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FDA advisory committee gives green light to Gardasil, a new HPV vaccine
The vaccine was 100% effective in preventing cervical dysplasias.
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The Food and Drug Administration’s (FDA) Vaccines and Related Biological Products Advisory Committee recently voted unanimously that the data support the efficacy and safety of Gardasil, Merck’s investigational human papillomavirus (HPV) vaccine.
“Merck is thrilled that the advisory committee has agreed that the extensive data from our decade-long, 27,000-patient clinical trial program support the use of Gardasil to reduce the burden of cervical cancer and other diseases caused by HPV,” Peter S. Kim, PhD, president, Merck Research Laboratories said in a statement following the committee’s vote. The FDA is not bound to follow the advisory committee’s decision but generally follows their recommendations.
“If approved, Gardasil will be the first and only vaccine to prevent cervical cancer and other serious HPV-related diseases,” Kim said.
Diseases caused by HPV represent a major burden in the United States.
Approximately 10,000 women are diagnosed with cervical cancer each year, and an average of 10 women die each day from this type of cancer. Merck officials presented data at the committee meeting that noted HPV causes approximately 40% to 50% of the more than 3,500 cases of vulvar and vaginal cancer that are diagnosed each year in the United States.
Both Merck and GlaxoSmithKline have developed HPV vaccines that are in large-scale clinical trials. Both vaccines target HPV16 and HPV18, which are responsible for approximately 70% of cervical cancer. The Merck vaccine also targets HPV6 and HPV11, which are responsible for approximately 90% of external genital warts.
The HPV vaccines are prophylactic vaccines, not a combined prophylactic/therapeutic vaccine, John T. Schiller, MD, told physicians at the 2006 Annual Meeting of the Pediatric Academic Societies held in San Francisco, a few weeks before the FDA’s committee met.
Vaccine effectiveness
Both Merck and GSK are conducting multicenter studies, and the vaccines have been found to be very effective, Schiller, who is from the National Cancer Institute, said.
“It is interesting to note that by 3.5 or four years after vaccination, the antibody levels have plateaued at a level that is considerably higher than that for natural infection. This bodes very well for long-term protection, although we don’t know how long it is going to last. The fact that we continue to get solid protection at this level even after antibody levels have plateaued is extremely encouraging,” he said.
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Source: Diane M. Harper, MD, MPH, MS |
Merck officials said in clinical trials, their vaccine was 100% effective in preventing cervical dysplasias. There were no cases in the 8,487 women who received Gardasil compared to 53 cases in the 8,460 women who received placebo. The vaccine also provided 100% protection against genital warts. Gardasil prevented 99.1% of HPV 6-, 11-, 16- or 18-related external genital lesions, including genital warts, vulvar intraepithelial neoplasia or vaginal intraepithelial neoplasia. There was one case in the 7,897 women who received the vaccine compared to 113 cases in the 7,899 women who received placebo.
“GSK has looked at the degree of cross-protection against other types of HPV. Statistically, the protection against type 45 is just as good as it is against types 16 and 18. They also showed 50% protection against type 31, which is related to type 16. Just as importantly, there was no protection whatsoever against three other virus types. So, while we think that vaccine protection may not be type specific, we think that it is definitely type restricted,” he said.
Schiller noted that a few outstanding questions remain. The vaccine’s duration of protection and the need for booster shots are still unclear. The extent of cross-protection against cervical intraepithelial neoplasia (CIN) types not in the vaccine is also uncertain.
The vaccine’s effect on acute infection is also unclear. It may be possible that vaccinating women with early acute infections could reduce the likelihood of persistence and regression. Researchers are also conducting safety and efficacy studies on HIV and other immunosuppressed patients.
Who should be vaccinated?
Schiller said young adolescent girls who have not yet been exposed to HPV are the most critical group to target for vaccination. Many girls acquire HPV very soon after becoming sexually active, so the vaccine will be most effective in early adolescence.
“Sexually active women could also benefit from the vaccine because some have not been exposed to all of the virus and some have not been exposed to any,” he said. Initially, most of the vaccine will be given to sexually active women because this is the group most likely to ask for the vaccine, he said.
“Although it is premature to discuss vaccinating men, the fact that the vaccine works against genital warts in women suggests quite strongly that the vaccine should also work in men for penile lesions. But from a public health point of view, only approximately 10% of HPV cancers occur in men. Also, some of the modeling studies suggest that herd immunity can be quite good if only women are vaccinated,” he said.
Vaccine concerns
Although the Merck vaccine has been deemed safe and effective, some concerns remain.
Clearly, price will be an important issue.
“While the companies have not yet announced the price of this vaccine, it is going to be expensive. In fact, it will probably be about $300 for three doses. The girls who really need this vaccine are the girls who are disadvantaged and who aren’t going to be adequately screened by Pap screening. We need to reduce their cervical cancer risk by vaccinating them,” Schiller said.
Delivering three doses of vaccines to adolescents is also going to be a challenge.
“Then, there is the whole idea of acceptance of a sexually transmitted disease vaccine versus a cervical cancer vaccine. We can’t hide the fact that this is a sexually transmitted disease, but clearly the main selling point is that it can prevent girls from getting cervical cancer,” he said.
Another important concern is the potential effect of these vaccines on cervical cancer screening recommendations and compliance. These vaccines should not and will not replace screening, he said.
Pap screening decreases cervical cancer rates by at least 80%, Schiller said. If the vaccine were type-specific, the current vaccine would only decrease cervical cancer by 70%, because this is the percentage that is caused by 16 and 18. So, vaccinated women will still need to comply with cervical cancer screening.
“This vaccine will prevent most high-grade cervical dysplasias and cervical cancers, but cancer rates won’t be decreased for many years — more than a decade — because we are preventing incident infection, and it takes a long time for incident infection to develop into cancer. We will not prevent many of the low-grade cervical abnormalities that appear soon after infection and are routinely detected in pap screening,” Schiller said.
The concern is that Pap smear abnormalities will appear in women who have been vaccinated, and they in turn may think the vaccine is not working and then refuse it for their daughters. Health care providers will need to educate their patients about these issues.
“We need to send a message to young women, parents, and health care providers that cervical cancer is caused by a sexually transmitted virus and that becoming HPV-infected is almost synonymous with being sexually active, with lifetime risk probably greater than 70%. The vaccine will likely be most effective if given before the onset of sexual activity. However, the vaccine will not replace pap screening,” he added.
While many women will initially ask their gynecologists about the vaccine after it is approved, ultimately, pediatricians will be the ones to deliver this vaccine, Schiller said. – by Michelle Stephenson
For more information:
- Schiller JT. Development of virus-like particles for immunization against human papillomavirus. Presented at: 2006 Annual Meeting of the Pediatric Academic Societies; April 29-May 2, 2006; San Francisco.