Pediatric Circulatory Support: An FDA Perspective

Rinaldi, Jean E.; Chen, Eric A.; Berman, Michael R.

doi:10.1097/01.mat.0000181508.26853.dc

Cited by 11 publications

(5 citation statements)

References 4 publications

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“…Because of this heterogeneity, clinicians and investigators will need to use caution in selecting patients for evolving mechanical circulatory support devices 26,27 and in developing selection criteria for clinical trials to obtain regulatory approval. 28,29 For example, patients with an estimated waiting list mortality of less than 10% (eg, stable children with cardiomyopathy who are on inotropes) are unlikely to benefit from device therapy if the device itself carries a risk that could be higher. The use of such devices in such patients could not only expose children to unnecessary risks but could also undermine the interpretability of data in support of a regulatory claim of efficacy or probable benefit, the legal threshold for Food and Drug Administration approval in the United States.…”

Section: Discussionmentioning

confidence: 99%

Waiting List Mortality Among Children Listed for Heart Transplantation in the United States

Almond¹,

et al. 2009

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Background Children listed for heart transplantation face the highest waiting list mortality in solid-organ transplantation medicine. We examined waiting list mortality since the pediatric heart allocation system was revised in 1999 to determine whether the revised allocation system is prioritizing patients optimally and to identify specific high-risk populations that may benefit from emerging pediatric cardiac assist devices. Methods and Results We conducted a multicenter cohort study using the US Scientific Registry of Transplant Recipients. All children <18 years of age who were listed for a heart transplant between 1999 and 2006 were included. Among 3098 children, the median age was 2 years (interquartile range 0.3 to 12 years), and median weight was 12.3 kg (interquartile range 5 to 38 kg); 1294 (42%) were nonwhite; and 1874 (60%) were listed as status 1A (of whom 30% were ventilated and 18% were on extracorporeal membrane oxygenation). Overall, 533 (17%) died, 1943 (63%) received transplants, and 252 (8%) recovered; 370 (12%) remained listed. Multivariate predictors of waiting list mortality include extracorporeal membrane oxygenation support (hazard ratio [HR] 3.1, 95% confidence interval [CI] 2.4 to 3.9), ventilator support (HR 1.9, 95% CI 1.6 to 2.4), listing status 1A (HR 2.2, 95% CI 1.7 to 2.7), congenital heart disease (HR 2.2, 95% CI 1.8 to 2.6), dialysis support (HR 1.9, 95% CI 1.2 to 3.0), and nonwhite race/ethnicity (HR 1.7, 95% CI 1.4 to 2.0). Conclusions US waiting list mortality for pediatric heart transplantation remains unacceptably high in the current era. Specific high-risk subgroups can be identified that may benefit from emerging pediatric cardiac assist technologies. The current pediatric heart-allocation system captures medical urgency poorly. Further research is needed to define the optimal organ-allocation system for pediatric heart transplantation.

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Section: Discussionmentioning

confidence: 99%

Waiting List Mortality Among Children Listed for Heart Transplantation in the United States

Almond¹,

et al. 2009

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“…Because most expect miniaturized VADs to replace ECMO as the preferred mode of mechanical circulatory support for bridge to heart transplantation, 13,[21][22][23] Food and Drug Administration (FDA) approval of first-generation VADs may benefit from clarification of the safety and efficacy profile of ECMO as a bridge to transplantation. [21][22][23] Yet, because ECMO has never been formally reviewed by the FDA for this indication, comprehensive benchmark data on the safety and efficacy of ECMO as a bridge to heart transplantation are lacking.…”

Section: Clinical Perspective On P 2984mentioning

confidence: 99%

“…[21][22][23] Yet, because ECMO has never been formally reviewed by the FDA for this indication, comprehensive benchmark data on the safety and efficacy of ECMO as a bridge to heart transplantation are lacking. Published reports have been limited to singleinstitution experiences [1][2][3][4][5][6][7][8][9] with success rates that vary considerably by center and/or case mix, with limited power to adjust simultaneously for multiple confounders or to perform important subgroup analyses (eg, single-ventricle patients).…”

Section: Clinical Perspective On P 2984mentioning

confidence: 99%

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Extracorporeal Membrane Oxygenation for Bridge to Heart Transplantation Among Children in the United States

et al. 2011

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Background-Extracorporeal membrane oxygenation (ECMO) has served for Ͼ2 decades as the standard of care for US children requiring mechanical support as a bridge to heart transplantation. Objective data on the safety and efficacy of ECMO for this indication are limited. We describe the outcomes of ECMO as a bridge to heart transplantation to serve as performance benchmarks for emerging miniaturized assist devices intended to replace ECMO. Methods and Results-Data from the Extracorporeal Life Support Organization Registry and the Organ ProcurementTransplant Network database were merged to identify children supported with ECMO and listed for heart transplantation from 1994 to 2009. Independent predictors of wait-list and posttransplantation in-hospital mortality were identified. Objective performance goals for ECMO were developed. Of 773 children, the median age was 6 months (interquartile range, 1 to 44 months); 28% had cardiomyopathy; and in 38%, a bridge to transplantation was intended at ECMO initiation. Overall, 45% of subjects reached transplantation, although one third of those transplanted died before discharge; overall survival to hospital discharge was 47%. Wait-list mortality was independently associated with congenital heart disease, cardiopulmonary resuscitation before ECMO, and renal dysfunction. Posttransplantation mortality was associated with congenital heart disease, renal dysfunction, ECMO duration of Ͼ14 days, and initial ECMO indication as a bridge to recovery. In the objective performance goal cohort (nϭ485), patients with cardiomyopathy had the highest survival to hospital discharge (63%), followed by patients with myocarditis (59%), 2-ventricle congenital heart disease (44%) and 1-ventricle congenital heart disease (33%). Conclusion-Although ECMO is effective for short-term circulatory support, it is not reliable for the long-term circulatory support necessary for children awaiting heart transplantation. Fewer than half of patients bridged with ECMO survive to hospital discharge. More effective modalities for chronic circulatory support in children are urgently needed. (Circulation. 2011;123:2975-2984.)

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“…2,3,4 Although computational and bench-top modeling techniques have been extensively used in the development process by each of the contract program participants, their importance in a regulatory submission remains unclear. As these devices progress toward a clinical trial, the appropriate use of information generated by the modeling techniques for an FDA submission needs to be defined for the contract participants and other developers of pediatric blood pumping systems.…”

Section: Introductionmentioning

confidence: 99%

Use of Computer and In Vitro Modeling Techniques during the Development of Pediatric Circulatory Support Devices

Pantalos

2009

ASAIO Journal

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Pediatric mechanical circulatory devices are currently being developed by several programs. Along with the engineering and testing challenges to be considered is the regulatory process which will be used to review applications to the Food and Drug Administration (FDA) to initiate clinical trials with these devices. This paper considers the appropriate use of computer and in vitro modeling data as a part of an FDA Investigational Device Exemption submission for a pediatric circulatory support device. Initially, the types and value of modeling techniques that may be used are discussed. How the unique physiology, flow requirements, and anatomy of pediatric patients may affect modeling efforts is then reviewed. Modeling assumptions, justification, and validation are key aspects of modeling data to be submitted as a part of an FDA submission. Finally, key recommendations are made for the appropriate use of modeling data for an FDA clinical trial submission. PANTALOS 11

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Pediatric Circulatory Support: An FDA Perspective

Cited by 11 publications

References 4 publications

Waiting List Mortality Among Children Listed for Heart Transplantation in the United States

Waiting List Mortality Among Children Listed for Heart Transplantation in the United States

Extracorporeal Membrane Oxygenation for Bridge to Heart Transplantation Among Children in the United States

Use of Computer and In Vitro Modeling Techniques during the Development of Pediatric Circulatory Support Devices

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