Study: Some breakthrough-designated devices have limited evidence supporting safety, effectiveness

The US Food and Drug Administration (FDA) evaluated most therapeutic devices granted breakthrough designation within established review goals, but according to recent research published in JAMA Internal Medicine, some devices had limited clinical evidence supporting their safety and effectiveness.

Many therapeutic breakthrough-designated devices are novel and were reviewed within established Medical Device User Fee Authorization (MDUFA) goals, but about 1 in 10 devices were authorized without clinical testing, 1 in 3 had surrogate markers for primary endpoints, 1 in 8 did not have a comparator when testing effectiveness, and 1 in 7 did not meet their primary endpoint for effectiveness, Kushal T. Kadakia of Harvard Medical School in Boston, and colleagues wrote.

“These results question whether the [Breakthrough Devices Program] is delivering on the Congressional mandate to expedite the development of devices that offer substantial advantages over existing alternatives,” Kadakia and colleagues wrote in their study.

The researchers performed a cross-sectional study of 75 therapeutic breakthrough-designated devices authorized by FDA between January 2016 and September 2024. Kadakia and colleagues evaluated whether the device was considered novel, the time it took the FDA to perform a premarket review of the device, and whether FDA required any postmarket studies from the sponsor.

They identified 34 high-risk devices (45.3%) that went through the premarket approval (PMA) pathway, which included 23 first-of-a-kind medical devices (67.6%) and 14 devices commercialized first in the US (41.4%). Other devices reviewed and included in the study were authorized through 510(k) (32%) or de novo pathways (22.7%). The most common products reviewed included devices that treated cardiovascular conditions (32%), orthopedic conditions (21.3%), and neurologic conditions (17.3%).

Overall, the mean FDA review time across therapeutic breakthrough-designated devices was 225.8 days, while the review time was 243.3 days for high-risk devices. For 30 high-risk devices that had applicable MDUFA goals, FDA reviewed 22 devices (73.3%) within statutory target timeframes.

In 39 of 75 studies (52%), randomized designs were used, while 34 of 75 trials (45.3%) used blinding in the study design, 61 of 75 studies (81.3%) used a comparator, and 44 of 75 studies (58.7%) had a sham or standard of care control arm.

Kadakia and colleagues found 70 of 75 studies (93.3%) evaluated primary effectiveness as an endpoint, and 5 studies used safety-based endpoints. For the 70 studies evaluating effectiveness, 62 studies (88.6%) had a single endpoint, while 8 studies (11.4%) had more than one endpoint. The researchers noted 67 of 75 devices (89.3%) had premarket clinical testing, which included 75 pivotal studies with 81 primary endpoints, and the median follow-up for all endpoints was 6 months.

When assessing primary endpoints across studies, researchers found 40 endpoints (49.4%) were surrogate endpoints, and 66 endpoints (81.5%) contained statistical testing, while 15 endpoints (18.5%) did not have statistical testing. Among endpoints with statistical testing, 54 endpoints (81.8%) were met across included devices. For endpoints that did have statistical testing, 43 endpoints (65.2%) evaluated superiority, 17 endpoints (25.8%) examined a performance goal or objective performance criteria for the device, and 6 endpoints (9.1%) looked at noninferiority.

There were 30 breakthrough-designated devices for which FDA required 46 total postmarket studies. Delays occurred in 19 of 40 postmarket studies (41.3%). Devices were on the market for a mean of 2.4 years, and 9 of 75 devices (12.0%) experienced a recall.

Kadakia and colleagues said their results suggest the Breakthrough Devices Program “has fostered manufacturer participation and expedited device availability more than prior FDA programs,” noting that FDA authorized 178 devices through expedited review between 1991 and 2015, and 127 devices since 2016 through the Breakthrough Devices Program.

“However, our results illuminate the tradeoffs between regulatory selectivity, speed, and rigor for breakthrough-designated devices,” the researchers explained. Devices authorized through the 510(k) pathway by establishing substantial equivalence to existing devices may not improve patient outcomes, they noted, while the use of surrogate endpoints in some pivotal trials may ultimately not result in clinical improvement. The agency has also not required postmarket studies for approximately 60% of therapeutic devices granted breakthrough designation, they said.

“Even when the FDA required postmarket studies, these studies predominantly used surrogate end points, raising doubts whether postmarket data are sufficient to validate the safety and effectiveness of breakthrough-designated devices,” they wrote. “Lack of available and adequate confirmatory studies may perpetuate uncertainties for patients and physicians seeking to make treatment decisions.”

To improve the program, Kadakia and colleagues suggested the agency could be more selective in its picks for devices it grants breakthrough designation, make sponsor plans for premarket clinical testing with primary endpoints a requirement for the pathway, and require postmarket studies that evaluate clinical benefit in devices that used surrogate markets or did not meet primary endpoints. FDA could also be more transparent when authorizing a device as to why it granted the device breakthrough designation to help patients assess safety and effectiveness, they said.

Other reforms could come from Congress, the researchers said. “Congress could grant the FDA authority to require postmarket study initiation at the time of authorization and withdraw breakthrough designation if postmarket studies fail to confirm clinical benefit,” they wrote. “The agency already has such authorities for drugs authorized under expedited review programs and has withdrawn designations for approximately 15% of breakthrough-designated drugs to date.”

JAMA Intern Med Kadakia et al

Study: Some breakthrough-designated devices have limited evidence supporting safety, effectiveness

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