International Cooperation on Alternative Test Methods
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.
In most years, ICATM member organizations hold at least one coordination meeting. The most recent coordination meeting was convened in August 2023 in Niagara Falls, Canada, in conjunction with the 12th World Congress on Alternatives and Animal Use in the Life Sciences. Representatives from the United States, European Union, Canada, Japan, South Korea, Taiwan, Brazil, and the Organisation for Economic Cooperation and Development (OECD) Test Guidelines Programme met to discuss ongoing efforts to update OECD Guidance Document 34. Participants shared perspectives on conduct of validation studies and the challenges presented by new technologies to conventional validation approaches.
“Guidance Document on the Validation and International Acceptance of New or Updated Test Methods for Hazard Assessment,” informally known as “Guidance Document 34,” has been since its publication in 2005 a key reference for the conduct of validation studies of new test methods. However, there is a growing consensus that a revision of Guidance Document 34 is needed to accommodate new approaches to validation.
Participants in the August 2023 ICATM coordination meeting felt that the traditional validation approach of conducting multi-laboratory ring trials to assess transferability and performance may not be practical for many new technologies upon which NAMs are based. Elements identified as key to successful validation included well-defined protocols that incorporate quality management principles; a diverse set of reference chemicals; clear acceptance criteria that consider standards other than prediction of in vivo animal data (e.g. human biological relevance); and coordinated peer review that minimizes duplication of effort.
The sections below provide summaries of other ICATM activities and background information on ICATM.
Interactions on Recent Validation Studies
NICEATM participated in a peer review of a JaCVAM-coordinated validation study of the EpiSensA skin sensitization test method. The method utilizes a reconstructed human epidermis model to evaluate changes in gene expression of four markers of keratinocyte response to skin sensitizers, the second key event of the adverse outcome pathway for skin sensitization. A poster presented at the 2023 Annual Meeting of the Society of Toxicology (Reinke et al., Alternatives to Mammalian Models II session) summarized the validation study.
TSAR: Resource for Tracking Alternative Methods
An overview of non-animal methods that have been proposed for regulatory safety or efficacy testing of chemicals or biological agents can be found in the Tracking System for Alternative Methods (TSAR) resource, provided by EURL ECVAM. TSAR tracks alternative method progress from submission for validation through to final adoption by inclusion into the regulatory framework. EURL ECVAM is an ICATM partner organization (see "About ICATM" below).
ICATM Activities to Promote Use of Non-animal Derived Antibodies
In 2020, EURL ECVAM, an ICATM partner organization, issued recommendations on use of non-animal derived antibodies. The EURL ECVAM recommendations were based on a scientific advisory committee review that found that:
- Animal-free technologies are able to produce affinity reagents with equal or better quality than that offered by antibodies produced using the conventional animal-based methods.
- Use of animal-free affinity reagents provides scientific benefits.
Use of animal-free affinity reagents was discussed at the 2020 ICCVAM Communities of Practice webinar. A webinar series co-organized by NICEATM, EURL ECVAM, and the PETA Science Consortium International e.V. and presented in July-November 2020 explored international activities in this area in more detail. Activities to promote this initiative were also discussed at the October 2020 ICATM coordination meeting.
ICATM Tenth Anniversary Workshop (2019)
ICATM observed its tenth anniversary at an October 2019 workshop at the European Commission Joint Research Centre in Ispra, Italy. 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 microphysiological systems.
ICATM Workshop on Skin Sensitization (2016)
In 2016, ICATM convened a workshop on "International Regulatory Applicability and Acceptance of Alternative Approaches to Skin Sensitization Assessment of Chemicals." Workshop participants reviewed current international regulatory requirements for skin sensitization testing, including currently available non-animal approaches, and considered what steps should be taken to support the regulatory acceptance of these approaches. Outcomes of the workshop included a review of international requirements for skin sensitization testing (Daniel et al. 2018) and a position paper (Casati et al. 2018) that proposes practical ways to evaluate and facilitate the regulatory adoption of non-animal defined approaches for skin sensitization assessments.
Workshop discussions also formed the basis for a proposal to develop a test guideline for defined approaches for skin sensitization testing and assessment. The proposal was approved at the April 2017 meeting of the Working Group of National Coordinators of the OECD Test Guidelines Programme. The resulting guideline, "Guideline No. 497: Defined Approaches on Skin Sensitisation", was adopted by OECD in 2021. Approval of the defined approach guideline will facilitate regulatory acceptance of specific defined approaches for skin sensitization. This is expected to more rapidly advance the goal to eliminate animal use for skin sensitization testing worldwide.
ICATM was originally established by a 2009 agreement signed by ICCVAM, EURL ECVAM, JaCVAM, and Health Canada.
ICATM's goals are:
- To establish international cooperation in validation studies, independent peer review, and development of harmonized recommendations in order to ensure worldwide acceptance of alternative methods and strategies.
- To establish international cooperation necessary to ensure that new alternative test methods/strategies adopted for regulatory use will provide equivalent or improved protection for people, animals, and the environment, while replacing, reducing, or refining animal use where scientifically feasible.
ICATM promotes voluntary international cooperation, collaboration, and communication among national validation organizations in order to:
- Ensure the optimal design and conduct of validation studies to support national and international regulatory decisions on the regulatory use of alternative methods.
- Ensure high-quality independent scientific peer reviews of alternative test methods.
- Support development of harmonized recommendations by national validation organizations on the regulatory use of alternative test methods.
- Achieve greater efficiency and effectiveness by avoiding duplication of effort and leveraging limited resources.
- Support the timely international adoption of alternative methods.
An updated Memorandum of Cooperation (MOC) adding the Korean Center for the Validation of Alternative Methods (KoCVAM) to the ICATM agreement was signed in March 2011.
Since 2015, China and Brazil have been participating in ICATM activities as observers. Both countries actively contributed to the 2016 workshop on skin sensitization. Brazil and Singapore were represented at the 2018 workshop on validation, and Brazil sent a representative to the 2019 tenth anniversary workshop. Taiwan has also participated in recent ICATM activities; a representative participated in the October 2020 coordination meeting.
ICATM Partner 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.
European Union Reference Laboratory for Alternatives to Animal Testing
EURL ECVAM 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 at the European Union level.
Japanese Center for the Validation of Alternative Methods
JaCVAM, part of the Japanese National Institute of Health Sciences, coordinates the evaluation of alternative test methods for Japan.
Health Canada was the signatory for both ICATM MOC agreements and is the official coordinator of Canadian participation in ICATM. The Canadian Centre for Alternatives to Animal Methods (CCAAM) and its subsidiary, the Canadian Centre for the Validation of Alternative Methods (CaCVAM) participate as partners with Health Canada in ICATM activities. CCAAM and CaCVAM, both located at the University of Windsor, aim to develop, validate, and promote methodologies in biomedical research, education, and chemical toxicity testing that do not require the use of animals.
Korean Center for the Validation of Alternative Methods
KoCVAM coordinates the evaluation of alternative test methods for South Korea. KoCVAM is part of the National Institute of Food and Drug Safety Evaluation of the South Korean Food and Drug Administration.
Status Updates from ICATM Partner Organizations
EURL ECVAM 2022 Status Report
EURL ECVAM has issued its 2022 Status Report, "Non-animal Methods in Science and Regulation.” The report describes research, dissemination and promotion activities undertaken by EURL ECVAM to further the uptake and use of non-animal methods and approaches in science and regulation. Activities described in the report include:
- Providing guidance and training on the validation of in vitro methods, application of Good In Vitro Methods Practices, and introduction of test readiness criteria.
- Evaluation of methods to measure cytotoxicity, skin sensitization, and genotoxicity.
- Validation of in vitro methods measuring different modes of action relevant to the thyroid endocrine system.
Status of JaCVAM Activities
Status of KoCVAM Activities
EURL ECVAM Validation Study in the Field of Toxicokinetics and Metabolism
EURL ECVAM coordinated a validation study of two in vitro assays to evaluate human liver metabolism and toxicity. Representatives from NICEATM and ICCVAM participated on the management team for this validation study.
In humans and other animals, chemical metabolism often involves liver enzymes called cytochrome P450s (CYPs). An EURL ECVAM study completed in 2013 assessed the potential for CYP enzyme induction at clinically relevant doses of pharmaceuticals in a human hepatoma cell line (HepaRG®) and cryopreserved human liver cells. This study provided a starting point for the development of novel in vitro platforms to assess chemical and drug metabolism and toxicity, with the ultimate goal of providing a metabolically competent in vitro alternative for long-term toxicity studies.
The EURL ECVAM validation report for this study was submitted to the EURL ECVAM Scientific Advisory Committee for peer review in 2014. Peer review reports for the method using the HepaRG cell line and cryopreserved human liver cells are available in the EURL ECVAM TSAR database. The peer review concluded that the approach was not yet ready for regulatory use.
A draft test guideline for in vitro measurement of CYP enzyme induction is currently under consideration by OECD. EURL ECVAM has provided support (Hakkola et al. 2018) for the usefulness of these methods for chemical toxicity assessments.