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Published 2015. This article is a U.S. Government work and is in the public domain in the USA
Invited Editorial
Working With the Food and Drug Administration’s Center for Devices to Advance Regulatory Science and Medical Device Innovation Within the US Food and Drug Administration (FDA), the mission of the Center for Devices and Radiological Health (CDRH) is to protect and promote public health by assuring that patients have timely and continued access to medical devices that are both safe and effective. Inherent in this mission is an obligation to facilitate innovation so that better medical devices can be developed and utilized as quickly as possible (1–3). To accomplish this goal, CDRH is actively engaged in advancing “regulatory science” for use in the product development and review process. Regulatory science research and practices provide industry and FDA with scientifically based assessment tools and approaches that can assist in the development, manufacture, and evaluation of new devices and technologies, as well as the creation of more efficient regulatory pathways (4,5). Most of the 1600 CDRH staff members (which include scientists, engineers, clinicians, statisticians, and public health specialists) support regulatory science processes by: (i) developing new standardized test methods and computational modeling techniques through laboratory-based device research; (ii) analyzing premarket bench, animal, and clinical trial testing and data for new devices; (iii) improving surveillance and epidemiological methods for monitoring and studying devices already on the market; (iv) preparing regulatory-based information and guidance documents to assist industry; and (v) bringing together interested parties and experts to address challenges in device development and assessment. With the fast-paced advances in science and the increasing complexity of new devices and technology, CDRH strives to collaboratively work with external stakeholders to continually update its regulatory science knowledge base. To enable this effort, CDRH has several initiatives by which private industry, the medical community, patient groups, and academia can partner with federal scientists to exchange doi:10.1111/aor.12505
information and remove barriers that may impede medical device development, thus fulfilling our collective goal of providing patients access to better devices. In the text of this article, we present several of the current CDRH programs and pathways that foster scientific collaboration and regulatory interaction, promote medical device innovation, and welcome your participation. A summary of all available programs (presented under three general categories including: Collaborative Research and Support Programs, Advancing Regulatory Science Expertise and Information Exchange, and Streamlining Regulatory Review Pathways) appears in Table 1 and includes website links to find more information. COLLABORATIVE RESEARCH AND SUPPORT PROGRAMS (TABLE 1, SECTION A) The Critical Path Initiative The Critical Path program supports intramural research and collaborative partnerships with medical, academic, and industrial organizations. This program was launched in 2004 as part of FDA’s strategy to improve the processes for translating scientific discoveries into new medical treatments and diagnostic modalities by addressing the important issues which could convolute the pathway to product development. FDA’s objective is to work with stakeholders to advance the science used to develop, evaluate, manufacture, and use all regulated medical products. At CDRH, the program focuses on reducing the time and resources needed to develop and evaluate new medical devices, and improving strategies for their assessment in the pre- and postmarket setting. About 20 CDRH projects are annually funded through this effort and have included the evaluation of bio-absorbable implants, additive manufacturing (3D printing) technology, spinal disc replacement devices, computer-aided imaging and diagnostic devices, metal-on-metal hip implant failures, devices and diagnostic tests that incorporate Artificial Organs 2015, 39(4):293–299
Description
Artif Organs, Vol. 39, No. 4, 2015
CDRH program to recruit entrepreneurs and innovators to join government employees in the development of solutions in areas that impact innovation. Recent project areas include streamlining clinical trials, accelerating FDA approval to reimbursement, and striking the right balance between pre- and postmarket device assessments.
FDA established Centers for Excellence with academic partners to promote cross-disciplinary regulatory scientific training, technical information exchange, and collaborative research.
SECTION C. Streamlining Regulatory Review Pathways National Medical Device Provides educational case studies for innovators on how to design, test, and clinically evaluate Curriculum medical devices, identify root causes of adverse patient events and malfunctions, and navigate the regulatory review process CDRH Division of Industry Direct CDRH contact point (via phone or email) that provides science-based regulatory information and Consumer Education to medical device industry, consumers/patients, and healthcare providers (DICE) FDA Guidance Documents Documents prepared for CDRH staff, regulated industry, and the public that provide recommendations and information related to: (i) the processing, content, and evaluation of regulatory submissions; (ii) the design, production, manufacturing, and testing of regulated products; and (iii) inspection and enforcement procedures Medical Device Development CDRH program to qualify “tools” that produce scientifically plausible measurements within a Tools (MDDT) Program specified context of use that sponsors can use in the development and evaluation of medical devices National Medical Device CDRH and external partners are integrating information and resources to enhance the surveillance, Postmarket Surveillance analysis, and reporting of the safety and effectiveness of medical devices after they have been System marketed.
Centers for Excellence in Regulatory Science and Innovation (CERSI) Entrepreneurs in Residence
SECTION B. Advancing Regulatory Science Expertise and Information Exchange Experiential Learning Program To gain awareness of existing and emerging medical device technologies, CDRH regulatory review staff visit research, clinical, manufacturing, and healthcare facilities to observe firsthand how medical devices are designed, developed, manufactured, and implemented in the clinic. Network of Experts Composed of over 35 professional organizations, this resource provides CDRH personnel with rapid access to independent experts in science, engineering, and medicine. Public Workshops CDRH sponsors open Public Workshops to discuss and receive feedback on regulatory and scientific issues related to a variety of medical devices and technologies. Medical Device Fellowship Provides fellowship opportunities for engineers, scientists, and physicians to learn about the Program (MDFP) regulatory process while sharing their knowledge and experience in the area of medical devices
SECTION A. Collaborative Research and Support Programs Critical Path Initiative An FDA strategy to modernize scientific tools and processes by which medical products are developed and evaluated for safety, effectiveness, and manufacturability Consensus Standards Program CDRH works with industry through national and international standards organizations (e.g., ASTM, AAMI, ISO) to develop consensus standards for characterizing and evaluating the performance of medical processes, materials, and devices. Medical Device Innovation Partnership between industry, FDA, NIH, and nonprofits (over 40 members) which provides a forum Consortium (MIDC) for open collaboration to improve patient access to cutting-edge medical technology NSF/FDA Scholar-inAnnual funding from the NSF enables 4–6 faculty, postdocs, and students in the areas of science, Residence Program engineering, and mathematics to participate in intramural research programs at CDRH Pediatric Device Consortia An FDA program that provides grants and support to domestic, public or private, nonprofit Grant Program consortia to facilitate the development, production, and distribution of innovative pediatric medical devices
Program
http://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDRH/ CDRHReports/ucm301912.htm Public–private partnership program: Medical Device Epidemiology Network (MDEpiNet) (http://www.MDEpiNet.org)
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ ContactUs--DivisionofIndustryandConsumerEducation/ ucm20041265.htm http://www.fda.gov/MedicalDevices/DeviceRegulationand Guidance/GuidanceDocuments/default.htm Searchable FDA Guidance Document database: http://www .fda.gov/RegulatoryInformation/Guidances/ http://www.fda.gov/medicaldevices/scienceandresearch/ medicaldevicedevelopmenttoolsmddt/default.htm
http://www.fda.gov/Training/CourseMaterialsforEducators/ NationalMedicalDeviceCurriculum/default.htm
http://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDRH/CDRHInnovation/ InnovationPathway/ucm286138.htm
http://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDRH/ucm289534.htm http://www.fda.gov/MedicalDevices/NewsEvents/ WorkshopsConferences/default.htm http://www.fda.gov/AboutFDA/WorkingatFDA/ FellowshipInternshipGraduateFacultyPrograms/ MedicalDeviceFellowshipProgramCDRH/default.htm http://www.fda.gov/scienceresearch/specialtopics/regulatoryscience/ ucm301667.htm
http://www.fda.gov/scienceresearch/sciencecareeropportunities/ ucm380676.htm
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseases Conditions/PediatricDeviceConsortiaGrantsProgram/
http://www.nsf.gov/funding/pgm_summ.jsp?pims_id=5605
http://mdic.org/
http://www.fda.gov/ScienceResearch/SpecialTopics/ CriticalPathInitiative/ucm076689.htm http://www.fda.gov/medicaldevices/deviceregulationandguidance/ guidancedocuments/ucm077274.htm
More information and how to participate
TABLE 1. CDRH programs to promote collaboration and innovation in medical device development
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INVITED EDITORIAL nanotechnologies, and improvements in computational evaluation methods. Key elements of the Critical Path Initiative are transparency and open dissemination of the results to provide beneficial knowledge to all researchers and device developers. For example, to explore the burgeoning use of computational fluid dynamics (CFD) in characterizing fluid flow and predicting blood damage safety in medical devices, CDRH worked with a planning committee of academic experts and professional organizations to create a project open to anyone who wanted to computationally evaluate blood flow through a simple medical device model (6). Twenty-eight academic and industry groups from six countries participated in the first computational analysis challenge, which included comparing CFD simulation results to experimental data (velocity measurements and in vitro hemolysis test results) collected at CDRH and in four academic research laboratories. To date, the results of the project have supported a publicly accessible technical database for a benchmark flow model that is being widely used to examine CFD simulation methodology, leading to the identification of “best practice” approaches and limitations for applying CFD techniques. In combination with other CDRH simulation efforts, this project contributed to the development of a Draft FDA Guidance Document on information reporting procedures that, upon finalization, will assist the industry in submitting computational analyses in premarket and postmarket studies of medical devices to CDRH (7). Consensus Standards Program The standards development process, which is part of the Consensus Standards Program at CDRH, defines another important collaborative pathway that directly impacts global medical device testing and evolution. Along with representatives from industry and academia, CDRH scientists serve on many standards organization committees (e.g., AAMI, ASTM, ASME, IEC, ISO, CLSI, IEEE, AIUM) to jointly develop new standardized test methods that are used nationally and internationally to characterize and evaluate medical processes, materials, and devices. Collaborative interlaboratory testing is a key component for assessing the usability, precision, and accuracy of many of the test methods. The Consensus Standards Program also reduces the burden of regulatory review documentation by allowing industry to voluntarily adhere to the methodology outlined in standards that have been recognized as valid and applicable by CDRH while characterizing nonclinical and clinical performance
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of their regulated products. By declaring conformance to a CDRH-recognized standard, industry does not always have to supply all of the testing protocols and supporting data. Moreover, conformance to standards facilitates review and determination of either substantial equivalence or a reasonable assurance of safety and effectiveness for many applicable aspects of medical devices in premarket submissions. To date, the CDRH database identifies over 1050 consensus standards that have been recognized for this purpose (Table 1, section A).
Medical Device Innovation Consortium (MDIC) Based on statistics from the US Department of Commerce, approximately 75% of US medical device manufacturers have fewer than 20 employees (8,9). Along with start-up companies that may financially rely on the success of one medical device, these small companies often have limited capital and resources to apply to research, development, and regulatory issues associated with biomedical discovery and evolving technologies. To aid new product development, MDIC created a public–private partnership (currently composed of over 40 members including individual companies, nonprofit organizations, patient groups, FDA, the National Institutes of Health (NIH), and the Centers for Medicare & Medicaid Services)) to foster medical device innovation by supporting collaborative interaction. The objective of the partnership is to address common issues facing industry, particularly in the early-stage development of new technologies, in a noncompetitive and nonproprietary space (9). Through MDIC, companies can pool their limited resources and work directly with federal agencies to evaluate scientific topics which may increase patient access to safer and more effective devices. MDIC’s project areas include computational modeling and simulation, patientcentered benefit–risk assessment, clinical trial innovation and reform (e.g., study design, data collection, and barriers to early feasibility studies in patients), and improving the manufacturing quality of medical devices. CDRH’s involvement in the modeling and simulation area is focused on developing methodology for assessing the credibility of computational approaches used in the evaluation of medical devices. This includes the creation of repositories for models and validation data that could potentially be employed to investigate magnetic resonance imaging heating and safety, whole heart modeling and pacemaker lead failures, orthopedic devices, and CFD predictions of blood flow patterns and thrombus formation. Artif Organs, Vol. 39, No. 4, 2015
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INVITED EDITORIAL
NSF/FDA Scholar-in-Residence Program In partnership with the National Science Foundation (NSF), the NSF/FDA Scholar-in-Residence Program allows faculty, postdocs, and students in the areas of science, engineering, and mathematics to advance the intramural CDRH laboratory research program concentrated on applied regulatory science. Project examples include characterization of nearinfrared spectroscopy systems for cerebral oximetry, cellular engineering of replacement cartilage tissue, safe electrode placement for retinal implants, biocompatibility assessment of nano-printed surfaces, isolation of cancer stem cells using flow-cytometry techniques, and assessing radiological medical image quality for the detection of abnormalities. ADVANCING REGULATORY SCIENCE EXPERTISE AND INFORMATION EXCHANGE (TABLE 1, SECTION B) Experiential Learning Program To keep abreast of the rapid developments in biomedical science and medical technology, and to utilize the best scientific information available when making regulatory decisions, CDRH has established programs to foster interaction with subject matter experts within the medical device industry, academia, and the clinical community (including NIH and the military) to provide practical training and relevant experience to regulatory review staff. For example, through the Experiential Learning Program, CDRH staff visit qualified companies and clinics to gain awareness of existing, emerging, and innovative medical device technologies. In 2013, over 250 CDRH staff participated in 22 site visits lasting 1–2 days each. Organizations volunteer to host CDRH personnel by responding to an annual announcement in the Federal Register. The program areas of interest for 2014 included manufacturing of robotic surgical devices, 3D printing of orthopedic devices, hemodialysis devices used in the home environment, brain-computer interface devices, tumor ablation devices, manufacturing of vascular sealants, artificial pancreas-related devices, antimicrobial resistance detection, and diagnostic x-ray imaging devices and user facilities (10). Network of Experts Program To further assist in understanding complex device issues related to cutting-edge technologies, CDRH established the Network of Experts program to leverage technical and medical expertise external to the agency. This independent network of specialists, vetted for conflicts of interest and with agreements to Artif Organs, Vol. 39, No. 4, 2015
maintain all information confidential, draws upon the membership of over 35 professional societies. These include the American Society for Dermatologic Surgery Association, American Society of Plastic Surgeons, American Academy of Ophthalmology, American Society for Radiation Oncology, as well as the American Association/Congress of Neurological Surgeons, to name a few, that have provided scientific and clinical expertise in response to explicit requests from CDRH staff. Public Workshops To openly discuss and receive feedback for regulatory and scientific issues related to specific medical device areas and emerging technologies, CDRH also engages external stakeholders by sponsoring about 20 public workshops each year. Recent public workshops focused on diverse, yet rapidly evolving fields and technologies such as brain-computer interface devices for patients with paralysis or amputation, device and healthcare cybersecurity, validation of proteomic methodologies for in vitro diagnostic tests, 3D printing of devices, evaluating the thrombosis potential of blood contacting devices, anti-biofilm technology, and microbiological test assays for contact lenses. CDRH Medical Device Fellowships To cultivate in-house expertise development, CDRH provides opportunities for external engineers, scientists, and clinicians to participate in interactive regulatory and research programs at the FDA campus. The CDRH Medical Device Fellowship Program (MDFP) offers short and long-term fellowships for participants to learn about the regulatory process and the governing medical device laws while sharing their knowledge and practical experience with CDRH device reviewers. STREAMLINING REGULATORY REVIEW PATHWAYS (TABLE 1, SECTION C) Each year, CDRH evaluates approximately 10 000 medical device submissions (i.e., original statutory premarket applications that require scientific review and regulatory decisions), which require substantial resources for industry to prepare and for CDRH personnel to review. To reduce the time spent on regulatory processes inside and outside of the agency, CDRH continuously looks for ways to streamline the regulatory review pathways and requirements that companies must follow to support device claims of being safe and effective.
INVITED EDITORIAL National Medical Device Curriculum The FDA believes that by providing mechanisms for industry to engage the agency early in the product development timeline, and by furnishing information that is comprehensive, interactive, and easily accessible, it will lead to better understanding of regulatory processes and in turn accelerate the availability of breakthrough medical devices for patients. In collaboration with academic partners, CDRH developed the National Medical Device Curriculum of educational case studies to assist our stakeholders in understanding how to choose the proper regulatory pathway for a new device, demonstrate safety assurance for the device through benchtop and clinical testing, and perform a risk management analysis. This supports a specific goal outlined within CDRH’s 2014–2015 Strategic Priorities that aims to improve the quality of device submissions, thus shortening the review time needed to gain approval for Investigational Device Exemption (IDE) clinical trials. Additional training and advisory resources for device developers and manufacturers, patients, consumers, students, and healthcare providers are also available through the CDRH Division of Industry and Consumer Education (DICE; see Table 1, section C for website). Guidance Documents CDRH has developed several specific approaches to data collection and utilization that can result in decreasing the evidentiary premarket data burden. For example, the Consensus Standards Program discussed earlier aims to reduce the burden of regulatory review documentation while still maintaining the safety requirements for the assessment of devices. CDRH also prepares Guidance Documents for use by industry and FDA personnel that expound upon issues concerning the design, manufacturing, and technical analysis of devices, as well as application processes for device approvals, inspection procedures, and enforcement policies. Guidance documents reflect FDA’s current thinking on a specific topic and incorporate feedback from external stakeholders to provide information and recommendations aimed at achieving regulatory goals in the most efficient manner. The FDA Guidance Document database is publicly accessible and currently includes over 700 CDRH-developed documents in final or draft form. About 24 CDRH Guidance Documents are finalized and added to the database each year. Recently issued guidances address processes for evaluating substantial equivalence between a new device and an acceptable predicate in 510(k) premarket notifications, considerations for
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determining whether a product involves nanotechnology, safety labeling recommendations for laparoscopic power morcellators, minimizing risk in children’s toy laser products, and establishing safety for passive implants in a magnetic resonance environment. CDRH has issued several guidances to reduce the burden of clinical data development in the evaluation of a medical device. In 2013, CDRH issued guidance for “Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies” (11). This guidance outlines new policy regarding approval of early feasibility study IDEs that may be based on less nonclinical data than would be expected for a traditional feasibility or a pivotal clinical study, and new approaches to facilitate timely device and clinical protocol modifications during an early feasibility study. Other guidances meant to improve clinical trial practices describe the use of Bayesian statistics, which may provide justification for reducing the size and duration of a pivotal trial, and the requirements for acceptance of foreign clinical studies in support of a device marketing application in the United States (12,13). Medical Device Development Tools (MDDT) To further streamline the regulatory evaluation of new devices and potentially reduce industry’s expenditure on costly resources, CDRH recently launched a new pilot initiative, the MDDT Program. CDRH plans to review evidence from internal and external applicants to qualify “tools” that produce scientifically plausible measurements and data within a specified context of use that sponsors can implement in the development and evaluation of medical devices in support of a marketing submission. Example tools are clinical assessment tests for patient-reported outcomes, biomarkers to assist in diagnosis and treatment, and nonclinical benchtop evaluations of devices. Another example of a potential MDDT is the use of Computational Modeling and Simulation, which, if qualified for a well-defined context of use, may augment or replace nonclinical and human clinical data development in specific device applications. Summary information about the qualified tool and its context of use will be provided to the public, but proprietary information will not be disclosed. National Medical Device Postmarket Surveillance System The evaluation of device safety extends throughout the total life cycle of a medical product and well beyond the initial premarket analysis stage. Artif Organs, Vol. 39, No. 4, 2015
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Postmarket studies and monitoring are essential to insure that devices function safely and effectively when used long term in real-world extended patient populations. Annually, CDRH processes over 800 000 individual medical device reports of confirmed or possible device-associated patient injuries, deaths, or device malfunctions. However, these reports are obtained through passive surveillance and may be incomplete or inaccurate, lack timeliness, and underreport the actual number of events. CDRH has been establishing a National Medical Device Postmarket Surveillance System to more quickly identify poorly performing devices, accurately provide real-time information about device performance and risk, reduce the burdens and costs of postmarket surveillance, and generate data to support premarket clearance of new devices and new uses of currently marketed devices (14). To accomplish these goals, CDRH launched in 2010 the Medical Device Epidemiology Network (MDEpiNet) initiative, which has evolved into a public–private partnership with over 40 national and international stakeholders (including from the device industry, patient medical registries, healthcare providers and facilities, academia, and patient groups) engaged in more than 50 ongoing studies. Through MDEpiNet, CDRH is collaboratively working to integrate enhanced surveillance and reporting methodological approaches, statistical and epidemiological tools, and various data sources, while promoting the development of device registries, scientific infrastructure, and operational practices to improve the real-time postmarket evaluation of new medical devices.
device establishments registered with the FDA, we invite you to partner with CDRH through the activities described in this article (or through individual Cooperative Research and Development Agreements or Research Collaboration Agreements) to impact the development of new medical devices. Suggestions for collaborative research projects or regulatory science interactions that will support innovation in a specific technology or device area can be discussed with CDRH scientists at any time or communicated to FDA via e-mail (CDRHRegScience @FDA.HHS.gov).
Summary Important strategies for fulfilling CDRH’s responsibility to protect and promote public health include providing our stakeholders (patients, medical practitioners, manufacturers) with access to safe and effective medical devices, up-to-date science-based information about products, and predictable and transparent regulatory pathways. Likewise, in order to facilitate the development of new and innovative devices and to keep pace with technological advances, CDRH has several initiatives that support science-based collaboration, information exchange, regulatory-based interaction, and relevant training for our staff and external stakeholders. Collectively, these efforts aim to provide advanced products to patients as efficiently as possible. Whether you are in academia, an individual product developer, medical personnel, a patient or caregiver, or an employee with one of the 24 000 domestic and foreign medical
REFERENCES
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Acknowledgments: Our thanks to CDRH staff for providing information and metrics for the different programs, and for article review (D. Marinac-Dabic, A. Dmitriev, W. Maisel, L. Grossman, D. Lochner, D. Mitchell, J. Cooper, T. Mizra, S. Colburn, R. Fischer, R. Moore, J. Kolonay, D. Gartner, M. Nguyen, I. Chang). *Richard A. Malinauskas, PhD, †Anindita Saha, BSE, and †Murray I. Sheldon, BS, MD *Offices of Science and Engineering Laboratories, and †the Center Director Center for Devices and Radiological Health FDA 10903 New Hampshire Avenue Silver Spring, MD 20993-0002, USA E-mail: [email protected] E-mail: [email protected] E-mail: [email protected]
1. US Food and Drug Administration. Driving Biomedical Innovation: Initiatives to Improve Products for Patients. 2011. Available at: http://www.fda.gov/downloads/aboutfda/ reportsmanualsforms/reports/ucm274464.pdf. Accessed March 3, 2015. 2. Maisel WH. Innovation at the Food and Drug Administration’s Device Center. JACC Cardiovasc Interv 2012;5:797–8. 3. Anatol R, Bauer S, Epstein S, et al. Continuing to strengthen FDA’s science approach to emerging technologies. Nanomedicine 2013;9:594–9. 4. US Food and Drug Administration. Regulatory Science in FDA’s Center for Devices and Radiological Health: A Vital Framework for Protecting and Promoting Public Health. 2011. Available at: http://www.fda.gov/downloads/AboutFDA/ CentersOffices/CDRH/CDRHReports/ucm274162.pdf. Accessed March 3, 2015. 5. Scully CG, Forrest S, Galeotti L, Schwartz SB, Strauss DG. Advancing regulatory science to bring novel medical devices for use in emergency care to market: the role of FDA. Ann Emerg Med 2014; PubMed PMID: 25128009. 6. US Food and Drug Administration. Computational Fluid Dynamics: An FDA Critical Path Initiative Project. Available at: https://fdacfd.nci.nih.gov. Accessed December 8, 2014.
INVITED EDITORIAL 7. US Food and Drug Administration. Reporting of Computational Modeling Studies in Medical Device Submissions— Draft Guidance for Industry and Food and Drug Administration Staff. 2014. Available at: http://www.fda .gov/medicaldevices/deviceregulationandguidance/guidance documents/ucm371016.htm. Accessed March 3, 2015. 8. US International Trade Administration. “Medical Devices Industry Assessment,” Report based on statistics from the U.S. Department of Commerce, Bureau of the Census. 2007. Available at: http://ita.doc.gov/td/health/medical%20device %20industry%20assessment%20final%20ii%203-24-10.pdf. Accessed March 3, 2015. 9. McMurry-Heath M, Hamburg MA. Creating a space for innovative device development. Sci Transl Med 2012;4:163fs43. 10. Federal Register. Center for Devices and Radiological Health: Experiential Learning Program, Vol. 79, No. 84. Washington, DC: National Archives and Records Administration. pp. 24729–24731, 2014. Available at: http://www.gpo.gov/fdsys/ pkg/FR-2014-05-01/pdf/2014-09916.pdf. Accessed March 3, 2015. Docket No. FDA-2013-N-0338.
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11. US Food and Drug Administration. Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies. 2013. Available at: http://www.fda.gov/downloads/ medicaldevices/deviceregulationandguidance/guidance documents/ucm279103.pdf. Accessed March 3, 2015. 12. US Food and Drug Administration. Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials. 2010. Available at: http://www.fda.gov/downloads/MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments/ ucm071121.pdf. Accessed March 3, 2015. 13. US Food and Drug Administration. Guidance for Industry— Acceptance of Foreign Clinical Studies. 2001. Available at: http://www.fda.gov/downloads/RegulatoryInformation/ Guidances/ucm124939.pdf. Accessed March 3, 2015. 14. US Food and Drug Administration. Strengthening our National System for Medical Device Postmarket Surveillance. 2012 Available at: http://www.fda.gov/downloads/AboutFDA/ CentersOffices/CDRH/CDRHReports/UCM301924.pdf. Accessed March 3, 2015.
Artif Organs, Vol. 39, No. 4, 2015
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Published 2015. This article is a U.S. Government work and is in the public domain in the USA
Invited Editorial
Working With the Food and Drug Administration’s Center for Devices to Advance Regulatory Science and Medical Device Innovation Within the US Food and Drug Administration (FDA), the mission of the Center for Devices and Radiological Health (CDRH) is to protect and promote public health by assuring that patients have timely and continued access to medical devices that are both safe and effective. Inherent in this mission is an obligation to facilitate innovation so that better medical devices can be developed and utilized as quickly as possible (1–3). To accomplish this goal, CDRH is actively engaged in advancing “regulatory science” for use in the product development and review process. Regulatory science research and practices provide industry and FDA with scientifically based assessment tools and approaches that can assist in the development, manufacture, and evaluation of new devices and technologies, as well as the creation of more efficient regulatory pathways (4,5). Most of the 1600 CDRH staff members (which include scientists, engineers, clinicians, statisticians, and public health specialists) support regulatory science processes by: (i) developing new standardized test methods and computational modeling techniques through laboratory-based device research; (ii) analyzing premarket bench, animal, and clinical trial testing and data for new devices; (iii) improving surveillance and epidemiological methods for monitoring and studying devices already on the market; (iv) preparing regulatory-based information and guidance documents to assist industry; and (v) bringing together interested parties and experts to address challenges in device development and assessment. With the fast-paced advances in science and the increasing complexity of new devices and technology, CDRH strives to collaboratively work with external stakeholders to continually update its regulatory science knowledge base. To enable this effort, CDRH has several initiatives by which private industry, the medical community, patient groups, and academia can partner with federal scientists to exchange doi:10.1111/aor.12505
information and remove barriers that may impede medical device development, thus fulfilling our collective goal of providing patients access to better devices. In the text of this article, we present several of the current CDRH programs and pathways that foster scientific collaboration and regulatory interaction, promote medical device innovation, and welcome your participation. A summary of all available programs (presented under three general categories including: Collaborative Research and Support Programs, Advancing Regulatory Science Expertise and Information Exchange, and Streamlining Regulatory Review Pathways) appears in Table 1 and includes website links to find more information. COLLABORATIVE RESEARCH AND SUPPORT PROGRAMS (TABLE 1, SECTION A) The Critical Path Initiative The Critical Path program supports intramural research and collaborative partnerships with medical, academic, and industrial organizations. This program was launched in 2004 as part of FDA’s strategy to improve the processes for translating scientific discoveries into new medical treatments and diagnostic modalities by addressing the important issues which could convolute the pathway to product development. FDA’s objective is to work with stakeholders to advance the science used to develop, evaluate, manufacture, and use all regulated medical products. At CDRH, the program focuses on reducing the time and resources needed to develop and evaluate new medical devices, and improving strategies for their assessment in the pre- and postmarket setting. About 20 CDRH projects are annually funded through this effort and have included the evaluation of bio-absorbable implants, additive manufacturing (3D printing) technology, spinal disc replacement devices, computer-aided imaging and diagnostic devices, metal-on-metal hip implant failures, devices and diagnostic tests that incorporate Artificial Organs 2015, 39(4):293–299
Description
Artif Organs, Vol. 39, No. 4, 2015
CDRH program to recruit entrepreneurs and innovators to join government employees in the development of solutions in areas that impact innovation. Recent project areas include streamlining clinical trials, accelerating FDA approval to reimbursement, and striking the right balance between pre- and postmarket device assessments.
FDA established Centers for Excellence with academic partners to promote cross-disciplinary regulatory scientific training, technical information exchange, and collaborative research.
SECTION C. Streamlining Regulatory Review Pathways National Medical Device Provides educational case studies for innovators on how to design, test, and clinically evaluate Curriculum medical devices, identify root causes of adverse patient events and malfunctions, and navigate the regulatory review process CDRH Division of Industry Direct CDRH contact point (via phone or email) that provides science-based regulatory information and Consumer Education to medical device industry, consumers/patients, and healthcare providers (DICE) FDA Guidance Documents Documents prepared for CDRH staff, regulated industry, and the public that provide recommendations and information related to: (i) the processing, content, and evaluation of regulatory submissions; (ii) the design, production, manufacturing, and testing of regulated products; and (iii) inspection and enforcement procedures Medical Device Development CDRH program to qualify “tools” that produce scientifically plausible measurements within a Tools (MDDT) Program specified context of use that sponsors can use in the development and evaluation of medical devices National Medical Device CDRH and external partners are integrating information and resources to enhance the surveillance, Postmarket Surveillance analysis, and reporting of the safety and effectiveness of medical devices after they have been System marketed.
Centers for Excellence in Regulatory Science and Innovation (CERSI) Entrepreneurs in Residence
SECTION B. Advancing Regulatory Science Expertise and Information Exchange Experiential Learning Program To gain awareness of existing and emerging medical device technologies, CDRH regulatory review staff visit research, clinical, manufacturing, and healthcare facilities to observe firsthand how medical devices are designed, developed, manufactured, and implemented in the clinic. Network of Experts Composed of over 35 professional organizations, this resource provides CDRH personnel with rapid access to independent experts in science, engineering, and medicine. Public Workshops CDRH sponsors open Public Workshops to discuss and receive feedback on regulatory and scientific issues related to a variety of medical devices and technologies. Medical Device Fellowship Provides fellowship opportunities for engineers, scientists, and physicians to learn about the Program (MDFP) regulatory process while sharing their knowledge and experience in the area of medical devices
SECTION A. Collaborative Research and Support Programs Critical Path Initiative An FDA strategy to modernize scientific tools and processes by which medical products are developed and evaluated for safety, effectiveness, and manufacturability Consensus Standards Program CDRH works with industry through national and international standards organizations (e.g., ASTM, AAMI, ISO) to develop consensus standards for characterizing and evaluating the performance of medical processes, materials, and devices. Medical Device Innovation Partnership between industry, FDA, NIH, and nonprofits (over 40 members) which provides a forum Consortium (MIDC) for open collaboration to improve patient access to cutting-edge medical technology NSF/FDA Scholar-inAnnual funding from the NSF enables 4–6 faculty, postdocs, and students in the areas of science, Residence Program engineering, and mathematics to participate in intramural research programs at CDRH Pediatric Device Consortia An FDA program that provides grants and support to domestic, public or private, nonprofit Grant Program consortia to facilitate the development, production, and distribution of innovative pediatric medical devices
Program
http://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDRH/ CDRHReports/ucm301912.htm Public–private partnership program: Medical Device Epidemiology Network (MDEpiNet) (http://www.MDEpiNet.org)
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ ContactUs--DivisionofIndustryandConsumerEducation/ ucm20041265.htm http://www.fda.gov/MedicalDevices/DeviceRegulationand Guidance/GuidanceDocuments/default.htm Searchable FDA Guidance Document database: http://www .fda.gov/RegulatoryInformation/Guidances/ http://www.fda.gov/medicaldevices/scienceandresearch/ medicaldevicedevelopmenttoolsmddt/default.htm
http://www.fda.gov/Training/CourseMaterialsforEducators/ NationalMedicalDeviceCurriculum/default.htm
http://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDRH/CDRHInnovation/ InnovationPathway/ucm286138.htm
http://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDRH/ucm289534.htm http://www.fda.gov/MedicalDevices/NewsEvents/ WorkshopsConferences/default.htm http://www.fda.gov/AboutFDA/WorkingatFDA/ FellowshipInternshipGraduateFacultyPrograms/ MedicalDeviceFellowshipProgramCDRH/default.htm http://www.fda.gov/scienceresearch/specialtopics/regulatoryscience/ ucm301667.htm
http://www.fda.gov/scienceresearch/sciencecareeropportunities/ ucm380676.htm
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseases Conditions/PediatricDeviceConsortiaGrantsProgram/
http://www.nsf.gov/funding/pgm_summ.jsp?pims_id=5605
http://mdic.org/
http://www.fda.gov/ScienceResearch/SpecialTopics/ CriticalPathInitiative/ucm076689.htm http://www.fda.gov/medicaldevices/deviceregulationandguidance/ guidancedocuments/ucm077274.htm
More information and how to participate
TABLE 1. CDRH programs to promote collaboration and innovation in medical device development
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INVITED EDITORIAL nanotechnologies, and improvements in computational evaluation methods. Key elements of the Critical Path Initiative are transparency and open dissemination of the results to provide beneficial knowledge to all researchers and device developers. For example, to explore the burgeoning use of computational fluid dynamics (CFD) in characterizing fluid flow and predicting blood damage safety in medical devices, CDRH worked with a planning committee of academic experts and professional organizations to create a project open to anyone who wanted to computationally evaluate blood flow through a simple medical device model (6). Twenty-eight academic and industry groups from six countries participated in the first computational analysis challenge, which included comparing CFD simulation results to experimental data (velocity measurements and in vitro hemolysis test results) collected at CDRH and in four academic research laboratories. To date, the results of the project have supported a publicly accessible technical database for a benchmark flow model that is being widely used to examine CFD simulation methodology, leading to the identification of “best practice” approaches and limitations for applying CFD techniques. In combination with other CDRH simulation efforts, this project contributed to the development of a Draft FDA Guidance Document on information reporting procedures that, upon finalization, will assist the industry in submitting computational analyses in premarket and postmarket studies of medical devices to CDRH (7). Consensus Standards Program The standards development process, which is part of the Consensus Standards Program at CDRH, defines another important collaborative pathway that directly impacts global medical device testing and evolution. Along with representatives from industry and academia, CDRH scientists serve on many standards organization committees (e.g., AAMI, ASTM, ASME, IEC, ISO, CLSI, IEEE, AIUM) to jointly develop new standardized test methods that are used nationally and internationally to characterize and evaluate medical processes, materials, and devices. Collaborative interlaboratory testing is a key component for assessing the usability, precision, and accuracy of many of the test methods. The Consensus Standards Program also reduces the burden of regulatory review documentation by allowing industry to voluntarily adhere to the methodology outlined in standards that have been recognized as valid and applicable by CDRH while characterizing nonclinical and clinical performance
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of their regulated products. By declaring conformance to a CDRH-recognized standard, industry does not always have to supply all of the testing protocols and supporting data. Moreover, conformance to standards facilitates review and determination of either substantial equivalence or a reasonable assurance of safety and effectiveness for many applicable aspects of medical devices in premarket submissions. To date, the CDRH database identifies over 1050 consensus standards that have been recognized for this purpose (Table 1, section A).
Medical Device Innovation Consortium (MDIC) Based on statistics from the US Department of Commerce, approximately 75% of US medical device manufacturers have fewer than 20 employees (8,9). Along with start-up companies that may financially rely on the success of one medical device, these small companies often have limited capital and resources to apply to research, development, and regulatory issues associated with biomedical discovery and evolving technologies. To aid new product development, MDIC created a public–private partnership (currently composed of over 40 members including individual companies, nonprofit organizations, patient groups, FDA, the National Institutes of Health (NIH), and the Centers for Medicare & Medicaid Services)) to foster medical device innovation by supporting collaborative interaction. The objective of the partnership is to address common issues facing industry, particularly in the early-stage development of new technologies, in a noncompetitive and nonproprietary space (9). Through MDIC, companies can pool their limited resources and work directly with federal agencies to evaluate scientific topics which may increase patient access to safer and more effective devices. MDIC’s project areas include computational modeling and simulation, patientcentered benefit–risk assessment, clinical trial innovation and reform (e.g., study design, data collection, and barriers to early feasibility studies in patients), and improving the manufacturing quality of medical devices. CDRH’s involvement in the modeling and simulation area is focused on developing methodology for assessing the credibility of computational approaches used in the evaluation of medical devices. This includes the creation of repositories for models and validation data that could potentially be employed to investigate magnetic resonance imaging heating and safety, whole heart modeling and pacemaker lead failures, orthopedic devices, and CFD predictions of blood flow patterns and thrombus formation. Artif Organs, Vol. 39, No. 4, 2015
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NSF/FDA Scholar-in-Residence Program In partnership with the National Science Foundation (NSF), the NSF/FDA Scholar-in-Residence Program allows faculty, postdocs, and students in the areas of science, engineering, and mathematics to advance the intramural CDRH laboratory research program concentrated on applied regulatory science. Project examples include characterization of nearinfrared spectroscopy systems for cerebral oximetry, cellular engineering of replacement cartilage tissue, safe electrode placement for retinal implants, biocompatibility assessment of nano-printed surfaces, isolation of cancer stem cells using flow-cytometry techniques, and assessing radiological medical image quality for the detection of abnormalities. ADVANCING REGULATORY SCIENCE EXPERTISE AND INFORMATION EXCHANGE (TABLE 1, SECTION B) Experiential Learning Program To keep abreast of the rapid developments in biomedical science and medical technology, and to utilize the best scientific information available when making regulatory decisions, CDRH has established programs to foster interaction with subject matter experts within the medical device industry, academia, and the clinical community (including NIH and the military) to provide practical training and relevant experience to regulatory review staff. For example, through the Experiential Learning Program, CDRH staff visit qualified companies and clinics to gain awareness of existing, emerging, and innovative medical device technologies. In 2013, over 250 CDRH staff participated in 22 site visits lasting 1–2 days each. Organizations volunteer to host CDRH personnel by responding to an annual announcement in the Federal Register. The program areas of interest for 2014 included manufacturing of robotic surgical devices, 3D printing of orthopedic devices, hemodialysis devices used in the home environment, brain-computer interface devices, tumor ablation devices, manufacturing of vascular sealants, artificial pancreas-related devices, antimicrobial resistance detection, and diagnostic x-ray imaging devices and user facilities (10). Network of Experts Program To further assist in understanding complex device issues related to cutting-edge technologies, CDRH established the Network of Experts program to leverage technical and medical expertise external to the agency. This independent network of specialists, vetted for conflicts of interest and with agreements to Artif Organs, Vol. 39, No. 4, 2015
maintain all information confidential, draws upon the membership of over 35 professional societies. These include the American Society for Dermatologic Surgery Association, American Society of Plastic Surgeons, American Academy of Ophthalmology, American Society for Radiation Oncology, as well as the American Association/Congress of Neurological Surgeons, to name a few, that have provided scientific and clinical expertise in response to explicit requests from CDRH staff. Public Workshops To openly discuss and receive feedback for regulatory and scientific issues related to specific medical device areas and emerging technologies, CDRH also engages external stakeholders by sponsoring about 20 public workshops each year. Recent public workshops focused on diverse, yet rapidly evolving fields and technologies such as brain-computer interface devices for patients with paralysis or amputation, device and healthcare cybersecurity, validation of proteomic methodologies for in vitro diagnostic tests, 3D printing of devices, evaluating the thrombosis potential of blood contacting devices, anti-biofilm technology, and microbiological test assays for contact lenses. CDRH Medical Device Fellowships To cultivate in-house expertise development, CDRH provides opportunities for external engineers, scientists, and clinicians to participate in interactive regulatory and research programs at the FDA campus. The CDRH Medical Device Fellowship Program (MDFP) offers short and long-term fellowships for participants to learn about the regulatory process and the governing medical device laws while sharing their knowledge and practical experience with CDRH device reviewers. STREAMLINING REGULATORY REVIEW PATHWAYS (TABLE 1, SECTION C) Each year, CDRH evaluates approximately 10 000 medical device submissions (i.e., original statutory premarket applications that require scientific review and regulatory decisions), which require substantial resources for industry to prepare and for CDRH personnel to review. To reduce the time spent on regulatory processes inside and outside of the agency, CDRH continuously looks for ways to streamline the regulatory review pathways and requirements that companies must follow to support device claims of being safe and effective.
INVITED EDITORIAL National Medical Device Curriculum The FDA believes that by providing mechanisms for industry to engage the agency early in the product development timeline, and by furnishing information that is comprehensive, interactive, and easily accessible, it will lead to better understanding of regulatory processes and in turn accelerate the availability of breakthrough medical devices for patients. In collaboration with academic partners, CDRH developed the National Medical Device Curriculum of educational case studies to assist our stakeholders in understanding how to choose the proper regulatory pathway for a new device, demonstrate safety assurance for the device through benchtop and clinical testing, and perform a risk management analysis. This supports a specific goal outlined within CDRH’s 2014–2015 Strategic Priorities that aims to improve the quality of device submissions, thus shortening the review time needed to gain approval for Investigational Device Exemption (IDE) clinical trials. Additional training and advisory resources for device developers and manufacturers, patients, consumers, students, and healthcare providers are also available through the CDRH Division of Industry and Consumer Education (DICE; see Table 1, section C for website). Guidance Documents CDRH has developed several specific approaches to data collection and utilization that can result in decreasing the evidentiary premarket data burden. For example, the Consensus Standards Program discussed earlier aims to reduce the burden of regulatory review documentation while still maintaining the safety requirements for the assessment of devices. CDRH also prepares Guidance Documents for use by industry and FDA personnel that expound upon issues concerning the design, manufacturing, and technical analysis of devices, as well as application processes for device approvals, inspection procedures, and enforcement policies. Guidance documents reflect FDA’s current thinking on a specific topic and incorporate feedback from external stakeholders to provide information and recommendations aimed at achieving regulatory goals in the most efficient manner. The FDA Guidance Document database is publicly accessible and currently includes over 700 CDRH-developed documents in final or draft form. About 24 CDRH Guidance Documents are finalized and added to the database each year. Recently issued guidances address processes for evaluating substantial equivalence between a new device and an acceptable predicate in 510(k) premarket notifications, considerations for
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determining whether a product involves nanotechnology, safety labeling recommendations for laparoscopic power morcellators, minimizing risk in children’s toy laser products, and establishing safety for passive implants in a magnetic resonance environment. CDRH has issued several guidances to reduce the burden of clinical data development in the evaluation of a medical device. In 2013, CDRH issued guidance for “Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies” (11). This guidance outlines new policy regarding approval of early feasibility study IDEs that may be based on less nonclinical data than would be expected for a traditional feasibility or a pivotal clinical study, and new approaches to facilitate timely device and clinical protocol modifications during an early feasibility study. Other guidances meant to improve clinical trial practices describe the use of Bayesian statistics, which may provide justification for reducing the size and duration of a pivotal trial, and the requirements for acceptance of foreign clinical studies in support of a device marketing application in the United States (12,13). Medical Device Development Tools (MDDT) To further streamline the regulatory evaluation of new devices and potentially reduce industry’s expenditure on costly resources, CDRH recently launched a new pilot initiative, the MDDT Program. CDRH plans to review evidence from internal and external applicants to qualify “tools” that produce scientifically plausible measurements and data within a specified context of use that sponsors can implement in the development and evaluation of medical devices in support of a marketing submission. Example tools are clinical assessment tests for patient-reported outcomes, biomarkers to assist in diagnosis and treatment, and nonclinical benchtop evaluations of devices. Another example of a potential MDDT is the use of Computational Modeling and Simulation, which, if qualified for a well-defined context of use, may augment or replace nonclinical and human clinical data development in specific device applications. Summary information about the qualified tool and its context of use will be provided to the public, but proprietary information will not be disclosed. National Medical Device Postmarket Surveillance System The evaluation of device safety extends throughout the total life cycle of a medical product and well beyond the initial premarket analysis stage. Artif Organs, Vol. 39, No. 4, 2015
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Postmarket studies and monitoring are essential to insure that devices function safely and effectively when used long term in real-world extended patient populations. Annually, CDRH processes over 800 000 individual medical device reports of confirmed or possible device-associated patient injuries, deaths, or device malfunctions. However, these reports are obtained through passive surveillance and may be incomplete or inaccurate, lack timeliness, and underreport the actual number of events. CDRH has been establishing a National Medical Device Postmarket Surveillance System to more quickly identify poorly performing devices, accurately provide real-time information about device performance and risk, reduce the burdens and costs of postmarket surveillance, and generate data to support premarket clearance of new devices and new uses of currently marketed devices (14). To accomplish these goals, CDRH launched in 2010 the Medical Device Epidemiology Network (MDEpiNet) initiative, which has evolved into a public–private partnership with over 40 national and international stakeholders (including from the device industry, patient medical registries, healthcare providers and facilities, academia, and patient groups) engaged in more than 50 ongoing studies. Through MDEpiNet, CDRH is collaboratively working to integrate enhanced surveillance and reporting methodological approaches, statistical and epidemiological tools, and various data sources, while promoting the development of device registries, scientific infrastructure, and operational practices to improve the real-time postmarket evaluation of new medical devices.
device establishments registered with the FDA, we invite you to partner with CDRH through the activities described in this article (or through individual Cooperative Research and Development Agreements or Research Collaboration Agreements) to impact the development of new medical devices. Suggestions for collaborative research projects or regulatory science interactions that will support innovation in a specific technology or device area can be discussed with CDRH scientists at any time or communicated to FDA via e-mail (CDRHRegScience @FDA.HHS.gov).
Summary Important strategies for fulfilling CDRH’s responsibility to protect and promote public health include providing our stakeholders (patients, medical practitioners, manufacturers) with access to safe and effective medical devices, up-to-date science-based information about products, and predictable and transparent regulatory pathways. Likewise, in order to facilitate the development of new and innovative devices and to keep pace with technological advances, CDRH has several initiatives that support science-based collaboration, information exchange, regulatory-based interaction, and relevant training for our staff and external stakeholders. Collectively, these efforts aim to provide advanced products to patients as efficiently as possible. Whether you are in academia, an individual product developer, medical personnel, a patient or caregiver, or an employee with one of the 24 000 domestic and foreign medical
REFERENCES
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Acknowledgments: Our thanks to CDRH staff for providing information and metrics for the different programs, and for article review (D. Marinac-Dabic, A. Dmitriev, W. Maisel, L. Grossman, D. Lochner, D. Mitchell, J. Cooper, T. Mizra, S. Colburn, R. Fischer, R. Moore, J. Kolonay, D. Gartner, M. Nguyen, I. Chang). *Richard A. Malinauskas, PhD, †Anindita Saha, BSE, and †Murray I. Sheldon, BS, MD *Offices of Science and Engineering Laboratories, and †the Center Director Center for Devices and Radiological Health FDA 10903 New Hampshire Avenue Silver Spring, MD 20993-0002, USA E-mail: [email protected] E-mail: [email protected] E-mail: [email protected]
1. US Food and Drug Administration. Driving Biomedical Innovation: Initiatives to Improve Products for Patients. 2011. Available at: http://www.fda.gov/downloads/aboutfda/ reportsmanualsforms/reports/ucm274464.pdf. Accessed March 3, 2015. 2. Maisel WH. Innovation at the Food and Drug Administration’s Device Center. JACC Cardiovasc Interv 2012;5:797–8. 3. Anatol R, Bauer S, Epstein S, et al. Continuing to strengthen FDA’s science approach to emerging technologies. Nanomedicine 2013;9:594–9. 4. US Food and Drug Administration. Regulatory Science in FDA’s Center for Devices and Radiological Health: A Vital Framework for Protecting and Promoting Public Health. 2011. Available at: http://www.fda.gov/downloads/AboutFDA/ CentersOffices/CDRH/CDRHReports/ucm274162.pdf. Accessed March 3, 2015. 5. Scully CG, Forrest S, Galeotti L, Schwartz SB, Strauss DG. Advancing regulatory science to bring novel medical devices for use in emergency care to market: the role of FDA. Ann Emerg Med 2014; PubMed PMID: 25128009. 6. US Food and Drug Administration. Computational Fluid Dynamics: An FDA Critical Path Initiative Project. Available at: https://fdacfd.nci.nih.gov. Accessed December 8, 2014.
INVITED EDITORIAL 7. US Food and Drug Administration. Reporting of Computational Modeling Studies in Medical Device Submissions— Draft Guidance for Industry and Food and Drug Administration Staff. 2014. Available at: http://www.fda .gov/medicaldevices/deviceregulationandguidance/guidance documents/ucm371016.htm. Accessed March 3, 2015. 8. US International Trade Administration. “Medical Devices Industry Assessment,” Report based on statistics from the U.S. Department of Commerce, Bureau of the Census. 2007. Available at: http://ita.doc.gov/td/health/medical%20device %20industry%20assessment%20final%20ii%203-24-10.pdf. Accessed March 3, 2015. 9. McMurry-Heath M, Hamburg MA. Creating a space for innovative device development. Sci Transl Med 2012;4:163fs43. 10. Federal Register. Center for Devices and Radiological Health: Experiential Learning Program, Vol. 79, No. 84. Washington, DC: National Archives and Records Administration. pp. 24729–24731, 2014. Available at: http://www.gpo.gov/fdsys/ pkg/FR-2014-05-01/pdf/2014-09916.pdf. Accessed March 3, 2015. Docket No. FDA-2013-N-0338.
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11. US Food and Drug Administration. Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies. 2013. Available at: http://www.fda.gov/downloads/ medicaldevices/deviceregulationandguidance/guidance documents/ucm279103.pdf. Accessed March 3, 2015. 12. US Food and Drug Administration. Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials. 2010. Available at: http://www.fda.gov/downloads/MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments/ ucm071121.pdf. Accessed March 3, 2015. 13. US Food and Drug Administration. Guidance for Industry— Acceptance of Foreign Clinical Studies. 2001. Available at: http://www.fda.gov/downloads/RegulatoryInformation/ Guidances/ucm124939.pdf. Accessed March 3, 2015. 14. US Food and Drug Administration. Strengthening our National System for Medical Device Postmarket Surveillance. 2012 Available at: http://www.fda.gov/downloads/AboutFDA/ CentersOffices/CDRH/CDRHReports/UCM301924.pdf. Accessed March 3, 2015.
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