The FDA’s Circulatory System Devices Panel gave the MitraClip clip delivery system (Abbott) a thumbs up on March 20 in its request for premarket approval, despite concerns detailed by the agency in its summary documents.

The panel voted 5-3 in favor, saying that the benefits outweigh the risks of the device, a percutaneously implanted mechanical clip for the reduction of mitral regurgitation. Abbott responded that it was "pleased" with the recommendation.

The FDA usually, but not always, follows the recommendation of its advisory committees.

The panel reviewed data from three trials, EVEREST II (Endovascular Valve Edge-to Edge Repair Study), EVEREST II High Risk and REALISM (Real World ExpAnded MuLtIcenter Study of the MitraClip System), which evaluated MitraClip therapy in high surgical risk patients with significant mitral regurgitation. The device is delivered to the heart through the femoral vein and is designed to reduce mitral regurgitation by clipping together a portion of the leaflets of the mitral valve to allow the heart to more efficiently pump blood.    

The committee’s recommendation was based on data on the safety of the procedure, reduction in mitral regurgitation, reverse left ventricular remodeling, heart failure symptoms, quality of life and rates of rehospitalization.  

In its memorandum, the FDA had outlined numerous concerns it had identified with the clinical evidence provided by Abbott. The agency argued that the EVEREST II randomized clinical trial failed to demonstrate “an appropriate benefit-risk profile when compared to standard mitral valve surgery in a selected mitral valve patient population” and that the EVEREST II High Risk Registry data were difficult to interpret.  

EVEREST II was designed to assess the safety and efficacy of the MitraClip system for patients with moderate to severe and severe mitral regurgitation. It included two arms: a randomized group and a High Risk Registry group.

“FDA believes that concerns related to the High Risk Registry [HRR] design and conduct are very significant,” according to the FDA document. “Using the HRR data alone, FDA is unable to determine that reasonable assurance of safety and effectiveness exists for the MitraClip CDS [Clip Delivery System] when used for the proposed indication for use in the designated target population.”

The agency also argued that REALISM High Risk was not designed to be a pivotal dataset and was difficult to interpret. “FDA believes that the number and severity of concerns related to the REALISM High Risk registry design and conduct are identical in nature and severity to those identified for the EVEREST HRR. These limitations make evaluation of whether there is a reasonable assurance of safety and effectiveness for use of the MitraClip device for the proposed indication and designated population challenging.”

In February 2012, the FDA conditionally approved the prospective, randomized, controlled, multicenter COAPT (Clinical Outcomes Assessment of the MitraClip Therapy Percutaneous Therapy for High Surgical Risk Patients) clinical trial to evaluate the safety and effectiveness of the MitraClip device in the treatment of symptomatic functional mitral regurgitation in patients who have comorbidities that put them at high risk for surgery.

COAPT’s primary safety endpoint is a composite of all-cause mortality, stroke, new onset or worsening of kidney dysfunction resulting in Stage 2 or 3 classification, left ventricular assist device implant and heart transplant at 12-month follow-up. The primary effectiveness endpoint is recurrent heart failure hospitalizations. The FDA described COAPT as a “reasonable pivotal trial” whose analysis may support PMA approval for heart failure patients with functional mitral regurgitation who are at extremely high surgical risk.

“FDA agrees this is a compelling population,” the agency wrote. “By definition, no current effective interventional or surgical therapy exists for this unfortunate and symptomatic group of patients. However, the effectiveness of invasive therapies in the treatment of these patients has not been demonstrated.”

Abbott Park, Ill.-based Abbott said it will continue discussions with the FDA as it assesses the device and that it expects a decision later this year. The MitraClip device received CE Mark in 2008 and is commercially available in Europe and other international markets. It is an investigational device in the U.S.