Clinical Evidence Gathering Shifting to Post-Approval

The U.S. relies on gathering clinical data to show a device is safe and effective before the FDA will grant approval. But that’s changing, according to a new study.

Harlan Krumholz, M.D., the Yale University professor who was hired by Medtronic plc to review all the Infuse data, has just co-authored a study that found that “the generation of clinical evidence to understand device safety and effectiveness is shifting from predominantly premarket [PMA] to continual study throughout the total product life cycle.”

That’s how the Europeans do it. They get devices out to patients faster, but require more post-approval data through device registries and other means.

Krumholz, along with post graduate student Vinay Rathi and others said that their study shows that many high-risk therapeutic devices get FDA approval with only one study proving their safety and efficacy before going to market.

The researchers looked at all clinical studies of high-risk therapeutic devices receiving initial market approval via the PMA pathway in 2010 and 2011 identified through ClinicalTrials.gov and publicly available FDA documents as of October 2014.

Here’s what they found.

• Eight high-risk therapeutic devices received initial marketing approval via the PMA pathway. They also identified 286 clinical studies of these devices: 82 (28.7%) premarket and 204 (71.3%) postmarket, among which there were 52 (18.2%) nonpivotal premarket studies, 30 (10.5%) pivotal premarket studies, 33 (11.5%) FDA-required PAS (post-approval studies), and 171 (59.8%) manufacturer/investigator-initiated postmarket studies.

• Six of 33 (18.2%) PAS and 20 of 171 (11.7%) manufacturer/investigator-initiated postmarket studies were reported as completed.

• No postmarket studies were identified for 5 (17.9%) devices; 3 or fewer were identified for 13 (46.4%) devices overall.

• Median enrollment was 65 patients (interquartile range [IQR], 25-111), 241 patients (IQR, 147-415), 222 patients (IQR, 119-640), and 250 patients (IQR, 60-800) for nonpivotal premarket, pivotal, FDA-required PAS, and manufacturer/investigator-initiated postmarket studies, respectively.

• Approximately half of all studies used no comparator (pivotal: 13/30 [43.3%]; completed postmarket: 16/26 [61.5%]; ongoing postmarket: 70/153 [45.8%]). Median duration of primary effectiveness end point follow-up was 3.0 months (IQR, 3.0-12.0), 9.0 months (IQR, 0.3-12.0), and 12.0 months (IQR, 7.0-24.0) for pivotal, completed postmarket, and ongoing postmarket studies, respectively.

They concluded that among high-risk therapeutic devices approved via the FDA PMA pathway, “total product life cycle evidence generation varied in both the number and quality of premarket and postmarket studies, with approximately 13% of initiated postmarket studies completed between 3 and 5 years after FDA approval.”