Recent policy changes by the U.S. Food and Drug Administration (FDA) mark a pivotal moment for preclinical drug development, especially for radiopharmaceuticals. The FDA’s Roadmap to Reducing Animal Testing in Preclinical Safety Studies, and its specific intention to phase out animal testing requirements for monoclonal antibodies and other drugs, signals a strategic embrace of New Approach Methodologies (NAMs). For companies developing radiopharmaceutical treatments, these changes have profound and positive implications for early clinical development of this class of drugs.

The FDA’s Roadmap and Regulatory Drivers

The FDA’s roadmap, released on April 10, 2025, outlines a stepwise approach to replace animal testing with scientifically validated NAMs, including organ-on-a-chip systems, computational modeling, and advanced in vitro assays. This shift is driven by scientific consensus that animal models are often poor predictors of human safety and efficacy, especially for complex diseases and immune-mediated therapies.

Over 90% of drugs that appear safe and effective in animals fail to gain FDA approval due to safety or efficacy issues in humans. The FDA Modernization Act 2.0, which was passed in 2022, explicitly authorizes the use of non-animal alternatives, such as cell-based assays and computer models, to support Investigational New Drug (IND) applications.

The roadmap also highlights the FDA’s commitment to partnering with federal agencies and the scientific community to accelerate the validation and adoption of these human-relevant methods.

Microdosing and PET Imaging

Microdosing, the administration of subtherapeutic doses of investigational drugs combined with PET imaging, offers a powerful strategy for early-phase human pharmacokinetic and biodistribution studies. While often conducted in healthy volunteers, microdosing studies are also increasingly used in patient populations when evaluating target engagement, especially in therapeutic areas like oncology and neuroscience where target expression is disease-specific.

A recent Journal of Nuclear Medicine article (Hicks 2025) highlights the value of microdosing PET studies in radiopharmaceutical development, particularly for assessing tissue distribution, receptor binding, and early safety signals. This approach can generate real-time, human-relevant data that often surpasses the predictive power of preclinical animal models, especially for radiopharmaceuticals, where interspecies differences in receptor expression and pharmacokinetics are significant.

Beyond radiopharmaceuticals, microdosing PET has growing relevance in broader drug development, particularly in neuroscience. It enables early confirmation of central target engagement—a critical checkpoint in CNS drug development that can de-risk later-stage trials. This methodology was foundational for groups like Invicro, who demonstrated its value in translational neuroimaging. As such, there is renewed interest in expanding the application of microdosing PET to non-radioactive drug pipelines as a means to improve early decision-making and reduce clinical trial attrition.

PET imaging allows for non-invasive, quantitative assessment of drug distribution, metabolism, and elimination in target tissues, offering insights that are difficult or impossible to obtain from animal models. While standardized uptake values (SUVs) are commonly used, PET allows for fully quantitative pharmacokinetic modeling when properly validated—though this requires more complex data acquisition and analysis. These capabilities apply to both radiopharmaceuticals and non-radioactive investigational drugs. For radiopharmaceuticals, PET imaging can include visualization of drug uptake in tumors, normal organs, and clearance pathways which constitute critical information for dose selection and safety assessment.

Regulatory Impact and Strategic Considerations

The FDA’s roadmap and recent policy changes create several opportunities and considerations for radiopharmaceutical developers:

• Earlier Human Data: Microdosing and PET imaging studies can be incorporated earlier in the development process, generating human-relevant pharmacokinetic and biodistribution data before traditional animal studies are completed. This aligns with the FDA’s goal of reducing reliance on animal testing and improving the predictive accuracy of preclinical assessments.
• Regulatory Flexibility: The FDA is actively encouraging the use of innovative approaches. Developers should engage early with regulators to discuss study designs and data requirements, ensuring that microdosing and imaging data are robust and fit-for-purpose.
• Risk Reduction: By leveraging human microdosing and imaging data, companies can make more informed go/no-go decisions, reducing the risk of late-stage failures due to unpredicted human safety or biodistribution issues.
• Cost and Time Savings: Reducing reliance on animal studies can lower development costs and shorten timelines, particularly as the cost and availability of animal models continue to rise.
• Integration with Other NAMs: Microdosing and PET imaging can be combined with other NAMs, such as in vitro human-derived systems and computational modeling, to build a comprehensive, human-relevant preclinical safety package.

Looking Ahead

The FDA’s roadmap and recent policy changes represent a significant opportunity for radiopharmaceutical companies to modernize and enhance their development strategies. By embracing microdosing and PET imaging in human volunteers, developers can generate more predictive data, accelerate regulatory review, and bring safer, more effective therapies to patients faster.

As the regulatory landscape evolves, ongoing dialogue between industry, regulators, and scientific experts will be essential to refine best practices and ensure the successful integration of these novel approaches into mainstream drug development.

Bracken’s regulatory and radiopharmaceutical expertise can help you accelerate progress, reduce risk and lead to better outcomes for patients and their families. Reach out to our experts to ensure your strategy is both compliant and competitive while engaging with these novel approaches and engaging with health authorities.