HESI Insights - July 2022

On 30 June 22, the Organisation for Economic Cooperation and Development (OECD) published Test #470: Mammalian Erythrocyte Pig-a Gene Mutation Assay, a Test Guideline (TG) that describes an in vivo gene mutation assay that can be combined with other genetic and general toxicology tests to promote the efficient use of animal resources. This TG is the culmination of fruitful discussions over more than a decade among HESI Genetic Toxicology Technical Committee (GTTC) Pig‐a Workgroup members who contributed directly to the Pig-a Assay Detailed Review Paper, the Pig-a Assay Retrospective Validation Report, the draft OECD TG, the OECD Expert Working Group, as wells as the recent GTTC best practices Review Paper.

“Starting in the late 2000s, the HESI GTTC Pig-a Workgroup was instrumental in acting as a clearing house for discussing protocol changes that greatly improved the precision of the assay, discussing results from several international interlaboratory validation studies, and later in organizing an International Workshops on Genotoxicity Testing meeting on the assay in Foz do Iguacu, Brasil. The Workgroup also had a major role in developing the OECD Standard Project Submission Form (SPSF), that initialed the OECD TG project in 2015.” – Robert Heflich (US FDA), GTTC Pig-A working group co-chair

“HESI staff provided key logistical support that kept the OECD Test Guideline endeavor organized and focused. Also, the importance of HESI-GTTC members’ recommendations regarding study designs and scoring approaches cannot be overstated—they laid the foundation for this OECD approval.” – Stephen Dertinger (Litron Laboratories), GTTC Pig-A working group co-chair

The HESI eSTAR committee is proud to announce that it was awarded a $250,000 USD grant (U01) as part of the USFDA’s Biomarker Qualification Program in June 2022. This funding will be partnered with Committee resources to support a four-site ring trial generating additional data on the TGx-DDI (TGx = toxicogenomics; DDI = DNA damage inducing) biomarker. The TgX-DDI biomarker is currently under review by the FDA as part of the FDA Biomarker Qualification program. Pending the results of this final study, the marker is anticipated to gain FDA approval for optional use as added weight of evidence in the assessment of genotoxicity. The marker has the potential to improve upon the low specificity of in vitro chromosome damage assays used in current testing and to aid drug development by providing mechanistic insights into transcriptional changes occurring in genes involved in key DNA damage pathways.

The focus of HESI’s Emerging Systems Toxicology for the Assessment of Risk (eSTAR) committee is to develop and deliver innovative systems toxicology approaches for risk assessment. The committee aims to catalyze adoption of new translational and predictive tools that guide decision making based on mechanistic understanding of toxicological response.

Have you ever wondered what HESI’s newest committee, Next Generation Ecological Risk Assessment, is all about? They recently published a Fact Sheet which outlines their outreach efforts, working groups, areas of focus for 2022 and much more. Born out the merger of two former HESI committees, Animal Alternatives in ERA and Bioaccumulation, their mission is to develop, refine, and communicate the scientific tools and approaches needed to support ecological risk assessment around the globe, with a focus on alternative, non-animal testing methods.

Link to EcoRisk Fact Sheet

If you would like to learn more, please see their webpage here: https://hesiglobal.org/ecorisk/

The Health and Environmental Sciences Institute (HESI) & Safety Pharmacology Society (SPS) present a new, on-demand training opportunity: A closer look at the new ICH E14/S7b Q&A’s and Training Materials. The target audience includes all sponsors (small and large; other stakeholders in pharma), safety pharmacologists and toxicologists participating in the delivery of the nonclinical data, clinicians, and regulators. See the course content below.

Overview of the ICH E14/7B Q&A Training Materials
Introduction – David Strauss, FDA, United States
Integrated Risk Assessment – Zhihua Li, FDA, United States
In Vitro – Derek Leishman, Lilly
In Vivo – Hugo Vargas, Amgen
Conclusions – David Strauss, FDA, United States

Case Studies and Scenarios for 5.1
Moderator: Christine Garnett, FDA, United States
Speakers – Corina Dota, EFPIA & Wendy Wu, FDA, United States
Topics covered: E14 Pathways and New Options, Clinical Scenarios, Integrated Nonclinical Data
(in vitro & in vivo)

Case Studies and Scenarios for 6.1
Moderator: Christine Garnett, FDA, United States
Speakers – Hugo Vargas, Amgen & Flora Musuamba Tshinanu, FAGG-AFMPS, Europe
Topics covered: E14 Pathways and New Options, Clinical Scenarios, Integrated Nonclinical Data
(in vitro & in vivo)
Summary of integrated risk data

Training Goals
1. Recognize when nonclinical data may be used in the regulatory QT assessment, including understanding the difference between 5.1 and 6.1.
2. Recognize quality hERG and in vivo studies:
a. Are the studies of reasonable quality with the appropriate quality measures?
b. Is the study consistent with the performing lab’s experience with reference agents?
3. Gain familiarity with clinical exposure definitions and how margins are defined to understand the hERG and in vivo margin.
4. Recognize a double-negative nonclinical package.
5. Understand what information is needed to justify the integrated QTc risk assessment.
6. Understand that there can be mitigation around some of the nonclinical study features.
7. Understand timing of various assays and how to progress to clinic.
8. Understand the flexibility of these guidelines and what alternatives may be implemented.

This training is being provided complimentary for SPS and HESI members, and offered to nonmembers for $49.00 USD until 31 December 2022.

Click to link to training course

Contact Jennifer Pierson at jpierson@hesiglobal.org for details.

Most global regulatory safety assessment standards for agrochemicals and pharmaceuticals require the rodent 2-year bioassay for evaluating the carcinogenic potential of a new chemical. The low-end estimate of resources required for said test is 3 years, 600 animals and ~$2–4M USD. There is increasing interest across industry and government to reduce reliance on these long animal studies with the use of novel genomic biomarkers, but more confidence in the newer tools is still required.

The HESI Emerging System Toxicology for the Assessment of Risk (eSTAR) Carcinogenomics Workgroup is a multi-stakeholder scientific collaboration working to develop genomic biomarkers to query established mechanisms of early carcinogenic processes that can be applied to samples already collected from required shorter duration studies and provide greater insights to relevancy for predicting human cancer risk.

This call-to-action paper describes the multi-sector collaboration seeking to accelerate the evaluation of biomarker tools in carcinogenicity studies which will facilitate the transition from current heavy reliance on conventional 2-year rodent carcinogenicity studies to more rapid animal- and resource-sparing approaches.

Click to read the full publication:
A Collaborative Initiative to Establish Genomic Biomarkers for Assessing Tumorigenic Potential to Reduce Reliance on Conventional Rodent Carcinogenicity Studies. J. Christopher Corton, Constance A. Mitchell, Scott Auerbach, J. Pierre Bushel, Heidrun Ellinger-Ziegelbauer, Patricia A. Escobar, Roland Froetschl, Alison H. Harrill, Kamin Johnson, James E. Klaunig, Arun R. Pandiri, Alexei A. Podtelezhnikov, Julia E. Rager, Keith Q. Tanis, Jan Willem van der Laan, Alisa Vespa, Carole L. Yauk, Syril D. Pettit, Frank D. Sistare. Toxicological Sciences. July 2022

Click to learn more about the Emerging Systems Toxicology for the Assessment of Risk (eSTAR) Committee

HESI’s Environmental Epidemiology Committee hosted a joint presentation by Dr. Tim Lash (Rollins School of Public Health, Emory University) and Dr. Brian Nosek (Center for Open Science). Dr. Lash spoke on the reproducibility in epidemiologic research with a focus on history, hysteria and hypothesis testing. Dr. Nosek spoke about the culture change toward more open, rigorous and reproducible research. Both talks were recorded and are available to watch at the link below.

Link to recording: https://youtu.be/iobUe_GYqUE

Save the date! HESI’s Developmental and Reproductive Toxicology (DART) committee will be hosting a hybrid workshop in Washington, DC, titled “Interpretation of developmental and reproductive toxicity in regulatory contexts and frameworks”. Registration will open in September.

Keep your eye on the event page here.

For more information contact Connie Chen (cchen@hesiglobal.org)

For many of us, the most powerful moment (many tears!) of this June 2022 HESI Annual Meeting was the talk by Dr. Courtney Horvath. Dr. Horvath bravely shared the story of her son Colby’s cancer journey as part of the HESI Thrive session and made an impassioned plea for less toxic therapeutics for pediatric cancer. Her family’s experiences – and those of millions of cancer survivors – are the reason the HESI Thrive seed grant program was launched in 2017. By making patient quality of life an active research priority via Thrive-supported research, we have the potential to transform patient experiences during and following curative and adjuvant therapy. You can see Dr. Horvath’s TedX talk on this topic here and can learn more about how to support or apply for the HESI Thrive grant program here. We are thrilled to know that Colby is now healthy and strong, and thank him for his advocacy and commitment to improving quality of life during and following cancer!

Kind Regards,

Syril D. Pettit, DrPH, MEM, HESI Executive Director