Understanding the Development, Standardization, and Validation Process of Alternative In Vitro Test Methods for Regulatory Approval from a Researcher Perspective

Abstract

Due to economic, practical, ethical, and scientific reasons, researchers, among others, are pushing for alternative in vitro test methods to replace or reduce existing animal experiments. In order for these tests to be more broadly used by the industrial sector and regulatory bodies, orchestrated efforts are required to show the robustness and reliability of in vitro methods, which can accelerate the use for early screening testing. Another way of increasing the use of alternatives is to coordinate validation studies, that is, multi‐laboratory trials, and to gain regulatory approval and instatement as test guidelines or standard method. However, awareness of the exact standardization, validation, and approval process has been a major obstacle for many researchers. Herein, the process has been broken down into three main phases: i) test method development; ii) intra‐ and inter‐laboratory validation; and iii) regulatory acceptance. This general process applies to all alternative methods seeking validation and approval, although the intricacies of different toxicological endpoints and/or chemical sectors may lead to additional work, particularly in the validation stage. The authors’ aim is to provide insight in the development process of alternative methods with a focus on in vitro cell culture methods over validation to regulatory acceptance.

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“…The development, standardization, and validation of these innovative methods cannot be achieved in accordance with existing regulatory standards or guidelines due to the limited scope of the latter. Therefore, scientific standards or guidelines are under development and validated regarding regulatory acceptance [ 26 ]. Scientific standards are more closely oriented to scientific practice, aiming at either enhancing comparability and reproducibility and therefore the communication and exchange of results from ENM studies or describing specific requirements for certain methods (method standards).…”

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“…Thus, it is expected that newly developed hazard characterization approaches are standardized in accordance with international protocols to promote their use within international regulatory frameworks, through the mutual acceptance of data (MAD). [ 4 ] This is a significant barrier toward the move away from animal testing because typically, validation of new methods and development of an internationally accepted OECD TG is measured against data generated using animal models, which in most cases, are scarce or unavailable. In addition, validation of methods and establishment of OECD TG can take more than 10 years.…”