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Regulatory Focus™ > News Articles > 2019 > 6 > FDA Panel Faces ‘Conundrum’ with Mortality Assessments on Paclitaxel-Coated Devices

FDA Panel Faces ‘Conundrum’ with Mortality Assessments on Paclitaxel-Coated Devices

Posted 19 June 2019 | By Ana Mulero 

FDA Panel Faces ‘Conundrum’ with Mortality Assessments on Paclitaxel-Coated Devices

Discussions at the first day of a two-day US Food and Drug Administration (FDA) advisory committee meeting cited a large amount of missing data and other flaws in conflicting analyses as barriers to finding a mechanism responsible for the increased late mortality rates linked to using paclitaxel-coated balloons (DCBs) and paclitaxel-eluting stents (DESs).

FDA officials, experts in the FDA-convened committee and industry agreed that limitations in mortality assessments remain, as the data analyses presented by the agency and the five manufacturers of their FDA-approved devices differed.

The panel will provide recommendations on the presence, magnitude and causality for the increased long-term mortality in peripheral arterial disease (PAD) patients treated with DCBs and DESs compared to patients treated with uncoated comparator devices. Yet missing data, including for pivotal randomized control trials (RCTs), additional RCTs outside of US (OUS), other paclitaxel-coated devices that patients may have received as well as registry studies, create difficulties to make informed decisions.

One issue is that only three trials having reached the five-year mark in the post-approval studies FDA mandated as part of the five devices’ conditional premarket application approvals between 2012 and 2018. Long-term follow-up data over 5 years are available for Cook Medical’s Zilver PTX DES, Bard’s LUTONIX DCB and Medtronic’s IN.PACT DCB but not for Philips’ Spectranetics Stellarex 035 nor Boston Scientific’s ELUVIA paclitaxel-eluting system.

Yet the panel has been presented with two different narratives. FDA concluded that the updated data show an increase in mortality between two to five years post-treatment, whereas manufacturers reported no significant mortality differences between patients treated with paclitaxel versus non-paclitaxel devices.

“The problem is that the numbers presented by industry and numbers presented by FDA are not the same,” said University of Pennsylvania Medical Center professor of medicine John Hirschfield. “We have a conundrum in terms of trying to decide what weight to place on each analysis that we see. I hope there is a way, it may not be feasible we get this achieved during this meeting, where we get a real common agreement of what the actual numbers are…so we know exactly what data we are dealing with.”

The agency reported needing further data analyses to help determine whether a biological mechanism is responsible for the increased late mortality rate, said FDA lead reviewer Eleni Whatley. Its analyses concluded that the currently available data may be insufficient for the panel to assess a potential late mortality signal to inform an FDA probe into the observed increased mortality rate.

Manufacturers, however, argued that FDA’s recent notices on the ongoing probe is impacting patient care and they called for safeguarding patients’ access to DCBs and DESs. Daniel Clair, an advisor to Medtronic and Boston Scientific and DCB consultant for Bard, noted that the impact of FDA’s January letter to health care providers “is significant” as “many clinicians, health care systems have unilaterally made the decision to withdraw these devices from their shelves.” And “for many physicians, the fear of potential lawsuits has led to these products being essentially unusable in the current environment.”

Clair further argued that PAD patients need DCBs and DECs. “The initial meta-analysis and follow up done by the FDA have flaws, which even the FDA has acknowledged in its communication.”

FDA’s analyses did not reflect all the updated information from the manufacturers. But panelist Bram Zuckerman, director at the Office of Cardiovascular Devices at FDA’s Center for Devices and Radiological Health, cautioned against using the manufacturers’ latest data.

“Industry has stepped up to the bar and this is a dynamic process,” he said. “However, I would be careful about utilizing the most up to date data analyses. They have not been checked by the FDA and I can say in general terms, because of a multitude of problems, the FDA has had a lot of back and forth with each company to verify data.”

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