FDA Ponders More Stringent Path for Accelerated Cancer Drug Approval

The FDA’s Oncologic Drugs Advisory Committee (ODAC) met last week to debate the value of the FDA's accelerated approval program for cancer drugs. The goal of the accelerated program is to provide novel and promising treatments to patients faster than through the traditional, longer route to FDA approval. Successful accelerated approval drugs include Gleevac, the oral drug for chronic myeloid leukemia, as well as most HIV treatments.
 
Accelerated approval is granted based on a surrogate endpoint study rather than the gold standard of overall survival, bona fide clinical efficacy, or quality of life improvement. Surrogate endpoint trials are generally faster than the traditional efficacy trials that are required for full drug approval because the surrogate endpoints are typically laboratory readouts that are available before direct measure of effectiveness.
 
Subsequent to an accelerated approval, drug makers are required to confirm clinical efficacy and demonstrate drug safety with post-marketing trials called Phase 4 confirmatory trials. If the drug does not live up to its anticipated clinical benefit, the FDA can use an expedited procedure to withdraw the drug from the market.
 
Last week’s meeting was prompted by the recent decisions to remove the breast cancer indication from Roche's cancer drug, Avastin, and Mylotarg, Pfizer’s drug for acute myeloid leukemia (AML) from the market. Accelerated approval is based on likely, but not yet proven clinical benefit. Therefore, the right surrogate marker study is crucial, as is the post-marketing effectiveness trial. The panel discussed both the design of trials required for accelerated approval as well as post-marketing studies. The committee debated whether a randomized, two-arm trial rather than a single-arm trial should be required in certain accelerated approval cases. The committee also discussed whether a minimum of two post-marketing trials is necessary and whether accelerated approval should be delayed until the confirmatory trials are actually underway. Ideally, the FDA Office of Oncology would like drug makers’ to have confirmatory trials underway, with set completion dates, at the time of accelerated approval.
 
Two years ago, the breast cancer indication for Avastin was approved under the accelerated program, however the FDA officially announced its recommendation to remove the breast cancer indication from Avastin’s label in December 2010, following an independent advisory committee’s 12-1 vote for indication removal. The greatest benefit that breast cancer patients have seen on Avastin is improvement in progression-free survival by a few months when the drug is combined with chemotherapy. Genentech responded to the FDA in January 2011 with evidence the company says demonstrate why the label should stay in place and has requested an FDA hearing. The company is still awaiting a response.
 
Within weeks of the Avastin advisory committee decision, the FDA suggested that Pfizer pull the plug on its AML drug, Mylotarg when the results of a 4-year trial that started after Mylotarg’s accelerated approval not only showed a lack of benefit but a significant number of patient deaths. Mylotarg was approved in 2000 when the drug was seen as having high efficacy potential for the devastating cancer. The accelerated approval was contingent upon Pfizer following through with a controlled post-marketing study. The drug company did not begin the study until 2004, and in 2008, the final results showed that Mylotarg’s efficacy potential was not realized.
 
The goal of the ODAC is not to remove the accelerated program but to improve the regulation, design, and conduct of the trials required for accelerated approval and for confirmatory trials. One reason for the debate is to prevent such practice as Pfizer’s 4-year delay in initiation of the Mylotarg post-marketing trial. If the FDA is able to put forth more stringent rules about accelerated approval trial design and enforce the timely execution of Phase 4 trials, this should, at least in theory, allow necessary access to promising medication while decreasing the time an ineffective treatment stays on the market.