Vascular Experts Say It’s Time to Let Paclitaxel Out of Regulatory Jail

Over the last few years, study after study has refuted the mortality signal for paclitaxel that was reported in a 2018 meta-analysis. Now, researchers are speaking out and asking how much more data regulatory authorities need to see before removing the restrictions on use of paclitaxel-coated endovascular devices in patients with PAD.

In a presentation at the Charing Cross International Symposium (CX2021), held virtually this year, Thomas Zeller, MD, PhD (University Heart Center Freiburg-Bad Krozingen, Germany), reviewed much of the long-term data showing no excess mortality with paclitaxel-based drug-coated balloons (DCBs) and DES, including: IN.PACT-SFA, IN.PACT Global, ZILVER PTX, pooled patient-level meta-analyses by dose, SAFE-PAD, and VOYAGER PAD. All of those efforts refute the conclusion of the meta-analysis led by Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece), suggesting a late mortality increase beginning at 2 to 3 years postprocedure.

“The meta-analysis by Katsanos was a single finding so far, not supported by any large-scale real-world studies. There was no dose response, there was no mechanism of action found,” Zeller said. “Withholding such devices [from] patients with severe peripheral artery disease may even harm them and result in increased global healthcare costs.”

Program chairman Roger Greenhalgh, MD (Imperial College, London, England), put Zeller on the spot following the presentation, asking him if he was calling for regulatory authorities to change their positions on paclitaxel. When Zeller answered “definitely,” Greenhalgh countered: “What do you want them changed to?”

“I'm wondering what the agencies are waiting for,” Zeller said. “For which data are they waiting for? Are they going to wait for redo meta-analyses of the randomized controlled studies? More data or what? What are they looking for?”

Greenhalgh pressed further, asking if it was correct to assume Zeller was saying that while the regulatory agencies had acted in the best interest of patients, they should now acknowledge that paclitaxel isn't a safety risk and should be used as needed to achieve better restenosis.

“Absolutely,” Zeller replied.

I'm wondering what the agencies are waiting for. Thomas Zeller

At the end of the session, Greenhalgh polled the virtual attendees, asking how many agreed with Zeller’s position. The result was an overwhelming 74% in agreement. In an email to TCTMD, Greenhalgh said he didn’t know the exact numbers of viewers who voted, but said he wasn’t surprised by the response.

"I think the data fail to link mortality and causation by [paclitaxel]," he added.

Regulatory Oversight of Paclitaxel Controversy

The US Food and Drug Administration has issued three letters to healthcare providers about paclitaxel since early 2019, and held a 2-day Circulatory System Devices panel meeting on the topic, after which the warnings about the potential risk were added to labels of paclitaxel devices. The FDA continues to advise that physicians reserve use of these products for patients at highest risk of restenosis. The most recent communication on the topic came in January 2021, in the form of a perspective published in the New England Journal of Medicine, after long-term safety data from SWEDEPAD 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. In the perspective, the FDA called the data “comforting” but noted that fewer than 300 SWEDEPAD patients have been followed to 4 years.

It's definitely an area that we need a lot more information on which patients can really benefit from these devices. Sara Royce

Speaking at CX2021 on behalf of the FDA’s plaque modification devices team, Sara Royce, PhD, noted there are a number of regulatory lessons that researchers can apply from the paclitaxel story to the development of next-generation devices, including the importance of rigorous data collection, follow-up planned out to 5 years, independent assessment and documentation of endpoints, wound-healing assessment, and “clear informed consent and appropriate device labeling to communicate the potential risks associated with these devices.”

The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) was represented by senior medical devices specialist Roopa Prabhakar, PhD. She noted that the MHRA still does not recommend paclitaxel DCBs or DES in the routine treatment of patients with intermittent claudication based on the conclusion that the mortality risk outweighs the benefits, but approves of their use in critical limb ischemia. Like the FDA, Prabhakar said, the MHRA will continue to seek further evaluation of the potential causal relationship between paclitaxel and mortality.

Moderator Andrew Holden, MBChB (Auckland Hospital, New Zealand), fielding an audience question, asked if any risk of mortality should be considered acceptable given that paclitaxel has not been shown to have any impact on limb salvage despite its efficacy in reducing restenosis.

“I think it really depends on what the patient's perspectives are and really what their risks are of restenosis,” the FDA’s Royce said. “It's definitely an area that we need a lot more information on: which patients can really benefit from these devices.”