The US Food and Drug Administration (FDA) can now approve Investigational New Drug (IND) applications for companies seeking to advance their candidates into human clinical trials without using animal studies where scientifically justified. This authority was granted in legislation signed by President Biden in December 2022.

For several years, regulatory authorities in Europe and the UK have been able to consider data packages where the development has only used in vitro and in silico data for scientifically relevant reasons. Few, however, have chosen to pursue that route to date. Similarly, there is no expectation that small-molecule and biologic drugs will suddenly enter human clinical studies without in vivo toxicology studies as a result of this legislative change in the United States.

But drug developers do now have the opportunity, with the backing of Congress, to have slightly different discussions with FDA during pre-IND meetings. Just because the FDA has the ability to approve an IND submitted without animal data, however, does not mean that it will do so.

Why would a sponsor want to eliminate animal studies for determining the safety and efficacy of their investigational products? There is a drive across all industries to adopt more ethical business practices, and reducing the use of animals in drug development is an important factor in this shift for biopharmaceutical companies. Governments, meanwhile, are seeking to reduce and ultimately remove animal testing for all types of products, and many of today’s consumers regard animal testing as an important ethical consideration in purchasing decisions.

There are scientific drivers for replacing animal testing with in vitro and in silico assays, too. Most biologic drugs in development today are highly human-specific and complex in their targeting and mode of action. Animal models are therefore becoming less relevant to current drug pipelines, and may lead to the generation of confusing or possibly even human-irrelevant data that must nonetheless be further investigated before moving to first-in-human trials. This typically increases the time and cost of drug development. Additionally animal in vivo studies may provide a false sense of security in moving to human trials if no safety concerns are noted.

In the in vitro space, researchers are generating relevant data in cell-based systems and are reaching a point where it is possible to investigate specific biological mechanisms. Some of those mechanisms, including immunogenicity, are important for many drugs. Some in vitro models for immunogenicity may even be more predictive than animal studies. Animals are highly likely to develop immune responses to administered human proteins, and many current safety issues with biologics in particular are driven by such immune responses.

There is also a lot of excitement about artificial intelligence (AI). Researchers are gathering massive amounts of data, and using AI algorithms to understand, distill and interpret these data. In vitro assays are then used to verify what is predicted in silico.

But for which drugs would an IND filing based on animal studies be most likely to receive FDA approval? Biologics are more likely than small molecules, because the effects of metabolites generated when small molecule chemical compounds break down and distribute in the body are more difficult to predict. Recombinant proteins and antibodies break down into amino acids, the metabolic behavior and distribution of which is well understood.

An in vitro / in silico testing approach is also more appropriate for drug candidates that are not first-in-class. Biologics directed at well-understood targets, and even conventional monoclonal antibodies (mAbs) that are novel in terms of targeting but are not expected to behave in an unusual way, are less likely to require extensive toxicology studies because the safety of such molecules is generally well understood.

Biosimilars are the obvious drug candidates to benefit from non-animal testing strategies. They are known proteins/antibodies going after known targets, and they are developed to be as similar as possible to products already on the market. The use of animals for safety and efficacy testing may not make much sense in this context. Impurities are the main issue with biosimilars, and it should be possible to evaluate them analytically or in vitro without the need for animal studies.

Next-generation therapies are also good candidates for animal-free safety and efficacy testing, as human-relevant animal models are particularly difficult to access for cell therapies. It is generally necessary to develop a transgenic animal or to develop an animal-relevant version of the human cell therapy, so in the end the actual human-intended product may not be tested in these tox studies.

As with anything related to drug development, there are no simple or obvious answers to the question of non-animal testing. Companies may, in the past, have conducted animal toxicology testing perhaps largely because in vivo toxicology studies were still required in the US, and development work is typically done from a global perspective.

Perhaps now that IND filings based solely on in vitro / in silico test data can be considered by the FDA, more companies will approach this option. While the agency appears supportive of the move away from animal testing, it expects any alternative methods to be scientifically sound and proven to provide evidence of safety and efficacy performance. The FDA itself has in fact received funding to launch a program focused on developing alternative methods to animal testing.

Lonza is ready to support any companies that want to explore non-animal testing strategies. With our new facility in Cambridge, Massachusetts (US), our Early Development Services are now easily accessible to US-based customers.

With more than 15 years’ experience and more than 1,000 finalized developability profiles, our EDS facility in Cambridge (UK) already helps customers to improve the safety and manufacturability of biotherapeutic candidates. Services are provided via a suite of in silico, early non-GMP protein expression and in vitro immunogenicity services.

The new US laboratory increases our capacity to provide early preclinical expression and in vitro immunogenicity services, enabling Biologics customers to de-risk and optimize drug candidates at an early stage and maximize their chances of success.

Latest content
Latest briefing from the Knowledge Center