Basic Concepts in Device Development
Early Feasibility Studies
Andrew Farb, MD
David G. Reuter, MD, PhD
Andrew Farb, MD
David G. Reuter, MD, PhD
The Device Development Process
Unlike drugs, in which the pharmaceutical agent represents a finished product, medical device development is an iterative process in which prototypes are often tested in a “learn-as-you-go” approach. Based on results from bench studies, animal experiments, and initial human use, medical devices, and the procedures used in their operation, are frequently modified to improve their performance (i.e., improve their safety and/or effectiveness).
Furthermore, although drugs may be targeted to treat specific disease states, they often have systemic off-target effects, and their precise mechanism of action is incompletely understood. In contrast, most medical devices act locally, providing opportunities to understand their physiological and mechanistic actions and directly observe local tissue responses to their implantation. Finally, most drugs can be administered simply by oral ingestion or parenteral delivery. However, the use of implantable devices typically requires highly skilled operators, and learning curves for optimal device performance can be steep. These special device development considerations have shaped the way devices are conceived, built, tested, and regulated.
With medical device development, the transition from animal studies to human studies represents a significant challenge because animal models (healthy or diseased) are an incomplete model of the human condition. To design a device, one needs to accurately understand the forces on the device. While a preliminary assessment of those forces can be characterized in animal models, it is important that designers understand the limitations of extrapolating findings to the clinical environment. Device modifications are often greatest in the early development stages, when clinical boundary conditions are used to fine-tune the information collected from animal studies. A device evaluation system that facilitates rapid device iteration and refinement, while protecting patients and minimizing risks associated with exposure to early prototypes, enhances the production of beneficial medical devices.
The past 2 decades witnessed a migration of the initial clinical testing of new medical devices from the United States to overseas sites. In 2004, 87% of clinical studies for medical technology products listed on ClinicalTrials.gov were conducted in the United States, but that number dropped to 45% by 2009. All too often, a novel medical device would be designed in the United States, but after conducting a limited set of nonclinical tests, the first clinical use of the investigational product would be conducted outside of the United States (e.g., in Europe). While initial clinical use was proceeding overseas, additional bench and animal tests would be conducted to meet U.S. regulatory requirements before starting a U.S. human study. Eventually, a U.S. clinical study would receive approval to commence, but this might occur after the device was made available for use in Europe. This paradigm had the effect of keeping ineffective or unsafe devices off the U.S. market, but at a cost of delaying the availability of useful devices for U.S. patients.
Accompanying this trend, there emerged a growing awareness of the time lag in the access to beneficial medical devices for U.S. patients, delays in the U.S. physician learning curve in the optimal use of new technologies, a recognition that some devices were being developed exclusively for non-U.S. markets, and a concern that the process of device innovation itself might follow offshore. Many clinical trial ecosystem factors contributed to these developments, but an important factor was the Food and Drug Administration’s (FDA) nonclinical testing requirements to initiate clinical studies of new devices in the United States.
The development of novel biomedical technologies is a team effort, with expertise derived from both clinical and engineering disciplines. An unintended barrier that developed when U.S. companies tested their products oversees was that engineers could not be as fully engaged in the real-time observation and analysis of the device performance. User-designer dialogue facilitated by testing in the same geography as the device was produced enables more efficient and thorough iteration. Further, the understanding of the technology that regulators achieve by early interaction with developers, especially in the early stages of device evolution, provides more informative feedback via a deeper appreciation and nuances of both the clinical condition and the novel therapy. These early contacts can ultimately provide a higher level of patient protection.
FDA’s central mission is the protection of public health, but an equally important mission is public health promotion. In an effort to begin to reverse the adverse trends in the early clinical evaluation of new promising medical devices, FDA’s Center for Devices and Radiological Health (CDRH) embarked on a process that resulted in creating an Early Feasibility Study (EFS) Program, the basis of which was an EFS Guidance document. Notably, the EFS Program was intended to facilitate EFS being performed in the United States under the current IDE regulations, which include important patient protection measures for research subjects participating in clinical trials. The EFS Guidance document and EFS Program will be discussed in more detail below.
What Is an EFS?
As defined in the FDA Guidance document, “Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies” (2), an EFS is a limited clinical investigation involving a small number of subjects (typically 20 patients or fewer) in a study of a device that may be early in development, typically before the device design has been finalized. An EFS is needed when information to advance device development cannot be practically obtained with additional nonclinical assessments, or if nonclinical tests are unavailable; at this stage of device development, clinical use in humans is necessary. The device being used in an EFS may be unapproved (investigational) or may involve a new intended use for a device that has already been in clinical use. An EFS may be done concurrently or in conjunction with non-U.S. clinical studies of the same device and procedure.
There are many potential objectives in conducting an EFS. For example, an EFS can provide important initial insights into device safety parameters, mechanisms of device failure, patient characteristics that may impact device performance, operator technique challenges, therapeutic parameters to improve device performance, human factors to facilitate device handling, and perhaps most importantly, whether the device performs as intended (that is, proof of concept). After the engineering, procedural, and clinical variables are refined and optimized during the early clinical testing, the finalized device can be evaluated through larger studies (including randomized controlled trials, when appropriate), which provide robust data to guide clinical and regulatory decisions.
EFS Versus First-in-Human, Traditional Feasibility, and Pivotal Studies
Although many FIH studies are EFS, an EFS is not the same as a FIH study. An FIH study is a type of clinical investigation in which a device for a specific indication is evaluated for the first time in human subjects, and not every first human use of a device requires an EFS. For example, the nonclinical evaluation for a device may be well-established by FDA guidance or recognized standards, such that a larger feasibility or even a pivotal study may be the appropriate initial study (and would still by definition be classified as an FIH study). Moreover, an EFS does not necessarily involve the first clinical use of a device; the device may have been used in in a few patients outside of the United States, but the early stage of device development still fits EFS criteria for initial clinical evaluation in the United States.
There are three basic IDE device study types: EFS, traditional feasibility studies, and pivotal trials (Figure 1). An EFS IDE usually involves a device that is earlier in development as compared to a traditional feasibility study. It is common for an EFS to be supported by fewer nonclinical data than would be expected for a traditional feasibility or pivotal study with some nonclinical testing deferred until the device design is finalized.
Figure 1. Types of Clinical Studies
Since they take place at a later stage in device development, traditional feasibility study IDEs are usually supported by more nonclinical testing data versus EFS. Traditional feasibility studies are larger than EFS and are often used to capture preliminary safety and effectiveness information on a near-final or final device design. Data on expected event rates captured in traditional feasibility studies are often used to plan a pivotal study. A traditional feasibility study does not necessarily need to be preceded by an EFS, but EFS data may support initiation of a traditional feasibility study.
A pivotal IDE study is designed to collect definitive evidence of the device’s safety and effectiveness. It typically includes a statistically justified number of subjects, and it may or may not be preceded by an early and/or a traditional feasibility study (depending on the available clinical and nonclinical data, and the data requirements for that type of device or indication for use).
FDA’s EFS Guidance Document
The primary goal of the EFS Guidance (1) was to provide a toolkit that would enable sponsors and regulators to think in new ways about device development, emphasizing the underlying clinical condition, and the availability, benefits, and risks of the current standard of care (if available) or alternative treatments. The information gained in conducting an EFS can also be used to identify appropriate modifications to the device or procedure, advance nonclinical test plans or methodologies, and develop subsequent clinical study protocols. EFS IDE submissions are expected to incorporate risk mitigation strategies to enhance patient safety. Risk mitigation is particularly helpful where there is limited knowledge regarding the safety and effectiveness of novel devices or procedures. Within this framework is an appreciation of different tolerances for risk — and perspectives on benefits — among patients who may be interested and eligible to participate in an EFS.
For medical devices, many factors affect the total time to market, but the largest impact of U.S. regulatory authorities is on the nonclinical test requirements needed to progress through each phase of device evaluation. The EFS Guidance provides a roadmap for justifying the appropriate evidence needed to move from the bench to initiating a human clinical study and allows for timely device and clinical protocol modifications. A key Guidance concept is that IDE approval of an EFS may be based on fewer nonclinical data than would be needed to support the initiation of a larger clinical study of a more finalized device design. The regulatory thinking behind requiring less nonclinical testing before patient treatment in an EFS is by applying a “Just-In-Time Testing” approach, which essentially means doing the right nonclinical tests at the appropriate time in the device development process. Just-In-Time Testing recognizes that comprehensive testing during early phases of device development may add cost without return, since testing could have limited future applicability if the device is modified. Time-consuming, non-informative testing delays access to the device for patients who may have limited treatment alternatives. “Right test/right time” data requirements acknowledge that it may be acceptable to defer some nonclinical testing until the device design has been finalized for use in a larger clinical study (such as a pivotal trial). In summary, the EFS Guidance presents a method for identifying appropriate data requirements that can be applied at each phase of device evolution.
There are important boundaries on accepting reduced nonclinical testing requirements for EFS IDE approval. The amount of nonclinical data to support approval of an EFS IDE often depends on whether information can be leveraged from the experience obtained from earlier prototypes instead of repeating testing on the device to be used in the EFS. The EFS Guidance does not recommend initiation of a clinical study when further useful nonclinical testing can be performed to advance device development. Further, EFS typically enroll highly selected patients who receive individualized care and monitoring, and these studies incorporate enhanced risk mitigation strategies and more patient protection measures compared to pivotal studies.
To communicate a nonclinical device evaluation plan that justifies Just-In-Time Testing, the EFS Guidance offers a methodology for documenting the appropriate testing to support clinical study initiation. The Guidance recommends the use of a device evaluation strategy (or DES), which provides a systematic approach to identify the information needed to support study initiation. The DES deconstructs the device into what it needs to do to perform as intended (device and procedure attributes), potential failure modes, and the effects of those failure modes on the device and/or the patient. To then address each potential failure mode, a DES presents information on how the device was designed, how it leveraged nonclinical or clinical information, and additional testing on the device to be used in the EFS to fill any outstanding information gaps to address potential failure modes. Finally, the DES includes mitigation strategies, specific for individual potential failure modes, that been incorporated into the clinical protocol to reduce risks for patients.
Investigational Plan, Risk Mitigation, and Informed Consent
When targeting IDE approval of an EFS, the Guidance notes that the following issues should be addressed in the submission to FDA:
— the clinical condition to be treated or assessed by the device;
— the standard of care for the clinical condition and expected clinical outcomes associated with the standard of care; the anticipated benefits associated with use of the study device; and
— whether the investigational plan includes a thorough benefit/risk analysis, sufficient risk mitigation strategies, adequate human subject protection measures, and an appropriate clinical study protocol.
As stated in the EFS Guidance, an EFS clinical study protocol should list study objectives (i.e., the rationale for performing an EFS) and a description of the appropriate patients to be enrolled (inclusion and exclusion criteria). EFS patients may have different characteristics from those who may be enrolled in a future pivotal study; for example, they may have more comorbidities or more advanced disease, but they should still have a potential for benefiting from participating in the study. Ideally, the clinical protocol includes clinical risk mitigation strategies, but some expected design elements of larger studies (e.g., traditional feasibility or pivotal studies) — such as a definition of study success, a pre-specified statistical analysis plan, and sequential subject enrollment — are not necessary for an EFS.
When considering benefit/risk, it is acknowledged that although the benefits from participating in an EFS may be substantial (particularly for EFS that address unmet clinical needs), EFS often carry greater unknown risks than traditional feasibility and pivotal studies. It is important not to overstate the anticipated benefits, and potential risks also include those associated with the study device, study procedures, and the underlying medical condition. The EFS Guidance notes that the benefit/risk analysis to support EFS IDE approval should explain why the potential risks are acceptable when weighed against the anticipated benefits.
Clinical risk mitigation strategies are important elements of an EFS investigational plan. They are intended to enhance the protection of EFS participants by minimizing the frequency or severity of adverse events and describing methods to recognize and address adverse events in a timely manner. Well thought-out clinical risk mitigation strategies increase the likelihood of IDE approval, especially for EFS that involve highly novel or high-risk devices. Examples of useful mitigation strategies include selective patient enrollment criteria, detailed subject follow-up and management plans, enhanced study oversight, approaches to continue enrollment based on the clinical outcomes of the preceding subjects, and frequent reporting of study progress and adverse events to FDA.
The basic regulatory requirements for informed consent for an EFS are the same as other types of studies and are described in 21 CFR part 50 subpart B – Informed Consent of Human Subjects (2). However, it is important to address the distinctive aspects of an EFS during the informed consent process. The EFS Guidance notes that the informed consent should identify the investigation as an EFS, which is a study of an innovative device or innovative clinical use of a device in a small number of patients designed to gain initial insights into basic safety and device function. It is appropriate to include language that there may be unforeseeable risks associated with participation in an EFS due to limitations in available data and experience with the device. If applicable, disclosure that the EFS involves the first human use of the device (i.e., the EFS is also an FIH study) is recommended. It is helpful to describe the clinical risk mitigation strategies that protect patients, and subjects should be advised that there may be limited information to support a likelihood of personal benefit (but that future patients with the same disease or condition may benefit from the information obtained during the EFS).
Device and Clinical Protocol Changes During an EFS
Additional important provisions of the EFS Guidance are new approaches to facilitate timely device and clinical protocol modifications during the EFS itself. Experience and knowledge gained from initial study subjects can guide device or protocol changes, and rounds of regulatory submissions and review can delay the implementation of changes and impede study progress. Recognizing that device development is often an iterative process based on knowledge gained from nonclinical tests and initial clinical use, the EFS Guidance provides processes that facilitate timely device and clinical protocol modifications while the EFS is in progress; these include broader use of 5-day notification, a new contingent approval process, and interactive review (all are described in detail in the Guidance).
CDRH’s EFS Program
The benefits of the EFS Program begin with patients, who gain early access to potentially improved treatments and better health outcomes provided by novel medical devices. For clinicians and their patients, the program offers new opportunities to address unmet clinical needs. The EFS Program provides a means for direct collaboration among the FDA, sponsors, and innovators. For FDA review teams, the early exposure to new devices allows for familiarity with the technology throughout the product development process; this can increase the efficiency of work performed by FDA staff, who can apply their knowledge about the clinical condition and early device experience to increase the efficiency of their regulatory review work. An EFS performed in the United States will collect data that is relevant to the U.S. population, and therefore the data collected can directly support subsequent U.S. clinical studies. This may foster smoother transitions between phases of clinical evaluation (e.g., from EFS through pivotal trials) and lead to more rapid approval of beneficial devices.
Within CDRH, the EFS Program resides within the Office of Device Evaluation (ODE) Clinical Trials Program. Each review division within the ODE has an EFS representative, who help sponsors prepare for interactions with subject matter experts on the FDA review teams. EFS representatives meet regularly to discuss challenges with EFS submissions with a focus on providing consistent approaches to cross-cutting nonclinical test requirements such as biocompatibility, sterility, and animal studies. Training of FDA reviewers on EFS principles is ongoing, and EFS Program leaders and divisional representatives participate in outreach to medical professional societies, industry, trade groups, and clinicians at medical conferences to promote EFS opportunities in the United States. CDRH EFS reviewers collaborate with review staff at FDA’s Center for Drug Evaluation and Research on studies involving device-drug combination products, and interactions with the coverage group at the Center for Medicare &and Medicaid Services (CMS) has been helpful in obtaining reimbursement for EFS (where appropriate).
Since the publication of the EFS Guidance and the rollout of the CDRH’s EFS Program, there has been a progressive increase in the number of EFS IDEs submitted to FDA and approved to start enrollment (Figure 2). The EFS Guidance and EFS Program encourage close collaboration between EFS sponsors and FDA review staff. Currently, approximately 80% of EFS IDE submissions are approved in one review cycle, and it is likely that frequent and early interactions between sponsors and FDA reviewers in pre-submission meetings have contributed to the high frequency of IDE approval. The EFS Program has been well-received by the cardiovascular device community with multiple EFS IDEs (many of which being FIH studies) submitted and approved for novel transcatheter heart valves, peripheral artery and aortic endovascular devices, cardiac arrhythmia treatment, and autonomic modulation therapy. Following the successful completion of EFS, some device programs have started to make the transition to pivotal studies.
Figure 2. Progressive Increase in the Number of EFS IDEs Submitted to FDA and Approved Since the Introduction of FDA’s EFS Program
Beyond FDA: The EFS Clinical Trial Ecosystem
Although the increasing number of EFS IDE approvals has been gratifying, the ultimate success of the U.S. EFS Program to increase patient access to novel devices depends on improving the clinical trial ecosystem. Beyond IDE approval by FDA, the initiation of a clinical study of an investigational device requires institutional review board approval, agreements between sites and sponsors on contracts and indemnification, and insurance coverage. These steps are often associated with delays in patient enrollment. The clinical sites themselves are critically important to achieving the goals of the EFS Program. Conducting EFS requires a commitment of resources from institutional leadership, access to the target patient population, appropriate investigator and support personnel expertise, teamwork among physicians, and a multidisciplinary research staff. Dedicated study coordinators play an essential role in supporting patient recruitment and enrollment, tracking adherence to study protocols, and assuring the collection of high-quality data.
Beyond FDA, the U.S. clinical study ecosystem includes inventors, industry sponsors, clinician investigators, site research staff, insurance carriers, payers (such as CMS and private insurers), and private funders. Efforts are underway to collaboratively develop EFS best practices that, when adopted at clinical sites, can improve the efficiency of conducting EFS via faster enrollment and study completion. A more streamlined device development process may also facilitate novel therapy development for an expanded group of patients (e.g., those with less common diseases). Making novel, safe, and effective therapies available for the broadest population of patients is the fundamental goal of all who support medical innovation.
The U.S. EFS Program has begun reversing the trend of the initial testing of new and novel medical devices being performed overseas. CDRH leadership is committed to the success of the EFS Program, which is completely aligned with CDRH’s vision that patients in the United States have access to high-quality, safe, and effective medical devices of public health importance first in the world. More U.S. EFS will help increase access of beneficial medical devices to U.S. patients, and the data generated from these investigations may help support and speed device approvals. Efforts to improve the clinical trials ecosystem to facilitate conducting EFS in the United States are underway.
- S. Food and Drug Administration, Center for Biologics Evaluation and Research. Investigational device exemptions (IDEs) for early feasibility medical device clinical studies, including certain first in human (FIH) studies: guidance for industry and Food and Drug Administration staff. 2013. Available at: https://www.fda.gov/media/81784/download. Accessed May 14, 2019.
- S. Food and Drug Administration. 21 CFR part 50 subpart B – Informed Consent of Human Subjects. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50&showFR=1&subpartNode=21:188.8.131.52.20.2. Accessed December 6, 2018.