local reactions, such as pain or tenderness at the site of injection.

The manufacturer has agreed to conduct several studies following licensure, including additional studies to further evaluate general safety and long-term effectiveness.  The manufacturer will also monitor the pregnancy outcomes of women who receive Gardasil while unknowingly pregnant.   Also, the manufacturer has an ongoing study to evaluate the safety and effectiveness of Gardasil in males. 

This summary was provided by Richard Pazdur, M.D., director of FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

  • Updated: July 1, 2013