Special initiatives exist in FDA’s Center for Devices and Radiological Health (CDRH), the Center for Drug Evaluation and Research, and the Center for Biologics Evaluation and Research to ensure the safety and effectiveness of medical products used in the vulnerable pediatric population. This article focuses on the special programs, projects, and special studies implemented by CDRH to ensure this safety and effectiveness in devices used in pediatric patients throughout the devices’ total product life-cycles. Pediatricians play a major role in keeping medical devices safe for use in children by reporting device problems to FDA.
Key Points
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The Food and Drug Administration (FDA) has special provisions in place to protect pediatric patients; this article focuses on medical device safety in this population.
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The FDA ensures device safety throughout the total product life cycle.
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Device registries are promising sources of device safety and effectiveness information.
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New legislation enhances the FDA’s ability to protect pediatric patients.
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Recent activities in pediatric radiation safety demonstrate how the FDA approaches device issues.
Introduction
The Center for Devices and Radiological Health (CDRH) defines the pediatric population as birth through 21 years, and has recognized the need to consider the unique characteristics of different stages of a child’s development by identifying the following subpopulations: neonate (birth–28 days), infant (>28 days–2 years), child (>2–12 years), and adolescent (>12–21 years). The Federal Food, Drug, and Cosmetic Act, Sec. 201(h)[321] defines a medical device as an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or similar articles that are not metabolized in the body and not a biologic, drug, or food. Medical devices and their use in pediatric patients was the subject of a 2006 Institute of Medicine study, “Safe medical devices for children,” commissioned by Congress.
In regulating devices, the CDRH uses a “total product-life cycle” (TPLC) approach, which seeks to improve device safety and effectiveness by coordinating and integrating premarket evaluation, postmarket surveillance and compliance actions, communication and outreach to consumers and industry, scientific research, standards development, and use of external pediatric expertise. The following sections touch on how the Food and Drug Administration (FDA) addresses pediatric safety issues in each of these areas.
Introduction
The Center for Devices and Radiological Health (CDRH) defines the pediatric population as birth through 21 years, and has recognized the need to consider the unique characteristics of different stages of a child’s development by identifying the following subpopulations: neonate (birth–28 days), infant (>28 days–2 years), child (>2–12 years), and adolescent (>12–21 years). The Federal Food, Drug, and Cosmetic Act, Sec. 201(h)[321] defines a medical device as an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or similar articles that are not metabolized in the body and not a biologic, drug, or food. Medical devices and their use in pediatric patients was the subject of a 2006 Institute of Medicine study, “Safe medical devices for children,” commissioned by Congress.
In regulating devices, the CDRH uses a “total product-life cycle” (TPLC) approach, which seeks to improve device safety and effectiveness by coordinating and integrating premarket evaluation, postmarket surveillance and compliance actions, communication and outreach to consumers and industry, scientific research, standards development, and use of external pediatric expertise. The following sections touch on how the Food and Drug Administration (FDA) addresses pediatric safety issues in each of these areas.
Premarket review of medical devices
Medical devices come to market via various regulatory pathways, which are the same for pediatric and adult devices: premarket notification or 510(k), premarket approval, de novo pathway, Humanitarian Device Exemption (HDE), and compassionate use or emergency use. All devices are evaluated using a risk-based regulatory process, with the level of evidence required to ensure a reasonable assurance of safety and effectiveness varying based on the intended use of the product and the technology involved. Some devices require the submission of clinical data, whereas, for others, laboratory testing is adequate to ensure safety and effectiveness. Devices are classified as Class I, II, or III depending on the risk the device poses to the patient and/or the user, with Class III devices posing the greatest risk.
Given the wide range of devices brought to market through various regulatory pathways, the FDA is committed to making sure that if a medical device is to be used in any pediatric patient, a reasonable assurance of safety and effectiveness must be demonstrated in the targeted pediatric subgroup. Some devices have a general indication (eg, syringes or many diagnostic radiographic imaging devices) and can be used in any age group (adults and children), whereas other devices target a specific subpopulation (eg, newborn screening diagnostic tests). Other medical devices may need to be sized for children (eg, heart valves). Manufacturers must recognize the unique host characteristics within each of the subpopulations and, when applicable, address these differences.
To this end, the FDA outlines points to consider for the pediatric population through the Guidance for Industry and FDA Staff document, “Premarket assessment of pediatric medical devices.” This guidance outlines the general fundamental, scientific, and regulatory principles and types of premarket submission information applicable to establishing a reasonable assurance of safety and effectiveness for all medical devices. In addition, it provides a framework for deciding when special consideration must be given to the pediatric subpopulation for which the device is intended. The FDA identifies common scientific approaches used for assessing safety and effectiveness (eg, biocompatibility, software design, human factors, toxicology, and statistical methods) and clearly advises that the instructions for use should take into consideration special issues for the different pediatric subgroups. By following the guidance, manufacturers are more likely to ensure that appropriate safeguards are in place for a medical device that is intended for the pediatric population.
Recent statutory enhancements
To spur pediatric device development and bring safe and effective devices to children, Congress passed the Pediatric Medical Device Safety and Improvement Act of 2007 (Title III of FDA Amendments Act). It provided the FDA with substantial new responsibilities and authorities regarding medical devices that have actual or potential pediatric uses. For example, Title III provides incentives to device manufacturers to create medical devices specifically designed to meet the needs of pediatric patients. It modifies the HDE (regulatory pathway to market for devices for which the intended population is very small) to allow manufacturers of devices specifically designed to meet a pediatric need to make a profit from the sale, which was not previously permitted. Currently, new guidance is being drafted that is designed to help FDA reviewers and manufacturers of medical devices identify and address these issues. In May 2012, Congress passed the FDA Safety and Innovation Act . This Act, among many other provisions, enhanced the pediatric safety provisions added in 2007. For example, to further encourage development of devices designed for the pediatric population, in addition to making a profit on devices sold under the HDE, now manufacturers may also request that the product be sold to a larger number of patients than the 4000 limit imposed by the HDE.
Pediatric device research and standards development
To stimulate pediatric-specific medical device research and surveillance, the FDA has provided funding mechanisms to facilitate gathering and analyzing data regarding safety and effectiveness in this patient population and to create external partnerships. For example, the Critical Path Initiative is an FDA pathway used to provide funding for various research projects, many of which have a pediatric focus. Specific Critical Path initiatives include collaboration with the American College of Cardiology (ACC) on the Improving Pediatric and Adult Congenital Treatment (IMPACT) Registry and an initiative to reduce radiation exposure from pediatric radiographic imaging (see later discussion).
Studies involving human subjects with medical devices are monitored through a designated Bioresearch Monitoring Office. The CDRH monitors ongoing device research through the Early Intervention Program, which focuses on active research of novel medical devices or vulnerable populations, such as the pediatric population, to assure that adequate systems are in place to protect the rights and welfare of human research subjects and to promote high-quality device research.
In addition to research, the development and use of standards is an important tool for evaluating safety and effectiveness for devices used in pediatric populations. Following FDA-recognized standards can reduce the burden to industry by providing a streamlined approach for satisfying many premarket submission requirements. CDRH’s Standards Program has committed to investigating the need for standards that address pediatric use issues; input from health care practitioners with pediatric expertise will be an important part of this endeavor.
Postmarket surveillance of medical devices
Once a device is in clinical use, new and unexpected problems may occur with its use, or there could be an unexpected increase in known problems that were not foreseen during the premarket review process. It is imperative that the FDA, device manufacturers, and the clinical community monitor device-related problems. The CDRH uses several surveillance tools to learn about problems with medical devices once they are in the marketplace. Once problems are identified, the CDRH works with device manufacturers to address them using various approaches, which may include (1) recommending recalls or corrective actions, such as updated labeling and improved device designs; (2) communicating information and recommendations to device users; (3) helping manage known risks by providing strategies to facilitate safe use; and (4) mandating and/or conducting observational studies.
Passive Surveillance
Manufacturers and importers are required to submit reports of device-related deaths, serious injuries, and malfunctions to the FDA. User facilities (eg, hospitals, outpatient diagnostic and treatment centers, and nursing homes) are required to submit reports of device-related deaths and serious injuries to the manufacturer and reports of deaths to the FDA. Health care providers and consumers may submit reports voluntarily through the MedWatch program. All reports obtained through this passive surveillance method are housed in the Manufacturer and User Facility Device Experience (MAUDE) database, established in 1996. Most reports in MAUDE (approximately 400,000 per year) are from manufacturers, with a small percentage from user facilities, voluntary sources, and importers. These reports, after redaction to protect the identity of the reporter and the patient, are available on-line for public review.
As is typical of other passive reporting systems, the FDA’s system has noticeable weaknesses including (1) data may be incomplete or inaccurate and are typically not independently verified; (2) data may reflect reporting biases driven by event severity, uniqueness, or publicity and litigation; (3) causality cannot be inferred from any individual report; and (4) events are generally underreported. Underreporting, in combination with lack of denominator (exposure) data, precludes determination of event incidence or prevalence.
Despite these limitations, the CDRH safety analysts use techniques to obtain valuable information about emerging device problems from MAUDE. In assessing these reports, in addition to specific patient characteristics, the following factors are considered (1) failure potential resulting from design or manufacturing problems or possible packaging errors; (2) use error potential due to human factors issues, such as inadequate design of the user interface or inadequate labeling (includes instructions for use); (3) use error due to misreading instructions, maintenance error, or incorrect clinical use; and (4) possible adverse environmental factors, including support system failures and adverse device interactions (eg, electromagnetic interference or toxic and/or idiosyncratic reactions).
To assist in detecting new signals, FDA safety analysts use statistical tools, such as Bayesian and other data mining methods, that have been automated to estimate the relative frequency of specific adverse event–device combinations compared with the frequency of the event with all other devices (in the same group) in the database. To aid this effort, and reporting and signal detection in general, an extensive hierarchical vocabulary for device failures also has been developed.
Enhanced Surveillance
In 2002, the CDRH launched the Medical Product Safety Network (MedSun) to create collaborations with hospitals to identify, understand, and solve problems with the use of medical devices, and to aid in overcoming underreporting from user facilities. Trained reporters, typically risk managers and biomedical engineers, from 290 hospitals across the United States report device-related problems to the FDA using a secure Web site. Not only deaths and serious injuries associated with the use of devices are reported, but also close calls and potential for harm, including human-factor problems with device designs. The MedSun hospitals also participate in CDRH-conducted focus groups, individual interviews, and surveys to learn more about emerging signals and to help the CDRH determine how useful a manufacturer’s action has been in improving patient safety.
KidNet, a specialty subnetwork of MedSun, has been implemented in 46 MedSun hospitals beginning in 2000. In an effort to obtain more detailed reports from hospital staff working directly with the equipment, KidNet expanded reporting from the risk manager and biomedical engineer levels deeper into the hospital, to the front-line users (eg, doctors and nurses). Notably, the KidNet sites submitted almost all the reports that MedSun received about problems in the pediatric and neonatal intensive care units. This is one example of a KidNet report that led to a recall of a pediatric product (manufacturer and the reporting hospital are deidentified):
Device: disposable cannula for C02 monitor.
A small piece of the pediatric-neonatal end tidal CO2 monitor (for intubated children) broke off and got stuck in the infant’s tracheostomy tube. Nurse found it before harm was caused.
Location: pediatric ICU.
Outcome: report contributed to a Class I recall ( http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=99419 ).
To view more examples of reports sent from MedSun hospitals about events occurring in the neonatal intensive care unit, please go to the Search Reports section of the MedSun Web site.
Active Postmarket Surveillance: Sentinel Initiative and Registries
To provide more robust surveillance and complement limited FDA postmarket monitoring systems, the FDA launched the Sentinel Initiative in 2007, which provides a national integrated electronic health care infrastructure for medical product active surveillance in the United States. The surveillance is conducted using nationally distributed data sources (with populations totaling in the tens of millions), transformed to common data models, against which FDA queries (including active surveillance protocols) can be run and aggregate data received. The absence of device-specific identifiers in most Sentinel data sources (eg, those based on claims) limits its current utility for device surveillance. Nonetheless, to prepare for and inform more widespread Sentinel efforts that will be enhanced through implementation of unique device identification (UDI; see later discussion), the FDA is exploring active device surveillance using data from several existing registries and databases, including the Massachusetts statewide coronary intervention registry and the Veterans Health Administration’s electronic health records system. In-hospital safety signals (eg, myocardial infarction) for recently introduced interventional cardiovascular devices (eg, drug-eluting coronary stents) have been explored using an automated computerized safety surveillance system, the Data Extraction and Longitudinal Trend Analysis (DELTA) system. DELTA was designed to support flexible prospective safety surveillance applicable to a broad range of medical devices, including those used in pediatric populations.
Another evolving FDA active surveillance effort effectively uses the Consumer Product Safety Commission’s (CPSC’s) National Electronic Injury Surveillance System (NEISS), which is designed to capture information on injuries in hospital emergency departments (EDs). The FDA collaborated with the CPSC to use NEISS to establish the first national estimates of device-related adverse events resulting in ED visits. More recent efforts have focused on examining reasons for device-related visits to the ED by pediatric patients. These efforts established that contact lenses and hypodermic needles were associated with the greatest percentage of pediatric devices related to ED visits (23% and 8%, respectively), out of nationally projected estimates of 145,000 device-related events over a 2-year period.
National registries, often maintained by professional societies, have become important means to actively monitor postmarket device performance, especially for high-risk devices. Registries have been defined as “an organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure, and that serves a predetermined scientific, clinical, or policy purpose(s).” The FDA has facilitated the development and/or enhancement of several procedure and/or device registries, including the Interagency Registry for Mechanically-Assisted Circulatory Support (INTERMACS), which attempts to collect high-quality information on procedures and outcomes associated with implanted ventricular-assist devices. Special issues in the pediatric population receiving this therapy are evaluated by the INTERMACS Pediatric Committee, or PediMACS. In another effort funded by the Critical Path Program, the FDA collaborated with the ACC to support the development and implementation of the IMPACT Registry. This registry aims to facilitate pediatric cardiovascular device review, expedite new device approval, facilitate postapproval studies by providing a national framework, and enhance ongoing postmarket surveillance. The FDA has also engaged a pediatric diabetes registry in a collaboration to obtain device information (eg, use of insulin pumps, continuous glucose monitors) related to adverse diabetic incidents.
The FDA use of these registry data sources extends to international collaborations, as exemplified by the FDA-initiated International Consortium of Orthopedic Registries (ICOR), with a goal to understand real world performance of orthopedic devices in both children and adults.
Mandated Postmarket Studies
Another tool that the FDA uses to achieve its surveillance and risk assessment goals is mandated postmarket studies. Depending on the device, these studies may be mandated as part of the approval to place the device on the market, or mandated after the device has already been marketed to further assess important public health issues. Results from these studies may drive revisions to the product’s labeling (including patient-related and clinician-related material).
Study approaches vary widely and are designed to capture the most practical, least burdensome approach to produce scientifically sound answers. Examples include: nonclinical testing of the device, enhanced surveillance, observational studies, and, rarely, randomized controlled trials. Current study status, study protocol outlines, and basic study results for the postapproval studies mandated as part of the permission for approval are posted on the FDA’s Web site. Of the more than 160 postapproval studies currently underway involving more than three dozen device types, approximately 75% include the pediatric population.
Mandated studies ordered after the device has been marketed are most typically obtained “for cause” (ie, when a significant public health issue has arisen). The FDA has discretionary authority to order a manufacturer of a Class II or Class III device to conduct a postmarket study if the device meets one of a specific set of conditions, one of which is an expected significant use in pediatric populations.
New sponsor-based registries or current national registries can also be used to perform FDA-mandated studies. Over 60 postapproval studies currently underway use registries. For example, the manufacturer of Olympic Cool Cap established a registry to assess the real-world performance of their device to treat neonatal hypoxic ischemic encephalopathy.
Other Data Sources
The FDA has also explored other large data sources to augment existing surveillance capabilities. For example, administrative and claims data captured by health care insurers, such as the Centers for Medicare and Medicaid Services fee-for-service claims, are a potentially valuable source of population exposures and health outcomes of interest. Device use and outcomes can be captured using national and international coding systems, such as Current Procedural Terminology codes and International classification of diseases, ninth revision, clinical modification ( ICD-9-CM ) diagnosis or procedure codes. A pilot study is being conducted, within the 50-state Medicaid and managed care pediatric population, assessing the use and relative hazard of adverse outcomes (retinal detachments, keratopathy, and glaucoma) associated with use of intraocular lenses following cataract surgery.
Administrative and claims data are also being used to explore the prevalence and nature of adverse medical device events, identified by ICD-9-CM discharge diagnoses, in a pediatric population that includes significant numbers of children with special health care needs. Underway is a retrospective claims-based cohort study of patients cared for at 42 not-for-profit hospitals in the Pediatric Health Information System, a source that includes data from 70% of the freestanding children’s hospitals in the United States, representing 17 of the 20 major metropolitan areas.
Device Identification
The FDA Amendments Act of 2007 directed the FDA to issue regulations establishing a UDI system for medical devices and a proposed rule was issued in July 2012. In conjunction with this initiative, the FDA is leading an effort to develop and implement a strategy for using health-related electronic data from large data sources, such as health insurers and integrated health systems, registries, and other sources, which incorporates UDIs to better understand device safety and effectiveness. Currently, because these data do not contain UDIs, they generally cannot be used to identify specific device exposures in patients.
The incorporation of UDI data into various health-related databases will greatly facilitate many important activities related to public health, including (1) reducing medical errors, (2) reporting and assessing device-related adverse events, (3) tracking of recalls, (4) assessing patient-centered outcomes and the risk-benefit profile of medical devices in large segments of the US population, and (5) providing an easily accessible source of device identification information to patients and health care professionals. UDIs will help expand the scope and impact of important efforts, such as the Sentinel Initiative previously described.
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