Passage of the FDA Modernization Act Enables New Era for Preclinical Testing

The 11th-hour passage of The FDA Modernization Act, in late December 2022, gave a much-needed boost to the advocates of new alternative methods (NAMs) for preclinical testing. For years, the scientific community has worked with the U.S. Food and Drug Administration (FDA) to create opportunities for the consideration of data generated from NAMs in the investigational new drug (IND) process. In the absence of clarifying legislation, many pharmaceutical companies have been reluctant to invest in new methods because they lacked confidence that the associated data would be accepted by regulators. Change has been slow, but the passage of the FDA Modernization Act will provide the assurance the pharmaceutical industry has been waiting for.

Why NAMs are needed

As part of the new drug application process, pharmaceutical companies must submit preclinical data on their compounds before they can advance into human clinical trials. Typically, companies collect and submit data from mice and larger animals, such as monkeys. While precise data on the number of animals used in research are not available, animal rights groups critical of the industry peg the number at more than 110 million animals globally. These studies have been the basis for IND approvals for many years, but large translation gaps that are contributing to alarming attrition rates (toxicological issues, poor replication of results in humans, subpar efficacy profiles) persist and widespread calls for reform have intensified.

NAMs can be used in experiments to understand how a compound or an environmental factor might impact a living human’s biological system. Examples of NAMs include cell models such as cell-based assays, organ-on-a-chip technologies, computer modeling and other micro-physiological systems. Collectively, these products can help improve the general understanding of how active ingredients in new drug products function in a human model (vs animal model) prior to their use in human testing. Approximately, 90% of drug candidates entering human clinical trials fail. These new approaches can help improve the percentage of promising drugs entering these trials where the benefit to patients is illustrated and approval for the market is ultimately decided. An additional benefit of NAMs is the ability to better account for diversity in age, race and gender/ethnicity across the human population as compared to animal models.

FDA interest isn’t enough to inspire change

The FDA has long recognized the need to broaden its acceptance of a wider range of data types as part of the IND process and has been actively engaging with the community on this issue for many years. For example, in 2017, the FDA released its Predictive Toxicology Roadmap. The document outlined the FDA’s thinking on emerging methods of conducting toxicology studies (including NAMs) and discussed how it envisioned one day incorporating these evidence types into FDA regulatory review. In 2020, the agency took another step towards incorporating NAMs into its guidelines by creating the Alternative Methods Working Group. The group cataloged the agency’s efforts within different offices to study NAMs, but this work served as more of a framework for regulators to draw on in evaluating data developed by NAMs rather than a clear roadmap the industry needed to broadly adopt these technologies.

The Roadmap did produce one example of true progress. In 2022, FDA approved the first IND for a company testing a therapy for a neurodegenerative disease which developed toxicology data using organ-on-a-chip technology in place of live animals. This was an important milestone for the industry because it showed that the data generated from NAMs could be acceptable to the agency for the first time. Even with this initial IND approval, a lack of clarity in regulation has remained a barrier to industry investment in making the use of NAM-based methods routine.

How new legislation changes the game

Despite exploration into NAMs by the FDA, pharmaceutical companies have had limited incentives to replace their animal testing work with NAMs in part due to the maturity of the field, and a lack of clarity in law and regulation about whether these data would be accepted by FDA regulators. The new legislation brings clarity to companies by passively creating the opportunity for organ-on-a-chip technologies and other alternative testing models to be used in place of live animals.

One of the most important components of the legislation is that it codifies the definition of a non-clinical test. While this may not sound critical, this definition is needed for pharmaceutical companies to feel confident that their use of non-clinical testing methods will be acceptable to the agency as part of an IND submission. It also defines the types of animal testing alternatives acceptable as part of non-clinical tests to include specific animal testing alternatives including cell-based assays, organ-on-a-chip models and other methods.

The legislation does not force pharmaceutical companies to adopt NAMs, or to transition away from animal testing, but it creates opportunities for companies to consider other methods that weren’t acceptable before. These are incremental changes, but they are critical next steps that will spur innovation and more experimentation using NAMs by the industry. Collectively, all players hope that by adopting NAMs, the use of animal models can be reduced, attrition rates and translation errors can be lessened, diversity can be better accounted for, and ultimately safer, more effective medicines can come to the market for patients in need.

About the author:

Dr. Trivia Frazier is the president, co-founder, and CEO of Obatala Sciences, Inc., a biotechnology company that manufactures stem cell-based biomaterials and microphysiological systems for drug screening in metabolic research. She has extensive training in physics, biomedical engineering, stem cell research and business finance.