• FDA advisory panel: PAD patients should be informed of risks, benefits of paclitaxel devices

    GAITHERSBURG, Md. – Paclitaxel devices used to treat peripheral artery disease (PAD) do show a signal for excess mortality beyond 1 year compared to control devices or treatments, and patients should be made aware of the risks and benefits, an advisory panel to the Food and Drug Administration concluded.

    The Circulatory System Devices Panel of the FDA’s Medical Devices Advisory Committee concluded its two-day meeting Thursday. About 240 people watched the panel’s deliberations on Wednesday at the Gaithersburg Holiday Inn, and about roughly 200 attended on Thursday.

    The FDA convened the panel to receive advice from experts on how it should handle the signal for late mortality in paclitaxel-coated balloons and paclitaxel-eluting stents used to treat patients with PAD.

    In total, the FDA asked the panel 12 questions. The two-day meeting also featured presentations from a variety of clinicians, researchers, statisticians, industry representatives, FDA officials and others.

    Bram Zuckerman, MD, director of the FDA’s Office of Cardiovascular Devices, said the agency would consider all of the information it received at the meeting in deciding what action to take next.

    The signal for long-term mortality was first reported in a meta-analysis by Konstantinos Katsanos, MD, PhD, MSc, EBIR, of Patras University Hospital, Greece, and colleagues, published in December in the Journal of the American Heart Association. That manuscript reported higher all-cause mortality beyond 1 year in patients undergoing treatment of femoropopliteal disease with paclitaxel-coated devices compared to control groups in a pooled analysis of 28 randomized controlled trials.

    The FDA reported that it replicated the meta-analysis’ findings with its own examination of the data. Industry presentations at the meeting concluded there was no signal for long-term mortality.


    Panel answers FDA questions

    The panel answered FDA’s first five questions Wednesday. (For details, click here.) Here is a summary of the deliberations for questions 6-12.

    The sixth question asked the panel to discuss the relationship between paclitaxel dose and mortality. Richard A. Lange, MD, MBA, president of Texas Tech University Health Sciences Center El Paso, serving as the panel’s chairman, summarized the members’ discussion of the issue by saying that the members feel the question of whether there is a dose relationship is inconclusive based on the available data; that it is complicated by patient variables, including length of lesion; and that there is a concern among panel members about high tissue levels of paclitaxel, both intra-arterial and intrapulmonary.

    Question 7 concerned whether the animal studies provided any insights into the late mortality signal in humans and what, if any, future animal studies might be helpful. Several panel members said the animal studies to date do not adequately address the concern about the late mortality signal in humans and that more animal studies are needed.

    Question 8 asked the panel to discuss the benefit-risk profile of paclitaxel DCB and DES.

    John W. Hirshfeld, MD, of the University Pennsylvania Medical Center, Philadelphia, said the decision on whether to use paclitaxel devices in PAD patients should at least include consideration of each patient’s risk.

    “If you start to think about this, you would begin to think that it would not be justifiable to use a device like this (paclitaxel DCB or DES) in a patient with low intrinsic risk and low recurrence risk,” he said. “But if the patient is high recurrence risk, then it would be very justifiable to give the patient whatever edge they can possibly get.”

    John C. Somberg, MD, of Rush University, Lake Bluff, Illinois, despite this discussion around the potential signal for late mortality and that treatment should be individualized for each patient, he said, “I just want to emphasize that I don’t think anyone around the table is talking about taking the drug or the device off the market.”

    The ninth question asked for input on post-marketing studies and surveillance and whether there is a need for new studies of paclitaxel devices in PAD patients. Several members said the FDA should communicate to the sponsors of ongoing studies the importance of long-term follow-up and ensuring that the problem of patients “lost to follow-up” – of which the pivotal randomized studies of each of the five approved paclitaxel devices had varying percentages – is minimized. Several also said that registries being developed by several societies representing clinicians, which were presented during the meeting during the public comments section, also could be part of the continuing evaluation of the devices’ performance. They expressed pessimism about launching a large new randomized study because of the cost, although Lange said that if there is still a late mortality signal two or three years from now with no certain answer as to why, “then we would demand” such a study.

    Question 10 asked whether current labeling in paclitaxel devices should be changed to reflect the concern for a late mortality signal. Lange summarized the panel discussion by saying the label should reflect the concern so the patient can make an informed decision.

    The 11th question asked several questions about the design of paclitaxel device studies in the peripheral arteries. The general consensus among members was that the efficacy endpoint should be clinically driven target lesion revascularization at 1 year and that mortality data of at least 3 years and preferably up to 5 years or beyond should be required as part of post-marketing surveillance.

    The 12th and final question was whether all of the discussion and data presented over the course of the meeting apply to other indications for paclitaxel-coated devices. Lange said that until there is a final determination, patients eligible for paclitaxel devices for any use should receive the information they need to make an informed decision.


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