Edwards Lifesciences’ Sapien transcatheter aortic valve met widespread expectations last week by gaining support for FDA approval from an agency advisory panel, but the experts urged FDA and Edwards to proceed cautiously.

In particular, members of FDA’s Circulatory System Devices panel said they wanted to ensure that the technology doesn’t reach too many patients too quickly and that the apparent risk of stroke associated with the breakthrough device is clearly communicated to doctors and patients.

Panelists and speakers at the meeting emphasized the complexity of the procedure and the need for close collaboration between interventional cardiologists, surgeons and other specialists to perform it effectively.

Such caution urged by the medical community leading up to the panel has already convinced Edwards to reduce the number of new U.S. centers (in addition to the approximately 25 pivotal trial centers) at which it plans to introduce Sapien during its first year on the market. Last year, it suggested 200-400 centers; now the target is 150-250 new centers where a heart team of cardiologists and a cardiac surgeon will be trained on the procedure.

“I’m strongly in favor of very tight controls on this as a rollout, not only to protect patients, but also to ensure that this device has the highest likelihood of success,” said panel member Norman Kato, a cardio-thoracic surgeon at the Cardiac Care Medical Group, in Encino, Calif.

Broad Agreement That Benefits Outweigh Risks

During the July 20 meeting in Gaithersburg, Md., the panel voted nine to zero (with one abstention) that the benefits of the Sapien valve, delivered via the femoral artery, outweigh the risks for patients with severe aortic valve disease deemed too sick to undergo conventional open heart valve replacement.

Due to the higher incidence of strokes reported in the Sapien-treated patients in the pivotal trial, panel members voted seven to three that the device was reasonably safe and nine to one that the device was reasonably effective.

Edwards’ CEO Michael Mussallem says the firm remains confident that Sapien will gain FDA approval for inoperable patients by October. The company is also sticking with its revenue guidance of $150-$250 million in the first year, Mussallem noted during the company’s July 21 second-quarter earnings call. He pointed out that although fewer centers will be trained on the procedure, there is an expectation that more patients will be treated per center.

Edwards’ Sapien transcatheter aortic valve is delivered via the femoral artery. (Photo: Edwards Lifesciences)

Edwards’ Sapien transcatheter aortic valve is delivered via the femoral artery. (Photo: Edwards Lifesciences)

Still, the CEO acknowledged the significant caution expressed by panel meeting participants.

“The FDA panel extensively explored a number of questions regarding the therapy’s complications and introduction pace, and we take their concerns seriously,” Mussallem said.

If Edwards’ PMA application is approved, Sapien would be the first percutaneous aortic heart valve to reach the U.S. market, a potential major new growth driver in the device space. It would also be years ahead of its next competitor, Medtronic ( CoreValve ), in reaching the U.S. market.

The panel reviewed data from the 358-patient cohort B of Edwards’ PARTNER trial, which showed a substantial survival benefit – 69.3% versus 50.3% – for patients treated with Sapien compared to those treated with standard medical therapy. (See “ Also see "Edwards' Sapien Valve: Big Survival Boost In Those Too Sick For Surgery" - Medtech Insight, 27 September, 2010. ” – “The Gray Sheet” Sept. 27, 2010.) The cohort A segment of the trial, directly comparing Sapien to open surgery in high-risk patients, is addressed in a separate PMA submission, for which Edwards hopes to gain approval in 2012.

Registry, Post-Approval Studies In The Works

Typically, FDA’s principal means of restraining adoption of new technologies is through labeling restrictions and various post-approval requirements including studies and training mandates.

There was lengthy discussion on the labeling front during the panel, but in the end the advisors did not recommend anything very significant.

Of note, the panel discussed revising Sapien’s indication for use statement to call for two cardiac surgeons to agree that a patient is truly too frail to undergo open heart valve surgery, but ultimately they decided to keep it at one. They did recommend making minor wording changes to the indication statement by adding that the device should be used to treat “symptomatic, native” aortic valve stenosis.

Post-approval data collection requirements were also a major point of focus, and based on the panel discussion, there will likely be several different post-market studies.

The Society of Thoracic Surgeons and the American College of Cardiology are working together to establish a mandatory patient registry for post-market surveillance of the Sapien device, long-term outcomes measurement and comparative effectiveness research.

The registry would collect a broad range of data points on aortic valve disease patients in a linked STS/ACC database. The goal would be to track all transcatheter valve procedures in the U.S. and construct a risk prediction model for the procedure, officials from the societies explained during the meeting.

The panel members supported the mandatory registry. But many also argued that there was a need for the types of data that can only be collected in more formalized studies. Thus, the registry should be created on top of the two post-approval studies proposed by Edwards, they noted. Other panel members and observers, however, questioned whether a new post-approval study would be needed alongside the proposed registry.

“A registry would represent the real-world adoption rather than a post-study design with inclusion, exclusion criteria. I think this post-market study is a little bit overkill,” said Ron Waksman, associate director of the Division of Cardiology at Washington Hospital Center, in an interview following the panel meeting.

Edwards’ two proposed post-approval studies include an extended follow-up of the PARTNER cohort B patients and a 750- to 1,000-patient new-enrollment observational study.

The PARTNER follow-up would include all inoperable randomized and continued access patients and would involve annual clinical and echocardiogram checks and quality-of-life measurements for five years.

The new-enrollment study would also include five years of follow up. The panel recommended that this study include rigorous data collection at 75 centers, with safety and effectiveness time points at 30 days and at one year.

“I think a great deal of information in future studies and post-marketing studies needs to be devoted to the better understanding of the impact of stroke” – Jeffrey Borer, cardiologist

Edwards’ Mussallem suggested that the development of these two studies is significantly farther along than that of the registry.

“There is a lot to be done between where we are right now and a registry that would really accomplish all the goals,” he said during the July 21 earnings call. “We are currently working with FDA on a post-approval study, and the registry really doesn’t exist yet.”

Stroke Risk Emphasized

One issue that most everybody agreed with on the panel regarding post-approval data collection was the need to dig further into the stroke risk associated with transcatheter valves.

The significantly increased stroke rate observed in the Sapien group compared to control in PARTNER was a topic of heated discussion among panel members. Based on FDA analysis of the trial results, the rate of stroke in the Sapien group was 4.5 times higher than the control group during the first 30 days, when more half of the strokes occurred.

The majority panel concluded that the increased rate of stroke was clinically significant, but that it did not overwhelm the great benefit from this procedure in the inoperable population that was studied.

“From the data we have right now, for this population which wouldn’t be expected to live a long time and might not suffer the impact of the multiple small lesions before death, I think the stroke issue is reasonably dealt with, but just for this population,” said Jeffrey Borer, chief of cardiovascular medicine at the State University of New York.

Such caveats suggest the stroke issue could play an even more pronounced role in consideration of the PARTNER cohort A PMA, for patients for whom surgery remains a viable option. Stroke rates were higher in cohort A data for Sapien compared to surgery.

The panel stated that the impact of stroke on the patient population needs to be correlated to the patient’s quality of life. Ultimately, undergoing the procedure improves quality of life, as long as the risk of stroke is mitigated, Borer suggested.

“I’m not so concerned about whether the mortality benefit is large or small; I don’t think in this patient population it’s the primary concern. I think the primary concern is quality of life. I’m concerned about strokes, but I think the preponderance of data suggest the quality of life is more likely to be improved for a patient that undergoes the procedure than not,” Borer said.

In any case, both the panel and FDA agreed that the causality of stroke needs to be further researched.

“I think a great deal of information in future studies and post-marketing studies needs to be devoted to the better understanding of the impact of stroke,” Borer said.

This includes Edwards’ post-approval studies, where stroke and other “neurological events” will likely be closely tracked.

Panel members also advised that the data safety monitoring board for the post-approval studies include a neurologist, a specialty that was not represented on the board for the pivotal trial.

Additionally, the panel supported a new anticoagulation/antiplatelet protocol proposed by Edwards for the new-enrollment post-approval study as a potential strategy to address stroke risk. It also recommended establishing the drug protocol for all patients who receive Sapien.

One panelist, David Slotwiner, a cardiologist at the Long Island Jewish Medical Center, recommended that FDA encourage the use of distal embolization protection devices in the post-market study as well.

Edwards acquired an embolic protection technology designed for aortic valve procedures in March. (See “ Edwards Lifesciences Grabs Embrella ” – “The Gray Sheet” March 21, 2011.) The firm said July 21 that it plans to initiate a trial in Europe by the end of the year to test whether the Embrella protection device improves Sapien outcomes.

But the company, panelists and FDA acknowledged that they do not know exactly what is causing the stroke rates and thus can’t know exactly how to reduce the risk.

Julie Swain, a cardiovascular surgeon in the Circulatory, Support & Prosthetics branch of CDRH, said the reasons for stroke are “multi-factorial.”

She alluded to a recent analysis of the cohort A data suggesting no neuroprotective benefit from implanting Sapien via the transapical, rib cage, route. (See “ Also see "Sapien Stroke Discussion Continues With Expanded PARTNER Analysis" - Medtech Insight, 16 May, 2011. ” – “The Gray Sheet” May 16, 2011.)

“If we thought it was just going around the aorta, then you’d expect transfemoral or transapical to have a big difference. We just don’t have the answer on strokes,” she said.

Clearer Warnings Needed

The panel also stressed that the stroke rate needed to be better emphasized in the patient brochures and the label warnings, which should include definitions of “neurological event” versus “stroke.”

“The brochure needs major modification; stroke is really down-played. If I were a person reading this, I’d have no impression that the risk of stroke is as high as it is. It definitely needs to be emphasized,” said David Good, a neurologist at Penn State Hershey Medical Center.

Valluvan Jeevanandam, a cardiac surgeon at University of Chicago Medical Center, added that stroke should be “isolated, bolded and put up front” in the label warnings.

By Rebecca Kern

Panel Supports Sapien But Urges Cautious Rollout

More from Archive

More from Medtech Insight