As of late December 2022, the US Food and Drug Administration (FDA) no longer needs drugs to be tested in animals to receive approval, according to legislation signed by President Joe Biden1 – the Modernization Act 2.0. This news has been shared widely as a landmark moment, especially in the eyes of animal welfare organisations but also among drug developers. DDW’s Megan Thomas looks into what this particular legislative change will mean for the industry.
What is it?
To assess whether or not the industry currently has what it needs to move into an era of animal-free drug testing, it is important to look at what the FDA Modernization Act 2.0 actually means, as well as observe what is already possible.
The Modernization Act 2.0 ends a federal mandate that experimental drugs need to be tested on animals before they can be used in human clinical trials2. As simplified in a press release by the National Association for Biomedical Research (NABR), the act amends the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) to clarify methods manufacturers and sponsors can use to investigate the safety and efficacy of a drug by inserting language on non-clinical tests, where non-clinical tests are defined broadly as follows3:
“A test or study that is most likely to predict human response based on scientific evidence and occurs before or during the clinical trial phase of the investigation of the safety and effectiveness of a drug. Such test or study may include the following:
- Cell-based assays
- Organ chips and microphysiological systems
- Sophisticated computer modelling
- Other human biology-based test methods
- Animal tests.”
The NABR clarifies: “The FDA previously had the authority to allow non-animal data to be considered during safety and efficacy reviews of new drugs and previously issued guidance regarding such. Ultimately, the FDA Modernization Act 2.0 may not materially change the current drug approval process at the FDA. It does not eliminate animal testing for drugs nor does it state or imply that animal testing is unnecessary. It simply clarifies the definition of a non-clinical test or study under the Food, Drug and Cosmetics Act to include adjunct and complementary testing methods like organs-on-a-chip, micro-physiological systems and computer simulations. A spokesperson for the FDA stated on the record that the new law does not change the regulatory process for drugs.”
It seems this is not a legislative milestone that will end animal testing in drug development, but rather a step in the right direction that will encourage scientists to explore non-animal innovation and embrace new approach methodologies (NAMs). Other such transitions have been made internationally in recent years, namely the measures put in place by the European Medicines Agency (EMA) in 2021 to encourage and accelerate the development and adoption of non-animal methods in the testing and approval of new human drugs4. The agency promoted three principles: replace, reduce and refine4. The agency claimed that this action, commonly referred to as the 3R’s by the EMA’s Innovation Task Force, would facilitate the development and implementation of NAMs that are in line with the EU legislation on the protection of animals used for scientific purposes.
Finding the balance
According to Science, Don Ingber, a Harvard University bioengineer whose lab developed organ chip technology that is now being commercialised by Emulate, said: “Animal models are wrong more often than they are right”1. On the flipside, the NABR’s press statement on the legislation said: “Animal testing followed by human clinical trials currently remains the best way to examine complex physiological, neuroanatomical, reproductive, developmental and cognitive effects of drugs to determine if they are safe and effective for market approval. The overwhelming majority of drugs on the market today relied on safety and efficacy data from multiple animal models before being allowed to move to human clinical trials as demonstrated by the Foundation for Biomedical Research Top 25 Drugs and Animal Models study.”3 It seems like both of these statements can be true at the same time, and that the balance may lie between them. This is why a transitionary move towards alternatives is a more attainable, realistic end-point than an outright ban.
Fund for the Replacement of Animals in Medical Experiments (FRAME), a medical research charity that aims to reduce the number of animals used in scientific testing, was awarded a total of £29,000 in February 2022 to fund three projects with the potential to replace animal use in biomedical research. In May 2022, DDW heard from FRAME’s Education and Outreach Manager Amy Beale, who discussed how current legislative and regulatory requirements for animal research could be strengthened to help prevent animal experiments and accelerate change. She also considers the factors influencing the lack of change within animal research, such as the ‘outdated’ view held by some researchers that animal tests are the ‘gold standard’, or the issue that animal use has been happening for decades, meaning there is a wealth of data. She said: “In the ongoing move away from animal research methods and the continuing development of non-animal methods that can provide the same, or more relevant information, there is a struggle to evidence the existence and value of modern ‘alternatives.’”
It seems unlikely that the FDA would ever suggest total abandonment of animal models – or rather, that this would happen any time soon until more evidence and data suggests it is a viable alternative. However, that does not prevent continued legislation that encourages reliable substitute methods and urges scientists to work on a case-by-case basis in this regard, while it also does not prevent scientists executing a degree of caution when choosing alternatives. Aliasger Salem, a professor at the University of Iowa’s College of Pharmacy, told NPR: “Companies need to be aware of the limitations of those technologies and their ability to identify or not identify potential toxicities. You don’t want to shift to systems that might not capture all of the types of toxicities that have been seen in the past without ensuring that the methods that you have will capture that.”5
As is to be expected in this industry, such caution is evident in collaborations such as that between the FDA and CN Bio, who have expanded their collaboration for the second time, with new research aiming to evaluate multi-organ microphysiological systems (MPS) using the PhysioMimix Multi-organ System. As reported by DDW, the system will initially be investigated for improving the preclinical estimation of human drug bioavailability compared to standard animal models.
This legislation, though arguably the tip of the iceberg, seems like a positive step change for the drug discovery industry.