ICCVAM Biennial Report 2016-2017

In June 2016, the U.S. Congress passed the Frank R. Lautenberg Chemical Safety for the 21^st Century Act, which amended the Toxic Substances Control Act, the primary chemicals management law in the United States. A key provision of the Lautenberg Chemical Safety Act required the EPA to develop a strategic plan to promote the development and implementation of alternative test methods and strategies to reduce, refine, or replace vertebrate animal testing. EPA collected public comment on draft goals and objectives for the strategic plan during the second half of 2017, an effort that included a public meeting convened in November 2017 at NIH. A first draft of the strategic plan will be completed by April 2018, with the final to be published by June 2018.

The EPA Hazard and Science Policy Committee supports implementation of the vision of the 2007 National Academy of Science report, Toxicity Testing in the 21st Century. One approach being taken is to waive toxicity studies that do not provide useful information. The committee reviews data waiver requests for a variety of toxicity studies, primarily immunotoxicity, acute and subchronic neurotoxicity, developmental, reproductive, and subchronic inhalation toxicity studies, and grants waivers where appropriate to avoid unnecessary testing.

• In Fiscal Year 2016 (October 2015-September 2016), waivers were granted for 153 of 180 requests resulting in savings of about 44,000 animals and over $16 million in the cost of conducting the studies.
• In Fiscal Year 2017 (October 2016-September 2017) waivers were granted for 70 of 78 requests resulting in savings of about 41,000 animals and approximately $10.4 million in the cost of conducting the studies.

A report released in January 2017 by the National Academies of Sciences, Engineering, and Medicine makes recommendations on the best ways to incorporate emerging science into risk-based evaluations of chemical safety. The report, Using 21st Century Science to Improve Risk-related Evaluations, was prepared at the request of the four Tox21 partner organizations: NTP at NIEHS, EPA, NCATS, and FDA. The new report discusses both the inherent opportunities and the challenges that will need to be met to achieve the vision described in two earlier National Research Council reports, Toxicity Testing in the 21st Century and Exposure Science in the 21st Century.

In December 2017, FDA announced publication of FDA’s Predictive Toxicology Roadmap for integrating predictive toxicology methods into safety and risk assessments.

The Predictive Toxicology Roadmap presents a framework for new or enhanced FDA engagement in the science of toxicology that includes six elements:

1. An organizing committee to help identify areas where research is needed and reduce duplication of efforts
2. Training in use of new test methods
3. Communication among the Agency, sponsors, and test method developers
4. Fostering collaborations across sectors and disciplines nationally and internationally
5. Research to identify data gaps and promote promising technologies
6. Oversight to track progress

FDA plans a workshop for 2018 to support efforts to foster opportunities for sharing ideas, discussing new technologies, and highlighting collaborations to develop and test new methods. A post on the FDA Voice blog provides links to the Predictive Toxicology Roadmap and related activities.

The FDA participates on 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. The organization plays an important role in ensuring that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner.

During 2016 and 2017, FDA collaborated with ICH partners to develop and update two guidance documents for safety testing with 3Rs relevance.

• ICH S3A Guidance: Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies—Questions and Answers facilitates interpretation of S3A Guidance: The Assessment of Systemic Exposure in Toxicity Studies, especially to address the benefit and use of microsampling techniques to reduce and refine animal use in these studies. The Q&A guidance is intended to provide points to consider before incorporating microsampling techniques into toxicokinetic studies, and acknowledges the benefits (and some limitations) of their use. FDA requested public comment on the draft Q&A guidance in September 2016. A final version of the document is expected to be issued in 2018.
• ICH S5(R3), Detection of Toxicity to Reproduction for Human Pharmaceuticals, clarifies the qualification and potential use of alternative assays to assess reproductive risk and includes a list of compounds suggested for qualification of assays. In November 2017, FDA requested data on potential additional compounds to be added to the list. FDA will be accepting comments on the draft guidance through February 2018.

The FDA Center for Devices and Radiological Health (CDRH) is continuing to expand acceptance of alternative information and non-animal testing to support biocompatibility evaluations of medical devices.

• In June 2016, CDRH published a Final Guidance on Use of International Standard ISO 10993-1, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process. This guidance highlights the concept that a biocompatibility assessment should begin with a risk-based approach instead of immediately considering new testing. If testing is needed, the guidance explains when in vitro tests can be substituted for in vivo thrombogenicity evaluations, and when chemical characterization and toxicological risk assessment can be substituted for in vivo systemic toxicity assessments. A webinar was held on July 21, 2016, to answer questions on this guidance, and the slides, audio presentation, and transcript can be found on the FDA website.
• In August 2017, CDRH published a Final Guidance on Qualification of Medical Device Development Tools. This guidance explains how new tools can be developed and qualified for a specific context of use, so that qualified tools can be used to support regulatory submissions to CDRH. The policy outlined in the guidance is applicable to in vitro models to replace animal testing where appropriate. A webinar was held on August 24, 2017, to answer questions on the guidance, and the slides, audio presentation, and transcript can be found on the FDA website. As tools become qualified under CDRH’s Medical Device Development Tool program, they will be published in the Medical Devices section of the FDA website.

NIEHS offers grants to U.S. small businesses to support development of novel testing approaches using state-of-the-art technologies. Some of this funding is provided through an omnibus solicitation of grant applications offered by the U.S. Department of Health and Human Services. Grants awarded under this program support development of cell-based assays to assess eye irritation, neurotoxicity, cardiotoxicity, skin and eye corrosivity, and DNA damage, as well as organotypic assays to assess cardiotoxicity, hepatotoxicity, and male reproductive toxicity.

During 2016 and 2017, NIEHS also issued the following Requests for Application for grants targeted towards specific testing applications:

• Validation and Commercialization of Approaches to Reduce Animal Use in Toxicology Testing: this opportunity supports development of in vitro assays, quantitative structure-activity relationship models, and computational methods to predict toxicity. Priority areas include ocular toxicity, developmental toxicity, carcinogenicity, and acute toxicity testing. A grant awarded through this program is currently supporting development of an in vitro human airway model for regulatory toxicity testing.
• Novel Assays for Screening the Effects of Chemical Toxicants on Cell Differentiation: this opportunity supports development of assays to provide information on mechanisms of chemically induced biological activity and potentially inform the role of genetic diversity in toxicological effects.
• Organotypic Culture Models Developed from Experimental Animals for Chemical Toxicity Screening: this opportunity supports development of systems that will facilitate comparisons between in vivo and in vitro test results.

More information about NIEHS small business grants is available on the NIEHS website. Current funding opportunities are listed on the NTP website.

In October 2016, the National Library of Medicine (NLM) released an extensive update of its 20-year-old online ToxTutor course. ToxTutor is a self-paced tutorial for users of toxicology resources, including NLM chemical and toxicology databases. The 2016 update incorporated advances in the science of toxicology, provided more information on alternatives to animal testing, and featured responsive design to support use on mobile devices. Additional content was added in September 2017 and included sections covering basic physiology, toxicokinetics, absorption, distribution, biotransformation, excretion, and cellular toxicology. If a certificate of completion is needed, the tutorial can be completed through a free learning management system. ToxTutor is being used in academic courses, for training in companies and elsewhere, and is approved for some continuing education contact hours. Additional topics will be included in future updates.