A Strategic Roadmap for Establishing New Approaches to Evaluate the Safety of Chemicals and Medical Products in the United States

The successful implementation of new approach methodologies (NAMs) will depend on research and development efforts developed cooperatively by industry partners and federal agencies. Currently, technologies too often emerge in search of a problem to solve. To increase the likelihood of NAMs being successfully developed and implemented, regulatory agencies and the regulated industries who will ultimately be using new technologies should engage early with test-method developers and stay engaged throughout the development of the technologies.

• Identify anticipated testing requirements. Agencies and industry stakeholders need to work together to identify and communicate their anticipated science and technology needs for safe product development and registration.
• Encourage the establishment of grant review criteria tailored to the development of alternative methods. Funding development of NAMs should begin as early in the research and development process as possible. However, most current grant review processes are tailored to reward research involving animal models. To better support NAM development, processes for influencing the distribution of funding to NAMs by the federal government should be explored.
• Develop mechanisms to improve communication between end users and researchers. One of the most cost-effective and impactful actions that can be taken immediately is to foster efforts that improve the dialog between end users and test-method developers. Federal agencies and industry stakeholders should collaborate to develop programs and processes that encourage an open dialog between test-method developers and end users. For example, end users could host workshops or webinar series aimed at identifying agency and industry priorities with accompanying examples of use cases within or outside of regulated testing space.

Stakeholders and federal agencies should work together to establish confidence in NAMs using flexible, robust, and integrated approaches spanning from early product development to the ultimate intended use.

• Clearly delineate testing requirements and context of use. Validation, by definition, is establishing fitness for a specific, intended purpose. However, data from a single guideline animal test can be used for multiple purposes, all of which need to be considered when developing a replacement. Failure to consider the ultimate context of use is one of the most frequently cited reasons for lack of agency and industry adoption of NAMs. It is, therefore, essential that agencies clearly communicate their needs along with all possible contexts for which data from both the existing animal study and NAM would be used.
• Promote the use of new approaches for establishing confidence. Agencies and stakeholders should use past experience as a guide for developing more flexible and efficient processes to evaluate fitness for purpose of a particular NAM. Developing these new approaches should be done in a collaborative, transparent, and inclusive manner. Activities to accomplish this might include:
  • Investigating approaches to establish confidence in NAMs that are driven by human biology, exposure, and mechanistic relevance (e.g., mode-of-action, adverse outcome pathways) and do not rely on animal data as the reference for evaluating performance
  • Establishing forums to discuss best approaches to expedite regulatory acceptance of methods already in use for in-house screening by industry
  • Providing agency and stakeholder case studies illustrating how alternative approaches have successfully been evaluated or implemented
• Utilize public-private partnerships to promote cross-sector communication and cooperation. The successful development of NAMs will depend on the ability of federal agencies and stakeholders to work closely together via public-private partnerships that facilitate the sharing of both knowledge and data. Extending collaborations into the private sector will allow knowledge and experience gained throughout the product development and registration cycle to be incorporated into new test method development and application. Such collaborations will also allow the resources and collective expertise of ICCVAM agencies and their stakeholders to be leveraged to address parallel testing needs and requirements across product sectors, providing opportunities to impact alternative test method research and development, acceptance, and implementation. These collaborations could, for example:
  • Identify and collate sources of high-quality human toxicological and exposure data
  • Create centralized data access points that are publicly available and easily accessible
  • Actively solicit the submission and collation of parallel data from animal studies and alternative methods

Federal agencies and stakeholders need to take an active role in facilitating the successful adoption and use of NAMs, both within the federal government and internationally.

• Provide clear language regarding the acceptance of NAMs. Industry stakeholders indicate that lack of clear guidance on the status of regulatory acceptance is a significant factor impeding the use of NAMs. Industries cannot be expected to use new methods if they are uncertain about whether the data will be accepted by regulators. To facilitate use by industry, agencies should provide clear guidance on the use and acceptance of data from NAMs.
• Collaborate with international partners to facilitate global harmonization and regulatory acceptance. In a global economy, efforts by individual countries to develop NAMs will have little impact without international adoption of the new methods, as companies will always test according to the requirements of the most conservative country. Frequent and transparent communication with international partners will ensure that development and evaluation of NAMs are harmonized, where feasible, to account for international regulatory requirements. A forum for such a collaboration already exists in the International Cooperation on Alternative Test Methods (ICATM), which was created to foster dialog among national validation organizations. In addition to its interaction with ICATM partners, federal agencies will also continue to be highly engaged with the OECD Test Guidelines program, placing increased emphasis on the need to develop new approaches for establishing confidence in NAMs, including the use of performance-based evaluation of test methods.
• Explore processes to incentivize and promote the use of NAMs. Simply establishing scientific confidence is often not sufficient justification for federal agencies or industry partners to abandon animal-based approaches in favor of NAMs. There are many practical non-scientific factors that must be considered prior to committing to the use of NAMs, such as confidence in historical results, legal considerations, and harmonization issues. The successful implementation of NAMs will depend on agencies and stakeholders working together to identify these factors and developing solutions that enable the widespread use of NAMs. For example, training programs on the use of a new method should be established for personnel who conduct or review toxicology studies.
• Identify appropriate metrics for prioritizing activities, monitoring progress, and measuring success. A challenge faced by all 3Rs efforts is determining the actual impact on the stated objective, whether it be reducing animal numbers or improving human relevance. Measuring the impact of implementation of new testing approaches is particularly difficult in the United States due to the limited ability to quantify animals used for toxicity testing. Despite these obstacles, agency-specific mechanisms that can be used to estimate the impact of a given activity may exist, such as tracking the number of waivers granted for a particular animal test. In order to assess the impact of this national strategy, effective metrics need to be created to track progress and identify objective criteria for measuring success.