The FDA oversees clinical trials exclusively within the United States. The FDA’s mission statement consists of two primary parts: (1) promoting public health by promptly and efficiently reviewing clinical research and taking appropriate action on marketing of regulated products in a timely manner; and (2) protecting public health by ensuring a reasonable assurance of safety and effectiveness of devices intended for human uses [1]. The Center for Devices and Radiological Health is the branch that oversees medical devices (including heart valves).

In the United States, there are three regulatory classes of devices based on the considered levels of risk involved with a given device. All class I–III devices are subject to general controls, meaning the FDA looks at factors like labeling, registrations, etc. Class I devices have the lowest amount of risk and regulatory controls (e.g., devices such as elastic bandages and surgical gloves). Class II devices must meet specific performance standards in addition to all class I requirements (e.g., devices such as surgical drapes). Most stringently, class III devices require premarket approvals (PMAs) to ensure both their safety and effectiveness. As such, class III devices are also considered as the riskiest category of devices, and include implantable pacemakers and heart valves.

It should be noted that the FDA regulations for medical device products are detailed in Title 21 of the Code of Federal Regulations (CFR). The most applicable parts of CFR 21 that apply to heart valve clinical trials include Part 812 (Investigational Device Exemption, or IDE) and Part 814 (PMA). Most new heart valves are required to undergo IDE clinical trials before receiving FDA approval.

More specifically, according to the FDA’s Heart Valves—Investigational Device Exemption (IDE) and Premarket Approval (PMA) Applications Draft Guidance (dated January 20, 2010): “a replacement heart valve is a device intended to perform the function of any of the heart’s natural valves” [2]. A replacement heart valve is defined as a pre-amendment type device, that is, a device marketed prior to passage of the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act (the Act).

Furthermore, this FDA’s Draft Guidance explains that clinical trials are needed to evaluate most new replacement heart valve designs and also recommends that clinical investigations of such a replacement heart valve are executed by following the methods described in ISO 5840:2005 or an equivalent document. Specifically, the document ISO 5840:2005 is a guide for cardiovascular implants and valve prostheses provided by the International Organization for Standardization (ISO) [3].

In Europe there are various notified bodies that provide oversight of clinical trials. The most prevalent regulatory oversight applies to the 27 countries in the European Economic Area; these are countries required to obtain a CE mark (“Conformité Européenne” or European Conformity). Importantly, the criteria to receive a CE mark in Europe are notably different than receiving FDA approval. As mentioned previously, to receive approval for a new heart valve technology in the United States, the manufacturer must demonstrate the device to be reasonably safe and effective. To receive approval to release a device to market in the European Union, the manufacturer must demonstrate that the heart valve is safe and that it performs in a manner consistent with the manufacturer’s intended use [4]. Interestingly, given these differences between geographic regulatory approvals, most manufacturers typically receive approval in Europe or other countries before the United States. Moving into other geographies poses different obstacles which may influence the intended quality and importance of every clinical trial completed for the new device.

Similar to the importance of following Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) when prototyping heart valves, it is important to follow guidelines for how to appropriately conduct clinical studies that could affect the safety and well-being of human participants. Good Clinical Practice (GCP) was developed by a collaborative group of regulatory authorities of various worldwide geographies including the European Union, Japan, and the United States by the International Conference on Harmonisation. GCP was finalized in 1996 and became effective in 1997; it provides international assurance that data and results of clinical investigations are credible and accurate, and that the rights, safety, and confidentiality of participants in the clinical research studies are respected and protected. More specifically, GCP consists of 13 principles (Table 17.1).

Prior to planning and execution of a heart valve trial, it is important to research and understand all current published information and relevant heart valve trial data. There is much to be gained from knowing the details of previous trial designs as well as the subsequent outcomes associated with those trials. For gaining FDA approval for any cardiac device, the importance of clinical evidence cannot be stressed enough. In other words, in the beginning stages of planning a clinical trial design, associated publications and previous research can help shape important components for the new trial, such as patient inclusion/exclusion criteria, statistical designs employed in such trials, and/or the general patient populations to be studied.

A well-controlled clinical investigation includes a clear objective and defined methods of analyses. More specifically, the objective should address the proposed medical claims for the investigational device and these should be refined to specifically address the safety and effectiveness of the heart valve in a defined population. Next, it is important to structure a trial so there can be a valid comparison to controls. For example, in current transcatheter valve therapy trials, the new therapy (transcatheter valves) is directly compared to a standard open-heart valve surgery. In other words, a control group in such a trial gives the trial results a meaningful comparison to an existing therapy or treatment. Often, an appropriate control group can be identified by performing a careful and thorough literature search. Furthermore, performing prior research on the specific disease or conditions that the newly designed heart valve will intended to treat is equally important in order to understand the natural progression of the disease or condition and the current benefits or limitation of other treatments. It should be noted that often this step of researching the disease or condition is completed in earlier phases of prototyping of the actual heart valve, but it is recommended that it be reviewed once again just prior planning your clinical trial. Finally, literature searches on similar treatments/heart valves can also assist in identifying the appropriate disease populations and justifying the inclusion and exclusion criteria for the trial.

When the patient population and treatment/control cohorts are clearly identified, one needs to consider the next set of factors to impact the ultimate design. First, the type of trial design must be determined, whether it is randomized, blinded, or double-blinded. Each of the designs may strengthen the significance of the obtained results, while also minimizing bias and providing comparability of groups. Well-defined trial endpoints are also of great significance for the overall success of a clinical trial. For example, typical heart valve trial endpoints should encompass both safety and effectiveness measures. Note that adverse events often comprise the safety endpoint for a given trial. Typically, effectiveness endpoints are found in the form of the presence or absence of a clear, definite effect on a patient, e.g., in a heart valve trial this may include death or the resultant effective orifice area (EOA). Table 17.3 provides a list of key steps to consider in designing a clinical trial for the development of a new heart valve technology.