Running a 3Rs award scheme is one way that biopharmaceutical companies can support scientists and animal care staff to put the 3Rs into practice. In this guest blog post, Paul Finnemore and Stewart Owen share how AstraZeneca is supporting communication and innovation in the 3Rs across its global sites.
For AstraZeneca, like all innovative biopharmaceutical companies, the use of laboratory animals remains a small but necessary part of developing new medicines for patients. Animal studies are currently required both for fundamental research and to meet regulatory needs to establish the efficacy and safety of candidate medicines before starting human clinical trials. We recognise the societal and ethical responsibilities that come with animal use, which is why we put the 3Rs at the heart of what we do. We use approximately 144,000 animals globally per year with around 75% of those used in-house at our own facilities. Mice are our most commonly used species – combined with rats and other rodents, they make up around 93% of our animal use. We also use smaller numbers of fish, ferrets, dogs and monkeys in developing life-changing medicines in oncology, cardiovascular, respiratory and metabolic disease. These numbers used are a reflection of the scale ($6bn per year) of our efforts to find new treatments for patients.
Whilst our total numbers have fallen significantly over recent years, numbers alone do not tell the full story. The breadth and nature of the research portfolio is the main driver of animal use; the important factor is making sure that however many animals we use, it is the smallest number necessary to achieve reliable results. Working across international boundaries and areas of medical speciality is complex and presents challenges for a global company. Consistent standards of animal care and welfare are an obvious necessity and AstraZeneca sets and maintains these through a network of compliance and technical experts, overseen by the Council for Science and Animal Welfare (C-SAW). Standards on their own, however, are not enough. Even with a network of enthusiastic and dedicated scientists, it is difficult to share everything that is happening related to animal welfare and the 3Rs across multiple time zones and global sites.
Constant efforts are needed to make sure we keep a focus on the 3Rs alongside all of the other priorities. One way we keep the 3Rs in the spotlight is through our annual award process. C-SAW run a competition that rewards 3Rs innovation, but much more importantly shares best practice to encourage wider uptake and promote further activity. This has evolved over many years to the prestigious level it has reached today, with endorsement and support from the CEO of the company. The Global C-SAW Awards currently accept nominations in three categories. Two are recent additions: “Openness” awards are for developing STEM outreach initiatives, including hosting visits to animal facilities, while “Culture of Care” awards recognise the values and behaviours around caring for animals and the people that look after them. However, at the core of the awards process, and the longest standing part, is “Excellence in the 3Rs”. Scientists and technicians are invited to submit their 3Rs innovations in a poster format that shows what issues they worked on and the impacts they have had. The posters are judged by a team of international experts from the company including veterinarians, in vivo and in vitro scientists statisticians and those from non-scientific backgrounds. For several years now we have also been grateful to have the external expertise of Dr Vicky Robinson CBE, Chief Executive of the NC3Rs, as a member of our panel.
Year on year, the depth and breadth of the submissions has evolved remarkably, in large part thanks to our iterative process of using previous entries to stimulate interest and activity in the following year’s competition. In 2019 there were 55 submissions involving more than 211 people, a new record for us. The submissions included everything from simple changes with local impacts, to large multi-year projects dedicated to changing the way we do pre-clinical experimentation and speeding our decision making. For example, a team of cardiovascular scientists implemented a simple change from tracheal intubation of rats in surgery to a nose cone method that demonstrated the same blood gas parameters and anaesthetic support as the previous method, but without the risks and difficulties of intubation. This refinement will positively impact several hundred rats per year locally and has already been shared with some external experts. The team also aim to publish this work soon.
Another entry took a novel approach to the issue of how to process more potential medicines without increasing the number of animals used. Some new technologies, such as using nano-particles to deliver immune therapies, present specific issues when moving from the in vitro to in vivo stages. In this case, there are potentially hundreds of combinations of particle size and coating that would traditionally need separate experiments, requiring the use of a large number of animals. The team overcame this issue by using mRNA to uniquely label (or “barcode”) lipid nano-particles and creating mixtures of these nano-particles to test efficacy in mice. This resulted in a five-fold decrease in the numbers of mice needed. Finding ways to apply new technologies like this is one way we are working towards a reduction in the number of animals we need.
In other cases, we have examples of work undertaken over a long period of time to effect change. One of our winning entries in 2019 was a case in point. Antibiotics are essential, not only as life-saving medicines, but also in enabling other treatment such as chemotherapy or surgery to be carried out safely. There are a wide range of regulatory conditions to register an antibiotic in Europe, and one essential step is to understand the impact on the environment. Previous regulations required tests on fish, but fish are not necessarily the most sensitive model. Working in collaboration with the University of Exeter, our winning team carried out a meta-analysis of the data to show that cyanobacteria (blue-green algae) provide a more sensitive and therefore appropriate model. On the basis of this evidence, the regulations have been revised: in the current revision of the European Medicines guidance, fish will no longer be required for environmental toxicity testing of antibiotics. This is a great example of the replacement of animal studies.
In many award schemes the focus is only on the winners, and few people get to see the rest of the submissions. For us, however, a key part of running a 3Rs award process is to communicate the fantastic work conducted by our teams across the globe, in order to inspire others. It isn’t just about the winners, it is also about sharing the submissions with the widest possible audience. For the past few years we have displayed all the poster submissions as a “travelling roadshow” at 3Rs events across our sites. We think this helps both with openness and innovation. In terms of openness it raises the awareness of the work with colleagues that don’t have contact with the animals, helping them understand more about what is involved in animal research and the importance of the 3Rs. For those who are involved with in vivo research, the posters provide an opportunity to see innovative approaches from other sites and in other parts of the business, spurring them on to try them out or develop their own ideas.
We know we are not unique amongst biopharmaceutical companies in running our own 3Rs award scheme, in addition to supporting those run by other organisations such as the NC3Rs. While we have made a significant difference to the 3Rs within AstraZeneca, the next step is to share the outcomes of these various schemes and the innovations they produce more widely across industry, contract research and academia. Ultimately, this will increase the impact of this work even further, advancing both the 3Rs and scientific innovation.
About the authors: Paul Finnemore is AstraZeneca’s Chief Veterinary Officer and Chair of C-SAW. Stewart Owen is Principal Scientist and Chairs the 3Rs awards.