PFO FDA Considerations for Labeling and Future Trials Andrew Farb, MD Division of Cardiovascular Devices Center for Devices and Radiological Health (CDRH) Food and Drug Administration andrew.farb@fda.hhs.gov Monday, February 20, 2017 7 mins 12:30 PM - 12:37 PM Room: Blue CRT Valve & Structural – FDA CRT 2017 Washington, DC February 20, 2017

Disclosures No conflicts of interest to report

FDA Device Labeling Considerations Indications for Use Identifies the clinical condition in the target population in which the device will provide clinically significant results without an unreasonable risk of illness or injury Other sections of the label include contraindications, warnings, precautions, adverse events, clinical studies (design and outcomes), and directions for use For the Amplatzer PFO Occluder, approved 28 October 2016, labeling reflects the RESPECT trial investigational plan and outcomes

AMPLATZER PFO Occluder Approved Indications for use: For percutaneous transcatheter closure of a PFO to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke

RESPECT Primary Endpoint ITT Population For percutaneous transcatheter closure of a PFO to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke Initial Data Lock Extended Follow-up RESPECT Primary Endpoint ITT Population Rate per 100 pt-yrs Device MM 0.61 1.25 Rate per 100 pt-yrs Device MM 0.65 1.01 Although the raw count analysis in the ITT population was the pre-specified primary analysis, recall that there was differential follow-up between treatment groups driven by a substantially larger number of MM subjects that withdrew from the trial. Therefore, event rates per pt-yr follow-up and Kaplan Meir estimates provide additional insights into the strength of the evidence supporting or not supporting a benefit of PFO closure and the magnitude of any potential benefit. In the initial data lock, the observed event rates per 100 pt-yrs in both treatment groups (shown in the Table on the left) were small and numerically favored the Device group, 0.61 vs. 1.25. In the K-M plot on the left, one can appreciate curve separation starting at around 1.5 years, with overlap of the 95% CIs. The HR is 0.50 with a wide CI, 0.22 to 1.13, and The p—value is non-significant at 0.089. With extended F/U on the right, it’s important to note that the event rate has dropped in the MM group to 1.01, and the difference between treatment groups has narrowed. In the K-M plots on the right, the event curves approach each other, raising a question about the durability of any potential Device benefit It is important to understand the benefit of PFO closure in context of an overall low risk of recurrent stroke (0.61 per 100 patient-years and 1.25 per 100 patient years in the device and MM groups, respectively) and a number needed to treat with the device of 27 to prevent one recurrent stroke at 5 years. An extended follow-up analysis (mean follow-up of 5.5 years in the device group and 4.9 years in the MM group) showed a 35% relative risk reduction in favor of the device group (recurrent stroke rate 0.65 per 100 patient-years vs. 1.01 per 100 patient years in the device and MM group, respectively) with a number needed to treat of 43 to prevent one recurrent stroke at 5 years NNT = 27 NNT = 43

Medical Management (N=481) For percutaneous transcatheter closure of a PFO to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke RESPECT trial age exclusion criterion Age <18 years to >60 years RESPECT Enrollment   PFO Occluder (N=499) Medical Management (N=481) Age, years 45.7 (9.7) 46.2 (10.0)

RESPECT trial elements For percutaneous transcatheter closure of a PFO to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke RESPECT trial elements Work-up guided by a neurologist and cardiology Qualifying stroke confirmed by a neurologist PFO confirmed by TEE So in thinking about the utility of PFO closure to prevent recurrent stroke, one should appreciate that RESPECT subjects were evaluated by a neurologist …and were highly selected to exclude patients who had a potential underlying cause of stroke based on a planned comprehensive neurologic and cardiovascular evaluation

Non-PFO cardioembolic sources, aortic arch atheroma For percutaneous transcatheter closure of a PFO to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke Evaluation Rule Out TEE Non-PFO cardioembolic sources, aortic arch atheroma Prolonged heart rhythm monitoring AFib MRI/CT Small vessel disease, lacunar infarct, non-stroke lesions Intra and extracranial artery imaging (MRA, CTA or contrast angiography) Atherosclerotic plaque, arterial dissection, other vascular diseases Hematological evaluation Hypercoagulable state The Baseline Screening Tests for Cryptogenic Stroke Determination required a neurologist-investigator evaluating the qualifying stroke with testing that included a TEE…ECG or Holter monitor…Brain MRI or CT….Comprehensive Imaging of the intra- and extracranial arterial circulation via MRA, CTA, or contrast arterial angiography, transcranial Doppler, and/or carotid duplex ultrasound… and screening for an underlying Hypercoagulable state RESPECT Baseline Screening Tests for Cryptogenic Stroke Determination Patient Selection for Treatment section of the IFU

Ongoing and Future Pivotal Trials PFO occluder vs. medical therapy Test PFO occluder vs. approved PFO occluder PFO closure “tool claim” studies not adequate to support use to reduce the risk of recurrent stroke

Ongoing and Future Pivotal Trials Test Device Control PFO occluder Medical therapy

Ongoing and Future Pivotal Trials Test Device Control Endpoint (Statistical Testing) PFO occluder Medical therapy Safety: Device, procedure, and medical therapy-associated SAEs Effectiveness 1: Recurrent stroke (superiority) Effectiveness 2: PFO closure rate Ongoing randomized trials REDUCE (ClinicalTrials.gov Identifier: NCT00738894) CLOSE (ClinicalTrials.gov Identifier: NCT00562289)

Ongoing and Future Pivotal Trials Test Device Control PFO occluder Approved PFO occluder

Ongoing and Future Pivotal Trials Test Device Control Endpoint (Statistical Testing) PFO occluder Approved PFO occluder Safety: Device and procedure-associated SAEs (superiority or non-inferiority) Effectiveness 1: Recurrent stroke (superiority or non-inferiority) Effectiveness 2: PFO closure rate (superiority or non-inferiority)

Ongoing and Future Pivotal Trials Test Device Control Endpoint (Statistical Testing) PFO occluder Approved PFO occluder Safety: Device and procedure-associated SAEs (superiority or non-inferiority) Effectiveness 1: Recurrent stroke (superiority or non-inferiority) Effectiveness 2: PFO closure rate (superiority or non-inferiority) FDA not ready for PFO closure tool claim pivotal studies Non-inferiority margin needs to avoid outcome drift such that a “win” for the new device allows for an event rate that is greater than a putative medical therapy control Safety events of interest: AFib and venous thromboembolism

Parting Thoughts A systematic assessment of underlying conditions and risks associated with ischemic stroke, guided by a neurologist and cardiologist, is needed in all patients who have a PFO. When determining whether to pursue device closure of a PFO, clinicians should understand the strengths and limitations of available clinical trial data, and engage in benefit-risk discussions with their patients. Interactions with FDA recommended to reach consensus on study designs to evaluate new PFO closure devices.

Outline • RESPECT trial results in perspective • Crafting the label to guide the selection of appropriate patients • Neurology community views appreciated • Future trials: Device vs. device, device vs. OMT, S&E considerations