Why is the Food and Drug Administration (FDA) issuing this information sheet?

FDA recently notified two manufacturers of its intent to formally propose to withdraw the HDE marketing approvals for two patent foramen ovale (PFO) occluders previously approved for the treatment of patients with recurrent cryptogenic (of unknown cause) stroke due to presumed paradoxical embolism through a PFO and who have failed conventional drug therapy; that is, patients who have had at least one additional stroke despite treatment with appropriate medications. The devices affected are the NMT Medical CardioSEAL® STARFlex ™ Septal Occlusion System and the AGA Medical AMPLATZER® PFO Occluder. On August 14, 2006, both manufacturers agreed to voluntarily withdraw their HDEs, effective October 31, 2006.

Although these devices will not be available for marketing once the HDEs are withdrawn, FDA wants physicians and patients to know that patients who currently meet the approved HDE indication will continue to have access to these devices through an FDA-approved Investigational Device Exemption (IDE) at health care facilities across the United States. FDA encourages Institutional Review Boards (IRBs) at these facilities to consider the proposed IDE protocols in an expedited manner when possible. For contact information, see “ Whom should patients and physicians contact to get more information about treatment with a PFO Occluder?” below.

What is a PFO and what is a PFO Occluder?

A PFO is a tunnel-like opening between the two upper chambers of the heart, the right and left atria. This opening is formed during the development of the heart in utero, and in most people, closes naturally after birth. In as many of 25% of people, however, the opening does not close completely. A PFO occluder is a device that is advanced into the heart through a catheter placed in a vein in the groin. The occluder closes the PFO and is a permanent implant that stays in the heart after the procedure.

What is an HDE?

Humanitarian Device Exemptions (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. FDA has granted two HDEs for PFO occluders. HDEs are a mechanism to encourage development of medical devices for rare conditions. They allow companies to market such devices so long as they are shown to be safe and have probable benefit. Devices that do not qualify for approval in an HDE application only reach the consumer after FDA has reviewed data demonstrating safety and effectiveness-- typically through long-term clinical studies.

In order to receive an HDE approval, a manufacturer must:

• First be granted a Humanitarian Use Device (HUD) designation by FDA’s Office of Orphan Products (OOPD) by demonstrating that the device is designed to treat or diagnose a disease or condition that affects or is manifested in fewer than 4,000 people in the U.S. per year.
• Submit an HDE application in which the manufacturer demonstrates the safety and probable benefit of the device in this population.

After FDA approval of an HDE, the IRB for a hospital or other health care facility must also approve use of the device at that institution before the device can be used in a patient.

For more information on HUD designation or HDE approval, please see Humanitarian Use Devices (HUDs).

Why did FDA propose to withdraw the HDEs?

Our regulations provide that sponsors of HDE devices must annually demonstrate continued compliance with the criteria for HUD designation after an HDE has been granted (21 CFR 814.126 (b)(1)(i)), including the criterion that the target population for use of the devices be 4,000 or fewer individuals annually. These regulations authorize FDA to withdraw an HDE approval if a device no longer meets the eligibility requirements.

After FDA’s most recent review, FDA concluded that the patient population described by the approved indication (patients with recurrent cryptogenic stroke due to presumed paradoxical embolism through a PFO and who have failed conventional drug therapy) is significantly in excess of 4,000 patients in the U.S. per year. This finding means that these devices are no longer eligible for HUD designation and therefore, no longer eligible for marketing under an HDE.

Given the larger number of patients eligible for the device, FDA 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.

How will FDA assess the safety and effectiveness of PFO occluders in patients with cryptogenic stroke?

There are several ongoing clinical trials to evaluate the safety and effectiveness of PFO occluders in patients who have had a single cryptogenic stroke and have a PFO. These studies are comparing implantation of a PFO closure device to drug therapy. When one or more of these trials is completed, FDA would expect to review an associated Pre-Market Application (PMA) under expedited timelines, in order to allow device(s) that have been shown to be safe and effective to be widely available for patients for whom the device is indicated as soon as possible.

If a patient previously had a PFO occluder implanted, should he/she be concerned?

FDA does not have any new safety concerns about previously placed devices. Patients should continue regularly planned follow-ups with their treating physicians.

 Whom should patients and physicians contact to get more information about treatment with a PFO Occluder?

More information regarding the NMT Medical CardioSEAL® STARFlex™ Septal Occlusion System is available on the NMT Medical, Inc. Web site. More information regarding the AGA Medical AMPLATZER® PFO Occluder is available on the AGA Medical Corporation's Web site.

Patients and physicians can also contact FDA:

Ashley Boam Chief, Interventional Cardiology Devices Branch [email protected]

Elisa Harvey, D.V.M., Ph.D Director, IDE/HDE Staff [email protected]

Office of Device Evaluation
Center for Devices and Radiological Health