Save the date October 25 - 26, 2022 Workshop
The DART committee provides a forum where scientists from industry, government, and academia can exchange information and initiate activities to advance science related to DART, and to develop consensus on the appropriate use of experimental data for human health risk assessment.
The non-human primate (NHP) is an important animal model to assess drug safety in development and reproduction, but it should only be used as a last resort based on unique pharmacologic or toxicologic attributes, heightened ethical concerns using NHP compared to other animal models, and limited availability. Recent survey data also indicate NHP use is higher than expected for drug safety assessments overall. This is at a time when there is also a shortage of NHPs available for research use, including sexually mature NHPs which are important for developmental and reproductive toxicity (DART) testing for biopharmaceuticals. A heightened regulatory awareness of this issue has prompted renewed interest in minimizing NHP use for DART safety assessment whenever scientifically appropriate.
The current HESI DART working group is reviewing NHP use in DART packages of approved products in US and EU but recognize that there may be important examples of when NHPs were or were not used to support DART safety assessment for products not currently approved and for which publicly available information is unavailable.
If you or your company have unusual case studies of drug development programs/products that would be informative of how to minimize use of sexually mature NHP for DART safety assessment (fertility assessment and/or pregnancy/developmental toxicity assessment) in the future, we would be very interested to hear about that example for the purposes of potentially including it in a white paper on this topic. Of particular interest would be case studies where an alternative assessment of DART safety (e.g., use of a surrogate molecule in the rodent or genetically modified rodents, etc.) failed to detect liability that was later identified. Please provide example by 31 Dec 2022.
The Health and Environmental Sciences Institute (HESI) DART Technical Committee is attempting to understand how and when dystocia is identified and reported in laboratory rodents and to identify how these calls may differ between organizations. As such, we are gathering qualitative data from various laboratories and animal facilities that conduct or support DART studies to understand laboratory practices and standard operating procedures (SOPs). Information gathered via this forum will be used to inform a best practices manuscript which will serve as a useful industry-wide tool to standardize the identification of dystocia and improve animal welfare practices.
On behalf of the committee, we would like to invite you to participate in this electronic survey by answering questions about your laboratory’s practices regarding identifying and reporting dystocia in the rodent. Should you be interested, we would also be happy to schedule a 1-hour teleconference to conduct the survey in an interview style format. (* Please note, the electronic survey contains a set of reference responses to assist you in understanding the expected responses).
We appreciate your assistance and value your contributions to this effort. Please note that all survey responses will be blinded from member company representatives and access to original submissions will be restricted to the HESI scientific program managers assigned to this project.
Questions regarding the aims of the project or the survey should be directed to the either of the project co-chairs: Rashin Ghaffari (Rashin.Ghaffari@corteva.com) or Pragati Coder (Pragati.Coder@crl.com).
If you are willing to participate, please complete the survey by Monday, February 6th, 2023, or submit a request for an interview style survey.
On behalf of the HESI DART Dystocia Working Group. Please don’t hesitate to contact us should you have any questions.
Pragati Coder (Charles River Laboratories)*
Rashin Ghaffari (Corteva Agriscience) *
Catherine Jaussely (Bayer)
Christopher Bowman (Pfizer)
Curtis Grace (Merck)
Edward Dere (Genentech)
Isabelle Leconte (Charles River Laboratories)
Jason Manton (Exponent)
Narinder Barraclough (LabCorp)
Nicola Powles-Glover (AstraZeneca)
Sheila Wason (Bayer)
Sonya Sobrian (Howard university)
Warren Foster (McMaster University)
*Denotes WG co-leads
To promote harmonization of anogenital distance (AGD) and nipple/areola retention measurement in male rats, this project aims to publish a review of existing methods and recommend best practices and considerations for these two methods.
In collaboration with the European Teratology Society, the joint working group has collected historical data on thyroid hormone measurement in rodent studies to determine best practices for these measurements.
The goal of this working group is to determine the degree of reliability and human relevance of in vitro rodent markers/assays for puberty timing endpoints by critically evaluating the epidemiological and toxicological literature on both normal development and altered development after exposures. A series of review articles are underway and anticipated to be completed in 2022.
Clinical pathology data from control animals in previously conducted juvenile animal toxicity studies has been gathered. Data analysis is underway, and a manuscript that could be used as a reference across the industry is in development.
A points-to-consider manuscript is in development, outlining initial approaches to inclusion, the role of nonclinical data, and common practices during global drug development plans.
This working group aims to enable better predictive toxicology for DART effects by sharing relevant knowledge of chemical-protein target interactions, pharmacokinetics, and major developmental toxicity study outcomes. To this end, the team has initiated two case studies on the well characterized teratogens, Retinoic Acid and Thalidomide.
This group strives to provide additional information and confidence that fetal skeletal examination using microCT is acceptable for regulatory use in nonclinical fetal evaluation studies. The study design and participants in a multi-site in vivo study comparing microCT and alizarin red staining is being finalized. Experimental work is anticipated to begin in 2022.
This working group, in collaboration with the HESI Immuno-Safety Technical Committee (ITC), convened key stakeholders to discuss both current and novel methodologies in preclinical and translational safety assessment of pregnancy risk associated with immunomodulatory therapy. This group will sunset after the workshop publication is completed.
This project aims to define which preweaning developmental landmarks (PDLs) have value, interpretation, and benchmark responses through both a survey and data collection.
This working group will collect data on a diverse set of compounds to increase the predictive power of a QSAR model for the prediction of placental transfer in rats; outputs from this model can be used as a tool to enhance the exposure based predictions of in vitro assays.
This working group is organizing a series of webinar modules to train federal and international regulators, clinicians, academic investigators, contract research organization scientists, and private sector scientists on the best practices and principles of interpreting DART data in the context of regulatory frameworks and processes.
The goal of the project is to survey labs using HanWister and Sprague Dawley rats in DART studies to understand if reproductive performance in the strain is waning/evolving. Team will publish findings on this analysis.
This scoping group aims to create a new approach methodologies (NAMs) toolbox that will provide for and clarify the context of use for alternative assays that will comply with various regulatory guidelines so that they can ultimately validate for us as a NAM.
This new initiative aims to leverage the HESI DART Committee’s membership and technical work to facilitate career development (with a focus on training and networking) of the next generation of developmental toxicologists. The program(s) will be advertised outside of the traditional and well-established networks to expand our reach to individuals who belong to historically under-represented groups, thereby broadening the pool of trainees.
National Institute of Environmental Health Sciences / National Toxicology Program
Save the date October 25 - 26, 2022 Workshop
It's never too early to start learning about training opportunities and career paths in Developmental and Reproductive Toxicology.
This is an internal DART Committee Meeting
The HESI DART Committee 2021 Spring Meeting will take place on April 20-21, 2021 from 9am-1pm EST. The virtual meeting is open to DART Committee participants only.
The goal of this workshop is to convene key stakeholders to discuss both current and novel methodologies in preclinical and translational safety assessment of pregnancy risk associated with immunomodulatory therapy. Through the sharing of case examples, followed by longer in-depth discussion within each session, the goal ...
Save the date! HESI DART Committee and European Teratology Society Workshop on Thyroid Hormone Assessment: Implications for Developmental and Reproductive Toxicology
Increased research to improve preclinical models to inform the development of therapeutics for neonatal diseases is an area of great need. This article reviews five common neonatal diseases – bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, perinatal hypoxic–ischemic ...
The liver represents a major eliminating and detoxifying organ, determining exposure to endogenous compounds, drugs, and other xenobiotics. Drug transporters (DTs) and drug-metabolizing enzymes (DMEs) are key determinants of disposition, efficacy, and toxicity of drugs. Changes in their mRNA and protein expression levels ...
Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for ...
This review provides insight in cross-species developmental differences of absorption, distribution, metabolism, and excretion properties in the kidney, which should be considered in neonate/juvenile study interpretation, hypotheses generation, and experimental design.
The HESI Developmental and Reproductive Toxicology (DART) Committee launched a multisector collaborative research effort to increase the knowledge base in the nonclinical neonatal space to better inform decisions made in the clinic.
This review is part of a multisector collaborative research effort coordinated by the HESI Developmental and Reproductive Toxicology (DART) Committee to increase the knowledge base in the nonclinical neonatal space to better inform clinical treatment decisions made for the newborn patient population (De Schaepdrijver et ...