Safer Medicines - putting patient safety first

Putting patient safety first

Medical research in the news

As the following news stories show, the safety of medicines is of very serious concern and the number of victims of side effects continues to grow. At the same time, a new generation of predictive human biology-based tests, which could improve the safety of new medicines, continues to expand in both variety and sophistication. Furthermore, evidence of the inability of government-required animal tests to predict safety (or other properties, such as effectiveness) in humans continues to mount.

This is a public health emergency. The time for governments to act is now.

Adverse drug reactions in the US

The Institute for Safe Medication Practices calculated that in 2011, prescription drugs were associated with two to four million people in the US experiencing “serious, disabling, or fatal injuries, including 128,000 deaths.”
Ref: Quarterwatch, 31 May 2012

Animal research – a broken model?
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Writing in the British Medical Journal, Dr Pandora Pound and Michael Bracken, Professor of Epidemiology at Yale University Schools of Public Health and Medicine, advise that: “urgent attention needs to be paid to the quality of animal research for important reasons.
Much clinical research follows on from animal research. If the foundations of the biomedical research enterprise are unsound, then whatever is built on these foundations will be similarly precarious.

The current situation is unethical. Poorly designed studies and lack of methodological rigour in preclinical research may result in expensive but ultimately fruitless clinical trials that needlessly expose humans to potentially harmful drugs or may result in other potentially beneficial therapies being withheld.

… if research conducted on animals continues to be unable to reasonably predict what can be expected in humans, the public’s continuing endorsement and funding of preclinical animal research seems misplaced.”

BMJ Editor Fiona Godlee suggests that: “Funds might be better directed towards clinical rather than basic research, where there is a clearer return on investment in terms of effects on patient care.”

She quotes John Ioannidis, Professor of health research and policy at Stanford University, who wrote in his 2012 paper “Extrapolating from animals to humans” (Science Translational Medicine 4: 1-3) that it is “nearly impossible to rely on most animal data to predict whether or not an intervention will have a favourable clinical benefit-risk ratio in human subjects.”

Fiona Godlee concludes her Editorial by asking: “Where would you place the balance of effort: investment in better animal research or a shift in funding to more clinical research?”
Ref: BMJ 348, 5 June 2014

Dogs do not predict safety

FRAME (Fund for the Replacement of Animals in Medical Experiments) has recently published an analysis of the value of studies in dogs for predicting the safety of human medicines. The salient feature of this study is the use of appropriate statistical metrics, which have not previously been applied to such data. The results shine a new light on our reliance on dogs for this purpose, suggesting that they contribute little or nothing to ensuring our safety. The paper and a presentation by lead author Dr Jarrod Bailey can be viewed from our website.
Ref: ATLA 41, 335-350, 2013

Mice mislead research

A major study by a large consortium of researchers has revealed why every one of nearly 150 drugs tested in patients with sepsis (the leading cause of death in intensive-care units) has failed. The trials were based on studies in mice. The study shows that ‘sepsis’ in mice is very different from the condition in humans and that the mouse model has been totally misleading for at least three major killers: sepsis, burns and trauma. The researchers commented that many years and billions of dollars have been wasted following false leads as a result. Furthermore, they added that their results raise troubling questions about other diseases that involve the immune system, including cancer and heart disease.

The investigators tried for more than a year to publish their paper. They submitted it to the journals Science and Nature, hoping to reach a wide audience. It was rejected from both.

“They are so ingrained in trying to cure mice that they forget we are trying to cure humans” – Ronald W. Davis, Professor of Biochemistry and Genetics, Stanford University School of Medicine and Director of Stanford Genome Technology Center.
“When I read the paper, I was stunned by just how bad the mouse data are. It’s really amazing — no correlation at all” – Dr Mitchell Fink, Vice Chair for Critical Care and Professor-in-Residence, University of California, Los Angeles

“It argues strongly – go to the patients. Get their cells. Get their tissues whenever you can. To understand sepsis, you have to go to the patients” – Dr Richard Hotchkiss, Professor of Anesthesiology, Medicine, Surgery, Molecular Biology and Pharmacology, Washington University School of Medicine
Ref: New York Times, 11 February, 2013

The journal Nature Medicine commented on the study in an editorial entitled: “Of men, not mice” (4 April 2013):
“Although the message that mice are an imperfect model for human disease is far from new, these recent results should prompt some soul-searching among disease researchers… Rather than over-relying on animal models to understand what happens in humans, isn't it time to embrace the human 'model' to move forward?”

USA acknowledging the problem

Dr Elias Zerhouni, former Director of the National Institutes of Health (the world's largest financial supporter of medical research), laments that researchers have over-relied on animal data, saying: 

“We have moved away from studying human disease in humans. With the ability to knock in or knock out any gene in a mouse—which can’t sue us—researchers have over-relied on animal data. The problem is that it hasn’t worked, and it’s time we stopped dancing around the problem…We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans.”
Ref: NIH Record, 21 June 2013

Dr Francis Collins, the current Director of the NIH, has made many powerful appeals to challenge the status quo, e.g.:

“The use of animal models for therapeutic development and target validation is time consuming, costly, and may not accurately predict efficacy in humans. As a result, many clinical compounds are carried forward only to fail in phase II or III trials; many others are probably abandoned because of the shortcomings of the model…  With earlier and more rigorous target validation in human tissues, it may be justifiable to skip the animal model assessment of efficacy altogether… We must move forward now. Science and society cannot afford to do otherwise.”
Ref: Science Translational Medicine 6 July 2011

Dr Margaret Hamburg, FDA Commissioner, has written:
“We must bring 21st-century approaches to 21st-century products and problems.
Most of the toxicology tools used for regulatory assessment rely on high-dose animal studies and default extrapolation procedures and have remained relatively unchanged for decades, despite the scientific revolutions of the past half-century.
… The FDA is … working to eventually replace animal testing with a combination of in silico and in vitro approaches… Policy-makers, industry leaders, and the scientific community have the opportunity and the power to answer this call to action. It cannot wait any longer.”
Ref: Editorial, Science, 25 February  2011

Why Are All the Cancer Cures Going to Mice? We're Still Waiting

US Charity, Gateway for Cancer Research, collected nearly 30,000 signatures for their petition (above), saying:
“We do not fund cancer research to cure mice, we fund cancer research to cure people. We are changing how cancer research is done. It should always and only be about the patients, not about interesting research findings. Please sign this pledge today to join us and demand cures today.”

According to Azra Raza, MD, Professor of Medicine at Columbia University: “An obvious truth that is either being ignored or going unaddressed in cancer research is that mouse models do not mimic human disease well and are essentially worthless for drug development.”

Her answer to the Edge.org annual question 2014: “What scientific idea is ready for retirement?” was: “Mouse models.” She concluded:

“The time is here to let go of the mouse models at least as surrogates for bringing drugs to the bedside. Remember what Mark Twain said, "What gets us into trouble is not what we don't know; it's what we know for sure that just ain't so."”

Human cells shown to predict toxicity more accurately

Newly published research demonstrates the ability of BioMAP Systems, a unique set of primary human cell and co-culture assays that model human disease, to identify important safety aspects of drugs and chemicals more efficiently and accurately than can be achieved by animal testing.

Data from 776 environmental chemicals, including reference pharmaceuticals and failed drugs, were analysed as part of the US EPA (Environmental Protection Agency) ToxCast Programme.

“This publication examines an unprecedentedly large data set…  Our results show such systems to be a highly useful and reproducible tool for predictive toxicology” – Dr Ellen Berg, Scientific Director of DiscoveRx’s BioSeek division
Ref: Nature Biotechnology, 18 May 2014

Computer models highly reliable

German company PharmaInformatic has developed a computerised expert system, called IMPACT-F, that calculates human oral bioavailability (drug uptake) much more precisely than animal trials. This system will increase the prospects of successful clinical trials in humans. “Now we have proof that they are significantly more efficient and reliable than animal trials and we hope they will replace useless animal trials soon” - Dr Wolfgang Boomgaarden, founder and CEO, PharmaInformatic.
Ref: Medical News Today 21 May 2013

Organ-on-a-chip models

Exciting progress is being made in the field of 3D microfluidic replicas of human organs, using human cells, to study disease processes and to test drugs and chemicals for both effectiveness and safety. Suction can be applied to the small, flexible devices to simulate the mechanical effects of breathing, in the case of the lung-on-a-chip, or peristalsis, in the case of the gut-on-a-chip. Along with the realistic blood-like flow of fluid, this allows the cells to grow and behave in a more life-like way than static cultures, greatly enhancing their predictive capabilities.

Several other organ mimics are under development, including kidney, spleen, liver, bone marrow and heart. Most exciting of all, these organ chips can be linked together to replicate coordinated organ systems. This is the ultimate aim of many of the projects, including Harvard University’s Wyss Institute, who have a number of excellent short video-clips on their website, some of which can also be viewed from our website.

NIH Director, Dr Francis Collins is impressed, writing that the lung-on-a-chip is already a game changer:
“This nifty little thumb-sized device offers a new way to model human diseases, and a cheaper and faster way to screen potential drugs.”
Explaining how the chip was used to model the serious condition pulmonary edema and how it revealed, for the first time, that the motion of breathing contributes to the problem and how it could be alleviated, he pointed out:

“This is something that would have been very hard to appreciate in an animal model – you can’t ask the animal to stop breathing!”
Ref: NIH Director’s blog, 26 November 2012

Hepregen’s human ‘HepatoPac’ micro-liver is predictive of liver damage from fialuridine (a potential treatment for hepatitis B) – an effect that was not predicted by animal studies, resulting in severe liver damage in 7 of 15 people in the 1993 clinical trial: five of whom died.
Ref: Nature 471, 661–665, 31 March 2011

New paradigm for Alzheimer's research

A review paper by Dr Gill Langley, senior science adviser to Humane Society International, says: “It’s time to move dementia research into the 21st century.
… Alzheimer’s is one of those disease research areas still very much dominated by the standard approach: studying the wrong condition in the wrong animal. The legacy of that approach is that despite a decade of effort using genetically modified mice, more than 300 potential treatments have been successful in animals but not a single one has proved effective in human patients. This is a public health emergency. The time for governments to act is now

… From patient-derived human brain cells in culture, to powerful neuroimaging machines, and super-computers combining multiple data to reconstruct the disease pathways, Alzheimer’s can be mapped within the framework of human biology in order to understand why and how the illness occurs and how best to treat it. These advanced techniques will allow a complexity of understanding of this uniquely human disease never before achieved using animal models.”
Ref: Drug Discovery Today, 21 May 2014

BBC series “Bang Goes the Theory” featured the work of Dr Rick Livesey’s team at the Gurdon Institute, Cambridge, who are growing 3D human ‘mini-brains’ to study Alzheimer’s disease. An iPlayer clip features presenter Liz Bonin enthusing:
“It's only because they can grow living brain cells that they can see the disease spreading – and can now test a multitude of different drugs on live human brain cells and watch the effects on a cellular level. It’s a very exciting time for Alzheimer’s disease research because this breakthrough – allowing us to understand the disease at its early stages, using live human nerve cells – is  completely transforming our understanding of how to find a cure.”
Ref: bbc.co.uk/programmes/p01wd83n

Animal Free Safety Testing of New Medicines

A symposium was held in Utrecht, Netherlands in May 2013 by Utrecht University and the Medicines Evaluation Board, in collaboration with Nefarma and Top Institute Pharma. Two expert panels with members from industry, regulatory authorities and academia were asked to design a scheme – if possible – to develop a medicine safely without the use of animal testing.

Both panels concluded that such a scheme would be challenging but feasible.
One of the organisers, Dr Peter van Meer wrote his PhD thesis on: “The scientific value of non-clinical animal studies in drug development”. His studies concluded that “animal studies to assess the safety of new drugs are not always needed and can be, in fact, unscientific, uninformative or irrelevant. This, in turn, increases the costs and limits the efficiency of drug development”.

He recommends a thorough revision of regulatory guidelines, increased dialogue between pharmaceutical companies and regulatory authorities, increased investment by pharmaceutical companies in technologies to improve safety assessment, along with economic and political incentives from governments. Another key necessity is that animal study reports need to be made available for research. This would enable unprecedented scientific analysis and discussion of the predictive value of animal studies and, he says, “an opportunity to reconsider when and how (and for how much longer) we use animals in drug development. This does require considerable effort and trust by pharmaceutical companies and regulatory authorities alike but the trade-off is an efficient non-clinical drug development process which is based on science.”

Ref: tipharma.com, Project T6-301 P.J. K. van Meer, 2013

Important 30 minute film about the risks of statins

Millions of people are prescribed statins to lower their cholesterol, often without adequate warning of their possible risks. There is much disagreement among doctors as to whether statins should be prescribed for primary prevention. We recommend this review from the NNT group: http://www.thennt.com/nnt/statins-for-heart-disease-prevention-without-prior-heart-disease/, as well as this 30 minute film from ABCTVCatalyst (Australia).

'Body on a chip' uses 3D printed human organs to test vaccines

Wake Forest Institute for Regenerative Medicine in North Carolina have used a 3D bio-printer to print organ-like structures made of human cells which mimic the functions of the heart, liver, lung and blood vessels, all linked together with a circulating blood substitute, similar to the type used in trauma surgery.

The blood substitute keeps the cells alive and can be used to introduce toxins, as well as potential treatments - e.g. to test for antidotes to sarin gas - into the system. Sensors which measure temperature, oxygen levels, pH and other factors feed back information on how the organs react and - crucially - how they interact with each other.

Dr Anthony Atala, institute director at Wake Forest and lead investigator on the project, said the technology would be used both to "predict the effects of chemical and biologic agents and to test the effectiveness of potential treatments".

"You are actually testing human tissue," he explained. "It works better than testing on animals."

See more...

New York Times 11 February:
It takes a million times more bacteria in the blood to kill a mouse than a man

Mice Fall Short as Test Subjects:

"For decades, mice have been the species of choice in the study of human diseases. But now, researchers report evidence that the mouse model has been totally misleading for at least three major killers - sepsis, burns and trauma. As a result, years and billions of dollars have been wasted following false leads, they say."

"They are so ingrained in trying to cure mice that they forget we are trying to cure humans."

"It argues strongly - go to the patients. Get their cells. Get their tissues whenever you can."

See more...

In an editorial entitled: "Of men, not mice", the journal Nature Medicine commented:

"Although the message that mice are an imperfect model for human disease is far from new, these recent results should prompt some soul-searching among disease researchers… Rather than overrelying on animal models to understand what happens in humans, isn't it time to embrace the human 'model' to move forward?"

See more... 

Gut-on-a-chip could replace animals in drug testing

Harvard University's Wyss Institute of Biologically Inspired Engineering produced a breathing lung on a microchip in 2010. Last year, Wyss researchers were awarded a grant to develop a spleen-on-a-chip to treat sepsis, a commonly fatal bloodstream infection. Now they have produced a physiologically realistic ‘gut-on-a-chip’, which enables them to study much more complex interactions than previous cell culture or animal models. They are currently working on more than 10 different organs, with the ultimate aim of linking them together with fluidic channels, like blood vessels, to produce a more representative model for testing medicines.

“A major problem in the pharmaceutical industry right now is that the drug development model is actually broken. It just does not work. It takes many, many years to get a drug to market, it’s incredibly expensive, innumerable animal lives are lost – and then the results from animals usually don’t predict what happens in humans. So this is a huge cost to the economy and to the pharmaceutical industry.”

Dr Don Ingber, director of Harvard University's Wyss Institute of Biologically Inspired Engineering.

Refs: Smart Planet, 28 March 2012 and Technology Review, July/August 2012 

What price our medicines?

As the number of clinical trials conducted in India by western pharmaceutical companies continues to grow (due to costs as much as 80% lower), so too does the death toll. The Indian government records that 1,725 people have lost their lives in drug trials in the last four years: rising from 132 deaths in 2007 to 688 in 2010. Dr Chandra Gulhati, who has led several clinical trials in the UK, says that because of gross under-reporting, the actual number of deaths would be much higher than we will ever know.

The purpose of the Safety of Medicines Bill is to protect not just patients but also – and especially – participants in clinical trials, who are currently used as guinea pigs to test drugs for which there is often no prior evidence of safety in humans. The most dramatic example we have seen in the UK of ‘proof of safety’ in animals meaning nothing for people was at Northwick Park Hospital in 2006. Perhaps the reason we have not seen more ‘Northwick Parks’ is because most of them happen on the other side of the world.

In response to Safer Medicines’ concerns about the inadequacy of preclinical testing, the UK Department of Health says, in its standard letters, that: “Without animal testing it is highly likely that a large number of potentially dangerous medicinal products would have to be tested in healthy volunteers and patients in clinical trials. This would be quite unacceptable.” We agree that it is unacceptable but the fact is that this is currently standard practice. Much of the blame for this can be laid at the door of government regulations that require evidence of safety in animals but do not require evidence of safety in the most sophisticated human-biology-based assays currently available.

Ref: Aditi Tandon, www.tribuneindia.com 8 August 2011

Mice an obstacle to heart disease research

Researchers at Washington University in the US studied two drugs to treat heart rhythm disorders, using mouse hearts. What they found was so promising that if it translated into humans, it would have been a major breakthrough. However, rather than put patients at risk in a clinical trial, so many of which end in failure, Dr Igor Efimov and Professor Colin G. Nichols decided to test the drugs using human hearts, which had been donated for research but were considered unsuitable for transplantation.

In human hearts, the drugs behaved completely differently, and the results suggested that they would have caused fatal arrhythmias had they been administered to people.

“The problem is that at least in the cardiac arrhythmia field, this [animal model] paradigm has had very few successes. Clinical trial after clinical trial has ended in failure… A mouse’s heart beats about 600 times per minute, so you can imagine it is a little different from humans, whose hearts beat on average 72 times per minute… You can mutate in mice the gene thought to cause heart failure in humans and you don’t get the same disease, because the mouse is so different. Since we’ve begun to work with human hearts, we’re finally starting to catch up with animal physiology” – Dr Igor Efimov, Distinguished Professor of Biomedical Engineering, Washington University

Ref: Diana Lutz, Washington University News, 3 August 2011

Call for non-furry immunology

Call for “non-furry immunology”

Vaccine researchers in Australia are calling on their government to invest in research into human immunology, rather than continuing to invest huge resources in transgenic mouse models.

“Use of murine models to study the immunobiology of infectious diseases, such as malaria and herpes simplex virus, has severely skewed our understanding of immune control of these pathogens in humans, and it could be argued that over reliance on these model systems may have slowed progress in the development of effective vaccines against many human pathogens” – Dr Rajiv Khanna and Dr Scott R Burrows, Australian Centre for Vaccine Development, Queensland Institute of Medical Research They anticipate that the large-scale collaborative human-focused studies they are proposing will be opposed by those who study immunology in animal models but they ask: “How long can we justify investing millions of dollars of taxpayers’ funds on delineating the murine immune system, which in most cases has limited application for human diseases?”

Ref: Immunology and Cell Biology (2011) 89, 330–331; doi:10.1038/icb.2010.173

 

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