Assessment of Clinical Trial Evidence for High-Risk Cardiovascular Devices Approved Under the Food and Drug Administration Priority Review Program

Abstract

This study uses publicly available FDA summaries to analyze the quality of evidence in pivotal studies that support cardiovascular premarket device approval under FDA priority review from 2007 to 2017.

This study evaluates the randomized clinical trials conducted to provide evidence of the safety and effectiveness of cardiovascular devices approved by the Food and Drug Administration (FDA). The FDA approves high-risk devices through premarket approval if it determines the device provides reasonable assurance of safety and effectiveness. The dual goals of this approval process are to ensure patient safety and facilitate access to beneficial technologies. For the past several decades, priority review mandated by legislation has intended to hasten FDA approval, whereby an application receives precedence in review and additional review resources, if needed. The 21st Century Cures Act of 2016 introduced the Breakthrough Devices program, an initiative that is built on but supersedes another program known as Priority Review. Under Breakthrough Devices, the FDA “may accept a greater degree of uncertainty of the benefit-risk profile for these devices if the uncertainty is sufficiently balanced by other factors […] and adequate postmarket controls to support premarket approval.”¹ The quality of evidence required for cardiovascular devices to be approved under Priority Review is not known.

Methods

Using publicly available FDA summaries, we conducted a descriptive analysis of pivotal studies that support all high-risk cardiovascular devices approved, from January 1, 2007, to December 31, 2017, through the original premarket process under the Priority Review program. Per the human research policies of the institutional review board of the University of California, San Francisco, this study did not require institutional review board approval, and informed consent was not obtained, as this study involved no human participants.

For all studies, we analyzed these design features: number of patients enrolled, randomization, blinding, use and type (active or retrospective) of controls, and post hoc analysis. For all primary end points, we analyzed these characteristics: composite, surrogate, type of analysis (noninferiority, superiority, or objective performance criteria), and achievement of end point. If a device went to an FDA expert device panel, we analyzed the panel’s recommendations. We tabulated the postapproval study requirements and the existence of either a Class I (“a reasonable probability that the use … will cause serious adverse health consequences or death”) or a Class II (“may cause temporary or medically reversible adverse health consequences or … the probability of serious adverse health consequences is remote”) recall.²

Results

Cardiovascular devices accounted for 14 of the 29 premarket devices (48%) approved under Priority Review between January 1, 2007, and December 31, 2017. For 8 of the 14 devices, the FDA summaries explained why Priority Review was granted.

Eighteen pivotal studies were conducted for the 14 cardiovascular devices, and a mean (SD) of 1.3 (0.5) pivotal studies supported each device. None of the 18 studies was double-blind, and 13 studies (72%) used surrogate end points (Table 1). The studies enrolled a mean (SD) of 499 (542) patients. Nine studies used a noninferiority hypothesis for at least 1 primary end point. Three device approvals included post hoc analyses, and 2 of these devices did not meet any prespecified primary end points.

Table 1. Characteristics and End Points of 18 Pivotal Studies and Their Primary End Points.

Variable	Studies, No. (%)
Randomized	9 (50)
Single-blind	3 (17)
Double-blind	0
Controls	14 (78)
Active	8 (44)
Retrospective	6 (33)
Used composite end points	16 (89)a
Used surrogate end points	13 (72)a
All primary end points met	10 (63)b
Some primary end points met	15 (94)b
No primary end points met	1 (6)b

^aThirteen (72%) of 18 pivotal studies used both composite and surrogate end points. Fifteen (83%) of 18 studies included separate primary safety and effectiveness end points.

^bTwo studies were excluded that did not have at least 1 primary end point, results, and statistical analysis of the results.

At the FDA’s request, the expert advisory panels reviewed 10 of these devices, including 2 devices that were reviewed for a second time after the requested additional information was provided. There were 9 panel votes on safety and effectiveness, and 4 of 9 votes did not find the devices to be effective (Table 2). The FDA required postapproval clinical studies for 13 of the 14 devices. As of May 23, 2018, there have been 2 Class I and 13 Class II recalls for 6 devices (Table 2).

Table 2. Approved High-Risk Cardiovascular Devices, Expert Advisory Panel Votes or Recommendations, and Recalls.

Device	Applicant	Approval Year	Safety Vote, No., Yes/No/Abstentiona	Effectiveness Vote, No., Yes/No/ Abstentiona	Risks-Outweigh-Benefits Vote, No., Yes/No/ Abstentiona	Recall, No. (Class)b
Micra Transcatheter Pacing System	Medtronic Inc	2016	NAc	NAc	NAc	0
Cheatham Platinum Stent System	NuMED Inc	2016	NA	NA	NA	0
Edwards SAPIEN 3 Transcatheter Heart Valve and accessories	Edwards Lifesciences LLC	2015	NA	NA	NA	1 (Class I)
WATCHMAN LAA Closure Implant	Boston Scientific Corp	2015	12/0/0	6/7/0d	6/5/1	2 (Class II)
ResQCPR System	Advanced Circulatory Systems Inc	2015	10/0/0	2/8/0	7/3/0	0
Melody TPV and Ensemble Transcatheter Valve Delivery System	Medtronic Inc	2015	NA	NA	NA	0
IN.PACT Admiral Paclitaxel-Coated PTA Balloon Catheter	Medtronic Inc	2014	NA	NA	NA	0
LUTONIX 035 Drug-Coated Balloon PTA Catheter	Lutonix Inc	2014	9/0/0	9/0/0	9/0/0	0
CardioMEMS HF System	St Jude Medical	2014	11/0/0	4/7/0	6/4/1	0
MitraClip Clip Delivery System	Abbott Vascular	2013	8/0/0	4/5/0d	5/3/0	1 (Class I)
Edwards SAPIEN Transcatheter Heart Valve and accessoriese	Edwards Lifesciences LLC	2012	10/2/0	12/0/0	11/0/1	2 (Class II)
Subcutaneous Implantable Defibrillator S-ICD System	Boston Scientific Corp	2012	8/0/0	7/1/0	7/1/0	6 (Class II)
AtriCure Synergy Ablation System	AtriCure Inc	2011	5/4/1d	9/0/0	5/3/1	0
Edwards SAPIEN Transcatheter Heart Valve and accessoriesf	Edwards Lifesciences LLC	2011	7/3/0	9/1/0	9/0/1	3 (Class II)

Abbreviations: HF, heart failure; LAA, left atrial appendage; NA, no advisory panel; PTA, percutaneous transluminal angioplasty; S-ICD, subcutaneous implantable cardioverter defibrillator; TPV, transcatheter pulmonary valve.

^aThe circulatory systems device or general issues advisory panel voted on the following 3 questions: Is there reasonable assurance that the device is safe? Is there reasonable assurance that the device is effective? Do the benefits outweigh the risks of this device for use in the indicated patient population?

^bAs of May 23, 2018.

^cIf a device went to an advisory panel more than once, the final panel vote is reported here. The Micra pacemaker went to a general issues panel, which gave recommendations instead of a vote.

^dThe panel chair placed the tie-breaking vote.

^eTransapical delivery.

^fTransfemoral delivery.

Discussion

We found that most FDA Priority Review approvals for the cardiovascular devices were granted on the basis of a single nonrandomized, nonblinded pivotal study that used surrogate end points, and nearly half of FDA expert advisory panels who reviewed these studies deemed the devices safe but not effective. Our results are consistent with findings in previous studies for cardiovascular devices approved between January 1, 2000, and December 31, 2007, mostly through standard review.^3,4

Most cardiovascular devices approved under Priority Review are implanted permanently; thus, their risks and benefits should be well understood before clinical use. High-quality preapproval data, studies with a large sample size, and longer follow-up than the mean of 15 months for the studies we reviewed may reduce the likelihood of recalls.

Priority Review places emphasis on confirmatory evidence from postapproval studies. However, previous research has shown that only 13% of postapproval studies were completed 3 to 5 years after FDA approval of a device.⁵ As of June 2018, the FDA has not imposed a penalty for the delay or failure to complete a postapproval study.⁶ To best ensure safety and effectiveness of high-risk devices, the FDA should require high-quality data under the new Breakthrough Devices program designation. To ensure that device manufacturers are completing postmarketing studies and acting on the resulting data, the FDA should issue time-limited approvals with mandated periodic re-review of the device’s safety and effectiveness.