ICCVAM Biennial Report 2018-2019

ICCVAM member agencies participate in the development and review of chemical testing guidelines issued by the OECD Test Guidelines Programme. OECD test guidelines are used by government, industry, and independent laboratories of the 36 OECD member countries to assess chemical safety. The U.S. National Coordinator for the OECD Test Guidelines Programme, an ex officio member of ICCVAM, solicits and collates U.S. comments on draft test guidelines and other documents of the Test Guidelines Programme. The National Coordinator represents the United States at the annual meeting of the Working Group of National Coordinators and in other test guideline development activities. Beginning in 2018, one or more ICCVAM subject matter experts have joined the U.S. National Coordinator at this meeting.

In 2018 and 2019, ICCVAM agencies commented on draft OECD documents through the U.S. National Coordinator. ICCVAM members and/or NICEATM staff also supported the Test Guidelines Programme during 2018 and 2019 by:

• Serving on an expert group developing a guideline for defined approaches for skin sensitization. The guideline will describe the adopted defined approaches with respect to their intended regulatory purposes of hazard identification or potency subcategorization.
• Serving on expert groups for skin sensitization and eye irritation, which are tasked with reviewing guidelines and guidance documents relevant to those endpoints.
• Serving on a peer review panel for an OECD-coordinated study evaluating the use of the kinetic direct peptide reactivity assay for classifying substances for skin sensitization potency.
• Serving on the Validation Management Group – Non-animal, which focuses on evaluation of new methods for identifying endocrine disruptors.
• Helping to develop a "Case Study on the Use of an Integrated Approach to Testing and Assessment for Identifying Estrogen Receptor Active Chemicals," submitted to the OECD Working Party on Hazard Assessment. This case study was published in September 2019, and has since been adapted to create a proposal for a defined approach for estrogenic activity, submitted to the OECD in November 2019.
• Helping to develop a "Case Study on the Use of an Integrated Approach to Testing and Assessment for Identifying Androgen Receptor Active Chemicals," submitted to the OECD Working Party on Hazard Assessment in 2019.

The International Cooperation on Alternative Test Methods (ICATM) was created to foster dialog among national validation organizations. This dialog facilitates international cooperation in the critical areas of validation studies, independent peer review, and development of harmonized recommendations. ICATM includes member organizations from the European Union, United States, Japan, Canada, and South Korea. Brazil and China have been participating in ICATM since 2015 as observers.

ICATM Participant Organizations

• ICCVAM is an interagency committee of the U.S. government that coordinates technical reviews of alternative test methods and cross-agency activities relating to validation, acceptance, and harmonization of test methods. NICEATM administers ICCVAM and provides scientific support for its activities.
• EURL ECVAM (European Union Reference Laboratory for Alternatives to Animal Testing) is a unit within the Institute of Health and Consumer Protection in the European Union’s Joint Research Centre. EURL ECVAM coordinates the validation of alternative test methods in the European Union.
• JaCVAM (Japanese Center for the Validation of Alternative Methods) coordinates the evaluation of alternative test methods for the Japanese National Institute of Health Sciences, its parent organization.
• Health Canada’s Environmental Health Science and Research Bureau coordinates the evaluation of alternative test methods in Canada. The Canadian Centre for Alternatives to Animal Methods and its subsidiary, the Canadian Centre for the Validation of Alternative Methods (CaCVAM) participate as partners with Health Canada in ICATM activities.
• KoCVAM (Korean Center for the Validation of Alternative Methods) is part of the National Institute of Food and Drug Safety Evaluation of the South Korean Food and Drug Administration.
• The Brazilian Center for the Validation of Alternative Methods (BraCVAM) functions as the focal point within Brazil to identify or receive requests for test method validation. It works to implement appropriate validation studies with the National Network of Alternative Methods to the Use of Animals within the Brazilian Ministry of Science, Technology, Innovations, and Communications.

In October 2018, representatives of NICEATM and ICCVAM attended an ICATM workshop on “Validation and Establishing Scientific Confidence” and subsequent coordination meeting. Workshop participants discussed challenges to address in evolving the process of validation, including demonstrating human health relevance without animal data, and establishing more efficient validation procedures. As a first step towards addressing the identified issues, ICATM representatives agreed that they would conduct a detailed review of OECD Guidance Document 34, the current standard for validation of chemical safety test methods. The goal of this review was to identify more specific issues to be addressed in moving forward with new approaches to validation.

ICATM observed its 10^th anniversary at an October 2019 workshop. ICATM representatives reflected on progress made in the last decade toward regulatory acceptance of alternatives to animal testing, and regulatory agency representatives identified challenges and opportunities to address. Specific topics discussed during the workshop and subsequent ICATM coordination meeting included:

• Strategies to promote regulatory adoption of defined approaches to testing.
• Challenges presented in the assessment of endocrine disruptors.
• Approaches to building confidence in regulatory application of MPS.

Representatives from BraCVAM, CaCVAM, and KoCVAM attended the 2018 SACATM meeting. Representatives from EURL ECVAM, JaCVAM, KoCVAM, and CaCVAM attended the 2019 SACATM meeting.

ICCVAM member agency scientists serve on management teams or peer review panels for test method validation studies conducted by ICATM partners.

• A JaCVAM-led validation study of the amino acid derivation reactivity assay for skin sensitization potential concluded in 2018. NICEATM staff served on the validation management team, and an ICCVAM member served on the peer review panel. The amino acid derivation reactivity assay was accepted by OECD in a 2019 revision to Test Guideline 442C.
• During 2018 and 2019, an NIEHS scientist served on the management team for a validation study led by JaCVAM. The study is evaluating the multi-immunotox assay, a screening assay that identifies potentially immunotoxic chemicals by assaying the activity of T cells and dendritic cells.

The following ICCVAM workgroups had ICATM member liaison representatives during 2018 and 2019.

OSHA and the DOT Pipeline and Hazardous Materials Safety Administration participated in meetings convened by the United Nations in 2018 and 2019 to harmonize international standards on safe handling of chemicals. OSHA attended meetings of the United Nations Subcommittee of Experts on the Globally Harmonized System of Classification and Labelling of Chemicals, and DOT attended meetings of the United Nations Subcommittee of Experts on the Transport of Dangerous Goods. Both ICCVAM agencies held public meetings to receive input from U.S. stakeholders in advance of the international meetings.

OSHA is currently leading the United States’ effort to update and expand the use of non-animal test data for GHS hazard classification. The GHS chapter on skin corrosion/irritation was updated in 2019 to reflect new in vitro test methods for classifying hazards as well as updating guidance on the use of data from in silico methods. The work will continue in 2020 with an update of the eye corrosion/irritation chapter. Updates to the eye chapter will include updated and expanded guidance on the use of in vitro and in silico test data for classification as well as introducing the use of defined approaches for use of data from multiple test methods. OSHA anticipates the GHS will adopt the changes to the eye corrosion/irritation chapter by the end of 2020.

Two FDA Centers, the Drug Evaluation and Research and Biologics Evaluation and Research, pursue international harmonization of nonclinical recommendations for human pharmaceutical development through their engagement with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH brings together regulatory authorities and the pharmaceutical industry to discuss scientific and technical aspects of drug registration. ICH's mission is to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner. These activities reduce repetition of studies and reduce and refine animal use in overall drug development. New guidances recently approved will continue to contribute to the 3Rs as will future guidances that are currently being developed or revised.

FDA Q&A documents issued on ICH guidances on toxicokinetics and anticancer pharmaceuticals are discussed elsewhere in this report. The Center for Drug Evaluation and Research is engaged with other ongoing activities of ICH.

• Revision of the ICH S5 (R3) guidance on reproductive toxicology was ongoing through 2018 and 2019. The revisions propose to expand circumstances under which the outcome of “preliminary embryofetal development studies” (per ICH M3(R2)) could support clinical trials, which could lead to fewer definitive studies being conducted. In addition, the revised guidance proposes basic principles that would assist in the development and potential regulatory use of alternative assays for evaluating adverse effects on embryofetal development.
• An ICH working group is also discussing revisions to guidances related to assessing proarrythmic potential (ICH S7B and E14). The potential changes to these guidances could include incorporation of multi-ion channel assays, in silico models, in vitro human primary cell assays, and induced pluripotent cardiomyocyte assays, in addition to in vivo evaluations.

The advent of NAMs for generating safety information on chemicals provides an opportunity to assess what chemical risk assessment should look like in the 21st century. EPA has a leadership role in Accelerating the Pace of Chemical Risk Assessment (APCRA; Kavlock et al. 2018), an international activity designed to bring together regulators from key international regulatory agencies such as the European Chemicals Agency and Health Canada to discuss progress in applying the new tools to prioritization, screening, and application to quantitative risk assessment of differing levels of complexity. An APCRA workshop hosted by EPA in 2019 further developed the case studies initially considered at workshops in 2016 and 2017 on the development and applications of NAMs for chemical risk assessment; an online workshop is planned for early 2020. These collaborations will examine how NAMs might transform regulatory evaluation of chemicals and help to overcome barriers to acceptance by increasing confidence in the use and acceptance of NAMs in regulatory chemical risk assessment.