Author + information
- Received June 14, 2016
- Accepted July 12, 2016
- Published online October 25, 2016.
- David R. Holmes Jr., MDa,∗ (, )
- Robert Califf, MDb,
- Andrew Farb, MDb,
- Dorothy Abel, BSBMEb,
- Michael Mack, MDc,
- Tamara Syrek Jensen, JDd,
- Bram Zuckerman, MDb,
- Martin Leon, MDe and
- Jeff Shuren, MDb
- aDepartment of Cardiology, Mayo Clinic, Rochester, Minnesota
- bFood and Drug Administration, Silver Spring, Maryland
- cBaylor Scott and White Health, Plano, Texas
- dCenters for Medicare & Medicaid Services, Baltimore, Maryland
- eCenter for Interventional Vascular Therapy, Columbia University Medical Center, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. David R. Holmes, Jr., Department of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
Initial clinical studies of new medical technologies involve a complex balance of research participant benefits versus risks and costs of uncertainty when novel concepts are tested. The Food and Drug Administration Center for Devices and Radiological Health has recently introduced the Early Feasibility Study (EFS) Program for facilitating the conduct of these studies under the Investigational Device Exemption regulations. However, a systematic approach is needed to successfully implement this program while affording appropriate preservation of the rights and interests of patients. For this to succeed, a holistic reform of the clinical studies ecosystem for performing early-stage clinical research in the United States is necessary. The authors review the current landscape of the U.S. EFS and make recommendations for developing an efficient EFS process to meet the goal of improving access to early-stage, potentially beneficial medical devices in the United States.
- equipment design
- new device development strategies
- research design
- research ethics committees
- United States Food and Drug Administration
Clinical evaluations of innovative medical technologies are designed to optimize care while offering opportunities for both research participants and society alike. An optimal approach takes into consideration the risk-benefit ratio needed for the efficient generation of robust evidence, while determining which technologies will evolve to address unmet, important clinical needs. There has been a migration of clinical studies for medical devices out of the United States: in 2004, 87% of clinical studies for medical technology products listed on ClinicalTrials.gov were conducted in the United States, whereas by 2009, that number dropped to 45% (1). This trend has stimulated an examination of the U.S. system of clinical trials, because the integration of research into practice is a critical component of the continuum of advancement of medical care and can provide early availability of potentially beneficial devices for U.S. patients with timely regulatory approval.
The Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH) has recognized that the migration of clinical studies can be partly explained by the more comprehensive regulatory requirements for conducting U.S. clinical studies (2). Historically in the United States, justification to initiate an early device clinical study has required extensive nonclinical testing to provide a sound scientific basis that exposing patients to the device is appropriate; however, it has been recognized that this amount of testing may have impeded effective device development, given the likelihood of early device design to change and the lack of predictability of the nonclinical testing on clinical outcomes. In addition, the ability to incorporate additional patient protection measures in early studies to mitigate potential risks has been missing.
Assessment of the appropriate regulatory requirements includes consideration of the fact that there are important differences between studying devices and studying drugs. In clinical trials of drugs, the structure of the drug to be studied is finalized at the start of the trial and does not change. In contrast to evaluation of new drugs, in device development, there is an expectation of an iterative process in which a prototype is modified, often many times, on the basis of information obtained in a relatively small number of initial research participants in early feasibility studies, and then the finalized design is assessed in a larger, pivotal study of safety and effectiveness. Recognizing the distinctive regulatory challenges associated with early device clinical studies, FDA CDRH introduced the Early Feasibility Study (EFS) Program (3), intended to transform the system and facilitate access to new medical device technology.
However, FDA guidance is not sufficient. For successful implementation of the EFS program, a holistic approach is required, in which all stakeholders in the clinical trial enterprise work collaboratively to optimize the speed, safety, data quality, and financial costs and reimbursement of U.S. medical device development, and to optimize evidence generation to determine their clinical safety and effectiveness. This new paradigm will require compromise and commitment by a consortium of all stakeholders (Table 1) to view EFS projects differently, accepting that changes to current clinical practice may be needed to fulfill the essential goal of providing the best available, safe, and effective technology to U.S. patients earlier than previously possible.
An illustration of the inadequacies of the current system is provided by the U.S. EFS transcatheter mitral valve replacement (TMVR) initial experience. Severe mitral regurgitation (MR) is a cause of heart failure in a large number of patients, many of whom are at high or prohibitive risk for open surgical mitral valve repair or replacement. Although 1 device is FDA-approved for catheter-based treatment of primary severe MR (4), additional approaches are required, especially for secondary severe MR. Several platforms have been developed, and TMVR EFS Investigational Device Exemption (IDE) applications have been approved for at least 5 devices. Although there has been great enthusiasm for these EFS studies in the United States, significant challenges have already been encountered that have delayed study initiation and execution: lengthy institutional review board (IRB) review, inadequate site administrative infrastructure, insufficient access to the requisite patient population, and difficulties in contract negotiations and reimbursement. This paper suggests approaches to improving the U.S. EFS ecosystem on the basis of the authors’ personal experience with the EFS Program.
Background on EFS
Studies of significant risk devices, such as heart valves, require FDA approval through an IDE application and site IRB approval before initiating participant enrollment (5,6). An EFS IDE involves a limited clinical investigation of a device that is either early in development or being evaluated for a novel intended use; it may be used to assess the device design concept with respect to initial clinical safety and device functionality in a small number of research participants when this information cannot practically be provided through nonclinical assessments. These pilot studies may inform subsequent device modifications and future clinical study designs (3) (Central Illustration).
Strengthening the environment for device innovation and helping patients gain earlier access to beneficial medical devices begins with acknowledging the unique benefits and motivations among the different stakeholders (Table 2).
Participation may provide the following benefits:
1. Patients may gain earlier access to a device that may improve their own health or advance the standard of care for others, without the need for travel to other countries. In addition, an IDE offers enhanced protection of a patient’s rights, safety, and welfare, including detailed mitigation strategies to minimize risks, such as careful patient selection, close monitoring of outcomes to allow for timely interventions, and heightened oversight by the FDA and IRBs through increased frequency of structured reporting.
2. U.S. investigators benefit from earlier access to new medical devices to help individual patients at their own institutions. Participation can also provide opportunities to contribute to device development. Academic accomplishments with publications and presentations provide an opportunity to achieve an investigator’s professional goals.
3. For a device developer or a U.S.-based industry sponsor, conducting an EFS in the United States, rather than overseas, offers geographical advantages beyond the financial costs of travel, housing, and language barriers. A U.S. EFS can facilitate direct interactions among U.S. investigators, health systems personnel, and sponsors and can enhance study monitoring. U.S. engineers and scientists can more readily observe elements of device use and procedural factors to advance device design. Familiarity with U.S. regulatory requirements can ease the transition from EFS through pivotal studies, and data generated in the United States are applicable to support future applications. Early exposure of U.S. clinicians to the device through EFS can facilitate the subsequent conduct of a pivotal study and adoption by the medical community post-approval by training a cadre of clinicians and developing a knowledge base that can aid in education and training.
4. Access to beneficial devices for U.S. patients under an EFS IDE supports the FDA’s mission to protect and promote public health and the CDRH’s vision that U.S. patients have access to beneficial devices early in the product life cycle under appropriate conditions (7–9). Beyond the public health benefit, the U.S. EFS allow FDA regulators to become familiar with new technologies early in development, increasing the efficiency of regulatory review. Starting with a U.S. EFS provides FDA staff with an opportunity to apply benefit-risk principles in regulatory decision making and to protect the rights, safety, and welfare of research participants at all phases of device development and evaluation.
5. IRB members benefit from valuable early exposure to new technologies, which can increase the efficiency of subsequent IRB evaluations of pivotal studies by familiarity with the device.
6. For a U.S. clinical study site, conducting EFS provides education and training for the research staff, enhances compliance with regulatory requirements, and increases the efficiency of study monitoring, all of which are essential for good clinical study conduct. As American health care has evolved, study sites for high-risk devices are often embedded in integrated health systems with a flagship academic center that has a primary mission of translation of scientific concepts into practice; conducting EFS is a direct manifestation of this mission. Financial support from study participation can lead to research program growth. In addition, successful EFS execution can increase the likelihood of the site participating in future studies, facilitating the retention of clinical investigators and research staff.
7. Payers, such as the Centers for Medicare & Medicaid Services (CMS) and private insurers, have the opportunity to participate in the evidence development ecosystem that gives an early assessment of potential benefits and risks of devices intended to address unmet clinical needs.
8. Funders of and investors in innovation can benefit from a more efficient, expeditious, and consistent EFS system that produces earlier definitive evidence for decision-making about when to continue or expand the iterative process of device development or, alternatively, to discontinue programs that lack promise.
Challenges in Executing EFS
Needed clinical studies ecosystem reform
Facilitating the conduct of a U.S. EFS requires several improvements affecting different aspects of the clinical studies ecosystem. Table 3 identifies the specific areas in which stakeholders in the clinical study ecosystem may contribute to improving the clinical research process.
FDA study approval and study conduct under an IDE
A core challenge when seeking IDE approval is insufficient predictability with respect to the information needed to justify study initiation. Impediments also exist related to clinical protocol stipulations, including potentially excessive data capture, and restrictions that limit enrollment to patients unlikely to derive benefit from use of the device because of poor health or advanced stage disease. Although intended to balance risks associated with a novel technology, incorporation of unrealistically strict conditions, imposed by company regulatory policies or regulatory agencies regarding patient selection and evaluation, may result in difficulties with recruiting investigators, IRB approval, patient enrollment, and protocol compliance. In addition, difficulties in making timely device and protocol changes on the basis of experiences gained from clinical use impede device development.
The 2013 EFS Guidance (3) provides a regulatory toolkit that enables sponsors and regulators to think creatively with respect to justifying the appropriate evidence needed to progress from nonclinical testing to a clinical study, and to allow timely device and clinical protocol modifications. The guidance also emphasizes the need to consider the clinical context, enhanced clinical mitigation strategies, and patient protection measures in EFS benefit/risk assessments, and encourages frequent and timely interactions between the FDA and sponsors, which are particularly critical during rapid phases of device iteration.
EFS entail unique IRB considerations and challenges compared with pivotal studies because of the greater uncertainty about risks. In the TMVR experience of the authors, individual clinical site IRB processes and perspectives varied considerably, which resulted in delays of >6 months from protocol receipt to approval. Long review times, which may discourage sponsors from pursuing U.S. EFS IDEs, may be related to: 1) the frequency of scheduled IRB meetings; 2) processes, such as the requirement to have all legal and contractual elements finalized before IRB review; and 3) the philosophical and ethical approach specific to each institution in regard to enrollment of its patients in EFS.
There are several potential approaches to address EFS IRB considerations (Table 4):
• Submission of well-organized, complete documents for IRB review, with enhanced risk mitigation strategies and informed consent forms addressing the unique aspects of EFS participation.
• Establishment of a site target (and commitment) for completion of IRB review (e.g., 30 days from receipt of the protocol, similar to FDA review times) to improve the predictability of the process.
• Agreement by the IRB to review contractual and legal issues in parallel with IRB review, reducing the time needed to complete these negotiations and processes.
• Establishment of a consortium approach to consider issues pertinent to human research participants’ rights and interests specific to EFS protocols, with FDA participation. The consortium would work with the human research protections community to establish educational webinars to explain the EFS program and develop practical solutions to issues and concerns.
• Standardization in the development of a common template for informed consent specific to an EFS study that can be approved without significant modification by multiple institutional IRBs or by a central IRB.
• The use of central IRBs. The ability to use central IRBs routinely, which would add efficiencies, will require legislative changes, as the law currently prohibits central IRBs for device trials (10).
Legal and contractual considerations
From our TMVR experience, it became clear that approaches to legal and contractual issues vary among clinical centers and can affect timely study initiation. Two components in particular may prolong negotiations: subject injury reimbursement (indemnification) and sponsor terminations.
Subject injury reimbursement
The United States has unique medical liability considerations requiring responsible parties to be clearly identified prior to the initiation of a clinical investigation; failure to do so can delay or discourage EFS conduct. For example, during the TMVR EFS, the scope of injuries/illnesses related to the new device and assignment of responsibility for covering the costs of study-related illness/injury (e.g., the sponsor, the clinical site, or the insurer) were contentious. The role of the sponsor, individual institution/clinical site, and insurance carriers/payers in this area is complex. All 3 parties may benefit by being able to offer new treatment alternatives to their patients and should consider subscribing to open discussions and, where feasible, an agreement of shared liability and indemnification. Optimally, a consortium of all centers in each EFS study should develop a common template for such an agreement.
The common template could include the following:
• General agreement that participation in an FDA-approved research protocol should not be used to deny payment for usual care expenses (11).
• When a protocol goes beyond usual care, a device sponsor agrees to reimburse any reasonable and necessary medical expenses incurred as part of the study protocol or not identified as a likely complication of the proposed new therapy. For instance, new TMVR procedures require careful baseline diagnostic computed tomography angiography prior to enrollment. Because this is beyond usual standard-of-care for patients previously treated by surgical mitral valve replacement, it cannot be considered usual care; therefore, sponsors fund these computed tomography tests.
• Regarding important clinical complications during EFS, the shared liability concept could include that sponsors do not bear the full burden of incremental reimbursement for generally anticipated complications from the procedure for the treatment of patients with similar clinical conditions. The terms under which the sponsor would be obligated to reimburse medical expenses could be specified, dependent on the relatedness of the event to a device failure and whether the cost would be covered under the patient’s insurance. This latter specific issue should also be addressed by a consortium approach of the stakeholders involved, with the goal of providing an unbiased assessment of the dividing line between routine care costs and research costs, as well as issues related to attribution of complications related to EFS participation.
• Issues related to sponsor termination of a site or an investigator, although important for all research initiatives, may be more challenging for EFS studies. Considerations include noncompliance with the study protocol, incomplete study data reporting, breach of confidentiality of data, failure to enroll patients, or inordinate delays in obtaining protocol approval or in implementation, as well as sponsors’ obligation to the specific research participants. This has particularly important implications when a trial is terminated early, in which case the continuing sponsor obligations to the participants must be honored.
Clinical site qualifications
Site selection is a crucial component of an EFS. Sites should have strong support for EFS from clinical center leadership, possess the infrastructure to fully and expeditiously implement the study, and have ready access to a clinical pool of potential research participants. In the case of TMVR, assumptions regarding EFS site eligibility were largely on the basis of past relationships borne out of familiarity or past performance of sites in clinical studies with other transcatheter structural or valvular therapies. Although this makes reasonable sense, insufficient due diligence was performed to fully ascertain if sites had access to the intended treatment population, resulting in study enrollment delays.
The ideal properties of EFS sites are identified in Table 5. Commitment at the institutional level is critical. It may be beneficial to create a national network of clinical study sites that have the components necessary to maximize EFS performance. These clinical centers will need to implement mechanisms for optimizing financial costs related to these EFS studies. Some “certification” of such a national network of clinical study sites should be considered.
Coverage and funding
Research, which includes evidence development, is important to payers such as the CMS and private payers. However, payers must balance participation in clinical studies with covering devices that are most clinically appropriate for their patient populations. The CMS, in an effort to support clinical research and promote predictability, national consistency, and administrative efficiency, established a new single pathway to consider coverage for FDA-approved IDE studies for Medicare beneficiaries. Under a rule that became effective January 1, 2015, the CMS shifted the responsibility of Medicare IDE approval from the CMS local contractors to the CMS Central Office, and published scientific and ethical criteria for qualifying studies (12). The revision of its IDE rule affirms the CMS’ support of clinical studies that promote devices that will potentially add value for the Medicare population.
Consideration for coverage begins with a recommendation from the FDA regarding whether the device meets the CMS categorization of either an experimental device (category A) or a nonexperimental/investigational device (category B) (13). It would be expected that most EFS IDEs will be designated as category A due to a greater degree of unknowns regarding the safety and effectiveness of these devices. For category A CMS-approved IDE studies, all routine care items and services are covered. That is, items and services that would be covered if a patient was treated outside of a study would also be covered for those participating in the IDE; under the regulation, the device itself is not covered (13).
As more is learned under a category A IDE, subsequent studies on the device could lead to re-evaluation of the device as meeting the criteria for category B devices. For category B CMS-approved IDE studies, Medicare covers the device itself and related items and services.
Shared Responsibilities, Necessary Concessions, Stakeholder Benefits, and Unresolved Issues
Participants in the clinical study ecosystem can contribute to improving the EFS process as follows:
1. Patients can potentially affect EFS IDEs by working through advocacy groups, highlighting the needs associated with their specific clinical conditions (14).
2. Investigators can influence the EFS in many areas that help benefit the participants. They are responsible for providing a comprehensive informed consent process, and they need to participate in the development of the IDE to ensure appropriate consideration of the clinical context, the incorporation of appropriate clinical study mitigation strategies, and a protocol that will more likely be accepted by the FDA and IRBs. They should also be committed to complying with investigator agreements and contracts. The investigator should be diligent about the rights and interests of the research participants, and hold companies developing devices accountable for protocols that respect the rights and interests of patients.
3. Sponsors should commit to applying the EFS Guidance and process, including improved communication both prior to and during the clinical study. They can expect advantages in return via more effective and efficient future interactions with FDA, and the potential for earlier U.S. market access for their device (Table 6).
4. FDA review teams and managers should apply the concepts described in the EFS Guidance, and should continue to develop effective approaches to a more interactive and collaborative process. This early expenditure of time should facilitate the entire device development process. This requires adequate resources for the FDA to effectively perform and facilitate these activities.
5. IRBs and their associated institutional human research protection programs influence site quality through their review processes and study oversight. Working together to develop effective solutions to the elements of EFS protocols that have delayed institutional decision making can enhance timely protocol review, enabling earlier access to potentially beneficial devices for their patients. Collaboration with the FDA is encouraged to enhance efficiency.
6. Because IRB approval, human research protection programs, contracting, and most other aspects of clinical study conduct are influenced by site selection, clinical sites and their associated institutions have a large influence on and responsibility within the clinical study ecosystem, as well as extensive motivation to streamline their EFS processes. In addition to supporting their IRBs and investigators to achieve their individual goals, sites should strive to accomplish the components identified in the preceding text to maximize performance of EFS, as well as to develop strategies to minimize costs.
7. Payers can support U.S. innovation by collaborating with other stakeholders to create avenues to support EFS that could benefit their patient populations. Finding ways to share the costs of medical device clinical studies may lead to more timely delivery of innovative technologies that will add value to the health care system.
8. Funders ideally will invest in EFS to obtain answers to important clinical questions sooner and more reliably in the evaluation of innovative devices or new intended uses.
These improvements in the EFS process will require that clinical study ecosystem participants accept a greater degree of risk, have greater accountability, and expend additional time and resources (Table 7). Risks include the uncertainty about the risk-benefit ratio for research participants and for those responsible for patient care and study oversight. Additionally, there are the risks of working within a relatively novel U.S. EFS clinical study system. These include risks related to returns on investment of time and money, such as those associated with study initiation, participation, conduct, and oversight.
Training and Education
Training and education opportunities related to the approval and conduct of U.S. EFS may include:
• Development of educational materials for patient advocacy groups emphasizing the informed consent section of the EFS Guidance;
• Training for sponsor-investigators;
• Sponsor-specific training through contact with FDA EFS representatives; and
• Workshops on the communication and review of the information needed to support study initiation.
Improving early access to potentially beneficial medical devices is a shared interest of all participants in the clinical studies ecosystem. The FDA CDRH EFS program provides an opportunity to reinvigorate medical device development and evidence generation in the United States by setting reasonable expectations for the information needed to justify study initiation. Early experience has identified potential areas of improvement in the EFS program and other aspects of the clinical studies ecosystem to establish a consistent, predictable process for conducting a U.S. EFS so that devices can be assessed efficiently, while protecting the rights and interests of research participants. To optimize the EFS process for their mutual benefit, all stakeholders will need to modify their usual practices and expectations.
Dr. Califf currently holds the post of Commissioner of Food and Drugs, U.S. Food and Drug Administration; prior to his appointment to the FDA, Dr. Califf received research grant funding from the Patient-Centered Outcomes Research Institute, the National Institutes of Health, the U.S. Food and Drug Administration, Amylin, and Eli Lilly and Company; research grants and consulting payments from Bristol-Myers Squibb, Janssen Research and Development, Merck, and Novartis; received consulting payments from Amgen, Bayer Healthcare, BMEB Services, Genentech, GlaxoSmithKline, Heart.org/Daiichi-Sankyo, Kowa, Les Laboratoires Servier, Medscape/Heart.org, Regado, and Roche; and held equity in N30 Pharma and Portola. Dr. Mack has served as an uncompensated coprimary investigator of the Partner 3 and COAPT trials. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Robert Harrington, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- Center for Devices and Radiological Health
- Centers for Medicare & Medicaid Services
- early feasibility study
- Food and Drug Administration
- Investigational Device Exemption
- Institutional Review Board
- mitral regurgitation
- transcatheter mitral valve replacement
- Received June 14, 2016.
- Accepted July 12, 2016.
- American College of Cardiology Foundation
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