FDA Workshop on Leveraging Human-Relevant Cardiomyocytes in Nonclinical Studies to Provide Mechanistic Insights into Cardiovascular Safety Liabilities
FDA Cardiac Safety Workshop
March 29, 2019
Silver Spring, Maryland, USA
The mission of the HESI Cardiac Safety Committee is to improve public health by reducing unanticipated cardiovascular-related adverse effects from drugs or chemicals, and to develop innovative approaches to support early detection and prediction as well as improved understanding of cardiovascular toxicology and pathobiology.
The HESI Cardiac Safety Committee seeks Postdoctoral or Early Career researchers working in cardiovascular safety science or related field for the Early Career Seminar Award Series. This award offers an opportunity to share your research, learn from and network with experts in the toxicology and safety pharmacology fields from academia, regulatory agencies and pharmaceutical companies.
This group is working to understand and characterize use of stem cell–derived cardiomyocytes in cardiac safety assessments. An article that included best practices for use of stem cell cardiomyocytes in cardiac safety assessments was published in Regulatory Toxicology and Pharmacology. A new group is planning a study to explore in vitro assay ability to detect cardiotoxicity.
Leadership Team:
Ksenia Blinova, PhD (US Food and Drug Administration)
Godfrey Smith, PhD (University of Glasgow)
HESI Staff:
Jennifer Pierson, MPH
This working group is dedicated to investigating mechanisms of proarrhythmic risk. They continue to collaborate with the CiPA Initiative and ICH, and recently published its anticipated high throughput systems (HTS) ion channel work. A new subteam is scoping a conduction/ sodium channel paper to discuss the history and challenges surrounding this topic.
A 3-phased project was conducted by the HESI Pro-Arrhythmia Working Group starting with a detailed literature review and followed by a collaborative HESI-FDA database of 150 new drug candidates to evaluate how predictive nonclinical studies are to clinical outcomes.
Leadership Team:
Jose Vicente Ruize, PhD (US Food and Drug Administration)
Jean-Pierre Valentin, PhD (UCB Biopharma)
HESI Staff:
Jennifer Pierson, MPH
This working group has examined the sensitivity within a preclinical species to assess the function of contractility. They continue their partnership with University of Surrey and Imperial College London on a mathematical model to predict blood pressure changes. The Implanted Telemetry Subteam explored the impact of telemetry lead placement in toxicology studies (a collaboration with the Pro-Arrhythmia Working Group).
Leadership Team:
Michael Pugsley, PhD (Cytokinetics)
Sandy Eldridge, PhD (National Cancer Institute)
HESI Staff:
Jennifer Pierson, MPH
Claire O’Brien, PhD
This working group is dedicated to investigating preclinical cardiac biomarkers of hypercoagulability induced under a thrombotic state, in both normal and diseased states. A manuscript was submitted detailing a study investigating the effects of doxorubicin in Zucker diabetic fatty rats. A new study is in the planning stages using xenobiotics to induce the procoagulant state and confirm measurements of biomarkers of interest.
Leadership Team:
Eric Schultze, PhD (Eli Lilly & Company)
Marjory Brooks, DVM (Cornell University)
The Cardiac Safety Steering Team established this subteam in early 2020 to develop and provide a structured resource for use when identifying compounds appropriate in a planned committee study. The database was published April 2024.
HESI Staff:
Jennifer Pierson, MPH
HESI has been awarded a multi-year U01 grant from the US FDA on the “Evaluation of Integrated Human-Relevant Approaches to Identify Drug Induced Cardiovascular Liabilities.” This grant supports HESI in funding and managing novel, in vitro experimental studies to develop targeted mechanistic data to inform drug safety assessment for key cardiac “failure modes.”
HESI received a Broad Agency Announcement (BAA) award from the US FDA to manage a multi-site study on manual and automated patch clamp platforms. The original study included 4 ionic currents (hERG, Nav1.5 peak, Nav1.5 late and Cav1.2) and 14 compounds and has been expanded to include a total of 28 compounds. The project aims to collect additional information on inter-laboratory variability as well as support the FDA in silico model. Learn more about the recommended ion channel protocols and in silico model here.
Associate Director for Program Development & Resourcing
jpierson@hesiglobal.orgUCB
US Food and Drug Administration
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March 29, 2019
Silver Spring, Maryland, USA
FDA Workshop on Leveraging Human-Relevant Cardiomyocytes in Nonclinical Studies to Provide Mechanistic Insights into Cardiovascular Safety Liabilities
Toxicological Sciences, 2019
A consortium, multi-site approach to testing in vitro assay technology for prediction of drug-induced TdP. The authors sought to test calcium transient assays using the CiPA 28 drugs.
British Journal of Pharmacology, 2017
The strengths and limitations of three nonclinical repolarization assays used to define the risk of clinical drug-induced delayed ventricular repolarization (a surrogate marker of the rare but potentially lethal arrhythmia Torsades de Pointes) were compared during a retrospective analysis of an anonymized database of 150 ...
Journal of Pharmacological and Toxicological Methods, 2017
Heart rate correction methods are frequently used when analyzing data collected during the drug development process to better understand the QT interval. There is variability in this methodology and the optimal heart rate correction formula is often debated. This paper details a study that explored the ...
International Journal of Toxicology, 2011
There are several recent examples where clinically significant, safety-related, drug effects on hemodynamics or cardiac function were not apparent until large clinical trials were completed or the drugs entered the consumer market.
Frontiers in Toxicology, 2024
This groundbreaking piece from the HESI Cardiac Safety Committee proposes a new alternative approach to preclinical drug safety assessment, using human cell-based models and computational methods to identify human-relevant liabilities earlier in the process.
Journal of Pharmacological and Toxicological Methods, 2024
The Health and Environmental Sciences Institute (HESI) Cardiac Safety Technical Committee (CSTC) has made significant strides in improving cardiovascular (CV) safety in drug development.
hesi@hesiglobal.org
Phone: +1-202-659-8404
Fax: +1-202-659-8403
740 15th Street NW, Suite 600
Washington, DC 20005
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