FDA Roadmap Paves Way for New Approach Methodologies in Preclinical Safety Studies

The U.S. Food and Drug Administration (FDA) has released a groundbreaking roadmap aimed at reducing animal testing in preclinical safety studies, signaling a significant shift towards New Approach Methodologies (NAMs). This initiative, coupled with a coordinated national effort involving multiple stakeholders, is set to transform the landscape of drug development and toxicology testing.

FDA's Strategic Approach to Implementing NAMs

The FDA's "Roadmap to Reducing Animal Testing in Preclinical Safety Studies" outlines a strategic, stepwise approach to incorporate scientifically validated NAMs into the drug development process. These alternatives include organ-on-a-chip systems, computational modeling, and advanced in vitro assays. The agency is partnering with federal entities such as the National Institutes of Health (NIH) and Veterans Administration through the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) to accelerate the validation and adoption of these human-relevant methods.

Stacey Adam, vice president in science partnerships at the Foundation for the National Institutes of Health (FNIH), revealed that the organization will soon announce the first concepts for validation and qualification of NAMs. These will be developed into proof-of-concept projects with the long-term goal of expediting therapies to patients.

Public-Private Partnership Drives NAMs Development

A large-scale public-private partnership is emerging to support the implementation of NAMs. The FNIH and NIH are spearheading the design of the Validation Qualification Network (VQN), which will define shared data elements and unify reporting practices across preclinical, clinical, and safety testing.

The initiative has garnered support from a diverse group of stakeholders, including:

• Federal agencies: Approximately 15 agencies are participating, with the FDA and EPA taking prominent roles.
• Private sector: Over 40 partners ranging from small methods developers to large pharmaceutical companies.
• International engagement: European Commission observers, Japanese regulators, and representatives from several ministries in India are involved.

Patrick Smith, senior vice president of Translational Science at Certara, noted that companies are weighing the pros and cons of being the first to undergo the validation process. Large pharmaceutical companies may have an advantage due to their broader portfolios and flexibility to run pilots and test new approaches.

Scientific Rationale and Potential Impact

The shift towards NAMs is driven by growing scientific recognition that animal models do not always provide adequate representations of human health and disease. NAMs offer several advantages:

• Faster insights: Technologies like microphysiological systems or organ-on-a-chip platforms can generate results in days or weeks, compared to multi-month animal studies.
• Personalized medicine: In oncology, patient-derived organoids or chip-based systems enable more tailored treatment strategies.
• Reduced animal use: The roadmap suggests starting with monoclonal antibodies (mAbs) as a promising area for reducing animal use in preclinical safety testing.

Adam highlighted that areas with high activity and obvious impact, such as liver and cardiac toxicity, will be well-represented in the NAMs portfolio. Additionally, there is an emphasis on addressing unmet needs in ocular and neurological applications.

Challenges and Future Outlook

Despite the promise of NAMs, significant challenges remain:

• Validation: Thorough technical validation, ideally replicated across multiple laboratories, is crucial for widespread adoption.
• Standardization: Limited standardization and advanced validation currently exist in the field.
• Regulatory acceptance: None of these technologies have yet been qualified through FDA programs like the Innovative Science and Technology Approaches for New Drugs (ISTAND) program.

Smith emphasized that demonstrating a clear, workable regulatory path with valid systems is critical for industry adoption. The VQN public-private partnership aims to address these challenges by thoroughly validating methods and producing supporting evidence for regulators.

As the field progresses, a combination of better assays and methodologies with AI and in silico modeling is expected to drive meaningful progress. While complete elimination of animal testing may not be immediately feasible, the industry is poised to significantly reduce animal use in preclinical safety studies.