A U.S. Food and Drug Administration advisory panel recommended against premarket approval of the Lutonix 014 drug-coated balloon (DCB) to treat below-the-knee (BTK) critical limb ischemia (CLI) after a daylong virtual meeting Wednesday.
In three votes, the FDA’s Circulatory System Devices Panel of the Medical Devices Advisory Committee determined that while the device was safe, it was not effective, and benefit to risk ratio could not be determined.
The first concern panel members raised was that the patient population in a pivotal randomized controlled trial did not appear to reflect true CLI patients, as 9.5% of patients enrolled were Rutherford Classification 3. Furthermore, in this study, the overall mortality rate was lower than what is seen in the real world, meaning the study patient population may not have been as sick as true CLI patients.
Another concern was that while the composite primary effectiveness endpoint showed a 10.5% absolute difference (p=0.0222) in favor of the Lutonix 014 DCB (BD/Bard) over percutaneous transluminal angioplasty, this finding was not statistically significant based on their pre-specified p-value of 0.0085. Furthermore, the difference between the two arms was largely driven by clinically driven target lesion revascularization (CD-TLR). Panel members noted that treating physicians were not blinded to which device the patients received and that “stagnant wounds” and new wounds, which were a component of the CD-TLR, were not adjudicated by a clinical events committee and instead were under the discretion of the unblinded treating physician.
Finally, there were concerns from the FDA panel on the degree of missing data during follow-up. Notably, there were proportionally higher amounts of missing data in the PTA arm as compared to the DCB arm. This difference made it hard for panel to draw meaningful clinical conclusions.
The proposed indications for use for the Lutonix 014 were for patients with CLI “who have obstructive de novo or non-stented restenotic lesions in native popliteal, tibial, and peroneal arteries up to 32 mm in length and 2.0 to 4.0 mm in diameter.”
The panel voted 15-2, with 1 abstention, to say that the device is safe based on the pivotal trial results.
However, the panel voted 15-2, with 1 abstention, to say that the device is not effective and 14-3, with 1 abstention, to say that the benefits do not outweigh the risks.
The device has had a history with the FDA. The agency denied an investigational device exemption (IDE) application for the Lutonix 014 DCB in February 2013. The manufacturer submitted a response to the disapproval, and FDA granted IDE approval in May 2013.
After several protocol changes and slow enrollment, including reducing the primary effectiveness endpoint time from 12 months to 6 months, the sponsor terminated the IDE pivotal trial early.
The sponsor then submitted the premarket approval application in October 2018. The FDA issued a “major deficiency letter” in January 2019 and two “not approvable decisions,” in June 2019 and April 2020.
In both decisions, the FDA told the sponsor that “reasonable assurance of effectiveness was not established” by the pivotal trial. This led the applicant to request that the advisory panel review the premarket application.
Panel members noted the signal of late mortality in BTK treatment by paclitaxel-coated devices raised by a 2018 meta-analysis that included the Lutonix 014 DCB. However, they also noted the recent interim analysis of the SWEDEPAD randomized trial, which found no difference in all-cause mortality in paclitaxel-coated DCB or uncoated endovascular devices.
The FDA will make a final decision and is not bound by the advisory panel’s recommendation, but the agency often does follow the panel’s guidance.