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An FDA advisory committee turned thumbs down on Becton Dickinson's Lutonix 014 drug-coated balloon (DCB) for peripheral artery disease (PAD) during a on Wednesday.

Circulatory System Devices Panel members voted 14-3 (with one abstention) that the benefits of the investigational angioplasty catheter do not outweigh its risks as a treatment for patients with critical limb ischemia (CLI) who have obstructive de novo or non-stented restenotic lesions in below-the-knee (BTK) arteries.

Committee members were largely unconvinced that the Lutonix DCB was supported by adequate efficacy data.

In the pivotal , the device showed a 10.5% absolute advantage in the primary efficacy endpoint (combined primary patency and limb salvage) at 6 months that was not significant under Bayesian analysis. Such improvement, if any, vanished by 12 months, and the endpoint started to favor the regular percutaneous transluminal angioplasty (PTA) arm by 36 months.

The DCB was also associated with no added benefit in terms of quality of life and Rutherford classification.

"Typically, I would think a 10.5% absolute improvement ... is a huge win, but in this case, it's not. I'm used to seeing drug trials and stent trials of a 1-2% absolute benefit, a 5-10% absolute benefit. Why is 10.5% absolute benefit of the DCB not of clinical significance here?" posed Joaquin Cigarroa, MD, of Oregon Health & Science University in Portland.

"It's because of the methodology of who was included, statistical challenges, a decrease in what we thought would have been the impact of the therapy, and the loss of data at followup. So the precision and how much I believe that 10.5% vanishes," Cigarroa continued. He voted against the device.

Also voting no was Robert Yeh, MD, MSc, of Harvard Medical School in Boston, who acknowledged the strong clinical need for such a device on the market, but said that "public health is best served when we have more certainty that the device works, and I felt we didn't get that today."

The Lutonix DCB features a proprietary coating containing paclitaxel and, if approved by the FDA, would be the first device indicated for BTK CLI beyond PTA and atherectomy.

FDA is not required to follow the advice of the advisory committee, but it often does.

Notably, the long-suffering pivotal BTK trial started in 2013 and was called off in 2018 after investigators were only able to enroll 442 people, approximately half the planned sample size.

During the intervening years, the trial underwent myriad protocol changes to increase chances for success, including:

• Removal of hemodynamic inclusion criteria after approximately 180 patients were already enrolled
• Addition of Rutherford category 3 patients (on top of original Rutherford 4-6 population) after approximately 270 patients were already enrolled
• Sample size increased and statistical considerations changed after approximately 270 patients were already enrolled
• Primary effectiveness endpoint shortened from 12 months to 6 months after approximately 325 patients were already enrolled

Other problems included very high loss to follow-up -- only 83.3% and 74.5% of DCB and PTA groups, respectively, were evaluable at 6 months -- and the subjectivity of unblinded investigators assessing wound healing and clinically-driven target lesion revascularization.

"Let me cut to the chase. I don't think there's any way this trial demonstrates efficacy," said Bernard Gersh, MD, of Mayo Clinic College of Medicine in Rochester, Minnesota. He said that all the Lutonix does is "postpone the inevitable," that is, "another revascularization procedure."

Compared with regular PTA, however, the DCB "doesn't appear to be any worse. I also felt that there is a need to have another tool in the toolbox," Gersh said in explaining how he came to be one of the few to vote in favor of the device for BTK CLI.

Safety was the most promising finding of the Lutonix BTK trial, as study investigators were able to show that the Lutonix 014 DCB was non-inferior to PTA in freedom from BTK major adverse limb events and perioperative deaths at 30 days.

Most advisory committee members agreed that the device was safe and did not dwell on prior speculation that paclitaxel-coated devices could damage the distal vessels in the long run.

A meta-analysis had sparked fears in 2018 that these PAD devices are associated with . Critics blamed bias and the lack of missing patient-level data in the studies included and have since countered with their own studies indicating paclitaxel's safety.

"It's important to recognize that the mortality signal that FDA commented on 18 months ago, and still has concerns about, seems to appear most prominently between 2 and 5 years," cautioned the FDA's Bram Zuckerman, MD.

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