An inflection point in the status quo?

There is great focus on improving the translational gap between the information the animal models currently provide, and what this means in terms of expected human responses. This has led to great interest and discussion on the use of New Approach Methodologies (NAMs), a term used to describe any non-animal model (such as human iPSC-based models).

However, despite the clear interest and potential of NAMs, there have been a number of barriers to their implementation in routine safety testing of pharmaceuticals, cosmetics, household products, and agrichemicals. Attention has therefore turned to addressing these barriers.

New Approach Methodologies like our iPSC-derived neuromuscular junction model have enormous potential in drug safety and discovery. We need alignment of industry, researchers and regulatory bodies to fulfil this potential.

Who are HESI/NC3Rs, and what was the aim of this meeting?

HESI is the Health and Environmental Sciences Institute, a non-profit institution whose mission is to collaboratively identify and help to resolve global health and environmental challenges by engaging with scientists from academia, industry, government, regulatory groups and NGOs.

NC3Rs is a UK-based scientific organization dedicated to helping the research community worldwide identify, develop, and use 3Rs technologies and approaches.

The aim of the meeting was to not be a “talking shop”, but instead to identify barriers to the widespread use of NAMs and to chart a practical path to incorporating NAMs into routine safety testing of chemicals within the next 5 years.

5 Key takeaways from the meeting

#1: Change is happening at pace!

Research conducted at the meeting found that NAMs are being used in ~70% of companies, so there is a clear drive to transition from current methods. This rate of change is challenging to suppliers, researchers, and regulators, so close coordination between all parties is important to keep up with the pace of change.

#2: The way industry does safety assessment needs to change

With a renewed outlook on safety standards, we can clearly see areas where the safety industry can improve. One clear example is shifting from hazard assessment (high dose toxicity testing) to exposure assessment based on proposed use / concentration. In this way, you can rethink the problem, prioritizing protection, not prediction (which uses large, unrealistic doses).

#3: Case studies are needed, and data transparency is important

As much of the information generated by Research & Development is confidential, it doesn’t make it to regulators. However, OECD (Organization for Economic Co-operation and Development) case studies enable this through sharing with all stakeholders. It’s also important for regulators to share cases where they have experienced NAMs in submissions.

#4: Acceptance of NAMs requires industry to submit more data

To effect change, the industry needs to push for greater usage of NAMs, with more sharing and submitting of data. By registering data in dossiers, with justification and data interpretation to help regulators to understand, the industry can more actively drive the adoption of NAMs. Guidelines need to adapt and be updated to accommodate this new form of data, to realize the potential of the FDA Modernization Act 2.0.

From our own market research, 55% of respondents stated that the FDA Modernization Act 2.0 is driving exploration into iPSCs. We can clearly see the opportunity in front of us, but fulfilling that will require a concerted, data-driven approach.

#5: The community needs more distinct allocation of funding

There is a need for more distinct funding allocation for NAMs validation, and greater governmental incentives to validate and utilize NAMs. To quote Jack Scannell (of Edinburgh University and co-author of the recently published Emulate paper), “…pharma get paid more using bad models than investing in new models”. The Emulate paper demonstrated that a human liver chip could improve patient safety and reduce small-molecule clinical trial failures due to liver toxicity by up to 87%, just one example of the tremendous potential that NAMs provide.

There is a great need to acknowledge that these methods do add value (in terms of a positive return on investment longer term), which should drive funding models to specifically address the “valley of death” of NAMs validation and qualification that is currently missing.

Future outlook

There is a clear scientific, social, and ethical drive to change. NAMs increasingly are proving their value by generating more relevant and useful in vitro models of human disease. In drug safety testing, they have been successful so far in addressing the mounting social and ethical concerns that both scientists and the public have with the use of animal models.

We need to remove barriers to the widespread use of NAMs, and this conference enabled a deep dive into pathways to overcoming these barriers for the routine incorporation of NAMs into safety testing.

For me personally, this quote from the meeting summed up my views:

“In order to arrive someplace, you need to leave where you are first” – Doug Wolf, Syngenta.

People want to change, but confidence in anything new needs to be earnt through adequate evidence (validation), transparency, and a willingness to take risks.

If you’d like to explore our work with NAMs and in vitro disease models, take a look at our current missions: Human iPSCs for better human disease models. (axolbio.com)