This article is more than 5 years old. Information may no longer be current.
Preliminary FDA analysis finds paclitaxel-related mortality signal
Click Here to Manage Email Alerts
An FDA official announced at a special meeting that the agency’s preliminary analysis of the possible link between paclitaxel-coated devices and mortality showed a signal of a link between the two, but no “smoking gun” to provide definitive proof or pinpoint a cause.
Also, at the Vascular Leaders Forum, VIVA Physicians announced it will conduct and fund a patient-level meta-analysis to determine whether aggregated findings from summary-level data hold up when patient-level data are aggregated.
As Cardiology Today’s Intervention previously reported, a summary-level meta-analysis published in the Journal of the American Heart Association by Konstantinos Katsanos, MD, PhD, MSc, EBIR, of the department of interventional radiology at Patras University Hospital in Rion, Greece, and colleagues found that patients with peripheral artery disease receiving paclitaxel-coated balloons or stents had higher mortality risk at 2 and 5 years compared with controls. The analysis prompted two trials of paclitaxel-coated devices to be paused, the FDA to launch its investigation and the manufacturers of the devices to make their trial data available for independent researchers to conduct patient-level analyses.
FDA investigation
Misti Malone, PhD, chief of the peripheral interventional devices branch of the FDA’s Center for Devices and Radiological Health, said the FDA’s investigation is aimed to confirm the results of the JAHA meta-analysis by with all 28 trials included in the meta-analysis and then evaluating all available long-term U.S. and global randomized controlled trial data, using similar and alternative statistical methodologies and assumptions and considering the intention-to-treat and as-treated populations. She noted the FDA does not have access to patient-level data for all 28 trials.
“Following preliminary review of the data and replicating the meta-analysis, we believe that a signal still persists and warrants additional investigation,” Malone said. “We are considering this a potential class effect, while also acknowledging that this may affect other disease states such as [arteriovenous fistulas and critical limb ischemia]. In other words, we are looking at the data from multiple different directions ... to consider what is the possible effect, and how to weigh the benefit and risk.”
Going forward, the agency plans to “evaluate temporal trends in the cause of death, any adverse events, whether there’s a trend in the patient-level dose that’s associated with mortality and whether there is susceptibility in particular patient populations by looking at baseline covariates and results,” she said.
Challenges include that death narratives contain limited information, that there is no consistency in how death has been categorized and adjudicated, that many patients have multiple comorbidities and unknown causes of death, that the control devices varied and that some patients were treated with other devices before or after enrollment in a trial of a drug-coated balloon or drug-eluting stent.
“We understand those associated limitations, and we are doing our best to work with the data that we have,” Malone said. “We will use this information to assess the risk for future recommendations.”
The process could result in the convening of an advisory panel to make recommendations on adjustments to trial designs, informed consent labeling and/or postmarket data collection, she said.
During a panel discussion, Malone said the FDA has not found “a smoking gun” to pinpoint why there might be a connection between paclitaxel-coated devices and mortality, so “more evaluation is needed” and FDA staff are discussing options internally.
Patient-level meta-analysis
During the forum, Krishna Rocha-Singh, MD, FACC, FAHA, chief scientific officer for the Prairie Heart Institute of Illinois at St. John’s Hospital in Springfield, Illinois, announced that VIVA Physicians will conduct and fund a meta-analysis using independent patient data, “the new gold standard for data synthesis.”
Industry has agreed to provide patient-level data for the project and will have the opportunity to review the findings, but the authors will be under no obligation to incorporate industry suggestions and no findings will be attributed to a single commercial product, according to Rocha-Singh, a member of the board of VIVA Physicians.
He said the project will use the PRISMA-IPD framework, “which calls out three important issues ... it has a methodology for assessing missing data, baseline imbalances of data across the field and understanding the patterns of randomization, which are very important and can be analyzed in a granular manner; it also provides a methodology for variations of subgroups ... and it provides a methodology for exploring unexpected observations.”
It will synthesize adjudicated data from randomized controlled trials and registries, Rocha-Singh said.
The individual patient data that industry has so far agreed to share includes 1,342 patients treated with a DCB in randomized controlled trials, 597 patients treated with percutaneous transluminal angioplasty in randomized controlled trials of DCBs, 801 patients treated with a DES in randomized controlled trials, 143 patients treated with PTA or bare-metal stents in randomized controlled trials of DES, 3,200 patients treated with DCBs in adjudicated registries, 904 patients treated with DES in adjudicated registries and 300 patients treated with BMS or PTA in adjudicated registries, he said.
“We have had some discussion about separation of DCBs from drug-eluting stents,” which was a complaint about the JAHA meta-analysis, he said.
“It will be very important to ... understand the complexity of the issues that we are going to be facing,” Rocha-Singh said. “I can assure you that VIVA Physicians takes our obligation of collaboration very, very importantly. We want to do this in a timely, transparent, unbiased and phased process [and] bring this out into the public space as soon as possible.” – by Erik Swain
References:
Malone M. The FDA interpretation of the meta-analysis and what we are looking for with the data we requested.
Rocha-Singh K. The power of combining patient-level data. Both presented at: Vascular Leaders Forum; March 1-2, 2019; Washington, D.C.
Katsanos K, et al. J Am Heart Assoc. 2018;doi:10.1161/JAHA.118.011245.
Disclosures: Malone reports she is an employee of the FDA. Rocha-Singh reports he is a consultant for Medtronic.
Collapse
Click Here to Manage Email Alerts