August 20, 2009
Consumers, parents, health care professionals and others have raised questions regarding the safety of the human papillomavirus (HPV) vaccine, Gardasil. FDA and the U.S. Centers for Disease Control and Prevention (CDC) take all concerns about vaccine safety seriously, and have been closely monitoring the safety of Gardasil.
Below is a summary of Gardasil vaccine safety monitoring activities and findings. Based on ongoing assessments of vaccine safety information, FDA and CDC continue to find that Gardasil is a safe and effective vaccine. FDA and CDC continue to monitor the safety of this vaccine, with the public’s health and safety our top priority.
FDA approved Gardasil on June 8, 2006. It is approved for females 9-26 years of age to protect against cervical, vulvar and vaginal cancers caused by Human Papillomavirus (HPV) types 16 and 18 and genital warts caused by HPV types 6 and 11. CDC’s Advisory Committee on Immunization Practices (ACIP) recommended a routine 3-dose vaccination series for girls 11 and 12 years of age. The vaccine is also recommended for girls and women ages 13 through 26 years who have not yet been vaccinated or who have not received all 3 doses.
Studies involving approximately 21,000 girls and women were conducted to evaluate the safety and effectiveness of Gardasil before receiving approval by FDA. Approximately half of the study participants received the vaccine, and the other half received a control. These studies showed that in women who have never been infected by HPV types 6, 11, 16 or 18, the vaccine is highly effective, both in preventing precancerous lesions that often develop into cancer of the cervix, vagina and vulva, and in preventing genital warts caused by these HPV types.
This vaccine is an important cervical cancer prevention tool that will potentially benefit the health of millions of women. Every year, about 12,000 women are diagnosed with cervical cancer and almost 4,000 die from this disease in the United States. Worldwide, cervical cancer is the second most common cancer in women, causing an estimated 470,000 new cases and 233,000 deaths per year.
Monitoring the Safety of Gardasil
Vaccine Safety Overview
FDA and CDC closely monitor the safety of all vaccines through the Vaccine Adverse Event Reporting System (VAERS). VAERS receives unconfirmed reports of possible side effects following the use of Gardasil and all vaccines licensed in the U.S. VAERS reports are regularly reviewed for safety concerns or trends of adverse events (possible side effects).
Vaccines are manufactured in batches called lots. All vaccine lots are routinely tested and must pass all tests before they can be used, and vaccine manufacturers must comply with strict manufacturing standards. FDA also analyzes adverse events (possible side effects) associated with individual lots to look for any unusual patterns. No such patterns have been observed in FDA’s review of HPV vaccine lots since the vaccine was licensed.
In addition to VAERS, CDC has two other systems in place to monitor the safety of all licensed vaccines. The Vaccine Safety Datalink (VSD) Project is a collaborative effort between CDC and eight managed care organizations that monitors vaccine safety and addresses the gaps in scientific knowledge about rare and serious side effects following immunization. The Clinical Immunization Safety Assessment (CISA) Network is a collaboration with six academic centers in the United States to conduct clinical research on vaccine-associated adverse events.
Adverse Event Reports following Gardasil
Given the large number of doses distributed, it is expected that, by chance alone, serious adverse events and some deaths will be reported in this large population during the time period following vaccinations. Our monitoring and analysis of reports, including in-depth medical review, statistical data mining techniques, and analysis of reporting rates (number of adverse events/number of doses distributed) are designed to detect serious events that occur at rates greater than expected.
VAERS receives reports of many events that occur following immunization. Some of these events may occur coincidentally during the time period following vaccination, while others may actually be caused by vaccination. In our analysis of VAERS data, we look for patterns of adverse events that may be plausibly linked to a vaccine. Such patterns of adverse events may require further study.
On August 19, 2009, the Journal of the American Medical Association (JAMA) published an article coauthored by FDA and CDC that reviews the safety data for Gardasil for select adverse events that have been reported to VAERS, from the time period starting from product licensure in June 2006 through December 31, 2008 (JAMA. 2009;302(7):750-757). The article describes 12,424 reports of adverse events following Gardasil vaccination. Of these, 772 were reports of serious events (6.2% of the reports) and the remaining 11,652 (93.8%) were classified as non-serious. During this time period, the manufacturer, Merck and Co., has distributed over 23 million doses of Gardasil in the United States. The information contained in this update is based on the same information contained in the article published in JAMA. FDA will provide a future update to information on the number of reports of adverse events and doses distributed.
The Gardasil safety review assessed the following adverse events: local injection site reactions, syncope, dizziness, and nausea, headaches, hypersensitivity reactions, such as rashes, hives, itching, anaphylaxis, Guillain-Barré syndrome (GBS), transverse myelitis, motor neuron disease, venous thromboembolic events (VTEs), pancreatitis, autoimmune disorders, pregnancy, and deaths. All of these events are included in Gardasil’s labeling. In VAERS, a higher proportion of Gardasil reports were of syncope and VTEs compared with other vaccines. However, none of the adverse events in the safety review, including syncope and VTEs, were reported at rates (number of adverse events/number of doses distributed) greater than expected in a population of this age and gender and with other known contributing factors to these adverse events.
VAERS reports include syncope (fainting), pain at the injection site, headache, nausea and fever. Fainting is common after injections and vaccinations, especially in adolescents. Falls after syncope 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. FDA and CDC have taken steps to remind immunization providers about the recommendation that individuals be watched carefully for 15 minutes after vaccination to avoid potential injury from a fall. FDA approved revised labeling on June 9, 2009, to highlight this information in the Warnings and Precautions section, and new information was added noting that individuals who faint sometimes have tonic-clonic (jerking) movements and seizure-like activity. As a part of a Back to School immunization campaign, FDA and CDC are also continuing to remind health care providers to take measures to prevent fainting and the possible traumatic injury resulting from fainting.
Thromboembolic disorders (blood clots) have been reported to VAERS in people who have received Gardasil. Most of these individuals had risk factors for blood clots such as use of oral contraceptives which are known to increase the risk of clotting. The JAMA article describes 56 cases, 31 of which were confirmed blood clot reports. Twenty eight reports (90%) had underlying known risk factors such as hormonal birth control, genetic clotting abnormalities, obesity, smoking, and immobility. In the CDC’s VSD, blood clots have not been found to occur more often than expected after over 450,000 doses of Gardasil.
Concerns have been raised about reports of deaths occurring in individuals after receiving Gardasil. As of December 31, 2008, 32 deaths had been reported to VAERS. There was not a common pattern to the deaths that would suggest they were caused by the vaccine. In the majority of cases with available autopsy, death certificate and medical records, the cause of death was explained by factors other than the vaccine.
Guillain-Barre Syndrome (GBS) has also been reported in individuals following vaccination with Gardasil. GBS is a rare neurological disorder that causes muscle weakness. It occurs spontaneously in unvaccinated individuals after a variety of specific infections. FDA and CDC have reviewed the reports of GBS that have been submitted to VAERS. To date, there is no evidence that Gardasil has increased the rate of GBS above that expected in the population. While we continue to carefully analyze all reports of GBS submitted to VAERS, the data do not currently suggest an association between Gardasil and GBS.
Because VAERS data are subject to many limitations of passive reporting systems, FDA and CDC also utilize additional surveillance tools. This includes the CDC’s VSD which incorporates eight large Managed Care Organizations, and now has health records linked to over 450,000 doses of Gardasil, and focuses on several potential risks: thrombotic events (blood clots), seizures, syncope, appendicitis, anaphylaxis, and GBS. Thus far, the VSD studies have not found safety signals or concerns for any of these events. The manufacturer has also committed to conduct a large postmarketing study to further assess the vaccine’s safety.
Based on the review of available information by FDA and CDC, Gardasil continues to be safe and effective, and its benefits continue to outweigh its risks.
CDC has not changed its recommendations for use of Gardasil. FDA has not made any changes to the prescribing information for how the vaccine is used. In addition, FDA routinely reviews manufacturing information, and has not identified any issues affecting the safety, purity and potency of Gardasil.
Public health and safety are priorities for FDA and CDC. As with all licensed vaccines, we will continue to closely monitor the safety of Gardasil. FDA and CDC continue to find that Gardasil is a safe and effective vaccine that will potentially benefit the health of millions of women by providing protection against the types of HPV in the vaccine that cause cervical, vulvar and vaginal cancer, genital warts, and other HPV-related genital diseases in females.