Characteristics of Clinical Studies Conducted Over the Total Product Life Cycle of High-Risk Therapeutic Medical Devices Receiving FDA Premarket Approval in 2010 and 2011

Abstract

Administration (FDA) approves high-risk medical devices, those that support or sustain human life or present potential unreasonable risk to patients, via the Premarket Approval (PMA) pathway. The generation of clinical evidence to understand device safety and effectiveness is shifting from predominantly premarket to continual study throughout the total product life cycle.OBJECTIVE To characterize the clinical evidence generated for high-risk therapeutic devices over the total product life cycle. DESIGN AND SETTINGAll 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. MAIN OUTCOMES AND MEASURESStudies were characterized by type (pivotal, studies that served as the basis of FDA approval; FDA-required postapproval studies [PAS]; or manufacturer/investigator-initiated); premarket or postmarket; status (completed, ongoing, or terminated/unknown); and design features, including enrollment, comparator, and longest duration of primary effectiveness end point follow-up. RESULTSIn 2010 and 2011, 28 high-risk therapeutic devices received initial marketing approval via the PMA pathway. We 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, 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.CONCLUSIONS AND RELEVANCE 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.

Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review

“…Our findings are consistent with previous studies showing that even postapproval studies required by the FDA to be conducted by manufacturers are not always performed in a timely manner [13][14][15] and with previous work demonstrating the variability in the number and completion of postmarketing studies of high risk medical devices. 25 The majority of the postapproval studies that we identified focused on surrogate markers of disease. Using surrogate markers instead of clinical outcomes for trial endpoints has become increasingly controversial, 26 with several approved drugs ultimately failing to confirm any clinical benefit [27][28][29] and an analysis of oncology surrogate markers finding variable correlation with overall survival.…”

Medical device transformation without delay

“…The FDA requires one pivotal and one non pivotal study for device approval, at minimum. A recent review of clinical trials found that the majority of devices have been approved with these minimal requirements, though some companies have ongoing studies throughout the device lifespan [7]. Regulatory bodies are left with the burden of navigating grey areas in approval and current accepted "best practices" in clinical trials.…”

“…Literature can be found on recommendations, with some suggesting device companies work toward the optimal clinical trial design and others suggesting cultural and understanding of clinical trial design be reformed. Recommendations also include the consideration that long term data is crucial to understand the device, safety and effectiveness, and can provide insight into new considerations and uses for the device [7].…”

“…Industry and academia expertise can be complimented by national and international regulatory guidance in consideration of best practices in clinical trial design. While clinical trials in medical devices may not be able to provide doubleblinded advantage, endpoint assessments in patient quality of life and subjective responses are valuable for the industry [7]. In ongoing evaluations, masking the investigator will allow distinct advantage in these newly considered endpoints.…”

The 21st Century Cures Act: can the regulatory framework survive the “cures”?

“…Over 43% of these studies did not use any comparator and enrolled a median number of patients of 241. The median duration of primary effectiveness end point follow-up was 3 months 8 .…”