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  /    /  II.4 Clinical Evaluations – Methods
Translational Pathway for Transcatheter Aortic Valves

Clinical Evaluations – Methods


Nicole Ibrahim, PhD


Nicole Ibrahim, PhD


Stanton Rowe

The clinical study of transcatheter aortic valve replacement (TAVR) technology has evolved in recent years, much like the U.S. regulatory pathway for TAVR devices has evolved since approval of the first device in 2011. The initial TAVR clinical trials were designed as strategy trials to demonstrate proof of concept for the transcatheter treatment of severe calcific stenosis of the native aortic valve. Early devices were evaluated in randomized controlled trials against the gold standard of surgical aortic valve replacement (SAVR) and took a surgical risk-based approach for patient selection. Patients at highest surgical risk for aortic valve replacement were randomized to TAVR versus optimal medical therapy, while patients considered to be candidates for surgery were randomized to TAVR versus SAVR. These early trials in extreme, high, and intermediate surgical risk populations helped to establish the foundation for the knowledge base of severe symptomatic aortic stenosis in the TAVR arena. Trials in low surgical risk patients are ongoing and will serve as an important piece of evidence for these series of strategy trials.

Beyond these seminal studies, new TAVR devices seeking the same indication as existing devices have been evaluated in device versus device trials. With several large randomized premarket trials and the accumulation of tens of thousands of patients captured post-market each year in the United States in the American College of Cardiology/Society for Thoracic Surgery Transcatheter Valve Therapy (TVT) Registry, there is an ever-expanding knowledge base in this device area. The technology is maturing and being optimized with second- and third-generation devices that incorporate new features that allow a lower profile, retrievability, and enhanced annular sealing. In addition to optimization of the device technology, advances in imaging, both pre- and intra-procedure, have led to rapid improvements in procedural planning, device placement, and outcomes. There is also a growing desire to explore TAVR in other patient populations where aortic valve replacement may be considered, such as asymptomatic severe aortic stenosis (AS), moderate AS, low-risk AS, aortic insufficiency, and even for bicuspid valve disease. Early results are being reported, but overall significant knowledge gaps remain in the clinical evaluation of TAVR in these disease states.

The regulatory approval pathways for iterative changes and indication expansions can vary depending on the design change and/or patient population being treated. For iterative changes, there are several considerations to take into account when determining the regulatory pathway, such as the purpose of the change and how the change will affect device delivery, acute performance, and long-term durability and performance. For minor design changes, preclinical engineering testing alone or in conjunction with in vivo animal studies may be sufficient to adequately assess the change. These types of alterations may include changes to the delivery system or minor changes to the implant. In some cases, a small amount of clinical data may be needed to support the safety and effectiveness of the modified device. This type of confirmatory clinical trial may be conducted with a smaller sample size and emphasis placed on acute procedural safety data with a confirmation of effectiveness that would include specific assessment of outcomes related to the purpose of the device change (e.g., reduced paravalvular leaks with addition of a skirt). For major design changes, a more traditional large clinical study with robust assessments of both procedural safety and clinically meaningful long-term effectiveness may be needed.

The regulatory approval pathway for indication expansions also vary depending on the disease state and patient populations. Important considerations include the incidence of the disease in the general population, the ability to identify an appropriate control group for clinical evaluation, and clinical equipoise for randomization in a clinical trial. Several mechanisms for clinical evaluation could be considered to support regulatory approval, which include nested single-arm registries, physician-sponsored studies, and use of real-world evidence. Nested singe-arm registries have become an important part of the regulatory toolbox for TAVR. The registries are typically embedded in a larger pivotal trial (often randomized) and they are intended to be of smaller sample sizes compared to the pivotal arms of the trial. The nested registries may or may not be statistically powered or hypothesis driven, and the data are generally evaluated descriptively. Importantly, the approval of the indication evaluated in a nested registry relies on the safety and effectiveness demonstrated in the pivotal trial comparison first followed by evaluation of the nested population. This approach has been used for indication expansion such as valve-in-valve and low-flow/low-gradient severe aortic stenosis.

Physician-sponsored studies may also be considered as another potential mechanism for indication expansion. This nontraditional pathway may be used when data collection is initiated by the physician rather than the device manufacturer. The clinical investigator assumes the responsibilities of both the regulatory sponsor and the investigator. Physician-sponsored studies have historically been used to treat patients that might not otherwise fall into the approved indication but have been used more recently to gather data that could support a marketing application. In the latter case, the trial would be designed to demonstrate reasonable assurance of safety and effectiveness for the proposed indication. Importantly, sponsor-investigator studies are subject to the same reporting requirements as traditional industry-sponsored trials and should comply with Part 812, Code of Federal Regulations Title 21 (also known as 21 CFR 812).

Finally, the use of real-world evidence may be considered for TAVR indication expansion. Real-world evidence has been used extensively for post-market surveillance of TAVR devices using the TVT Registry and, to a lesser extent, in the support of premarket decisions for TAVR indication expansion. When real-world evidence is used for regulatory decision making, the quality and quantity of the data are assessed in depth, including the accrual, adequacy, assurance, acceptability, and aggregate nature of the data. Consideration is given to the reliability of the data, the ability of the data to adequately address key endpoints in the appropriate patient population with adequate patient protection measures in place, the robustness of the data, the acceptance of the data in the larger clinical community, and whether aggregate data as are traditionally collected as part of real-world evidence are sufficient to make a regulatory decision. With the fast-growing accumulation of evidence for TAVR, reliable, robust, and relevant real-world evidence has the potential to be a very important regulatory tool for indication expansion.

Following approval of a new TAVR design, indication expansion, or iterative design change, a post-approval study may be required to address any remaining uncertainties that were not addressed during the pre-market phase. These conditions of approval may include a newly enrolled cohort of patients followed prospectively for a specified number of years or collection of real-world data in the form of active surveillance. The TVT Registry has been utilized as a means of post-market surveillance for approved TAVR devices and is linked to the Centers for Medicare & Medicaid Services (CMS) database for long-term surveillance (beyond 1 year).

A rapidly evolving device space with constant iterative design change and numerous gaps in the clinical knowledge base necessitate regulatory pathways for TAVR devices that are nimble yet robust. Creative approaches for both device iterations and indication expansion such as confirmatory studies, nested registries, physician-sponsored studies, and the collection of real-world data can facilitate efficient collection of evidence for regulatory approval. Finally, outcomes can continue to be monitored through traditional post-approval studies or the use of active surveillance through the TVT Registry.

The FDA has been actively collaborating with Japanese and European regulatory authorities in an effort to harmonize regulations across these diverse regions. Proof of safety and efficacy as well as manufacturing performance are universal requirements. Harmonizing regulations could simplify processes for approval, and there may be a day in the future where clinical trials across these three regions are performed under one protocol, and approval is granted across all three regions based upon such studies.

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