The US Food and Drug Administration (FDA) this week published a citizen petition denial to a group seeking to pre-emptively block the approval of a supplemental New Drug Application (sNDA) for Gilead Sciences' Truvada for preventing the transmission of HIV-1.
The group, the AIDS Healthcare Foundation (AHF), had filed the petition on 7 March 2012-part of a subsequent campaign by the group to call attention to the drug. In a series of advertisements, AHF asked, "What rotten at FDA?" and called for FDA Commissioner Margaret Hamburg to resign in light of what it called "questionable product reviews."
"Under the leadership of Commissioner Hamburg, the FDA has proven that it cannot be trusted with protecting the American public from unsafe and ineffective drugs," remarked the group in one of its advertisements.
FDA would ultimately grant reviewers at the Center for Drug Evaluation and Research (CDER) an additional three months to review the drug, though both an FDA advisory committee and the FDA would eventually vote to approve the drug. It was unclear in reports whether the additional time was a function of AHF's petition or other factors.
Petition Lists 'Grave Concerns'
In its citizen petition, AHF "respectfully" requested that FDA not approve Truvada based on AHF's "grave concerns. Among AHF's specific concerns about the drug's effectiveness in women, the statistical significance of the studies used to support approval, potential kidney damage resulting from the long-term use of the drug, the drug's real-world effectiveness outside of heavily-controlled support settings, and the potential for drug-resistant forms of HIV to form.
While FDA did not outright dismiss AHF's concerns in its 16 July letter-sent the same day it approved Truvada-its arguments do speak to a risk balance that is, on whole, favorable in the eyes of the agency.
In its denial of AHF's letter, FDA notes several trials in which Truvada showed a positive benefit assessment relative to risk, and said a Risk Evaluation and Mitigation Strategies (REMS) plan required of Gilead would allow the product to be prescribed appropriately "as part of a comprehensive prevention strategy."
Other arguments made by AHF were treated more harshly by FDA. "The agency finds your assertions that the Partners PrEP trial results are unlikely to be representative of the population of women as a whole to be without merit," explained FDA. "Sexual transmission of HIV is not dependent on the relationship status of the infected or uninfected individual."
"The agency believes the results of the Partners PrEP trial can be extrapolated to all women who are at high risk of sexually acquired HIV infection," continued FDA.
Other factors cited by AHF-kidney damage and adherence-were cited by FDA as areas that, while potentially problematic, could be "clinically managed" and were not grounds for the denial of the application.
Finally, FDA admitted the risk of new drug-resistant HIV strains is "a serious one," and noted Truvada's approved REMS requires prescribers to undergo testing before being allowed to start a Truvada regimen.
A Favorable Benefit:Risk Balance
"The public health reality is that despite widespread knowledge of HIV/AIDS, decades of intensive condom promotion and availability of antiretroviral drugs to treat HIV infections, the incidence of new HIV infections in the US has remained at a constant level of approximately 50,000 annual HIB infections," FD explained. "Against this backdrop, the risks posed by Truvada for PrEP that you list… must be balanced against the totality of the data from various clinical trials of oral PrEP."
With all factors considered, FDA said it "therefore believes that the benefits of Truvada for reduction in the risk of sexually acquired HIV-1 infection in high risk individuals outweigh its risks when taken as directed and used in combination with a comprehensive strategy for risk reduction including safer sex practices."
AIDS Healthcare Foundation - Citizen Petition
FDA/CDER to AIDS Healthcare Foundation - Petition Denial