FDA Modernization Act

What is the FDA Modernization Act 2.0?


The FDA Modernization Act 2.0, signed into law by Joe Biden in December of 2022, represents a significant step forward in the regulation of drug development as the bill was passed “to allow for alternatives to animal testing for purposes of drug and biological product applications.”


This legislative initiative marks a departure from the Federal Food, Drug, and Cosmetics Act of 1938, which had mandated animal testing for all new drug development protocols in the United States. The origin of the 1938 Act can be traced back to a tragic event involving a US pharmaceutical company that formulated a sulfanilamide preparation using the toxic compound diethylene glycol. Alarmingly, this drug was introduced to the market without undergoing any animal testing, resulting in the loss of hundreds of American lives. This devastating occurrence highlighted the urgent need for robust safety measures and pre-clinical evaluations to ensure the well-being of the consumer which were put in place in the 1938 Act.


However, since the enactment of the 1938 Act, significant advancements in biotechnological have taken place, prompting the United States Senate to reconsider the requisites for pre-clinical trials.


The In Vitro models as an alternative to traditional animal models

Over the past decade, there has been a noticeable shift away from the conventional reliance on animal models when researching drugs for rare monogenic liver and metabolic diseases. This shift has been driven by the realization of species-specific differences, which may render animal livers as an inaccurate representation of the human liver.

In vitro testing models have gained popularity as viable alternatives to animal models. These in vitro models can employ various cell lines, including primary human hepatocytes, HepG2s, and DefiniGEN’s HLCs derived from iPSCs. The utilization of sophisticated in vitro approaches presents promising prospects for scientific research and drug testing. By establishing more robust pre-clinical models, these advanced methodologies can enhance the accuracy and predictive value of pre-clinical assessments. As a result, when the drug progresses to the clinical trial stage, the efficacy of these trials may be improved, as researchers can make more informed decisions about drug candidates based on their performance in the refined in vitro models. This advancement can contribute to a more efficient and effective drug development process, ultimately benefiting patients and advancing medical science.

In the context of in vitro models for drug testing and research, various approaches exhibit varying levels of hepatocyte phenotypic relevance. Notably, primary human hepatocytes are considered the gold standard during the initial 5-day period due to their superior ability to recapitulate human liver physiology. However, it is essential to acknowledge that after this initial timeframe, primary human hepatocytes tend to rapidly lose their phenotypic relevance, necessitating consideration of alternative models for extended experimental durations.

DefiniGEN’s iPSCs derived HLCs demonstrate functional maturity like that of immature hepatocyte cells. These HLCs express characteristic and functional features akin to those of mature hepatocytes, albeit at a reduced rate. One significant advantage of our iPSC derived HLCs is their extended shelf life, lasting up to a month while retaining a strong hepatocyte phenotype. This prolonged functionality and maintenance of hepatocyte characteristics can make them valuable tools for in vitro studies, as they provide researchers with an extended window of time to conduct experiments and analyze relevant liver-related processes.

HepG2 cells are derived from a cancerous liver line, which may pose limitations on their ability to accurately express rare monogenic liver diseases with phenotypic relevance. The presence of cancerous genes activated in HepG2s can interfere with their ability to faithfully mimic the disease characteristics observed in normal liver cells. Despite this drawback, HepG2 cells exhibit indefinite proliferation, making them advantageous for certain research applications where a constant and abundant supply of liver cells is required. However, researchers must exercise caution and consider the potential impact of the cancerous nature of HepG2 cells when studying specific liver diseases to ensure accurate and reliable results.


Benefits of DefiniGEN’s cell lines

The substantial volume of HLCs that DefiniGEN can generate at a high level of consistency can offer significant advantages in research. The ability to produce a large volume of HLCs allows for the replication of experiments and facilitates the creation of extensive data sets. This repeatability and scalability in generating HLCs enhances the statistical power of studies and enables us to perform more robust analyses, which may lead to more reliable and comprehensive findings.

Each rare monogenic liver disease can arise from multiple mutations, and even the same mutation can be influenced by different polymorphisms, leading to variations in drug efficacy. The genetic heterogeneity observed in these diseases introduces complexities in drug development and treatment strategies. Using CRISPR/Cas9, DefiniGEN can precisely engineer cell lines with specific genetic mutations that mimic the exact molecular alterations found in patients with monogenic liver diseases. This level of precision allows us to create cell models that closely replicate the disease-causing mutations at a molecular level.

DefiniGEN possesses a wide-ranging collection of cell lines, encompassing multiple iPSC lines, which have been derived from individuals of distinct ethnicities, genders, and age groups. This extensive diversity in cell lines allows for rigorous investigation into the influence of these factors on drug response during the pre-clinical trial stage, thus contributing valuable insights to the drug development process before advancing to the clinical trial phase.

The development of models utilizing primary human hepatocytes to investigate rare monogenic liver diseases poses notable challenges due to the scarcity of patients with specific mutations and the necessity to encompass diverse age groups, genders, and ethnic backgrounds. The dependence on obtaining rare patient samples for primary human hepatocytes limits their availability and may not adequately represent the heterogeneity of the affected populations.

Similarly, HepG2 cells exhibit limitations in addressing the variabilities associated with age, ethnicity, and gender during drug testing. These cells originate from a 15-year-old Caucasian male with hepatocellular carcinoma, thereby constraining their ability to encompass the broader impact of these factors on drug responses.

The approval of the FDA Modernization Act 2.0 by the United States Senate has ushered in a new era of drug development, enabling the adoption of advanced cell line approaches to enhance the efficacy of pre-clinical testing of liver and metabolic diseases.

DefiniGEN's pursuit of becoming the standard in pre-clinical approaches aligns with the Act's objective of promoting alternatives to animal testing. As the field embraces these transformative methodologies we strive to optimize ours.


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