Human models for human drug development

By FRAME (Fund for the Replacement of Animals in Medical Experiments) CEO, Celean Camp, FRAME Alternatives Laboratory Director, Dr Andrew Bennett and FRAME Scientific Liaison Officer, Amy Beale.

Animals remain the first choice for testing and research in drug discovery and development, despite scientific advances across a range of other methodologies, and some tightening of regulation in recent years. There is a growing range of human-relevant methods that are valid and reliable for predicting human outcomes.

FRAME has been working in this field for more than 50 years, and we know that the development of non-animal research techniques is a necessary part of improving the quality and efficacy of our drug development process, but that on their own, the existence of alternative methods is not sufficient to create change in such an entrenched area of scientific practice. We are therefore adopting a systems thinking approach to looking at the problem, and believe the answer, in the truest nature of scientific advancement, involves incremental small advances in a number of areas which will need to build over many years to create a fundamental shift away from the reliance on animals.

The fact that change is slow or difficult does not mean it is not worthwhile, and we can all play a part. The long-term benefits will be improved treatments for human conditions, developed and brought to market more quickly and cost-effectively, as well the saving of animal lives.

In this article, we discuss the need for a shift in ‘replacement’ thinking, what needs to be done to make responsible, reproducible, human-relevant approaches a first choice for research teams across industry and academia, and what part we believe industry insiders can play.

Animal replacement

Animals have been used in mandatory product safety testing since the 1930s and it is still necessary for drug companies to use them to demonstrate the safety and efficacy of compounds to regulatory bodies such as the FDA, MHRA and EMA.

However, in a proportion of cases, using animals is an unreliable predictor of drug safety and efficacy in humans. There have been many examples of drugs failing in humans after being deemed efficacious and safe in animal tests, such as the anti-inflammatory drug, Vioxx [i] and the diabetes drug Avandia [ii].

In addition, a 2018 study by the Massachusetts Institute of Technology showed that 86% of drugs that reach clinical trials in the US never make it to market [iii]. Whilst there are many reasons for this, a significant proportion is due to the failure of the preclinical animal tests to predict human responses. Regardless of the reason why these compounds don’t make it to market, this 86% still represents millions of pounds, as well as hundreds of thousands of animal lives wasted. A more efficient system must surely be in everyone’s interests.

The argument for continuing to use animals is the need – both regulatory (and we shall come on to that later) and scientific – to study the action of drugs in a whole living system to enable us to predict their actions on patients. Ironically, this is also the thing animal models are least equipped to do. Basic biological species differences mean that at a whole organism-level study, results are not likely to provide good predictive validity. The literature is littered with examples of compounds shown to be safe and effective in animals, but which do not produce the expected outcomes in humans, and fewer, but still present, examples of drugs which are toxic or ineffective in animals, but which are safe and effective for humans.

Animals have served medical science to a greater or lesser extent over the past century, and their use has become embedded in culture and practice, as well as education and regulation, often with little critical examination.  Where such examination occurs and flaws are exposed (such as the current ‘reproducibility crisis’), that system makes change very difficult. There are barriers to using different methodologies, a number of which will be discussed below, as well as forces both human and systemic which preference inertia. For example, journals might invite findings to be validated via an animal model (which ironically have themselves never been validated) in order to publish study outcomes, therefore reducing academic incentives to use other methods.

The move to human-focused drug development and research methods will involve changes at a variety of levels (funders, institutions, regulators, individuals) and so responsibility cannot reasonably be laid solely at the doors of industry. However, responsible companies are extremely well-placed to influence the shape of research moving forward. There are competitive and economic incentives, as well as arguably a moral obligation, to do so.

In the past year, there has been a shift in attitudes towards the use of animals in research in the UK and an acknowledgement of the future of human-relevant research, with two leading research funding bodies, the Medical Research Council and the Wellcome Trust scaling back their animal testing facilities. “Our science strategy is changing. It is as simple as that.” The Wellcome Trust told The Observer at the time[iv]. “New laboratory techniques have recently been developed which mean we simply do not need the numbers of animals that were once required for our experiments. We still need animals for our research, but not as many as in the past.”

Reducing animal use is a good outcome, but when this is the focus of scientists’ time and energy, it perhaps makes it harder to think creatively and to focus on completely animal-free methods. This is where we would argue that we need to replace, ‘replacement’ thinking.

Non-animal methods include for example, in vitrotesting, in silico modelling, organ-on-a-chip, human volunteer studies and analysis of patient data. There is much written about these different types of methods, what they are and their various advantages and limitations, but what is sometimes unappreciated is that conducting biomedical research without using animals is not really about ‘replacement’ or finding ‘alternatives.’ It is not necessarily logical to look at a test that uses mice and think ‘is there something I can replace those mice with?’ Rather, the new experimental design needs to focus on the desired outcomes, rather than replacing the animals. Unfortunately, trying to identify a single like-for like replacement is what people’s training and experience of the 3R’s [v] leads them to do, and is what our regulatory system, admittedly one of the best in the world – but still flawed – requires.

So, what needs to be done, and what role can industry play?  The list below is an overview of the developments and initiatives needed to create a formative action plan for system change from the perspective of those involved in drug development.

1. First and foremost, think hard about research questions. What specifically do you want to find out, and what it the most appropriate and relevant test to do that? Replacing animals in a study might actually involve using a suite of other methods rather than a single test that attempts to replace the animal. For example, answering the question might require some human cell work, alongside some modelling, and micro-dosing of human volunteers. This may be both more complex, and potentially time consuming in the short term, but if this approach generates more reliable results and effective treatments then this will be far more productive and has a definite cost-benefit advantage.
2. Challenge faulty logicin the allocation of your resources and design of your studies. The major health threats facing the world today (COVID-19 aside) are systemic, often chronic, conditions of physical and mental health (depression, heart disease, cancer), heavily influenced by human lifestyle factors and often by ageing. These are particularly challenging for animal models as animals do not experience the same levels of obesity, pollution and other contributing lifestyle and environmental factors. We have been able to cure cancer in mice for many years but with markedly less success in humans, so really what value is there in continuing research on the same basis? On a purely practical level, rodents obviously do not live as long as humans and keeping them alive for as long as possible in an attempt to replicate gerontological factors is incredibly resource intensive and costly. In 2019, 1.67million experimental procedures were carried out for the creation and maintenance of genetically altered animals to study cancer, Alzheimer’s and other diseases[vi]. Why is so much time and effort going into models which more often than not fail to replicate human ailments? What could be accomplished if this funding was reallocated to develop more human-relevant methods?
3. Develop more animal-free methods. We acknowledge that sustainable, validated, human-based alternatives do not yet exist to replace many of the uses of animals in the drug development and testing process. Indeed, it will in all likelihood, be many decades before they do. However, it is not satisfactory to just accept this and move on. If your car had a flat tyre and you didn’t have a spare, you wouldn’t just keep driving forever – at some point you’d have to stop and get it repaired.                                      Animal models are similar; they keep us going roughly where we want to, but are at worst dangerous and unreliable. At some point, we need to stop and fix the system even if that requires substantial investment of time and money. Pharmaceutical companies invest heavily in R&D to develop new products – better outcomes could be achieved by putting some of this investment into the development of new methodologies as well.

4. Encourage and empower researchersto explore new animal-free methodologies. If your organisation strapline or values include ‘fostering innovation,’ ‘nurturing creativity,’ ‘developing cutting-edge science,’ or similar, then we challenge you to live up to them in this area. As each generation becomes more socially and environmentally aware and demands greater integrity from employers, your future employees will expect it.
5. Use your voice to challenge the system. Powerful external agencies such as regulators, funders, and journals can sometimes make change difficult, often falling prey to either an inherently overcautious approach or some of the faulty logic previously discussed. An example is the practice of using two species to assess pharmaceutical drugs prior to clinical trials. This been commonplace for 40 years and is still the advised approach for regulatory toxicology testing for small molecule drugs. The international guidelines established in the 1980s by the Organisation for Economic Co-operation and Development (OECD) and the International Conference on Harmonization for Registration of Pharmaceuticals for Human Use (ICH) have been regularly reviewed and updated over the years, resulting in small changes that have allowed animal numbers to be reduced and notably provide the option to use a single species (the ‘most relevant’ species) in some tests. Widespread uptake of single species testing where it is permissible and where the research supports that the use of two species adds no additional value would save time, money and reduce the number of animals used. But despite this option, many organisations continue to use two species in a ‘belt and braces’ approach for fear that regulators will turn down their applications or question the robustness of their evidence.  Do not accept this. Be strong and vocal in defending your choices.
6. Invest in improved pharmacovigilance and responsible reporting. Long term monitoring and reporting of adverse drug reactions is essential for mitigating risks to human health. This should be being done with greater rigour now, but short-term thinking means it is not necessarily of high priority (until something major goes wrong). As more non-animal methods are used in the field of drug discovery, there will naturally be concern from regulators and indeed the general public over safety, given the novelty and lack of a large historical evidence base for such methods. The establishment of sophisticated pharmacovigilance units which are integrated with primary care prescribers would allow regulators to feel more confident in approving drugs tested using different approaches.

These are some ideas of how drug development companies can play a part in adding momentum in the move away from animal testing, and some of the reasons why they should. As stated at the outset however, there are a number of other key players in this field, notably government and academia, and we would also call for the following changes and initiatives from them. We hope that industry would see the value of these, support their introduction and in some cases work in partnership to achieve these long-term goals.

• Development of a (inter)national cell bank. There is a pressing need for in vitromodels of tissues and organs to be developed using human cells. Whilst primary human tissue is a valuable resource, it can never sustainably meet the demands of either industry or academia. The development of an accessible stem cell bank – focussing on iPSC but also ESC lines with clearly defined and standardised protocols for cell differentiation should be a priority. Such a resource could also address the fact that animal models lack the genetic variability in the human population which is responsible for sporadic adverse reactions and influences efficacy. The development of stem cell banks, including cell lines with defined polymorphisms known to influence adverse outcomes would be a major step forward.  Trust needs to be built with the public to encourage tissue donation and greater volunteer engagement with research.
• A national preclinical trial registry. Protocols for all animal studies should be published and open to scrutiny. This could be done without any overt identification of individuals or research groups.
• Mandatory reporting of animal trial outcomes. License holders should be required to publish the outcome of their studies, including null or negative results. The current inherent publication bias that leads to disproportionate representation of positive results makes secondary and meta-analyses unreliable and makes it difficult to truly assess the value for money of ongoing trials in particular areas, creating the very real risk of throwing good money after bad.
• Journals to require reporting using the ARRIVE 2.0 guidelines. Scientific method is built on the principle of reproducibility. Research that is not replicable due to poor reporting is at best unreliable and at worst unethical. All published animal research should be reported using the ARRIVE 2.0 checklist [vii] to ensure that the methodology is transparent, robust and replicable.

There is a lot to do to fully embed human-focused methods in the drug development and testing process, and organisations and agencies need to work together to play a part. Global drugs companies are in an influential position to challenge the system and push for changes that, in the longer term, will be more economical, humane and better for human health. Will you take up the challenge?

Main Image Credit: Sharon McCutcheon

Celean Camp is Chief Executive Officer at FRAME and works with the FRAME team, Board of Trustees and the charity’s partners to drive forward necessary changes in policy and practice and help FRAME to achieve its ultimate aim of eliminating the need to use laboratory animals in any kind of medical and scientific procedures.

Dr Andrew Bennett is Director of the FRAME Alternatives Laboratory (FAL) based at the University of Nottingham Medical School. Funded by FRAME, the FAL uses cells derived from human tissues to produce in vitro models of human organs, and provides support for PhD students, postdocs and undergraduates from the University of Nottingham to develop research projects that focus on alternatives to animals.

Amy Beale is Scientific Liaison Officer at FRAME and works with the charity’s supporters to facilitate collaborations and vital research projects and raise awareness of FRAME’s research into alternatives amongst both the general public and the scientific community.

References

1. nhs.uk. 2008. Vioxx risk confirmed. [online] Available at: <https://www.nhs.uk/news/medication/vioxx-risk-confirmed/>
2. nhs.uk. 2010. Avandia diabetes drug suspended[online] Available at: <https://www.nhs.uk/news/diabetes/avandia-diabetes-drug-suspended/>
3. Wong, C., Siah, K. and Lo, A., 2018. Estimation of clinical trial success rates and related parameters. Biostatistics, 20(2), pp.273-286.
4. McKie, R., 2019. Scientists Split as Genetics Lab Scales Down Animal Tests. [online] The Guardian. Available at: <https://www.theguardian.com/science/2019/jun/09/genetics-laboratory-scales-down-animal-tests>
5. Nc3rs.org.uk. 2020. The 3Rs | Nc3rs. [online] Available at: <https://www.nc3rs.org.uk/the-3rs>
6. Gov.uk. 2020. Annual Statistics of Scientific Procedures On Living Animals Great Britain 2019. [online] Available at: <https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/901224/annual-statistics-scientific-procedures-living-animals-2019.pdf>
7. ARRIVE. 2020. ARRIVE Guidelines. [online] Available at: <https://arriveguidelines.org/>