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The FDA Modernization Act 2.0: A patient-centric paradigm shift in drug development

Published by HUB Organoids on Jan 16, 2023

The FDA Modernization Act 2.0: A patient-centric paradigm shift in drug development
The FDA Modernization Act 2.0: A patient-centric paradigm shift in drug development

Explore what the new legislative bill means for the future of organoid technology in drug development

The use of animals to test human pharmaceuticals dates back to 1937 when an untested formulation of a sulfa antibiotic resulted in the deaths of 100s of adults and children in the United States. Popularly known as the “1937 Elixir Sulfanilamide Incident” tightened the regulatory loops of drug approvals and led to the implementation of the 1938 Food, Drug, and Cosmetic Act, which required pharmaceutical companies to perform animal safety tests for all new drug development protocols. Despite plenty of literary evidence that question the translatability of animal models, drug development still relies on animal data to evaluate the efficacy of new compounds before they reach market approval.

From the wild to the lab: animal models in drug development

Research on animal models has bettered our understanding of human biology and disease pathobiology and populated the timeline of pharmaceutical discoveries with groundbreaking wonders – from vaccines, contraceptives, anti-microbials to anti-cancer drugs. Despite these advances, the drug development industry is challenged with a high attrition rate. In oncology, only 1 in 10,000 compounds that show efficacy at the preclinical stage turn out to be safe and effective for patient use. This results in enormous drug development costs and lengthy timelines to get a promising drug to patients. Experts suggest “translational failure” – wherein animal trials do not translate into human trials— as one of the contributors to this attrition. Additionally, oncology drug development faces new challenges with the rise in immuno-oncology and the corresponding lack of animal models that can recapitulate the human immune system.

Animal models represent the best possible approximations of human diseases and disorders and are often used as they manifest a functional phenotype with measurable readouts that can be tested before and after drug exposure. As an example, inflammatory bowel disease (IBD) animal models are developed by chemically-induced damage to the gut epithelium that results in acute inflammation, which can then be monitored following specific biomarkers in the presence or absence of treatment. These widely used models however are not representative of chronic inflammation, which is a lower grade, longer exposure to proinflammatory cytokines that can lead to gut damage in IBD patients.

The cost of animal research is also substantially high – in vivo studies are lengthy and expensive and require large, well-equipped facilities, which delay the selection and prioritization of the right drug candidate for human use. Moreover, the overreliance on animal studies for drug development highlights critical ethical concerns.

FDA Modernization Act 2.0 and the future of drug development

After several decades of research, there remains an absence of published, substantial, comprehensive data to justify the mandated use of animals in preclinical drug testing.

As a result, the governing bodies that oversee drug approvals such as the US FDA and European EMA have taken measures in recent years to limit the requirement for animal testing. The latest passing of the FDA Modernization Act 2.0 has removed the mandate for animal testing to assess the safety and efficacy of a drug. While we can anticipate that the future of drug development won’t be completely animal-free, this measure paves the way for a significant shift toward alternative technologies.

The bill approval comes with the proposal to launch a new alternative methods program, that shall focus on the 3 renowned R’s of animal ethics – replacing, reducing, and refining the use of lab animals for faster and more accurate discoveries in drug development. Initiatives to promote animal-friendly measures have already been resonating worldwide. The European Medicines Agency launched the New Approach Methodologies (NAM) in 2021, a landmark measure to promote the use of alternative approaches to animal models in drug discovery and development.

Dawn of an organoid era

The pursuit of patient relevance in experimental models used in drug testing that pushed drug developers towards adopting animal systems remains an important aspect for the selection of the next-gen preclinical models. The drug development industry has recently registered a shift towards patient-derived in vitro models that can recapitulate the key features of the original disease while offering speed and scalability. Patient-derived organoids represent a new frontier in drug development as they can be developed from both normal and disease tissue to test the efficacy and toxicity of new drugs and most importantly, remain stable when expanded ex vivo in the lab, which makes them an invaluable tool for drug screening.

Unlike pluripotent stem cell-derived organoids, patient-derived organoids do not require additional reprogramming of stem cells to develop in fully functional mini-organs, hence, preserve the genetic and epigenetic makeup of the original tissue through passages, including the pathophysiology of the patient’s disease.

PDOs offers a powerful tool for developing and validating drugs, supporting the screening of the efficacy of both small and big molecules, and reducing the time and cost required to develop compounds that increase patient benefits. The feasibility of reducing and replacing animal models in drug development has been demonstrated by a recent paper published in Nature Cancer, where colorectal cancer (CRC) PDOs were used to identify a lead bispecific antibody that reached clinical trials within 5 years from the initial development.

Organoid Technology is exponentially growing, with the innovation of novel assays that extends the utility of the PDO screening platform as clinically relevant preclinical models in immuno-oncology, inflammatory diseases, infectious diseases, and toxicology.

The FDA Modernization Act 2.0 marks a revolutionary moment for modern medicine. Drug companies now need to rebuild their scientific arsenal with translation tools that can lead the impending era of patient-centric drug development and discovery.

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