Headlines Have Distorted the Intent of the Bill
This message was incorrectly portrayed by media, politicians and organizations that aim to profit from the increase in services in the contract research arena for non-animal testing approaches.
The headlines read falsehoods[i] such as “The FDA no longer requires all drugs to be tested on animals before human trials”[ii]; “FDA: New Drugs Don’t Need Animal Testing Before Human Trials”[iii], and others. The USA Today’s article read, “Animal Testing no Longer Required for FDA Approval. But high-tech Substitutes Are Not ready” gave a more thorough assessment of the reality of the situation, albeit with a title that is misleading relative to the intent of the amendment to the bill. Often the articles would dig down into the reality of the situation, but these headlines have created much confusion within the biotechnology community and society.
The amendment specifically addressed the following text in the bill:
- Substitute the term “nonclinical tests” for the current “preclinical tests” (including tests on animals),
- Substitute the term “animal” for “nonclinical tests” and,
- Add a new section defining “nonclinical tests” to include human-relevant testing methods such as cell-based assays, microphysiological systems (such as Organ-Chips), or bioprinted or computer models.
Use all available tools to advance new therapies
In actuality, the impact of the bill in practice is to promote the use of all the tools in the toolbox to enhance our ability to advance new therapies in a way that is efficient and effective. The most important parameter being the ability to adequately predict adverse outcomes and thereby protect humans by using the most representative test systems.
There are many cases where efficient and effective non-animal methods have been employed for years to help de-risk or better characterize new technologies (i.e., HERG to assess cardiovascular risk; in vitro mutagenicity batteries; in vitro ADME in human and animal cells for bridging of toxicology to clinical studies, focused validated in vitro assessments). Further, non-animal methods are used effectively to evaluate target engagement or specific liabilities such as immune response or hepatotoxicity. Even though these techniques have been around for decades, much of the industry has coined the use of non-animal methods as “new approach methods,” or NAMs.
There are, in addition, new technologies such as organ on a chip or computer modeling that have shown great utility in modeling discrete test environments for questions related to target organ pharmacology or even toxicity mechanisms. As part of this broader initiative, the FDA has been funding research at numerous labs to advance these technologies.
In addition to target engagement and ADME, NAMs are being proposes for toxicity evaluations that are used in risk assessments. The OECD has published an interesting framework for the integration of these tools with animal and other data; Integrated Approaches to Testing and Assessment (IATA) - OECD. This approach recognizes that the NAMs are not often well suited for broader screening of human risk, but for targeted questions and in the context of broader data on a compound class. An integrated assessment can be valuable both in protecting humans and reducing the reliance on animal testing. Of course this does not replace animal testing, but may reduce the use and make all of the data more informative.
With human safety as the goal, animal testing will remain as an important part of the Safety Assessment Framework
Despite the important utility of alternative test systems-both historically and into the future, they are not going to replace animals in the evaluation of therapeutics any time soon. Despite their limitations, animal models are a critical piece in ensuring the safety and effectiveness of new therapies. There are no means to replace the complexity of a living system, and often this requires the use of higher order mammals that provide a bridge to the clinic.
Unfortunately, much of the scientific and academic knowledge in the field of toxicology is left unpublished. This is because the majority of toxicology work is performed under confidentiality within pharmaceutical and biotech companies, or with the contract research labs they are working with.
In the field of pharmaceutics and toxicology, we see biological surprises every week. Many of these are non-target organ immune, central nervous system or general physiological responses that are difficult to predict when we are studying novel technologies. Unfortunately, without making our failures public through transparency and publication, we are not able to learn from our mistakes and even worse the field gains a collective ignorance about issues such as the topic at hand.
Luckily, based on my experience the FDA seems to understand both the importance of continuing to implement animal test systems, and the utility of NAMS to hopefully improve our understanding, efficiency and translatability of results. They have seen the importance of an IATA type framework, and have used it to help bridge gaps and identify ways to reduce, not replace, animal use. Our interactions to date confirm that, for the time being, animal test systems as the primary driver of approval towards use in the clinic. This is the best way to ensure human safety.
Looking forward, the NAM technology will continue, as it has been, to be an important component of bridging the translation to human safety. Ideally, continued research into new technologies will help us all reach higher plateaus in coherent evidence integration and advancing biological understanding, improving the efficiency and effectiveness of bringing new treatments to society.
As a component of this, I know that the research community also hopes for technologies or approaches that can continue to refine and reduce our reliance on animal models in the pharmaceutical industry.