The demands of global population growth and new technologies have put pressure on the pharmaceutical, chemical, food, cosmetic and agriculture industries for products which use chemicals, either as a core ingredient or a component part.  

The protection of the public and the environment from unsafe chemicals rests on the shoulders of regulatory authorities who must rely on the data and results of toxicological and other testing from commercial research, development, and production processes to inform and guide their regulatory approval decisions; decisions that ultimately decide the marketability and financial success or failure of these products.  

Technological progress is driven by innovation, and the breakneck speed at which this is happening in industry is creating a gap, with the pace of advances in research outstripping the evolution of regulation.

Innovation comes at a cost, and in the last 50 years investment in research and development has increased significantly across every sector.  At the same time, taking drug development as an example, there has been a reduction in the number of new treatments successfully reaching the market.  The failure rate of new drug candidates in the clinical stages is >90%, meaning that only 1 in 20 new drug candidates achieve a marketing authorisation. This high attrition rate and the complexity of current drug development processes makes regulators more cautious and demanding for evidence of safety, efficacy, and quality.

Innovation and different viewpoints increase the gap between research and regulation
Regulatory toxicology – which includes mandatory in vivo animal testing - is often unreliable, necessarily slow, and expensive.  Regulatory change is slow too.  But with new technologies, science is moving ahead rapidly.  In particular, in the field of toxicology testing, the development of innovative New Approach Methodologies (NAMs) is racing ahead of regulatory progress.

NAMs in toxicology include non-animal testing approaches that hold great promise for improving the predictive value of safety testing, which is what regulators seek.  But these approaches are yet to deliver the level of confidence that naturally cautious regulators seek to guide their decision-making.  

This may be partly due to different viewpoints between toxicologists and regulators.   

Toxicologists in industry and academia use hypothesis-based investigation to explain the natural mechanisms of a chemical entity.  Regulators on the other hand - who rightly fear authorising unsafe products - seek quality data to solve problems and guide decisions.  

As a result of these differing viewpoints, current chemical risk assessment by regulators struggles to keep up with the constantly increasing numbers of chemicals that require testing, as well as with the validation of emerging testing methodologies such as NAMs. Put another way, what industry presents to regulators is extensively-researched scientific evidence of a new chemical’s toxicological characteristics.  But for regulators such evidence often raises more questions than answers, leaving them with little choice than to err on the side of caution.

Integrated data across testing methodologies can close the gap - with other benefits
It is generally understood that completely abandoning traditional in vivo testing methods in favour of NAMs is not possible.  But an integrated approach - in which data is collated from in vivo, in vitro and in silico testing methodologies - has the potential to bring new insights into the construction of regulatory risk assessment frameworks and aid regulatory decision-making relating to the hazardous characteristics of new chemicals. 

Many organisations have started to use in silico alongside in vivo and in vitro methods, integrating data from all three methodologies to better understand Pathways to Toxicity (PoT) and Adverse Outcome pathways (AOP) with the aim of providing more robust and predictive data to regulators.

Such an integrated approach delivers other benefits on both sides of the divide, some of which are related to the 3Rs.  The use of historical in vivo data alongside improvements to study design (such as the use of control groups for multiple experiments) has potential to reduce the number of animals used in regulatory toxicology testing.  Caring for fewer laboratory animals is a refinement to current systems and means their living conditions can be improved, leading to reduced stress, improved behaviours and ultimately more accurate results.  Finally, as in silico models and NAMs gain traction, replacement is increased because these testing methods do not require animals or harvesting of animal tissues.  

Global harmonisation in toxicity testing guidelines and striking the right balance between in vivo, in vitro and in silico testing could help to close the gap between research and regulation and move the needle on the 3Rs, but it requires collaboration and synergy between regulators, industry and academia to define and follow a regulatory pathway that gets more products to market safely and in a timely manner.