Hello. In these ever-changing times, the team here at Safer Medicines Trust felt it may be useful to provide our supporters with some interesting news from all things related to medicines development, hence this new blog page. Latest posts at the top.
Please let us know of any topics you would like us to cover and any feedback you may have on the blogs themselves.

World Liver Day: Human-relevant research is needed into liver disease and Drug Induced Liver Injury (DILI)

By Rebecca Ram

This month marks World Liver Day (held every year on 19 Apr) to raise awareness about diseases of the second largest organ in the body. After the brain, the liver is the most complex organ and is vital to the efficient control of the gastrointestinal (digestive) system.

Liver diseases account for approximately 2 million deaths per year worldwide, including cirrhosis, viral hepatitis and hepatocellular carcinoma. Cirrhosis and liver cancer are among the global leading causes of fatality, responsible for 3.5% of all deaths worldwide.  According to the British Liver Trust, liver disease is expected to overtake heart disease as the biggest cause of premature death in the next few years and there is an urgent need for new treatments.

In addition to liver disease, specific liver damage as a result of medication continues to be a long-term patient safety problem. The symptoms of Drug Induced Liver Injury, or DILI, can vary from mild to severe, but in the worst cases DILI can lead to permanent liver failure and/ or death. DILI is associated with many drugs currently on the market, accounting for approximately 14 cases per 100,000 patients and is a leading cause of drug failure, both during clinical trials and post-market withdrawal.

‘In vivo’ (animal) models are routinely used to try to replicate characteristics of liver damage, for example the use of carbon tetrachloride is a common procedure to induce liver injury in rodents.  Attempts to artificially recreate human lifestyle factors which can result in liver disease such as chronic alcohol consumption or a high sugar/fat diet are also repeatedly used in animals, which have often been genetically modified (GM).  However, there is widespread concern over the limitations of animals to mimic the complexities of liver conditions in humans.  Despite such concern, animal studies continue to be cited (mainly by those that use them) as ‘essential’ for gaining a better understanding of liver diseases, whilst at the same time scientists acknowledge how little is known despite decades of animal use. Systematic reviews (SR) of animal models of liver disease have also raised questions over the ability of animal models to replicate the human response.

Furthermore, as many liver adverse effects are idiosyncratic in humans, they are not adequately predicted by animal studies, with species differences being described as ‘drastic’, for example when comparing the liver responses of dogs to humans. Again, despite this problem being widely recognised, animal studies are still the conventional approach for testing for potential DILI.

Between January and June 2020, UK research projects related to liver disease were approved which will use over a quarter of a million animals (279,325) in the UK over the following five years. The majority of projects involve mice and rats, as well as many other species, including beagle dogs, rabbits and guinea pigs. Projects range from direct liver disease or DILI projects, to other projects where liver injury is involved or the toxicity testing of new drugs. Just one study for example to investigate DILI will use over 40,000 mice. Of further grave concern is that only 25% of these projects will be independently assessed afterwards to see if they met their scientific objectives. In ‘lay summaries’ describing these projects it is often stated that there is a ‘liver disease crisis’  and that there are ‘urgent unmet clinical needs’, yet these sit alongside claims such as ‘these animal models have been used for years’.

We cannot afford to continue testing unrealistically high experimental doses of drugs or creating artificial diseases in GM animals. New, human-relevant methods are available, including in-vitro approaches using human tissues and cells, e.g. primary human liver cells, or hepatocytes; 3D spheroids (which act as ‘mini-organs’ to predict human responses) and advances in liver on a chip or ‘microphysiological’ systems. These are small but sophisticated devices containing micro-sized channels which are supplied with human liver cells or tissue, to which potential new drugs can be applied to test for human safety, or used as models of human liver diseases. Recent systematic reviews of mechanistic in-vitro assays have shown them to effectively predict DILI for several drugs where preclinical (animal) and other studies previously failed.

Other methods include in-silico (or computational) methods and advanced artificial intelligence ‘deep learning’ models to predict liver toxicity, as well as many other sources of human-derived data. No single method can be used alone, instead different method types can be combined as bespoke, new approach methodologies (or NAMs) to reveal pathways of events right through from a molecular level to physical effects as they manifest in patients.

Due to the enormous expense and time-consuming nature of using animal models, the number of substances that can be effectively tested using in vivo liver toxicity assays is limited. The development of human-based approaches (e.g., in vitro methods to test for liver injury (or hepatotoxicity)  allow many substances to be tested more cheaply and quickly. Indeed, cost reductions of over 90% have been estimated when compared to many typical animal tests.
For further insight, follow this link to see a recent presentation on ‘In vitro models for assessment of DILI’ by Safer Medicines Trust’s Pharmaceutical Director Dr. Gerry Kenna.


New Approach Methodologies in COVID-19: systematic review into the neurological effects of SARS-CoV-2 infection presented at SOT (Society of Toxicology) Congress 2022

By Rebecca Ram

Launched nearly two years ago, the CIAO project (Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway Framework) involves the collaboration of scientific experts to identify the chemical and biological events involved in the body’s response to the SARS-CoV-2 virus. Expert working groups are established across a number of areas, for example acute respiratory distress, lung fibrosis, neurological, liver and cardiovascular injury.

At the US Society of Toxicology (SOT) 2022 congress in San Diego last week, research was presented by the project’s literature review working group on the key central nervous system (CNS) events in COVID-19. Using a systematic review (SR) approach, the group, led by the EBTC (Evidence Based Toxicology Collaboration) identified and analysed data relevant to the neurological adverse outcomes of SARS-CoV-2 infection and to further identify potential gaps in knowledge to inform the COVID-19 AOP framework. The results were presented by Donna Macmillan in a poster at the SOT congress, including quantitative analysis and data extraction demonstrated in a systematic evidence map. The SR protocol used has been published as a general approach and guidance to other research areas.

The Adverse Outcome Pathway (AOP) is a game changing pathway-based concept, developed over the last two decades to provide highly mechanistic information on the effects of a ‘stressor’ (for example any chemical or virus – in this case the SARS-CoV-2 spike protein) triggering a  ‘molecular initiating event’ (MIE) and progressing through higher level ‘key events’ (KEs) at cell, organ and tissue level; the relationships between those key events (KERs) through to adverse outcomes observed in the individual and potentially, populations.

The AOP was originally intended to establish toxicity pathways in response to chemicals, but as all diseases, bacteria and viruses act in a similar way to trigger MIEs, AOPs have application across chemical safety, basic and applied/translational disease research. Key events and adverse outcomes are not necessarily unique to one AOP and so can be connected to form almost infinite adverse outcome ‘networks’.

Data resulting from different types of test method can be integrated to map events in AOPs, for example in silico (computational) models for chemical screening (from simpler analysis models through to artificial intelligence, or AI, derived data from machine learning algorithms), in vitro assays (advanced human cell based models such as stem cells or 3D organoids) to assess biological activity, as well as a variety of human based data (e.g. clinical trials, biomonitoring and ‘real world data’ from epidemiological and observational studies). Combinations of these methods are termed ‘New Approach Methodologies’ (NAMs) and they are designed to overcome limitations in the predictive capabilities of conventionally used methods (‘in vivo’ animal models). Case study evidence in NAMs continues to emerge, aiming to provide practical guidance and overcome the bottleneck in achieving regulatory acceptance.

Although the basic AOP is visualised as a linear ‘left to right’ concept, the AOP can be used in any direction or started at any point and all AOPs are ‘dynamic’, as new and updated information can be added to them continuously. In simple terms, AOPs might be very broadly compared to jigsaw puzzles. As pieces (or ‘data gaps’) are filled, they show what is still missing.

Read our previous post on the CIAO project here

The poster above can also be accessed on the CIAO publications page

To find out much more on the successful outcomes of the project to date and how to become involved, visit 

Further information on AOPs, including useful training and educational resources can be found here


‘Five For Friday’; Starting 2022 with five examples of human-relevant science using new approach methodologies (NAMs)

By Rebecca Ram

Many research methods which focus on human-relevant biology (NAMs) are in use worldwide.

However, a co-ordinated analysis of all existing methods that could be harmonised for global regulatory approval, as well as diversion of funding to the development of new methods are both long overdue. Encouraging signs were seen in Europe towards the end of 2021, when Parliament voted in favour of an EU wide action plan to accelerate the development of NAMs to improve human safety prediction and phase out animal use, with strong support from scientific stakeholders. Follow up action is now awaited from the European Commission.

As 2022 begins, we continue our ‘Five for Friday’ theme with a summary of some examples of positive progress in human-relevant research…..

  1. There is inevitably a continued focus on COVID-19. A collaborative project using state- of- the- art in silico methods (computer simulations) has recently published its findings on the cause of blood clots in response to the AstraZeneca vaccine.
  2. Researchers at Hebrew University reported a complete elimination of animal use with their ‘organ on a chip’ technology to measure kidney injury (nephrotoxicity). The technology also predicted the effects found in earlier clinical trials of patients who had taken the same drug combinations. Approval of just one new drug takes on average 10 years, uses many thousands of animals and costs £2 billion. In contrast, the Hebrew University technology is reported to provide results ‘ in eight months, without a single animal, and at a fraction of the cost.” and is planned for a submission to the US FDA (Food & Drug Administration).
  3. Advances in artificial intelligence (AI) have been combined with stem cell technology to test thousands of potential new drugs on ‘miniaturized patients-on-a-chip’ devices, to rapidly predict clinical effects and overcome the inaccuracies of animal tests with focus on brain, liver disease and cancer as ‘three areas where safety and efficacy failures of drugs are especially high’. The first ‘AI drug’ is planned to start clinical trials this year, described by the research team at Quris AI as ‘a test case to demonstrate how our system can bring a drug to market in five years with millions of dollars, not 20 years with billions’.
  4. Published within the last few days, a new study has further developed the in vitro−in silico-based NAM safety testing strategy for prediction of human gut metabolism using PBPK modelling (Physiologically Based Pharmacokinetics) The results obtained also highlighted interspecies differences between traditionally used rodents (rats) and humans.
  5. With regard to chemical safety, last month the US Environmental Protection Agency (EPA)  updated its ongoingNew Approach Methods Work Plan’ which includes a number of key objectives including  ‘Establish Scientific Confidence in NAMs and Demonstrate Application to Regulatory Decisions’ and ‘Develop NAMs to Address Scientific Challenges and Fill Important Information Gaps’. This follows on from the earlier 2021 publication of its latest ‘ List of Alternative Test Methods to Animal Testing | ‘ in order to meet requirements of the TSCA (Toxic Substances Control Act) as part of the EPA ‘2035’ directive.

Human-relevant coronavirus research: Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway Framework- the CIAO Project

By Rebecca Ram

As we approach the end of 2021 (and almost two years since the pandemic began) an innovative project continues to investigate the biological mechanisms underlying COVID-19, using the ground breaking concept of Adverse Outcome Pathways (AOPs).

Launched in May 2020, the CIAO project (Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway Framework) has involved the collaboration of scientific experts across many disciplines including (but not limited to) molecular biology, virology, toxicology, immunology and clinical research. I was pleased to contribute to the project during late 2020 and early 2021.

The AOP is a concept which maps a specific pathway to provide highly mechanistic information on the effects of a ‘stressor’, beginning with ‘molecular initiating events’ (MIEs) and progressing through higher level ‘key events’ (KEs) at cell, organ and tissue level, through to adverse outcomes observed in the individual and ultimately populations.

The AOP concept was originally developed to establish pathways of toxicological responses to chemicals as stressors, but as diseases, bacteria and viruses can act in a similar way to trigger MIEs, AOPs have far broader application beyond chemical safety into the pathogenesis of disease. Key events and adverse outcomes are not necessarily unique to one AOP and so can be connected to form adverse outcome ‘networks’.

Image reproduced from: Nymark P, Sachana M, Leite SB, Sund J, Krebs CE, Sullivan K, Edwards S, Viviani L, Willett C, Landesmann B and Wittwehr C (2021) Systematic Organization of COVID-19 Data Supported by the Adverse Outcome Pathway Framework. Front. Public Health 9:638605. doi: 10.3389/fpubh.2021.638605

Therefore, the CIAO project is reviewing and organising the ‘big data’ available on the key events involved in the body’s response to the SARS-CoV-2 virus, also making use of extensive research on related coronaviruses (e.g. SARS-CoV-1). Expert working groups collaborate on an ongoing basis and four comprehensive workshops have been held to date, with a number of modelling outcomes in progress, including for example acute respiratory distress, lung fibrosis, neurological, liver and cardiovascular injury.  These are very top-level descriptions and much more detail on the achievements of the project so far, as well as publications are available on the CIAO website.

To find out much more including how to join the CIAO project, visit

Presentation: Ending animal testing to advance human relevant research via New Approach Methodologies’

By Rebecca Ram

I was pleased to be invited to give a presentation on the issues concerning use of animals in research at a recent workshop hosted by Advocates for Animals, the UK’s first legal organisation devoted to animal protection. The theme of the workshop was “Animal experiments; the law, the framework and the alternatives”.

The topic of my talk was ‘Ending animal testing to advance human relevant research via New Approach Methodologies’ or ‘NAMs’- a term increasingly used to describe modern, animal-free methods. In particular, I addressed the ongoing challenges due to a lack of NAMs funding and regulatory acceptance and how these might be addressed within a legal framework, similar to the EU cosmetics testing bans implemented between 2009 and 2013.  Despite a twenty-year campaign, major setbacks and frustration concerning conflict with other chemicals legislation (e. g. REACH) the bans represent a major legal landmark towards animal replacement and a means of holding the relevant authorities to account.

It’s often noted that there’s a lack of ‘level playing field’ when comparing conventionally used animal ‘models’ to NAMs, with the latter being subjected to a lengthy validation process and frequent bias or rejection, despite proof of reliable and human relevant information on a mechanistic level. Key examples of NAMs include 3D spheroid models, ‘organ on a chip’ technologies and in silico (computer derived) methods. These are three broad categories incorporating countless ‘NAM’ techniques, which can be combined to provide a fit for purpose, clinically relevant picture of human safety and disease.

In contrast, animal tests have never been validated in this way but continue to be used, often in repetitive and routine procedures linked to similarly routine funding sources, despite the well-known limitations of the 3 million animals used each year in the UK (and 10 million across the EU) and acknowledged failure to provide adequate ‘bench to bedside’ translation. As a patient safety organisation, Safer Medicines Trust follows this issue closely, given that clinical trial failure rates exceed 90% and drug side effects are reported to account for more than a million hospital admissions and 10,000 deaths in the UK each year.

Furthermore, less than 20% of animal procedures are retrospectively checked to see if they’ve met their scientific objectives and the public are often shocked to find that the vast majority of animal tests have no legal requirement to be performed.

On a positive note, NAMs are in use to some extent, for example in silico modelling in drug development, or ‘read across’ in chemical safety testing, though often to complement animal use, rather than replace it. NAMs uptake is still on a relatively small scale which is disappointing given that so much more could be achieved with a ‘top down’ government approach, combined with international harmonisation to ensure the global acceptance of all currently available NAMs and the development of urgently needed new ones.

There are infinite business opportunities for NAMs research, optimisation, scale up, training and outsourcing. Risk aversion is understandably a key concern, but this could be safely addressed with trial or pilot studies, used regularly in so many other areas of technology. Such ‘actions instead of words’ for kickstarting genuine progress in human health and patient safety are long overdue.

For further detail, the presentation can be seen here


Safer Medicines Trust at the 11th World Congress on Alternatives (WC11) 

Scientific consultant Rebecca Ram presented during a virtual session as part of the ‘YOU-WC11’ mentoring programme. The session theme was ‘Challenges and Opportunities for Expanding the 3Rs’’ and was particularly aimed at early career scientists. The session was further divided to discuss two topics;

  1. Dropping an R: Is it Time to Retire Refinement?‘ featuring Charu Chandrasekera of the Canadian Centre for Alternatives to Animal Methods and Lars Lewejohann of the German Centre for the Protection of Laboratory Animals (Bf3R).
  2. Funding and Regulation: Does One Pose a Greater Threat to Advancement?’

Rebecca spoke in the second debate, with specific focus on the ‘funding’ aspects and the need for greater investment in more human-relevant, mechanistic research methods, also termed ‘new approach methodologies’(NAMs), which offer better solutions for human health. Rebecca also outlined an apparent level of bias and ‘lock in’ leading to repetitive funding of animal models and the need for redirection of funding away from their use, which continues despite concerns over the reliability of animals to predict human responses.

Presenting alongside Rebecca during the session was Elizabeth Baker of the Physicians Committee for Responsible Medicine (PCRM), who provided expert perspective on the need to update regulations to incorporate NAMs.

Aside from the scientific and ethical advantages, NAMs offer infinite opportunities in business, training and outreach that only a paradigm shift in human-relevant scientific research and development can provide. Rebecca also spoke of concerns raised that many NAMs aren’t yet available to replace animals and how this in large part relates back to more funding needed to a) develop new methods and b) optimise, scale up or improve existing methods which require further work to become validated and approved.

Engaging early career researchers in NAMs dialogue and training is key to paving the way for the next generation of scientific experts, who will become accustomed to using them as standard rather than ‘alternatives’, from early basic research through to drug development and regulatory testing.

Amid concerns over high drug attrition rates in clinical trials, the pharmaceutical industry has started to use NAMs, but a long overdue, wholescale change in government action is still urgently needed. There are some encouraging signs. For example, the European Parliament has recently voted for a targeted strategy to be established to phase out the use of 10 million animals every year in favour of more scientific, human relevant methods. The vote has its opponents and still requires approval from the Commission, but it is a positive political step in the right direction.

Rebecca’s slides and recording can be viewed here  

Dr. Pandora Pound: Lock-in to animal research within academia

When I was asked to talk on this topic for the 11th World Congress on Alternatives and Animal use in the life sciences – held online this year – I was happy to oblige. Having worked in academia for many years, I know how conservative universities can be. I recall how difficult it was to question the practice of animal research with academic colleagues, there seemed to be a taboo against it. Animal research was a ‘sacred cow’ and it was unacceptable to raise the possibility that it might not be a valid method for advancing human medicine. Very little had changed by the time I left academia in 2017.

Animal research is a topic that is tip-toed around within universities. It’s permitted to talk about some things, but not others. For example, it is possible to be a professor and study the welfare of laboratory animals, or the ethics, or sociology of animal research. It is even possible to be a professor and challenge the way animal research is conducted and reported. However, the professor who critiques the founding assumptions of animal research, or its value for humans, is a rare creature.

The reason for this, as I suggest in my talk, can perhaps be found in the mid-19th century, when the famous French physiologist, Claude Bernard, was developing a new approach to research. He believed that medicine was more likely to advance from within laboratories, where experimental evidence could be collected and hypotheses tested, rather than from the careful observation of patients in clinics and hospital, as was customary at the time. He proposed that studying animals under controlled laboratory conditions and then extrapolating the results to humans was a more scientific approach than directly observing humans.

Bernard’s efforts were successful. The laboratory setting, and his use of experimental groups and statistics all helped create the impression that animal experimentation was ‘proper science’. There was considerable public opposition to the practice but scientists responded by appealing to the need for treatments for humans. Although there was little concrete evidence that animal experiments would provide these treatments, the rhetoric was successful; research using animals became inextricably linked with science and the promise of medical progress.

This, I believe, helps explain why academics are reluctant – even today – to openly challenge the practice. To question the dogma that animal research is proper science and that it benefits humans implies that the questioner either does not understand science, or is ‘anti-science’, or puts the interests of animals before those of humans. Consequently, academics tend to keep their mouths shut in public, even if they might share their misgivings in private.

Can animal research be good science though, if it involves disregarding basic, accepted, biological principles? At the same time as Bernard was developing his laboratory based experiments, Charles Darwin was writing the ‘On the Origin of Species’, his ground breaking theory of evolution by natural selection. Bernard rejected Darwin’s evolutionary theory, believing that animals are all basically similar and that the differences between species are differences of degree only. But he was wrong. Each species is the result of their own unique, evolved history. As Professor of Pathology, Todd Preuss puts it: ‘Every lineage has undergone its own independent history of adaptation and specialisation. Every species is special. That’s why we call them species. It’s the same root for the same reason.’ Unfortunately, those conducting animal research are still under the influence of Bernard, because in assuming that one species (usually rats) can ‘stand in’ for another (humans), they disregard the significance of species differences.

To break the lock-in to animal research within academia then, we need to be very clear that animal research involves the rejection of evolutionary theory and that this is unscientific. But we also need to create opportunities for dialogue between those conducting animal research and those developing new, human-relevant technologies. This is the inspirational approach taken by the Dutch in their Transition to Innovation without Laboratory Animals Initiative. In Dutch ‘Helpathons’, animal researchers ask the scientific community to help them answer their research questions without using animals, and those with knowledge and experience of new, human-relevant technologies and approaches are happy to oblige. Where both parties genuinely want to advance human medicine, there is a common ground for moving forward.

Building confidence in animal free innovations – does requesting animal data to justify publication of a non-animal method help?

The 11th World Congress (WC11) on Alternatives and Animal Use in the Life Sciences recently took place online with the five themes of the congress being Safety, Disease, Ethics, Welfare and Regulation and Innovative Technologies. Both Dr Pandora Pound and Rebecca Ram from Safer Medicines Trust presented at WC11 and future blogs will discuss the subject of their talks in more detail. Their slides can be seen here.

Speakers noted that some of the challenges to building confidence in animal free innovations were about the innovations themselves, in other words the new methodologies need to be valid, reliable and fit for purpose. However, an important topic addressed during the conference, was the need to change the mindset and policy of those who review research papers about new, animal-free innovations, i.e. peer reviewers and journal editors. It was noted that reviewers and editors frequently demand that additional animal experiments are carried out in order to validate in vitro, human-based new approaches before a paper is accepted for publication. Clearly this is a completely inappropriate, but apparently widespread issue; over 50% of academics surveyed reported that they had been asked for this extra work to be carried out following review of their manuscripts. Some comments from these authors were presented at the conference in a talk by Marcia Triunfol, from Humane Society International:

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Triunfol reported that when asked why, most reviewers admitted they were unaware of new technologies that could be used instead of animals. Lack of understanding of these human-biology based approaches, status quo bias, journal editorial policy, scientific justification, regulatory requirement and avoiding sunk costs (animal facilities/husbandry etc) were all suggested as playing a part in perpetuating the practice of demanding animal studies.

The session panel suggested potential solutions could include a commitment by journals to scrutinise, and demand a higher level of justification for, reviewers’ requests for animal data and to publicly disclose when such requests are made. In line with these discussions, another recommendation was to educate funding agencies about the power of human-focused technologies, to encourage a better understanding of these novel approaches and ultimately their widespread adoption. Ironically, it was claimed that the United States’ primary medical research agency, the National Institutes of Health, has no funding streams totally dedicated to NAMs and that often grants are not given unless animal work is included in the project proposal.

Clearly something needs to be done to break these practices which continue to rely on animal data, often for unjustified reasons, and which are preventing more relevant, human-biology based methods from seeing the light of day.

Related: Organ chips, organoids and the animal testing conundrum

World Alzheimer’s Day: New approach methodologies are urgently needed

This week marks World Alzheimer’s Day (21 Sept) and greater public support than ever for investment in research to provide effective treatments.

An estimated 45 million people worldwide suffer with AD and other dementias. It remains one of the world’s biggest killers and has been investigated with substantial global research funding for decades.

Public support is at an ‘all time high’ for research into AD. For example, 69% of respondents are keen to be directly involved in AD research, according to a recent survey, also driven by concerns over the COVID-19 pandemic.  Yet 99.6% of AD drugs fail in human trials. This is due in large part to the inadequacy of current research methods (predominantly animal based) to mimic human disease pathogenesis and response to drugs.

Large scale use of animals has produced some characteristics of dementia, but generally failed to reproduce the complexities of human AD, which is considered to be a human specific disorder. Rats and mice do not naturally develop AD and so are genetically modified to try to overcome this major species difference. The number of failed treatments over many years demonstrates a ‘lost in translation’ problem. During the decade 2002-2012, only 1 of 244 new drugs was approved for AD.

In 2015, the UK Government launched the Dementia Institute and a budget of up to £150 million. However, despite a priority focus ‘to drive forward research and innovation’, research into AD, other dementias and neurological diseases overall is still heavily invested in animal models.

Since 2015 in the UK, over 1.5 million animals have been used in basic research into the nervous system and/or applied/translational research into human nervous and mental disorders, which includes AD and other dementias. Many more animals have been used during the same period for regulatory testing of new drugs to treat dementia, which typically use rodents, dogs or monkeys.

High pressure exists within the ongoing race to find new treatments for AD, driven by concerns over poor failure rates to date and an urgent need to help increasing numbers of patients. Controversy continues over the recent ‘fast-track’ approval of the amyloid beta-directed monoclonal antibody Aduhelm (aducanumab), with many scientists and physicians voicing concerns that it is experimental and unproven.  Safer Medicines Trust reported on this in a recent post and we continue to follow Aduhelm’s progress.

The need to address the dementia problem aligns with the mission of Safer Medicines Trust and the Alliance for Human Relevant Science, to improve patient safety and accelerate better drug development by promoting high quality, human relevant research. Drug development is in crisis, with 86-95% of new drugs failing somewhere during the clinical trial process.

It’s time to embrace exciting developments in New Approach Methodologies (NAMs) which offer high quality research potential for Alzheimer’s Disease and other dementias. Examples include microphysiological systems (MPS) such as ‘Alzheimer’s on a chip’ models and 3D human derived brain models. These methods offer more human relevant predictions and overcome many limitations of both animals and earlier in vitro cell culture models. No single model is enough – instead intelligent ‘integrated testing strategies’ which combine models can achieve success. NAMs also offer the capability to be continually enhanced and optimised as technologies evolve and provide mechanistic, human relevant information which cannot be studied in animals. For AD and other conditions, this is critical and patients should not be kept waiting.

Use of new approach methodologies has started in the pharmaceutical industry, however a wholescale shift in both industry and academia is still urgently needed and long overdue.

Combining such approaches with calls for increased funding in clinical and epidemiological studies for AD to identify risk and lifestyle factors would achieve the paradigm shift that is urgently needed to achieve 21st century ‘fit for purpose’ dementia research.

World Patient Safety Day 2021 

World Patient Safety Day was established in 2019 to enhance global understanding of patient safety, increase public engagement in health care safety, and promote global action to prevent and reduce avoidable harm in health care.

This year’s theme is “Safe maternal and newborn care” and calls on all stakeholders to accelerate the actions necessary for ensuring safe and respectful childbirth.

The Day is firmly grounded in the fundamental principle of medicine – first do no harm – and at Safer Medicines Trust, we believe a key aspect of “safe and respectful childbirth” is just that, do no harm.

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Mat Fraser, actor and thalidomider. Safer Medicines Trust Patron

Without a doubt, events such as the thalidomide tragedy in the late 1950s and early 60s was an abject failure of this principle. More recently, the Cumberlege report released in July 2020, also entitled First Do No Harm, concluded that of the three interventions it investigated, the two taken during pregnancy – Primodos, a hormone based pregnancy test discontinued in the UK in 1978 after concerns were raised about an increase in the number of birth deformities seen in babies born to mothers who had been given the drug and sodium valproate, a drug used to treat epilepsy, the use of which in pregnancy has been linked to an increased risk of developmental problems and serious birth defects – had caused avoidable harm to patients.

While some of the recommendations from the Cumberlege report are now being reviewed and actioned by the government, the fact remains that drugs such as these had obviously not been tested adequately and in a way that enabled patients to truly understand their potential side effects. We believe passionately at the Safer Medicines Trust that this needs to change. Our vision is that scientifically valid, human-focused research will deliver safe and effective treatments for patients and believe that by facilitating a transition to human-focused drug development and testing, we can make medicines safer. Technologies are already available to look at human responses to drug candidates and consequently, there is no reason to have another case of harm caused to patients by the likes of thalidomide, primodos or sodium valproate in our lifetimes.

Related: After 60 years, scientists uncover how thalidomide produced birth defects; Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome; Primodos scandal: Relief for campaigners as review demands compensation for victims of hormone pregnancy test; Guidance – Valproate use by women and girls

‘Five for Friday’… 5 new approach methodologies (NAMs) revolutionising disease research for COVID-19 and other conditions…

Examples of research prioritising new approach methodologies (NAMs) in the fight against COVID-19 and other diseases, making use of ‘real world’ human data and cutting edge technologies…

Solidarity PLUS: an international clinical trial to improve Covid-19 medicine discovery

Although vaccination has reduced markedly the UK population risk of serious illness and fatality during the ongoing third wave of the Covid-19 pandemic, it has become clear that vaccination does not provide complete protection against serious illness or prevent virus transmission. Additional medicines, which can block Covid-19 viral infection and transmission and can treat the many adverse symptoms that arise in susceptible individuals, continue to be needed urgently. Many potentially useful drugs have been proposed.  However so far relatively few have been shown to be effective.

A key bottleneck has been the need to undertake rigorous trials, which are essential to differentiate between effective and ineffective treatments. Conventional clinical trials require many months, or years, to complete and typically cost up to tens of millions of pounds per medicine. Alternative approaches are needed, which are quicker and cheaper and yet equally rigorous. The opportunity to undertake quicker and cheaper clinical studies was demonstrated in 2020 by the UK’s RECOVERY trial, which demonstrated that the anti-inflammatory drug dexamethasone greatly reduced fatalities in Covid-hospitalised patients.

The World Health Organisation has now announced a major international trial which will enable researchers in 600 hospitals, located in 52 countries, to assess multiple treatments at the same time and using a single protocol. This impressive international collaboration (Solidarity PLUS) will utilise a single adaptive protocol and will standardise the evaluation methods using in the different hospitals. It will enable useful drugs to be identified quickly and effectively and will ensure that ineffective drugs can be replaced promptly with alternative candidates throughout the course of the trial. WHO’s approach is expected to improve greatly the speed with which better treatments for Covid-19 infection, and Covid-induced illnesses, can be identified and implemented.


Accelerated drug approvals compromise safety and efficacy

Our previous blog showed how missing or misrepresented data from clinical or preclinical trials can harm patients by allowing medicines to be approved with insufficient evidence of safety and/or efficacy. It is very disturbing how often pharmaceutical companies fail to provide requisite data to the drug regulators (FDA in America, MHRA in UK, EMA in Europe) and how often regulators fail to demand that data or take any action when companies fail to comply. More disturbing still is that schemes which were originally intended to help patients access life-saving treatments more quickly are being misused as an easier, faster and cheaper route to approval because they require less evidence of risks and benefits. These accelerated access schemes include the FDA’s Fast Track process, the Early Access to Medicines Scheme in the UK, and the EU’s Compassionate Use and Early Access Adaptive Licensing program. They all allow the use of truncated testing regimes, where the normal requirements for evidence of safety are relaxed to varying degrees, making the much-criticised bar for approval even lower.
Early access to potentially life-saving medicines for seriously ill patients may sound compassionate in theory. However, we know that more than 90% of medicines fail in human trials due to lack of safety or benefit, even after the full standard package of preclinical studies. To expose the most vulnerable patients to potential new drugs whose likelihood of success is clearly lower than 10% seems far from compassionate in reality. Human-relevant testing approaches could play an invaluable role here, to improve the safety and efficacy profiles of these experimental medicines, which may not have completed any human clinical trials. Adverse effects which are too subtle or rare to be detected before exposure to large numbers of patients following drug approval can be detected by human-relevant testing, e.g. using organ-on-chip or patient-on-chip devices. This would reduce the risks – not only to the vulnerable patients for whom these schemes were designed – but to all of us, since many treatments are now gaining approval via such reduced-evidence pathways.

MPS world summit: towards regulatory approval

A recent one day virtual conference brought scientists, charities, regulators and policy makers together in order to start the process of creating a roadmap for widespread use and acceptance of Microphysiological Systems (MPS) within both industry and regulatory agencies. MPSs are technologies such as human tissues and organs cultured on miniature chips (also termed Organ-on-Chip) that mimic the properties and function of that organ or tissue. They are promising tools for advancing the understanding of the mechanisms of human disease and toxicity and may therefore help accelerate drug development.  Talks from scientists discussing the standardization, scaling up and quality control of the platforms and cells used were given followed by presentations describing initiatives to overcome regulatory hurdles to acceptance of these models. It was clear that these exciting technologies offer huge potential in the field of drug discovery and development but their acceptance by regulatory agencies is needed before they are used routinely in this field. What was interesting about this meeting was that all regulatory representatives present on the panel agreed that they would like to see more MPS data included in sponsors submissions to the agencies and were keen to learn more about how and where they may be used in drug discovery and biomedical sciences.

Related: Advancing Regulatory Science Through Innovation- In Vitro Microphysiological Systems; Organ-on-Chip in Development: Towards a European roadmap for Organ-on-Chip: Organ-on-Chip In Development ORCHID Final Report

How do I know if a new medicine is safe? Clinical trial data transparency

Data from clinical trials, such as those we have become familiar with recently for the COVID vaccines, is key to understanding the effectiveness and potential side effects of any new treatment. These clinical study reports from sponsors – typically pharmaceutical and medical device companies – are reviewed by regulators such as the FDA, EMA and MHRA worldwide when assessing whether new medicines or devices are safe and effective, before making them widely available to patients. However, a recent report concluded that “notable gaps” in the quality and availability of clinical trial data in a European registry “harms both patients and taxpayers” who typically fund these studies. A similar finding was also reported in the US last year.

The report notes that 14 of the most important national regulators in Europe have failed to ensure the publication of at least 5,976 clinical trial results. Italy performed worst, with an estimated 1,221 trials missing results, followed by Spain with 884 results missing, and the Netherlands, whose regulator failed to ensure publication of 839 trial results.

I recently gave a talk at the Evidence-Based Toxicology Collaboration (EBTC) Scientific Symposium : Overcoming data availability obstacles in the way of evidence-based toxicology describing how missing or misrepresented data from both preclinical studies carried out before human clinical trials – where drugs are tested in both animals and in cells or tissues often derived from human samples – and clinical studies, can have major ramifications for the apparent safety and effectiveness of drugs which are selected for development and subsequently marketed as treatments. One such example was reported very recently for antihypertensive drugs in The Lancet.

Mechanisms exist within regulatory jurisdictions to measure the quality and availability of that data but there are real concerns that 1. Sponsors are either not submitting all data or are selectively reporting data and 2. That regulators are failing to pursue sponsors to submit completed results. The authors of this report are suggesting that regulators, at least in some countries, are part of the problem with their inadequate and inconsistent oversight of this data. If it is not possible to know if a research project was carried out or a clinical trial occurred, when it was completed or whether results are available, trust and scrutiny of regulatory decisions made regarding the approval of drugs will always be compromised. Patients who are desperately waiting for new and better treatments for potentially life-threatening and debilitating diseases deserve better.

Related: ICMRA and WHO Joint Statement on Transparency and Data Integrity; Oxford TB vaccine study calls into question selective use of animal data; Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions; Publication rate in preclinical research: a plea for preregistration.

How patient advocacy groups can help speed innovation of new treatments

Many people live with debilitating conditions and life-threatening diseases for which there are no treatments and often they are in the terrible position of having to wait for the scientific advances to reach the market, even though these patients lack the luxury of time.

A recent opinion piece by Margaret Goldberg, President and Chief Operating Officer of the Christopher & Dana Reeve Foundation suggests that novel partnerships between patient advocacy groups and pharmaceutical and medical device companies are emerging as one of the driving forces behind the creation and accelerated development of products that are fit for purpose and of real benefit to patients.

These relationships can accelerate the rate of progress by creating an understanding that speeds and better directs drug and therapy development by allowing companies to draw on the deep knowledge and personal connections of patient advocacy groups. They know what’s important to patients and what will provide the biggest impact in their lives. Those with lived experience of disease or disability inform the creation of products that are fit for purpose by contributing input all along the way, from research and development to market rollout. These expanded partnerships are a win-win-win for patient advocacy groups and companies and, most of all, for the people waiting for scientific advancements to improve their lives. While strongly supportive of such initiatives, there are potential opportunities for exploitation of such relationships which may lead to patient groups, unwittingly or otherwise, promoting new drugs so it is pertinent that these partnerships are subject to relevant checks and balances. The creation of patient advocacy teams within pharma and guiding principles of engagement, such as that seen at GSK, would alleviate such concerns.

Related: The history of patient engagement in drug discovery; How drug developers are embracing patient advocacy; How regulatory agencies are collaborating with patients; James Lind Alliance.

UK government funding of biomedical research

A question in Parliament from Chi Onwurah, the Shadow Minister for Business, Energy and Industrial Strategy on 6th July 2021 challenged the Government on its funding commitments for medical research. Ms. Onwurah had recently visited Newcastle University’s dementia research centre where she found that many scientists had lost grants as COVID devastated medical research charities excluded from Government support.  Many post-doctoral scientists doing fundamental research into this terrible disease, were working two jobs at once or working for free and were unable to apply for funding in their own name. Additionally, institutes were closing or had closed as the Government’s international development funding was slashed.

Despite promises of £50m funding from BEIS and £5m from DHSC to support early career researchers, this money is clearly not reaching those biomedical scientists and we should question what further research will be impacted by these cuts. Research of this nature cannot be subject to rollercoaster funding when long term projects are just that, for the long term. Removing funding in this way can set a project back months and years and the implications for both those carrying out this vital work and patients desperately needing treatments and therapies to alleviate their suffering, is profound. This is why Safer Medicines Trust, as part of the Alliance for Human Relevant Science and the All Party Parliamentary Group on Human Relevant Science, is calling for strategic funding of biomedical research to be directed to human based technologies relevant to human disease, such as Alzheimer’s (note – rats and mice don’t get Alzheimer’s!!), in order to find better and safer medicines for these conditions.

Related: Biomedical Research Must Change — But a Shift Toward Human-specific Research Methods Is Only Part of What Is Needed; Accelerating the Growth of Human Relevant Life Sciences in the United Kingdom


New drug for Alzheimer’s

Talking of Alzheimer’s disease (AD), there is fierce debate in the US about the FDA’s recent approval of an Alzheimer’s drug from Biogen. The drug called Aduhelm, works by targeting a brain protein many believe is responsible for the cognitive decline seen in AD, beta amyloid. It is the first drug which works in this way to be approved after many others before with a similar mode of action have failed. Controversy exists around Aduhelm’s approval, with many observers raising concerns about regulatory approval standards and the extent to which patients may actually benefit. As well as this, Aduhelm will cost $56,000 per patient and for Medicaid, the US’s public health insurance program for people with low income, this represents a potential cost to the program of more than $2.1 billion, which is equal to 7% of current Medicaid net spending. And for at least half a dozen of the private health insurers in some of the nation’s largest states, hesitancy about covering the drug is apparent, with them saying it is an experimental and unproven treatment. Watch this space for what we are sure will be a number of developments with this drug from patient, scientific and regulatory perspectives.

Related: Medicare starts process that could limit access to Biogen’s new Alzheimer’s drug; What does a clear majority of the biopharma industry think of the FDA approval of aducanumab? ‘Horrifying’ ‘Dangerous’ ‘Confusing’ ‘Disaster’;

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