FDA Wants Longer Studies and Harder Endpoints for Drug-Eluting Stent Approvals

By Peggy Peck
ROCKVILLE, Md., March 26 -- The FDA proposed today that new drug-eluting stents accumulate at least 12 months of data, with twice that experience for a substantial number of patients, before the devices are submitted for approval.
Moreover, novel drug-eluting stents should be required to submit clinical data from at least one study that used a hard clinical endpoint from a study "appropriately powered for statistical demonstration of superiority or non-inferiority against an appropriate control." The preferred control should be a drug-eluting stent or a bare-metal device plus a drug-eluting stent.
Those recommendations, not unexpected, were included in a draft document that contains the FDA's new guidance to industry on the approval process for drug-eluting stents. The agency said it would consider comments on the proposal for the next 120 days.
The requirement for at least 12 months of clinical data is an increase from the nine months of data that were the basis of the FDA approval for the sirolimus-eluting stent (Cypher) and the paclitaxel-eluting stent (Taxus).
A zotarolimus-eluting stent (Endeavor) was approved last month, but all patients in clinical trials of that stent had at least one-year follow-up and the average follow-up was four years (See: FDA Approves Third Drug-Eluting Coronary Stent).
The FDA has been working on changes to the approval process since late 2006 when it convened a two-day advisory panel to review drug-eluting stent safety following a series of reports linking them to an increased risk of stent thrombosis (See: FDA Stent Panel Agrees that Benefits of On-Label Use Outweigh Risk).
The new document addresses several of the safety issues raised at the safety-panel meetings: reliance on angiographic endpoints rather than hard clinical endpoints, duration of dual antiplatelet therapy, trial design -- both pre- and post-approval -- and independent oversight of trials.
Among the new FDA recommendations:
Although nonclinical imaging endpoints such as late lumen loss and percent diameter stenosis are "potentially powerful effectiveness endpoints," they can only be used as the sole primary endpoint for iterative modifications of already-approved drug-eluting stents.
Angiography and IV ultrasound should "be captured in a study separate from the pivotal trial," or protocol-mandated angiography should be conducted after the 12-month clinical visit.
Secondary endpoints can include quantitative coronary angiography.
When using an unstudied drug with a drug-eluting stent, the sponsor should include liver enzyme values pre- and post-procedure, white blood cell counts, information on hypersensitivity reactions, ECG parameters, ECG changes (especially QT invervals), and data on concomitant medications.
The use of data-monitoring committees for all DES studies, called a strong recommendation, and when sponsors are conducting multiple studies the same data monitoring committee should monitor all studies.
The FDA also recommended standard post-marketing studies similar to the five-year follow-up it required when it approved the zotarolimus-eluting stent.