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Successful translation of new and innovative medical products from concept to clinical use is a complex endeavor that requires understanding and overcoming a variety of challenges. In particular, regulatory pathways and processes are often unfamiliar to academic researchers and start-ups, and even larger companies. Growing evidence suggests that the successful translation of ideas to products requires collaboration and cooperation between clinicians, researchers, industry, and regulators. A multi-stakeholder group developed this review to enhance regulatory knowledge and thereby improve translational success for medical devices. Communication between and among stakeholders is identified as a critical factor. Current regulatory programs and processes to facilitate communication and translation of innovative devices are described and discussed. Case studies are used to highlight the importance of flexibility when considering evidence requirements. We provide a review of emerging strategies, opportunities, and best practices to increase the regulatory knowledge base and facilitate medical device translation by all stakeholders.
Clinicians, regulators, industry, and researchers require regulatory knowledge and collaboration for successful translation of innovative medical devices
The translation of novel medical devices from discovery through development, testing, and regulatory review, and finally to clinical use, is well known to contain a metaphorical “valley of death” in which products fail to advance from the development and testing phases to successful clinical use [1]. To bring new and innovative medical devices to market efficiently and effectively, a greater understanding of challenges faced and how to overcome those challenges is needed. One area, for academic researchers, start-ups, and small companies in particular, is understanding the various regulatory processes that must be navigated before most products can be used in patients or commercially marketed [2–4]. A multi-stakeholder group representing a cross-section of the medical device field, including clinicians, academic researchers, industry professionals, and regulators from the United States Food and Drug Administration (FDA), all of whom play critical roles in maintaining a vibrant and productive network for the development of medical devices, prepared this review of salient points and best practices toward a goal of increasing knowledge and advancing medical device translation through the regulatory process from concept to clinic [5].
As the FDA center responsible for the regulatory oversight of medical devices, CDRH plays a crucial role in facilitating device development by interacting with all stakeholder groups in the medical device ecosystem. CDRH activities relevant to improving translational processes include engaging with patients and the community to bring a product to market, the work of the FDA Office of Science and Engineering Laboratories (OSEL), special considerations related to pediatric populations, the Breakthrough Devices Program, Early Feasibility Studies (EFS), Q-submissions, current initiatives related to National Evaluation System for health Technology (NEST) and real-world evidence (RWE), evolution of regulatory pathways, global harmonization, and training.
Early engagement with key stakeholders including patients, clinicians, and payers is critical for regulatory and commercial success given the many pitfalls on the path from product concept to marketing, adoption, and reimbursement. In particular, patients are at the heart of CDRH activities and patient input, preference, and benefit-risk decisions are important parts of product development and regulatory decision-making. Involvement of patient advocacy groups and FDA as part of a patient-caregiver collaborative community can provide expert input from the patient perspective, bring together key stakeholder groups to solve shared problems, and provide community-driven solutions that may be accepted by FDA [6]. Systems and solutions identified and developed by collaborative communities are often designed not just for use by FDA, but also to meet the needs of industry and other stakeholders such as patients, caregivers, healthcare providers, and payers. Communicating with FDA, innovation hubs, and regional consortiums throughout the development process builds connections to stakeholders who can help address various scientific and regulatory issues to accelerate innovation.
As new technologies are rapidly developed, FDA expertise must also advance. To address this challenge, OSEL supports pre-market reviews and post-market surveillance requirements by engaging in practical research and problem solving, and developing tools to better assess and understand new and cross-cutting technologies. Research areas include in silico clinical trials that can be completed in days rather than years, identification of early biomarkers for age-related conditions, and additive manufacturing, among many others. Through OSEL, FDA can align common research interests and goals with academia and other partners and provide expertise and laboratory capabilities that can help enable optimal review of novel products.
The use of innovative regulatory pathways such as the Breakthrough Devices Program, Safer Technologies Program (STeP), and EFS Program has rapidly expanded over time [7]. These programs and other efforts to de-risk the product development process for innovative technologies help attract investment and continue to drive innovative product development efforts in the USA. The Breakthrough Devices Program is intended to improve timely access to novel and innovative technologies that provide more effective treatment or diagnosis of a life-threatening or irreversibly debilitating disease or condition, often in areas of unmet clinical need, whereas STeP is intended for devices that do not meet the breakthrough criteria but still provide important safety advantages over existing technologies [8]. Both programs offer opportunities to engage early and frequently with FDA. To consider the suitability of a device for the Breakthrough Program, the product design should be developed at least to the point of understanding specific risks and key performance characteristics. Additionally, the intended use, patient population to be treated, and existing treatment options should be known, along with information to support why the proposed treatment would be more effective than existing options. Demonstration of expected effectiveness could include clinical data, bench or animal data, or a scientifically supported theoretical argument, depending on the technology. At that point, one approach may be to reach out to the assistant director for the relevant review team at FDA and have a brief informal conversation to help determine if there is enough information for a more formal discussion and/or breakthrough designation request.
The Q-Submission process is a helpful and popular pathway for communicating with FDA [9]. Gaining a clearer understanding of regulatory requirements early in the development process can help de-risk the business aspects of projects, which can be especially important for small innovators. A sponsor can share information and obtain FDA’s feedback on a particular question(s) to keep a product moving forward on the translational pathway. Q-Submissions, including Informational Meetings and Pre-Submissions, can be especially helpful for complex products such as indwelling or implantable devices, new technology, or innovative non-clinical or clinical testing strategies. Very early in the development process, an Informational Meeting can help FDA gain a deeper understanding of new technology by providing an overview of the device and optionally demonstrating a prototype; having an opportunity for FDA personnel to interact with a device in a hands-on environment, or in a video-conference setting, can be extremely beneficial. Working with an expert who understands the Q-Submission process and can provide guidance may help optimize the benefit of the program.
In addition to allowing more concrete feedback from FDA, Pre-Submissions also provide an opportunity to engage with both FDA and payors, including CMS and private payors, together as part of the Early Payor Feedback Program [10]. A clinically successful device that makes it through the regulatory process can still fail to be integrated into medical practice if there is no or poor reimbursement. Therefore, it is often important to develop a reimbursement strategy early during product development and clinical planning. Including payors in a Pre-Submission meeting allows payors to consider and provide feedback on the type of clinical evidence that could support payment for a technology (e.g., reasonable and necessary criteria for CMS) along with FDA feedback on clinical evidence that can potentially demonstrate a reasonable assurance of safety and effectiveness.
Real-world evidence is an increasingly important concept to support device development and evaluation. Continuing improvements in infrastructure, data completeness, definitions, and harmonization may provide increased opportunities for RWE to support regulatory and clinical decision-making. FDA has identified numerous cases where RWE has been accepted to support pre-market authorizations and fulfill post-market requirements [11]. RWE can be leveraged not only to support regulatory decisions, but also to facilitate hypothesis generation or finding appropriate patients. When using RWE, it is important to understand not just the device and clinical space, but also the data source quality and the relevance and reliability of the data. NEST is working to help advance the use of RWE to support regulatory decision-making and has drafted data quality and methods frameworks. Discussing RWE use in advance with FDA, again potentially as part of a Pre-Submission, is highly encouraged.
The role of post-market surveillance has evolved over time beyond merely serving as a regulatory requirement to also helping answer important clinical questions that may not have been fully addressed in pre-market studies. For example, post-market surveillance offers an opportunity to fill in evidence gaps in the patient population being treated or to collect information on how a device could be used in a real-world setting. This multi-purpose use provides a potential role for patient registries or coordinated registry networks that in a total product lifecycle environment can then be used as RWE to support expanding a device indication and identify unmet clinical needs.
The mission of CDRH is not just to protect the public health, but also to promote the public health. This includes facilitating medical device innovation by advancing regulatory science and providing efficient regulatory pathways. The vision and values supporting this mission include being a leader in regulatory science and medical device innovation by challenging the status quo and testing and adopting new approaches to foster positive change and more effectively and efficiently accomplish the CDRH mission. As a future consideration to support innovation, additional flexibility could be considered in regulations to allow a more agile regulatory process; for example, leveraging of individual building blocks as appropriate to meet requirements. A risk-based and least-burdensome approach would remain at the core, but regulatory processes may be tailored to a specific technology. This more agile approach could be particularly relevant for innovative, rapidly changing technologies, such as digital health, as well as small, underserved patient populations and rare diseases. As one example, the current ecosystem is not well-designed to support development of innovative products for small and complex patient populations, such as pediatrics, due to high risks and limited investment incentives. As a result, physicians often must attempt to leverage technology designed for adults for use in children. For devices designed to treat or diagnose a disease or condition that affects not more than 8000 individuals in the USA on an annual basis, the Humanitarian Device Exemption (HDE) program provides a regulatory pathway based on demonstration of safety and probable benefit, but there remain numerous additional requirements tied to the program such as institutional review board (IRB) reviews, profit limitations, and other challenges that have limited widespread use of this pathway [12]. For larger patient populations, the pre-market approval (PMA) pathway may still be too difficult for pediatric devices to be commercially viable. A hypothetical future hybrid approach could envision a device coming to market with the HDE standard of safety and probable benefit, but without all of the currently associated requirements, and then developing additional evidence of a reasonable assurance of safety and effectiveness (PMA standard) in a streamlined manner. While this approach would require changes to US law, it may ultimately provide a more effective pathway to market along with greater confidence in the technology.
Similarly, efforts are ongoing within the International Medical Device Regulators Forum (IMDRF) to develop globally harmonized essential principles for pre-market review, which could potentially be used as building blocks to support a multi-national single review program [13]. A number of challenges remain, including differences in the current US regulatory framework compared to many other regions and the need to ensure confidence in whichever entities would conduct pre-market review for a new technology. The Medical Device Single Audit Program provides one example of success for international harmonization [14]. An effective single review program that allows for near-simultaneous entry of technology to multiple marketplaces could better drive innovation and boost global health.
Providing regulatory training to new scientists and engineers is an important facet for maintaining a robust innovation ecosystem for translation. Programs around medical device development provide an opportunity to walk trainees through the entire life cycle of a product, including regulatory components such as practical applications of regulatory science to develop and evaluate innovative technologies. Use cases, including those developed by FDA, can provide examples of how regulatory principles integrate into the medical device development process. Having students engaged in regulatory science working in the field with developers, FDA, and other stakeholders such as patients, providers, and payers would be a robust opportunity to develop skills and provide an investment for the future. Recent reports indicate a large gap is expected between the supply and demand for skilled regulatory professionals, highlighting the need for expanding educational opportunities and pathways [15]. It is hoped that ongoing discussions will serve to motivate further development of regulatory-focused training programs for scientists, engineers, and other stakeholders.
One starting point for device development is to consider the question: “How do we start with a breakthrough idea from an inventor’s mind and translate that idea to a product that actually reaches patients?” Three critical pieces are necessary to be successful in medical device translation: people, processes, and product selection. Additionally, one of the biggest current challenges to success is the increasing cost of medical device development due to regulatory burdens, dilution of capital by project failures and inefficient management, and falling product prices and reimbursement. Together, these factors result in decreased margins for innovation and drive the need to further optimize the pathway.
The first critical piece for success is people. Stakeholders that understand the medical device ecosystem and with the experience to provide leadership and knowledge on where to focus limited resources must be included. These leaders can assemble the right team of scientific experts, financial experts, clinicians, and supply chain necessary to guide development and source capital. Examples of collaborative efforts to develop this leadership within the translational ecosystem include the CTSIs, International Society of Cardiovascular and Translational Research (ISCTR), standards organizations, and international harmonization efforts such as Harmonization By Doing (HBD).
The next piece is having the right processes in place to accelerate the product development stages (Fig. 1 ). A good process will eliminate wasted effort from inexperience and mistakes, carefully coordinate to identify efficiencies and avoid pitfalls, and accelerate development by maximizing parallel processes to achieve the most efficient project plan. Combining the right people with the right process leads to development of successful engineering, testing, clinical, and regulatory strategies. This includes developing strategies around user needs, test models, simulations, and acceptance criteria, and planning and performing bench and animal testing. Developing a clinical and regulatory plan early, simultaneous with product development, allows feeding requirements and findings back into the development process to create a more efficient overall path.
