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Prostate cancer vaccine increases scrutiny on FDA’s review process
Despite public outcry, the FDA will not lower the bar for safety and efficacy data on sipuleucel-T.
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In March, the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee endorsed sipuleucel-T for the treatment of androgen-independent prostate cancer, despite the concerns of leading prostate cancer experts and statisticians that the data are not strong enough to endorse the treatment’s efficacy.
In May, the FDA subsequently ruled and agreed with the dissenters: More data are needed before the sipuleucel-T vaccine (Provenge, Dendreon) can be approved. This decision sparked protests from patients and advocates who urged the FDA to reverse its ruling.
Although the available data indicated the vaccine was safe, the standard for efficacy was not reached. Neither of the two small trials presented to the committee reached their primary endpoints of time to progression. Both trials showed better overall survival for patients treated with sipuleucel-T; however, this was not a planned primary or secondary endpoint for either trial. The benefit was identified during a follow-up analysis.
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For prostate cancer, the only treatment proven to extend survival is docetaxel (Taxotere, Sanofi Aventis)-based chemotherapy. However, docetaxel is a cytotoxic drug associated with moderate toxicity. If data from an ongoing phase-3 trial are favorable, sipuleucel-T could be an alternative, less-toxic treatment and lay groundwork for research of combination therapies, according to Donald L. Trump, MD, section editor of the Genitourinary Cancers section for Hem/Onc Today.
“To have another treatment agent, particularly an agent that is as well-tolerated as Provenge appears to be, would be a great advance,” Trump, CEO of the Roswell Park Cancer Institute, told Hem/Onc Today. “The problem is that it is a little premature to conclude that Provenge is absolutely safe. A relatively small number of individuals were treated in the trials. Most importantly, the usual criteria that we apply for determining efficacy, from what I can tell, have not been satisfied for this treatment.”
The FDA said that it will accept data from a planned interim analysis of the ongoing trial, which began before the advisory committee met. The trial was designed with a primary endpoint of overall survival. The final survival analysis for this study is expected in 2010.
“I see patients weekly who vitally need something better than I can offer them for therapy, so I would be absolutely delighted if this trial has positive results,” Trump said. “But the treatment has to be judged on the same criteria that other drugs are judged on.”
The two trials
Before drugs are approved by the FDA, they must meet rigorous standards for safety and efficacy. The gold standard for determining the efficacy of any oncology treatment is a randomized, controlled trial designed to measure overall survival. Neither of the sipuleucel-T trials was designed with overall survival as an endpoint.
Both trials presented by Dendreon at the advisory committee meeting were phase-3, multicenter, randomized, double blind, placebo-controlled studies.
The initial analysis of the first study suggested a trend in delaying progression that was not significant. Participants were then followed for 36 months to analyze overall survival. The 36-month analysis showed that patients treated with sipuleucel-T had a 41% reduced risk for death compared with patients treated with placebo (HR=1.71; 95% CI, 1.13-2.58).
Enrollment for the second study ended early because the first study did not demonstrate a significant delay in time to progression. The trial remained blinded, however, and the patients were followed for overall survival.
Participants in the sipuleucel-T group had a 21% reduction in risk for death compared with those in the placebo group (HR=1.27; 95% CI, 0.78-2.07). More patients in the sipuleucel-T group (32%) were alive at 36 months compared with 21% of the patients in the placebo group.
The researchers conducted an analysis of the integrated efficacy data for both studies and found a 33% reduction in the risk for death for patients treated with sipuleucel-T compared with placebo (HR=1.50; 95% CI; 1.10-2.05).
“A level of discomfort arises when a nonplanned or nonprimary endpoint turns out to be positive,” Trump said. “There are many things that can affect survival in patients with cancer, and one has to have a sufficiently large study to be sure you are not being misled.”
Sufficient evidence
The development of vaccines to treat cancer is a prominent topic, as early research has shown promising results related to the use of immunotherapy treatment. If proven effective in the ongoing trial, sipuleucel-T would be the first therapeutic vaccine approved for human cancer.
One member of the advisory committee advocated the drug’s approval because of a need to have vaccines available to test and stated that if sipuleucel-T was not approved, vaccine development would be set back. However, drug approval is separate from the issue of drug development and clinical research, according to Trump. Drugs are approved or disapproved because they meet the tests that have been prescribed when a study is initiated to show a specific endpoint.
“[The data for sipuleucel-T] have been interpreted as safe and effective by people who are committed and devoted to the area of vaccine development,” Trump said. “On one level, you can’t blame people who are deeply committed to making new treatments available for being enthusiastic. On the other hand, the bar for proving safety and efficacy has not been achieved. It’s an important issue to solve, and there are some strong feelings about it.”
Strong feelings are evident. According to news reports, patient advocacy groups planned a rally in Washington, and a demonstration took place in Chicago at the 2007 ASCO Annual Meeting.
An editorial published in Nature Clinical Practice Oncology stressed the importance of “substantial evidence of efficacy” when evaluating drugs for approval and applauded the FDA for not lowering standards. – by Emily Shafer
For more information:
- DeVita VT. The Provenge decision. Nat Clin Pract Oncol. 2007:doi.org/10.1038/ncponc0854. Accessed June 13, 2007.