Medical Device Daily Associate

After the FDA recently notified NMT Medical (Boston) and AGA Medical (Golden Valley, Minnesota) of its intent to formally propose to withdraw the Humanitarian Device Exemptions (HDE) marketing approvals for those companies' two patent foramen ovale (PFO) occluders – previously approved for the treatment of patients with recurrent cryptogenic stroke – both firms have agreed to voluntarily withdraw their marketing approvals under that designation.

The devices affected by the reclassification are NMT's CardioSEAL STARFlex septal occlusion system and the AGA Amplatzer PFO occluder.

The companies agreed on Aug. 14, to the voluntary withdrawal, which becomes effective on Oct. 31.

In a press statement, the FDA assured physicians and patients that those who currently meet the approved HDE indication will continue to have access to these devices through an FDA-approved investigational device exemption (IDE) at healthcare facilities across the U.S.

The FDA said it encourages institutional review boards at these facilities “to consider the proposed IDE protocols in an expedited manner when possible.”

HDEs are a special type of marketing approval granted for devices intended to treat fewer than 4,000 people a year in the U.S., and the FDA uses them as a mechanism to encourage development of medical devices for rare conditions. Companies are allowed to market devices under an HDE so long as they are shown to be safe and have probable benefit.

Given the larger number of patients eligible for the device, the FDA said it believes that the devices should be subject to the same requirement that applies to all class III (highest risk) devices that do not meet the narrow criteria for the HDE, namely, a demonstration of reasonable assurance of both safety and effectiveness, not just safety and probable benefit.

One of the companies, NMT, said it sees the FDA action as a mostly positive step for the use of the technology in the treatment of cryptogenic stroke.

The company said that the FDA made the decision because it believes that since the HDE was approved back in 2000, clinical conditions have significantly changed and the subset of patients who once qualified for consideration for PFO closure has increased beyond the 4,000-patient threshold.

NMT stressed that the withdrawal does not reflect a device safety issue. It also noted that the CardioSEAL will continue to be commercially available in the U.S. under a pre-market approval (PMA) indication for ventricular septal defects.

In conjunction with the decision, the company said it also received FDA approval for a new PFO/stroke IDE called CARS (Closure After Recurrent Stroke). NMT said the CARS IDE will supplement its ongoing CLOSURE I clinical trial to evaluate the connection between PFO and stroke.

The company will provide eligible patients of both CARS and CLOSURE I with NMT's newer STARFlex implant technology. Patients previously covered by the HDE only had access to NMT's original CardioSEAL device.

While the CARS IDE will provide continued PFO closure access to certain patients who previously were eligible for treatment under the HDE, it noted that patients in the CLOSURE I trial receive the implant at no cost, while those covered under the new CARS IDE can be charged for the device.

“Approval of the CARS IDE, combined with our ongoing CLOSURE I trial, allows the company to maintain two sources for PFO closure in the United States,” said John Ahern, president/CEO of NMT in a company statement. “We remain focused on our stroke/transient ischemic attack (TIA) objective to complete CLOSURE I and become the first company to gain PMA for these indications – a potential market of 250,000 U.S. patients annually,” he added.

Both companies have spent several years trying to enroll patients that have suffered an embolic stroke and have been found to have a PFO in trials – NMT with the 1,600 patient CLOSURE 1 trial and AGA with its 500 patient RESPECT (Randomized Evaluation of Recurrent Stroke comparing PFO Closure to Established Current Standard of Care Treatment) trial – and both have experienced significant delays in completing enrollment. The HDE approvals – specifically for the treatment of patients with recurrent cryptogenic stroke due to presumed paradoxical embolism through a PFO and who have failed conventional drug therapy – were viewed as a stepping stone towards the ultimate goal of the slow-in-coming ischemic stroke indication

Ahern had an answer for that as well – saying that his company “continues[s] to work with our investigators, the clinical community and the FDA to make changes to the CLOSURE I study design in order to accelerate patient enrollment.” He added that the company “anticipates a shift of some recurrent stroke patients with PFOs to the CARS IDE from the original HDE since patients will have access to the new STARFlex technology.”

While he was mostly upbeat about what the designation change would mean for the PFO technology, he acknowledged that at this time “it is difficult to determine the impact on product revenue in the U.S. as a result of the transition from paid-for HDE devices to the paid-for devices under CARS.”

That said, he also feels that the new CARS IDE “is a significant competitive achievement for NMT and is necessary to accommodate the growing demand for more advanced PFO/stroke treatments.”