To prompt drugmakers to follow through more quickly on post-marketing studies required as part of the controversial acceleted approval program, several FDA officials suggest the agency make use of an existing provision of a 2007 law - issuing fines of up to $10 million. And the FDA may also require post-marketing studies get under way before expedited approval is granted, according to agency officials who floated the possibilities in a new article in the Journal of the National Cancer Institute.
The tougher approach for oncology meds is being considered in the wake of considerable handwringing after two episodes last year that questioned the veracity of the FDA accelerated approval program. Last June, Pfizer withdrew a drug used to treat acute myeloid leukemia, or AML, after a study found a lack of clinical benefit and an unexpected number of deaths. But the study didn’t get under way until four years after approval was granted in 2000 (back story).
Last December, the FDA decided the breast-cancer indication for Roche’s Avastin should be withdrawn after studies found patients on the med and chemotherpay didn’t survive longer than those given chemo alone. And Avastin patients suffered more serious side effects. The decision, which Roche and its Genentech unit are appealing, amounted to an about-face, given that the FDA endorsed the indication in 2008 under accelerated approval (see this).
Subsequently, the FDA’s Oncologic Drugs Advisory Committee urged the FDA to require drugmakers to submit at least one controlled trial for approval for their cancer meds. That's because more than half of the drugs passing through accelerated approval do so by relying on a single-arm trial. And the FDA panel was concerned that drugmakers are failing to conduct required post-marketing studies to verify surrogate endpoints on a timely basis, undermining the accelerated approval program.
The FDA authors agreed, writing that "such a requirement would ensure that accelerated approval is part of the development plan of a drug for a new indication and not an afterthought." They noted that from December 1992 to July 2010, the FDA granted accelerated approval of 47 new indications for 35 anticancer drugs. Of the 47 accelerated approvals, 19 were based on randomized comparative trials and 28 were based on single-arm trials. But as of last July, follow-up studies were not yet finished for 14 drugs that were granted accelerated approval i nthe past 12 years, they wrote (read the abstract).
Despite the criticisms, the FDA officials noted in their article that the median time between accelerated approval and regular approval of oncology meds was 3.9 years, while the mean time was 4.7 years, "representing a substantial time savings in terms of earlier availability of drugs to cancer patients." Still, they conclude that "indications that have received accelerated approval should not be on the market for unacceptably prolonged intervals in the absence of completed confirmatory trials.” The authors include John Johnson, a clinical team leader at the agency’s Division of Drug Oncology Products, and Richard Pazdur, who heads the FDA's Office of Oncology Drugs.
But forcing drugs to be withdrawn is not desirable, they maintain. "...removing a drug from the market solely because of lack of due diligence when the only available evidence of efficacy is that the drug is reasonably likely to have better clinical benefit than available therapy may be an appropriate sanction against the pharmaceutical company, but may not be in the best interest of cancer patients. Thus, this is not an attractive option and has never been done for an anticancer drug," they also wrote.
However, in an accompany editorial, Susan Ellenberg of the Department of Biostatistics and Epidemiology at the University of Pennsylvania School of Medicine, takes issue with the notion that the FDA could save time with the suggestions offered. "The time to complete a study aimed at achieving regular approval from the start would likely be far shorter than the time under the current scenario to complete an initial study to achieve accelerated approval plus the time to conduct a confirmatory story aimed at regular approval, unless (perhaps) the confirmatory study was a continuation of the initial study. Thus, the time to availability of a new drug, although undoubtedly shorter with accelerated approval as an option, may not be as impressive as Johnson et al suggest."