The development of new drugs and biological products has traditionally mandated animal testing, but the FDA Modernization Act 2.0 allows for alternative non-clinical testing, allowing reliable alternatives for drug discovery and biological product applications.
In this blog post, we answer 10 key questions about these alternative technologies, including in vitro organoids and ex vivo patient tissue platforms that can provide clinically relevant data.
- How does the FDA Modernization Act 2.0 impact drug development in general?
By easing regulatory requirements for animal testing for every new drug, the Act is promoting greater use of alternative innovative/leading edge technologies in drug development, which brings the legislation into the modern age. This can lead to reduced time to reach approvals and a more cost-effective drug development process, especially where animal models have been limiting.
- What are the benefits of using alternative technologies?
The use of alternative technologies in drug development can reduce the time it takes to reach approvals of novel therapeutics for human trials and offer a more cost-effective drug development process. This supports the 3Rs (replace, reduce, and refine animal use) and has the potential to help patients get the right treatment at the right time faster.
- What are in vitro and ex vivo models, and how do they benefit drug development?
In vitro and ex vivo models are laboratory models that use human cells or tissues to study biological processes and test drug efficacy. These models are more clinically relevant than traditional 2D and 3D cell lines and can be applied to functional/phenotypic screening, proof of concept, lead optimization, and combination analysis, which can be used for candidate drug predomination.
Technology developments in high content imaging (HCI) also add significant value to drug discovery, as well as access to quality biobanks containing models of numerous types of cancer. By leveraging patient-relevant models, researchers can make more informed decisions on progressing compounds to the clinic, potentially reducing the need for animal testing.
- What are organoids and how can they be used in drug development?
Organoids are three-dimensional (3D) organ-specific in vitro cell cultures that mimic the structure, function, and biological complexity of organs. They are derived from stem cells that can self-organize, self-renew, and differentiate from both normal and disease tissue. Organoids can be used in drug development to test the efficacy and toxicity of new drugs.
Matched normal and tumor organoids can be used in parallel for off-target effects in drug development. This can help to identify any potential harmful effects of a drug on healthy tissue.
- What are the advantages of using patient-derived organoids?
Patient-derived organoids offer a powerful tool for developing and validating drugs, supporting the screening of the efficacy of both small and big molecules with higher throughput in a 384-well format, and reducing the time and cost required to develop compounds that increase patient benefits.
Unlike pluripotent stem cell-derived organoids, patient-derived organoids preserve the genetic and epigenetic makeup of the original tissue through passages, including the pathophysiology of the patient’s disease.
- How are organoids used in oncology research?
Tumor organoids can be developed directly from tumors, unlike pluripotent stem-cell derived organoids which require an additional step to introduce oncogenic drivers. Organoids can be applied to target validation, functional/phenotypic screening, POC, lead optimization, and combination analysis for oncology drug discovery. They are more clinically relevant than 2D and 3D cell lines and offer patient-relevant in vitro models that can be leveraged for early discovery or late translational solutions.
- In which other fields can organoids be used?
Organoid technology is exponentially growing and can be used as clinically relevant preclinical models in immuno-oncology, inflammatory diseases, infectious diseases, and toxicology.
- How could the use of PDXO-PDX platforms be utilized?
Patient-derived xenografts (PDXs) are derived directly from patients and like organoids preserve the original patient tumor histo- and molecular pathology, representing patient diversity and heterogeneity and predicting clinical response.
Because PDX-derived organoids (PDXOs) are derived from PDXs, they closely match the tumors from which they are derived. This means that they can be used to predict in vivo treatment response and we have therefore leveraged our vast collection of PDX models representing patent diversity and heterogeneity to create matched in vitro:in vivo patient-derived models, creating a large living biobank >500 matched models across 15 cancer types.
These models can be used repeatedly for cancer research and drug discovery by cryopreserving them and then reanimating them back into culture or mice. Under the Act, alternative technologies to animal models, such as organoids, will have a beneficial impact because of their predictive potential and ensuring early drug discovery preclinical decision-making is more relevant not only to the patient but also downstream animal studies.
- What are EVPT platforms and how can they be used in drug development?
Ex Vivo Patient Tissue (EVPT) platforms are the most patient-relevant translational systems available. They use fresh patient tissue with native tumor microenvironment (TME) and preserve the heterogeneity and molecular/genetic complexity of human tumors.
EVPT platforms can be used in drug development to test the efficacy of new drugs targeting both the tumor and the immune cells. Combined with automated 3D phenotypic HCI and analysis, deeper understanding of the drug effect enables more informed decision-making on how to progress oncology and/or immuno-oncology drug candidates.
- How can integrated solutions help de-risk and advance into later stages of drug development?
Taking an integrated approach to drug development from early discovery to late translational solutions can yield more comprehensive and accurate data, enabling better-informed decision making. Selecting the most suitable tools and solutions to develop assets can be identified through collaboration with industry.
For example, in vitro and ex vivo platforms are designed to leverage patient-relevant in vivo models for optimization of screens and execution of studies for different therapeutic modalities and applications. Through the integration of these platforms more comprehensive data on drug efficacy, toxicity, and pharmacokinetics and pharmacodynamics is achieved as a result.
Also, using large biobanks of models enables the identification of responder/non-responder profiles and potential biomarkers for the selection of promising candidates for further development.
In conclusion, the use of alternative technologies in drug development, such as in vitro and ex vivo models, can reduce the time it takes to reach approvals of novel therapeutics for human trials and offer a more cost-effective drug development process. The FDA Modernization Act 2.0 supports the 3Rs (replace, reduce, and refine animal use) and has the potential to help patients get the right treatment at the right time faster.
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