Assessments of Agency Needs and Practices

The 2018 ICCVAM Strategic Roadmap identified the definition of agency information needs as a key step in its implementation. ICCVAM member agencies are collaborating both within ICCVAM workgroups and independently to define agency information needs and make those needs known to stakeholders. Areas considered in 2020 and 2021 included carcinogenicity, liver and kidney toxicity, ecotoxicity, and nanomaterials toxicity.

FDA/CDER Perspective on Use of New Approach Methodologies (NAMs) in Drug Development

Nonclinical testing of human pharmaceuticals is conducted to assess the safety of compounds to be studied in human clinical trials and for marketing of new drugs. Recent advances in science have led to the emergence of numerous NAMs for nonclinical testing that are currently being used in various aspects of drug development. A paper by scientists within the FDA Center for Drug Evaluation and Research (CDER) and the FDA National Center for Toxicological Research (Avila et al. 2020) discusses CDER’s view on the opportunities and challenges of using NAMs in drug development, especially for regulatory purposes. The paper includes examples where NAMs are currently being used in nonclinical safety assessments and where they may supplement or enhance current testing methods.

In Silico Approaches in Carcinogenicity Hazard Assessment: Current Status and Future Needs

Historically, identifying carcinogens has relied primarily on tumor studies in rodents, which require enormous resources in both money and time. In silico models have been developed for predicting rodent carcinogens but have not yet found general regulatory acceptance, in part due to the lack of a generally accepted protocol for performing such an assessment as well as limitations in predictive performance and scope. There remains a need for additional, improved in silico carcinogenicity models, especially ones that are more human-relevant, for use in research and regulatory decision-making. As part of an international effort to develop in silico toxicological protocols, FDA and NIEHS scientists participated in a consortium of toxicologists, computational scientists, and regulatory scientists across several industries and governmental agencies to evaluate the extent to which in silico models exist for each of the recently defined 10 key characteristics of carcinogens. A position paper developed by the group (Tice et al. 2021) summarizes the current status of in silico tools for the assessment of each key characteristic and identifies the data gaps that need to be addressed before a comprehensive in silico carcinogenicity protocol can be developed for regulatory use.

In Silico Approaches in Organ Toxicity Hazard Assessment: Current Status and Future Needs in Predicting Liver Toxicity

Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic, and one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. Faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative are critically needed. A review (Bassan et al. 2021) coauthored by ATSDR, FDA, and NIEHS scientists summarizes biological mechanisms and processes underpinning hepatotoxicity and describes experimental approaches to support the prediction of hepatotoxicity, including toxicokinetic considerations. The paper describes the increasingly important role of in silico approaches and highlights challenges to the adoption of these methods, including the lack of a commonly agreed upon protocol for performing such an assessment and the need for in silico solutions that take dose into consideration. A proposed framework for the integration of in silico and experimental information is provided, along with a case study describing how computational methods have been used to successfully respond to a regulatory question concerning non-genotoxic impurities in chemically synthesized pharmaceuticals.

In Silico Approaches in Organ Toxicity Hazard Assessment: Current Status and Future Needs for Predicting Heart, Kidney, and Lung Toxicities

The kidneys, heart, and lungs are vital organ systems evaluated as part of acute or chronic toxicity assessments. New methodologies are being developed to predict adverse effects based on in vitro and in silico approaches. A review coauthored by ATSDR, FDA, and NIEHS scientists considered the current state of the art in predicting these organ toxicities (Bassan et al. 2021). The review outlines the biological basis, processes, and endpoints for kidney toxicity, pulmonary toxicity, respiratory irritation and sensitization, and functional and structural cardiac toxicities. The review also covers current experimental approaches, including off-target panels from secondary pharmacology batteries. Current in silico approaches for prediction of these effects and mechanisms are described as well as obstacles to the use of in silico methods. Ultimately, a commonly accepted protocol for performing in silico assessments would be a valuable resource to expand the use of such approaches across different regulatory and industrial applications. The review identifies factors impeding the widespread deployment of in silico approaches, including lack of a comprehensive understanding of the mechanisms of toxicity, limited in vitro testing approaches, limited in vivo databases suitable for modeling, a limited understanding of how to incorporate ADME considerations into the overall process, a lack of in silico models designed to predict a safe dose, and a need for an accepted framework for organizing the key characteristics of these organ toxicants.

Assessment of U.S. Federal Agency Ecotoxicity Information and Testing Needs

U.S. regulatory and research agencies use ecotoxicity test data to assess the hazards and risks associated with substances that may be released into the environment, including but not limited to industrial chemicals, pharmaceuticals, pesticides, food additives, and cosmetics. These data are used to conduct hazard assessments and evaluate potential risks to non-target animals and plants. To identify opportunities for regulatory uses of non-animal replacements for ecotoxicity tests, the needs and uses for these types of test data must first be clarified. The ICCVAM Ecotoxicology Workgroup prepared a review (Ceger et al. 2022) that identifies the ecotoxicity test data relied upon by U.S. federal agencies. The review describes the standards, test guidelines, guidance documents, and endpoints that are used to address each of the responding agencies’ regulatory and research needs regarding ecotoxicity testing in the context of their application to decision-making. This information will be useful for coordinating efforts to develop and implement alternative test methods to reduce, refine, or replace animal use in chemical safety evaluations.

U.S. Federal Agency Interests and Key Considerations for New Approach Methodologies for Nanomaterials

Engineered nanomaterials (ENMs) come in a wide array of shapes, sizes, surface coatings, and compositions, and often possess novel or enhanced properties compared to larger‑sized particles of the same elemental composition. To ensure the safe commercialization of products containing ENMs, it is important to thoroughly understand their potential risks. Given that ENMs can be created in an almost infinite number of variations, it is not feasible to conduct in vivo testing on each type of ENM. Instead, NAMs such as in vitro or in chemico test methods may be needed, given their capacity for high-throughput testing, lower cost, and ability to provide information on toxicological mechanisms. However, the different behaviors of ENMs compared to dissolved chemicals may challenge safety testing of these substances using NAMs. The ICCVAM Nanomaterials Workgroup queried ICCVAM member agencies about what types of ENMs are of agency interest and whether there is agency-specific guidance for ENMs toxicity testing (Petersen et al. 2021). To support the ability of NAMs to provide robust results in ENM testing, two key issues in the usage of NAMs, namely dosimetry and interference/bias controls, are thoroughly discussed.

Applying IVIVE to Facilitate the Use of In Vitro Toxicity Data in Risk Assessment and Decision-making

In vitro toxicity assays are being applied to transform toxicology from an observational to a predictive science, improve throughput, and reduce costs. The qualitative linkage between in vitro and in vivo toxicity endpoints can be strengthened via application of IVIVE, which relates an in vitro concentration associated with bioactivity to an external exposure level. In some contexts, applications of IVIVE have advanced past the exploratory research stage and are beginning to gain acceptance for risk assessment of chemicals. The ICCVAM IVIVE Workgroup requested information from ICCVAM member agencies regarding the extent and context of their use of IVIVE. Surveyed agencies were also asked about programmatic needs, data gaps, and agency-specific guidance documents or publications related to IVIVE, as well as for information about modeling tools or software they had used or may use for facilitating IVIVE analysis and decision-making. This information was compiled into a review summarizing the workgroup’s findings, current challenges, and future needs (Chang et al. 2022). The review also proposes operational definitions for IVIVE, presents literature examples for several common toxicity endpoints, and highlights implications of IVIVE use in decision-making processes.

Request for Information on Efficacy Testing of Ectoparasiticide Products

In a December 2021 Federal Register notice (86 FR 72251), NICEATM requested available data and information on approaches and/or technologies currently used for efficacy testing of ectoparasiticide products, such as products to prevent flea and tick infestations on dogs and cats. Submitted information will be used to assess the state of the science and determine technical needs for non-animal test methods used to evaluate the efficacy of ectoparasiticides on dogs and cats and to facilitate their incorporation into a testing strategy for regulatory purposes.