Shares of Edwards Lifesciences (NYSE:EW) slid 2.2% yesterday after an analysis published in the British Medical Journal claimed that "many" of the heart valve replacements using its flagship Sapien heart valve "cannot be justified" and leveled accusations of conflict of interest and unethical conduct against Edwards and Sapien inventor Dr. Martin Leon.
A trio of Belgian researchers said their "rigorous analysis of all the available data, in combination with a study of real world [transcatheter aortic valve implant] practice in Europe, led us to conclude that the arguments supporting the widespread use of TAVI do not stand up to scrutiny."
"In addition, the Partner trial seems to have important problems, the most relevant being publication bias and lack of data transparency, unbalanced patient characteristics, and incompletely declared conflicts of interest," wrote Hans Van Brabandt, Mattias Neyt and Frank Hulstaert, who were commissioned by the Belgian government to run the analysis.
Edwards shares closed yesterday at $101.20, down 2.2%, but gained some of that back with a $102.09 open and were up another 1.2% as of about 9:40 a.m. today.
The BMJ researchers wrote that Belgian health authorities should pay for only about 10% of the patients now considered for transcatheter aortic valve replacements in the lowland country – procedures using the Sapien heart valve and a competing device, Medtronic‘s (NYSE:MDT) CoreValve implant, should be limited to patients who aren’t good candidates for traditional open heart surgery. The CoreValve device is not yet approved for the U.S. market.
Edwards’ Partner trial for the Sapien valve was flawed due to potential bias on the part of Leon, according to the researchers. Leon founded a company to develop the implant that Edwards acquired in 2004, triggering a $6.9 million payout that was disclosed. But other milestone payments due to Leon were not disclosed, they wrote, creating "substantial financial interests that we do not believe were fully disclosed."
“We believe Dr. Marty Leon has conducted himself throughout the Partner trial in accordance with the highest ethical standards. In his role as co-principal investigator of the trial, he has only been reimbursed for travel-related expenses,” an Edwards spokeswoman told MassDevice.com in an email today. “Dr. Leon also has – throughout the Partner trial – remained in compliance with the strict conflict-of-interest standards of both the FDA and Columbia University. As previously reported, the sale of PVT to Edwards took place in 2004 and the single milestone payment (that Dr. Leon donated to charity) was made in 2006, well before the beginning of the pivotal trial.”
The Partner study was also biased by imbalance between the treatment and control groups in the TAVI cohort that favored Sapien, they wrote. But Edwards said those differences were "known, analyzed and discussed at the FDA panel that resulted in an overwhelmingly positive panel recommendation for FDA approval and was subsequently approved by the FDA in November 2011," according to an emailed statement.
Brabandt, Neyt and Hulstaert also claimed that repeated requests to Edwards and Leon for access to data from an FDA-ordered follow-on study of the Sapien device "went unanswered."
"In our view, this behaviour is both ethically and scientifically unacceptable and should be legally regulated in future [sic]," they wrote. "Study sponsors should be obliged to make the results of a negative trial public so that policy makers can reach rational and balanced decisions.”
Some of that data, from a 90-patient study of inoperable candidates, was presented at an FDA meeting in July 2011, according to the Belgian researchers. Those results demonstrated a higher risk of mortality after a year among the cohort treated with the Sapien valve (34.3% vs. 21.6%, they wrote).
"The data referenced by the authors of this editorial and presented at the July 2011 FDA panel meeting was a small subset of the large continued access protocol and is not powered and not statistically meaningful on its own," the Edwards spokeswoman told us in a separate email. "The continued access protocol of Partner Cohort B, which enrolled more than 1,800 patients, completed patient enrollment in January of this year. We expect the results from the continued access portion of the trial to be published in an appropriate peer-reviewed journal in 2013 when all patients have reached their 1-year endpoint."
The Belgian researchers also took a shot at the New England Journal of Medicine, which they approached after being rebuffed by Edwards and Leon. The NEJM editors passed the researchers’ "objections" on to the investigators, but the response convinced the editors that "while each of the points we raised deserved a thoughtful review, they did not, either individually or together, fundamentally place the findings of the Partner trial in serious doubt."
"NEJM has, however, published 2-year follow-up results that essentially confirmed the one year data. However, it did so without demanding that the study sponsor publish or discuss the negative results of the follow-on trial. It is difficult to understand this decision," the Belgian researchers wrote.
"Based on current evidence, and considering efficient use of limited resources, it is difficult to see how healthcare payers can justify reimbursing TAVI for patients suitable for surgery, given that the risk of stroke is twice as high after TAVI," the researches concluded. "In addition, TAVI is much more expensive, on average about €20,000 more per patient in our analysis of Belgian data. Based on observational data, the costs during the initial hospital admission, inclusive of an Edwards Sapien valve of €18,000, are on average €43,600 for TAVI versus €23,700 for surgical valve replacement."
Edwards said multiple studies have shown TAVI to be cost-effective.
"In Cohort B patients, published data in NEJM demonstrated TAVR was very cost-effective given the life years added and the quality of life improvements," according to an emailed statement. "For Cohort A, transfemoral access was shown to be more cost-effective than traditional surgery in this high risk patient population. While this was not demonstrated for transapical access, this is likely due to the small size of that cohort and the very early experience associated with the procedure. It is expected to improve in the larger continued access cohort."