ICCVAM Biennial Report 2022-2023

In June 2023, CPSC updated its Policy on Animal Testing webpage. It has been redesigned to be more user-friendly and have direct access to necessary information and documents.

One of the resources available on the CPSC webpage is CPSC’s “Guidance for Industry and Test Method Developers: CPSC Staff Evaluation of Alternative Test Methods and Integrated Testing Approaches and Data Generated from Such Methods to Support FHSA Labeling Requirements.” CPSC developed this guidance, building on its Animal Testing Policy, to assist stakeholders in determining what test methods are deemed reliable for determining compliance with the labeling requirements under the Federal Hazardous Substances Act. This includes clarification of CPSC informational requirements and process for evaluating new approach methodologies and integrated approaches to testing and assessment.

DOT classifies substances to establish precautions that may need to be taken when materials are handled or transported. Two rulemaking activities during 2022 and 2023 brought DOT regulations into alignment with international regulations that enable reduction of animal use for this purpose. These resulted from ongoing collaborations with the United Nations to expand options for non-animal testing for classifying hazardous materials for transportation.

• The Final Rule for HM-215P (87 FR 44944) was published in July 2022. It incorporates the 2016 version of OECD Test No. 431, “In Vitro Skin Corrosion: Reconstructed Human Epidermis (RHE) Test Method.” This test method is used to assign a packing group to Class 8 (corrosive) materials under 49 CFR § 173.137. Since the RHE test method does not distinguish between packing groups II (“medium danger”) and III (“low danger”), DOT added language to allow corrosive materials classified using this method to be assigned to the more conservative packing group without further testing.
• A Notice of Proposed Rulemaking for HM-215Q (88 FR 34568) was published in May 2023. This Notice proposed incorporating a new in vitro test method, OECD Test No. 439, “In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method,” to allow a material to be ruled into or out of Class 8. DOT also proposed revising 49 CFR 173.137 to allow corrosive materials to be assigned to the most conservative applicable packing group when tested using test methods that cannot distinguish between each packing group. As of early 2024, DOT is finishing the Final Rule that will incorporate these changes.

EPA, in collaboration with NICEATM and nongovernmental organizations, is developing a new framework for identifying eye irritation and corrosion hazards for new chemicals reviewed under TSCA. With this new framework, EPA will prioritize data from non-animal test methods that are more reproducible and provide results more relevant to humans than the corresponding in vivo animal model test. Under the framework, information is collected and evaluated in the following order: (1) data from human cell/tissue-based test methods that have been demonstrated to be reproducible and relevant to eye irritation; (2) data from in chemico or non-human in vitro and/or ex vivo test methods that have been demonstrated to be reproducible and provide information on the mechanisms of toxicity relevant to eye irritation in humans; and (3) data from in vivo animal studies. If no acceptable information on eye irritation is available, the framework allows for consideration of skin irritation data that predict irritating or corrosive properties to make inferences about eye irritation hazard of the new chemical substance. Evaluation of skin irritation and corrosion data follows the same prioritization order as presented above for eye irritation information. This framework will streamline the decision-making process and increase efficiency through a standard process for EPA to use each time it evaluates eye irritation or corrosion hazards test data. The new framework supports EPA’s mandate under TSCA to promote the development and implementation of alternative test methods and strategies that can provide information on chemical hazards without vertebrate animal testing. This framework also supports EPA’s ongoing efforts to reduce the use of animal testing and make the Agency’s review of new chemicals more efficient, helping to bring new chemicals to market more quickly while protecting human health.

New approach methodologies (NAMs) can provide human-relevant information that may be challenging to obtain from whole-animal tests. EPA’s Office of Pesticide Programs is interested in using NAMs to reduce the reliance on default assumptions for risk assessment, including the application of 10X default uncertainty factors each for interspecies and intraspecies extrapolations. To this end, the Office of Pesticide Programs collaborated with EPA’s Office of Research and Development, academia, and industry to use NAM data to inform extrapolation/uncertainty and safety factors. As a part of this effort, EPA held a public meeting of the Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel in September 2020 to consider and review the use of NAMs to derive extrapolation factors and evaluate developmental neurotoxicity (DNT) for human health risk assessment. The panel was supportive of using the DNT NAM battery in weight-of-evidence evaluations of DNT potential, while recognizing that the battery should be a “living and evolving process.” The panel also supported the use of chemical-specific in vitro data to inform interspecies extrapolation factors for organophosphate pesticides, but provided recommendations to reanalyze the data in a manner more consistent with the EPA’s “Guidance for Applying Quantitative Data to Develop Data-Derived Extrapolation Factors.” EPA responded to the panel’s recommendations in a March 2023 memorandum, available with related documents on the Regulations.gov website.

“Qualification of Medical Device Development Tools: Guidance for Industry, Tool Developers, and FDA Staff,” was issued in July 2023. This document, an update of guidance issued is 2017, provides guidance on a voluntary program for qualification of medical device development tools for use in evaluating devices subject to regulation by FDA’s Center for Devices and Radiological Health. Medical device development tools are methods, materials, or measurements used to assess the safety, effectiveness, or performance of medical devices. They can include new approach methodologies, biomarker tests, and clinical outcome assessments.

Drug development tools are methods, materials, or measures that have the potential to facilitate drug development. FDA established the Innovative Science and Technology Approaches for New Drugs (ISTAND) pilot program in 2020 to encourage innovation of drug development tools that are out-of-scope for existing qualification programs but may still be useful for drug development. Approaches that could be considered under the pilot program include:

• Using microphysiological systems to assess safety or efficacy questions.
• Developing novel nonclinical pharmacology or toxicology assays.
• Using artificial intelligence-based algorithms to evaluate patients, develop novel endpoints, or inform study design.

In the pilot phase, FDA anticipates accepting two to four submissions into the ISTAND program each year with a triage and selection process that focuses on public health impact and feasibility of implementation. There were three projects accepted into ISTAND during 2022 and 2023, including one representing both the first artificial intelligence-based and digital health technology-based project and the first project in neuroscience to be accepted into the program. The Drug Development Tools Research Grant Cycle will be open through May 13, 2024 for Fiscal Year 2024, and through May 13, 2025 for Fiscal Year 2025.

In November 2023 FDA published guidance on “Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions.” Computational modeling and simulation can be used in a variety of ways in medical device applications, including to perform in silico device testing or as part of software embedded in a device. This guidance provides a risk-informed framework for credibility assessment of computational modeling and simulation used in medical device regulatory submissions. The guidance is intended to promote consistency and facilitate efficient review of medical device submissions, to increase confidence in the use of computational modeling and simulation in regulatory submissions, and to facilitate improved interpretation of computational modeling and simulation credibility evidence submitted in regulatory submissions. The guidance will be discussed in a presentation at the January 2024 ICCVAM Communities of Practice webinar.

In June 2023 FDA finalized the guidance document, “Nonclinical Evaluation of the Immunotoxic Potential of Pharmaceuticals.” The purpose of this guidance is to assist sponsors in the nonclinical evaluation of the immunotoxic potential of drug products and biopharmaceuticals.

The guidance addresses evaluation of topical pharmaceuticals for skin sensitization potential. Specifically, the guidance states that, for individual chemicals, “FDA will consider a battery of studies (e.g., in silico, in chemico, in vitro) that have been shown to adequately predict human skin sensitization with an accuracy similar to existing in vivo methods.”

In a November 2022 Federal Register notice (87 FR 66195), FDA announced availability of a final guidance for industry, “S1B(R1) Addendum to S1B Testing for Carcinogenicity of Pharmaceuticals.” The guidance was prepared under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, and offers an integrative approach that provides specific weight-of-evidence criteria that inform whether a 2-year rat study is likely to add value in completing a human carcinogenicity risk assessment. This final guidance considered comments received from the public in response to release of the draft guidance in October 2021.