Few medical devices are designed and marketed specifically for children. Instead, adult devices are often repurposed and used off-label in pediatrics. The innovation gap between pediatric and adult devices is complex and multifactorial. This review aims to summarize the medical device landscape, describe barriers to pediatric device development, and provide an update on current strategies to help overcome these limitations. Medical devices are regulated by the Food and Drug Administration. They are registered, cleared, or approved on the basis of a 3-tier risk classification system and a differentiated set of regulatory pathways. This includes some for products that receive special designations on the basis of specific aspects that warrant more rapid review and approval. Pediatric devices number only one-quarter of those developed for adults for multiple reasons. Clinically, innovators must adjust their products to address the smaller sizes, growth, and longer duration of use in children. Smaller sample sizes and population heterogeneity also challenge the ability to obtain sufficient safety data for regulatory submissions. Financial concerns stem from lower pediatric reimbursement rates coupled with a lack of nationally standardized coverage. There are a number of promising initiatives, including the Pediatric Device Consortia Program, Early Feasibility Studies, and the new System of Hospitals for Innovation in Pediatrics – Medical Devices. However, the gap will likely not be narrowed without broad cooperation across stakeholders from industry, academia, patient advocacy groups, health care providers, investors, payors, regulators, and Congress.
Medical devices are critical tools for the diagnosis and management of disease in children. However, the development and regulation of medical devices do not feature prominently in medical school or residency curricula and are less well understood by physicians.1 In pediatrics, this problem is further compounded by the lack of devices developed, tested, and approved specifically for children. Instead, many pediatric medical device applications are “off-label” or “physician directed” and are often repurposed or modified from adult devices. For example, adult biliary stents were initially used to treat stenotic cardiac vessels in infants.2 The end result is fewer solutions specifically designed for pediatrics and, consequently, a paucity of safety and efficacy data regarding that population. This review was developed by evaluating the published literature and by reviewing regulatory guidance documents and discussions with subject matter experts. The goal of this review is to provide an overview of the medical device development and approval process, to describe common technical, scientific, financial, and regulatory barriers to pediatric medical device development, and finally, to provide an update on current strategies intended to accelerate pediatric medical device innovation.
What is a Medical Device?
The United States Food and Drug Administration (FDA) defines a medical device as “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article…which is not dependent on being metabolized for the achievement of its primary intended purpose.” The spectrum of diagnostic and therapeutic medical products regulated as medical devices by the Center for Devices and Radiologic Health (CDRH) ranges from tongue depressors, thermometers, and pregnancy tests to mechanical heart valves, ventriculoperitoneal shunts, and MRI machines; there are over 1700 distinct types of devices.3 In addition to traditional devices, there are several special product types listed in Table 1.4–10
How Are Medical Devices Developed?
Medical devices are a $156 billion dollar industry in the United States, representing 40% of the global market (compared to the biopharmaceutical industry’s $1.3 trillion in yearly economic output).11,12 More than 6500 medical device manufacturers in the United States employ over 2 million individuals, 300 000 of whom are directly involved in technology development, mostly located in California, Massachusetts, and Minnesota.11,13 For comparison, in 2015 there were 860 917 active practicing physicians in the United States.14 The largest medical device manufacturers, like Medtronic, Johnson & Johnson, and GE Healthcare, are well known to most physicians, but over 80% of medical device companies have <50 employees and generate no sales revenue. Instead, they are focused on research and development and are funded either through grants or venture capital, with the goal of either being acquired by a larger company, licensing their technology, or going to market on their own. Although it is difficult to generalize costs across the wide variety of medical devices, 1 industry survey estimated that the average cost to develop and commercialize a low- to moderate-risk device was $31 million; for a high-risk device it was $94 million.15 These factors place unique market pressures on medical device development. Beyond industry and startups, universities and academic medical centers are also important players, generating hundreds of new ideas, patents, licenses, and spin-off companies every year.16,17
The development process often begins by identifying and validating an unmet clinical need. This is followed by generating concepts and prototypes that are evaluated by key stakeholders, undergo bench testing, and are iteratively improved. Biocompatibility, safety, and quality testing occurs when the design is in final or near-final form. Depending on the type of device and intended use, animal and human testing may be required. Clinical studies require local institutional review board (IRB) approval and often the submission of an investigational device exemption application to the FDA. Once all necessary evidence is generated, a company can finalize its regulatory submission to the FDA to obtain a marketing decision. There are several existing frameworks that describe this device development process in detail.18–20
How are Medical Devices Regulated?
Congress gave the FDA the authority to review all medical devices in 1976 through the Medical Device Amendments Act.21 The FDA, a part of the Department of Health and Human Services, is responsible for regulating and supervising the safety and effectiveness of medical devices. Since 1976, the number of laws and regulations related to medical devices have increased in both number and complexity.22 Within the FDA, CDRH is the center responsible for medical devices.
The company or entity submitting a medical device to the FDA for review is commonly called the sponsor. Medical devices can be registered without preclearance or can require clearance or approval for registration. Devices registered without preclearance are low risk and need only follow general controls, rules that govern appropriate promotion, labeling, and report management. Some, but not all, are also subject to good manufacturing practices.23 No testing or evidence must be submitted before marketing these types of registered devices. Cleared devices need to follow both general controls and special controls, a series of device-specific standards intended to provide assurance of safety, performance, and effectiveness. Most cleared devices will demonstrate that they are substantially equivalent to an existing device that is already on the market (referred to as a predicate). In those situations, testing and evidence generation ensures that the new device is as safe and efficacious as its predicate. Clinical data and human testing are often not required or limited in scope. Approved devices go through more extensive safety and effectiveness testing and almost always require clinical trials. Only the riskiest devices require this level of scrutiny.
A device receives a regulatory decision or status on the basis of 3 decision points related to classification, designation, and regulatory pathway:
Device Classification
The FDA classifies devices based on a 3-tier, risk-based system (Fig 1). As the potential risk to the patient increases, the required safety and regulatory controls also increase.
Class I devices, such as thermometers, tongue depressors, and surgical tools are characterized as low-risk devices. Approximately 47%24 of all medical devices are in this class. Among Class I devices, 93% are exempt from review and only need to follow general controls.23 Some need to implement good manufacturing practices, and a few need to practice design controls, as discussed below.
Class II devices, such as powered wheelchairs, magnetic resonance imagers, and surgical clips, are considered moderate risk and cover ∼43%24 of medical devices. The majority must satisfy both general and special controls before commercialization.
Class III devices have the highest risks and are intended to support or sustain life. Ten percent24 of all devices, including pacemakers, artificial joints, and ventilators, fall into this category. Class III devices have rigorous regulatory requirements and must demonstrate safety and efficacy in clinical trials before approval. Once approved, Class III devices require postmarketing surveillance and the submission of annual device reports to the FDA.
Device Designation
Some medical devices can receive special designations from the FDA that provide certain regulatory benefits. The 2 most relevant designations for pediatrics are Humanitarian Use Device (HUD) and Breakthrough Device Designation (BDD).
HUD designation was established in 1990 by the Safe Medical Devices Act to create a modified path for devices that diagnose or treat people with rare diseases and that, therefore, could not feasibly generate sufficient clinical data to satisfy the usual regulatory requirements.25 To qualify, the device must be intended to treat a condition that occurs in no more than 8000 people per year.26 Sponsors can apply for a HUD designation from the Office of Orphan Product Development (OOPD). If granted, the device becomes eligible to apply for the Humanitarian Device Exemption pathway, which requires less clinical data to demonstrate probable benefit rather than clinical efficacy.27
(BDD is awarded to devices for a serious condition that meet ≥1 other requirement: it represents a significant technological breakthrough; no adequate alternatives exist; it offers a significant improvement over existing alternatives; or its availability would be in the best interest of patients.28 The BDD program was established in 2017 as part of the 21st Century Cures Act29 to ensure that patients have timely access to needed breakthrough technologies. Sponsors can apply for BDD from the CDRH, and if awarded, are eligible for priority review as well as additional interactions and discussions with the FDA intended to make the regulatory process more efficient.30
Regulatory Pathway
For devices to be either cleared or approved, they require some form of FDA review. The most common review pathways are the premarket notification 510(k), De Novo classification request, premarket approval (PMA), and Humanitarian Device Exemption (HDE) pathways. These, along with designations and other less common pathways, are summarized in Table 2.27,30–36
Premarket notification 510(k) is the most common option for Class II devices. Through this pathway, a sponsor must demonstrate that its device is substantially equivalent to another predicate device that has already been commercialized. Substantial equivalence means that the new device has the same intended use as the predicate; it is as safe and effective as the predicate; and it works either on the same or modified technological principles, or different principles that raise no new questions regarding safety and efficacy. However, to be substantially equivalent, the product does not need to be identical. For example, the Abbott FreeStyle Libre 2 continuous glucose monitor (CGM) received its 510(k) clearance in June 2020 by using the Dexcom G6 CGM as its predicate. These 2 devices have multiple differences, but they have the same indication (the management of diabetes) and use similar technological principles (amperometric measurement of glucose concentration in interstitial fluid).37 Abbott was able to demonstrate safety and effectiveness through both benchtop and clinical testing.37
De Novo classification request is intended for low- to medium-risk devices, similar to other Class I or Class II devices, for which no predicates exist. These devices often incorporate innovative technologies, accomplish a new function or a combination of functions, or treat a different intended population. Without a predicate, the device cannot be cleared by using the 510(k) pathway. Once a device has been approved through the De Novo route, which is similar to that used for premarket approvals, a new product class is created and the new device can be used as a predicate for future 510(k) applications. Continuing the CGM example above, the Dexcom G6 that served as the predicate for the Abbott FreeStyle Libre 2 was itself approved via the De Novo pathway in 2018.38
Premarket approval is the most stringent scientific and regulatory review process for devices and is most similar to the NDA pathway for novel drugs.39 It governs the approval of high-risk (Class III) devices whose significant risk and intended use to sustain or support life justify the need for clinical data to demonstrate safety and effectiveness through well-designed clinical trials. PMA trials are often done in partnership with academic institutions because they can be complex in design, implementation, and monitoring. They can be lengthy and expensive; under certain conditions, the FDA may allow data collected outside of the United States to be used toward PMA.40 The Medtronic MiniMed 770G System, a hybrid closed loop that both monitors glucose continuously and automatically adjusts basal insulin delivery, received its PMA in August of 2020 for use in children ≥2 years old.41
Humanitarian Device Exemptions can be granted to devices that have already received a HUD designation. Devices meeting HUD criteria are often moderate- to high-risk devices (Class II or Class III) but are intended for use in rare diseases or conditions, where it would not be possible, ethical, or practical to accrue sufficient numbers of patients to generate the necessary clinical data for a different regulatory pathway. The HDE pathway requires that devices show probable benefits that outweigh the risk of the disease under currently available treatments.27 Two additional differences exist between an HDE- and a PMA-approved device. First, an HDE device can only be used at institutions under IRB oversight, although no informed consent is needed. Second, restrictions are placed on the sale of HDE-approved devices. For adult devices, the profits from the sales cannot exceed the costs of its research and development. For pediatric devices, however, no limit on profit is needed under certain conditions. Instead, sales are restricted to an Annual Distribution Number (ADN) calculated by estimating the number of devices needed in a single patient and multiplying that by 8000. If sales exceed this number, the exemption does not hold for the additional devices. The Berlin Heart EXCOR Pediatric Ventricular Assist Device, intended to provide mechanical circulatory support as a bridge to cardiac transplantation, is a classic example of a pediatric device approved through the HDE pathway.42
How Are Pediatric Medical Devices Different?
The availability and technological sophistication of pediatric devices lag behind their adult counterparts by as much as 10 years.43 The FDA reported to Congress in 2018 that novel pediatric devices number only one-quarter of those designed, evaluated, and approved of those for adults.44 Few devices are designed or intended specifically for children.43,45 Moreover, most of these approvals address the needs of individuals ≥18 years, because the FDA defines the pediatric population as ranging up to 21 years of age for medical devices.43,46 Few options exist for younger patients; in 2017, the FDA’s report to Congress identified only 5 (9%) devices approved for infants and neonates, although delivery rooms and neonatal intensive care units are technology-intensive care settings.46 Thus, off-label use of adult devices is common and has been recognized by the US Supreme Court as both acceptable and necessary given the FDA’s mission to “regulate in this area without directly interfering with the practice of medicine.”47 Nonetheless, most physicians agree that the off-label use of medical devices, particularly high-risk devices, is not ideal, and that more should be done to encourage the design, testing, labeling, and market availability of pediatric-specific solutions.48 However, many unique hurdles impact pediatric device development in clinical, technical, regulatory, and financial domains. Some have been explored at length in government and academic publications and are summarized here below and in Table 3.
Clinical Considerations
Children are physiologically, neurodevelopmentally, and epidemiologically distinct from adults. Their disease processes, even when nominally the same as those in adults, often present differently, and may be diagnosed and treated differently. Medical device developers must consider the progressive growth of pediatric patients, which may impact the size, function, and design of a device.49 Physiologically, multiple organ systems, such as the cardiovascular, respiratory, and renal systems change from childhood to adulthood, with significant implications for medical devices.50,51
Developmentally, devices that require active participation from the patient may not be appropriate in younger children. For example, dry powder inhalers are difficult for young children to use in the management of asthma.52 Activities of daily living are also specific to the age of the patient. The types of play and physical activities in certain groups have often caused unexpected problems. In the early 2000s, several electronic failures of cochlear implants in children were caused by the discharge of static electricity as children slid down plastic slides in winter snowsuits. Ultimately, these reports and the accompanying research inspired the St. Louis County Parks and Recreation department to consider antistatic coating measures for the equipment in their parks.
Technical Considerations
The smaller size of children can pose engineering challenges. Some technologies cannot be miniaturized or are less effective when made smaller. In some cases, miniaturization requires that a completely different technology be used. Further, devices that can expand with the child’s growth can be difficult to engineer. For example, in congenital heart disease, children treated with fixed-size devices such as prosthetic valves, shunts, and annuloplasty rings may need 3 to 5 surgeries over their lifetime.53 Duration of use is another consideration; an implantable device in a 7-year-old patient must last decades, compared to a similar device in a 70-year-old patient. This can introduce new safety concerns with regard to biocompatibility, leaching, and degradation of materials over time.
Regulatory and Ethical Considerations
Several of the regulatory pathways discussed above can be used by pediatric devices, but none were designed specifically for pediatrics. It is difficult to conduct trials on small numbers of patients from heterogeneous populations spread across many institutions. Further, study blinding is difficult to ensure. Medical device expertise may be lacking in the local IRB, which may delay approvals. Patients can be difficult to recruit if parents are hesitant, and ethical challenges surround how and when device research should be conducted in critically ill children. All of these issues can serve as barriers for generating the data needed for a regulatory application.54 For Class III products, pivotal trials, which are generally intended to be the primary source of clinical data to demonstrate a “reasonable assurance of safety and effectiveness,” can be particularly difficult for pediatric devices.55 For Class II devices seeking regulatory clearance, identifying an appropriate predicate may be difficult, if no similar devices have yet been approved for use in children. After approval, postmarket surveillance can also be challenging with pediatric populations. The overall complexity of medical device regulation has increased over the past several decades, and the associated regulatory uncertainty and increased time to clearance or approval creates additional financial pressures that small pediatric medical device developers may be less able to tolerate.22
Medical device labeling can also present difficulties. As of this writing, the FDA does not have specific guidance for pediatric device labeling, although pediatric drug guidance has been published by the agency.56 Without such guidance, confusion and heterogeneity occurs in the labeling of pediatric devices.57 The labeling sets the boundaries for promotion and marketing, so it can affect coverage and reimbursement decisions. Finally, although the FDA has pediatric-specific guidance for its reviewers, not all reviewers have extensive pediatric expertise. This can cause inconsistent interpretation and application of existing rules and regulations, which can introduce variability and delay into the review process.
Financial Considerations
Pediatric health care and research are chronically underfunded in the United States compared to that for adults.58,59 The market for pediatric medical devices is smaller than for adults, even though the regulatory and technical challenges are often greater. Therefore, few financial incentives exist for companies to pursue the development of pediatric-specific solutions. A hypothetical diagnostic device that could be used in the treatment of patients with cancer could be used by 1.8 million new adult cases every year, but only 15 990 new pediatric cases in the United States.60 The fact that pediatric care is often reimbursed at a lower rate than adult care further exacerbates this financial inequality.61 Finally, whereas adult device manufacturers often interact with Medicare for national coverage decisions, over 50% of children are covered by Medicaid, whose coverage decisions are made at the state rather than the national level. This results in a highly variable reimbursement landscape requiring complex business strategies and greater market uncertainties.
What Can Be Done to Support Pediatric Medical Device Innovation?
Several strategies have been suggested to support pediatric medical device development, including most recently in a report from a group of subject matter experts and industry stakeholders that focused on regulatory changes.62 These include measures to increase funding opportunities, reform certain regulatory disincentives, develop a supportive ecosystem, create novel incentives, and advocate for legislative changes. A number of organizations and stakeholders are actively engaged in these strategies to advance pediatric medical device innovation:
Office of Orphan Product Development (OOPD)
Separate from the CDRH, the FDA has created the OOPD and tasks it to evaluate and assist with the development of drugs and devices designed to diagnose or treat rare diseases or conditions. The HUD program is available for devices benefitting patients with rare conditions. To offset the financial risks incurred when targeting these smaller markets, the OOPD offers incentives including grants via the Orphan Products Grants Program and vouchers via the Rare Pediatric Disease designation. This voucher allows sponsors who have received an approval for a product intending to treat a “rare pediatric disease” to qualify for priority review of a subsequent marketing application for a different product.
The Pediatric Device Consortia (PDC)
In 2007, Congress passed legislation that established funding for the PDC program, intended to help stimulate projects to promote the development, production, and distribution of pediatric medical devices.63 It has awarded $37 million to various consortia across 4 funding cycles since 2009.64 To date, the program has supported over 1000 medical device projects from concept to commercialization. The fourth and current PDC cycle grant cycle (2018–2023) includes the 5 consortia listed in Table 4.
The American Academy of Pediatrics (AAP)
The pediatric community is also determined to help bring pediatric devices to market. The AAP has a Section on Advances in Therapeutics and Technology founded with the goal to foster dialogue among AAP members in industry, academia, and government about measures to improve quality, safety, understanding, and efficiency of new technologies.65 The Section of Advances in Therapeutics and Technology offers a newsletter, an active E-mail listserv, section activities, and subcommittees to engage, educate, support, and mobilize its members. The AAP also participates in legislative advocacy activities related to medical devices and innovation, including participation in the FDA’s 2018 public meeting on pediatric medical device development.66 The AAP has also issued policy statements on the off-label use of pediatric medical devices, with recommendations for clinicians, researchers, and regulators.48
Industry Organizations
The Advanced Medical Technology Association (AdvaMed) is a global trade association that fosters growth and innovation by advocating for “the highest ethical standards, rapid product approvals, appropriate reimbursement, and access to international markets.”67 Their Pediatric Working Group helps identify barriers to market and proposes possible solutions to regulatory agencies. Some of these suggestions have included designation of pediatric devices as breakthrough products, development of a pediatric-specific review team to improve the attention and consistency of pediatric evaluations, and acceptance of valid scientific evidence other than well-controlled trials.68
The Medical Device Manufacturers Association (MDMA) is a national trade association that also advocates for innovator interests in front of Congress, the FDA, Centers for Medicare and Medicaid Services (CMS), and other federal agencies.69 MDMA provides educational and advocacy assistance to innovative and entrepreneurial medical technology companies. To date, they have helped more than 270 members. As identified in their 2020 annual report,70 MDMA provides support with FDA federal policies for Medical Device User Fee Amendments, Current Procedural Technology coding process, reimbursement strategies, and “liquidity” activities.
Real-World Evidence and NEST
In 2016, The FDA awarded a grant to the Medical Device Innovation Consortium, a 501(c)(3) public-private partnership, to establish the National Evaluation System for Health Technology (NEST), an ecosystem built to use real-world evidence (RWE). The goal of this initiative is to leverage meaningful data (eg, clinical registries, electronic health records, and medical billing claims, etc.) for regulatory decision-making, potentially reducing the need for expensive trials that reflect similar data to RWE.71 NEST’s activities so far have focused on establishing collaborations between health systems, payors, manufacturers, and research networks, and funding demonstration projects that can be used to evaluate the feasibility of using real-world data to generate regulatory quality evidence to support premarket submission, label expansions, and postmarket surveillance.72
System of Hospitals for Innovation in Pediatrics – Medical Devices (SHIP-MD)
SHIP-MD is a preconsortium funded by a cooperative agreement with the FDA. This group, composed of multiple stakeholders including the Critical Path Institute, CDRH, AdvaMed, and AAP, aims to enhance the pediatric medical device ecosystem by derisking and accelerating developmental processes. The preconsortium had their first meeting in February 2021 to outline their main roles (facilitate evidence generation and evaluation, assist with tasks adjacent to regulatory approval, and engender an ecosystem where all stakeholders can interact) and define how innovators can interact with SHIP-MD.73
Regulatory and Legislative Initiatives
The FDA and Congress have introduced a number of regulatory and legislative initiatives over the past 2 decades intended to support pediatric medical device innovation. Major legislative acts and regulatory initiatives include the Pediatric Medical Device Safety and Improvement Act (PMDSIA),74 The PDC program,75 Early Feasibility Study (EFS) program,76 The 21st Century Act,29 the reorganization of CDRH,77 and the proposed progressive approval pathway78 (not yet approved) (Fig 2).
Conclusions
Medical devices are critical to supporting the health and well-being of children. However, the complexities of how they are developed, financed, regulated, and commercialized are often unknown or misunderstood by both the general public and the medical community. The gap between pediatric and adult innovation in medical devices is made wider by regulatory, technical, physiologic, and financial hurdles. A number of promising initiatives have made progress in the field, but the gap will likely not be narrowed without broad cooperation across stakeholders from industry, academia, patient advocacy groups, health care providers, investors, payors, regulators, and Congress. The medical device market is heavily regulated, and as such, is amenable to legislative and regulatory mechanisms to incentivize and require change, but not without the appropriate prioritization and funding from Congress and the FDA.
Dr Espinoza conceptualized and designed the review, outlined the initial manuscript, and reviewed and revised the manuscript; Ms Shah and Dr Nagendra drafted the initial manuscript, developed the figures and tables, and reviewed and revised the manuscript. Drs Bar-Cohen and Richmond critically reviewed the manuscript for important intellectual content and provided edits and revisions; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: This article was supported by the Food and Drug Administration (FDA) of the US Department of Health and Human Services as part of awards totaling $1.3 million with 0% financed with nongovernmental sources. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA, Department of Health Human Services, or the US Government. For more information, please visit FDA.gov. The FDA had no role in the design, writing, or editing of this manuscript.
CONFLICT OF INTEREST DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
- AAP
The American Academy of Pediatrics
- BDD
Breakthrough Device Designation
- CDRH
The Center for Devices and Radiologic Health
- CGM
continuous glucose monitor
- FDA
The United States Food and Drug Administration
- HDE
Humanitarian Device Exemption
- HUD
Humanitarian Use Device
- IRB
institutional review board
- MDMA
The Medical Device Manufacturers Association
- NEST
The National Evaluation System for health Technology
- OOPD
The Office of Orphan Product Development
- PDC
The Pediatric Device Consortia program
- PMA
premarket approval
- PMN
premarket notification
- RWE
real-world evidence
- SaMD
Software as a Medical Device
- SHIP-MD
System of Hospitals for Innovation in Pediatrics – Medical Devices
