Edwards Lifesciences is facing enrollment delays in its U.S. pivotal trial of a less invasive heart valve, though the company still says it will complete the patient sign-up effort by the end of next year.

Edwards, which leads the market for conventional open-heart surgery tissue valve replacement and repair, is facing increased competition. To pick up the slack, the firm is banking on getting a head start in cath lab-based valve replacements with its Sapien transcatheter valve.

The product is already being sold on a limited basis in Europe and sales are expected to pick up in the region next year, but FDA approval is still at least two years away (¹ 'The Gray Sheet' Sept. 10, 2007, In Brief).

Last week, Edwards disclosed some unexpected challenges in getting all 15 medical centers to begin enrollments in its 600-patient, pivotal PARTNER trial, in part due to delays with institutional review board approvals. The company has so far enrolled about 60 patients at about six centers.

FDA also is taking longer than expected to approve Edwards' request that centers be allowed to employ the Ascendra transapical valve delivery approach - inserting the valve through a small incision in the rib cage - as part of the study, Edwards notes.

Currently, FDA has only cleared Edwards to enroll patients in PARTNER who receive a Sapien valve by the transfermoral approach - percutaneously via the groin - which is a difficult access point for some patients. The agency is still assessing whether the transapical and transfemoral data can be pooled in a statistically sound manner, Edwards says.

"We are straining the limits of what we can do with femoral access no matter how carefully we screen patients," said Martin Leon, Columbia University, the principal investigator for PARTNER, at TCT Oct. 23.

Rib Cage Delivery Could Kick-Start Trial

PARTNER is a complex four-arm study in which patients who are surgical candidates are randomized to receiving either Sapien or a surgical valve, and patients who do not qualify for surgery are randomized to Sapien or medical management. The primary endpoint is all-cause mortality.

Leon, a leading interventional cardiologist, said a major challenge of the study is getting the different specialists involved to collaborate. "We have struggled to find 12 sites in the United States [the rest will be international] where we can actually get interventionalists and surgeons to sit in a room, talk about patients, and actually work together," he noted.

"It would help us enormously in terms of engagement with our surgical colleagues if we could more quickly generalize the transapical approach and provide that as another access possibility," Leon said.

Edwards CEO Michael Mussallem is hopeful that FDA will approve the transapical approach for the trial within the next few months, though the firm has not dismissed the possibility of needing a second trial. Mussallem says he expects all centers will be enrolling by the end of the year and enrollment will be completed by the end of 2008, with all patients followed for one year.

"We continue to believe our progress in the U.S. gives us a two-year lead over the next closest competitor," Mussallem said on the company's third quarter earnings call Oct. 22. CoreValve also is pursuing transcatheter valve development, but has yet to begin its pivotal trial.

Enrollment Is Not The Only Challenge

Assuming the enrollment issues clear up, it will not necessarily be smooth sailing. "We have real challenges in powering these trials for one-year outcomes when we don't know what those [outcomes] are for high-risk surgical patients and ... for nonsurgical patients," said Stanton Rowe, Edwards' corporate-VP for advanced technology, at TCT Oct. 23. "We are making best guesses," he added.

Meeting the all-cause mortality primary endpoint will be difficult since the study population consists of older patients who tend to have many co-morbidities. "We are already seeing that half of the deaths are co-morbidity-related," Leon said.

Overall success of the trial could depend in part on secondary endpoints, which include measures of valve performance and quality of life. At TCT, Matthew Hillebrenner, from the FDA device center's circulatory support and prosthetic devices branch, said it will come down to the "totality of data" on Sapien.

- David Filmore (d.filmore@elsevier.com)

Edwards Hits Snags With Trial Of Catheter-Delivered Heart Valve

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