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New Approach Methodologies (NAMs) based on human biology have the potential to reduce, and ideally eliminate, toxicities that arise during drug discovery and development. Pharmaceutical companies are already using NAMs in early drug development, with considerable success. However, there are areas of unmet need where NAMs might deliver more predictive power, potentially improving and expediting drug development. At present there is no overarching consensus on how NAMs may be incorporated within regulatory guidelines and numerous hurdles are hampering action. Guidance is needed especially for academic researchers and small biotech start-ups that drive NAM development, yet may be unfamiliar with the precise needs of regulators and other end users.

NAMs need to be included within a scientifically valid, integrated human-relevant pharmaceutical safety assessment strategy that will be acceptable to industry and regulators. With this in mind, we held a series of 5 workshops with 13 international experts (regulators, preclinical scientists and NAMs developers), to identify feasible NAMs and discuss how to use them in specific safety assessment contexts.

Participants generated four decision tree ‘maps’ showing how NAMs could be used to assess safety for the liver, respiratory, cardiovascular and central nervous systems. These organ system maps provide guidance on how specific human-relevant tests may be used in each context, as well as a template that could be applied to additional organ systems, or testing in other contexts. Maps like these have potential to guide stakeholders and generate confidence in using NAMs to complement and ultimately replace in vivo animal methods.

Converting these maps into interactive decision trees would allow users to ask specific questions and select the most appropriate NAM for their purpose, so the development of a more dynamic and user-friendly version of these maps is an important project for the future. This work could lead to greater adoption of NAMs, improved pharmaceutical productivity and, most importantly, safer medicines. The findings from this workshop have potential to contribute to implementation of the recently passed FDA Modernisation Act, which enables the use of NAMs for regulatory purposes in the US. We hope others will build on this work and use it to speed the transition to greater human relevance, which is so urgently needed.

We were delighted to work alongside partners from the Alliance for Human Relevant Science, including Animal Free Research UK and Cruelty Free International. Cruelty Free International conceived the idea for the project and we are grateful to the Cruelty Free International Trust for funding this project and to all participants for so generously giving their time and expertise.

Read the paper in ALTEX here

15 minute interview with Dr Jan Turner, who explains how organoids and organs on chips are enabling new knowledge of human biology and disease. These miniature models of human systems provide human-relevant insights and can be personalised to individual diseases, allowing studies that have never been possible before. These infinitely adaptable tools overcome the insurmountable limitations of animal models, ushering in a future of better, more efficient drug development and safer medicines for patients.

Listen here:
cytivalifesciences.com/en/gb/podcast

Thanks to Cytiva and Dr Jan Turner, our much-missed former Director.

On 27th October, the Royal Society of Medicine in London was the venue for an exceptionally thought-provoking and inspiring  talk by Dr Azra Raza, Professor of Medicine at Columbia University in New York, international authority on leukaemia, acclaimed author of ‘The First Cell: And the Human Costs of Pursuing Cancer to the Last’ (Amazon’s ‘best science book of the year 2019’) and Science Adviser to Safer Medicines Trust.

Dr Raza’s themes were then eloquently expanded upon by Professor Geoff Pilkington, Emeritus Professor of Neuro-oncology at the University of Portsmouth and former Head of the Brain Tumour Research Centre, Member of the Alliance for Human Relevant Science, Trustee of Animal Free Research UK and The Childhood Cancer Charity and Science Adviser to Safer Medicines Trust.

An expert audience then participated in a Q&A chaired by Dr James Le Fanu, well-known columnist and historian of science and medicine, acclaimed author of ‘The Rise and Fall of Modern Medicine’, Fellow of the Royal Society of Medicine and Patron of Safer Medicines Trust. 

Dr Raza explained why the global cancer research effort should change direction to:
1) focus on prevention and early detection, with the aim of finding the first malignant cell instead of attacking late-stage disease, to which end she has established The Oncology Think Tank and the First Cell Coalition for Cancer Survivors; and

2) focus research exclusively on humans and their tissues, rather than on mice, rats and other animal models. For this purpose, she has founded the First Cell Center, to study her tissue repository of more than 60,000 samples collected from her patients over the past 38 years.

We are so grateful to all the speakers for such an inspirational discussion. The whole event can be viewed below:

A one-of-its-kind online community aimed at improving communication among biomedical scientists has been launched by the Alliance for Human Relevant Science and Animal Free Research UK.

The Animal Free Research Community of Practice is an interactive network for members to share their work, ideas, challenges and passion among likeminded peers.

With free membership for academic and early career scientists, students, industry and other stakeholders involved in biomedical research, members can interact online 24/7 as well as attend planned events, including open houses, roundtables and Helpathons.

A user-friendly website features up to date news, resources, tools, networking and project collaboration opportunities, latest research papers, job vacancies and academic openings. The community is curated by members and hosted by Animal Free Research UK coordinators.

New members can sign up and join the community by clicking here: Join the Community of Practice

Members are invited to create and add content to the online forum, share events and resources, and to collaborate on projects such as writing reviews, articles and much more. The Animal Free Research Community of Practice will bring scientists closer. It will raise awareness, deepen knowledge, drive creativity and spark passion for a science that benefits animals as well as humans.

We urge all who want to practice modern medical research – that which truly delivers benefits for human health – to sign up and become part of this important, exciting community.

A new paper in the 50th Anniversary issue of Alternatives to Laboratory Animals, co-authored by Dr Jan Turner, analyses the origins of regulations requiring animal safety tests for new medicines and whether they were justified then or now.

The thalidomide tragedy shocked the world and led to new laws requiring ‘proof of safety’ in animals, despite the irony that it was thalidomide’s near-total safety in animals that helped to cause the tragedy and would not have prevented it. This new analysis shows that moving away from animal testing is limited not by scientific possibilities, but by historical precedents and persistent beliefs that animal tests will prevent future tragedies. No amount of animal testing can eliminate the risks inherent in introducing new drugs to the market. Regarding animal tests as the gold standard gives a false sense of security, which acts as a barrier to creating potentially safer medicines and leads to human health risks, as well as the use and killing of many animals without a sound scientific basis.

Greater public and political awareness of the risks to public health that result from a continued reliance on animal testing can contribute to a shift in paradigm toward increased reliance on human-based safety testing. For scientists and regulatory bodies to contribute effectively to the transition away from animal testing, it is important that they continually reflect upon, and highlight how, an (often implicit) belief in animal testing as the gold standard continues to affect research, education, regulations, funding practices, etc. This should include a critical reflection on the 3Rs paradigm, as well as the critical perspectives of scholars from the humanities and social sciences, all of which are needed to break free from the confines of the current paradigm.

Read the whole paper here

On 28 and 29 June, Animal Free Research (AFR) held its 2022 conference on ‘Modernising Medical Research’,  a welcome return to ‘in person’ events following the COVID-19 pandemic and several members of the Safer Medicines Trust team attended over both days.

The event had a very positive atmosphere, with the aim of exchanging knowledge and ideas in the transition towards modern, human relevant medical research to benefit public health. This aligns with the objective of the Safer Medicines Trust that patient safety can and must be improved by utilising better science.

Day one provided a series of talks from experts across many areas of research, for example on advances in in vitro technologies such as 3D organoids (‘mini organs’) or ‘Organ on a Chip’ models (also called microphysiological systems, or MPS). As shown in the image above, these are small devices lined with microchannels containing human cells, fluids and tissues which can test responses to drugs or monitor the progress of disease, to provide better prediction of the human response than conventionally used (animal) methods. A keynote speaker was Dr. Don Ingber, the founding director of the Wyss Institute at Harvard University who pioneered MPS technology with the ‘Lung On A Chip’, first developed in 2010. Exciting advances in this technology over the last decade have resulted in many more models such as brain, liver and even the beating heart, ultimately working towards a ‘human on a chip’ to revolutionise drug discovery and disease research. Dr Ingber was also presented with  an ‘Animal Free Research Pioneer’ Award.

Other talks presented human relevant methods that could be used to study brain tumours, liver disease and colorectal cancer and how such methods provide better translation from ‘bench to bedside’ when compared to animal models. One speaker for example, highlighted how the results of chemotherapy found in mice translate to humans less than 10% of the time. The importance of use of human tissue removed during surgery (which would otherwise be discarded) was also discussed.

Speakers also showcased their in silico research, which can very broadly be defined as ‘computer based’ methods, but includes a vast range of techniques from simpler drug screening analyses to complex ‘deep learning’ and artificial intelligence approaches, for example advanced computer simulations to investigate cardiac arrest and in silico analysis to examine the genetic traits of chronic diseases.

The methods described above are just a few examples of what are also collectively termed ’New Approach Methodologies’, or NAMs. A common barrier to the use of NAMs is the misperception that any one technique is expected to replace a corresponding animal method. This has never been the case. Instead, combinations of many techniques, for example in silico, in vitro and data from studies in humans can be combined to provide human relevant answers to research questions, where animal models often fail or do not even exist. This important issue (among others) was discussed at day two of the AFR conference, which was a ’round table’ event, bringing together scientists, campaigners and lobbyists to discuss how to effectively communicate to the research industry, regulators, political audiences and the public on the need to modernise scientific research by shifting to NAMs and ‘human relevant science for humans’.  The need for change is already recognised by many in industry. For example, the in vitro toxicology testing market was valued at 8.3 billion US dollars in 2019 and is projected to be worth over 18 billion US dollars by 2027.

Safer Medicines Trust and AFR are founder members of the Alliance for Human Relevant Science, a collaboration of companies, charities and organisations launched in 2017 to accelerate awareness and use of human relevant approaches within industry and the scientific research community.

For more info on the Alliance for Human Relevant Science visit www.humanrelevantscience.org

For more info on the ‘Modernising Medical Research’ event visit Science Conference – Animal Free Research UK

3-minute highlights video now available: http://www.animalfreeresearchuk.org/scienceconference-2022/

Despite resisting scientific scrutiny for decades, animal studies have, over the last twenty years, been revealed by systematic reviews to be poorly conducted and unreliable, with the result that humans have, on occasion, been seriously harmed. Such troubling exposures have prompted several initiatives to improve the quality of animal studies and their reporting, but these have had little impact so far on improving their translation to humans. Could it be that fundamental differences between species constitute an insurmountable problem for biomedical research? Given that transformative human relevant technologies such as organ-chips and organoids are now available, could now be the time for a new paradigm?

Highly recommended reading! The role of systematic reviews in identifying the limitations of preclinical animal research, 2000 – 2022, Ritskes-Hoitinga M, Pound P (2022)

Our Pharmaceutical Director, Dr Gerry Kenna, recently presented a virtual seminar on “In vitro models for assessment of drug-induced liver injury (DILI): a personal perspective” to the Liver Toxicity Working Group of the US regulator, the FDA. The illustrated talk is 45 minutes long and gives a valuable insight, from an expert with decades of experience, into the state of the art of drug safety testing to avoid the risk of DILI. DILI is an important cause of drug-related ill health, which can be serious and even fatal, and is a leading reason for failed development and use of many otherwise promising new drugs.

The talk is technical, so you may wish to focus just on the Summary in the final 7 minutes. Here, Gerry explains that numerous methods which use human-derived cells are available, and provide data that are much more useful than animal safety studies. Because DILI is complicated, no single method can be used and multiple endpoints need to be analysed. Gerry highlights that there is an urgent need for scientists to reach consensus on which assays to use and how best to analyse and interpret the data that they provide. There is also a need for strong regulatory guidance that requires in vitro methods be used to assess the risk of DILI, thus reducing the incidence of this serious but often avoidable adverse drug reaction.

The availability of data from both preclinical and clinical studies of drugs is key to understanding the effectiveness and safety of any treatment before it is approved for use in patients. In a recent webinar our Director Dr Jan Turner, described why gaps in this data either through selective reporting or omission of significant data all together, can have profound effects on the decision-making of regulatory agencies and ultimately lead to unsafe drugs being placed on the market. Jan’s slides are available here.

“The future of medicines regulation in the UK” was the subject of a recent Westminster Health Forum meeting at which our Director, Dr Jan Turner described why innovation and the development of methods to ensure safe and effective medicines, is imperative for the UK. The talk drew on a previous meeting in July 2020 where Jan also spoke but included some reflections this time on lessons learned from the COVID pandemic which may be exploited to develop safer medicine, and post-Brexit opportunities for the UK regulatory body MHRA to support the approval and inclusion of human relevant methods into medicines testing. Dr Turner’s slides are available here..

Safer Medicines Trust was a partner in a world-first comparative study led by the US Evidence-based Toxicology Collaboration (EBTC) and the Norwegian Institute of Public Health.

The collaboration conducted a comprehensive comparison of the in vivo (animal and human) and in vitro tests currently available to assess drug safety and compared their findings against ‘real world data’ on adverse drug reactions. They focused on two diabetes drugs: troglitazone (Rezulin), which was withdrawn from the market due to severe and fatal liver toxicity and rosiglitazone (Avandia), which remains on the market in the US.

Neither drug indicated a strong hazard signal in either preclinical animal studies or human trials. In contrast, in vitro data (using human cells and tissues) found that Rezulin exhibited strong signals for off-target effects on the liver, while Avandia did not.

This world-first comparative approach found that preclinical animal and clinical human trials – despite being mandatory – did not predict Rezulin’s potential to cause harm. Tests on human cells and tissues could have clearly revealed the hazard, which caused hundreds of liver injuries and killed at least 63 people. Sophisticated human-relevant technologies now offer a new paradigm for preventing adverse drug reactions and saving patients’ lives.

View the open access publication in Nature Scientific Reports here: www.nature.com/articles/s41598-021-85708-2

A new All-Party Parliamentary Group for Human Relevant Sciences held its first AGM on Tuesday 6th October 2020, with the aim of accelerating the development and uptake of human relevant life sciences in the UK.

The APPG will be a discussion forum for politicians, the human relevant life sciences sector, third sector groups, scientists and stakeholders to promote new approach methodologies that provide unique insights into human biology, transform our ability to understand human disease and can develop effective new medicines more quickly and without the use of animals.

Speaking at the launch, the APPG’s Chair and Safer Medicines Trust Patron, Labour MP Grahame Morris, said, “I am delighted to Chair the new All-Party Parliamentary Group on Human Relevant Science. The COVID-19 pandemic has demonstrated that the current approach to developing new treatments is simply not fast enough to meet humanity’s needs. We urgently need a moonshot to transition to new approach methodologies which promise to deliver safer and more effective medicines, more quickly and at less cost.”

APPG Vice Chair and Safer Medicines Trust Patron, Conservative MP Sir David Amess said, “I am thrilled to be Vice Chair of the new All-Party Parliamentary Group on Human Relevant Science. With the cancellation of the Autumn Budget, the Government now has more time to think about what it can do to provide much-needed financial support to boost growth in the human relevant life sciences sector and enable the UK to remain an innovative science superpower.

“As the country seeks a COVID-19 vaccine, this is the perfect time for parliamentarians to take seriously the growing evidence in favour of the pioneering human relevant medical research techniques that are replacing the outdated use of animals.”

For more information on the APPG, please contact us at 0300 302 0521 or email info@SaferMedicines.org

“The future for UK regulation of medicines, medical devices and clinical trials – transparency and public trust, safety and enforcement, and support for innovation” was the subject of a recent Westminster Health Forum meeting at which our Director, Dr Jan Turner described why innovation and the development of methods to ensure safe and effective medicines, is imperative for the UK now and importantly, post Brexit. A recording of the talk is here and Dr Turner’s slides are here