Two years ago, the FDA approved Avastin to combat breast cancer, even though an advisory panel determined that risks such as high blood pressure and death outweighed the benefit of slowing the spread of tumors. The agency, however, acted under its accelerated approval program and the move pumped up sales of a Roche drug that is also used to treat brain, lung and colon tumors.
Now, though, Avastin is on trial again. Another FDA panel today will decide whether use of the $50,000-a-year med should be continued, expanded, or halted after two studies - which were undertaken as a condition of approval - found patients given Avastin and chemotherpay didn't survive longer than those given chemo alone. And Avastin patients also suffered more serious side effects.
This is the second time in recent weeks that a drug approved as part of the FDA's accelerated approval program is being scrutinized anew. Last month, Pfizer withdrew Mylotarg, a drug used to treat acute myeloid leukemia, or AML, at the agency's behest after a study, which was begun four years after approval, found a lack of clinical benefit and an unexpected number of deaths (back story).
These back-to-back episodes are casting a spotlight on the accelerated approval program, which some say is working. "I think it has done what it set out to do: get drugs to market faster with less evidence than is typical and confirmed a drug's risk-benefit profile once more evidence becomes available," says Ramsey Baghdadi of Prevision Policy. "Every so often, that evidence turns out unfavorable for the drug in question...overall, I think it has achieved what it was supposed to do."
Nonetheless, we asked the FDA about the extent to which the program is being reviewed. In response, Richard Pazdur, who heads the Office of Oncology Drugs, wrote to say the agency will be asking drugmakers to provide required confirmatory studies, not just accelerated approval studies, (see here) and completion dates, as well. And since these trials are expected to be under way at the time of approval, any delays would have to be explained.
All this should occur "definitely before or at the end of Phase II meetings. These plans should include populations to be studied, planned enrollment, and estimated completion dates and any anticipated effect that the accelerated approval would have on the completion of confirmatory trials," he writes, adding drugmakers "strongly" encouraged to have more than one study serve as a confirmatory trial. And they should be prepared to add trial sites, if necessary, to meet their promised schedules.
But what if a drugmaker fails to pass muster? What kind of stick does the FDA have to work with? The agency could impose penalties and withhold approval, according to Tamy Kim, associate director regulatory affairs in the OCD. "We could make it a requirement that, if they don’t have a confirmatory trial or even plans under way, it would be a condition of approval," she tells us. "...Since the FDAAA was passed in 2007 and implemented in 2008, there’s a provision that states if a sponsor doesn’t conduct a confirmatory trial under subpar H with due diligience, it would be violation of the post-marketing requirement...These give us greater teeth than we had before." She adds, however, this is just now being considered.
As for the carrot, Pazdur notes the agency has exercised "regulatory flexibility" in allowing confirmatory trials to be conducted in "a different setting" than the approved indication. So if a trial turns out positive, it would not only satisfy the subpart H (or subpart E for biologics) requirement, but also effectively serve as a new marketing application for a supplemental NDA or BLA.
Just how fast the OCD will move is unclear. Pazdur says he plans to hold oncology drugs advisory committee meetings (that's meetings, not a meeting) to discuss the subpart H commitments, and the possibility of a yearly meeting to review confirmatory trials is being discussed. But no, accelerated approval is not being eliminated.