Bringing the global biologics community together

Last year, the NC3Rs published a report recommending opportunities for the wider adoption of 3Rs approaches within World Health Organisation (WHO) guidance documents for the quality, safety and efficacy of vaccines and biological therapeutics. The work was co-funded by the Bill & Melinda Gates Foundation, who awarded us further funding to deliver the 3Rs impacts of our recommendations.

Six months on, Dr Elliot Lilley reflects on how the global biologics community came together to drive the success of the project to review animal testing requirements in WHO guidelines and shares the progress towards their implementation.

Working for a 3Rs centre, it can be easy to assume that the 3Rs principles are the most important thing in all of biomedical science. Staff at the NC3Rs live and breathe all things replacement, reduction and refinement and we sometimes expect the rest of the scientific community to think the same way.

My 3Rs journey started long before I joined the NC3Rs in October 2020, first as a lab head in the pharmaceutical industry where I was encouraged to invest time and money to advance animal welfare alongside drug discovery, and then in the animals in science department of the RSPCA. In over 20 years of working in laboratory animal science and the 3Rs I have come across a wide range of viewpoints on the importance of animal welfare and the replacement of animals in research. There are those for whom the 3Rs are viewed as bureaucratic barriers to scientific freedom (a thankfully quite rare viewpoint) and those who feel that animal research is completely unethical and of limited value. The majority of the scientific community fit somewhere in between, acknowledging the limitations of some animal models and the importance of high standards of animal care and welfare where valid alternative approaches are not available.

This has meant that many policy projects I have worked on over the years have represented a middle-ground – not going far enough for some and being too bold for others.

Before joining the NC3Rs I ran several expert working groups to explore opportunities to apply the 3Rs to areas of research with the potential of a high welfare burden for animals, including epilepsy, multiple sclerosis, sepsis and spinal cord injury. In all cases, not all experts shared a similar enthusiasm for the 3Rs, animal welfare and ethics and the resulting reports, whilst representing clear progress for each research area, did not perhaps go as far as I would have hoped.

The first NC3Rs project I managed was a very different experience. We were approached as an independent scientific organisation by the WHO to review their guidance documents and manuals related to quality control and batch-release testing of vaccines and biological therapeutics (collectively known as biologics). I came onboard to manage the project, effectively an audit of where animal tests are required or recommended and to highlight opportunities to implement the 3Rs. We established a large international working group of experts from organisations that manufacture, regulate and test biologics. As I began working with this group of more than 30 scientific experts from 18 countries (including Argentina, Brazil, Canada, India, Japan, South Africa and the USA) I became aware of something remarkable. Without exception they all agreed that animal tests were inaccurate and unreliable for quality control of biologicals and that in vitro assay systems were superior. They all agreed that the rate of validation and adoption of in vitro assays was too slow, and they all wanted to accelerate this rate of change. We reached out extensively to stakeholders with surveys and regional workshops, engaging with several hundred individuals during the project, and again found an overwhelming acknowledgment of the limitations of animal tests and the scientific superiority of in vitro alternative methodologies. 

The worldwide biologics community was, uniquely in my experience, united in its wish to transition away from animal testing for quality control purposes.

I believe that two factors are at play here. Firstly, the biologics community is frustrated that the poor reliability of animal test methods means that safe products are unnecessarily restricted from communities of patients that need them urgently. Secondly, that mechanistic insight into the critical quality attributes (CQAs) that define product efficacy and safety are well characterised for many biologics. This means that in vitro assays that can reliably measure these CQAs offer improved quality control than animal approaches, meaning that fewer batches are unnecessarily rejected and patient access to life saving therapies is improved.

During the project, we reviewed 63 WHO guidance documents and identified nearly 350 mentions of animal tests. For each of these, we drafted alternative text that encourages a shift to the use of non-animal tests where scientifically justified and refined methods where replacement is not yet possible. We published our report in October 2023 along with a searchable database to make our recommendations widely accessible to the biologics community.

This incredible undertaking would not have been possible without the commitment of the many expert stakeholders that supported our work and who shared a unified vision of a testing strategy based on the latest advances in non-animal technologies.

All of this work took place during the COVID-19 pandemic when most biologics manufacturers and regulators were dealing with the enormous pressure to develop and evaluate new vaccines. The fact that we delivered this project to a successful conclusion, on time, is testament to the amazing passion and dedication of the biologics community and in particular the experts in our international working group.

We are grateful to the Gates Foundation for funding this project and for their continuing support for our work in this area with £0.5M follow-on funding to build on the findings of the WHO guidelines review and to facilitate the adoption of 3Rs in biologics testing. This is an exciting time for the NC3Rs as we await the formal response from WHO following the positive feedback to the report at the Expert Committee on Biological Standardization meeting in October 2023.

It is immensely gratifying to continue to work with a stakeholder community that is as committed to change as we are.