Drug development is complex

Developing new medicines is a complex, multi-stage process involving both non-clinical and clinical testing to ensure the new treatment works properly and is safe for patients.

• Non-clinical testing refers to testing in the laboratory, often on animal ‘models’.
• Clinical testing refers to human trials.

Understanding disease biology is key—researchers study how cells and biological systems function in health and disease to identify drug targets. To do that, researchers study how cells normally work and how they behave differently in disease. Once they know which part of a cell, like a protein or receptor, is involved, they can look closely at its shape and structure. Basically, what it looks like at the molecular level.

If they know the shape of that “target,” they can design a drug molecule that fits it, like a key fitting a lock. That’s how they create treatments that specifically act on the faulty parts of cells causing the disease.

100,000s of thousands of different molecules can sometimes be screened at this stage to produce just one new drug.

Those that show promise undergo extensive testing before receiving approval for clinical trials in humans. A range of models that differ in their ability to replicate biological complexity are used.

These methods include:

• in silico (computational) models
• in vitro (cell- or tissue-based)
• ex vivo (tissue- or organ based)
• in vivo (whole animal)

Often media reports of ‘breakthroughs’ refer to the animal studies of this pre-clinical phase. These early findings, even when extremely promising, may take years to become actual treatments, if indeed they ever do.

Replacement Technologies in the Drug Development Process

Animal studies are still seen to be a regulatory cornerstone for safety by industry and regulators.

But, animal biology doesn’t always predict human responses and can lead to failure in later drug development stages. Many human also conditions can not be modelled in animals.

So aside from industry and academia’s commitment to the legislative framework of the 3Rs, where Replacement should be the first priority, there is growing momentum to develop and use human-relevant methods that better reflect human biology.

Pharmaceutical companies have already been replacing animal studies in the early phases of drug development for a decade or two. They have been developing and integrating techniques such as organ-on-a-chip technology, organoids, high throughput in vitro assays and in silico modelling into their drug development pipelines.

They are also collaborating with regulatory and policymaking experts to reduce animal numbers further. For example, the VICT3R project “Developing and implementing VIrtual Control groups To reducE animal use in toxicology Research”, is a public-private partnership funded by the Innovative Health Initiative (IHI).

The project is dedicated to reducing animal use in toxicology research by developing Virtual Control Groups. They estimate that eliminating the need for animals in experimental control groups could reduce animal use in this phase of drug development

Regulatory Concerns

While there is growing interest in using New Approach Methodologies (NAMs) in developing new medicines, the primary concern for regulators is protecting human health.

Any new approach must demonstrate that it can support safe and effective decision making for patients. NAMs must therefore not only show scientific validity and predictive relevance to humans, but also show that important decisions that affect patients, such as whether a clinical trial progresses, and what doses they are given, are based on data that is as reliable  as (or even outperforms) animal data.

Which leads to a conundrum: if regulatory bodies only trust animal data, how do they prove that non-animal data is as effective? Conversation. It requires a lot of dialogue between regulators and those developing drugs about what data they will accept as being equivalent to, or exceed, what they accept from animal studies.

NAMs are already increasingly used, both within academia and industry and especially where no suitable animal ‘model’ exists, and drug developers are submitting NAMs data as part of their applications to carry out human trials.

As NC3Rs recently reported, where medical need also allows for greater regulatory flexibility and risk tolerance, there are now examples of medicines being used in clinic without any, or very limited, animal testing. For example, the approval of the immunotherapy Tebentafusp, to treat uveal melanoma, progressed to clinical trials and approval without any in vivo data, due to lack of relevant animal models.

But most drug development does still rely on animal data.

Regulatory Approval of NAMs

Currently, there are only a few non-animal methods approved for regulatory use, and only in specific situations. For example:

• ‘quantitative systems pharmacology modelling’ allows evaluation of critical aspects related to the efficacy of a drug candidate.
• Physiologically based pharmacokinetic models are increasingly used to predict human drug exposure and support starting dose selection and escalation.
• Certain human stem cell-based assays are now recognised under the International Council for Harmonisation of technical requirements for pharmaceuticals for human use guidelines, for example ICH S5(R3) for particular reproductive toxicity assessments.
• Microphysiological systems (e.g. Newcell’s 3D retinal organoid model, made from human stem cells) are also being included in drug applications, showing how advanced NAMs are starting to play a meaningful role in regulatory decision making.

Medicine development is Global

But medical research, drug development, and approval, is a global endeavour.

The UK Government’s published their phase out strategy on 11 November, and other parts of the world like the US FDA and European Commission, and the international pharmaceutical industry, are also actively working to phase out animal use where possible, and investing heavily in NAMs in the process.

But internationally, many regulatory guidelines still rely on animal data, creating uncertainty for drug developers about how to ensure their data will be acceptable in a global marketplace

Because medicines are sold worldwide, all countries’ regulators need to agree on which tests are acceptable. If only one country allows data from a non-animal method, companies will still have to do animal tests to get approval elsewhere, otherwise, they can only sell the medicine in that one country, which isn’t financially favourable.

What about in University research?

While drug developers are making leaps and bounds in transitioning away from animal use, we must keep in mind that over half of all animal procedures in the UK still happen in universities, rather than in regulatory testing of new drugs.

Working together

While the NAMs technologies themselves are developed across both academic and industrial settings, their application in drug development lies primarily within industry.

Greater collaboration between academia, industry, and regulatory bodies, supported by education on the medicines development process, will help ensure NAMs are designed to meet regulatory and practical requirements – such as scalability, cost-effectiveness, ease of implementation, and compatibility with high-throughput workflows.

The adoption of NAMs and the phase out of animal use needs a harmonised approach, which means collaboration among academia, industry, and regulators. There is precedent for this, and we already see many collaborative efforts making headway.

We can be hopeful that it will indeed be possible to develop human medicines, without animals, sooner rather than later.