HPV VACCINE RECOMMENDED BY FDA PANEL FOR ANAL CANCER PREVENTION

November 18, 2010 — Human papillomavirus (HPV) quadrivalent (types 6, 11, 16, and 18) vaccine, recombinant (Gardasil; Merck), was recommended for an expanded indication — prevention of anal cancer in males and females ages 9 through 26 years — at a US Food and Drug Administration (FDA) advisory panel meeting yesterday.

The FDA's Vaccines and Related Biological Products Advisory Committee mulled over the recent data to consider the expanded indication.

Panelists were asked to comment on 2 discussion topics: the strength of the data to support an indication for the prevention of anal intraepithelial neoplasia (AIN) and anal cancer in males and the scientific rationale for extrapolating efficacy in the prevention of AIN and anal cancer to females.

According to background information provided by the FDA, the HPV quadrivalent (types 6, 11, 16, and 18) vaccine is currently licensed for prevention of cervical, vulvar, and vaginal cancer and the associated precancerous lesions in females aged 9 to 26 years and for the prevention of genital warts in males and females aged 9 to 26 years.

During the session, the panel reviewed data from a phase 3 double-blind, placebo-controlled study of 4065 men, 602 of whom were men who have sex with men (MSM), a subgroup on which the panel focused. Patients were randomly assigned in a ratio of 1:1 to receive 3 doses of the HPV vaccine or an aluminum-based placebo.

After 36 months, 3% of the MSM subgroup receiving vaccine developed AIN or anal cancer compared with 12% of the MSM placebo group.

On the primary composite endpoint of prevention of HPV (strains 6, 11, 16 and 18)-related AIN (any grade) and anal cancer, the point estimate of efficacy was 78% (95% confidence interval [CI], 40% - 93%). For advanced dysplasia, the point estimate of efficacy was 75% (95% CI, 9% - 95%).

Panelists for the most part agreed that the efficacy data in study participants who were aged 16 to 26 years would likely be generalizable to boys as young as 9. Some panelists questioned whether the data in males could be extrapolated to females, although 1 panelist noted that females will receive the vaccine for cervical cancer prevention anyway.

"The diseases do not appear to be different in males and females — the pathophysiology seems to be quite similar, and so I think these are all logical extensions," said panelist Jose Romero, MD, from the Arkansas Children's Hospital Institute, in Little Rock.

However, Vicky Debold, PhD, RN, director of patient safety at the National Vaccine Information Center, in Vienna, Virginia, maintained that the issue was not so straightforward. "Efficacy values ranged from 24% to 90%. We're dealing with a lot of extremely wide confidence intervals — it's hard to know what the true point estimate is, and I am much less comfortable."

According to the US Centers for Disease Control and Prevention, as of September 30, 2010, there were 17,160 Vaccine Adverse Events Reporting System reports of adverse events after vaccination with the quadrivalent HPV vaccine in the United States. Of these reports, 92% were reports of events considered to be nonserious, including fainting, pain and swelling at the injection site, headache, nausea, and fever.

Serious adverse events reported, making up 8% of the reports to Vaccine Adverse Events Reporting System, include Guillain-Barré syndrome, blood clots, and deaths, although the CDC states that experts have "not found a common medical pattern to the reports of serious adverse events reported for Gardasil that would suggest that they were caused by the vaccine."

At this time, 2 HPV vaccines are available in the United States: the quadrivalent vaccine, the subject of the panel discussion, targets the types 6, 11, 16, and 18, and a bivalent HPV vaccine that targets types 16 and 18 is also available.

According to the National Cancer Institute, HPV types 16 and 18 cause an estimated 70% of cervical cancers, and HPV types 6 and 11 cause approximately 90% of genital warts.

"We are pleased with the outcome of today's meeting and look forward to continued discussions with the FDA as it evaluates the data for the proposed indication," Elizabeth Garner, MD, MPH, director, clinical research, Merck Research Laboratories, stated in a company press release.

The FDA does not always follow the recommendations of its advisory committees, but it often does.