Transforming Drug Safety: FDA’s Pathway to Animal-Free Preclinical Testing

“Animal-Free Innovation: FDA’s New Safety Standard”

Rationale for Change: Animal testing has significant scientific and ethical limitations. Over 90% of drugs that pass animal tests fail in humans, with animal models often poorly predicting human outcomes, particularly for diseases like cancer and Alzheimer’s. Some widely used human medications, like aspirin, might not have passed animal tests, while drugs deemed safe in animals have proven lethal in humans, highlighting fundamental physiological differences. In 2022, Congress passed the FDA Modernization Act 2.0, allowing non-animal alternatives (e.g., cell-based assays, computer models) for investigational new drug (IND) applications and removing the animal testing requirement for biosimilar biologic license applications (BLAs). A recent survey also showed that over 85% of Americans, across political lines, support phasing out animal testing in favor of modern methods.

What Are New Approach Methodologies (NAMs):

NAMs offer human-relevant alternatives to animal testing for drug safety, efficacy, and pharmacology. Key approaches include:

• In Vitro Systems: Human organoids and organs-on-chips (like the Liver-Chip) mimic organ functions, enabling real-time detection of toxicities critical for monoclonal antibody (mAb) evaluation.
• In Silico Tools: AI, machine learning, and modeling (e.g., PBPK, QSP) predict drug behavior, safety, and immunogenicity, reducing reliance on animal data.
• Other Platforms: Use of ex vivo human tissues, high-throughput human cell screening, microdosing studies, and refined animal models further decrease animal use while enhancing human relevance.

Integration Strategy: Combining these methods can effectively replace traditional animal testing, with regulatory support steadily growing to make NAMs the future of drug development.

Initial Focus: Monoclonal Antibodies (mAbs):

The roadmap starts with mAbs, where animal testing is especially problematic and expensive. Animal immune responses to human mAbs are not predictive of human outcomes.  Despite appearing safe in monkeys, TGN1412 caused life-threatening reactions in humans, highlighting the need for better human-specific in vitro tests. NAMs can better predict human-specific effects and reduce the need for costly, lengthy animal studies.

Animal testing for mAbs faces serious practical hurdles. Development costs can reach $750 million over nine years, requiring about 144 non-human primates — now costing up to $50,000 each. Long, expensive studies slow patient access, and many drug failures are due to issues animal tests miss. Using more predictive methods earlier could cut costs, speed up development, and improve decision-making.

“The Next Generation of Safety: FDA’s Commitment to Animal-Free Testing”

FDA Plan to Reduce Animal Toxicity Testing Over the Next 3 Years:

Use Global Human Data: If approved abroad under similar standards, existing human data can replace new studies; extra data required only if necessary.

Promote NAM Submissions: Encourage companies to submit organoid, MPS, and AI data alongside animal studies. Strong NAM results may reduce or replace animal testing.

Expand Toxicity Databases: Grow Tox21 into a global repository combining human and animal toxicity data to strengthen NAM models.

Shorten Primate Testing for mAbs: Cut primate toxicity studies from 6 to 3 months when early studies and NAMs show no concerns.

Shorten Animal Testing for Other Drugs: Apply reduced testing durations to more drugs, supported by clinical data, AI modeling, and new comparative studies.

Track and Report Progress: Monitor reductions in animal use, costs, and approval times every six months.

Future Goal (3–5 Years): Make NAMs the default for safety testing, using animal studies only when absolutely necessary.

Scientific and Technical Steps for FDA Adoption of NAMs:

Identify Key Endpoints and Gaps: Map critical drug safety and efficacy questions (toxicity, PK/PD, immune responses) where NAMs can replace animals. Prioritize gaps where NAMs offer the biggest impact.

Invest in NAM Development: Collaborate with NIH and others to create organoid models, expand human/animal toxicity databases, study NAM vs animal costs and efficacy, and define risk thresholds for reducing animal testing.

“Ethical, Efficient, Effective: FDA’s New Approach to Drug Safety”

Validate and Qualify NAMs:

• Use retrospective analyses comparing past drug outcomes to NAM predictions.
• Run prospective trials comparing NAMs, animals, and clinical outcomes.
• Ensure reproducibility across labs with standardized methods.
• Benchmark against human clinical/post-market data.
• Use FDA’s DDT Qualification Program to formalize acceptance of NAMs for specific uses.

Create Regulatory Guidance and Standards:

• Issue new guidance on when NAMs can replace animal studies.
• Set technical standards for conducting NAMs (like GLP for animal studies).
• Provide real-world case examples.
• Push for international harmonization (e.g., updating ICH guidelines to reflect NAM acceptance).

Training, Communication, and Culture Shift:

• Train FDA reviewers on interpreting NAM data (organ-chips, AI models, PBPK simulations).
• Foster openness to NAM science while maintaining critical review.
• Host public meetings to discuss NAM progress.
• Encourage early sponsor engagement with FDA on NAM plans.

Monitor Outcomes and Improve: Track NAM performance by comparing predictions to clinical results. Investigate any misses, measure development efficiencies, and adjust strategies to continuously improve the system.

Interagency Coordination through ICCVAM: The FDA will partner with ICCVAM, a coalition of 18 federal agencies (including NIH, DoD, EPA, VA), to develop and validate alternative testing methods by pooling expertise, data, and resources.

“The Next Generation of Safety: FDA’s Commitment to Animal-Free Testing”

Key collaboration areas:

• Validation Studies:
  FDA, with NICEATM support, will lead multi-agency validation of promising NAMs (e.g., organoid models) to enhance credibility and speed acceptance.
• Funding and Research:
  NIH can direct funding to FDA-priority NAMs (e.g., Complement-ARIE program), with NIH-VA-FDA collaborations supporting research and innovation.
• Shared Databases:
  FDA and NIH will contribute to ICCVAM’s CAMERA database (beta by mid-2025), compiling validated NAMs and toxicology data.
• Workgroups and Outreach:
  FDA will lead ICCVAM workgroups and use public forums to update and engage stakeholders on NAM development.
• Training and Exchange:
  FDA scientists will cross-train with NIH, VA, and NTP experts to align scientific development with regulatory standards.
• Public-Private Partnerships:
  FDA will promote ICCVAM forums linking agencies, industry, and academia to advance NAMs, modeled on the IQ Consortium’s MPS Affiliate.

Recommendations and Policy Considerations:

FDA plans to combine scientific rigor with flexible policies to reduce animal testing in preclinical safety.

Key Actions:

• Clear Guidance and Flexibility:
  Update regulations to allow alternatives (NAMs), with case-by-case waivers and acceptance of NAM-only data when appropriate.
• Incentives and Success Stories:
  Speed up regulatory processes for NAM users and highlight successful non-animal approvals to shift industry practices.
• Scientific Rigor:
  Ensure NAMs meet or exceed animal tests in protecting patients, using validated, human-relevant models.
• Legislative and Funding Support:
  Work with Congress for dedicated NAM funding and legislative backing to phase out animal tests when alternatives are available.
• Global Leadership:
  Promote NAMs in international guidelines (ICH, EMA, PMDA) to encourage worldwide adoption.

In Conclusion: The FDA’s roadmap envisions that within 3–5 years, animal testing in preclinical safety studies will be rare and only used when absolutely necessary. Validated New Approach Methodologies (NAMs) will become the standard, making drug development faster, safer, more cost-effective, and more relevant to humans. The plan emphasizes rigorous validation, phased implementation, interagency collaboration, and continuous improvement. By adopting NAMs, the FDA aims to enhance patient safety, reduce animal use, and establish itself as a global leader in ethical, modern regulatory science.

“A New Era of Drug Safety: FDA’s Animal-Free Testing Roadmap”

Disclaimer
This blog is for informational purposes only and does not represent official FDA policy or regulatory guidance. The strategies and timelines discussed are based on proposed initiatives and may evolve with new scientific, legislative, or regulatory developments. Readers should refer to official FDA sources for the most current information.