One of the most alarming facts about the ongoing debate regarding a late mortality signal associated with paclitaxel-coated devices is that this isn't the industry's first rodeo with this sort of issue.
"Some of us are having a deja vu all over again moment remembering December 2006 when we had the late stent thrombosis issue with paclitaxel- and sirolimus-eluting stents," John Hershfeld Jr, MD said during the second of a two-day FDA advisory panel meeting about the paclitaxel-coated device issue. "That was, like this situation, discovered by independent investigators and not in any way affiliated with the regulatory agency, but turned the industry and the clinical world on its head."
And just like the current debate, the late-stent thrombosis concern prompted FDA to hold a special meeting of its Circulatory System Devices Panel to investigate the safety issues of drug-eluting stents and to recommend potential actions the agency should take.
"At that time there was a lot of discussion about 'we need better post-market surveillance.' That was 13 years ago and we're having the same conversation now," Hershfeld said. "I would challenge everyone here, this is something that will happen again if we don't close the loop on this process."
The key frustration for FDA and the experts who served on the Circulatory System Devices Panel last week (June 19-20) was the fact that a lot of important information that should have come from required post-market surveillance studies of paclitaxel-coated balloons and paclitaxel-eluting stents is missing.
Missing data was, in fact, a central theme throughout the two-day meeting. All of the companies who sponsored randomized clinical trials on paclitaxel-coated devices were missing a significant percentage of long-term data. Medtronic started out with about 19% of its long-term data missing but the company did go back and find a lot of the data and were able to bring that percentage down to 2.7% in time for the panel meeting.
"Nobody would come [to FDA] with pre-market data that was missing 30% to 40% of the data and expect to get [the product] approved so I don't think people should come with 30% of the post-market study missing and think that's acceptable either," said Richard Lange, MD, chairperson of the panel and the president of Texas Tech University Health Sciences Center El Paso.
Lange pointed out that many times FDA advisory panels will recommend approval of a device based upon the data currently available but with the recommendation to continue studying the device through post-market surveillance.
"And sometimes I think people take that with a various amount of seriousness and rigorousness," Lange said. "In the end, when we look at the three-, or four-, of five-year data afterward and we don't have the data it just makes it very difficult, and we may or may not find ourselves in this situation again."
"So my plea to the sponsors and to the FDA," Lange continued, "is when a panel says we're interested in continuing and looking at it for the next four or five years, that's usually pretty good advice and we would want our FDA and our industry sponsors to take that seriously so we can perform the best possible analysis of that data."
Col. Todd Rasmussen, MD, an attending vascular and endovascular surgeon at Walter Reed National Military Medical Center who served as a temporary voting member on the panel, pointed out that multidisciplinary professional societies can also help FDA and industry tackle this problem through the registries they run.
FDA seemed to hear the panel's concerns loud and clear.
"This emphasis on improving clinical trial quality and decreasing missing data won't stop after this panel has met," said Bram Zukerman, MD, director of the office of cardiovascular devices at FDA's Center for Devices and Radiological Health. "To the credit of the industry in other areas where these companies have participated, such as in the coronary arena, we've had much better success with a pre- to post-market balance where we're able to stimulate innovation with early approvals."
FDA released a five-pronged Medical Device Safety Action Plan in April 2018 full of rhetoric aimed at convincing the public that this new plan will enhance the agency's commitment to patient safety and recognition that safety and innovation should go hand in hand. Included in that plan is a call to advance the use of a total product life cycle approach to device safety. In other words, the agency has said it will take steps to ensure that devices not only meet the gold standard for getting to market but continue to monitor the product's benefit-risk profile in real-world settings.
"This is a very disappointing experience for all I want to assure the industry that with our increased emphasis on our Medical Device Safety Action Plan this problem that we have right now has significant ramifications and we all need to work harder," Zukerman said. "... I think Doctor Rasmussen's comments though are also quite apropos in that everyone in the sandbox has to play ball here. There are tremendous problems with our clinical trials ecosystem right now and the ability of the multi-society groups to help in this process to improve peripheral vascular disease trial quality is going to be essential."