Keeping patients safe: Accelerating change in the regulations around animals used in drug testing in favour of more effective human-focused tools
Published on April 27, 2023
Liver injury is a common side effect of taking medicinal drugs. Known as drug-induced liver injury, or ‘DILI’, it is a stark example of where we could better protect patients by using human-focused tools that effectively predict these harmful side effects.
A group of DILI experts and stakeholders recently met at the prestigious Royal Society in London, for an event sponsored by the Alliance for Human-Relevant Science and hosted by Animal Free Research UK. Through sharing their knowledge, recent advances and determining current challenges and unknowns, the goal was to begin building a collaborative community and a framework to drive forward the pace of change in the regulations around drug testing and DILI prevention, ultimately embedding a more human-focused, safer and effective approach.
Animal testing’s failure to predict liver injury from drugs and the need for policy change
All drugs ultimately go to our liver where our bodies chemically alter or ‘metabolise’ them so that they can be used or eliminated. Preclinical testing uses animals to predict harmful side effects from drugs but attempts to successfully reproduce DILI in animals have been hitherto unsuccessful. Numerous drugs have made it onto the market, only to be subsequently withdrawn following deaths from acute liver failure. Troglitazone (an antidiabetic and anti-inflammatory drug) is just one, of many examples of this, having been linked to 63 liver-failure deaths. DILI is the major cause of acute liver failure and the leading cause of failed and withdrawn drug licenses.
The close of 2022 saw the publication of a ground-breaking paper that we featured in our news, proving that the Emulate Liver-on-chip (a ‘mini-liver’), made from human tissue, vastly outperformed animal tests in predicting liver damage from drugs (DILI). This landmark study adds to the growing consensus that conventional drug development is ineffective and is letting patients down and that there’s a pressing need to adopt human-focused tools to predict DILI.
Dr Jarrod Bailey, Science Director at Animal Free Research UK, introduced the event, highlighting the pressing need to provide clear and shining examples (such as DILI) which highlight the failures of animal experiments.
“We want to build the foundations that will set the ball rolling for change, through engaging policy makers and regulators, and presenting them with irrefutable evidence and examples of where animal experiments do not translate to benefits for people, and human-specific approaches do a much better or similar job.”
Co-host, DILI expert and Pharmaceuticals Director at the Safer Medicines Trust, Dr Gerry Kenna, re-iterated this need to engage 
MPs as key influencers of government-sourced funders of scientific research. He outlined the inadequacy of the current regulatory guidelines for DILI testing, suggesting that now is a key opportunity for the UK to be a global contributor to an updated and improved drug testing policy.
“We need an improved scientific framework, supported by updated regulatory guidances, that can improve the ability of companies in particular to develop and commercialise effective and safe drugs”
Dr Mihael Polymeropoulos, President and CEO of Vanda Pharmaceuticals, detailed the career-long challenges he has faced in the US in implementing change within the Food and Drug Administration (FDA – who are responsible for protecting and promoting public health, including drug control). He continues to urge the FDA to seriously question, based on the evidence, whether it is morally and scientifically justifiable to use sentient animals in toxicology (drug) testing.
A small step but encouraging sign that marks the beginning of a transition towards a human-focused drug development was the recently passed FDA Modernisation Act 2.0 in the US, a bill authorising the use of certain alternatives to animal testing.
Challenges faced by researchers and clinicians in testing for, diagnosing and managing DILI
DILI only affects certain patients, making it challenging to predict. This is further complicated by patient-specific factors which could increase a person’s susceptibility such as age, gender, genetics, diet and underlying disease.
Professor Guruprasad Aithal, Head of the Nottingham Digestive Diseases Centre, at Nottingham University covered the challenges faced in diagnosing DILI, highlighting the fact that by presenting itself in multiple ways with no specific pattern, DILI is detected in just half of patients. He-reiterated the need for effective tools to detect DILI to avoid inappropriate diagnoses, mis-management of patients and potential liver failure.
The DILI experts highlighted that the choice of model and experimental design is critical to successful drug testing. Some of the current challenges are around how to determine which laboratory models are most suited to studying and testing for DILI, both in the lab and in patients, and how best to interpret the resulting data from these tests.
To ensure the safety of patients, there’s an urgent need for human-focused tools that will accurately and effectively predict how a drug will behave when it reaches the liver.
Professor Chris Goldring, a lecturer at the Centre for Drug Safety Science at Liverpool University, is working closely with hepatobiliary (liver) surgeons to establish a biobank of healthy and diseased liver tissues, enabling him to scrutinise the complex changes liver cells and their associated blood vessels that give rise to DILI. He put forward a potential ‘roadmap’ for the development of a ‘tiered’ system of model complexity to study and predict DILI in different patients.
Industry scientists developing and refining lab liver models to predict liver damage from drugs
Dr Caroline Bauch, Principal Scientist presented the 2D and 3D models to test for DILI at Cyprotex. She discussed the pros and cons of these models, having determined that the 3D models provide the best predictability of how a drug will affect the liver and how transcriptomics (a way of reading the information recorded in an organism’s DNA) provides even greater accuracy and insights.
Dr Bhumika Singh, Chief Scientific Officer, presented the interconnected fluidic (liquid flow) systems developed at Kirkstall Ltd. These mimic the liver environment, enabling liver cells to grow and respond to drugs as they would within the body. To encourage regulators to get on board with this new technology, she’s refining this technology so that it’s easy to use, robust, reproducible and can screen thousands of drug compounds quickly (this is known as ‘high throughput’). Dr Singh described the path towards human-focused drug testing as ‘a long road’ but re-affirmed her belief in its achievability through the notion that ‘the crucial common factor is the patient’.
Dr Tomasz Kostrzewski, VP of Science and Technology, presented the ‘liver-on-chips’ developed at CN-Bio Innovations. Livers are effectively re-created on a plastic chip. Tiny amounts of fluid (microfluids) run within channels, enabling the control of glucose and oxygen levels and therefore cell growth. He’s using this technology to test drug responses in both healthy and damaged livers, with the ultimate goal of predicting how drugs affect the livers of individual patients so that they can receive drugs tailored for them. Dr Kostrzewski is also collaborating with the FDA to ensure regulators’ familiarity with these new technologies and awareness of their advantages over animal drug testing.
Dr Lorna Ewart, Chief Scientific Officer, presented Emulate’s liver chip and the recently published results we blogged about showing the liver chip had an 87 per cent chance of predicting liver injury from drugs, compared to a staggering 0 per cent chance using animals. Of the twenty seven drugs tested (that had not been predicted to cause DILI by animals,), eleven drugs that made it to market and had previously passed animal preclinical testing ultimately led to 242 deaths and 10 liver transplants. Dr Ewart stated that the liver chip would have predicted all of these outcomes, saving lives. She said, ‘the time is now for some next-generation toxicity assessments to be brought in”. She described how a number of risk categories from ‘no risk’ to ‘certain to cause death could be generated from a ‘DILI score’. This would inform drug developers whether to stop, re-evaluate or proceed in developing the drug, ensuring patients are safer.
The future: A roadmap to change based on evidence of the superiority of human-focused drug testing over animal drug testing
The next step will be a roundtable discussion and proceedings (record of the discussions and outcomes), involving all the event participants, on the way forward for the continued collaboration, sharing of knowledge and documentation of irrefutable, concrete examples that prove the shortcomings of animals and the promise of human-focused approaches in drug testing. This will inevitably bring about the urgent policy changes that are needed, ultimately leading to more effective and safer drugs for people.
