US Food and Drug Administration–Mandated Postmarketing Studies for High-risk Cardiovascular Devices Approved 2015-2019

Abstract

This qualitative study assesses the availability and strength of evidence of postapproval studies for high-risk cardiovascular devices subsequent to the 21st Century Cures Act.

Regulation of medical devices by the US Food and Drug Administration (FDA) is a balance between ensuring safety and efficacy and the timely availability of novel devices. The 21st Century Cures Act of 2016¹ shifted this balance toward expediting approval. The Cures Act stated that the FDA must “consider the role of postmarket information in determining the least burdensome means”¹ for approval. As set forth in the FDA guidance document on balancing premarket and postmarket data, the Secretary of Health and Human Services can reduce premarket data on effectiveness “through reliance on postmarket controls.”²

Prior to the Cures Act, 65% of FDA approvals for high-risk cardiovascular devices were based on a single study with a median follow-up of less than 1 year, and fewer than one-third of the approvals were supported by a randomized clinical trial.³ Although postapproval studies were required for about half of high-risk devices, the studies were limited because of small sample sizes, frequent delays, and restricted accessibility of the data.⁴ For high-risk devices approved between 2010 and 2011, only 13% of postapproval studies were completed within 3 to 5 years of approval, and 55% within 8 to 10 years, while 37% reported final results via ClinicalTrials.gov or journal publication within 8 to 10 years.^5,6 In this qualitative study, we assessed the availability and strength of evidence of postapproval studies subsequent to the Cures Act.

Methods

We searched the FDA Premarket Approval database to identify all original class III (highest risk) cardiovascular devices approved from January 1, 2015, through December 31, 2019. We used January 1, 2017, to divide devices approved before and after the Cures Act. We identified all corresponding postapproval studies in the FDA Post-Approval Studies database as well as study status (eg, completed, ongoing, terminated), study design (eg, prospective cohort, randomized clinical trial), blinding, randomization, control group, and primary end points (eMethods in the Supplement). We abstracted data between April 1, 2020, and May 5, 2021. Analyses were performed using Microsoft Excel for Mac 2011, version 14.5.6. Per University of California, San Francisco Institutional Review Board rules, this study was exempt owing to its use of publicly available data.

Results

From 2015 through 2019, the FDA approved 71 high-risk cardiovascular devices. There was no significant increase in the frequency of postapproval studies associated with passage of the Cures Act: 59% (16 of 27) beforehand and 75% (33 of 44) afterward (P = .16). Of the 68 postapproval studies mandated for 49 devices, 48 (71%) were unblinded prospective cohort studies (Table). The 12 (18%) randomized clinical trials were the only studies with active control groups. Across the 68 postapproval studies, there were 105 primary outcomes. Most studies had 1 primary outcome (n = 46); some studies had 2 because they included both a safety and an efficacy primary outcome (n = 18), and 4 studies had more than 2 primary outcomes because they included multiple studies. Thirty-seven postapproval studies used primary outcomes that included surrogate measures, whereas 31 used strictly clinical outcomes.

Table. Characteristics of FDA-Mandated Postapproval Studies for 49 High-risk Cardiovascular Devices Approved Between 2015 and 2019.

Characteristic	No. (%) (n = 68)
Type of study
Prospective cohort	48 (71)
Randomized clinical trial	12 (18)
Active surveillance	8 (12)
Blinding
Single blinding	5 (7)
No blinding	63 (93)
Controls
Active	12 (18)
Historical	7 (10)
OPCa	23 (34)
None	23 (34)
Unknown	3 (4)
Primary outcomes per PAS
1	46 (68)
2	18 (26)
3	1 (2)
4	1 (2)
8	2 (3)
PAS primary outcome measures
Surrogateb	37 (55)
Clinical	31 (46)

Abbreviations: FDA, US Food and Drug Administration; OPC, objective performance criterion; PAS, postapproval study.

^a The OPC is a fixed number or performance standard that is based on published literature or registries and used in place of a control group. As an example, the Melody valve (Medtronic) OPC was 36% for freedom from transcatheter pulmonary valve dysfunction 5 years after implant.

^b Surrogate measures are measurements that substitute for a clinically meaningful end point, such as primary patency of a stent based on Doppler velocities (surrogate) rather than claudication (clinical).

At a median follow-up of 4 years, 26 (38%) studies were completed, 30 (44%) were ongoing, and 12 (18%) had been delayed, revised, or terminated; the FDA Post-Approval Studies database provided no explanations. Of the completed studies, 25 of 26 (96%) listed results, compared with 10 of 30 (33%) for ongoing studies and none of the 12 delayed, revised, or terminated studies.

Discussion

Since the implementation of the Cures Act, our study found no significant increase in the frequency of FDA postapproval study mandates for the highest-risk cardiovascular devices, despite increased reliance on such data for some devices. Postapproval studies were limited by delays, revisions, and terminations; lack of active control groups; and an emphasis on surrogate rather than clinical outcomes. Limitations of our study include the focus on cardiovascular devices only, lack of consideration of additional postapproval studies completed after May 2021, and exclusive reliance on the FDA website for data.

To improve the timeliness, quality, and availability of postmarketing evidence, the FDA should consider requiring postmarket randomized clinical trials that use clinical end points. The FDA should also consider implementing time-limited device approvals, whereby continued marketing would be contingent on timely generation and reporting of clinically meaningful postapproval data.

Supplement.

eMethods.