Medical devices include items used for the diagnosis, cure, mitigation, treatment, or prevention of a disease. These devices range from simple tools like bandages and surgical clamps to complicated devices like pacemakers; unless exempt by FDA regulations, devices are generally subject to FDA premarket review. Pediatric patients may be among those a device is intended to treat and generally are defined as those age 21 years or younger. FDAAA included provisions to support and track pediatric device development. Unless exempt by regulation, medical devices are generally subject to FDA premarket review before they may be legally marketed in the United States. The extent of the premarket review is generally correlated with the level of risk the device poses. Applications to market medical devices are primarily submitted to and reviewed by FDA’s Center for Devices and Radiological Health (CDRH). Under the PMA premarket review process, FDA reviews and makes approval decisions on applications for class III devices. Among other things, PMA applications must include the indication for use—including the disease and population the medical device is intended to treat—and evidence (typically clinical data) providing reasonable assurance that the device is safe and effective. After an initial screening of an application and determination that the review should proceed, FDA’s reviewers conduct a scientific review of the application and may refer applications to an external advisory committee composed of individuals with expertise in a particular medical specialty, such as cardiovascular or neurology— known as a medical specialty panel. FDA charges manufacturers a fee to review PMA applications, but PMA applications for devices intended solely for pediatric use are exempt from any fees. For devices that have been approved through the PMA process, a manufacturer that wants to add a pediatric population (or otherwise significantly change the approved indication for use) must submit and receive FDA approval for a PMA panel-track supplement. manufacturers a fee to review PMA panel-track supplements, but those intended solely for pediatric use are exempt. In 1990, Congress authorized FDA to exempt from the premarket review requirement to demonstrate effectiveness certain medical devices in order to provide an incentive for the development of devices that treat or diagnose rare diseases or conditions, including those in children. Manufacturers of such devices still must show that the probable benefit outweighs the risk of using the device and that the device will not expose patients to unreasonable or significant risk of illness or injury. These devices, called HUDs, are intended to treat or diagnose a disease or condition that affects fewer than 4,000 individuals in the United States. In order to market an HUD in the United States, an HDE application must be submitted to and approved by FDA. Although FDA reviews and approves other types of PMA supplements, a panel-track supplement is required if the manufacturer wants to change the indication for use of an approved PMA device to add a pediatric population, according to FDA officials. must also provide a description of the device and scientific rationale for the use of the device for the rare disease or condition. Once the HUD designation is granted, the manufacturer can then seek device approval by submitting an HDE application. In addition to including the indication for use, the HDE application must include a detailed description of the device, along with evidence demonstrating device safety, and data and a rationale supporting the probable benefit of the device. Device labeling is also reviewed and must include a statement indicating that the device is a humanitarian device. According to FDA guidance, criteria for HDE approval are focused on safety, probable benefit, and lack of a comparable device. FDA does not charge manufacturers a fee to review HDE applications. Manufacturers of HDE devices are allowed to recover certain development and production costs but are generally prohibited from making a profit on their device. Unless exempt, HDE applications must include a cost assessment to demonstrate that the amount charged for the HDE device does not exceed the cost of research and development, fabrication, and distribution. After FDA approval, in order for an HDE device to be used in patient care, it must be reviewed and approved by an institutional review board (IRB) to assess the safety of the device. If FDA review results in premarket approval, FDA issues an approval order to the manufacturer, which includes the approved indication for use statement. FDA also approves all printed material accompanying the device—known as the device labeling. The approval order, labeling, and a summary of safety and effectiveness data are available on FDA’s website; all three documents contain the approved indication for use statement. Although the upper age limit experts use to define the pediatric population varies, for purposes of certain statutory provisions for PMA and HDE device applications, FDA considers pediatric patients as those who are age 21 years or younger at the time of diagnosis or treatment. FDA issued guidance in 2004 that specifies age ranges for four main pediatric subpopulations: neonate, infant, child, and adolescent (see table 1). According to FDA officials, the agency defined an additional subpopulation, transitional adolescents, for its internal application review purposes. These officials noted that in some cases patients in this age range may not require special considerations compared to adults. A pediatric medical device may be indicated for use in more than one pediatric subpopulation. According to FDA officials, some pediatric devices are indicated for use in both pediatric and adult patients, such as devices with an indication for all patients with a given condition above a certain age. Additionally, a device’s indication for use statement might not specify the age of the intended population, but based on additional clinical information that may be included in the approval documents, FDA might consider a device labeled for pediatric use. For example, the indication for use statement for an influenza diagnostic test might not specify a pediatric population, but FDA could consider the device labeled for patients of all ages. In addition, a device’s indication for use statement might specify a minimum blood vessel size or body weight rather than a certain patient age, and if pediatric patients meet the criteria, the device could be considered labeled for pediatric use. To stimulate pediatric medical device development, FDAAA exempted HDE devices labeled for use in pediatric patients (including those for both pediatric and adult patients) from the HDE profit prohibition for applications approved on or after September 27, 2007, when FDAAA was signed into law.prohibition, HDE applications must include data to prove that the device In order to receive the exemption from the profit can safely be used in a pediatric population and to support the number of individuals likely to use the device each year. Based on this information, FDA determines an upper limit on the number of devices that can be distributed or sold each year—to treat both pediatric and adult patients— known as the annual distribution number (ADN). Manufacturers may only receive profits from the sale of HDE devices exempt from the profit prohibition and indicated for pediatric or pediatric and adult use up to the ADN. In addition, FDAAA requires that FDA’s Pediatric Advisory Committee annually review all HDE devices granted exemption from the profit prohibition to ensure that the exemption remains appropriate for the pediatric populations for which it is granted. FDAAA also required PMA and HDE applications to include, if readily available, a description of any pediatric population or subpopulation(s) that suffer from the disease or condition that the device is intended to treat, diagnose, or cure and the number of affected pediatric patients. FDAAA further required FDA to annually report to congressional committees on the number of PMA and HDE devices approved in the preceding year (1) for which there is a pediatric subpopulation that suffers from the disease or condition that the device is intended to treat, diagnose, or cure; (2) labeled for use in pediatric patients; and (3) exempt from user fees because the device was intended solely for pediatric use. To help connect individuals with ideas for pediatric medical devices with experienced professionals to assist them through the medical device development process, FDAAA also authorized demonstration grants for pediatric device consortia to promote pediatric device development. Pediatric device consortia receive 2-year grants, administered by FDA, to conduct certain activities for device projects, such as mentoring and managing the development process, assessing the scientific merit of a proposed device, and providing assistance and advice as needed on business development and navigating the regulatory process. In their demonstration grant applications, consortia were not only required to demonstrate their capability to develop pediatric devices—by having members with medical and scientific expertise in device development and relationships with manufacturers—but they were also required to identify two to five device projects that the consortia would directly support under the demonstration grant. Grantees must submit quarterly and annual reports to FDA describing how they have used grant funds to support innovation and the phase of development for the devices for which they provided assistance. Phases of development include, for example, concept, prototype (during which a model is developed), clinical (during which the device is tested), and marketing (during which the device goes through the regulatory process). Certain characteristics unique to pediatric populations—including physiological differences in pediatric patients and challenges with recruiting pediatric participants for clinical trials—are barriers to developing pediatric medical devices that were cited by stakeholders. Pediatric patients are composed of different subpopulations with differences in size, growth rate, metabolism, heart rate, activity level, and other differences. For example, younger pediatric patients— neonates, infants, and children—have higher heart rates or respiratory rates than adults. This difference, as cited by some stakeholders, makes some devices used for adults, such as certain heart valves, not appropriate for use in young children; thus a device that has already been developed for an adult may have to be redesigned for a pediatric population. Another unique characteristic cited is the range of pediatric subpopulations and the difficulty in developing potentially different devices for each of these subpopulations. For example, a device that is developed for a toddler may not be appropriate for use in an adolescent, even if they have the same disease or condition. As a result, manufacturers may have to develop and test a different device for each subpopulation although the disease or condition may be the same.