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Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic.

Limited knowledge exists regarding the forces that act on devices implanted in the mitral annulus. Determining the peak magnitudes, directions, rates, variation throughout the cardiac cycle, and change with left ventricular pressure (LVP) will aid in device development and evaluation.Novel transducers with the ability to measure forces in the septal-lateral and transverse directions were implanted in six healthy ovine subjects. Forces were measured for cardiac cycles reaching a peak LVP of 90, 125, 150, 175, and 200 mm Hg.The septal-lateral force was observed to significantly increase from 3.9 ± 0.8 N (90) to 5.2 ± 1.0 N (125) p0.001, 5.9 ± 0.9 N (150) p0.001, 6.4 ± 1.2 N (175) p0.001, and 6.7 ± 1.5 N (200 mm Hg) p0.001. Similarly, the transverse force was seen to increase from 2.6 ± 0.6 N (90) to 3.8 ± 1.0 N (125) p0.01, 4.6 ± 1.3 N (150) p0.001, 4.3 ± 1.2 N (175) p0.001, and 3.5 ± 0.7 N (200 mm Hg) p0.05. In comparison, the septal-lateral force was significantly greater than the transverse force at 90 (p0.05), 125 (p0.05), 175 (p0.001), and 200 mm Hg (p0.0005).Annular forces and their variations with LVP through the cardiac cycle are described. The results demonstrate differences in force magnitude and rate for increasing levels of LVP between the septal-lateral and transverse directions. These directional differences have strong implications in the development of future mitral devices.

The United States Food and Drug Administration (FDA) regulates medical devices to ensure their safety and effectiveness. Prosthetic heart valves implanted by minimally invasive surgery are Class III life supporting and life sustaining devices that are covered by the IDE and PMA regulations. FDA recently published a draft heart valve guidance document (HVGD) for public comment, which is primarily intended for heart valves implanted by open chest, open heart surgery. The HVGD is intended to supplement ISO 5840:2005 and both of these documents serve as a good basic starting point for testing requirements for percutaneous heart valves (PHV). FDA has worked interactively in the drafting of a new ISO standard for PHV, which could ultimately be recognized by the FDA. In regulating PHV, FDA is concerned with identifying the proper boundary conditions for in vitro testing, and with the use of new materials such as Nitinol in the dynamic environment of heart valve implantation sites. FDA also believes that complete in vivo data answering questions that a clinical trial can typically not address, and demonstrating that a valve can be reliably delivered and is reasonable safe, is essential before a first in man study. A robust clinical trial design is critical to a premarket review of PHV, and the current evidence base dictates that PHV be studied in randomized controlled trials, comparing the PHV to the treatment a patient would have otherwise received. As always, FDA reviews the totality of data available for a particular device when making approvability decisions.

Introduction: Falls are a major cause of morbidity and mortality in children, but are also reported falsely in child abuse. Therefore, it is of interest to understand those factors which may lead to a higher likelihood of injury in a feet-first freefall. Methods: We used laboratory freefall experiments and a 3-year-old Hybrid III anthropomorphic test dummy (ATD) to assess head and femur injury risk. Wet and dry linoleum impact surfaces were used from three fall heights: 22, 35 and 47 in. Results: For a given fall height, dry surfaces were associated with higher head injury criteria (HIC) values than wet surfaces. Changes in fall height 22–47 in. did not significantly affect HIC values for falls onto either surface. Generally, compressive and bending femur loading increased significantly for wet as compared to dry linoleum. Conclusions: In simulated feet first freefall experiments up to 47 in. using a 3-year-old test dummy, a low risk of contact type head injury and femur fracture was found. However, both fall height and surface conditions influenced femur loading and head injury measures. Future efforts should explore the risk of head injury associated with angular acceleration in freefalls.

Background. Stair falls are common among young children and are also common false histories in cases of child abuse. When a child presents with a femur fracture and a stair-fall history, a judgment of plausibility must be made. A lack of objective injury and biomechanical data makes plausibility determination more difficult. Our objective was to characterize key features associated with femur fractures from reported stair falls, to develop a model for assessing injury plausibility (IP).Methods. Children 2 to 36 months of age who presented with a femur fracture from a reported stair fall were studied prospectively. Detailed history recording, examinations, fracture characterization, and injury scene analyses were conducted, and biomechanical measures associated with injury prediction were calculated. With our proposed IP model, all cases were then scored for the detail of history, biomechanical compatibility of fracture morphologic features, time to seeking care, and presence of other injuries.Results. Twenty-nine children were diagnosed with a femur fracture resulting from a reported stair fall. The IP model made a clear distinction between 2 groups, designated plausible and suspicious. Significant differences were observed for the detail of history, biomechanical compatibility of fracture, time to seeking care, presence of other injuries, and total IP scores. In the plausible group, the minimal linear momentum associated with a transverse fracture was almost 10-fold greater than that for spiral or buckle fracture types.Conclusions. This study adds new information to the current body of knowledge regarding injury biomechanics and fractures among children. The IP model provides an objective means of assessing plausibility of reported stair-fall–related femur fractures and identifies key characteristics to facilitate decision-making.

OBJECTIVE: The objectives of our study were to assess biomechanics associated with feet-first free falls in 3-year-old children and to investigate the influence of impact surface type and fall height on key biomechanical measures associated with injury risk. METHODS: Repeatable feet-first free fall experiments were conducted in a laboratory mock-up environment using an instrumented Hybrid II 3-year-old test dummy. Impact surface type and fall height were varied to examine their influence on biomechanical measures. RESULTS: Feet-first falls from short distances (27 in.) (0.69 m) were found to have a low risk of contact-type head injury, regardless of impact surface type. When comparing different types of impact surfaces in a 27 in. (0.69 m) fall, head acceleration associated with falls onto playground foam was significantly less than that associated with falls onto wood, linoleum or padded carpet. For falls onto playground foam, femoral compressive loads and bending moments were found to significantly increase as fall height increased. CONCLUSIONS: Impact surface type and fall height were found to influence biomechanics associated with injury risk in feet-first free falls as assessed through experimental mock-ups using an instrumented child test dummy. Feet-first falls from short distances (27 in.) (0.69 m) were associated with a low risk of contact-type head injury as assessed using HIC, irrespective of impact surface type.

In January 2010, the US Food and Drug Administration (FDA) and AdvaMed organized a workshop for developing a pathway to market for pediatric heart valves. This meeting included representatives from the device industry, medical community, academia, and the FDA. It resulted in a detailed pathway for gaining market approval for pediatric-sized heart valves to address the unmet need for these heart valves. The article titled, ‘‘A new paradigm for obtaining marketing approval for pediatric-sized prosthetic heart valves,’’ by Yoganathan and colleagues, presents this pathway to evaluate the safety and effectiveness of specific types of pediatric heart valves. In particular, this pathway is presented for smaller sizes of surgically implanted heart valves that already have premarket approval in the United States, comprising the samematerials andmanufactured by the same processes, and could be reviewed through a premarket approval supplement application. The underlying theme of this pathway is leveraging our existing knowledge about adult-sized heart valves and encouraging a more global approach for future device development. A key component of this pathway is the total product life cycle approach, with which we can leverage the many facets of the review process to bring these devices to market. With this approach, accelerated wear testing, hydrodynamic testing, flow visualization analysis, and kinematic assessment would be conducted for the new valve sizes. If the new valve size represents worst-case loading conditions, new fatigue testing would also be conducted. Because the new sized valve has the same design and is made of the same materials, however, new animal testing and testing for biocompatibility and sterilization would not need to be conducted. Because there is also presumably extensive clinical experience with the valve model, we can

Background Short-distance falls, such as from a bed, are often falsely reported scenarios in child abuse. In attempting to differentiate between abusive and nonabusive injury, knowledge of factors that affect injury risk in falls could prove useful. Objectives To assess the biomechanics associated with simulated short-distance falls in children (one fall scenario, without attempting to maximize injury potential) and to investigate the effect of impact surface type on injury risk. Methods Repeatable fall experiments from bed height (0.68 m) onto different surfaces were conducted using an instrumented side-lying Hybrid II 3-year-old test dummy. Biomechanical measures assessed in falls included head acceleration, pelvis acceleration, femur loading, and head injury criteria. Results Fall dynamics resulted in the pelvis or legs making first contact. Biomechanical measures assessed in simulated bed falls were below known head injury criteria and lower extremity injury thresholds. The impact surface type had a significant effect on head injury risk and lower extremity loading. Playground foam proved to have the lowest associated injury risk of all the tested surfaces. Conclusions The biomechanics of a child falling from a short distance, such as from a bed, were investigated using an experimental laboratory mock-up and an instrumented test dummy. Despite the impact surface having an effect on injury risk, rolling from a 0.68-m (27-in) horizontal surface from a side-lying posture presented low risk of contact-type head injury and leg injury on all tested impact surfaces.

Objectives To demonstrate the usefulness of computer simulation techniques in the investigation of pediatric stair falls. Since stair falls are a common falsely reported injury scenario in child abuse, our specific aim was to investigate the influence of stair characteristics on injury biomechanics of pediatric stair falls by using a computer simulation model. Our long-term goal is to use knowledge of biomechanics to aid in distinguishing between accidents and abuse. Methods A computer simulation model of a 3-year-old child falling down stairs was developed using commercially available simulation software. This model was used to investigate the influence that stair characteristics have on biomechanical measures associated with injury risk. Since femur fractures occur in unintentional and abuse scenarios, biomechanical measures were focused on the lower extremities. Results The number and slope of steps and stair surface friction and elasticity were found to affect biomechanical measures associated with injury risk. Conclusions Computer simulation techniques are useful for investigating the biomechanics of stair falls. Using our simulation model, we determined that stair characteristics have an effect on potential for lower extremity injuries. Although absolute values of biomechanical measures should not be relied on in an unvalidated model such as this, relationships between accident-environment factors and biomechanical measures can be studied through simulation. Future efforts will focus on model validation.

Objective Forces acting on mitral annular devices in the setting of ischemic mitral regurgitation are currently unknown. The aim of this study was to quantify the cyclic forces that result from mitral annular contraction in a chronic ischemic mitral regurgitation ovine model and compare them with forces measured previously in healthy animals. Methods A novel force transducer was implanted in the mitral annulus of 6 ovine subjects 8 weeks after an inferior left ventricle infarction that produced progressive, severe chronic ischemic mitral regurgitation. Septal–lateral and transverse forces were measured continuously for cardiac cycles reaching a peak left ventricular pressure of 90, 125, 150, 175, and 200 mm Hg. Cyclic forces and their rate of change during isovolumetric contraction were quantified and compared with those measured in healthy animals. Results Animals with chronic ischemic mitral regurgitation exhibited a mean mitral regurgitation grade of 2.3 ± 0.5. Ischemic mitral regurgitation was observed to decrease significantly septal–lateral forces at each level of left ventricular pressure ( P .01). Transverse forces were consistently lower in the ischemic mitral regurgitation group despite not reaching statistical significance. The rate of change of these forces during isovolumetric contraction was found to increase significantly with peak left ventricular pressure ( P .005), but did not differ significantly between animal groups. Conclusions Mitral annular forces were measured for the first time in a chronic ischemic mitral regurgitation animal model. Our findings demonstrated an inferior left ventricular infarct to decrease significantly cyclic septal–lateral forces while modestly lowering those in the transverse. The measurement of these forces and their variation with left ventricular pressure contributes significantly to the development of mitral annular ischemic mitral regurgitation devices.