Perinatal and maternal research has been a cornerstone of NCTR regulatory-science research for more than 30 years. Throughout the years, NCTR has conducted this work collaboratively with the FDA Product Centers such as the Center for Drug Evaluation and Research (CDER), external partners such as the Mayo Clinic, and academic institutions such as the University of Arkansas for Medical Science.
NCTR is providing the infrastructure to stimulate robust research efforts through faster, less expensive, and more predictive approaches and models, leading the way to improved safety and/or efficacy of FDA-regulated products in susceptible populations, including pregnant women and infants — focusing on the perinatal period (the period-of-time including pregnancy, child birth, and infant/child development). Many drugs and other medical products provided to pregnant women, neonates, and infants are used off-label because of the difficulties with performing clinical trials needed for drug approval in these populations. Therefore, these populations represent a vastly understudied stage of development.
In addition to drugs and devices, environmental exposure through foods represent another area where vast knowledge gaps exist. Infants consume more food per kilogram of body weight than any other age group, resulting in the potential for higher dietary exposures to chemicals. Often there are no available data for humans from which to assess the potential risks associated with these exposures. Thus, safety and risk assessments for foodborne chemicals, and biological- and chemical-threat agents rely upon data obtained from animal models and in vitro cellular-toxicology studies.
Below are examples of research performed by NCTR in these populations.
There is limited drug-safety data related to pediatrics and NCTR scientists are working to bridge the gap in perinatal assessments. Advancements at NCTR’s bio-imaging facility allow FDA to gather information not previously obtainable to help the medical community understand pediatric-anesthetic use and its adverse effects on children. These effects are assessed using minimally invasive imaging technology, allowing visualization of biological processes in “real time,” with as little interference as possible with life processes. This research aims to translate these imaging technologies from the laboratory animal to the clinical setting to reduce adverse effects to children.
- An important accomplishment in this area is that NCTR researchers demonstrated significant changes and nerve-cell damage in brains of infant animals exposed to certain concentrations of anesthetics. This research on pediatric anesthetics led to an FDA Drug Safety Communication in 2017, where the FDA approved label changes for the use of general anesthetics and sedation drugs in young children. The changes to the labeling includes a warning about cumulative exposures for long periods of time (several surgeries), as well as one-time exposures of more than three hours that may affect the developing brain.
- Even more importantly, NCTR scientists in collaboration with CDER, identified a chemical that provides neuroprotective properties when given prior to and during the administration of anesthesia — desflurane. An abstract for the study can be found in The Toxicologist created for the 2017 Society of Toxicology Annual Meeting and ToxExpo™. In general, these data provide the scientific framework critical to updating the best practices for minimally-invasive pediatric anesthetic-assessment methods.
- The effects of pediatric anesthesia are also being studied in collaboration with colleagues at the Mayo Clinic in Rochester, Minnesota using an NCTR-developed method for assessing brain function in children. This method has been used extensively in nonhuman primate studies conducted at NCTR. This collaborative study has aims to determine if there are significant adverse effects of general anesthesia on subsequent brain function when given in the important period of rapid brain development after birth. This information may inform agency decisions about labeling and/or best practices for pediatric general anesthesia.
- The FDA Opioid Action Plan provides comprehensive guidance for reestablishing safe-use standards for these products. NCTR scientists supported opioid research in 2017 by completing a methods-development protocol which enabled FDA to gain hands-on-experience in neural stem-cell growth and differentiation. Based on the success of and insight gained from this initial experiment and in relation to perinatal-related FDA Drug Safety Communications, NCTR is conducting a larger study to assess perinatal opioid exposure. NCTR plans to report preliminary findings regarding opioid exposure to brain cells during perinatal development in 2018 and finalize data on its potential neurotoxicity in 2019.
- NCTR scientists also conduct research to identify potential biomarkers (biological indicators) and to understand the effects of drugs, such as acetaminophen, on children. Researchers have found markers in urine and blood that may be used as biomarkers of liver injury.
FDA scientists working independently have recognized the need to have a coordinated effort and have come together to address a special public-health need. NCTR has formed the virtual Perinatal Center of Excellence (PHCE) that is focused on the perinatal period as defined to include: maternal, premature, neonatal periods, and development throughout childhood. With the support of collaborating product centers and ORA, NCTR staff is coordinating the activities of the PHCE to conduct studies that address important regulatory-science needs facing FDA. Broadly speaking, the PHCE-funded research falls into the categories of in silico models, stem cell systems and other in vitro models, laboratory animal studies, translational and clinical studies, mathematical modeling, bioanalytical chemistry, exposure science, and bioinformatics targeting the perinatal period. The highest priority during the selection process is given to projects with a potential for 1) regulatory impact including policy changes and industry standards and 2) changing medical practice or research approaches in the areas of perinatal health.
In fiscal year 2019, PHCE received 22 research proposals that were reviewed by the PHCE Leadership Council – which includes one representative from each product center and ORA – and 14 of those proposals were awarded funds totaling $1,898,095.