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Office of Science and Engineering Laboratories Annual Report - Fiscal Year 2005U.S. Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Devices and Radiological Health
PREFACE
REGULATORY SUPPORT ACTIVITIES
DIVISION DESCRIPTIONS
DESCRIPTION OF OSEL LABORATORIES
Biological Risk Assessment (Division of Biology)
Radiation Biology (Division of Biology)
Biotechnology (Division of Biology)
Cardiovascular and Interventional Therapeutics (Division of Biology)
Toxicology (Division of Biology)
Biomolecular Mechanisms (Division of Biology)
Electronics (Division of Electronics and Software Engineering)
Software (Division of Electronics and Software Engineering)
Systems Engineering (Division of Electronics and Software Engineering)
Materials Chemistry (Division of Chemistry and Materials Science)
Experimental Pathology
Medical Imaging and Diagnostics (Division of Imaging and Applied Mathematics)
Ionizing Radiation Metrology (Division of Imaging and Applied Mathematics)
Electrophysiology and Electrical Stimulation (Division of Physics)
Electromagnetics and Wireless Technology (Division of Physics)
Optical Radiation Safety and Devices (Division of Physics)
Optical Diagnostics and Therapeutics (Division of Physics)
Fluid Dynamics (Division of Solid and Fluid Mechanics)
Ultrasonics (Division of Solid and Fluid Mechanics)
Mechanics (Division of Solid and Fluid Mechanics)
Standards Management Staff
APPENDIX A – OSEL Publications
APPENDIX B – OSEL Presentations
APPENDIX C – OSEL Academic Affiliations
APPENDIX D – OSEL Patents
APPENDIX E – OSEL-Sponsored Seminars
APPENDIX F – Interagency Agreements
APPENDIX G - OSEL Laboratories and Laboratory Leaders
The mission of the Food and Drug Administration’s (FDA) Center for Devices and Radiological Health (CDRH) is to promote and protect the health of the public by ensuring the safety and effectiveness of medical devices and the safety of radiological products.
The Office of Science and Engineering Laboratories (OSEL), one of seven Offices within the Center for Devices and Radiological Health (CDRH), contributes to accomplishing the Center’s mission. OSEL serves as the laboratory science nucleus for the Center. Specifically, OSEL supports the scientific basis for the Agency’s regulatory decision- making by developing independent laboratory information for regulatory and other public health activities of CDRH. In addition to providing consultation to the Center’s regulatory experts, OSEL researchers are involved in mission-oriented science activities including test methods development, risk assessments, forensic investigations, product evaluations, and technology forecasting.
From a science standpoint, OSEL conducts laboratory and field research in the areas of physical, life, and engineering sciences as related to the human health effects of medical devices. CDRH relies upon this work to support its efforts ensuring public safety in areas as varied as accredited mammography facilities, breast implants, or drug eluting stents.
Since mid-2003, the Office has undergone at least three major transformations which have helped shape a strong organization. The first was the move of the newly reorganized Division of Biology to the newly constructed FDA Life Science Laboratories in White Oak, Maryland. This move was the beginning of a planned consolidation of FDA facilities. The remaining OSEL divisions are expected to move to the White Oak facilities in 2007. The second change involves what has been termed the science prioritization process. In the beginning of 2004, the Office instituted an ongoing process of conducting reviews of all OSEL research programs. This process is continuing to evolve and has made significant changes in the way research is proposed and how its value to the Center is evaluated. The third major change is the reorganization itself. OSEL was formally reorganized in early 2004 to improve the overall operating efficiency of the Office and to better integrate it into the mission and functions of CDRH. The reorganization created a new structure in which six new divisions replaced four former divisions in the Office and effectively removed all designated branches.
This reorganization has taken place at a crucial time. Over the past few years, with MDUFMA (Medical Device User Fee and Modernization Act of 2002) legislation and accompanying resources, the Office has been broadening and improving its scientific program. This provides OSEL management an excellent opportunity to increase collaboration with other components of CDRH. Finally, with the recent move of the life sciences staff to White Oak and the impending construction of the engineering and physics building, the prospects for OSEL are promising.
OSEL long-term goals focus on the following:
The OSEL Annual Report provides current information about the Office’s organization and intramural science activities; provides a summary of the Office’s direct laboratory support for pre-market review and post-market evaluation; and provides a bibliography of scientific publications, presentations, and research seminars for the fiscal year. The report is presented along the line of OSEL organization structure where the divisions are described first, followed by descriptions of the research laboratories. The laboratory descriptions contain abstracts of research projects as well as their accomplishments. This report also summarizes the regulatory support work that OSEL provides to the Center’s post-and pre-market offices.
OSEL management welcomes comments on the programs described in this report. We hope you find this document useful and informative, and your comments are welcome.
For additional information, please visit the OSEL web site at http://www.fda.gov/cdrh/osel or contact us at 301.827.4777.
Larry G. Kessler, Sc.D.
Director
Office of Science and Engineering Laboratories
The two primary functions of the Office are:
Both activities are coordinated within OSEL in an effective manner so as to best meet the Center’s regulatory and science needs. The strategically managed research of the Office is described in subsequent sections in great detail. This research activity is the cornerstone upon which the Office provides the regulatory support function. The laboratory research is largely based on investigations related to the mechanistic understanding of the device performance or test procedures to enable the Center and device manufacturers to gain an improved understanding of issues related to the safety and efficacy. In general, though the research is directed toward issues identified at the pre-market approval level, in reality, the research has the major impact on the post-market end of the Center’s business because most often the research is anticipatory in terms of potential issues of medical devices identified at the pre-market level.
The regulatory support function of the Office is provided through consults in support of both pre-market decisions and post-market actions using expertise developed in the laboratory. A consult is a request for expert advice or information of a specific nature, where it is perceived that expertise is more discipline related than medical device related. Consult provides information which contributes to sound regulatory decisions. Consults may be based on acknowledged scientific/engineering principles or on independent data generated in OSEL laboratories.
The following provides a consolidated picture of the breadth of consults that OSEL provides to Center’s offices in 2005:
Number of consults to pre-market issues: 1023
Number of consults to post-market issues: 173
Number of consults to other Centers and agencies: 60
Number of activities related to standards: 116
The information provided by a consult is used in some of the following ways:
In many post-market as well as pre-market regulatory issues, OSEL reviews and investigations may provide an independent assessment of claims made by a manufacturer or other party concerning safety or effectiveness. In other cases, OSEL reviews may assess the adequacy of a design, a failure investigation, a production process, or a quality process employed by the manufacturer. These reviews and analyses rely on in-house expertise and are often augmented by expertise solicited from colleagues in academia, other government laboratories, or even other industry sectors. OSEL laboratory investigations may be undertaken in instances where the veracity of a performance claim needs to be independently verified by testing, or when the claimant lacks the resources to conduct the investigation. Specifically, OSEL provides analytical support to post-market regulatory activities in a variety of ways:
- Scientific and engineering reviews and analyses
- Laboratory investigations of product performance
- Participation in inspections of medical device establishments
- Forensic reviews and investigations
- Identify device safety and performance issues
- Provide training to FDA and industry
- Contributions to Center-wide teams on issues identification as well as science- based analysis of post-market device performance
Standards and measurements are important products of this office. OSEL provides innovative solutions to public health problems through the development of generic techniques that lead to national and international standards to enhance product safety and effectiveness. A major activity related to standards is staff participation in standards development at the national as well as international level by conducting research to develop standard procedures and by managing, developing, and supporting standards used for regulatory assessments.
The following is an illustration from the past of a regulatory support activity in which OSEL participated. A few years ago, the reuse of single use devices was a major issue. OSEL established a major research project on this issue in response to a request from the Office of Compliance and Office of Surveillance and Biometrics to address issues related to reuse of single use devices. OSEL researchers organized a team and initiated a preliminary study to determine the effects of a variety of disinfection and sterilization methods on variety of generic materials. The team worked with other Center Offices to set up a retrieval program of cardiac catheters after single use at two local hospitals. These catheters were marketed for single use only but were reprocessed for reuse in many hospitals and third party facilities. To identify the nature and scope of potential problems with reuse of these devices, the team identified key performance characteristics and developed laboratory test methods to study the effects of use and simulated reuse on these characteristics. OSEL also developed methods for simulating reuse. The laboratory data demonstrated that the performance of some devices does not meet manufacturers’ specifications after a single use, and that these properties are further altered after simulated reuse, re-cleaning or resterilization. These laboratory data have had a major impact on the Center's deliberations on the subject as well as incorporation of the data in standards development.
The following examples illustrate the depth and breath of OSEL consults:
1. Computational fluid dynamics of left ventricular assist device
OSEL laboratory expertise in experimental and computation fluid dynamics was recently utilized to aid in the evaluation of a post-approval study change for a pediatric left ventricular assist device (LVAD). The sponsor proposed to make a change to the blood flow path within the pump that could have adversely affected hemolysis and thrombogenesis in the pump such that patient safety and/or device efficacy could have been compromised. It would have been extremely difficult, if not impossible, to validate the design changes using animal or human data. After discussions and a meeting with FDA staff, the sponsor agreed to provide experimental (flow visualization, hemolysis) and analytical (computational fluid dynamics [CFD]) testing to support the design changes. CDRH experts recommended appropriate CFD models to the sponsors and analyzed the results. In this instance, our efforts eliminated the need for the sponsor to perform expensive and time-consuming animal testing and/or clinical testing. The proposed design changes were approved, thus expediting the availability of this innovative device.
2. Computer-assisted diagnostic systems
OSEL scientists have also played a leading role in the development of new models and methods for the assessment of computer-assisted diagnostic systems. The techniques were first developed during our review of digital mammography systems, and have since been extended to the development of systems for breast cancer screening, lung cancer screening, and CT colonoscopy. CDRH scientists who have developed these methods have played an important role on the review team for applications for these devices. Having these tools and methods available has greatly assisted developers of these innovative imaging and CAD-assist devices.
3. Performance testing of pulse oximeters
CDRH scientists and engineers have developed test methods for a range of non-invasive monitoring devices. CDRH laboratory studies on pulse oximeter performance, for example, enabled substantial improvements in the ISO/IEC standard and the CDRH Guidance Document. This testing facilitated the development of a single test protocol for SpO2 accuracy studies, which simplified the pre-market evaluation process by unifying the basis for establishing substantial equivalence. The work has established the groundwork to enable the extensions of claims being made for perfusion measurements and established acceptable performance criteria. In a related initiative, CDRH laboratory work on surface temperature properties was central in defining the limits for the General Standard for Electromedical Safety, 3 rd edition of IEC 60601-1, and for the particular standard for the safety and essential performance of pulse oximeters, ISO/IEC 9919. CDRH laboratory scientists, working with industry experts, provided computational models and relevant literature that established that the existing limit could be relaxed by 2°C, making possible new device types and extending applications of existing devices. CDRH laboratory efforts were also instrumental in the establishment of a reliable test method for validating the design of pulse oximeter cables. This work is being incorporated in the next revision of the ISO/IEC standard.
4. Test methods for high intensity focused ultrasound
CDRH is receiving increasing numbers of regulatory submissions for high intensity focused ultrasound (HIFU) surgery. HIFU holds the potential for radically advanced surgical techniques, including ablation of both malignant and benign lesions and cessation of internal bleeding in injured vessels and organs, all with minimal damage to the surrounding tissue. However, the lack of standardized methods to assess the acoustic and thermal characteristics of the focused beams has challenged the regulatory review of these devices, especially in the pre-clinical phase, and has been burdensome to the industry. In the past CDRH scientists and engineers have developed measurement instrumentation and computational modeling techniques for characterizing other types of medical ultrasound devices such as diagnostic imaging and therapeutic ultrasound, and this work has resulted in the creation of numerous regulatory guidance and standards documents. This expertise is being used to accelerate the review of submissions for HIFU devices. For example, in a device for the ablation of uterine fibroids, CDRH-developed computational modeling was used to predict the performance of the device under conditions that would have been difficult to investigate experimentally, thus shortening the review time. CDRH laboratory staff members are now collaborating with outside research institutions and the affected industry to develop standard measurement and analysis methods as input to international standards for HIFU that will be used to facilitate the regulatory review process.
5. Guidance for extracorporeal shock wave lithotripsy
Extracorporeal shock wave lithotripsy is a minimally invasive technology that employs focused, high pressure ultrasonic waves for fragmentation of kidney and ureteral calculi. When first introduced, these devices were deemed Class III because of the new intended use coupled with the potential for serious collateral damage to non-targeted tissue. At the time there were no accepted means for measuring the very high pressures produced by these devices, which complicated the regulatory reviews. Based on CDRH laboratory efforts, performance requirements for measurement instruments and appropriate measurement procedures were developed and documented in a pre-clinical testing guidance for the industry. This guidance eventually led to two international consensus standards, which in turn were instrumental in allowing CDRH to down-classify these devices to Class II, thus saving the industry from lengthy human clinical trials.
6. Expediting intraocular lens evaluations
OSEL laboratory scientists have played a leading role in the development of new test methods for measuring the optical parameters of intraocular lens implants (IOLs). An estimated 20 million Americans over the age of 40 have cataracts in at least one eye, most of which can be corrected through the implantation of IOLs. The focal length (or dioptic power) is a fundamental parameter whose precise measurement is of critical importance for evaluating the safety and effectiveness of IOLs. Testing the dioptic power of IOLs has been difficult because conventionally used test methods are limited in terms of accuracy and the dynamic range over which measurements can be performed. To overcome these problems, CDRH laboratory scientists developed a novel confocal fiber-optic laser method (CFOLM) for precise measurement of IOL dioptic power which provides high accuracy (exceeding 1 um) in spatially locating the focal point and in measuring the IOL dioptic power. Such accurate measurements have not been achievable previously. The new CFOLM measurement system has been used to evaluate the dioptic power of a variety of new IOL designs from several different manufacturers, and to resolve questions about the accuracy of the labeled dioptic power, expediting decision making by facilitating agreement between industry and CDRH. This new test method will be considered for incorporation in international product performance standards for testing IOLs.
In addition, experimental and theoretical work in the laboratories on the mechanism of formation of vacuoles in foldable, hydrophobic intraocular lenses (IOLs) has led to an understanding of differential osmotic forces as the root cause of these artifacts. Characterization of the kinetics of vacuole formation revealed that changes in the lens environment (both thermal and chemical) can modulate the size and number of vacuoles. These observations allowed for the rapid acceptance of changes in the storage solutions proposed by the sponsors of a new class of hydrophobic IOL materials. The computational and experimental tools developed in these studies will allow for rapid evaluation of optical stability of future classes of IOL materials.
7. Spinal implant evaluation
FDA has received a dramatic increase in the number of submissions for new spinal implants, a sector of the orthopedic medical device industry whose revenues were estimated at $3.6 billion in 2005, signifying an increase of 17% over the previous year. Motion-preserving devices and novel concepts such as minimally invasive fracture repair strategies have been responsible for much of this growth. Under the auspices of MDUFMA, CDRH laboratories initiated a research program into vertebroplasty, a minimally invasive procedure for treatment of spinal compression fractures, with the goal of providing reviewers with better scientific information on the mechanical benefits of the treatment in order to accelerate and improve reviews of product safety and labeling. This laboratory initiative resulted in developing information clarifying the mechanical stability of the spine after this treatment which has substantially assisted CDRH's scientific review staff, enabling more efficient interactions with manufacturers and expediting the review process. CDRH laboratory staff have also become active participants on CDRH's spine review team as well as an international standards organization that writes standard testing methods for medical implants, ASTM F04 Medical & Surgical Materials and Devices. In fact, CDRH laboratory staff have assumed the chairmanship of the ASTM subcommittee F04.25 on spinal devices. In addition, CDRH laboratory scientists have provided the device reviewers in CDRH's Office of Device Evaluation with information on the use of these testing standards which, complemented with physical models of testing fixtures, has enabled improved understanding of how standard test methods are being used by device companies. This understanding has greatly facilitated their reviews of new products.
DIVISION OF BIOLOGY (DB)
DB participates in the Center's mission by conducting research, participating in device review activities, developing consensus standards both domestic and international, developing regulatory guidance, testing forensic and regulatory samples, and providing educational programs in the area of biological sciences. Specifically, DB conducts research to support the Center’s mission to assure the safety and effectiveness and promote the improvement of medical devices in the areas of biological risk assessment, biosensors/nanotechnology, genomic and genetic technologies, infection control and sterility, tissue-device interactions, toxicity/biocompatibility, and radiation bioeffects. Through laboratory studies, researchers evaluate the potential adverse effects of medical devices on host biological systems and, in collaboration with engineering divisions, identify the source and impact of product degradation on organ systems both under acute and chronic conditions. The Division staff develops measurements methods and analytical procedures to characterize and evaluate devices and products, studies molecular and cellular mechanisms and bioeffects of biomaterials, and supports the Center’s enforcement and product testing activities.
The DB staff members are primarily biologists, chemists, and biomaterials scientists.
Laboratories
DIVISION OF CHEMISTRY AND MATERIALS SCIENCES (DCMS)
DCMS participates in the Center's mission by conducting research, participating in device review activities, developing consensus standards both domestic and international, developing regulatory guidance, testing forensic and regulatory samples, and providing educational programs in the area of chemistry and materials sciences. Specifically, the DCMS focus is on the developing experimental data, test methods and protocols for regulatory and scientific activities involving multicomponent mass transfer, reaction kinetics, absorption and swelling of network polymers, polymer processing, modeling of physiological processes, and materials degradation. Research conducted in the division includes polymer synthesis; synthesis of polymeric nanocomposite materials; sensors; thermodynamics; thermal transitions and phase stability; hydrogel and biopolymer synthesis and characterization; polymer formulation; separations; spectroscopy; small-angle x-ray and neutron scattering; and shelf-life and service life prediction. DCMS tests the performance of chemical processes of importance to medical devices, such as mass transfer through membranes used in dialysis and blood oxygenation, and manufacturing processes used to fabricate materials.
The technical disciplines of the DCMS staff include physical chemistry, chemical physics, polymer science, pharmacology, materials science, and biomedical and chemical engineering.
Laboratories
DIVISION OF ELECTRICAL AND SOFTWARE ENGINEERING (DESE)
DESE participates in the Center's mission by conducting research, participating in device review activities, developing consensus standards both domestic and international, developing regulatory guidance, testing forensic and regulatory samples, and providing educational programs in the area of electrical engineering and software. Specifically, the DESE works in the application of electronics, software engineering, and systems engineering body of knowledge to the regulation of medical devices and electronic products that emit radiation. The division addresses the cutting edge of medical devices through all phases of the product life cycle and all aspects of the product manufacturer’s business, from research and development through procurement, production, and ongoing customer support. DCMS hosts the following resources and capabilities: analog and digital circuit design, data acquisition and display, embedded microprocessor and PC-based systems, software-based virtual instruments, quality management and risk management as applicable to electronics and software, testing for hazards arising from the use of electrical and electronic technology in medical products, and electronic design including components, circuits, and analytical techniques for controlling high voltages and/or currents.
DESE staff members are primarily electronics engineers, physicists, biomedical engineers, and general engineers.
Laboratories
DIVISION OF IMAGING AND APPLIED MATHEMATICS (DIAM)
DIAM participates in the Center's mission by conducting research, participating in device review activities, developing consensus standards both domestic and international, developing regulatory guidance, testing forensic and regulatory samples, and providing educational programs in the area of medical imaging and applied mathematics. Specifically, DIAM provides scientific expertise and carries out a program of applied research in support of CDRH regulation of radiation-emitting products, medical imaging systems, and other devices utilizing computer-assisted diagnostic technologies. Medical imaging research encompasses ionizing and non-ionizing radiation from data capture through image display and observer performance. The computer-assisted diagnostics work of DIAM is focused on the appropriate mathematical evaluation methodologies for sophisticated computational algorithms used to aid medical practitioners interpret diagnostic device results. The Division is charged with developing and disseminating performance assessment methodology appropriate to these modalities. DIAM operates a calibration laboratory for ionizing radiation detection instruments and participates in a full range of programs in support of the Public Law 90-602 mission of the Center.
DIAM staff members are primarily physicists, mathematicians, and physical science technicians.
Laboratories
DIVISION OF PHYSICS (DP)
DP participates in the Center's mission by conducting research, participating in device review activities, developing consensus standards both domestic and international, developing regulatory guidance, testing forensic and regulatory samples, and providing educational programs in the area of physics. Specifically, DP conducts research and engineering studies to support the Center’s mission to assure the safety and effectiveness of medical devices and electronic products, and to promote their improvement. Scientific and technical specialties in the division include optical physics and metrology, sensors, fiber optics, electromagnetics, electromagnetic compatibility and electromagnetic interference, electrophysics and electrical stimulation technologies, electrophysiology, radiofrequency/microwave metrology, and minimally invasive optical and electromagnetic technologies. The Division develops measurement methods, instrument calibration capabilities and analytical procedures to characterize and evaluate devices and products, and supports the Center’s enforcement and product testing activities. DP evaluates interactions of electromagnetic and optical energy with matter, analyzes implications for the safety and effectiveness of devices and products, and develops and evaluates procedures for minimizing or optimizing human exposure from such devices.
The technical disciplines of DP staff include physics, mathematics, biophysics, biomedical engineering, electronics, and general engineering.
Laboratories
DIVISION OF SOLID AND FLUID MECHANICS (DSFM)
DSFM participates in the Center's mission by conducting research, participating in device review activities, developing consensus standards both domestic and international, developing regulatory guidance, testing forensic and regulatory samples, and providing educational programs in the area of solid and fluid mechanics. Specifically, the core responsibilities of this division involve issues for which mechanical interactions or transport are of primary concern, such as those involving motion; structural support, stabilization, or vibrations; device and material mechanical integrity; materials durability; and biologically relevant parameters of device and materials. The division has expertise in the areas of fluid dynamics, solid mechanics and materials, acoustics and ultrasonics. DSFM develops measurement methods, instrument calibration capabilities, and analytical procedures to characterize and evaluate devices, device materials, and products, and supports the Center's enforcement and product testing activities. The division staff also evaluate interactions of ultrasound energy with matter and the implications of these interactions on the safety and effectiveness of devices and products.
Technical disciplines of the DSFM staff include mechanical engineering, materials science, biomedical engineering, general engineering, and physics.
Laboratories
STANDARDS MANAGEMENT STAFF (SMS)
The SMS is responsible for managing the Center’s standards program. The staff in this program is responsible for developing, managing, and supporting standards used for regulatory assessments. SMS supports participation in medical device standards committees. The staff accomplishes these tasks with the help of Standards Task Groups (STGs). This involves working closely with the Standards Developing Organizations (SDOs), advertising standards liaison representative positions, facilitating a Center recommendation to serve on a particular standards activity, maintaining a standards database that provides access to established standards to all CDRH staff and field inspectors.
SMS increases the recognition of voluntary consensus standards for medical devices and radiation-emitting electronic products. The Standards Program was created as a result of the Food and Drug Administration Modernization Act (FDAMA) of 1997. Although CDRH had been involved in the development of medical device standards for decades, FDAMA formalized the process. As part of this responsibility, the staff publishes lists of recognized standards annually and consistently increases the list of available standards.
MANAGEMENT SUPPORT STAFF (MSS)
MSS provides leadership and support to the Office of the Director, Division Directors, and laboratory professionals on all administrative, general management, and knowledge management issues. MSS is responsible for planning, developing, and implementing Center and OSEL programmatic matters concerning financial management, personnel, procurement, contracts, inter-agency agreements, employee training, and facilities.
MSS is tasked with the managing and administering OSEL resources designed to support ongoing programs. The staff ensures the proper distribution of operating and payroll dollars, facility plans, procurement and property, travel requests and ADP needs. MSS advises the Office of the Director on potential issues that may affect resources, staffing, and management issues to comply with policies and avoid potential conflicts. In addition, MSS directs and conducts special assignments or projects for the Center as well as the Office Director.
MSS is also tasked with Knowledge Management Support (KMS) responsibility for the office. The KMS team provides technical support for the acquisition, retrieval, and analyses of data supporting the office’s mission including developing specialized databases and related applications where needed. Additionally, the staff performs specialized activities associated with the development, design, installation, and administration of data processing systems, particularly those that are integral to laboratory functioning.
The KMS team collaborates with the Office of Systems and Management (OSM) and the Office of IT Shared Services (OITSS) in developing major initiatives involving OSEL, CDRH, and FDA data and systems. The KMS staff also coordinates OSEL activities with these offices to assure compliance with Center and FDA policies regarding data structure and format and with FDA initiatives to assure data consistency and compatibility.
Scope
Risk assessment is the process of determining the extent of human health hazard relative to exposure conditions. Staff in the OSEL laboratory of Biological Risk Assessment: 1) conduct research to address CDRH’s regulatory need for improved methods of detecting and quantifying risks associated with chemical compounds, microbial agents, and radiation released from medical device materials; and 2) conduct risk assessments to support risk management decision-making in the Center. Research is focused in three areas:
Development of clinically relevant biomarkers and preclinical animal models: Research in this was identified as being central to the FDA Critical Path Initiative
(http:// www.fda.gov/cdrh/present/criticalpath and (http://www.fda.gov/oc/speeches/2005/ddtd0810.html).
Safety of reprocessed medical devices: Research in this area includes the assessment of the toxicity of residual disinfectants/sterilants and the efficacy of methods to remove residual bioburden on reprocessed devices.
Bioeffects of ultrasound and ultrasound contrast agents: Assessment of the extent of the vascular endothelial and smooth muscle damage by microbubble-based ultrasound contrast agents and its role in the pathogenesis atherosclerotic changes.
Background
OSEL staff has long been responsible for conducting risk assessments of compounds or microbial agents released from medical device materials. These risk assessments have been directly used to support regulatory decision making in the Center (e.g., microbial risk assessment to support Sterility Assurance Levels, DEHP Safety Assessment to support the issuance of a Public Health Notification and draft labeling guidance, ethylene oxide risk assessment to support the revision of the ISO 10993-7 standard). The hazard identification stage of risk assessment requires that we have the necessary tools to detect the effects produced by compounds or infectious agents released from medical devices. Consistent with the Critical Path objectives, these new tools include clinically relevant biomarkers and preclinical models to detect adverse effects at the earliest stages. Toxicity studies used for the risk assessment of compounds released from medical devices are almost always conducted using healthy animals; however, patients exposed to these compounds may be critically ill or injured. A number of studies have demonstrated that the potency of some compounds is potentiated by conditions such as renal failure, liver failure, and sepsis. To address this broad issue, animal and in vitro (cell culture) models of compromised health are being developed in the laboratory and will be used to examine whether the potency of compounds is increased in experimental animals with compromised health or injured cells compared to healthy animals and cells. Animal models of compromised health are also being used to assess the impact of ultrasound contrast agents on the vascular endothelium and to develop new devices that can be used to assess tissue damage and functional changes in diabetic patients.
Research Program Description
FDA's Center for Devices and Radiological Health (CDRH) is responsible for ensuring the safety and effectiveness of medical devices and eliminating unnecessary human exposure to man-made radiation from medical, occupational and consumer products. This broad mandate requires chemical, microbial, and radiation risk assessments to be performed to support regulatory decision making in these areas. Chemical risk assessment activities in CDRH focus on three areas: 1) the development and validation of new risk assessment methodologies, 2) bench-top research to provide information for the hazard identification and dose-response assessment stages of the risk assessment process, and 3) the application of risk assessment approaches to assist with regulatory decision making. The research component of the laboratory’s effort is key in addressing uncertainties regarding the response of sensitive subpopulations to the effects of chemical compounds and ultrasound energy and to determine the effectiveness of reprocessing strategies for medical devices that are cleaned and reused.
Relevance to FDA/CDRH’s Mission and Public Health Impact
The OSEL program in risk assessment involves laboratory-based efforts to address risk assessment uncertainties, development and validation of new risk assessment methodologies, and use of risk assessment to support regulatory decision-making.
The goal of research in the Biological Risk Assessment laboratory is consistent with the goal of FDA’s Critical Path Initiative to stimulate the development of new evaluative tools for assessing the safety and efficacy of new medical products, specifically, tools such as proven biomarkers and clinically relevant animal models. A key laboratory-based effort is directed towards examining whether critically ill or injured patients represent a sensitive subpopulation and can be more susceptible to adverse effects of chemicals.
Research is also being conducted to address the effectiveness of cleaning/reprocessing strategies for reused devices and uncertainties in biocompatibility assessment. Data from these efforts will be directly used in the ISO and ASTM standards development process.
Research on the bioeffects of ultrasound and contrast agents may have an impact on the regulation of this imaging technique and standards addressing ultrasound exposure
Three-Year Goals
Accomplishments
Scope
This laboratory conducts research to investigate the publ c health impact of electromagnetic radiation exposure from medical devices and non-medical electronic products.
Background
One important example of possible radiation bioeffects involves the use of cellular phones. Currently over 100 million Americans use wireless phones. Data relating to the safety of radiation from wireless phones are inadequate; however, they suggest that exposures to radio frequency radiation at levels relevant to wireless phone use may cause biological effects. In this area, the OSEL bioeffects project serves as the coordinator of independent research conducted in several laboratories.
Research Program Description
Current efforts are d irected toward better understanding of the r isks of non- ioniz ng radiat ions from wireless telecommun icat ion devices, assess ng the skin cancer problem associated with use of tann ng lamps, and quantify ing the differences in UV response in differently pigmented populationsin the U.S. Also,in line with the Center’s new initiat ive to focus on the most pressing radiological problems and to anticipate the evolution of new medical radiation systems, we are concentrating our research efforts in ionizing radiation to better understand radiation-drug and radiation-heat interactions, and to provide the Center with expertise on a new class of low dose x-ray therapeutic devices entering the market. The laboratory also monitors the scientific literature and maintains expertise in other radiation areas, such as laser, visible, and extremely low-frequency radiation.
Relevance to FDA/CDRH’s Mission and Public Health Impact
Three-Year Goals
Accomplishments
Radiofrequency studies and oversight of CRADA on cell phones
Laboratory research on models for therapies that use low LET ionizing radiation, drugs and hyperthermia
Human Photosciences Research
Scope
The biotechnology laboratory’s mission is to study various aspects of microbial pathogen contamination of medical devices and to reduce the risk of microbial infection from contaminated medical devices. The laboratory’s main research projects are focused on microbial detection and analysis, using an interdisciplinary research approach that integrates engineering and molecular biology.
Background
Microbial infections associated with medical devices are a major health risk factor, especially with the use of intravascular catheters. The common hospital practice of reuse of single use devices, the spread of antibiotic resistance microbial strains and the potential use of microbial pathogens as bioweapons all add to the need for better microbial detection and diagnostics.
Research Program Description
The laboratory is working on six major research projects related to detection and analysis of microbial pathogens funded in part by the FDA’s Office of Science and Health Communication and by the USDA:
Relevance to FDA/CDRH Mission and the Public Health Impact
CDRH-regulated products such as heart valves and intravascular catheters are a cause of microbial infections, which is a major health risk factor in hospitals. The common hospital practice of reusing single use devices, the spread of antibiotic resistance microbial strains (especially S. aureus) and the potential use of microbial pathogens as bioweapons all add to the need for better microbial detection and diagnostics for medical devices.
Three-Year Goals
Accomplishments
Development of a hand-held microfluidics multi-channel biosensor for detection of microbial pathogens: The biosensor consists of a three-layer plastic cartridge assembled with a thermal press. Samples and reagents for the sandwich assay are delivered to the membrane through microcapillaries using a miniature built-in manual vacuum pump. A prototype immunosensor was tested for detection of detection of staphylococcal Toxic Shock Syndrome Toxin (TSST), a women health concern.
Scope
The Laboratory of Cardiovascular and Interventional Therapeutics (LCIT) investigates the safety and effectiveness of a range of interventional therapeutics, including cardiovascular and minimally invasive devices and related adjunctive agents. This includes the application of emerging imaging technologies to guide the delivery of novel therapeutic devices and agents. Local delivery of therapeutic devices alone or in combination with other agents via percutaneous catheters or direct surgical access has shown great clinical promise for the treatment and prevention of vascular disease and cancer. The laboratory’s Research Program includes both normal biology and the pathologic basis for disease and device failure at the genetic, molecular and tissue levels and the development of animal models that are predictive of clinical safety and effectiveness.
The focus is on studying existing models and developing more predictive models of device use and related failure modes including identification, evaluation and development of more optimal clinical treatment algorithms for image guided interventions and drug delivery, e.g., tumor ablation. In addition, retrospectively, the models have been used to support applications for vascular devices. The in vivo models under study include both normal swine and swine models of human disease, i.e., those with vasculopathy induced by diet (atherogenic high fat/high cholesterol diets), mechanical manipulation (iatrogenic injury from balloon angioplasty or stenting), hormonal manipulation (castration, hormone replacement therapy), hemodynamic alterations (vascular ligation, fistulas) and/or metabolic manipulation (diabetes mellitus). These preclinical animal studies address the problem of identification and assessment of regulatory science issues associated with novel interventional and combination therapeutics and delivery technology including image guidance tools for the treatment of vascular disease and cancer.
Together, these studies will identify the critical scientific and safety issues for current and emerging technologies based on failure modes analysis and clinical outcome. For cardiovascular, neurovascular and peripheral vascular devices, this represents a critical component of review of device applications prior to entry into clinical trials, market access and post-approval study outcomes.
Background/Research Program Description
Coronary, peripheral and neurovascular disease represent the leading cause of death in the United States in both men and women. There are gender differences in both the development of disease and in patient treatment and survival following myocardial infarction. Over one million angioplasty balloons and stents are deployed in the United States each year. Interventional devices, alone or in combination with drugs and biologics, and novel delivery technology to treat vascular disease represents greater than 50% of the IDE and PMA activity in the Center.
Cancer, as a whole, is the second major cause of death. Under the current NCI strategic plan, there is a major push to substantially eliminate suffering and death due to cancer by the year 2015. Currently, CDRH (ODE and OSEL) are working closely with NCI to facilitate investigations of image guided therapies for cancer. These efforts, together with complementary efforts by NIBIB, will accelerate the development of new technologies and progression into clinical trials and marketing.
Relevance to FDA/CDRH Mission and the Public Health Impact
The identification of intervention-specific safety and effectiveness issues as they relate to vascular function, vessel wall injury and tissue remodeling will allow for more consistent and accurate recommendations regarding preclinical study, clinical study and labeling. In addition, the significant increase in the clinical investigation of combined therapies (e.g., estrogen, paclitaxel, rapamycin, etc.) or hybrid interventional devices with novel local delivery technology require a greater understanding by the Agency of these interventions and related regulatory science. The findings of these studies are expected to provide support for the regulatory input to 1) predictive pre-clinical modeling for endovascular grafts, combination drug-device products and novel local delivery technology; 2) identification and evaluation of safety (and effectiveness) of emerging local delivery and combination technology; 3) development of Instructions For Use and labeling for these devices alone or in combination with drug and biologic therapeutics; and, 4) appropriate clinical trial design, study endpoints and expected outcomes, based on the predictive preclinical studies.
Devices that deliver or release therapeutic agents in order to mitigate disease or enhance device performance are being developed and entered into clinical trials. These devices require greater understanding through preclinical bench and animal models in order to ensure their safety and efficacy and the identification of regulatory science issues prior to entry into clinical trials and broader marketing. In these studies, the safety and effectiveness of delivery technology and the treatments will be evaluated at the tissue-device interface along with the pharmacodynamics and pharmacokinetics. This study will result in formal recommendations for the conduct of predictive preclinical studies and clinical trials as well as regulatory review of these emerging technologies to be used in the management and treatment of vascular disease.
The utilization of thermal ablation techniques is increasing with rapid advances in image guided robotic control and placement of devices. For thermal ablation techniques, adequate treatment may be challenging due to lesion size, configuration, proximity to critical anatomic structures and the limited ability to treat large volumes. Treatment failure occurs at the margins of the ablation or adjacent to vascular structures due to incomplete heating. This body of work will lead to more accurate treatment planning and should improve the safety and effectiveness of thermal ablation.
Three-Year Goals
Animal Models of Vascular Disease, Intervention and Local Drug Delivery
Image-guided device therapeutics and targeted drug delivery
Accomplishments
Participated in Agency Outreach with Professional Organizations, and Agency Cardiovascular Web Site
Developed facilities and content for new 6-hour course with FDA/CDRH Staff College: “Emerging Technology: Preclinical Animal Models, Studies and Data Evaluation.” Course began in May 2005 and is ongoing.
Designed a series of on-line training programs with Staff College in parallel with the above-listed course.
Developed several funding/extramural collaborations and/or Material Transfer Agreements with University Of Pennsylvania, NIH, Diagnostic Radiology Department and NIH Clinical Center, Interventional Therapeutics, EndobionicsBiopal, Lenox Hospital, Hartford Hospital, and Sonus Pharmaceutical.
Developed significant number of current Animal Use Protocols, including Models of therapeutic intervention for vascular disease, biomechanics and genomics of vascular dysfunction, congenital and acquired cardiovascular abnormalities, intravascular radiofrequency ablation for hemostasis: preclinical study, intravascular radiofrequency ablation for hemostasis, and biomechanics and genomics of vascular dysfunction.
Toxicology (Division of Biology)
Scope
The Laboratory of Toxicology, located in the Division of Biology, is an interconnected program of laboratory research, risk assessment, and standards development activities designed to provide a scientific basis for regulatory decision making in CDRH. Researchers evaluate the potential adverse effects of medical device materials and chemicals, including nano-sized particles, using in vivo and in vitro experimental models and approaches. Scientists use data to reduce uncertainties in assessing risks to patients exposed to physical and chemical exposures, and ultimately protect their health.
Background
The 1983 merger of the Bureau of Radiological Health and the Bureau of Medical Devices resulted in the Center for Devices and Radiological Health. This merger presented the new Center with a unique challenge for its research programs: to bridge the discontinuity that existed between classical chemical toxicology research and the potential adverse health effects posed by exposure to materials or compounds associated with medical devices. The primary emphasis of this program that has evolved since the merger is the development of research approaches and methodologies for toxicological risk assessment for compounds and materials associated with medical devices, including nanoparticles.
One primary focus of the program in 2005-06 is evaluating bioeffects of nanoparticles. The unique properties of nanoparticles (very small size, large surface area, increased biological activity) drive the current explosion in nanotechnology innovation in health care delivery. In FY 2005, the federal government spent over $1 billion on nanotechnology R&D. FDA-regulated products expected to utilize nanotechnology include: implants and prosthetics, sensors for disease diagnosis, and drug delivery and personal care products. In contrast, these same properties may impart negative or undesirable effects on biological systems. Attempts to understand the potential adverse effects of nanoparticles are limited, and very few resources have been committed to research needed to address and understand risks to patients.
Research Program Description
The Laboratory of Toxicology research program:
Studies in this laboratory currently fall into several major subcategories:
Biological effects of nano-sized materials
The nanoparticle bioeffects project received a highly favorable peer review in 2005 from FDA’s Office of Science and Health Coordination.
Toxicity of compounds released from medical device materials
In mid-2005, the laboratory terminated a multi-year research project devoted to understanding potential hormone disrupting effects of bisphenol A, an estrogen-mimicking chemical that migrates out of medical plastics. The highly successful project produced 6 peer-reviewed publications and numerous presentations at national and international scientific meetings. Expertise gained was useful for OSEL scientist to participate in the OSTP Inter-Agency Workgroup on Endocrine Disruptors.
Relevance to FDA Mission and Public Health Impact
The experimental studies in this laboratory generate independent data for use in assessing toxicological risks and for developing standards and guidance documents, thus providing a firm foundation for OSEL and CDRH to remain at the forefront in medical device toxicology.
FDA Critical Path: The goals of this laboratory are responsive to the Critical Path initiative that calls for a “new product development toolkit” containing powerful scientific and technical methods such as more predictive and clinically relevant animal models, and the development of more sensitive and clinically relevant biomarkers of safety and effectiveness.
Regulatory Impact:
Pre-market – Laboratory data serves as a scientific basis for development of Standards, such as:
Public Health Impact:
The recent explosion in nanotechnology R&D for health care delivery will result in an increasing number of patients exposed to nanoparticles. Developing in vivo and in vitro experimental models, discovering more sensitive biomarkers, and quantitating the release of chemicals from medical products will help reduce uncertainties in the preclinical safety assessments of medical devices and other FDA-regulated products.
Three-Year Objectives
Accomplishments
Two studies were conducted under the laboratory goal of developing analytical test methods to identify and quantitate chemicals or residues released either intentionally or unintentionally from medical device materials.
Two related studies were conducted under the Laboratory goal to develop test methods to evaluate adverse effects of medical devices and device materials, including nanoparticles.
Biomolecular Mechanisms (Division of Biology)
New genomic and genetic technologies are expected to impact CDRH in major ways. The Center is beginning to receive submissions of genomic and genetic diagnostic microarray devices and expects more--some in co-development with drug or biological therapeutics. In addition, these technologies will be used to evaluate the safety of products such as implants and materials (toxico-genomics). However, considerable technical uncertainties impede the acceptance of these products and data. The Genomics Laboratory is providing support to the Center via 1) prioritization of the technical issues affecting microarray data that impact product review, and 2) application of the new technologies to both new and long-standing problems, including medical device adverse events, identification of medical device pathogen contaminants, and safety evaluation of products.
Background
New genetic and genomic technologies provide opportunities and challenges for CDRH. The opportunities include new products to improve human health and new methods for the evaluation of medical devices. Challenges arise when the new technologies must be judged for appropriate practical application in new products. Keeping up with new technologies as they evolve is an ongoing challenge. The OSEL Genomics Laboratory provides a resource to the Center via laboratory projects that utilize and evaluate the new technologies (e.g., microarrays). We maintain expertise as a test laboratory for new instruments and reagents. Scientists from the regulatory review and statistical branches are involved in our projects, and we participate in their discussion groups. These activities aid the conjunction of Genomics Laboratory activities and regulatory need.
Research Program Description
There are different types of microarray devices coming to CDRH for review, including genetic and genomic testing devices. Both endpoints can be detected by microarrays, but the basic molecules, sample preparation and analytical/ bioinformatic issues are quite diverse. Although microarrays can accomplish multiple high throughput reactions, substantial problems related to the reproducibility and value of microarray data have been and are still being reported. Presently the laboratory is covering technical issues related to genetic testing (DNA-based) and gene-expression (RNA based) microarrays. We are the lead laboratory in a multi-center OSHC genomics project which addresses and prioritizes the variables affecting genomic microarray data. Within this project we are addressing the lack of an RNA standard for genomic microarrays as a proposed ERCC consortium (government/industry) test site for RNA controls. Another gene-expression project employs genomic profiling to understand a medical device adverse event. A third project uses genetic microarray technology to rapidly identify pathogens that contaminate medical devices. A fourth project is proposed to use the new genomic technology in the safety evaluation of medical devices.
Relevance to FDA/CDRH Mission and Public Health Impact
Data obtained in several of the projects should facilitate the development of appropriate standards for microarrays, in particular the OSHC project, with the major focus on the factors leading to the highest levels of variability in microarray data. All of the projects are cross-Center and/or cross-Office projects. They provide a basis for continued inter-Center/external collaboration on technical issues, as the technology evolves. The knowledge and experience gained will enable OSEL scientists to 1) participate effectively in the CDRH regulatory review of pre-market device applications, 2) critically evaluate data obtained with diagnostic devices based on genomic and genetic technology, and 3) contribute to writing standards and guidance documents. The latex allergy genomics project will also demonstrate ways in which new genetic and genomic approaches can enhance public health. The pathogen project is designed to prepare us for possible future projects involving the rapid detection of microorganisms and human host responses associated with biodefense. The projects in this program support the CDRH Strategic Plan, especially the Total Product Life Cycle and Magnet for Excellence. In addition, collaborations within FDA, with other government organizations, academia and industry have provided ample opportunity for significant leveraging of resources and expertise.
Three-Year Goals
Accomplishments
4. Genetic testing microarray development
Scope
The scope of this laboratory’s activities is the support of CDRH pre-market and post-market activities through the establishment of relevant in house expertise and the identification, qualification, quantification and communication of conformity assessment techniques and criteria which the center can use to fulfill its mission.
Background
Electronics is an enabling technology for many, if not most, classes of medical devices. Devices that incorporate this technology are inherently complex and require that engineers must be able to skillfully peel back many layers of abstraction from the underlying mathematical and physical models that govern device operation, to their hardware and software realizations, and down to the physical characteristics of component parts.
A large body of knowledge has developed within the electronics, embedded software, and systems engineering communities to assure successful application of these technologies. The mission of the DESE Electronics Laboratory is to apply this body of knowledge to the regulation of electronic medical devices and electronic products that emit radiation.
The breadth of the engineering disciplines needed poses a significant challenge. The body of knowledge is segmented into numerous areas of specialization, power engineering, electromagnetic and static immunity, microminiaturization and signal processing. Within industry, large manufacturers typically have sizable organizational components to address those engineering segments (specialties) having most relevance to their needs. Small manufacturers typically have specialists in just a few key areas and rely on consultants or other external resources to augment their in-house capabilities.
We maintain a suite of special-purpose, computer-aided engineering tools and laboratory facilities having broad applicability to medical device electronics and embedded software and we rely on external sources for specialized capabilities that are needed on an occasional basis.
Research Program Description and Relevance to FDA/CDRH Mission and Public Health Impact
The Electronics Laboratory embraces three key aspects of medical electronics having immediate applicability to the mission of the Center and relevance to the public health.
Electronic Instrumentation . We provide custom instrumentation, i.e., measurement and control systems, for use by internal FDA customers and regulatory partners. Our capabilities include analog and digital circuit design, data acquisition and display, signal processing, embedded microprocessor and PC-based systems, and software-based virtual instruments. This work provides two benefits to the Center. First, we provide an in-house R&D capability which is easy to access and attuned to the unique needs of our stakeholders. Second, the engineers in this laboratory gain insight into the problems (and solutions) confronting medical device manufacturers as well as maintaining institutional knowledge of the latest developments in electronic technologies.
Electrical Safety. This activity focuses on the design of medical devices to assure that the risk of harm due to electrical shock and electrical fire is adequately mitigated in the design. The laboratory also addresses other hazards arising from the use of electrical and electronic technology in medical products, including thermal burns and fires, electromagnetic interference and coordinating with other agencies innovation in wireless communications related to medical devices.
Power Electronics . This activity focuses on an aspect of electronic design that poses continuing challenges to designers of medical devices. It deals with components, circuits, and analytical techniques for controlling high voltages and/or currents as well as challenges derived from the use of cutting edge battery and fuel cell technology. Historically, power electronics has been a factor in many medical device recalls. Our strategy is to stay abreast of the evolving body of knowledge in the power electronics area so that we are prepared to probe for design weaknesses in the pre-market review, thus heading off potential problems. We also maintain a suite of analytical tools and measuring equipment that can be brought to bear on emergent problems.
Three-Year Goals
The laboratory is focused on both maintaining its current knowledge base and in increasing it substantially to incorporate expertise in evaluating nano-technology, micro-electronic systems, oximetry motion artifact removal, operating room of the future and new battery technologies.
Accomplishments
Postmarket regulatory support. DESE engineers provided just-in-time analytical support in a substantial number of recalls, adverse event investigations, and enforcement actions, helping to clarify the root cause of reported problems and shaping the regulatory response to each.
This work often required gathering information from sources that were less than completely candid. We had to make reasonable inferences about the nature and likely causes of the problem, then work cooperatively with other Center experts to understand the public health implications of our findings. In a number of these cases, our analyses led the manufacturers in question to expand the scope of the recall and/or undertake a more comprehensive corrective action than was originally proposed. The cases involved a range of issues such as microprocessor circuit design, basic electrical safety, battery and charging circuitry performance, software functional errors, and user interface designs that were flawed from a human factors standpoint.
Software (Division of Electronics and Software Engineering)Scope
The scope of this laboratory’s activities is to support CDRH pre-market and post-market software evaluation activities by establishing relevant in-house expertise and identifying, qualifying, quantifying, and communicating conformity assessment techniques and criteria which the Center can use to fulfill its mission.
Background
Software is one of the most ubiquitous enabling technologies for many, if not most, classes of medical devices. Devices that incorporate this technology are inherently extremely complex and require that engineers must be able to skillfully peel back many layers of abstraction from the underlying mathematical, behavioral and physical models that govern device operation, to their hardware and software realizations, and down to the physical characteristics of component parts.
A large body of knowledge has developed within the software engineering community, embedded software industry, and systems engineering communities to assure successful application of these technologies. The mission of the DESE Software Laboratory is to apply this body of knowledge to the regulation of electronic medical devices and electronic products that emit radiation.
The breadth of the engineering disciplines needed poses a significant challenge. The body of knowledge is segmented into numerous areas of specialization, embedded systems, formal methods, advanced verification techniques and software quality assurance. Within industry, large manufacturers typically have sizable organizational components to address those engineering segments (specialties) having most relevance to their needs. Small manufacturers typically have specialists in just a few key areas and rely on consultants or other external resources to augment their in-house capabilities.
As regulators, we have followed a similar approach, building depth in those key areas that repeatedly surface as regulatory concerns and augmenting our in-house capability by leveraging additional “just-in-time” knowledge from our colleagues in academia, other government laboratories (e.g., NSA, NIST, ARO, TATRC, JPL), and the standards community.
Our strategy for maintaining the required depth is to recruit senior engineers from industry, each having broad experience in a number of engineering specialties. While each staff member brings a unique mix of engineering skills and experience, we strive to maintain enough overlap to maintain critical mass in the key areas. We also place strong emphasis on staff development. It is notable that two of our experienced staff members have acquired graduate degrees in recent years, and our research activities are conducted by doctorate-level staff, postgraduate students, and external faculty hosted during sabbaticals, thus, significantly enhancing our capability in the emerging areas of technical risk management and software engineering.
Another essential element of the program is to identify and develop in-house specialized analytical tools and laboratory facilities. We maintain a suite of special-purpose, computer-aided verification tools and laboratory facilities having broad applicability to medical device software and embedded software, and we continue to leverage external sources for specialized capabilities that are needed on an occasional basis.
Research Program Description and Relevance to FDA/CDRH Mission and Public Health Impact
The Software Laboratory embraces several key aspects of medical software having immediate applicability to the mission of the Center and relevance to the public health.
Three-Year Objectives
The laboratory is focused on both maintaining its current knowledge base and increasing it substantially to incorporate expertise in evaluating a nascent house capability to perform advanced static analysis routinely as part of pre-market and post-market assessment. This will be the basis for a forensic analysis tool set which will grow throughout 2007 and 2007.
Accomplishments
Software Forensic Laboratory. In FY2005, DESE engineers took the first concrete steps toward implementing a new generation of software forensic laboratories.
Historically, FDA's oversight of software development in medical products has concentrated on the software life cycle processes used by manufacturers to develop and maintain the software. There is currently no process that will consistently yield error-free code.
Scope
This laboratory applies a systems engineering perspective to medical device regulatory issues.
Background
With the advent of systems of devices, closed-loop devices, and intelligent devices, the fabric of regulation and FDA’s historic enforcement discretion policy needs to be continually revisited to determine its ongoing ability to get as many safe systems to market and to allow them to remain safe while there.
Research Program Description
The laboratory is currently focusing in three distinct areas:
Quality Systems and Risk Management. This program aims to improve industry practices in the area of quality management and risk management, principally those practices which are applicable to electronics and software. The conceptual framework that we have been developing to accomplish this is finding its way into relevant consensus standards, industry guidance, professional engineering publications, and education and training for both FDA and personnel and the regulated industry
Advanced Medical Systems. This program is directed at the development of methods and tools that can be used by device manufacturers, users, and regulators to objectively assess the monitoring and diagnostic performance of intelligent medical devices. Intelligent medical devices operate by acquiring and analyzing physiological waveforms to monitor and diagnose clinical conditions. The program seeks to develop methods to assess specific aspects of the safety and performance of these devices in the health care environment of the future, such as detection ability in the presence of physiological and environmental noise and artifact, and to understand and quantify the effects of these conditions. Our research is intended to stimulate the development of more effective diagnostic and monitoring products, thus improving the public health.
Cybersecurity in medical devices. This program is directed toward assessing the risks and providing leadership in the emerging field of malware threats to medical devices currently fielded in use in healthcare facilities.
Relevance to FDA Mission and the Public Health Impact
The expertise developed through this laboratory is being used to educate reviewers across the Center and provide a basis for the evaluation and drafting of new classification regulations, guidance documents and enforcement policy.
Three-Year Goals
The laboratory will sustain its commitment to Center-wide reviewer education in the use of the key standard ISO 14971 as part of pre-market review, while contributing to the measured development of assessment methods pertaining to ORA’s inclusion of the risk management processes in their inspections. The development of advance operating room environments will receive further input in order to calibrate FDA’s view of unfinished devices (components) as part of an integrated assembly of systems. Finally, the industry adherence to the recently published cybersecurity guidance will be monitored to measure its utility in helping manufacturers of device systems maintain those systems in the marketplace.
Accomplishments
Cybersecurity. DESE staff took the lead in developing a guidance document addressing cybersecurity of networked medical devices.
Risk Management. DESE engineers are helping to make new medical devices safer by teaching manufacturers how to manage risk in the design of new medical products.
Scope
This program conducts research and testing in support of the Center's mission related to materials characterization, degradation, and materials-tissue interactions as they affect medical devices, in both pre-market evaluations and post-market surveillance. The program was established to provide CDRH and other FDA Centers the scientific and engineering capability to test and evaluate medical device materials safety and effectiveness in the total product life cycle (TPLC). The testing and evaluation services include development of instrumentation and testing protocols, procurement of appropriate research and regulatory device/materials samples and providing recommendations for the product performance criteria, accuracy, precision, and safety of medical devices.
Background
The laboratory's testing and evaluation activities contribute to evaluating medical device materials safety and effectiveness in TPLC. These activities are directed not only toward solving the specific device-related regulatory issues, but also in finding ways to apply the knowledge gained to publish in medical device peer-reviewed journals.
Research Program Description
The program addresses materials synthesis, processing, and fabrication as they influence medical device performance. These processes are affected by the molecular structure, phase, and ultimately the physical-chemical interactions in materials. The research includes characterization of residue and contamination analysis, purity, chemical structure and formulations, thermal stability, phase stability and transformation, transport and thermodynamic properties, and viscoelastic and adhesive properties.
The laboratories are capable of testing the performance of physical and chemical processes of importance to medical devices, such as mass transfer through membranes used in dialysis and manufacturing processes used to fabricate materials. This program provides the Center with independent data as well as intramural knowledge and experience concerning the use of preclinical/post-market studies for the evaluation of medical device materials safety and performance. Additionally, the program evaluates the degradation of materials in storage or use in vivo or ex vivo, identifying potential materials issues related to failure modes, and also contributes to the development of regulatory guidance and test methods to ensure the safety and effectiveness of medical devices and their material components.
Materials characterization focuses on surface and interface chemistry, bulk and surface morphology, bulk composition, and chemical/physical parameters for structure determination. The materials degradation area evaluates the chemical, thermal, and environmental degradation of materials and the affect of degradation on medical device performance and safety. The polymer/materials degradation area focuses on materials integrity, materials interactions; chemical, physical, and thermal degradation; in-vitro and in-vivo studies for medical device/materials; and shelf and service-life. This work includes post-market evaluations of device failures and forensic investigations such as unidentified particles in PVC blood bags, defective IV set fabrication, adhesion barriers, and counterfeit hernia repair mesh.
Relevance to FDA's and CDRH’s Mission, Program, and the Public Health Impact
The FDA/CDRH mission is to assure the safety and effectiveness of medical devices. The materials characterization, polymer degradation, materials-tissue interactions programs play a pivotal role in pre-market evaluation, and post-market monitoring activities. Materials will continue to be an essential component of medical devices, and OSEL's laboratory capability to evaluate materials will help the Agency make regulatory decisions based on the best available expertise and independent scientific information. It is anticipated that a focused program in which the materials characterization, degradation, and tissue-materials interactions laboratories will help determine product performance criteria, accuracy, precision, reliability and safety of medical devices which will help the Center in its mission in every phase of TPLC. This program's activities will help ODE, OC, OSB and other FDA Centers to develop guidance documents and a substantial number of standards.
Three-Year Goals
Accomplishments
Assessment of Calcium Phosphate Deposition Mechanisms in Dental, Orthopedic and Cardiovascular Device Applications
Characterizing Cross-linked Viscous Abdominal-Pelvic Adhesion Barriers
Vacuolar Behavior and Morphology in `Glistened’ Intraocular Lenses
Experimental Pathology (Division Of Chemistry And Materials Science)
Scope
The laboratory is research-based and is intended to provide the Center with independent data as well as intramural knowledge and experience concerning the use of preclinical in vitro and in vivo studies for the evaluation of medical device materials safety and performance. The major output of the laboratory specialty areas include independent assessment of manufacturers' claims and data, test methods, standards, regulatory guidance, and publications related to the public health impact of medical device materials design and safety.
Background
The program's research activities contribute to evaluating medical device materials safety and effectiveness in TPLC. These activities are directed not only toward solving the specific device-related regulatory issues, but also in finding ways to apply the knowledge gained to publish in medical device peer-reviewed journals. Research efforts have been focused on the development of in vitro science and engineering studies suitable for the characterization, degradation, and biomaterials applications.
Research Program Description
This program's experimental pathology laboratory is designed to evaluate the explant pathology of medical devices utilizing gross pathology, histopathology, immunohistochemical staining and molecular pathology studies. This research program has provided independent data identifying heart valve failure modes associated with emerging polymeric and tissue-derived materials as well as identifying a mechanism for the loss of cuspal cells in viable allograft heart valves following implantation. The research results have supported the regulatory decisions and recommendations made concerning four generations of replacement valves.
The materials-tissue interactions area conducts experimental research in support of pre-clinical models for evaluating dental, orthopedic, and cardiovascular device applications with respect to calcification and other phenomena. There is new focus is on materials processing, and materials science-related issues relevant to in-vitro diagnostic devices. The research is directed toward developing and establishing the in vitro and in vivo studies and models suitable for evaluating materials-tissue interactions, failure modes and effects analysis, the assessment of medical device-related pathology, peer-reviewed basis for regulatory guidance recommendations and standards development.
Relevance to FDA's and CDRH’s Mission, Program, and the Public Health Impact
The research in this program area is directed toward the development and establishment of in-vitro and in-vivo studies and models suitable for the evaluation of medical device materials safety. The peer-reviewed findings of these research projects serve as the scientific basis for regulatory guidance recommendations and standard development. The quality of new device materials must be assured by the appropriate pre-market testing and post-market surveillance. The goal is to develop the quality regulatory science base to meet the new challenges.
Three-Year GoalsAccomplishments
Controlled R x Delivery
Assessing the Stability of Nano-scale Constructs
Scope
A wide variety of new digital imaging and display devices is under development by academia and industry, with a broad range of performance characteristics. The Center requires augmented support for the evaluation of such devices. To this end, OSEL scientists are developing evaluation methodologies for diagnostic medical imaging systems such as mammography and fluoroscopy, computed tomography, nuclear medicine, diagnostic ultrasound, and magnetic resonance imaging, as well as novel soft-copy display devices for viewing medical images.
Background
The Medical Imaging Program at CDRH was initiated in the early 1970s by its predecessor, the Bureau of Radiological Health (BRH). The goal was to go beyond the traditional BRH laboratory approach of simply measuring the level of radiation emitted by an electronic or diagnostic modality, to measurement of the level of imaging performance as well. Laboratory measurement methods were developed for assessing the performance of contemporary and new technologies in the fields of radiography, mammography, computed tomography, diagnostic ultrasound, radioisotope imaging, magnetic resonance imaging, with current emphasis on digital detectors and displays. The program led to contributions to consensus measurement methodology and international standards that are used here today in the approval process for new technologies, in particular, digital radiography and mammography, and diagnostic ultrasound. In-house research and collaboration with academic investigators have also led to laboratory and clinical systems that optimize the ratio of imaging performance to radiation exposure in mammography.
In the late 1980s it was realized that many of the multivariate statistical methods developed for image evaluation were applicable to the assessment of conventional and neural-network systems for computer-aided diagnosis (CAD) in medicine. These include the fundamental paradigm of the receiver operating characteristic or ROC plot of true-positive fraction (or sensitivity) versus the false-positive fraction (or one minus the specificity). The ROC paradigm provides the unifying framework for the evaluation of all diagnostic devices. Starting in the m