Contributed by Shetarra Walker, MD, MSCR, Lead Physician and Clinical Team Leader, Office of Rare Disease, Pediatrics, Urologic and Reproductive Medicine, CDER, and Salim F. Idriss, MD, PhD, Executive Co-Director, Duke Pediatric and Congenital Heart Center and Director, Pediatric Cardiac Electrophysiology, Duke University Medical Center.
The FDA utilizes an electrocardiogram (ECG) data warehouse to support the agency’s cardiac safety review of therapeutic product development programs. The ECG data warehouse allows the agency to review large volumes of ECG data collected from adult participants of clinical trials to detect abnormalities that may signal an increased risk for cardiac adverse events. Besides facilitating the storage of large amounts of data, the ECG data warehouse supports efforts to streamline and standardize the collection and curation of ECG raw data. To date, there is no equivalent pediatric ECG data warehouse to enhance cardiac safety review for therapeutic product development for children.
Sudden cardiac death in the young (SCDY) is caused by various mechanisms, some of which are not well understood. Sudden cardiac arrest may occur in healthy-appearing children for whom no pre-existing life-threatening condition, potentially related to an abnormal heart rhythm, had been recognized. It is not uncommon for SCDY to occur in children who had not previously manifested symptoms of disease. Many of the diseases known to cause SCDY in children are genetic and, therefore, may be passed down from parents or grandparents1. Although some children who have a sudden cardiac arrest may be successfully resuscitated if attended to immediately, a large proportion do not survive or experience long-term effects. Therefore, the identification of children at risk for SCDY is critical, allowing for early initiation of medical interventions to reduce the SCDY risk.
FDA’s mission regarding SCDY can be described as two-fold. First, in its commitment to advance public health through the development of safe and effective medical products, the agency must work to ensure that approved drug products do not pose hazardous risks related to SCDY. Second, because FDA strives to provide the public with “science-based” information, insights into the etiology and preventability of SCDY may be gained through the proper use and analysis of pediatric ECG data. In addition, SCDY represents an unmet public health need that arises in part from a lack of accurate and reliable screening methods to identify underlying risks. Thus, accurate interpretation of pediatric ECGs is critical to identify children at risk for SCDY and prevent the mislabeling of children as having risk for SCDY when they do not. More generally, the development of improved therapies is a goal for all stakeholders committed to pediatric health, particularly regarding the prevention and treatment of life-threatening abnormal heart rhythms in children.
In this context, developing a first-of-kind pediatric ECG data warehouse is an important goal shared broadly across the biomedical community. This goal can benefit from the expertise that the FDA has with respect to adult patients in the purview of its ECG data warehouse. This expertise encompasses several elements, including 1) the development of community ECG standards; 2) the protection of patients from drug products that prolong heart muscle contraction; 3) the curation of high-volume data concerning drugs that affect heart function; and 4) the assessment of ECG characteristics as possible biomarkers to drive hypothesis generation.
Building a First-of-Kind Pediatric ECG Data Warehouse
Screening for SCDY risk factors in children includes collecting demographic and health information and, in many cases, performing tests such as recording an ECG or even getting a cardiac ultrasound (echocardiogram). Currently in the United States, there are many public screening groups (PSGs; primarily parent-led foundations) that perform screenings in children in various venues, including schools. For the establishment of a useful data warehouse, FDA and collaborators recruited PSGs from across the United States to learn their current practices, their methods of data collection at screenings, and to collaborate to provide collected screening data, including digital ECGs. In collaborating with the PSGs in these efforts (as described below), FDA staff partnered (through the Cardiac Safety Research Consortium) with Duke University (serving as lead academic institution) and multiple medical industry members.
We surveyed the PSGs to better understand their technical resources and pertinent workflow-information. Given the variability of methods and the ranges of data obtained by the PSGs, we developed a core set of essential data elements to promote uniform practices. Many PSGs have relied on paper forms for data collection. Therefore, we created a universal scannable form, in electronic and paper format, to enable direct digital data transfer to the data warehouse through software processing of images of the form. Because screenings performed by PSGs most frequently involve volunteer staff, we also developed materials to help train staff to perform standard ECGs in children and to capture high-quality data. Furthermore, to create a pediatric ECG data warehouse comparable in effectiveness to the current FDA (adult) ECG warehouse, the digital ECGs collected from children will be stored in the standardized (FDA-annotated ECG XML) format, amenable to all the analysis tools already in use with the current FDA (adult) ECG warehouse. The software developed to convert pediatric ECGs into the standardized format functions, moreover, regardless of the type of ECG machine used by any contributing PSG.
Leaders in pediatric cardiology at Duke and other institutions have worked with the FDA and the PSGs to implement a pilot project and promote a trajectory for the long-term establishment of the national data warehouse. Through this multidisciplinary collaboration, innovative tools have been developed for the harmonization of digital technology, empowering PSGs to collect standardized information from children and attain high-quality ECG data collection. Collaboration with the public has been essential in the creation of the database. Despite interruptions to their screening efforts owing to the COVID-19 pandemic, the PSGs provided almost 40,000 ECGs to the database to date.
Public Health Implications
Although data collection and data warehouse refinement are ongoing, the innovative tools described above, such as scannable forms and real-time transmission of ECG data to a central database, have already improved the efficiency and quality of data collection by PSGs. Beyond these improvements, the evolving first-of-kind pediatric ECG data warehouse promises significant public health advances, including the elaboration of clinical guidelines for assessing risk in children (including risk for SCDY), better pre- and post-market cardiac safety evaluation in children, and the development of biomarkers for use in pediatric clinical trials. Pediatric clinical trials in the context of abnormal heart rhythms have long been challenging, owing in part to uncertainties in the selection of endpoints and in the collection and interpretation of data from diverse screening sites. And after all, children cannot simply be regarded as small adults. Our efforts to create a pediatric ECG national data warehouse, encompassing the establishment of norms for the use of pediatric ECG markers, aim fundamentally to facilitate the execution of meaningful pediatric clinical trials and the rigorous assessment of pediatric cardiac safety signals.
1 Bagnall, Richard D., et al. “A Prospective Study of Sudden Cardiac Death among Children and Young Adults.” New England Journal of Medicine, vol. 374, no. 25, 2016, pp. 2441–2452., doi:10.1056/nejmoa1510687.
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