Prior to passage, the FDA had already been considering data from non-animal methods in submission and relying on the weight of the evidence in applications. We know from internal data that results from Microphysiological Systems (MPS) and other complex in vitro methods have already been included in numerous Investigative New Drug (IND) applications and MPS data was used solely for label expansion of a previously approved drug.
Therefore, the passage of FDA Modernization Act 2.0 is not expected to cause drastic changes in the regulatory environment. The FDA and biomedical research field are still gaining confidence with technologies related to MPS & In Silico data. However, the passage of this act indicates support for replacement technologies and a movement towards more regulatory acceptance of these models. Furthermore in 2023, additional funding was provided for a new FDA initiative to promote qualification and adoption of alternative methods for regulatory applications.
Much of this work is highlighted in the FDA’s 2021 report and alternative method website including the 2019 launch of the FDA Alternative Methods Working Group. Additionally, in 2021, the FDA established a program (called ISTAND) to advance drug development for tools out of scope for existing qualification programs, such as microphysiological systems. Although we note that formal qualification of alternative methods is not required for them to be used in drug development programs, as long as sufficient validation evidence is provided. Of course, their qualification would likely lead to more widespread use. Outside of internal programs, the FDA also has numerous partnerships with other organizations to advance non-animal methods, including the 3Rs Collaborative. Together, we are working on a cross-platform project to establish confidence in and validation metrics for MPS to address the issue of drug-induced liver injury. These types of research collaborations will result in practical information which will allow broader implementation of complex in vitro methods in drug development. As we review the proposed FDA Modernization Act 3.0 (as written on March 29, 2024), many of the proposed programs are already in progress as outlined above. The resources applied to lobbying for and implementing the proposed FDA Modernization Act 3.0 would be more productive supporting scientific efforts to establish confidence and standards in these systems, such as our cross-platform project with the FDA. The proposed act increases burden without adding value.
MPS are miniaturized systems that mimic the physiology of tissues, organs, or organ systems. They contain major organ-specific cell types attempting to mimic structures in human organs to allow for cell-cell interactions. They can model healthy or diseased tissues for up to 3 months. MPS have been designed for 17 major organ systems and are sometimes linked together to form multi-organ systems. MPS hold potential for generating mechanism of action and other data to inform computational models that may ultimately replace some animal testing.
MPS cannot fully recapitulate and replace all important features of a single organ system or even approach the complex interactions of full body physiology. Neither the larger biomedical research community nor regulators have full confidence in MPS as a core model system due to these limitations. More time, data, and further development of MPS will be needed to improve confidence and define limitations. MPS are not appropriate for all paradigms such as behavior, mental health, large fractures, or cardiac output. Additionally, there are still many questions about how representative of the larger population that MPS can be when many are developed and tested with a limited number of donors. They are also not shaped by external stimuli/environmental factors. Furthermore, interactions between organs are limited. Additionally, these systems may not be highly scalable, affordable, or validated.
For example, potential drug candidates are already being screened with human MPS to eliminate compounds that may ultimately fail in clinical trials due to human-specific toxicity. MPS are used for internal portfolio decision in a number of pharmaceutical companies, as evidenced by the IQ MPS Affiliate which includes 20+ companies committed to addressing MPS. MPS can also be used during clinical trials or for precision-medicine using cells from selected patients to determine what compounds may be most effective for a particular patient or type of patient.
Animal models give us the complexity of a whole, living animal system. MPS can provide data derived from human cells and from patients with specific diseases model. MPS may be extremely useful for assessing mechanisms of action or when animal models are known to be non-predictive of human disease. In instances where many different mechanisms of action are involved, and where knowledge is still lacking, animal models and screening of drug candidates in animals are likely to still be necessary.
If you want to look at some of the exact statutory wording related to the FDA Modernization Act 2.0, we recommend this FDA Law Blog Post.