FDA regulation of invasive neural recording electrodes: a daunting task for medical innovators

The U.S. Food and Drug Administration (FDA) is charged with assuring the safety and effectiveness of medical devices. Before any medical device can be brought to market, it must comply with all federal regulations regarding FDA processes for clearance or approval. Navigating the FDA regulatory process may seem like a daunting task to the innovator of a novel medical device who has little experience with the FDA regulatory process or device commercialization. This review introduces the basics of the FDA regulatory premarket process, with a focus on issues relating to chronically implanted recording devices in the central or peripheral nervous system. Topics of device classification and regulatory pathways, the use of standards and guidance documents, and optimal time lines for interaction with the FDA are discussed. Additionally, this article summarizes the regulatory research on neural implant safety and reliability conducted by the FDA's Office of Science and Engineering Laboratories (OSEL) in collaboration with Defense Advanced Research Projects Agency (DARPA) Reliable Neural Technology (RE-NET) Program. For a more detailed explanation of the medical device regulatory process, please refer to several excellent reviews of the FDA's regulatory pathways for medical devices [1]-[4].     

Characteristics of Pivotal Trials and FDA Review of Innovative Devices

When patients lack sufficient treatment options for serious medical conditions, they rely on the prompt approval and development of new therapeutic alternatives, such as medical devices. Understanding the development of innovative medical devices, including the characteristics of premarket clinical trials and length of Food and Drug Administration (FDA) review, can help identify ways to expedite patient access to novel technologies and inform recent efforts by FDA to more quickly get these products to patients and physicians. We analyzed publicly available information on clinical trials and premarket FDA review for innovative medical devices that fill an unmet medical need. In this first-of-its-kind study focusing on these products, we extracted data on the length of the pivotal trials, primary study endpoint and FDA review; number of patients enrolled in trials; and in what country the device was available first. We identified 27 approved priority review devices from January 2006 through August 2013. The median duration of pivotal clinical trials was 3 years, ranging from 3 months to approximately 7 years. Trials had a median primary outcome measure evaluation time of one year and a median enrollment of 297 patients. The median FDA review time was 1 year and 3 months. Most priority review devices were available abroad before they were approved in the United States. Our study indicates that addressing the length of clinical studies—and contributing factors, such as primary outcome measures and enrollment—could expedite patient access to innovative medical devices. FDA, manufacturers, Congress and other stakeholders should identify the contributing factors to the length of clinical development, and implement appropriate reforms to address those issues.     

FDA regulation of computerized cytology devices

When talking about computerized cytology devices, a "different" aspect of quality assurance must be addressed. Any medical device intended for in vitro diagnostic use in the United States must be cleared or approved by the Food and Drug Administration (FDA): the May 28, 1976, Medical Device Amendments to the Federal Food, Drug and Cosmetic Act granted authority to the FDA to regulate medical devices. The FDA regulatory process as it relates to computerized cytology devices is discussed. This includes an explanation of the differences between the two types of documents used to clear a medical device: (1) premarket notification [510(k)] and (2) premarket approval (PMA) application. Devices intended for "research use only" are also discussed. A computerized cytology device of current interest, the "automated Pap smear reader," is used as an example to further discuss performance and software considerations.     

Regulatory initiatives for natural latex allergy: US perspectives

The US Food and Drug Administration (FDA) has regulatory authority over foods, human drugs, cosmetics, medical devices, radiological products, biologics, and veterinary products. Among these products, FDA believes that the use of medical devices, including medical gloves, condoms, catheters, and breathing bags, represents the greatest source of natural latex proteins to exposed individuals. A medical device is defined in the Federal Food Drug and Cosmetic Act (FFDCA) as an instrument, apparatus, implement, machine, etc., that is intended for use in the diagnosis or treatment of disease or is intended to affect the structure or any function of the body of a human or other animal, and that does not achieve any of its principal intended purposes through chemical action in the body. This article provides some brief, general background about FDA's medical device regulatory process and then addresses the issue of natural latex allergy. Finally we discuss the steps the Agency has taken to evaluate the magnitude and nature of the problem, and FDA's efforts to assist manufacturers, health professionals, and others in minimizing exposure and sensitization to natural latex proteins in medical devices.     

Flow simulation-based particle swarm optimization for developing improved hemolysis models

The improvement and development of blood-contacting devices, such as mechanical circulatory support systems, is a life saving endeavor. These devices must be designed in such a way that they ensure the highest hemocompatibility. Therefore, in-silico trials (flow simulations) offer a quick and cost-effective way to analyze and optimize the hemocompatibility and performance of medical devices. In that regard, the prediction of blood trauma, such as hemolysis, is the key element to ensure the hemocompatibility of a device. But, despite decades of research related to numerical hemolysis models, their accuracy and reliability leaves much to be desired. This study proposes a novel optimization path, which is capable of improving existing models and aid in the development of future hemolysis models. First, flow simulations of three, turbulent blood flow test cases (capillary tube, FDA nozzle, FDA pump) were performed and hemolysis was numerically predicted by the widely-applied stress-based hemolysis models. Afterward, a multiple-objective particles swarm optimization (MOPSO) was performed to tie the physiological stresses of the simulated flow field to the measured hemolysis using an equivalent of over one million numerically determined hemolysis predictions. The results show that our optimization is capable of improving upon existing hemolysis models. However, it also unveils some deficiencies and limits of hemolysis prediction with stress-based models, which will need to be addressed in order to improve its reliability.

     

Safety monitoring of disposable medical products

In 1988 medical devices have become a part of the German AMG. According to this law safety monitoring similar to the one with drugs should be introduced. In the United States the so called medical device report regulation is responsible for safety monitoring. They have demonstrated that the risks of these instrument cannot be neglected. Therefore medical organisations or technical supervising institutions in Germany should take care of safety monitoring with medical devices, because otherwise supranational organisations, which are already present in different countries, or European community authorities will become responsible after the introduction of the free European market in 1992.     

Integrated data acquisition system for medical device testing and physiology research in compliance with good laboratory practices

In seeking approval from the US Food and Drug Administration (FDA) for clinical trial evaluation of an experimental medical device, a sponsor is required to submit experimental findings and support documentation to demonstrate device safety and efficacy that are in compliance with Good Laboratory Practices (GLP). The objective of this project was to develop an integrated data acquisition (DAQ) system and documentation strategy for monitoring and recording physiological data when testing medical devices in accordance with GLP guidelines mandated by the FDA. Data aquisition systems were developed as stand-alone instrumentation racks containing transducer amplifiers and signal processors, analog-to-digital converters for data storage, visual display and graphical user-interfaces, power conditioners, and test measurement devices. Engineering standard operating procedures (SOP) were developed to provide a written step-by-step process for calibrating, validating, and certifying each individual instrumentation unit and the integrated DAQ system. Engineering staff received GLP and SOP training and then completed the calibration, validation, and certification process for the individual instrumentation components and integrated DAQ system. Eight integrated DAQ systems have been successfully developed that were inspected by regulatory affairs consultants and determined to meet GLP guidelines. Two of these DAQ systems were used to support 40 of the pre-clinical animal studies evaluating the AbiCor artificial heart (ABIOMED, Danvers, MA). Based in part on these pre-clinical animal data, the AbioCor clinical trials began in July 2001. The process of developing integrated DAQ systems, SOP, and the validation and certification methods used to ensure GLP compliance are presented in this article.     

Classifying medical devices according to their maintenance sensitivity: a practical, risk-based approach to PM program management

Many medical equipment items need periodic attention to ensure that they continue to operate properly and safely; and most inspecting agencies require healthcare facilities to have a competent equipment maintenance program that is focused on the most critical of those devices. There is however a long-standing lack of consensus on how best to determine which devices should be included in this critical device category, and which can reasonably be excluded. A new methodology is proposed for establishing a logical, fact-based framework for determining which devices should be included. It is based in part on a new FDA-sanctioned definition of what an appropriate regimen of planned maintenance activities for a medical device should include. This new definition addresses the medical device users' concerns about periodic performance verification and safety testing as well as detecting and correcting the wear or progressive deterioration of any non-durable parts, which is the primary focus of the conventional preventive maintenance programs found in less critical industries. The analytical approach proposed utilizes technical information that is either already available or which can be easily developed. It characterizes each different device by means of a 3-letter maintenance sensitivity profile that can be used to analyze the effectiveness of the maintenance procedures as well as quantify the device's sensitivity to planned maintenance. A collaborative effort to assemble and organize this data would provide the industry with a sound, logical platform for narrowing the scope of most PM programs and allow us to redirect a significant amount of scarce technical manpower into more productive activities such as device user training.     

Development of a program model to evaluate the potential for reuse of single-use medical devices: results of a pilot test study

Single-use medical devices (SUDs, or disposables) have become a major expense in hospital budgets. The need for cost reduction and the availability of sterilization technologies other than the autoclave have prompted hospitals worldwide to begin reusing disposables, in many cases without proper assessment of the true costs (time, personnel, etc) and ease/difficulty of implementation of an institutional reuse program. Our group has developed a rigorous program model to evaluate SUDs for reuse. The program comprises 3 sequential protocols: (1) device audit, (2) laboratory evaluation, and (3) clinical evaluation. Use of this model can produce scientific and financial data sufficient for any institution interested in reuse to reach an initial decision about its feasibility. In addition to the testing outcomes, regulatory requirements, the position of manufacturers and third-party reprocessors, and legal and ethical concerns must be considered. A successful reuse program must include ongoing evaluations to ensure that the safety levels and cost savings established during the initial audit and evaluation phases continue. Herein, we give the rationale and details of our program model and discuss results of our pilot application of the "ideal" protocol in a real-world context.     

Medical Device Industry Approaches for Addressing Sources of Failing Cytotoxicity Scores

To ensure patient safety, medical device manufacturers are required by the Food and Drug Administration and other regulatory bodies to perform biocompatibility evaluations on their devices per standards, such as the AAMI-approved ISO 10993-1:2018 (ANSI/AAMI/ISO 10993-1:2018).However, some of these biological tests (e.g., systemic toxicity studies) have long lead times and are costly, which may hinder the release of new medical devices. In recent years, an alternative method using a risk-based approach for evaluating the toxicity (or biocompatibility) profile of chemicals and materials used in medical devices has become more mainstream. This approach is used as a complement to or substitute for traditional testing methods (e.g., systemic toxicity endpoints). Regardless of the approach, the one test still used routinely in initial screening is the cytotoxicity test, which is based on an in vitro cell culture system to evaluate potential biocompatibility effects of the final finished form of a medical device. However, it is known that this sensitive test is not always compatible with specific materials and can lead to failing cytotoxicity scores and an incorrect assumption of potential biological or toxicological adverse effects. This article discusses the common culprits of in vitro cytotoxicity failures, as well as describes the regulatory-approved methodology for cytotoxicity testing and the approach of using toxicological risk assessment to address clinical relevance of cytotoxicity failures for medical devices. Further, discrepancies among test results from in vitro tests, use of published half-maximal inhibitory concentration data, and the derivation of their relationship to tolerable exposure limits, reference doses, or no observed adverse effect levels are highlighted to demonstrate that although cytotoxicity tests in general are regarded as a useful sensitive screening assays, specific medical device materials are not compatible with these cellular/in vitro systems. For these cases, the results should be analyzed using more clinically relevant approaches (e.g., through chemical analysis or written risk assessment).

Medical devices are engineered to be of durable construction and to accommodate the functionality needed for proper device application. The biocompatibility of the materials, as well as their processing, is also important to ensure that the patients are not negatively affected by the devices when they enter the clinical setting. Certain materials of constructions used for medical devices (and manufacturing processes or processing aids) may contain chemicals that can lead to failing cytotoxicity scores using traditional, regulatory-mandated methodologies. Examples of common materials include plastics (e.g., polyethylene or polypropylene [co]polymers, polyvinyl chloride [PVC]) and metals (e.g., nitinol, copper [Cu]-containing alloys). Although providing stable and reliable materials for use in relation to performance parameters, various metals/alloys and plastics may evoke undesired cytotoxic effects. These effects might be observed as reduced cellular activity or decay in the in vitro assay, especially when standard methods and test parameters (e.g., extraction ratios) are used.1,2To prevent adverse effects (e.g., toxicity, or other types of biocompatibility-related issues) from occurring among patients and clinical end users, manufacturers are required to perform biocompatibility evaluations per guidance provided in e.g., ANSI/AAMI/ISO 10993-1:2018.3 This standard provides an overall framework for the biological evaluation, emphasizing a risk-based approach, as well as general guidance on relevant tests for specific types of contact to patients or users. Of note, traditional biocompatibility tests, within the battery of both in vivo and in vitro methods, could take up to 6 months (or take years, in the case of long-term systemic toxicity testing). Lengthy turnaround times stem from in vivo test methods, which are performed on animal models and include irritation, sensitization, systemic toxicity, genotoxicity, and carcinogenicity studies. Traditional in vitro tests involve exposure of cells or cellular material to device extracts in order to characterize toxicity in terms of cytotoxicity, genotoxicity, cellular metabolic activity, and aspects of hemocompatibility.3In recent years, as a complement to or a substitute for traditional testing methods, a risk-based approach using a chemical and materials characterization for evaluation of patient safety has become mainstream. The framework for this approach is provided in ISO 10993-18:2020.4 Moreover, the Association for the Advancement of Medical Instrumentation (AAMI) and, by extension, regulatory bodies (including the Food and Drug Administration [FDA] and International Organization for Standardization [ISO]) have driven the use of chemical and material characterization. Particularly for medical devices in long-term contact with patient (e.g., implantable devices), use of chemical and material characterization can reduce unnecessary animal testing and provide results that are scientifically sound and detailed, while being more cost and time efficient. For example, ISO 10993-13 highlights that a correctly conducted risk assessment can provide justification to exclude long-term biological testing, where the nature and extent of exposure confirms that the patient is being exposed to very low levels of chemicals that are below relevant toxicological thresholds.3Throughout the ISO 10993 series, it also is emphasized that conducting animal testing for biological risk evaluation should only be considered after all alternative courses of action (review of prior knowledge, chemical or physical characterization, in vitro evaluations, or alternative means of mitigation) have been exhausted. In addition, analytical chemistry used for chemical characterization can be used as a means for investigating possible culprits when traditional biocompatibility tests, such as cytotoxicity tests, fail, especially in cases where a known substance(s) in the material has cytotoxic potential (e.g., silver-infused wound dressing that provides antibacterial properties).However, it should be kept in mind that although chemistry can be a powerful tool in many cases, not all medical devices extracts are compatible with the analytical methods and instruments used, and these studies may not provide the full understanding of the toxicity profile of the device. In those cases, animal testing or further justification may still be needed to demonstrate a safe biocompatibility profile for the device.Cytotoxicity testing per AAMI/ISO 10993-5:2009/(R)20145 has historically been one of the most used (and is considered the most reactive) of the biocompatibility tests6,7 and can be efficiently used to detect abnormal effects to cells that may arise if harmful chemicals are present in device extracts. However, it also is recognized that cell-based test methods do not necessarily correlate to in vivo toxicological effects and actual clinical patient safety, often showing a reaction when no clinical adverse effects are known or expected to occur. For instance, some soluble metal ions (e.g., Cu, nickel [Ni]) are known to exert toxic effects on cells in an in vitro setting; however, their presence in surgical instruments and implants has demonstrated high patient tolerance and negligible effects upon clinical use.This article provides a brief evaluation of the clinical impact of metals and plasticizers commonly used in medical device materials that may lead to patient exposure during the use of devices, with emphasis given to those that may result in cytotoxicity failures in an in vitro setting. In addition, an approach to evaluating valid clinical risks using a toxicological risk assessment is discussed.     

A Device for Cutting Brain Slices

A device for cutting brain slices is described as an alternative to cutting angle guides and the “brain macrotome”. With this new device, slices of uniform thickness optimal for assessing morphological detail and photography can be produced. A similar but smaller device for cutting pieces of tissue for paraffin embedding is also presented. These devices should be useful in either the histopathology laboratory or mortuary.     

Translation of proteomic biomarkers into FDA approved cancer diagnostics: issues and challenges

Tremendous efforts have been made over the past few decades to discover novel cancer biomarkers for use in clinical practice. However, a striking discrepancy exists between the effort directed toward biomarker discovery and the number of markers that make it into clinical practice. One of the confounding issues in translating a novel discovery into clinical practice is that quite often the scientists working on biomarker discovery have limited knowledge of the analytical, diagnostic, and regulatory requirements for a clinical assay. This review provides an introduction to such considerations with the aim of generating more extensive discussion for study design, assay performance, and regulatory approval in the process of translating new proteomic biomarkers from discovery into cancer diagnostics. We first describe the analytical requirements for a robust clinical biomarker assay, including concepts of precision, trueness, specificity and analytical interference, and carryover. We next introduce the clinical considerations of diagnostic accuracy, receiver operating characteristic analysis, positive and negative predictive values, and clinical utility. We finish the review by describing components of the FDA approval process for protein-based biomarkers, including classification of biomarker assays as medical devices, analytical and clinical performance requirements, and the approval process workflow. While we recognize that the road from biomarker discovery, validation, and regulatory approval to the translation into the clinical setting could be long and difficult, the reward for patients, clinicians and scientists could be rather significant.     

A manufacturer's perspective: Hewlett Packard Y2K action plan

Medical device manufacturers must ensure that their devices are safe and effective including investigating issues involved with the century rollover. Manufacturers must begin early to evaluate their products in order to allow time to correct and distribute these product corrections and communicate to their customers so they can prepare for the Y2K event.     

浅析PLM系统在医疗器械行业的实施应用

阐述了PLM的基本概念、原理、行业研究和应用现状基础。针对医疗器械行业产品研发和产品监管的特点,结合企业的实际现状,详细分析了该医疗器械企业的PLM应用需求。该文还结合企业PLM系统项目开展的实际过程给出了设计、实施方案,并对实施效果进行了评估。     

Improving communication skill training in patient centered medical practice for enhancing rational use of laboratory tests: The core of bioinformation for leveraging stakeholder engagement in regulatory science

Requests for laboratory tests are among the most relevant additional tools used by physicians as part of patient''s health problemsolving. However, the overestimation of complementary investigation may be linked to less reflective medical practice as a consequence of a poor physician-patient communication, and may impair patient-centered care. This scenario is likely to result from reduced consultation time, and a clinical model focused on the disease. We propose a new medical intervention program that specifically targets improving the patient-centered communication of laboratory tests results, the core of bioinformation in health care. Expectations are that medical students training in communication skills significantly improve physicians-patient relationship, reduce inappropriate use of laboratorial tests, and raise stakeholder engagement.     

Fungal Biofilms: Relevance in the Setting of Human Disease

The use of indwelling medical devices is rapidly growing and is often complicated by infections with biofilm-forming microbes that are resistant to antimicrobial agents and host defense mechanisms. Fungal biofilms have emerged as a clinical problem associated with these medical device infections, causing significant morbidity and mortality. This review discusses the recent advances in the understanding of fungal biofilms, including the role of fungal surface components in adherence, gene expression, and quorum sensing in biofilm formation. We propose novel strategies for the prevention or eradication of microbial colonization of medical prosthetic devices.     

Radiation and Ethylene Oxide Terminal Sterilization Experiences with Drug Eluting Stent Products

Radiation and ethylene oxide terminal sterilization are the two most frequently used processes in the medical device industry to render product within the final sterile barrier package free from viable microorganisms. They are efficacious, safe, and efficient approaches to the manufacture of sterile product. Terminal sterilization is routinely applied to a wide variety of commodity healthcare products (drapes, gowns, etc.) and implantable medical devices (bare metal stents, heart valves, vessel closure devices, etc.) along with products used during implantation procedures (catheters, guidewires, etc.). Terminal sterilization is also routinely used for processing combination products where devices, drugs, and/or biologics are combined on a single product. High patient safety, robust standards, routine process controls, and low-cost manufacturing are appealing aspects of terminal sterilization. As the field of combination products continues to expand and evolve, opportunity exists to expand the application of terminal sterilization to new combination products. Material compatibility challenges must be overcome to realize these opportunities. This article introduces the reader to terminal sterilization concepts, technologies, and the related standards that span different industries (pharmaceutical, medical device, biopharmaceuticals, etc.) and provides guidance on the application of these technologies. Guidance and examples of the application of terminal sterilization are discussed using experiences with drug eluting stents and bioresorbable vascular restoration devices. The examples provide insight into selecting the sterilization method, developing the process around it, and finally qualifying/validating the product in preparation for regulatory approval and commercialization. Future activities, including new sterilization technologies, are briefly discussed.     

KeeT Stephen, Gehl Julie and LeeW Edward: Clinical aspects of electroporation

Human factors is the study of the relationship between people and devices or systems. The goal of considering human factors in the design of medical devices is to create devices that take into consideration the way people use technology and process information to create a man-machine interface that leads to the best possible performance. This text describes the significant aspects of human factors issues related to medical device design. It is well written and is useful for medical device designers and for others who use or evaluate medical equipment.     

Diagnostic kits in parasitology: which controls?

The development of new diagnostic tools particularly for some parasitic "neglected diseases", is slowed or even hindered by limited resources assigned for basic and applied research in public institution and private sector. Even if the time-line and costs needed for developing a new In Vitro Diagnostic (IVD) test are generally lower compared to vaccines or new drugs, industry is poorly engaged in investing resources due to the perception of limited markets. To accelerate the development of diagnostics for the world's most deadly diseases, the World Health Organization's (WHO) Special Programme for Research and Training in Tropical Diseases (TDR), the United Nations Development Programme, the World Bank and the Gates Foundation, last year launched a new initiative, FIND (Foundation for Innovative New Diagnostics, www.finddiagnostics.org). The aim is to "apply the latest biotechnology innovations to develop and validate affordable diagnostic tests for diseases of the developing world". Ideally, a new diagnostic test should be accurately evaluated prior to use in medical practice. The first step would be a pre-clinical evaluation, an analytic study to determine its laboratory performance. A crucial point in this phase is the calibration of reagents (antigens, antibodies, DNA probes, etc.) against a standard reference preparation. WHO, through the WHO International Laboratories for Biological Standards, "provides International Biological Reference Preparations which serve as reference sources of defined biological activity expressed in an internationally agreed unit" (www.who.int/biologicals/IBRP/index.htm). Standardization allows "comparison of biological measurements worldwide" and ensures the reliability of diagnostic procedures. These preparations are generally intended for use in the characterization of the activity of secondary reference preparations (regional, national or in-house working standards). Unfortunately, international reference standards for parasitic diseases are not available at present, except for Toxoplasma antibodies. The first international standard reagent for Anti-Toxoplasma Serum was established in 1968 and at present, an international standard reference serum, Anti-toxoplasma serum, human TOXM is available at the National Institute for Biological Standards and Control (NIBSC) in UK. Several collaborative, multicenter studies were carried out to assess the performance of different methods and commercial tests for the diagnosis of toxoplasmosis, by providing to participating laboratories a panel of well-defined sera to be tested. A four-phase process following well-accepted methodological standards for the development of diagnostics, analogous to those internationally accepted for drugs and vaccines was recently proposed. The pre-clinical evaluation, the analytic study to assess sensitivity, specificity, predictive values in laboratory (phase I), should be followed by a proof of principle study to distinguish diseased from healthy persons in easily accessible populations (phase II). The evaluation of test performance in populations of intended use (phase III), and finally the delineation of cost-effectiveness and societal impact of new tests in comparison with existing tools (phase IV) should complete the validation procedure. In this context, national regulatory agencies play a major role in pre-market approval and post-market surveillance of IVDs. The European Community in 1998 approved a directive (Directive 98/79/EC) which rules the marketing of IVD medical devices, in order to harmonise the performance levels and standards in European countries. But, among IVDs for parasitic diseases, only those to detect congenital toxoplasmosis are submitted to defined procedures to provide the verification of products before their placing on the market and the surveillance after their marketing by a notified body, which perform appropriate examinations, tests and inspections to production facilities to verify if the device meets the requirements of the directive. In U.S.A., the Food and Drug Administration (FDA), through the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), provides a comprehensive and regulatory activity for IVDs through pre-market evaluation and post-market surveillance. In developing countries, the scarcity of resources limits the procedures through which the national control authority can assure safety, quality and efficacy of products marketed, both imported and locally manufactured.