MVARC Document Offers Template for Mitral Valve Therapeutics Research

A group of 44 international experts across numerous specialties has released guidance aimed at easing and standardizing the study of new transcatheter mitral valve (MV) therapies, particularly those targeting mitral regurgitation (MR).

In 2 separate papers published in the July 21, 2015, issue of the Journal of the American College of Cardiology, members of the Mitral Valve Academic Research Consortium (MVARC) delve into clinical trial design and provide consensus definitions needed to establish consistency across studies.

“We felt that we needed to go beyond what had been done in any of the prior Academic Research Consortium meetings,” coauthor Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview.

Although the focus is on MR, “any of the principles in this document may also be applied to other MV conditions, including treatment of mitral stenosis, degenerated mitral bioprostheses, and failed surgical valvuloplasty,” Dr. Stone and colleagues write. 

Currently, there is only 1 approved transcatheter system for treating MV disease—MitraClip (Abbott Vascular). But EVEREST II, the trial used to evaluate that device, as well as the emergence of dozens of other products in the pipeline “have exposed the complexities required to properly evaluate MR therapies, specifically regarding the appropriate study population and control group, background medications and procedures, efficacy and safety endpoints, learning curve issues, and analysis cohort and statistical considerations,” they say, adding that a particular limitation of prior research has been the lack of standardized definitions.

Furthermore, in the realm of valvular disorders, MR presents challenges that aortic stenosis does not, according to Dr. Stone and colleagues.

“In contrast to calcific aortic stenosis, a relatively simple disease with limited etiologies and a straightforward pathophysiology,” they explain, “MR is a more complicated entity, due to the greater complexity of the MV structure and the numerous lesions and mechanisms that may lead to its failure.”

Treatment of MR therefore requires a multidisciplinary approach, which is exemplified by the inclusion of specialists spanning general and interventional cardiology, heart failure, valvular disorders, imaging, cardiac surgery, clinical trials, and statistics when creating the 2-part consensus document, with input from FDA representatives.

Part 1 focuses on the pathophysiology and prognosis of MR and the design of clinical trials; part 2 provides detailed definitions of relevant endpoints, including death, hospitalization, neurological events, bleeding, and several others.

“The adoption of these recommendations will afford robustness and consistency in the comparative-effectiveness evaluation of new devices and approaches to treat MR,” the authors say. “These principles may be useful for regulatory assessment of new transcatheter MV devices, as well as for monitoring local and regional outcomes to guide quality-improvement initiatives.”

In addition, according to Dr. Stone, the 2 parts of the document will be valuable to the practicing clinician outside of a research setting.

“I think that if the clinician takes the time to read these documents, they’ll develop greater understanding of the pathophysiology and approach to mitral regurgitation, current standard of care, therapies, prognosis, as well as the options that are available to their patients both today and tomorrow,” he said.

Importantly, the committee acknowledges the “highly dynamic and evolving” field of MV therapeutics and anticipates that regular revisions will be made to the recommendations.

FDA’s Viewpoint

The consensus document “offers important suggestions on the design and endpoints of clinical trials intended to support premarket approval applications,” John C. Laschinger, MD, Nicole G. Ibrahim, PhD, and Bram D. Zuckerman, MD, of the FDA’s Center for Devices and Radiological Health (Silver Spring, MD), write in an accompanying editorial.

“Appropriate adoption of the common definitional framework and trial design recommendations put forward in these documents will help avoid future problems with trial design that can adversely affect the ability to analyze data,” they continue. “Failure to identify and classify appropriate study populations or failure to define and use suitable individual or composite endpoints that are adequate for providing reasonable assurance of safety or effectiveness can be obstacles to device approval. The MVARC documents aim to address these issues proactively.”

They say the guidance is especially helpful as numerous transcatheter mitral repair and replacement devices are entering early stages of development.

“It is our hope that publication of the MVARC document will encourage sponsors and investigators to make use of early interaction with the [FDA],” they conclude. “For this field to mature at an optimal pace in the United States, it is essential that the FDA, sponsors, and investigators continue to collaborate closely to develop high-quality nonclinical and clinical data that ultimately result in beneficial devices for patients.”

Noting the perception that the United States trails behind the rest of the world in bringing new technologies to market, Clifford J. Kavinsky, MD, PhD, of Rush University Medical Center (Chicago, IL), told TCTMD in a telephone interview that the consensus document will help smooth the process of getting new transcatheter MV therapies approved.

“It generates a uniform way of looking at the mitral valve and establishing benchmarks for carrying out clinical research in a way that is approved by the FDA, so that when these trials are done they are readily received by the FDA, leading to earlier approvals and promulgation to the public,” said Dr. Kavinsky, who is a spokesperson for the Society for Cardiovascular Angiography and Interventions. “I think this is very important as we move towards the next frontier, which is now the mitral valve.”

Note: Dr. Stone and several other MVARC participants on both documents are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

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Sources: 
1. Stone GW, Vahanian AS, Adams DH, et al. Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: part 1: clinical trial design principles: a consensus document from the Mitral Valve Academic Research Consortium. J Am Coll Cardiol. 2015;66:278-307.
2. Stone GW, Adams DH, Abraham WT, et al. Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: part 2: endpoint definitions: a consensus document from the Mitral Valve Academic Research Consortium. J Am Coll Cardiol. 2015;66:308-321.
3. Laschinger JC, Ibrahim NG, Zuckerman BD. Mitral Valve Academic Research Consortium consensus report: the US Food and Drug Administration perspective [editorial]. J Am Coll Cardiol. 2015;66:322-323.

Disclosures:

• The MVARC initiative was funded by unrestricted grant support from Abbott Vascular, Boston Scientific, Cardiac Dimensions, Cordis, Edwards Lifesciences, Guided Delivery Systems, Medtronic, Mitralign, and Valtech.
• Dr. Stone reports having served as a consultant for multiple pharmaceutical and device companies and having equity in the Biostar and MedFocus family of funds, Caliber, Guided Delivery Systems, MiCardia, and Vascular Nanotransfer Technologies.
• Drs. Laschinger, Ibrahim, Zuckerman, and Kavinsky report no relevant conflicts of interest. 

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