From application-first to science-first: A two-phase validation framework for complex in vitro NAMs

Area of Science:

• Toxicology
• In vitro model development
• Regulatory science

Background:

• New Approach Methodologies (NAMs) require a defined context of use (CoU) for validation.
• The initial CoU strategy can limit the scientific scope and validation of complex in vitro models.
• Existing validation frameworks may not fully capture the scientific potential of advanced models.

Purpose of the Study:

• To propose a novel two-phase framework for validating new approach methodologies (NAMs).
• To separate the scientific validation of a model from its context-specific qualification.
• To overcome the limitations imposed by a context of use (CoU) first approach in model validation.

Main Methods:

• Development of a two-phase validation framework.
• Implementation of a shared data repository to bridge scientific validation and qualification.
• Separation of intrinsic model capabilities assessment from application-specific qualification.

Main Results:

• The proposed framework allows for broader scientific validation before specific applications are defined.
• A shared data repository facilitates the communication of model performance and limitations.
• The approach enables informed selection of applications based on scientifically established model capabilities.

Conclusions:

• Separating scientific validation from context-specific qualification offers a more flexible and comprehensive approach to NAMs validation.
• This framework enhances the utility and credibility of complex in vitro models.
• The proposed structure supports the wider adoption and understanding of NAMs in regulatory science.