FDA Advisors Unconvinced by Lutonix BTK Drug-Coated Balloon

Despite having no significant safety concerns, an advisory panel to the US Food and Drug Administration said yesterday that it could not find enough evidence of efficacy and benefit to recommend premarket approval (PMA) of a below-the-knee drug-coated balloon (DCB) for the treatment of PAD.

After a full day of discussion, the Circulatory Devices Panel of the Medical Devices Advisory Committee voted 15-2 (with one member abstaining) that reasonable assurance of safety was demonstrated for the DCB, made by Lutonix, a subsidiary of Becton, Dickinson and Company (BD).

On the question of reasonable assurance of efficacy, however, the vote was the same—15-2 (with one member abstaining)—that efficacy was not demonstrated. Similarly, on the question of whether the panel believed that the benefits outweighed the risks, the vote was 14-3 (with one member abstaining) that they did not.

The FDA initially granted IDE approval for the device in 2013. BD applied for PMA in late 2018, but after reviewing the clinical data, the agency issued a Major Deficiency Letter in January 2019, which was followed by two Not Approvable letters in 2020. The advisory panel met yesterday in response to a request by the company to look at additional data from the pivotal IDE trial, as well as supplementary real-world studies of the device.

During the daylong meeting, the panel struggled with a number of issues related to the single-blind pivotal IDE trial that pitted the paclitaxel DCB against percutaneous transluminal angioplasty (PTA) in patients with critical limb ischemia and obstructive de novo or nonstented restenotic lesions in native popliteal, tibial, or peroneal arteries that were 2.0 to 4.0 mm in diameter and as long as 320 mm. More generally, as a press release from the company also acknowledged, the panel wrestled with drawing efficacy and risk-benefit conclusions based largely on a challenging study in this complex patient population that took over 8 years to complete.

What I'm hearing is that there's no convincing data that's been shared with the panel that makes them believe that there's clinical effectiveness. Richard Lange

Summing up the panel’s opinion on efficacy, chairman Richard Lange, MD (Texas Tech University Health Sciences Center, El Paso), called it the “crux” of their challenge.

“What I'm hearing is that there's no convincing data that's been shared with the panel that makes them believe that there's clinical effectiveness,” he said. Lange added that there was no evidence supporting an advantage for the DCB in improving wounds, quality of life, ankle or toe brachial indexes, or amputation rates compared with PTA.

The primary effectiveness endpoint in the IDE trial was the composite of limb salvage and primary patency at 6 months, expressed as freedom from primary effectiveness failure, which was 74.7% in the DCB group and 64.2% in the PTA group (P = 0.0222). The difference was nonsignificant because a P value of 0.0085 was required for superiority. Furthermore, beyond 6 months, the difference between the device and PTA group diminished, with the long-term efficacy actually favoring PTA at 12, 24, and 36 months.

According to Lange, there was genuine concern among the panel that the statistically insignificant difference demonstrated at 6 months also was not clinically significant.

Lange and colleagues also were challenged by issues of missing data in both treatment arms at multiple time points, and protocol changes that occurred after a substantial number of patients had been enrolled. The protocol changes included enrolling Rutherford category 3 patients to increase enrollment and shortening the primary effectiveness time point from 12 to 6 months.

Although the freedom from clinically driven TLR rate was numerically higher in the DCB arm than the PTA arm at 36 months (90.8% vs. 82.6%), some panel members voiced concern that there was no way to reasonably adjudicate the clinical decisions about TLR.  

Panel member Joaquin E. Cigarroa, MD (Oregon Health & Science University, Portland), said the addition of the real-world data didn’t help clarify the issues with the pivotal IDE trial, “nor does it change my position on the interpretation of the study.”

Need for New Technologies for BTK

Haraldur Bjarnason, MD (Mayo Clinical College of Medicine and Science, Rochester, MN), said he understood the desire on the part of clinicians to have a DCB in their toolbox for BTK patients and expressed hope that a post hoc analysis might yield more answers given the lack of a signal for harm and a suggestion of potential benefit.

Following the voting, there was a sense of disappointment by most members of the panel that the data were not strong enough to recommend use of the device despite acknowledging that BTK is a space that needs new technologies to prevent amputations and save lives.

Once something that's ‘possibly effective’ gets out there, you never have the opportunity to find out whether it actually is. John Hirshfeld

Three panel members, including Bernard Gersh, MD (Mayo Clinical College of Medicine and Science, Rochester, MN), voted in favor of a risk-benefit for the DCB. Gersh also said he abstained from voting on the efficacy question because he believes that flaws in trial design may have obscured the efficacy signal.

One member who voted no on all three questions was Michael Miller, DO (Miller Care Group, Indianapolis, IN). “I was really bothered by the loss of treatment effect after 6 months, and that the treatment appeared to be inferior to normal angioplasty. [We] could be looking at . . . the tip of the iceberg of a problem,” he said.

Conversely, Edwin Gravereaux, MD (Brigham & Women’s Hospital, Boston, MA), said he voted yes on all three questions, explaining that the DCB seemed no riskier than a PTA.

John Hirshfeld, MD (University of Pennsylvania School of Medicine, Philadelphia), summed up the day by saying he had thought the DCB should be effective and hoped to see data to support that.

“But it appears, perhaps, that the overwhelming impact of severe disease obscured whatever benefit the device and the combination of the device and the drug might provide,” he said. Hirshfeld urged caution in moving too quickly to get a DCB in the toolbox based on a conclusion that it is “possibly” effective.

“Once something that's ‘possibly effective’ gets out there, you never have the opportunity to find out whether it actually is,” he concluded.