Study Takes Aim at Safety Issues, Trial Data in Medical Device Approval Process

Patrice Wendling

July 19, 2016

CAMBRIDGE, MA — Cardiovascular, neurologic, and orthopedic devices first approved in the Europe Union are nearly three times more likely to be subject to safety alerts and recalls than those first approved in the US, new research reveals[1].

The adjusted hazard ratio [HR] was 2.9 for postmarketing safety alerts and recalls (95% CI 1.4–6.2; P=0.005) and reached 4.6 for recalls alone (95% CI 1.5–14.0; P=0.006).

Overall, a quarter of the 309 devices in the study were associated with safety issues after they reached the market, Dr Thomas Hwang (Harvard University, Cambridge, MA) and colleagues reported recently in the BMJ.

Examples include Abiomed's AB-5000 console biventricular support system, recalled in 2010 because of a defect that could cause the device to stop pumping without warning, and the 2015 safety alert and label change for Medtronic's deep brain stimulation device, warning that reducing or stopping stimulation could worsen seizure frequency or severity.

Commenting to heartwire from Medscape, Dr Steve Nissen (Cleveland Clinic Foundation, OH) said, "The fundamental understanding here is that medical devices are essentially unregulated in Europe . . . and it does not protect the public."

There is no central regulatory process that allows the Europe Union to oversee medical devices, which is why many devices are first developed and tested in Europe and then brought to the US.

Indeed, 67% of the 309 devices identified in the analysis as receiving a Conformité Européenne (CE) mark between 2005 and 2010 were also approved in the US, of which 63% were first approved in the European Union.

"You can get a device approved in the United States with limited data, but you have to have some evidence of safety and efficacy. All you need in Europe is a CE mark, and it's extremely easy to get," said Nissen, adding that this "can be done by hiring a private company to do the analysis for you."

Where Are the Data?

Hwang and colleagues point out that Europeans have substantially less and lower-quality information available on the potential benefits and harms of new devices than Americans, "which raises ethical concerns because CE marking may be misinterpreted as signifying that devices are safe and clinically effective."

After combing public and commercial sources to identify the 309 devices (245 cardiovascular, 28 neurologic, and 36 orthopedic), the investigators searched Medline, Embase, and Web of Science for peer-reviewed publications.

Overall, publication rates 1, 2, and 5 years after regulatory approval were only 7%, 17%, and 37%, respectively.

Pivotal trial results were published for only 49% of 75 devices categorized as major innovations, defined as a device that was first in class, involved new technology, and made new claims with respect to its safety or effectiveness or both or involved new technology and was to be used in a new or expanded patient population.

"That's truly shocking," Nissen commented. "We've closed a lot of the gap here on drugs via the clinicaltrials.gov process where you have to register, and there are reporting registries for drugs, but there are still huge gaps on the device side."

Hwang and colleagues write that "at a minimum, policy makers should require greater transparency, including a public register of all CE-marked devices and summaries of their regulatory decisions (as is the case for drugs in the European Union and both drugs and devices in the United States)."

The European Society of Cardiology and others have called for a centralized system to evaluate high-risk drugs, public education about CE marking, and more transparency regarding clinical data.

The authors note in the article that as of January 2016, proposed revisions of the EU's directives on medical devices have failed to include a new regulatory body for devices. A new agreement between the European Parliament and European Council of European Communities, published June 27, 2016, does not include a new regulatory body but calls for, among other things, "stricter premarket control of high-risk devices with the involvement of a pool of experts at the EU level."

Not Just an EU Problem

The study raises serious question on both sides of the Atlantic, particularly given the antiregulatory climate on Capitol Hill and Congress's unwillingness to fund regulatory agencies, Nissen said.

In particular, he pointed to the 21st Century Cures Act, a package of bills before the Senate that would "further deregulate both devices and drugs" by providing faster approval.

Nissen said he also believes that the US Food and Drug Administration overuses the 510(k) provision rather than using the more rigorous premarket authorization (PMA) pathway that generally requires good randomized controlled trials and other studies designed to establish safety and efficacy. "In many ways the medical device world is a little bit like the wild, wild West," he added.

Hwang and colleagues report that devices approved in the US through the PMA process were nearly nine times more likely to have trial data published than non–PMA-approved devices (adjusted HR 8.6; 95% CI 2.8–26.9; P<0.001).

Balancing Interests

The investigators observe, however, that approving devices without first requiring evidence of safety and efficacy can shorten the time to market for new technologies. Most notable among these is transcatheter aortic-valve replacement, which was approved for symptomatic aortic stenosis in the European Union in 2007—3 years before its effectiveness was established in a published randomized trial and 4 years before gaining US approval.

On the other hand, widespread use of new devices without adequate testing can make informed treatment decisions difficult and may expose patients to an "increased risk of harms from devices of uncertain utility," they write.

Nissen acknowledged that cardiology is a very dynamic field, but said there is also a "boys-with-toys problem, particularly in interventional cardiology" where the "newest gee-whiz stent or gee-whiz guidewire will often get a lot of attention."

He added that the public and cardiologists need to understand that regulation is good because it allows physicians to have confidence that the devices and drugs they use will do their job safely and effectively.

"I want to point out that when you put a device in someone's body, putting it in and taking it out is not a trivial matter. I lived through the Björk-Shiley heart valve, where the valves were breaking and you had to make the agonizing choice of having a second open-heart operation to replace the faulty valve or take your chances that it wouldn't break."

Hwang has received funding from Harvard University and the Interfaculty Initiative in Health Policy and was employed by Blackstone and Bain Capital. Disclosures for the coauthors are listed in the paper. Nissen reports no relevant financial disclosures.

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org, follow us on Twitter and Facebook.

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