https://ntp.niehs.nih.gov/go/838220

Strategic Roadmap: Introduction

Illustration from roadmap introduction

Regulatory agencies in the United States are charged with protecting human health and the environment. To this end, agencies must determine the health hazards presented by substances such as pesticides, consumer products, cosmetics, pharmaceuticals, medical devices, workplace chemicals, and chemicals in transportation. Testing these substances provides information about possible hazards, and enables informed decisions regarding responsible manufacture, use, storage, and disposal.

Many currently accepted methods for assessing potential hazards use laboratory animals. However, animal-based testing has a number of recognized limitations: it can be expensive and time consuming, it raises moral and ethical issues, and it does not always identify toxic effects relevant to humans.

A more efficient, predictive, and economical system for assessing the effects of chemical substances on human health was envisioned in the seminal National Research Council report, Toxicity Testing in the 21st Century: A Vision and a Strategy (NRC 2007). In the decade since this report was published, investments in technology development and biomedical research have produced transformative scientific breakthroughs. However, these advances have not yet resulted in similar improvements in our ability to predict adverse human health effects caused by exposure(s) to chemicals and medical products. This limited translational impact can be partly attributed to the inability of relevant institutional practices to keep pace with rapid scientific advancements. Left unaddressed, the growing disparity between the capabilities offered by 21st century science and continued reliance on animal data for safety evaluations could impede our ability to capitalize on the remarkable progress made by, for example, the ToxCast and Tox21 programs, the NIH Tissue Chip program, and the Precision Medicine Initiative.

Alternative test methods replace animal use with non-animal test systems or use of phylogenetically lower species, reduce the number of animals required for a specific test, or refine animal use to lessen or avoid pain and distress. Replacement, reduction, and refinement of animal use, known as the 3Rs, have been important principles in biomedical research for over 50 years. More recently, the term “new approach methodologies” (NAMs) has been adopted as a broadly descriptive reference to any non-animal technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment. These new approaches include integrated approaches to testing and assessment (IATAs), defined approaches for data interpretation, and performance-based evaluation of test methods.

ICCVAM was formally established in 2000 by the ICCVAM Authorization Act as a permanent committee of NIEHS. ICCVAM’s mission is to facilitate the development, validation, and regulatory acceptance of test methods that replace, reduce, or refine the use of animals. The committee is composed of representatives from 16 U.S. federal agencies that use, generate, or disseminate toxicological and safety testing information. NICEATM provides scientific and administrative support to ICCVAM. The ICCVAM Authorization Act also specified the establishment of SACATM, representatives drawn from specific stakeholder groups to advise ICCVAM and NICEATM on activities relevant to the act.

During its first 15 years, ICCVAM’s evaluations of new methods followed a linear, stepwise validation model that proved to be lengthy, inefficient, and resource-intensive. This validation paradigm can no longer be solely relied on to meet the needs of federal agencies. Moreover, it is not compatible with many modern approaches to toxicity testing, which place less emphasis on replacement of in vivo tests with a single alternative method and more emphasis on NAMs that incorporate batteries of assays, in silico approaches, and computational models. It is important to understand and address the shortcomings of the historical approach as we move forward with a new paradigm for establishing confidence in NAMs.

  • In the past, development of alternative methods was often initiated by researchers and test method developers with little input from the end users: federal agencies and regulated industries. This lack of understanding of regulatory needs, and particularly the various contexts of use, tended to produce methods that did not adequately meet the testing requirements of end users. Consequently, these methods were either not accepted by federal agencies, or accepted by the agencies but not used by the regulated community. The likelihood of regulatory acceptance and industry adoption would be greatly increased if NAMs are developed “with the end in mind” to ensure fitness for purpose. Achieving this objective requires end users to be actively engaged during the research and development process. Likewise, it is critical that federal agencies provide clear guidance on their information needs, context of use, and willingness to accept NAMs in place of traditional animal-based tests.
  • Previous validation efforts coordinated by ICCVAM typically adhered to principles described in OECD Guidance Document (GD) 34, Guidance Document on the Validation and International Acceptance of New or Updated Test Methods for Hazard Assessment (OECD 2005). GD34 provides guidance on the design and conduct of validation studies, including the assessment of reliability, reproducibility, and relevance. Conforming to GD34 was intended to improve the expediency and efficiency of regulatory acceptance and incorporation of new methods into OECD test guidelines. While GD34 allows a great deal of flexibility via a “modular approach” to validation, this flexibility was not usually applied to ICCVAM-coordinated validation studies, a practice that contributed greatly to the expense and duration of these studies. In addition, GD34, published in 2005, does not fully address all considerations required for the effective evaluation of many modern technologies and approaches. Although GD34 will continue to serve as the default validation standard for the near future, the timely incorporation of 21st-century science into modern risk assessment and hazard identification will require new approaches for establishing confidence in NAMs that incorporate the overarching principles described in GD34 in a more flexible and efficient manner.
  • Historically, most validation studies were coordinated by a central organization (i.e., NICEATM). In many cases, it may be more appropriate for other organizations or agencies to coordinate the evaluation of NAMs. Moving forward, the United States needs to develop an approach for establishing confidence in NAMs that is better suited to capitalize on its vast but highly decentralized resources.

In 2013 ICCVAM underwent a strategic shift aimed at adjusting the validation paradigm for new test methods to be more productive, more responsive to stakeholders, and more engaged internationally. This shift led ICCVAM to consider how a comprehensive U.S. national strategy could facilitate realization of the vision articulated in the 2007 National Research Council report. The concept of developing a strategic roadmap to establish new approaches for toxicity testing in the United States was proposed and endorsed at the 2015 SACATM meeting and further developed at the 2016 SACATM meeting. Acting on this endorsement, federal scientists from 16 agencies and multiple interagency workgroups met in February 2017 at NIH in Bethesda, Maryland, to discuss and develop the key elements of a new strategy for toxicity testing that would improve human relevance and reduce the use of animals.

The primary objective of this strategy, details of which are presented on the main page of this site, is to expedite the development and use of NAMs that provide information more relevant to human health than existing animal-based methods. While the current focus is on human health, the generalized framework could be applied to other disciplines within toxicology such as ecological toxicology. Focusing on human relevance will, in time, obviate the need for testing in animals, while also reducing the cost of product development and registration. A strategic roadmap will help establish the use of NAMs by providing a conceptual framework to support the development, evaluation, and use of NAMs, and facilitate communication and collaboration within and between government agencies, stakeholders, and international partners.