FDA Says Newer Paclitaxel Data Are ‘Comforting’ but Limited

The US Food and Drug Administration has responded to recent, favorable long-term safety data on paclitaxel-based devices used in PAD but continues to maintain that additional follow-up is needed.

A perspective published online Saturday, ahead of print in the New England Journal of the Medicine, marks the first written statement from the agency addressing the paclitaxel mortality signal in nearly a year and a half. In December 2018, a meta-analysis by Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece), suggested a late mortality increase beginning at 2 to 3 years postprocedure in patients treated with paclitaxel-based DES or drug-coated balloons (DCB)—since then the FDA has issued three letters to healthcare providers and held a 2-day Circulatory System Devices panel meeting on the topic.

Following the last letter issued in August 2019, investigators for a number of pivotal randomized controlled trials and trial series including IN.PACT, ILLUMENATE, and LEVANT have published or publicly presented newly available long-term data showing no increased mortality signal. These were supplemented by several analyses of Medicare patients, also showing no evidence of increased mortality.

Most recently, an unplanned interim analysis from the SWEDEPAD trial showed no difference in all-cause mortality at a mean of 2.5 years between PAD patients treated with coated versus uncoated devices, regardless of the extent of limb disease (critical limb ischemia or intermittent claudication).

In response to those findings, the FDA’s Andrew Farb, MD, Misti Malone, PhD, and William H. Maisel, MD, MPH, say in the perspective piece that while SWEDEPAD is “comforting,” fewer than 300 patients have been followed for 4 years. This is in contrast to more than 1,000 patients with 5-year follow-up who were part of the FDA’s own meta-analysis of pivotal RCTs of approved paclitaxel-coated devices.

“This gap underscores the importance of continued patient follow-up for ongoing randomized trials,” Farb and colleagues write. “Because of the demonstrated short-term benefits of the devices and the limitations of the available data, the FDA believes that clinical studies of these devices should continue and should collect long-term mortality data.”

In an email on behalf of the authors to TCTMD, the FDA did not reveal why it chose to respond publicly to the SWEDEPAD analysis. The agency said, however, that it continues to review long-term clinical outcomes from patients enrolled in the pivotal paclitaxel-device RCTs, as well as data from other clinical trials, registries, and administrative databases.

“The FDA will continue to work with clinical investigators, medical professional societies, and the device industry to facilitate data development, and when FDA has more complete information regarding the late mortality question, we intend to update the FDA’s August 2019 letter to healthcare providers,” the email concludes.

Farb and colleagues note in their article that the COVID-19 pandemic has delayed some answers to the paclitaxel question due to studies first being suspended then subjected to slow enrollment when they restarted.

As with the August 2019 recommendations, the perspective reiterates to clinicians that “benefits and risks associated with available PAD treatment options should be carefully considered and discussed with individual patients.” They add that paclitaxel-based devices “may be the best treatment for some patients, particularly those judged to be at particularly high risk for restenosis and repeat femoropopliteal interventions,” calling for more data that could help to refine risk profiles for restenosis through incorporation of patient- and lesion-specific factors.