FDA and CDC to Consider Gardasil for Anal Cancer Prevention

The agency takes issue with Merck’s inclusion of cases of condyloma acuminatum under the grouping of AIN 1 in the primary end point. These low-grade lesions are simply warts and unlikely to progress to advanced dysplasia, Dr. Roberts said. Consequently, their inclusion in an anal neoplasia/anal cancer end point is of questionable value, and the agency’s review instead emphasizes the AIN 2+ end point.

Dr. Roberts concludes that data linking anal high-risk HPV infection to AIN and subsequent anal cancer are persuasive. "AIN (particularly AIN 2+) is a reasonable correlate end point for evaluating an intervention for the prevention of anal cancer."

A key issue is the extent to which there are differences in the natural history of anal HPV infection in males and females, such as the progression of AIN.

"CBER reviewers are not aware of data to suggest that there are fundamental differences between males and females, in terms of anal anatomy, histology, or physiology. There are not, therefore, reasons to presume, a priori, that there are fundamental differences in the pathophysiology of anal HPV infections," Dr. Roberts writes.

Data show that specific behavioral and immune variables are strongly correlated with the risk of HPV acquisition and progression of HPV-associated neoplasia. "However, gender, in and of itself, does not appear to be one of the factors that modulate these risks to any substantial degree," Dr. Roberts said, adding that the percentage of anal cancers linked to HPV is approximately 90% in both men and women.

Consequently, it is reasonable to extrapolate efficacy data in males to support the AIN/anal cancer indication for females based on available epidemiological, histological, and pathophysiological data, he concludes.

CBER has not altered its overall assessment of the safety data, and no changes in the vaccine’s current postmarketing program are recommended. "Gardasil continues to have an acceptable safety profile. No new safety signals were identified," Dr. Roberts said.

Eyeing ACIP’s February 2011 Meeting

FDA approval of the AIN/anal cancer indication later this year would likely spur ACIP to revisit, at its Feb. 23-24, 2011, meeting, an earlier decision not to recommend routine administration of Gardasil to males.

ACIP currently recommends routine vaccination of females aged 11-12 years with either Gardasil or Cervarix. Vaccination is also recommended for females aged 13-26 years who have not been previously inoculated.

However, ACIP does not recommend routine use of Gardasil, the only HPV vaccine approved for both genders, in males.

ACIP met in October 2009, shortly after the FDA approved the male genital warts indication, to consider a recommendation on routine use in boys and men.

A Morbidity and Mortality Weekly Report (MMWR) article reflecting ACIP’s October 2009 deliberations cites mathematical modeling suggesting that adding male vaccination is not a cost-effective strategy for reducing the overall burden of HPV-associated conditions when vaccination coverage of females is high. Instead, improving coverage in 11- and 12-year-old girls could be a more effective and cost-efficient strategy.

ACIP nevertheless provided guidance that Gardasil may be given to males who are 9-26 years old to reduce their likelihood of acquiring genital warts. The MMWR article notes that Gardasil appeared to have high efficacy for prevention of AIN in the MSM population, but this information was not available before the committee’s October 2009 meeting and had not yet been reviewed by the FDA.

At its most recent meeting on Oct. 28, 2010, one day before the FDA’s Gardasil briefing documents were released, ACIP heard a presentation from Merck on the AIN/anal cancer data. The committee also heard presentations on provider attitudes and practices regarding HPV vaccine use in males, cost-effectiveness of male vaccination, and other considerations for vaccination recommendations in males.

Dr. Lauri Markowitz, a CDC epidemiologist who serves as the agency’s lead on the ACIP HPV working group, said in an interview that the committee requested additional data on modeling, epidemiology, and HPV infection, among other issues. She said the committee could ultimately decide to vote on routine administration to males or on a strong recommendation targeting use in the MSM population.

Internal Medicine News and "The Pink Sheet" are published by Elsevier.