Since 1938, animal testing has been a regulatory requirement and expected proof point to determine drug safety and efficacy before entering clinical trials. Although animal models have unraveled many disease mechanisms, evidence demonstrates that physiological and genetic differences between animals and humans often contribute to failures during clinical trials, with significant socioeconomic consequences. Between 2007 and 2010, 66% of Phase III failures were due to lack of efficacy and 21% because of drug toxicity, which reflects the clear need for better predictive data during preclinical evaluation of clinical candidates 1. It is a compelling argument for innovation in this space that in 221 animal experiments reviewed, only 50% had results in agreement with posterior human studies 2. In addition, it has been shown that animal testing fails to predict toxicity in almost 50% of drugs in the pipeline between Phase I trials and early post-market withdrawals 3.
The FDA Modernization Act of 2021 allows drug manufactures and sponsors to incorporate alternative testing platforms in drug discovery 4. The bill does not completely ban animal testing, but enables drug developers to use other platforms to supplement and reduce animal testing. This gives more freedom to choose the most physiologically relevant model to establish the drug's safety and effectiveness.
There is mounting evidence that human induced pluripotent stem cells (iPSCs) provide a powerful alternative to animal testing in preclinical drug development. They preserve donors’ genetic background and can recapitulate specific disease-linked phenotypes and underlying mechanisms 5. Several diseases that were found difficult to mimic with animals, have been successfully modeled using iPSC technology and are already facilitating more confident drug development 6, 7. As an example, there are at least 35 clinical trials currently running for neurodegenerative diseases with drug candidates that were identified using iPSC platforms 6.
Bringing relevant human biology into preclinical target identification and evaluation enables assessment of clinically relevant parameters earlier in the process. This paradigm raises the confidence and speed in identifying the right drug candidates and the ones that would preclude further development, increasing the chances of success in clinical trials.
Dr. Shushant Jain, Director of Discovery Technology at Ncardia said
“It has been demonstrated that in vitro models based on human biology can predict drug safety and efficacy with high accuracy, representing an undoubtedly powerful tool to fill the translation gap. It is good to see regulatory authorities facilitating the incorporation of these iPSC-based models in drug discovery and we are here to help pharmaceutical companies making the switch”.
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- Arrowsmith J. Trial watch: Phase III and submission failures: 2007–2010. Nat Publ Gr. Published online 2011. doi:10.1038/nrd3375
- Perel P, Roberts I, Sena E, et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. Published online 2006. doi:10.1136/bmj.39048.407928.BE
- Van Norman GA. Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Is it Time to Rethink Our Current Approach? JACC Basic to Transl Sci. 2019;4(7):845-854. doi:10.1016/J.JACBTS.2019.10.008
- “FDA Modernization Act of 2021.” Accessed March 24, 2022. https://www.nabr.org/view_file/6916/3406/3039/H.R.2565 - FDA_Modernization_Act_of_2021.pdf
- Matsa E, Burridge PW, Yu KH, et al. Transcriptome Profiling of Patient-Specific Human iPSC-Cardiomyocytes Predicts Individual Drug Safety and Efficacy Responses In Vitro. Cell Stem Cell. 2016;19(3):311-325. doi:10.1016/J.STEM.2016.07.006
- Pasteuning-Vuhman S, de Jongh R, Timmers A, Pasterkamp RJ. Towards Advanced iPSC-based Drug Development for Neurodegenerative Disease. Trends Mol Med. 2021;27(3):263-279. doi:10.1016/J.MOLMED.2020.09.013
- Karakikes I, Termglinchan V, Wu JC. Human Induced Pluripotent Stem Cell Models of Inherited Cardiomyopathies. Curr Opin Cardiol. 2014;29(3):214. doi:10.1097/HCO.0000000000000049