Developmental and Reproductive Toxicology (DART) Committee

Mission Statement

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.

Call for Case Studies

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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.

Please contact Chris Bowman (christopher.j.bowman@pfizer.com) for scientific questions and Shermaine Mitchell-Ryan (smitchell-ryan@hesiglobal.org) to submit information on the case study.

DART Dystocia Assessment Survey

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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.

Sincerely,

Shermaine Mitchell-Ryan PhD,  HESI Scientific Program Manager (smitchell-ryan@hesiglobal.org) &
Connie Chen, PhD, MPH, HESI Senior Scientific Program Manager (cchen@hesiglobal.org)

On behalf of the HESI DART Dystocia Working Group. Please don’t hesitate to contact us should you have any questions.

 

The HESI DART – Dystocia Working Group

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

Working Groups

  • Anogenital Distance and Nipple Retention

    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.

  • Thyroid Hormone Assessments

    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.

  • Pubertal Assessment

    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.

  • Juvenile Clinical Pathology Endpoints

    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.

  • Preclinical Considerations for Pregnant and Lactating Women in Clinical Trials

    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.

  • DARTable Genome

    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.

  • microCT

    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.

  • Immunomodulators and Pregnancy Risk

    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.

  • Preweaning Developmental Endpoints

    This project aims to define which preweaning developmental landmarks (PDLs) have value, interpretation, and benchmark responses through both a survey and data collection.

  • QSAR Model of Rodent Placental Transfer

    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.

  • Adverse DART Effects Training Course

    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.

  • Dysotcia

    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.

  • DART NAMs/Alternatives

    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.

  • DART Trainee Program

    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.

HESI Staff

Leadership Team

  • Vicki Sutherland, PhD

    National Institute of Environmental Health Sciences / National Toxicology Program

  • Kary Thompson, PhD

    Janssen Pharmaceuticals

Committee Events

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HESI DART Fall Career Symposium

September 16, 2022

Virtual, Webinar

It's never too early to start learning about training opportunities and career paths in Developmental and Reproductive Toxicology.

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HESI DART Committee 2021 Spring Meeting

April 20, 2021 – April 21, 2021

Virtual meeting, hosted by the HESI DART Committee

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.

Read more

FDA/CDER – HESI Immunomodulators and Pregnancy Risk Assessment Workshop

February 11, 2020

Silver Spring, Maryland, USA

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 ...

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				FDA CDER Immunomodulators and Pregnancy Workshop
	
ABOUT THE EVENT


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 a longer in-depth discussion within each session, the goal is to begin to address gaps in biology, current tools, and other aspects of pregnancy risk that need to be considered during drug development.


 


The  workshop is intended to provide an interdisciplinary forum for industry, academia and regulatory scientists to discuss:


    

  1. The current state of reproductive immunology
    2. 

  2. How adequate are the current set of tools/methodologies to address pregnancy risk under immunomodulatory therapies
    3. 

  3. What additional tools/methods are currently being developed that could address gaps
    4. 

  4. Global regulatory considerations across various immunomodulatory modalities
    5. 



 


Requirements: To gain building access, you must bring acceptable and valid government issued identification (ID).


 


Registration: Up-to-date information and registration can be found here. Registration will close on February 5, 2020. Due to the format and structure of this workshop, attendance is restricted to in-person attendees only.


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				Thyroid Workshop_Logo1 (003)
	
Recent updates to OECD developmental/reproductive toxicology guidelines and other regulatory guidelines and guidance require the measurement of thyroid hormone levels in the blood of mammalian laboratory species during development.  Preliminary analyses indicate that there is a wide variability across laboratories in the methods being used to measure thyroid hormones in young rodents, as well as in the success of obtaining reliable data.  Even though publicly available regulatory guidelines and guidance address study design, they allow varied approaches to thyroid hormone measurement in rodents, and an optimal study design or logical approach to thyroid hormone testing in young rodents has not yet been established in a regulatory testing context.  Validity, accuracy, sensitivity and reproducibility of the assays are issues of concern.  It is not clear to what extent variability in the data can be attributed to methodological issues or to innate biological variability.


WORKSHOP AIMS


    

  1. Present the state-of-the-science on thyroid hormone assessments, specifically as it relates to preclinical methods and data collection, and identify gaps and knowledge as it relates to regulatory DART testing,
    2. 

  2. Provide clarification and guidance regarding the collection (timing and methods), assessment (standardization and validation), and interpretation of thyroid hormone data (as it relates to adversity) for regulatory toxicology and risk assessment,
    3. 

  3. Discuss and come to consensus on recommendations on how to improve data interpretation/understanding of thyroid changes and their relationship to adverse outcomes
    4. 


				dreamstime_s_127655942
	
WORKSHOP AGENDA


Click here to download the workshop agenda.


 


Session 1: Setting the Stage

The Thyroid Axis - Overview of Anatomy, Physiology, Regulation in Mammalian Systems

Mary Gilbert, U.S. EPA (Download presentation)
An AOP Network for Thyroid Hormone Disruption and Adverse Outcomes

Kevin Crofton, R3Fellows, LLC (Download presentation)
Mild Thyroid Dysfunction During Pregnancy; Consequences for Pregnancy Outcome and Fetal Development

Robin Peeters, Erasmus University (Download presentation)

 


Session 2: Methodologies & Interpretation

Regulatory Requirements for Evaluation of Thyroid Status

Sue Marty, Dow (Download presentation)
Pathology Endpoints: Evaluation of Thyrotoxicants in Animal Studies

Brent Walling, Charles River (Download presentation)
Overview of In Vitro Assays to Investigate Chemicals for Thyroid-Axis Disrupting Potential

Michael Hornung, U.S. EPA (Download presentation)

 


Session 3: Global Thyroid Activities

Overview of Ongoing Thyroid Activities in the European Union and United States

Manon Beekhuijzen, Charles River (Download presentation)
HESI DART - ETS Thyroid Hormone Survey - Results & the Path Forward

Pragati Coder, Charles River (Download presentation)

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Committee Publications

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The benefits, limitations and opportunities of preclinical models for neonatal drug development

Disease Models & Mechanisms, 2022

Sarah Campion, Amy Inselman, Belinda Hayes, Costanza Casiraghi, ...

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 ...

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Ontogeny of Hepatic Transporters and Drug-Metabolizing Enzymes in Humans and in Nonclinical Species

Pharmacological Reviews, 2021

van Groen BD, Nicolaï J, Kuik AC, Van Cruchten S, van Peer E, ...

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 ...

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Approaches to Dose Finding in Neonates, Illustrating the Variability Between Neonatal Drug Development Programs

Pharmaceutics, 2020

Van den Anker JN, McCune S, Annaert P, Baer GR, Mulugeta Y, ...

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 ...

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Ontogeny and Cross-Species Comparison of Pathways Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Neonates (Review): Kidney

Drug Metabolism and Disposition, 2020

Bueters R, Bael A, Gasthuys E, Chen C, Schreuder MF, Frazier KS

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.

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Physiology of the Neonatal Gastrointestinal System Relevant to the Disposition of Orally Administered Medications

Drug Metabolism and Disposition, 2019

Neal-Kluever A, Fisher J, Grylack L, Kakiuchi-Kiyota S, ...

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 ...

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