Dive Brief:

• FDA published results of a patient-level meta-analysis it says demonstrate a late mortality safety signal associated with paclitaxel-coated devices intended to treat femoropopliteal disease. Notably, the agency could not determine causality for the mortality rate increase and called for additional data to better understand patient sub-groups at greater risk. FDA also wants to update benefit-risk considerations for the class of devices.
• Expert advisors to the agency will consider the data at a panel meeting June 19-20. The agency will seek feedback on the clinical significance of the late mortality safety signal, if it represents a class effect for paclitaxel-coated devices, and the current benefit-risk profile of paclitaxel-coated drug coated stents and drug eluting stents.
• Five paclitaxel-coated devices with varying dosing levels are FDA-approved: drug-eluting stents from Cook Medical (Zilver PTX) and Boston Scientific (Eluvia), and drug-coated balloons from BD (Lutonix), Medtronic (In.Pact Admiral) and Philips (Stellarex).

Dive Insight:

FDA convened the advisory panel after a meta-analysis published December in the Journal of the American Heart Association observed an increased risk compared to patients treated with control devices such as non-coated balloons or bare metal stents.

In briefing documents posted ahead of the panel meeting, the agency was unable to determine an association between dose and mortality when conducting its independent analysis, but noted that the small sample size for many of the dose range groups limited its ability to interpret the data.

FDA said the LEVANT 2 randomized clinical trial of BD's device "suggested possible increased mortality with increased dose, while no clear relationship between dose and mortality was identified" in Zilver PTX RCT (Cook Medical), IN.PACT SFA I & II (Medtronic) and ILLUMENATE RCT (Philips). FDA said it did not include Boston Scientific's IMPERIAL study because it did not have an uncoated device control group.

All five companies that submitted panel briefings made similar statements concluding there was not sufficient evidence to blame paclitaxel for the heightened mortality signal.

“It remains questionable and unproven that the root cause of the observed higher mortality in certain retrospective meta-analyses has a direct relationship to the presence of paclitaxel in the evaluated devices,” Boston Scientific wrote in a prepared summary. In light of the upcoming FDA review, the company cut its 2019 revenue target for Eluvia in half on an April earnings call.

BD similarly last month forecast a 50% drop in its drug-coated balloon sales.

Industry is open to collecting more safety data over an extended five-year period if the panel determines it necessary. BD, Medtronic, Cook Medical, Philips and Boston Scientific all suggested in briefing documents that an industrywide partnership with physician societies and FDA to examine larger datasets could be used to probe causality.

On the first day of the advisory panel, each company will present on the presence and magnitude of the safety signal. 

In January, FDA released a letter to healthcare providers recommending avoiding paclitaxel-coated balloons and stents due to initial data showing a 50% higher risk of mortality in people treated with with the devices compared to a control group. And earlier this week, the U.K.'s Medicines and Healthcare products Regulatory Agency released a notice warning against use of the devices to treat patients with intermittent claudication due to the potential mortality risk generally outweighing the benefits.