Partnership Between Japan and the United States for Early Development of Pediatric Medical Devices　- Harmonization By Doing for Children.

BACKGROUND: The Harmonization By Doing (HBD) program was established in 2003 as a partnership among stakeholders of academia, industry and regulatory agencies in Japan and the United States, with a primary focus on streamlining processes of global medical device development for cardiovascular medical devices. While HBD has traditionally focused on development of devices intended to treat conditions prevalent in adults, in 2016, HBD established the "HBD-for-Children" program, which focuses on the development of pediatric devices as the development of medical devices for pediatric use lags behind that of medical devices for adults in both countries.Methods and Results:Activities of the program have included: (1) conducting a survey with industry to better understand the challenges that constrain the development of pediatric medical devices; (2) categorizing pediatric medical devices into five categories based on global availability and exploring concrete solutions for the early application and regulatory approval in both geographies; and (3) facilitating global clinical trials of pediatric medical devices in both countries. CONCLUSIONS: The establishment of the HBD-for-Children program is significant because it represents a global initiative for the introduction of pediatric medical devices for patients in a timely manner. Through the program, academia, industry and regulatory agencies can work together to facilitate innovative pediatric device development from a multi-stakeholder perspective. This activity could also encourage industry partners to pursue the development of pediatric medical devices.

Regulatory Science, and How Device Regulation Will Shape Our Future.

Pediatric medical device approvals lag behind adult approvals. Historically, medical devices have rarely been designed specifically for children, but use in children has most often borrowed from adult or general use applications. While a variety of social, economic, and clinical factors have contributed to this phenomenon, the regulatory process remains a fundamental aspect of pediatric device development and commercialization. FDA's Center for Devices and Radiological Health (CDRH) has established programmatic and technological areas of advancement to support innovation that serves the public health needs of children and special populations. We highlight four regulatory areas that have the potential to shape the future of pediatric cardiology: the CDRH Early Feasibility Study Program, advancements in 3D printing or additive manufacturing, computational modeling and simulation, and the use of real-world evidence for regulatory applications. These programs have the potential to impact all stages of device development, from early conception, design, and prototyping to clinical evidence generation, regulatory review, and finally commercialization. The success of these programs relies on a collaborative community of stakeholders, including government, regulators, device manufacturers, patients, payers, and the academic and professional community societies.

In situ deformations in the immature brain during rapid rotations.

Head trauma is the leading cause of death and debilitating injury in children. Computational models are important tools used to understand head injury mechanisms but they must be validated with experimental data. In this communication we present in situ measurements of brain deformation during rapid, nonimpact head rotation in juvenile pigs of different ages. These data will be used to validate computational models identifying age-dependent thresholds of axonal injury. Fresh 5 days (n=3) and 4 weeks (n=2) old piglet heads were transected horizontally and secured in a container. The cut surface of each brain was marked and covered with a transparent, lubricated plate that allowed the brain to move freely in the plane of rotation. For each brain, a rapid (20-28 ms) 65 deg rotation was applied sequentially at 50 rad/s, 75 rad/s, and 75 rad/s. Each rotation was digitally captured at 2500 frames/s (480x320 pixels) and mark locations were tracked and used to compute strain using an in-house program in MATLAB. Peak values of principal strain (E(peak)) were significantly larger during deceleration than during acceleration of the head rotation (p<0.05), and doubled with a 50% increase in velocity. E(peak) was also significantly higher during the second 75 rad/s rotation than during the first 75 rad/s rotation (p<0.0001), suggesting structural alteration at 75 rad/s and the possibility that similar changes may have occurred at 50 rad/s. Analyzing only lower velocity (50 rad/s) rotations, E(peak) significantly increased with age (16.5% versus 12.4%, p<0.003), which was likely due to the larger brain mass and smaller viscoelastic modulus of the 4 weeks old pig brain compared with those of the 5 days old. Strain measurement error for the overall methodology was estimated to be 1%. Brain tissue strain during rapid, nonimpact head rotation in the juvenile pig varies significantly with age. The empirical data presented will be used to validate computational model predictions of brain motion under similar loading conditions and to assist in the development of age-specific thresholds for axonal injury. Future studies will examine the brain-skull displacement and will be used to validate brain-skull interactions in computational models.

Decision analysis of retrievable inferior vena cava filters in patients without pulmonary embolism.

BACKGROUND: Retrievable filters are increasingly implanted for prophylaxis in patients without pulmonary embolism (PE) but who may be at transient risk. These devices are often not removed after the risk of PE has diminished. This study employs decision analysis to weigh the risks and benefits of retrievable filter use as a function of the filter's time in situ. METHODS: Medical literature on patients with inferior vena cava (IVC) filters and a transient risk of PE were reviewed. Weights reflecting relative severity were assigned to each adverse event. The risk score was defined as weight × occurrence rate and combines the frequency and severity for each type of adverse event. The value function in the decision model combines the following risks: (1) risk in situ; (2) risk of removal, and (3) relative risk without filters. A decreasing net risk score represents a net expected benefit, and an increasing net risk score indicates the expected harm outweighs the expected benefit. RESULTS: The net risk score reaches its minimum between day 29 and 54 postimplantation. This is consistent with an increasing net risk associated with continued use of retrievable IVC filters in patients with transient, reversible risk of PE. The results were insensitive to reasonable variations in the assessed weights and adverse event occurrence rates. CONCLUSIONS: For patients with retrievable IVC filters in whom the transient risk of PE has passed, quantitative decision analysis suggests the benefit/risk profile begins to favor filter removal between 29 and 54 days after implantation.

Influence of age and fall type on head injuries in infants and toddlers.

UNLABELLED: Age-based differences in fall type and neuroanatomy in infants and toddlers may affect clinical presentations and injury patterns. OBJECTIVE: Our goal is to understand the influence of fall type and age on injuries to help guide clinical evaluation. DESIGN/SETTING/PARTICIPANTS: Retrospectively, 285 children 0-48 months with accidental head injury from a fall and brain imaging between 2000 and 2006 were categorized by age (infant ≤1 year and toddler=1-4 years) and fall type: low (≤3 ft), intermediate (>3 and <10 ft), high height falls (≥10 ft) and stair falls. OUTCOME MEASURES: Clinical manifestations were noted and head injuries separated into primary (bleeding) and secondary (hypoxia, edema). The influence of age and fall type on head injuries sustained was evaluated. RESULTS: Injury patterns in children <4 years varied with age. Despite similar injury severity scores, infants sustained more skull fractures than toddlers (71% vs. 39%). Of children with skull fractures, 11% had no evidence of scalp/facial soft tissue swelling. Of the patients with primary intracranial injury, 30% had no skull fracture and 8% had neither skull fracture nor cranial soft tissue injury. Low height falls resulted in primary intracranial injury without soft tissue or skull injury in infants (6%) and toddlers (16%). CONCLUSIONS: Within a given fall type, age-related differences in injuries exist between infants and toddlers. When interpreting a fall history, clinicians must consider the fall type and influence of age on resulting injury. For young children, intracranial injury is not always accompanied by external manifestations of their injury.

Biomechanics of the toddler head during low-height falls: an anthropomorphic dummy analysis.

OBJECT: Falls are the most common environmental setting for closed head injuries in children between 2 and 4 years of age. The authors previously found that toddlers had fewer skull fractures and scalp/facial soft-tissue injuries, and more frequent altered mental status than infants for the same low-height falls (

Physiological and pathological responses to head rotations in toddler piglets.

Closed head injury is the leading cause of death in children less than 4 years of age, and is thought to be caused in part by rotational inertial motion of the brain. Injury patterns associated with inertial rotations are not well understood in the pediatric population. To characterize the physiological and pathological responses of the immature brain to inertial forces and their relationship to neurological development, toddler-age (4-week-old) piglets were subjected to a single non-impact head rotation at either low (31.6 +/- 4.7 rad/sec(2), n = 4) or moderate (61.0 +/- 7.5 rad/sec(2), n = 6) angular acceleration in the axial direction. Graded outcomes were observed for both physiological and histopathological responses such that increasing angular acceleration and velocity produced more severe responses. Unlike low-acceleration rotations, moderate-acceleration rotations produced marked EEG amplitude suppression immediately post-injury, which remained suppressed for the 6-h survival period. In addition, significantly more severe subarachnoid hemorrhage, ischemia, and axonal injury by beta-amyloid precursor protein (beta-APP) were observed in moderate-acceleration animals than low-acceleration animals. When compared to infant-age (5-day-old) animals subjected to similar (54.1 +/- 9.6 rad/sec(2)) acceleration rotations, 4-week-old moderate-acceleration animals sustained similar severities of subarachnoid hemorrhage and axonal injury at 6 h post-injury, despite the larger, softer brain in the older piglets. We conclude that the traditional mechanical engineering approach of scaling by brain mass and stiffness cannot explain the vulnerability of the infant brain to acceleration-deceleration movements, compared with the toddler.