FDA News

FDA panel: Keep paclitaxel-coated devices on market, but amend labeling, trial designs

In the second day of deliberations by the FDA’s Circulatory System Devices Panel, members advised that paclitaxel-coated devices should remain on the market despite a possible long-term mortality signal, but efforts to better inform patients about the issue and to further investigate the signal should be made.

Labeling for the devices to treat peripheral artery disease should be amended to note that the devices may confer long-term mortality risk, and current and future trials of such devices must be more rigorous in following patients long term and adjudicating deaths, the panel stated.

“No one is suggesting that we take these devices off the market,” panel member John C. Somberg, MD, clinical research program director at Rush University in conjunction with The University of Chicago, said during the hearing. “We just need to get better information out there.”

Benefits vs. risks

Several panelists said the benefits of the devices in terms of reducing clinically driven target lesion revascularization and improving quality of life have been consistently proved, and thus outweigh concerns over long-term mortality risks, which were shown in a summary-level meta-analysis and confirmed in an FDA analysis, but not shown in randomized controlled trials or large observational studies.

“On the benefit side, we have a number of randomized controlled trials, observational studies, near-unanimous support for the quality-of-life benefits from the clinical community and oncologists telling us that paclitaxel has shown to be safe in their patients,” said Col. Todd E. Rasmussen, MD, USAF MC, professor of surgery and associate dean for clinical research at The Uniformed Services University F. Edward Hebert School of Medicine. “On the other side, we have a meta-analysis that was done extremely well and was replicated by the FDA, but may have ascertainment bias. Continued marketing of paclitaxel-coated devices for patients with lesions in the superficial femoral artery or proximal popliteal artery should be allowed.”

However, “there is a signal of harm, and FDA cannot walk away from the issue and declare that everything is OK,” John W. Hirschfeld Jr., MD, professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, said during the hearing. “It is impossible to ignore, and we need to tread carefully.”

Improved data essential

The panel members agreed that better long-term data are needed, and current and future trials of paclitaxel-coated devices should follow patients for at least 5 years, diligently pursue follow-up equally with patients from the intervention arm and control arm and do a more thorough job of adjudicating causes of death.

There was no consensus on whether a new trial should be undertaken. FDA staff calculated that a randomized controlled trial to definitively reject the null hypothesis of a mortality harm from paclitaxel-coated devices at 5 years would require 32,000 patients, and panel members said that would not be feasible.

Some panelists suggested the agency compel sponsors of ongoing trials to follow patients for 5 years and provide the agency with detailed data about long-term mortality, but Bram Zuckerman, MD, director of the Office of Cardiovascular Devices at FDA’s Center for Devices and Radiological Health, said the FDA does not have the authority to do that.

Other panelists suggested conducting a smaller randomized controlled trial whose goal would be to rule out a 5-year mortality RR of 1.4, and Michael W. Krucoff, MD, FACC, FAHA, FSCAI, professor of medicine/cardiology at Duke University Medical Center and director of the Cardiovascular Devices Unit and director of ECG core laboratories at Duke Clinical Research Institute, was one of several panelists to suggest an approach of “registry-based prospective randomization,” as is commonly done in Sweden.

The panel members stated that there is no conclusive evidence of a dose-response relationship between paclitaxel exposure and mortality, existing animal studies have not given any mechanistic explanations for the mortality signal and labeling should be updated to mention the mortality signal, including a patient guide in language a layperson might understand.

Some also noted that until better data are available, interventions with paclitaxel-coated devices should be more strongly considered in high-risk patients, such as those with critical limb ischemia, than in lower-risk patients.

“The well-educated patient will not choose to have an intervention for claudication if they are informed they are not going to lose their leg either way,” Frank W. LoGerfo, MD, William V. McDermott Distinguished Professor of Surgery at Harvard Medical School and Beth Israel Deaconess Medical Center, said during the hearing. “They get just as good a benefit from stopping smoking and exercising.”

After the conclusion of the panel meeting, BD, manufacturer of the Lutonix paclitaxel-coated balloon, issued a statement which read in part: “Over the past several months, BD has been working diligently to obtain all available patient follow-up data and collaborating with FDA, professional clinical organizations and industry to investigate the important issue of DCB safety. BD continues to stand behind the safety of its Lutonix DCBs and is committed to improving the quality of life for patients with PAD. BD will continue to collaborate with FDA, industry and professional organizations to collect and analyze data for the benefit of patients. To ensure patients with PAD continue to receive the best care possible, BD will continue to ensure physicians and patients have access to BD’s broad range of treatment options for this serious disease.”

Medtronic, which makes the IN.PACT Admiral paclitaxel-coated balloon, also issued a statement, which read in part: “Patient safety is our top priority — and has been since our company's founding more than 60 years ago. These panel deliberations are critically important as the FDA, societies, physicians and industry consider and address the recent questions around the safety of paclitaxel devices in PAD above the knee. As an industry leader, we take our responsibility to patients and physicians very seriously and look forward to further collaboration on a response to the panel's recommended next steps.”

Boston Scientific, which makes the Eluvia paclitaxel-coated stent, wrote that “When considering the panel recommendations, it is important to understand that data on the Eluvia stent was not included in the meta-analyses demonstrating a late mortality signal. Additionally, the Eluvia stent is unique in its design, dose and drug delivery, as it is the only paclitaxel-based device which uses a polymer to enable a controlled, sustained drug release. The Eluvia stent has the lowest drug dose density of any paclitaxel-based peripheral device, up to 20 times lower than other drug-coated devices.  We will work with the FDA and key stakeholders to address the questions and recommendations discussed during the panel meeting and continue our robust collection of long-term data on patients treated with the Eluvia stent. We remain steadfast in our commitment to providing effective treatment options to the millions of patients who experience this debilitating condition.” – by Erik Swain

Reference:

FDA Executive Summary.

Disclosures: The members of the Circulatory System Devices Panel report no relevant financial disclosures.

 

In the second day of deliberations by the FDA’s Circulatory System Devices Panel, members advised that paclitaxel-coated devices should remain on the market despite a possible long-term mortality signal, but efforts to better inform patients about the issue and to further investigate the signal should be made.

Labeling for the devices to treat peripheral artery disease should be amended to note that the devices may confer long-term mortality risk, and current and future trials of such devices must be more rigorous in following patients long term and adjudicating deaths, the panel stated.

“No one is suggesting that we take these devices off the market,” panel member John C. Somberg, MD, clinical research program director at Rush University in conjunction with The University of Chicago, said during the hearing. “We just need to get better information out there.”

Benefits vs. risks

Several panelists said the benefits of the devices in terms of reducing clinically driven target lesion revascularization and improving quality of life have been consistently proved, and thus outweigh concerns over long-term mortality risks, which were shown in a summary-level meta-analysis and confirmed in an FDA analysis, but not shown in randomized controlled trials or large observational studies.

“On the benefit side, we have a number of randomized controlled trials, observational studies, near-unanimous support for the quality-of-life benefits from the clinical community and oncologists telling us that paclitaxel has shown to be safe in their patients,” said Col. Todd E. Rasmussen, MD, USAF MC, professor of surgery and associate dean for clinical research at The Uniformed Services University F. Edward Hebert School of Medicine. “On the other side, we have a meta-analysis that was done extremely well and was replicated by the FDA, but may have ascertainment bias. Continued marketing of paclitaxel-coated devices for patients with lesions in the superficial femoral artery or proximal popliteal artery should be allowed.”

However, “there is a signal of harm, and FDA cannot walk away from the issue and declare that everything is OK,” John W. Hirschfeld Jr., MD, professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, said during the hearing. “It is impossible to ignore, and we need to tread carefully.”

Improved data essential

The panel members agreed that better long-term data are needed, and current and future trials of paclitaxel-coated devices should follow patients for at least 5 years, diligently pursue follow-up equally with patients from the intervention arm and control arm and do a more thorough job of adjudicating causes of death.

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There was no consensus on whether a new trial should be undertaken. FDA staff calculated that a randomized controlled trial to definitively reject the null hypothesis of a mortality harm from paclitaxel-coated devices at 5 years would require 32,000 patients, and panel members said that would not be feasible.

Some panelists suggested the agency compel sponsors of ongoing trials to follow patients for 5 years and provide the agency with detailed data about long-term mortality, but Bram Zuckerman, MD, director of the Office of Cardiovascular Devices at FDA’s Center for Devices and Radiological Health, said the FDA does not have the authority to do that.

Other panelists suggested conducting a smaller randomized controlled trial whose goal would be to rule out a 5-year mortality RR of 1.4, and Michael W. Krucoff, MD, FACC, FAHA, FSCAI, professor of medicine/cardiology at Duke University Medical Center and director of the Cardiovascular Devices Unit and director of ECG core laboratories at Duke Clinical Research Institute, was one of several panelists to suggest an approach of “registry-based prospective randomization,” as is commonly done in Sweden.

The panel members stated that there is no conclusive evidence of a dose-response relationship between paclitaxel exposure and mortality, existing animal studies have not given any mechanistic explanations for the mortality signal and labeling should be updated to mention the mortality signal, including a patient guide in language a layperson might understand.

Some also noted that until better data are available, interventions with paclitaxel-coated devices should be more strongly considered in high-risk patients, such as those with critical limb ischemia, than in lower-risk patients.

“The well-educated patient will not choose to have an intervention for claudication if they are informed they are not going to lose their leg either way,” Frank W. LoGerfo, MD, William V. McDermott Distinguished Professor of Surgery at Harvard Medical School and Beth Israel Deaconess Medical Center, said during the hearing. “They get just as good a benefit from stopping smoking and exercising.”

After the conclusion of the panel meeting, BD, manufacturer of the Lutonix paclitaxel-coated balloon, issued a statement which read in part: “Over the past several months, BD has been working diligently to obtain all available patient follow-up data and collaborating with FDA, professional clinical organizations and industry to investigate the important issue of DCB safety. BD continues to stand behind the safety of its Lutonix DCBs and is committed to improving the quality of life for patients with PAD. BD will continue to collaborate with FDA, industry and professional organizations to collect and analyze data for the benefit of patients. To ensure patients with PAD continue to receive the best care possible, BD will continue to ensure physicians and patients have access to BD’s broad range of treatment options for this serious disease.”

Medtronic, which makes the IN.PACT Admiral paclitaxel-coated balloon, also issued a statement, which read in part: “Patient safety is our top priority — and has been since our company's founding more than 60 years ago. These panel deliberations are critically important as the FDA, societies, physicians and industry consider and address the recent questions around the safety of paclitaxel devices in PAD above the knee. As an industry leader, we take our responsibility to patients and physicians very seriously and look forward to further collaboration on a response to the panel's recommended next steps.”

Boston Scientific, which makes the Eluvia paclitaxel-coated stent, wrote that “When considering the panel recommendations, it is important to understand that data on the Eluvia stent was not included in the meta-analyses demonstrating a late mortality signal. Additionally, the Eluvia stent is unique in its design, dose and drug delivery, as it is the only paclitaxel-based device which uses a polymer to enable a controlled, sustained drug release. The Eluvia stent has the lowest drug dose density of any paclitaxel-based peripheral device, up to 20 times lower than other drug-coated devices.  We will work with the FDA and key stakeholders to address the questions and recommendations discussed during the panel meeting and continue our robust collection of long-term data on patients treated with the Eluvia stent. We remain steadfast in our commitment to providing effective treatment options to the millions of patients who experience this debilitating condition.” – by Erik Swain

Reference:

FDA Executive Summary.

Disclosures: The members of the Circulatory System Devices Panel report no relevant financial disclosures.