Acting Division Director: Richard Beger, Ph.D.
About the Division
The division focuses on the development and evaluation of new technologies and the identification of new biomarkers (disease indicators) to support the FDA's mission. The division's mission is to address problems of food, drug, and medical-product safety using systems biology approaches and innovative technology:
- Translational Safety Biomarkers and Mechanisms
- Alternative Models to Assess Drug Safety
- Technology to Assess Product Safety
- Computational Modeling
- Cross-species Predictions and Translation
- Translational prognostic and/or predictive biomarkers for improving pharmaceutical product safety
- Delineated mechanisms for 1) species, tissue, sex, and sub-population specificity in drug toxicity, 2) opioid addiction, and 3) next-generation pharmaceutical toxicity
- In vitro models to evaluate reproductive, developmental, and clinical toxicity
- In silico models for predicting relevant toxicities
- Robust technologies for drug adulteration/compounding
- Use as a tool, classes of drugs with known toxicities such as anthracyclines, tyrosine kinase inhibitors, oligonucleotide therapeutics
- Characterize systems-biology effects with state-of-the-art tools: mRNA and miRNA transcriptomics, epigenomics, metabolomics, proteomics, lipidomics, and imaging
- Integrate data with systems-biology informatics accounting for species, tissue, sex, and sub-population differences
- Incorporate innovative in vitro, computational and instrumental technology e.g. MALDI imaging
Select DSB Accomplishments in 2020
Using Computational Models to Assess Structure of Addictive Chemicals
Opioid-addiction and related deaths remain a serious crisis in the US, and FDA is particularly concerned with evaluating new pain-relieving medications for addiction potential. NCTR scientists have developed a set of unique computational models to assess the structure of addictive chemicals. This project should create a better understanding of the structural requirements associated with a strong addiction potential and would allow an accurate prediction of this potential for opioids, cannabinoids, and other structurally diverse chemicals. This technology could be used to prioritize the testing of chemicals with strong addiction potentials (such as synthetic opioids and cannabinoids), thus shortening the FDA regulatory-review process. This project is expected to be completed in 2021. Archives of Toxicology.
DSB Scientists and CDER’s Office of New Drugs Form Montelukast Working Group
Montelukast pulmonary therapeutics are used chronically by millions of Americans, primarily pediatrics, and are associated with concerns of neuropsychiatric events that were discussed at the September 2019 Pediatric Advisory Committee and Drug Safety and Risk Management Advisory Committee meeting. To address these concerns and coordinate research investigating drug-related neurological effects, a Montelukast Working Group (MWG) was formed between DSB scientists and CDER Pharmacology and Toxicology nonclinical reviewers in the Office of New Drugs. The MWG designed studies that will investigate potential mechanisms of central nervous system (CNS) effects, CNS exposure, drug accumulation potential, blood brain barrier transport, withdrawal and long-term sequelae with chronic montelukast administration. The cumulative scientific information obtained by this work will directly address the regulatory neuropsychiatric safety concerns, may impact labeling decisions for montelukast products, and will better inform healthcare providers and patients of the associated risks that should be considered for individual disease management and treatment action plans with chronic montelukast treatments.
Studies Examine the Effects of Anti-Cancer Agents on Mitochondrial Functions
The adverse reactions to many drugs, including effects to the liver and heart, are the result of their unintended interference with mitochondria, the microscopic powerplants of all cells. DSB completed the studies examining the effects of a series of anti-cancer agents (tyrosine kinase inhibitors) on mitochondrial functions. The drug pexidartinib was identified as a strong inhibitor of key mitochondrial functions at clinically relevant concentrations. This study suggests that examining drugs at an early stage of development for such effects can help predict potential toxicities. The studies have been described in a review manuscript in Expert Opinion on Drug Metabolism and Toxicology.
In Vitro Model to Improve Prediction of Drug Cardiotoxicity
Cardiotoxicity remains a primary cause of drug withdrawal from the market due to the prevalence of adverse events not detected during drug development. Preclinical assessments to determine potential risks for cardiotoxicity are predominantly dependent on in vitro human gene assays and in vivo animal studies. However, to better predict cardiotoxic potential at early stages of drug development, an in vitro model using human induced pluripotent stem cellderived cardiomyocytes (hiPSC-CMs) to identify drug-related effects on myocyte function is being explored. As part of an ongoing collaboration with the Medical College of Wisconsin, the effects of various kinase inhibitors, with known cardiotoxicity in some patients, on hiPSC-CMs from multiple donors are being evaluated to determine if individual patient-derived cell lines can recapitulate the heterogeneity found in the population. Further study is being done to analyze the role of other functional parameters and gene expression to better understand the inter-individual variability. Initial results presented at national and international scientific conferences and a review article was published in Current Opinion in Toxicology.
PHCE Develops 3D Human Placental Barrier Model
A placenta has many tasks, including the transfer of nutrients and oxygen to the barrier. Between 50-70% of pregnant women take at least one medication. Through placental transfer, a fetus may be exposed to a drug that a mother was given, resulting in an increased risk of birth defects. However, current models for assessing toxicity of placental drug transfer do not mimic the placental transfer system in humans. To explore the similar human placental transfer model for assessing placenta toxicity testing, a study funded by PHCE is developing a human placental barrier model using a 3D microphysiological system and the translative correlation to in vivo data is being determined. The collection of in vivo measurement of drug concentration and Pharmacokinetic (PK) analysis has been completed at NCTR and a placenta-on-a-chip has been developed and deployed to evaluate in vitro drug concentration in media and PK analysis. A manuscript about placenta-on-a-chip and associated in vitro PK analysis is currently being written. A follow up study, “Evaluation of drug toxicity on placenta immunity using a microphysiological human placental barrier model,” has been funded by PHCE in collaboration with CBER.
2021 Select Research Projects
Investigating Virus Inactivation to Enhance Safety and Design of Future Research Labs
Much is unknown about the SARS-Cov2 virus responsible for the devastating Covid-19 epidemic. Because of its infectious nature, research on this virus must be conducted in specialized containment laboratories (BSL-3). Samples from such research could be analyzed elsewhere if procedures could be established that definitively inactivated the virus. To address this question DSB initiated a project with the University of Tennessee Health Sciences Center (UTHSC) to investigate virus inactivation, using samples generated in UTHSC’s BSL-3 facility, subjected to different inactivation procedures, and then analyzed at NCTR laboratories. Results of this project will be used to inform the safety and design of future research.
Resources for You
- NCTR Grand Rounds: "Overview of FDA's Perinatal Health Center of Excellence: Development and Validation of Predictive Systems" (Presentation recorded in Adobe Connection on July 13, 2019)
- Perinatal Health Center of Excellence (PHCE)
- Annual Report
- Meet the Principal Investigators
- MitoChip: An NCTR-Developed Mitochondrial Research Tool
- National Center for Toxicological Research
Food and Drug Administration
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